5 - Fluorouracilo Ficha Tecnica

25/10/12
FLUOROURACIL
Evaluaciones de DRUGDEX
OVERVIEW
1) Class
a) This drug is a member of the following class(es):
Antimetabolite
Antineoplastic, Dermatological
Antineoplastic Agent
2) Dosing Information
a) Adult
1) use patient's actual weight for dosage calculation; use the estimated lean body mass (dry weight)
if the patient is obese or had spurious weight gain due to edema, ascites or other forms of abnormal
fluid retention [1]
a) Actinic keratosis
1) cover lesions TOPICALLY with 2 or 5% solution or cream twice daily for 2 to 6 weeks [80], or
with 0.5% microsphere formulation once daily for up to 4 weeks [81]
b) Breast cancer, Palliative
1) 12 mg/kg IV daily for 4 days, if tolerated then 6 mg/kg IV daily on days 6, 8, 10, 12 (MAX dose
800 mg/day); if tolerated maintenance therapy may be given by repeating the first course every 30
days, after the last day of the previous treatment cycle or 10 to 15 mg/kg/week after toxic signs
resulting from the initial course of therapy have subsided; MAX dose 1 g/week [1]
c) Carcinoma of pancreas, Palliative
d) Colorectal cancer, Adjuvant
1) Oxaliplatin 85 mg/m(2) IV on weeks 1,3, 5 for three 8-week cycles with an IV bolus of fluorouracil
500 mg/m(2) and leucovorin 500 mg/m(2) IV weekly for 6 weeks of an 8-week cycle for 3 cycles
[33]
e) Colorectal cancer, Palliative
f) Gastric cancer, Palliative
thomsonhc.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.IntermediateToDocumentPrintLink
resulting from the initial course of therapy have subsided; MAX
dose 1 g/week [1]
1/317
25/10/12
Drug details - MICROMEDEX 2.0
g) Superficial basal cell carcinoma
1) cover lesions TOPICALLY with 5% cream or solution twice daily for 3 to 6 weeks up to 10 to 12
weeks
b) Pediatric
1) safety and effectiveness in children has not been established [1]
3) Contraindications
a) Bone marrow depression
b) Dihydropyrimidine dehydrogenase enzyme deficiency (topical route) [205]
c) Hypersensitivity to fluorouracil or capecitabine
d) Poor nutritional state
e) Pregnancy, existing or potential (topical)
f) Serious infection
4) Serious Adverse Effects
a) Anaphylaxis
b) Angina
c) Bleeding
d) Cardiotoxicity
e) Cerebellar syndrome, acute
f) Coronary arteriosclerosis
g) EKG finding
h) Eye / vision finding
i) Finding of lacrimation
j) Gastrointestinal ulcer
k) Immune hypersensitivity reaction
l) Myelosuppression, Anemia, leukopenia, thrombocytopenia
m) Nystagmus
n) Photophobia
o) Stenosis of lacrimal system
p) Thrombophlebitis
5) Clinical Applications
a) FDA Approved Indications
1) Actinic keratosis
2) Breast cancer, Palliative
3) Carcinoma of pancreas, Palliative
2/317
25/10/12
4) Colorectal cancer, Palliative

5) Gastric cancer, Palliative
6) Superficial basal cell carcinoma
b) Non-FDA Approved Indications
1) Colorectal cancer, Adjuvant
DOSING INFORMATION
Drug Properties
A) Information on specific products and dosage forms can be obtained by referring to the
Tradename List (Product Index)
B) Synonyms
5-Fluorouracil
5-FU - 5-Fluorouracil
Fluorouracil
C) Orphan Drug Status
1) Fluorouracil has been designated an orphan drug product for use in the treatment of
esophageal carcinoma, colorectal carcinoma, and colorectal adenocarcinoma in conjunction with
other agents.
D) Physicochemical Properties
1) Molecular Weight
a) 130.08 [368][360]
2) pH
a) Injection: approximately 9.2 [368]; topical cream: approximately 8.5 [549]
3) pKa
a) 8, 13 [550]
4) Solubility
a) Sparingly soluble in water; slightly soluble in alcohol; 1 g is soluble in 100 mL of propylene
glycol [360][549].
Storage and Stability

A) Preparation
1) General Information
a) Use proper procedures for the handling and disposal of chemotherapy [203].
b) Fluorouracil injection is for IV use only [203].
2) Intravenous route
3/317
25/10/12
a) Dilution is not required before fluorouracil IV administration [203].

b) When transferring the fluorouracil solution from a pharmacy bulk vial, the contents must be
transferred within 4 hours after puncturing the vial. The vial should only be punctured one time.
Additionally, the transferred drug solution should be administered within 4 hours [203].
3) Topical application route
a) Apply Efudex(R) with a non-metallic applicator or suitable glove. If Efudex(R) is applied with
fingers, wash hands immediately after application [82].
b) Apply a thin film of Carac(R) cream 10 minutes after thoroughly washing, rinsing, and drying
the area; may apply with fingertips; wash hands immediately after application [81].
B) Parenteral route
1) Fluorouracil solutions should be stored at 15 to 30 degrees Celsius (C) (59 to 86 degrees
Fahrenheit (F)) and protected from light. Solutions may discolor slightly but potency and safety
are not adversely affected. Any precipitate which forms may be resolubilized by heating to 140
degrees F and agitating; allow to cool to body temperature before using [207].
2) Fluorouracil solution (Roche) maintained 98% to 100% potency over 48 hours after dilution
and storage in syringes or ethylene vinyl acetate infusion-pump reservoirs. Fluorouracil was
diluted to 12 and 40 mg/mL with normal saline or 5% dextrose injection and stored in 60-mL
polypropylene syringes for 72 hours. It was also diluted to 15 and 45 mg/mL with normal saline
and stored in ethylene vinyl acetate infusion-pump reservoirs. High-performance liquid
chromatography and thin-layer chromatography were used to measure fluorouracil concentrations
and urea, a product of fluorouracil degradation [405].
3) Fluorouracil in 5% dextrose injection showed a biphasic decrease in potency in both glass and
plastic containers. In glass, however, the initial decrease was greater and more rapid. The
decrease of fluorouracil content in glass was 10% by seven hours; however, a 10% decrease was
not observed until 43 hours in plastic [406].
4) The stability of fluorouracil prepared for infusion in plastic containers used in IV administration
systems intended for home use was investigated. Fluorouracil 500 mg was diluted in 5% dextrose
to a total volume of 50 mL in a plasticized polyvinylchloride container (MVP drug reservoir) or 60
mL in an elastomeric balloon used in a disposable drug pump (Infusor). Storage without
protection from light at room temperature and at 5 degrees C was continued for 4 months with
periodic sampling. High performance liquid chromatography (HPLC) assays revealed no significant
loss of potency and no degradation over 16 weeks in the MVP drug reservoir and change in
concentrations in Infusor bags was less than 10% over this time period at room temperature. In
MVP reservoirs, a progressive increase in fluorouracil concentration was observed (presumably
due to water loss due to evaporation through the container) with a predicted change of 10% in
concentration occurring at 55 days. Infusor bags were not studied at room temperature. The
investigators concluded that fluorouracil is stable in 5% dextrose in these containers for at least
16 weeks when stored at 5 degrees C [407].
5) The stability of aqueous fluorouracil 50 mg/mL was studied in portable infusion pumps under
simulated infusion conditions. The drug was found to be stable for 7 days at 37 degrees C.
However, at 25 degrees C a fine white precipitate was reported after 48 to 96 hours in the
extension tubing of the devices containing Roche brand fluorouracil. Precipitate formation was
also reported in all solutions adjusted to below pH 8.7 [408].
6) Fluorouracil 50 mg/mL was stable in polypropylene infusion-pump syringes at 30 degrees C for
4/317
25/10/12
21 days [409].
C) Latex/Polyvinylchloride Gloves
1) Using a radiotracer method, the permeability of latex and polyvinylchloride gloves to
fluorouracil and methotrexate were determined. Both types of gloves demonstrated timedependent permeability to both agents. Intra-lot variability was seen, suggesting exposure of
personnel could be variable [410].
D) Microwave Thawing
1) Precipitate in fluorouracil injection can be redissolved by heating to 60 degrees C in a
microwave oven without significantly affecting the drug's stability [411].
Adult Dosage
Normal Dosage
Intra-arterial route
1) Intra-arterial administration of fluorouracil 800 to 1200 milligrams/m(2) as a
continuous infusion on days 1 to 4, followed by 600 milligrams/m(2) as a continuous
infusion on days 5 to 21 has been used for hepatic tumor involvement [4]. Also,
hepatic artery infusion of fluorouracil in doses of 10 to 30 milligrams/kilogram/day and
15 milligrams/kilogram/week as maintenance/adjuvant therapy have been used in
hepatic carcinoma and hepatic metastases [194][155][195][196]. Adjuvant hepatic
arterial bolus infusions (over 10 minutes) of fluorouracil 15 milligrams/kilogram/week
(duration of 6 months) were administered to 20 patients undergoing curative
resection of colorectal liver metastases [194].
Intralesional route
1) In one study, intradermal fluorouracil (15 to 150 milligrams twice weekly by
infiltration of tumor sites) was useful in infiltrating basal cell carcinoma [197]. In
another study, patients were treated with 1 to 3 milliliters of fluorouracil for
keratoacanthomas. Each treatment included injections to the periphery and the center
of the lesions. Injections were given at 1- to 4-week intervals. Lesions were
successfully cleared [151].
Intravenous route
Breast cancer, Palliative
a) The recommended intravenous dose of fluorouracil is 12 milligrams/kilogram
(mg/kg) once daily for 4 successive days. In the absence of toxicity, 6 mg/kg
may be given on the 6th, 8th, 10th and 12th days unless toxicity occurs, with
therapy being discontinued after the 12th day. No therapy is given on the 5th,
7th, 9th or 11th days; total daily dose should not exceed 800 mg [1].
b) Maintenance therapy may be considered in patients tolerating fluorouracil
toxicity by repeating the first course every 30 days, after the last day of the
previous treatment cycle. Alternatively, a single maintenance dose of 10 to 15
mg/kg/week may be given after toxic signs resulting from the initial course of
therapy have subsided; a dose of 1 gram weekly should not be exceeded [1].
Carcinoma of pancreas, Palliative
5/317
25/10/12
Cervical cancer
a) HIGH-RISK CERVICAL CANCER
1) The study group in this trial was administered cisplatin 75 milligrams/square
meter (mg/m(2)) infused over 4 hours followed by fluorouracil (5-FU) 4000
mg/m(2) infused over 96 hours plus a total of 85 Gy radiation. Chemotherapy
was given every 3 weeks for a total of 3 cycles. Again, when compared to
radiation alone, this regimen achieved significantly better survival [545].
b) In a trial by the Radiation Therapy Oncology group (RTOG), CISPLATIN (75
milligrams/square meter on day 1 of weeks 1, 5, 8, and 11) in combination with
FLUOROURACIL (1 gram/square meter continuous infusion on days 1 through 4
of weeks 1, 5, 8, and 11), and RADIATION (50 Gy delivered in 25 fractions) was
administered to patients with nondisseminated squamous or adenocarcinoma of
the thoracic esophagus. This combination achieved significantly greater survival
than radiation alone [546].
1) LOCALLY ADVANCED CERVICAL CANCER
a) This trial was divided into 3 groups. The first group received cisplatin 40
milligrams/square meter (mg/m(2)) over 4 hours at weeks 1 through 6. The
second group received cisplatin 50 mg/m(2) on days 1 and 29,
FLUOROURACIL 4 grams/square meter as a 96 hour infusion on days 1 and 29,
and HYDROXYUREA 2 grams/square meter orally twice a week at weeks 1
through 6. The CONTROL group was administered only hydroxyurea 3
grams/square meter orally twice weekly on weeks 1 through 6. All groups
received RADIATION at varying doses depending on stage of disease. Actual
survival rates among the first, second, and the control groups were 66%,
67%, and 49.7%, respectively [547].
Colorectal cancer, Adjuvant
a) Based upon studies using the combination of oxaliplatin, fluorouracil and
leucovorin the following regimens have been used. The FLOX regimen consists
of oxaliplatin 85 milligrams per square meter (mg/m(2)) intravenously (IV) on
weeks 1,3 and 5 for three 8-week cycles added to leucovorin 500 mg/m(2) IV
and IV bolus fluorouracil 500 mg/m(2) weekly for 6 weeks of an 8-week cycle
for 3 cycles [33]
Colorectal cancer, Palliative
6/317
25/10/12

Esophageal cancer
a) HIGH-RISK CERVICAL CANCER
1) The study group in this trial was administered cisplatin 75 milligrams/square
meter (mg/m(2)) infused over 4 hours followed by fluorouracil (5-FU) 4000
mg/m(2) infused over 96 hours plus a total of 85 Gy radiation. Chemotherapy
was given every 3 weeks for a total of 3 cycles. Again, when compared to
radiation alone, this regimen achieved significantly better survival [545].
b) In a trial by the Radiation Therapy Oncology group (RTOG), CISPLATIN (75
milligrams/square meter on day 1 of weeks 1, 5, 8, and 11) in combination with
FLUOROURACIL (1 gram/square meter continuous infusion on days 1 through 4
of weeks 1, 5, 8, and 11), and RADIATION (50 Gy delivered in 25 fractions) was
administered to patients with nondisseminated squamous or adenocarcinoma of
the thoracic esophagus. This combination achieved significantly greater survival
than radiation alone [546].
Gastric cancer
a) Advanced Gastric Adenocarcinoma: Docetaxel, Cisplatin, Fluorouracil (TCF)
1) A regimen consisting of docetaxel, cisplatin, and fluorouracil improved
overall survival compared to cisplatin and fluorouracil in patients with advanced
gastric adenocarcinoma (n=445), including adenocarcinoma of the
gastroesophageal junction [60].
Administer sequentially in the following order:
Premedicate docetaxel with dexamethasone 8 mg orally twice daily for 3 days,
starting 1 day prior to docetaxel (day 0)
Docetaxel 75 mg/m(2) intravenously over 1 hour on day 1, followed by:
Cisplatin 75 mg/m(2) intravenously over 1 to 3 hours on day 1, followed by:
Fluorouracil 750 mg/m(2)/day intravenously over 24 hours on days 1, 2, 3, 4,
and 5
Repeat all doses every 3 weeks
mg/m(2) = milligrams/square meter

7/317
25/10/12
2) In the clinical trial, granulocyte-colony stimulating factor (G-CSF) was

recommended during the second and/or subsequent cycles in case of febrile
neutropenia, documented infection with neutropenia, or neutropenia lasting
more than 7 days [60].
Gastric cancer, Palliative
c) Continuous 5-day infusions may provide greater efficacy than 5-day
intermittent bolus injections in gastrointestinal carcinoma. However, further
study is warranted [65]. Continuous ambulatory infusions of fluorouracil
produced better response rates than traditional bolus infusions in patients with
advanced colorectal cancer [66].
Head and neck cancer
a) In untreated good-risk patients with advanced, resectable carcinoma of the
head and neck, mitoguazone has been given in doses of 400 milligrams/square
meter over 90 minutes on days 1 and 8, combined with continuous infusions of
cisplatin 30 milligrams/square meter plus 5-fluorouracil on days 8 to 12. Three
cycles were administered (every 28 days); complete responders or those with
tumor downstaging to T1N1 were given radiation therapy (total doses of
approximately 70 Gy) [544]. This regimen enabled organ preservation without
an apparent compromise of survival.
The fluorouracil dosage is based on actual body weight; however, lean body weight is
used if the patient is obese or if there is weight gain secondary to edema or ascites
[1].
Oral route
Breast cancer
a) A 28-day regimen (5-week courses) has been administered to previously
treated advanced BREAST CANCER patients [548]. Doses of eniluracil and 5fluorouracil were 10 milligrams/square meter (mg/m(2)) and 1 mg/m(2),
respectively, each given twice daily.
Fluorouracil 20 milligrams/kilogram/day was administered orally for 5 days, then
repeated at 5 weeks in patients with colorectal carcinoma. Fluorouracil 15
milligrams/kilogram/day was administered orally for 6 days, then once weekly to 20
patients with advanced colorectal cancer on an outpatient basis [198][199].
An oral dose of fluorouracil 15 milligrams/kilogram/week was used in patients with
hepatoma [200].
8/317
25/10/12
Oral and intravenous administration of fluorouracil 15 milligrams/kilogram/week was

compared in patients with pancreatic cancer. Oral administration was associated with
a greater incidence of toxicity than the intravenous route [201].
Intraoral Mouthwash
a) Fluorouracil 1 gram was used intraorally as a mouthwash for inducing remission in
patients with residual or localized relapsing cancer of the lip, buccal mucosa or soft
palate. The mouthwash was administered for 10 days and repeated for 2 to 10
courses (Umsawasdi et al, 1975).
Topical application route
Actinic keratosis
a) Fluorouracil cream 0.5% incorporated into a microsphere (Microsponge(R))
should be applied once daily to actinic keratosis lesions and the surrounding
skin; only a thin layer of cream is needed. Ten minutes before applying the
cream, the skin should be thoroughly washed, rinsed, and dried. Treatment
should be continued for up to 4 weeks (Prod Info fluorouracil Microsponge(R),
2000) [81].
b) The manufacturer of Efudex(R) (fluorouracil cream (5%), solution (2%,
5%)) recommends a twice daily application with a sufficient amount to cover
the lesion. Therapy should be continued until the inflammatory response
reaches the erosion, necrosis and ulceration stage; usually 2 to 4 weeks
(complete healing may not occur for 1 to 2 months after cessation of therapy).
Normal response to therapy is erythema, usually followed by vesiculation,
erosion, ulceration, necrosis and epithelialization [80].
c) In the treatment of multiple actinic (solar) keratoses, the manufacturer of
Fluoroplex(R) (fluorouracil 1%) recommends a twice daily application to
affected areas. A sufficient amount should be used to cover entire affected
areas; use a nonmetallic applicator or fingertips to apply. The treatment period
is usually 2 to 6 weeks, but may be longer, especially when treating areas other
than the head and neck [85].
d) Weekly pulse dosing with topical fluorouracil 5% solution was reported
effective and acceptable in patients with actinic keratosis. Ten patients applied
the solution to affected areas morning and evening 1 day a week. If the lesions
were not flattening and desquamating, the weekly pulse was increased to two
consecutive days of treatment a week. The average duration of therapy was 6.7
weeks with a recovery period of 2 to 4 weeks [86].
Superficial basal cell carcinoma
a) Apply the 5% cream or solution (only the 5% strength is recommended)
twice daily in an amount sufficient to cover lesions and continue for at least 3 to
6 weeks. Therapy may be required for as long as 10 to 12 weeks for obliteration
of lesions [80].
Dosage in Other Disease States
A) Obesity
1) The American Society of Clinical Oncology guidelines on appropriate chemotherapy
dosing for obese adult patients with cancer include the following highlights [202]:
1). Chemotherapy doses should be calculated using actual body weight in overweight,
obese, and morbidly obese adult patients (BMI greater than 25). Toxicity is no greater for
9/317
25/10/12
obese patients with appropriate dosing; however, comorbidities must be considered.

2). Full weight-based dosing (IV or oral) should be administered to obese patients,
especially when the goal of treatment is cure.
3). BSA can be calculated using any of the standard formulas such as Mosteller, Dubois
and Dubois, Haycock, Gehan and George, or Boyd.
4). Depending on the type and severity of a toxicity, comorbid conditions, and the intent of
the treatment (ie, curative or palliative), the same guidelines for dose reductions,
regardless of obesity, should be followed. If a dose reduction is needed, consider returning
to the appropriate weight-based dose upon resolution, and closely monitor.
5). Fixed dosing is only recommended for select cytotoxic agents which can safely be
dosed independently of weight or body surface area (eg, carboplatin and bleomycin, or
when vincristine is capped at a maximum dose of 2 mg when used in the CHOP and CVP
regimens).
B) Poor Risk - Inadequate Nutritional Status
1) Lower doses of fluorouracil should be used in poor risk patients (poor nutritional state,
history of high-dose pelvic irradiation, previous use of alkylating agents, or widespread
involvement of bone marrow by metastatic tumors, or impaired hepatic or renal function).
Initial intravenous doses for these patients should be 6 milligrams/kilogram/day for 3 days,
continuing with 3 milligrams/kilogram on days 5, 7, and 9, if no toxicity occurs. No therapy
is administered on days 4, 6, or 8. The total daily dose in these patients should not exceed
400 milligrams [1].
Pediatric Dosage
Normal Dosage
Intravenous route
1) The safety and effectiveness of fluorouracil in pediatric patients has not been
established [1].
PHARMACOKINETICS
Drug Concentration Levels
A) Therapeutic Drug Concentration
1) Colorectal cancer, 2000 to 3000 mcg/L [374].
a) This therapeutic range was used for determining the dose of a weekly 8-hour infusion. It
provided a high survival rate and was well tolerated; acute toxicity was linked to a plasma
concentration greater than 3000 mcg/L [374].
10/317
25/10/12
2) Colorectal cancer, mean steady state concentration (Css): 94 ng/mL [380].

a) In a study of 61 patients with colorectal cancer receiving 5-FU 300 mg/m(2)/day via
protracted venous infusion for up to 26 weeks, the mean 5-FU Css was 94 ng/mL with 27%
interpatient and 20% intrapatient coefficients of variation, respectively. 5-FU Css did not
correlate with response or toxicity [380].
B) Time to Peak Concentration
1) Intrapericardial, infusion: 45 minutes [377].
a) After intrapericardial administration to 1 patient, the peak concentration was 1.74 mg/mL; the
concentration decreased to 0.113 mg/mL at 5 hours [377].
2) Oral: 35 minutes [379]
3) Intravenous bolus: 0.45 and 0.69 hour for the catabolite, 5-fluoro-5,6-dihydrouracil, after 5-FU
doses of 250 and 370 mg/m(2), respectively [375].
a) The mean peak concentrations (Cmax) of the parent drug 5-FU were 18.15 and 48.41 mcg/mL
after IV bolus doses of 250 and 370 mg/m(2), respectively, in 20 patients with colorectal cancer.
Corresponding average Cmax values for the catabolite, 5-fluoro-5,6-dihydrouracil, were 3.6 and
5.26 mcg/mL appearing at mean Tmax of 0.45 and 0.69 hour, respectively [375].
4) Topical: 1 hour [376].
a) One patient in the 0.5% fluorouracil group demonstrated a maximum observed drug
concentration (Cmax) value of 0.768 nanograms (ng)/milliliter (ml) and time to maximum drug
concentration (Tmax) of 0.996 hours. Six patients receiving 5% fluorouracil demonstrated a
mean Cmax of 11.492 ng/ml (range, 5.050 to 27.2 ng/ml) and a mean Tmax of 1.025 hours
(range, 0.999 to 1.075 hours. A randomized, open label, parallel group study involving 21
patients (mean age, 64 years) with actinic keratosis, patients received topical 0.5% fluorouracil
cream 1 gram (g) daily and 5% fluorouracil cream 1 g twice daily for up to 28 days. [376].
C) Area Under the Curve
1) Intravenous, 16 to 24 mg x h/L [374]; Intravenous, 3.77 to 13.61 mcg/mL x h [375]; Topical,
22.4 ng x h/mL [376]; Intrapericardial, 4.739 mg x hr/mL [377].
a) This was determined from 0 to 8 hours during a continuous 8-hour infusion; acute toxicity was
linked to an AUC from 0 to 8 hours greater than 24 mg x h/L [374].
b) The mean AUC's of the parent drug 5-FU were 3.77 and 13.61 mcg/mL x h after IV bolus
doses of 250 and 370 mg/m(2), respectively. Corresponding average AUC's for the catabolite, 5fluoro-5,6-dihydrouracil (5-FDHU), were 5.39 and 8.75 mcg/mL x hr [375].
c) The AUC in one patient receiving 0.5% fluorouracil cream was 2.803 ng x h/ml and in 6
patients receiving 5% fluorouracil cream was 22.390 ng x h/ml (range, 14.507 to 37.518 ng x
h/ml). In a randomized, open label, parallel group study involving 21 patients (mean age, 64
years) with actinic keratosis, patients received TOPICAL 0.5% fluorouracil cream 1 gram (g)
daily (n=11) and 5% fluorouracil cream 1 g twice daily (n=11) for up to 28 days. Only, 7
patient's data were evaluable [376].
d) In a study evaluating fluorouracil as a one-hour infusion in 22 patients with gastrointestinal
tract cancers, the median AUC on day four was 2018 microM x min compared with 1721 microM
x min on day one (p less than 0.001). Patients were administered interferon alfa-2a (5 million
units subcutaneously on days 1-7), followed immediately by leucovorin 500 milligrams
(mg)/square meter intravenously (IV) over 30 minutes on days 2-6, and fluorouracil 370
mg/square meter IV over one hour on days 2-6. The median
Cmax value for the fluorouracil 370

11/317
25/10/12
mg/square meter IV over one hour on days 2-6. The median Cmax value for the fluorouracil 370
mg/square meter dose cycle was significantly higher on day four compared with day one (32.2
microM versus 22.1 microM, respectively; p=0.006). One-hour fluorouracil infusion data was
compared retrospectively with five-minute fluorouracil injection data from a study utilizing an
identical dose schedule and modification guidelines. The Cmax and AUC following fluorouracil 370
mg/square meter as a five-minute injection were 7.3-fold and 2.4-fold higher, respectively, than
following the one-hour infusion. The lower decreased systemic exposure with the one-hour
infusion was associated with a lower apparent clinical toxicity [378].
e) The AUC was estimated after intrapericardial administration of fluorouracil 200 mg to 1
patient [377].
ADME
Absorption
A) Bioavailability
1) Oral: 0% to 80% (Iyer & Ratain, 1999)[381]
a) Oral FLUOROURACIL is incompletely absorbed from the gastrointestinal tract (Bruckner
& Cresey, 1974)[382].
b) Bioavailability of oral dose was 50% to 80% that of intravenous administration [379].
2) Topical: Systemic absorption is minimal [376][381].
a) The systemic absorption of TOPICAL 0.5% and 5% fluorouracil cream was 0.55% and
2.4%, respectively, in an open label, parallel group study involving 21 patients with actinic
keratosis [376].
B) Effects of Food
1) Consumption of food 20 minutes before oral administration of 5-FU 20 mg/m(3)
decreased the rate, but not the extent, of 5-FU absorption in patients receiving oral
eniluracil (50 mg). In this randomized, two-way crossover study, pharmacokinetic data was
obtained for a group of 12 patients who either ate a full meal 20 minutes before 5-FU
administration or fasted for 2 hours before 5-FU administration. When patients consumed
meal before 5-FU administration, they showed a 25% decrease in maximal plasma
concentration (Cmax) and a 2.4-fold increase in the time to peak plasma concentration
(Tmax) compared to when they fasted before receiving a dose of 5-FU. The average Cmax
and median Tmax values were 1092 mcg/L and 0.8 hours for the fasting group and 822
mcg/L and 1.95 hours for the fed group, respectively [383].
Distribution
A) Distribution Sites
1) Tissues and Fluids
a) TISSUES
1) FLUOROURACIL distributes in tissue and extracellular fluid, including intestinal
mucosa, bone marrow, liver, brain, cerebral spinal fluid, and neoplastic tissue
[385][381][386]. Best overall concentrations are in blood, portal blood, liver, draining
lymph nodes, tumor, and bowel wall following intramural injection. Poorest distribution
followed intraluminal administration [387].
12/317
B) Distribution Kinetics
1) Distribution Half-Life
a) Distribution phase half-life (t1/2-alpha) was 3.6 and 1.2 minutes for parent drug 5-FU
after IV bolus doses of 250 and 370 mg/m(2), respectively, in 20 patients with colorectal
cancer. Corresponding mean t1/2-alpha for the catabolite, 5-fluoro-5,6- dihydrouracil, were
7.8 and 8.4 minutes, respectively [375].
2) Volume of Distribution
a) Volume of distribution ranged from 13 to 27 L in five studies of intravenous bolus
administration (Iyer & Ratain, 1999). The mean steady-state Vd after IV bolus doses of
250 and 370 mg/m(2) were 9.14 and 4.15 L/m(2), respectively, in a study of 20 patients
with colorectal cancer [375].
Metabolism
A) Metabolism Sites and Kinetics
1) LIVER, primary site [385][386]
a) The rate-limiting step in the metabolism of 5-fluorouracil (5-FU) is conversion to 5-6dihydrofluorouracil by the enzyme dihydropyrimidine dehydrogenase (DPD). Individuals
with genetic DPD deficiency have altered 5- FU pharmacokinetic profiles and have
experienced severe 5-FU-related toxicity (Iyer & Ratain, 1999).
b) In a study of 21 patients with colorectal carcinoma who received folinic acid 200
mg/m(2) over 2 hours, then 5-FU 400 mg/m(2) over 10 minutes followed by a continuous
infusion of 600 g/m(2) over 22 hours, investigators determined that the pharmacokinetics
of 5-FU are consistent with the two-compartment model with nonlinear (saturable,
Michaelis-Menten) elimination. The corresponding average maximum rate of elimination
(Vmax) was 1390 mg/h, while the half-saturating plasma concentration (Km) was 5.57
mg/L (mean). The interpatient variabilities in these parameters were 20% to 22%. Body
surface area and the degree of metastatic liver involvement were positively correlated with
Vmax; no such correlations existed for Km [388].
B) Metabolites
1) Dihyro-5-fluorouracil, potentially active [381]
2) Carbon monoxide urea and alpha-fluoro-beta-alanine, inactive metabolites [385]
Excretion
A) Kidney
1) Renal Clearance (rate)
a) 170 to 180 mL/min [386]
1) Based upon urinary excretion data in a open label, parallel group study involving 21
patients with actinic keratosis, the cumulative fluorouracil excreted over 24 hours was 3
micrograms (mcg) (range, 0 to 15 mcg), with a mean maximum excretion rate of 0.39
mcg/hour in patients treated with topical 0.5% fluorouracil cream. The corresponding
values in patients treated with topical 5% fluorouracil cream were 120 mcg over 24 hours
(range, undetectable to 330 mcg) and 40 mcg/hour, respectively [376].
2) Renal Excretion (%)
a) 7% to 20% [385][381]
25/10/12
B) Total Body Clearance

1) Intravenous bolus, range of 777 to 1410 mL/min; Continuous intravenous infusion, range
of 3097 to 7000 mL/min(Iyer & Ratain, 1999). Intravenous Bolus, 54.64 and 25.43
L/h/m(2)[375]. One-hour infusion, 1297 to 1764 mL/min/sq meter (Green et al, 2001).
a) Range of 777 to 1410 mL/min in five studies of intravenous bolus administration; range
of 3097 to 7000 mL/min in four studies of continuous intravenous infusion (Iyer & Ratain,
1999). Following IV bolus doses of 250 and 370 mg/m(2) in 20 patients with colorectal
cancer, the mean total body clearances of the parent drug 5-FU were 54.64 and 25.43
L/h/m(2), respectively [375].
b) In a study evaluating fluorouracil as a ONE-HOUR INFUSION in 22 patients with
gastrointestinal tract cancers, the median day one clearance of all fluorouracil doses was
significantly higher than on day four (1764 versus 1297 ml/min/square meter, respectively;
p=0.003). Patients were administered interferon alfa-2a (5 million units subcutaneously on
days 1-7), followed immediately by leucovorin 500 milligrams (mg)/square meter
intravenously (IV) over 30 minutes on days 2-6, and fluorouracil 370 mg/square meter IV
over one hour on days 2-6 [378].
C) Other
1) OTHER EXCRETION
a) Bile, trace amounts [381]
b) Lung, expired as carbon dioxide [386]
Elimination Half-life
A) Parent Compound
1) ELIMINATION HALF-LIFE
a) 6 to 22 minutes [385][375]; (Iyer & Ratain, 1999)[381]
1) After intrapericardial administration of fluorouracil 200 mg to 1 patient, the elimination
half-life was 169 minutes [377].
B) Metabolites
1) 52.2 and 48 minutes after IV 5-FU bolus doses of 250 and 370 mg/m(2), respectively, in
20 patients with colorectal cancer [375].
CAUTIONS
Black Box Warning
1) Intravenous (Solution)
a) It is recommended that fluorouracil be given only by or under the supervision of a qualified
physician who is experienced in cancer chemotherapy and who is well versed in the use of potent
antimetabolites. Because of the possibility of severe toxic reactions, it is recommended that
patients be hospitalized at least during the initial course of therapy.
b) These instructions should be thoroughly reviewed before administration of fluorouracil [204].
14/317
25/10/12
Contraindications
A) Bone marrow depression
B) Dihydropyrimidine dehydrogenase enzyme deficiency (topical route) [205]
C) Hypersensitivity to fluorouracil or capecitabine
D) Poor nutritional state
E) Pregnancy, existing or potential (topical)
F) Serious infection
Precautions
A) Dihydropyrimidine dehydrogenase enzyme deficiency (intravenous route) [204]
B) Avoid application of topical FLUOROURACIL to mucous membranes or irritated skin, and do not
use occlusive dressing
C) Carcinogenic, mutagenic, impaired fertility
D) Metastases involving bone marrow
E) Previous high dose pelvic irradiation
F) Previous treatment with alkylating agents
G) Renal or hepatic impairment
H) Use proper procedures for handling and disposal of chemotherapy
Adverse Reactions
Cardiovascular Effects
Acute coronary syndrome
1) A 48-year-old male developed acute coronary syndrome, similar to Tako-Tsubo
cardiomyopathy, following a chemotherapy regimen including 5-fluorouracil for the
adjunctive treatment of colic adenocarcinoma. Chemotherapy was initiated with a
FOLFOX regimen consisting of 5-fluorouracil 400 mg/m(2) (followed by slow infusion
of 2400 mg/m(2) over 46 hours), oxaliplatin 85 mg/m(2) and calcium folinate 200
mg/m(2). Twenty-four hours later, the patient presented to the emergency room with
chest pain radiating toward both arms, diarrhea, vomiting, and a mildly increased
troponin T level (0.5 nanograms/mL). Blood pressure and heart rate were stable and
there were no signs of cardiac failure. ECG results showed severe hypokinesia in all
apical and median segments and a left ventricular ejection fraction (LVEF) of 15%.
The patient was stabilized following dobutamine administration and placement of an
intraaortic balloon pump. Ramipril 10 mg/day and bisoprolol 5 mg/day (later changed
to diltiazem 240 mg/day) was prescribed and the patient was discharged. Total
recovery of left ventricular dysfunction was confirmed 1 month later by MRI and a
second cycle of chemotherapy was administered at half of the initial dose. The cycle
was well tolerated and diltiazem was discontinued. Two weeks later, a third cycle was
administered using a full dose regimen and on the second day of therapy the patient
complained of chest pain radiating to the upper limbs. A few hours following the end
of the 5-fluorouracil infusion, the patient developed convulsive status epilepticus,
received cardiopulmonary resuscitation for cardiac arrest, and was transferred to the
cardiology intensive care unit. Clinical examination found no signs of cardiac failure;
15/317
25/10/12
however, transthoracic echocardiography showed an abnormal left ventricle with

diffuse hypokinesia, an LVEF of 35%, and low cardiac output indexes. After several
days, the LVEF was 62% and no rhythm disturbances occurred during the rest of the
hospitalization. The FOLFOX regimen was discontinued, ramipril was continued, and
bisoprolol was restarted at 3.75 mg/day. The Naranjo adverse drug reaction
probability scale revealed a probable relationship (score of 8) between the
development of Tako-Tsubo-like syndrome and 5-flurouracil in this case [216].
Angina
1) ISCHEMIC CHEST PAIN and myocardial ischemia may occur with intravenous
fluorouracil administration [207]. Associated symptoms of nausea, vomiting, and
diaphoresis or signs of electrocardiogram changes may occur [217][218]. Onset of
pain in many cases occurs within hours of receiving a second or third dose but may be
associated with the first dose [219][220]. ANGINAL ATTACKS often recur upon
rechallenge, but may or may not be prevented with vasodilators such as nitrates or
calcium channel blockers [220][219].
2) Ischemic chest pain was described in a 67-year-old man on the third day of a 5-day
continuous infusion of fluorouracil (1500 mg/day). This was the first course of
combined chemotherapy and radiation therapy for a Duke's B colorectal cancer. The
patient experienced crushing central chest pain at rest and transient
electrocardiogram changes, which improved after discontinuation of the fluorouracil
infusion. Although a subsequent cardiac catheterization revealed severe triple-vessel
disease, the onset of pain at rest and within 3 days of the start of fluorouracil infusion
suggested that fluorouracil was the precipitating cause of the chest pain. Further
fluorouracil therapy was discontinued and the patient proceeded with radiation
therapy alone for his colorectal cancer [221].
3) VARIANT ANGINA during weekly intravenous fluorouracil therapy in a 63-year-old
male with no history of angina pectoris was reported. Diltiazem given for 24 hours
prior to subsequent fluorouracil courses prevented further episodes. It is speculated
that fluorouracil can induce CORONARY ARTERY SPASM, although studies must
confirm this [222].
4) A bolus dose of fluorouracil 250 mg induced coronary artery spasm. Angina at rest
occurred in a 70-year-old man on two different occasions at 72 and 24 hours after the
initiation of continuous fluorouracil (1000 mg/square meter/day). The coronary artery
spasm recurred upon rechallenge with fluorouracil [223].
Cardiogenic shock
1) Cardiogenic shock, unresponsive to inotropic and vasopressor treatment, occurred
in a 72-year-old woman on the 4th day of the 5th monthly 5-day treatment with 5-FU
(425 milligrams (mg)/square meter (m(2)) per day) and folinic acid (20
mg/m(2)/day) for resected rectal adenocarcinoma. An intra-aortic balloon pump
(IABP) maintained systemic perfusion with dramatic improvement within 48 hours;
ejection fraction improved from 20% with severe global hypokinesia to 50% with
septoapical hypokinesia (10 days after IABP) and finally to normal (30th day) (David
et al, 2000).
2) A case of reversible cardiogenic shock was associated with continuous fluorouracil
infusion in a 48-year-old male with no cardiac history. After 50 hours (3750
milligrams), the patient had chest pain with nausea and diaphoresis; within 58 hours
he developed hypotension that required dopamine and norepinephrine. After
fluorouracil discontinuation, angiography revealed a dilated, hypokinetic left ventricle
with an ejection fraction of 7%; hemodynamic parameters also indicated cardiogenic
16/317
25/10/12
with an ejection fraction of 7%; hemodynamic parameters also indicated cardiogenic

shock. Clinical status improved over the next day [224].
3) Another case describes reversible cardiogenic shock related to continuous
fluorouracil infusion intravenously (750 mg/m(2)/day) and intraperitoneally (1000
mg/m(2)/day) each for 5 days in a 38-year-old male with no cardiac history. On day 4,
the patient was dyspneic, tachycardiac, and hypotensive; on day 5, fluorouracil was
discontinued. Chest radiograph revealed right pleural effusion and infiltrate;
electrocardiogram indicated a dilated, hypokinetic left ventricle. Clinical status
improved with dobutamine and furosemide [225].
Cardiomyopathy
1) Acute DILATED CARDIOMYOPATHY was described in a 41-year-old male with
heart failure and renal failure following fluorouracil therapy [226]. The patient
developed cardiac and renal failure approximately 1 day after a 5-day course of 5fluorouracil and cisplatin for laryngeal neoplasm. Dopamine administration was
required to control blood pressure. Echocardiography and right heart catheterization
confirmed alteration of the myocardial contractility. The patient recovered uneventfully
after a period of 2 weeks. This appears to be the first case report of acute dilated
myocardiopathy secondary to 5-fluorouracil.
2) A case of fatal acute dilated cardiomyopathy associated with continuous infusion of
fluorouracil (1 gram/square meter(m(2)/day for 120 hours) pretreated with cisplatin
100 mg/m(2) on day 1 has been reported. Symptoms from a massive aortic embolism
began 16 hours after the end of the infusion. Despite, moderate ethanol consumption,
the patient had no previous cardiac symptoms or ECG/chest radiogram abnormalities
[227].
Cardiotoxicity
1) Summary
a) Although uncommon, fluorouracil has been associated with chest pain, anginal
attacks, ischemic electrocardiographic changes, myocardial infarction,
cardiomyopathy, and very rarely, sudden death [228][229][226][230][231][232].
Death has occurred secondary to cardiogenic shock [233][234]. Most commonly,
these effects occur when the drug is administered as a continuous infusion and within
several hours from the start of the infusion. Patients with pre-existing coronary artery
disease (CAD) appear to be at greater risk; however, most reported cases are in
those with no previous history of CAD [230][231].
2) Two patients undergoing chemotherapy with IV fluorouracil (425 mg/m(2)/day)
and folinic acid (25 mg/m(2)/day) developed cardiotoxicity (chest pain and ECG
changes) requiring discontinuation of fluorouracil. The first patient was a 40-year-old
woman with no prior history of heart disease being treated for adenocarcinoma of the
cecum and who developed cardiotoxicity on the third day of the first cycle of
fluorouracil. ECG showed ST segment elevation in leads, II, III, aVF, V5, and V6.
Fluorouracil was discontinued and sublingual nitroglycerin provided immediate, but
temporary relief. The patient was admitted to the cardiac care unit and given heparin
and a nitroglycerin infusion. Serum levels of cardiac enzymes and echocardiography
were normal. Coronary angiography revealed normal cardiac physiology. Diagnostic
testing showed no signs of coronary artery stenosis. The patient was discharged on
oral diltiazem 90 mg/day and different chemotherapy agents were started. She had no
cardiac symptoms on follow-up. The second patient was a 63-year-old man with a
17/317
history significant for coronary artery disease with adenocarcinoma of the duodenum
who developed cardiotoxicity on the third day of fluorouracil. The patient had ST
segment elevation in leads II, III, aVF, V4, V5, and V6. IV nitroglycerin and diltiazem
were initiated in the cardiac care unit and his chest pain resolved within 30 minutes.
There were no elevations in cardiac enzymes and echocardiography was normal.
Atherosclerotic plaques were identified in the left anterior descending and circumflex
arteries. The right coronary artery was totally occluded proximally. The patient was
discharged on an oral nitrate and diltiazem and fluorouracil was discontinued [232].
3) In a review of fluorouracil (5-FU)-associated cardiotoxicity, investigators estimated
the overall incidence as varying from 1.2% to 18% with resultant mortality in 2.2% to
13.3% of cases. Although several hypotheses regarding the mechanism of this
adverse effect are under investigation, such as coronary vasospasm, endothelial cell
damage with thrombus formation, increased myocardial oxygen demand, interference
with myocardial cell metabolism and dihydropyrimidine dehydrogenase deficiency,
results are inconclusive. Available data do not permit clinicians to predict which
patients are at risk, as pre-existing cardiac disease or chest irradiation, dose and
route of administration, concomitant medications, age and gender do not consistently
correlate with 5-FU-associated cardiotoxicity. The typical onset is within hours of the
initial 5-FU dose; most cases are fully reversible within a few days. 5-FU should be
discontinued when cardiotoxicity arises and should not be reinstituted due to a high
incidence of recurrence [228].
4) A prospective, cohort study identified 9 (1.9%) cases of suspected cardiotoxicity
during high-dose, continuous infusion of fluorouracil (5-FU) which was lower than
reported in other studies (7.6% to 68%). Seven of 9 cases required termination of the
infusion. Other treatments consisted of topical or sublingual nitroglycerin and an
increased oxygen rate. The predominant symptom was chest pain but dysrhythmia
and marked hypotension were also noted. Patients with pre-existing ischemic heart
disease or myocardial infarction showed a higher risk for cardiotoxicity than patients
without these conditions. Five of the 9 patients were rechallenged with 5-FU; only 1
had a recurrence of symptoms. Results of this study were similar to others except
high-dose, continuous infusion resulted in a low incidence of cardiotoxicity compared
to earlier studies [235].
5) A 7.6% incidence of cardiotoxicity associated with high-dose continuous infusion
fluorouracil in a prospective study of 367 patients was reported. Based upon
retrospective and anecdotal reports it appears that the incidence of fluorouracilinduced toxicity has increased from 1.6% to approximately 10% during the 1980 to
1990 period, and may be due to the administration of high-dose fluorouracil
[236][237]; (de Forni et al, 1992). The mechanism of fluorouracil-induced
cardiotoxicity is the topic of much speculation. Proposed mechanisms include: direct
myocardial toxicity, coronary vasospasm, autoimmune phenomena, thrombogenic
effect, and fluoroacetate formation [235][238]; (de Forni et al, 1992).
6) Fluoroacetaldehyde has been found in fluorouracil vials (manufactured by Roche
Pharmaceuticals; France distribution). This compound may be metabolized to
fluoroacetate (FAC), a highly cardiotoxic substance [239]. Nuclear magnetic
resonance (NMR) spectroscopic analysis of Roche fluorouracil vials, displayed 6
fluorinated compounds accounting for 1 to 1.5 mol% of the total contents. FAC was
not present, however; four major impurities including fluoracetaldehyde-acetal, due to
acetalisation by tris, were present. Experimentation with animal models has
18/317
25/10/12
demonstrated that the conversion of fluoracetaldehyde to FAC does occur in vivo, and
FAC has been detected in urine in patients receiving Roche fluorouracil; some, but not
all of whom experienced cardiotoxicity [239]; (De Forni et al, 1992).
Coronary arteriosclerosis
1) Myocardial ischemia has been reported in patients receiving intravenous
fluorouracil [207]. Four cases of chest pain occurring after fluorouracil treatment were
reported. Each patient developed ISCHEMIC CHEST PAIN within 18 hours of the
second or third dose of 5-fluorouracil and a rechallenge was positive in 3 of the 4
patients. There were EKG abnormalities in 3 of the patients which included T-wave
inversion, S-T elevation and peaked T-waves. Two of the 4 patients had normal predose EKGs and none had a history of myocardial ischemia or hypertension. All patients
had received left ventricular irradiation prior to drug treatment, but only these 4 out of
140 total patients treated similarly developed chest pain [242].
2) Two cases of 5-FU cardiotoxicity manifested by ECG or cardiac enzyme changes
while they were receiving 5-FU by prolonged infusion were reported (Sanani, 1981).
3) Thirty-five cases of fluorouracil-associated myocardial ischemia were summarized
by 2 investigators [220].
EKG finding
1) Twenty-five patients with carcinomas of the head and neck were monitored for
electrocardiogram (ECG) changes from baseline during fluorouracil infusion (4 to 5
grams/square meter over 96 to 120 hours). Continuous ambulatory Holter monitoring
revealed 17 of 25 patients with ST segment changes, suggestive of ischemia, during
therapy as compared to 6 of 25 at baseline. Of the patients with ST elevations or
depressions, episodes of "ischemia" recorded during therapy and baseline were 356
and 28, respectively. Premature ventricular depolarizations were also more common
during therapy. Only one patient experienced angina; two others died suddenly 4 and
12 hours, respectively, after the administration/monitoring period. The authors
cautioned that patients with preexisting coronary artery disease may be at greater
risk for these changes [231].
a) Two patients died suddenly 4 and 12 hours, respectively, after the
administration/monitoring period in a prospective study of electrocardiogram (ECG)
changes from baseline during fluorouracil infusion (4 to 5 grams/square meter over
96 to 120 hours) in 25 patients with carcinoma of the head and neck [231]. During
infusion, both patients had ST segment changes (with no ischemic evidence at
baseline) and increased incidence of premature ventricular depolarizations. In
addition, others have hypothesized the occurrence of sudden death in association
with fluorouracil exposure. One review very briefly summarizes 10 cases of sudden
death associated with high-dose fluorouracil infusions in a retrospective review of 244
patients [230].
b) Conduction disorders were reported in a 45-year-old male following fluorouracil
500 mg/m(2)/day therapy. The patient had interventricular septal defect since
childhood and was receiving digoxin for atrial flutter. Upon rechallenge with
fluorouracil 1 month later, the patient redeveloped conduction abnormalities, which
continued for 1 month after discontinuation of fluorouracil [240].
c) Raised ST segment and inverted T-waves were reported in a 33-year-old male
who developed cardiotoxic effects secondary to 5-fluorouracil [233]. Cardiac enzymes
were also elevated (creatine phosphokinase and aspartate transaminase) and chest
19/317
25/10/12
x-ray revealed pulmonary edema. ST elevations and ANTEROLATERAL ISCHEMIA

with inverted T-waves has also been reported elsewhere [217].
Myocardial infarction
1) There are reports of 2 cases of cardiotoxicity secondary to 5-fluorouracil (5-FU).
Both patients were on single-agent therapy for adenocarcinoma of the colon. Neither
patient had a history of angina or of hypertension. A 65-year-old female developed
severe central chest pains several hours after the sixth bolus of 20 mg/kg 5-FU with
concomitant features of sweating, nausea, vomiting and dyspnea; she rapidly
developed cardiogenic shock and died. Acute transmural anterolateral MYOCARDIAL
INFARCTION was evidenced by the EKG. The second case, a 43-year-old male,
developed severe central chest pain that radiated into the left arm 7 hours after a
second bolus dose of 5-FU (15 mg/kg). Glyceryl trinitrate failed to relieve pain, which
responded to diamorphine. Some ST depression was evidenced on EKG, with cardiac
enzyme activities remaining within normal limits. Chest pains again occurred, but not
as severe, after 1 intravenous bolus of 5-fluorouracil, dosage 10 mg/kg 4 days later
[234].
2) Cardiac arrest was described in a 61-year-old male, with no prior history of heart
disease, during a continuous infusion of 5-fluorouracil (third day of the third treatment
cycle which consisted of 1.84 g daily for 4 days). Electrocardiogram (EKG) monitoring
suggested coronary artery spasm as the underlying event in this patient. Serial cardiac
enzymes in the this patient revealed no evidence of myocardial infarction. The patient
responded to diltiazem and isosorbide therapy. It was recommended that fluorouracil
be used cautiously in individuals with previous heart disease, especially in patients
with a history of recent myocardial infarction, unstable angina, or documented
coronary artery spasm. If 5-fluorouracil infusions are administered to these patients, it
is recommended that concurrent use of calcium channel-blocking agents be
considered [241].
Thrombophlebitis
1) Thrombophlebitis has been reported in patients receiving intravenous fluorouracil
[207].
Dermatologic Effects
Contact dermatitis
1) After using topical fluorouracil (5-FU) 5% cream intermittently for 4 years, a 61year-old man developed severe contact sensitivity at application sites and later had a
similar reaction to the first intravenous dose of 5-FU. The reaction to topical 5-FU
began within 2 to 3 hours after application; areas of blistering and exudation
developed. Patch testing demonstrated a strong reaction to 5-FU in 1% petrolatum on
days 2 and 4, but no reaction to propylene glycol occurred. Rectal adenocarcinoma
was later diagnosed; treatment consisted of surgery, radiotherapy, and 5-FU 1 g/week
administered intravenously. After the first dose of intravenous 5-FU, the patient
developed acute dermatitis, head and neck edema, and an erythematous, vesicular
rash on the face, scalp, neck, and both hands. The reaction was more severe on the
right arm where the 5-FU was administered. Due to the severity of this reaction, 5-FU
could not be used in this patient. The authors caution that rapid development of
acute, localized dermatitis soon after application of 5-FU cream should raise the
suspicion of an allergic contact dermatitis reaction.
2) Topical 5-fluorouracil has been associated with allergic contact DERMATITIS in
20/317
25/10/12
patients with actinic keratosis and basal cell epitheliomas [291][292]. Topical 5fluorouracil ointment (5%) was reported to exacerbate dermatitis when it was
mistakenly given instead of fluocinonide ointment [293].
Dermatological finding
1) Alopecia, DRY SKIN, FISSURING, hand-foot syndrome, nail changes, rash,
PHOTOSENSITIVITY, and VEIN PIGMENTATION have been reported in patients
receiving intravenous fluorouracil [207].
Discoloration of skin
1) Serpentine supravenous fluorouracil HYPERPIGMENTATION was reported in a 56year-old black male following IV 5-fluorouracil 750 mg/m(2)/week over 24 weeks for
stage D prostatic carcinoma. The patient developed nasal mucosal friability, diffuse
hyperpigmentation of the face and hands and markedly increased pigmentation of skin
immediately overlying the veins used for multiple fluorouracil infusion. Many irregular
dark streaks were noted which extended from the hand to the shoulder. These streaks
were 1 to 1.5 cm wide and serpignous in their course. This is the first case of its kind
reported in the literature to date [303].
Drug-induced erythema
1) A causal relationship between infusion of 5-fluorouracil (5-FU) and the
development of bilateral persistent supravenous erythematous eruption in a 47-yearold-male with squamous cell carcinoma was described (Rujol et al, 1998). The patient
received intravenous 5-FU in both forearms. No apparent extravasation or phlebitis
was detected. Four days following therapy, a linear eruption developed on both upper
extremities and later extended to the trunk and legs. The linear erythematous streaks
followed the superficial linearity of the veins. Non-itchy, erythematous macules and
plaques of 0.4 to 5 cm in diameter also were observed on the trunk, lumbosacral area,
and thighs. Biopsy results showed prominent vacuolar alteration of basal cells,
necrotic keratinocytes, pigment incontinence, and perivascular lymphocytic infiltrates.
The cutaneous eruption remitted over several weeks; however, residual serpentine
supravenous pigmentation became apparent. This cleared within a 3-month period.
Hair finding
1) ALOPECIA is also a commonly occurring effect following systemic fluorouracil
therapy [208]; (Prod Info fluorouracil injection, 1997).
Hand-foot syndrome due to cytotoxic therapy
1) The administration of fluorouracil (alone or in combination regimens, via
continuous or intermittent infusions or bolus doses) has been associated with a
syndrome characterized by varying degrees of painful, erythematous, symmetric
swollen palms of hands and soles of feet [207][294]. The reaction has been described
as PAINFUL RED HANDS, ACRAL ERYTHEMA, PALMAR-PLANTAR
ERYTHRODYSESTHESIA, or hand-foot syndrome [295]. Tingling, tenderness, and
desquamation may also occur. Onset of the reaction has ranged from 3 days to 10
months [296][294]. Severity appeared dose related in one case [297]. The condition
gradually subsides over 5 to 7 days when the drug is discontinued; pyroxidine has
been reported to ameliorate symptoms [207]; however, recurrence may occur upon
rechallenge [296].
2) A meta-analysis of 6 randomized trials comparing intravenous fluorouracil by
continuous infusion or bolus injection found that toxicities associated with the 2
methods were similar in frequency, with the exception
of neutropenia and hand-foot

21/317
25/10/12
methods were similar in frequency, with the exception of neutropenia and hand-foot
syndrome. In 1,219 patients with colorectal cancer, the incidence of grade 3 to 4
diarrhea, nausea and vomiting, mucositis was similar between groups (13% versus
14%, RR 0.96). The incidence of hand-foot syndrome, however, was nearly doubled
when fluorouracil was administered by continuous infusion (34% versus 13%, RR
1.87, p less than 0.001). Hematologic toxicity, primarily neutropenia, occurred
significantly more often in patients receiving bolus injections (31% versus 4%, RR
0.14, p less than 0.0001). Anemia and thrombocytopenia occurred in less than 5% of
all patients. Factors increasing the risk for hematologic toxicity included a poor
performance status and fluorouracil administration by bolus injection, while increased
age, female gender, and a good performance status significantly increased the risk for
nonhematologic toxicities. In hand-foot syndrome, continuous administration of
fluorouracil was an additional prognostic factor [259].
Nail damage
1) Diffuse blue superficial pigment, ONYCHOLYSIS, dystrophy, pain and thickening of
the nail bed, transverse striations, half and half nail changes, loss of nail, paronychial
inflammation, and hyperpigmentation have been reported with 5-fluorouracil therapy
[207][298][299][300][301]. It has further been reported that the blue pigment may
be scraped off [299].
Pemphigus
1) A case of BULLOUS PEMPHIGOID was reported in an 84-year-old male following
topical therapy with 5-fluorouracil 1% solution daily over several days for actinic
keratosis. All treated lesions became bullous with development of a few bullae on
untreated areas of normal skin. Bullous lesions were pruritic and sore and some
contained hemorrhagic fluid. Leukocytosis (11,700) was present. Blister fluid
contained predominantly eosinophils and immunofluorescent studies of the serum and
blister fluid revealed basement-membrane antibody titers of 1:640 and 1:160,
respectively. Fluorouracil was discontinued, and the patient was treated with steroids
and saline compresses with a subsidence of symptoms [302].
Rash
1) 5-Fluorouracil is associated with many types of skin reactions, the most common
being a pruritic MACULOPAPULAR RASH appearing on the extremities and most
frequently the trunk. This is usually reversible upon withdrawal of 5-fluorouracil [207].
2) Following a course of systemic 5-fluorouracil for colon cancer, a 72- year-old male
developed pruritic rash evolving into lichenified plaques of the forearms in areas of
preexisting actinic keratoses, which investigators described as a selective
inflammatory reaction. Topical midpotency corticosteroids were initially ineffective.
The lesions resolved following a 6-week course of topical 5-FU followed by topical
triamcinolone for 10 days (Nabai et al, 1999).
Telangiectasia
1) Four patients receiving topical 1% 5-fluorouracil in propylene glycol applied TID for
7 to 28 days. Two patients developed herpes labialis 7 to 10 days after initiation of
therapy and 2 patients developed persistent telangiectasia at the application site
[304].
Endocrine/Metabolic Effects
Hypercalcemia
22/317
25/10/12
1) A case of malignant hypercalcemia was reported in a 36-year-old female with

metastatic carcinoma of the breast following 5-fluorouracil 6 mg/kg IV daily for 5 days.
Serum calcium level was 9.4 mg% with leukopenia, tachycardia, weakness, nausea
and vomiting, and a semi-comatose state. Intravenous sodium sulfate, administered
with dexamethasone 36 mg daily IV, resulted in rapid response [256].
Hypocalcemia
1) Of 25 patients receiving low-dose leucovorin (20 mg/m(2)) and fluorouracil (425 to
600 mg/m(2)), 15 (65%) developed hypocalcemia, and two each had tetany or
hiccups. The latter 4 patients were treated with calcium supplementation which led to
resolution of symptoms. Parathyroid and vitamin D levels were measured in 12
patients at the end of a single course of chemotherapy. Parathyroid levels were within
the normal range, but vitamin D levels were low in 4 patients. The authors suggest
that calcium levels should be monitored in patients receiving this regimen, and
calcium supplementation should be provided if calcium levels are low [257].
Gastrointestinal Effects
Abdominal pain
1) A series of 6 adults, aged 40 to 70 years, developed severe abdominal pain and
diarrhea associated with intravenous fluorouracil and leucovorin administration for
adenocarcinoma of the colon. All patients underwent prior surgical resection. SMALL
BOWEL PERFORATION accompanied by severe ulceration and inflammation was
documented laparoscopically in 2 patients and required resection. Rechallenge during
subsequent chemotherapy courses was generally well tolerated, with recurrent
toxicity observed in 2 patients. Symptoms improved with supportive care, bowel rest,
and dosage reduction in most instances. The mechanisms for this toxicity may include
direct vascular injury and increased thrombus formation which result in impaired
gastric mucosal blood flow and injury [261][262].
Diarrhea
1) Toxicity was reduced with the administration of irinotecan prior to a 48-hour
infusion of fluorouracil (5-FU) modulated by leucovorin (LV) compared with
administration of irinotecan after 5-FU/LV in 23 chemotherapy-naive metastatic
colorectal cancer patients. Grade 3/4 toxicity with the irinotecan/5-FU/LV regimen
compared with the 5-FU/LV/irinotecan regimen included DIARRHEA (4% versus
17%), neutropenia (22% versus 39%), and febrile neutropenia (4% versus 17%).
The area under the curve (AUC) of SN-38, the active metabolite of irinotecan, was
40% lower when irinotecan was administered prior to 5-FU/LV versus after 5FU/LV (p
less than 0.05)[211].
2) Oral glutamine supplementation attenuated fluorouracil/folinic acid (5-FU/FA)induced changes in intestinal absorption and permeability in a placebo-controlled,
double-blind, randomized trial of 70 chemotherapy-naive patients with colorectal
cancer. Starting 5 days prior to the first 5-FU/FA cycle, patients consumed 6-gram
sachets of either glutamine or placebo dissolved in water 3 times daily for a total of 15
days. Chemotherapy dosing included FA 100 milligrams/square meter (mg/m(2))/day
plus 5-FU 450 mg/m(2)/day, each given for 5 days. Intestinal absorption of D-xylose
decreased significantly more in the placebo group than in the glutamine group (7.1%
versus 3.8%, p=0.02). As measures of intestinal integrity, urinary recovery of
mannitol and the cellobiose/mannitol ratio also favored glutamine recipients. Average
loperamide dosage requirements were significantly lower with glutamine (0.4 tablet)
23/317
25/10/12
than with placebo (2.5 tablets, p=0.002). Differences in the extent and duration of
diarrhea between groups failed to reach statistical significance [263].
3) A 64-year-old man developed NEUTROPENIC ENTEROCOLITIS after receiving 3
courses of 5-fluorouracil 370 mg/m(2)/day and leucovorin 200 mg/m(2)/day
administered as a bolus infusion for 5 consecutive days and repeated every 4 weeks.
Treatment was for liver metastases associated with colon adenocarcinoma. About 2
weeks after the third course, he was admitted to the hospital with fever, jaundice,
diarrhea, right lower quadrant pain; the leukocyte count and absolute neutrophil count
were 1700/microliter and 270/microliter. Treatment consisted of antibiotics including
ticarcillin, gentamicin, and metronidazole and furosemide and spironolactone for bowel
wall edema and ascites. After discharge, he had persistent abdominal pain, fever, and
diarrhea which required readmission. Additional diagnostic tests were consistent with
enterocolitis. Treatment comprised bowel rest, intravenous fluids, pain medications,
and ranitidine. Subsequent computed tomography showed a normal bowel. No further
chemotherapy was administered, and the patient remains in complete remission. This
patient had an unusual course in that enterocolitis failed to resolve despite an
increase in neutrophil count and appropriate therapy; this complication usually occurs
in patients with hematologic malignancies [264].
4) Of 17 patients with previously diagnosed inflammatory bowel disease (IBD), nine
(53%) developed grade III/IV diarrhea during treatment with fluorouracil (5-FU) for
gastrointestinal cancer. The incidence of diarrhea reported in this small series of
patients is higher than that reported in previous clinical trials. The dosage or method
of administering 5-FU or concurrent use of radiation therapy did NOT appear to
influence development of severe diarrhea. Based on data obtained in this small group
of patients with IBD, it appears that the increased risk of toxicity should NOT preclude
use of this therapy in patients with potentially curative disease. However, the
increased risk of toxicity should be carefully weighed in patients with incurable
gastrointestinal cancer. Although this was a small, retrospective review, it addresses
a clinically important question since patients with IBD have an increased risk of
developing gastrointestinal cancer [265].
5) Diarrhea followed by neutropenia and life-threatening or fatal sepsis occurred in
two of 55 patients with advanced colorectal carcinoma in a pilot study of continuous
infusion fluorouracil (750 mg/m(2)/day for 5 days) plus subcutaneous recombinant
interferon alfa-2a (6 to 18 million units/day) [266].
6) After 36 treatments with intravenous 5-fluorouracil (5-FU) 700 mg and folinic acid
150 mg, colitis suggestive of pseudomembranous colitis (PMC) developed in a 67year-old man with metastatic colon cancer. Presenting symptoms included fever,
abdominal cramps, and liquid stools with blood. Endoscopy showed yellowish white
plaques surrounded by hyperemic mucosa suggestive of PMC. Cultures did NOT grow
Clostridium difficile; however, treatment with oral vancomycin 500 mg 4 times daily
resulted in a decrease of symptoms by 48 hours and complete resolution by 7 days.
The mechanism by which 5-FU causes PMC is potentially related to its antimitotic
effect on intestinal crypt and its antibacterial activity which may alter the intestinal
flora [267]. Two other cases of 5-FU-induced diarrhea and colitis associated with
Clostridium difficile have been reported; both cases responded to oral vancomycin
[268].
Gastrointestinal tract finding
1) Commonly occurring symptoms during IV fluorouracil therapy are stomatitis,
ESOPHAGOPHARYNGITIS, NAUSEA, VOMITING,
ANOREXIA and DIARRHEA
24/317
25/10/12
ESOPHAGOPHARYNGITIS, NAUSEA, VOMITING, ANOREXIA and DIARRHEA

[207][258][208]. Fluorouracil should be withdrawn at the first signs of stomatitis or
esophagopharyngitis, intractable vomiting, severe diarrhea, or GASTROINTESTINAL
ULCERATION and BLEEDING [207].
2) The clinical toxicity observed in a study involving 22 patients with gastrointestinal
tract cancers was substantially lower in a trial utilizing a combination chemotherapy
regimen with fluorouracil given as a ONE-HOUR INFUSION compared retrospectively
with those observed in a study using the same regimen except fluorouracil was
administered as a five-minute injection. Patients were administered interferon alfa-2a
(5 million units subcutaneously on days 1-7), followed immediately by leucovorin 500
milligrams (mg)/square meter intravenously (IV) over 30 minutes on days 2-6, and
fluorouracil 370 mg/square meter IV on days 2-6. A significantly higher number of
patients receiving fluorouracil over five minutes experienced grade 2 or greater
mucositis (p=0.0001) and diarrhea (p=0.009) compared with patients receiving
fluorouracil as a one-hour infusion. Nine (41%) patients receiving fluorouracil as a
one- hour infusion tolerated a dose escalation to 425 mg/square meter or above,
while seven (32%) required a dose reduction. The fluorouracil maximum observed
drug concentration (Cmax) and area under the plasma concentration-time curve
(AUC) following a dose of 370 mg/square meter as a five-minute injection were 7.3fold and 2.4-fold higher, respectively, than following the one-hour infusion [210].
3) An unexpectedly HIGH DEATH RATE occurring within 60 days after the initiation of
treatment in patients receiving a regimen of IRINOTECAN, FLUOROURACIL, and
LEUCOVORIN for colorectal cancer was revealed in an interim analysis of data from
two separate cooperative-group clinical trials sponsored by the National Cancer
Institute and conducted throughout out the United States and Canada. One trial of
patients with metastatic colon cancer compared the regimen of irinotecan,
fluorouracil, and leucovorin (described by Saltz et al, 2000) with a regimen of
oxaliplatin, fluorouracil, and leucovorin and a regimen of oxaliplatin and irinotecan. The
other trial, an adjuvant study of patients with resected stage III colon cancer,
compared fluorouracil and leucovorin with the irinotecan, fluorouracil, and leucovorin
regimen. Dose modifications were made in both trials in an attempt to ameliorate the
toxicity of the regimen. Enrollment in both trials has been suspended. Common
characteristics in the deaths of 12 of the 14 deaths in patients with advanced disease
included: dehydration (from DIARRHEA, NAUSEA, and VOMITING), NEUTROPENIA,
and SEPSIS [212]. It has been suggested that the early deaths reported by Sargent et
al may be due to the bolus administration of fluorouracil, leucovorin, and irinotecan.
Three large ongoing European trials have not reported an increased incidence of early
deaths with infusional fluorouracil, leucovorin, and irinotecan [213].
all patients. Factors increasing the risk for hematologic
toxicity included a poor
25/317
25/10/12
5) In patients with dihydropyrimidine dehydrogenase (DPD) enzyme deficiency
administered INTRAVENOUS fluorouracil, rare, life-threatening toxicities such as
STOMATITIS, DIARRHEA, neutropenia, and neurotoxicity have been reported. One
case of life-threatening systemic toxicity has been reported with the TOPICAL use of
fluorouracil in a patient with DPD enzyme deficiency. Symptoms included SEVERE
ABDOMINAL PAIN, BLOODY DIARRHEA, VOMITING, fever, and chills. Physical
examination revealed included STOMATITIS, erythematous skin rash, neutropenia,
thrombocytopenia, and INFLAMMATION OF THE ESOPHAGUS, STOMACH, and SMALL
BOWEL. Although this case was observed with 5% fluorouracil cream, it is unknown
whether patients with profound DPD enzyme deficiency would develop systemic
toxicity with lower concentrations of topically applied fluorouracil [205].
a) One occurrence of severe fluorouracil (5-FU) toxicity secondary to
dihydropyrimidine dehydrogenase deficiency has been reported. The 5-FU doses
received by the 35-year-old woman treated with the adjuvant protocol for breast
carcinoma were not unusually high. Chemotherapy had been initiated 3 weeks after
surgery with a combination of cyclophosphamide (orally 100 mg/day/square meter)
for 14 days, and methotrexate (50 mg/square meter) in combination with 5-FU (600
mg/square meter) on days 1 and 8. Following day 8 of the protocol, the patient
experienced severe gastrointestinal (NAUSEA, prolonged VOMITING, DIARRHEA,
STOMATITIS), and hematologic (neutropenia) toxicity that required hospitalization.
She had a leukocyte count of 1,100, with 5% neutrophils (no bands) and fever. In
addition, she experienced what was classified as mild neurologic toxicity manifest as
difficulty with balance, and spelling simple words which persisted for about 2 weeks.
Dihydropyrimidine dehydrogenase (DPD) as the initial enzyme responsible for the
breakdown of 5-FU, accounts for greater than 80% of the drugs catabolism. Only a
few cases of DPD deficiency have been identified; however, all cases exhibited
remarkable toxicity. Enhanced toxicity occurring at normal doses is what usually sets
these patients apart. The authors suggest that monitoring DPD activity may be
appropriate in the management of those experiencing severe toxicity from 5-FU
[215].
6) Severe GI toxicity secondary to 5-fluorouracil was reported in a 53-year-old male
following a side to side ileo descending colostomy for disseminated carcinoma [260].
5-fluorouracil was given in doses of 15 mg/kg for 4 days then 7.5 mg/kg on the 6th
and 8th day IV. The patient developed severe diarrhea and severe ulceration of the
bypassed portion of the colon resulting in necrosis of the bypassed portion. The
patient died of bronchopneumonia. Autopsy revealed ulcerations from ileocecal valve
to the ileocolostomy site. The mucosa of the stomach, small intestine and colon distal
to the colostomy were not involved.
Gastrointestinal ulcer
1) Gastric ulceration and bleeding have been reported in patients receiving
intravenous fluorouracil [207]. One patient receiving 5-fluorouracil by intrahepatic
infusion via percutaneous catheterization in doses of 20 to 30 mg/kg for 4 days
followed by 15 mg/kg over 17 days developed gastric ulceration. Symptoms were
26/317
25/10/12
observed from 4 to 20 days after starting therapy [271].

2) GI bleeding occurred in 3 patients and death in 1 patient following intra-arterial 5fluorouracil [272].
Nausea
See Drug Consult reference: CHEMOTHERAPY AND RADIOTHERAPY TREATMENT
GUIDELINES FOR NAUSEA AND VOMITING
Stomatitis
1) Literature Reports
a) The results of a meta-analysis of 731 patients (402 men and 329 women) who
received fluorouracil-based chemotherapy demonstrated that women are more likely
to experience stomatitis than men. Six clinical trials utilizing 8 different
chemotherapeutic regimens were included in the analysis. No regimen was received
by more than 40% of the patients included in the analysis and 95% of the patients
had colorectal cancer. Overall, stomatitis was reported by 57% of the patients (52%
male and 63% female; p=0.002) with 17% of these reports being severe or very
severe (12% male and 22% female; p=0.0006). Confounders such as fluorouracil
regimen and smoking status did not affect the incidence of stomatitis reported.
However, patients older than 65 years of age reported more stomatitis than those
younger than 65 [269].
2) Prevention
a) To prevent oral mucositis in patients receiving bolus 5-fluorouracil chemotherapy,
the Multinational Association of Supportive Care in Cancer and the International
Society for Oral Oncology recommend 30 minutes of oral cryotherapy [270].
Vomiting
See Drug Consult reference: CHEMOTHERAPY AND RADIOTHERAPY TREATMENT
GUIDELINES FOR NAUSEA AND VOMITING
Hematologic Effects
Hematology finding
1) Summary
a) LEUKOPENIA is the most common hematologic toxicity associated with
fluorouracil (5-FU) with the nadir typically between 9 and 14 days after treatment.
The white blood cell count usually returns to normal by the 30th day; maximum
depression may be delayed as long as day 20 [207]. AGRANULOCYTOSIS, ANEMIA,
EPISTAXIS, PANCYTOPENIA, and THROMBOCYTOPENIA have also been reported
during treatment with intravenous 5-FU [207][208][209].
2) The clinical toxicity observed in a study involving 22 patients with gastrointestinal
tract cancers was substantially lower in a trial utilizing a combination chemotherapy
regimen with fluorouracil given as a ONE-HOUR INFUSION compared retrospectively
with those observed in a study using the same regimen except fluorouracil was
administered as a five-minute injection. Patients were administered interferon alfa-2a
(5 million units subcutaneously on days 1-7), followed immediately by leucovorin 500
milligrams (mg)/square meter intravenously (IV) over 30 minutes on days 2-6, and
fluorouracil 370 mg/square meter IV on days 2-6. A significantly higher number of
patients receiving fluorouracil over five minutes experienced grade 2 or greater
leukopenia (0.0001) and granulocytopenia (p=0.0001) compared with patients
27/317
25/10/12
receiving fluorouracil as a one-hour infusion. Nine (41%) patients receiving fluorouracil

as a one-hour infusion tolerated a dose escalation to 425 mg/square meter or above,
while seven (32%) required a dose reduction. The fluorouracil maximum observed
drug concentration (Cmax) and area under the plasma concentration-time curve
(AUC) following a dose of 370 mg/square meter as a five-minute injection were 7.3fold and 2.4-fold higher, respectively, than following the one-hour infusion [210].
3) Toxicity was reduced with the administration of irinotecan prior to a 48-hour
infusion of fluorouracil (5-FU) modulated by leucovorin (LV) compared with
administration of irinotecan after 5-FU/LV in 23 chemotherapy-naive metastatic
colorectal cancer patients. Grade 3/4 toxicity with the irinotecan/5-FU/LV regimen
compared with the 5-FU/LV/irinotecan regimen included diarrhea (4% versus 17%),
neutropenia (22% versus 39%), and febrile neutropenia (4% versus 17%). The area
under the curve (AUC) of SN-38, the active metabolite of irinotecan, was 40% lower
when irinotecan was administered prior to 5-FU/LV versus after 5FU/LV (p less than
0.05)[211].
oxaliplatin, fluorouracil, and leucovorin and a regimen of oxaliplatin and irinoteca. The
and SEPSIS [212]. It has been suggested that the early deaths reported by Sargent et
al may be due to the bolus administration of fluorouracil, leucovorin, and irinotecan.
Three large ongoing European trials have not reported an increased incidence of early
deaths with infusional fluorouracil, leucovorin, and irinotecan [213].
28/317
25/10/12

stomatitis, diarrhea, NEUTROPENIA, and neurotoxicity have been reported. One case
of life-threatening systemic toxicity has been reported with the TOPICAL use of
fluorouracil in a patient with DPD enzyme deficiency. Symptoms included severe
abdominal pain, bloody diarrhea, vomiting, fever, and chills. Signs and symptoms
included stomatitis, erythematous skin rash, neutropenia, thrombocytopenia, and
inflammation of the esophagus, stomach, and small bowel. Although this case was
observed with 5% fluorouracil cream, it is unknown whether patients with profound
DPD enzyme deficiency would develop systemic toxicity with lower concentrations of
topically applied fluorouracil [205].
a) The occurrence of severe fluorouracil (5-FU) toxicity secondary to
dihydropyrimidine dehydrogenase deficiency has been reported. The 5-FU doses
received by a 35-year-old woman treated with the adjuvant protocol for breast
carcinoma were not unusually high. Chemotherapy had been initiated 3 weeks after
surgery with a combination of cyclophosphamide (orally 100 mg/day/square meter)
for 14 days, and methotrexate (50 mg/square meter) in combination with 5-FU (600
mg/square meter) on days 1 and 8. Following day 8 of the protocol, the patient
experienced severe gastrointestinal (nausea, prolonged vomiting, diarrhea,
stomatitis), and hematologic NEUTROPENIA toxicity that required hospitalization.
She had a leukocyte count of 1100 with 5% neutrophils (no bands) and fever. In
addition, she experienced what was classified as mild neurologic toxicity manifest as
difficulty with balance and spelling simple words which persisted for about 2 weeks.
Dihydropyrimidine dehydrogenase (DPD) as the initial enzyme responsible for the
breakdown of 5-FU, accounts for greater than 80% of the drugs catabolism. Only a
few cases of DPD deficiency have been identified; however, all cases exhibited
remarkable toxicity. Enhanced toxicity occurring at normal doses is what usually sets
these patients apart. The authors suggest that monitoring DPD activity may be
appropriate in the management of those experiencing severe toxicity from 5-FU
[215].
Hepatic Effects
Ascites
1) In a retrospective analysis of a phase I-II study of N-phosphonacetyl-L-aspartate
(250 mg/square meter) followed by weekly boluses of fluorouracil (600 to 800
mg/square meter) in 44 metastatic colorectal cancer patients, 5 of 17 patients with
complete or partial response to therapy developed transient ascites (with or without
associated hypoalbuminemia) compared to 1 of 27 without such a response [273].
Other significant findings in some of the responders included elevated bilirubin and
transaminase levels from baseline. Although 40 of 44 patients had liver metastasis,
the authors cautioned that the adverse effects observed do not necessarily represent
disease progression.
Hepatotoxicity
1) One report described diffuse hepatic necrosis in a 29-year-old male patient
receiving 500 mg daily for 4 days (route of administration unspecified) for
adenocarcinoma. The patient developed nausea, vomiting, diarrhea and massive and
diffuse hepatic necrosis. The drug was withdrawn, and the patient died 2 days later (6
days after starting medication). However, the role of 5-fluorouracil in inducing hepatic
29/317
25/10/12
disease in this patient is unclear [274].

2) Three case reports of HEPATIC INJURY in nurses following years of handling
cytostatic drugs (bleomycin, vincristine, cyclophosphamide, doxorubicin, dacarbazine,
fluorouracil, and methotrexate) were described [275]. All patients had neurological
symptoms associated with elevated serum alanine aminotransferase and alkaline
phosphatase levels, and liver biopsy revealed portal hepatitis with piecemeal necrosis
in one, and hepatic fibrosis and fat accumulation in the others. It is suggested that
HANDLING OF CYTOSTATIC AGENTS may insidiously produce hepatic damage and
possibly irreversible fibrosis.
Immunologic Effects
Anaphylaxis
1) ALLERGIC REACTIONS and anaphylaxis have been reported in patients receiving
intravenous fluorouracil [207].
2) An anaphylactic reaction occurred 4 hours after initiation of 5- fluorouracil
continuous infusion in a 46-year-old male. Signs and symptoms included skin flushing,
cyanosis, nausea, dyspnea, and hypotension (60/40 millimeters of mercury). Prompt
treatment with parenteral hydrocortisone and promethazine reversed the reaction,
except for hypotension, which finally remitted after 24 hours of dopamine support
[305].
3) A case of an anaphylactic reaction with shock following a 10th dose of 900 mg of
5-fluorouracil intravenously was reported in a 60-year-old white male undergoing
treatment for colorectal adenocarcinoma. Two minutes following his tenth dose of 5FU 900 mg, he became cyanotic and diaphoretic, and collapsed with a rapid thready
pulse of 120. His blood pressure was 30/0 mm Hg. Epinephrine, 1 mL of 1:1,000, was
administered with immediate and prompt signs of recovery. Within 25 minutes, BP,
pulse, and skin color had returned to normal [306].
Neurologic Effects
Central nervous system finding
1) Neurological effects reported with the administration of fluorouracil include
CONFUSION, disorientation, euphoria, nystagmus, headache, and ACUTE
CEREBELLAR SYNDROME [207].
Cerebrovascular accident
1) A possible association between development of ISCHEMIC STROKE following an
infusion of 5-fluorouracil and cisplatin was reported in 5 cancer patients [243]. The
theory that the stroke may have been drug-induced is based on the inability to identify
any other causative factors, and the fact that all of the cases occurred 2 to 5 days
after chemotherapy and during the second (3 patients) and third (2 patients) courses
of treatment.
Demyelinating disease of central nervous system, Cerebral
1) Clinicians attributed multifocal cerebral demyelination to a chemotherapy regimen
of fluorouracil (5-FU) and levamisole in a 57-year-old male with colon cancer. One
month after receiving the second cycle of 5-FU (cumulative dose: 8.25 grams) and
levamisole (cumulative dose: 1.5 grams), the patient presented with confusion,
diplopia, insomnia and diminished level of consciousness. The only abnormalities
noted on diagnostic work-up were elevated protein in the cerebrospinal fluid (0.78
gram/liter) and two non-contrast-enhanced areas on computed brain tomography.
30/317
25/10/12
Dexamethasone 16 milligrams/day for 28 days then tapered off led to improvement.

No further cycles of 5-FU/levamisole were administered. Follow-up magnetic
resonance imaging of the brain at one month indicated demyelination in the form of
multifocal hyperintensities. Over the next 30 months, most lesions gradually
disappeared (Yeo et al, 1999).
Encephalopathy
1) Summary
a) LEUKOENCEPHALOPATHY associated with fluorouracil (5-FU) has been described
in numerous case reports. Symptoms were variable and may include ATAXIA,
SPEECH DISTURBANCES, confusion, MEMORY LOSS, MUSCLE WEAKNESS, APHASIA,
GAIT DISTURBANCES, SEIZURES, and COMA. Patients ranged in age from 31 to 65
years and were treated with 5-FU alone or in combination with other agents (eg,
levamisole, mitomycin, and others). This adverse effect usually occurs early in
therapy between 7 and 19 weeks. Chemotherapy is usually stopped; however, in
some cases, it has been continued with improvement in symptoms. In addition,
dexamethasone 12 mg daily and immunoglobulins have been used. The course is
variable with some patients showing partial and others complete reversal of
symptoms with or without treatment. Although the cause of this adverse effect is
unknown, it has been suggested that 5-FU has a toxic effect on myelin, and
levamisole causes an immune response to the damaged myelin
[245][246][247][248][249]; (Gottleib & Luce, 1971). In some patients with
encephalopathy, partial or complete deficiency of dihydropyrimidine dehydrogenase
(DPD), an enzyme necessary for metabolism of fluorouracil, has been detected. It is
estimated that 3% of cancer patients have partial deficiency of DPD and that 1:1000
births may have complete DPD deficiency [250].
2) Continuous intravenous infusion of 5-fluorouracil (5-FU) 1500 milligrams/day for 4
days was followed 48 hours later by new-onset confusion, cognitive dysfunction and
ataxia in a 73-year-old male. He developed three generalized tonic-clonic seizures,
accompanied by electroencephalographic changes. A thorough diagnostic work-up
ruled out other possible etiologies. The patient was treated with phenytoin and
thiamine. His mental status normalized within 72 hours, with no further seizure
activity. However, limb ataxia was not completely reversible, necessitating use of a
walker two weeks later. The authors discuss possible mechanisms of 5-FU-induced
neurotoxicity, including Krebs cycle blockade and deficiencies of thiamine or
dihydropyrimidine dehydrogenase [251].
3) Of 280 patients treated with fluorouracil (5-FU) 24-hour infusion (dose up to 2600
mg/m(2)/week), 16 (5.7%) developed encephalopathy characterized by
disorientation, confusion, agitation, hearing impairment, seizure, stupor, and coma.
Severe nausea and vomiting and Kussmaul's respirations were also noted in 15 and 16
patients, respectively. Metabolic abnormalities were detected at the same time as
symptoms and consisted of hyperammonemia (149 to over 500 micromoles/L), lactic
acidosis (4 to over 12 mg/dL), and hypocapnia (pCO2 15 to 30 mmHg).
Electroencephalogram (n=8) revealed diffuse cortical dysfunction which suggests
metabolic or toxic encephalopathy. The onset of symptoms was a median of 19.5
hours after the infusion started, and median duration was 15 hours. All of the patients
recovered except 1 who had bilateral neurosensory hearing impairment. Careful
monitoring is recommended for this adverse effect especially in patients with gastric
cancer, breast cancer, and colorectal cancer who are treated with high-dose 5-FU
31/317
25/10/12
infusions [252].
4) Severe neurotoxicity consisting of encephalopathy, motor and sensory neuropathy
occurred in a 57-year-old male after receiving 3 doses of 5-fluorouracil (5-FU) for
treatment of colon cancer. The patient also experienced severe myelosuppression,
mucositis and dermatitis. After 1 month in the intensive care unit and several months
of rehabilitation, the patient recovered. Clinicians determined the cause of this
exacerbation of 5-FU toxicity to be dihydropyrimidine dehydrogenase deficiency [253].
5) One investigator reported severe toxicity secondary to dihydropyrimidine
dehydrogenase (DPD) deficiency in a 35-year-old woman receiving standard dose 5fluorouracil for breast cancer. Chemotherapy had been initiated 3 weeks after surgery
with a combination of cyclophosphamide, methotrexate, and 5-FU. Following day 8 of
the protocol, the patient experienced severe gastrointestinal (nausea, prolonged
vomiting, diarrhea, stomatitis), and hematologic (neutropenia) toxicity that required
hospitalization. She had a leukocyte count of 1100 with 5% neutrophils (no bands)
and fever. In addition, she experienced what was classified as mild NEUROLOGIC
toxicity manifest as difficulty with balance and spelling simple words which persisted
for about 2 weeks. DPD, the initial enzyme responsible for the breakdown of 5-FU,
accounts for greater than 80% of the drugs catabolism. Isolated cases of DPD
deficiency have been identified; however, all cases exhibited remarkable toxicity.
Enhanced toxicity occurring at normal doses is what usually sets these patients apart.
The authors suggest that monitoring DPD activity may be appropriate in the
management of those experiencing severe toxicity from 5-FU [215].
Impaired cognition
1) There appears to be an association between the administration of adjuvant
chemotherapy for BREAST CANCER and the development of cognitive deficits. The
study group consisted of 39 patients who had received 6 cycles of CMF
(cyclophosphamide, methotrexate, and fluorouracil). Twenty of these patients also
received tamoxifen for 3 years. The study group was compared to a control group
(n=34) that was not treated with systemic therapy. Subjective data (self-reported)
showed that patients receiving CMF reported having more cognitive problems with
respect to memory and concentration when compared to controls. Objective data
demonstrated higher depression scores and worse performance on neuropsychologic
tests than controls, many of which were statistically significant. Neuropsychologic
tests evaluated attention/concentration, mental flexibility, speed of information
processing, memory, motor function, visuospatial functioning, and verbal functioning.
Twenty-eight percent of the CMF patients were classified as impaired in cognitive
functioning, whereas 12% of controls were. The risk for cognitive impairment was
greatly increased for patients in the CMF group compared to controls (odds ratio=6.4,
p=0.013). No differences in test performance were found between those treated with
CMF plus tamoxifen and CMF alone [244].
Neurotoxicity
stomatitis, diarrhea, neutropenia, and neurotoxicity have been reported. One case of
life-threatening systemic toxicity has been reported with the TOPICAL use of
fluorouracil in a patient with DPD enzyme deficiency. Symptoms included severe
abdominal pain, bloody diarrhea, vomiting, fever, and chills. Signs and symptoms
included stomatitis, erythematous skin rash, neutropenia, thrombocytopenia, and
32/317
25/10/12
observed with 5% fluorouracil cream, it is unknown whether patients with profound
DPD enzyme deficiency would develop systemic toxicity with lower concentrations of
topically applied fluorouracil [205].
a) A 50-year-old patient receiving 5-fluorouracil-based chemotherapy for relapsed
metastatic hepatocellular carcinoma developed a severe neurotoxic reaction
secondary to dihydropyrimidine dehydrogenase (DPD) deficiency. Combination
chemotherapy also contained paclitaxel and leucovorin. Gastrointestinal side effects
and confusion were mild, but the patient was hospitalized for dehydration. After a
second course of combination chemotherapy with reduced paclitaxel, the patient had
mild nausea and confusion, elevated liver enzymes, and progressed to COMA within
72 hours of starting the second cycle. An EEG detected metabolic encephalopathy.
Twelve hours after initiation of rescue therapy with THYMIDINE 8 grams/square
meter/day, the patient rapidly recovered his normal mental status. Thymidine was
continued for 3 days, and the patient was discharged on day 12. At 19-months followup, the patient remained metastatic, but neurologic complications had completely
resolved [254].
Peripheral neuropathy
1) INCIDENCE
a) Rare (incidence less than 0.1%) [255].
2) OUTCOME
a) Moderate (treatment withdrawal required or requested) [255].
3) ASSOCIATED SYMPTOMS
a) PAIN, NUMBNESS and WEAKNESS in the lower legs, DISTAL HYPOESTHESIA,
DECREASED VIBRATORY SENSATION, and instability in walking [255].
4) ONSET/DURATION
a) After earlier exposure to 5-FU and levamisole (LV), symptoms occurred during
subsequent courses. Although 5-fluorouracil (5-FU) was stopped, symptoms improved
and stabilized in 1 patient each but neurophysiologic studies remained unchanged.
Upon rechallenge, symptoms developed with the first course [255].
5) CLINICAL MANAGEMENT
a) In 2 cases, discontinuation of 5-FU and LV resulted in stabilization or
improvement, but neurologic studies did NOT improve. A peroneal splint improved the
ability to walk in 1 patient [255].
6) DOSE-RELATED
a) It is unknown whether dose or duration has any effect on neurotoxicity [255].
7) PROBABLE MECHANISM
a) Idiosyncratic (genetically determined abnormal reactivity due to a metabolic or
enzymatic deficiency). A link between 5-FU-induced neurotoxicity and hepatic
dysfunction or dihydrodipyrimidine dehydrogenase deficiency has been suggested.
Both would result in decreased clearance of 5-FU [255].
8) DOCUMENTATION
a) Good
9) CASE REPORTS
33/317
25/10/12
a) Two patients with colorectal cancer treated with 5-FU and LV developed
peripheral neuropathy. Both patients received 5-FU and LV with radiotherapy followed
by 5-day courses every 4 weeks. During the 5-day courses, each patient complained
of pain, numbness, and weakness of the legs. Neurophysiologic studies identified
large-fiber demyelinating polyneuropathy which did NOT improve after stopping 5-FU
and LV. Rechallenge 3 months later for treatment of metastases resulted in similar
symptoms; neurologic studies showed worsening compared to earlier studies [255].
Other causes of neuropathy were excluded with appropriate clinical and laboratory
evaluation.
Ophthalmic Effects
Ankyloblepharon
1) Ankyloblepharon (adherence of eyelids resulting in narrowing of the palpebral
aperture) was reported in a 59-year-old male during 5-fluorouracil therapy for
metastatic adenocarcinoma of the stomach [288]. It appeared that bilateral
conjunctival ulcers secondary to fluorouracil, and ulcerative blepharitis, resulted in
ankyloblepharon. Withdrawal of chemotherapy resulted in improvement, and
reinitiation of therapy resulted in recurrence of ocular lesions.
Eye / vision finding
1) Summary
a) Numerous ocular adverse effects may occur following topical, intravenous, or
intraocular administration of fluorouracil such as lacrimal duct stenosis, VISUAL
CHANGES, lacrimation, and PHOTOPHOBIA [207].
2) OPTIC NERVE ATROPHY has been reported after using fluorouracil (5-FU),
intrathecal methotrexate, and cranial irradiation [276]. Bilateral cicatricial
ECTROPION was reported in a patient who used 5-FU for treating facial actinic
keratoses [277]. Corneal erosions, early wound leakage, bleb rupture, cystic bleb
formation, hypotony, and Dellen corneal erosions occurred when 5-FU injections were
used after trabeculectomy [278].
3) A 38-year-old man developed CORNEAL ECTASIA, (KERATECTASIA or protusion of
a thinning cornea), after a trabeculectomy with injection of 5-fluorouracil (5-FU) 10
mg daily for 14 days [279]. Following daily injections, the patient was instructed to
massage his eye three times daily with three 10-second compressions; however, upon
questioning, he admitted to massaging his eye vigorously for a minute or more up to
50 times daily. This man presented with rapid worsening of visual acuity and an
elevated intraocular pressure. It is unclear if use of 5-FU after surgery contributed to
this adverse effect or if it was entirely due to vigorous massage of the eye. Corneal
ectasia may be prevented by instructing patients on the appropriate massage
technique and cautioning them not to use vigorous massage.
4) Of 31 eyes exposed to fluorouracil (5-FU) after trabeculectomy, no spontaneous
BLEB LEAKAGE was observed; however, after applying digital pressure, leakage was
observed in 10 (32.2%) eyes as determined by the Seidel test. Bleb leakage is a
potentially serious complication because it may predispose patients to
endophthalmitis, a flat anterior chamber, hypotony, peripheral anterior synechiae, or
choroidal detachment. Fluorouracil 25 mg/mL was applied to the scleral flap for 5
minutes during the surgical procedure. All patients were assessed at least 6 months
after surgery [280].
34/317
25/10/12
5) Postoperative subconjunctival injections of fluorouracil (5-FU) following

trabeculectomy often improve the success of the procedure. However, because of
potential unwanted effects from 5-FU, and usually good success rates for
trabeculectomy, 5-FU is reserved for those eyes identified to be at high risk for
success due to scarring of the conjunctival bleb. Following trabeculectomy and
postoperative 5-FU use, Two investigators reported the occurrence of complications
after using a total of 50 mg in 49 eyes; 5 mg daily for 7 days, then 5 mg on days 9, 11,
and 13. Early complications included CORNEAL EROSIONS (16%), early wound
leakage (25%), and bleb rupture in 3 of 49 treated. CYSTIC BLEB FORMATION (20 of
49), HYPOTONY (10 of 49), and DELLEN CORNEAL EROSIONS (3 of 49) all occurred
as late complications [278].
6) One report describes a case of STRIATE MELANOKERATOSIS in a 64-year-old
black male who received daily subconjunctival fluorouracil injections of 5 milligrams for
14 days following trabeculectomy. In this condition, pigment-bearing cells invade the
central corneal epithelium in a whorl-like pattern. Noted in the patient were diffuse
keratopathy within 4 days and the whorl-like pattern by 5 weeks postoperatively.
Normalization of pigmentation and visual acuity began over the next 3 months [281].
Finding of lacrimation
1) Excessive lacrimation and other OCULAR DISTURBANCES have been reported
secondary to IV 5-fluorouracil therapy [283][284][285][276]. Symptoms can occur
within 15 minutes of administration of the drug IV and consist of excessive
lacrimation, excessive nasal discharge, reddening of the eyes, blurring of the vision.
Symptoms usually subside within 2 or 3 weeks after discontinuing the drug but persist
throughout therapy.
2) TEAR DUCT FIBROSIS has been reported in association with persistent
lacrimation. One report described persistent lacrimation in 6 patients receiving 5fluorouracil IV weekly for 6 to 10 months. Lacrimation symptoms persisted in 5
patients after withdrawing 5-fluorouracil suggesting an irreversible DACRYOSTENOSIS
[286]. Indeed, LACRIMAL DUCT STENOSIS has been reported [207]. LACIMAL
CANALICULAR FIBROSIS with permanent EPIPHORA (outflow of tears down cheek)
has been reported in 3 breast cancer patients following systemic treatment with 5fluorouracil in combination with cyclophosphamide and methotrexate [283]. The
SCLEROSING CANALICULITIS ranged from focal stenosis to widespread occlusion.
Onset of epiphora was within 3 months after commencing chemotherapy. A review of
the literature revealed 5-fluorouracil as the primary agent likely responsible for the
epiphora.
3) Two new cases, along with 18 previously published cases, of lacrimal canalicular
stenosis have been attributed to 5-fluorouracil therapy. A 65- year-old female
presented to the ophthalmologist after 1 year of progressively worsening lacrimation
and epiphora. A conjunctivo- dacryocystorhinostomy was the only therapeutic option
in light of completely stenosed canaliculi. A 56-year-old male was referred in the early
stages of epiphora, whose punctal stenosis was surgically corrected. A review of all
cases revealed that 5-FU was the likely causative agent due to its temporal
relationship to lacrimal symptoms, its presence in the tears of patients with epiphora
but not in unaffected patients, and its ability to cause mucosal inflammation and act
on rapidly dividing tear duct cells. Early recognition and management is important to
avoid permanent sequelae [287].
Infectious crystalline keratopathy
35/317
25/10/12
1) A case of noninfectious crystalline keratopathy is described in a 69-year-old female

5 days following a subconjunctival injection of 5-fluorouracil (5 milligrams) and 6 days
following trabeculectomy and sponge application of 5-fluorouracil for uncontrolled
exfoliative glaucoma. Slit-lamp examination of the cornea revealed white, intrastromal
crystalline material. The patient was asymptomatic. The corneal deposits had
completely resolved by the next examination 4 days later. Medications administered
during this time included topical prednisolone acetate, ciprofloxacin, and scopolamine.
Although noninfectious crystalline keratopathy has been associated with
fluoroquinolones, the time course and the lack of an epithelial defect or ulceration
usually seen with fluoroquinolones makes the subconjunctival administration of 5fluorouracil a more likely causative factor [282].
Respiratory Effects
Respiratory finding
1) PULMONARY TOXICITY was reported in the form of FIBROSING ALVEOLITIS in a
55-year-old male with gastric adenocarcinoma. The patient received 1 g 5-fluorouracil
IV weekly for 9 weeks followed 6 months later with 1 g 5-fluorouracil and 10 mg
mitomycin C IV every 3 weeks. The patient developed severe dyspnea after 12
treatments. Although mitomycin C is most likely the agent responsible for pulmonary
toxicity of this patient, combined use with 5-fluorouracil as a contributing factor
cannot be ruled out [289]. Investigators confirmed at necropsy the patient had
interstitial fibrosis thought to be a result of therapy with 5-fluorouracil and mitomycin
C [290].
Other
Anomaly of chromosome pair
1) An increased incidence in the number of chromosomally aberrant lymphocytes was
observed in nurses handling cytostatic agents (cyclophosphamide, doxorubicin,
vincristine, fluorouracil and methotrexate). The number of chromosome-type breaks
was increased significantly among nurses as compared to a control group [307].
Sepsis
oxaliplatin, fluorouracil, and leucovorin and a regimen of oxaliplatin and irinotecan. The
and SEPSIS [212].
2) A case of BACILLUS CEREUS BACTEREMIA possibly associated with 5-fluorouracil
was reported in a 66-year-old female receiving the drug for metastatic breast cancer.
5-Fluorouracil was given in doses of 750 mg weekly
by hepatic infusion for 3 weeks.

36/317
25/10/12
5-Fluorouracil was given in doses of 750 mg weekly by hepatic infusion for 3 weeks.
The patient developed symptoms of infection (without fever) and leukocytosis. She
recovered spontaneously and the authors suggest that the presence of an indwelling
cannula, cytotoxic therapy and the underlying metastasis may have contributed to the
infection [308].
Teratogenicity/Effects in Pregnancy/Breastfeeding
A) Teratogenicity/Effects in Pregnancy
1) U.S. Food and Drug Administration's Pregnancy Category: Category X (All Trimesters)
a) Studies in animals or human beings have demonstrated fetal abnormalities or there is
evidence of fetal risk based on human experience or both, and the risk of the use of the drug in
pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women
who are or may become pregnant.
2) Australian Drug Evaluation Committee's (ADEC) Category: D
a) Drugs which have caused, are suspected to have caused, or may be expected to cause an
increased incidence of human fetal malformations or irreversible damage. These drugs may also
have adverse pharmacological effects. Accompanying texts should be consulted for further
details.
See Drug Consult reference: PREGNANCY RISK CATEGORIES
3) Crosses Placenta: Unknown
4) Clinical Management
a) Teratogenic effects have been reported with fluorouracil. In general, antineoplastic agents
when given during the first trimester are believed to cause increases in the risk of congenital
malformations, but when given during the second or third trimesters are believed to only
increase the risk of growth retardation [369][370]. Depending upon the nature of the
malignancy, the progression of the disease, and how advanced the gestation, chemotherapy can
in some cases be deferred to allow fetal maturation to occur, and in some cases earlier-thanterm delivery provides an acceptable compromise between maternal and fetal risk [371][370].
a) Twin neonates exposed to 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) from week 13
of gestation through delivery were born with no evidence of teratogenicity or intrauterine growth
retardation and remained developmentally normal at their 2-year follow up. A 26-year-old woman
diagnosed with metastatic colorectal cancer in week 10 of pregnancy received 10 courses of a
full-dose biweekly modified FOLFOX-6 regimen (oxaliplatin 85 mg/m(2) 2-hour infusion with
leucovorin 400 mg/m(2), then 5-FU 400 mg/m(2) bolus and 5-FU 2400 mg/m(2) 46-hour
infusion). The last FOLFOX exposure occurred 15 days before delivery at 33 weeks via cesarean
section; the fraternal twins both had birth weights of about 2200 g and had one-minute Apgar
scores of 10 [362].
b) One case report describes a 33-year old patient treated with 5 courses of FEC regimen (5fluorouracil 600 mg/m(2), epirubicin 90 mg/m(2), and cyclophosphamide 600 mg/m(2) every 3
weeks) during the first 28 weeks of pregnancy, who subsequently delivered a healthy infant at
week 35 of gestation. She was not pregnant when she was diagnosed with locally advanced
37/317
25/10/12
malignant neoplasm of the left breast. After complaining of dilatation of the abdomen and
bloating, an ultrasound showed pregnancy of 28 weeks gestation. The 2070 g infant, delivered by
cesarian section and without complications, was developing normally at 1 year of age [363].
c) One birth defect (cleft lip and palate) has been reported in the newborn of a patient using
topical fluorouracil (Efudex(R)) as recommended. One birth defect (ventricular septal defect) and
cases of miscarriage have been reported when Efudex(R) was applied to mucous membrane
areas. Multiple birth defects have been reported in a fetus of a patient treated with intravenous
fluorouracil [360].
d) Potential neonatal toxicity secondary to 5-fluorouracil therapy during the third trimester of
pregnancy was described. The patient received 15 doses of 500 mg IV 5-fluorouracil (7500 mg
total) over a period of 2.5 months for metastatic breast cancer. Progression of the mediastinal
mass was noted, and the patient was admitted for an elective C-section with bilateral partial
salpingectomy and bilateral oophorectomy. Approximately 1.5 hours post delivery, the infant
developed cyanosis of the extremities and ash-gray discoloration of the trunk. Jerking in all 4
extremities and shallow respirations were noted. The infant was placed in an oxygen bed with
34% oxygen and recovered within 24 hours [364].
e) Multiple congenital anomalies were found in an aborted fetus exposed to 5-fluorouracil during
the eleventh and twelfth week of gestation. Chemotherapy was given at a dose of 600 mg five
times weekly for 1 month. Abnormalities observed in the abortus included bilateral limb defects,
bilateral absence of thumbs, missing fingers (2 on left and 1 on the right hand), and visceral
defects (lungs, kidneys, and intestines) [365].
f) Topical fluorouracil used during gestation to treat vaginal and vulvar papillomavirus infections
and lesions did not cause adverse effects in the infants [366][367].
g) The manufacturer's product information for the injectable form of fluorouracil has an FDA
pregnancy category D rating [368].
B) Breastfeeding
1) World Health Organization Rating: Avoid breastfeeding.
2) Thomson Lactation Rating: Infant risk cannot be ruled out.
a) Available evidence and/or expert consensus is inconclusive or is inadequate for determining
infant risk when used during breastfeeding. Weigh the potential benefits of drug treatment
against potential risks before prescribing this drug during breastfeeding.
3) Clinical Management
a) While there is some systemic absorption of fluorouracil after topical administration, maternal
use of topical preparations generally carries less risk than systemically administered drug; risk to
the infant should be considered relative to the inherent toxicity of the drug [360]. Since
fluorouracil inhibits DNA, RNA, and protein synthesis, nursing is discouraged with the use of this
drug [368]. However, a 36-year-old breastfeeding female diagnosed with rectal cancer had
undetectable levels of 5-fluorouracil in milk samples obtained prior to, during, and up to 10 days
following 5-fluorouracil administration [373].
a) A 36-year-old breastfeeding female diagnosed with rectal cancer had undetectable levels of 5fluorouracil in milk samples obtained prior to, during, and up to 10 days following 5-fluorouracil
administration. The patient discontinued breastfeeding and continued to pump breast milk twice
38/317
25/10/12
daily during the 5-fluorouracil-based chemoradiotherapy 200 mg/m(2)/day IV. Despite plasma
concentrations between 11.14 and 114.95 micromolar, in 33 milk samples evaluated using high
performance liquid chromatography (limit of detection 0.5 micromolar), the levels of 5fluorouracil in milk were undetectable at any time during or following 5-fluorouracil administration
[373].
5) Drug Levels in Breastmilk
a) Active Metabolites
1) Dihyro-5-fluorouracil, potentially active [392]
Drug Interactions
Drug-Drug Combinations
Adenovirus Vaccine Type 4, Live
1) Interaction Effect: an increased risk of infection by the live vaccine
2) Summary: Vaccination with a live vaccine in a patient immunocompromised by a
chemotherapeutic agent has resulted in severe and fatal infections[314][315]. One
patient experienced disseminated vaccinia infection after receiving a smallpox vaccine
while on concomitant methotrexate therapy [316]. Live virus and bacterial vaccines
should not be administered to a patient receiving an immunosuppressive
chemotherapeutic agent. At least three months should elapse between the
discontinuation of chemotherapy and vaccination with a live vaccine [313].
3) Severity: major
4) Onset: delayed
5) Substantiation: established
6) Clinical Management: Patients receiving chemotherapy for leukemia and other
hematopoietic malignancies, for solid tumors, or after solid organ transplant should be
assumed to have altered immunocompetence and should not be vaccinated with a live
vaccine. Patients with leukemia, lymphoma, or other malignancies whose disease is in
remission, who have restored immunocompetence, and whose chemotherapy has
been discontinued for at least 3 months can receive a live vaccine[313].
7) Probable Mechanism: decreased immune response allows live vaccine to produce
infection
Adenovirus Vaccine Type 7, Live
3) Severity: major
4) Onset: delayed
hematopoietic malignancies, for solid tumors, or
after solid organ transplant should

be
39/317
25/10/12
infection
Bacillus of Calmette and Guerin Vaccine, Live
3) Severity: major
4) Onset: delayed
infection
Cimetidine
1) Interaction Effect: an increased risk of fluorouracil toxicity
2) Summary: Concomitant fluorouracil and cimetidine therapy has resulted in
increased peak plasma levels and area under the plasma concentration-time curve
(AUC) for fluorouracil[354]. These effects were observed after long-term (four weeks)
therapy with cimetidine but not after a single dose.
3) Severity: minor
4) Onset: delayed
5) Substantiation: probable
6) Clinical Management: Monitor patients who have received long-term (four or more
weeks) therapy with cimetidine for an increased incidence of adverse effects to
fluorouracil. If possible, discontinue the cimetidine prior to the administration of
fluorouracil. An alternative H-2 antagonist could also be substituted for cimetidine.
7) Probable Mechanism: inhibition of fluorouracil metabolism
a) Concomitant oral 5-fluorouracil and cimetidine therapy resulted in increased peak
plasma levels and area under the plasma concentration-time curve (AUC) for 5fluorouracil in 15 ambulant patients with carcinoma [353]. These effects were
observed after doses of cimetidine 1 gram daily for 4 weeks, but a single
pretreatment dose of cimetidine 400 mg or daily doses of 1 g for 1 week did not alter
40/317
25/10/12
the pharmacokinetics of fluorouracil. Similarly, the AUC for intravenous 5-fluorouracil

was significantly increased following 4 weeks of cimetidine pretreatment. The
mechanism of the interaction seems to be related to the combination of drug
metabolism inhibition and reduction of liver blood flow induced by cimetidine.
Fosphenytoin
1) Interaction Effect: increased plasma phenytoin (the active metabolite of
fosphenytoin) concentrations
2) Summary: The concomitant use of fluorouracil and fosphenytoin may result in
elevated phenytoin (the active metabolite of fosphenytoin) plasma concentrations,
and monitoring of phenytoin levels may be warranted[349].
3) Severity: moderate
4) Onset: unspecified
5) Substantiation: theoretical
6) Clinical Management: The concomitant use of fluorouracil and fosphenytoin may
result in elevated phenytoin (the active metabolite of fosphenytoin) plasma
concentrations, and monitoring of phenytoin levels may be warranted[349].
7) Probable Mechanism: unknown
Gemcitabine
1) Interaction Effect: enhanced fluorouracil systemic exposure and possible toxicity
2) Summary: A significant increase in systemic fluorouracil exposure occurs when
gemicitabine is coadministered. This may be useful in maximizing the antitumor
effects and reduce the occurrence of side effects of fluorouracil[348].
3) Severity: minor
4) Onset: delayed
6) Clinical Management: Synergistic antitumor activity and positive pharmacological
interactions can occur between gemcitabine and fluorouracil (and folinic acid) and
may also increase the toxicity of fluorouracil in cancer patients.
a) Gemcitabine enhances systemic exposure to fluorouracil in cancer patients.
Twenty patients with advanced gastroenteric carcinoma were included in the
experimental group and received gemcitabine and folinic acid (FUFA). Sixteen
patients with gastroenteric carcinoma were included in the control group and
received FUFA therapy. Patients in the experimental group had a higher fluorouracil
area under the concentration-time curve (AUC), plasma half-life, lower mean total
clearance, and volume of distribution. The fluorouracil AUC in patients taking
gemcitabine and FUFA was 555 +/- 209 mcg/mL/min and in patients taking FUFA 244
+/- 89 (p less than 0.001). The author suggests that the results of this study should
be taken into account when designing clinical trials testing gemcitabine and
fluorouracil in combination in order to maximize the antitumor effects and reduce the
occurrence of side effects [347].
Hydrochlorothiazide
1) Interaction Effect: myelosuppression (granulocytopenia)
2) Summary: Thiazide diuretics may enhance the myelosuppressive effects of
antineoplastic agents. Fourteen breast cancer patients treated with a
cyclophosphamide, methotrexate, 5-fluorouracil combination and a thiazide diuretic
41/317
25/10/12
experienced significantly higher levels of granulocytes during treatment cycles without

the thiazides as compared with cycles that included thiazides[317].
4) Onset: delayed
6) Clinical Management: If concurrent therapy is required, monitor closely for
myelosuppression, by obtaining periodic CBC's.
Influenza Virus Vaccine, Live
3) Severity: major
4) Onset: delayed
infection
Leucovorin
1) Interaction Effect: fluorouracil toxicity (myelosuppression, stomatitis, GI toxicity)
2) Summary: The therapeutic efficacy of fluorouracil may be enhanced by leucovorin
coadministration[324], as may fluorouracil toxicity [325][326]. A pharmacokinetic
study did not find significant differences in fluorouracil pharmacokinetics with this
combination [327].
4) Onset: delayed
6) Clinical Management: Fluorouracil plus leucovorin is routinely used therapeutically
in the treatment of cancer. Monitor patients, especially the elderly, for increased
toxicity (myelosuppression, stomatitis, GI toxicity).
a) Thirty patients with advanced colorectal and gastric adenocarcinomas were
treated with fluorouracil combined with high-dose folinic acid. The treatment used
was based on biochemical and cell culture studies which have demonstrated that an
excess of intracellular reduced folates is necessary to provide optimal inhibition of
thymidylate synthetase and to increase the cytotoxic effect of fluorouracil. It was
42/317
25/10/12
concluded that folinic acid at high doses (200 mg/m(2)) increases the effectiveness
of fluorouracil given simultaneously [322].
b) Pharmacokinetics of fluorouracil were compared when fluorouracil was
administered alone and coadministered with leucovorin. High-dose leucovorin (500
mg/m2) was infused over two hours to five patients with metastatic colorectal cancer
who were receiving fluorouracil treatment. Increases were seen in the time of
distribution and volume of distribution of fluorouracil when both drugs were given
concurrently. However, area under the concentration-time curve (AUC), plasma
clearance, and elimination of fluorouracil were unaltered by leucovorin [323].
Levamisole
1) Interaction Effect: hepatotoxicity
2) Summary: A prospective, randomized study of 1,025 colon cancer resection
patients who received either no treatment, treatment with levamisole alone, or
treatment with fluorouracil plus levamisole demonstrated a significantly higher rate of
hepatotoxicity with the combination (39.6%) than with levamisole alone (16.3%) or
no treatment (16.1%)[346]. Hepatotoxicity was described as reversible and
characteristically mild and asymptomatic, most commonly taking the form of an
elevated alkaline phosphatase, often accompanied by increased transaminases or
serum bilirubin.
4) Onset: delayed
6) Clinical Management: Monitor patients for mild and asymptomatic hepatotoxicity,
specifically, elevated alkaline phosphatase accompanied by increased transaminases
or serum bilirubin. This hepatotoxicity is usually reversible.
7) Probable Mechanism: additive hepatotoxic effects
Levoleucovorin
1) Interaction Effect: fluorouracil toxicity (myelosuppression, stomatitis, GI toxicity)
2) Summary: Levoleucovorin increases the concentration of 5-fluorouracil and
enhances its toxicity. Death from severe enterocolitis, diarrhea, and dehydration have
been reported in elderly patients receiving levoleucovorin and fluorouracil[359]. The
therapeutic efficacy of fluorouracil may be enhanced by levoleucovorin
coadministration, although some patients may experience fluorouracil toxicity [359].
4) Onset: delayed
6) Clinical Management: Fluorouracil plus levoleucovorin is used therapeutically in the
treatment of cancer. Monitor patients, especially the elderly, for increased toxicity
(myelosuppression, stomatitis, gastrointestinal toxicity).
Measles Virus Vaccine, Live
43/317
25/10/12

3) Severity: major
4) Onset: delayed
infection
Metronidazole
1) Interaction Effect: increased fluorouracil serum concentrations and fluorouracil
toxicity (granulocytopenia, anemia, thrombocytopenia, stomatitis, vomiting)
2) Summary: Coadministered metronidazole significantly reduces fluorouracil
clearance resulting in more severe fluorouracil side effects, without enhanced
therapeutic results[352].
3) Severity: major
4) Onset: delayed
6) Clinical Management: Avoid concurrent administration of fluorouracil and
metronidazole, if possible. Should it become clinically necessary to combine these
agents, monitor patients for fluorouracil toxicity. The occurrence and progression of
hematologic and gastrointestinal adverse effects may limit the duration of combined
therapy.
7) Probable Mechanism: reduced fluorouracil clearance
a) A total of 27 patients with metastatic colorectal cancer received daily
metronidazole 750 mg/m(2) followed in an hour by fluorouracil 600 mg/m(2), both
drugs given intravenously, for five consecutive days. This treatment was repeated
every four weeks until prohibitive toxicity or disease progression occurred. The
pharmacokinetics of fluorouracil, measured in 10 patients, showed a reduction in
fluorouracil clearance of 26.9%, and increases of 34% and 38%, respectively, in the
area under the concentration-time curve (AUC) and half-life of fluorouracil during
combined therapy. The incidence of toxic effects of the metronidazole-fluorouracil
regimen included granulocytopenia (74%), anemia (41%), thrombocytopenia (19%),
severe stomatitis and oral ulceration (34%), intractable nausea and vomiting (22%),
and peripheral neuropathy with paresthesia and weakness (7%). In vitro,
metronidazole combined with fluorouracil did not enhance antitumor activity over 5FU alone [351].
Mumps Virus Vaccine, Live
44/317
25/10/12
3) Severity: major
4) Onset: delayed
infection
Phenytoin
1) Interaction Effect: an increase in serum phenytoin levels and phenytoin toxicity
(ataxia, hyperreflexia, nystagmus, tremor)
2) Summary: An increased risk of phenytoin toxicity exists with the concomitant use
of fluorouracil[321].
6) Clinical Management: Phenytoin levels should be frequently measured in all
patients receiving phenytoin and fluorouracil. Monitoring should continue after
chemotherapy has been completed to ensure that the phenytoin level is sufficient to
prevent seizures.
a) A 65-year-old Asian male with a 10-year history of generalized tonic clonic
epilepsy, as well as Dukes' B adenocarcinoma of the colon, experienced an increase
in serum phenytoin following palliative 5FU/FA at doses of 370 and 20 mg/m2 weekly.
His epilepsy was controlled with phenytoin 300 mg and phenobarbital 90 mg daily.
Seven weeks after starting chemotherapy he was admitted with a 10-day history of
progressive confusion, drowsiness, generalized weakness, and fatigue preventing him
from walking. He was drowsy, dysarthric, had bilateral gaze evoked nystagmus and
marked limb ataxia on examination. He was unable to stand unsupported. His serum
phenytoin level was 162 mcmol/L (40-80). His phenobarbitone level was 89 mcmol/L
(65-170). Phenytoin was withheld for 5 days until his serum level was less than 80
mcmol/L. His symptoms and signs resolved with the decreasing serum phenytoin
level. When his serum level was 67 mcmol/L, phenytoin was restarted at a reduced
dose of 230 mg daily. His serum phenytoin level increased to 75 mcmol/L on this dose
before dropping to 22 mcmol/L 5 weeks after stopping chemotherapy. The
chemotherapy was stopped after two cycles due to progression of the disease [320].
b) A 60-year-old man with a history of post-traumatic generalized tonic clonic
epilepsy was being treated with phenytoin 430 mg daily with stable phenytoin serum
levels (75 mcmol/L). He was diagnosed with Dukes' C adenocarcinoma of the
45/317
25/10/12
transverse colon and was started on adjuvant 5FU/FA at doses of 370 and 20 mg/m2
weekly. At 4 weeks post chemotherapy initiation, the patient presented with a 6-day
history of progressive light-headedness and inability to stand unsupported. His
phenytoin level was 213 mcmol/L. His phenytoin was withheld for 7 days, until
phenytoin levels reached 42 mcmol/L. He was restarted on a reduced dose (300 mg
daily). His serum phenytoin level rose from 42 to 118 mcmol/L at this dose. His
phenytoin dose was further reduced and he was discharged on phenytoin 100 mg
daily with ongoing chemotherapy. Since his discharge from the hospital he has had a
seizure associated with a subtherapeutic serum phenytoin level of 24 mcmol/L and
his phenytoin dose has been increased to 200 mg daily [320].
c) A 45-year-old female with a greater than 10-year history of poorly controlled
generalized tonic clonic epilepsy was taking phenytoin 400 mg daily, clobazam 10 mg
and sodium valproate 1 gm twice daily. Serum phenytoin levels at this time were 141
mcmol/L. After developing breast cancer she underwent adjuvant treatment with
intravenous cyclophosphamide, methotrexate, and 5-FU (CMF) chemotherapy. She
was placed on palliative chemotherapy (doxorubicin, followed by docetaxel, and twice
daily capecitabine, completing two cycles) after her cancer progressed. The protocol
used for CMF was: cyclophosphamide 100 mg/m2 day 1-14, methotrexate 40 mg/m2
days 1 and 8, 5-FU 600 mg/m2 days 1 and 8 in a 4 weekly cycle and capecitabine was
prescribed at a dose of 1500 mg twice daily for 14 days, repeating 3 weekly. Six
weeks after starting therapy she was admitted with a 2-day history of an unsteady
gate, recurrent falls, weakness, poor balance, and limb ataxia. Her serum phenytoin
level was 161 mcmol/L (40-80). Her phenytoin was withheld for 5 days until her
serum phenytoin level was under 80 mcmol/L and the dose was reduced to 300 mg
daily. She became lightheaded again and her serum phenytoin level increased on this
reduced dose (level of 104 mcmol/L). She was discharged on 260 mg phenytoin daily.
Her serum phenytoin level fell to 18 mcmol/L after 2 months. Her capecitabine was
stopped after 2 cycles due to progressive disease. The mechanism of this interaction
is postulated to be at the level of the CYP2C9 isoenzyme system. Capecitabine is an
orally administered prodrug of fluorouracil. Fluorouracil may competitively inhibit the
clearance of phenytoin by the CYP2C9 isoenzyme or may reduce its synthesis [320].
Rotavirus Vaccine, Live
3) Severity: major
4) Onset: delayed
46/317
25/10/12

infection
Rotavirus Vaccine, Live
while on concomitant methotrexate therapy [357]. The administration of the rotavirus
vaccine is contraindicated in patients who are immunosuppressed due to
chemotherapeutic agents [358].
3) Severity: contraindicated
4) Onset: delayed
6) Clinical Management: Vaccination with rotavirus vaccine is contraindicated in
patients receiving immunosuppressive chemotherapy.
infection
Rubella Virus Vaccine, Live
3) Severity: major
4) Onset: delayed
infection
Smallpox Vaccine
47/317
25/10/12

3) Severity: major
4) Onset: delayed
infection
Tamoxifen
1) Interaction Effect: an increased risk of thromboembolism
2) Summary: The addition of a regimen of cyclophosphamide, methotrexate, and
fluorouracil to tamoxifen has been shown to increase the risk of thromboembolic
events in postmenopausal women being treated for breast cancer[319]. Controlled
studies are needed to further evaluate whether tamoxifen and fluorouracil alone may
cause an increased risk of thromboembolism.
3) Severity: major
4) Onset: delayed
6) Clinical Management: In patients undergoing therapy with tamoxifen for breast
cancer, the risks of adding fluorouracil should be weighed against the potential
benefits.
a) In a multicenter randomized trial of 705 postmenopausal women undergoing
treatment for breast cancer, the incidence of thromboembolism while undergoing
therapy with tamoxifen for two years was compared to tamoxifen therapy for two
years plus a six-month regimen of intravenous cyclophosphamide, methotrexate, and
fluorouracil (CMF). Out of 353 women receiving tamoxifen plus CMF, 48 women
(13.6%) experienced one or more thromboembolic events, compared to nine out of
352 women (2.6%) in the tamoxifen-only group. In addition, significantly more
serious thromboembolic events (such as deep venous thromboses, pulmonary emboli,
arterial events, or fatal events) were seen in the tamoxifen plus CMF group compared
to the tamoxifen-only group [318].
Tinidazole
1) Interaction Effect: increased fluorouracil serum concentrations and potential
fluorouracil toxicity (granulocytopenia, anemia, thrombocytopenia, stomatitis,
vomiting)
2) Summary: Tinidazole, a nitroimidazole, is chemically-related to
metronidazole[350]. Co-administered metronidazole significantly reduced fluorouracil
clearance resulting in more severe fluorouracil side effects, without enhanced
therapeutic results [352]. Although not specifically studied with tinidazole, similar to
metronidazole, concurrent administration of tinidazole and fluorouracil may result in
fluorouracil toxicity. If possible, avoid concomitant use of fluorouracil and tinidazole.
However, if concomitant use is clinically warranted,
48/317
monitor patients for fluorouracil
25/10/12
However, if concomitant use is clinically warranted, monitor patients for fluorouracil

toxicity (granulocytopenia, anemia, thrombocytopenia, stomatitis, vomiting) [350].
3) Severity: major
6) Clinical Management: Avoid concomitant use of fluorouracil and tinidazole, if
possible, as this may result in fluorouracil toxicity without additional therapeutic
benefits. If concomitant use cannot be avoided, monitor patients for fluorouracil
toxicity (granulocytopenia, anemia, thrombocytopenia, stomatitis, vomiting)[350].
7) Probable Mechanism: reduced fluorouracil clearance
a) A total of 27 patients with metastatic colorectal cancer received daily
metronidazole 750 milligrams per square meter (mg/m(2)) followed in an hour by
fluorouracil 600 mg/m(2), both drugs given intravenously, for five consecutive days.
This treatment was repeated every four weeks until prohibitive toxicity or disease
progression occurred. The pharmacokinetics of fluorouracil, measured in 10 patients,
showed a reduction in fluorouracil clearance of 26.9%, and increases of 34% and
38%, respectively, in AUC and half-life of fluorouracil during combined therapy. The
incidence of toxic effects of the metronidazole-fluorouracil regimen included
granulocytopenia (74%), anemia (41%), thrombocytopenia (19%), severe stomatitis
and oral ulceration (34%), intractable nausea and vomiting (22%), and peripheral
neuropathy with paresthesia and weakness (7%). In vitro, metronidazole combined
with fluorouracil did not enhance antitumor activity over 5-FU alone [351].
Typhoid Vaccine
3) Severity: major
4) Onset: delayed
infection
Varicella Virus Vaccine
49/317
25/10/12

3) Severity: major
4) Onset: delayed
infection
Warfarin
1) Interaction Effect: an increased risk of bleeding
2) Summary: In patients on concomitant warfarin, elevated prothrombin times (PT)
were experienced within 15 days in 2 patients treated with a fluorouracilchemotherapy regimen and in another patient treated with vinblastine and
fluorouracil. Two of the patients experienced symptoms of epistaxis and either gross
hematuria or microscopic hematuria[329][328]. An additional 5 case reports of
elevated PT with fluorouracil with and without other chemotherapy agents and
concomitant warfarin have been identified in the literature
[338][339][340][341][342]. The manufacturers do not identify cyclophosphamide,
methotrexate, or fluorouracil as drugs that interact with warfarin
[343][344][345][203]. Monitor INR closely and monitor for signs of bleeding when
warfarin is used concomitantly with fluorouracil-chemotherapy regimens. Warfarin
dosage may require adjustment to maintain the desired level of anticoagulation.
3) Severity: major
4) Onset: delayed
6) Clinical Management: In patients receiving oral anticoagulant therapy with
warfarin, the prothrombin time ratio or INR should be closely monitored with the
addition and withdrawal of treatment with fluorouracil, and should be reassessed
periodically during concurrent therapy. Adjustments of the warfarin dose may be
necessary in order to maintain the desired level of anticoagulation .
7) Probable Mechanism: decreased synthesis of cytochrome P450 2C9 enzymes which
metabolize warfarin
a) A 58-year-old male on warfarin 1 mg/day to prevent catheter-associated
thrombosis experienced asymptomatic elevated prothrombin times (PT) after
initiation of fluorouracil and vinblastine. His PT prior to chemotherapy was 11.6 sec.
He received intravenous vinblastine 2 mg/day and intravenous fluorouracil 800
mg/day for 5 consecutive days at monthly intervals for the treatment of small cell
carcinoma of the lung with lymph node and hilar invasion. PT were not measured with
each cycle; however, 16 days after the initiation of the last cycle, the PT was
50/317
25/10/12
elevated at 62.3 sec. The following day the PT decreased to 48.8 sec. Warfarin was
stopped and intravenous phytonadione 10 mg was administered on the next day. The
PT continued to decrease to 19.6, 16.8 and 14.1 sec over a week. The patient
remained well for several months but subsequently died from brain metastases [328].
b) After starting warfarin, a 70-year-old woman treated with cyclophosphamide,
methotrexate, and fluorouracil for breast cancer experienced elevated prothrombin
times (PT) by day 15 on 4 chemotherapy cycles; furthermore, she experienced gross
hematuria on the first occasion and epistaxis on each occasion. Her PT ranged from
8.2 to 21 sec with a stable warfarin dose. The PT increased to 44.2, 39, 31, and 29
sec, respectively, by day 15 of each subsequent cycle of chemotherapy. The PT
returned to pretreatment levels within 48 to 72 hours. Epistaxis and hematuria
responded to discontinuation and reduction of warfarin dosage [329].
c) After starting warfarin, a 57-year-old woman treated with cyclophosphamide,
methotrexate, and fluorouracil for breast cancer experienced elevated prothrombin
times (PT) and microscopic hematuria by day 15 of each cycle. She also experienced
epistaxis on 1 occasion. Her PT ranged from 14.8 to 17.2 sec over 3 weeks. The PT
increased to a range of 24.6 to 26 sec by day 15 of each subsequent cycle of
chemotherapy. The PT returned to pretreatment levels within 48 hours [329].
d) A case was reported where a 73-year-old man with prosthetic mitral and aortic
valve replacement was stabilized on warfarin 22.5 mg weekly with a mean INR of
2.43. After colon resection for colon cancer, he received maintenance doses of
levamisole (50 mg every 8 hours for 3 days every other week) and fluorouracil (450
mg/m(2)/week). Within 4 weeks of beginning antineoplastic therapy, his INR
increased from 3.04 to 39.56; thereafter, his warfarin was reduced to 7.5 mg weekly.
With a decline in neutrophil count, he discontinued the levamisole-fluorouracil for 5
weeks. During this period, his INR dropped below therapeutic levels. When he was
restarted on levamisole-fluorouracil, he again experienced a significant rise in
prothrombin time [330].
e) A case was reported where an elderly man with colon cancer was treated with
heparin and warfarin for deep vein thrombosis. His oral warfarin dose was 5 mg daily,
at which time his PT was 11.3 seconds. After starting fluorouracil 1200 mg daily by
continuous infusion, he had a rise in PT to 12.7 seconds on day 2 and 15.8 seconds on
day 3, even though his warfarin dose was decreased to 2.5 mg daily on day 2. With a
continuing rise in PT, warfarin was discontinued. Five days after cessation of
warfarin, his PT came down to 13.1 seconds from a peak of 22.5 seconds [331].
f) In a study of colon cancer patients administered combined fluorouracil-warfarin, 3
of 25 patients experienced serious gastrointestinal bleeding even though their PT was
within the therapeutic range at the time. These patients were known to have
intracolonic lesions at study entry. Patients who began the study free of intraluminal
lesions did not develop significant bleeding problems. While these investigators found
a lengthening of fluorouracil half-life in rabbits given concomitant fluorouracilwarfarin, that effect was not reproduced in human subjects [332].
g) Five patients received warfarin and fluorouracil for a period of 3 years. Before
fluorouracil, the weekly mean dose of warfarin was 40.66 mg and with fluorouracil the
mean was 24 mg. As an average, all patients required a warfarin dose reduction of
44% [333].
51/317
25/10/12
h) A 59-year-old man with colon cancer experienced epistaxis, hematemesis,

hematuria, and hematochezia. The patient was being treated with 5-fluorouracil and
warfarin. Laboratory results showed a prothrombin time of 70.7 seconds and an INR
of 35.9 four weeks after starting 5-fluorouracil therapy. Previously his INR was
maintained between 2 and 3. It is suggested that 5-fluorouracil may inhibit the
synthesis of cytochrome P450 2C9, leading to impaired warfarin metabolism [334].
i) A case report of a 39-year-old female describes an interaction between fluorouracil
(5-FU) and warfarin leading to a prolonged prothrombin time (PT). The patient was
being hospitalized and treated for gastric adenocarcinoma (stage IIIB) with her first
cycle of chemotherapy. A radical total gastrectomy was performed and subsequent
administration of the appropriate chemotherapy regimen was initiated. The
chemotherapy regimen consisted of 5-FU, cisplatin, and etoposide. Three days later
the patient began to complain about right lower extremity pain. An ultrasound
revealed deep venous thrombosis. Heparin infusions were initiated during
chemotherapy. Laboratory tests (liver function tests, WBC, PT, activated partial
thromboplastin time, D-dimer, and fibrinogen levels) before heparin infusions were all
within normal ranges. Warfarin was added to the existing drug regimen 2 days later.
Warfarin was subsequently discontinued on day 3 of therapy as the patient's INR
reached 5.5 and PT reached 31 seconds. Symptoms were improving and her PT
values began to decrease on day 7 after warfarin discontinuation [335].
j) Concomitant use of warfarin and fluorouracil resulted in fluctuating INR in a 60year-old female. The patient had colon cancer and received an intravenous
chemotherapy regimen consisting of 6 cycles of fluorouracil and leucovorin. The drugs
were given for 5 consecutive days during a month. The patient was diagnosed with
deep venous thrombosis in the left leg. Warfarin was initiated. Her baseline INR was
1.1. The INR rose above the targeted INR range of 2 to 3 three to four weeks after
the last fluorouracil and leucovorin dose of each chemotherapy cycle. The INR peaked
at 4.2 three weeks after the last cycle and the total weekly warfarin dose was
reduced from 9 mg/week to 7 mg/week. The INR dropped to 1.58 four weeks after
the completion of the final cycle of chemotherapy . In order to maintain an INR of 2 to
3, the weekly warfarin dose needed to be doubled from 7 mg/week to 14 mg/week.
Fluorouracil may inhibit the synthesis of cytochrome P450 2C9 and thus inhibit the
metabolism of warfarin. Close monitoring of the INR is recommended when warfarin
is added to fluorouracil therapy. Warfarin dosage may need to be reduced by 20 to
70% during concomitant therapy with fluorouracil and then increased within 30 days
after discontinuation of fluorouracil to maintain the INR within the desired range
[336].
k) Continuous-infusion fluorouracil (FU)-based chemotherapy and minidose warfarin
(1 mg/day) has been shown to increase the incidence of INR abnormalities. Ninetyfive cancer patients treated with continuous-infusion FU-based chemotherapy were
evaluated. Four-hundred eighty eight INR determinations were performed, 50 of
which (10%) showed an INR of more than 1.5. Thirty-one patients (33%) had a
significant elevation in their INR levels. Of these, 6 patients had minimal INR
elevations (between 1.18 and 1.5). Bleeding was observed in 8 patients (INR 1.34 to
8.8). Epistaxis with no gross blood loss was observed in 6 patients, and hematuria
was observed in 2 patients. The proportion distribution of increased INR was the
following: the INR became elevated in 12 (57%) of 21 patients treated with the
52/317
FOLFOX regimen, 11 (27%) of 40 patients treated with the de Gramont regimen, and
5 (26%) of 19 patients treated with the FOLFIRI regimen. Analysis of 80 patients
treated with these regimens showed a statistically significant association between
INR elevation and FOLFOX treatment (p = 0.041). This study demonstrated that
coadministration of warfarin and FU resulted in an INR elevation in 33% of patients
and that of the 8 patients who developed bleeding problems, 7 had an elevated INR.
No relationship was observed between liver metastasis, hepatic function, age,
performance status, number of previous chemotherapy regimens administered or
chemotherapy toxicity or INR alteration or bleeding. Clinicians should regularly
monitor the prothrombin time in patients receiving warfarin and FU [337].
Yellow Fever Vaccine
3) Severity: major
4) Onset: delayed
infection
Intravenous Admixtures
Drugs
Allopurinol Sodium
1) Compatible
a) Allopurinol sodium 3 mg/mL in Sodium chloride 0.9% injection with
fluorouracil 16 mg/mL in Sodium chloride 0.9% injection, compatible for up to 4
hours at 22 degrees C [604]
Aluminum
1) Compatible
a) Aluminum as a component of a chemotherapy-dispensing pin, immersed in a
solution containing fluorouracil 50 mg/mL had no visible reaction after 7 days at
24 degrees C [603]
Amifostine
1) Compatible
a) Amifostine 10 mg/mL in Dextrose 5% in water with fluorouracil 16 mg/mL in
5% Dextrose injection, compatible during simulated Y-site administration [597]

Aztreonam
1) Compatible
a) Aztreonam 40 mg/mL in 5% Dextrose in water with fluorouracil 16 mg/mL
in Dextrose 5% in water, compatible for up to 4 hours at 23 degrees C [612]
Bleomycin Sulfate
1) Compatible
a) Bleomycin sulfate 20 or 30 U/L with fluorouracil 1 g/L, visually compatible in
Sodium chloride 0.9% and greater than 90% bleomycin activity retained for 1
week at 4 degrees C; fluorouracil activity not tested [564]
b) Bleomycin 1.5 U/0.5 mL with fluorouracil 25 mg/0.5 mL, visually compatible
in syringe for 5 minutes at 25 degrees C followed by 8 minutes of centrifugation
[565]
c) Bleomycin 3 U/mL with fluorouracil 50 mg/mL, visually compatible when the
drugs were injected sequentially into a Y-site without flushing the Y-side arm
between injections [565]
Calcium Gluconate
1) Compatible
a) Calcium gluconate compatible with fluorouracil (Adrucil(R)); concentrations
not specified [601]
Cephalothin
1) Compatible
a) Cephalothin 1 g/L with fluorouracil 500 mg/L, visually compatible with no
alteration of ultraviolet spectra in 8 hours at 25 degrees C in Dextrose 5% in
water [606]
Cisplatin
1) Conflicting Data
a) Incompatible
1) Cisplatin 0.5 mg/mL with fluorouracil 10 mg/mL, greater than 80% cisplatin
loss in 24 hours at room temperature in a polyvinylchloride container [593]
2) Cisplatin 0.2 or 0.5 mg/mL with fluorouracil 1 or 10 mg/mL in Sodium
chloride 0.9% in polyvinylchloride bags at 25 degrees C, 10% cisplatin loss in
1.5 hours whether protected from light or not; no loss of fluorouracil potency
reported [594]
b) Compatible
1) Cisplatin (0.5 mg/0.5 mL with fluorouracil 25 mg/0.5 mL visually compatible
in syringe for 5 minutes at 25 degrees C followed by 8 minutes of
centrifugation; cisplatin 1 mg/mL with fluorouracil 50 mg/mL visually
compatible when the drugs were injected sequentially into a Y-site without
flushing the Y-side arm between injections) [595]
Cyclophosphamide
25/10/12
1) Compatible
a) An admixture of fluorouracil 30 milligrams/milliliter (mg/mL) (in normal
saline diluent) and cyclophosphamide 5 mg/mL is stable for 7 days at room
temperature (25 degrees Celsius) in a PVC reservoir bag [570].
b) Cyclophosphamide (10 mg/0.5 mL with fluorouracil 25 mg/0.5 mL visually
compatible in syringe for 5 minutes at 25 degrees C followed by 8 minutes of
centrifugation; cyclophosphamide 20 mg/mL with fluorouracil 50 mg/mL visually
flushing the Y-side arm between injections) [571].
Cytarabine
1) Incompatible
a) Cytarabine (400 mg/L with fluorouracil 250 mg/L in Dextrose 5% in water,
ultraviolet spectrum of cytarabine was altered within 1 hour at room
temperature) [554]
b) Fluorouracil (250 mg/L with cytarabine 400 mg/L in Dextrose 5% in water,
ultraviolet spectrum for cytarabine altered with 1 hour at room temperature; no
change observed in fluorouracil spectrum) [598]
Dacarbazine
1) Compatible
a) Dacarbazine (with fluorouracil, analysis of the ultraviolet/visible spectra did
not detect any interaction between the two drugs; drug concentrations and
conditions not specified) [609]
b) Fluorouracil (with dacarbazine, analysis by UV/visible spectrometry revealed
no alteration in the spectrum of either drug when they were combined in
solution; drug concentrations and conditions not specified) [610]
Diazepam
1) Incompatible
a) Diazepam (with fluorouracil, immediate precipitate formation reported; drug
concentrations and test conditions not specified) [581]
b) Fluorouracil (with diazepam, concentrations not specified, precipitate
formation reported) (Tech Info Cetus, 1988)
Doripenem
1) Compatible
a) Doripenem 5 mg/mL with fluorouracil 16 mg/mL in either 5% dextrose
injection or in 0.9% sodium chloride injection is physically compatible for 4
hours at room temperature (approximately 23 degrees C) under fluorescent
light during simulated Y-site administration [556].
Doxorubicin
1) Conflicting Data
a) Incompatible
1) Fluorouracil (250 mg/L with doxorubicin 10 mg/L in Dextrose 5% in water,
solution reported to change color to deep purple; conditions not specified)
55/317
[555]
b) Compatible
1) Doxorubicin (1 mg/0.5 mL with fluorouracil 25 mg/0.5 mL visually
centrifugation; doxorubicin 2 mg/mL with fluorouracil 50 mg/mL visually
flushing the Y-side arm between injections) [595]
Droperidol
1) Incompatible
a) Droperidol 1.25 mg/0.5 mL with fluorouracil 25 mg/0.5 mL, immediate
precipitate formation reported in syringe for 5 minutes at 25 degrees C followed
by 8 minutes of centrifugation [605]
b) Droperidol 2.5 mg/mL with fluorouracil 50 mg/mL, immediate precipitate
formation reported when the drugs were injected sequentially into a Y-site
without flushing the Y-side arm between injections [605]
Filgrastim
1) Incompatible
a) Filgrastim 30 mcg/mL in Dextrose 5% in water with fluorouracil 16 mg/mL
in Dextrose 5% in water, particles and long filaments formed in 1 hour; visually
observed with high-intensity light enhancement [602]
Fludarabine
1) Compatible
a) Fludarabine 1 mg/mL with fluorouracil 16 mg/mL, both in Dextrose 5% in
water, visually compatible for a 4-hour study period at room temperature under
fluorescent light [611]
Furosemide
1) Compatible
a) Fluorouracil (25 mg/0.5 ml with furosemide 5 mg/0.5 ml visually compatible
in direct admixture in syringe for 5 minutes at 25 degrees C followed by 8
minutes of centrifugation; fluorouracil 50 mg/mL with furosemide 10 mg/mL
visually compatible when the drugs were injected sequentially into a Y-site
without flushing the Y-side arm between injections) [586]
Gallium Nitrate
1) Incompatible
a) Fluorouracil (undiluted) 50 mg/mL admixed in a 1:1 ratio simulating Y-site
administration with gallium nitrate (Ganite(R)) 1 mg/mL in Sodium chloride
0.9% from a plastic syringe, immediate precipitate which cleared after 60
minutes and remained clear for 24-hour study period stored at room
temperature under fluorescent light in a glass container; chemical stability not
tested [577]
Granisetron Hydrochloride
1) Compatible
56/317
25/10/12
a) Fluorouracil 200 mg in 100 mL of 0.9% Sodium chloride in PVC bag

(protected from light) with granisetron hydrochloride 1 mg/mL in Sterile water
for injection, stable for 4 hours when mixed in 1:1 ratio during simulated Y-site
administration [613]
b) Granisetron hydrochloride diluted with 5% dextrose injection to a
concentration of 50 mcg/mL is compatible with fluorouracil at a concentration
of 16 mg/mL (D5W) during simulated Y-site injection. Compatibility was
measured using visual examinations in fluorescent light and in high-intensity
monodirectional light. Turbidity, particle size and particle counts were
completed for certain solutions. The mixtures were assessed at 1 and 4 hours
(Trissel, 1997).
Heparin
1) Compatible
a) Fluorouracil 25 mg/0.5 mL with heparin 500 U/0.5 mL, visually compatible
for 5 minutes at 25 degrees C followed by 8 minutes of centrifugation [587]
b) Fluorouracil 50 mg/mL with heparin 1000 U/mL, visually compatible when
the drugs were injected sequentially into a Y-site without flushing the Y-side
arm between injections [587]
c) Fluorouracil 50 mg/mL with heparin 1000 U/L, visually compatible,
macroscopically and microscopically, for 4 hour study period at 25 degrees C in
the following solutions [588]:
Dextrose 5% in lactated Ringer's injection
Dextrose 5% in Ringer's injection
Dextrose 5% in water
Lactated Ringer's injection
Sodium chloride 0.9%
Hydrocortisone Sodium Succinate

1) Compatible
a) Fluorouracil 50 mg/mL with hydrocortisone sodium succinate 10 mg/L
visually compatible, macroscopically and microscopically, for a 4-hour study
period at 25 degrees C in the following solutions [608]:
57/317
Hydromorphone
1) Compatible
a) Hydromorphone 0.5 mg/mL admixed with fluorouracil 1 mg/mL in dextrose
5% and NaCl 0.9% is physically compatible and chemically stable for 7 days at
32 degrees C and 35 days at 23, 4, and -20 degrees C [566].
b) Hydromorphone 0.5 mg/mL admixed with fluorouracil 16 mg/mL in dextrose
5% and NaCl 0.9% is physically compatible and chemically stable for 3 days at
32 degrees C, 7 days at 23 degrees C, and 35 days at 4 and -20 degrees C
[566].
Leucovorin
1) Conflicting Data
a) Incompatible
1) Fluorouracil 50 mg/mL with leucovorin 20 mg/mL (as the calcium salt), with
or without Dextroxe 5% in water, incompatible when mixed in different
amounts and stored at 4, 23, or 32 degrees C in polyvinyl chloride containers
[552]; however, another source reported conditions under which these drugs
were found to be incompatible [553].
b) Compatible
1) Fluorouracil 25 mg/0.5 mL with leucovorin 5 mg/0.5 mL, visually compatible
in direct admixture in syringe for 5 minutes at 25 degrees C followed by 8
minutes of centrifugation [584]
2) Fluorouracil 50 mg/mL with leucovorin 10 mg/mL, visually compatible when
3) Fluorouracil 50 mg/mL (undiluted) with leucovorin 10 mg/mL and 20
mg/mL, no macroscopic precipitation, microscopic aggregation, color change,
gas production, or pH changes during simultated Y-site administration;
mixtures were stored in glass containers at 21 to 23 degrees C for 4 hours
[585]
4) Fluorouracil 7 mg/mL and 0.7 mg/mL in 0.9% Sodium chloride with
leucovorin 10 mg/mL and 20 mg/mL, no macroscopic precipitation, microscopic
aggregation, color change, gas production, or pH changes during simultated Ysite administration; mixtures were stored in glass containers at 21 to 23
degrees C for 4 hours [585]
58/317
25/10/12
degrees C for 4 hours [585]

5) Fluorouracil 0.7 mg/mL in Dextrose 5% in water with leucovorin 10 mg/mL
and 20 mg/mL, no macroscopic precipitation, microscopic aggregation, color
change, gas production, or pH changes during simulated Y-site administration;
mixtures were stored in glass containers at 21 to 23 degrees C for 4 hours
[585]
Levoleucovorin Calcium
1) Incompatible
a) 5-Fluorouracil 50 mg/mL and levoleucovorin calcium 20 mg/mL are
incompatible when mixed in various ratios (with or without 5% dextrose
injection) in polyvinyl chloride containers at 4, 23, or 32 degrees Centigrade;
crystalline particulate formation was observed in some solutions within 24
hours [573]. Separate administration of these agents is suggested.
Linezolid
1) Compatible
a) Fluorouracil 16 mg/mL (diluted in 5% dextrose injection) with linezolid 2
mg/mL (tested undiluted) is physically compatible for 4 hours at room
temperature (approximately 23 degrees C) under fluorescent light during
simulated Y-site administration [563].
Magnesium Sulfate
1) Compatible
a) Fluorouracil (Adrucil(R)) compatible with magnesium sulfate; concentrations
not specified [579]
Mannitol
1) Compatible
a) Fluorouracil 1 and 2 mg/mL in Dextrose 5% injection, 0.9% Sodium chloride
injection, and Dextrose 5% and 0.45% Sodium chloride injection with mannitol
20%, visually compatible and chemically stable for 24 hour-study (stored at 25
degrees C under constant fluorescent lighting) and during Y-site administration
[572]
Methotrexate
1) Conflicting Data
a) Incompatible
1) Fluorouracil 250 mg/L with methotrexate 200 mg/L, UV spectra for both
drugs were altered within 1 hour at room temperature in Dextrose 5% in
water [568]
b) Compatible
1) Fluorouracil (25 mg/0.5 mL with methotrexate 12.5 mg/0.5 mL visually
compatible in direct admixture in syringe for 5 minutes at 25 degrees Celsius
followed by 8 minutes of centrifugation; fluorouracil 50 mg/mL with
methotrexate 25 mg/mL visually compatible when the drugs were injected
sequentially into a Y-site without flushing the Y-side arm between injections)
[557]. However, it has been recommended that these two drugs not be mixed
59/317
25/10/12
in the same solution [558][559].

2) An admixture of methotrexate 0.96 milligram/milliliter (mg/mL) (in normal
saline diluent) and fluorouracil 48 mg/mL is stable for 14 days at room
temperature (25 degrees Celsius) in a PVC reservoir bag [560].
Metoclopramide
1) Conflicting Data
a) Incompatible
1) Fluorouracil 840 mg/16.8 mL with metoclopramide 10 mg/2 mL
incompatible; precipitate formed upon mixing (Tech Info Reglan(R), 1990)
b) Compatible
1) Fluorouracil 2.5 mg/mL and metoclopramide 0.1 mg/mL (as the
hydrochloride salt) in Dextrose 5% in water, stable for 4 hours at 25 degrees C
and for 120 hours at 4 degrees C in methyl-methacrylate-butadiene-styrene
containers [561]
2) Fluorouracil 25 mg/0.5 mL with metoclopramide 2.5 mg/0.5 mL, visually
compatible for 5 minutes at 25 degrees C followed by 8 minutes of
centrifugation [562]
3) Fluorouracil 50 mg/mL with metoclopramide 5 mg/mL, visually compatible
when the drugs were injected sequentially into a Y-site without flushing the Yside arm between injections [562]
Mitomycin
1) Compatible
a) Fluorouracil 25 mg/0.5 mL with mitomycin 0.25 mg/0.5 mL, visually
b) Fluorouracil 50 mg/mL with mitomycin 0.5 mg/mL, visually compatible when
Morphine Sulfate
1) Incompatible
a) Morphine sulfate 1 mg/mL admixed with fluorouracil 1 mg/mL and 16 mg/mL
in dextrose 5% and NaCl 0.9% is physically incompatible, forming an
immediate precipitate [574].
Ondansetron
1) Conflicting Data
a) Incompatible
1) Fluorouracil 16 mg/mL in Dextrose 5% in water with ondansetron 1 mg/mL
in Sodium chloride 0.9% resulted in the formation of a white, translucent, gellike precipitate [589][590]
b) Compatible
1) 5-Fluorouracil up to 0.8 mg/mL added at 20 mL/hr via a Y-site to
ondansetron - UK NON-PRESERVED FORMULATION - 0.016 to 0.16 mg/mL
is
60/317
25/10/12
ondansetron - UK NON-PRESERVED FORMULATION - 0.016 to 0.16 mg/mL is

physically compatible for 24 hours at 25 degrees C under ambient lighting in a
polyvinylchloride container [599][600].
Oxaliplatin
1) Incompatible
a) Oxaliplatin solution is incompatible with alkaline medications such as 5fluorouracil. Do not mix together or administer simultaneously through the
same infusion line. Flush the infusion line with dextrose 5% injection (D5W)
prior to administration [592].
Paclitaxel
1) Compatible
a) Fluorouracil 16 mg/mL in Dextrose 5% injection with paclitaxel 1.2 mg/mL
in Dextrose 5% injection in glass container, no visual or turbidimetric evidence
of incompatibility in simulated Y-site injection for a 4-hour study period,
admixture stored at room temperature under fluorescent light [591]. However,
this admixture was not tested for chemical stability.
Piperacillin Sodium/Tazobactam Sodium
1) Compatible
a) Piperacillin sodium 40 mg/mL plus tazobactam 5 mg/mL in Dextrose 5% in
water with fluorouracil 16 mg/mL in Dextrose 5% in water, compatible for 4
hours at 22 degrees C [578]
Potassium Chloride
1) Compatible
a) Fluorouracil 50 mg/mL with potassium chloride 40 mEq/L, visually
compatible, macroscopically and microscopically, for a 4-hour study period at
25 degrees C in the following solutions [551]:
Prednisolone
1) Compatible
a) Fluorouracil (250 mg/L with prednisolone 200 mg/L visually compatible in
61/317
25/10/12
Dextrose 5% in water with no alteration of ultraviolet spectrum of either drug

in 8 hours at room temperature) [576]
Prednisolone Sodium Phosphate
1) Compatible
a) Prednisolone sodium phosphate (200 mg/L with fluorouracil 250 mg/L
physically compatible in Dextrose 5% in water with no alteration of the
ultraviolet spectra in 8 hours at room temperature) [554]
Propofol
1) Compatible
a) Propofol 1% injectable emulsion and fluorouracil 16 milligrams/milliliter in a
1:1 volume mixture (simulated Y-site administration) are visually compatible in
polycarbonate test tubes at 15 minutes and 1 hour at approximately 23 degrees
Celsius as determined by visualization with fluorescent light and a highintensity, mono-directional light source (Tyndall beam) [567].
Sargramostim
1) Compatible
a) Fluorouracil 16 mg/mL with sargramostim 10 mcg/mL, both in sodium
chloride 0.9%, visually compatible for a 4-hour study period at 22 degrees C
under fluorescent light [607]
Vinblastine
1) Compatible
a) Fluorouracil 25 mg/0.5 mL with vinblastine 0.5 mg/0.5 mL, visually
b) Fluorouracil 50 mg/mL with vinblastine 1 mg/mL, visually compatible when
Vincristine
1) Compatible
a) Fluorouracil 10 mg/L with vincristine 4 mg/L, visually compatible and no
alterations in UV spectra were reported in 8 hours at room temperature in
Dextrose 5% in water [582]
b) Fluorouracil 25 mg/0.5 mL with vincristine 0.5 mg/0.5 mL, visually
compatible in direct admixture in syringe for 5 minutes at 25 degrees C
followed by 8 minutes of centrifugation [583]
c) Fluorouracil 50 mg/mL with vincristine 1 mg/mL, visually compatible when
Vinorelbine Tartrate
1) Incompatible
a) Fluorouracil 16 mg/mL in Sodium chloride 0.9% with vinorelbine tartrate 1
mg/mL in Sodium chloride 0.9%, heavy white precipitate formed immediately
62/317
25/10/12
[575]
Vitamin B Complex/Ascorbic Acid
1) Compatible
a) Vitamin B complex with C (2 mL/L with fluorouracil 50 mg/mL visually
compatible, macroscopically and microscopically, for a 4-hour study period at
25 degrees C in the following solutions) [580]:
Solutions
Dextrose 10% in Sodium chloride 0.225%
1) Compatible
a) Fluorouracil 500 mg/L in Dextrose 10% in Sodium chloride 0.225%,
compatible for 24 hours in glass or polyolefin containers; conditions not
specified (Tech Info American McGaw, 1985)
b) Fluorouracil 500 mg/L in Dextrose 10% in Sodium chloride 0.225%,
specified (Tech Info American McGaw, 1985):
1) Compatible
1) Compatible
a) Fluorouracil 500 mg/L in Dextrose 10% in Sodium chloride 0.9%, compatible
for 24 hours in glass or polyolefin containers; conditions not specified (Tech
Info American McGaw, 1985)
63/317
25/10/12
b) Fluorouracil 500 mg/L in Dextrose 10% in Sodium chloride 0.9%, compatible

Info American McGaw, 1985):
1) Compatible
a) Fluorouracil 500 mg/L in Dextrose 10% in water, compatible for 24 hours in
glass or polyolefin containers; conditions not specified (Tech Info American
McGaw, 1985)
Dextrose 2.5% in Sodium chloride 0.45%
1) Compatible
a) Fluorouracil 500 mg/L in Dextrose 2.5% in Sodium chloride 0.45%,
b) Fluorouracil 500 mg/L in Dextrose 2.5% in Sodium chloride 0.45%,
1) Compatible
a) Fluorouracil 500 mg/L in Dextrose 2.5% in Sodium chloride 0.9%,
b) Fluorouracil 500 mg/L in Dextrose 2.5% in Sodium chloride 0.9%,
Dextrose 2.5% in water
1) Compatible
a) Fluorouracil 500 mg/L in Dextrose 2.5% in water, compatible for 24 hours in
McGaw, 1985)
1) Compatible
a) Dextrose 3.3% in Sodium chloride 0.3% with fluorouracil 1.5 g/L, stable for
8 weeks at ambient temperature in glass or polyvinylchloride containers in the
dark or under fluorescent light (Biondi & Nairn, 1986)
Dextrose 5% in Lactated Ringer's injection
1) Compatible
a) Dextrose 5% in Lactated Ringer's injection with fluorouracil 500 mg/L,
1) Compatible
a) Dextrose 5% in Ringer's injection with fluorouracil 500 mg/L, compatible for
64/317
25/10/12
24 hours in glass or polyolefin containers; conditions not specified (Tech Info

American McGaw, 1985)
1) Compatible
1) Compatible
1) Compatible
1) Compatible
1) Compatible
65/317
25/10/12
1) Conflicting Data
a) Incompatible
1) Dextrose 5% in water with fluorouracil 8.3 g/L in a glass container, 10%
decrease in fluorouracil concentration in 7 hours at room temperature when
tested in glass container; however, 10% decrease in fluorouracil concentration
in 43 hours at room temperature when tested in polyvinyl chloride container
[614]
b) Compatible
1) Fluorouracil 500 mg/L in Dextrose 5% in water, compatible for 24 hours in
McGaw, 1985)
2) Dextrose 5% in water with fluorouracil 8.3 g/L in a polyvinylchloride
container, 10% decrease in fluorouracil concentration in 43 hours at room
temperature [406]
3) Dextrose 5% in water with fluorouracil 10 g/L, no decrease in fluorouracil
concentration reported in 16 weeks at 5 degrees C or in 7 days at 25 degrees
C in a plasticized polyvinylchloride container or an elastomeric balloon used in
a disposable drug pump (Quebbemen et al, 1984)
4) Dextrose 5% in water with fluorouracil 1.5 g/L, stable for 8 weeks at
ambient temperature in glass or polyvinylchloride containers in the dark or
under fluorescent light (Biondi & Nairn, 1986)
5) Dextrose 5% in water with fluorouracil 1 or 2 g/L, physically compatible
and no fluorouracil decomposition observed by ultraviolet spectroscopy or thin
layer chromatography in 48 hours at room temperature [581]
6) Dextrose 5% in water with fluorouracil 10 mg/mL, stable for up to 28 days
at 4, 22, or 35 degrees C protected form light in ethylene vinylacetate portable
infusion-pump reservoirs (Rochard et al, 1992)
LACTATED RINGER'S INJECTION
1) Compatible
a) Lactated Ringer's injection (with fluorouracil 500 mg/L compatible for 24
hours in glass or polyolefin containers; conditions not specified) (Tech Info
American McGaw, 1985)
1) Compatible
a) Fluorouracil 500 mg/L in Sodium chloride 0.45%, compatible for 24 hours in
McGaw, 1985):
1) Compatible
a) Fluorouracil 500 mg/L in Sodium chloride 0.9%, compatible for 24 hours in
66/317
25/10/12
McGaw, 1985):
b) Fluorouracil 1.5 g/L in Sodium chloride 0.9%, stable for 8 weeks at ambient
temperature in glass or polyvinylchloride containers in the dark or under
fluorescent light [615]
c) Fluorouracil 1 or 2 g/L in Sodium chloride 0.9%, physically compatible and no
fluorouracil decomposition observed by ultraviolet spectroscopy or thin layer
chromatography in 48 hours at room temperature [616]
TOTAL PARENTERAL NUTRITION
1) Conflicting Data
a) Incompatible
1) Fluorouracil 16 mg/mL in Dextrose 5% in water added to total parenteral
nutrition solution in simulated Y-site administration, formation of a slight haze,
small crystals (both visible only in high-intensity light) and amber discoloration
were reported in 1 to 4 hours at 23 degrees C; specific composition of total
parenteral nutrition solution listed below [620]:
Amino acids 10% (Aminosyn(R) II)
Dextrose
Sterile water for injection
Potassium phosphates
Sodium chloride
Potassium chloride
Magnesium sulfate
Multivitamins
Trace elements
Calcium gluconate
3.5%
5%
516.8 mL
3.5 mM
25 mEq
35 mEq
8 mEq
10 mL
1 mL
9.3 mEq

nutrition solution in simulated Y-site administration, formation of a slight haze,
small crystals (both visible only in high-intensity light) and amber discoloration
were reported in 1 to 4 hours at 23 degrees C; specific composition of total
parenteral nutrition solution listed below [620]:
Amino acids 10% (FreAmine(R) III)
Dextrose
Sodium chloride
Potassium chloride
Magnesium sulfate
Multivitamins
Trace elements
Calcium gluconate
3.5%
5%
516.75 mL
37.5 mEq
40 mEq
8 mEq
10 mL
1 mL
5 mEq

nutrition solution in simulated Y-site administration, immediate formation of
turbidity reported; specific composition of total parenteral nutrition solution
67/317
25/10/12
listed below [620]:

Amino acids 10% (Aminosyn(R) II)
Dextrose
Sodium chloride
Potassium chloride
Magnesium sulfate
Multivitamins
Trace elements
Calcium gluconate
4.25%
25%
161 mL
15 mM
25 mEq
18 mEq
8 mEq
10 mL
1 mL
9.15 mEq

nutrition solution in simulated Y-site administration, immediate formation of
turbidity reported; specific composition of total parenteral nutrition solution
listed below [620]:
Amino acids 10% (FreAmine(R) III)
Dextrose
Sodium chloride
Potassium chloride
Magnesium sulfate
Multivitamins
Trace elements
Calcium gluconate
4.25%
25%
158.6 mL
5.75 mM
40 mEq
25 mEq
8 mEq
10 mL
1 mL
7.5 mEq
5) Fluorouracil (1 or 4 g/L in a total parenteral nutrition solution physically

compatible for 42 hours at room temperature, but compatibility is questionable
because HPLC results were erratic; specific composition of total parenteral
nutrition solution described below) [621]:
Amino acids 8.5% with electrolytes 500 mL/L
Dextrose 50%
500 mL/L
Calcium gluconate
1 g/L
Multivitamins
5 mL/L
b) Compatible
1) Total parenteral nutrition (amino acids 4.25% in dextrose 25%, with
fluorouracil 500 mg/L exhibited no significant change in appearance,
particulate matter levels or pH in 24 hours at 5 degrees C) [617]
2) Total parenteral nutrition (with fluorouracil 1 g/L visually compatible and
fluorouracil chemically stable for 48 hours at room temperature in ambient
light; specific composition of total parenteral nutrition solution described
below) [618]:
Amino acids 8.5% with electrolytes 500 mL
Dextrose 50%
500 mL
68/317
25/10/12
Dextrose 50%
Calcium gluconate 10%
Multivitamins
500 mL
10 mL
5 mL
3) Total parenteral nutrition (with fluorouracil 1 or 4 g/L physically compatible

for 42 hours at room temperatures, but compatibility is questionable because
HPLC results were erratic; specific composition of total parenteral nutrition
solution described below) [619]:
Amino acids 8.5% with electrolytes 500 mL/L
Dextrose 50%
500 mL/L
Calcium gluconate
1 g/L
Multivitamins
5 mL/L
4) Total parenteral nutrition (ProcalAmine(R) - with fluorouracil 500 mg/L

physically compatible for 48 hours under refrigeration followed by 24 hours at
25 degrees C; specific composition of total parenteral nutrition solution listed
below) (Tech info ProcalAmine(R), 1985):
Amino acids
Glycerol
Electrolytes
3%
3%
present
CLINICAL APPLICATIONS
Monitoring Parameters
A) Therapeutic
1) Laboratory Parameters
a) Monitor white blood counts with differential before each intravenous dose [402].
2) Physical Findings
a) Intravenous
1) Monitor for improvement of signs and symptoms of specific carcinoma.
b) Topical
1) Monitor for improvement signs and symptoms of actinic/solar keratosis or superficial basal
cell carcinoma [403].
B) Toxic
1) Laboratory Parameters
a) Intravenous
1) Monitor white blood count with differential prior to each dose of the drug [402].
2) Monitor serum glucose in diabetic patients. Patients with hyperglycemia are at risk of
developing severe life-threatening toxicity with 5-fluorouracil [404].
69/317
25/10/12
Patient Instructions
A) Fluorouracil (Injection)
Fluorouracil
Treats cancer of the colon, rectum, breast, pancreas, and stomach. Also called 5-FU.
When This Medicine Should Not Be Used:
You should not be treated with this medicine if you have had an allergic reaction to fluorouracil.
How to Use This Medicine:
Injectable
This medicine is very strong. Make sure you understand why you are getting it and what the risks
and benefits of treatment are. It is important for you to work closely with your doctor.
Your doctor will prescribe your dose and tell you how often it will be given.
Your medicine will be given through a tube that is put in a vein, usually in your arm, wrist, or hand
and sometimes in your chest. This is called intravenous (in-tra-VEEN-us), or IV.
A nurse or other caregiver trained to give cancer drugs will give your treatment.
If a Dose is Missed:
This medicine needs to be given on a regular schedule. If you miss a dose, call your doctor, home
health caregiver, or the clinic where you get your treatments for instructions.
How to Store and Dispose of This Medicine:
If you get your treatments at a clinic, the staff at the clinic will keep your medicine there.
If you get your treatments at home, you may need to store your medicine. Keep the IV liquid at
room temperature, away from heat, moisture, and light.
Keep all medicine out of the reach of children.
If you get your treatments at home, you should be given a special container for the used needles,
medicine bag, and tubes. Put it where children or pets cannot reach it.
Drugs and Foods to Avoid:
Ask your doctor or pharmacist before using any other medicine, including over-the-counter
medicines, vitamins, and herbal products.
You should not use aspirin or any product that has aspirin it (such as some cold medicines)
unless you have talked to your doctor.
Avoid drinking alcohol.
Talk to your doctor before getting any vaccines (such as flu shots).
Warnings While Using This Medicine:
Do not breastfeed while you are being given this medicine.
Before you start your treatments, tell your doctor if you have any infections, bone marrow
problems, or liver or kidney disease.
You may get infections more easily while getting this medicine. Stay away from crowds or people
with colds, flu, or other infections.
70/317
25/10/12
with colds, flu, or other infections.

This medicine may make your mouth sore and irritated. Keep your mouth clean to prevent
infection. Brush your teeth with a soft-bristle toothbrush or mouth swab.
This medicine can cause nausea and vomiting. Your doctor may prescribe medicine to keep you
from feeling sick and throwing up. If the medicine does not help (you can't keep liquids down),
call your doctor.
Do not get pregnant while you or your sexual partner are receiving fluorouracil. Use an effective
method of birth control while you are getting this medicine.
If you are pregnant, talk to your doctor before you start your treatments.
Possible Side Effects While Using This Medicine:
Call your doctor right away if you notice any of these side effects:
Fever, chills, or sore throat
Unusual bleeding or bruising
Diarrhea, loose watery stools
Mouth sores that keep you from drinking liquids
Severe vomiting
Wheezing, trouble breathing
Severe rash or hives
If you notice these less serious side effects, talk with your doctor:
Loss of appetite
Stomach cramps
Hair loss
Mild rash
Darkening of skin
If you notice other side effects that you think are caused by this medicine, tell your doctor.
B) Fluorouracil (On the skin)
Fluorouracil
Treats actinic keratoses or solar keratoses (red wart-like growth on the skin). Also treats skin
cancer (superficial basal cell carcinoma).
When This Medicine Should Not Be Used:
You should not use this medicine if you have had an allergic reaction to fluorouracil. Do not use
this medicine if you are or may become pregnant. Do not use this medicine if you have
dihydropyrimidine dehydrogenase (DPD) enzyme deficiency.
How to Use This Medicine:
Cream, Liquid
Your doctor will tell you how much of this medicine to use and how often. Do not use more
medicine or use it more often than your doctor tells you to.
This medicine is for use on the skin only. Do not get it in your eyes, nose, or mouth. Do not use it
on skin areas that have cuts or scrapes. If it does get on these areas, rinse it off right away.
Wash your hands with soap and water before and after using this medicine.
Wash the skin to be treated with soap and water and wait 10 minutes before applying the
71/317
25/10/12
medicine.
Apply a thin layer to the affected area. Rub it in gently.
You may use a glove, nonmetal applicator, or your fingers to apply this medicine.
Do not cover the treated area with a bandage unless your doctor has told you to.
If your doctor tells you to use a bandage, use a gauze bandage with tape. A plastic bandage is
more likely to cause skin irritation.
If a Dose is Missed:
If you miss a dose or forget to use your medicine, apply it as soon as you can. If it is almost time
for your next dose, wait until then to apply the medicine and skip the missed dose. Do not apply
extra medicine to make up for a missed dose.
How to Store and Dispose of This Medicine:
Keep the medicine at room temperature, away from heat and direct light. Do not freeze.
Ask your pharmacist, doctor, or health caregiver about the best way to dispose of the used
medicine container and any leftover medicine after you have finished your treatment. You will also
need to throw away old medicine after the expiration date has passed.
Keep all medicine away from children and never share your medicine with anyone.
Drugs and Foods to Avoid:
Ask your doctor or pharmacist before using any other medicine, including over-the-counter
medicines, vitamins, and herbal products.
Do not use cosmetics or other skin care products on the treated skin areas.
Warnings While Using This Medicine:
Using this medicine while you are pregnant can harm your unborn baby. Use an effective form of
birth control to keep from getting pregnant. If you think you have become pregnant while using
the medicine, tell your doctor right away.
Make sure your doctor knows if you are breast feeding. Tell your doctor if you are sensitive to
preservatives, or if you have any other medical conditions.
This medicine may make your skin more sensitive to sunlight. Use a sunscreen when you are
outdoors. Avoid sunlamps and tanning beds.
Possible Side Effects While Using This Medicine:
Call your doctor right away if you notice any of these side effects:
Allergic reaction: Itching or hives, swelling in your face or hands, swelling or tingling in your
mouth or throat, chest tightness, trouble breathing
Fever, chills, or vomiting.
Severe skin rash or itching.
Stomach pain, or diarrhea that contains blood.
If you notice these less serious side effects, talk with your doctor:
Change in skin color where medicine is put on.
Eye burning, itching, stinging, or watering.
Hair loss.
Mild skin itching or burning.
72/317
25/10/12
Pain where the medicine is put on.

Swelling, blistering, redness, or peeling of skin.
If you notice other side effects that you think are caused by this medicine, tell your doctor.
Place In Therapy
A) In combination with other chemotherapeutic agents, fluorouracil is commonly considered as a
first-line therapy for breast cancer (CMF or CMFP), gastric cancer (with doxorubicin and cisplatin),
squamous cell head and neck cancer (with cisplatin), islet cell carcinoma (with streptozocin
and/or doxorubicin), and prostatic cancer (with cisplatin, cyclophosphamide, and doxorubicin).
Fluorouracil is indicated for the palliative management of pancreatic cancer; fluorouracil-based
chemoradiation is recommended as adjuvant therapy. Fluorouracil is considered an alternate
therapy for bladder cancer, cervical cancer, endometrial cancer, and ovarian cancer.
B) In the late 1980s, breast cancer became the most common indication for stem-cell
transplantation. There was a perception that treatment with high-dose chemotherapy and
transplantation resulted in an improved outcome over historical controls using conventional-dose
chemotherapy. However, in a randomized trial comparing conventional-dose chemotherapy with
high-dose chemotherapy (with cyclophosphamide, carboplatin, thiotepa) and autologous stem-cell
transplant, overall survival and time to disease progression were not favorably affected by use of
the latter treatment. This also held true when subgroups were analyzed according to estrogenreceptor status and primary site of metastasis. It is recommended that this approach of high-dose
chemotherapy with transplant be abandoned in favor of well-justified alternative experimental
approaches [3][10].
Mechanism of Action / Pharmacology

A) MECHANISM OF ACTION
1) 5-Fluorouracil (5-FU) is a fluorinated pyrimidine antimetabolite which undergoes anabolic and
catabolic reactions the same as uracil except it is converted to thymidine. 5-Fluorouracil blocks
the methylation reaction of deoxyuridylic acid to thymidylic acid and interferes with DNA synthesis
and to a lesser extent inhibits the formation of RNA [385][400]. This creates a thymine deficiency
resulting in cell death, especially in cells which grow more rapidly and take up fluorouracil rapidly
[385].
2) Evidence has been provided that the mechanism of action of CMF therapy (fluorouracil,
methotrexate and cyclophosphamide) as adjuvant chemotherapy in early breast cancer may be
secondary to ovarian suppression in premenopausal patients. In this study, prolongation of time
to recurrence and survival was observed primarily in premenopausal patients as compared to a
postmenopausal population. The efficacy of the combination was observed only when permanent
amenorrhea occurred in premenopausal patients [401].
Therapeutic Uses
Actinic keratosis
FDA Labeled Indication
73/317
25/10/12
1) Overview
FDA Approval: Adult, yes (Topical); Pediatric, no
Efficacy: Adult, Effective
Recommendation: Adult, Class IIa
Strength of Evidence: Adult, Category B
See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS
2) Summary:
Topical fluorouracil is indicated in the treatment of actinic and solar keratoses [82][81]
Safety and effectiveness have been demonstrated with 0.5% fluorouracil incorporated in
microsphere applied once daily for up to 4 weeks [81]
Several studies have documented the efficacy of a 2% or 5% solution or cream applied 1 to
2 times daily for 2 to 4 weeks (Breza et al, 1976; Robinson & Kligman, 1975; Dogliotti,
1973; Litwin, 1972; Simmonds, 1972; Eaglstein et al, 1970).
Lesions may not completely heal for 1 to 2 months after treatment discontinuation of 2% or
5% solution or cream [82]
3) Adult:
a) In a 52-week, prospective, randomized, double-blind, vehicle-controlled study evaluating
the safety and effectiveness of topical 0.5% fluorouracil cream (Carac(TM)) as
pretreatment prior to cryosurgery among patients with at least 5 visible or palpable actinic
keratosis (AK) lesions on the face (n=144), the combination of cryosurgery with topical
fluorouracil cream was more effective in reducing the mean number of AK lesions on sunexposed areas compared to cryosurgery with vehicle cream. The study comprised of 3
treatment cycles, during which patients (mean age 62.6 +/- 10.6 years) applied either
0.5% fluorouracil or vehicle cream once daily for 7 days to the face and 1 or more
treatment areas, including scalp, ears, neck, and lips. Patients were assessed 4 weeks
post-treatment at week 5, week 26, and week 52 prior to optional cryosurgical removal of
residual AK lesions per investigator discretion. Based on the intent-to-treat analysis, the
reduction of AK lesion in all treatment areas was statistically significant for both treatment
groups long term; however, fluorouracil cream resulted in fewer mean AK lesion count in all
treatment areas than vehicle cream: 8.2 vs 13.2 at week 5 (p less than 0.001); 4.5 vs 7.7
at week 26 (p=0.002); and 7.9 vs 7 at week 52 (p=0.007). The proportional reduction in
total AK lesions from baseline was consistently greater with fluorouracil than vehicle cream
(p less than 0.001 each cycle). Compared with vehicle cream, fluorouracil resulted in total
AK lesion clearance in all treatment areas at week 5 (12.5% vs 0%, p=0.002), at week 26
(51.4% vs 15.4%, p less than 0.001), and at week 52 (36.8% vs 26.7%, p=0.028). New
involvement of AK lesions on all treatment areas was lower with fluorouracil than vehicle
cream at the start of week 26 (80% vs 93.8%; p=0.015) but was similar between the 2
groups at week 52 (79.4% vs 90%; p=0.122). Rash (6.9% vs 0%) and application site
reactions (18.1% vs 4.2%), including erythema, pain and burning, were more prevalent
with fluorouracil than vehicle cream. Basal cell carcinoma and squamous cell carcinoma
were the most common serious adverse events [83].
74/317
25/10/12
b) A combination of topical fluorouracil and oral isotretinoin was effective in treating

disseminated actinic keratoses (AK) on photo-damaged skin in 27 patients. Patients
received topical fluorouracil 5% twice daily plus oral isotretinoin 20 milligrams twice daily
for a median of 21 days. All patients developed anticipated severe inflammation with
erosions and crusting. Palpable AKs regressed completely in 22 of the 27 subjects and
almost completely in the remaining five. Over the ensuing 10 to 26 months, 3 patients
developed recurrent AKs [84].
Anal cancer
1) Overview
FDA Approval: Adult, no; Pediatric, no
Efficacy: Adult, Evidence favors efficacy
Recommendation: Adult, Class IIb
2) Summary:
Cisplatin-based induction chemotherapy and chemoradiation failed to improve disease-free
survival and resulted in increased colostomy rates compared with standard mitomycinbased chemoradiation in patients with carcinoma of the anal canal (n=644) [89].
Combination chemotherapy with fluorouracil and radiotherapy was active in the treatment
of anal cancer in a trial of 35 patients [90].
Radiation therapy, fluorouracil, and cisplatin resulted in a complete response rate of 68% of
19 patients with anal cancer in a phase II study [91].
3) Adult:
a) Cisplatin-based induction chemotherapy and chemoradiation failed to improve diseasefree survival and resulted in increased colostomy rates compared with standard mitomycinbased chemoradiation in patients with carcinoma of the anal canal in the United States
Radiation Therapy Oncology Group (US RTOG) 98-11 trial. Patients (n=644) with
squamous, basaloid, or cloacogenic carcinoma of the anal canal with T2 to T4, any N, and
M0 tumors were randomized to receive mitomycin-based chemotherapy (mitomycin 10
milligrams/square meter (mg/m(2)) intravenous (IV) bolus on days 1 and 29 (maximum, 20
mg/course) plus fluorouracil 1000 mg/m(2)/day as a continuous IV infusion on days 1 to 4
and 29 to 32) with concurrent radiation (n=324) or cisplatin-based chemotherapy (cisplatin
75 mg/m(2) IV over 60 minutes on days 1, 29, 57, and 85, and fluorouracil 1000
mg/m(2)/day as a continuous IV infusion on days 1 to 4, 29 to 32, 57 to 60, and 85 to 88,
with days 57 and 85 corresponding to radiotherapy days 1 and 29) (n=320). All patients
received at least 45 gray (Gy) in 25 fractions over 5 weeks to the primary tumor while
patients with T3, T4, node-positive disease, or T2 residual disease after 45 Gy received an
additional 10 to 14 Gy in 2-Gy fractions. The total radiation dose administered was 55 to 59
Gy in 30 to 32 fractions over 5.5 to 6.5 weeks. Baseline characteristics were similar with
the exception of more anal canal and perianal cancers in the cisplatin-based group (24%)
vs the mitomycin-based group (16%; p=0.045). The study was designed to detect an
75/317
25/10/12
improvement in 5-year disease-free survival (DFS) from 63% with the mitomycin-based
group to 73% with the cisplatin-based group. Results were released when the second
interim analysis found that results crossed the futility boundary and would not show a
statistically significant difference in DFS even with additional events. After a median followup time of 2.51 years, the 5-year estimated DFS rates were 60% (95% confidence interval
(CI), 53% to 67%) in the mitomycin-based group and 54% (95% CI, 46% to 60%) in the
cisplatin-based group (p=0.17). Independent prognostic factors for worse DFS were male
sex (p=0.02), clinically positive nodes (p less than 0.001), and tumor size greater than 5
centimeters (p=0.004). The 5-year overall survival rate was 75% (95% CI, 67% to 81%) in
the mitomycin-based arm and 70% (95% CI, 63% to 76%) in the cisplatin-based arm.
Cancer-related deaths were lower in the mitomycin-based group (28 patients) compared
with the cisplatin-based group (54 patients). Cumulative colostomy rates were significantly
higher at 3 years (16%; 95% CI, 12% to 20% vs 10%; 95% CI, 6% to 14%) and 5 years
(19%; 95% CI, 13% to 24% vs 10%; 95% CI, 6% to 14%) in the cisplatin-based group vs
the mitomycin-based group, respectively (hazard ratio, 1.68; 95% CI, 1.07-2.65; p=0.02).
Radiotherapy and chemotherapy adherence rates were similar between groups. Grade 3 or
4 hematologic toxicity occurred in 61% in the mitomycin-based group and 42% in the
cisplatin-based group [89]
b) Combination chemotherapy/radiotherapy with fluorouracil and cisplatin resulted in a
complete response rate of 94% with 6% local recurrence in 35 patients with untreated
epidermoid cancer of the anus. On days 1 and 21, patients received a 24-hour intravenous
infusion of fluorouracil 750 milligrams/square meter (mg/m(2)) days 1 through 4, and a 60minute infusion of cisplatin 100 mg/m(2) on day 1. Concurrent radiotherapy was
administered at a daily 1.8 Gy dose up to a total of 38 Gy in 4 weeks. The anoperineal
region and metastatic inguinal nodes received a total dose of 18 to 24 Gy in 10 fractions. A
third cycle of chemotherapy was administered 6 weeks after the start of therapy to younger
patients who had shown minimal toxicity to earlier courses. Investigators considered this
combination similar in efficacy to a traditional chemoradiotherapy regimen of fluorouracil,
mitomycin, and radiation, but having a lower local recurrence rate (6% vs 24%) [90].
c) In a phase II clinical trial, radiation therapy (RT), fluorouracil, and cisplatin resulted in a
complete response in 68% of patients with biopsy-proven, measurable anal cancer at 33
months of follow-up. Radiation therapy (59.4 Gy) was delivered over 60 days with a 2-week
break after delivery of 36 Gy. On days 1 to 4 of RT, a continuous infusion of fluorouracil
1000 milligrams/square meter/day (mg/m(2))/day was administered. On day 1, cisplatin 75
mg/m(2) was administered intravenously. When RT was restarted after the 2-week break,
a second course of chemotherapy was administered, however, 2 patients received only one
course of chemotherapy. Of 19 treated patients, 15 developed toxicity of grade 3 or higher,
and one treatment related death occurred. The incidence of toxicity with this regimen was
similar to that of standard treatment with RT, fluorouracil, and mitomycin-C. Therefore, RT,
fluorouracil, and cisplatin are not recommended at this time for treating patients with anal
cancer [91].
Breast cancer, Palliative
1) Overview
FDA Approval: Adult, yes (Injectable); Pediatric, no
76/317
25/10/12

2) Summary:
Fluorouracil is indicated in the palliative management of breast cancer [1].
A 27% overall response rate was achieved with combination oxaliplatin plus fluorouracil in
advanced or metastatic breast cancer patients (n=64) with prior taxane and anthracycline
treatment [2].
No difference in survival or time to disease progression when stem-cell transplant is added
to combination high-dose therapy and compared to standard-dose therapy [3].
3) Adult:
a) General Information
Approaches to the therapy of breast cancer include surgery, radiotherapy, chemotherapy
and endocrine therapy. Surgical resection is most frequently used, and radiotherapy
controls residual microscopic cancer, decreasing the likelihood of relapse. Chemotherapy
and endocrine therapy reduce cancer recurrence in early disease (usually in high-risk
patients), in advanced disease, and in patients with distant metastases [4][5][6].
Fluorouracil is indicated in the palliative management of breast cancer [7], and is included
among the drugs of choice recommended by the Medical Letter consultants for adjuvant
treatment of both primary and metastatic disease [8]. For primary disease:
cyclophosphamide plus methotrexate plus fluorouracil;
cyclophosphamide plus doxorubicin with or without fluorouracil;
tamoxifen
For metastatic disease, (receptor-negative and/or hormone refractory patients):
cyclophosphamide plus methotrexate plus fluorouracil; or
cyclophosphamide plus doxorubicin with or without fluorouracil;
tamoxifen for receptor-positive and/or hormone-responsive disease
Response rates of 60 to 80% have been achieved with combination chemotherapy,
whereas single agents (doxorubicin, cyclophosphamide, methotrexate) have produced
responses rates of 20% to 40% (Skeel, 1991, Holleb et al, 1991). Adjuvant chemotherapy
also provided better relapse-free survival and total survival for node-positive breast cancer
patients than surgery alone [9].
1) In the late 1980s, breast cancer became the most common indication for stem-cell
transplantation. There was a perception that treatment with high-dose chemotherapy and
transplantation resulted in an improved outcome over historical controls using
conventional-dose chemotherapy. However, in a randomized trial comparing conventionaldose chemotherapy with high-dose chemotherapy (with cyclophosphamide, carboplatin,
77/317
25/10/12
dose chemotherapy with high-dose chemotherapy (with cyclophosphamide, carboplatin,

thiotepa) and autologous stem-cell transplant, overall survival and time to disease
progression were not favorably affected by use of the latter treatment. This also held true
when subgroups were analyzed according to estrogen-receptor status and primary site of
metastasis. It is recommended that this approach of high-dose chemotherapy with
transplant be abandoned in favor of well-justified alternative experimental approaches
[3][10]. This study is described in greater detail below in the subsection entitled: Regimen
Comparisons.
2) Analysis of data from 1581 patients with metastatic breast cancer (MBC) treated with
doxorubicin-containing chemotherapy revealed a 16.6% complete response (CR) and a
48.5% partial response (PR); the median progression free survival (PFS) and median
overall survival (OS) were 11.5 and 21.3 months, respectively. Patients who achieved a CR
had a median PFS and OS of 22.2 and 41.8 months, respectively, compared to 14 and 24.6
months for patients with a PR. All patients were treated at M.D. Anderson Cancer Center
and were enrolled in clinical trials all of which included doxorubicin. The primary regimens
used (period of study - 1973 to 1982) were: (1) fluorouracil, doxorubicin, and
cyclophosphamide (FAC); (2) vincristine, doxorubicin, and cyclophosphamide (VAC) plus
fluorouracil and methotrexate; (3) fluorouracil, doxorubicin, and ifosfamide (FAI), or (4)
the above combinations with bacillus Calmette- Guerin, levamisole, vitamin E, or hormonal
therapy. This analysis provides a useful reference for comparison of new single-agent
chemotherapy agents [11].
b) Combination Therapy
1) Metastatic Disease
a) A 27% overall response rate was achieved with combination oxaliplatin plus
fluorouracil in advanced or metastatic breast cancer patients (n=64) with prior taxane and
anthracycline treatment. This regimen was well tolerated. Patients received oxaliplatin
130 milligrams/square meter on day 1 plus fluorouracil 1000 milligrams/square meter/day
on days 1 to 4, repeated every 3 weeks; patients received a median of 6 treatment cycles.
Treatment-related toxicity included grade 3/4 neutropenia, leukopenia, and
thrombocytopenia occurring in 34%, 19%, and 16% of patients, respectively. Thirty-three
percent of patients experienced grade 2/3 peripheral neuropathy (8% with grade 3) [2].
b) A 15-day continuous ambulatory infusion of fluorouracil 350 milligrams/square meter
(mg/m(2)) daily with oral cyclophosphamide 100 mg/m(2)/day, and weekly vincristine 0.8
mg/m(2) and doxorubicin 15 mg/m(2) on day 1, day 8, and day 15, enhanced efficacy and
reduced toxicity in metastatic breast cancer. The overall response rate of 48% included
complete response in 23% of patients. Cycles were repeated every 28 days in 34 patients
as first-line therapy and 49 patients as second- line therapy [12].
2) With Bone Marrow Transplantation
Survival is NOT improved for women with metastatic breast cancer undergoing treatment
with standard-dose chemotherapy followed by high-dose chemotherapy and autologous
stem-cell transplant when compared to standard-dose chemotherapy alone. Of 553
patients enrolled, 110 achieved either a complete or partial response to induction
chemotherapy and were subsequently randomized. Standard- and high-dose chemotherapy
were administered according to the following schema:
Induction and Maintenance High-Dose (Continuous
Infusion)
Doxorubicin
30 mg/m(2) days 1 and 8
78/317
25/10/12
Doxorubicin

IV
Cyclophosphamide 100 mg/m(2)/day for 14
days oral
Fluorouracil
500 mg/m(2)days 1 and 8
IV
Methotrexate*
IV
Thiotepa
1500 mg/m(2)/day for 4 days

IV

IV
Carboplatin
IV
*methotrexate substituted for doxorubicin when the total dose of doxorubicin
previously received was 400 to 500 mg.
Four to six cycles of induction therapy were given every 28 days. Patients randomized to
standard-dose (maintenance) chemotherapy received a median of 8 cycles. Median followup was 37 months. At 3 years, overall survival in this intention-to-treat analysis was not
significantly different between standard- and high-dose/transplant therapy (38% and 32%,
respectively; p=0.23). Likewise, median time to progression was not different between the
standard- and high- dose/transplant groups (9 and 9.6 months, respectively; p=0.31).
Subgroup analyses (estrogen-receptor status, predominant site of metastatic disease) also
revealed no differences in these endpoints between the 2 groups. A greater incidence of
severe leukopenia, thrombocytopenia, and anemia was observed in the highdose/transplant group; mucositis occurred at a similar rate for both groups [3]. High-dose
chemotherapy with stem-cell transplantation is ineffective for women with metastatic
breast cancer and therefore cannot be recommended and should be abandoned in favor of
well- justified alternative experimental approaches [10][3].
a) No difference in survival or progression free survival was detected in patients with
breast cancer receiving high-dose chemotherapy with peripheral blood progenitor cell
(PBPC) support compared to those who did not. This randomized study analyzed 81
patients with extensive axillary lymph-node involvement. All patients received up-front
chemotherapy with fluorouracil, (500 milligrams/square meter (mg/m(2)), epirubicin (120
mg/m(2), and cyclophosphamide (500 mg/m(2) (repeated every 3 weeks for 3 courses)
followed by surgery. All randomized patients received a fourth course of the up-front
chemotherapy regimen, radiation therapy and 2 years of tamoxifen therapy. In addition to
that, those randomized to the high-dose regimen received cyclophosphamide 6
grams/square meter, thiotepa 480 mg/m(2), carboplatin 1600 mg/m(2) and PBPC
reinfusion. Toxicities were greater in the high-dose group but both groups experienced
nausea, vomiting, alopecia, fatigue, mucositis, phlebitis, diarrhea, and neutropenia. Three
cases of reversible renal failure were reported in the high-dose group [13].
Carcinoid tumor
1) Overview
Efficacy: Adult, Evidence is inconclusive
79/317
25/10/12

2) Summary:
In randomized phase 2 and 3 studies of patients with unresectable metastatic carcinoid
tumor, fluorouracil plus streptozocin therapy produced an overall response rate (ORR) of
3% [100] to 22% [101] and a median progression free survival (PFS) of 5.3 [102] to 5.5
months [100]. Additionally, there was no significant differences in ORR for patients who
received fluorouracil plus streptozocin compared with doxorubicin [101], fluorouracil plus
doxorubicin [102], or interferon alfa [100]. Overall survival for the fluorouracil plus
streptozocin regimen ranged from 64 weeks [101] to 30.4 months [100].
3) Adult:
a) In a randomized phase 2 and 3 study (n=232), treatment with fluorouracil plus
streptozocin produced similar overall response rates (ORR) compared with doxorubicin in
patients with metastatic carcinoid tumor. Patients (median age, 60 years; range, 28 to 83
years) with unresectable or progressive disease, no heart disease or prior chemotherapy
were randomized to receive fluorouracil 400 mg/m(2) IV daily on days 1 to 5 and 36 to 40
plus streptozocin 500 mg/m(2) IV daily on days 1 to 5 of a 10 week cycle (n=86) or
doxorubicin 60 mg/m(2) IV on days 1, 22, 43, and every 4 weeks thereafter (n=86 );
crossover was allowed at disease progression. The remainder of patients who were
included in the study (n=38) were assigned directly to the appropriate treatment arm
based on prior chemotherapy or a history of heart disease. Patients must have completed
any major surgery, radiation therapy, or chemotherapy 4 weeks prior to study entry. There
was no difference in the overall response rate (ORR) for fluorouracil plus streptozocin
(n=80; 22% (95% CI, 13% to 31%); complete response (CR), n=2) compared with
doxorubicin (n=81; 21% (95% CI, 12% to 30%); CR, n=1). The median duration of
response and the median survival were 31 weeks (range, 5 to 110 weeks) and 64 weeks for
the fluorouracil plus streptozocin arm and 26 weeks (range, 4 to 73 weeks) and 48 weeks
(p less than 0.25) for the doxorubicin arm. Patients who failed fluorouracil plus streptozocin
and were switched to doxorubicin (n=33) experienced an ORR of 18% and those who failed
doxorubicin and were switched to fluorouracil plus streptozocin (n=35) had an ORR of
29%. Patients (n=200) receiving fluorouracil plus streptozocin or doxorubicin experienced
myelosuppression (grade 3 or 4 white blood cell and platelets; 20%, 25%), vomiting (grade
3; 27%, 4%), and grade 4 heart failure (0%, 2%), respectively. Two patients in the
fluorouracil plus streptozocin arm died from hematologic toxicity. Renal toxicity was
reported in 10 patients who received fluorouracil plus streptozocin, including 1 death from
renal failure with tubular necrosis. Two doxorubicin patients died from heart failure [101].
b) In a randomized phase 2 and 3 study (n=249), overall survival (OS) was significantly
prolonged in patients with unresectable advanced carcinoid tumors who received
fluorouracil plus streptozocin compared with fluorouracil plus doxorubicin; however, there
were no significant differences in overall response rate (ORR) or progression free survival
(PFS) . Patients previously untreated with chemotherapy were randomized to receive
fluorouracil 400 mg/m(2) IV on days 1 to 5 and 36 to 40 plus streptozocin 500 mg/m(2) IV
on days 1 to 5 every 10 weeks (n=88; median age, 62.5 years) or fluorouracil 400 mg/m(2)
IV daily on days 1 to 5 plus doxorubicin 40 mg/m(2) IV on day 1 every 5 weeks (n=88;
median age, 58.2 years). The remainder of patients who were included in the study (n=73)
were assigned directly to the appropriate treatment arm based on prior chemotherapy or a
80/317
25/10/12
history of heart or renal disease. Patients who received prior therapy with fluorouracil or
both doxorubicin and streptozocin, with heart and renal disease, or who experienced
disease progression during the study while receiving combination chemotherapy were
assigned to receive dacarbazine 250 mg/m(2) IV daily on days 1 to 5 every 4 weeks
(n=21). Major surgery was required to be completed 3 weeks before study entry and prior
chemotherapy or radiation therapy needed to be completed 1 month prior. There was no
difference in ORR in the fluorouracil plus streptozocin arm (16%; 12 partial response (PR))
compared with the fluorouracil plus doxorubicin arm (13.5%; 2 complete response (CR), 9
PR; p=0.82). The median OS was significantly prolonged for fluorouracil plus streptozocin
(24.3 months) compared with fluorouracil plus doxorubicin (15.7 months; p=0.0267);
however, there was no significant difference in median PFS between the 2 groups (4.5 vs
5.3 months; p=0.17). In patients who received second-line therapy with dacarbazine
(n=61), the ORR was 8.2% (2 CR, 3 PR) and the median PFS was 11.9 months. Among all
patients, severe hematologic toxicity occurred in 15, 24, and 9 patients with life-threatening
cases in 8 (1 fatality), 13, and 3 patients who received fluorouracil plus streptozocin
(n=115), fluorouracil plus doxorubicin (n=113), and second-line dacarbazine (n=91),
respectively. Renal toxicity occurred in 34.8% of patients who received fluorouracil plus
streptozocin, including life-threatening renal failure in 2 patients [102].
c) In a randomized, multicenter, phase 3 trial (n=64), there were no statistically significant
differences in progression free survival (PFS) or overall survival (OS) in patients with
unresectable malignant carcinoid tumor who received fluorouracil plus streptozocin or
interferon alfa; however, the study was not powered to detect a difference in PFS. Patients
(median age, 60 +/- 10 years) were randomized to fluorouracil 400 mg/m(2) plus
streptozocin 500 mg/m(2) IV over 2 hours daily on days 1 to 5 of a 6-week cycle (n=32;
lymph node metastasis, 53%) or interferon alfa 3 x 10(6) subQ three times weekly (6 week
cycle; n=32; lymph node metastasis, 28%). Each treatment was administered for at least
12 weeks and for a maximum of 8 cycles. Prior immunotherapy and radiotherapy to the
primary area of measurable disease was not allowed; chemotherapy must have been
completed at least 6 weeks prior to study entry. After a median follow-up of 46 months
(range, 1 to 83 months), the median PFS was 5.5 months (95% CI, 2.9 to 25 months) in
the fluorouracil plus streptozocin arm compared with 14.1 months (95% CI, 6.7 to 21.2
months) in the interferon alfa arm (p=0.34); the 1-year PFS (primary endpoint) was 44%
(95% CI, 26% to 60%) and 51% (95% CI, 31% to 68%), respectively. There were no
statistically significant differences in median time to progression (8.5 months (95% CI, 2.9
to 60.4 months) vs 19.6 months (95% CI, 6.7 months to not reached; p=0.21) or median
OS (30.4 months (95% CI, 21 months to not reached) vs 44 months (95% CI, 23 to 59
months); p=0.83) in the fluorouracil plus streptozocin arm compared with interferon alfa,
respectively. Response rates, according to WHO criteria, were low in both arms
(fluorouracil plus streptozocin, 3%; interferon alfa, 9%). Adverse events (all grades) that
were more common in the fluorouracil plus streptozocin arm compared with interferon alfa
included proteinuria (41% vs 6%) and nausea (50% vs 22%). In the interferon alfa arm,
hematologic toxicity (63% vs 31%) and fever (25% vs 6%) were more common compared
with fluorouracil and streptozocin [100].
Carcinoma of bladder
1) Overview
81/317
25/10/12

2) Summary:
Fluorouracil is most effective against transitional cell carcinoma of the bladder and Stage III
squamous cell carcinoma [95]. Early studies indicated no advantage of intravenous
fluorouracil in combination with radiotherapy over radiotherapy alone in bladder carcinoma
(Edland et al, 1970; Prout et al, 1970). Two studies, however, reported improved survival
rates with intra-arterial fluorouracil combined with mega-voltage radiation versus radiation
alone in patients with advanced bladder carcinoma and non-resectable estrogen-resistant
prostate carcinoma (Nevin et al, 1973; Nevin et al, 1974)
3) Adult:
a) Hypogastric intra-arterial infusion of fluorouracil achieved partial to complete responses
in 19 of 30 patients with advanced bladder carcinoma. The drug was administered initially
in doses of 15 milligrams/kilogram/day for 10 days followed by 2500 mg every other week
[95].
b) One study reported good results in 17 of 19 patients with carcinoma of the bladder
following treatment with Adriamycin(R) (doxorubicin), fluorouracil, and levamisole
combined with radiotherapy [96].
Carcinoma of pancreas, Adjuvant
1) Overview
2) Summary:
An open-label, phase 3, randomized, multicenter trial (ESPAC-3) demonstrated no
difference in overall survival between adjuvant treatment with fluorouracil plus folinic acid
(n=551) and gemcitabine (n=537) in patients with completely resected pancreatic cancer
[67].
A multicenter randomized trial (n=289; ESPAC-1) demonstrated a statistically significant
increase in 2-year survival for patients receiving chemotherapy compared with resection
alone, but failed to show a benefit in 2-year survival for patients receiving
chemoradiotherapy compared with no chemoradiotherapy in the adjuvant treatment of
pancreatic cancer [68].
In a randomized, multicenter, phase 3 trial no benefit in overall survival or progression-free
survival was demonstrated in patients with pancreatic head and periampullary cancers
receiving adjuvant chemoradiotherapy compared with
observation [69].
82/317
25/10/12
receiving adjuvant chemoradiotherapy compared with observation [69].

3) Adult:
a) An international, open-label, phase 3, randomized, multicenter trial (European Study
group for Pancreatic Cancer; ESPAC-3) demonstrated no difference in overall survival
between adjuvant treatment with fluorouracil plus folinic acid and gemcitabine in patients
with completely resected pancreatic cancer. Patients with a successful complete resection
of ductal adenocarcinoma were randomized to receive either folinic acid 20 mg/m(2) IV
bolus plus fluorouracil 425 mg/m(2) IV bolus on 5 consecutive days every 28 days for 6
cycles (n=551; median age, 63 years; range, 34 to 85) or gemcitabine 1000 mg/m(2)
infused IV over 30-minute once per week for 3 out of 4 weeks for 6 cycles (n=537; median
age, 63 years; range, 31 to 81 years). At a median follow-up of 34.2 months, the median
survival was 23 months (95% confidence interval (CI), 21.1 to 25) and 23.6 months (95%
CI 21.4 to 26.4) for patients treated with fluorouracil plus folinic acid and gemcitabine,
respectively. There was no statistically significant difference in overall survival (primary
endpoint) (hazard ratio (HR), 0.94; 95% CI, 0.81 to 1.08; p=0.39 ) or progress-free survival
(HR, 0.96; CI, 0.84 to 1.10; p=0.53) between the two treatment groups. The most
significantly increased grade 3 or 4 toxicities for patients receiving fluorouracil were
diarrhea (p less than 0.001) and stomatitis (p less than 0.001); while the most significantly
increased toxicity for patients receiving gemcitabine was hematologic toxicity (p=0.003).
There was no significant difference between treatment groups in quality-of-life scores
(p=0.08) [67].
b) A multicenter randomized trial (ESPAC-1) demonstrated a statistically significant
increase in 2-year survival for patients receiving chemotherapy compared with resection
alone, but failed to show a benefit in 2-year survival for patients receiving
chemoradiotherapy compared with no chemoradiotherapy in the adjuvant treatment of
pancreatic cancer. Patients with resected pancreatic ductal adenocarcinoma were randomly
assigned to receive chemotherapy (n=75), chemoradiotherapy (n=73), neither (n=69), or
both treatments (n=72). Chemotherapy consisted leucovorin 20mg/m(2) IV bolus followed
by fluorouracil 425 mg/m(2) IV bolus for 5 consecutive days every 28 days for a total of 6
cycles. Chemoradiotherapy consisted of 20 Gray administered in 10 daily fractions over a 2week period plus fluorouracil 500 mg/m(2) IV bolus on each of the first 3 days of
radiotherapy and again after a planned break of 2 weeks. Combination therapy consisted of
the radiochemotherapy followed by chemotherapy. Two- year survival rates between the
chemotherapy versus no chemotherapy groups and the chemoradiotherapy versus no
chemoradiotherapy groups were the primary outcomes. At a median follow-up of 47
months, the median survival for patients receiving chemotherapy (n=147) was 20.1 months
(95% confidence interval (CI), 16.5 to 22.7) compared with 15.5 months (95% CI, 13.0 to
17.7) for the patients not receiving chemotherapy (n=142). Risk of death in the
chemotherapy group was reduced by 21% compared to the non-chemotherapy group
(hazard ratio (HR) 0.71; 95% CI, 0.55 to 0.92; p=0.009). Median survival for patients
receiving chemoradiotherapy (n=145) was 15.9 months (95% CI, 13.7 to 19.9) compared
with 17.9 months for patients not receiving chemoradiotherapy (n=144) (95% CI, 14.8 to
23.6). Risk of death in the chemoradiotherapy group was increased by 28% compared to
the non-chemoradiotherapy group (HR 1.28; 95% CI, 0.99 to 1.66; p=0.05). The median
time to recurrence was 15.3 months and 9.4 months (p=0.02) among patients in the
chemotherapy and non-chemotherapy groups. Among patients in the chemoradiotherapy
and no chemoradiotherapy groups, the median time to recurrence was 10.7 months and
83/317
25/10/12
15.2 months (p=0.04), respectively. . Grade 3 or 4 adverse events were reported in 29 of

220 patients receiving chemotherapy (13%). There were no significant differences in
quality of life between patients who received chemotherapy and those who did not receive
chemotherapy or between patients who received chemoradiotherapy and those who did not
receive chemoradiotherapy (p=0.17) [68].
c) In a randomized, multicenter, phase 3 trial no benefit in overall survival or progressionfree survival was demonstrated in patients with pancreatic head and periampullary cancers
receiving adjuvant chemoradiotherapy compared with observation. Patients with T1-3N01aM0 pancreatic head cancer or T1-3N0-1aM0 periampullary cancer were randomized to
chemoradiotherapy (n=104; median age, 59 years; range, 24 to 78 years) or observation
(n=103; median age, 62 years; range, 39 to 80 years). Chemoradiotherapy consisted of
radiotherapy starting 2 to 8 weeks after surgery (absorbed daily dose 2 gray (Gy), 5
fractions a week during 2 weeks). After 2 weeks the treatment was repeated to total
absorbed dose of 40 Gy. Fluorouracil 25 mg/kg/24 hours (maximum 1500 mg) was started
on the same day before radiotherapy. The second course consisted of 0, 3, or 5 days of
fluorouracil, depending on toxicity. Median survival and 2-year survival rates were 24.5
months and 51% (95% confidence interval (CI), 41% to 61%) in the chemoradiotherapy
group compared with 19 months and 41% (95% CI, 31% to 51%; p=0.208) in the
observation group. The 2-year progression-free survival rates for the chemoradiotherapy
and observation groups were 37% (95% CI, 27% to 47%) and 38% (95% CI, 28% to
48%), respectively (p= 0.643). Median duration of survival for patients with pancreatic
head cancer receiving chemoradiotherapy was 17.1 months compared with 12.6 months for
observation. Of the 81 patients evaluated for toxicity, 47% of patients developed no signs
of toxicity and only 1 patient developed major toxicity (major duodenal ulcer). The most
commonly reported toxicity was nausea and vomiting [69].
Carcinoma of pancreas, Palliative
1) Overview
2) Summary:
Fluorouracil is indicated for the palliative management of pancreatic cancer [1].
Combination chemotherapy has demonstrated minimal activity [70][71].
3) Adult:
a) Monotherapy
1) Among 13 patients enrolled in a pilot study, the hepatic arterial infusion of fluorouracil
was tolerated but minimally effective in the treatment of liver metastases from pancreatic
carcinoma. Intraarterial fluorouracil was administered continuously at a rate of 500
84/317
25/10/12
milligrams (mg)/square meter daily for five days with 100 mg of hydrocortisone and 5000
units of heparin every four weeks through a battery-operated ambulatory infusion pump.
Ten of the 13 patients received external-beam radiation therapy. Patients were evaluated
every four weeks after the start of treatment by computed tomography. One treatment
cycle was administered to seven patients, two cycles in one patient, three cycles in one
patient, four cycles in three patients, and five cycles in one patient. One patient (8%)
demonstrated a partial response, six patients (46%) showed no change, and six patients
(46%) had progressive disease. Of the six patients with no change, two patients showed a
minor response. The overall response rate was 8% (95% confidence interval: 0 to 22%).
Discontinuation of treatment occurred in eight patients (62%) with hepatic or extra
hepatic disease progression, three patients (23%) with hepatic artery obstruction, and one
patient with nausea and vomiting. The most common treatment-related toxicity was
nausea and vomiting (grade 1 in two patients, grade 2 in 10 patients, and grade 3 in one
patient). Disease progression was evident in all 13 patients, with hepatic tumor
progression observed in 10 patients (77%) and extra hepatic progression observed in nine
patients (69%). The median survival time was 15.9 weeks, and the six-month and oneyear survival rates were 38% and 0%, respectively [72].
b) Combination therapy
1) Unresectable/Advanced disease
a) Of 30 patients with unresectable, neuroendocrine tumors (NET) (15 pancreatic, 9
carcinoid, and 6 other), 2 (pancreatic NET and Merkel cell carcinoma) and 7 patients
achieved a complete and partial response, respectively, during treatment with fluorouracil,
dacarbazine, and epirubicin. Six patients underwent surgery with a complete pathologic
response in 2 patients. none of the patients with endocrine hypersecretion syndrome (ie,
diarrhea with or without flushing) had a symptomatic response. This regimen was
tolerated well although 14 patients required a treatment delay due to myelotoxicity. On 3
consecutive days, patients received fluorouracil 500 milligrams/square meter (mg/m(2))
as a bolus, dacarbazine 200 mg/m(2), and epirubicin 30 mg/m(2); cycles were repeated
every 3 weeks. NETs are a heterogeneous group of neoplasms for which there is no
standard chemotherapy regimen or a standard time for initiation of chemotherapy. While
this regimen showed about a 30% response rate, more active regimens are needed [73].
b) A 37% total response rate was achieved in 32 patients with unresectable pancreatic
cancer, using regional delivery of mitomycin-C and fluorouracil followed by hemofiltration.
Prior to chemotherapy, extracorporeal hemofiltration was initiated and continued until 30
minutes after completion of drug administration. Chemotherapy was delivered via intraarterial infusion; mitomycin C 20 to 24 milligrams/square meter (mg/m(2)) was delivered
over 20 to 25 minutes, followed by fluorouracil 500 to 700 mg/m(2) over 10 minutes. After
3 treatments, mitoxantrone 20 to 25 mg/m(2) replaced fluorouracil in 9 patients. One
patient with Stage II/III localized disease was resected after treatment and remained
disease-free 14 months after surgery [74].
c) Combination chemotherapy regimens containing fluorouracil have demonstrated
minimal activity in advanced pancreatic cancer. Only 2 objective responses were obtained
in a phase II trial of prolonged continuous infusion fluorouracil plus subcutaneous
interferon-alfa 2b three times weekly [75].
d) Combination leucovorin as a 2-hour infusion followed by fluorouracil, and oral
hydroxyurea 6 hours later, produced partial responses in 12.5% of 40 chemotherapy-naive
85/317
25/10/12
patients with advanced disease, and had no advantage over fluorouracil monotherapy.
Median survival was only 5.8 months [71].
e) Fluorouracil plus folinic acid (leucovorin) achieved 1 partial response and fluorouracil
plus leucovorin plus ifosfamide resulted in 1 complete and 2 partial responses among 51
chemotherapy-naive patients with advanced pancreatic cancer. Response duration ranged
from 39 to 74 weeks. Hematologic toxicity was mild; however, one death occurred
following leukopenia and grade 4 diarrhea [76].
2) With Radiotherapy
a) The National Comprehensive Cancer Center (NCCN) Guidelines state that
chemoradiation is a popular conventional option for the management of unresectable
locoregional pancreatic cancer. In a study conducted by the Gastrointestinal Tumor Study
Group (GITSG; 1981), median survival was increased from 22.9 weeks to 42.2 weeks with
the use of fluorouracil and radiation therapy compared with radiation alone. The
combination of fluorouracil and split-course radiation (total dose 4000 centigray (cGy))
was compared with the combination of fluorouracil and 6000 cGy radiotherapy and with
radiotherapy alone [77].
b) In a phase II trial involving 20 patients with nonresectable pancreatic cancer, the
median progression-free survival and the median overall-survival was 4.9 months and 10.3
months, respectively. The chemoradiotherapy-regimen consisted of: (1) radiation therapy
50.4 gray (Gy) in 28 fractions over 5.5 weeks and (2) protracted infusion of 5-fluorouracil
200 milligrams/square meter/day (mg/m(2)/day) throughout radiotherapy. One week
after chemoradiotherapy, fluorouracil 500 mg/m(2) bolus was given weekly until disease
progression. Seventeen patients (85%) completed the scheduled chemoradiotherapy. Four
patients developed Grade 3 toxicities (nausea, vomiting, and mucositis); one patient
experienced Grade 3 hepatic toxicity, which recovered after terminating chemoradiation.
Partial response was achieved in 2 patients and disease was stable in 16 (80%) patients.
Death from cancer was documented in 14 [78].
c) The median survival was 8.5 months for 24 patients with locally advanced or locally
recurrent gastric (8 patients), pancreatic (11 patients) or extrapelvic colon cancer (5
patients) who were treated with fluorouracil, leucovorin, and radiation therapy. The
regimen consisted of: (1) 45 Gray (Gy) in 25 fractions of radiation, followed by 5.4 to 9 Gy
of radiation in 3 to 5 fractions; (2) oral leucovorin 10 milligrams/day; (3) continuous
infusion of fluorouracil 125 milligrams/square meter/day beginning on the first day of
radiation, and increasing the fluorouracil dose in 25-mg increments in subsequent
patients. Grade 4 (life-threatening) anorexia and nausea was observed in 6 patients
receiving 125 mg/m(2)/day of fluorouracil. Six of the 15 patients receiving 150 mg/m(2)
day experienced Grade 3 (severe) toxicity (vomiting, nausea, diarrhea, skin toxicity, handfoot syndrome, catheter-related infection, and stomatitis). This regimen was only
investigational and phase III trials must be done before using this regimen clinically [79].
d) The addition of epirubicin and cisplatin to combination fluorouracil and radiation did
NOT prolong survival in patients with locally advanced pancreatic cancer and is NOT
recommended for further study [70].
Carcinoma of penis
1) Overview
86/317
25/10/12

2) Summary:
In a retrospective study (n=208), combination therapy with 5-fluorouracil plus carbon
dioxide laser vaporization and interferon alfa-2a yielded the least number of treatment
failures compared with other standard therapies for the treatment of penile intraepithelial
neoplasia (PIN) [174].
In a retrospective case series of adult male patients with biopsy confirmed erythroplasia of
Queyrat (n=7), topical 5-fluorouracil therapy resulted in lesion clearing in all patients [175].
3) Adult:
a) In a retrospective study (n=208), combination therapy with 5-fluorouracil plus carbon
dioxide laser vaporization and interferon alfa-2a yielded the least number of treatment
failures compared with other standard therapies for the treatment of penile intraepithelial
neoplasia (PIN). Patients (n=208; age between 26 and 35 years, 81.81%; PIN I, n=101;
PIN II, n=40; PIN III, n=67) were treated with various combinations depending on the PIN
lesion: 5-fluorouracil 5% cream topically every night for 5 days (followed by 5 treatmentfree days) for 4 courses (n=19; PIN I only), carbon dioxide laser vaporization alone (n=33;
PIN II and III only), 5-fluorouracil topically (two 5-day courses) followed by carbon dioxide
vaporization (n=62; PIN I and III only), 5-fluorouracil topically (two 5-day courses) followed
by interferon alfa-2a 1.5 x 10(6) international units subQ daily for 6 days (low-dose; n=32;
PIN I and II only), carbon dioxide vaporization plus interferon alfa-2a 3 x 10(6) International
Units subQ daily for 6 days (high-dose, n=10; PIN I only), or 5-fluorouracil topically (two 5day courses) followed by carbon dioxide vaporization plus interferon alfa-2a high dose subQ
for 6 days (n=43; PIN I, II, and III). Treatment failure was defined as a recurrence within
the first year of therapy. Regardless of grade of lesion (among all patients), 5-fluorouracil
followed by carbon dioxide vaporization plus interferon alfa-2a high-dose resulted in the
lowest number of treatment failures (n=2/52), corresponding to a success rate of 96.15%.
This was followed by success rates of 87.09%, 80%, 68.75%, 54.54% and 36.84%,
respectively, for 5-fluorouracil followed by carbon dioxide vaporization, carbon dioxide
vaporization plus interferon alfa-2a high-dose, 5-fluorouracil followed by interferon alfa-2a
1.5 x 10(6) low dose, carbon dioxide laser vaporization alone, and 5-fluorouracil alone. For
patients with PIN I, the best treatment was 5-fluorouracil followed by carbon dioxide
vaporization plus interferon alfa-2a high-dose (100% success). For patients with PIN II,
there was no significant difference between treatments (p>0.05). For patients with PIN III,
the best treatment was 5-fluorouracil followed by carbon dioxide vaporization (96.29%
success). Recurrences of PIN 1 (n=7), PIN II (n=4), and PIN III (n=2) occurred in 3 to 6
months in patients who received 5-fluorouracil plus carbon dioxide laser vaporization, 5fluorouracil plus interferon alfa-2a low dose, and 5-fluorouracil plus carbon dioxide laser
vaporization plus interferon alfa-2a high dose, respectively. Adverse events of topical 5fluorouracil treatment included inflammation of the penis and scrotum, with or without
urethritis, 7 to 24 days following administration (14%). Inflammation subsided 2 to 4 weeks
87/317
later after treatment with chamomile washings [174].

b) In a retrospective case series of adult male patients with biopsy confirmed erythroplasia
of Queyrat (n=7), topical 5-fluorouracil therapy resulted in lesion clearing in all patients.
Patients (age range, 23 to 72 years; duration of lesions, 9 weeks to 10 years) applied 5fluorouracil 1% to 5% cream or liquid topically twice daily for 3 to 7 weeks. Lesion clearing
was noted after an average of 9 weeks (range, 4 to 17 weeks) following the beginning of 5fluorouracil therapy; additionally, biopsy in 4 patients revealed histologically normal
epidermis. After a follow-up of 3 to 70 months, no recurrences were reported [175].
Cervical cancer
1) Overview
2) Summary:
In Stage IIB to IVA disease, radiation plus fluorouracil-containing regimens yield high
response rates (97.6%) survival rates (66%) and 2- to 3-year disease-free survival rates
(56% to 97.6%) [103][104]
Fluorouracil with high-dose leucovorin yields poor response and undesirable toxicity; NOT
recommended [105]
3) Adult:
a) In a Phase III trial of 388 subjects with locally advanced stage IIB to IVA cervical
carcinoma, the combination of fluorouracil and cisplatin was superior to hydroxyurea alone
as an adjunct to radiation therapy. Cisplatin 50 milligrams/square meter/day (mg/m(2))
was administered 4 hours prior to radiation on days 1 and 29, while fluorouracil was dosed
at 1 gram/m(2)/day on days 2, 3, 4, 5, 30, 31, 32, and 33. Patients randomized to oral
hydroxyurea received 80 milligrams/kilogram/day twice weekly. The median duration of
therapy in both groups was 9 weeks. After a median follow-up of 8.7 years, the rates of
disease progression were 43% and 53% in the fluorouracil/cisplatin and hydroxyurea
groups, respectively. Corresponding overall mortality rates were 45% and 57% (p=0.018).
Relative risks for progression/death and mortality were 0.79 (90% confidence interval, 0.62
to 0.99) and 0.74 (90% CI, 0.58 to 0.95), respectively, both favoring the
fluorouracil/cisplatin regimen. The only statistically significant difference in toxicity was
more frequent/severe neutropenia with hydroxyurea (p less than 0.00001) [106].
b) Combined chemotherapy and radiation therapy (with brachytherapy) resulted in a 97.6%
complete response and 2-year overall disease-free survival of 97.6% in patients with Stage
IIB to IVA cervical cancer. All patients received external irradiation; some also received
intracavitary brachytherapy. Twenty-one patients received etoposide 100 milligrams/square
meter (mg/m(2)) over 1 hour, cisplatin 50 mg/m(2) over 2 hours, and bleomycin 50
mg/m(2) as a continuous infusion over 48 hours, repeated every 2 weeks for 3 planned
25/10/12
cycles. Another 21 patients received etoposide 50 mg/m(2), cisplatin 20 mg/m(2),

bleomycin 10 mg/m(2), and fluorouracil 800 mg/m(2) administered weekly as a continuous
infusion over 24 hours for 5 or 6 cycles [103].
c) In a phase II study, fluorouracil with high-dose leucovorin produced a response of 8.8%
and grade 3 or 4 toxicity in 30% of patients which makes this an unattractive regimen for
patients with recurrent squamous cell carcinoma of the cervix. Fifty patients were treated
with fluorouracil 370 milligrams/square meter (mg/m(2)) and leucovorin 200 mg/m(2) for 5
days every 4 weeks for 2 cycles; therapy was repeated every 5 weeks. Toxicity consisted of
granulocytopenia, anemia, thrombocytopenia, diarrhea, stomatitis, and nausea. Further
study of this regimen is NOT recommended since other regimens have produced higher
response rates [105].
d) External/intracavitary radiotherapy and concurrent chemotherapy with fluorouracil and
cisplatin resulted in 3-year disease-free survival in 56% and overall survival in 66% of
women with Stage IIIB cervical cancer. Fluorouracil 750 milligrams/square meter
(mg/m(2)) was administered as a continuous infusion on days 1 to 5 and days 15 to 19;
cisplatin 6 mg/m(2) was administered as a 30-minute infusion on days 8 to 12 and days 22
to 26. Chemotherapy was given concurrently with external radiation therapy. No grade 4
toxicity or deaths were reported [104].
Colorectal cancer, Adjuvant
1) Overview
2) Summary:
For adjuvant therapy, fluorouracil plus levamisole or leucovorin is recommended
Addition of oxaliplatin to adjuvant therapy with fluorouracil and leucovorin (FL) improved 3year disease-free survival and reduced the risk of relapse in patients with stage II/III colon
cancer [34]
For rectal cancer, adjuvant therapy consists of fluorouracil plus radiation; preoperative
chemo-radiotherapy more beneficial than postoperative chemoradiotherapy
3) Adult:
a) Important Note
1) an unexpectedly high death rate occurring within 60 days after the initiation of
treatment in patients receiving a regimen of irinotecan, fluorouracil, and leucovorin for
colorectal cancer was revealed in an interim analysis of data from two separate
cooperative-group clinical trials sponsored by the national cancer institute and conducted
throughout out the united states and canada. one trial of patients with metastatic colon
cancer compared the regimen of irinotecan, fluorouracil, and leucovorin (described by Saltz
89/317
25/10/12
et al, 2000) with a regimen of oxaliplatin, fluorouracil, and leucovorin and a regimen of
oxaliplatin and irinotecan. The other trial, an adjuvant study of patients with resected
stage III colon cancer, compared fluorouracil and leucovorin with the irinotecan,
fluorouracil, and leucovorin regimen. Dose modifications were made in both trials in an
attempt to ameliorate the toxicity of the regimen. Enrollment in both trials was suspended.
Common characteristics in the deaths of 12 of the 14 deaths in patients with advanced
disease included: dehydration (from diarrhea, nausea, and vomiting), neutropenia, and
sepsis. In the surgical adjuvant study, the reported causes of 14 deaths included
pulmonary emboli (n=3), sepsis (n=3), aspiration (n=3), myocardial infarction (n=1),
dehydration and neutropenia (n=1), cerebrovascular accident (n=1), bowel
ischemia/infarct (n=1), and unknown (n=1). The regimen should continue to be an option
in the treatment of patients with advanced colorectal cancer; an alternative is the FDAapproved infusional schedule described in the dosing section of this monograph. However,
vigilant monitoring of all patients who are receiving the combination of irinotecan,
fluorouracil, and leucovorin is recommended. specific clinical factors that increase the risk
of adverse effects have not been identified. [16].
2) It has been suggested that the early deaths reported by Sargent et al may be due to
the bolus administration of fluorouracil, leucovorin, and irinotecan. Three large ongoing
European trials have not reported an increased incidence of early deaths with infusional
fluorouracil, leucovorin, and irinotecan [17].
b) Clinical Trials
1) In a randomized, phase III trial, patients receiving oxaliplatin, fluorouracil, and
leucovorin (FLOX) for colon cancer had a better disease-free survival (DFS) rate at three
years than patients on fluorouracil and leucovorin alone (FULV) [abstract]. Patients
(n=2407) with stage II or III colon cancer were eligible. FULV was defined as bolus
fluorouracil 500 milligrams/square meter (mg/m(2)) intravenously (IV) and leucovorin 500
mg/m(2) IV weekly for six weeks of an 8-week cycle for three cycles. FLOX was the same
FULV regimen plus oxaliplatin 85 mg/m(2) IV on weeks 1, 3, and 5 for three, 8-week
cycles. Median follow-up was 34 months and the oxaliplatin protocol-stipulated cumulative
dose of 765 mg/m(2) was received by 73% of patients assigned to the FLOX arm. DFS at
three years was significantly greater in the FLOX group compared to FULV (76.5% and
71.6%, respectively; p=0.004) [powered at 89% to detect a 5.4% improvement in DFS].
The hazard ratio was calculated to be 0.79 (95% confidence interval, 0.67 to 0.93),
representing a 21% reduction in risk for the FLOX regimen. The global test to determine
interaction between treatment and tumor stages II and III was not significant (p=0.7).
Neurotoxicity (grade 3) was observed in 8% and 1% of FLOX and FULV patients,
respectively. Fifty-six patients in the FLOX arm experienced diarrhea and dehydration
requiring hospitalization, whereas there were 34 in the FULV arm. Overall, grade 3/4
toxicities were observed in 60 patients in the FLOX group and 50 patients in the FULV
group. While on treatment, there were 15 and 14 deaths in the FLOX and FULV groups,
respectively [33].
2) In a randomized, open-label phase III trial, the combination of oxaliplatin with
fluorouracil and leucovorin (FL) reduced the risk of relapse of colon cancer when compared
to FL alone. Eligible patients (n=2246) had previously undergone surgical resection of
stage II or III disease, had no prior anti-tumor therapy (including radiotherapy), and a
Karnofsky performance status score of at least 60. An intravenous (IV) bolus of fluorouracil
400 milligrams/square meter (mg/m(2)) was given followed by a 600 mg/m(2) 22-hour
90/317
25/10/12
infusion on days 1 and 2 of a 14-day cycle for 12 cycles. Fluorouracil was preceded by
leucovorin 200 mg/m(2). For those randomized to receive oxaliplatin, the dose was 85
mg/m(2) IV on day one of the cycle (given simultaneously with leucovorin). Each group
received a median of 12 cycles with a cumulative oxaliplatin dose of approximately 1020
mg/m(2)). At a median follow-up of 37.9 months, 21.1% of patients had died or relapsed
in the oxaliplatin group compared to 26.1% in the FL-only group. The hazard ratio (HR) for
recurrence was 0.77 (p=0.002), representing a reduction in risk relapse of 23%. At three
years, the probability of disease-free survival for those in the oxaliplatin group was 78.2%
(95% confidence interval (CI), 75.6% to 80.7%) and those receiving FL alone it was
72.9% (95% CI, 70.2% to 75.7%; p=0.002 for comparison between groups). Relapses of
the non-colorectal tumors type were disregarded in the analysis of disease-free survival.
For those with stage III disease in the oxaliplatin group, the HR for recurrence was 0.76
(95% CI, 0.62 to 0.92), and DFS at three years for this group was 72.2% compared to
65.3% for the FL-only group. For stage II disease, the HR for recurrence was 0.80 (95%
CI, 0.56 to 0.1.15) in the oxaliplatin group and DFS at three years for this group was 87%
compared to 84.3% for the FL-only group. The reduced risk of recurrence was similar in
patients with stage II and III disease when given oxaliplatin plus FL (p=0.77). One
hundred thirty-three patients had died from the treatment group at the primary analysis
cutoff date compared to 146 in the control group. The hazard ratio for death was 0.90
(95% CI, 0.71 to 1.13). Survival probability was 87.7% and 86.6% for the treatment and
control groups, respectively. Grade 3/4 paresthesia, neutropenia, neutropenia with fever or
infection, thrombocytopenia, nausea, diarrhea, vomiting, allergic reaction all occurred more
often in patients in the FL plus oxaliplatin group compared to FL only (all p values less than
0.001). The most common grade 3/4 adverse reactions in the treatment group were
neutropenia (41.1%), diarrhea (10.8%), nausea (5.1%), and vomiting (5.8%) [34].
3) Postoperative adjuvant chemotherapy with oral doxifluridine was as effective as
intravenous fluorouracil, improved quality of life, and was less toxic in 166 post curative
surgery patients with stage II/III advanced rectal cancer. The rate of recurrence was 6.5%
versus 12.1% (p=0.937) for doxifluridine and fluorouracil, respectively. Quality of life
scores were measured after the first, second, third, and sixth cycle of chemotherapy. A
nadir good quality of life score was noticed after the first cycle (49% versus 19.5%), which
increased after the second (72% versus 47%) and plateaued thereafter (79% versus
47%; 88% versus 52%) in both the doxifluridine and fluorouracil groups, respectively.
Patients were randomly assigned to either oral doxifluridine 700 milligrams per square
meter per day (mg/m(2)/d) plus oral leucovorin 20 mg/m(2)/d on days 1-21 followed by 1
week of rest every month or an intravenous bolus infusion of fluorouracil 450 mg/m(2)/d
with leucovorin 20 mg/m(2)/d for 5 consecutive days every month. Treatment continued
for 12 cycles. By the third cycle all patients were also receiving radiotherapy. Toxicities in
the doxifluridine and fluorouracil groups included grade I/II of nausea and vomiting (30%
versus 53%), anorexia (20% versus 18%), and abdominal pain (17% versus 9%).
Significant differences between the groups included all grades of diarrhea (39% versus
20%; p less than 0.05), with 3 patients being hospitalized secondary to electrolyte
imbalances, alopecia (14% versus 28%; p less than 0.05), and leukopenia (18% versus
41%; p less than 0.05), with no reports of grade III/IV leukopenia in the doxifluridine
group. Higher quality of life, comparable efficacy and less toxicities make the oral
doxifluridine and leucovorin regimen an alternative option for patients with advanced rectal
cancer [35].
4) No difference in disease-free survival (DFS) or overall survival (OS) was observed in a
comparison of adjuvant fluorouracil and levamisole with or without concomitant interferon
91/317
25/10/12
comparison of adjuvant fluorouracil and levamisole with or without concomitant interferon

alfa-2a in patients with colorectal cancer. Patients with stage II or III disease and an
Eastern Cooperative Oncology Group (ECOG) status of less than or equal to 2 were eligible
to participate in this prospective, randomized, double-blind trial. All patients received
levamisole 500 milligrams/square meter (mg/m(2)) over 2 hours and fluorouracil 600
mg/m(2) at mid-infusion every 6 weeks followed by a 2 week rest. The control group did
not receive interferon-alfa-2a (n=138). Patients randomized to receive interferon-alfa-2a
received 3 million units of interferon-alfa-2a 3 times a week for 1 year (n=141). No
difference in 3-year DFS was observed between the two groups (83.1% for control and
75.9% for interferon-alfa-2a). In addition, OS was not affected by the addition of
interferon-alfa-2a. Control therapy was associated with 23 deaths (16.7%) compared to
interferon-alfa-2a therapy with 30 deaths (21.3%). No significant difference in the
occurrence of severe toxicities was demonstrated between the two treatment groups [36].
5) No difference in clinical efficacy was observed in a prospective, randomized, doubleblind study of adjuvant fluorouracil with levamisole, high-dose folinic acid, low-dose folinic
acid, or alone in patients with colorectal cancer. The Quick And Simple And Reliable
(QUASAR) study enrolled almost 5,000 patients to compare various fluorouracil
chemotherapeutic regimens. Fluorouracil was administered to all patients as 30 doses of
370 milligrams/square meter (mg/m(2)). Patients randomized to receive folinic acid
received L-folinic acid and were either in the high-dose group at 175 mg (n=2464) or the
low-dose group at 25 mg (n=2463). Twenty-five mg of L-folinic acid is equivalent to 50 mg
DL-folinic acid. The remaining patients were given levamisole 50 mg 3 times daily for 3
days every 2 weeks for 12 courses (n=2429) or matching placebo (n=2434). Recurrence
rates, 3-year risk of recurrence, and 3-year survival were not different between the 2 folinic
acid groups. High-dose folinic acid was associated with slightly more deaths (801)
compared to the low-dose arm (775). Patients who received levamisole experienced a
greater risk of recurrence at 3 years (37.0%) than the placebo group (34.9%). More
deaths were reported in the levamisole arm (815) compared to the placebo arm (755). No
advantage of high-dose folinic acid or levamisole therapy was observed following subgroup
analysis. Levamisole therapy was associated with significantly more reports of toxic
dermatologic events (p less than 0.0001) and 20% more reports of nausea, vomiting, and
other toxic events than placebo. Most side effects reported were anticipated with the
respective chemotherapeutic regimens (Anon, 2000).
6) The addition of levamisole to a regimen of adjuvant fluorouracil plus leucovorin (FULV)
did not provide additional clinical benefit to patients with Dukes' B or C colon cancer.
Patients were randomized to receive FULV, fluorouracil+levamisole, or FULV+levamisole in
this prospective study. The FULV regimen consisted of six 8-week cycles of leucovorin 500
milligrams/square meter (mg/m(2)) over 2 hours weekly for 6 weeks and fluorouracil 500
mg/m(2) over 1 hour weekly for 6 weeks followed by 2 weeks of rest. The
fluorouracil+levamisole regimen consisted of fluorouracil 450 mg/m(2) daily for 5 days then
once weekly beginning on day 29 and levamisole 50 mg three times a day for 3 days
repeated every 14 days. The FULV+levamisole regimen received the same treatment as
the FULV patients and levamisole in the same dose used in the fluorouracil+levamisole
regimen. Efficacy was analyzed in 691 FULV patients, 691 fluorouracil+levamisole patients,
and 696 FULV+levamisole patients. Combination therapy with fluorouracil+levamisole was
associated with significantly longer disease-free survival than the FULV group (p=0.04).
Five-year disease-free survival was 65% in the FULV arm and 60% in the
fluorouracil+levamisole arm. The addition of levamisole to FULV treatment was not
associated with a survival advantage. Diarrhea was the major side effect reported in 92/317
25/10/12
associated with a survival advantage. Diarrhea was the major side effect reported in
patients who received leucovorin and stomatitis was more frequently reported in the
fluorouracil+levamisole group [37].
7) A pooled analysis of data from 5 studies in which 1016 subjects with B2 colon cancer
were randomized to fluorouracil plus leucovorin or observation alone after surgical
resection failed to demonstrate survival benefit after a median 5.75 years of follow-up.
Median event-free survival rates in the treatment and control groups were 76% and 73%,
respectively, while corresponding overall survival rates were 82% and 80%, respectively.
Adjusted and unadjusted hazards ratios for both outcome variables ranged from 0.81 to
0.88 and failed to reach statistical significance. These investigators concluded that a notreatment control arm is appropriate for this patient population [38]. In contrast, a pooled
analysis of 4 trials employing different chemotherapy regimens (ie,
semustine/vincristine/fluorouracil, fluorouracil via portal venous infusion,
fluorouracil/leucovorin with or without levamisole) after surgical resection found an overall
mortality reduction of 30% after 5 years follow-up with adjuvant therapy as compared to
observation alone in the subset with Dukes' B colon carcinoma (n=1565). These
investigators concluded that adjuvant chemotherapy should be considered for all such
patients, regardless of prognostic factors [39]. The conflicting conclusions presented here
highlight the limitations of retrospective analyses and the need for additional prospective
research to delineate the optimal management of Dukes' B colon cancer following surgical
resection.
For high-risk patients with complete resection of adenocarcinoma of the colon, 6 months
of chemotherapy was as effective as 12 months; however, the 3-drug regimen consisting
of fluorouracil plus leucovorin plus levamisole was superior to fluorouracil plus levamisole
[40].
(a) Fluorouracil plus levamisole arm: This regimen consisted of intravenous (IV) push
fluorouracil 450 milligrams/square meter/day (mg/m(2)) for 5 days followed by once
weekly administration beginning on day 29; oral levamisole 50 mg 3 times daily was
started on days 1 to 3 and was repeated every 2 weeks beginning on day 15.
(b) Fluorouracil plus levamisole and levamisole arm: This regimen consisted of IV push
fluorouracil 370 mg/m(2) on days 1 to 5; 5-day courses were repeated on day 29 and day
57 and then every 5 weeks. IV push levamisole 20 mg/m(2) was administered
immediately before fluorouracil on days 1 to 5 with re-treatment on day 29 and day 57 and
then every 5 weeks. Levamisole 50 mg 3 times daily was given on days 1 to 3 and days 15
to 17 of each treatment cycle.
Patients receiving each regimen were treated for 6 or 12 months. At 5-years median
follow-up, 60% and 70%, respectively, of patients receiving treatment for 6 months with
fluorouracil plus levamisole versus fluorouracil plus leucovorin plus levamisole were alive.
With 12 months of chemotherapy, survival was greater with triple versus double drug
therapy
8) In a randomized, multicenter trial involving 2176 patients with Dukes' stage B or C
colon cancer who had recently undergone curative resection, the addition of interferon alfa2a did not produce any significant benefits beyond that seen with fluorouracil plus
leucovorin [41]. Patients received six 28-day cycles. During the first 5 days of each cycle, a
bolus infusion of leucovorin 500 milligrams/square meter (mg/m(2)) intravenously over 30
minutes daily was administered followed 1 hour later by fluorouracil 270 mg/m(2) bolus
infusion (1088 patients). Patients assigned to the interferon arm received subcutaneous
93/317
25/10/12
interferon (5 x 10(6) Units/m(2)) 24 hours before the first dose of leucovorin, then daily
immediately before chemotherapy for the first 5 days of each cycle. A seventh dose of
interferon was administered in each cycle 24 hours after the last bolus dose of fluorouracil.
Toxicity was noted to increase with addition of interferon.
9) Adjuvant, high-dose leucovorin (FA) and fluorouracil improved event-free and overall
survival. Patients with histologic confirmation of Dukes B2 and C colon cancer were
randomly assigned to adjuvant treatment with fluorouracil 370 milligrams/square meter
(mg/m(2)) plus FA 200 mg/m(2) daily for 5 days every 4 weeks; 6 cycles were planned.
Since racemic FA was no longer available, the last 148 patients were treated with pure LFA at 100 mg/m(2). At 5 years, 66% and 54% of patients were alive without a recurrence
in the treatment and control group, respectively; similarly, 72% and 65% were alive in the
treatment and control group, respectively. Patients in the treatment group with Dukes B
had higher overall survival and event free survival than patients with Dukes C. At
randomization, 6 months, and 12 months, a quality-of-life questionnaire did NOT reveal any
significant differences between the treatment and control groups. Adjuvant FA and
fluorouracil is tolerated well and is effective for reducing recurrences and prolonging
survival in patients with colon cancer [42].
10) Surgery plus fluorouracil and leucovorin was superior to surgery alone in preventing
tumor relapse and improving survival in patients with colon cancer. All patients (n=309)
had complete resection of the primary tumor (Stage II or Stage III colon cancer) but were
at high-risk for tumor relapse. Patients were randomly assigned to surgery only or adjuvant
chemotherapy consisting of leucovorin 20 milligrams/square meter/day (mg/m(2))
followed by fluorouracil 425 mg/m(2)/day administered by intravenous push for 5
consecutive days. this regimen was repeated at 4 and 8 weeks and then every 5 weeks for
a total of 6 cycles. toxicity was tolerable and was managed by adjusting the dose of
fluorouracil. Response duration and survival were significantly longer (p=0.004 and p=0.02,
respectively) in patients receiving chemotherapy and surgery compared with those
undergoing surgery only [43].
11) A meta-analysis of published clinical trials and abstracts presented at the 1996
American Society of Clinical Oncology (ASCO) revealed that adjuvant treatment with highdose leucovorin/fluorouracil in patients with Dukes' stage B and C colorectal cancer
demonstrates significant improvements in disease-free survival (62% to 77%) and overall
survival (69% to 89%) compared to controls (58% to 64% and 63% to 77%,
respectively). In four randomized trials, high-dose leucovorin ranged from 200
milligrams/square meter (mg/m(2)) administered every day for 5 days to 500 mg/m(2)
weekly and fluorouracil dosage ranged from 350 to 425 mg/m(2) administered every day
for 5 days. In one trial, low-dose leucovorin (20 mg/m(2) and fluorouracil (425 mg/m(2))
was administered daily for 5 days. Diarrhea was the most common side effect associated
with high-dose leucovorin; whereas, stomatitis, diarrhea, and leukopenia were more
common in patients receiving low-dose leucovorin. In patients with Dukes' stage C
colorectal cancer, the results of these trials suggest that high-dose leucovorin/fluorouracil
is as effective as levamisole/fluorouracil [42].
a) With Radiotherapy
1) According to a randomized trial (n=799), preoperative chemoradiotherapy proved
advantageous compared to postoperative chemoradiotherapy in patients with stage T3 or
T4 or node-positive resectable rectal cancer; advantages included reduced local
recurrences, reduced toxicity, superior compliance, and an increased rate of sphincter
94/317
25/10/12
preservation in patients with low-lying tumors. However, survival benefits, either

progression-free or overall, were not significantly different comparing preoperative with
postoperative chemoradiotherapy. Radiotherapy consisted of a total of 5040 centi- Grays
(cGy) delivered in 28 fractions of 180 cGy, five times weekly. During the first and fifth
weeks of radiotherapy, fluorouracil was given as a 120-hour continuous infusion at a dose
of 1000 milligrams (mg) per square meter (m(2)) per day. Radiotherapy was identical in
both the preoperative and postoperative groups, except for a 540-cGy boost delivered to
the tumor bed in the postoperative group. Four cycles of bolus fluorouracil (500
mg/m(2)/day, five times weekly, every 4 weeks) were started 4 weeks after surgery in
the preoperative treatment group (PREOP group, n=415) or 4 weeks after
chemoradiotherapy in the postoperative treatment group (POSTOP group, n=384).
Surgery consisted of total mesorectal excision. Median follow-up was 45 months and 49
months in the PREOP and POSTOP groups, respectively. Overall 5-year survival rates
were 76% and 74%, respectively (p=0.80). Five-year cumulative incidence of local
relapse was 6% and 13% among those in the PREOP and POSTOP groups, respectively
(p=0.006). Acute toxicity of grade 3 or 4 severity occurred in 27% and 40% of the
PREOP- and POSTOP- treated subjects, respectively (p=0.001), while corresponding rates
of long-term toxicity were 14% and 24%, respectively (p=0.01) [44].
2) In an interim analysis of a prospective randomized phase-III trial, neoadjuvant
preoperative radiochemotherapy was well tolerated and effective compared to standard
postoperative adjuvant radiochemotherapy in patients with advanced operable rectal
cancer. A total of 628 patients with histologically confirmed stage II or III locally
advanced operable rectal cancer were randomized to receive postoperative
radiochemotherapy (n=310) or preoperative radiochemotherapy (n=318). Patients in the
postoperative radiochemotherapy group received chemotherapy within four weeks after
immediate surgery. Fluorouracil was administered as a 120-hour continuous infusion at a
dose of 1000 milligrams (mg)/square meter daily during the first and fifth week of
radiotherapy. Following concurrent radiochemotherapy, an additional four cycles of bolus
injection fluorouracil were administered at a dose of 500 mg/square meter daily for five
consecutive days every four weeks for a total of six cycles. Patients in both treatment
groups received radiotherapy to the tumor bed and pelvic lymph nodes at a total of 50.4
Gray (Gy) delivered in 28 fractions (single dose 1.8 Gy), with the postoperative study
group receiving an additional small-volume boost at 5.4 Gy for three days. In the
preoperative radiochemotherapy group, surgery was scheduled four to six weeks after
completion of an identical concurrent radiochemotherapy regimen and the four cycles of
fluorouracil bolus injections were to be started within three to four weeks following
surgery. The stratification according to surgeons involved was provided for, while surgery
techniques were standardized and quality-controlled. Complete toxicity data was
available for 162 and 230 patients in the postoperative and preoperative
radiochemotherapy study groups, respectively. The most common toxicity was Grade 3
diarrhea, occurring in 12% and 10% of the postoperative and preoperative
radiochemotherapy treatment groups, respectively. Grade 4 diarrhea was evident in 1%
of patients in both treatment groups. Other frequent toxicities included erythema,
leukopenia and nausea, with less than 3% of patients in each treatment group
experiencing grade 3 or greater leukopenia or nausea. Surgical mortality and morbidity
information was available for 280 postoperative radiochemotherapy group patients and
258 preoperative radiochemotherapy group patients. Overall postoperative complication
rates were similar between the two study groups, occurring in 34% and 34.5% of
95/317
25/10/12
patients in the postoperative and preoperative radiochemotherapy study groups,

respectively [45].
3) In a prospective randomized multicenter trial, adjuvant postoperative treatment with
fluorouracil plus leucovorin was well tolerated and significantly more effective than
fluorouracil plus levamisole in surgically curative stage III colon cancer patients. Among
the 702 patients enrolled, 680 (96.9%) patients were eligible to begin adjuvant treatment
within 42 days after tumor resection. Three hundred forty nine patients were randomized
to receive 12 cycles of leucovorin 100 milligrams (mg)/square meter plus fluorouracil 400
mg/square meter (increased to 450 mg/square meter after the first cycle) intravenously
(IV) over 30 minutes on days 1-5 every four weeks. Three hundred thirty one patients
were randomized to receive levamisole 50 mg orally three times daily for three days every
two weeks and fluorouracil 450 mg/square meter daily IV over 30 minutes for five days.
Twenty-eight days following the induction cycle, fluorouracil was administered once a
week for 44 weeks with four weekly infusions considered one chemotherapy cycle. After a
median follow- up time of 46.5 months, adjuvant therapy with fluorouracil plus leucovorin
demonstrated a significantly superior disease-free survival and overall survival on
univariate analysis compared with fluorouracil plus levamisole (p=0.037 and p=0.0089,
respectively). A multivariate proportional hazards model established a significant overall
survival advantage for the fluorouracil plus leucovorin treatment in comparison with the
fluorouracil plus levamisole treatment (p=0.0059). Relapse occurred in 117 (33.5%)
patients in the fluorouracil plus leucovorin group and in 130 (39.3%) patients in the
fluorouracil plus levamisole group after a median time of 15 and 12 months, respectively
(p=0.025). The total number of toxic reactions per chemotherapy course was higher but
not significant in the fluorouracil plus leucovorin group compared with the fluorouracil plus
levamisole group. Diarrhea, mucositis, and nausea/vomiting occurred in 22.9%, 13.8%,
and 36.1%, respectively, of patients receiving fluorouracil plus leucovorin compared with
13.6%, 4.5%, and 28.2%, respectively, of patients receiving fluorouracil plus levamisole
[46].
In patients with locally advanced rectal cancer, combination chemotherapy/radiotherapy
does NOT provide a significant advantage in disease-free or overall survival compared
with single-agent FLUOROURACIL with radiotherapy. This was a prospective, randomized
study involving 1696 chemotherapy- and radiotherapy-naive patients with a median
follow-up of 48 months. All patients received radiotherapy equal to 45 Gray (Gy; a unit of
absorbed radiation dose equal to 100 rads) delivered in daily treatments of 1.8 Gy over 5
weeks; a boost of 5.4 Gy also was given. Chemotherapy was delivered in 3 separate
regimens:
ARM 1:
Fluorouracil 500 milligrams/square meter (mg/m(2)) daily on days 1 through 5 and 29
through 33, and for 3 days during weeks 1 and 5 of radiation therapy. After
radiotherapy, fluorouracil 450 mg/m(2)/day on days 1 through 5 and 29 through 33.
ARM 2:
Fluorouracil 425 mg/m(2)/day with leucovorin 20 mg/m(2)/day on days 1 through 5 and
29 through 33, and for 4 days during weeks 1 and 5 of radiotherapy (but fluorouracil
dose reduced to 400 mg/m(2)/day). After radiotherapy, fluorouracil 380 mg/m(2)/day
and leucovorin 20 mg/m(2)/day on days 1 through 5 and 29 through 33.
96/317
25/10/12
ARM 3:
Fluorouracil 450 mg/m(2)/day on days 1 through 5 and 29 through 33 with levamisole
50 mg 3 times daily for 3 days every 2 weeks for 4 cycles. During radiation, fluorouracil
500 mg/m(2)/day for 3 days during weeks 1 and 5 without levamisole. After radiation, 2
cycles of fluorouracil 400 mg/m(2)/day on days 1 through 5 and 29 through 33 with 4
cycles of levamisole as above.
ARM 4:
Fluorouracil 425 mg/m(2)/day and leucovorin 20 mg/m(2)/day on days 1 through 5 and
29 through 33; levamisole was given as in arm 3. During radiation therapy, fluorouracil
400 mg/m(2)/day and leucovorin 20 mg/m(2)/day for 4 days during weeks 1 and 5.
After radiation, same regimen as before radiation, but fluorouracil dose reduced to 380
mg/m(2)/day
Levamisole plus fluorouracil provided no benefit versus fluorouracil alone; however, the
benefit with leucovorin and fluorouracil is possible and awaits long-term follow-up.
Toxicity affected primarily the gastrointestinal and hematologic systems; and was
greatest in the leucovorin-containing arm [47].
c) Bolus versus Continuous Infusion
1) A protracted infusion of fluorouracil was superior to a bolus injection when used as
adjuvant therapy in a study of 660 patients with Stage II or III rectal cancer. patients
received fluorouracil plus semustine or fluorouracil alone before and after radiation therapy.
In addition, patients received either intermittent bolus injections (n=332) or protracted
venous infusions (n=328) of fluorouracil during postoperative radiation of the pelvis. the
protracted infusion consisted of fluorouracil 225 milligrams/square meter (mg/m(2)) daily
via ambulatory infusion pump administered during the entire period of radiation therapy (5
weeks) or until severe chemotherapy-induced toxicity occurred. patients receiving bolus
fluorouracil received 500 mg/m(2) for 3 consecutive days during weeks 1 and 5 of radiation
therapy. patients receiving the protracted infusion had longer remission and an improved
survival versus patients receiving bolus injections. however, the patients receiving bolus
injections potentially received far less total fluorouracil than patients receiving protracted
infusions [48].
Colorectal cancer, Palliative
1) Overview
Recommendation: Adult, Class I
2) Summary:
Fluorouracil is indicated for palliative management of colorectal cancer [1]
97/317
25/10/12
Treatment with weekly irinotecan in combination with high-dose fluorouracil infusion

(FUIRI) was as effective as biweekly irinotecan plus fluorouracil and leucovorin (FOLFIRI)
as first-line treatment for patients with metastatic colorectal cancer in a multicenter,
prospective, randomized, phase 3 trial (n=346) [14]
The addition of oxaliplatin to therapy with leucovorin and fluorouracil for advanced
colorectal cancer (n=420) resulted in significantly longer progression-free survival (9.0
versus 6.2 months; p=0.0001) and better response rate (50% versus 21.9%; p=0.0001);
overall survival also increased, but not significantly (16.2 versus 14.7 months; p=0.12)
[15].
The combination of irinotecan, and bolus fluorouracil/ leucovorin (as described by Saltz et
al, 2000) was associated with an unexpectedly high death rate (2.5% to 3.5%) in one
study of patients with advanced colorectal cancer and one surgical adjuvant study [16] but
may be due to bolus versus infusional administration [17].
Intrahepatic arterial fluorouracil plus leucovorin (folinic acid) offered no survival benefit
compared to IV fluorouracil plus folinic acid in patients with colorectal cancer with
unresectable liver metastases (n=290) [18].
3) Adult:
a) Important Note
An unexpectedly high death rate occurring within 60 days after the initiation of treatment
in patients receiving a regimen of irinotecan, fluorouracil, and leucovorin for colorectal
cancer was revealed in an interim analysis of data from two separate cooperative-group
clinical trials sponsored by the National Cancer Institute and conducted throughout out the
United States and Canada. One trial of patients with metastatic colon cancer compared the
regimen of irinotecan, fluorouracil, and leucovorin (described by Saltz et al, 2000) with a
regimen of oxaliplatin, fluorouracil, and leucovorin and a regimen of oxaliplatin and
irinotecan. The other trial, an adjuvant study of patients with resected stage III colon
cancer, compared fluorouracil and leucovorin with the irinotecan, fluorouracil, and
leucovorin regimen. Dose modifications were made in both trials in an attempt to
ameliorate the toxicity of the regimen. Enrollment in both trials was suspended. Common
included: dehydration (from diarrhea, nausea, and vomiting), neutropenia, and sepsis. In
the surgical adjuvant study, the reported causes of 14 deaths included pulmonary emboli
(n=3), sepsis (n=3), aspiration (n=3), myocardial infarction (n=1), dehydration and
neutropenia (n=1), cerebrovascular accident (n=1), bowel ischemia/infarct (n=1), and
unknown (n=1). The regimen should continue to be an option in the treatment of patients
with advanced colorectal cancer; an alternative is the FDA-approved infusional schedule
described in the dosing section of this monograph. However, vigilant monitoring of all
patients who are receiving the combination of irinotecan, fluorouracil, and leucovorin is
recommended. Specific clinical factors that increase the risk of adverse effects have not
been identified. [16].
It has been suggested that the early deaths reported by Sargent et al may be due to the
bolus administration of fluorouracil, leucovorin, and irinotecan. Three large ongoing
European trials have not reported an increased incidence of early deaths with infusional
98/317
25/10/12
fluorouracil, leucovorin, and irinotecan [17].

In an outpatient, open-label, multicenter trial in patients with metastatic colorectal cancer
(n=46), the safety and efficacy of irinotecan and bolus fluorouracil/leucovorin (Saltz
regimen) were demonstrated [19]. An overall response rate of 35% was similar to that
established in the initial Saltz trial (39%), with the majority of patients tolerating the
regimen; severe gastrointestinal toxicity and thromboembolic events were rare and never
fatal. Close monitoring and early aggressive treatment are paramount.
b) Clinical Trials
1) In a multicenter, prospective, randomized, phase 3 trial (n=346), weekly irinotecan in
combination with high-dose fluorouracil (FUIRI) was as effective as biweekly irinotecan
plus fluorouracil and leucovorin (FOLFIRI) as first-line treatment for patients with
metastatic colorectal cancer. Patients (median age 63 years) with histologically confirmed
metastatic colorectal cancer (MCRC), chemotherapy naive or prior adjuvant chemotherapy
were randomized to receive either irinotecan 80 milligrams/square meter (mg/m(2))
intravenously (IV) infused over 30 minutes (min) followed immediately by fluorouracil 2250
mg/m(2) IV as a 48 hour (hr) continuous infusion administered weekly without rest periods
(FUIRI; n=173) or irinotecan 180 mg/m(2) IV infused over 90 min on day 1 with
fluorouracil 400 mg/m(2) bolus and 600 mg/m(2) as 22-hr continuous infusion, plus
leucovorin 200 mg/mg(2) on days 1 and 2, administered every 2 weeks (FOLFIRI; n=173).
For each arm, the treatment cycle lasted for 6 weeks and therapy was continued until
disease progression, severe toxicity, death, treatment refusal, or until the patient was lost
to follow-up. The median number of cycles administered was 4 (range, 1 cycle to 24
cycles) . The overall response rate for the patients who received FUIRI was 51% (95%
confidence interval (CI), 43% to 59%) compared with 57% of patients who received
FOLFIRI (95% CI, 49% to 64%) (p=0.2809). After a median follow-up of 17.2 months
(mo) 91% of the patients who received FUIRI and 92% of the patients who received
FOLFIRI had progressed or died. The median progression free survival was 8.4 mo (95%
CI, 7.1 mo to 9.1 mo) compared to 8.3 mo (95% CI, 7.3 mo to 8.9 mo) in the FUIRI arm
compared with the FOLFIRI arm, respectively (p=0.4339). For the patients in the FUIRI
arm, the median overall survival (OS) was 19.2 mo (95% CI, 17.4 mo to 23.8 mo)
compared to 21.6 mo (95% CI, 19.9 mo to 25.3 mo) in the FOLFIRI arm (p=0.2941).
Diarrhea (grade 3 or 4) occurred more frequently in the FUIRI arm compared to the
FOLFIRI arm (p less than 0.00001) and the FOLFIRI arm experienced neutropenia (grade 3
or 4) with a higher frequency compared to the FUIRI arm (p less than 0.00001). Four
deaths occurred in the FUIRI arm (therapy related septic shock (n=2), sudden death
(n=1), and diarrhea (n=1)) compared to 5 the FOLFIRI (therapy related sepsis (n=1) and
febrile neutropenia (n=1)) during the first 60 days [14].
2) In a multicenter phase 2 trial (n=31), triple drug therapy utilizing irinotecan, oxaliplatin,
and fluorouracil/leucovorin produced a 58.1% response rate, a 9-month median duration of
response, and a 13-month median time to disease progression, with manageable toxicity,
as first-time treatment of patients with inoperable metastatic colorectal cancer. After
median 11 months of follow-up, median survival time had not been reached, but projected
probability was 75% at 1 year. The study was conducted by the Greek Cooperative Group
for Colorectal Cancer. The chemotherapeutic regimen consisted of: irinotecan 150
milligrams/square meter (mg/m(2)) as a 30-minute intravenous (IV) infusion on day 1;
leucovorin given at a dose of 200 mg/m(2) as a 2-hour (hr) IV infusion, followed by
fluorouracil 400 mg/m(2) via IV bolus and then 600 mg/m(2) as a 22-hr continuous IV
99/317
25/10/12
infusion on days 2 and 3; oxaliplatin 65 mg/m(2) on day 2 was administered as a 2-hr IV

infusion in parallel with leucovorin dosing. Treatment was given every 2 weeks until
disease progression, unacceptable toxicity, or patient withdrawal. Of 31 subjects, 2 (6.5%)
experienced complete response and 16 (51.6%) partial response, for an overall response
rate of 58.1%. Eight subjects (25.8%) had stable disease and 5 (16.1%) had disease
progression. Of 14 patients who presented with abdominal pain, 12 reported relief of pain.
Most common adverse effects were diarrhea and neutropenia; 14 patients (45%) had
grade 3 to 4 neutropenia, and 2 of these developed febrile neutropenia, requiring
hospitalization and IV antibiotics. Ten patients (32%) suffered grade 3 to 4 diarrhea, 3
(9%) had grade 3 to 4 neurotoxicity, and 16 (52%) had grade 2 to 3 fatigue [20].
3) The addition of oxaliplatin to therapy with leucovorin and fluorouracil for advanced
colorectal cancer (n=420) resulted in significantly longer progression-free survival (9.0
versus 6.2 months; p=0.0001) and better response rate (50% versus 21.9%; p=0.0001);
overall survival also increased, but not significantly (16.2 versus 14.7 months; p=0.12).
Patients with adenocarcinoma of the colon or rectum with unresectable metastases were
included; any previous adjuvant chemotherapy must have been completed at least 6
months prior to study entrance. In both arms of the study, a 2-hour infusion of leucovorin
(200 milligrams(mg)/square meter(m(2))/day) followed by fluorouracil (bolus of 400
mg/m(2)/day and 22-hour infusion of 600 mg/m(2)/day) was administered for 2
consecutive days every 2 weeks. In the oxaliplatin arm, a 2-hour infusion of oxaliplatin (85
mg/m(2) on day 1 only) was administered concurrently with leucovorin; antiemetic
prophylaxis was administered only to patients in the oxaliplatin arm. Toxicity was more
common in patients receiving oxaliplatin and included Grade 3/4 neutropenia (41.7%
versus 5.3%; p less than 0.001), grade 3 neurotoxicity (18.2% versus 0.0%; p less than
0.001), grade 3/4 diarrhea (11.9% versus 5.3%; p=0.015), and grade 3/4 mucositis (5.8%
versus 1.5%; p=0.019) [15].
4) Dose optimization of fluorouracil using pharmacokinetic monitoring improved the overall
response rate (43.4%), median recurrence-free survival duration (11 months), and median
survival duration (19 months). In this open study, patients (n=152) with metastatic colon
or rectal cancer were treated with an initial dose of fluorouracil 1300 milligrams/square
meter (mg/m(2)) weekly administered as an 8-hour continuous infusion with leucovorin
200 mg/m(2) administered immediately before and 4 hours into the infusion. Subsequent
doses were adjusted to obtain a therapeutic plasma concentration between 2000 and 3000
micrograms/liter (mcg/L) and to minimize toxicity. The mean dosage of fluorouracil after 3
months was 1803 mg/m(2). Dosage adjustments were required for all but 6 of 152
patients with 58 patients requiring at least a 50% increase in dose; whereas, 14 patients
required an immediate reduction in dose due to toxicity. A significant (p=0.029) correlation
was identified between response and the number of cycles required to reach optimal
plasma concentrations; patients with disease control reached the optimal dose within 1 to
3 courses. In this study, fluorouracil doses required to reach therapeutic plasma
concentrations varied widely; response rates and survival were higher than reported
previously. Additional, controlled studies of pharmacokinetic dosage adjustment are
needed to verify the positive results obtained [21].
5) Double biochemical modulation of fluorouracil with methotrexate and levo-folinic acid
(LFA) was administered to 94 patients with advanced digestive tract malignancies,
involving the colon-rectum, stomach, or biliary tract. Patients received methotrexate 500
milligrams/square meter (mg/m(2)) as a 2-hour infusion on day 1, followed by LFA 250
100/317
mg/m(2) as a 2-hour infusion and fluorouracil 600 mg/m(2) bolus on day 2, with cycles
every 2 weeks until tumor progression (maximum, 24 courses). The study identified that a
24-hour methotrexate serum concentration greater than 2 micromoles was significantly
predictive of response (37% versus 5%), longer progression-free survival (5.3 versus 2.3
months), and overall survival (10.8 versus 8.3 months). Responses were correlated with a
24-hour methotrexate level above 2 micromoles in 31% of previously treated colorectal
patients and in 38% of chemotherapy-naive colorectal patients [22].
6) Of 36 patients with gastric or colorectal adenocarcinoma and progressive disease, 3%
achieved a complete response and 27% a partial response following treatment with
leucovorin 500 milligrams/square meter (mg/m(2)) over 2 hours, fluorouracil 600 mg/m(2)
bolus after the first hour of leucovorin infusion, and hydroxyurea 35 mg/kilogram/day
divided and given every 8 hours starting 6 hours after fluorouracil. treatment was
administered weekly for 6 weeks followed by a 2-week rest. mean response duration was
21 weeks, median survival was 28 weeks. twenty-four patients were treated previously
with chemotherapy including leucovorin, fluorouracil, cisplatin, or epirubicin [23].
7) The addition of azidothymidine greater than or equal to 6 grams/square meter (g/m(2))
to combination fluorouracil and leucovorin produced an overall response rate of 44% in
previously untreated patients with metastatic colorectal adenocarcinoma. Thirty-five
patients received standard-dose fluorouracil and leucovorin followed by zidovudine in doses
ranging from 0.5 to 10 g/m(2) (90-minute infusion for doses of 7 g/m(2) or less; 120minute infusion for higher doses) for a maximum of 26 to 34 weeks (median, 24). Of 34
assessable patients, 15% had a complete response and 29% had a partial response within
a median of 8 weeks. Median response duration was 44 weeks and complete responses
lasted 50 to 76 weeks. There was a slight zidovudine dose-response relationship: overall
response was 54.5% in patients who received at least 7 g/m(2), and 33% in patients
receiving 2 g/m(2) or less. Six patients (17%) had severe diarrhea. Dose-related
hypotension occurred in all 11 patients receiving zidovudine 7 to 10 g/m(2). The
investigators recommend an zidovudine dose of 8 grams/m(2) with this combination [24].
8) The combination of fluorouracil, leucovorin, and oxaliplatin effectively downstaged
initially unresectable colorectal liver metastases so that aggressive surgical resection could
be performed. A total of 53% of 33 patients responded to fluorouracil 700 to 1200
milligrams/square meter (mg/m(2)) daily, leucovorin 300 mg/m(2)/day, and oxaliplatin 25
mg/m(2)/day for 4 to 5 days, administered via time/dose pump infusion and repeated
every 2 to 3 weeks. This technique achieved a 5-year disease-free survival in 36% of
patients, which is comparable to primary liver resections for colorectal metastases [25].
c) Routes of Administration
1) Bolus versus Continuous Infusion
a) In a meta-analysis of controlled studies (n=7) of patients (n=1219) with metastatic
colorectal cancer, fluorouracil administered as a continuous infusion versus a bolus
injection demonstrated a higher tumor response (22% versus 14%) and a better median
survival advantage (12.1 months versus 11.3 months). Grade 3 or 4 toxicity was primarily
hematologic with bolus administration versus the hand-foot syndrome with the continuous
infusion. The dosage of fluorouracil administered via continuous infusion ranged from 200
to 750 milligrams/square meter/day (mg/m(2)); the duration varied from 5 days per cycle
to continuous infusion without interruption. For bolus administration, the dosage ranged
from 400 to 600 mg/m(2) for 5 days; repeat courses were administered from every 7 to
101/317
25/10/12
35 days. In most trials, patients randomized to continuous infusions received 2 to 3 times

more fluorouracil than with bolus injection. Although not directly comparable due to
potential differences in patient condition, the response rates obtained with administration
via continuous infusion were similar to those achieved with fluorouracil plus leucovorin
[26].
b) In patients with metastatic colorectal cancer, combination therapy with low-dose
intravenous leucovorin plus fluorouracil given by bolus injections was more effective in
decreasing tumor size than high-dose fluorouracil as a continuous infusion (CI); however,
there was no significant difference between the 2 regimens with regard to patient
survival, time to progression, or toxicity [27]. In a randomized trial, 306 consecutive
patients with histologically proven colorectal cancer received either of two drug regimens:
Arm A: intravenous leucovorin 20 milligrams/square meter (mg/m(2)/day) by bolus
injection followed immediately by fluorouracil 425 mg/m(2)/day by rapid intravenous
infusion, repeated for 5 consecutive days every 4 weeks for 2 cycles then every 5 weeks
thereafter (151 patients); Arm B: fluorouracil 3.5 grams(g)/m(2) in 500 milliliters (mL) of
normal saline over 48 hours every week (155 patients). Patients were well matched with
regard to age, sex, primary tumor site, site of metastases, tumor stage, and performance
status. The median number of courses was 5 (range of 1 to 22; fluorouracil dose intensity
of 0.53 g/m(2)/week) in Arm A and 18 (range of 1 to 27; fluorouracil dose intensity of 3.1
g/m(2)/week) in Arm B. The overall objective response rate was 19.2% for the modulated
regimen and 30.3% for the continuous infusion schedule (p less than 0.05). The median
time to progression and overall survival for Arm A was 23.5 weeks and 42 weeks,
respectively; for Arm B, 25 and 48 weeks, respectively (p=ns). Toxicities were similar.
c) One phase II study demonstrated that a fluorouracil bolus can safely be replaced by a
fluorouracil infusion at a higher dose. a combination of leucovorin and fluorouracil
continuous infusion was found to have lower toxicity, permitting its use in combination
with other drugs. the study was performed in 101 patients with advanced colorectal
carcinoma. a 2-hour infusion of leucovorin 500 milligrams/square meter (mg/m(2)) was
given on 2 consecutive days and a 48-hour infusion of fluorouracil (1.5 to 2 grams/m(2)
per 24 hours was started on day 1 of leucovorin treatment; this regimen was repeated
every 2 weeks until evidence of progression. The overall response rate was 33.7% with
15% of patients experiencing Grade 3 to 4 toxicity. Median progression-free survival was 8
months, and median survival was 18 months [28].
2) Hepatic Arterial Infusion
a) In a multicenter, randomized study, arterial fluorouracil plus leucovorin (folinic acid)
offered no progression-free or overall survival advantage compared to intravenous
fluorouracil plus folinic acid in patients with colorectal cancer with unresectable
metastases confined to the liver. Patients (n=290) were randomly assigned to receive
fluorouracil by either the intravenous (IV) or intrahepatic arterial (IHA) route. In the IHA
group (n=145), folinic acid (200 milligrams per square meter (mg/m(2)), maximum 350
mg) IV over 2 hours, followed by 400 mg/m(2) fluorouracil IHA infusion in 100 milliliters
(mL) saline over 15 minutes and fluorouracil 1600 mg/m(2) over 22 hours, on day 1 and 2,
was administered every 14 days. The IV group (n=145) received folinic acid 200 mg/m(2)
(maximum 350 mg) IV over 2 hours, then fluorouracil 400 mg/m(2) IV bolus and
fluorouracil 600 mg/m(2) IV infusion over 22 hours, on day 1 and 2, every 14 days (de
Gramont regimen). Analysis was based on the intention to treat population. Thirty of 145
(22%) patients in the IHA group could not start treatment due to catheter problems
(abnormal vasculature or catheter malfunction); 36%
of all IHA patients experienced

102/317
25/10/12
(abnormal vasculature or catheter malfunction); 36% of all IHA patients experienced

catheter thrombosis and 14% were unable to complete at least 6 cycles of IHA treatment
for this reason. Only 38% of IHA patients received 6 or more chemotherapy cycles; of the
patients who did not start treatment or received fewer than 6 cycles, 45 (51%) switched
to the IV regimen. No significant differences were seen in progression-free survival (PFS)
or overall survival (OS) between the groups. Median PFS was 7.7 months and 6.7 months,
and median OS was 14.7 months and 14.8 months for the IHA and IV groups, respectively.
Twelve weeks after the start of chemotherapy, response rates were 22% and 19% in the
IHA and IV groups, respectively. No group differences were reported for serious adverse
events (grades 3 or 4). A higher number of early deaths was observed in the IHA group
(23% by 12 weeks after start of chemotherapy, versus 9% in IV group). The delay in
starting chemotherapy in the IHA group while patients waited for laparotomy for catheter
insertion might account for this difference (median time from randomization to start of
chemotherapy, 14 days in IV group versus 35 days in IHA group). The authors do NOT
recommend use of the IHA regimen for unresectable metastatic colorectal cancer outside
of a clinical trial setting [18].
b) Planned interim analysis of a randomized trial using adjuvant hepatic arterial infusion
(HAI) of fluorouracil plus folinic acid versus surgery alone in patients with radical resection
of colorectal liver metastases did not show clinical benefit with chemotherapy and
resulted in early termination of the study. The chemotherapy regimen was given every 28
days and consisted of fluorouracil 1000 milligrams/square meter (mg/m(2)) daily for 5
days as a 24-hour continuous HAI plus folinic acid 200 mg/m(2)/day for 5 days over 10
minutes. One hundred twenty-nine patients with follow-up of at least 18 months were
assessed for tumor recurrence (adjuvant therapy n=69, resection only n=60). Relapse
rates at 18 months were not different between the two groups with a rate of 33.3% in the
chemotherapy group compared to 36.7% in control. Chemotherapy was associated with a
median survival time of 34.5 months compared to 40.8 months for the resection only
group. Using the intent-to-treat analysis, an increase in the risk of death in the
chemotherapy arm was observed. The most frequently reported adverse events in the
chemotherapy arm were stomatitis, nausea, skin reaction, alopecia, pain, and diarrhea
[29].
c) Adjuvant portal-vein infusion of fluorouracil with heparin is NOT recommended as the
only adjuvant treatment for patients with colorectal cancer at risk for recurrence. Patients
(n=1232) with histologically confirmed colon or rectal cancer and no evidence of distant
metastases were randomly assigned to surgery only or surgery plus continuous infusion of
fluorouracil 500 milligrams/square meter per 24 hours and heparin 5000 International
Units for 7 days. The infusion was made into the portal vein and began as soon as
catheter placement was confirmed. Radiotherapy was permitted in patients with rectal
cancer but only 39 patients with Dukes C tumors received adjuvant systemic
chemotherapy. Overall survival was similar for both treatment groups. Univariate analysis
showed a poorer prognosis for older patients (p less than 0.01), men (p less than 0.01),
patients with rectal cancer (p=0.02), and patients with more advanced stage (p less than
0.01); none of these factors showed a significant interaction with treatment. This study
did NOT exclude a small benefit if this therapy is used with mitomycin or with systemic
chemotherapy [30].
d) A combination of floxuridine alternating with fluorouracil administered by hepatic artery
infusion (HAI) resulted in a 54.4% overall response rate (6 complete) among 57 patients
103/317
25/10/12
with nonresectable colorectal cancer and liver metastases. Median survival was 18
months and 3 of the 6 complete responders were alive and disease-free at 14 to 71
months. Treatment consisted of floxuridine 0.1 milligram/kilogram/day (mg/kg/day) for 7
days and fluorouracil 15 mg/kg on days 15, 22, and 29 administered via HAI. This cycle
was repeated every 35 days. Toxicity consisted of elevated alkaline phosphatase or
bilirubin requiring interruption of floxuridine (24.6%), biliary sclerosis (3.5%), and
systemic side effects (8.8%) (ie, nausea, vomiting, diarrhea, thrombocytopenia). The
majority of patients (82.4%) maintained normal work and home activities during
treatment [31].
3) Intraperitoneal
a) Cytoreductive surgery and intraperitoneal chemotherapy in patients with peritoneal
carcinomatosis secondary to colon cancer resulted in a 23% disease-free survival and a
16% survival with disease at a median follow-up of 12 months. Long-term survival was
statistically correlated with no tumor or distant tumor less than 5 cm (p=0.0001),
involvement of 1 or 2 abdominopelvic regions (p=0.0001), histopathology-intestinal type
adenocarcinoma (p=0.012), and complete cytoreduction (p=0.0001). During cytoreductive
surgery, a Tenckhoff catheter was placed for administration of intraperitoneal
chemotherapy on postoperative days 1 to 5. Mitomycin 10 to 12 milligrams/square meter
in 1 L of dextrose 1.5% was instilled by gravity on postoperative day 1 and drained after
23 hours. fluorouracil 15 milligrams/kilogram added to 1 L of dialysis fluid (buffered with
sodium bicarbonate 50 mEq/L) was instilled on postoperative days 2 to 5 and drained
after 23 hours each day [32].
Condyloma acuminatum
1) Overview
2) Summary:
In women with vaginal condylomas, intravaginal fluorouracil 1% gel cured significantly more
women than placebo (83.3% vs 13.3%) in a randomized, placebo-controlled, double-blind
trial (n=60) [107].
In men with flat or acuminata condylomata, cures were reported in 76.6% of subjects who
were treated with fluorouracil 5% cream in a randomized, controlled trial (n=505) [108].
3) Adult:
a) Intravaginal fluorouracil 1% gel cured significantly more women with vaginal condylomas
than placebo in a randomized, placebo-controlled, double-blind trial (n=60), Women (mean
age, 24.6 years) with vaginal condylomas (mean, 5.2 warts/patient) were randomized to
fluorouracil 1% hydrophilic gel (n=30) or to placebo gel (n=30) administered intravaginally
at bedtime 3 times/week (days 1, 3, 5) for 4 weeks; women were instructed to refrain from
sexual intercourse during the 4-week treatment period.
Women with external condylomas,

104/317
25/10/12
sexual intercourse during the 4-week treatment period. Women with external condylomas,
women who had used immunosuppressive or topical antiviral medication within 2 months,
and women who had received treatment for intravaginal warts within 8 weeks were
excluded. Preparation of 1% fluorouracil hydrophilic gel incorporated 1% fluorouracil by
weight into hydroxyethylcellulose Natrosol(R) 1% solution in distilled water. After 4 weeks,
cure (total elimination of vaginal warts with no signs of infection by colposcopy and
negative human papillomavirus (HPV) DNA) was achieved by 83.3% of women and 87% of
lesions in the fluorouracil group and 13.3% of women and 14% of lesions in the placebo
group (p less than 0.0001). Adverse effects in the fluorouracil group and the placebo group,
respectively, included erythema (3 and 0 patients), erosion (4 and 1 patients), edema (4
and 0 patients), and relapse after 8 months (2 and 1 patients) [107].
b) Fluorouracil 5% cream cured 75.75% of men with condyloma acuminata, 81.41% of
men with flat condylomata, and 51.72% of men with combined flat and acuminata
condylomata in a randomized, controlled trial (n=505). Nonimmunosuppressed men (62%
between 21 and 30 years old; sexual partners of women with flat condylomata,
condylomata acuminata, or cervical intraepithelial neoplasia) who had human
papillomavirus (HPV) lesions identified on peoscopy were assigned to 1 of 3 treatment
groups: condylomata acuminata (n=102), flat condylomata (n=325), or combination of flat
and acuminata condylomata (n=78). Men in each treatment group were randomized to 1 of
4 to 6 treatments (see Table). The fluorouracil treatment consisted of topical application of
fluorouracil 5% cream in the condylomatous region (preceded by an application of vaseline
oxide de zinc 10% to the area) every night for 5 consecutive nights; if no response,
treatment continued for 3 more courses of 5 days of treatment followed by 5 days without
treatment. The carbon dioxide (CO2) laser + fluorouracil treatment was two 5-day courses
of topical fluorouracil followed by CO2 laser vaporization. The fluorouracil + low-dose
interferon alfa-2a treatment was two 5-day courses of topical fluorouracil followed by
interferon alfa-2a 1.5 x 10(6) international units subQ daily for 6 consecutive days. The
fluorouracil + high-dose interferon alfa-2a treatment was two 5-day courses of topical
fluorouracil followed by interferon alfa-2a 3 x 10(6) international units subQ abdominally
daily for 6 consecutive days. The CO2 laser vaporization + fluorouracil + high-dose
interferon alfa-2a consisted of two 5-day courses of topical fluorouracil followed by CO2
laser vaporization and interferon alfa-2a 3 x 10(6) international units subQ daily for 6
consecutive days. After a mean follow-up of 18.05 months (range, 6 to 49 months), CO2
laser vaporization + fluorouracil + high-dose interferon alfa-2a was the best treatment
(proportion of men without 1-year recurrence) for condyloma acuminata (100%) and
combined flat and acuminata condylomata (81.25%), and CO2 laser + fluorouracil was the
best treatment for flat condylomata (100%)(see Table). Adverse effects occurred in
73.96% of patients at initiation of therapy with interferon alfa-2a and included fever, chills,
fatigue, and malaise. Mild pain was reported by 4% of patients during laser therapy. Acute,
erosive chemoinflammation of the penis or scrotum with or without urethritis occurred in
11% of patients who received fluorouracil [108].
Table: Proportion of Men Without a Recurrence Within 1 Year
Condyloma
Flat
Combined
Acuminata Condylomata
Fluorouracil
CO2 laser vaporization
75.75%
(n=33)
81.41%
(n=156)
66.66%
69.23%
(n=12)
(n=39)
Total
51.72% 76.6%
(n=29) (n=218)
30%
57.74%
(n=20)
(n=71)
105/317
25/10/12
(n=12)
(n=39)
(n=20)
(n=71)
CO2 laser + fluorouracil
n=0
100%
(n=34)
53.84%
(n=13)
87.23%
(n=47)
Fluorouracil + low-dose
interferon alfa-2a
74.07%
(n=27)
88.88%
(n=18)
n=0
80%
(n=45)
Fluorouracil + high-dose
interferon alfa-2a
n=0
98.2%
(n=58)
n=0
98.27%
(n=58)
CO2 laser vaporization +

fluorouracil + high-dose
interferon alfa-2a
100%
(n=30)
95% (n=20)
81.25%
(n=16)
93.93%
(n=66)
CO2, carbon dioxide
c) In a randomized, controlled trial, penile and urethral condylomata acuminata was cured
in 6 of 18 men who were treated with 5% fluorouracil cream and 10 of 19 men who were
treated with podophyllin. Men (n=42) with condylomata acuminata (mean age, 24 years;
range, 19 to 36 years; no treatment for genital warts within previous 6 months) were
randomized to self-applied topical application of 5% fluorouracil cream every evening for 2
weeks (n=18) or to physician-administered 25% podophyllin once weekly for 4 weeks
(n=19). Patients were advised to refrain from sexual intercourse during the 4-week
treatment period and to use a condom during the follow-up period. Four weeks after start
of treatment, cures were achieved by 10/18 men in the fluorouracil group and 11/19 men in
the podophyllin group. At the final visit (mean follow-up, 5.8 months; range, 4 to 9
months), cures were recorded in 6/18 men in the fluorouracil group and 10/19 men in the
podophyllin group. Adverse effects were reported in 55% of the fluorouracil group and
included erythema, itching, and superficial painful ulcerations. Adverse effects with
podophyllin were small erosions on the glans after the third application in 1 patient [109].
Esophageal cancer
1) Overview
2) Summary:
Although chemotherapy has only moderate activity, specific drugs or combination drug
regimens of choice are recommended by the Medical Letter consultants. The preferred
regimen is cisplatin plus fluorouracil. alternative single-agent therapies include either
doxorubicin, paclitaxel, methotrexate, or mitomycin. These recommendations do not imply
that these agents have been approved for use in this indication by the U.S. Food & Drug
Administration (Anon, 1997). Regardless of therapy, the 5-year survival rate for esophageal
carcinoma remains approximately 5%; however, approximately 60% of patients will receive
palliative benefit from combined radiation and chemotherapy (Braunwald et al, 1987; Skeel,
1991; Holleb et al, 1991). A major goal in the treatment of esophageal cancer is restoration
106/317
25/10/12
and long-term maintenance of the swallowing function. High-dose radiation and

chemotherapy resulted in rapid improvement in dysphagia with restoration of normal
swallowing in 120 patients. Patients with locally controlled disease and distant metastases
are candidates for systemic chemotherapy, usually with radiotherapy (Coia et al, 1993).
3) Adult:
a) Preoperative Chemoradiation vs Surgery Alone: The addition of a preoperative
chemoradiation regimen offered no statistical survival advantage over surgery alone in a
randomized trial of 100 patients with previously untreated locoregional adenocarcinoma
(n=75) or squamous cell carcinoma (n=25) of the esophagus. Chemoradiation consisted of
cisplatin 20 milligrams/square meter (mg/m(2))/day as a continuous infusion on days 1
through 5 and days 17 through 21; fluorouracil 300 mg/m(2)/day as a continuous infusion
on days 1 through 21; vinblastine 1 mg/m(2)/day on days 1 through 4 and days 17 through
20; and twice- daily radiation on days 1 through 5, 8 through 12 and 15 through 19 for a
total dose of 45 Gy. On day 42, subjects underwent transhiatal esophagectomy. Forty-five
patients in each arm obtained complete surgical resection of the carcinoma. The median
survival in the preoperative chemoradiation and surgery-only groups were 16.9 and 17.6
months, respectively (p=NS). Corresponding 1-year (72% versus 58%) and 3-year (30%
versus 16%) survival rates did not differ statistically. This trial was powered to detect only
large overall survival differences. Significant negative independent prognostic factors
included tumor size greater than 5 centimeters, squamous cell histology and age over 70
years. Of the subset (n=14) who attained complete histologic response to the preoperative
regimen, 86% and 64% were alive at 1 year and 3 years, respectively (median survival:
49.7 months) [115].
b) Seven (12%) complete and 22 (36%) partial responses were achieved in patients
receiving paclitaxel, cisplatin, and fluorouracil for squamous cell (n=31) or adenocarcinoma
(n=30) of the esophagus. The regimen consisted of paclitaxel 175 milligrams/square meter
(mg/m(2)) on day 1, cisplatin 20 mg/m(2) on days 1 through 5 (attenuated to 15 mg/m(2)
after cycle 3), and a continuous infusion of fluorouracil on days 1 through 5 at a dose of
1000 mg/m(2) in the first 10 patients and an attenuated dose of 750 mg/m(2) in the
remaining 51 patients. Cycles were repeated every 28 days. Complete responses were
significantly higher in patients with squamous cell carcinoma than in patients with
adenocarcinoma (20% versus 3%; p=0.04 Chi squared). However, response duration and
median survival were comparable between the two groups. Complete responses were
durable for up to 15 months, partial responses for up to 18 months. The overall median
survival duration was 10.8 months, and 2 patients were alive at more than 2 years, one
without relapse. High-grade hematologic toxicities were manageable with dose reduction,
but 11 patients (18%) had a debilitating peripheral neuropathy, which was an unexpected
side effect. Generalized fatigue of grade 3 or higher severity occurred in 35% of patients
[116].
c) Complete response was observed in 44% of 32 eligible patients with locoregional
esophageal carcinoma receiving a regimen of radiotherapy, continuous fluorouracil, and
cisplatin. Patients underwent radiotherapy for 5 weeks, accompanied by continuous
fluorouracil 250 milligrams/square meter (mg/m(2)) daily, and cisplatin 25 mg/m(2)/day on
days 1 through 3 during weeks 1 and 4. Following completion of radiotherapy, patients
received additional cisplatin 75 mg/m(2) on day 1 of weeks 7 and 11, and continuous
fluorouracil 300 mg/m(2)/day for 21 days during weeks 7 through 9 and weeks 11 through
107/317
25/10/12
13. Median survival was 20 months and the 1-year survival rate was 59%. This regimen
was associated with severe toxicity, dose delays and reductions, and 4 early deaths. As a
result, investigators question the utility of this complex and toxic regimen [117].
d) In an open study, 8 (30%) of 27 patients with esophageal or stomach cancer treated
with epirubicin, cisplatin, and fluorouracil followed by surgery were alive at a median of 36
months; only 1 patient had recurrent disease. Symptoms improved in 62% of patients,
objective responses occurred in 56%. Eleven patients underwent surgical resection.
Patients received a maximum of 4 courses of chemotherapy before surgery: epirubicin 50
milligrams/square meter (mg/m(2)) and cisplatin 60 mg/m(2) administered every 3 weeks.
fluorouracil 200 mg/m(2)/day was administered as a continuous infusion via an ambulatory
pump for 12 weeks. Dosage adjustments were necessary for myelosuppression (13%),
vomiting, mucositis, and exfoliation, but there were no treatment-related deaths [53].
e) An overall response rate of 65% (1 complete, 14 partial) and 30% survival at 2 years
was achieved with fluorouracil, interferon-alfa-2b, and cisplatin in a phase II study. The
major toxicity was hematologic (eg, thrombocytopenia); other toxicities included fatigue,
dizziness, gait disturbance, hearing loss, and hallucinations. Treatment was administered in
the following order: Interferon-alfa-2b 10 million units subcutaneously on day 1; cisplatin
100 milligrams/square meter (m(2)) for one dose, then 25 mg/m(2) weekly; and
fluorouracil 750 milligrams/m(2) daily for 5 days, then 750 mg/m(2) weekly. Sargramostim
5 micrograms/kilogram was administered subcutaneously on days 2 to 5 and days 7 to 13
after chemotherapy. While the results appear favorable, a randomized, controlled trial is
required to thoroughly evaluate the efficacy and toxicity of this regimen [118].
f) Three (27%) of 11 patients had a partial response to interferon alfa-2a 5 x 10(6)
units/square meter (m(2)) on days 1 to 7, fluorouracil 370 milligrams (mg) per m(2) on
days 2 to 6, leucovorin 500 mg/m(2) on days 2 to 6, and cisplatin 40 mg/m(2) on day 6
(increased to 50 mg/m(2) if well-tolerated), for 2 to 3 cycles. Nine patients underwent
surgical resection after completing chemotherapy; 2 developed metastatic disease and
were not candidates for surgery. During 26 months of follow-up, 7 of 9 resected patients
relapsed; 5 died. Four patients are alive at 27 months, 2 are disease-free. Adverse effects
included neutropenia (grade intravenous in 3 patients), diarrhea, nausea, vomiting, and
stomatitis [119].
g) Combination cisplatin, fluorouracil, and mitomycin, with irradiation and esophagectomy
elicited a 61% complete response rate among 13 esophageal cancer patients, versus 33%
among 12 patients who did not undergo surgical resection. the chemotherapy regimen
included cisplatin 100 milligrams/square meter (mg/m(2)) and mitomycin 10 mg/m(2) on
day 1, and continuous infusion fluorouracil 1000 mg/m(2) per day on days 1 through 4. All
patients received concurrent radiation therapy. Median survival was significantly longer (10
versus 5 months) among patients undergoing surgery [120].
h) Poor results were observed with combination cisplatin and fluorouracil in esophageal
cancer patients who had not undergone palliative surgical resection. Patients were
randomized to receive either no chemotherapy (n=68) or cisplatin and fluorouracil (n=52)
in 5-day courses every 28 days. Among treated patients, tumor resection was complete in
46% and incomplete in 54%. Among control patients, resection was complete in 56% and
incomplete in and 44%. Median survival of 14 months was similar between the two groups;
however, all patients having undergone incomplete tumor resection died within 4 years
whereas 6 patients (9%) with complete resection survived to 7 years. This marked
108/317
25/10/12
difference in actuarial and median survival times was independent of treatment or nontreatment assignment [121].
Gastric cancer, Adjuvant or neoadjuvant
1) Overview
2) Summary:
Fluorouracil may be useful for adjuvant or neoadjuvant treatment of gastric cancer
3) Adult:
a) Numerous chemotherapy regimens have been evaluated for gastric cancer to increase
resectability of tumors and to prevent relapse after potential surgical cure. An early study
found that fluorouracil monotherapy was as effective as combination therapy (with
doxorubicin and mitomycin) [49]. While most studies have determined no improvement in
survival with combination chemotherapy, one study indicates that doxorubicin, fluorouracil,
and leucovorin did improve survival rates in patients who had undergone curative surgery
[50]. Another study found that leucovorin significantly increased toxicity (although not to
unacceptable levels) when added to epirubicin, mitomycin, and fluorouracil [51].
b) Preoperative and postoperative intraperitoneal chemotherapy with fluorouracil, cisplatin
and 5-fluoro-2'-deoxyuridine decreased recurrence rates and possibly increased survival in
patients with gastric carcinoma. In patients who undergo resection of gastric carcinomas,
the peritoneal cavity is often the first site of cancer recurrence. Fifty-nine patients with
invasive primary gastric adenocarcinoma were enrolled in a clinical trial and received
systemic chemotherapy prior to surgery, followed by intraperitoneal chemotherapy 3 to 4
weeks postoperatively. Preoperative systemic chemotherapy included: (1) Intravenous (IV)
cisplatin 100 milligrams/square meter (mg/m(2)) followed by fluorouracil 200 mg/m(2)/day
on days 1 through 21. Leucovorin IV 20 mg/m(2) was given and repeated weekly during
fluorouracil therapy. Surgery was scheduled 3 to 4 weeks after chemotherapy. After surgery
(21 to 42 days), intraperitoneal (IP) chemotherapy was administered as (1) fluoro-2'deoxyuridine (FUdR) 3000 milligrams daily for 3 days followed on day 4 by cisplatin 200
mg/m(2). A second cycle was repeated in 3 weeks. Toxicity associated with systemic
chemotherapy included Grade 4 thrombocytopenia (7 patients). Nonhematological toxicity
included nausea and vomiting, stomatitis, mild diarrhea, and mild skin rashes. There were
two deaths associated with surgery. Granulocytopenia was the most common side effect
from IP chemotherapy, occurring in 4 patients and lasting 3 to 4 days. Of the 40 patients
with stage 0 to III B gastric carcinoma that underwent curative surgery, nine had recurrent
carcinoma. At 14 to 18 months follow-up, all 15 patients with stage IV gastric carcinoma
died after palliative surgery. At a median follow-up of 43 months, 31 out of 59 patients
(53%) were alive, which was not observed in previous trials. The authors conclude that a
prospective randomized trial is needed to confirm the long median survival observed in this
trial [52].
109/317
25/10/12
c) In an open study, 8 (30%) of 27 patients with esophageal or stomach cancer treated

with epirubicin, cisplatin, and fluorouracil followed by surgery were alive at a median of 36
months; only 1 patient had recurrent disease. Symptoms improved in 62% of patients,
objective responses occurred in 56%. Eleven patients underwent surgical resection.
Patients received a maximum of 4 courses of chemotherapy before surgery: epirubicin 50
milligrams/square meter (mg/m(2)) and cisplatin 60 mg/m(2) administered every 3 weeks,
and fluorouracil 200 mg/m(2)/day administered as a continuous infusion via an ambulatory
pump for 12 weeks. Dosage adjustments were necessitated by myelosuppression (13%),
vomiting, mucositis, and exfoliation, but there were no treatment-related deaths [53].
d) Combination doxorubicin (epidoxorubicin), fluorouracil, and leucovorin improved survival
rates in node-positive patients with advanced gastric cancer (n=103) who had undergone
curative surgery. Patients were randomized to receive either 7 months of combination
chemotherapy (n=48) or no treatment (n=55) during the 32-month study. Median relapsefree survival was significantly extended with chemotherapy; 20.4 months for treated
patients versus 13.6 months for untreated patients. Death resulted from relapse in 48
control patients (87.3%) and 36 treated patients (75%). During the first 7 months of the
study (chemotherapy treatment period), relapse occurred in only 10% of treated patients,
versus 38% of control patients [50].
e) Fluorouracil, epirubicin, and mitomycin did NOT produce a statistically significant
difference in disease-free survival compared with no chemotherapy in patients with Stage I
to III gastric cancer who had undergone complete resection of the tumor and lymph nodes,
or who had poorly differentiated tumors. However, patients with lymph node metastases or
low grade tumor differentiation showed a trend toward longer overall survival. Within two
weeks of surgery, 92 patients were randomly assigned to treatment with mitomycin 10
milligrams/square meter (mg/m(2)) on day 1, fluorouracil 600 mg/m(2) days 1, 8, 29, and
36, epirubicin 45 mg/m(2) days 1 and 29. This cycle was repeated 3 times. Toxicity was
manageable and included neutropenia, mucositis, nausea/vomiting, diarrhea, and alopecia.
Patients were followed for a median of 5 years [54].
Gastric cancer, Palliative
1) Overview
2) Summary:
Fluorouracil is indicated for palliative management of gastric cancer [1].
3) Adult:
a) Response rates with combinations in advanced disease have ranged from 35% with
etoposide, leucovorin, and fluorouracil, to 45% with cisplatin and fluorouracil [55][56].
Fluorouracil with doxorubicin and mitomycin has produced responses ranging from 25% to
110/317
25/10/12
55% [8][57][4][5][58][59]. While most studies have determined no improvement in

survival with combination chemotherapy, one study indicates that doxorubicin, fluorouracil,
and leucovorin did improve survival rates in patients who had undergone curative surgery
[50]. Another study found that leucovorin significantly increased toxicity (although not to
unacceptable levels) when added to epirubicin, mitomycin, and fluorouracil [51]. Although
chemotherapy has only minor activity in gastric cancer, the Medical Letter consultants
recommend fluorouracil with or without leucovorin as the regimen of choice [8].
b) The addition of docetaxel (T) to cisplatin (C) and fluorouracil (F) improved overall
survival in patients with advanced gastric adenocarcinoma. An open-label clinical trial
randomized patients (n=445; median age, 55 years) with advanced gastric
adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who had not
received prior chemotherapy for advanced disease, to TCF (docetaxel 75 milligrams/square
meter (mg/m(2)) on day 1, cisplatin 75 mg/m(2) on day 1, fluorouracil 750 mg/m(2)/day
for 5 days) every 3 weeks or CF (cisplatin 100 mg/m(2) on day 1, fluorouracil 1000
mg/m(2)/day for 5 days) every 4 weeks. Each patient received a median number of 6
cycles of TCF (range, 1 to 16) or 4 cycles of CF (range, 1 to 12). The primary endpoint was
time to progression (TTP). Median TTP was 5.6 months (95% confidence interval (CI), 4.86
to 5.91) in the TCF arm (n=221) and 3.7 months (95% CI, 3.45 to 4.47) in the CF arm
(n=224; hazard ratio (HR), 1.47; 95% CI, 1.19 to 1.83; p=0.0004). Median survival was 9.2
months (95% CI, 8.38 to 10.58) in the TCF arm compared to 8.6 months (95% CI, 7.16 to
9.46) in the CF arm (HR, 1.29; 95% CI, 1.04 to 1.61; p=0.0201). Overall response rate was
36.7% for the TCF group and 25.4% for the CF group (p=0.0106) [60].
c) In a phase II study, the intravenous administration of fluorouracil combined with
leucovorin and interferon-alpha produced minimal therapeutic benefit and moderate
toxicities in 28 adults with advanced gastric carcinoma. In 24 evaluable patients, a median
of 3 cycles per patient was associated with 3 partial responses, for an overall response rate
of 12.5%. Grade 3 or 4 toxicities included granulocytopenia (25%), stomatitis, (35.7%) and
diarrhea (28.6%). Fluorouracil dosage reductions were required during the first or second
cycles in 7 patients (29%) due to toxicity. Treatment was comprised of recombinant
interferon-alpha-2b (5 million units per square meter (m(2)) administered subcutaneously
daily on days 1 to 7 of each 4-week cycle. On days 2 through 6, this was followed by an
intravenous infusion of leucovorin (500 milligrams (mg)/m(2) over 30 minutes and an
intravenous bolus of fluorouracil 370 mg/m(2). The low response rate was responsible for
early termination of the study and suggests that further study of this combination in the
treatment of advanced gastric carcinoma cannot be supported [61].
d) In a phase II study (n=65), median survival was similar for 5-FU/6S-LV (fluorouracil and
leucovorin; 8 months) and EEP-L (epirubicin, etoposide, cisplatin, lonidamine; 9 months).
Neither regimen produced a complete response; however, partial responses were achieved
in 18.2% and 21.9% of patients treated with 5-FU/6S-LV and EEP-L, respectively. In both
groups, partial responses were more frequent in patients with resection of the primary
tumor and a performance status of 0 or 1. Treatment was tolerated well with no treatmentrelated deaths. The 5-FU/S-LV regimen consisted of 6S-LV 100 milligrams/square meter
(mg/m(2)) followed by fluorouracil 370 mg/m(2) daily on days 1 to 5; both were
administered by intravenous bolus injection. EEP-L consisted of epirubicin 30 mg/m(2) on
days 1 and 5; etoposide 100 mg/m(2) on days 1, 3, and 5; cisplatin 30 mg/m(2) on days 2
and 4; and lonidamine 50 mg orally 3 times daily continuously. Both regimens were
repeated every 4 weeks [62].
111/317
25/10/12
e) In a phase II study, cisplatin, fluorouracil, and epi-doxorubicin with modulation by

leucovorin produced an objective tumor response of 62% and a median survival time of 11
months; the 1- and 2-year survival rates were 42% and 5%, respectively, in patients with
advanced gastric cancer. Response rates and median survival times compared favorably to
other chemotherapy regimens; however, this must be confirmed in a long-term,
randomized, controlled trial. This regimen consisted of weekly administration of cisplatin 40
milligrams/square meter (mg/m(2)) given as a 30-minute infusion, fluorouracil 500
mg/m(2) given as a 30-minute infusion, the 6S-stereoisomer of leucovorin 250 mg/m(2)
given over 4 hours, and epi-doxorubicin 35 mg/m(2) given as a bolus injection. To prevent
neurotoxicity and hematologic toxicity, patients also received glutathione 1.5 grams/m(2)
and filgrastim 5 micrograms/kilogram from the day after to the day before each course of
chemotherapy. This regimen was repeated weekly for 8 weeks; patients with a response or
stable disease received 6 additional weeks of therapy. The primary grade III to IV toxicity
was hematologic with few episodes of mucositis (n=6) and nausea/vomiting (n=6); no
grade III or IV neurotoxicity or treatment related deaths were reported [63].
f) double biochemical modulation of fluorouracil with methotrexate and levo-folinic acid
(LFA) was administered to 94 patients with advanced digestive tract malignancies,
involving the colon-rectum, stomach, or biliary tract. Patients received methotrexate 500
milligrams/square meter (mg/m(2)) as a 2-hour infusion on day 1, followed by LFA 250
mg/m(2) as a 2-hour infusion and fluorouracil 600 mg/m(2) bolus on day 2, with cycles
every 2 weeks until tumor progression (maximum, 24 courses). The study identified that a
24-hour methotrexate serum concentration greater than 2 micromoles was significantly
predictive of response (37% versus 5%), longer progression-free survival (5.3 versus 2.3
months), and overall survival (10.8 versus 8.3 months). Responses were correlated with a
24-hour methotrexate level above 2 micromoles in 31% of previously treated colorectal
patients and in 38% of chemotherapy-naive colorectal patients [22].
g) Combination therapy with fluorouracil, epirubicin, mitomycin, and leucovorin produced a
survival duration similar to this combination without leucovorin; however, toxicity was
greater in the group receiving leucovorin. Eighty-eight patients with advanced gastric
cancer were randomly assigned to receive fluorouracil 600 milligrams/square meter
(mg/m(2)) per day on days 1, 8, 29, and 36; epirubicin 45 mg/m(2)/day on days 1 and 29;
and mitomycin 10 mg/m(2)/day on day 1, or the same regimen plus leucovorin 200
mg/m(2)/day administered on the same days as fluorouracil. chemotherapy was repeated
every 8 weeks for 6 cycles or until disease progression. there were no differences in
complete or partial responses; however, in the leucovorin group, more patients had stable
disease (p=0.048), and fewer had progressive disease (p=0.003). Toxicity was significantly
greater with the leucovorin regimen and consisted of neutropenia, thrombocytopenia,
mucositis, diarrhea, and fatigue. Dose reductions among the other agents also were
greater in the leucovorin regimen. Overall, the toxicity of the leucovorin-containing regimen
was acceptable, and this regimen resulted in a greater number of patients with stable
disease [51].
h) Median survival was 30 weeks from 42 (34 had gastric carcinomas and 8 had
gastroesophageal junction carcinomas) previously untreated patients involved in a multiinstitutional, phase-II trial. The chemotherapy regimen which included fluorouracil,
leucovorin, doxorubicin, and cisplatin (FLAP) was as follows: (1) Intravenous (IV)
leucovorin 500 milligrams/square meter (mg/m(2)) over 2 hours weekly during weeks 1
through 6; (2) fluorouracil 500mg/m(2) IV delivered midway through leucovorin infusion
112/317
25/10/12
from weeks 1 through 6; (3) On weeks 1 and 4 IV bolus doxorubicin 30 mg/m(2) along with
cisplatin IV 60 mg/m(2) over 60 minutes. Myelosuppression (Grade 3 to 4 leukopenia) was
found in 18 patients, and Grade 3 thrombocytopenia was found in 3 patients. Grade 3 to 4
diarrhea was noted in 4 patients. Complete and partial response was observed in 2 (5%)
and 13 (31%) patients, respectively. Median time to disease progression and survival for
responders was 28 weeks, and 40 weeks, respectively. The response rate found with this
FLAP regimen is similar to other phase II trials using doxorubicin and fluorouracil in gastric
carcinomas [64].
i) Combination etoposide, leucovorin, and UFT (a prodrug of fluorouracil and uracil in a 4:1
molar ratio), produced a 9% complete response and 26% partial response in a phase II
study of patients with advanced adenocarcinoma of the stomach. Median survival was 9
months in complete responders and 13 months in partial responders. The regimen
comprised etoposide 100 milligrams/square meter (mg/m(2)) and leucovorin 500 mg/m(2)
as an intravenous infusion on day 1, oral etoposide 100 mg/m(2) every 12 hours on days 2
and 3, oral UFT 195 mg/m(2) every 12 hours on days 1 to 14, and oral leucovorin 15 mg
every 12 hours on days 2 to 14. Therapy was repeated every 28 days for a minimum of 3
courses. Major toxicities included grade III/IV hematologic or gastrointestinal effects. This
regimen may be useful for treating patients on an outpatient basis [55].
j) Combination fluorouracil and low-dose cisplatin has shown activity in advanced gastric
cancer, but survival rates have not been remarkable compared with other chemotherapy
regimens. In 31 patients with locally advanced or metastatic cancer, the overall response
rate was 45%, with a median survival of 11 months. A particularly higher response of 60%
was observed in patients with liver metastases [56].
k) Survival rates with fluorouracil alone were similar to those observed with
FLUOROURACIL plus doxorubicin with or without mitomycin in patients with advanced
pancreatic and gastric carcinoma (n=305). Single-agent FLUOROURACIL was administered
as 500 milligrams/square meter per day for 5 days, repeated at 4 and 8 weeks, and every 5
weeks thereafter. Due to the greater cost and toxicity of combination therapy, the authors
advocate FLUOROURACIL monotherapy in advanced pancreatic or gastric cancer [49].
Glaucoma
1) Overview
2) Summary:
Fluorouracil significantly decreases intraocular pressure when administered as a
subconjunctival injection after trabeculectomy or applied directly by sponge during surgery
in patients with glaucoma [122][123] (Gandolfi & Vecchi, 1997). Trabeculectomy usually
fails due to fibroblast proliferation and scarring which are prevented by FLUOROURACIL, an
inhibitor of fibroblast proliferation [122].
113/317
25/10/12
3) Adult:
a) In a prospective study of 50 eyes (n=43 patients) with uveitis-associated glaucoma
undergoing primary trabeculectomy with intraoperative fluorouracil 25 milligrams/milliliter
for 5 minutes, the 6-month, 1-year and 5-year rates of intraocular pressure (IOP) control
were 90%, 88%, and 67%, respectively. A successful outcome indicated IOP reduction to
less than 21 millimeters of mercury with (partial) or without (complete) topical glaucoma
medications. The requirement for systemic glaucoma medications and/or additional surgery
constituted failure of primary trabeculectomy. Clinicians also treated eight of 50 eyes with
postoperative fluorouracil injections. Neither intraoperative nor postoperative fluorouracil
produced ocular toxicity [124].
b) Post-trabeculectomy low-dose subconjunctival fluorouracil injections failed to show any
benefit with respect to long-term intraocular pressure (IOP) control in a randomized trial of
80 eyes (n=80 patients) with low-risk glaucoma. The fluorouracil regimen consisted of
three 5-milligram injections over 11 days. With a mean 1-year follow-up, the average IOP
reductions were 11.5 and 10.2 millimeters of mercury (mmHg) in those who did and did not
receive fluorouracil, respectively. Only 31.6% and 26.3% of the fluorouracil and control
groups, respectively, attained a target IOP of less than 21 mmHg without additional
medication or intervention. The most common postoperative complication was bleb
encapsulation (16% to 18% incidence), with significantly more fluorouracil recipients
experiencing cataract formation (16%) than the controls (2.6%, p less than 0.02) [125].
c) During 5 years of follow-up, there were significantly fewer treatment failures among 105
eyes treated with trabeculectomy and subconjunctival fluorouracil compared with 108 eyes
treated with trabeculectomy alone (51% vs 74%; p less than 0.001). Treatment failure was
defined as reoperation for control of intraocular pressure or an intraocular pressure
exceeding 21 mmHg after one year. All patients had previously undergone cataract surgery
or had failed filtering surgery. Patients randomized to subconjunctival fluorouracil received
5-milligram postoperative injections twice daily on days 1 through 7 and once daily on days
8 through 14. At one month, visual acuity had decreased significantly, but vision recovered
by 6 months and remained similar to untreated patients at 5 years. Fluorouracil treatment
was associated with a significant increase in leakage of a filtering bleb (9% vs 2%;
p=0.032) compared with trabeculotomy only. This was a multicenter, randomized trial, also
called the Fluorouracil Filtering Surgery Study [123].
d) In a 16-month retrospective study of 140 eyes, fluorouracil with trabeculectomy
significantly decreased intraocular pressure (iop) and also reduced the number of
postoperative medications needed to control glaucoma (p less than 0.001). High-risk
patients were less likely to maintain IOP below recommended guidelines (less than 15
mmHg) without medications. A sponge soaked in fluorouracil 50 mg/mL was directly
applied during surgery, and subconjunctival injections were used postoperatively as needed
[122].
e) Subconjunctivally injected fluorouracil resulted in significantly lower intraocular
pressures (IOP) 1 year after combined cataract and trabeculectomy surgery for control of
glaucoma. In this small study (24 eyes with open-angle glaucoma and cataract), patients
were randomly assigned to receive no treatment or fluorouracil 5-milligram injections on
postoperative days 8, 15, 22, 30, and 37 if the IOP was elevated above 20 mmHg during the
first 7 days after surgery. One year later, 10 of 12 fluorouracil-treated eyes and 1 of 12
untreated eyes had an IOP less than 15 mmHg (p=0.00064). Laser suture lysis was
performed in 10 fluorouracil-treated eyes and 9 untreated eyes. Complications occurred
114/317
25/10/12
primarily in the fluorouracil eyes and consisted of conjunctival redness, a foreign body
sensation, and transient epithelial keratopathy (Gandolfi & Vecchi, 1997).
f) The results of a retrospective study involving 304 patients (385 consecutive eyes) who
underwent trabeculectomy with fluorouracil or mitomycin C (MMC) identified 7 cases with a
late bleb leak. Mitomycin C was used in 192 (49.9%) eyes and fluorouracil was used in 193
eyes (50.1%). Five to 8 subconjunctival injections of fluorouracil (0.1 milliliter of 5
milligrams/0.1 milliliters) were given 2 weeks after surgery. The incidence of late (9 to 44
months) bleb formation was 1.8% (7 eyes; 5 treated with fluorouracil and 2 treated with
MMC). Three of the 5 eyes treated with fluorouracil required surgical excision that revealed
areas of thinned or absent conjunctival epithelium with stroma degeneration [126].
g) In patients with uncontrolled open angle glaucoma undergoing glaucoma filtration
surgery, preliminary data suggest that postoperative subconjunctival injections of
fluorouracil, administered within the first 3 postoperative months only when clinical
evidence of bleb failure is likely, is safe and may increase the success rate after
trabeculectomy. Complications currently observed when fluorouracil is used during surgery
may be minimized (eg, conjunctival wound leaks, corneal epithelial defects) [127]. Further
controlled studies with a larger number of patients are required to confirm the efficacy of
delayed postoperative use of fluorouracil.
Granular myringitis
1) Overview
2) Summary:
Topical fluorouracil treatment resulted in significant improvements in symptoms
(granulations and amount of discharge) of granular myringitis in adults compared with
placebo according to a randomized, double blind study (n=60) [193].
3) Adult:
a) Topical fluorouracil treatment resulted in statistically significant improvements in
symptoms of granular myringitis in adults compared with placebo according to a
randomized, double blind study (n=60). Outcome measures included patient-reported
discharge and endoscopically-observed granulation tissue at 3 months (mo) and persistent
disease at 24 mo. Patients (mean age, 35.5 yr; range, 18 to 53 yr) with endoscopically
confirmed granular myringitis defined as a granulation over the intact tympanic membrane
with normal audiography and a type A tympanogram were included in the study. Patients
were excluded if there was marked external auditory canal stenosis, multiple exostoses, or
eustachian tube dysfunction. At baseline 8.3% (n=5) patients had both ears affected and
15% had grade 1, 46.7% grade 2, 30% grade 3, and 8.3% grade 4 granular myringitis.
Following cleansing of the external auditory canal and tympanic membrane surface,
patients were randomized to receive either placebo (n=30) or 3 cm of 5-fluorouracil 5%
115/317
25/10/12
cream (n=30) applied to a 5 cm piece of gauze and using an operating microscope was
packed on the outer side of the drum transmeatally, which was removed after 2 days. The
treatment was repeated every 2 wk for a total of 3 treatments. At the 3-mo assessment,
there were significant differences between treatment groups in patient-reported discharge,
endoscopically-assessed granulation tissue, and persistent disease (p less than 0.001):
Assessment at 24 months
Discharge (patient reported)
Granulations (endoscopically
evaluated)
fluorouracil
(n=30)
placebo
(n=30)
resolved
60.7% (17/30)
7.4%
(2/30)
moderate
improvement
21.4% (6/30)
14.8%
(4/30)
no improvement
10.7% (3/30)
59.3%
(16/30)
worse
7.1% (2/30)
18.5%
(5/30)
resolved
53.6% (15/30)
7.4%
(2/30)
moderate
improvement
35.7% (10/30)
18.5%
(5/30)
no improvement
7.1% (2/30)
63%
(17/30)
worse
3.6% (1/30)
11.1%
(3/30)
There was also a significant difference between the fluorouracil and placebo groups in the
percentage of patients with persistent disease at 24 months (10.7% (n=3) vs 74%
(n=20); p less than 0.001). In the fluorouracil group 3 patients experienced a mild local
allergic reaction to the first treatment which included itching, redness, and mild canal
edema which resolved upon subsequent applications [193].
Head and neck cancer
1) Overview
2) Summary:
Head and neck cancers account for approximately 5% of all malignancies, and the majority
are head and neck squamous cell carcinomas. Surgery and radiation therapy remain the
major curative modalities; however, chemotherapy may induce tumor regression in up to
50% of patients with metastatic or recurrent disease [128][129]. Although chemotherapy
has only moderate activity, the Medical Letter consultants recommend fluorouracil with
116/317
25/10/12
cisplatin as the regimen of choice in head and neck cancer and methotrexate as the
monotherapy of choice [8].
Induction usually consists of cisplatin 100 milligrams/square meter (mg/m(2)), vincristine 1
mg, bleomycin 30 units, OR cisplatin 100 mg/m(2) plus fluorouracil 1000 mg/m(2). These
regimens have produced good response rates (typically dependent on the extent of the
disease) [130][4][131][132].
For palliative therapy, the highest responses (50 to 95%) have been achieved with
combination cisplatin, vincristine, bleomycin, or cisplatin and fluorouracil, but these
regimens have not improved survival, and complete remissions have remained low (less
than 30%) [132][4][131][133][134][135][136]. The duration of remission is usually less
than or equal to 6 months. Even with combination therapy, results are disappointing when
treating advanced (Stage III to IV) disease [137].
3) Adult:
a) Combination with Cisplatin
1) In a phase III trial (n=497), time to laryngectomy was significantly increased in
patients with stage III/IV potentially resectable cancer of the larynx who received
concurrent cisplatin and radiotherapy (Arm A) compared to patients who received
induction chemotherapy with cisplatin and fluorouracil followed by radiotherapy (Arm B;
p=0.0094) and compared to patients who received radiotherapy alone (Arm C;
p=0.00035). The 2-year laryngectomy-free survival rates were 58% for Arm A, 66% for
Arm B, and 52% for Arm C. There were no significant differences in overall survival among
the 3 groups; induction chemotherapy showed no advantage over radiotherapy alone.
Induction chemotherapy consisted of cisplatin (100 milligrams/square meter (mg/m(2) on
day 1) and fluorouracil (1000 mg/m(2)/day continuous infusion for 5 days) every 21 days
for 2 or 3 courses. Concurrent chemotherapy consisted of cisplatin (100 mg/m(2)) on days
1, 22, and 43 of radiotherapy. Radiotherapy (2 Gray/fraction (Gy/fx)) was administered in
35 fractions in 7 weeks. Patients with N2 or N3 neck disease at presentation received neck
dissection 8 weeks after completing radiation. Laryngectomy and neck dissection was
performed for persistent or recurrent local or regional disease. Grade 3/4 toxicity was
experienced by 66% of patients during induction chemotherapy (grade 5=2%), 50% of
patients during radiotherapy following induction, 78% of patients during concurrent
chemotherapy/radiotherapy (grade 5=2%), and 48% of patients who received only
radiotherapy [138]. In a discussion of this phase III trial, it was noted that none of the 3
approaches provided better survival rates than surgery. Potential complications of
concurrent chemotherapy and radiotherapy are stricture, radiation necrosis, chronic
laryngeal edema, tracheotomy dependence, and swallowing disorders. [139].
2) In patients with locally advanced head and neck carcinoma, adding granulocyte-colony
stimulating factor (G-CSF) to a radiochemotherapeutic regimen did not reduce the acute
mucosal or hematological toxicity. In a phase I/II trial, 70 patients with stage III and IV
head and neck carcinoma were treated with: (1) hyperfractionated radiation at 1.20 grays
(Gy) twice daily 4 to 6 hours apart on days 2 through 43; (2) fluorouracil 1000
milligrams/square meter/24 hours (mg/m(2)/24 hours) as a continuous infusion for 72
hours on weeks 1, 5, 8; (3) weeks 1, 5 and 8, cisplatin 50 mg/m(2) before fluorouracil; and
(4) Mitomycin C 8 mg/m(2) on week 5. After 34 patients, G-CSF 5
117/317
25/10/12
micrograms/kilogram/day subcutaneously Monday through Friday was administered on

days of radiation therapy. Toxicity for both treatments included: Grade 3 to 4 mucositis
(65%), Grade 3 dermatitis (44%), Grade 3 to 4 neutropenia (39%), Grade 3 to 4
thrombocytopenia (25%), Grade 3 to 4 anemia (17%). Swallowing dysfunction was a
chronic long-term toxicity, with a significant correlation between patients who had severe
mucositis for longer than 3 months. At 41 months, locoregional control rate was 68% for
patients with disease above the clavicle. At 12 months, 46 patients were alive [140].
3) Cisplatin 100 milligrams/square meter (mg/m(2)) plus fluorouracil 1 gram/m(2) was
superior to single agent fluorouracil or cisplatin in patients with advanced head and neck
cancer (n=249). patients were randomized to either cisplatin (n=84), fluorouracil (n=84)
or a combination of both (n=81) for 3 weeks. Overall response rates were 32% with
combination therapy, 17% with cisplatin, and 13% with fluorouracil. However, there were
no complete responses and there was no significant difference in median survival (5.7
months) among the 3 groups [141].
4) The use of cisplatin, methotrexate, vincristine, bleomycin, and fluorouracil in various
combinations has been disappointing in the treatment of patients with advanced head and
neck cancer. Although overall responses have been as high as 70%, few patients achieve a
complete response [141][137]. In a phase II study, fluorouracil, cisplatin, and bleomycin
achieved a complete response in only 1 of 31 patients [142]. However, another study
reported that cisplatin plus fluorouracil produced complete responses in 9 of 49 patients
with advanced or recurrent head and neck cancer [133].
b) Combination with Cisplatin and Leucovorin
1) Concomitant cisplatin 100 milligrams/square meter (mg/m(2)) on day 1, 5-day
continuous infusion of fluorouracil 1000 mg/m(2)/day, and high-dose oral leucovorin 100
mg every 4 hours during infusion resulted in a 29% complete response rate in 31
previously untreated patients with advanced head and neck cancer (Stage III & IV); the
overall response rate was 84%. This induction regimen was used on the front end of a
protocol involving concomitant chemoradiotherapy [143].
2) Induction therapy with high-dose leucovorin, fluorouracil, and cisplatin in 35 patients
with advanced head and neck cancer produced an overall response rate of 80%, with
complete responses in 23 patients (66%). The regimen consisted of cisplatin 25
milligrams/square meter (mg/m(2)) on days 1 through 5; fluorouracil 800 mg/m(2) on
days 2 through 6; and leucovorin 500 mg/m(2) on days 1 through 6; the cycle was
repeated every 28 days for 2 to 3 cycles [136].
3) The addition of vindesine to a cisplatin-based neoadjuvant chemotherapy did not
improve antitumor efficacy in the treatment of 28 consecutive patients with Stage IV head
and neck cancer. Chemotherapy consisted of cisplatin 100 milligrams/square meter
(mg/m(2)) on day 1, fluorouracil 600 mg/m(2) and vindesine 0.8 mg/m(2) infused over
days 1 through 4, and folinic acid (leucovorin) 150 mg/m(2) every 6 hours for 96 hours.
This cycle was repeated every 21 days. Complete response was achieved in 13% of
patients and partial response occurred in 42%. Adverse effects included grade IV
neutropenia (62%) and oral mucositis (65%). Median survival at 2 years was 27% [144].
c) Combination with Radiation Therapy
1) Impressive response rates (overall, 100%; complete, 75% and 89%) have been
reported with chemotherapy (ie, cisplatin, fluorouracil, bleomycin) plus radiation in patients
118/317
25/10/12
with advanced and inoperable recurrent head neck cancer (Gasparini et al, 1991)[145][4];
(Taylor et al, 1989).
2) Survival was substantially improved (median, 37 months versus 12 months) compared
with previous study in patients with recurrent, advanced, inoperable head and neck cancer
who were treated with simultaneous chemotherapy and radiation. The complete response
rate was 55% (comparable to previous results). The 5-day chemotherapeutic regimen
consisted of cisplatin 60 milligrams/square meter (mg/m(2)) on day 1; fluorouracil 800
mg/m(2) on days 1 through 5. This cycle was given every other week with concurrent
radiation 2 Gray (Gy; a unit of absorbed radiation dose equal to 100 rads) daily for 5 days.
Although the protocol called for 7 cycles, only 64% (34/53) received full treatment (Taylor
et al, 1989).
3) The addition of fluorouracil to cisplatin and fractionated radiation resulted in doselimiting mucositis, which forced subtherapeutic fluorouracil doses. Twenty-seven
postoperative patients with advanced and recurrent disease were enrolled in this study
[146].
d) Combination with Hydroxyurea and Radiation
1) Five-year progression-free survival was 82% for patients (n=60) with stage II or III
head and neck cancer treated with hydroxyurea, fluorouracil and radiation therapy. Patients
were administered hydroxyurea 1 gram orally every 12 hours starting the day before
radiotherapy for a total of 11 doses. Fluorouracil was given as a continuous infusion at a
dosage of 800 milligrams/square meter/day for 5 days. Radiotherapy was administered in
1.8- to 2-Gy fractions for 5 days. This cycle was repeated every 14 days until a total
radiation dose of up to 70 Gy was administered. The total radiation dose was dependent
upon extent of disease and location. The 5-year overall survival was 65% and ultimate
local/regional control at 2 years and beyond was 91%. ECOG grade 3 and 4 mucositis was
experienced by 34 patients. Forty-five patients developed grade 3 or 4 neutropenia.
Concomitant chemotherapy and radiotherapy is feasible with very good tumor control and
acceptable toxicity for this patient population [147].
Hepatoblastoma
1) Overview
Efficacy: Pediatric, Evidence favors efficacy
Recommendation: Pediatric, Class IIb
Strength of Evidence: Pediatric, Category B
2) Summary:
Two cisplatin-containing regimens were equivalent in efficacy but not toxicity in a
randomized trial of 173 children with hepatoblastoma. [148]
3) Pediatric:
a) Two cisplatin-containing regimens were equivalent in efficacy but not toxicity in a
randomized trial of 173 children with hepatoblastoma. The cisplatin dosage for both
regimens was 90 milligrams/square meter (mg/m(2))
for patients at least 1 year of age

or
119/317
25/10/12
regimens was 90 milligrams/square meter (mg/m(2)) for patients at least 1 year of age or
3 mg/kilogram for patients under 1 year of age, infused over 6 hours on day 1 of each cycle.
Cisplatin was combined with either vincristine 1.5 mg/m(2) plus fluorouracil 600 mg/m(2)
via intravenous push on day 2 (regimen A), or with doxorubicin 20 mg/m(2)/day as a 96hour continuous infusion starting on day 1 (regimen B). Four to eight cycles were
administered, with some patients undergoing post-induction surgery. Five-year event-free
survival rates (57% and 69%) and overall survival rates (69% and 72%) were statistically
similar in groups A and B, respectively. Survival was significantly improved with Stage Iunfavorable histology and Stage II disease as compared to Stage III or IV disease (p less
than 0.0001). Hematologic, cardiac, gastrointestinal and renal toxicities occurred at higher
frequencies in group B than in group A (p less than 0.03). Duration of hospitalization and
parenteral nutritional support requirements also significantly favored regimen A [148].
Intracranial tumor
1) Overview
2) Summary:
Combination thioguanine, procarbazine, dibromodulcitol, CCNU (lomustine), fluorouracil,
and hydroxyurea demonstrated significant anti-tumor activity in patients with recurrent
metastatic brain tumors associated with breast and small cell lung cancer (Kaba et al,
1997). A combination of carmustine and fluorouracil arrested tumor progression in 83% of
29 patients [98]
3) Adult:
A combination of thioguanine, procarbazine, dibromodulcitol, lomustine, fluorouracil, and
hydroxyurea demonstrated significant anti-tumor activity in patients with recurrent
metastatic brain tumors associated with breast and small cell lung cancer (n=115). Overall
response rate among 97 assessable patients was 28%; 4 complete, 14 partial, and 9 minor.
Stable or progressive disease was observed in 26% and 46%, respectively. Primary disease
sites included breast (n=28), non-small cell lung (n=39), small cell lung (n=9), melanoma
(n=9), and other origins such as colon, kidney, bladder, stomach, or "unknown" (n=12). The
16-day chemotherapy regimen included:
days 1 through 3: oral thioguanine 40 milligrams/square meter (mg/m(2)) every 6 hours
day 3 (hour 60): oral dibromodulcitol 400 mg/m(2), 4 doses of oral procarbazine 50
mg/m(2) every 6 hours;
hour 72: oral lomustine 110 mg/m(2);
day 14: fluorouracil 1 gram/m(2) continuous 48-hour infusion;
days 15 and 16: 3 doses of oral hydroxyurea 1 gram/m(2)
every 4 hours.
120/317
25/10/12
days 15 and 16: 3 doses of oral hydroxyurea 1 gram/m(2) every 4 hours.

Dose reductions were required in 54% of patients because of hematologic complications.
Objective response rates and disease-free survival among primary tumor groups were
highest among patients with small cell lung cancer (6 patients/67%; 133 weeks) and breast
cancer (10 patients/36%; 27 weeks). Anti-tumor activity also was evident, but to a lesser
extent, in patients with non-small cell lung cancer (objective responses in 10 patients/25%,
disease-free survival 21 weeks). Median survival was 25 weeks among all patients, and 24%
were alive at 1 year. Younger patients and those previously treated with surgery or
chemotherapy progressed significantly faster. Myelosuppression was evident in 60% of
patients and mild nausea/vomiting occurred in 35%. Adverse effects necessitated treatment
withdrawal in only 2 patients, one because of fatigue and the other because of severe
gastrointestinal effects [99].
a) A carmustine (BCNU)-fluorouracil combination was superior to either BCNU alone or a
BCNU-procarbazine in recurrent malignant brain tumors. Among 29 patients, 83% had
arrested tumor progression [98].
Keratoacanthoma
1) Overview
2) Summary:
Topical 5% cream was effective in 2 case reports [150]
Intralesional injection has also been effective [151][152]; (Dubanks et al, 1982)[153].
3) Adult:
a) Keratoacanthomas of the outer ear and forehead in two elderly males were successfully
treated with topical 5% fluorouracil cream. With daily application of fluorouracil for up to 8
weeks, the benign tumor rapidly shrank and resolved completely in one patient, while the
other experienced an 80% reduction in size with the remainder removed via shave biopsy
and electrodesiccation. No scarring or adverse effects were noted. The authors advocate
topical fluorouracil for keratoacanthomas whose size or location render surgical excision
less desirable [150].
b) In several uncontrolled studies, intralesional fluorouracil produced regression of
keratoacanthomas [151][152]; (Dubanks et al, 1982)[153]. The volume of fluorouracil
intralesional injections ranged from 0.1 to 3 milliliters (mL) per treatment. The frequency of
injection ranged from weekly to every 4 weeks. In 2 studies, fluorouracil resulted in a 60%
to 80% regression of the lesion.
Leukoplakia
1) Overview
121/317
25/10/12

2) Summary:
Evidence supports the use of topical fluorouracil in leukoplakia [176][177][178]
Lung carcinoma
1) Overview
2) Summary:
Fluorouracil and mitomycin, in combination with doxorubicin or vincristine, has elicited
overall response rates of 33% to 41%, respectively in patients with lung cancer. However,
survival has ranged from only 28 weeks with the vincristine regimen to 10 months with the
doxorubicin regimen [159][160]. .
Fluorouracil monotherapy was significantly enhanced with concomitant radiation therapy
[161]
3) Adult:
a) Thirty patients with unresectable adenocarcinoma of the lung were treated with
fluorouracil, doxorubicin and mitomycin C. Objective responses were seen in 10 patients
with one complete response and nine partial responses. Median survival for responding
patients was 10 months or longer, while non-responders had a median survival of 5.21
months [160].
b) Fifty-six patients with extensive adenocarcinoma and large cell undifferentiated
carcinoma of the lung were treated with fluorouracil, vincristine and mitomycin C. The
overall response rate was 41% with four patients receiving a complete response and 19
patients achieving a partial response [159].
c) Overall responses were higher in patients treated with a combination of radiation
therapy and fluorouracil (P=0.035) versus radiation alone. However, there were no
significant differences in overall or progression-free survival or in palliation of symptoms.
Two hundred patients with non-small cell lung cancer were randomized to receive radiation
20 Gray (Gy; a unit of absorbed radiation dose equal to 100 rads) in 5 daily fractions either
with or without a continuous infusion of fluorouracil (1 gram/square meter daily) for 5 days
122/317
25/10/12
[161].
Malignant neoplasm of adrenal cortex
1) Overview
2) Summary:
Fluorouracil, in combination therapy, is reasonable medical therapy at some point in the
management of adrenocortical carcinoma [179][180][181][182][183]
Malignant neoplasm of endometrium of corpus uteri
1) Overview
Strength of Evidence: Adult, Category C
2) Summary:
Evidence supports the use of fluorouracil for the treatment of endometrial carcinoma
[112][113]
The Medical Letter consultants recommend two specific drugs or combination drug
regimens of choice in the treatment of endometrial cancer: megestrol or other progestin; or
doxorubicin plus cisplatin with or without cyclophosphamide. Alternative agents as
monotherapy can include either fluorouracil, carboplatin, paclitaxel, tamoxifen, or
altretamine. These recommendations do not imply that these agents have been approved
for use in this indication by the U.S. Food & Drug Administration (Anon, 1997).
Malignant neoplasm of liver
1) Overview
123/317
25/10/12
2) Summary:
Epirubicin, cisplatin, and fluorouracil was well-tolerated and produced a 40% response rate
in 20 evaluable patients with advanced biliary tumors [94].
3) Adult:
a) Intrahepatic arterial infusions of fluorouracil have been used in patients with advanced
disease [154][155][156]. Also, fluorouracil infusion via the portal vein and intravenous
administration with concomitant artery ligation have been used for hepatocellular
carcinoma and hepatic sarcoma [157][158].
b) There has been no effective systemic treatment for the rare and poor-prognosis
hepatobiliary tumors. Epirubicin, cisplatin, and fluorouracil was well-tolerated and produced
a 40% response rate in 20 evaluable patients with advanced biliary tumors. patients
received epirubicin 50 milligrams/square meter (mg/m(2)) and cisplatin 60 mg/m(2) on day
1, each given every 21 days, and fluorouracil 200 mg/m(2)/day as a continuous 24-hour
infusion throughout the treatment course. Median duration of response was 10 months
[94].
Malignant tumor of biliary tract
1) Overview
2) Summary:
Of 14 patients with histologically confirmed, unresectable gallbladder or biliary tree
carcinoma, 1 and 2 patients had a complete and partial response, respectively, to
carboplatin and fluorouracil modulated with leucovorin [92]
Of 32 assessable patients receiving treatment with fluorouracil and recombinant interferon
alfa-2b for biliary tract cancer, 34% had a partial response with a median survival of 12
months [93]
Combination leucovorin, fluorouracil, and hydroxyurea produced partial responses in 9
(30%) of 30 patients with previously untreated advanced gallbladder carcinoma; median
survival was 6.5 months [71]
3) Adult:
a) Of 14 patients with histologically confirmed, unresectable gallbladder or biliary tree
carcinoma, 1 and 2 patients had a complete and partial response, respectively, to
carboplatin and fluorouracil modulated with leucovorin. The duration of response was 8, 7,
and greater than 26 months (complete response) for the 3 responding patients. Carboplatin
300 milligrams/square meter was administered as an intravenous infusion on day 1 only
followed by fluorouracil 400 mg/m(2) and leucovorin 25 mg/m(2) given as a bolus on days 1
124/317
to 4. Each cycle was repeated every 28 days with a maximum of 6 courses.

Myelosuppression was the dose-limiting toxicity with 29% of cycles followed by neutropenia
and fever. This regimen produced objective responses suggesting a possible role for biliary
cancer but further evaluation in controlled studies is needed [92].
b) Of 32 assessable patients receiving treatment with fluorouracil and recombinant
interferon alfa-2b for biliary tract cancer, 34% had a partial response with a median survival
of 12 months. In this phase II study, all patients with measurable cholangiocarcinoma and
gallbladder carcinoma were treated with a continuous infusion of fluorouracil 750
milligrams/square meter/day for 5 days with subcutaneous injection of interferon-alfa-2b 5
million units/square meter on days 1, 3, and 5 of the infusion, repeated every 2 weeks.
Toxicity was manageable [93].
c) Combination leucovorin, fluorouracil, and hydroxyurea produced partial responses in 9
(30%) of 30 patients with previously untreated advanced gallbladder carcinoma; median
survival was 6.5 months. The regimen included leucovorin 100 milligrams/square meter
(mg/m(2)) as a 2-hour infusion followed by fluorouracil 600 mg/m(2) as an intravenous
injection, followed in 6 hours by 3 doses of oral hydroxyurea (1500 mg for a body surface
area (BSA) less than or equal to 1.7 m(2) or 2000 mg for a BSA greater than 1.7 m(2)).
This regimen was repeated weekly for 6 weeks followed by a 2-week rest. After restaging,
treatment was continued until disease progression or unacceptable toxicity occurred.
Toxicity was mild. Only 6% of patients developed grade 3 diarrhea with the remainder of
patients reporting primarily grade 1 or 2 toxicity. Response rates in this trial are consistent
with previous trials using fluorouracil, doxorubicin, and mitomycin C or fluorouracil and
cisplatin; however, this regimen is tolerated better [71].
d) There has been no effective systemic treatment for the rare and poor-prognosis
hepatobiliary tumors. Epirubicin, cisplatin, and fluorouracil was well-tolerated and produced
a 40% response rate in 20 evaluable patients with advanced biliary tumors. Patients
received epirubicin 50 milligrams/square meter (mg/m(2)) and cisplatin 60 mg/m(2) on day
1, each given every 21 days, and fluorouracil 200 mg/m(2)/day as a continuous 24-hour
infusion throughout the treatment course. Median duration of response was 10 months
[94].
Malignant tumor of Islets of Langerhans
1) Overview
2) Summary:
One study reported that streptozocin plus doxorubicin was superior to either streptozocin
plus fluorouracil or chlorozotocin alone in the treatment of advanced islet-cell carcinoma in
a multicenter study enrolling 105 patients [149].
3) Adult:
a) One study reported that streptozocin plus doxorubicin was superior to either
streptozocin plus fluorouracil or chlorozotocin alone in the treatment of advanced islet-cell
carcinoma in a multicenter study enrolling 105 patients. Tumor regression occurred in 69%
and 45% of patients receiving streptozocin plus doxorubicin and streptozocin plus
fluorouracil, respectively; time to tumor progression was 20 versus 6.9 months,
respectively. survival also was extended in the streptozocin plus doxorubicin group, 2.2
versus 1.4 years, respectively. Chlorozotocin alone produced a 30% regression rate with
length of time to tumor progression and survival time equivalent to the streptozocin plus
fluorouracil group [149].
Malignant tumor of nasopharynx
1) Overview
2) Summary:
In a phase 2 trial, in 59 patients with undifferentiated, stage 3 or 4 nasopharyngeal
carcinoma, the use of paclitaxel, fluorouracil and hydroxyurea with concurrent radiation
resulted in a 3-year overall-survival rate of 72% and progression-free survival of 54% [162]
Undifferentiated carcinoma of the nasopharynx differs from squamous cell carcinomas of
the head and neck with respect to chemosensitivity and histology. Protracted continuous
infusion of fluorouracil 300 milligrams/square meter daily for 6 consecutive weeks was
palliative in previously-treated and refractory patients with nasopharyngeal cancer . Toxicity
was mild and the response rate was 25% with a median time to progression of 4 months
and median survival of 10 months [163]
3) Adult:
a) In a phase 2 trial, in 59 patients with World Health Organization (WHO) type III,
undifferentiated, stage 3 or 4 nasopharyngeal carcinoma, the use of paclitaxel, fluorouracil,
and hydroxyurea with concurrent radiation resulted in a 3-year overall-survival rate and
progression-free survival of 72% and 54%, and locoregional and distant control rates of
83% and 64%, respectively. Patients were 75% Chinese males with a median age 47
years, who had no prior chemotherapy or radiotherapy to the head and neck region. The
chemotherapy regimen administered on weeks 1, 4, and 7 consisted of hydroxyurea 500
milligrams (mg) orally twice daily for 9 doses, with concomitant continuous intravenous
infusion of fluorouracil 600 mg/square meter (m(2))/day, and paclitaxel 20 mg/m(2)/day
for 4 days. Complete response (CR) was defined as the absence of local tumor with no
progression of primary tumor, and no residual cervical lymphadenopathy. A partial response
(PR) was defined as the presence of residual tumor with no progression of primary tumor,
or residual cervical lymphadenopathy of at least 1.5 centimeter maximum length.
Progressive disease (PD) was defined as an increase of 25% or greater of the diameters of
tumor lesions, or the appearance of new lesions. Four and 12 months after
chemoradiotherapy, the locoregional tumor response was CR of 86% and 71%, PR of 10%
chemoradiotherapy, the locoregional tumor response was CR of 86% and 71%, PR of 10%
and 2%, and PD of 0% and 8%, respectively. The median time to relapse was 17 months,
occurring in 39% (n=23) of patients. Distant failure occurred in 36% (n=21) of patients,
locoregional failures 15% (n=9), concomitant distant and locoregional failure 12% (n=7),
and death occurred in 16 patients. All patients experienced oropharyngeal mucositis,
radiation dermatitis, and weight loss with grade 3/4 incidences of these adverse events of
81%, 63%, and 32%, respectively. Other adverse events included severe neutropenia
(22%), neutropenic fever (14%), and the need for insertion of feeding tubes (53%).
Completion of all 3 cycles of chemotherapy occurred in 59% of patients, and 2 cycles in
98% of patients, with non-completions mostly related to toxicity. The authors noted that
due to the good locoregional control achieved by this chemotherapy regimen, future studies
should address non-cross resistant cisplatin-based neoadjuvant therapy to reduce the
distant failure rate [162]
b) In a phase II study, the combined intravenous (IV) administration of fluorouracil,
bleomycin, epirubicin, and cisplatin produced durable responses and manageable toxicities
in 49 patients with undifferentiated carcinoma of nasopharyngeal type. Patients were
mostly male, 15 to 69 years in age, with a World Health Organization performance status of
0 to 1. Twenty-six patients had metastatic or recurrent disease (group A) and 23 patients
were previously untreated with locally advanced nonmetastatic disease (group B). Every 3
weeks, patients in group A received fluorouracil (700 milligrams per square meter per day
(mg/m(2)/d) by continuous IV infusion on days 1 through 4); epirubicin (70 mg/m(2) IV on
day 1; bleomycin 10 mg IV push on day 1, followed by 12 mg/m(2) by continuous IV
infusion on days 1 through 4; and cisplatin 100 mg/m(2) IV on day 5. Bleomycin was
omitted during the last 3 cycles. A total of 6 cycles were administered. Group B patients
received the same regimen for 3 cycles, followed by locoregional radiation. Of 23 evaluable
patients in group A, complete and partial responses were achieved in 9 and 9 patients,
respectively, for an overall response rate of 78% (95% confidence interval (CI), 56 to 92).
Median duration of response was 11 months for complete responses and 8.5 months for
partial responses. Of 23 evaluable patients in group B, 5 patients achieved a complete
response (22%) and 16 patients achieved a partial response (69.5%), for an overall
response rate of 91.5% (95% CI, 72 to 99). At a median follow-up of 51 months, 15
patients (65%) were alive without evidence of disease. In group A, Grade 3 or 4 toxicities
were frequent, and included neutropenia (84.5% of patients), thrombocytopenia (34.5%),
anemia (23%), and mucositis (42.3%). Three treatment-related deaths were recorded. In
group B, severe toxicity was less frequent, and included neutropenia (56.5% of patients),
thrombocytopenia (17%), and mucositis (8%). No treatment-related deaths occurred. The
authors conclude that this regimen provides good activity against this type of cancer, but
requires careful monitoring and supportive care of toxicities in patients with metastatic or
recurrent disease [164].
c) Symptomatic nasopharyngeal carcinoma (NPC) with distant metastasis follows a
progressive course with less than 10% of patients surviving 2 years. Although systemic
chemotherapy is usually recommended, the median survival is only 8 to 12 months [165]. In
a trial involving 44 patients with NPC and distant metastasis previously treated with
radiation and/or chemotherapy, weekly treatment with fluorouracil 1250 to 1667
milligrams/square meter (mg/m(2)) plus cisplatin 25 to 33.3 mg/m(2) as a 24-hour
continuous intravenous infusion produced very mild toxicity but only some short-term tumor
regression. Patients were treated until disease progression, patient refusal, and a maximum
of 24 cycles. The survival rate was not improved. Median survival response for the group
was 9 months (range, 2 to 25 months) with only 40% surviving 1 year.
127/317
25/10/12
was 9 months (range, 2 to 25 months) with only 40% surviving 1 year.

Malignant tumor of vagina
1) Overview
2) Summary:
In uncontrolled studies, topical fluorouracil has achieved responses (primarily complete) in
75% to 93% of patients with intraepithelial or squamous cell carcinoma of the vagina
[171][172] (Sillman et al, 1981; Caglar et al, 1981; Hull et al, 1977), and has been
determined to be as effective as laser treatment (Krebs, 1989).
3) Adult:
a) In a retrospective study, topical fluorouracil was as effective as laser treatment in
vaginal intraepithelial neoplasia. In addition, vaginal application of 1.5 grams of 5%
fluorouracil cream once weekly at bedtime for 10 consecutive weeks was reported as
effective as daily application of 1.125 grams vaginally at bedtime for 7 days, with 3 courses
being given 1 week apart. The periodic regimen produced fewer adverse effects than the
continuous regimen [173].
b) Twelve of 15 patients (80%) had remission of vaginal intraepithelial neoplasia for 2 to
60 months after a 7-day course of intravaginal fluorouracil 5% cream (5 cubic centimeters)
twice daily for 7 days. Because these patients developed severe ulceration of vulvar and
vaginal tissue, treatment was modified to a 5-day course after satisfactory response to a
test application. There were no systemic side effects [171].
c) A 5-day course of topical fluorouracil 20% cream produced an overall response rate of
75% among 8 women with postirradiation squamous cell carcinoma in situ of the vagina,
with no serious sequelae [172].
d) Intraepithelial carcinoma of the vagina was successfully treated with topical fluorouracil
5% cream applied in doses of 2.5 grams twice daily for 2 weeks. The vagina healed
normally and cytology remained normal for 3 years (Hull et al, 1977).
Malignant tumor of vulva
1) Overview
128/317
25/10/12
2) Summary:
Evidence supports the use of fluorouracil in vulvar carcinoma [185][186][187][188]
Metastatic renal cell carcinoma
1) Overview
2) Summary:
Fluorouracil with interleukin-2 produced a response in 17% of patients with metastatic
renal cancer [169]
3) Adult:
a) In a phase-II study, an overall response rate of 17% (1 complete response, 3 partial
responses) was observed in 24 patients with metastatic renal cancer who were treated
with fluorouracil 200 milligrams/square meter/day combined with subcutaneous interleukin2 9 to 27 x 10(6) international units/day on day 1, 2, 3, 4, 5, 6 of week 1, Monday to Friday
of weeks 2 and 3. Vascular leak syndrome requiring inotropic support was the major toxicity
occurring in 6 patients. Other toxicities included nausea and vomiting (64%), erythema
(39%), malaise (35%), and anemia (31%) [169].
Ovarian carcinoma
1) Overview
2) Summary:
Cyclophosphamide plus hexamethylmelamine, alternating with doxorubicin and a 5-day
course of cisplatin (CHAP-5), produced more complete remissions, better overall response,
and longer survival than combination hexamethylmelamine, cyclophosphamide,
methotrexate, and fluorouracil (Hexa-CAF) in the treatment of advanced ovarian cancer.
Complete remission occurred in 40% and 19%, respectively, of the CHAP-5 and Hexa-CAF
treatment groups. Overall survival was 30.7 months in CHAP-5 treated patients and 19.6
months in Hexa-CAF treated patients (Neijt et al, 1984).
Pancreatic cancer
129/317
25/10/12
See Drug Consult reference: FOLFIRINOX - USED FOR PANCREATIC CANCER

Proliferative vitreoretinopathy
1) Overview
2) Summary:
Adjuvant combination therapy with fluorouracil and low molecular weight heparin
significantly reduced the rate of postoperative proliferative vitreoretinopathy after
vitrectomy and retinal detachment surgery [166]
3) Adult:
a) Adjuvant combination therapy with fluorouracil and low molecular weight heparin
(LMWH) significantly reduced the incidence of postoperative proliferative vitreoretinopathy
(PVR) in 174 high-risk patients following vitrectomy and retinal reattachment surgery in a
randomized, double blind, placebo controlled trial. The risk of developing PVR was
determined by the presence of clinical factors, which included aphakia, preoperative PVR,
size of retinal detachment, anterior uveitis, previous cryotherapy, and vitreous hemorrhage.
Patients were randomized to receive intraoperative, intravitreal, infusions of fluorouracil 200
micrograms/milliliter and LMWH 5 international units/milliliter (n=87) or normal saline
(n=87). The intraoperative infusions were timed from the beginning of the infusion and
stopped when air exchange was complete. The volume of infusion was determined by
weighing the infusion bag at the end of surgery. Postoperative PVR occurred in 23 of 87
patients in the placebo group compared with 11 of 87 patients in the combined treatment
group (26.4% versus 12.6%, respectively; p=0.02). The total number of one or more
reoperations in the combined treatment group and placebo group were 17 (19.5%) and 22
(25.3%), respectively. The number of reoperations resulting from PVR in the combined
treatment group was nine (52.9%) compared with 16 (72.7%) in the placebo group.
Successful retinal attachment without additional surgery was demonstrated in 71.3% and
78.2% of the placebo-treated patients and combined treatment group patients,
respectively. The final visual acuity outcome was not significantly different between the two
treatment groups, however the visual acuity outcome was significantly worse in those
patients developing postoperative PVR (p less than 0.0001). Complications were limited and
not significantly different between the two treatment groups. Postoperative hyphemas were
evident in five patients from each treatment group, while two intraoperative complications
occurred in the combined treatment group, including retinal incarceration and choroidal
hemorrhage [166].
Psoriasis
1) Overview
130/317
25/10/12

2) Summary:
Topical or intralesional fluorouracil may be useful for small patches of psoriasis [167][168].
3) Adult:
a) A case report describes the clinical and functional improvement in psoriatic
trachyonychia with topical administration of 5% fluorouracil. A 48-year-old white female
with a 12 year history of nail dystrophy was diagnosed with nail psoriasis following physical
and clinical examination. Medical history included type II diabetes mellitus and asthma.
Concomitant medications included glipizide, albuterol inhaler, and triamcinolone inhaler.
Eight weeks of topical corticosteroid treatment did not result in any improvement and was
therefore discontinued. Next, the patient was treated with 5% fluorouracil topical cream for
20 minutes every other day for 2 weeks. Due to periungual irritation, the treatment regimen
was changed to every fourth day with resolution of the event. Following 16 weeks of
therapy, the patient has experienced clinical and functional improvement and is maintained
on once weekly administration of 5% fluorouracil cream [167].
b) Topical fluorouracil may be useful in treating patients with small patches of psoriasis
[168]. When used topically, fluorouracil 5% is usually applied as an ointment 1 to 3 times
weekly. If effective, once weekly application is preferred because the incidence of ulceration
is lower. The response to topical therapy is usually slow.
c) Intralesional fluorouracil 50 milligrams resulted in complete remission of lesions after 1
to 3 doses in 82% of patients. Remission was maintained in 32% of patients for 3 months
or more. No systemic adverse effects were detected; however, localized hyperpigmentation
developed [168].
Queyrat's erythroplasia
1) Overview
2) Summary:
Evidence supports the use of topical fluorouracil in Queyrat's erythroplasia
[189][190][191][192]
Skin cancer, Metastatic
1) Overview
131/317
25/10/12

2) Summary:
The combination of fluorouracil and cisplatin demonstrated efficacy in a small (n=8) study
of patients with locoregional/metastatic metastatic squamous cell carcinoma [184]
Squamous cell carcinoma in situ of skin
1) Overview
2) Summary:
Weekly administration of topical fluorouracil cream was effective in the treatment of
Bowen's disease [97]
3) Adult:
a) Weekly administration of topical fluorouracil cream was effective in the treatment of
Bowen's disease. In a prospective, open-label study, 26 women with Bowen's disease of
the lower leg were treated with fluorouracil cream in the morning and evening one day per
week for a minimum of 3 months. Improvement of disease was observed in 24 patients
(92%) while no response to treatment was observed in 8% of patients. Twelve of 26
patients experienced inactivation of disease and were followed for 33 months. Disease
recurred in 5 of these patients; specifically, 2 were disease free for 3 years and one
developed new lesions. This treatment regimen was not associated with allergic or
irritating adverse reactions [97].
Squamous cell carcinoma of conjunctiva
1) Overview
2) Summary:
132/317
Early, pilot study data suggest efficacy and tolerability of fluorouracil 1% ocular drops [110]
3) Adult:
a) Topical administration of fluorouracil 1% ocular drops eradicated conjunctival squamous
cell carcinoma in 8 of 8 patients in a prospective, nonrandomized trial. The study sample
(mean age: 70) included incompletely excised tumor (n=3), recurrent carcinoma (n=3) and
untreated disease (n=2). Instilled 4 times daily for 4 weeks, topical fluorouracil induced
complete disappearance of malignant cells as assessed by periodic cytological smears and
confirmed by biopsy at the end of follow-up (average: 27 months). One individual required a
second fluorouracil course to attain remission. The only adverse effect of local fluorouracil
was a transient keratoconjunctivitis during week 3 or 4 in all subjects that was relieved by
artificial tears and antibiotics [110].
b) In a case series of 7 men (mean age: 74 years) with conjunctival and/or corneal
intraepithelial neoplasia, topical 1% fluorouracil therapy was effective and well-tolerated.
For the initial treatment course, topical 1% fluorouracil was instilled four times daily for 2
to 4 days, repeated every 30 to 45 days for two to five cycles. Three of seven tumors
disappeared without additional treatment and no recurrence for 15 to 36 months of followup. Fluorouracil-induced shrinkage of one bulky, fixed tumor facilitated surgical excision.
After responding initially, two patients experienced recurrence that was successfully
eradicated with five and six additional cycles of topical 1% fluorouracil. One patient
required a switch to topical mitomycin-C after fluorouracil failed to alleviate a recurrent
tumor. Investigators reported no adverse effects [111].
Squamous cell carcinoma - Xeroderma pigmentosum
1) Overview
2) Summary:
Topical fluorouracil may provide palliative treatment in multiple and superficial squamous
cell carcinoma of the face secondary to xeroderma pigmentosum [170]
3) Adult:
a) In an open study, the topical administration of fluorouracil demonstrated palliative
benefit in 10 patients with histologically confirmed multiple facial squamous cell carcinoma
associated with xeroderma pigmentosum. The patients (median age, 19.8 years) received
topical fluorouracil (Efudex(R), Roche Pharmaceutical Laboratories) twice daily to all
histologically proven or suspected lesions. The median number of treated lesions per
patient was four (range, 3 to 15) and the median duration of treatment was six months
(range, 2 to 36 months). Topical fluorouracil produced skin dryness associated with
superficial tumor regression in seven of 10 patients, and good cosmetic outcome with crust
disappearance and tumor reduction in eight of 10 patients. Post treatment skin biopsies
25/10/12
were performed in five patients, with one patient experiencing tumor necrosis and
resolution of epidermal ulceration with superficial fibrosis. The remaining four patients with
biopsies demonstrated persistent carcinoma in the deeper dermal layer, accompanied with
good cosmetic result. Treatment was well tolerated with occasional pruritus and erythema
[170].
Superficial basal cell carcinoma
1) Overview
FDA Approval: Adult, yes (Topical); Pediatric, no
2) Summary:
Topical fluorouracil 5% cream was beneficial in patients with basal cell carcinomas and is
indicated for multiple and recurrent epitheliomas that have not responded well to surgery or
x-ray therapy (Prod Info Efudex(R), 1997; Litwin & Krementz, 1971; Sykes et al, 1971).
However, early evidence indicated a recurrence rate of 21.4% (Reymann, 1979), and one
trial determined that topical fluorouracil may conceal deep foci of invasive basal cell
carcinomas with the appearance of complete healing (Mohs et al, 1978).
3) Adult:
a) One report described successful treatment of nodular superficial pigmented basal
epitheliomas in a patient receiving topical fluorouracil 5% cream applied daily for 9 months.
Although clinical response was observed within 2 weeks, treatment was continued for a full
9 months. The authors attribute successful therapy to the depth of the lesion [87].
b) A recurrence rate of 21.4% in basal cell carcinomas treated with topical fluorouracil 5%
ointment was the result of a 10-year follow-up study. The author concluded that there is
hardly any indication for using fluorouracil in local treatment of nodular basal cell carcinoma
[88].
Systematized epidermal nevus
1) Overview
Efficacy: Pediatric, Evidence favors efficacy
Recommendation: Pediatric, Class IIb
Strength of Evidence: Pediatric, Category C
2) Summary:
Topical administration of 0.1% tretinoin and 5% fluorouracil resulted in significant
improvement of non-inflamed epidermal verrucous nevus in a pediatric patient [114]
134/317
25/10/12
3) Pediatric:
a) The combination therapy of topical tretinoin and fluorouracil produced significant
improvement in a 7-year-old male with non-inflamed linear verrucous epidermal nevus. The
patient presented with a large, dark-brown linear verrucous epidermal nevus on the right
side of his face that extended from the forehead to the base of the neck. The parents
stated the first evidence of the nevus occurred at the age of 3 months, which continued to
increase in size and darkness. Following biopsy confirmation of linear verrucous epidermal
nevus, a test administration of 0.05% tretinoin cream once in the morning and 5%
fluorouracil once in the evening was applied to a small area of the lesion at the posterior
base of the neck and covered with a bandage. Following evidence of clinical and
histopathologic improvement of the test area, the entire lesion was treated. Inadequate
patient compliance over subsequent years did not allow for appropriate assessment of
treatment. The patient resumed therapy at the age of 11 years with a 1:1 combination of
topical 0.1% tretinoin cream and 5% 5- FU applied once daily under gauze bandage. The
creams were applied separately and rubbed into the skin sequentially. Excellent clearing of
the epidermal nevus was evident following 10 weeks of reliable administration. The
treatment was well tolerated with the exception of redness and maceration of the skin
during the initial administration phase. The patient was lost to follow-up during a 3-year
period in which discontinuation of therapy resulted in recurrence of the nevus, suggesting
an indication for maintenance therapy [114].
Comparative Efficacy / Evaluation With Other Therapies

Aldesleukin
Renal cell carcinoma, Metastatic
a) The combination of interleukin-2 with interferon-alfa and 5-fluorouracil (5-FU) has
demonstrated significant therapeutic efficacy in patients with metastatic renal cell
carcinoma compared to tamoxifen. In this study (n=78), patients were treated with
interferon-alfa (5 x 10(6) international units/square meter (IU/m(2)), day 1 weeks 1
and 4; days 1, 3, 5 weeks 2 and 3; 10 x 10(6) IU/m(2) days 1, 3, 5 weeks 5-8) plus
interleukin-2 (10x 10(6) IU/m(2), twice-daily days 3-5 weeks 1 and 4; 5 x 10(6)
IU/m(2) days 1,3,5 weeks 2 and 3) plus 5-FU (1000 milligrams/square meter
(mg/m(2)), day 1 weeks 5-8). The tamoxifen group received 80 mg twice daily for 8
weeks. Results of the study showed an overall survival of 24 months and an objective
response rate of 39.1% (17% complete response, 21.9% partial response) in the
combination therapy group compared to an overall survival of 13 months and no
objective remissions in the tamoxifen group (Atzpodien et al., 2001).
Bevacizumab
Metastatic breast cancer, HER2-negative, as first-line therapy in combination
with capecitabine or taxane- or anthracycline-based chemotherapy
a) The addition of bevacizumab to capecitabine or to a taxane- or anthracycline-based
chemotherapy regimen significantly improved progression-free survival (PFS) in
women with human epidermal growth factor receptor 2-negative, locally recurrent or
metastatic breast cancer previously untreated with chemotherapy, in the
international, multicenter, randomized, placebo-controlled, phase 3 Regimens in
Bevacizumab for Breast Oncology (RIBBON-1) trial (n=1237). The choice of
135/317
25/10/12
capecitabine (1000 mg/m(2) orally twice daily on days 1 to 14 of each 21-day cycle),
a taxane-based regimen (docetaxel 75 to 100 mg/m(2) IV every 3 weeks or paclitaxel
protein-bound particles 260 mg/m(2) IV every 3 weeks), or an anthracycline-based
regimen (fluorouracil 500 mg/m(2), epirubicin 90 to 100 mg/m(2), and
cyclophosphamide 500 mg/m(2) IV every 3 weeks; fluorouracil 500 mg/m(2),
doxorubicin 50 mg/m(2), and cyclophosphamide 500 mg/m(2) IV every 3 weeks;
doxorubicin 50 to 60 mg/m(2) and cyclophosphamide 500 to 600 mg/(2) IV every 3
weeks; epirubicin 90 to 100 mg/m(2) and cyclophosphamide 500 to 600 mg/m(2) IV
every 3 weeks) was made by the investigators before randomization in a 2:1 ratio to
chemotherapy plus bevacizumab 15 mg/kg IV every 3 weeks or chemotherapy plus
placebo. After a median follow-up of 15.6 months, median PFS (primary outcome) was
8.6 months with capecitabine plus bevacizumab (n=409; median age, 56 years; range,
28 to 91 years) compared with 5.7 months with capecitabine plus placebo (n=206;
median age, 57 years; range 23 to 88 years; hazard ratio (HR), 0.69; 95% confidence
interval, 0.56 to 0.84; p less than 0.001). With a median follow-up of 19.2 months,
median PFS was 9.2 months with a taxane- or anthracycline-based regimen plus
bevacizumab (n=415; median age, 55 years; range, 28 to 88 years) compared with 8
months with a taxane- or anthracycline-based regimen plus placebo (n=207; median
age, 55 years, range 29 to 85 years; HR, 0.64; 95% CI, 0.52 to 0.8; p less than
0.001). Among patients with measurable disease at baseline, the objective response
rate (Response Evaluation Criteria in Solid Tumors (RECIST)) was significantly better
with capecitabine plus bevacizumab (n=325) compared with capecitabine plus
placebo (n=161; 35.4% (95% CI, 30.2% to 40.6%) vs 23.6% (95% CI, 17.6% to
30.7%; p=0.0097) and with a taxane- or anthracycline-based regimen plus
bevacizumab (n=345) compared with a taxane- or anthracycline-based regimen plus
placebo (n=177; 51.3% (95% CI, 45.9% to 56.7%) vs 37.9% (95% CI, 30.7% vs
45.2%); p=0.0054). The median duration of response was longer with capecitabine
plus bevacizumab compared with capecitabine plus placebo (9.2 (95% CI, 8.5 to 10.4
months) vs 7.2 months (95% CI, 5.1 to 9.3 months)) and with a taxane- or
anthracycline-based regimen plus bevacizumab compared with a taxane- or
anthracycline-based regimen plus placebo (8.3 (95% CI, 7.2 to 10.7 months) vs 7.1
months (95% CI, 6.2 to 8.8 months)). Overall survival (OS) and 1-year survival were
not significantly different with bevacizumab than with placebo, but the majority of
patients received additional systemic treatment that might have affected OS. Grade 3
to 5 adverse effects were higher with bevacizumab than with placebo in the
capecitabine arm (35.4% vs 21.9%), the taxane arm (57.2% vs 38.3%), and the
anthracycline arm (34.3% vs 15%). Hypertension, proteinuria and febrile neutropenia,
respectively, were also higher consistently with bevacizumab than with placebo in the
capecitabine arm (10.1%, 1%, 0% and 2.2%, 0%, 0%), the taxane arm (8.9%, 2%,
8.4% and 3.9%, 0%, 2%), and the anthracycline arm (10.5%, 0%, 3.8% and 2.9%,
0%, 5%) [413].
Neoplasm of colon
a) In a randomized phase II study involving previously untreated patients with
metastatic colorectal cancer (n=104), objective responses were seen in 40% (95% CI
24% to 58%) and 24% (95% CI 12% to 43%) of those treated with intravenous
bevacizumab 5 milligrams/kilogram (mg/kg) and 10 mg/kg, respectively, every 2
weeks in combination with the standard chemotherapy regimen of 5-fluorouracil plus
leucovorin (Roswell Park regimen); a response rate of 17% (95% CI 7% to 34%) was
136/317
25/10/12
observed in patients treated with standard chemotherapy alone. Times to disease

progression in these three groups were 9 months (95% CI 5.8 to 10.9; p= 0.005), 7.2
months (95% CI 3.8 to 9.2; p= 0.217), and 5.2 months (95% CI 3.5 to 5.6),
respectively. Median survival was 21.5, 16.1, and 13.8 months, respectively; 37% of
patients in the 5-mg/kg arm were alive at 18-months. imbalances in randomization
(i.e. sex, ECOG performance status, and baseline serum albumin) in this study was a
limitation and may be a possible explanation, along with small sample size and chance
for the more effective outcome seen with the lower dose bevacizumab (Kabbinavar et
al, 2004).
b) In a phase III trial the addition of bevacizumab to bolus irinotecan/ 5- fluorouracil
(5-FU)/leucovorin (LV) (IFL) therapy resulted in increased survival, progression-free
survival, response rate, and duration of response as compared to bolus IFL alone.
Patients (n=925) with untreated, metastatic colorectal cancer were randomized to
bolus IFL/bevacizumab (n=403), bolus IFL/placebo (n=412), or 5-FU/LV/bevacizumab
(n=110). The IFL regimen consisted of intravenous (IV) irinotecan 125
milligrams/square meter (mg/m(2)), bolus IV 5-FU 500 mg/m(2), and LV 20 mg/m(2)
repeated every 4 to 6 weeks; the 5- FU/LV regimen consisted of bolus IV 5-FU 500
mg/m(2), LV 500 mg/m(2) repeated every 6 to 8 weeks. All doses of bevacizumab
were 5 mg/kilogram IV every two weeks. Results reported for the primary comparison
group (bolus IFL/bevacizumab vs. bolus IFL/placebo) were as follows: survival (20.3
vs. 15.6 months), progression-free survival (10.6 vs. 6.2 months), response rate
(44.9% vs. 34.7%; p=0.0029), and duration of response (10.4 vs. 7.1 months;
p=0.0014). Grade 3/4 adverse events potentially related to bevacizumab included
bleeding (3.1%), hypertension (10.9%), proteinuria (0.8%), and gastrointestinal
perforation (1.5%). Thrombotic events such as deep vein thrombosis, pulmonary
embolism, and myocardial infarction occurred in 9%, 4%, 1.5% of patients
respectively (Hurwitz et al, 2003).
c) In a phase II trial (E2200) the addition of bevacizumab to full or reduced dose IFL
(bolus irinotecan/5-fluorouracil (5-FU)/leucovorin (LV)) was safe and efficacious in
patients with untreated metastatic colorectal cancer. Patients (n=20) received
intravenous (IV) bevacizumab 10 milligrams/kilogram every other week, irinotecan
125 mg/square meter (mg/m(2)) IV, bolus IV 5-FU 500 mg/m(2), and LV 20 mg/m(2)
weekly for 4 of 6 weeks. The remaining patients enrolled into the study received
REDUCED dose IFL; irinotecan 100 mg/m(2), 5-FU 400 mg/m(2), and LV 20 mg/m(2).
Overall (OR) response rate (based on Response Evaluation Criteria In Solid Tumors
(RECIST)) was 45.7% (n=70). The OR obtained in the full and reduced IFL dose
groups was 33.3% and 48.3%, respectively. Time to progression was similar
regardless of IFL regimen used (full IFL group 12.1 months, reduced IFL group 10.8
months). Toxicity data (n=83) showed no statistical difference between grade 3 or 4
toxicities based on the starting dose of IFL (p value not reported). Grade 3/4 toxicities
included; diarrhea, neutropenia, febrile neutropenia, bleeding events,
thromboembolism and hypertensions. Proteinuria was infrequent (Giantonio et al,
2003).
d) Preliminary results from a randomized phase III trial (E3200) indicate that the
addition of bevacizumab to FOLFOX4 (5-fluorouracil (5-FU)/leucovorin (LV)) and
oxaliplatin) is safe in patients with advanced/metastatic colorectal cancer. Primary
endpoints of the study (response rate, time to progression, and overall survival) have
not yet been determined but are anticipated since the results of a recent study
137/317
25/10/12
(bevacizumab plus IFL) indicate a improvement in survival (20 months) equal to

FOLFOX alone. In abstract form, it appears that the toxicities associated with the
addition of bevacizumab to FOLFOX (10 milligrams (mg)/kilogram intravenously (IV)
every two weeks plus oxaliplatin 85 mg/square meter (m(2)) IV on day 1/leucovorin
200 mg/m(2) IV and 5-FU 400 mg/m(2) IV followed by 5-FU 600 mg/m(2) IV infused
continuously over 22 hours on days 1 and 2; regimen repeated every 2 weeks) were
increased bleeding and hypertension; serious bleeding seen in 3% of the bevacizumab
patients and none of the FOLFOX patients (Benson et al, 2003; D'Orazio & Lee, 2003).
Capecitabine
Breast cancer, Adjuvant therapy, in women 65 years of age or older
a) In a randomized trial (n=633), noninferiority for relapse-free survival (RFS) was
not established between single-agent capecitabine and standard therapy with
cyclophosphamide and doxorubicin (AC) or cyclophosphamide, methotrexate, and
fluorouracil (CMF) as adjuvant therapy in elderly patients with early stage breast
cancer. Women 65 years (yr) of age or older with operable, stage I to IIIB breast
cancer and a tumor diameter greater than 1 centimeter were randomized to
treatment with oral capecitabine (n=307; hormone receptor-negative tumors, 32%)
or standard chemotherapy (n=326; hormone receptor-negative tumors, 33%).
Adjuvant therapy with capecitabine consisted of 6 cycles of 2000 milligrams/square
meter (mg/m(2))/day in 2 divided doses for 14 days every 3 weeks. Standard
adjuvant chemotherapy consisted of 4 cycles of AC with cyclophosphamide 600
mg/m(2) intravenously (IV) and doxorubicin 60 mg/m(2) IV given on day 1 every 21
days (n=184) or 6 cycles of CMF with cyclophosphamide 100 mg/m(2)/day orally days
1 to 14 and methotrexate 40 mg/m(2) IV and fluorouracil 600 mg/m(2) IV on days 1
and 8 every 28 days (n=133). After chemotherapy, patients with hormone receptorpositive tumors could receive tamoxifen or an aromatase inhibitor. All scheduled
cycles of chemotherapy were received by 80%, 92%, and 62% of patients treated
with capecitabine, AC, and CMF, respectively. Following the enrollment of 600
patients, the futility of capecitabine therapy was determined using a Bayesian
predictive probability method and the trial was closed. At the time of this preplanned
interim analysis, 24 patients in the capecitabine arm and 16 patients in the standard
chemotherapy arm had experienced disease recurrence, distant metastases, or death
from any cause, resulting in a hazard ratio (HR) for disease recurrence (standard
chemotherapy compared with capecitabine) of 0.53 (probability of HR less than
0.8046 was 96% which was greater than the limit of 80% predicting futility). At a
median follow-up of 2.4 yr, 60 patients (20%) in the capecitabine arm and 35 patients
(11%) in the standard chemotherapy arm experienced a relapse. Additionally, 18 of
38 deaths (47%) in the capecitabine arm and 8 or 24 deaths (33%) in the standard
chemotherapy arm were attributed to breast cancer. In multivariate analyses,
significantly worse RFS (HR, 2.09; 95% confidence interval (CI), 1.38 to 3.17; p less
than 0.001) and overall survival (OS) (HR, 1.85; 95% CI, 1.11 to 3.08; p=0.02) with
capecitabine compared with standard therapy were confirmed. Unplanned post hoc
analyses demonstrated that patients with hormone receptor-negative tumors who
received capecitabine had significantly worse RFS (HR, 4.39; 95% CI, 2.9 to 6.7; p
less than 0.001) and OS (HR, 3.76; 95% CI, 2.23 to 6.34; p less than 0.001)
compared with patients with hormone receptor-negative tumors who received
standard therapy. One or more serious (grade 3 or higher) hematologic adverse
events (AE) occurred less frequently with capecitabine (2%) compared with standard
138/317
25/10/12
therapy (AC, 54%; CMF, 52%) and one or more serious nonhematologic AE occurred
in 33%, 24%, and 40% of patients who received capecitabine, AC, and CMF,
respectively. Treatment-related death occurred in 2 patients in the capecitabine arm
and in no patients in the standard therapy arm [412].
Gastric cancer, First-line therapy for advanced or metastatic disease, in
combination with chemotherapeutic agents
a) First-line therapy with combination capecitabine/cisplatin was significantly
noninferior to 5-fluorouracil/cisplatin for the treatment of advanced gastric cancer in
an international, multicenter, randomized, open-label, phase 3 trial (n=316). Adults
with advanced gastric cancer, who were chemotherapy-naive other than neoadjuvant
induction, no radiotherapy to target lesions, and a Karnofsky performance status of 70
or greater were randomized to receive cisplatin 80 milligrams/square meter
(mg/m(2)) intravenous (IV) infusion over 2 hours on day 1 with hyperhydration plus
either capecitabine 1000 mg/m(2) twice daily on days 1 to 14 every 3 weeks (XP:
n=160; median age 56 years (yr); range, 26 to 74 yr)) or 5-fluorouracil 800
mg/m(2)/day continuous infusion on days 1 to 5 every 3 weeks (FP: n=156; age 56
yr; range, 22 to 73 yr) until disease progression, lack of benefit, or toxicity.
Noninferiority of XP to FP was declared if the upper limit of the 95% confidence
interval (CI) for the hazard ratio for PFS was less than 1.25. Analysis of the per
protocol population revealed a median progression-free survival (PFS; primary
endpoint) of 5.6 months (mo) (95% CI, 4.9 to 7.3 mo) for the XP group (n=139)
compared with 5 mo (95% CI, 4.2 to 6.3 mo) for the FP group (n=137), yielding an
unadjusted PFS hazard ratio (HR) of 0.81 (95% CI, 0.63 to 1.04), thus meeting the
prespecified noninferior margin and revealing statistically significant noninferiority (p
less than 0.001). Similarly, the median PFS was 5.6 mo (95% CI, 4.8 to 6.9 mo) and 5
mo (95% CI, 3.9 to 5.7 mo) in the XP and FP groups, respectively in the intent-totreat population, yielding a unadjusted PFS hazard ratio (HR) of 0.8 (95% CI, 0.63 to
1.03; p less than 0.001). Additionally, the XP regimen was noninferior to the FP
regimen for overall survival (10.5 mo vs 9.3 mo; unadjusted HR, 0.85; 95% CI, 0.64 to
1.13; p=0.008), objective response rate (46% versus (vs) 32%; odds ratio, 1.8; 95%
CI, 1.11 to 2.94; p=0.02) and mean time to response (3.7 mo vs 3.8 mo; unadjusted
HR, 1.61 to 2.35; p=0.015). The results for the adjusted analyses were consistent
with the results for the unadjusted analyses, thus demonstrating robustness. The
most common treatment-related, grade 3/4 adverse events were neutropenia (16%
vs 19%), vomiting (7% vs 8%) and stomatitis (2% vs 6%) in the XP vs FP groups,
respectively [470].
139/317

0%, 5%) [413].
Neoplasm of colon
a) An overall response rate of 24.8% was achieved in patients with advanced or
metastatic colorectal cancer who received capecitabine compared to a response rate
of 11.6% in patients who received fluorouracil and leucovorin (5-FU/LV) (p=0.0001) in
a randomized phase III trial (n=605). There were no significant differences between
the capecitabine group and the 5-FU/LV group in overall survival (12.5 months and
13.3 months, respectively), median duration of response (9.1 months and 9.5 months,
respectively), and median time to disease progression (4.3 months and 4.7 months,
respectively). Patients with advanced or metastatic colorectal cancer who had not
received prior chemotherapy for metastatic disease were randomized to receive
capecitabine orally (1250 milligrams/square meter (mg/m(2)) twice daily for 14 days
25/10/12
followed by a 7-day rest period) or 5-FU/LV (rapid intravenous (IV) injection of 20

mg/m(2) LV followed by an IV bolus of 425 mg/m(2) 5-FU on days 1 to 5 every 4
weeks). Dose reduction for adverse reactions was required in 40.5% of patients in the
capecitabine group (usually hand-foot syndrome or diarrhea) and 49.3% of patients in
the 5-FU/LV group (usually stomatitis or diarrhea. A comparison of grade 3/4 toxicity
in the capecitabine group and 5- FU/LV group included diarrhea (15.4%, 13.9%),
hand-foot syndrome (18.1%, 0.7%), stomatitis (3.0%, 16.0%), vomiting (3.6%,
4.7%), neutropenia (2.6%, 25.9%) and hyperbilirubinemia (17.3%, 5.4%). A
significantly lower incidence of any grade of diarrhea, stomatitis, nausea, and alopecia
occurred in the capecitabine group (p less than 0.00002). However, a significantly
greater incidence of hand-foot syndrome occurred in patients who received
capecitabine. The authors conclude that capecitabine is an acceptable alternative for
the treatment of advanced colorectal cancer based on its response rate, favorable
toxicity profile, and the convenience of oral therapy (Hoff et al, 2001).
b) In another randomized phase III trial (n=602) comparing capecitabine to
fluorouracil (5-FU) plus leucovorin in patients with advanced or metastatic colorectal
cancer, an overall response rate of 19% was achieved with capecitabine compared to
15% with fluorouracil/leucovorin. No significant differences were seen between the
capecitabine group and the 5-FU/leucovorin group in overall survival (13.2 months
versus 12.1 months), median duration of response (7.2 months versus 9.4 months),
median time to disease progression (5.2 months versus 4.7 months), and time to
treatment failure (4.2 months versus 4.0 months). Chemotherapy-naive patients
received either capecitabine 1250 milligrams/square meter (mg/m(2)) orally twice
daily for 14 days followed by a 7-day rest period or a rapid intravenous (IV) injection
of 20 mg/m(2) of leucovorin followed by an IV bolus of 5-FU 425 mg/m(2) on days 1
to 5 every 4 weeks. There were significantly lower incidences of stomatitis, grade 3/4
stomatitis, grade 3/4 neutropenia and alopecia (p less than 0.0001) and significantly
higher incidences of cutaneous hand- foot syndrome, grade 3 hand-foot syndrome (p
less than 0.00001), and uncomplicated grade 3/4 hyperbilirubinemia (p less than
0.0001) with capecitabine compared with 5-FU/leucovorin. Time to first onset of
treatment-related grade 3/4 adverse reaction was significantly later in the
capecitabine group (p=0.008). Oral capecitabine has at least equivalent efficacy
compared with intravenous fluorouracil/leucovorin with clinically meaningful safety
advantages (Cutsem et al, 2001).
c) In a large multicenter prospective, randomized phase III clinical trial, capecitabine
therapy was shown to substantially reduce medical resource use and to improve
response rate and tolerability compared to the Mayo Clinic Regimen of 5-fluorouracil
(5-FU)/leucovorin (LV) in patients with advanced or metastatic colorectal cancer.
Patients (n=602) were randomized to receive either capecitabine (1250 mg/m2 orally
twice daily for 2 weeks followed by 1 week rest) or 5 FU/LV (20 mg/m2 of LV as a
rapid IV injection followed by 425 mg/m2 of 5-FU as an IV bolus given daily for 5 days,
every 4 weeks). Treatment was continued for 30 weeks or until the development of
progressive disease or unacceptable toxicity. Capecitabine treatment resulted in
superior response rates (26.6% versus 17.9%) and improved safety compared to 5FU/LV. Capecitabine patients also required fewer hospital visits for drug
administration, or for the management of treatment related adverse effects, and had
reduced expenses for managing adverse events. However, patients receiving
capecitabine needed more frequent unscheduled home, daycare, office, and telephone
141/317
consultations with physicians (Twelves et al, 2001).

Carboplatin
Breast cancer
a) Survival is NOT improved for women with metastatic breast cancer undergoing
treatment with standard-dose chemotherapy followed by high- dose chemotherapy
and autologous stem-cell transplant when compared to standard-dose chemotherapy
alone. Of 553 patients enrolled, 110 achieved either a complete or partial response to
induction chemotherapy and were subsequently randomized. Standard- and high-dose
chemotherapy were administered according to the following schema:
INDUCTION AND
HIGH-D0SE (CONTINUOUS
MAINTENANCE
INFUSION)
Doxorubicin
30 mg/m(2) days 1
and 8 IV
Cyclophosphamide 100 mg/m(2)/day for 1500 mg/m(2)/day for 4 days IV
14 days PO
Fluorouracil
500 mg/m(2) days 1
and 8 IV
Methotrexate*
40 mg/m(2) days 1
and 8 IV
Thiotepa
125 mg/m(2)/day for 4 days IV
Carboplatin
*methotrexate substituted for doxorubicin when the total dose of
doxorubicin previously received was 400 to 500 mg.
mg/m(2)=milligrams/square meter
IV=intravenous
PO=oral
b) Four to six cycles of induction therapy were given every 28 days. Patients
randomized to standard-dose (maintenance) chemotherapy received a median of 8
cycles. Median follow-up was 37 months. At 3 years, overall survival in this intentionto-treat analysis was not significantly different between standard- and highdose/transplant therapy (38% and 32%, respectively; p=0.23). Likewise, median time
to progression was not different between the standard- and high- dose/transplant
groups (9 and 9.6 months, respectively; p=0.31). Subgroup analyses (estrogenreceptor status, predominant site of metastatic disease) also revealed no differences
in these endpoints between the 2 groups. A greater incidence of severe leukopenia,
thrombocytopenia, and anemia was observed in the high-dose/transplant group;
mucositis occurred at a similar rate for both groups [414]. High-dose chemotherapy
with stem-cell transplantation is ineffective for women with metastatic breast cancer
and therefore cannot be recommended and should be abandoned in favor of welljustified alternative experimental approaches [415][414].
c) No difference in survival or progression free survival was detected in patients with
breast cancer receiving HIGH-DOSE CHEMOTHERAPY WITH PERIPHERAL BLOOD
PROGENITOR CELL (PBPC) support compared to those who did not. This randomized
study analyzed 81 patients with extensive axillary lymph-node involvement. All
patients received up-front chemotherapy with FLUOROURACIL (500 milligrams/square
meter (mg/m(2))), EPIRUBICIN (120 mg/m(2), and CYCLOPHOSPHAMIDE (500
mg/m(2) (repeated every 3 weeks for 3 courses) followed by surgery. All randomized
142/317
25/10/12
patients received a fourth course of the up-front chemotherapy regimen, radiation

therapy and 2 years of TAMOXIFEN therapy. In addition to that, those randomized to
the high-dose regimen received CYCLOPHOSPAMIDE 6 grams/square meter,
THIOTEPA 480 mg/m(2), CARBOPLATIN 1600 mg/m(2) and PBPC reinfusion.
Toxicities were greater in the high-dose group but both groups experienced nausea,
vomiting, alopecia, fatigue, mucositis, phlebitis, diarrhea, and neutropenia. Three
cases of reversible renal failure were reported in the high-dose group (Rodenhuis et
al, 1998).
d) Following breast cancer surgery, a tailored FEC (fluorouracil (5-FU), epirubicin,
cyclophosphamide) dosage regimen was associated with improved relapse-free
survival compared to standard FEC followed by high-dose chemotherapy and stem-cell
support in a randomized trial of 525 women under age 60 with high-risk primary
breast cancer. Group 1 patients received up to nine cycles of FEC with granulocytecolony stimulating factor (G-CSF) support, with doses adjusted according to
hematologic toxicity (initial doses: 600 milligrams/square meter (mg/m(2)) 5-FU, 75
mg/m(2) epirubicin and 900 mg/m(2) cyclophosphamide). Group 2 patients were
administered two courses of FEC without G-CSF support (600 mg/m(2) 5-FU, 60
mg/m(2) epirubicin, 600 mg/m(2) cyclophosphamide), a third FEC course with higher
cyclophosphamide dosing (1200 mg/m(2)) and G-CSF support, then high- dose
chemotherapy: 6000 mg/m(2) cyclophosphamide, 500 mg/m(2) thiotepa and 800
mg/m(2) carboplatin prior to stem cell transfusion. Grade 3 and 4 gastrointestinal
toxicities and infection were significantly less frequent in group 1 than group 2 (p less
than 0.0001). All subjects underwent post-chemotherapy radiation and tamoxifen
therapy. The estimated 3-year relapse-free survival rate (72% versus 63%, p=0.01)
but not overall survival (83% versus 77%, p=NS) favored group 1 over group 2,
respectively. A drawback to the tailored FEC regimen was the development of acute
myeloid leukemia (n=6) and myelodysplastic syndrome (n=3) (Bergh et al, 2000).
e) No difference in survival or progression free survival was detected in patients with
al, 1998).
Cisplatin
Breast cancer
a) A randomized, phase II study demonstrated comparable efficacy between ECycloF
(EPIRUBICIN, CYCLOPHOSPHAMIDE, and FLUOROURACIL (5-FU) and ECisF
(CISPLATIN substituted for cyclophosphamide) for metastatic or locally advanced,
inoperable breast cancer (Eisen et al, 1998). Patients in both groups received 5-FU
200 milligrams/square meter (mg/m(2)) every 24 hours via continuous infusion,143/317
and
25/10/12
200 milligrams/square meter (mg/m(2)) every 24 hours via continuous infusion, and
epirubicin 60 mg/m(2) every 3 weeks. By 2 to 1 randomization, patients were
allocated to cyclophosphamide 600 mg/m(2) or cisplatin 60 mg/m(2) every 3 weeks.
Six cycles were planned. The overall response rate was 68% and 69% for the ECisF
and ECycloF groups, respectively. The overall survival for ECisF was 10 months
compared to 13 months for ECycloF. Patients with locally advanced disease had higher
response rates (83% to 85%) and higher 1-year survival (80% to 83%) than patients
with metastatic disease. Stomatitis, plantar-palmar syndrome, lethargy, constipation,
and thrombosis related to the Hickman catheter occurred more frequently in the ECisF
group. ECycloF offers a regimen with comparable efficacy, fewer toxicities, and
greater ease of administration than ECisF (Eisen et al, 1998).
b) A randomized, phase II study demonstrated comparable efficacy between ECycloF
(EPIRUBICIN, CYCLOPHOSPHAMIDE, and FLUOROURACIL (5-FU)) and ECisF
200 milligrams/square meter (mg/m(2)) every 24 hours via continuous infusion,
than ECycloF group. ECycloF offers a regimen with comparable efficacy, fewer
toxicities, and greater ease of administration than ECisF.
c) A randomized, phase II study demonstrated comparable efficacy between ECycloF
Six cycles were planned. The overall response rate were 68% and 69% for the ECisF
and thrombosis (related to the Hickman catheter) occurred more frequently in the
ECisF than ECycloF group. ECycloF offers a regimen with comparable efficacy, fewer
toxicities, and greater ease of administration than ECisF
Cervical cancer
a) In a Phase III trial of 368 eligible subjects with locally advanced stage IIB to IVA
cervical carcinoma, the combination of 5-fluorouracil (5-FU) and cisplatin was superior
to hydroxyurea alone as an adjunct to radiation therapy. Cisplatin 50
milligrams/square meter/day (mg/m(2)) was administered 4 hours prior to radiation
on days 1 and 29, while 5-FU was dosed at 1 gram/m(2)/day on days 2, 3, 4, 5, 30,
31, 32, and 33. Patients randomized to oral hydroxyurea received 80
144/317
25/10/12
milligrams/kilogram/day twice weekly. The median duration of therapy in both groups

was 9 weeks. After a median follow-up of 8.7 years, the rates of disease progression
were 43% and 53% in the 5-FU/cisplatin and hydroxyurea groups, respectively.
Corresponding overall mortality rates were 45% and 57% (p=0.018). Relative risks
for progression/death and mortality were 0.79 (90% confidence interval, 0.62 to 0.99)
and 0.74 (90% CI, 0.58 to 0.95), respectively, both favoring the 5- FU/cisplatin
regimen. The only statistically significant difference in toxicity was more
frequent/severe neutropenia with hydroxyurea (p less than 0.00001) (Whitney et al,
1999).
b) The combination of CISPLATIN and RADIATION therapy or CISPLATIN,
FLUOROURACIL, HYDROXYUREA, and RADIATION therapy produced significantly
better survival than a control group receiving hydroxyurea and radiation for the
treatment of STAGE IIB, III or IVB cancer of the cervix. There were 3 arms in this
large (n=526), randomized, multicenter, controlled trial. The first study group received
cisplatin 40 milligrams/square meter (mg/m(2)) over 4 hours before radiotherapy at
weeks 1 through 6. The second study group received cisplatin 50 mg/m(2) on days 1
and 29, fluorouracil 4 grams/square meter as a 96 hour infusion on days 1 and 29, and
hydroxyurea 2 grams/square meter orally twice a week before radiation therapy at
weeks 1 through 6. The control group was administered only hydroxyurea 3
grams/square meter orally twice weekly before radiation therapy on weeks 1 through
6. All groups received radiation at varying doses depending on stage of disease. The
median follow-up was 35 months. Actual survival rates among the first study group,
the second study group, and the control group were 66%, 67%, and 49.7%
respectively. Progression-free survival relative risk was 0.57 and 0.55 for the first and
second study groups respectively when compared to the control group. The rates of
progression-free survival at 24 months for the first and second study group and the
control group were 67%, 64%, and 47% respectively. The occurrence of grade 3/4
toxicities was greatest in the 3-drug regimen, but was similar in the other 2 groups.
Grade 3/4 leukopenia was double the rate in the 3-drug group compared to the other
2 groups. This was also true for the other hematologic effects. There were no
treatment-related deaths (Rose et al, 1999).
c) In a large, randomized, open-label, multicenter, controlled, PHASE III trial, patients
receiving CISPLATIN and FLUOROURACIL with RADIATION therapy had significantly
better survival (73%) versus patients receiving radiation alone (58%) in the
treatment of cervical cancer (p=0.004). A total of 388 women were evaluated having
STAGE IIB through IVA cancer of the cervix and followed for a median of 43 months.
The study group was administered cisplatin 75 milligrams/square meter (mg/m(2))
infused over 4 hours followed by fluorouracil 4000 mg/m(2) infused over 96 hours plus
a total of 85 Gy radiation. Chemotherapy was given every 3 weeks for a total of 3
cycles. The control group received only radiation (85 Gy). Disease-free survival at 5
years was also better in the study group (67%) compared to radiation alone (40%).
When stratified according to stage IB, IIA, or IIB, again the study group showed
better survival (77%) compared to radiation only (58%). There was no difference in
survival between the 2 groups with stage III or IVA disease. Rates of distant relapse
and (14%, relative risk=0.39) locoregional recurrence (19%, relative risk=0.47) were
significantly lower in the study group compared to the radiation-only group (33% and
35% respectively). Grade 3 and 4 toxicities occurred more frequently with combined
therapy but were usually self-limited. Hematologic effects were generally moderate
145/317
25/10/12
(Morris et al, 1999).

Esophageal cancer
a) The addition of a preoperative chemoradiation regimen offered no statistical
survival advantage over surgery alone in a randomized trial of 100 patients with
previously untreated locoregional adenocarcinoma (n=75) or squamous cell carcinoma
(n=25) of the esophagus. Chemoradiation consisted of CISPLATIN 20
milligrams/square meter (mg/m(2))/day as a continuous infusion on days 1 through 5
and days 17 through 21; FLUOROURACIL 300 mg/m(2)/day as a continuous infusion
on days 1 through 21; VINBLASTINE 1 mg/m(2)/day on days 1 through 4 and days 17
through 20; and twice-daily radiation on days 1 through 5, 8 through 12 and 15
through 19 for a total dose of 45 Gy. On day 42, subjects underwent transhiatal
esophagectomy. Forty-five patients in each arm obtained complete surgical resection
of the carcinoma. The median survival in the preoperative chemoradiation and
surgery-only groups were 16.9 and 17.6 months, respectively (p=NS). Corresponding
1-year (72% versus 58%) and 3-year (30% versus 16%) survival rates did not differ
statistically. This trial was powered to detect only large overall survival differences.
Significant negative independent prognostic factors included tumor size greater than 5
centimeters, squamous cell histology and age over 70 years. Of the subset (n=14)
who attained complete histologic response to the preoperative regimen, 86% and
64% were alive at 1 year and 3 years, respectively (median survival: 49.7 months)
(Urba et al, 2001).
b) The addition of a preoperative chemoradiation regimen offered no statistical
(Urba et al, 2001).
Esophagogastric cancer
a) Combination therapy with epirubicin, cisplatin, and fluorouracil (ECF regimen)
resulted in longer survival, tolerable toxicity, and a better quality of life compared to
fluorouracil, doxorubicin, and methotrexate (FAMTX regimen). All patients (n=219)
entered into the trial had inoperable adenocarcinoma or undifferentiated carcinoma of
the esophagus or stomach. The ECF regimen consisted of intravenous (IV) epirubicin
50 milligrams/square meter (mg/m(2)) and cisplatin 60 mg/m(2) every 3 weeks for
up to 8 cycles and a continuous infusion of fluorouracil 200 mg/m(2)/day via a
146/317
25/10/12
portable infusion pump for up to 6 months. The FAMTX regimen consisted of IV

methotrexate 1500 mg/m(2) followed by IV fluorouracil 1500 mg/m(2) on day 1.
Doxorubicin 30 mg/m(2) was administered IV on day 15. Cycles were repeated every
28 days up to a maximum of 24 weeks. Leucovorin rescue 30 mg every 6 hours for 48
hours was started 24 hours after methotrexate. Objective responses including
complete and partial responses occurred in 45% (p=0.0002) of patients treated with
the ECF regimen compared to 21% of patients treated with the FAMTX regimen. With
the ECF regimen, 9 patients underwent complete resections versus 4 patients treated
with the FAMTX regimen. Mucositis, nephrotoxicity, and hematologic toxicity resulting
in infections occurred significantly more often in patients treated with the FAMTX
regimen; whereas, the ECF regimen resulted in more alopecia and central venous line
complications. Median survival time was significantly (p=0.0009) longer with ECF (8.9
months) compared to FAMTX (5.7 months) [416]. Based on this trial, the ECF
regimen should be offered to all patients with advanced esophagogastric cancer who
have an acceptable performance status.
Gastric cancer
a) There was no statistically significant difference in objective response rate (ORR,
complete response plus partial response), progression free survival (PFS), median
overall survival (OS), or 1- or 2-year survival rates when docetaxel, cisplatin, and 5fluorouracil (5-FU) combination therapy, epirubicin, cisplatin, and 5-FU combination
therapy, and cisplatin/5-FU therapy were compared in patients with advanced stage
gastric carcinoma. Patients (median age, 53 years) who had not received
chemotherapy and had an Eastern Cooperative Oncology Group performance status of
2 or less were randomized to 1 of 3 groups: docetaxel 75 mg/m(2) and cisplatin 75
mg/m(2) on day 1 with 5-FU 750 mg/m(2) daily for 5 days every 3 weeks (DCF,
n=40), epirubicin 50 mg/m(2) and cisplatin 60 mg/(m2) every 3 weeks plus 5-FU 250
mg/m(2) daily (ECF, n=40), or cisplatin 100 mg/m(2)/d on Day 1 with 5-FU 1000
mg/m(2) daily for 5 days every 4 weeks (CF, n=36). The DCF, ECF, and CF groups
received a median of 6, 5, and 5 cycles of chemotherapy. Objective response rates in
the DCF, ECF, and CF groups, respectively, were 40%, 30%, and 18% (p=0.127), PFS
was 5.8 months, 4.4 months, and 4.3 months (p=0.054), median OS was 9.6 months,
10.1 months, and 7.4 months (p=0.106), 1-year survival was 41%, 40%, and 18%,
and 2-year survival was 27%, 9%, and 3%. The DCF group had significantly more
cases of neutropenia and neuropathy compared to ECF or CF, and dose reductions
were required in 50% of patients receiving DCF, 38% receiving ECF, and 39%
receiving CF [441].
Head and neck cancer, Advanced
a) CISPLATIN 100 mg/m(2) plus FLUOROURACIL 1 gram/m(2) may be superior to
SINGLE AGENT FLUOROURACIL or CISPLATIN in patients with advanced HEAD AND
NECK CANCER (Jacobs et al, 1992). Two hundred forty-nine patients were randomly
assigned to either cisplatin (n=84), fluorouracil (n=84) or cisplatin plus fluorouracil
(n=81) for 3 weeks. The overall response rate with the combination therapy (32%)
was superior to that of either single agent cisplatin (17%) or fluorouracil (13%).
However, no complete responses occurred and there was no significant difference in
median survival (5.7 months) among the 3 groups.
Metastatic colorectal cancer
a) Bimonthly high-dose leucovorin and bolus fluorouracil plus continuous infusion
fluorouracil was more effective and less toxic than
a monthly low-dose leucovorin

and
147/317
fluorouracil was more effective and less toxic than a monthly low-dose leucovorin and
bolus fluorouracil regimen in patients (n=448) with previously untreated metastatic
colorectal cancer [425].
b) In a randomized trial of patients (n=429) with metastatic colorectal cancer, the
combination of fluorouracil and leucovorin demonstrated a therapeutic advantage
(improved tumor response rates and survival) over fluorouracil alone. Only low-dose
leucovorin plus fluorouracil was associated with a significant (p less than 0.05)
superiority in quality of life, performance status, weight gain, and symptomatic relief.
The following 6 regimens were compared [426]:
Fluorouracil 500 mg/m(2)/day IV bolus Days 1 through 5; Repeat course every 5
weeks OR
Fluorouracil 325 mg/m(2)/day IV bolus; Cisplatin 20 mg/m(2)/day over 2 hours; All
repeated days 1 through 5; Repeat course every 5 weeks OR
Methotrexate 200 mg/m(2) IV over 4 hours; Fluorouracil 900 mg/m(2) bolus IV (7 hrs
after the beginning of methotrexate); Leucovorin 14 mg/m(2) orally every 6 hrs for 8
doses (begin 24 hrs after the start of the methotrexate infusion); Repeat course at 3,
6 weeks and then every 4 weeks OR
Methotrexate 40 mg/m(2) IV on days 1 and 8; Fluorouracil 700 mg/m(2) IV bolus 24
hrs after each dose of methotrexate; Repeat cycle every 28 days OR
Leucovorin 200 mg/m(2)/day IV bolus followed by Fluorouracil 370 mg/m(2)/day IV
bolus; All repeated days 1 through 5; Repeat course at 4, 8 weeks, then every 5
weeks OR
Leucovorin 20 mg/m(2)/day IV bolus immediately followed by Fluorouracil 370
mg/m(2)/day IV bolus; All repeated days 1 through 5; Repeat course at 4, 8 weeks,
then every 5 weeks
mg/m(2) = milligrams/square meter; IV = intravenous; CIV = continuous intravenous
infusions; hrs = hours;
Neoplasm of gastrointestinal tract
a) In a phase II study (n=65), median survival was similar for 5-FU/6S-LV5
(fluorouracil and leucovorin; 8 months) and EEP-L (epirubicin, etoposide, cisplatin,
lonidamine; 9 months). Neither regimen produced a complete response; however,
partial responses were achieved in 28.2% and 21.9% of patients treated with 5FU/6S-LV and EEP-L, respectively. In both groups, partial responses were more
frequent in patients with resection of the primary tumor and a performance status of 0
or 1. Treatment was well tolerated with no treatment-related deaths. The 5-FU/6S-LV
regimen consisted of 6S-LV 100 milligrams/square meter (mg/m(2)) followed by 5-FU
370 mg/m(2) daily on days 1 to 5; both administered by intravenous bolus injection.
EEP-L consisted of epirubicin 30 mg/m(2) on days 1 and 5; etoposide 100 mg/m(2) on
days 1,3,and 5; cisplatin 30 mg/m(2) on days 2 and 4; and lonidamine 50 mg orally 3
times daily, continuously. Both regimens were repeated every 4 weeks (Barone et al,
1998).
b) The FAMTX regimen (methotrexate 1.5 grams/square meter (g/m(2)), fluorouracil

1.5 g/m(2), and doxorubicin 30 milligrams/m(2) produced comparable results to the
EAP regimen with much less toxicity in one study. Sixty patients with advanced gastric
cancer were randomly assigned to the EAP or FAMTX regimen. Objective responses
were observed in 20% of the patients in the EAP group and 30% in the FAMTX group.
Three patients in the FAMTX experienced complete remissions, but none occurred in
the EAP group. The median survival in the 2 groups were similar (EAP, 6.1 months;
FAMTX, 7.3 months) [424].
Ovarian cancer
a) Cyclophosphamide plus hexamethylmelamine, alternating with doxorubicin and a 5day course of cisplatin (CHAP-5), was reported more effective than the combination of
hexamethylmelamine, cyclophosphamide, methotrexate, and 5-fluorouracil (HexaCAF)
in the treatment of advanced ovarian carcinoma. CHAP-5 treatment resulted in more
complete remissions, better overall response and longer survival. Complete remission
occurred in 40% of CHAP-5-treated patients as compared with 19% of HexaCAFtreated patients. Overall survival duration was 30.7 months in CHAP-5-treated
patients and 19.6 months in Hexa-CAF-treated patients [417].
Colony Stimulating Factor
Breast cancer
a) A multicenter phase III study comparing NEOADJUVANT chemotherapy regimens
demonstrated that dose intensified EPIRUBICIN and CYCLOPHOSPHAMIDE (EC) did
not provide improved progression-free survival (PFS), overall survival (OS), or
response rate compared to a standard delivery schedule of CYCLOPHOSPHAMIDE,
EPIRUBICIN, and FLUOROURACIL (CEF) in women with locally advanced breast
cancer. Eligible patients had no evidence of metastasis and no prior treatment for
breast cancer. Patients (n=448) were randomly assigned to receive dose intensified
EC plus granulocyte colony-stimulating factor (G-CSF) or standard schedule CEF; all
patients received prophylactic therapy with trimethoprim-sulfamethoxazole during
treatment and tamoxifen (20 milligrams (mg) per day) following chemotherapy until
progression or for 5 years if no progression. The dose intensified EC group (n=224)
received epirubicin (120 mg per square meter (mg/m(2))) intravenously (IV) on day 1,
cyclophosphamide (830 mg/m(2)) IV on day 1, and G-CSF (5 micrograms per kilogram
per day (mcg/kg/day)) subcutaneously (SC) days 2 through 13, every 14 days for 6
cycles. The CEF group (n=224) received cyclophosphamide (75 mg/m(2)) orally day 1
through 14, epirubicin (60 mg/m(2)) IV days 1 and 8, and fluorouracil (500 mg/m(2))
IV days 1 and 8, cycled every 28 days. Complete clinical response (CR) rates were
31.3% and 26.5% for the CEF and EC groups, respectively. Following chemotherapy,
382 patients had local therapy; 195 had surgery then radiotherapy, 94 had surgery
alone, 59 had radiotherapy alone, and 34 had radiotherapy then surgery. With a
median follow up of 5.5 years, median PFS was 34 months and 33.7 months in the CEF
and EC groups, respectively. Five year OS was 53% and 51% in the CEF and EC
groups, respectively. A subgroup analysis compared PFS and OS in patients with
locally advanced and inflammatory breast cancer; median PFS was 44 months and
23.5 months (p=0.0019) and OS was 59% and 44% (p=0.0043) for the locally
advanced (n=242) and inflammatory (n=206) subgroups, respectively. There were no
significant differences in the incidence of grade 3 to 4 toxicity between the CEF and
EC groups; 46 patients had a significant drop in left ventricular ejection fraction (19
25/10/12
CEF, 27 EC) that led to congestive heart failure in 4 patients (2 CEF, 2 EC). Two toxic
deaths, 1 due to congestive heart failure and 1 due to febrile neutropenia, were
reported in the CEF group (Therasse el al, 2003).
b) Following breast cancer surgery, a tailored FEC (fluorouracil (5-FU), epirubicin,
c) In a phase III study of women with metastatic breast cancer (n=151), a
comparison of an accelerated-intensified regimen of CYCLOPHOSPHAMIDE,
EPIRUBICIN, and FLUOROURACIL (CEF) with GRANULOCYTE COLONY-STIMULATING
FACTOR (G-CSF) support and a standard CEF regimen showed no significant
differences in overall response rate (51% versus 49%), median time to disease
progression (12.8 versus 14.3 months), or overall survival (27.2 versus 32.7 months).
The complete response rate was slightly higher in the accelerated-intensified CEF
regimen (HD-CEF14) compared with the standard CEF regimen (CEF21; 20% versus
15%) but toxicities were increased. The HD-CEF14 regimen consisted of
cyclophosphamide 1000 milligrams/square meter (mg/m(2)), epirubicin 80 mg/m(2),
and fluorouracil 600 mg/m(2) intravenously (IV) on day 1, every 14 days. G-CSF
(lenograstim) 263 micrograms was self-administered subcutaneously on days 4
through 11 after each cycle of HD-CEF14. The CEF21 regimen consisted of
cyclophosphamide 600 mg/m(2), epirubicin 60 mg/m(2), and fluorouracil 600
mg/m(2) IV on day 1, every 21 days. Grade 3/4 toxicity in the HD-CEF14 arm
compared with the CEF21 arm included anemia (18.6% versus 2.8%), leukopenia
(22.7% versus 4.2%), thrombocytopenia (9.3% versus 1.4%), mucositis (13.3%
versus 2.8%), nausea/vomiting (14.7% versus 15.3%), alopecia (88.0% versus
95.8%), bone pain (6.7% versus 0%), and asthenia (6.7% versus 2.8%). The authors
do not recommend the use of an accelerated-intensified regimen of CEF outside the
setting of clinical trials (Del Mastro et al, 2001).
Cyclophosphamide
Breast cancer
a) Goserelin was as effective and well-tolerated as the three-drug cytotoxic
combination of cyclophosphamide, methotrexate, and fluorouracil (CMF) when used in
premenopausal, estrogen-receptor (ER) positive, node-positive early localized breast
150/317
cancer. CMF was preferred in ER-negative patients, as well as those with unknown
status. The Zoladex Early Breast Cancer Research Association (ZEBRA) trial
randomized 1,614 premenopausal or perimenopausal women 50 years old or younger
with node-positive stage II operable breast cancer without metastasis. After local
therapy (surgical with or without radiotherapy), 797 patients randomized to goserelin
(3.6 milligrams (mg) depot subcutaneously every 28 days for 2 years) and 817
randomized to CMF (per cycle: C=500 mg per meter square IV on day 1 and 8 or 100
mg/m(2) orally days 1 through 14; M=40 mg/m(2) IV days 1 and 8; F 600 mg/m(2) IV
days 1 and 8) for 6 28-day cycles became the primary efficacy population cohorts.
Disease-free (DFS) and overall survival (OS) were the primary outcomes. Trial design
anticipated 688 outcome events; data analysis was performed after 684 events. After
adjusting for age, tumor size, and number of positive lymph nodes, the following
hazard ratios (HR), confidence intervals (CI) and statistical significance were
calculated (HR ratios less than 1 favor goserelin) for the median follow up time of 6
years:
DISEASE-FREE SURVIVAL
SUBGROUP ANALYSIS
HR
CI
All (n=1614)
1.2
1.0-1.4
ER+ (n=1189)
1.0
0.8-1.2
ER- (n=304)
1.8
1.3-2.4
ER unknown (n=121)
2.0
1.1-3.8
OVERALL SURVIVAL
SUBGROUP ANALYSIS
HR
CI
All (n=1614)
1.2
1.0-1.5
ER+ (n=1189)
1.0
0.8-1.3
ER- (n=304)
1.8
1.2-2.6
ER unknown (n=121)
1.8
0.8-4.1
p
0.029
0.94
0.0006
0.026
p
0.67
0.92
0.0043
0.14
b) From overall survival statistics, 183 of 194 deaths due to breast cancer were
recorded among goserelin patients, compared to 151 of 165 for CMS patients (overall
death rates of 25% verus 20%). Side effect profiles (cytotoxic dominant or endocrinerelated) were reflective of the type of treatment received; overall approximately 15%
of either treatment group reported a serious adverse event, but leading to treatment
withdrawal in fewer than 2% (Jonat et al, 2002).
c) A randomized, phase II study demonstrated comparable efficacy between ECycloF
151/317
25/10/12
d) Survival is NOT improved for women with metastatic breast cancer undergoing
INDUCTION AND
MAINTENANCE
INFUSION)
Doxorubicin
30 mg/m(2) days 1
and 8 IV
14 days PO
Fluorouracil
500 mg/m(2) days 1
and 8 IV
Methotrexate*
40 mg/m(2) days 1
and 8 IV
Thiotepa
Carboplatin
IV=intravenous
PO=oral
e) Four to six cycles of induction therapy were given every 28 days. Patients
f) In one study, 1- or 2-year therapy with CMFVP (CYCLOPHOSPHAMIDE,
METHOTREXATE, FLUOROURACIL, VINCRISTINE, PREDNISONE) produced
statistically similar survival or disease-free survival rates. Median follow-up duration in
this study was 8.6 years (maximum of 11.3 years) and 445 ER-negative, node-positive
breast cancer patients were enrolled. Five-year survival was 57% and 62% in the 1and 2-year therapy groups, respectively. Although, not statistically different, 2 years of
therapy produced a moderate improvement in survival over 1 year of therapy (57% vs
62%). This improvement should be weighed against the difficulty (ie, toxicity) of
152/317
25/10/12
administering 2 years of CMFVP therapy (Rivkin et al, 1993).

g) A multicenter phase III study comparing NEOADJUVANT chemotherapy regimens
h) No difference in survival or progression free survival was detected in patients with
al, 1998).
i) Following breast cancer surgery, a tailored FEC (fluorouracil (5-FU), epirubicin,
153/317
25/10/12

j) Five-year disease-free survival (DFS) and 5-year overall survival (OS) were
significantly increased in patients with breast cancer and axillary node involvement
(n=565) who received ADJUVANT chemotherapy with FLUOROURACIL, EPIRUBICIN,
and CYCLOPHOSPHAMIDE (FEC) with an epirubicin dose of 100 milligrams/square
meter (mg/m(2)) (FEC 100) compared to an epirubicin dose of 50 mg/m(2) (FEC 50).
Five-year DFS was 66.3% with FEC 100 and 54.8% with FEC 50 (p=0.03); 5-year OS
was 77.4% for FEC 100 and 65.3% for FEC 50 (p=0.007). Patients with operable
breast cancer with either three positive nodes or between one and three positive
nodes with Scarff Bloom Richardson (SBR) grade of 2 or greater and both estrogen
and progesterone receptor negativity were enrolled. Patients were randomized to
receive 6 cycles of FEC 100 (fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2), and
cyclophosphamide 500 mg/m(2) every 21 days) or 6 cycles of FEC 50 (fluorouracil 500
mg/m(2), epirubicin 50 mg/m(2), and cyclophosphamide 500 mg/m(2) every 21
days). Treatment was started within 42 days after initial surgery. Tamoxifen (30
mg/day) was prescribed to postmenopausal patients for 3 years starting with the first
chemotherapy cycle. A comparison of grade 3/4 toxicity in the FEC 100 group versus
the FEC 50 group included neutropenia (25.2%, 11.1%), anemia (0.8%, 0%),
nausea/vomiting (34.7%, 23.3%), stomatitis (3.8%, 0%), alopecia (78.8%, 20.1%),
and infection (3.4%, 0%). During chemotherapy, 13 cardiac abnormalities were
diagnosed (7 in the FEC 100 group, 6 in the FEC 50 group) which included 3 grade 2
conditions requiring treatment interruptions (2 in the FEC 100 group, 1 in the FEC 50
group). There were 10 cases of delayed cardiac toxicity (decrease in left ventricular
ejection fraction or congestive heart failure and one myocardial infarction) in patients
who had received regional radiation. Contralateral breast cancer developed in 21
patients (FEC 100, n=7; FEC 50, n=14), acute leukemia occurred in 2 patients (FEC
100, n=1; FEC 50, n=1), and 14 patients developed second malignancies (FEC 100,
n=7; FEC 50, n=7). This study was not powered for a subset analysis, however the
authors note that the difference in 5-year DFS and 5-year OS was significant only in
patients with more than three positive nodes (Anon, 2001).
k) Two doxorubicin-containing regimens were equally effective in the treatment of
154/317
25/10/12
advanced breast cancer in a Phase III trial (n=177). The FAC regimen consisted of 5fluorouracil (5-FU) 500 milligrams/square meter (mg/m(2)), doxorubicin 50 mg/m(2)
and cyclophosphamide 500 mg/m(2), each given intravenously on day 1 of a 21-day
cycle for a median duration of 5 cycles. The NA regimen included doxorubicin (same
dose and frequency) plus vinorelbine 25 mg/m(2) on days 1 and 8 of a 21-day cycle
for a median of 4 cycles. The average dose intensity of doxorubicin was 90% with FAC
and 83% with NA. The overall response rates for FAC and NA were 74% and 75%,
respectively (p = NS). Corresponding median overall survival rates were 17.3 and 17.8
months, respectively (p = NS). The subset of patients with liver metastases had
significantly improved survival with NA as compared to FAC (p = 0.04). The only
significant differences in toxicity profiles were higher incidences of constipation,
neuropathy, phlebitis and cutaneous toxicity with NA, and a higher incidence of
cardiotoxicity with FAC (Blajman et al, 1999).
l) In a multicenter phase III randomized study, CYCLOPHOSPHAMIDE,
MITOXANTRONE, and FLUOROURACIL (CNF) demonstrated an improved disease-free
survival compared with cyclophosphamide, methotrexate, and fluorouracil (CMF) as
adjuvant therapy for stage II lymph-node positive breast cancer. All patients had
undergone either modified radical mastectomy or lumpectomy with axillary lymph
node dissection. Of the 145 evaluable patients, 77 (average age 46.3 years) received
CMF and 68 (average age 45.5 years) received CNF. The CMF regimen included
cyclophosphamide 600 milligrams/square meter (mg/m(2)), methotrexate 40
mg/m(2), and fluorouracil 600 mg/m(2). The CNF regimen included cyclophosphamide
500 mg/m(2), mitoxantrone 12 mg/m(2), and fluorouracil 500 mg/m(2). Both
chemotherapy regimens were administered every 21 days for 6 courses. The overall
survival demonstrated no significant difference between the 2 regimens at a median
follow up of 4.5 years (mean survival time of 4.6 and 4.4 years for CMF and CNF
regimens, respectively). Disease-free survival was significantly lower for the CMF
regimen compared with the CNF regimen (2.7 years versus 4.4 years, respectively; p
= 0.04). Relapse occurred in 14 and 30 patients treated with the CNF and CMF
regimens, respectively. Alopecia occurred in significantly more patients receiving the
CNF regimen compared with the CMF regimen (29% versus 17%, respectively; p less
than 0.05). Thrombocytopenia (p less than 0.01), leukopenia (p less than or equal to
0.001), and decreased hemoglobin (p less than or equal to 0.001) were reported in
significantly more patients treated with the CNF regimen compared with the CMF
regimen. However, no patient required treatment discontinuation or dose reduction
due to toxicity (Ron et al, 2001).
m) Escalating doses of ACMF (DOXORUBICIN, CYCLOPHOSPHAMIDE,
METHOTREXATE, 5-FLUOROURACIL) over a shorter period, even with doses within
the conventional range, were superior to low-dose, prolonged therapy. A study was
conducted in premenopausal, node- positive breast cancer patients receiving either 6
cycles of conventional-dose ACMF or 12 cycles of low-dose ACMF (n=93, n=97,
respectively). Although both treatment regimens were well tolerated overall, more
patients receiving the low-dose 12-cycle refused therapy. Also, there were nonsignificant trends toward better disease-free and overall survival rates in the highdose, six-cycle ACMF group (Fukutomi et al, 1995).
n) No difference in survival or progression free survival was detected in patients with
155/317
25/10/12

al, 1998).
o) The combination regimen CEF (CYCLPHOSPHAMIDE, EPIRUBICIN,
FLUOROURACIL) demonstrated superior survival benefit compared to CMF
(CYCLOPHOSPHAMIDE, METHOTREXATE, FLUOROURACIL) in a large study (n=710)
evaluating premenopausal women with node-positive breast cancer. Women
previously untreated for breast cancer were randomized to receive monthly
treatments of either CEF (cyclophosphamide 75 milligrams/square meter (mg/m(2))
orally days 1 through 14, epirubicin 60 mg/m(2) intravenously (IV) days 1 and 8,
fluorouracil 500 mg/m(2) IV days 1 and 8) or CMF (cyclophosphamide 100 mg/m(2)
orally days 1 through 14, methotrexate 40 mg/m(2) IV days 1 and 8, fluorouracil 600
mg/m(2) IV days 1 and 8). Both regimens were administered for 6 cycles. Relapsefree survival at 5 years in the CEF and CMF groups was 63% and 53% respectively
(p=0.009). Overall survival was 77% and 70% in the CEF and CMF groups
respectively (p=0.03). Survival stratified to 1 to 3 nodes or greater than 3 nodes was
82% and 70% in the CEF group respectively. For patients in the CMF group it was
78% and 58% respectively. Quality-of-life summary scores were identical in both
groups by 6 months after chemotherapy, however, the mean score in the CEF group
decreased to a nadir more quickly than in the CMF group. This was possibly due to a
difference in acute toxicity between the 2 regimens. Greater toxicity was noted in
patients receiving the CEF regimen. Comparison of grade 3/4 toxicities in the CEF and
CMF groups respectively was nausea (13.4%, 3.1%), vomiting (11.4%, 4.1%),
diarrhea (0.9%, 2.2%), stomatitis (12.3%, 1.9%), alopecia (42.2%, 6.7%),
granulocytopenia (97.7%, 78.3%), thrombocytopenia (9.4%, 3.7%), leukopenia
(94.1%, 60.4%) (Levine et al, 1998).
p) In one study, 1-year or 2-year therapy with CMFVP (CYCLOPHOSPHAMIDE,
statistically similar survival or disease-free survival rates (Rivkin et al, 1993). Median
follow-up duration in this study was 8.6 years (maximum of 11.3 years) and 445 ERnegative, node- positive breast cancer patients were enrolled. Five-year survival was
57% and 62% in the 1- and 2-year therapy groups, respectively. Although, not
statistically different, 2 years of therapy produced a moderate improvement in survival
over 1 year of therapy (57% vs 62%). This improvement should be weighed against
the difficulty (ie, toxicity) of administering 2 years of CMFVP therapy.
q) The combination regimen CEF (CYCLOPHOSPHAMIDE, EPIRUBICIN,
156/317
25/10/12

mg/m(2) IV days 1 and 8). Both regimens were administered for 6 cycles. Relapsefree survival at 5 years in the CEF and CMF groups was 63% and 53%, respectively
(p=0.009). Overall survival was 77% and 70% in the CEF and CMF groups,
82% and 70% in the CEF group, respectively. For patients in the CMF group, it was
78% and 58%, respectively. Quality-of-life summary scores were identical in both
groups by 6 months after chemotherapy; however, the mean score in the CEF group
decreased to a nadir more quickly then in the CMF group. This was possibly due to a
CMF groups, respectively, was nausea (13.4%, 3.1%), vomiting (11.4%, 4.1%)
(94.1%, 60.4%) (Levine et al, 1998).
r) No advantage was achieved with 12 versus 6 cycles of CMF (CYCLOPHOSPHAMIDE,
METHOTREXATE, FLUOROURACIL) in the treatment of breast cancer in 622 women
with positive axillary nodes. Following mastectomy, patients were randomized to CMF
for 6 or 12 cycles; those with greater than or equal to 4 positive nodes were
randomized to 1 of the CMF groups or regional radiotherapy followed by 6 cycles of
CMF. No difference in survival or disease-free survival was found among the 3 groups
at 10 years median follow-up. The strongest predictors of survival were positive nodes
(negative correlation) and ideal or full dose of CMF (positive correlation) (Velez-Garcia
et al, 1992).
s) Escalating doses of DOXORUBICIN, CYCLOPHOSPHAMIDE, METHOTREXATE, and
FLUOROURACIL (ACMF) over a short period, even with conventional doses, were
superior to low-dose, prolonged therapy in premenopausal, node-positive breast
cancer patients (n=190). Patients received either 6 cycles of ACMF or 12 cycles of
low-dose ACMF. Both regimens were well tolerated, but more patients receiving the
low-dose 12-cycle regimen refused therapy. Also, there were non-significant trends
toward better disease-free and overall survival rates in the high-dose, 6-cycle ACMF
group (Fukutomi et al, 1995).
t) In a study of 445 patients with node-positive, receptor-negative breast cancer, 1and 2-year therapy with CYCLOPHOSPHAMIDE, METHOTREXATE, FLUOROURACIL,
VINCRISTINE, and PREDNISONE (CMFVP) produced similar survival/disease-free
survival rates. Median follow-up duration was 8.6 years. The 2-year therapy produced
a moderate improvement in survival over the 1-year therapy (57% vs 62%), but the
difficulty (ie, toxicity) of 2-year administration may outweigh the benefit (Rivkin et al,
1993). In another study, maintenance therapy with cyclophosphamide, methotrexate,
and fluorouracil prolonged time to progression, but did not alter overall survival (Muss
et al, 1991).
u) Adjuvant chemotherapy with CMF (CYCLOPHOSPHAMIDE, METHOTREXATE and 5FLUOROURACIL) provided better relapse-free and total survival than SURGERY alone
in node-positive breast cancer patients (n=179, n=207, respectively) in a 20-year
157/317
25/10/12
follow-up study. Relapse-free and overall survivals in premenopausal patients after 20

years were 37% and 47%, respectively, in the CMF-treated group; and for
postmenopausal patients, 26% and 22%, respectively. Relapse-free and overall
survivals in premenopausal patients after 20 years were 26% and 24%, respectively,
in the surgery-alone group; and for the postmenopausal patients, 24% and 22%,
respectively (Bonadonna et al, 1995).
v) A sixteen-week multidrug regimen achieved only marginally better outcomes than
CYCLOPHOSPHAMIDE, DOXORUBICIN, AND FLUOROURACIL (CAF) with similar
toxicity but lower during-treatment quality of life in an intergroup study of 646 nodepositive, receptor-negative breast cancer patients. The patients were randomly
assigned to receive either the 16-week regimen or six cycles of CAF. Each 28-day
cycle of CAF involved cyclophosphamide 100 milligrams/square meter (mg/m(2))
orally days 1 through 14, doxorubicin 30 mg/m(2) and fluorouracil (5-FU) 500
mg/m(2) intravenously (IV) days 1 and 8. The 16-week regimen consisted of greater
doxorubicin and 5-FU dose intensity than CAF and sequential administration of
methotrexate and 5-FU, as well as continuous 5-FU infusion. The 16-week regimen
involved weekly treatments, ODD-NUMBERED WEEKS as cyclophosphamide 100
mg/m(2) orally days 1 through 7, doxorubicin 40 mg/m(2) IV day 1, methotrexate 100
mg/m(2) IV day 1, vincristine 1 mg IV day 1, 5-FU 600 mg/m(2) IV day 2 at 20 hours
after methotrexate. Leucovorin 10 mg/m(2) was administered orally every 6 hours for
six doses, beginning 24 hours after methotrexate. During EVEN-NUMBERED WEEKS,
patients received 5-FU 300 mg/m(2) daily continuous IV infusion days 1 and 2. Dose
modification occurred based upon toxicity evaluated and classified by the Common
Toxicity Criteria. The 4-year recurrence- free survival rate for the 16-week regimen
was 67.5% versus 62.7% for CAF (P=0.19, two-sided; P=0.095, one-sided), with a
median follow-up of 3.9 years. The estimated 4-year survival rate was 78.1% for the
16-week regimen and 71.4% for CAF (P=0.10, two-sided; P=0.05, one-sided).
Leukopenia, granulocytopenia, and thrombocytopenia were significantly worse with
CAF than with the 16-week regimen (P=0.0001, 0.003, and 0.0001 respectively).
Anemia was significantly higher with the 16-week regimen (P=0.0001). Febrile
neutropenia hospital admission was not significantly different between the two
regimens. Other significantly worse adverse events in the 16-week regimen were
stomatitis (P=0.0001), skin toxicity (P=0.0003), neurotoxicity (P=0.0001 to 0.04),
nausea (P=0.05) and weight loss (P=0.0001). Of the 163 patients participating in the
quality-of-life study, the during-treatment evaluation was significantly lower in the 16week regimen than with CAF (P=0.04), but was insignificant by 4 months posttreatment (P=0.60). Due to the complicated schedule and only marginally improved
outcomes as compared with CAF, the 16-week regimen should not be substituted for
CAF without careful consideration (Fetting et al, 1998).
w) In a phase III study of women with metastatic breast cancer (n=151), a
158/317
25/10/12

x) In a phase III trial of women with metastatic breast cancer (n=267), median time
to disease progression, overall survival, and response rate were significantly increased
with DOXORUBICIN and PACLITAXEL (AT) versus FLUOROURACIL, DOXORUBICIN,
and CYCLOPHOSPHAMIDE (FAC) as first-line therapy for metastatic disease. Median
time to disease progression was 8.3 months with AT compared with 6.2 months with
FAC (p=0.034) and overall survival was 23.3 months and 18.3 months, respectively
(p=0.013). Overall response rate was 68% in the AT arm and 55% in the FAC arm
(p=0.032). The AT regimen consisted of doxorubicin 50 milligrams/square meter
(mg/m(2)) administered intravenously (IV) on day 1 followed 24 hours later with
paclitaxel 220 mg/m(2) administered IV over 3 hours. The FAC regimen consisted of
5- fluorouracil 500 mg/m(2) IV, doxorubicin 50 mg/m(2) IV, and cyclophosphamide
500 mg/m(2) IV. Both regimens were administered every 3 weeks for 8 cycles. Grade
3/4 toxicity with the AT regimen compared with the FAC regimen included
neutropenia (89% versus 65%, p less than 0.001), thrombocytopenia (2% versus
3%), anemia (9% versus 7%), fever (8% versus 4%), infection (2% versus 0%),
arthralgia/myalgia (10% versus 0%; p less than 0.001), peipheral neuropathy (12%
versus 0%; p less than 0.001), nausea/vomiting (8% versus 19%; p=0.028), diarrhea
(2% versus 0%), and stomatitis (1% for both)(Jassem et al, 2001).
y) In a phase III trial of women with metastatic breast cancer (n=281), a comparison
of MITOXANTRONE and VINORELBINE (MV) with FLUOROURACIL,
CYCLOPHOSPHAMIDE, and either DOXORUBICIN or EPIRUBICIN (FAC/FEC) showed
that there was no significant difference in overall response (OR) rate (34.5% versus
33.3%), median overall survival (20 versus 17 months), or progression- free survival
(PFS; 7 months for both). Patients who had received prior neoadjuvant/adjuvant
therapy with FAC/FEC and subsequently received MV rather than FAC/FEC had a
higher OR rate (33% versus 13%, p=0.025), a longer PFS (8 versus 5 months;
p=0.0007), and a longer OS (20 versus 16 months; p=0.25). Patients who had not
received prior neoadjuvant/adjuvant therapy and subsequently received FAC/FEC
rather than MV had a higher OR rate (43% versus 35%, p=0.26), a longer PFS (9
versus 6 months, p=0.014), and a longer OS (22 versus 16 months, p=0.027). Febrile
neutropenia and delayed hematological recovery was more frequent in the MV arm
(p=0.001) but grade 3/4 nausea/vomiting was greater in the FAC/FEC arm (p=0.031)
as was alopecia (p=0.0001). The MV regimen consisted of mitoxantrone 12
milligrams/square meter (mg/m(2)) administered intravenously (IV) on day 1 and
vinorelbine 25 mg/m(2) IV on days 1 and 8. The choice of FAC or FEC was decided by
participating institution preference with all patients at one institution receiving the
159/317
same regimen. The FAC/FEC regimen consisted of fluorouracil 500 mg/m(2) IV on day
1, doxorubicin or epirubicin 50 mg/m(2) on day 1, and cyclophosphamide 500
mg/m(2) IV on day 1. Cycles of both MV and FAC/FEC were repeated every 21 days.
Grade 3/4 neutropenia occurred in 15% of cycles of MV and 8% of cycles of FAC/FEC
with febrile neutropenia in 15% of patients in the MV arm and 2% of patients in the
FAC/FEC arm (p=0.001). A comparison of grade 3/4 nonhematologic toxicity in the
FAC/FEC group and the MV group included nausea/vomiting (16% versus 8%,
p=0.031) and alopecia (30% versus 7%, p=0.001)(Namer et al, 2001).
z) A randomized, phase II study demonstrated comparable efficacy between ECycloF
aa) The French Epirubicin Study Group compared varying doses of epirubicin in 3
regimens of FLUOROURACIL, EPIRUBICIN, and CYCLOPHOSPHAMIDE (FEC) in a
phase III, randomized trial of patients with metastatic breast cancer (n=417).
Regimen A (11 cycles of fluorouracil 500 milligrams/square meter (mg/m(2)),
epirubicin 75 mg/m(2), and cyclophosphamide 500 mg/m(2) (FEC 75) every 21 days)
produced a response rate of 56.9% (20.8% complete response (CR), 36.1% partial
response (PR)). Regimen B (12 cycles with the same doses of fluorouracil and
cyclophosphamide; the first 4 cycles with an epirubicin dose of 100 mg/m(2) (FEC
100) followed by 8 cycles of an epirubicin dose of 50 mg/m(2) (FEC 50)) produced a
response rate of 64.0% (16.9% CR, 47.1% PR). Regimen C (4 cycles of FEC 100 with
the same regimen restarted at disease progression or stabilization) produced a
response rate of 47.6% (7.9% CR, 39.7% PR) (p=0.06). For regimens A, B, and C,
median duration of response was 8.9 months, 8.5 months, and 6.3 months,
respectively (p=0.012), median time to disease progression was 10.3 months, 8.3
months, and 6.2 months, respectively (p less than 0.001), and median overall survival
was 17.9 months, 18.9 months, and 16.3 months, respectively (p=0.49). There were
no significant differences in hematologic toxicity among the 3 regimens. A comparison
of grade 3/4 toxicities in regimens A, B, and C included neutropenia (21.1%, 18.8%,
15.0%), anemia (3.9%, 3.8%, 1.8%), nausea/vomiting (24.6%, 39.6%, 33.9%),
stomatitis (2.4%, 11.2%, 18.3%), alopecia (75.2%, 81.3%, 81.5%), and grade 4
infection (3.2%, 0.8%, 1.7%). Six patients (4 who received regimen A and 2 who
received regimen C) died of sepsis. During chemotherapy, 19 cardiac abnormalities
were diagnosed (regimen A, n=9; regimen B, n=8; regimen C, n=2) which included a
decrease in left ventricular ejection fraction (n=12) and lower limb edema (n=1);
there were no cases of congestive heart failure or cardiac deaths. Although there was
160/317
25/10/12
no significant difference in overall survival among the 3 regimens, the results suggest
that epirubicin dose escalation improves the response rate, whereas longer treatment
improves the duration of responses and the time to disease progression (Anon, 2000).
ab) Tamoxifen 10 mg PO twice daily was reported as effective as a combination of
cyclophosphamide, methotrexate and 5-fluorouracil (CMF) in the initial treatment of
stage IV breast cancer in elderly woman (over the age of 65 years). Response rates
were 45% and 38% in tamoxifen and CMF-treated patients, respectively; an
additional 33% and 45% of patients treated with tamoxifen and CMF, respectively,
had disease stabalization for at least 2 months. Survival rates favored tamoxifen as
initial therapy (23 months versus 21 months for CMF), which reached a border line
level of significance (p=0.08) in the proportional hazards model. Additional disease
control with hormone withdrawal was observed in 23% of patients, and was
correlated highly with prior hormonal response. Upon crossover to the opposite
treatment, response to either tamoxifen or the CMF regimen was less than that
observed when given as initial therapy (29% and 31%, respectively). A previous
response to CMF tended to be associated with a better chance for tamoxifen
response; however, a previous response with tamoxifen did not predict CMF response.
Initiation of hormone therapy as opposed to CMF chemotherapy is recommended in
most elderly patients (Taylor et al, 1986).
ac) In an intent-to-treat analysis, overall response rate was improved in metastatic
breast cancer patients who received CYCLOPHOSPHAMIDE, EPIRUBICIN, and
FLUOROURACIL (CEF; n=223) compared to those who received
CYCLOPHOSPHAMIDE, METHOTREXATE, and FLUOROURACIL (CMF; n=237; P=0.01).
In an analysis of assessable patients, response rates were 66% for CEF (n=189) and
52% for CMF (n=200; p=0.005). Median time to progression was 8.7 months for CEF
versus 6.3 months for CMF (p=0.01) but overall survival was not significantly different
for CEF and CMF (20.1 months and 18.2 months, respectively; p=0.23). Patients were
randomized to receive either cyclophosphamide (400 milligrams/square meter
(mg/m(2) intravenously (IV)), epirubicin (50 mg/m(2) IV), and fluorouracil (500
mg/m(2) IV on days 1 and 8 of each cycle), or cyclophosphamide (500 mg/m(2) IV),
methotrexate (40 mg/m(2) IV), and fluorouracil (600 mg/m(2) on days 1 and 8 of
each cycle). Cycles were repeated every 3 or 4 weeks (depending on toxicity
recovery) for a total of 6 cycles (or until disease progression, toxicity, or patient
refusal occurred) or for a total of 9 cycles if complete or partial response occurred. A
comparison of grade 3/4 toxicity in the CEF versus the CMF group included
granulocytopenia (78%, 68%), leukopenia (66%, 58%), nausea/vomiting (21%,
14%), diarrhea (1%, 2%), and mucositis (12%, 15%). Other toxicities in the CEF
versus CMF group included grade 4 infections (0.5%, 1%), febrile neutropenia (11%,
8%), and alopecia (66%, 14%). In the CEF group, 19 patients had a significant
decrease in left ventricular ejection fraction (LVEF)(greater than 20% from baseline or
greater than 10% below the lower limit of normal) with a median cumulative dose of
epirubicin of 582 mg/m(2). Fifteen patients in the CEF group discontinued treatment
because of adverse cardiac events including 6 patients with declines in LVEF, 3
patients with congestive heart failure (CHF), and 3 patients with changes on
electrocardiogram (ECG). In the CMF group, 2 patients had significant falls in LVEF as
previously described. The authors conclude that this dose and schedule of CEF is a
safe and effective option as first-line chemotherapy for metastatic breast cancer
(Ackland et al, 2001).
161/317
25/10/12
ad) MITOMYCIN plus high-dose MEDROXYPROGESTERONE was comparable to CAF

(CYCLOPHOSPHAMIDE, DOXORUBICIN, FLUOROURACIL) in the treatment of
metastatic breast cancer. Following first relapse, 34 patients were randomized to
either treatment (n=18, n=18, respectively). Nine of 18 patients receiving mitomycin
plus medroxyprogesterone had objective responses; median time to treatment failure
was 5.7 months; median survival was 22.5 months. Twelve of the 18 patients
receiving CAF had objective responses; median time to treatment failure was 7.6
months; median survival was 16.7 months. Objective responses were not significantly
different between the 2 regimens (Falkson et al, 1992).
ae) The combination regimen CEF (CYCLPHOSPHAMIDE, EPIRUBICIN,
orally days 1 through 14, methotrexate 40 mg/m(2) IV days 1 and 8, and fluorouracil
600 mg/m(2) IV days 1 and 8). Both regimens were administered for 6 cycles.
Relapse-free survival at 5 years in the CEF and CMF groups was 63% and 53%
respectively (p=0.009). Overall survival was 77% and 70% in the CEF and CMF
groups respectively (p=0.03). Survival stratified to 1 to 3 nodes or greater than 3
nodes was 82% and 70% in the CEF group respectively. For patients in the CMF group
it was 78% and 58% respectively. Quality-of-life summary scores were identical in
both groups by 6 months after chemotherapy, however; the mean score in the CEF
group decreased to a nadir more quickly than in the CMF group. This was possibly due
to a difference in acute toxicity between the 2 regimens. Greater toxicity was noted in
(94.1%, 60.4%) (Levine et al, 1998).
af) In premenopausal women with node-positive operable breast cancer, FEC
(FLUOROURACIL, EPIRUBICIN, and CYCLOPHOSPHAMIDE) provided better overall
and relapse-free survival than CMF (FLUOROURACIL, METHOTREXATE, and
CYCLOPHOSPHAMIDE). The authors compared two separate dosing schedules for
each adjuvant combination (CMF1 and CMF2; FEC1 and FEC2) and observed a
clinically significant benefit only when FEC2 was compared with CMF2. Both schedules
included cyclophosphamide and fluorouracil in equivalent doses of 600
milligrams/square meter. CMF2 was administered on days 1 and 8 and included
methotrexate 40 milligrams/square meter. The FEC2 combination included epirubicin
50 milligrams/square meter on day 1, the other two agents being given without
epirubicin on day 8. Five-year survival rates among the CMF2 group (n=199) and the
FEC2 group (n=200) were 73.8% and 86.6%, respectively, (p=0.03). Nausea,
vomiting, and alopecia were more frequent with either of the two FEC combinations
compared with the CMF combinations (Coombes et al, 1996).
ag) The combination regimen CEF (CYCLOPHOSPHAMIDE, EPIRUBICIN,
162/317
25/10/12
(CYCLOPHOSPHAMIDE, METHOTREXATE FLUOROURACIL) in a large study (n=710)

patients receiving the CEF regimen. Comparison of grade 3 and 4 toxicities in the CEF
and CMF groups, respectively, were nausea (13.4%, 3.1%), vomiting (11.4%, 4.1%)
granulocytopenia (97.7%, 78.3%), thrombocytopenia (9.4%, 3.7%), and leukopenia
(94.1%, 60.4%) (Levine et al, 1998).
ah) In an intent-to-treat analysis, overall response rate was improved in metastatic
CYCLOPHOSPHAMIDE, METHOTREXATE, and FLUOROURACIL (CMF; n=237; p=0.01).
each cycle). Cycles were repeated every 3 or 4 weeks for a total of 6 cycles or for a
total of 9 cycles if complete or partial response occurred. A comparison of grade 3/4
toxicity in the CEF versus the CMF group included granulocytopenia (78%, 68%),
leukopenia (66%, 58%), nausea/vomiting (21%, 14%), diarrhea (1%, 2%), and
mucositis (12%, 15%). Other toxicities in the CEF versus CMF group included grade 4
infections (0.5%, 1%), febrile neutropenia (11%, 8%), and alopecia (66%, 14%). In
the CEF group, 19 patients had a significant decrease in left ventricular ejection
fraction (LVEF)(greater than 20% from baseline or greater than 10% below the lower
limit of normal) with a median cumulative dose of epirubicin of 582 mg/m(2). Fifteen
patients in the CEF group discontinued treatment because of adverse cardiac events
including 9 patients with declines in LVEF, 3 patients with congestive heart failure
(CHF), and 3 patients with changes on electrocardiogram (ECG). In the CMF group, 2
patients had significant falls in LVEF as previously described. The authors conclude
that this dose and schedule of CEF is a safe and effective option as first-line
chemotherapy for metastatic breast cancer (Ackland et al, 2001).
163/317
25/10/12
ai) In a randomized comparison (n=78), an FAC regimen (intravenous doxorubicin,

oral cyclophosphamide, intravenous fluorouracil) and an FPC regimen (intravenous
pirarubicin, oral cyclophosphamide, intravenous fluorouracil) were comparable in
efficacy in predominantly pretreated patients with advanced breast cancer. Objective
responses (complete or partial) were observed in 30% and 35% of patients,
respectively. A complete response was reported in 1 patient in each group. Durations
of partial response were 19 weeks with FPC and 14 weeks in the FAC group. Alopecia
was significantly less frequent with the FPC regimen; electrocardiogram abnormalities
occurred in 3 of 16 evaluable patients in the FAC group (18%) but in none of 23
evaluated in the FPC group (Tominaga et al, 1989).
aj) Escalating doses of ACMF (DOXORUBICIN, CYCLOPHOSPHAMIDE,
conducted in premenopausal, node-positive breast cancer patients receiving either 6
cycles of ACMF or 12 cycles of low-dose ACMF (n=93, n=97, respectively). Although
both treatment regimens were well tolerated overall, more patients receiving the lowdose 12-cycle refused therapy. Also, there were non-significant trends toward better
disease-free and overall survival rates in the high-dose, six-cycle ACMF group
(Fukutomi et al, 1995).
ak) No advantage was observed with 12 versus 6 cycles of CMF
(CYCLOPHOSPHAMIDE, METHOTREXATE, FLUOROURACIL) in the treatment of breast
cancer in 622 women with positive axillary nodes. Following mastectomy, patients
were randomized to CMF for 6 or 12 cycles; those with greater than or equal to 4
positive nodes were randomized to 1 of the CMF groups or regional radiotherapy
followed by 6 cycles of CMF. There was no difference in survival or disease-free
survival among the 3 groups at approximately 10 years median follow-up. The
strongest predictors of survival were positive nodes (negative correlation) and ideal or
full dose of CMF (positive correlation) (Velez-Garcia et al, 1992).
al) In one study, 1-year or 2-year therapy with CMFVP (CYCLOPHOSPHAMIDE,
this study was 8.6 years (maximum of 11.3 years) and 445 estrogen receptor (ER)negative, node- positive breast cancer patients were enrolled. Five-year survival was
(57% vs 62%) over 1 year of therapy. This improvement should be weighed against
the difficulty (ie, toxicity) of administering 2 years of CMFVP therapy (Rivkin et al,
1993).
am) Prolonged survival, reduced myleosuppression, and a slightly higher quality of life
rating was observed following first-line treatment with paclitaxel as compared to the
combination of cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone in
patients with metastatic breast cancer. Two hundred and nine women (median age 54
years) were randomized to receive paclitaxel (200 milligrams per square meter
(mg/m(2)) every 21 days for 8 courses (n=107) or cyclosphosphamide (100 mg/m(2)
orally (PO) on days 1 to 14), methotrexate (40 mg/m(2) intravenously (IV) on days 1
and 8), 5-fluorouracil (600 mg/m(2) IV on days 1 and 8), and prednisone (40 mg/m(2)
PO on days 1 to 14) every 28 days for 6 courses (n=102). Objective response rates
were similar in paclitaxel-treated patients (29%: 2% complete, 27% partial) and in
164/317
25/10/12
those treated with combination therapy (35%: 6% complete, 29% partial).

Multivariate analysis revealed a signifcantly improved survival with paclitaxel therapy
(17.3 months versus 13.9 months, p=0.025). Leukopenia, thrombocytopenia,
mucositis, and nausea/vomiting were less severe with paclitaxel treatment. Febrile
neutropenia with or without infection occurred significantly less frequently with
paclitaxel as compared to combination therapy (10% versus 27%, p=0.001) and
required fewer hospital days for appropriate treatment (1.5 days versus 4.4 days,
p=0.0006). However, paclitaxel caused more alopecia, myalgia, and peripheral
neuropathy than combination therapy. Quality of life measures, including physical wellbeing, mood, and appetite were slightly better in paclitaxel-treated patients, but the
differences between groups were not statistically significant.
an) An overall response rate of 65% (2 complete, 18 partial) was achieved with
combination MITOXANTRONE, LEUCOVORIN, and FLUOROURACIL among 31 patients
with metastatic breast cancer. Patients received intravenous mitoxantrone 12
milligrams/square meter (mg/m(2)) on day 1, and leucovorin 300 milligrams as a 1hour infusion followed by fluorouracil 350 milligrams/square meter IV push on days 1,
2 and 3, repeated every 21 days. Response duration ranged from 3 to 16+ months
(Hainsworth et al, 1991). The above regimen was tested in another study with the
addition of fluorouracil (NFL) 350 mg/m(2) IV bolus on days 1,2,and 3 (Hainsworth et
al, 1997). The regimen was compared to combination (CMF) cyclophosphamide 600
mg/m(2) IV, methotrexate 40 mg/m(2) IV, and fluorouracil 600 mg/m(2) given on day
one. The regimens were repeated at 21-day intervals and given to chemotherapynaive patients with metastatic breast cancer. The NFL and CMF regimens produced a
45% vs 26% response rate, respectively, which was significantly different, (p=0.021).
Although median survival was similar in both groups, the median duration of response
was 9 months and 6 months in the NFL and CMF groups respectively, (p=0.06).
ao) A randomized, phase II study demonstrated comparable efficacy between
ECycloF (EPIRUBICIN, CYCLOPHOSPHAMIDE, and FLUOROURACIL (5-FU)) and ECisF
ap) EPIRUBICIN (E) on days 1 and 8 in combination with 5-FLUOROURACIL (FU) and
CYCLOPHOSPHAMIDE (C) provided no advantage in efficacy over epirubicin on day 1
only in a phase II study of 104 patients with metastatic breast cancer. Patients were
randomized to receive C and FU 500 milligrams per square meter (mg/m(2)) on day 1
and E 40 mg/m(2) on days 1 and 8 (n=52) or C and FU (same doses) plus E 80
mg/m(2) on day 1 (n=52) every 21 days for 6 cycles. There was no difference
between treatment schedules regarding overall response rates (50% versus 52%),
165/317
25/10/12
duration of response (11 months versus 10 months), or overall survival (16 months
versus 14 months). A significantly higher relative dose- intensity for E was observed
for the day 1 versus day 1 plus 8 scheduling (89% versus 78%, p=0.0006), as well as
for C and FU (90% versus 80%, p=0.0037). Most dosage reductions and delays in
therapy were due to hematologic toxicity (van Toorn et al, 2000).
aq) Patients treated with HIGH-DOSE EPIRUBICIN (EPI), FLUOROURACIL (5-FU),
and CYCLOPHOSPHAMIDE (CYC) (FEC-100) had a higher objective response rate
(p=0.007) but no difference in duration of response or survival was demonstrated
compared to LOW-DOSE EPIRUBICIN (FEC-50). This was a multicenter, international
study (n=453) conducted in women with metastatic breast cancer, many of whom
had undergone radical mastectomy with some also receiving adjuvant chemotherapy
at the time of initial diagnosis (cumulative anthracycline dose 60 mg/m(2) or less).
Upon study entry patients were randomly assigned to receive EPI 100 mg/m(2), 5-FU
500 mg/m(2), and CYC 500 mg/m(2) or EPI 50 mg/m(2) with the same dose of 5-FU
and CYC. Each cycle was repeated every 21 days, if toxicity allowed, and 6 cycles
were planned. With the FEC-100 regimen, grade IV neutropenia and infections
occurred in 57% and 8% of patients, respectively, versus 9% and 0.4% of patients,
respectively, for the FEC-50 regimen; deaths from infectious complications were
reported in 2 patients in each arm. Significant decreases in left ventricular enddiastolic pressure (LVEF) were noted in 23 and 12 patients receiving FEC-100 and
FEC-50, respectively. Two patients (1 in each arm) developed congestive heart failure.
While toxicity was acceptable in this study and overall response was greater with
FEC-100, it did NOT increase survival. Further study of this regimen is needed in the
adjuvant setting or of epirubicin in combination with highly active new agents
(taxoids) (Brufman et al, 1997).
ar) Paclitaxel alone demonstrated efficacy equivalent to that of the combination of
doxorubicin, fluorouracil and cyclophosphamide as neoadjuvant therapy of operable
(stage IIA to IIIA) breast cancer in a randomized trial (n=174). When administered
preoperatively as four 21-day cycles, paclitaxel 250 milligrams/square meter
(mg/m(2)) as a 24-hour intravenous (IV) infusion resulted in an 80% response rate
(27% complete plus 53% partial). The combination regimen, consisting of fluorouracil
500 mg/m(2) IV on days 1 and 4, cyclophosphamide 500 mg/m(2) IV on day 1 and
doxorubicin 50 mg/m(2) as a 72-hour IV infusion, elicited a statistically similar 79%
response rate (24% complete plus 55% partial). The incidences of in situ or no
residual disease in the breast at surgery were 14% and 23% in the paclitaxel and
combination arms, respectively (p not significant). Other parameters including nodal
disease at surgery, pathologic stage after neoadjuvant therapy, type of surgery and
use of irradiation also did not differ significantly between groups. Toxicities such as
neutropenic fever, myalgias and paresthesias were numerically more frequent in the
paclitaxel group, but were not analyzed statistically (Buzdar et al, 1999).
as) The French Epirubicin Study Group (Anon, 1991) compared EPIRUBICIN alone (75
milligrams/square meter) with 2 FEC regimens (EPIRUBICIN 75 milligrams/square
meter plus FLUOROURACIL and CYCLOPHOSPHAMIDE (FEC-75) or EPIRUBICIN 50
milligrams/square meter plus FLUOROURACIL and CYCLOPHOSPHAMIDE (FEC-50)) in
a randomized trial involving 412 advanced breast cancer patients. Patients had not
received prior chemotherapy for advanced disease. Overall response rates were
identical with FEC-75 and FEC-50 (45%), and both combination regimens were
statistically superior to EPIRUBICIN alone (overall response rate, 31%). Complete
166/317
25/10/12
responses were more frequent with the FEC-75 regimen (16%) as compared to FEC50 (7%) and EPIRUBICIN alone (4%). Median durations of response were similar with
all regimens (315 to 395 days); times to progression and survival were not different
among the 3 groups, although more early relapses occurred in patients receiving
EPIRUBICIN alone and FEC-50. Therapy had to be discontinued due to cardiac toxicity
more frequently in the EPIRUBICIN and FEC-75 arms.
167/317
25/10/12

168/317
25/10/12
0%, 5%) [413].
Cytarabine
Gastric cancer
a) Postoperative maintenance adjuvant immunotherapy with intramuscular PICIBANIL
alone has been significantly more effective than commensurability with intramuscular
picibanil plus MFC (mitomycin, fluorouracil, and cytarabine) in patients with advanced
untreated gastric cancer following palliative gastrectomy. All patients received
induction commensurability with intramuscular picibanil plus MFC for 6 weeks
following surgery; 8 weeks after surgery, patients were randomized to picibanil alone
or picibanil plus MFC, and maintenance therapy was continued until death. Survival
rates following 8 months of therapy were 81% and 57% in patients receiving
maintenance picibanil alone and picibanil plus MFC, respectively. However, analysis
based on carcinoma histology revealed a significant difference in survival rates only in
patients with an undifferentiated histology (poorly differentiated adenocarcinoma,
signet-ring cell carcinoma) as compared to those with differentiated histology. It is
speculated that the MFC regimen may have concealed the immunopotentiating effect
of picibanil, accounting for greater benefits with picibanil alone. Based on these
results, picibanil maintenance therapy alone appears preferable to picibanil plus MFC,
particularly in patients with undifferentiated gastric cancer (Yasue et al, 1981).
However, further studies are required to confirm these findings.
Dexamethasone
Metastasis from malignant tumor of colon
a) In 156 patients who underwent complete resection of hepatic metastases from
colorectal cancer, the postoperative combination of hepatic arterial infusion of
floxuridine (FUDR) and systemic intravenous fluorouracil (5-FU), with or without
leucovorin, demonstrated an improved two-year overall survival and decreased rate of
recurrence compared with systemic chemotherapy alone. Beginning four weeks after
resection, a total of 74 patients were randomized to receive six cycles of the
combination therapy, administered as a intravenous bolus of 5-FU 325 milligrams
(mg)/square meter daily for 5 days, preceded each day by a 30- minute infusion of
leucovorin 200 mg/square meter. Two weeks later, hepatic arterial infusion of FUDR
0.25 mg/kilogram (kg)/day, dexamethasone 20 mg, and heparin 50,000 units was
administered for 14 days, followed by a 1-week rest period. Among the 82 patients
randomized to receive six cycles of systemic monotherapy beginning 4 weeks after
resection, 5-FU was administered as 370 mg/square meter intravenously for 5 days
every four weeks, following leucovorin 200 mg/square meter. If a patient in either
study group had previously received 5-FU and leucovorin, 5-FU alone was
administered by continuous infusion at a dose of 850 mg/square meter for 5 days
every five weeks in the combination therapy group and 1000 mg/square meter for 5
days every four weeks in the monotherapy group. The two-year overall actuarial
survival rate was 86% in the combination therapy group compared with 72% in the
monotherapy group (p=0.03). The estimated median survival was 72.2 months in the
combination therapy group and 59.3 months in the monotherapy group, with a median
follow-up of 62.7 months. After adjustment for the location of primary tumor (rectum
versus colon) and largest liver lesions (greater than or equal to 5 centimeters (cm)
versus less than 5 cm), the risk ratio for death at two years in the systemic therapy
alone group as compared with the combination therapy
group was 2.34 (95%
169/317
25/10/12
alone group as compared with the combination therapy group was 2.34 (95%
confidence interval, 1.10 to 4.98; p=0.027). The rate of survival free of hepatic
recurrence after two years was 90% in the combination therapy group and 60% in the
monotherapy group (p less than 0.001). The two-year actuarial rates of overall
progression-free survival were 57% in the combination therapy group and 42% in the
monotherapy group (p=0.07). The median duration of progression- free survival was
37.4 and 17.2 months in the combination therapy and monotherapy groups,
respectively. Adverse effects of moderate severity were similar in both groups, with
the exception of a higher frequency of diarrhea (29% versus 14%) and hepatic effects
in the combination therapy group. In the combination therapy group, doubling of the
serum alkaline phosphatase level occurred in 29%, tripling of the serum aspartate
aminotransferase level occurred in 65%, and increased total bilirubin levels to more
than 3.0 mg per deciliter occurred in 18% of patients. Hospitalization for diarrhea,
leukopenia, mucositis, or small bowel obstruction was required in 29 and 18 patients
in the combination therapy and monotherapy groups, respectively (p=0.02) (Kemeny
et al, 1999).
Docetaxel
Breast cancer
a) DOCETAXEL MONOTHERAPY was associated with a significantly longer time to
progression (6.3 months) compared to METHOTREXATE and 5-FLUOROURACIL (MF)
combination therapy (3.0 months; p less than 0.001) in patients (n=282) with
advanced breast cancer who had failed anthracycline treatment. Patients enrolled in
this open-label, randomized study received docetaxel 100 milligrams/square meter
(mg/m(2)) over 1 hour every 3 weeks or sequential methotrexate 200 mg/m(2) and
5-fluorouracil 600 mg/m(2) on days 1 and 8 every 3 weeks. Patients who relapsed on
randomized study treatment were encouraged to crossover to the alternate
treatment. Eight percent of docetaxel patients and 3% of MF patients experienced
complete response. Almost twice as many docetaxel patients experienced a partial
response (34%) compared to MF (18%). Docetaxel was associated with more toxicity
than MF with 3 treatment related deaths in the docetaxel arm and one in the MF arm
(Sjostrom et al 1999).
Gastric cancer
10.1 months, and 7.4 months (p=0.106), 1-year
survival was 41%, 40%, and 18%,

170/317
25/10/12
receiving CF [441].
171/317
0%, 5%) [413].
Doxifluridine
Colorectal cancer
a) SUMMARY: Oral DOXIFLURIDINE and 5-FLUOROURACIL have similar efficacy in
the treatment of gastric cancer. Adverse effects profiles favor doxifluridine in some
investigations, but not in others.
b) According to a randomized prospective study, DOXIFLURIDINE (5-DFUR) proved
to be as efficacious as 5-FLUOROURACIL (5-FU) in patients with advanced gastric
cancer who needed supportive therapy, but in whom intensive chemotherapy was not
an option; the adverse effect profile of 5-DFUR was slightly more favorable compared
with 5-FU [429]. Enrollees in the 5-DFUR group (n=75) received oral 5-DFUR 800
milligrams (mg)/body/day and those in the 5-FU group (n=75) received oral 5-FU 200
mg/body/day, both therapies continuing daily for 4 weeks or more until evidence of
disease progression was observed (use of body terminology in dosing not explained).
There were no significant differences between groups in survival time (median survival
time 223 and 165 days for 5-DFUR and 5-FU, respectively). Median hospital-free
survival time and median time to disease progression were 159 and 89 days for 5DFUR, and 111 and 66 days for 5- FU. Adverse drug reactions occurred in 4.9% of the
5-DFUR group compared with 9.9% of the 5-FU group. Grade 3 and higher adverse
events occurred in 2.4% of 5-DFUR-treated patients (stomatitis, leukopenia)
compared with 6.2% of 5-FU-treated patients (diarrhea, anorexia, and abdominal
pain).
c) In a large randomized study (n=222), intravenous doxifluridine was similarly as
effective as intravenous 5-fluorouracil in the treatment of patients with locally
advanced or metastatic colorectal carcinoma. Doxifluridine 4 grams/square meter/day
and 5-fluorouracil 400 milligrams/square meter/day were each given as a 1-hour
infusion for 5 days every 28 days. Response rates of 5% and 0.9%, respectively, were
observed (not a significant difference). The median duration of response was similar
in each group (26 to 27 weeks), as was median survival time (48 weeks with
doxifluridine, 39 weeks with 5-fluorouracil). The median time to progression was,
however, significantly longer in the doxifluridine group (18 weeks versus 13 weeks).
Toxicity with doxifluridine was significant, and greater than that of 5-fluorouracil
(leukopenia, gastrointestinal toxicity, neurologic toxicity) [430].
d) Smaller comparative studies employing daily intravenous bolus doses or 1-hour
infusions of doxifluridine (4 grams/square meter) and 5-fluorouracil (450
milligrams/square meter) for 5 days every 3 to 4 weeks have suggested an advantage
of doxifluridine (response rates of 20% versus 7%) [431][432]; however, the small
number of patients treated in these studies does not enable an adequate comparison,
and the larger trial is more relevant [430]. Neurotoxicity and cardiotoxicity were
greater with doxifluridine in the study using intravenous bolus doses [432].
Malignant tumor of rectum
a) No differences were noted in efficacy, toxicity, and quality of life when intravenous
172/317
25/10/12
(IV) fluorouracil (5-FU) and leucovorin were compared to oral DOXIFLURIDINE and
leucovorin in 28 patients with advanced rectal cancer. Complete and partial responses
were observed in 21% and 14%, 50% and 43%, respectively (p=0.168; p=0.235).
Mean follow-up period was 15 months with local (oral groups) and 3 systemic failures
(1 IV, 2 oral; p=0.307). Fair and good quality of life scores showed no difference
between the 2 groups. Patients received either a intravenous bolus infusion of 5-FU
450 milligrams per square meter/day (mg/ m(2)/d) (mean age 50 years; n=14) in
combination with leucovorin 20 mg/ m (2)/d for 5 consecutive days on the first and
fifth weeks of concurrent radiotherapy or oral DOXIFLURIDINE 700 mg/ m(2)/d (mean
age 52 years; n=14)in combination with leucovorin 20 mg/m(2)/d continuously during
radiotherapy. Toxicities included diarrhea, stomatitis and leukopenia (not different
between the 2 groups). In this small prospective study, DOXIFLURIDINE, a synthetic
5-deoxynucleoside derivative, offered no significant advantage over intravenous 5-FU
in preoperative concurrent chemoradiotherapy (Kim et al, 2001).
Neoplasm of rectum
Mean follow-up period was 15 months with 1 local (oral group) and 3 systemic failures
among the 2 groups. Patients received either a intravenous bolus infusion of 5-FU 450
milligrams per square meter/day (mg/ m(2)/d) (mean age 50 years; n=14) in
combination with leucovorin 20 mg/m(2)/d for 5 consecutive days on the first and fifth
weeks of concurrent radiotherapy or oral DOXIFLURIDINE 700 mg/ m(2)/d (mean age
52 years; n=14)in combination with leucovorin 20 mg/m(2)/d continuously during
radiotherapy. Toxicities included diarrhea, stomatitis and leukopenia (no difference
5-deoxynucleoside derivative, offered no significant advantage over intravenous 5- FU
Doxorubicin
Breast cancer
INDUCTION AND
MAINTENANCE
INFUSION)
Doxorubicin
30 mg/m(2) days 1
and 8 IV
14 days PO
Fluorouracil
500 mg/m(2) days 1
and 8 IV
Methotrexate*
40 mg/m(2) days 1
173/317
25/10/12
and 8 IV
Thiotepa
Carboplatin
IV=intravenous
PO=oral
c) Two doxorubicin-containing regimens were equally effective in the treatment of
d) Escalating doses of ACMF (DOXORUBICIN, CYCLOPHOSPHAMIDE,
174/317
25/10/12
e) Escalating doses of DOXORUBICIN, CYCLOPHOSPHAMIDE, METHOTREXATE, and

f) A sixteen-week multidrug regimen achieved only marginally better outcomes than
g) In a phase III trial of women with metastatic breast cancer (n=267), median time
175/317

h) In a phase III trial of women with metastatic breast cancer (n=281), a comparison
i) MITOMYCIN plus high-dose MEDROXYPROGESTERONE was comparable to CAF
j) In a randomized comparison (n=78), an FAC regimen (intravenous doxorubicin, oral
cyclophosphamide, intravenous fluorouracil) and an FPC regimen (intravenous
176/317
25/10/12

k) Escalating doses of ACMF (DOXORUBICIN, CYCLOPHOSPHAMIDE,
l) Paclitaxel alone demonstrated efficacy equivalent to that of the combination of
resulted in longer survival, tolerable toxicity, and a better quality of life compared with
the ECF regimen compared with 21% of patients treated with the FAMTX regimen.
With the ECF regimen, 9 patients underwent complete resections versus 4 patients
treated with the FAMTX regimen. Mucositis, nephrotoxicity,
and hematologic toxicity

177/317
25/10/12
treated with the FAMTX regimen. Mucositis, nephrotoxicity, and hematologic toxicity
resulting in infections occurred significantly more often in patients treated with the
FAMTX regimen; whereas, the ECF regimen resulted in more alopecia and central
venous line complications. Median survival time was significantly (p=0.0009) longer
with ECF (8.9 months) compared with FAMTX (5.7 months) [438]. Based on this trial,
the ECF regimen should be offered to all patients with advanced esophagogastric
cancer who have an acceptable performance status.
Gastric cancer
a) Survival rates with FLUOROURACIL ALONE were similar to those observed with
FLUOROURACIL plus DOXORUBICIN with or without MITOMYCIN in patients with
advanced pancreatic and gastric carcinoma (n=305). Single-agent fluorouracil was
administered as 500 milligrams/square meter per day for 5 days, repeated at 4 and 8
weeks, and every 5 weeks thereafter. Due to the greater cost and toxicity of
combination therapy, the authors advocate FLUOROURACIL monotherapy in advanced
pancreatic or gastric cancer (Cullinan et al, 1985).
b) Fluorouracil alone (500 milligrams/square meter (mg/m(2)) daily for 5 days per
course, repeated at 4 and 8 weeks and every 5 weeks thereafter) was as effective as
a combination of fluorouracil plus doxorubicin, or a combination of fluorouracil plus
doxorubicin plus mitomycin C, with regard to patient survival in the treatment of
advanced pancreatic and gastric carcinoma in a study involving 305 patients with
advanced disease. Except for diarrhea and stomatitis, blood dyscrasias and nonhematologic toxicity (GI disturbances, alopecia) were greater with the combination
regimens; both stomatitis and diarrhea occurred more frequently in patients receiving
fluorouracil alone. The authors indicate that, due to failure to induce improved survival
or palliation combined with excessive cost of combination therapy and greater toxicity,
neither combination is indicated over fluorouracil alone in advanced pancreatic or
gastric cancer (Cullinan et al, 1985).
a) The combination of STREPTOZOCIN plus DOXORUBICIN was superior to
STREPTOZOCIN plus 5-FLUOROURACIL or CHLOROZOTOCIN alone in the treatment
of advanced islet-cell carcinoma in a multicenter study enrolling 105 patients. The
dose of streptozocin was 500 milligrams/square meter (mg/m(2))/day given every 6
weeks. Doxorubicin was administered at 50 mg/m(2) on day 1 of streptozocin and for
day 22 of each 6-week cycle. Tumor regression occurred in 69% and 45% of patients
receiving streptozocin plus doxorubicin and streptozocin plus 5-fluorouracil,
respectively; time to tumor progression was 20 versus 6.9 months, respectively.
Survival was also extended in the streptozocin plus doxorubicin group, 2.2 versus 1.4
years, respectively. Chlorozotocin alone produced a 30% regression rate with length
of time to tumor progression and survival time equivalent to the streptozocin plus 5fluorouracil group (Moertel et al, 1992).
b) A later retrospective analysis of 16 patients receiving the previously described
regimen of streptozocin and doxorubicin revealed only a 6% (ie, 1 of 16) response
rate to therapy. Nine patients (56%) had stable disease, and 6 patients (38%)
showed disease progression. Proposed reasons for this discrepancy are that previous
trials have accepted a so-called "biologic response" and the clinical measurement of
hepatomegaly on physical examination or measurement on radionuclide liver-spleen
scan as indicators of a major objective response. The authors conclude that an
expectation of frequent major tumor regressions after treatment with this regimen
178/317
25/10/12
may be overly optimistic (Cheng & Saltz, 1999).

a) The FAMTX regimen (methotrexate 1.5 grams/square meter (g/m(2)), fluorouracil
Pancreatic cancer
Doxorubicin Hydrochloride
179/317
25/10/12
180/317
25/10/12
0%, 5%) [413].
Epirubicin
Breast cancer
a) A randomized, phase II study demonstrated comparable efficacy between ECycloF
b) A multicenter phase III study comparing NEOADJUVANT chemotherapy regimens
181/317
al, 1998).
182/317
25/10/12
e) Five-year disease-free survival (DFS) and 5-year overall survival (OS) were
f) No difference in survival or progression free survival was detected in patients with
al, 1998).
g) The combination regimen CEF (CYCLPHOSPHAMIDE, EPIRUBICIN,
183/317

(94.1%, 60.4%) (Levine et al, 1998).
h) The combination regimen CEF (CYCLOPHOSPHAMIDE, EPIRUBICIN,
(94.1%, 60.4%) (Levine et al, 1998).
i) In a phase III study of women with metastatic breast cancer (n=151), a
j) In a phase III trial of women with metastatic breast cancer (n=281), a comparison
k) A randomized, phase II study demonstrated comparable efficacy between ECycloF
25/10/12

l) The French Epirubicin Study Group compared varying doses of epirubicin in 3
regimens of FLUOROURACIL, EPIRUBICIN, and CYCLOPHOSPHAMIDE (FEC) in a
phase III, randomized trial of patients with metastatic breast cancer (n=417).
Regimen A (11 cycles of fluorouracil 500 milligrams/square meter (mg/m(2)),
epirubicin 75 mg/m(2), and cyclophosphamide 500 mg/m(2) (FEC 75) every 21 days)
produced a response rate of 56.9% (20.8% complete response (CR), 36.1% partial
response (PR)). Regimen B (12 cycles with the same doses of fluorouracil and
cyclophosphamide; the first 4 cycles with an epirubicin dose of 100 mg/m(2) (FEC
100) followed by 8 cycles of an epirubicin dose of 50 mg/m(2) (FEC 50)) produced a
response rate of 64.0% (16.9% CR, 47.1% PR). Regimen C (4 cycles of FEC 100 with
the same regimen restarted at disease progression or stabilization) produced a
response rate of 47.6% (7.9% CR, 39.7% PR) (p=0.06). For regimens A, B, and C,
median duration of response was 8.9 months, 8.5 months, and 6.3 months,
respectively (p=0.012), median time to disease progression was 10.3 months, 8.3
months, and 6.2 months, respectively (p less than 0.001), and median overall survival
was 17.9 months, 18.9 months, and 16.3 months, respectively (p=0.49). There were
no significant differences in hematologic toxicity among the 3 regimens. A comparison
of grade 3/4 toxicities in regimens A, B, and C included neutropenia (21.1%, 18.8%,
15.0%), anemia (3.9%, 3.8%, 1.8%), nausea/vomiting (24.6%, 39.6%, 33.9%),
stomatitis (2.4%, 11.2%, 18.3%), alopecia (75.2%, 81.3%, 81.5%), and grade 4
infection (3.2%, 0.8%, 1.7%). Six patients (4 who received regimen A and 2 who
received regimen C) died of sepsis. During chemotherapy, 19 cardiac abnormalities
were diagnosed (regimen A, n=9; regimen B, n=8; regimen C, n=2) which included a
decrease in left ventricular ejection fraction (n=12) and lower limb edema (n=1);
there were no cases of congestive heart failure or cardiac deaths. Although there was
no significant difference in overall survival among the 3 regimens, the results suggest
that epirubicin dose escalation improves the response rate, whereas longer treatment
improves the duration of responses and the time to disease progression (Anon, 2000).
m) In an intent-to-treat analysis, overall response rate was improved in metastatic
186/317

n) The combination regimen CEF (CYCLPHOSPHAMIDE, EPIRUBICIN,
orally days 1 through 14, methotrexate 40 mg/m(2) IV days 1 and 8, and fluorouracil
600 mg/m(2) IV days 1 and 8). Both regimens were administered for 6 cycles.
Relapse-free survival at 5 years in the CEF and CMF groups was 63% and 53%
respectively (p=0.009). Overall survival was 77% and 70% in the CEF and CMF
groups respectively (p=0.03). Survival stratified to 1 to 3 nodes or greater than 3
nodes was 82% and 70% in the CEF group respectively. For patients in the CMF group
it was 78% and 58% respectively. Quality-of-life summary scores were identical in
both groups by 6 months after chemotherapy, however; the mean score in the CEF
group decreased to a nadir more quickly than in the CMF group. This was possibly due
to a difference in acute toxicity between the 2 regimens. Greater toxicity was noted in
(94.1%, 60.4%) (Levine et al, 1998).
o) In premenopausal women with node-positive operable breast cancer, FEC
25/10/12

p) The combination regimen CEF (CYCLOPHOSPHAMIDE, EPIRUBICIN,
(94.1%, 60.4%) (Levine et al, 1998).
q) In an intent-to-treat analysis, overall response rate was improved in metastatic
188/317
r) A randomized, phase II study demonstrated comparable efficacy between ECycloF
s) EPIRUBICIN (E) on days 1 and 8 in combination with 5-FLUOROURACIL (FU) and
CYCLOPHOSPHAMIDE (C) provided no advantage in efficacy over epirubicin on day 1
only in a phase II study of 104 patients with metastatic breast cancer. Patients were
randomized to receive C and FU 500 milligrams per square meter (mg/m(2)) on day 1
and E 40 mg/m(2) on days 1 and 8 (n=52) or C and FU (same doses) plus E 80
mg/m(2) on day 1 (n=52) every 21 days for 6 cycles. There was no difference
between treatment schedules regarding overall response rates (50% versus 52%),
duration of response (11 months versus 10 months), or overall survival (16 months
versus 14 months). A significantly higher relative dose- intensity for E was observed
for the day 1 versus day 1 plus 8 scheduling (89% versus 78%, p=0.0006), as well as
for C and FU (90% versus 80%, p=0.0037). Most dosage reductions and delays in
therapy were due to hematologic toxicity (van Toorn et al, 2000).
t) Patients treated with HIGH-DOSE EPIRUBICIN (EPI), FLUOROURACIL (5-FU), and
CYCLOPHOSPHAMIDE (CYC) (FEC-100) had a higher objective response rate
(p=0.007) but no difference in duration of response or survival was demonstrated
compared to LOW-DOSE EPIRUBICIN (FEC-50). This was a multicenter, international
study (n=453) conducted in women with metastatic breast cancer, many of whom
had undergone radical mastectomy with some also receiving adjuvant chemotherapy
at the time of initial diagnosis (cumulative anthracycline dose 60 mg/m(2) or less).
Upon study entry patients were randomly assigned to receive EPI 100 mg/m(2), 5-FU
500 mg/m(2), and CYC 500 mg/m(2) or EPI 50 mg/m(2) with the same dose of 5-FU
and CYC. Each cycle was repeated every 21 days, if toxicity allowed, and 6 cycles
were planned. With the FEC-100 regimen, grade IV neutropenia and infections
189/317
25/10/12
occurred in 57% and 8% of patients, respectively, versus 9% and 0.4% of patients,

respectively, for the FEC-50 regimen; deaths from infectious complications were
reported in 2 patients in each arm. Significant decreases in left ventricular enddiastolic pressure (LVEF) were noted in 23 and 12 patients receiving FEC-100 and
FEC-50, respectively. Two patients (1 in each arm) developed congestive heart failure.
While toxicity was acceptable in this study and overall response was greater with
FEC-100, it did NOT increase survival. Further study of this regimen is needed in the
adjuvant setting or of epirubicin in combination with highly active new agents
(taxoids) (Brufman et al, 1997).
u) The French Epirubicin Study Group (Anon, 1991) compared EPIRUBICIN alone (75
milligrams/square meter) with 2 FEC regimens (EPIRUBICIN 75 milligrams/square
meter plus FLUOROURACIL and CYCLOPHOSPHAMIDE (FEC-75) or EPIRUBICIN 50
milligrams/square meter plus FLUOROURACIL and CYCLOPHOSPHAMIDE (FEC-50)) in
a randomized trial involving 412 advanced breast cancer patients. Patients had not
received prior chemotherapy for advanced disease. Overall response rates were
identical with FEC-75 and FEC-50 (45%), and both combination regimens were
statistically superior to EPIRUBICIN alone (overall response rate, 31%). Complete
responses were more frequent with the FEC-75 regimen (16%) as compared to FEC50 (7%) and EPIRUBICIN alone (4%). Median durations of response were similar with
all regimens (315 to 395 days); times to progression and survival were not different
among the 3 groups, although more early relapses occurred in patients receiving
EPIRUBICIN alone and FEC-50. Therapy had to be discontinued due to cardiac toxicity
more frequently in the EPIRUBICIN and FEC-75 arms.
resulted in longer survival, tolerable toxicity, and a better quality of life compared with
the ECF regimen compared with 21% of patients treated with the FAMTX regimen.
With the ECF regimen, 9 patients underwent complete resections versus 4 patients
treated with the FAMTX regimen. Mucositis, nephrotoxicity, and hematologic toxicity
resulting in infections occurred significantly more often in patients treated with the
FAMTX regimen; whereas, the ECF regimen resulted in more alopecia and central
venous line complications. Median survival time was significantly (p=0.0009) longer
with ECF (8.9 months) compared to FAMTX (5.7 months) [420]. Based on this trial,
the ECF regimen should be offered to all patients with advanced esophagogastric
cancer who have an acceptable performance status.
Gastric cancer
a) MITOMYCIN, EPIRUBICIN, and FLUOROURACIL did NOT produce a statistically
190/317
25/10/12
significant difference (p=0.310) in disease-free survival compared to NO

chemotherapy in patients with operable gastric cancer. However, patients with lymph
node metastases or low grade differentiation of the tumor showed a trend toward
longer overall survival, although not statistically significant. This study enrolled 92
patients with STAGE I to III disease who had complete resection of the tumor and
lymph nodes or who had poorly differentiated tumors. Within two weeks of surgery,
patients were randomly assigned to treatment with 5-FU 600 milligrams/square meter
(mg/m(2)) (days 1, 8, 29, 36), epirubicin 45 mg/m(2) (days 1 and 29), and mitomycin
10 mg/m(2) (day 1). This 8-week chemotherapy cycle was repeated three times.
Toxicity was manageable and included neutropenia (eg, eight treatment- related
infectious episodes), mucositis, nausea/vomiting, diarrhea, and alopecia. Patients
were followed for a median of 5 years (Tsavaris et al, 1996).
1998).
Epirubicin Hydrochloride
Gastric cancer
191/317
25/10/12
receiving CF [441].
192/317
25/10/12
0%, 5%) [413].
Etoposide
Gastric cancer
a) The combination of etoposide 120 milligrams/square meter (mg/m(2)), epirubicin
30 mg/m(2) and cisplatin 40 mg/m(2) on days 1 and 8 every 4 weeks for a median 3
cycles achieved a disappointing 20% overall response rate in the treatment of
advanced gastric cancer in a Phase III trial (n=131). Substitution of etoposide in a
regimen consisting of 5-fluorouracil 600 mg/m(2), epirubicin 60 mg/m(2) and cisplatin
80 mg/m(2) on day 1 every 4 weeks for a median 2.5 cycles resulted in a statistically
similar 15% response rate. Median progression-free survival was 6 months with the
etoposide regimen versus 7 months with the 5-FU regimen; corresponding overall
survival was 6 and 5 months, respectively (p = NS). The regimens were generally
well-tolerated with no major differences in toxicity. Neither regimen can be
recommended for advanced gastric carcinoma [471].
1998).
Excision of tumor of stomach
Gastric cancer
a) MITOMYCIN, EPIRUBICIN, and FLUOROURACIL did NOT produce a statistically
Floxuridine
193/317
25/10/12

et al, 1999).
a) Meta-analysis of 6 studies showed significantly better 1 (p=0.002) and 2 (p=0.026)
year survival in patients with colorectal cancer and metastases to the liver who were
treated with hepatic regional floxuridine (FUDR) infusion versus systemic FUDR or
fluorouracil (5-FU). When all studies were included, a 1-year survival advantage of
12.9% was noted; however, if studies permitting cross-over to regional therapy after
disease progression were excluded, the survival advantage increased to 19.1%. The
2-year survival advantage was 7.5% or 8.6% if cross-over studies were excluded.
194/317
25/10/12
While regional chemotherapy offers the benefit of relatively few systemic adverse
effects, complications associated with hepatic artery cannulation and hepatic toxicity
are possible. Before regional chemotherapy is considered the treatment of choice for
liver metastases associated with colorectal cancer, additional study is needed to
answer questions concerning quality of life [469].
Gemcitabine
Carcinoma of pancreas, First-line therapy
a) The overall survival was increased by 4.3 months with the combination regimen
(oxaliplatin, leucovorin, irinotecan, fluorouracil (FOLFIRINOX)) treatment compared
with gemcitabine alone in patients with metastatic pancreatic adenocarcinoma who
had not received prior chemotherapy for advanced disease in a multicenter,
randomized, phase 2/3 trial (n=342). Patients (median age, 61 years) were
randomized to the FOLFIRINOX group (oxaliplatin 85 mg/m(2) IV over 2 hours,
immediately followed by leucovorin 400 mg/m(2) IV over 2 hours, with the addition,
after 30 minutes, of irinotecan 180 mg/m(2) IV over 90 minutes through a Yconnector, immediately followed by fluorouracil 400 mg/m(2) IV bolus followed by
fluorouracil 2.4 g/m(2) IV over 46 hours continuous infusion repeated every 2 weeks
(n=171) or gemcitabine 1000 mg/m(2) IV over 30 minutes once weekly for 7
consecutive weeks, followed by one week off treatment; subsequent cycles were
administered once weekly for 3 weeks, followed by one week off treatment (n=171).
The recommended duration of chemotherapy was 6 months. At a median duration of
follow-up of 26.6 months (95% confidence interval (CI), 20.5 to 44.9 months), the
median overall survival (primary endpoint for phase 3) was 11.1 months (95%
confidence interval (CI), 9 to 13.1 months) and 6.8 months (95% CI, 5.5 to 7.6
months) for the FOLFIRINOX and gemcitabine groups (hazard ratio (HR) was 0.57
(95% CI, 0.45 to 9.73; p less than 0.001), respectively. The overall survival rates for
the FOLFIRINOX group and gemcitabine group, respectively, were 75.9% vs 57.6% at
6 months, 48.4% vs 20.6% at 12 months, and 18.6% vs 6% at 18 months. The
adjusted HR for death in the FOLFIRINOX was 0.57 (95% CI, 0.45 to 0.73; p less than
0.001. The objective response (complete + partial response) rate, the primary
endpoint for phase 2, was 31.6% (95% CI, 24.7% to 39.1%) in the FOLFIRINOX
group and 9.4% (95% CI, 5.4% to 14.7%; p less than 0.001) in the gemcitabine
group. The median progression-free survival was 6.4 months (95% CI, 5.5 to 7.2
months) in the FOLFIRINOX group and 3.3 months (95% CI, 2.2 to 3.6 months) in the
gemcitabine group (HR, 0.47 (95% CI, 0.37 to 0.59; p less than 0.001). Grade 3 or 4
adverse events and corresponding rates for the FOLFIRINOX and gemcitabine groups,
respectively, were neutropenia (45.7% vs 21%; p less than 0.001), febrile
neutropenia (5.4% vs 1.2%; p=0.03), thrombocytopenia (9.1% vs 3.6%; p=0.04),
diarrhea (12.7% vs 1.8%; p less than 0.001). sensory neuropathy (9% vs 0%; p less
than 0.001), and elevated level of alanine aminotransferase (7.3% vs 20.8%; p less
than 0.001) [442].
Pancreatic cancer
a) Gemcitabine demonstrated superior efficacy to 5-fluorouracil (5- FU) in the
treatment of chemotherapy-naive patients (n=126) with advanced, nonresectable
pancreas cancer in a randomized, single- blind study. The gemcitabine regimen
consisted of 1000 milligrams/square meter as a 30-minute intravenous infusion once
weekly for 7 weeks, followed by 1 week of rest, then resumed for 3 consecutive weeks
195/317
25/10/12
out of every 4 weeks. 5-FU was administered as 600 milligrams/square meter as a 30minute intravenous infusion once weekly. For the primary outcome measure of clinical
benefit, defined as sustained improvement in a composite of pain, functional
impairment and weight for at least 4 weeks, 24% of gemcitabine-treated patients and
5% of 5-FU-treated patients were classified as responders (p=0.0022). Median
survival (5.65 months versus 4.41 months) and 12-month survival probabilities (18%
versus 2%) increased significantly with gemcitabine compared to 5- FU [421][421].
Goserelin
Breast cancer
years:
SUBGROUP ANALYSIS
HR
CI
All (n=1614)
1.2
1.0-1.4
ER+ (n=1189)
1.0
0.8-1.2
ER- (n=304)
1.8
1.3-2.4
ER unknown (n=121)
2.0
1.1-3.8
OVERALL SURVIVAL
SUBGROUP ANALYSIS
HR
CI
All (n=1614)
1.2
1.0-1.5
ER+ (n=1189)
1.0
0.8-1.3
ER- (n=304)
1.8
1.2-2.6
ER unknown (n=121)
1.8
0.8-4.1
p
0.029
0.94
0.0006
0.026
p
0.67
0.92
0.0043
0.14
196/317
25/10/12
Hemopoietic stem cell transplant

Breast cancer
INDUCTION AND
MAINTENANCE
INFUSION)
Doxorubicin
30 mg/m(2) days 1
and 8 IV
14 days PO
Fluorouracil
500 mg/m(2) days 1
and 8 IV
Methotrexate*
40 mg/m(2) days 1
and 8 IV
Thiotepa
Carboplatin
IV=intravenous
PO=oral
197/317
25/10/12

al, 1998).
Heparin
198/317
25/10/12
et al, 1999).
Hydroxyurea
Cervical cancer
a) In a Phase III trial of 388 subjects with locally advanced stage IIB to IVA cervical
carcinoma, the combination of 5-fluorouracil (5-FU) and cisplatin was superior to
hydroxyurea alone as an adjunct to radiation therapy. Cisplatin 50 milligrams/square
meter/day (mg/m(2)) was administered 4 hours prior to radiation on days 1 and 29,
while 5-FU was dosed at 1 gram/m(2)/day on days 2, 3, 4, 5, 30, 31, 32, and 33.
Patients randomized to oral hydroxyurea received 80 milligrams/kilogram/day twice
weekly. The median duration of therapy in both groups was 9 weeks. After a median
follow-up of 8.7 years, the rates of disease progression were 43% and 53% in the 5FU/cisplatin and hydroxyurea groups, respectively. Corresponding overall mortality
rates were 45% and 57% (p=0.018). Relative risks for progression/death and
mortality were 0.79 (90% confidence interval, 0.62 to 0.99) and 0.74 (90% CI, 0.58 to
0.95), respectively, both favoring the 5-FU/cisplatin regimen. The only statistically
significant difference in toxicity was more frequent/severe neutropenia with
hydroxyurea (p less than 0.00001) [423].
b) In a Phase III trial of 368 eligible subjects with locally advanced stage IIB to IVA
199/317
25/10/12
1999).
c) The combination of CISPLATIN and RADIATION therapy or CISPLATIN,
Interferon Alfa
Colon cancer
a) After enrolling 142 patients with advanced colorectal cancer, a study comparing
fluorouracil (5-FU) to 5-FU plus interferon alpha-2a (IFN) was stopped due to a lower
than expected response to 5-FU plus IFN [458]. Patients were randomly assigned to
receive 5-FU 500 milligrams (mg) on days 1 to 5 followed by 5-FU 500 mg weekly
starting on day 15 or the same dose and schedule of 5-FU plus IFN 1.5 million units
(mU) on days 6 to 12 followed by 3 mU/day thereafter. The overall response
(complete and partial) for 5-FU alone was 12.5% compared to 8.7% for 5-FU plus
IFN; the median time to progression and median survival were the same for both
treatments. Drug-related toxicity was minimal in patients treated with 5-FU alone but
was rated moderate in patients treated with the combination. The combination
regimen is NOT recommended for routine use in clinical practice since it does NOT
improve survival.
Neoplasm of colon
a) The addition of interferon-alfa to FLUOROURACIL and leucovorin was associated
with higher toxicity, especially hematologic, and the combination offered no clinical
advantage in the treatment of metastatic colorectal carcinoma in 50 patients. This
phase II regimen consisted of a 2-hour infusion of leucovorin 500 milligrams/square
meter (mg/m(2)) on 2 consecutive days, and a 48-hour infusion of FLUOROURACIL
1.5 to 2 grams/m(2) per 24 hours starting the day after leucovorin, every two weeks
200/317
25/10/12
until disease progression. Subcutaneous interferon-alfa was given 3 times weekly: 3

million units for a body surface area (BSA) less than 1.75 m(2), or 4.5 million units for
a BSA of 1.75 m(2) or more. Overall response rate was 44% with 21 patients
experiencing Grade 3 to 4 toxicity. The median progression-free survival was 9 months
and the median survival was 25 months (Tournigand et al, 1997).
Interferon Alfa-2a
Colon cancer
a) After enrolling 142 patients with advanced colorectal cancer, a study comparing
fluorouracil (5-FU) to 5-FU plus interferon alpha-2a (IFN) was stopped due to a lower
than expected response to 5-FU plus IFN [464]. Patients were randomly assigned to
receive 5-FU 500 milligrams (mg) on days 1 to 5 followed by 5-FU 500 mg weekly
starting on day 15 or the same dose and schedule of 5-FU plus IFN 1.5 million
international units (mU) on days 6 to 12 followed by 3 mU/day thereafter. The overall
response (complete and partial) for 5-FU alone was 12.5% compared to 8.7% for 5FU plus IFN; the median time to progression and median survival were the same for
both treatments. Drug-related toxicity was minimal in patients treated with 5-FU
alone but was rated moderate in patients treated with the combination. The
combination regimen is NOT recommended for routine use in clinical practice since it
does NOT improve survival.
Interferon Alfa-2b
Neoplasm of colon
a) A phase III randomized study demonstrated that combination interferon alfa-2a
and FLUOROURACIL did not significantly improve response rates or offer a survival
advantage in 245 advanced colorectal cancer patients in comparison with
FLUOROURACIL alone. The combination was associated with greater toxicity resulting
in treatment withdrawal, and the authors discourage further study of this combination
in advanced colorectal cancer patients (Greco et al, 1996).
b) In a comparative trial, FLUOROURACIL plus leucovorin resulted in a higher initial
response rate, a longer disease-free interval, and a longer duration of survival than
FLUOROURACIL and leucovorin plus interferon alfa-2B in patients with advanced
colorectal cancer. One hundred patients were randomly assigned to receive racemic
leucovorin 200 milligrams/square meter (mg/m(2)) and FLUOROURACIL 370 mg/m(2)
for 5 consecutive days, or the same regimen plus subcutaneous interferon alfa-2b 3 x
10(6) international units subcutaneously 3 times
weekly from days 6 through 27.

201/317
25/10/12
10(6) international units subcutaneously 3 times weekly from days 6 through 27.
Severe toxicity (hematologic, gastrointestinal) was more prevalent in the group
receiving interferon (Recchia et al, 1996).
c) Leucovorin (LV) plus 5-fluorouracil (5-FU) increased the objective response rate
and increased time to progression compared to interferon alfa-2b (IFN) plus 5-FU or
LV plus IFN plus 5-FU in patients with metastatic colorectal cancer. Median survival
was 16.2 months (p=0.02) for the 5-FU/LV arm versus 12.7 months for the 5-FU/IFN
arm. Patients (n=236) were randomly assigned to 3 treatment regimens of which all
included a weekly 24-hour continuous intravenous infusion (CI) of 5-FU 2600
milligrams/square meter (mg/m(2)) for 6 weeks with a 2-week rest modulated by: (1)
LV 500 mg/m(2) as a 2-hour infusion before 5-FU, (2) IFN 3 million units 3 times per
week before 5-FU, or (3) LV and IFN at the same doses. Due to toxicity (primarily
diarrhea, mucositis), the 5-FU dose was reduced by 20% in all treatment arms within
the first or second cycle. At an interim analysis, accrual to the 5-FU/LV/IFN arm was
stopped due to 3 toxic deaths (Kohne et al, 1998).
Irinotecan
Colorectal cancer
a) Based on results from a PHASE III trial (n=267) demonstrating improved survival
with irinotecan over high-dose 5-fluorouracil (5-FU) infusion regimens, investigators
recommend irinotecan as the standard second- line therapy for advanced colorectal
cancer resistant to first-line 5- FU. Irinotecan was dosed at 350 milligrams/square
meter (mg/m(2)) as a 90-minute intravenous infusion every 3 weeks for a median
duration of 4.2 months. The dose was reduced to 300 mg/m(2) in subjects over 70
years and those with a performance status of 2. Patients randomized to 5-FU received
one of 3 different regimens at the discretion of the investigator for a median duration
of 2.8 months. Despite these differences, all 5-FU-treated patients were grouped
together for outcome assessment. Median survival was significantly longer in the
irinotecan arm than in the 5-FU arm (10.8 versus 8.5 months, p = 0.04), with 45%
and 32% alive at 1 year, respectively. The only secondary survival endpoint to reach
statistical significance was median progression-free survival, which favored irinotecan
(4.2 versus 2.9 months, p = 0.03). Quality of life measures were statistically
equivalent between groups, with no unexpected toxicities reported [459][460].
Neoplasm of colon
a) In a phase III trial the addition of bevacizumab to bolus irinotecan/ 5- fluorouracil
202/317
25/10/12

b) In a phase II trial (E2200) the addition of bevacizumab to full or reduced dose IFL
2003).
c) Based on results from a PHASE III trial (n=267) demonstrating improved survival
with irinotecan over high-dose 5-fluorouracil (5-FU) infusion regimens, investigators
recommend irinotecan as the standard second-line therapy for advanced colorectal
cancer resistant to first- line 5-FU. Irinotecan was dosed at 350 milligrams/square
meter (mg/m(2)) as a 90-minute intravenous infusion every 3 weeks for a median
duration of 4.2 months. The dose was reduced to 300 mg/m(2) in subjects over 70
years and those with a performance status of 2. Patients randomized to 5-FU received
one of 3 different regimens at the discretion of the investigator for a median duration
of 2.8 months. Despite these differences, all 5-FU-treated patients were grouped
together for outcome assessment. Median survival was significantly longer in the
irinotecan arm than in the 5-FU arm (10.8 versus 8.5 months, p=0.04), with 45% and
32% alive at 1 year, respectively. The only secondary survival endpoint to reach
statistical significance was median progression-free survival, which favored irinotecan
(4.2 versus 2.9 months, p=0.03). Quality of life measures were statistically equivalent
between groups, with no unexpected toxicities reported (Van Cutsem & Blijham, 1999;
Rougier et al, 1998).
d) Treatment with IRINOTECAN, FLUOROURACIL, and LEUCOVORIN increased
progression-free survival and median survival compared to fluorouracil, and leucovorin
in patients with metastatic colorectal cancer (Saltz et al, 2000). However, subsequent
studies using this regimen were associated with unexpectedly higher death rates
(Sargent et al, 2001). In the phase III, open-label, multicenter trial (Saltz et al, 2000),
683 treatment-naive (for metastatic disease) patients were assigned via random
allocation to one of the following regimens:
e) Triple therapy - Intravenous (IV) infusion of irinotecan 125 milligrams/square
meter (mg/m(2)) over 90 minutes plus Leucovorin 20 mg/m(2) as an IV bolus plus
Fluorouracil 500 mg/m(2) as an IV bolus All given weekly for 4 weeks every 6 weeks
or Double therapy - Leucovorin 20 mg/m(2) as an IV bolus plus Fluorouracil 500
mg/m(2) as an IV bolus Both given daily on days 1 to 5 every 4 weeks or - Irinotecan
203/317
25/10/12
125 mg/m(2) IV over 90 minutes Given weekly for 4 weeks every 6 weeks
f) Progression-free survival (primary endpoint) was 7 and 4.3 months after triple and
double therapy, respectively (p=0.004); median survival was also extended from 12.6
to 14.8 months with triple therapy (p=0.04). The objective response rate (defined as
a 50% reduction in measurable lesions) increased from 28% to 50% in patients
receiving triple therapy (p less than 0.001). Irinotecan alone was generally
comparable to double therapy. Grade III or IV diarrhea (22.7%) and vomiting (9.7%)
occurred at a higher incidence with triple therapy; whereas, mucositis (16.9%),
neutropenia (66.2%), and neutropenic fever (14.6%) were more common after double
therapy. Results of this study suggest that triple therapy may become a new standard
of care (Mayer, 2000).
g) Treatment with irinotecan, fluorouracil, and leucovorin increased progression-free
survival and median survival compared to fluorouracil, and leucovorin in patients with
metastatic colorectal cancer (Saltz et al, 2000). However, subsequent studies using
this regimen were associated with unexpectedly higher death rates (Sargent et al,
2001). In this phase III, open-label, multicenter trial (Saltz et al, 2000), 683
treatment-naive (for metastatic disease) patients were assigned via random
h) Triple therapy - Intravenous (IV) infusion of irinotecan 125 milligrams/square
i) Progression-free survival (primary endpoint) was 7 and 4.3 months after triple and
therapy.
Irinotecan Hydrochloride
The recommended duration of chemotherapy was 6 months. At a median duration
of
204/317
25/10/12

than 0.001) [442].
a) In a randomized, multicenter, phase 3, noninferiority trial (n=491), second-line
treatment of metastatic colorectal cancer with irinotecan was noninferior in overall
survival (OS) compared with infusional fluorouracil, leucovorin, and oxaliplatin
(FOLFOX4). Patients (median age, 63 yr; range, 25 to 86 yr) refractory to a
fluorouracil-based regimen (or within 6 months of adjuvant fluorouracil) were
randomized to irinotecan 350 mg/m(2) IV on day 1, given every 3 wk (for patients
with an Eastern Cooperative Oncology group performance score of 2, age greater than
or equal to 70 yr, or a history of pelvic radiotherapy, 300 mg/m(2) IV on day 1, given
every 3 wk) or oxaliplatin 85 mg/m(2) IV on day 1, fluorouracil 400 mg/m(2) plus
leucovorin 200 mg/m(2) IV bolus followed by fluorouracil 600 mg/m(2) in 22-hr IV
infusions on days 1 and 2 (FOLFOX4). Median OS, the primary endpoint, in the intentto-treat population was 14.3 months (mo) (95% confidence interval (CI), 12 to 15.9
mo) for the irinotecan arm and 13.8 mo (95% CI, 12.2 to 15 mo) for the FOLFOX4
arm (p=0.38; hazard ratio (HR)=0.92; 95% CI, 0.8 to 1.1), demonstrating
noninferiority. With respect to the secondary endpoints, the tumor response rate (RR)
in the FOLFOX4 arm was significantly better compared with irinotecan (28% vs 15.5%
respectively; p=0.0009), and time to progression (TTP), was significantly better with
FOLFOX4, median 6.2 mo (95% CI, 5.3 to 7.4 mo) compared with a median of 4.4 mo
(95% CI, 3.3 to 5.5 mo) in the irinotecan arm (HR=0.73; 95% CI, 0.6 to 0.9;
p=0.0009). Significantly more patients discontinued the FOLFOX4 regimen due to
adverse reactions (17% vs 5% for irinotecan; p less than or equal 0.0001) while
irinotecan was discontinued more often due to disease progression (67% vs 57% for
FOLFOX4; p=0.027). Grade 3 or worse nausea, diarrhea, and febrile neutropenia were
statistically significantly more common in the irinotecan arm, while grade 3 or worse
neutropenia and paresthesias were statistically more common in the FOLFOX4 arm.
Crossover to the other treatment arm was required if disease progressed during
205/317
25/10/12
second-line therapy; consequently 227 patients (46%) also received third-line

therapy. A significantly better RR was observed in the FOLFOX4 crossover arm
compared with irinotecan (13.6% vs 5.2%, respectively; p=0.039). FOLFOX4
crossover patients also had a significantly longer TTP (median 5.8 mo, 95% CI; 4.9 to
6.7 mo; p=0.0022), compared with the irinotecan arm (median 3.3 mo, 95% CI; 2.6
to 4.1 mo; HR=0.65; 95% CI; 0.5 to 0.9). For the entire study period, OS was not
significantly different in those patients who continued on to third-line therapy whether
the original treatment assignment was FOLFOX4 with subsequent irinotecan therapy
(median 15.9 mo; 95% CI; 14.3 to 17.5 mo), or was initially irinotecan followed by
FOLFOX4 (median 14.9 mo; 95% CI; 13.2 to 17.5 mo) [462].
b) A randomized multicenter trial demonstrated that a regimen of infused
FLUOROURACIL/LEUCOVORIN and OXALIPLATIN (FOLFOX) was more effective and
better tolerated than either IRINOTECAN and OXALIPLATIN (IROX) or IRINOTECAN
and bolus FLUOROURACIL/LEUCOVORIN (IFL) in patients with previously untreated
metastatic colorectal cancer. The IFL regimen (control regimen; n=264) was
intravenous (IV) irinotecan 125 milligrams per square meter (mg/m(2)) and
fluorouracil 500 mg/m(2) plus leucovorin 20 mg/m(2) as an IV bolus on days 1, 8, 15,
and 22 every 6 weeks. This IFL regimen (described by Saltz et al., 2000) led to a
higher death rate within the first 60 days of treatment in this IFL group; the patients
described in this study received the full dose regimen, but doses of irinotecan and
fluorouracil were subsequently reduced in that study arm. The FOLFOX regimen
(n=267) consisted of IV oxaliplatin 85 mg/m(2) on day 1 and fluorouracil 400
mg/m(2) plus leucovorin 200 mg/m(2) as an IV bolus followed by fluorouracil 600
mg/m(2) in 22 hour infusions on days 1 and 2 every 2 weeks. The IROX regimen
(n=264) was IV oxaliplatin 85 mg/m(2) and IV irinotecan 200 mg/m(2) every 3
weeks. Median time to disease progression was superior in the FOLFOX group (8.7
months) compared to either the IROX group (6.5 months, p=0.001) or the IFL group
(6.9 months, p=0.0014); no significant difference was found between the IROX and
IFL groups (p greater than 0.5). Median survival for the FOLFOX, IROX, and IFL
groups was 19.5 months, 17.4 months, and 15 months, respectively. The median
survival in the FOLFOX and IROX groups was significantly better than the IFL group
(p=0.0001 for FOLFOX, p=0.04 for IROX); survival in the FOLFOX and IROX groups
was not significantly different (p=0.09). Response rate in the FOLFOX group (45%)
was also significantly higher than either the IROX (35%, p=0.03) or the IFL groups
(31%, p=0.002). In addition, the adverse event profile was more favorable in the
FOLFOX group than the other groups. In the IFL and IROX groups, patients had higher
rates of diarrhea, nausea, vomiting, febrile neutropenia, and dehydration while
patients in the FOLFOX groups had higher rates of paresthesias and neutropenia. The
authors conclude that the results of this study support FOLFOX as a first-line standard
of care for patients with advanced colorectal cancer (Goldberg et al, 2004).
c) In a phase III study comparing two sequential therapies in metastatic colorectal
cancer patients, FOLFIRI then FOLFOX6 (upon disease progression or unacceptable
toxicity) and FOLFOX6 then FOLFIRI (upon disease progression or unacceptable
toxicity), no difference was found in survival and efficacy between the two arms. Two
hundred and twenty patients were randomized to either arm A (n=109), FOLFIRI then
to FOLFOX6, or arm B (n=111), FOLFOX6 then to FOLFIRI. Each FOLFIRI cycle
consisted of a 2-hour infusion of l- or dl-leucovorin (LV) (200 or 400 milligrams per
square meter (mg/m(2)), respectively) and irinotecan 180 mg/m(2) given as a 90thomsonhc.com/micromedex2/librarian/PFDefaultActionId/evidencexpert.IntermediateToDocumentPrintLink
206/317
25/10/12
minute infusion followed by a bolus of fluorouracil 400 mg/m(2) and then a 46-hour
infusion of fluorouracil 2,400 mg/m(2) for 2 cycles, increased to 3,000 mg/m(2) from
cycle 3 in cases where toxicities greater than grade 1 did not occur during the first
two cycles. Each FOLFOX6 consisted of the same LV + FU regimen, with the addition
of a 2-hour infusion of oxaliplatin 100 mg/m(2) on day 1. Arm A offered a median
survival of 21.5 months compared to 20.6 months in patients treated with arm B
(p=0.99). Likewise, when response rate (RR) was compared in the first-line
therapies, FOLFIRI resulted in a 56% RR when compared to a 54% RR in the
FOLFOX6 group (p= NS); median progression-free survival (PFS) was found to be 8.5
months and 8.0 months (p=0.26), respectively. In second-line therapy, FOLFIRI when
compared to FOLFOX6 resulted in a 4% RR versus 15% RR (p= 0.05), respectively,
and 2.5 months versus 4.2 months median PFS (p=0.003), respectively. As first-line
therapy, gastrointestinal (except for diarrhea), alopecia, and fatigue were more
frequent with FOLFIRI and hematologic toxicities were more frequent with FOLFOX6.
Grade 3 oxaliplatin- induced neurotoxicity was reported at a high rate (34%) [463].
Lentinan
Gastric cancer
a) A combination of intraarterial lentinan, 5-fluorouracil, and mitomycin-C (FML) has
been superior to a regimen of intraarterial 5-fluorouracil plus mitomycin-C (FM), each
following gastrectomy and hepatectomy, in improving the prognosis of gastric cancer
patients with liver metastases [461].
Leucovorin
Breast cancer
a) A sixteen-week multidrug regimen achieved only marginally better outcomes than
neutropenia hospital admission was not significantly
different between the two 207/317
25/10/12
b) An overall response rate of 65% (2 complete, 18 partial) was achieved with
Carcinoma of pancreas
a) Results from a randomized controlled trial of patients with resectable pancreatic
cancer (European Study Group for Pancreatic Cancer trial ESPAC-1) suggest that
postoperative chemotherapy with fluorouracil and leucovorin improves survival
whereas postoperative chemoradiotherapy negatively affects survival. However
limitations in the trial design, large drop out rates and potential bias hamper the
interpretation of these results. A total of 289 patients were randomized in a 2-by-2
factorial design to receive no treatment (n=69), chemoradiotherapy (n=73),
chemotherapy (n=75), or combination chemoradiotherapy and chemotherapy (n=72).
Chemoradiotherapy was administered as a 20 Gray dose to the previous tumor bed in
10 daily fractions over 2 weeks with fluorouracil 500 milligrams/square meter
(mg/m(2)) intravenous (IV) bolus on days 1 through 3, repeated after a 2-week
break. Chemotherapy consisted of leucovorin 20 mg/m(2) as an IV bolus followed by
an IV bolus of fluorouracil 425 mg/m(2) on days 1 through 5 every 28 days for 6
cycles. The same regimens of chemoradiotherapy followed by chemotherapy were
used for the combination therapy. Intent-to-treat analysis was used to conduct 2
comparisons: patients who received chemotherapy with patients who did not receive
chemotherapy and patients who received chemoradiotherapy with patients who did
not receive chemoradiotherapy. The calculated hazard ratio for death was 1.28 (95%
confidence interval (CI) 0.99 to 1.66; p=0.05) for patients who received
chemoradiotherapy. Median survival did not significantly differ between those who
received chemotherapy and those who did not. Chemotherapy was associated with a
0.71 hazard ratio for death (95% CI 0.55 to 0.92; p=0.009). Median survival times
also did not significantly differ between patients who received chemotherapy and
208/317
25/10/12
those who did not. However only 70% of patients assigned to receive
chemoradiotherapy received a total of 40 Gray according to the protocol and only 50%
of patients assigned to receive chemotherapy received all 6 cycles of therapy. Analysis
of patient drop out was not presented. Although these results are suggestive, the
ESPAC-3 trial and the Radiation Therapy Oncology Group trial 97-04 will shed further
light on the role of chemoradiotherapy and chemotherapy in this patient population
[439].
than 0.001) [442].
a) A 12-month course of fluorouracil (5-FU) plus leucovorin offered no significant
advantage over a 6-month course in the postoperative treatment of patients with
stage II or III RECTAL cancer (n=263). Dosing consisted of leucovorin 100
milligrams/square meter (mg/m(2)) over 15-30 minutes then 5-FU 450 mg/m(2) over
60 minutes on days 1 to 5 of a 4-week cycle. During the second cycle only, all subjects
209/317
25/10/12
received daily pelvic radiotherapy (up to 50.4 Gy total exposure) with weekly
leucovorin and reduced-dose 5-FU 350 mg/m(2). Based on data from 223 evaluable
subjects with a median 34 months of follow-up, the median times to recurrence were
16.3 and 17.8 months in the 12-month and 6-month groups, respectively (p=NS).
Corresponding 3-year mortality rates were 20.5% and 23.7%, respectively (p=NS).
However, only 51% of patients randomized to 12 cycles actually completed them. The
additional six cycles of 5-FU/leucovorin exposure was not associated with greater
toxicity (Queiber et al, 2000).
b) No differences were noted in efficacy, toxicity, and quality of life when intravenous
Mean follow-up period was 15 months with local (oral groups) and 3 systemic failures
between the 2 groups. Patients received either a intravenous bolus infusion of 5-FU
450 milligrams per square meter/day (mg/ m(2)/d) (mean age 50 years; n=14) in
combination with leucovorin 20 mg/ m (2)/d for 5 consecutive days on the first and
fifth weeks of concurrent radiotherapy or oral DOXIFLURIDINE 700 mg/ m(2)/d (mean
age 52 years; n=14)in combination with leucovorin 20 mg/m(2)/d continuously during
radiotherapy. Toxicities included diarrhea, stomatitis and leukopenia (not different
5-deoxynucleoside derivative, offered no significant advantage over intravenous 5-FU
a) Monthly low dose LEUCOVORIN (LV) plus 5 FLUOROURACIL (5-FU) increased
progression-free survival (6.2 versus 3.9 months; p=0.003), overall survival (12.4
versus 10 months; p=0.02), and objective responses (p=0.0002) compared to 5-FU
alone for measurable, metastatic colorectal cancer. The 309 eligible patients were
randomly assigned to 5-FU 400 milligrams/square meter/day (mg/m(2)) for 5 days
repeated every 28 days or the same dose of 5-FU plus LV 20 mg/m(2)/day. LV was
administered immediately before 5-FU; both were given as a rapid intravenous push
injection. Combination therapy versus 5-FU alone resulted in a significant (p=0.0001)
increase in World Health Organization grade 2 or greater nausea/vomiting, diarrhea,
stomatitis, alopecia, and other primarily hematologic toxicity but no therapy related
deaths were reported. Results of this study confirm that 5-FU plus LV provides a
survival advantage for patients with advanced colorectal cancer, with acceptable
toxicity (Borner et al, 1998).
b) In a randomized study enrolling 208 patients, FLUOROURACIL plus LEUCOVORIN
was found to be superior to FLUOROURACIL alone. Patients with colorectal cancer
were randomized to receive FLUOROURACIL 500 milligrams/square meter (mg/m(2))
for 5 consecutive days (repeated every 5 weeks) or FLUOROURACIL plus
LEUCOVORIN in either a high-dose or low-dose regimen. A greater extension in
survival occurred with FLUOROURACIL/LEUCOVORIN than with FLUOROURACIL
alone. Interval to tumor progression, measurable tumor response rates and quality of
life also were improved in the FLUOROURACIL/LEUCOVORIN group. The highest
objective response rate was observed with low-dose LEUCOVORIN (43%) versus
high-dose LEUCOVORIN regimen (26%) (O'Connell, 1989). A similar study of 309
patients demonstrated that combining leucovorin 20 mg/m(2)/day with 5-fluorouracil
210/317
25/10/12
(5-FU) 400 mg/m(2)/day for 5 days every month resulted in significantly higher
response rates and longer survival than when 5-FU alone was administered (Borner et
al, 1998).
c) There was no difference in response, survival, or toxicity in patients with 3
DIFFERENT LEUCOVORIN FORMULATIONS in combination with 5-FLUOROURACIL (5FU). Only the l-isomer of leucovorin is active. The possibility that the d-isomer
interferes with enhancement of 5-FU activity by competition with the l-isomer for the
carrier was tested in a study of 926 patients with unresectable or metastatic colon
cancer. Patients were given intravenous l-leucovorin, oral leucovorin (of the racemic
mixture, l-leucovorin is preferentially absorbed from the intestine), or intravenous d,lleucovorin (standard). Doses were: l-leucovorin 100 milligrams/square meter
(mg/m(2)); oral d,l-leucovorin 125 mg/m(2) on hours 0, 1, 2, and 3; intravenous d,lleucovorin 200 mg/m(2). Leucovorin doses were followed by 5-FU 370 mg/m(2) in all
cases. Drugs were administered for 5 consecutive days at weeks 0,4, and 8 and every
5 weeks thereafter. Time to progression (median, 6 months) did not differ for the 3
treatments, nor did time to death (median survival, 1 year). Toxic effects did not differ
significantly among treatments (Goldberg et al, 1997).
d) In a randomized trial with 433 assessable colorectal cancer patients, a HIGH-DOSE
LEUCOVORIN INFUSION, followed by bolus 5-fluorouracil (5FU) and then continuous
infusion of 5FU, on a 2-week cycle produced a significantly better response rate than
did LOW-DOSE BOLUS LEUCOVORIN, followed by a 5FU bolus, on a 4-week cycle. The
high-dose leucovorin regimen was leucovorin 200 mg/m(2) infused over 2 hours,
followed by 5FU bolus 400 mg/m(2) and then 600 mg/m(2) infused over 22 hours; this
was repeated on day 2. The low-dose leucovorin regimen was an intravenous bolus of
leucovorin 20 mg/m(2), followed by an intravenous bolus of 5FU 425 mg/m(2),
repeated on 5 consecutive days. The reponse rate (complete and partial) was 32.6%
for the high-dose regimen and 14.5% for the low-dose regimen (p=0.0004). For the
high-dose regimen, the median progression-free survival was greater (p=0.001); the
median survival time was 65.0 weeks for the high-dose regimen and 56.8 for the lowdose regimen (p=0.067). With the high-dose leucovorin regimen, 11% experienced
grade 3-4 toxicities, compared to 24% with the low-dose regimen (deGramont et al,
1997).
e) Increasing the dose of leucovorin (LV) and administering higher doses of 5fluorouracil (5FU) in a continuous infusion (without bolus) produced about the same
results as other regimens that used lower doses and a combination of bolus and
infusion of 5FU. Ninety-nine patients with confirmed colorectal adenocarcinoma and
who had received no previous chemotherapy received a 2-hour infusion of LV 500
milligrams/square meter (mg/m(2)) on days 1 and 2; a 48-hour infusion of 5-FU, 1.5
to 2 grams/m(2)/24 hours was given after day 1 LV treatment. This regimen was
repeated every 2 weeks. The overall response rate was 33.7% with 5% of patients
having a complete response. Fifteen percent experienced Grade 3 to 4 toxicity. Median
progression-free survival was 8 months, and median survival was 18 months
(Beerblock et al, 1997). Addition of interferon-alpha-2a (IFA) to this regimen in
another study (n=50) gave an overall response of 44%, with median progression-free
survival of 9 months and median survival of 25 months. However, 42% experienced
Grade 3 to 4 toxicity (Tournigand et al, 1997).
f) Clinical response was similar when FLUOROURACIL (425 milligrams/square meter
(mg/m(2) intravenously (IV)) plus low-dose LEUCOVORIN (20 mg/m(2) IV) for 5 days
211/317
25/10/12
was compared with weekly FLUOROURACIL (600 mg/m(2) IV) and high-dose
LEUCOVORIN (500 mg/m(2) IV) in the management of metastatic colorectal cancer.
The 5-day regimen resulted in more stomatitis and leukopenia, but the weekly
regimen resulted more often in diarrhea and other adverse effects requiring
hospitalization (Buroker et al, 1994). Similar results were reported when IV
fluorouracil 500 mg/m(2) was administered weekly with high-dose leucovorin (500
mg/m(2) IV) or low-dose leucovorin (20 mg/m(2) IV) (n=291) (Jager et al, 1996).
g) In a multicenter, randomized study, INTRAHEPATIC arterial FLUOROURACIL plus
LEUCOVORIN (FOLINIC ACID) offered no progression-free or overall survival
advantage compared to intravenous FLUOROURACIL plus FOLINIC ACID in patients
with colorectal cancer with unresectable metastases confined to the liver. Patients
(n=290) were randomly assigned to receive fluorouracil by either the intravenous (IV)
or intrahepatic arterial (IHA) route. In the IHA group (n=145), folinic acid (200
milligrams per square meter (mg/m(2)), maximum 350 mg) IV over 2 hours, followed
by 400 mg/m(2) fluorouracil IHA infusion in 100 milliliters (mL) saline over 15 minutes
and fluorouracil 1600 mg/m(2) over 22 hours, on day 1 and 2, was administered every
14 days. The IV group (n=145) received folinic acid 200 mg/m(2) (maximum 350 mg)
IV over 2 hours, then fluorouracil 400 mg/m(2) IV bolus and fluorouracil 600 mg/m(2)
IV infusion over 22 hours, on day 1 and 2, every 14 days (de Gramont regimen).
Analysis was based on the intention to treat population. Thirty of 145 (22%) patients
in the IHA group could not start treatment due to catheter problems (abnormal
vasculature or catheter malfunction); 36% of all IHA patients experienced catheter
thrombosis and 14% were unable to complete at least 6 cycles of IHA treatment for
this reason. Only 38% of IHA patients received 6 or more chemotherapy cycles; of the
patients who did not start treatment or received fewer than 6 cycles, 45 (51%)
switched to the IV regimen. No significant differences were seen in progression-free
survival (PFS) or overall survival (OS) between the groups. Median PFS was 7.7
months and 6.7 months, and median OS was 14.7 months and 14.8 months for the
IHA and IV groups, respectively. Twelve weeks after the start of chemotherapy,
response rates were 22% and 19% in the IHA and IV groups, respectively. No group
differences were reported for serious adverse events (grades 3 or 4). A higher number
of early deaths was observed in the IHA group (23% by 12 weeks after start of
chemotherapy, versus 9% in IV group). The delay in starting chemotherapy in the IHA
group while patients waited for laparotomy for catheter insertion might account for
this difference (median time from randomization to start of chemotherapy, 14 days in
IV group versus 35 days in IHA group). The authors do NOT recommend use of the
IHA regimen for unresectable metastatic colorectal cancer outside of a clinical trial
setting (Kerr et al, 2003).
h) In a randomized, multicenter, phase 3, noninferiority trial (n=491), second-line
212/317
25/10/12
i) A randomized multicenter trial demonstrated that a regimen of infused
213/317
25/10/12
j) In a phase III study comparing two sequential therapies in metastatic colorectal
square meter (mg/m(2)), respectively) and irinotecan 180 mg/m(2) given as a 90minute infusion followed by a bolus of fluorouracil 400 mg/m(2) and then a 46-hour
k) In 156 patients who underwent complete resection of hepatic metastases from
214/317
25/10/12
et al, 1999).
Neoplasm of colon
a) In a randomized phase II study involving previously untreated patients with
metastatic colorectal cancer (n=104), objective responses were seen in 40% (95% CI
24% to 58%) and 24% (95% CI 12% to 43%) of those treated with intravenous
bevacizumab 5 milligrams/kilogram (mg/kg) and 10 mg/kg, respectively, every 2
weeks in combination with the standard chemotherapy regimen of 5-fluorouracil plus
leucovorin (Roswell Park regimen); a response rate of 17% (95% CI 7% to 34%) was
observed in patients treated with standard chemotherapy alone. Times to disease
progression in these three groups were 9 months (95% CI 5.8 to 10.9; p= 0.005), 7.2
months (95% CI 3.8 to 9.2; p= 0.217), and 5.2 months (95% CI 3.5 to 5.6),
respectively. Median survival was 21.5, 16.1, and 13.8 months, respectively; 37% of
patients in the 5-mg/kg arm were alive at 18-months. imbalances in randomization
(i.e. sex, ECOG performance status, and baseline serum albumin) in this study was a
limitation and may be a possible explanation, along with small sample size and chance
for the more effective outcome seen with the lower dose bevacizumab (Kabbinavar et
al, 2004).
b) In a phase III trial the addition of bevacizumab to bolus irinotecan/ 5- fluorouracil
were 5 mg/kilogram IV every two weeks. Results
215/317
reported for the primary comparison
25/10/12
c) In a phase II trial (E2200) the addition of bevacizumab to full or reduced dose IFL
2003).
d) In a randomized, open-label, North American phase III trial of patients with
metastatic or advanced colorectal cancer (n=964), there was no significant difference
in median overall survival between the group that received oral eniluracil plus
fluorouracil (EU/5-FU) compared with the group who received intravenous (IV)
fluorouracil plus leucovorin (5-FU/LV; 13.3 months versus 14.5 months; p=0.31).
However, the EU/5-FU regimen did not meet the protocol-specified definition of
equivalence; EU/5-FU did not demonstrate a median survival of at least 80% that of
the 5-FU/LV regimen because the lower limit of the two-sided 95% confidence interval
(CI) around the hazard radio did not exceed 0.80 (hazard radio, 0.880; 95% CI 0.75 to
1.03). Patients with no chemotherapy for advanced or metastatic disease, and no
adjuvant therapy in the 12 months prior to receiving a study regimen, were included.
Oral eniluracil 11.5 milligrams/square meter (mg/m(2)) and oral fluorouracil 1.15
mg/m(2) were administered twice daily for 28 days followed by a 7-day rest period in
5-week cycles. Intravenous leucovorin 20 mg/m(2) followed by IV fluorouracil 425
mg/m(2) were administered once daily for the first 5 days of each 28-day cycle. The
overall response rate was 12.2% in the oral eniluracil/fluorouracil group and 12.7% in
the IV fluorouracil/leucovorin group; median duration of response was 27.9 and 28.7
weeks, respectively. Median progression-free survival was 20 weeks in the EU/5-FU
group compared with 22.7 weeks in the 5-FU/LV group (p=0.0106). Grade 3/4
hematologic toxicity in the 5-FU/LV group compared with the EU/5-FU group included
granulocytopenia (47% versus 5%; p less than 0.001) and febrile neutropenia (9.4%
versus 0.2%; p less than 0.001). There were significant differences between the 5FU/LV group and the EU/5-FU group in the following grade 3/4 nonhematologic
216/317
25/10/12
toxicities: nausea (7% versus 3%; p=0.012), hyperbilirubinemia (9% versus 22%; p
less than 0.001), mucositis 12% versus 1%; p less than 0.001), and fever 7% versus
0%; p less than 0.001). The authors note that the overall survival in the 5-FU/LV
group (median, 14.5 months) was superior to those reported in most other studies of
5-FU/LV in this patient population (Schilsky et al, 2002).
e) A randomized, open-label, phase III trial conducted outside of North America
compared oral eniluracil plus fluorouracil (EU/5-FU) with intravenous (IV) fluorouracil
plus leucovorin (5-FU/LV) in patients with advanced colorectal cancer (n=531). The
overall response rate was 11.6% in the EU/5-FU arm compared with 14.4% in the 5FU/LV arm; median overall survival was 47.4 weeks and 63.7 weeks, respectively. The
duration of overall survival was statistically inferior in the EU/5-FU group (hazard ratio
0.770; 95% confidence interval (CI): 0.62, 0.95) as was progression-free survival
(hazard ratio 0.831; 95% CI: 0.69, 1.00)(Van Cutsem et al, 2001).
f) An overall response rate of 24.8% was achieved in patients with advanced or
metastatic colorectal cancer who received capecitabine compared to a response rate
of 11.6% in patients who received fluorouracil and leucovorin (5-FU/LV) (p=0.0001) in
a randomized phase III trial (n=605). There were no significant differences between
the capecitabine group and the 5-FU/LV group in overall survival (12.5 months and
13.3 months, respectively), median duration of response (9.1 months and 9.5 months,
respectively), and median time to disease progression (4.3 months and 4.7 months,
respectively). Patients with advanced or metastatic colorectal cancer who had not
received prior chemotherapy for metastatic disease were randomized to receive
capecitabine orally (1250 milligrams/square meter (mg/m(2)) twice daily for 14 days
followed by a 7-day rest period) or 5-FU/LV (rapid intravenous (IV) injection of 20
mg/m(2) LV followed by an IV bolus of 425 mg/m(2) 5-FU on days 1 to 5 every 4
weeks). Dose reduction for adverse reactions was required in 40.5% of patients in the
capecitabine group (usually hand-foot syndrome or diarrhea) and 49.3% of patients in
the 5-FU/LV group (usually stomatitis or diarrhea. A comparison of grade 3/4 toxicity
in the capecitabine group and 5- FU/LV group included diarrhea (15.4%, 13.9%),
hand-foot syndrome (18.1%, 0.7%), stomatitis (3.0%, 16.0%), vomiting (3.6%,
4.7%), neutropenia (2.6%, 25.9%) and hyperbilirubinemia (17.3%, 5.4%). A
significantly lower incidence of any grade of diarrhea, stomatitis, nausea, and alopecia
occurred in the capecitabine group (p less than 0.00002). However, a significantly
greater incidence of hand-foot syndrome occurred in patients who received
capecitabine. The authors conclude that capecitabine is an acceptable alternative for
the treatment of advanced colorectal cancer based on its response rate, favorable
toxicity profile, and the convenience of oral therapy (Hoff et al, 2001).
g) In another randomized phase III trial (n=602) comparing capecitabine to
fluorouracil (5-FU) plus leucovorin in patients with advanced or metastatic colorectal
cancer, an overall response rate of 19% was achieved with capecitabine compared to
15% with fluorouracil/leucovorin. No significant differences were seen between the
capecitabine group and the 5-FU/leucovorin group in overall survival (13.2 months
versus 12.1 months), median duration of response (7.2 months versus 9.4 months),
median time to disease progression (5.2 months versus 4.7 months), and time to
treatment failure (4.2 months versus 4.0 months). Chemotherapy-naive patients
received either capecitabine 1250 milligrams/square meter (mg/m(2)) orally twice
daily for 14 days followed by a 7-day rest period or a rapid intravenous (IV) injection
of 20 mg/m(2) of leucovorin followed by an IV bolus of 5-FU 425 mg/m(2) on days 1
217/317
to 5 every 4 weeks. There were significantly lower incidences of stomatitis, grade 3/4
stomatitis, grade 3/4 neutropenia and alopecia (p less than 0.0001) and significantly
higher incidences of cutaneous hand- foot syndrome, grade 3 hand-foot syndrome (p
less than 0.00001), and uncomplicated grade 3/4 hyperbilirubinemia (p less than
0.0001) with capecitabine compared with 5-FU/leucovorin. Time to first onset of
treatment-related grade 3/4 adverse reaction was significantly later in the
capecitabine group (p=0.008). Oral capecitabine has at least equivalent efficacy
compared with intravenous fluorouracil/leucovorin with clinically meaningful safety
advantages (Cutsem et al, 2001).
h) In a large multicenter prospective, randomized phase III clinical trial, capecitabine
therapy was shown to substantially reduce medical resource use and to improve
response rate and tolerability compared to the Mayo Clinic Regimen of 5-fluorouracil
(5-FU)/leucovorin (LV) in patients with advanced or metastatic colorectal cancer.
Patients (n=602) were randomized to receive either capecitabine (1250 mg/m2 orally
twice daily for 2 weeks followed by 1 week rest) or 5 FU/LV (20 mg/m2 of LV as a
rapid IV injection followed by 425 mg/m2 of 5-FU as an IV bolus given daily for 5 days,
every 4 weeks). Treatment was continued for 30 weeks or until the development of
progressive disease or unacceptable toxicity. Capecitabine treatment resulted in
superior response rates (26.6% versus 17.9%) and improved safety compared to 5FU/LV. Capecitabine patients also required fewer hospital visits for drug
administration, or for the management of treatment related adverse effects, and had
reduced expenses for managing adverse events. However, patients receiving
capecitabine needed more frequent unscheduled home, daycare, office, and telephone
consultations with physicians (Twelves et al, 2001).
i) Preliminary results from a randomized phase III trial (E3200) indicate that the
j) Modulation of FLUOROURACIL with folinic acid (leucovorin) plus methotrexate in
patients with advanced colorectal cancer resulted in a higher response rate but similar
survival when compared with modulation using only leucovorin. Eighty-three patients
with recurrent or metastatic colon or rectal cancer, were randomly assigned to receive
one of the following regimens: Group A, intravenous leucovorin 300 milligrams/square
meter (mg/m(2))/day followed by FLUOROURACIL 500 mg/m(2)/day administered
over 1 hour for 4 days; Group B, methotrexate 130 mg/m(2)/day 20 hours before
leucovorin 300 mg/m(2)/day followed by FLUOROURACIL 500 mg/m(2)/day
administered over 1 hour for 4 days. Twenty-four hours after the methotrexate
infusion, leucovorin 15 mg every 6 hours for 6 doses was administered. Both regimens
were repeated every 21 days for 6 cycles. Three patients in group B versus one in
218/317
25/10/12
group A had a complete response; 15 patients in group B versus 7 in group A had a

partial response. Toxicity consisting of neutropenia, thrombocytopenia, mucositis,
nausea/vomiting, and diarrhea occurred at a higher incidence and was more severe in
group B (Polyzos et al, 1996).
k) The addition of oxaliplatin to the North Central Cancer Treatment Group/Mayo
Clinic regimen of 5-fluorouracil (FU)/leucovorin (LV) (LV5FU2) demonstrated a
prolonged progression-free survival (PFS), acceptable toxicities, and maintenance of
quality of life as first-line therapy in advanced colorectal cancer. Four hundred and
twenty chemotherapy-nave patients with metastatic colorectal cancer were
randomized in a multi-center study to treatment with LV5FU2 which consisted of a 2hour infusion of LV 200 milligrams per square meter/day (mg/m(2)) followed by a
bolus of FU 400 mg/m(2)/day and then a 22-hour infusion of FU 600 mg/m(2)/day
repeated for 2 consecutive days every 14 days (arm A) or oxaliplatin (85 mg/m(2)) on
day 1 plus LV5FU2 group (arm B; FOLFOX4). The results indicate that when added to
the bimonthly two- hour infusion of LV5FU2, oxaliplatin extends PFS significantly (8.2
months versus 6.0 months; p=0.0003). Intent-to-treat response rates were reported
as 21.9% (95% confidence interval (CI), 17.9% to 25.9%) in arm A and 50.0% (95%
CI, 46.1% to 54.9%; p=0.0001) in arm B. Median overall survival (14.7 months for
arm A versus 16.2 months for arm B), however, was not statistically different
between the two treatment groups (log-rank test p=0.12; Wilcoxon p=0.05). In arm
A, patients experienced grade 3 neutropenia and diarrhea mostly. Grade 3/4 toxicities
(neutropenia, diarrhea, mucositis, and neuropathy) were more common in arm B than
arm A were. Although there were significant increases in grade 3/4 toxicities in arm B,
quality of life (QOL) measurements for that group were not significantly influenced;
the overall QOL scores were comparable for the two arms [440].
l) The safety and efficacy of single-agent oxaliplatin in patients with metastatic
colorectal cancer (n=459) was compared to oxaliplatin in combination with 5fluorouracil (5-FU)/leucovorin (LV) and to the same dose and schedule 5-FU/LV in a
multicenter, randomized, controlled trial. Patients with advanced colorectal cancer
who had relapsed/progressed during or within 6 months of first line therapy were
randomized to single-agent oxaliplatin (n=156; day 1: 85 milligrams/square meter
(mg/m(2)), oxaliplatin/5-FU/LV (n=152; day 1: oxaliplatin 85 mg/m(2) + LV 200
mg/m(2) followed by 5-FU 400 mg/m(2) bolus, 600 mg/m(2) (22 hour infusion), day
2: LV 200 mg/m(2) followed by 5-FU 400 mg/m(2) bolus, 600 mg/m(2) (22 hour
infusion), or 5-FU/LV (n=151; same dose and schedule). All regimens were repeated
every 2-weeks. At an interim analysis, patients treated with oxaliplatin/5-FU/LV had
an increased response rate and median time to progression (9%, 4.6 months) versus
patients given 5-FU/LV (0%; p=0.0002, 2.7 months) or oxaliplatin alone (1%, 1.6
months). The most common grade 3/4 adverse events reported in the oxaliplatin/5FU/LV group were neuropathies (7%), neutropenia (44%), and
nausea/vomiting/diarrhea (11%, 9%, 11%) (Prod Info Eloxatin (TM), 2002).
m) A combination of oxaliplatin with fluorouracil plus leucovorin resulted in better
response rates than oxaliplatin alone in patients with progressive colorectal cancer in
a non-randomized study. All patients had progressive disease despite prior treatment
with fluorouracil-containing regimens (23 receiving treatment within 6 months of
study; 2 treated more than 6 months before study). Oxaliplatin 130 milligrams/square
meter (mg/m(2)) was infused over 2 hours every 21 days. Fluorouracil was
administered by continuous infusion via central venous catheter at a dose of 200 up to
219/317
25/10/12
300 mg/m(2)/day, or as a bolus infusion of 375 mg/m(2) over 5 days with leucovorin
100 mg/m(2). Of 12 patients treated with combination therapy, 4 achieved partial
remission and 4 achieved stable disease; of the 4 partial responders, 2 received the 5day bolus infusion of fluorouracil with leucovorin and 2 received continuous infusion of
only fluorouracil. Of the 13 patients receiving oxaliplatin alone, none achieved
remission and 4 had stable disease. While the results suggest a better response with
combination therapy, patient selection may have influenced results in this nonrandomized study, since combination therapy was given to those who were receiving
fluorouracil at the time the study began, whereas oxaliplatin alone was given to those
who were not receiving the drug at that time (deBraud et al, 1998).
n) A bimonthly regimen of leucovorin plus 48-hour continuous fluorouracil and
oxaliplatin achieved higher responses in patients with colorectal cancer but was not as
well-tolerated as the same regimen with a lower dose of oxaliplatin. Responses with
the leucovorin plus continuous infusion regimen (46% overall) had been recorded
during a previous study, with an oxaliplatin dose of 100 milligrams/square meter
(mg/m(2)). The present study included patients refractory to the previous regimen.
The regimen in the second study included leucovorin 500 mg/m(2) plus oxaliplatin 85
mg/m(2) (through separate infusion lines) as a 2-hour infusion, followed by
fluorouracil 1.5 to 2 grams/m(2) as a 22-hour infusion. This regimen was given for two
consecutive days every two weeks for a median of 9.5 cycles. Among 30 assessable
patients, 6 had a partial response (20%) lasting 37 weeks, and 15 had stabilization
lasting 27 weeks. Progression-free survival lasted a median of 26 weeks, with a
median survival of 57 weeks. Grade 3 to 4 toxicities were observed in 27% of
patients; the most common adverse events were non-febrile neutropenia in 20% of
patients, and thrombocytopenia in 13%. After 11 to 15 cycles, 4 patients had severe
sensory neuropathy that was of prolonged duration following discontinuation of
chemotherapy. Whether the between-regimen difference in response and toxicity was
a result of the lower oxaliplatin dose or patient selection was not established (Andre
et al, 1998).
o) Combined fluorouracil/leucovorin is advocated as the regimen of choice for
advanced colorectal carcinoma by many specialists (Anon, 1997). A direct comparison
of raltitrexed and the Mayo regimen of fluorouracil/leucovorin (Cunningham et al,
1995) revealed no significant differences in objective response rate, time to
progression, survival, or quality of life; response rates were low with both treatments
(20% and 13%, respectively). The potential advantages of raltitrexed emerging from
this trial were its greater convenience in administration (once every 3 weeks) and
potentially lower propensity for toxicity (reduced mucositis and severe leukopenia),
although liver enzyme elevations occurred only in the raltitrexed arm.
p) A phase III randomized study demonstrated that combination interferon alfa-2a
and FLUOROURACIL did not significantly improve response rates or offer a survival
advantage in 245 advanced colorectal cancer patients in comparison with
FLUOROURACIL alone. The combination was associated with greater toxicity resulting
in treatment withdrawal, and the authors discourage further study of this combination
in advanced colorectal cancer patients (Greco et al, 1996).
q) In a comparative trial, FLUOROURACIL plus leucovorin resulted in a higher initial
response rate, a longer disease-free interval, and a longer duration of survival than
FLUOROURACIL and leucovorin plus interferon alfa-2B in patients with advanced
colorectal cancer. One hundred patients were randomly assigned to receive racemic
220/317
25/10/12
leucovorin 200 milligrams/square meter (mg/m(2)) and FLUOROURACIL 370 mg/m(2)

for 5 consecutive days, or the same regimen plus subcutaneous interferon alfa-2b 3 x
10(6) international units subcutaneously 3 times weekly from days 6 through 27.
Severe toxicity (hematologic, gastrointestinal) was more prevalent in the group
receiving interferon (Recchia et al, 1996).
r) Leucovorin (LV) plus 5-fluorouracil (5-FU) increased the objective response rate
and increased time to progression compared to interferon alfa-2b (IFN) plus 5-FU or
LV plus IFN plus 5-FU in patients with metastatic colorectal cancer. Median survival
was 16.2 months (p=0.02) for the 5-FU/LV arm versus 12.7 months for the 5-FU/IFN
arm. Patients (n=236) were randomly assigned to 3 treatment regimens of which all
included a weekly 24-hour continuous intravenous infusion (CI) of 5-FU 2600
milligrams/square meter (mg/m(2)) for 6 weeks with a 2-week rest modulated by: (1)
LV 500 mg/m(2) as a 2-hour infusion before 5-FU, (2) IFN 3 million units 3 times per
week before 5-FU, or (3) LV and IFN at the same doses. Due to toxicity (primarily
diarrhea, mucositis), the 5-FU dose was reduced by 20% in all treatment arms within
the first or second cycle. At an interim analysis, accrual to the 5-FU/LV/IFN arm was
stopped due to 3 toxic deaths (Kohne et al, 1998).
s) Treatment with IRINOTECAN, FLUOROURACIL, and LEUCOVORIN increased
progression-free survival and median survival compared to fluorouracil, and leucovorin
in patients with metastatic colorectal cancer (Saltz et al, 2000). However, subsequent
studies using this regimen were associated with unexpectedly higher death rates
(Sargent et al, 2001). In the phase III, open-label, multicenter trial (Saltz et al, 2000),
683 treatment-naive (for metastatic disease) patients were assigned via random
t) Triple therapy - Intravenous (IV) infusion of irinotecan 125 milligrams/square meter
(mg/m(2)) over 90 minutes plus Leucovorin 20 mg/m(2) as an IV bolus plus
u) Progression-free survival (primary endpoint) was 7 and 4.3 months after triple and
therapy. Results of this study suggest that triple therapy may become a new standard
of care (Mayer, 2000).
v) Treatment with irinotecan, fluorouracil, and leucovorin increased progression-free
survival and median survival compared to fluorouracil, and leucovorin in patients with
metastatic colorectal cancer (Saltz et al, 2000). However, subsequent studies using
this regimen were associated with unexpectedly higher death rates (Sargent et al,
2001). In this phase III, open-label, multicenter trial (Saltz et al, 2000), 683
treatment-naive (for metastatic disease) patients were assigned via random
w) Triple therapy - Intravenous (IV) infusion of irinotecan 125 milligrams/square
221/317
25/10/12

x) Progression-free survival (primary endpoint) was 7 and 4.3 months after triple and
therapy.
y) The addition of interferon-alfa to FLUOROURACIL and leucovorin was associated
with higher toxicity, especially hematologic, and the combination offered no clinical
advantage in the treatment of metastatic colorectal carcinoma in 50 patients. This
phase II regimen consisted of a 2-hour infusion of leucovorin 500 milligrams/square
meter (mg/m(2)) on 2 consecutive days, and a 48-hour infusion of FLUOROURACIL
1.5 to 2 grams/m(2) per 24 hours starting the day after leucovorin, every two weeks
until disease progression. Subcutaneous interferon-alfa was given 3 times weekly: 3
million units for a body surface area (BSA) less than 1.75 m(2), or 4.5 million units for
a BSA of 1.75 m(2) or more. Overall response rate was 44% with 21 patients
experiencing Grade 3 to 4 toxicity. The median progression-free survival was 9 months
and the median survival was 25 months (Tournigand et al, 1997).
z) Preliminary toxicity results favor a biweekly over a monthly regimen of fluorouracil
(5-FU) plus leucovorin in the treatment of recently resected stage B2 or C colorectal
adenocarcinoma in an open-label, randomized phase III trial (n=905). Intravenous
(IV) d,l-leucovorin 200 milligrams/square meter (mg/m(2)) or l-leucovorin 100
mg/m(2) as a 2-hour infusion, then bolus 5-FU 400 mg/m(2) then 600 mg/m(2) as a
22-hour continuous infusion on 2 consecutive days every 14 days characterized the
biweekly regimen, while the comparative regimen included d,l-leucovorin 200 mg/m(2)
or l-leucovorin 100 mg/m(2) as a 15-minute infusion, then 5-FU 400 mg/m(2) as a 15minute bolus for 5 consecutive days every 28 days. The cycles continued for 24 or 36
weeks. The overall incidence of grade 3 or 4 toxicities was significantly lower with the
biweekly versus monthly regimen (10% versus 26%, p less than 0.001), with
statistical significance noted for grade 3 or 4 neutropenia, diarrhea and mucositis.
Efficacy data are forthcoming (Andre et al, 2001).
aa) Monthly low-dose leucovorin (LV) plus 5-fluorouracil (5-FU) increased
progression-free survival (p=0.003; 6.2 versus 3.9 months), overall survival (p=0.02;
12.4 versus 10 months), and objective responses (p=0.0002) compared to 5-FU alone
for measurable, metastatic colorectal cancer. This study enrolled 310 patients of
whom 309 were eligible and were randomly assigned to 5-FU 400 milligrams/square
meter/day (mg/m(2)) for 5 days repeated every 28 days or the same dose of 5-FU
plus LV 20 mg/m(2)/day. LV was administered immediately before 5-FU; both were
given as a rapid intravenous push injection. Combination therapy versus 5-FU alone
resulted in a significant (p=0.0001) increase in World Health Organization grade 2 or
greater nausea/vomiting, diarrhea, stomatitis, alopecia, and other primarily
222/317
25/10/12
hematologic toxicity but no therapy-related deaths were reported. Results of this

study confirm that 5-FU plus LV provides a survival advantage for patients with
advanced colorectal cancer with acceptable toxicity (Borner et al, 1998).
ab) Biochemical modulation of fluorouracil (5-FU) with the intravenous (IV) l-isomer
of leucovorin (LV), the oral d,l-isomer of LV, and the IV d,l-isomer of LV resulted in a
comparable response rate, survival, and toxicity (Goldberg et al, 1997). In this phase
III study, 926 patients with metastatic colon cancer received 5-FU 370
milligrams/square meter (mg/m(2)) with 1 of the following LV regimens: (1) IV bolus
of l-LV 100 mg/m(2) immediately before 5-FU, (2) oral d,l-LV 125 mg/m(2) (total dose
500 mg/m(2)) at hours 0, 1, 2, and 3 followed by 5-FU, or (3) IV bolus of d,l-LV 200
mg/m(2) followed by 5-FU. Both drugs were given for 5 consecutive days with repeat
courses at 4 and 8 weeks and then every 5 weeks. Dose-limiting toxicity comprised
diarrhea, stomatitis, and vomiting. Another phase III trial which compared intravenous
racemic LV with 5-FU to l-LV with 5-FU also showed comparable efficacy between the
2 forms of LV (Scheithauer et al, 1997).
ac) Bimonthly leucovorin and FLUOROURACIL bolus plus continuous infusion produced
more objective responses (p=0.0004), longer median progression-free survival
(p=0.001), and longer median survival than monthly leucovorin and FLUOROURACIL in
patients with advanced colorectal cancer. Patients were randomly assigned to receive
either: (Monthly) bolus leucovorin 20 milligrams/square meter/day (mg/m(2)/day)
followed by bolus FLUOROURACIL 425 mg/m(2)/day, repeated for 5 consecutive days
every 4 weeks; or (bi-monthly) 2-hour infusion of leucovorin 200 mg/m(2)/day
followed by bolus FLUOROURACIL 400 mg/m(2)/day, and a 22-hour infusion of
FLUOROURACIL 600 mg/m(2)/day repeated for 2 consecutive days at 2-week
intervals. Grade 3 to 4 toxicity was reported in 23.9% of patients in the monthly group
and 11.1% of patients in the bimonthly group (p=0.004). One treatment-related death
occurred in the monthly group. The objective response rate was higher in patients
receiving the bimonthly versus monthly regimen; however, overall survival was not
significantly different (de Gramont et al, 1997).
ad) For metastatic colorectal cancer, 5-fluorouracil (5-FU) plus leucovorin (LV) is
more effective than 5-FU alone. Although this regimen is useful for palliation, a
survival advantage has NOT been demonstrated. Numerous studies have evaluated
the combination of 5-FU and LV; however, the optimal dose, schedule, and method of
administration have NOT been determined (Machover, 1997; Schmoll, 1996).
ae) In 2 randomized, controlled clinical trials which included patients with advanced
colorectal cancer (total patients=713), there was no difference in response or survival
between low-dose and high-dose leucovorin (LV) (Labianca et al, 1997; Jager et al,
1996); however, toxic diarrhea occurred at a higher incidence in the high-dose group
(27% versus 16%) (Jager et al, 1996). In 1 study, patients (n=422) were randomized
to receive 1-LV 100 milligrams/square meter (mg/m(2)) or 10 mg/m(2) as an
intravenous bolus followed by FLUOROURACIL 370 mg/m(2) administered as a 15minute infusion. Each cycle was administered for 5 consecutive days, repeated every 4
weeks (Labianca et al, 1997). In the second study, 148 patients were randomized to a
2-hour infusion of leucovorin 500 milligrams/square meter (mg/m(2)) plus bolus
FLUOROURACIL 500 mg/m(2) after 1 hour of the leucovorin infusion. The remaining
143 patients received the same regimen but at a leucovorin-dose of 20 mg/m(2)
(Jager et al, 1996).
223/317
25/10/12

1998).
Neoplasm of rectum
Mean follow-up period was 15 months with 1 local (oral group) and 3 systemic failures
among the 2 groups. Patients received either a intravenous bolus infusion of 5-FU 450
milligrams per square meter/day (mg/ m(2)/d) (mean age 50 years; n=14) in
combination with leucovorin 20 mg/m(2)/d for 5 consecutive days on the first and fifth
weeks of concurrent radiotherapy or oral DOXIFLURIDINE 700 mg/ m(2)/d (mean age
52 years; n=14)in combination with leucovorin 20 mg/m(2)/d continuously during
radiotherapy. Toxicities included diarrhea, stomatitis and leukopenia (no difference
5-deoxynucleoside derivative, offered no significant advantage over intravenous 5- FU
Pancreatic cancer
a) In interim results of a randomized controlled trial of patients with resectable
pancreatic cancer (European Study Group for Pancreatic Cancer trial ESPAC-1), a
median survival of 19.7 months was achieved in patients who received ADJUVANT
CHEMOTHERAPY with FLUOROURACIL and LEUCOVORIN (n=238) compared with
14.0 months in patients who received chemoradiotherapy or no treatment (n=235;
p=0.0005). However, this survival benefit was not significant in patients randomized
in the original 2-by-2 factorial trial design with a median survival of 17.4 months for
patients who received chemotherapy (n=146) versus 15.9 months for patients who
did not (n=139). In a comparison of patients who received CHEMORADIOTHERAPY
(n=175) and those who received chemotherapy or no treatment (n=178), there was
no significant difference in survival (15.5 versus 16.1 months; p=0.24). Of 541
patients, 285 were randomized in a 2-by-2 factorial design to receive no treatment
(n=69), chemoradiotherapy (n=70), chemotherapy (n=74), or chemoradiotherapy and
chemotherapy (n=72). The trial was expanded to allow clinicians to enroll patients in
the original trial design as above or to select randomization to either
chemoradiotherapy/no chemoradiotherapy (n=68) or chemotherapy/no chemotherapy
(n=188) and to provide any additional treatment of their choosing prior to enrollment.
Chemoradiotherapy consisted of 20 Gray (Gy) tumor
dose in 10 daily fractions over

2
224/317
25/10/12
Chemoradiotherapy consisted of 20 Gray (Gy) tumor dose in 10 daily fractions over 2

weeks with fluorouracil 500 milligrams/square meter (mg/m(2)) intravenous (IV)
bolus on days 1 through 3, repeated after a 2-week break. Chemotherapy consisted of
leucovorin 20 mg/m(2) IV bolus followed by fluorouracil 425 mg/m(2) IV bolus on days
1 through 5 every 28 days for 6 cycles. The same regimens of chemoradiotherapy
followed by chemotherapy were used for the combination therapy. Toxicity data was
collected on a subset of 246 patients (74 chemoradiotherapy, 118 chemotherapy, and
54 combination. Grade 3/4 toxicity was reported by 1 patient in the
chemoradiotherapy group, 28 in the chemotherapy group, and 15 in the combination
group and included stomatitis (32%), neutropenia (25%) and diarrhea (23%). Further
trials are needed to confirm the survival benefit of chemotherapy (Neoptolemos et al,
2001).
b) In interim results of a randomized controlled trial of patients with resectable
2001).
Leucovorin Calcium
225/317
25/10/12

weeks OR
weeks OR
then every 5 weeks
Levamisole
Colon cancer
a) The combination of oral levamisole and intravenous fluorouracil is more effective
than levamisole alone as adjunctive therapy in patients with resected Dukes stage C
colon cancer [466]. A pharmacoeconomic evaluation of patients with colorectal cancer
led to a better cost-effectiveness ratio with intraportal chemotherapy (with mitomycin
and fluorouracil) as compared to systemic chemotherapy (with fluorouracil and
levamisole). An indirect comparison derived a cost-effectiveness ratio per discounted
life-year gained of $1,210 for intraportal chemotherapy and $2,094 for systemic
chemotherapy, suggesting that the latter represents an inferior pharmacoeconomic
choice [467].
Lonidamine
Breast cancer
a) Preliminary results from a large randomized trial (n=199) have indicated the
superiority of oral lonidamine 600 milligrams daily plus FAC (5-fluorouracil,
doxorubicin, cyclophosphamide) over FAC alone in patients with metastatic breast
cancer [468]. Response rates of 63% and 44%
were observed with lonidamine/FAC

226/317
25/10/12
cancer [468]. Response rates of 63% and 44% were observed with lonidamine/FAC
and FAC alone, respectively; a significantly longer progression-free survival was also
reported in the lonidamine/FAC group. Toxicity was similar with either regimen.
1998).
Medroxyprogesterone
Breast cancer
a) MITOMYCIN plus high-dose MEDROXYPROGESTERONE was comparable to CAF
Methotrexate
Breast cancer
227/317
25/10/12
years:
SUBGROUP ANALYSIS
HR
CI
All (n=1614)
1.2
1.0-1.4
ER+ (n=1189)
1.0
0.8-1.2
ER- (n=304)
1.8
1.3-2.4
ER unknown (n=121)
2.0
1.1-3.8
OVERALL SURVIVAL
SUBGROUP ANALYSIS
HR
CI
All (n=1614)
1.2
1.0-1.5
ER+ (n=1189)
1.0
0.8-1.3
ER- (n=304)
1.8
1.2-2.6
ER unknown (n=121)
1.8
0.8-4.1
p
0.029
0.94
0.0006
0.026
p
0.67
0.92
0.0043
0.14
c) Survival is NOT improved for women with metastatic breast cancer undergoing
INDUCTION AND
MAINTENANCE
INFUSION)
Doxorubicin
30 mg/m(2) days 1
and 8 IV
14 days PO
Fluorouracil
500 mg/m(2) days 1
and 8 IV
Methotrexate*
40 mg/m(2) days 1
and 8 IV
Thiotepa
Carboplatin
IV=intravenous
PO=oral
d) Four to six cycles of induction therapy were given every 28 days. Patients
randomized to standard-dose (maintenance) chemotherapy
received a median of
8
228/317
25/10/12

e) In one study, 1- or 2-year therapy with CMFVP (CYCLOPHOSPHAMIDE,
f) In a multicenter phase III randomized study, CYCLOPHOSPHAMIDE,
g) Escalating doses of ACMF (DOXORUBICIN, CYCLOPHOSPHAMIDE,
conducted in premenopausal, node- positive breast
cancer patients receiving either

6
229/317
25/10/12

h) The combination regimen CEF (CYCLPHOSPHAMIDE, EPIRUBICIN,
(94.1%, 60.4%) (Levine et al, 1998).
i) In one study, 1-year or 2-year therapy with CMFVP (CYCLOPHOSPHAMIDE,
j) The combination regimen CEF (CYCLOPHOSPHAMIDE, EPIRUBICIN,
mg/m(2) IV days 1 and 8). Both regimens were administered for 6 cycles. Relapsefree survival at 5 years in the CEF and CMF groups
was 63% and 53%, respectively

230/317
25/10/12
free survival at 5 years in the CEF and CMF groups was 63% and 53%, respectively
(94.1%, 60.4%) (Levine et al, 1998).
k) No advantage was achieved with 12 versus 6 cycles of CMF
followed by 6 cycles of CMF. No difference in survival or disease-free survival was
found among the 3 groups at 10 years median follow-up. The strongest predictors of
survival were positive nodes (negative correlation) and ideal or full dose of CMF
(positive correlation) (Velez-Garcia et al, 1992).
l) Escalating doses of DOXORUBICIN, CYCLOPHOSPHAMIDE, METHOTREXATE, and
m) In a study of 445 patients with node-positive, receptor-negative breast cancer, 1and 2-year therapy with CYCLOPHOSPHAMIDE, METHOTREXATE, FLUOROURACIL,
et al, 1991).
n) Adjuvant chemotherapy with CMF (CYCLOPHOSPHAMIDE, METHOTREXATE and 5FLUOROURACIL) provided better relapse-free and total survival than SURGERY alone
o) A sixteen-week multidrug regimen achieved only
marginally better outcomes231/317

than
o) A sixteen-week multidrug regimen achieved only marginally better outcomes than

p) Tamoxifen 10 mg PO twice daily was reported as effective as a combination of
25/10/12

q) In an intent-to-treat analysis, overall response rate was improved in metastatic
r) The combination regimen CEF (CYCLPHOSPHAMIDE, EPIRUBICIN, FLUOROURACIL)
demonstrated superior survival benefit compared to CMF (CYCLOPHOSPHAMIDE,
METHOTREXATE, FLUOROURACIL) in a large study (n=710) evaluating
premenopausal women with node-positive breast cancer. Women previously untreated
for breast cancer were randomized to receive monthly treatments of either CEF
(cyclophosphamide 75 milligrams/square meter (mg/m(2)) orally days 1 through 14,
epirubicin 60 mg/m(2) intravenously (IV) days 1 and 8, fluorouracil 500 mg/m(2) IV
days 1 and 8) or CMF (cyclophosphamide 100 mg/m(2) orally days 1 through 14,
methotrexate 40 mg/m(2) IV days 1 and 8, and fluorouracil 600 mg/m(2) IV days 1
and 8). Both regimens were administered for 6 cycles. Relapse-free survival at 5 years
in the CEF and CMF groups was 63% and 53% respectively (p=0.009). Overall
survival was 77% and 70% in the CEF and CMF groups respectively (p=0.03). Survival
stratified to 1 to 3 nodes or greater than 3 nodes was 82% and 70% in the CEF group
respectively. For patients in the CMF group it was 78% and 58% respectively. Qualityof-life summary scores were identical in both groups by 6 months after chemotherapy,
however; the mean score in the CEF group decreased to a nadir more quickly than in
the CMF group. This was possibly due to a difference in acute toxicity between the 2
regimens. Greater toxicity was noted in patients receiving the CEF regimen.
Comparison of grade 3/4 toxicities in the CEF and
CMF groups respectively was 233/317
25/10/12
Comparison of grade 3/4 toxicities in the CEF and CMF groups respectively was
nausea (13.4%, 3.1%), vomiting (11.4%, 4.1%), diarrhea (0.9%, 2.2%), stomatitis
(12.3%, 1.9%), alopecia (42.2%, 6.7%), granulocytopenia (97.7%, 78.3%),
thrombocytopenia (9.4%, 3.7%), leukopenia (94.1%, 60.4%) (Levine et al, 1998).
s) In premenopausal women with node-positive operable breast cancer, FEC
t) The combination regimen CEF (CYCLOPHOSPHAMIDE, EPIRUBICIN,
(94.1%, 60.4%) (Levine et al, 1998).
u) In an intent-to-treat analysis, overall response rate was improved in metastatic
for CEF and CMF (20.1 months and 18.2 months,
respectively; p=0.23). Patients234/317

were
25/10/12
v) DOCETAXEL MONOTHERAPY was associated with a significantly longer time to
progression (6.3 months) compared to METHOTREXATE and 5-FLUOROURACIL (MF)
combination therapy (3.0 months; p less than 0.001) in patients (n=282) with
advanced breast cancer who had failed anthracycline treatment. Patients enrolled in
this open-label, randomized study received docetaxel 100 milligrams/square meter
(mg/m(2)) over 1 hour every 3 weeks or sequential methotrexate 200 mg/m(2) and
5-fluorouracil 600 mg/m(2) on days 1 and 8 every 3 weeks. Patients who relapsed on
randomized study treatment were encouraged to crossover to the alternate
treatment. Eight percent of docetaxel patients and 3% of MF patients experienced
complete response. Almost twice as many docetaxel patients experienced a partial
response (34%) compared to MF (18%). Docetaxel was associated with more toxicity
than MF with 3 treatment related deaths in the docetaxel arm and one in the MF arm
(Sjostrom et al 1999).
w) Escalating doses of ACMF (DOXORUBICIN, CYCLOPHOSPHAMIDE,
x) No advantage was observed with 12 versus 6 cycles of CMF
followed by 6 cycles of CMF. There was no difference in survival or disease-free
survival among the 3 groups at approximately 10
years median follow-up. The
235/317
survival among the 3 groups at approximately 10 years median follow-up. The

strongest predictors of survival were positive nodes (negative correlation) and ideal or
full dose of CMF (positive correlation) (Velez-Garcia et al, 1992).
y) In one study, 1-year or 2-year therapy with CMFVP (CYCLOPHOSPHAMIDE,
1993).
z) Prolonged survival, reduced myleosuppression, and a slightly higher quality of life
aa) An overall response rate of 65% (2 complete, 18 partial) was achieved with
was 9 months and 6 months in the NFL and CMF groups respectively, (p=0.06).236/317
25/10/12
Neoplasm of colon
a) Methotrexate and leucovorin are equally effective modulators of FLUOROURACIL in
patients with metastatic colorectal cancer. High-dose FLUOROURACIL with
methotrexate resulted in a significantly higher response rate (23% versus 11%,
p=0.025) and a 3-month increase in survival compared with FLUOROURACIL alone in
patients with advanced unresectable or metastatic colorectal cancer. All 297 patients
received FLUOROURACIL 60 milligrams (mg) per kilogram as a continuous infusion
over 48 hours; 146 patients also received methotrexate 40 mg/square meter (m(2))
as an intravenous injection immediately before the FLUOROURACIL infusion.
Chemotherapy was administered weekly for 4 courses and then biweekly for 4
courses. Stomatitis occurred in significantly more patients receiving combination
therapy versus FLUOROURACIL alone (p less than 0.001); nausea and vomiting also
occurred in more patients receiving combination therapy (48% versus 35%) (Blijham
et al, 1996).
b) Modulation of FLUOROURACIL with folinic acid (leucovorin) plus methotrexate in
patients with advanced colorectal cancer resulted in a higher response rate but similar
survival when compared with modulation using only leucovorin. Eighty-three patients
with recurrent or metastatic colon or rectal cancer, were randomly assigned to receive
one of the following regimens: Group A, intravenous leucovorin 300 milligrams/square
meter (mg/m(2))/day followed by FLUOROURACIL 500 mg/m(2)/day administered
over 1 hour for 4 days; Group B, methotrexate 130 mg/m(2)/day 20 hours before
leucovorin 300 mg/m(2)/day followed by FLUOROURACIL 500 mg/m(2)/day
administered over 1 hour for 4 days. Twenty-four hours after the methotrexate
infusion, leucovorin 15 mg every 6 hours for 6 doses was administered. Both regimens
were repeated every 21 days for 6 cycles. Three patients in group B versus one in
group A had a complete response; 15 patients in group B versus 7 in group A had a
partial response. Toxicity consisting of neutropenia, thrombocytopenia, mucositis,
nausea/vomiting, and diarrhea occurred at a higher incidence and was more severe in
group B (Polyzos et al, 1996).
a) The FAMTX regimen (methotrexate 1.5 grams/square meter (g/m(2)), fluorouracil
Methotrexate Sodium
237/317
25/10/12

238/317
25/10/12
weeks OR
weeks OR
then every 5 weeks
Methyl Aminolevulinate
Squamous cell carcinoma
a) In an unpublished phase III study involving patients with early squamous cell skin
carcinoma (n=229), a complete lesion response rate of 93% was reported with
methyl aminolevulinate photodynamic therapy (PDT), compared to 83% with topical
5-fluorouracil and 86% with cryotherapy. Respective rates of excellent cosmetic
outcome were 59%, 45%, and 30%. Dose/study details and statistical analysis were
not provided [427][428].
Mitomycin
Anal cancer
a) Combined radiotherapy and chemotherapy resulted in significantly better
locoregional control, fewer colostomies, and improved event-free survival in patients
with advanced anal cancer. In this phase III study, 110 patients received either
radiotherapy alone or radiotherapy with chemotherapy. Radiotherapy consisted of 45
Gray (Gy; a unit of absorbed radiation dose equal to 100 rads) administered over 5
weeks (1.8 Gy daily); this was followed by a 6-week rest and an additional boost of 15
to 20 Gy depending on initial response. Patients assigned to combination therapy also
received continuous infusion fluorouracil 750 milligrams/square meter(mg/m(2)) per
24 hours on days 1 to 5 and 29 to 33, and a bolus dose of mitomycin 15 mg/m(2) on
day 1. Nineteen patients required fluorouracil dose reductions during the second
course. The complete remission rate increased from 54% to 80% with the addition of
chemotherapy to radiotherapy, and this difference persisted throughout the follow-up
period, significantly lowering the locoregional recurrence rate (p=0.02). Although
239/317
25/10/12
surgical resection was planned only for non-responders, 15 patients (7 partial

responders and 8 complete responders) underwent surgery. Acute side effects (skin
reactions and diarrhea) and late complications (fistula, skin ulceration, stenosis,
fibrosis) did not differ between treatment groups; however, 1 patient receiving
combination therapy died during neutropenic sepsis, and the combination group had a
higher incidence of anal ulcers. While overall survival did not improve with combination
therapy, event-free survival was significantly improved (p=0.03) (Bartelink et al,
1997).
b) Concurrent radiation therapy and chemotherapy with fluorouracil and mitomycin
resulted in significantly fewer local failures than radiation therapy alone in patients
with epidermoid anal cancer. There was no overall survival advantage for patients
treated with combination therapy; however, 3-year mortality was significantly higher
(p=0.02) in the radiotherapy group versus combination therapy group. Combination
therapy consisted of fluorouracil 1000 milligrams/square meter (mg/m(2)) daily on
days 1 to 4, or radiotherapy plus fluorouracil 750 mg/m(2)/day on days 1 to 5 and
mitomycin 12 mg/m(2) on day 1. An additional cycle of fluorouracil was given during
the final week of radiotherapy. Partial or complete responders received a boost course
of radiotherapy; patients with a less than 50% response were recommended for
radical surgery (Anon, 1996).
Breast cancer
a) MITOMYCIN plus high-dose MEDROXYPROGESTERONE was comparable to CAF
Gastric cancer
b) MITOMYCIN, EPIRUBICIN, and FLUOROURACIL did NOT produce a statistically
240/317
25/10/12

c) Fluorouracil alone (500 milligrams/square meter (mg/m(2)) daily for 5 days per
course, repeated at 4 and 8 weeks and every 5 weeks thereafter) was as effective as
a combination of fluorouracil plus doxorubicin, or a combination of fluorouracil plus
doxorubicin plus mitomycin C, with regard to patient survival in the treatment of
advanced pancreatic and gastric carcinoma in a study involving 305 patients with
advanced disease. Except for diarrhea and stomatitis, blood dyscrasias and nonhematologic toxicity (GI disturbances, alopecia) were greater with the combination
regimens; both stomatitis and diarrhea occurred more frequently in patients receiving
fluorouracil alone. The authors indicate that, due to failure to induce improved survival
or palliation combined with excessive cost of combination therapy and greater toxicity,
neither combination is indicated over fluorouracil alone in advanced pancreatic or
gastric cancer (Cullinan et al, 1985).
d) Postoperative maintenance adjuvant immunotherapy with intramuscular PICIBANIL
Glaucoma
a) Intraoperative fluorouracil (5-FU) 50 milligrams/milliliter (mg/mL) for 5 minutes
and mitomycin-C 0.4 mg/mL for 2 minutes exhibited equivalent efficacy as an adjunct
to primary trabeculectomy in a multicenter, randomized trial of 113 eyes (n=113
patients) with various forms of glaucoma. The average reductions in intraocular
pressure (IOP) were 50% and 46% for 5-FU and mitomycin-C recipients, respectively
(p=NS), with over 90% of both groups attaining an IOP target of less than 21
millimeters of mercury. With over 300 days of average follow-up, other postoperative
measures such as complications, changes in visual acuity and necessity for 5-FU
injections, argon laser suture lysis or IOP-lowering medication also did not differ
statistically between groups [433].
b) Mitomycin C versus fluorouracil (5-FU) used intraoperatively during trabeculectomy
resulted in a significantly (p=0.05) lower postoperative intraocular pressure in a black
West African population [433]. Eighty-one patients were randomly assigned to receive
either mitomycin C 0.5 milligram/milliliter (mg/mL) for 3.5 minutes or 5-FU 50 mg/mL
for 5 minutes on the trabeculectomy flap. At a mean follow-up of 10 months, none of
the patients had developed a persistent wound leak or endophthalmitis. Although
241/317
25/10/12
mitomycin C produced a lower mean postoperative intraocular pressure than 5-FU, 5FU is still preferred in this population because it is less expensive, easier to store, and
possibly less intimidating to the novice surgeon. This study differed from those in
developed countries in the following respects: (1) Many patients had decreased vision
at the time of surgery; (2) Medical therapy is often prohibitively expensive and
inaccessible; and (3) Postoperative follow-up care is often suboptimal. Due to these
limitations, an antimetabolite trabeculectomy is the preferred treatment in this
population.
c) Greater reduction of intraocular pressure after trabeculectomy was achieved with
single intraoperative application of MITOMYCIN compared with postoperative
subconjunctival injection of 5-FLUOROURACIL multiple-dose therapy in patients with
refractory open angle glaucoma. The most significant differences were observed at 2week and 3-month follow-up. Twelve months postoperatively, mitomycin-treated
patients retained lower intraocular pressures than 5-fluorouracil-treated patients
without medication. Mild choroidal detachment occurred in 3 patients receiving
mitomycin, and drug-induced corneal epithelial defects occurred in 3 patients receiving
5-fluorouracil [434].
Pancreatic cancer
Mitoxantrone
Breast cancer
a) In a multicenter phase III randomized study, CYCLOPHOSPHAMIDE,
242/317
25/10/12
b) In a phase III trial of women with metastatic breast cancer (n=281), a comparison
c) An overall response rate of 65% (2 complete, 18 partial) was achieved with
Oxaliplatin
with gemcitabine alone in patients with metastatic pancreatic adenocarcinoma 243/317
who
25/10/12

than 0.001) [442].
a) In a randomized, multicenter, phase 3, noninferiority trial (n=491), second-line
244/317
25/10/12
b) A randomized multicenter trial demonstrated that a regimen of infused
245/317
25/10/12
c) In a phase III study comparing two sequential therapies in metastatic colorectal
square meter (mg/m(2)), respectively) and irinotecan 180 mg/m(2) given as a 90minute infusion followed by a bolus of fluorouracil 400 mg/m(2) and then a 46-hour
Neoplasm of colon
a) Preliminary results from a randomized phase III trial (E3200) indicate that the
b) The addition of oxaliplatin to the North Central Cancer Treatment Group/Mayo
Clinic regimen of 5-fluorouracil (FU)/leucovorin (LV) (LV5FU2) demonstrated a
prolonged progression-free survival (PFS), acceptable toxicities, and maintenance of
quality of life as first-line therapy in advanced colorectal cancer. Four hundred and
twenty chemotherapy-nave patients with metastatic colorectal cancer were
randomized in a multi-center study to treatment with LV5FU2 which consisted of a 2hour infusion of LV 200 milligrams per square meter/day (mg/m(2)) followed by a
bolus of FU 400 mg/m(2)/day and then a 22-hour infusion of FU 600 mg/m(2)/day
246/317
25/10/12
repeated for 2 consecutive days every 14 days (arm A) or oxaliplatin (85 mg/m(2)) on
day 1 plus LV5FU2 group (arm B; FOLFOX4). The results indicate that when added to
the bimonthly two- hour infusion of LV5FU2, oxaliplatin extends PFS significantly (8.2
months versus 6.0 months; p=0.0003). Intent-to-treat response rates were reported
as 21.9% (95% confidence interval (CI), 17.9% to 25.9%) in arm A and 50.0% (95%
CI, 46.1% to 54.9%; p=0.0001) in arm B. Median overall survival (14.7 months for
arm A versus 16.2 months for arm B), however, was not statistically different
between the two treatment groups (log-rank test p=0.12; Wilcoxon p=0.05). In arm
A, patients experienced grade 3 neutropenia and diarrhea mostly. Grade 3/4 toxicities
(neutropenia, diarrhea, mucositis, and neuropathy) were more common in arm B than
arm A were. Although there were significant increases in grade 3/4 toxicities in arm B,
quality of life (QOL) measurements for that group were not significantly influenced;
the overall QOL scores were comparable for the two arms [440].
c) The safety and efficacy of single-agent oxaliplatin in patients with metastatic
colorectal cancer (n=459) was compared to oxaliplatin in combination with 5fluorouracil (5-FU)/leucovorin (LV) and to the same dose and schedule 5-FU/LV in a
multicenter, randomized, controlled trial. Patients with advanced colorectal cancer
who had relapsed/progressed during or within 6 months of first line therapy were
randomized to single-agent oxaliplatin (n=156; day 1: 85 milligrams/square meter
(mg/m(2)), oxaliplatin/5-FU/LV (n=152; day 1: oxaliplatin 85 mg/m(2) + LV 200
mg/m(2) followed by 5-FU 400 mg/m(2) bolus, 600 mg/m(2) (22 hour infusion), day
2: LV 200 mg/m(2) followed by 5-FU 400 mg/m(2) bolus, 600 mg/m(2) (22 hour
infusion), or 5-FU/LV (n=151; same dose and schedule). All regimens were repeated
every 2-weeks. At an interim analysis, patients treated with oxaliplatin/5-FU/LV had
an increased response rate and median time to progression (9%, 4.6 months) versus
patients given 5-FU/LV (0%; p=0.0002, 2.7 months) or oxaliplatin alone (1%, 1.6
months). The most common grade 3/4 adverse events reported in the oxaliplatin/5FU/LV group were neuropathies (7%), neutropenia (44%), and
nausea/vomiting/diarrhea (11%, 9%, 11%) (Prod Info Eloxatin (TM), 2002).
d) A combination of oxaliplatin with fluorouracil plus leucovorin resulted in better
response rates than oxaliplatin alone in patients with progressive colorectal cancer in
a non-randomized study. All patients had progressive disease despite prior treatment
with fluorouracil-containing regimens (23 receiving treatment within 6 months of
study; 2 treated more than 6 months before study). Oxaliplatin 130 milligrams/square
meter (mg/m(2)) was infused over 2 hours every 21 days. Fluorouracil was
administered by continuous infusion via central venous catheter at a dose of 200 up to
300 mg/m(2)/day, or as a bolus infusion of 375 mg/m(2) over 5 days with leucovorin
100 mg/m(2). Of 12 patients treated with combination therapy, 4 achieved partial
remission and 4 achieved stable disease; of the 4 partial responders, 2 received the 5day bolus infusion of fluorouracil with leucovorin and 2 received continuous infusion of
only fluorouracil. Of the 13 patients receiving oxaliplatin alone, none achieved
remission and 4 had stable disease. While the results suggest a better response with
combination therapy, patient selection may have influenced results in this nonrandomized study, since combination therapy was given to those who were receiving
fluorouracil at the time the study began, whereas oxaliplatin alone was given to those
who were not receiving the drug at that time (deBraud et al, 1998).
e) A bimonthly regimen of leucovorin plus 48-hour continuous fluorouracil and
oxaliplatin achieved higher responses in patients with colorectal cancer but was not as
247/317
25/10/12
well-tolerated as the same regimen with a lower dose of oxaliplatin. Responses with
the leucovorin plus continuous infusion regimen (46% overall) had been recorded
during a previous study, with an oxaliplatin dose of 100 milligrams/square meter
(mg/m(2)). The present study included patients refractory to the previous regimen.
The regimen in the second study included leucovorin 500 mg/m(2) plus oxaliplatin 85
mg/m(2) (through separate infusion lines) as a 2-hour infusion, followed by
fluorouracil 1.5 to 2 grams/m(2) as a 22-hour infusion. This regimen was given for two
consecutive days every two weeks for a median of 9.5 cycles. Among 30 assessable
patients, 6 had a partial response (20%) lasting 37 weeks, and 15 had stabilization
lasting 27 weeks. Progression-free survival lasted a median of 26 weeks, with a
median survival of 57 weeks. Grade 3 to 4 toxicities were observed in 27% of
patients; the most common adverse events were non-febrile neutropenia in 20% of
patients, and thrombocytopenia in 13%. After 11 to 15 cycles, 4 patients had severe
sensory neuropathy that was of prolonged duration following discontinuation of
chemotherapy. Whether the between-regimen difference in response and toxicity was
a result of the lower oxaliplatin dose or patient selection was not established (Andre
et al, 1998).
Paclitaxel
Breast cancer
a) In a phase III trial of women with metastatic breast cancer (n=267), median time
b) Prolonged survival, reduced myleosuppression, and a slightly higher quality of life
248/317
25/10/12

c) Paclitaxel alone demonstrated efficacy equivalent to that of the combination of
Paclitaxel Protein-Bound
249/317
25/10/12
0%, 5%) [413].
Picibanil
Gastric cancer
a) Postoperative maintenance adjuvant immunotherapy with intramuscular PICIBANIL
Pirarubicin
250/317
25/10/12
Breast cancer
a) In a randomized comparison (n=78), an FAC regimen (intravenous doxorubicin,
oral cyclophosphamide, intravenous fluorouracil) and an FPC regimen (intravenous
Prednisone
Breast cancer
a) In one study, 1- or 2-year therapy with CMFVP (CYCLOPHOSPHAMIDE,
b) In one study, 1-year or 2-year therapy with CMFVP (CYCLOPHOSPHAMIDE,
c) In a study of 445 patients with node-positive, receptor-negative breast cancer, 1and 2-year therapy with CYCLOPHOSPHAMIDE, METHOTREXATE, FLUOROURACIL,
et al, 1991).
d) In one study, 1-year or 2-year therapy with CMFVP (CYCLOPHOSPHAMIDE,
251/317
1993).
e) Prolonged survival, reduced myleosuppression, and a slightly higher quality of life
Radiation therapy
Anal cancer
a) Combined radiotherapy and chemotherapy resulted in significantly better
locoregional control, fewer colostomies, and improved event-free survival in patients
with advanced anal cancer. In this phase III study, 110 patients received either
radiotherapy alone or radiotherapy with chemotherapy. Radiotherapy consisted of 45
Gray (Gy; a unit of absorbed radiation dose equal to 100 rads) administered over 5
weeks (1.8 Gy daily); this was followed by a 6-week rest and an additional boost of 15
to 20 Gy depending on initial response. Patients assigned to combination therapy also
received continuous infusion fluorouracil 750 milligrams/square meter(mg/m(2)) per
24 hours on days 1 to 5 and 29 to 33, and a bolus dose of mitomycin 15 mg/m(2) on
day 1. Nineteen patients required fluorouracil dose reductions during the second
course. The complete remission rate increased from 54% to 80% with the addition of
chemotherapy to radiotherapy, and this difference persisted throughout the follow-up
period, significantly lowering the locoregional recurrence rate (p=0.02). Although
surgical resection was planned only for non-responders, 15 patients (7 partial
responders and 8 complete responders) underwent surgery. Acute side effects (skin
reactions and diarrhea) and late complications (fistula, skin ulceration, stenosis,
fibrosis) did not differ between treatment groups; however, 1 patient receiving
combination therapy died during neutropenic sepsis, and the combination group had a
higher incidence of anal ulcers. While overall survival did not improve with combination
therapy, event-free survival was significantly improved (p=0.03) (Bartelink et al,
1997).
b) Concurrent radiation therapy and chemotherapy with fluorouracil and mitomycin
resulted in significantly fewer local failures than radiation therapy alone in patients
with epidermoid anal cancer. There was no overall survival advantage for patients
treated with combination therapy; however, 3-year mortality was significantly higher
(p=0.02) in the radiotherapy group versus combination therapy group. Combination
therapy consisted of fluorouracil 1000 milligrams/square meter (mg/m(2)) daily on
days 1 to 4, or radiotherapy plus fluorouracil 750 mg/m(2)/day on days 1 to 5 and
mitomycin 12 mg/m(2) on day 1. An additional cycle of fluorouracil was given during
the final week of radiotherapy. Partial or complete responders received a boost course
of radiotherapy; patients with a less than 50% response were recommended for
radical surgery (Anon, 1996).
Breast cancer
a) No difference in survival or progression free survival was detected in patients with
al, 1998).
Carcinoma of pancreas
a) Results from a randomized controlled trial of patients with resectable pancreatic
cancer (European Study Group for Pancreatic Cancer trial ESPAC-1) suggest that
postoperative chemotherapy with fluorouracil and leucovorin improves survival
whereas postoperative chemoradiotherapy negatively affects survival. However
limitations in the trial design, large drop out rates and potential bias hamper the
interpretation of these results. A total of 289 patients were randomized in a 2-by-2
factorial design to receive no treatment (n=69), chemoradiotherapy (n=73),
chemotherapy (n=75), or combination chemoradiotherapy and chemotherapy (n=72).
Chemoradiotherapy was administered as a 20 Gray dose to the previous tumor bed in
10 daily fractions over 2 weeks with fluorouracil 500 milligrams/square meter
(mg/m(2)) intravenous (IV) bolus on days 1 through 3, repeated after a 2-week
break. Chemotherapy consisted of leucovorin 20 mg/m(2) as an IV bolus followed by
an IV bolus of fluorouracil 425 mg/m(2) on days 1 through 5 every 28 days for 6
cycles. The same regimens of chemoradiotherapy followed by chemotherapy were
used for the combination therapy. Intent-to-treat analysis was used to conduct 2
comparisons: patients who received chemotherapy with patients who did not receive
chemotherapy and patients who received chemoradiotherapy with patients who did
not receive chemoradiotherapy. The calculated hazard ratio for death was 1.28 (95%
confidence interval (CI) 0.99 to 1.66; p=0.05) for patients who received
chemoradiotherapy. Median survival did not significantly differ between those who
received chemotherapy and those who did not. Chemotherapy was associated with a
253/317
25/10/12
0.71 hazard ratio for death (95% CI 0.55 to 0.92; p=0.009). Median survival times
also did not significantly differ between patients who received chemotherapy and
those who did not. However only 70% of patients assigned to receive
chemoradiotherapy received a total of 40 Gray according to the protocol and only 50%
of patients assigned to receive chemotherapy received all 6 cycles of therapy. Analysis
of patient drop out was not presented. Although these results are suggestive, the
ESPAC-3 trial and the Radiation Therapy Oncology Group trial 97-04 will shed further
light on the role of chemoradiotherapy and chemotherapy in this patient population
[439].
Cervical cancer
a) In a Phase III trial of 368 eligible subjects with locally advanced stage IIB to IVA
1999).
b) The combination of CISPLATIN and RADIATION therapy or CISPLATIN,
c) In a large, randomized, open-label, multicenter, controlled, PHASE III trial, patients
254/317
25/10/12
receiving CISPLATIN and FLUOROURACIL with RADIATION therapy had significantly

better survival (73%) versus patients receiving radiation alone (58%) in the
treatment of cervical cancer (p=0.004). A total of 388 women were evaluated having
STAGE IIB through IVA cancer of the cervix and followed for a median of 43 months.
The study group was administered cisplatin 75 milligrams/square meter (mg/m(2))
infused over 4 hours followed by fluorouracil 4000 mg/m(2) infused over 96 hours plus
a total of 85 Gy radiation. Chemotherapy was given every 3 weeks for a total of 3
cycles. The control group received only radiation (85 Gy). Disease-free survival at 5
years was also better in the study group (67%) compared to radiation alone (40%).
When stratified according to stage IB, IIA, or IIB, again the study group showed
better survival (77%) compared to radiation only (58%). There was no difference in
survival between the 2 groups with stage III or IVA disease. Rates of distant relapse
and (14%, relative risk=0.39) locoregional recurrence (19%, relative risk=0.47) were
significantly lower in the study group compared to the radiation-only group (33% and
35% respectively). Grade 3 and 4 toxicities occurred more frequently with combined
therapy but were usually self-limited. Hematologic effects were generally moderate
(Morris et al, 1999).
Esophageal cancer
(Urba et al, 2001).
a) A 12-month course of fluorouracil (5-FU) plus leucovorin offered no significant
advantage over a 6-month course in the postoperative treatment of patients with
stage II or III RECTAL cancer (n=263). Dosing consisted of leucovorin 100
milligrams/square meter (mg/m(2)) over 15-30 minutes then 5-FU 450 mg/m(2) over
60 minutes on days 1 to 5 of a 4-week cycle. During the second cycle only, all subjects
received daily pelvic radiotherapy (up to 50.4 Gy total exposure) with weekly
leucovorin and reduced-dose 5-FU 350 mg/m(2). Based on data from 223 evaluable
subjects with a median 34 months of follow-up, the median times to recurrence were
16.3 and 17.8 months in the 12-month and 6-month groups, respectively (p=NS).
Corresponding 3-year mortality rates were 20.5% and 23.7%, respectively (p=NS).
255/317
25/10/12
However, only 51% of patients randomized to 12 cycles actually completed them. The
additional six cycles of 5-FU/leucovorin exposure was not associated with greater
toxicity (Queiber et al, 2000).
Pancreatic cancer
a) In interim results of a randomized controlled trial of patients with resectable
2001).
Raltitrexed
Colorectal cancer
a) SUMMARY: A single dose of raltitrexed every three weeks has been comparable in
efficacy to the Mayo regimen of 5-fluorouracil/leucovorin in the treatment of patients
with advanced colorectal carcinoma. Survival, quality of life, and time to disease
progression were similar with each regimen, although toxicity tended to be less with
raltitrexed. However, the low response rates observed with each regimen suggest the
need for additional comparisons.
b) Raltitrexed 3 mg/m(2) every 3 weeks offered no significant therapeutic advantage
over the Mayo regimen of combined 5-fluorouracil/leucovorin (425/20 mg/m(2) daily
for 5 consecutive days every 4 to 5 weeks) in one phase III comparison involving
untreated patients with advanced metastatic or recurrent colorectal carcinoma
(n=434) [435]. At a mean duration of follow-up of 5.3 months, objective (complete or
partial) response rates were slightly higher in the raltitrexed group (20% versus
256/317
25/10/12
13%), although this was not significant. Median time to disease progression in
raltitrexed and 5-fluorouracil/leucovorin groups (two-sided alpha (5%) significance
level) also did not differ significantly (20 and 15 weeks, respectively), and there was
no difference in survival. Modest and similar improvements in quality of life,
performance status, and body weight were observed. Grade 3 or 4 leukopenia and
mucositis were more common with the 5-fluorouracil/leucovorin regimen, whereas
liver enzyme abnormalities occurred only with raltitrexed (10% of patients); there
was no difference in the incidence of infection or occurrence of fever between
regimens. A shorter time for drug administration in the hospital was evident in the
raltitrexed group.
c) Objective response rates with 5-fluorouracil/leucovorin in this study were low,
suggesting flaws in trial design. Other trials evaluating 5-fluorouracil plus leucovorin in
advanced colorectal carcinoma revealed response rates of up to 45% [436][437];
with the addition of interferon-alpha(2a), a response rate of 54% has been
demonstrated in preliminary studies [436]. In the Cunningham study, one potential
reason to explain low response rates was the unusually long interval between
response evaluations (12 weeks); 6-week evaluation periods would have been more
appropriate. Other flaws (eg, differences in patient characteristics) may have been
operative and suggest the need for a confirmatory comparative trial.
d) Considering available data, raltitrexed does not offer an advantage with respect to
survival or quality of life; its principal advantages are the potential for less toxicity and
greater convenience. However, even these attributes have been questioned by at
least one oncologist, who offers the practical reminder that 5-fluorouracil/leucovorin
chemotherapy does not require hospitalization [437]. At present, data are insufficient
to recommend raltitrexed over conventional 5-fluorouracil/leucovorin.
Neoplasm of colon
a) Combined fluorouracil/leucovorin is advocated as the regimen of choice for
advanced colorectal carcinoma by many specialists (Anon, 1997). A direct comparison
of raltitrexed and the Mayo regimen of fluorouracil/leucovorin (Cunningham et al,
1995) revealed no significant differences in objective response rate, time to
progression, survival, or quality of life; response rates were low with both treatments
(20% and 13%, respectively). The potential advantages of raltitrexed emerging from
this trial were its greater convenience in administration (once every 3 weeks) and
potentially lower propensity for toxicity (reduced mucositis and severe leukopenia),
although liver enzyme elevations occurred only in the raltitrexed arm.
Streptozocin
a) The combination of STREPTOZOCIN plus DOXORUBICIN was superior to
STREPTOZOCIN plus 5-FLUOROURACIL or CHLOROZOTOCIN alone in the treatment
of advanced islet-cell carcinoma in a multicenter study enrolling 105 patients. The
dose of streptozocin was 500 milligrams/square meter (mg/m(2))/day given every 6
weeks. Doxorubicin was administered at 50 mg/m(2) on day 1 of streptozocin and for
day 22 of each 6-week cycle. Tumor regression occurred in 69% and 45% of patients
receiving streptozocin plus doxorubicin and streptozocin plus 5-fluorouracil,
respectively; time to tumor progression was 20 versus 6.9 months, respectively.
Survival was also extended in the streptozocin plus doxorubicin group, 2.2 versus 1.4
years, respectively. Chlorozotocin alone produced a 30% regression rate with length
257/317
25/10/12
of time to tumor progression and survival time equivalent to the streptozocin plus 5fluorouracil group (Moertel et al, 1992).
b) A later retrospective analysis of 16 patients receiving the previously described
regimen of streptozocin and doxorubicin revealed only a 6% (ie, 1 of 16) response
rate to therapy. Nine patients (56%) had stable disease, and 6 patients (38%)
showed disease progression. Proposed reasons for this discrepancy are that previous
trials have accepted a so-called "biologic response" and the clinical measurement of
hepatomegaly on physical examination or measurement on radionuclide liver-spleen
scan as indicators of a major objective response. The authors conclude that an
expectation of frequent major tumor regressions after treatment with this regimen
may be overly optimistic (Cheng & Saltz, 1999).
Sulodexide
Trabeculectomy ab externo
a) In a randomized prospective trial, postoperative SULODEXIDE (SDX) adjunctive
treatment provided comparable success rates and similar levels of intra-ocular
pressure (IOP) to 5-FLUOROURACIL (5-FU), without the adverse side effects
associated with 5-FU, in glaucoma patients undergoing trabeculectomy. Forty-one
consecutive patients had standard- technique trabeculectomy operations. Afterwards,
in randomized fashion, 22 eyes received SDX treatment and 19 eyes received 5-FU
therapy. Five subconjunctival injections of SDX or 5-FU were given postoperatively on
days 10, 17, 24, 31, and 38. Each SDX injection was comprised of 0.1 milliliter (mL) of
drug at a concentration of 300 USL/mL. 5-FU injections were given as 0.1 mL at a
concentration of 50 milligrams (mg)/mL (total 25 mg). No significant differences in
IOP were found between the 2 groups at any time point (2, 6, 12, 18, 24 months
postop). No ocular complication occurred in 73% of the SDX group compared with
63% of the 5-FU group. No cases of superficial punctate keratopathy occurred in SDXtreated cases, compared with 6 in the 5-FU group. Six cases of modest
subconjunctival hemorrhage suffusion were associated with SDX and 1 case with 5FU. A common side effect/complication associated with 5-FU use is perforation of the
filtering bleb; 2 cases in the 5-FU group occurred, requiring surgical repair; no case of
this complication occurred with SDX. All study subjects received a subconjunctival
injection of betamethazone acetate 1.5 mg at the inferior conjunctival fornix at the
end of the operation. Six-week topical therapy given to all patients included
dexamethazone 0.2% eyedrops and tobramycin 0.3% eyedrops 6 times a day, along
with tropicamide 0.1% eyedrops twice daily [465].
Surgical procedure
Breast cancer
a) Postoperative sequential therapy with intravenous methotrexate and fluorouracil,
followed by leucovorin, was not associated with a survival advantage as compared to
no postoperative therapy in a randomized study involving 679 patients with primary
breast cancer, histologically negative axillary nodes, and estrogen-receptor negative
tumors [418]. In this study, intravenous methotrexate 100 mg/m(2) and intravenous
fluorouracil 600 mg/m(2) were given as bolus doses on days 1 and 8 every 4 weeks,
with fluorouracil being given 1 hour after the methotrexate; intravenous leucovorin 10
mg/m(2) was given every 6 hours for 6 consecutive doses beginning 24 hours after
the methotrexate. The methotrexate with fluorouracil therapy was initiated no sooner
than 2 weeks and no later than 35 days after mastectomy, and an average of 10.2
258/317
25/10/12
courses per patient were administered. At 4 years, the survival of patients who
received adjunctive chemotherapy was almost identical to survival in patients treated
with surgery alone (87% versus 86%). However, a significant prolongation of diseasefree survival was observed in women who had received sequential therapy as opposed
to those who had not (80% versus 71%). An advantage was seen both in women
over 50 years and women less than 50 years. At 4 years, treatment failure was
reduced by 24% in the younger group and 50% in the older group.
b) Adjuvant chemotherapy with CMF (CYCLOPHOSPHAMIDE, METHOTREXATE and 5FLUOROURACIL) provided better relapse-free and total survival than SURGERY alone
Esophageal cancer
(Urba et al, 2001).
Tamoxifen
Breast cancer
a) Tamoxifen 10 mg PO BID was reported as effective as a combination of
stage IV breast cancer in elderly women (over the age of 65 years). Response rates
were 45% to 38% in tamoxifen and CMF-treated patients, respectively; an additional
33% and 45% of patients treated with tamoxifen and CMF, respectively, had disease
stabalization for at least 2 months. Survival rates favored tamoxifen as initial therapy
(23 months versus 21 months for CMF), which reached a borderline level of
significance (P=0.08) in the proportional hazards model. Additional disease control
with hormone withdrawal was observed in 23% of patients, and was correlated highly
259/317
25/10/12
with prior hormonal response. Upon crossover to the opposite treatment, response to
either tamoxifen or the CMF regimen was less than that observed when given as initial
therapy (29 and 31%, respectively). A previous response to CMF tended to be
associated with a better chance for tamoxifen response, however, a previous
response with tamoxifen did not predict CMF response. Initiation of hormone therapy
as opposed to CMF chemotherapy is recommended in most elderly patients [419].
b) No difference in survival or progression free survival was detected in patients with
al, 1998).
c) Five-year disease-free survival (DFS) and 5-year overall survival (OS) were
260/317
25/10/12
d) No difference in survival or progression free survival was detected in patients with
al, 1998).
e) Tamoxifen 10 mg PO twice daily was reported as effective as a combination of
Tegafur
261/317
25/10/12
Breast cancer
a) Women with biopsy-proven metastatic breast cancer had an overall response of
48.4% with a UFT(R) (tegafur and uracil)-containing regimen versus 35.5% with a
fluorouracil-containing regimen; the difference was not statistically significant [444].
The overall survival duration was NOT reported. Frequently reported adverse effects
included alopecia, nausea/vomiting, stomatitis, and anemia; with the exception of
grade I anemia and stomatitis, the incidence of toxicity was comparable for both
treatments. Patients (n=62) were randomly assigned to receive cyclophosphamide
500 milligrams/square meter (mg/m(2)) and doxorubicin 50 mg/m(2) on day 1
followed by fluorouracil 500 mg/m(2) on days 1 and 8 or UFT(R) 350 mg/m(2)/day
orally in 2 divided doses from day 1 to 14. Both regimens were repeated every 4
weeks for 6 cycles. Additional large, long-term studies are needed to evaluate this
regimen before using it as standard therapy; tegafur offers the advantage of oral
administration.
Malignant tumor of digestive organ
a) SUMMARY: Intravenous tegafur, either alone or in combination regimens, has
offered no advantage over 5-fluorouracil (5-FU) in the treatment of gastrointestinal
malignancies; toxicity has been greater with intravenous tegafur compared to 5-FU.
b) Intravenous tegafur as single-agent therapy in relatively high doses (2.5
grams/square meter/day for 5 days every 3 to 5 weeks) has produced objective
responses (complete or partial) in 4% to 11% of patients (previously treated or
untreated) with advanced colorectal carcinoma [445][446][447]. Although direct
comparative studies are lacking, response rates with single-agent intravenous tegafur
have generally been lower than those reported for 5-fluorouracil in colorectal
carcinoma (17% in 1 series of 359 patients) [448]. In addition, gastrointestinal
toxicity (persistent nausea and vomiting) and central nervous system toxicity
(dizziness, visual changes, headache, ataxia) have been frequent and severe with
intravenous tegafur, and have occasionally been intolerable [445].
c) Combination therapy with intravenous tegafur and intravenous doxorubicin plus
intravenous mitomycin C (FAM II) appears less effective than the conventional FAM
regimen (intravenous 5-fluorouracil, doxorubicin, and mitomycin C) in gastrointestinal
malignancies [446][449][450][451]. A response rate of only 20% has been reported
with FAM II compared to 42% to 50% with FAM. In addition, toxicity has been
greater with the FAM II regimen (nausea, vomiting, central nervous system
symptoms).
d) In other studies, the combination of intravenous tegafur plus mitomycin C or
methyl-CCNU did not appear to offer any advantage over the use of 5-fluorouracil in
these regimens. Central nervous system toxicity with tegafur regimens was
significant, occurring in up to 36% of patients treated [446][451][452]. The efficacy
of the MFC + F regimen (induction therapy with intravenous 5-fluorouracil, mitomycin
C, and cytosine arabinoside, followed by intermittent oral therapy with 5-fluorouracil
for 2 years) was compared with that of MF'C + F', where intravenous/oral tegafur was
substituted for 5-fluorouracil, as adjunctive therapy following curative gastrectomy in
patients with gastric cancer. Patients were randomized to either MFC + F, MF'C + F',
or a control group (surgery only) on the 7th to 10th day following surgery. MFC + C
was statistically superior to the control group with regard to postoperative survival; 5year survival rates in combined subsets of stages 1, II, and I II were 72% and 53%,
respectively. In the MF'C + F' group, the 5-year survival rate was 66%, which was not
262/317
25/10/12
significantly different than the control group. Gastrointestinal toxicity (nausea,

vomiting, diarrhea) occurred more frequently in the MF'C + F' group (53%) compared
to patients treated with MFC + F (40%). The authors concluded that the 5-fluorouracil
regimen was preferable to the tegafur regimen [453].
e) SUMMARY: Oral tegafur was as effective as intravenous 5-fluorouracil (5-FU) in
treating patients with gastrointestinal malignancies; although the convenience of oral
therapy with tegafur and its lesser myelosuppression are advantages over intravenous
5-fluorouracil. These are countered by the higher incidence of other toxic effects
(particularly gastrointestinal/cutaneous toxicity) observed with this agent;
substitution of oral tegafur for 5-FU in combination regimens has not been associated
with improved efficacy or reduced toxicity.
f) In a phase II study, UFT(R) (tegafur and uracil) and leucovorin (LV) produced an
overall response of 42% in patients with metastatic colorectal cancer; preliminary
survival data suggest a survival rate similar to intravenous fluorouracil (5-FU) and LV.
Of the 45 treated patients, 7 received UFT 350 milligrams/square meter/day
(mg/m(2)/day) with LV 150 mg/day for 28 days; due to grade 3 diarrhea, the dose of
UFT was reduced to 300 mg/m(2)/day in the subsequent 38 patients. Doses of UFT
and LV were divided and administered every 8 hours. Efficacy appeared similar for the
lower dose. Toxicity, mostly grade 1 or 2 consisted of diarrhea, nausea, vomiting,
abdominal cramping, anorexia, and fatigue; neutropenia or mucositis were not
reported. The place of UFT(R) in therapy awaits the results of phase III trials
comparing UFT and LV to 5-FU and LV for adjuvant therapy in Dukes' B and C colon
cancer and for metastatic colorectal cancer [454].
g) Oral tegafur (1 gram/square meter/day (g/m(2)) or 30 milligrams/kilogram/day
(mg/kg) for 14 to 21 days, with each cycle being repeated every 4 to 6 weeks) has
produced responses comparable to those achieved with intravenous 5-fluorouracil in
direct comparative trials involving patients with gastric or colorectal carcinoma
[455][456][443]. The duration of survival has been similar with tegafur and 5fluorouracil, although a nonsignificant trend toward more prolonged survival has been
observed in 5-fluorouracil-treated patients in some studies [443][456]. Hematologic
toxicity and stomatitis have generally been less with oral tegafur as compared to
intravenous 5-fluorouracil; however, nausea, vomiting, skin rashes, and sometimes
diarrhea have been more frequent with oral tegafur, and have necessitated
withdrawal of therapy in some patients [456][443][455][457]. A trend toward a
higher incidence of neurologic symptoms (particularly dizziness and malaise) has been
observed in tegafur-treated patients [443][456].
h) The combination of oral tegafur (1 gram/square meter/day (g/m(2)) from day 1 to
21) plus intravenous doxorubicin (50 milligrams/square meter/day (mg/m(2)/day on
days 1 and 21) offered no advantage over intravenous 5-fluorouracil (500 mg
m(2)/day on days 1, 7, 14, and 21) plus intravenous doxorubicin in the same doses in
previously untreated patients with advanced gastric carcinoma in 1 randomized trial.
Time to progression and overall survival were similar with each regimen, and no
toxicity advantage was realized in patients treated with tegafur; diarrhea was
significantly more frequent in the tegafur/doxorubicin group [457].
a) A randomized study in patients with metastatic colorectal cancer was conducted to
compare the relative efficacy and toxicities of oral tegafur (1 g/m(2) days 1 to 21)
with those of 5-FU (IV 500 mg/m(2) days 1 to 4, then 250 mg/m(2) on days 6, 8, 10,
263/317
25/10/12
12). Oral tegafur and IV 5-FU were equally effective but tegafur was associated with
minimal myelosuppression [443].
Thiotepa
Breast cancer
Doxorubicin
INDUCTION AND
MAINTENANCE
30 mg/m(2) days 1
and 8 IV
INFUSION)

14 days PO
Fluorouracil
500 mg/m(2) days 1
and 8 IV
Methotrexate*
40 mg/m(2) days 1
and 8 IV
Thiotepa
Carboplatin
IV=intravenous
PO=oral
meter (mg/m(2))), EPIRUBICIN (120 mg/m(2),
and CYCLOPHOSPHAMIDE (500264/317
25/10/12

al, 1998).
e) No difference in survival or progression free survival was detected in patients with
al, 1998).
Vinblastine
Esophageal cancer
265/317
25/10/12

(Urba et al, 2001).
b) The addition of a preoperative chemoradiation regimen offered no statistical
(Urba et al, 2001).
Vincristine
Breast cancer
a) In one study, 1- or 2-year therapy with CMFVP (CYCLOPHOSPHAMIDE,
b) In one study, 1-year or 2-year therapy with CMFVP (CYCLOPHOSPHAMIDE,
266/317

c) In a study of 445 patients with node-positive, receptor-negative breast cancer, 1and 2-year therapy with CYCLOPHOSPHAMIDE, METHOTREXATE, FLUOROURACIL,
et al, 1991).
d) A sixteen-week multidrug regimen achieved only marginally better outcomes than
267/317
25/10/12
e) In one study, 1-year or 2-year therapy with CMFVP (CYCLOPHOSPHAMIDE,
1993).
Vinorelbine
Breast cancer
a) Two doxorubicin-containing regimens were equally effective in the treatment of
b) In a phase III trial of women with metastatic breast cancer (n=281), a comparison
268/317
25/10/12
Non-small cell lung cancer
a) The results of a prospective, randomized study indicate that monotherapy with
vinorelbine is more effective than the combination regimen of 5-fluorouracil/leucovorin
(5-FU/LV) in patients with advanced non-small cell lung cancer (NSCLC). In this study
involving 211 patients with stage IV NSCLC, patients received either vinorelbine (30
milligrams/square meter (m(2)) weekly intravenously) or the combination of 5-FU/LV
(425 milligrams/m(2) and 20 milligrams/m(2), respectively) for 5 consecutive days
every 4 weeks. Median survival time for patients receiving vinorelbine was 30 weeks
with 25% alive at 1 year compared with a median survival time of 22 weeks with 16%
alive at 1 year for patients receiving 5-FU/LV. Although not statistically significant, in
an intent-to-treat analysis, treatment with vinorelbine was associated with a higher
response rate (12% vs 3%) and time to treatment failure (10 weeks vs 8 weeks)
compared with 5-FU/LV. There were no differences between the two treatments with
respect to relief of cancer symptoms (eg. arthralgia, asthenia, cough, dyspnea,
hemoptysis, and pain). Grade 3 or 4 granulocytopenia was reported in 54% of patients
receiving vinorelbine compared with 24% receiving 5-FU/LV. Grade 1/2 anemia was
seen in 70% of patients given vinorelbine compared with 42% given 5-FU/LV.
Vinorelbine caused a higher incidence of peripheral neuropathy compared with 5FU/LV (20% and 4%, respectively) [422].
REFERENCES
1. Product Information: fluorouracil IV injection solution, fluorouracil IV injection solution. Sandoz Inc
(per DailyMed), Princeton, NJ, 2011.
2. Zelek L, Cottu P, Tubiana-Hulin M, et al: Phase II study of oxaliplatin and fluorouracil in taxane- and
anthracycline- pretreated breast cancer patients. J Clin Oncol 2002; 20:2551-2558.
3. Stadtmauer EA, O'Neill A, Goldstein LJ, et al: Conventional-dose chemotherapy compared with
high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic
breast cancer. N Engl J Med 2000; 42:1069-1076.
4. Skeel RT: Handbook of Cancer Chemotherapy, 3rd. Little, Brown, and Co, Boston, MA, 1991.
5. Holleb AI, Fink DJ, & Murphy GP: Clinical Oncology, 1st. The American Cancer Society, Inc, Atlanta,
GA, 1991.
6. Braunwald E, Isselbacher KJ, Petersdorf RG, et al (Eds): Harrison's Principles of Internal Medicine,
11th. McGraw-Hill Book Company, New York, NY, 1987.
7. Product Information: Adrucil(R), fluorouracil injection. Sicor Pharmaceuticals, Inc., Irvine, CA, USA,
2003.
269/317
25/10/12
2003.
8. Anon: Drugs of choice for cancer chemotherapy. Med Lett Drugs Ther 1997; 39(996):21-28.
9. Bonadonna G, Valagussa P, Moliterni A, et al: Adjuvant cyclophosphamide, methotrexate, and
fluorouracil in node-positive breast cancer. N Engl J Med 1995; 332:901-906.
10. Lippman ME: High-dose chemotherapy plus autologous bone marrow transplantation for
metastatic breast cancer. N Engl J Med 2000; 342:1119-1120.
11. Rahman ZU, Frye DK, Smith TL, et al: Results and long term follow-up for 1581 patients with
metastatic breast carcinoma treated with standard dose doxorubicin-containing chemotherapy.
Cancer 1999; 85(1):104-111.
12. Raymond E, Palangie T, Jouve M, et al: Protracted continuous infusion of 5-fluorouracil in
combination with doxorubicin, vincristine, and oral cyclophosphamide in advanced breast cancer.
Cancer Invest 1996; 14:91-97.
13. Rodenhuis S, Richel DJ, van der Wall E, et al: Randomised trial of high-dose chemotherapy and
haemopoietic progenitor-cell support in operable breast cancer with extensive axillary lymph-node
involvement. Lancet 1998; 352:515-521.
14. Aranda E, Valladares M, Martinez-Villacampa M, et al: Randomized study of weekly irinotecan
plus high-dose 5-fluorouracil (FUIRI) versus biweekly irinotecan plus 5-fluorouracil/leucovorin
(FOLFIRI) as first-line chemotherapy for patients with metastatic colorectal cancer: a Spanish
Cooperative Group for the Treatment of Digestive Tumors Study. Ann Oncol 2009; 20(2):251-257.
PubMed Abstract: http://www.ncbi.nlm.nih.gov/...
PubMed Article: http://www.ncbi.nlm.nih.gov/...
15. de Gramont A, Figer A, Seymour M, et al: Leucovorin and fluorouracil with or without oxaliplatin
as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18(16):2938-2947.
16. Sargent DJ, Niedzwiecki D, O'Connell MJ et al: Recommendation for caution with irinotecan,
fluorouracil, and leucovorin for colorectal cancer (letter). NEJM early release notice posted. Available
at: http://www.nejm.org/content/sargent/1.asp (cited 5/17/01), May 17, 2001.
17. Van Cutsem E, Douillard J-Y, & Kohne C-H: Toxicity of irinotecan in patients with colorectal cancer
(editorial). N Engl J Med 2001; 345(18):1351-1352.
18. Kerr DJ, McArdle CS, Ledermann J, et al: Intrahepatic arterial versus intravenous fluorouracil and
folinic acid for colorectal cancer liver metastases: a multicentre randomised trial. Lancet 2003;
361:368-373.
19. Moehler M, Hoffmann T, Zanke C, et al: Safety and efficacy of outpatient treatment with CPT-11
plus bolus folinic acid/5-fluorouracil as first-line chemotherapy for metastatic colorectal cancer.
Anticancer Drugs 2003; 14:79-85.
20. Souglakos J, Mavroudis D, Kakolyris S, et al: Triplet combination with irinotecan plus oxaliplatin
270/317
25/10/12
plus continuous- infusion fluorouracil and leucovorin as fist-line treatment in metastatic colorectal
cancer: a multicenter phase II trial. J Clin Oncol 2002; 20(11):2651-2657.
21. Gamelin E, Boisdron-Celle M, Delva R, et al: Long-term weekly treatment of colorectal metastatic
cancer with fluorouracil and leucovorin: results of a multicentric prospective trial of fluorouracil
dosage optimization by pharmacokinetic monitoring in 152 patients. J Clin Oncol 1998; 16:1470-1478.
22. Comella P, Palmieri G, Lorusso V, et al: Double biochemical modulation of 5-fluorouracil by
methotrexate and levo-folinic acid in the treatment of advanced digestive tract malignancies. Eur J
Cancer 1996; 32A:1719-1726.
23. Di Costanzo F, El-Taani H, Parriani D, et al: Hydroxyurea may increase the activity of fluorouracil
plus folinic acid in advanced gastrointestinal cancer: phase II study. Cancer Invest 1996; 14:234-238.
24. Falcone A, Danesi R, Dargenio F, et al: Intravenous azidothymidine with fluorouracil and
leucovorin: a phase I-II study in previously untreated metastatic colorectal cancer patients. J Clin
Oncol 1996; 14:729-736.
25. Bismuth H, Adam R, Levi F, et al: Resection of nonresectable liver metastases from colorectal
cancer after neoadjuvant chemotherapy. Ann Surg 1996; 224:509-522.
26. Anon: Efficacy of intravenous continuous infusion of fluorouracil compared with bolus
administration in advanced colorectal cancer. J Clin Oncol 1998; 16(1):301-308.
27. Aranda E, Diaz-Rubio E, Cervantes A, et al: Randomized trial comparing monthly low-dose
leucovorin and fluorouracil bolus with weekly high-dose 48-hour continuous-infusion fluorouracil for
advanced colorectal cancer: a Spanish Cooperative Group for Gastrointestinal Tumor Therapy (TTD)
study. Ann Oncol 1998; 9:727-731.
28. Beerblock K, Rinaldi Y, Andre T, et al: Bimonthly high dose leucovorin and 5-fluorouracil 48-hour
continuous infusion in patients with advanced colorectal carcinoma. Cancer 1997; 79:1100-1105.
29. Lorenz M, Muller H-H, Schramm H, et al: Randomized trial of surgery versus surgery followed by
adjuvant hepatic arterial infusion with 5-fluorouracil and folinic acid for liver metastases of colorectal
cancer. Ann Surg 1998; 228(6):756-762.
30. Rougier P, Sahmoud T, Nitti D, et al: Adjuvant portal-vein infusion of fluorouracil and heparin in
colorectal cancer: a randomised trial. Lancet 1998; 351:1677-1681.
31. Davidson BS, Izzo F, Chase JL, et al: Alternating floxuridine and 5-fluorouracil hepatic arterial
chemotherapy for colorectal liver metastases minimizes biliary toxicity. Am J Surg 1996; 172:244-247.
32. Sugarbaker PH, Schellinx MET, Chang D, et al: Peritoneal carcinomatosis from adenocarcinoma of
the colon. World J Surg 1996; 20:585-592.
33. Wolmark N, Wieand HS, Kuebler JP, et al: A phase II trial comparing FULV to FULV + oxaliplatin in
stage II or III carcinoma of the colon: results of NSABP protocol C-07. ASCO Annual Meeting [abstr
LBA3500 and oral presentation], 2005.
271/317
25/10/12
34. Andre T, Boni C, Mounedji-Boudiaf L, et al: Oxaliplatin, fluorouracil, and leucovorin as adjuvant
treatment for colon cancer. N Engl J Med 2004; 350(23):2343-2351.
35. Min JS, Kim NK, Park JK, et al: A prospective randomized trial comparing intravenous 5fluorouracil and oral doxifluridine as postoperative adjuvant treatment for advanced rectal cancer.
Ann Surg Oncol 2000; 7(9):674-679.
36. Fountzilas G, Zisiadis A, Dafni U, et al: Fluorouracil and leucovorin with or without interferon alfa2a as adjuvant treatment, in patients with high- risk colon cancer. Oncology 2000; 58:227-236.
37. Wolmark N, Rockette H, Mamounas E, et al: Clinical trial to assess the relative efficacy of
fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin, and levamisole in
patients with Dukes' B and C carcinoma of the colon: results from National Surgical Adjuvant Breast
and Bowel Project C-04. J Clin Oncol 1999; 17(11):3553-3559.
38. Anon: Efficacy of adjuvant fluorouracil and folinic acid in B2 colon cancer. J Clin Oncol 1999;
17(5):1356-1363.
39. Mamounas E, Wieand S, Wolmark N, et al: Comparative efficacy of adjuvant chemotherapy in
patients with Dukes' B versus Dukes' C colon cancer: results from four national surgical adjuvant
breast and bowel project adjuvant studies (C-01, C-02, C-03, and C-04). J Clin Oncol 1999;
17(5):1349-1355.
40. O'Connell MJ, Laurie JA, Kahn M, et al: Prospective randomized trial of postoperative adjuvant
chemotherapy in patients with high-risk colon cancer. J Clin Oncol 1998; 16(1):295-300.
41. Wolmark N, Bryant J, Smith R, et al: Adjuvant 5-fluorouracil and leucovorin with or without
interferon alfa-2a in colon carcinoma: National Surgical Adjuvant Breast and Bowel Project Protocol C05. J Natl Cancer Inst 1998; 90(23):1810-1816.
42. Zaniboni A, Labianca R, Marsoni S, et al: GIVIO-SITAC 01: A randomized trial of adjuvant 5fluorouracil and folinic acid administered to patients with colon carcinoma - long term results and
evaluation of the indicators of health-related quality of life. Cancer 1998; 82(11):2135-2144.
43. O'Connell MJ, Mailliard JA, Kahn MJ, et al: Controlled trial of fluorouracil and low-dose leucovorin
given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol 1997; 15:246-250.
44. Sauer R, Becker H, Hohenberger W, et al: Preoperative versus postoperative chemoradiotherapy
for rectal cancer.. N Engl J Med 2004; 351(17):1731-1740.
45. Sauer R, Fietkau R, Wittekind C, et al: Adjuvant versus neoadjuvant radiochemotherapy for locally
advanced rectal cancer. Strahlenther Onkol 2001; 4:173-181.
46. Porschen R, Bermann A, Loffler T, et al: Fluorouracil plus leucovorin as effective adjuvant
chemotherapy in curatively resected stage III colon cancer: results of the trial adjCCA-01. J Clin
Oncol 2001; 19:1787-1794.
272/317
25/10/12
Oncol 2001; 19:1787-1794.

47. Tepper JE, O'Connell MJ, Petroni GR, et al: Adjuvant postoperative fluorouracil-modulated
chemotherapy combined with pelvic radiation therapy for rectal cancer: initial results of intergroup
0114. J Clin Oncol 1997; 15:2030-2039.
48. O'Connell MJ, Martenson JA, Wieand HS, et al: Improving adjuvant therapy for rectal cancer by
combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med
1994; 331:502-507.
49. Cullinan SA, Moertel CG, & Fleming TR: A comparison of three chemotherapeutic regimens in the
treatment of advanced pancreatic and gastric carcinoma. JAMA 1985; 253:2061-2067.
50. Neri B, de Leonardis V, Romano S, et al: Adjuvant chemotherapy after gastric resection in nodepositive cancer patients: a multicentre randomised study. Br J Cancer 1996; 73:549-552.
51. Tsavaris NB, Tentas K, Kosmidis P, et al: 5-Fluorouracil, epirubicin, and mitomycin C versus 5fluorouracil, epirubicin, mitomycin C and leucovorin in advanced gastric carcinoma: a randomized trial.
Am J Clin Oncol 1996; 19:517-521.
52. Crookes P, Leichman CG, Leichman L, et al: Systemic chemotherapy for gastric carcinoma
followed by postoperative intraperitoneal therapy: a final report. Cancer 1997; 79:1767-1775.
53. Melcher AA, Mort D, & Maughan TS: Epirubicin, cisplatin and continuous infusion 5-fluorouracil
(ECF) as neoadjuvant chemotherapy in gastro-oesophageal cancer. Br J Cancer 1996; 74:1651-1654.
54. Tsavaris N, Tentas K, Kosmidis P, et al: A randomized trial comparing adjuvant fluorouracil,
epirubicin, and mitomycin with no treatment in operable gastric cancer. Chemotherapy 1996a;
42:220-226.
55. Feliu J, Baron MG, Garcia-Giron C, et al: Treatment of patients with advanced gastric carcinoma
with combination of etoposide plus oral tegafur modulated by uracil and leucovorin. Cancer 1996;
78:211-216.
56. Kondo K, Murase M, Kodera Y, et al: Feasibility study on protracted infusional 5-fluorouracil and
consecutive low-dose cisplatin for advanced gastric cancer. Oncology 1996; 53:64-67.
57. Anon: Chemotherapy and antibiotic fluid standardizations and fluid minimums, MD Anderson
Hospital and Tumor Institute at Houston, Pharmacy Bulletin, 1993, pp Vol 11.
58. Braunwald E, Isselbacher KJ, Petersdorf RG, et al (Eds): Harrison's Principles of Internal
Medicine, 12th. McGraw-Hill Book Company, New York, NY, 1990.
59. DeVita VT, Hellman S, & Rosenberg SA (Eds): Cancer: Principles & Practice of Oncology, 3rd. JB
Lippincott Co, Philadelphia, PA, 1989.
60. Product Information: TAXOTERE(R) intravenous solution, docetaxel intravenous solution. Aventis
Pharmaceuticals Inc., Bridgewater, NJ, 2006.
273/317
61. Hudes GR, Lipsitz S, Grem J, et al: A phase II study of 5-fluorouracil, leucovorin, and interferonalpha in the treatment of patients with metastatic or recurrent gastric carcinoma. An Eastern
Cooperative Oncology Group Study (E5292). Cancer 1999; 85(2):290-294.
62. Barone C, Corsi DC, Pozzo C, et al: Treatment of patients with advanced gastric carcinoma with a
5-fluorouracil-based or a cisplatin-based regimen: two parallel randomized phase II studies. Cancer
1998; 82(8):1460-1467.
63. Cascinu S, Labianca R, Alessandroni P, et al: Intensive weekly chemotherapy for advanced gastric
cancer using fluorouracil, cisplatin, epi-doxorubicin, 6S-leucovorin, glutathione, and filgrastim: a report
from the Italian Group for the Study of Digestive Tract Cancer. J Clin Oncol 1997; 15(11):3313-3319.
64. Vaughn DJ, Meropol NJ, Holroyde C, et al: A phase II study of 5-fluorouracil, leucovorin,
adriamycin, and ciplatin (FLAP) for metastatic gastric and gastroesophageal junction
adenocarcinoma: a Penn Cancer Clinical Trial Group and Roswell Park Cancer Institute Community
Oncology Research Program Trial. Am J Clin Oncol 1997; 20:242-246.
65. Lokich JJ: Optimal schedule for 5-fluorouracil chemotherapy. Am J Clin Oncol 1985; 8:445-448.
66. Hansen R, Quebbeman E, Ausman R, et al: Continuous systemic 5-fluorouracil infusion in
advanced colorectal cancer: results in 91 patients. J Surg Oncol 1989; 40:177-181.
67. Neoptolemos JP, Stocken DD, Bassi C, et al: Adjuvant chemotherapy with fluorouracil plus folinic
acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA 2010;
304(10):1073-1081.
68. Neoptolemos JP, Stocken DD, Freiss H, et al: A randomized trial of chemoradiotherapy and
chemotherapy after resection of pancreatic cancer. N Engl J Med 2004; 350(12):1200-1210.
69. Klinkenbijl JH, Jeekel J, Sahmoud T, et al: Adjuvant radiotherapy and 5-fluorouracil after curative
resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC
gastrointestinal tract cancer cooperative group. Ann Surg 1999; 230(6):776-782.
70. Wagener DJT, Hoogenraad WJ, Rougier P, et al: Results of a phase II trial of epirubicin and
cisplatin (EP) before and after irradiation and 5-fluorouracil in locally advanced pancreatic cancer: an
EORTC GITCCG study. Eur J Cancer 1996; 32A(8):1310-1313.
71. Gebbia V, Majello E, Testa A, et al: Treatment of advanced adenocarcinomas of the exocrine
pancreas and the gallbladder with 5-fluorouracil, high dose levofolinic acid and oral hydroxyurea on a
weekly schedule. Cancer 1996; 78:1300-1307.
72. Furuse J, Maru Y, Yoshino M, et al: Hepatic arterial infusion of 5-fluorouracil for liver metastases
from pancreatic carcinoma: results from a pilot study. Hepatogastroenterology 2001; 48:208-211.
274/317
25/10/12
73. Bajetta E, Rimassa L, Carnaghi C, et al: 5-fluorouracil, dacarbazine, and epirubicin in the
treatment of patients with neuroendocrine tumors. Cancer 1998; 83(2):372-378.
74. Muchmore JH, Carter RD, Preslan JE, et al: Regional chemotherapy with hemofiltration: a
rationale for a different treatment approach to advanced pancreatic cancer. Hepatogastroenterology
1996; 43:346-355.
75. Sparano JA, Lipsitz S, Wadler S, et al: Phase II trial of prolonged continuous infusion of 5fluorouracil and interferon-alpha in patients with advanced pancreatic cancer: Eastern Cooperative
Oncology Group Protocol 3292. Am J Clin Oncol 1996; 19:546-551.
76. Recchia F, Nuzzo A, Lalli A, et al: Randomized trial of 5-fluorouracil and high-dose folinic acid with
or without alpha-2B interferon in advanced colorectal cancer. Am J Clin Oncol 1996; 19:301-304.
77. Tempero M, Abbruzzese J, Benson AB et al: National Comprehensive Cancer Network Practice
guidelines in oncology - Pancreatic adenocarcinoma v.1.. Available at
http://www.nccn.org/physician_gls/PDF/pancreatic.pdf (cited 6/24/2002), 2002.
78. Ishii H, Okada S, Tokuuye K, et al: Protracted 5-fluorouracil infusion with concurrent radiotherapy
as a treatment for locally advanced pancreatic carcinoma. Cancer 1997; 79:1516-1520.
79. Martenson JA, Swaminathan R, Burch PA, et al: Pilot study of continuous-infusion 5-fluorouracil,
oral leucovorin, and upper-abdominal radiation therapy in patients with locally advanced residual or
recurrent upper gastrointestinal or extrapelvic colon cancer. Int J Radiat Oncol Biol Phys 1997;
37:615-618.
80. Product Information: Efudex(R), flourouracil. Roche Laboratories, Nutley, NJ, 1997.
81. Product Information: Carac(R), fluorouracil cream. Dermik Laboratories Inc., Berwyn, PA, 2003.
82. Product Information: EFUDEX(R) topical cream, solution, fluorouracil topical cream, solution. ICN
Pharmaceuticals Inc, Costa Mesa, CA, 2005.
83. Jorizzo J, Weiss J, & Vamvakias G: One-week treatment with 0.5% fluorouracil cream prior to
cryosurgery in patients with actinic keratoses: a double-blind, vehicle-controlled, long-term study. J
Drugs Dermatol 2006; 5(2):133-139.
84. Sander CA, Pfeiffer C, Kligman AM, et al: Chemotherapy for disseminated actinic keratoses with 5fluorouracil and isotretinoin. J Am Acad Dermatol 1997; 36:236-238.
85. Product Information: Fluoroplex(R), fluorouracil. Roche Laboratories, Nutley, NJ, 1995.
86. Pearlman DL: Weekly pulse dosing: effective and comfortable topical 5-fluorouracil treatment of
multiple facial actinic keratoses. J Am Acad Dermatol 1991; 25:665-667.
275/317
25/10/12
87. Shelley WB & Wood MG: Nodular superficial pigmented basal cell epitheliomas. Arch Dermatol
1982; 118:928-930.
88. Reymann F: Treatment of basal cell carcinoma of the skin with 5-fluorouracil ointment: a 10-year
follow-up study. Dermatologica 1979; 158:368-372.
89. Ajani JA, Winter KA, Gunderson LL, et al: Fluorouracil, mitomycin, and radiotherapy vs
fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial.
JAMA 2008; 299(16):1914-1921.
90. Doci R, Zucali R, La Monica G, et al: Primary chemoradiation therapy with fluorouracil and
cisplatin for cancer of the anus: results in 35 consecutive patients. J Clin Oncol 1996; 14:3121-3125.
91. Martenson JA, Lipsitz SR, Wagner H, et al: Initial results of a phase II trial of high dose radiation
therapy, 5-fluorouracil, and cisplatin for patients with anal cancer (E4292): an eastern cooperative
oncology group study. Int J Radiat Oncol Biol Phys 1996; 35:745-749.
92. Sanz-Altamira PM, Ferrante K, Jenkins RL, et al: A phase II trial of 5-fluorouracil, leucovorin, and
carboplatin in patients with unresectable biliary tree carcinoma. Cancer 1998; 82(12):2321-2325.
93. Patt YZ, Jones DV, Hoque A, et al: Phase II trial of intravenous fluorouracil and subcutaneous
interferon alfa-2b for biliary tract cancer. J Clin Oncol 1996; 14:2311-2315.
94. Ellis PA, Norman A, Hill A, et al: Epirubicin, cisplatin and infusional 5-fluorouracil (5-FU) (ECF) in
hepatobiliary tumours. Eur J Cancer 1995; 31:1594-1598.
95. Nevin JE, Melnick I, Baggerly JT Jr, et al: Arterial infusion of 5-fluorouracil as a treatment for
carcinoma of the prostate. J Urol 1974; 112:114-119.
96. Lundbeck F & Christophersen IS: Phase II study of adriamycin, 5-fluorouracil, and Levamisole
combined with radiotherapy. Cancer Treat Rep 1979; 63:183-188.
97. Stone N & Burge S: Bowen's disease of the leg treated with weekly pulses of 5% fluorouracil
cream. Br J Dermatol 1999; 140:987-988.
98. Levin VA, Hoffman WF, Pischer TL, et al: BCNU-5-fluorouracil combination therapy for recurrent
malignant brain tumors. Cancer Treat Rep 1978; 62:2071-2076.
99. Kaba SE, Kyritsis AP, Hess K, et al: TPDC-FuHu chemotherapy for the treatment of recurrent
metastatic brain tumors. J Clin Oncol 1997; 15:1063-1070.
100. Dahan L, Bonnetain F, Rougier P, et al: Phase III trial of chemotherapy using 5-fluorouracil and
streptozotocin compared with interferon alpha for advanced carcinoid tumors: FNCLCC-FFCD 9710.
Endocr Relat Cancer 2009; 16(4):1351-1361.
276/317
25/10/12
101. Engstrom PF , Lavin PT , Moertel CG , et al: Streptozocin plus fluorouracil versus doxorubicin
therapy for metastatic carcinoid tumor. J Clin Oncol 1984; 2(11):1255-1259.
102. Sun W , Lipsitz S , Catalano P , et al: Phase II/III study of doxorubicin with fluorouracil compared
with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors:
Eastern Cooperative Oncology Group Study E1281. J Clin Oncol 2005; 23(22):4897-4904.
103. Lin JC, Ho ESC, Jan JS, et al: High complete response rate of concomitant chemoradiotherapy for
locally advanced squamous cell carcinoma of the uterine cervix. Gynecol Oncol 1996; 61:101-108.
104. Hsu WL, Shueng PW, Jen YM, et al: Concurrent 5-fluorouracil, daily low-dose cisplatin, and
radiotherapy in stage IIIB cervical cancer. Am J Clin Oncol 1996; 19:263-267.
105. Look KY, Blessing JA, Gallup DG, et al: A phase II trial of 5-fluorouracil and high-dose leucovorin
in patients with recurrent squamous cell carcinoma of the cervix: a gynecologic oncology group study.
Am J Clin Oncol 1996; 19:439-441.
106. Whitney CW, Sause W, Bundy BN, et al: Randomized comparison of fluorouracil plus cisplatin
versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with
negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group
Study. J Clin Oncol 1999; 17(5):1339-1348.
107. Syed TA, Qureshi ZA, Ahmad SA, et al: Management of intravaginal warts in women with 5fluorouracil (1%) in vaginal hydrophilic gel: a placebo-controlled double-blind study. Int J STD AIDS
2000; 11(6):371-374.
108. Relakis K, Cardamakis E, Korantzis A, et al: Treatment of men with flat (FC) or acuminata (CA)
condylomata with interferon alpha-2a. Eur J Gynaecol Oncol 1996; 17(6):529-533.
109. Wallin J: 5-Fluorouracil in the treatment of penile and urethral condylomata acuminata. Br J
Vener Dis 1977; 53(4):240-243.
110. Midena E, Angeli CD, Valenti M, et al: Treatment of conjunctival squamous cell carcinoma with
topical 5-fluorouracil. Br J Ophthalmol 2000; 84:268-272.
111. Yeatts RP, Engelbrecht NE, Curry CD, et al: 5-Fluorouracil for the treatment of intraepithelial
neoplasia of the conjunctiva and cornea. Ophthalmology 2000; 107:2190-2195.
277/317
112. Reviewers' responses to Hemotologic and Oncologic Disease Advisory Panel Memo #26 of
8/28/89.. ., .
113. Reviewers' responses to Hematologic and Oncologic Disease Advisory Panel Memo #9 of
1/30/97.. ., .
114. Kim J, Chang M, & Schwayder T: Topical tretinoin and 5-fluorouracil in the treatment of linear
verrucous epicermal nevus. J Am Acad Dermatol 2000; 43:129-132.
115. Urba SG, Orringer MB, Turrisi A, et al: Randomized trial of preoperative chemoradiation versus
surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol 2001; 19(2):305-313.
116. Ilson DH, Ajani J, Bhalla K, et al: Phase II trial of paclitaxel, fluorouracil, and cisplatin in patients
with advanced carcinoma of the esophagus. J Clin Oncol 1998; 16(5):1826-1834.
117. Poplin EA, Jacobson J, Herskovic A, et al: Evaluation of multimodality treatment of locoregional
esophageal carcinoma by Southwest Oncology Group 9060. Cancer 1996; 78:1851-1856.
118. Wadler S, Haynes H, Beitler JJ, et al: Phase II clinical trial with 5-fluorouracil, recombinant
interferon-alpha-2b, and cisplatin for patients with metastatic or regionally advanced carcinoma of the
esophagus. Cancer 1996; 78:30-34.
119. Temeck BK, Liebmann JE, Theodossiou C, et al: Phase II trial of 5-fluorouracil, leucovorin,
interferon-alpha-2a, and cisplatin as neoadjuvant chemotherpay for locally advanced esophageal
carcinoma. Cancer 1996; 77:2432-2439.
120. Stewart FM, Harkins BJ, Hahn SS, et al: Cisplatin, 5-fluorouracil, mitomycin C, and concurrent
radiation therapy with and without esophogectomy for esophageal carcinoma. Cancer 1989; 64:622628.
121. Pouliquen X, Levard H, Hay JM, et al: 5-fluorouracil and cisplatin therapy after palliative surgical
resection of squamous cell carcinoma of the esophagus: a multicenter randomized trial. Ann Surg
1996; 223:127-133.
122. Mora JS, Nguyen N, Iwach AG, et al: Trabeculectomy with intraoperative sponge 5-fluorouracil.
Ophthalmology 1996; 103:963-970.
123. Anon: Five-year follow-up of the fluorouracil filtering surgery study. Am J Ophthalmol 1996a;
121:349-366.
124. Towler HMA, McCluskey P, Shaer B, et al: Long-term follow-up of trabeculectomy with
intraoperative 5-fluorouracil for uveitis-related glaucoma. Ophthalmology 2000; 107:1822-1828.
125. Chaudhry IA, Pasha MA, O'Connor DJ, et al: Randomized, controlled study of low-dose 5fluorouracil in primary trabeculectomy. Am J Ophthalmol 2000; 130:700-703.
126. Belyea DA, Dan JA, Stamper RL, et al: Late onset of sequential multifocal bleb leaks after
glaucoma filtration surgery with 5-fluorouracil and mitomycin C. Am J Ophthalmol 1997; 124:40-45.
25/10/12
glaucoma filtration surgery with 5-fluorouracil and mitomycin C. Am J Ophthalmol 1997; 124:40-45.
127. Mastropasqua L, Carpineto P, Ciancaglini M, et al: Delayed post-operative use of 5-fluorouracil as
an adjunct in medically uncontrolled open angle glaucoma. Eye 1998; 12:701-706.
128. DeVita VT, Hellman S, & Rosenberg SADeVita VT, Hellman S, & Rosenberg SA (Eds): Cancer:
Principles & Practice of Oncology, 3rd. JB Lippincott Company, Philadelphia, PA, 1989.
129. Rubin P (Ed): Clinical Oncology A Multidisciplinary Approach, 6th. American Cancer Society, Inc,
Atlanta, GA, 1983.
130. Anon: Drugs of choice for cancer chemotherapy. Med Lett Drugs Ther 1993; 35:43-50.
131. Holleb AI, Fink DJ, & Murphy GPHolleb AI, Fink DJ, & Murphy GP (Eds): American Cancer Society
Textbook of Clinical Oncology, The American Cancer Society Inc, Atlanta, GA, 1991.
132. Clark JR & Dreyfuss AI: The role of cisplatin in treatment regimens for squamous cell carcinoma
of the head and neck. Semin Oncol 1991; 18:34-48.
133. Paccagnella A, Pappagallo GL, Segati R, et al: Response and toxicity of cisplatin and 120-h 5fluorouracil infusion in pretreated and untreated patients with advanced epidermoid cancer of the
head and neck. Am J Clin Oncol 1990; 13:194-198.
134. Vokes E, Schilsky RL, Weichselbaum RR, et al: Induction of chemotherapy with cisplatin,
fluorouracil, and high-dose leucovorin for locally advanced head and neck cancer: a clinical and
pharmacologic analysis. J Clin Oncol 1990; 8:241-247.
135. Gonzalez-Baron J, Vincente J, Tomas M, et al: Phase II trial of cisplatin and tegafur (Ftorafur) as
initial therapy in squamous-cell carcinoma of the head and neck. Am J Clin Oncol 1990; 13:312-314.
136. Dreyfuss AI, Clark JR, Wright JE, et al: Continuous infusion high-dose leucovorin with 5Fluorouracil and cisplatin for untreated stage IV carcinoma of the head and neck. Ann Intern Med
1990; 112:167-172.
137. Recloux P, Dodion PF, Andry G, et al: Neoadjuvant chemotherapy with cisplatin, methotrexate,
bleomycin and vincristine (CABO) in patients with stage III and IV squamous cell carcinoma of the
head and neck. Eur J Surg Oncol 1989; 15:568-574.
138. Forastiere A, Berkey B, Maor M et al: Phase III trial to preserve the larynx: induction
chemotherapy and radiotherapy vs concurrent chemotherapy and radiotherapy vs radiotherapy,
intergroup trial R91-11. Presented at the 37th Annual Meeting of the American Society of Clinical
Oncology; San Francisco,CA, USA, May 12-15, 2001.
139. Wolf GT: Discussion: Phase III trial to preserve the larynx - intergroup trial, R91-11. Presented
at the 37th Annual Meeting of the American Society of Clinical Oncology; San Francisco, CA, USA,
May 12-15; 2001.
140. Abitbol AA, Sridhar KS, Lewin AA, et al: Hyperfractionated radiation therapy and 5-fluorouracil,
279/317
25/10/12
cisplatin, and mitomycin-C (+/- granulocyte-colony stimulating factor) in the treatment of patients
with locally advanced head and neck carcinoma. Cancer 1997; 80:266-276.
141. Jacobs C, Lyman G, Velez-Garcia E, et al: A phase III randomized study comparing cisplatin and
fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head
and neck. J Clin Oncol 1992; 10:257-263.
142. Tellez-Bernal E, Belehradek M, Recondo G, et al: Phase II study of cisplatin and continuousinfusion 5-fluorouracil and bleomycin for recurrent and metastatic head and neck squamous-cell
carcinoma. Am J Clin Oncol 1990; 13:452-454.
143. Vokes E, Schilsky RL, Weichselbaum RR, et al: Induction of chemotherapy with cisplatin,
fluorouracil, and high-dose leucovorin for locally advanced head and neck cancer: a clinical and
pharmacologic analysis. J Clin Oncol 1990; 8:241-247.
144. Bensmaine ME, Guillot T, Bernal ET, et al: Neoadjuvant chemotherapy with cisplatin-vindesine-5fluorouracil and folinic acid for locally advanced head and neck carcinoma. Am J Clin Oncol 1996;
19:356-362.
145. Fontanesi J, Beckford NS, Lester EP, et al: Concomitant cisplatin and hyperfractionated external
beam irradiation for advanced malignancy of the head and neck. Am J Surg 1991; 162:393-396.
146. Denham JW & Abbott RL: Concurrent cisplatin, infusional fluorouracil, and conventionally
fractionated radiation therapy in head and neck cancer: dose-limiting mucosal toxicity. J Clin Oncol
1991; 9:458-463.
147. Haraf DJ, Kies M, Rademaker AW, et al: Radiation therapy with concomitant hydroxyurea and
fluorouracil in stage II head and neck cancer. J Clin Oncol 1999; 17(2):638-644.
148. Ortega JA, Douglass EC, Feusner JH, et al: Randomized comparison of
cisplatin/vincristine/fluorouracil and cisplatin/continuous infusion doxorubicin for treatment of
pediatric hepatoblastoma: a report from the children's cancer group and the pediatric oncology group.
J Clin Oncol 2000; 18:2665-2675.
149. Moertel CG, Lefkopoulo M, Lipsitz S, et al: Streptozocin-doxorubicin, streptozocin-fluorouracil or
chlorozotocin in the treatment of advanced islet-cell carcinoma. N Engl J Med 1992; 326:519-523.
150. Gray RJ & Meland NB: Topical 5-fluorouracil as primary therapy for keratoacanthoma. Ann Plast
Surg 2000; 44:82-85.
151. Parker CM & Hanke CW: Large keratoacanthomas in difficult locations treated with intralesional
5-fluorouracil. J Am Acad Dermatol 1986; 14(5 pt 1):770-777.
152. Odom RB & Goette DK: Treatment of keratoacanthomas with intralesional fluorouracil. Arch
Dermatol 1983; 114:1779-1783.
153. Kurtis B & Rosen T: Treatment of cutaneous neoplasms by intralesional injection of 5-fluorouracil
(5-FU). J Dermatol Surg Oncol 1980; 6:122-127.
280/317
25/10/12
154. Nagasue N, Ogawa Y, & Inokuchi K: Hemangiosarcoma of liver and spleen treated by hepatic
artery ligation, intraportal infusion chemotherapy, and splenectomy. Cancer 1976; 38:1386-1388.
155. Ansfield FJ, Ramirex G, Davis HL Jr, et al: Further clinical studies with intrahepatic arterial
infusion with 5-fluorouracil. Cancer 1975; 36:2413-2417.
156. Ansfield FJ, Ramirez G, Skibba JL, et al: Intrahepatic arterial infusion with 5-fluorouracil. Cancer
1971; 28:1147-1151.
157. Tanner AR, Bolton PM, & Powell LW: Primary sarcoma of the liver: report of a case with
excellent response to hepatic artery ligation and infusion chemotherapy. Gastroenterology 1978;
74:121-123.
158. Huys J, Otte H, Gatera G, et al: Intraportal chemotherapy in hepatic metastases. Nouv Presse
Med 1973; 2:1701-1702.
159. Miller TP, McMahon LJ, & Livingston RB: Extensive adenocarcinoma and large cell
undifferentiated carcinoma of the lung treated with 5-FU, vincristine, and mitomycin C (FOM). Cancer
Treat Rep 1980; 64:1241-1245.
160. Rosi DR, Nogeire C, Brown B, et al: 5-fluorouracil, adriamycin, and mitomycin C (Hi-FAM)
chemotherapy for adenocarcinoma of the lung. Cancer 1981; 48:21-25.
161. Ball D, Smith J, Bishop J, et al: A phase III study of radiotherapy with and without continuousinfusion fluorouracil as palliation for non-small-cell lung cancer. Br J Cancer 1997; 75:690-697.
162. Wong AS, Soo RA, Lu JJ, et al: Paclitaxel, 5-fluorouracil and hydroxyurea concurrent with
radiation in locally advanced nasopharyngeal carcinoma. Ann Oncol 2006; 17(7):1152-1157.
163. Fandi A, Taamma A, Azli N, et al: Palliative treatment with low-dose continuous infusion 5fluorouracil in recurrent and/or metastatic undifferentiated nasopharyngeal carcinoma type. Head
Neck 1997; 19(1):41-47.
164. Taamma A, Fandi A, Azli N, et al: Phase II trial of chemotherapy with 5-fluorouracil, bleomycin,
epirubicin, and cisplatin for patients with locally advanced, metastatic, or recurrent undifferentiated
carcinoma of the nasopharyngeal type. Cancer 1999; 86(7):1101-1108.
165. Lin J-C, Jan J-S, & Hsu C-Y: Outpatient weekly chemotherapy in patients with nasopharyngeal
carcinoma and distant metastasis. Cancer 1998; 83:635-640.
166. Asaria RHY, Kon CH, Bunce C, et al: Adjuvant 5-fluorouracil and heparin prevents proliferative
vitreoretinopathy. Results from a randomized, double-blind, controlled clinical trial. Ophthalmology
2001; 108:1179-1183.
281/317
25/10/12
167. Schissel DJ & Elston DM: Topical 5-fluorouracil treatment for psoriatic trachyonychia. Cutis 1998;
62(1):27-28.
168. Rotstein H & Baker C: The treatment of psoriasis. Med J Aust 1990; 152:153-154.
169. Savage P, Costelna D, Moore J, et al: A phase II study of continuous infusional 5-fluorouracil (5FU) and subcutaneous interleukin-2 (IL-2) in metastatic renal cancer. Eur J Cancer 1997; 33:11491151.
170. Hamouda B, Jamila Z, Najet R, et al: Topical 5-fluorouracil to treat multiple or unresectable
facial squamous cell carcinomas in xeroderma pigmentosum (letter). J Am Acad Dermatol 2001;
6:1054.
171. Petrilli ES, Townsend DE, Morrow CP, et al: Vaginal intraepithelial neoplasia: biologic aspects
and treatment with topical 5-fluorouracil and the carbon dioxide laser. Am J Obstet Gynecol 1980;
38:321-328.
172. Piver MS, Barlow JJ, Tsukada Y et al: Postirradiation squamous cell carcinoma in situ of the
vagina: treatment by topical 20% 5-FU cream. Am J Obstet Gynecol 1979; 377-380, 1979.
173. Krebs HB: Treatment of vaginal intraepithelial neoplasia with laser and topical 5-fluorouracil.
Obstet Gynecol 1989; 73:657-660.
174. Cardamakis E , Relakis K , Ginopoulos P , et al: Treatment of penile intraepithelial neoplasia
(PIN) with interferon alpha-2a, CO2 laser (vaporization) and 5-fluorouracil 5% (5-FU). Eur J Gynaecol
Oncol 1997; 18(5):410-413.
175. Goette DK & Carson TE: Erythroplasia of Queyrat: treatment with topical 5-fluorouracil. Cancer
1976; 38(4):1498-1502.
176. Cavins JA: Topical chemotherapy of cutaneous neoplasms. J Indiana State Med Assoc 1972;
65(9):911-912.
177. Midana A & Leigheb G: 5-fluorouracil (5-FU) ointment in the treatment of benign and malignant
skin lesions. Dermatologica 1970; 140:Suppl-81.
178. Klein E, Stoll HL, Milgrom H, et al: Tumors of the skin. XII. Topical 5-Fluorouracil for epidermal
neoplasms. J Surg Oncol 1971; 3(3):331-349.
282/317
25/10/12

179. Schlumberger M, Brugieres L, Gicquel C, et al: 5-Fluorouracil, doxorubicin, and cisplatin as
treatment for adrenal cortical carcinoma.. Cancer 1991; 67:2997-3000.
180. Lokich JJ & Skarin AT: Five-drug combination chemotherapy for disseminated adenocarcinoma..
Cancer Chemother Rep 1972; 56:761-7.
181. Kruimel JW, Smals AG, Beex LV, et al: Favourable response of a virilizing adrenocortical
carcinoma to preoperative treatment with ketoconazole and postoperative chemotherapy.. Acta
Endocrinol (Copenh) 1991; 124:492-6.
182. Visconti EB, Peters RW, Cangir A, et al: Unusual case of adrenal cortical carcinoma in a female
infant.. Arch Dis Child 1978; 53:342-4.
183. Ostuni JA & Roginsky MS: Metastatic adrenal cortical carcinoma. Documented cure with
combined chemotherapy.. Arch Intern Med 1975; 135:1257-8.
184. Khansur T & Kennedy A: Cisplatin and 5-fluorouracil for advanced locoregional and metastatic
squamous cell carcinoma of the skin. Cancer 1991; 67(8):2030-2032.
185. Landoni F, Maneo A, Zanetta G, et al: Concurrent preoperative chemotherapy with 5-fluorouracil
and mitomycin C and radiotherapy (FUMIR) followed by limited surgery in locally advanced and
recurrent vulvar carcinoma.. Gynecol Oncol 1996; 61:321-7.
186. Thomas G, Dembro A, DePetrillo J, et al: Concurrent radiation and chemotherapy in vulvar
carcinoma.. Gynecol Oncol 1989; 34:263-7.
187. Lupi G, Raspagliesi F, Zucali R, et al: Combined preoperative chemoradiotherapy followed by
radical surgery in locally advanced vulvar carcinoma: a pilot study.. Cancer 1996; 77:1472-8.
188. Koh W, Wallace HJ, Greer BE, et al: Combined radiotherapy and chemotherapy in the
management of local-regionally advanced vulvar cancer.. Int J Radiat Oncol Biol Phys 1993; 26:80916.
189. Goette DK, Elgart M, & DeVillez RL: Erythroplasia of Queyrat. Treatment with topically applied
fluorouracil. JAMA 1975; 232(9):934-937.
190. Goette DK: Review of erythroplasia of Queyrat and its treatment. Urology 1976; 8(4):311-315.
191. Goette DK & Carson TE: Erythroplasia of Queyrat: treatment with topical 5-fluorouracil. Cancer
1976; 38(4):1498-1502.
283/317
25/10/12

192. Lewis RJ & Bendl BJ: Erythroplasia of Queyrat: repor. of a patient successfully treated with
topical 5-fluorouracil. CMAJ 1971; 104(2):148-149.
193. Atef AM, Hamouda MM, Mohamed AH, et al: Topical 5-fluorouracil for granular myringitis: a
double-blinded study. J Laryngol Otol 2010; 124(3):279-284.
194. Curley SA, Roh MS, Chase JL, et al: Adjuvant hepatic arterial infusion chemotherapy after
curative resection of colorectal liver metastases. Am J Surg 1993; 166:743-748.
195. Ramming KP: The effectiveness of hepatic artery infusion in treatment of primary hepatobiliary
tumors. Semin Oncol 1983; 10:199-205.
196. Oberfield R: Intraarterial hepatic infusion chemotherapy in metastatic liver cancer. Semin Oncol
1983; 10:206-214.
197. Avant WH & Huff RC: Intradermal 5-fluorouracil in the treatment of basal cell carcinoma of the
face. South Med J 1976; 69:561-563.
198. Hahn RG, Moertel CG, Schutt AJ, et al: A double-blind comparison of intensive course 5-FU by
oral versus intravenous route in the treatment of colorectal carcinoma. Cancer 1975; 35:1031-1035.
199. Lahiri SR, Boileau G, & Hall TC: Treatment of metastatic colorectal carcinoma with 5-fluorouracil
by mouth. Cancer 1971; 28:902-906.
200. Kennedy PS, Lehane DE, Smith FE, et al: Oral fluorouracil therapy of hepatoma. Cancer 1977;
39:1930-1935.
201. Stolinsky DC, Pugh RP, & Bateman JR: 5-fluorouracil (NSC-19893) therapy for pancreatic
carcinoma: comparison of oral and intravenous routes. Cancer Chemother Rep 1975; 59:1031-1033.
202. Griggs JJ, Mangu PB, Anderson H, et al: Appropriate chemotherapy dosing for obese adult
patients with cancer: american society of clinical oncology clinical practice guideline. J Clin Oncol
2012; 30(13):1553-1561.
203. Product Information: fluorouracil iv injection, fluorouracil iv injection. Sicor Pharmaceuticals Inc.,
Irvine, CA, 1999.
204. Product Information: Adrucil(R) fluorouracil inj., USP. Sicor Pharmaceuticals, Inc., Irvine, CA,
2003.
284/317
25/10/12
205. Product Information: Efudex(R) topical solutions, cream, fluorouracil topical solutions, cream.
ICN Pharmaceuticals, Inc, Costa Mesa, CA, 2004.
206. Efudex package insert (RocheUS). Rev Rec 7/97., 5/95.
207. Product Information: Adrucil(R), fluorouracil injection. Sicor Pharmaceuticals, Inc., Irvine, CA,
USA, 2003.
208. Piro AJ, Wilson RE, Hall TC, et al: Toxicity studies of fluorouracil used with adrenalectomy in
breast cancer. Arch Surg 1972; 105:95-99.
209. Cohn I Jr: Complications and toxic manifestations of surgery and adjuvant chemotherapy for
breast cancer. Surg Gynecol Obstet 1968; 127:1201-1209.
210. Grem JL, Quinn M, Ismail AS, et al: Pharmacokinetics and pharmacodynamic effects of 5fluorouracil given as a one-hour intravenous infusion. Cancer Chemother Pharmacol 2001; 47:117-125.
211. Falcone A, DiPaolo A, Masi G, et al: Sequence effect of irinotecan and fluorouracil treatment on
pharmacokinetics and toxicity in chemotherapy-naive metastatic colorectal cancer patients. J Clin
Oncol 2001; 19(15):3456-3462.
212. Sargent DJ, Niedzwiecki D, O'Connell MJ et al: Recommendation for caution with irinotecan,
fluorouracil, and leucovorin for colorectal cancer (letter). NEJM early release notice posted. Available
at: http://www.nejm.org/content/sargent/1.asp (cited 5/17/01), May 17, 2001.
213. Van Cutsem E, Douillard J-Y, & Kohne C-H: Toxicity of irinotecan in patients with colorectal
cancer (editorial). N Engl J Med 2001; 345(18):1351-1352.
214. Anon: Toxicity of fluorouracil in patients with advanced colorectal cancer: effect of
administration schedule and prognostic factors. J Clin Oncol 1998a; 16(11):3537-3541.
215. Harris BE, Carpenter JT, & Diasio RB: Severe 5-fluorouracil toxicity secondary to
dihydropyrimidine dehydrogenase deficiency: a potentially more common pharmacogenetic syndrome.
Cancer 1991; 68:499-501.
216. Basselin C, Fontanges T, Descotes J, et al: 5-Fluorouracil-induced Tako-Tsubo-like syndrome.
Pharmacotherapy 2011; 31(2):226-226.
217. Dent RG & McColl I: 5-Fluorouracil and angina. Lancet 1975; 1:347-348.
218. Vorobiof DA: Cardiotoxicity of 5-fluorouracil. S Afr Med J 1982; 61:634-635.
219. Patel B, Kloner RA, Ensley J, et al: 5-fluorouracil cardiotoxicity: left ventricular dysfunction and
effect of coronary vasodilators. Am J Med Sci 1987; 294:238-243.
220. Freeman NJ & Costanza ME: 5-fluorouracil-associated cardiotoxicity.
285/317
Cancer 1988; 61:36-45.
25/10/12
220. Freeman NJ & Costanza ME: 5-fluorouracil-associated cardiotoxicity. Cancer 1988; 61:36-45.
221. Farooqi IS & Aronson JK: Iatrogenic chest pain: a case of 5-fluorouracil cardiotoxicity. Q J Med
1996; 89:953-955.
222. Kleiman NS, Lehane DE, Geyer CE Jr, et al: Prinzmetal's angina during 5-fluorouracil
chemotherapy. Am J Med 1987; 82:566-568.
223. Luwaert RJ, Descamps O, Majois F, et al: Coronary artery spasm induced by 5-fluorouracil. Eur
Heart J 1991; 12:468-470.
224. McKendall GR, Shurman A, Anamur M, et al: Toxic cardiogenic shock associated with infusion of
5-fluorouracil. Am Heart J 1989; 118:184-186.
225. Misset B, Escudier B, Leclercq B, et al: Acute myocardiotoxicity during 5-fluorouracil therapy.
Intensive Care Med 1990; 16:210-211.
226. Coronel B, Madonna O, Mercatello A, et al: Myocardiotoxicity of 5 fluorouracil. Intensive Care
Med 1988; 14:429-430.
227. Martin M, Diaz-Rubio E, Furio V, et al: Lethal cardiac toxicity after cisplatin and 5-fluorouracil
chemotherapy: report of a case with necropsy study. Am J Clin Oncol 1989; 12:229-234.
228. Becker K, Erckenbrecht JE, Haussinger D, et al: Cardiotoxicity of the antiproliferative compound
fluorouracil. Drugs 1999; 57(4):475-484.
229. Hamill NJ, Freije JE, & Fedok FG: Complications of 5-fluorouracil therapy in head and neck cancer
patients. Am J Otolaryngol 1995; 16:74-76.
230. Gradishar W, Vokes E, Schilsky R, et al: Vascular events in patients receiving high-dose
infusional 5-fluorouracil-based chemotherapy: the University of Chicago experience. Med Pediatr
Oncol 1991; 19:8-15.
231. Rezkalla S, Kloner RA, Ensley J, et al: Continuous ambulatory ECG monitoring during fluorouracil
therapy: a prospective study. J Clin Oncol 1989; 7:509-514.
232. Atar A, Korkmaz ME, & Ozin B: Two cases of coronary vasospasm induced by 5-fluorouracil.
Anadolu Kardiyol Derg 2010; 10(5):461-462.
233. Stevenson DL, Mikhailidis DP, & Gillett DS: Cardiotoxicity of 5-fluorouracil. Lancet 1977; 2:406407.
234. Soukop M, McMvie JG, & Calman KC: Fluorouracil cardiotoxicity (letter). Br Med J 1978; 1:1422.
235. Meyer CC, Calis KA, Burke LB, et al: Symptomatic cardiotoxicity associated with 5-fluorouracil.
Pharmacotherapy 1997; 17:729-736.
286/317
25/10/12
236. Gradishar WJ, Vokes EE, Schilsky RL, et al: Catastrophic vascular events in patients receiving 5fluorouracil based chemotherapy (abstr). Proc Am Assoc Can Res 1990; 31:1128.
237. Labianca R, Berreta G, Clerici M, et al: Cardiac toxicity of 5-FU: a study of 1083 patients. Tumori
1982; 68:505-510.
238. Lemaire L, Malet-Martino MC, de Forni M, et al: Cardiotoxicity of commercial 5-fluorouracil vials
stems from the alkaline hydrolysis of this drug. Br J Cancer 1992; 66:119-127.
239. Lemaire L, Malet-Martino MC, Longo S, et al: Fluoroacetaldehyde as cardiotoxic impurity in
fluorouracil (Roche). Lancet 1991; 337:560.
240. Barbe L, Lesur G, Turner L, et al: Cardiac toxicity of 5 fluorouracil - auriculoventricular conduction
disease. Gastroenterol Clin Biol 1993; 17:603-604.
241. Millward MJ, Ganju V, & Buck M: Cardiac arrest - a manifestation of 5-fluorouracil cardiotoxicity.
Aust N Z J Med 1988; 18:693-695.
242. Pottage A, Holt S, Ludgate S, et al: Fluorouracil cardiotoxicity. Br Med J 1978; 1:547.
243. El Amrani M, Heinzlef O, Debroucker T, et al: Brain infarction following 5-fluorouracil and
cisplatin therapy. Neurology 1998; 51:899-901.
244. Schagen SB, van Dam FSAM, Muller MJ, et al: Cognitive deficits after postoperative adjuvant
chemotherapy for breast carcinoma. Cancer 1999; 85(3):640-650.
245. Luppi G, Zoboli A, Barbierie F, et al: Multifocal leukoencephalopathy associated with 5fluorouracil and levamisole adjuvant therapy for colon cancer: a report of two cases and review of the
literature. Ann Oncol 1996; 7:412-415.
246. Bixenman WW, Nicholls JV, & Warwick OH: Oculomotor disturbances associated with 5fluorouracil chemotherapy. Am J Ophthalmol 1977; 83:789-793.
247. Nichols M, Bergevin PR, Vyas AC, et al: Neurotoxicity from 5-fluorouracil (NSC-19893)
administration reproduced by mitomycin C (NSC-26980). Cancer Treat Rep 1976; 60:293-294.
248. Bergevin PR, Patwardhan VC, Weissman J, et al: Neurotoxicity of 5-fluorouracil (letter). Lancet
1975; 1:410.
249. Boileau G, Piro AJ, Lahiri SR, et al: Cerebellar ataxia during 5-fluorouracil (NSC-19893) therapy.
Cancer Chemother Rep 1971; 55:595-598.
250. Risso ME, Hasson NK, & Lum BL: Dihydropyrimidine dehydrogenase deficiency: a potential
etiology for 5-fluorouracil-induced neurotoxicity. Pharmacotherapy 1997; 17(4):847-848.
251. Pirzada NA, Ali II, & Dafer RM: Fluorouacil-induced neurotoxicity. Ann Pharmacother 2000;
34:35-38.
287/317
25/10/12
252. Yeh KH & Cheng AL: High-dose 5-fluorouracil infusional therapy is associated with
hyperammonaemia, lactic acidosis and encephalopathy. Br J Cancer 1997; 75:464-465.
253. Shehata N, Pater A, & Tang S-C: Prolonged severe 5-Fluorouracil-associated neurotoxicity in a
patient with dihydropyrimidine dehydrogenase deficiency. Cancer Invest 1999; 17(3):201-205.
254. Takimoto CH, Zhi-Hong L, Zhang R, et al: Severe neurotoxicity following 5-fluorouracil-based
chemotherapy in a patient with dihydropyrimidine dehydrogenase deficiency. Clin Cancer Res 1996;
2:477-481.
255. Stein ME, Drumea K, Yarnitsky D, et al: A rare event of 5-fluorouracil-associated peripheral
neuropathy: a report of two patients. Am J Clin Oncol 1998; 21(3):248-249.
256. Barnes WE & Harrah JD: Malignant hypercalcemia complicating metastatic carcinoma of the
breast. W V Med J 1974; 70:103-105.
257. Kido Y, Okamura T, Tomikawa M, et al: Hypocalcemia associated with 5-fluorouracil and low
dose leucovorin in patients with advanced colorectal or gastric carcinomas. Cancer 1996; 78:17941797.
258. Souchon EA, Copeland EM, Watson P, et al: Intravenous hyperalimentation as an adjunct to
cancer chemotherapy with 5-fluorouracil. J Surg Res 1975; 18:451-454.
259. Anon: Efficacy of intravenous continuous infusion of fluorouracil compared with bolus
administration in advanced colorectal cancer. J Clin Oncol 1998; 16(1):301-308.
260. Barrett ON: Fluorouracil toxicity following gastrointestinal surgery. Arch Surg 1965; 91:10021004.
261. Fata F, Ron Ron NG, Kemeny N, et al: 5-flurouracil-induced small bowel toxicity in patients with
colorectal carcinoma. Cancer 1999; 86(7):1129-1134.
262. Kennedy BJ: 5-Fluorouracil toxicity. Cancer 1999; 86(7):1099-1100.
263. Daniele B, Perrone F, Gallo C, et al: Oral glutamine in the prevention of fluorouracil induced
intestinal toxicity: a double blind, placebo controlled, randomised trial. Gut 2001; 48:28-33.
264. Kronawitter U, Kemeny NE, & Blumgart L: Neutropenic enterocolitis in a patient with colorectal
265. Tiersten A & Saltz LB: Influence of inflammatory bowel disease on the ability of patients to
tolerate systemic fluorouracil-based chemotherapy. J Clin Oncol 1996; 14:2043-2046.
266. Wadler S, Lyver A, & Wiernik PH: Clinical toxicities of the combination of 5-fluorouracil and
recombinant interferon alfa-2a: an unusual toxicity profile. Oncol Nurs Forum 1989; 16(suppl):12-15.
267. Trevisani F, Simoncini M, Alampi G, et al: Colitis associated with chemotherapy with 5fluorouracil. Hepatogastroenterol 1997; 44:710-712.
288/317
25/10/12
fluorouracil. Hepatogastroenterol 1997; 44:710-712.

268. Cudmore MA, Silva J Jr, Fekety R, et al: Clostridium difficile colitis associated with cancer
chemotherapy. Arch Intern Med 1982; 142:333-335.
269. Sloan JA, Loprinzi CL, Novotny PJ, et al: Sex differences in fluorouracil- induced stomatitis. J Clin
Oncol 2000; 18(2):412-420.
270. Keefe DM, Schubert MM, Elting LS, et al: Updated clinical practice guidelines for the prevention
and treatment of mucositis. Cancer 2007; 109(5):820-831.
271. Narsete T, Ansfield F, & Wirtanen G: Gastric ulceration in patients receiving intrahepatic infusion
of 5-fluorouracil. Ann Surg 1977; 186:734-736.
272. Rousselot LM, Cole DR, Grossi CE, et al: Gastrointestinal bleeding as a sequel to cancer
chemotherapy. Am J Gastroenterol 1965; 43:311-316.
273. Kemeny N, Seiter K, Martin D, et al: A new syndrome: ascites, hyperbilirubinemia, and
hypoalbuminemia after biochemical modulation of fluorouracil with N-phosphonacetyl-L-aspartate
(PALA). Ann Intern Med 1991; 115:946-951.
274. Vestfrid MA, Castelleto L, & Gimenez PO: Diffuse liver necrosis in treatment with 5-fluorouracil.
Rev Clin Esp 1972; 125:549-550.
275. Sotaniemi EA, Sutinen S, Arranto AJ, et al: Liver damage in nurses handling cytostatic agents.
Acta Med Scand 1983; 214:181-189.
276. Griffin JD & Garnick MB: Eye toxicity of cancer chemotherpay: a review of the literature. Cancer
1981; 48:1539-1549.
277. Galentine P, Sloas H, Hargett N, et al: Bilateral cicatricial ectropion following topical
administration of 5-fluorouracil. Ann Ophthalmol 1981; 13(5):575-577.
278. Franks WA & Hitchings RA: Complications of 5-fluorouracil after trabeculectomy. Eye 1991;
5:385-389.
279. Baldassare RD, Brunette I, Desjardins DC, et al: Corneal ectasia secondary to excessive ocular
massage following trabeculectomy with 5-fluorouracil. Can J Ophthalmol 1996; 31:252-254.
280. Susanna R, Takahashi W, & Nicolela M: Late bleb leakage after trabeculectomy with 5fluorouracil or mitomycin C. Can J Ophthalmol 1996; 31:296-300.
281. Peterson MR, Skuta GL, Phelan MJ, et al: Striate melanokeratosis following trabeculectomy with
5-fluorouracil. Arch Ophthalmol 1990; 108:1216-1217.
282. Rothman RF, Liebmann JM, & Ritch R: Noninfectious crystalline keratopathy after postoperative
subconjunctival 5-fluorouracil. Am J Ophthalmol 1999; 128(2):236-237.
289/317
25/10/12
subconjunctival 5-fluorouracil. Am J Ophthalmol 1999; 128(2):236-237.

283. Lee V, Bentley CR, & Olver JM: Sclerosing canaliculitis after 5-fluorouracil breast cancer
chemotherapy. Eye 1998; 12:343-349.
284. Christophidis N, Vajda FJ, Lucas I, et al: Ocular side effects with 5-fluorouracil. Aust N Z J Med
1979; 9:143-144.
285. Hamersley J, Luce JK, Florentz TR, et al: Excessive lacrimation from fluorouracil treatment.
JAMA 1973; 225:747-748.
286. Haidak DJ, Hurwitz BS, & Yeung KY: Tear-duct fibrosis (dacryostenosis) due to 5-fluorouracil.
Ann Intern Med 1978; 88:657.
287. Prasad S, Kamath GG, & Phillips RP: Lacrimal canalicular stenosis associated with systemic 5fluorouracil therapy. Acta Ophthalmol Scand 2000; 78:110-113.
288. Insler MS & Helm CJ: Ankyloblepharon associated with systemic 5-fluorouracil treatment. Ann
Ophthalmol 1987; 19:374-375.
289. Fielding JW, Stockley RA, & Brookes VS: Interstitial lung disease in a patient treated with 5fluorouracil and mitomycin C. Br Med J 1978; 2:602.
290. Fielding JW, Crocker J, Stockley RA, et al: Interstitial fibrosis in a patient treated with 5fluorouracil and mitomycin C. Br Med J 1979; 1:551-552.
291. Sams WM: Untoward response with topical fluorouracil. Arch Dermatol 1968; 97:14-22.
292. Goette DK, Odom RB, & Owens R: Allergic contact dermatitis from topical fluorouracil. Arch
Dermatol 1977; 113:196-198.
293. Clemons DE: Dermatitis medicamentosa: a pitfall for the unwary. Arch Dermatol 1976;
112:1178-1179.
294. Curran CF & Luce JK: Fluorouracil and palmar-plantar erythrodysesthesia. Ann Intern Med 1989;
111:858.
295. Comandone A, Bretti S, La Grotta G, et al: Palmar-plantar erythrodysestasia syndrome
associated with 5-fluorouracil treatment. Anticancer Res 1993; 13:1781-1783.
296. Jorda E, Galan A, Betloch I, et al: Painful, red hands: a side effect of 5-fluorouracil by continuous
perfusion. Int J Dermatol 1991; 30:653.
297. Feldman LD & Ajani JA: Fluorouracil-associated dermatitis of the hands and feet. JAMA 1985;
254:3479.
298. Granstein RD & Sober AJ: Drug and heavy metal-induced hyperpigmentation. J Am Acad
Dermatol 1981; 5:1-8.
290/317
299. Nixon DW, Pirozzi D, York RM, et al: Dermatologic changes after systemic cancer therapy. Cutis
1981; 27:181-194.
300. Norton LA: Nail disorders. J Am Acad Dermatol 1980; 2:451-467.
301. Katz ME & Hansen TW: Nail plate-nail bed separation. An unusual side effect of systemic
fluorouracil administration. Arch Dermatol 1979; 115:860-861.
302. Bart BJ & Bean SF: Bullous pemphigoid following the topical use of fluorouracil. Arch Dermatol
1970; 102:457-460.
303. Hrushesky WJ: Unusual pigmentary changes associated with 5-fluorouracil therapy. Cutis 1980;
26:181-182.
304. Burnett JW: Two unusual complications to topical fluorouracil therapy (letter). Arch Dermatol
1975; 111:398.
305. Biswal BM: Anaphylaxis following continuous 5-fluorouracil infusion chemotherapy. Aust NZ J
Med 1999; 29:743-744.
306. DeBeer R & Kabakow B: Anaphylactic reaction - associated with intravenous administration of 5fluorouracil. N Y State J Med 1979; 79:1750-1751.
307. Nikula E, Kivinitty K, Leisti J, et al: Chromosome aberration in lymphocytes of nurses handling
cytostatic agents. Scand J Work Environ Health 1984; 10:71-74.
308. Barnham M & Taylor AJ: A case of bacillus cereus bacteraemia. Postgrad Med J 1977; 53:397399.
309. Fluoroplex product information (HerbertUS). PDR., 1992.
310. Fluorouracil injection package insert (RocheUS). Rev Rev 11/90; Rev 6/91., 2/88.
311. Adrucil package insert (Pharmacia-UpjohnUS). Rev Rec 4/30/97., 4/1/96.
312. Adrucil package insert (AdriaUS). Rev Rev 1/29/90; Rev 8/21/91., 6/23/87.
313. Centers for Disease Control and Prevention : General Recommendations on Immunization.
MMWR 2011; 60(2):3-.
314. MMWR: General recommendations on immunization. MMWR 1989; 38:205-214, 219-227.
315. Rosenbaum EH, Cohen RA, & Glatstein HR: Vaccination of a patient receiving
immunosuppressive therapy for lymphosarcoma. JAMA 1966; 198:737-740.
316. Allison J: Methotrexate and small pox vaccination (letter). Lancet 1968; 2:1250.
291/317
25/10/12
317. Orr LE: Potentiation of myelosuppression from cancer chemotherapy and thiazide diuretics. Drug
Intell Clin Pharm 1981; 15:967-970.
318. Pritchard KI, Paterson AH, Paul NA, et al: Increased thromboembolic complications with
concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with
breast cancer. J Clin Oncol 1996; 14:2731-2737.
319. Pritchard KI, Paterson AH, Paul NA, et al: Increased thromboembolic complications with
concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with
breast cancer. J Clin Oncol 1996; 14:2731-2737.
320. Brickell K, Porter D, & Thompson P: Phenytoin toxicity due to fluoropyrimidines
(5FU/capecitabine): three case reports. British Journal of Cancer 2003; 89:615-616.
321. Brickell K, Porter D, & Thompson P: Phenytoin toxicity due to fluoropyrimidines
(5FU/capecitabine): three case reports. British Journal of Cancer 2003; 89:615-616.
322. Machover D, Schwarzenberg L, Goldschmidt E, et al: Treatment of advanced colorectal and
gastric adenocarcinomas with 5-FU combined with high dose folinic acid: a pilot study. Cancer Treat
Rep 1982; 66:1803-1807.
323. Stein TA, Burns GP, Bailey B, et al: 5-fluorouracil pharmacokinetics in patients with metastatic
colorectal carcinoma after high-dose leucovorin. Cancer Invest 1994; 12:375-378.
324. Machover D, Schwarzenberg L, Goldschmidt E, et al: Treatment of advanced colorectal and
gastric adenocarcinomas with 5-FU combined with high dose folinic acid: a pilot study. Cancer Treat
Rep 1982; 66:1803-1807.
325. Product Information: Adrucil(R), fluorouracil injection USP. SICOR Pharmaceuticals Inc, Irvine,
CA, 2003.
326. Product Information: Leucovorin calcium for injection. Immunex, US, 97.
327. Stein TA, Burns GP, Bailey B, et al: 5-fluorouracil pharmacokinetics in patients with metastatic
colorectal carcinoma after high-dose leucovorin. Cancer Invest 1994; 12:375-378.
328. Brown MC: An adverse interaction between warfarin and 5-fluorouracil: A case report and review
of the literature. Chemotherapy 1999; 45(5):392-395.
329. Seifter EJ, Brooks BJ, & Urba WJ: Possible interactions between warfarin and antineoplastic
drugs. Cancer Treat Rep 1985; 69(2):244-245.
330. Scarfe MA & Israel MK: Possible drug interaction between warfarin and combination of
levamisole and fluorouracil. Ann Pharmacother 1994; 28:464-467.
292/317
25/10/12
331. Wajima T & Mukhopadhyay P: Possible interactions between warfarin and 5-fluorouracil (letter).
Am J Hematol 1992; 40:238.
332. Chlebowski RT, Gota CH, Chan KK, et al: Clinical and pharmacokinetic effects of combined
warfarin and 5- fluorouracil in advanced colon cancer. Cancer Res 1982; 42:4827-4830.
333. Kolesar JM, Johnson CL, Freeberg BL, et al: Warfarin-5FU interaction - a consecutive case series.
Pharmacotherapy 1999; 19:1445-1449.
334. Brown MC: Multisite mucous membrane bleeding due to a possible interaction between warfarin
and 5-fluorouracil. Pharmacotherapy 1997; 17:631-633.
335. Aki A, Kotiloglu G, & Ozyilkan O: A patient with a prolonged prothrombin time due to an adverse
interaction between 5-fluorouracil and warfarin (letter). Am J Gastroenterol 2000; 95:1093-1094.
336. Carabino J & Wang F: International normalized ratio fluctuation with warfarin-fluorouracil
therapy. AM J Health-System Pharm 2002; 59:875.
337. Masci G, Magagnoli M, Zucali A, et al: Minidose warfarin prophylaxis for catheter-associated
thrombosis in cancer patients: can it be safely associated with fluorouracil-based chemotherapy?. J
Clin Oncol 2003; 21(4):736-739.
338. Wehbe TW & Warth JA: A case of bleeding requiring hospitalization that was likely caused by an
interaction between warfarin and levamisole. Clin Pharmacol Ther 1996; 59(3):360-362.
339. Malacarne P & Maestri A: Possible interactions between antiblastic agents and warfarin inducing
prothrombin time abnormalities. Recenti.Prog Med 1996; 87(3):135-135.
340. Brown MC: Multisite mucous membrane bleeding due to a possible interaction between warfarin
and 5-fluorouracil. Pharmacotherapy 1997; 17(3):631-633.
341. Scarfe MA & Israel MK: Possible drug interaction between warfarin and combination of
levamisole and fluorouracil. Ann Pharmacother 1994; 28(4):464-467.
342. Wajima T & Mukhopadhyay P: Possible interactions between warfarin and 5-fluorouracil. Am J
Hematol 1992; 40(3):238-238.
293/317
343. Product Information: COUMADIN(R) oral tablets, IV injection, warfarin sodium oral tablets, IV
injection. Bristol-Myers Squibb Company, Princeton, NJ, 2007.
344. Product Information: CYTOXAN(R) injection, oral tablets, cyclophosphamide injection, oral
tablets. Bristol-Myers Squibb Company, Princeton, NJ, 2005.
345. Product Information: methotrexate oral tablets, methotrexate oral tablets. Roxane
Laboratories,Inc, Columbus, OH, 2006.
346. Moertel CG, Fleming TR, MacDonald JS, et al: Hepatic toxicity associated with fluorouracil plus
levamisole adjuvant therapy. J Clin Oncol 1993; 11:2386-2390.
347. Correale P, Cerretani D, Marsili S, et al: Gemcitabine increases systemic 5-fluorouracil exposure
in advanced cancer patients. Eur J Cancer 2003; 39:1547-1551.
348. Correale P, Cerretani D, Marsili S, et al: Gemcitabine increases systemic 5-fluorouracil exposure
in advanced cancer patients. Eur J Cancer 2003; 39:1547-1551.
349. Product Information: CEREBYX(R) intravenous injection, fosphenytoin sodium intravenous
injection. Parke-Davis (per FDA), New York, NY, 2011.
350. Product Information: TINDAMAX(R) oral tablets, tinidazole oral tablets. Mission Pharmacal
Company, San Antonio, TX, 2007.
351. Bardakji Z, Jolivet J, Langelier Y, et al: 5-Fluorouracil-metronidazole combination therapy in
metastatic colorectal cancer. Cancer Chemother Pharmacol 1986; 18:140-144.
352. Bardakji Z, Jolivet J, Langelier Y, et al: 5-Fluorouracil-metronidazole combination therapy in
metastatic colorectal cancer. Cancer Chemother Pharmacol 1986; 18:140-144.
353. Harvey VJ, Slevin ML, Dilloway MR, et al: The influence of cimetidine on the pharmacokinetics of
5-fluorouracil. Br J Clin Pharmacol 1984; 18:421-430.
354. Harvey VJ, Slevin ML, Dilloway MR, et al: The influence of cimetidine on the pharmacokinetics of
5-fluorouracil. Br J Clin Pharmacol 1984; 18:421-430.
355. MMWR: General recommendations on immunization. MMWR 1989; 38:205-214, 219-227.
356. Rosenbaum EH, Cohen RA, & Glatstein HR: Vaccination of a patient receiving
immunosuppressive therapy for lymphosarcoma. JAMA 1966; 198:737-740.
357. Allison J: Methotrexate and small pox vaccination (letter). Lancet 1968; 2:1250.
358. Product Information: RotaShield(R), rotavirus vaccine, live, oral, tetravalent. Wyeth-Ayerst
Laboratories, Philadelphia, PA, 1998.
359. Product Information: levoleucovorin solution for IV injection, levoleucovorin solution for IV
injection. Spectrum Pharmaceuticals,Inc, Irvine, CA, 2008.
25/10/12
360. Product Information: EFUDEX(R) topical cream, topical solution, fluorouracil topical cream,
topical solution. Valeant Pharmaceuticals North America, Costa Mesa, CA, 2005.
361. Australian Government Department of Health and Ageing Therapeutic Goods Administration:
Prescribing medicines in pregnancy database. Australian Government Department of Health and
Ageing Therapeutic Goods Administration. Woden, Australia. 2012. Available from URL:
http://www.tga.gov.au/hp/medicines-pregnancy.htm. As accessed 2012-05-31.
362. Jeppesen JB & Osterlind K: Successful twin pregnancy outcome after in utero exposure to
FOLFOX for metastatic colon cancer: a case report and review of the literature. Clin Colorectal Cancer
2011; 10(4):348-352.
363. Andreadis C, Charalampidou M, Diamantopoulos N, et al: Combined chemotherapy and
radiotherapy during conception and first two trimesters of gestation in a woman with metastatic
breast cancer. Gynecol Oncol 2004; 95:252-255.
364. Stadler HE & Knowles J: Fluorouracil in pregnancy: effect on the neonate. JAMA 1971; 217:214215.
365. Stephens JD, Golbus MS, Miller TR, et al: Multiple congenital anomalies in a fetus exposed to 5fluorouracil during the first trimester. Am J Obstet Gynecol 1980; 137(6):747-9.
366. Odom LK, Plouffe L, & Butler WJ: 5-Fluorouracil during the period of conception: report on two
cases. Am J Obstet Gynecol: 1990; 163:76-77.
367. Van Le L, Pizzuti DJ, Greenberg M, et al: Accidental use of low-dose 5-fluorouracil in pregnancy.
J Reprod Med 1991; 36:872-874.
368. Product Information: Fluorouracil IV injection, Fluorouracil IV injection. APP Pharmaceuticals,
LLC, Schaumburg, IL, 2008.
369. Glantz JC: Reproductive toxicology of alkylating agents. Obstet Gynecol 1994; 49:709-715.
370. Doll DC, Ringenberg QS, & Yarbro JW: Management of cancer during pregnancy. Arch Intern
Med 1988; 148:2058-2064.
371. Cunningham FG, MacDonald PC, Leveno KF, et alCunningham FG, MacDonald PC, Leveno KF, et
al (Eds): Williams Obstetrics, 19th. Appleton & Lange, Norwalk, CT, 1993.
372. Anon: Breastfeeding and Maternal Medication. World Health Organization, Geneva, Switzerland,
2002.
373. Peccatori FA, Giovannetti E, Pistilli B, et al: "The only thing I know is that I know nothing": 5fluorouracil in human milk. Ann Oncol 2012; 23(2):543-544.
295/317
25/10/12

374. Gamelin E, Boisdron-Celle M, Delva R, et al: Long-term weekly treatment of colorectal
metastatic cancer with fluorouracil and leucovorin: results of a multicentric prospective trial of
fluorouracil dosage optimization by pharmacokinetic monitoring in 152 patients. J Clin Oncol 1998;
16:1470-1478.
375. Bocci G, Danesi R, Di Paolo A, et al: Comparative pharmacokinetic analysis of 5-fluorouracil and
its major metabolite 5-fluoro-5,6-dihydrouracil after conventional and reduced test dose in cancer
patients. Clin Cancer Res 2000; 6:3032-3037.
376. Levy S, Furst K, & Chern W: A pharmacokinetic evaluation of 0.5% and 5% fluorouracil topical
cream in patients with actinic keratosis. Clin Ther 2001; 23(6):908-920.
377. Lerner-Tung MB, Chang AYC, Ong LS, et al: Pharmacokinetics of intrapericardial administration
of 5-fluorouracil. Cancer Chemother Pharmacol 1997; 40:318-320.
378. Grem JL, Quinn M, Ismail AS, et al: Pharmacokinetics and pharmacodynamic effects of 5fluorouracil given as a one-hour intravenous infusion. Cancer Chemother Pharmacol 2001; 47:117-125.
379. Cohen JL, Irwin LE, Marshall GJ, et al: Clinical pharmacology of oral and intravenous 5fluorouracil (NSC-19893). Cancer Chemother Rep 1974; 58:723-731.
380. Jodrell DI, Stewart M, Aird R, et al: 5-Fluorouracil steady state pharmacokinetics and outcome in
patients receiving protracted venous infusion for advanced colorectal cancer. Br J Cancer 2001;
84(5):600-603.
381. Diasio RB & Harris BE: Clinical pharmacology of 5-fluorouracil. Clin Pharmacokinet 1989; 16:215237.
382. Clarkson B: The physiologic disposition of 5-fluorouracil and 5-fluoro-2 deoxyuridine in man. Clin
Pharmacol Ther 1964; 5:581.
383. Shepard DR, Mani S, Kastrissios H, et al: Estimation of the effect of food on the disposition of
oral 5-fluorouracil in combination with eniluracil. Cancer Chyemother Pharmacol 2002; 49:398-402.
384. Product Information: Efudex. Roche, US, 95.
385. Product Information: Adrucil(R), fluorouracil injection. Sicor Pharmaceuticals, Inc., Irvine, CA,
USA, 2003.
386. Anderson RJ, Gambertogolio JG, & Schrier RWAnderson RJ, Gambertogolio JG, & Schrier RW:
Clinical Use of Drugs in Renal Failure, Charles C Thomas Publisher, Springfield, IL, 1976.
387. Shukla HS, Hughes LE, Davis PW, et al: Distribution of 5-fluorouracil to body tissues compared
after intraluminal, intravenous, and intramural administration in gastrointestinal cancer. Am J Surg
1977; 133:346-350.
296/317
25/10/12
388. Terret C, Erdociain E, Guimbaud R, et al: Dose and time dependencies of 5-fluorouracil
pharmacokinetics. Clin Pharmacol Ther 2000; 68:270-279.
389. Devita: Cancer: principles and practice of oncology 5th ed, Lippincott-Raven, Philadelphia, PA,
1997, pp 437.
390. Product Information: Adrucil. Pharmacia-Upjohn, US, 96.
391. Product Information: Adrucil. Adria, US, 87.
392. Diasio RB & Harris BE: Clinical pharmacology of 5-fluorouracil. Clin Pharmacokinet 1989; 16:215237.
393. Anon: Five-year follow-up of the fluorouracil filtering surgery study. Am J Ophthalmol 1996;
121:349-66.
394. Belyea DA, Dan JA, Stamper RL, et al: Late onset of sequential multifocal bleb leaks after
glaucoma filtration surgery with 5-fluorouracil and mitomycin C.. Am J Ophthalmol 1997; 124:40-5.
395. Gandolfi SA & Vecchi M: 5-fluorouracil in combined trabeculectomy and clear-cornea
phacoemulsification with posterior chamber intraocular lens implantation. Ophthalmology 1997;
104(2):181-6.
396. Maas B & Kraemer I: Zytostatikazubereitungen fuer Glaukomoperationen..
Krankenhauspharmazie 1995; 16:192-7.
397. Mastropasqua L, Carpineto P, Ciancaglini M, et al: Delayed post-operative use of 5-fluorouracil as
an adjunct in medically uncontrolled open angle glaucoma.. Eye 1998; 12:701-6.
398. Mora JS, Nguyen N, Iwach AG, et al: Trabeculectomy with intraoperative sponge 5-fluorouracil..
Ophthalmology 1996; 103:963-70.
399. Reviewers' consensus, 12/29/2000.
400. Horton J & Hill GJHorton J & Hill GJ (Eds): Clinical Oncology, WB Saunders Co, Philadelphia, PA,
1977.
401. Padmanabhan N, Howell A, & Rubens RD: Mechanism of action of adjuvant chemotherapy in
early breast cancer. Lancet 1986; 2:411-414.
402. Product Information: ADRUCIL(R) IV injection, fluorouracil IV injection. Teva Parenteral
Medicines, Inc, Irvine, CA, 2007.
403. Product Information: EFUDEX(R) topical solutions, cream, fluorouracil topical solutions, cream.
ICN Pharmaceuticals, Inc., Costa Mesa, CA, 2006.
404. Sadoff L: Overwhelming 5-fluorouracil toxicity in patients whose diabetes is poorly controlled.
Amer J Clin Oncol 1998; 21:605-607.
297/317
25/10/12
405. Baud-Camus F, Crauste-Manciet S, Klein E, et al: Stability of fluorouracil in polypropylene

syringes and ethylene vinyl acetate infusion-pump reservoirs. Am J Health Syst Pharm 1996; 53:14571458.
406. Benvenuto JA, Anderson RW, Kerkof K, et al: Stability and compatibility of antitumor agents in
glass and plastic containers. Am J Hosp Pharm 1981; 38:1914-1918.
407. Quebbeman EJ, Hamid AAR, Hoffman NE, et al: Stability of fluorouracil in plastic containers used
for continuous infusion at home. Am J Hosp Pharm 1984; 41:1153-1156.
408. Stiles ML, Allen LV Jr, & Tu Y-H: Stability of fluorouracil administered through four portable
infusion pumps. Am J Hosp Pharm 1989; 46:2036-2040.
409. Stiles ML, Allen LV Jr, & Prince SJ: Stability of deferoxamine mesylate, floxuridine, fluorouracil,
hydromorphone hydrochloride, lorazepam, and midazolam hydrochloride in polypropylene infusionpump syringes. Am J Health Syst Pharm 1996; 53:1583-1588.
410. Stoikes ME, Carlson JD, & Farris FF: Permeability of latex and polyvinyl chloride gloves to
fluorouracil and methotrexate. Am J Hosp Pharm 1987; 44:1341-1346.
411. Kleinberg ML, Stauffer GL, & Latiolais CJ: Effect of microwave radiation on redissolving
precipitated matter in fluorouracil injection. Am J Hosp Pharm 1980; 37:678-679.
412. Muss HB, Berry DA, Cirrincione CT, et al: Adjuvant chemotherapy in older women with earlystage breast cancer. N Engl J Med 2009; 360(20):2055-2065.
413. Robert NJ, Dieras V, Glaspy J, et al: RIBBON-1: randomized, double-blind, placebo-controlled,
phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human
epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin
Oncol 2011; 29(10):1252-1260.
414. Stadtmauer EA, O'Neill A, Goldstein LJ, et al: Conventional-dose chemotherapy compared with
high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic
breast cancer. N Engl J Med 2000; 42:1069-1076.
415. Lippman ME: High-dose chemotherapy plus autologous bone marrow transplantation for
metastatic breast cancer. N Engl J Med 2000; 342:1119-1120.
416. Webb A, Cunningham D, Scarffe JW, et al: Randomized trial comparing epirubicin, cisplatin, and
fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer. J
Clin Oncol 1997; 15:261-267.
417. Neijt JP, Ten Bokkel Huinink WW, Van Der Burg MEL, et al: Randomised trial comparing two
298/317
25/10/12
combination chemotherapy regimens (Hexa-CAF versus CHAP-5) in advanced ovarian carcinoma.

Lancet 1984; 2:594-600.
418. Fisher B, Redmond C, Dimitrov NV, et al: A randomized clinical trial evaluating sequential
methotrexate and fluorouracil in the treatment of patients with node-negative breast cancer who
have estrogen-receptor-negative tumors. N Engl J Med 1989; 320:473-478.
419. Taylor SG, Gelman RS, Falkson G, et al: Combination chemotherapy compared to tamoxifen as
initial therapy for stage IV breast cancer in elderly women. Ann Intern Med 1986; 104:455-461.
Clin Oncol 1997; 15:261-267.
421. Burris HA, Moore MJ, Andersen J, et al: Improvements in survival and clinical benefit with
gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J
Clin Oncol 1997; 15:2403-2413.
422. Crawford J, O'Rourke M, Schiller JH, et al: Randomized trial of vinorelbine compared with
fluorouracil plus leucovorin in patients with stage IV non-small cell lung cancer. J Clin Oncol 1996;
14:2774-2784.
423. Whitney CW, Sause W, Bundy BN, et al: Randomized comparison of fluorouracil plus cisplatin
versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with
negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group
Study. J Clin Oncol 1999; 17(5):1339-1348.
424. Kelsen D, Atiq O, Saltz L, et al: FAMTX versus EAP: A random assignment trial in gastric
cancer.. J Clin Oncol 1992; 10(4):541-8.
425. de Gramont A, Vignoud J, Tournigand C, et al: Oxaliplatin with high-dose leucovorin and 5fluorouracil 48-hour continuous infusion in pretreated metastatic colorectal cancer. Eur J Cancer
1997; 33:214-219.
426. Poon MA, O'Connell MJ, Moertel CG, et al: Biochemical modulation of fluorouracil: evidence of
significant improvement of survival and quality of life in patients with advanced colorectal carcinoma.
J Clin Oncol 1989; 7(10):1407-1418.
427. Anon: Press Release: PhotoCure - Positive Metvix(R) PDT results. PhotoCure. Available at:
http://www.photocure.com, April 2, 2003.
428. Anon: Press Release: Clinical studies show positive results with Metvix PDT. Medical Industry
Week, April 8, 2003a.
429. Kondo K, Sakamoto J, Nakazato H, et al: A phase III randomized study comparing doxifluridine
and 5-fluorouracil as supportive chemotherapy in advanced and recurrent gastric cancer. Oncol Rep
2000; 7:485-490.
299/317
25/10/12
430. Bajetta E, Colleoni M, Rosso R, et al: Prospective randomised trial comparing fluorouracil versus
doxifluridine for the treatment of advanced colorectal cancer. Eur J Cancer 1993; 29A:1658-1663.
431. Calabresi F & Repetto M: Doxifluridine in advanced colorectal cancer. J Surg Oncol 1991;
2(suppl):124-128.
432. Alberto P, Mermillod B, Germano G, et al: A randomized comparison of doxifluridine and
fluorouracil in colorectal carcinoma. Eur J Cancer Clin Oncol 1988; 24:559-563.
433. Singh K, Egbert PR, Byrd S, et al: Trabeculectomy with intraoperative 5-fluorouracil vs mitomycin
C. Am J Ophthalmol 1997; 123:48-53.
434. Zadok D, Zadok J, Turetz J, et al: Intraoperative mitomycin versus postoperative 5-fluorouracil in
primary glaucoma filtering surgery. Ann Ophthalmol 1995; 27:336-340.
435. Cunningham D, Zalcberg JR, Rath U, et al: Tomudex (ZD1694): results of a randomised trial in
advanced colorectal cancer demonstrate efficacy and reduced mucositis and leucopenia. Eur J Cancer
1995; 31A:1945-1954.
436. van Triest B, van Groeningen, & Pinedo HM: Current chemotherapeutic possibilities in the
treatment of colorectal cancer. Eur J Cancer 1995; 31A:1193-1197.
437. Herrmann R: Thymidylate synthase inhibition, a dead end?. Eur J Cancer 1995; 31A:1919-1920.
Clin Oncol 1997; 15:261-267.
439. Neoptolemos J, Stocken D, Friess H, et al: A randomized trial of chemoradiotherapy and
chemotherapy after resection of pancreatic cancer. N Engl J Med 2004; 350(12):1200-1210.
440. de Gramont A, Figer A, Seymour M, et al: Leucvorin and fluorouracil with or without oxaliplatin
441. Kilickap S, Yalcin S, Ates O, et al: The first line systemic chemotherapy in metastatic gastric
carcinoma: A comparison of docetaxel, cisplatin and fluorouracil (DCF) versus cisplatin and
fluorouracil (CF); versus epirubicin, cisplatin and fluorouracil (ECF) regimens in clinical setting.
Hepatogastroenterology 2011; 58(105):208-212.
442. Conroy T , Desseigne F , Ychou M , et al: FOLFIRINOX versus gemcitabine for metastatic
pancreatic cancer. N Engl J Med 2011; 364(19):1817-1825.
300/317
25/10/12
443. Bedikian AY, Stroehleim J, Korinek J, et al: A comparative study of oral tegafur and intravenous
5-fluorouracil in patients with metastatic colorectal cancer. Am J Clin Oncol 1983; 6:181-186.
444. Villalon AH, DeGuzman LMB, Samson MCYC, et al: A comparative, randomized trial of UFT(R)
and 5-fluorouracil in combination with cyclophosphamide and doxorubicin in the treatment of
advanced breast cancer patients at the Philippines General Hospital. Oncology 1997; 54(suppl 1):2-6.
445. Schutt AJ, Hahn RG, Moertel CG, et al: Phase II study of ftorafur in previously untreated and
treated patients with advanced colorectal cancer. Cancer Treat Rep 1983; 67:505-506.
446. Friedman MA & Ignoffo RJ: A review of the United States clinical experience of the
fluoropyrimidine, ftorafur (NSC-148958) (review). Cancer Treat Rev 1980; 7:205-213.
447. Buroker T, Padilla F, Groppe C, et al: Phase II evaluation of ftorafur in previously untreated
colorectal cancer: Southwest Oncology Group Study. Cancer 1979; 44:48-51.
448. Moertel CG: Clinical management of advanced gastrointestinal cancer. Cancer 1975; 36:675-682.
449. Woolley PV, MacDonald JS, Smythe T, et al: A phase 2#trial of ftorafur, adriamycin and
mitomycin-C (FAM 2) in advanced gastric adenocarcinoma. Cancer 1979; 44:1211-1214.
450. Treat J, Falchuk SC, Woolley PV, et al: Therapy of advanced gastric carcinoma: the GeorgetownLombardi Cancer Center experience. Am J Clin Oncol 1989; 12:162-168.
451. Hadfield AF & Sartorelli AC: The pharmacology of prodrugs of 5-fluorouracil and 1-beta-Darabinofuranosylcytosine (review). Adv Pharmacol Chemother 1984; 20:21-67.
452. Buroker T, Wojtaszak B, Dindogru A, et al: Phase II#trial of ftorafur with mitomycin C versus
ftorafur with methyl-CCNU in untreated colorectal cancer. Cancer Treat Rep 1978; 62:689-692.
453. Nakajima T, Takahashi T, Takagi K, et al: Comparison of 5-fluorouracil with ftorafur in adjuvant
chemotherapies with combined inductive and maintenance therapies for gastric cancer. J Clin Oncol
1984; 2:1366-1371.
454. Pazdur R: Phase II study of UFT(R) plus leucovorin in colorectal cancer. Oncology 1997;
54(suppl 1):19-23.
455. Andersen E & Pedersen H: Oral ftorafur versus intravenous 5-fluorouracil: a comparative study in
patients with colorectal cancer. Acta Oncol 1987; 26:433-436.
456. Bjerkeset T & Fjosne HE: Comparison of oral ftorafur and intravenous 5-fluorouracil in patients
with advanced cancer of the stomach, colon or rectum. Oncology 1986; 43:212-215.
457. Vestlev PM & Pedersen H: Doxorubicin and 5-fluorouracil versus doxorubicin and oral ftorafur in
the treatment of advanced gastric cancer - a phase II and III trial. Acta Oncol 1990; 29:945-946.
458. Piga A, Cascinu S, Latini L, et al: A phase II randomised trial of 5-fluorouracil with or without
interferon alpha-2a in advanced colorectal cancer. Br J Cancer 1996; 74:971-974.
301/317
25/10/12
459. Van Cutsem E & Blijham GH: Irinotecan versus infusional 5- fluorouracil: a phase III study in
metastatic colorectal cancer following failure on first-line 5-fluorouracil. Semin Oncol 1999; 26(1 suppl
5):13-20.
460. Rougier P, Van Cutsem E, Bajetta E, et al: Randomised trial of irinotecan versus fluorouracil by
continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet
1998; 352:1407-1412.
461. Okuyama K, Isono K, Juan IK, et al: Evaluation of treatment for gastric cancer with liver
metastasis. Cancer 1985; 55:2498-2505.
462. Kim GP, Sargent DJ, Mahoney MR, et al: Phase III noninferiority trial comparing irinotecan with
oxaliplatin, fluorouracil, and leucovorin in patients with advanced colorectal carcinoma previously
treated with fluorouracil: N9841. J Clin Oncol 2009; 27(17):2848-2854.
463. Tournigand C, Andre T, Achille E, et al: FOLFIRI followed by FOLFOX6 or the reverse sequence
in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004; 22(2):229-237.
464. Piga A, Cascinu S, Latini L, et al: A phase II randomised trial of 5-fluorouracil with or without
interferon alpha-2a in advanced colorectal cancer. Br J Cancer 1996; 74:971-974.
465. Quaranta L, Bettelli S, & Gandolfo E: Efficacy of sulodexide as adjunct in trabeculectomy; a twoyear randomized clinical study. Acta Ophthalmol Scan Suppl 2000; 78(232):63-65.
466. Moertel CG, Fleming TR, Macdonald JS, et al: Levamisole and fluorouracil for adjuvant therapy of
resected colon carcinoma. N Engl J Med 1990; 322:352-358.
467. Messori A, Bonistalli L, Costantini M, et al: Cost effectiveness of adjuvant intraportal
chemotherapy in patients with colorectal cancer. J Clin Gastroenterol 1996; 23:269-274.
468. Rosso R, Amoroso D, Gardin G, et al: Lonidamine in metastatic breast cancer. Semin Oncol
1991; 18(suppl 4):62-65.
469. Harmantas A, Rotstein LE, & Langer B: Regional versus systemic chemotherapy in the treatment
of colorectal carcinoma metastatic to the liver. Cancer 1996; 78:1639-1645.
470. Kang YK, Kang WK, Shin DB, et al: Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as firstline therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial. Ann
Oncol 2009; 20(4):666-673.
471. Icli F, Celik I, Aykan F, et al: A randomized phase III trial of etoposide, epirubicin, and cisplatin
versus 5-fluorouracil, epirubicin, and cisplatin in the treatment of
patients with advanced gastric

302/317
25/10/12
versus 5-fluorouracil, epirubicin, and cisplatin in the treatment of patients with advanced gastric
472. Hutchins LF, Green SJ, Ravdin PM, et al: Randomized, controlled trial of cyclophosphamide,
methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and
without tamoxifen for high-risk, node-negative breast cancer: treatment results of Intergroup Protocol
INT-0102. J Clin Oncol 2005; 23(33):8313-8321.
473. Basch E, Prestrud AA, Hesketh PJ, et al: Antiemetics: American Society of Clinical Oncology
clinical practice guideline update. J Clin Oncol 2011; 29(31):4189-4198.
474. Kris MG, Hesketh PJ, Somerfield MR, et al: American Society of Clinical Oncology guideline for
antiemetics in oncology: update 2006. J Clin Oncol 2006; 24(18):2932-2947.
475. Grunberg SM, Warr D, Gralla RJ, et al: Evaluation of new antiemetic agents and definition of
antineoplastic agent emetogenicity--state of the art. Support Care Cancer 2011; 19 Suppl 1:S43-S47.
476. Roche H, Fumoleau P, Spielmann M, et al: Sequential adjuvant epirubicin-based and docetaxel
chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial. J Clin Oncol 2006;
24(36):5664-5671.
477. Poole CJ, Earl HM, Hiller L, et al: Epirubicin and cyclophosphamide, methotrexate, and
fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med 2006; 355(18):1851-1862.
478. Tournigand C, Cervantes A, Figer A, et al: OPTIMOX1: a randomized study of FOLFOX4 or
FOLFOX7 with oxaliplatin in a stop-and-Go fashion in advanced colorectal cancer--a GERCOR study. J
Clin Oncol 2006; 24(3):394-400.
479. de Gramont A, Figer A, Seymour M, et al: Leucovorin and fluorouracil with or without oxaliplatin
480. Tournigand C, Andre T, Achille E, et al: FOLFIRI followed by FOLFOX6 or the reverse sequence
303/317
25/10/12
in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004; 22(2):229-237.
481. Maindrault-Goebel F, de Gramont A, Louvet C, et al: Evaluation of oxaliplatin dose intensity in
bimonthly leucovorin and 48-hour 5-fluorouracil continuous infusion regimens (FOLFOX) in pretreated
metastatic colorectal cancer. Oncology Multidisciplinary Research Group (GERCOR). Ann Oncol 2000;
11(11):1477-1483.
482. Allegra CJ, Yothers G, O'Connell MJ, et al: Initial safety report of NSABP C-08: A randomized
phase III study of modified FOLFOX6 with or without bevacizumab for the adjuvant treatment of
patients with stage II or III colon cancer. J Clin Oncol 2009; 27(20):3385-3390.
483. Kanemitsu Y, Kato T, Shimizu Y, et al: A randomized phase II/III trial comparing hepatectomy
followed by mFOLFOX6 with hepatectomy alone as treatment for liver metastasis from colorectal
cancer: Japan Clinical Oncology Group Study JCOG0603. Jpn J Clin Oncol 2009; 39(6):406-409.
484. Kuebler JP, Wieand HS, O'Connell MJ, et al: Oxaliplatin combined with weekly bolus fluorouracil
and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from
NSABP C-07. J Clin Oncol 2007; 25(16):2198-2204.
485. Douillard JY, Cunningham D, Roth AD, et al: Irinotecan combined with fluorouracil compared
with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre
randomised trial.. Lancet 2000; 355(9209):1041-7.
486. Andre T, Louvet C, Maindrault-Goebel F, et al: CPT-11 (irinotecan) addition to bimonthly, highdose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic
colorectal cancer. GERCOR. Eur J Cancer 1999; 35(9):1343-1347.
487. Hurwitz HI, Fehrenbacher L, Hainsworth JD, et al: Bevacizumab in combination with fluorouracil
and leucovorin: an active regimen for first-line metastatic colorectal cancer. J Clin Oncol 2005;
23(15):3502-3508.
488. Jager E, Heike M, Bernhard H, et al: Weekly high-dose leucovorin versus low-dose leucovorin
combined with fluorouracil in advanced colorectal cancer: results of a randomized multicenter
trial.Study Group for Palliative Treatment of Metastatic Colorectal Cancer Study Protocol 1. J Clin
304/317
25/10/12
Oncol 1996; 14(8):2274-2279.

489. Haller DG, Catalano PJ, Macdonald JS, et al: Phase III study of fluorouracil, leucovorin, and
levamisole in high-risk stage II and III colon cancer: final report of Intergroup 0089. J Clin Oncol
2005; 23(34):8671-8678.
490. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al: Adjuvant docetaxel or vinorelbine with or
without trastuzumab for breast cancer. N Engl J Med 2006; 354(8):809-820.
491. Bonadonna G, Zambetti M, & Valagussa P: Sequential or alternating doxorubicin and CMF
regimens in breast cancer with more than three positive nodes. Ten-year results. JAMA 1995;
273(7):542-547.
492. Ackland SP, Anton A, Breitbach GP, et al: Dose-intensive epirubicin-based chemotherapy is
superior to an intensive intravenous cyclophosphamide, methotrexate, and fluorouracil regimen in
metastatic breast cancer: a randomized multinational study. J Clin Oncol 2001; 19(4):943-953.
493. Goldberg RM, Sargent DJ, Morton RF, et al: A randomized controlled clinical trial of fluorouracil
plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated
metastatic colorectal cancer. J Clin Oncol 2004; 22:23-30.
494. Andre T, Bensmaine MA, Louvet C, et al: Multicenter phase II study of bimonthly high-dose
leucovorin, fluorouracil infusion, and oxaliplatin for metastatic colorectal cancer resistant to the same
leucovorin and fluorouracil regimen. J Clin Oncol 1999; 17(11):3560-3568.
495. Harvey RD, Pfeiffer D, Shifflett SL, et al: 1998 guide to cancer chemotherapeutic regimens.
Pharm Pract News 1998; .:25-32.
496. Fisher B, Brown AM, Dimitrov NV, et al: Two months of doxorubicin-cyclophosphamide with and
without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate,
and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results
from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 1990; 8(9):14831496.
305/317
25/10/12
497. Mamounas EP, Bryant J, Lembersky B, et al: Paclitaxel after doxorubicin plus cyclophosphamide
as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol
2005; 23(16):3686-3696.
498. Henderson IC, Berry DA, Demetri GD, et al: Improved outcomes from adding sequential
Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients
with node-positive primary breast cancer. J Clin Oncol 2003; 21(6):976-983.
499. Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally
scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant
treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and
Leukemia Group B Trial 9741. J Clin Oncol 2003; 21(8):1431-1439.
500. Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant chemotherapy for operable
HER2-positive breast cancer. N Engl J Med 2005; 353(16):1673-1684.
501. Product Information: TAXOL(R) IV injection, paclitaxel IV injection. Bristol-Myers Squibb
Company, Princeton, NJ, 2007.
502. Product Information: HERCEPTIN(R) IV injection, trastuzumab IV injection. Genentech,Inc,
South San Francisco, CA, 2008.
503. Fleming GF, Brunetto VL, Cella D, et al: Phase III trial of doxorubicin plus cisplatin with or
without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group
study. J Clin Oncol 2004; 22:2159-2166.
504. Early Breast Cancer Trialists' Collaborative Group: Effects of chemotherapy and hormonal
therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised
trials. Lancet 2005; 365(9472):1687-1717.
505. Assikis V, Buzdar A, Yang Y, et al: A phase III trial of sequential adjuvant chemotherapy for
operable breast carcinoma: final analysis with 10-year follow-up. Cancer 2003; 97(11):2716-2723.
506. Hortobagyi GN, Gutterman JU, Blumenschein GR, et al: Combination chemoimmunotherapy of
metastatic breast cancer with 5-fluorouracil, adriamycin, cyclophosphamide, and BCG. Cancer 1979;
43(4):1225-1233.
306/317
25/10/12
507. O'Shaughnessy J., Miles D., Vukelja S., et al: Superior survival with capecitabine plus docetaxel
combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial
results. J Clin Oncol 2002; 20(12):2812-2823.
508. Skarlos DV, Samantas E, Briassoulis E, et al: Randomized comparison of early versus late
hyperfractionated thoracic irradiation concurrently with chemotherapy in limited disease small-cell
lung cancer: a randomized phase II study of the Hellenic Cooperative Oncology Group (HeCOG). Ann
Oncol 2001; 12(9):1231-1238.
509. Schmittel A, Fischer von Weikersthal L, Sebastian M, et al: A randomized phase II trial of
irinotecan plus carboplatin versus etoposide plus carboplatin treatment in patients with extended
disease small-cell lung cancer. Ann Oncol 2006; 17(4):663-667.
510. Levine MN, Bramwell VH, Pritchard KI, et al: Randomized trial of intensive cyclophosphamide,
epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and
fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of
Canada Clinical Trials Group. J Clin Oncol 1998; 16(8):2651-2658.
511. Winton T., Livingston R., Johnson D., et al: Vinorelbine plus cisplatin vs. observation in resected
non-small-cell lung cancer. N Engl J Med 2005; 352(25):2589-2597.
512. Arriagada R, Bergman B, Dunant A, et al: Cisplatin-based adjuvant chemotherapy in patients
with completely resected non-small-cell lung cancer. N Engl J Med 2004; 350(4):351-360.
513. Fossella F, Pereira JR, vonPawel J, et al: Randomized, multinational, phase III study of docetaxel
plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer:
the TAX 326 study group. J Clin Oncol 2003; 21(16):3016-3024.
514. Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for
advanced non-small-cell lung cancer. N Engl J Med 2002; 346(2):92-98.
515. Berry DL, Moinpour CM, Jiang CS, et al: Quality of life and
pain in advanced stage prostate307/317
25/10/12
515. Berry DL, Moinpour CM, Jiang CS, et al: Quality of life and pain in advanced stage prostate
cancer: results of a Southwest Oncology Group randomized trial comparing docetaxel and
estramustine to mitoxantrone and prednisone. J Clin Oncol 2006; 24(18):2828-2835.
516. Petrylak DP, Tangen CM, Hussain MH, et al: Docetaxel and estramustine compared with
mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;
351(15):1513-1520.
517. Walczak JR & Carducci MA: Phase 3 randomized trial evaluating second-line hormonal therapy
versus docetaxel-estramustine combination chemotherapy on progression-free survival in
asymptomatic patients with a rising prostate-specific antigen level after hormonal therapy for
prostate cancer: an Eastern Cooperative Oncology Group (E1899), Intergroup/Clinical Trials Support
Unit study. Urology 2003; 62 Suppl 1:141-146.
518. Dreicer R, Manola J, Schneider DJ, et al: Phase II trial of gemcitabine and docetaxel in patients
with advanced carcinoma of the urothelium: a trial of the Eastern Cooperative Oncology Group.
Cancer 2003; 97(11):2743-2747.
519. Tannock IF, deWit R, Berry WR, et al: Docetaxel plus prednisone or mitoxantrone plus
prednisone for advanced prostate cancer. N Engl J Med 2004; 351(15):1502-1512.
520. Piccart MJ, DiLeo A, Beauduin M, et al: Phase III trial comparing two dose levels of epirubicin
combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in nodepositive breast cancer. J Clin Oncol 2001; 19(12):3103-3110.
521. Langley RE, Carmichael J, Jones AL, et al: Phase III trial of epirubicin plus paclitaxel compared
with epirubicin plus cyclophosphamide as first-line chemotherapy for metastatic breast cancer: United
Kingdom National Cancer Research Institute trial AB01. J Clin Oncol 2005; 23(33):8322-8330.
522. Sundstrom S, Bremnes RM, Kaasa S, et al: Cisplatin and etoposide regimen is superior to
cyclophosphamide, epirubicin, and vincristine regimen in small-cell lung cancer: results from a
randomized phase III trial with 5 years' follow-up. J Clin Oncol 2002; 20(24):4665-4672.
308/317
523. Robak T, Dmoszynska A, Solal-Celigny P, et al: Rituximab plus fludarabine and

cyclophosphamide prolongs progression-free survival compared with fludarabine and
cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol 2010;
28(10):1756-1765.
524. Crump M , Baetz T , Couban S , et al: Gemcitabine, dexamethasone, and cisplatin in patients
with recurrent or refractory aggressive histology B-cell non-Hodgkin lymphoma: a Phase II study by
the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG). Cancer 2004; 101(8):18351842.
525. Meluch AA, Greco FA, Burris HA, et al: Paclitaxel and gemcitabine chemotherapy for advanced
transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research
network. J Clin Oncol 2001; 19(12):3018-3024.
526. Albain KS, Nag SM, Calderillo-Ruiz G, et al: Gemcitabine plus Paclitaxel versus Paclitaxel
monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol
2008; 26(24):3950-3957.
527. Noda K, Nishiwaki Y, Kawahara M, et al: Irinotecan plus cisplatin compared with etoposide plus
cisplatin for extensive small-cell lung cancer. N Engl J Med 2002; 346(2):85-91.
528. Thomas ES, Gomez HL, Li RK, et al: Ixabepilone plus capecitabine for metastatic breast cancer
progressing after anthracycline and taxane treatment. J Clin Oncol 2007; 25(33):5210-5217.
529. Geyer CE, Forster J, Lindquist D, et al: Lapatinib plus Capecitabine for HER2-Positive Advanced
Breast Cancer. N Engl J Med 2006; 355(26):2733-2743.
530. Buzdar AU, Valero V, Ibrahim NK, et al: Neoadjuvant therapy with paclitaxel followed by 5fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human
epidermal growth factor receptor 2-positive operable breast cancer: an update of the initial
randomized study population and data of additional patients treated with the same regimen. Clin
Cancer Res 2007; 13(1):228-233.
25/10/12

531. Skinner DG, Daniels JR, Russell CA, et al: The role of adjuvant chemotherapy following
cystectomy for invasive bladder cancer: a prospective comparative trial. J Urol 1991; 145(3):459-464.
532. Strauss GM, Herndon JE, Maddaus MA, et al: Adjuvant paclitaxel plus carboplatin compared with
observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group
B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J
Clin Oncol 2008; 26(31):5043-5051.
533. Kelly K, Crowley J, Bunn PA, et al: Randomized phase III trial of paclitaxel plus carboplatin
versus vinorelbine plus cisplatin in the treatment of patients with advanced non--small-cell lung
cancer: a Southwest Oncology Group trial. J Clin Oncol 2001; 19(13):3210-3218.
534. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody
against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;
344(11):783-792.
535. Hanna N, Neubauer M, Yiannoutsos C, et al: Phase III study of cisplatin, etoposide, and
concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage
III non-small-cell lung cancer: the Hoosier Oncology Group and U.S. Oncology. J Clin Oncol 2008;
26(35):5755-5760.
536. Kewalramani T , Zelenetz AD , Nimer SD , et al: Rituximab and ICE as second-line therapy
before autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell
lymphoma. Blood 2004; 103(10):3684-3688.
537. Martin M, Pienkowski T, Mackey J, et al: Adjuvant docetaxel for node-positive breast cancer. N
Engl J Med 2005; 352(22):2302-2313.
538. Jones SE, Savin MA, Holmes FA, et al: Phase III trial comparing doxorubicin plus
cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast
cancer. J Clin Oncol 2006; 24(34):5381-5387.
310/317
25/10/12

539. Perez EA: Carboplatin in combination therapy for metastatic breast cancer. Oncologist 2004;
9(5):518-527.
540. Robert N, Leyland-Jones B, Asmar L, et al: Randomized phase III study of trastuzumab,
paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2overexpressing metastatic breast cancer. J Clin Oncol 2006; 24(18):2786-2792.
541. Burstein HJ, Kuter I, Campos SM, et al: Clinical activity of trastuzumab and vinorelbine in women
with HER2-overexpressing metastatic breast cancer. J Clin Oncol 2001; 19(10):2722-2730.
542. Diaz-Rubio E, Tabernero J, Gomez-Espana A, et al: Phase III study of capecitabine plus
oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in
metastatic colorectal cancer: final report of the Spanish Cooperative Group for the Treatment of
Digestive Tumors Trial. J Clin Oncol 2007; 25(27):4224-4230.
543. Buzdar AU, Ibrahim NK, Francis D, et al: Significantly higher pathologic complete remission rate
after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a
randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin
Oncol 2005; 23(16):3676-3685.
544. Urba SG, Forastiere AA, Wolf GT, et al: Intensive induction chemotherapy and radiation for organ
preservation in patients with advanced resectable head and neck carcinoma. J Clin Oncol 1994;
12:946-953.
545. Morris M, Eifel PJ, Lu J, et al: Pelvic radiation with concurrent chemotherapy compared with
pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 1999; 340:1137-1143.
546. Cooper JS, Guo MD, Herskovic A, et al: Chemoradiotherapy of locally advanced esophageal
cancer. JAMA 1999; 281(17):1623-1627.
547. Rose PG, Bundy BN, Watkins EB et al: Concurrent cisplatin-based radiotherapy and
chemotherapy for locally advanced cervical cancer. N Engl J Med 1999; 1144-1153, 1999.
548. Hohneker JA: Clinical development of eniluracil: current status. Oncology 1998; 12(10):52-56.
549. Product Information: FLUOROPLEX(R) topical cream, fluorouracil 1% topical cream. Allergan,
311/317
Inc, Irvine, CA, 2004.

550. Baselt RC & Cravey RH: Disposition of Toxic Drugs and Chemicals in Man, 3rd ed, Year Book
Medical Publishers, Chicago, IL, 1989.
551. Allen LV & Stiles ML: Compatibility of various admixtures with secondary additives at Y-injection
sites of intravenous administration sets. Part 2. Am J Hosp Pharm 1981; 38:380-381.
552. Trissel LA, Martinez JF, & Xu QA: Incompatibility of fluorouracil with leucovorin calcium or
levoleucovorin calcium. Am J Health Syst Pharm 1995; 52:710-715.
553. Personal Communication: Kim M Murray, PharmD, Senior Professional Services Associate.
Immunex Corp, Seattle, WA, February, 1996.
554. McRae MP & King JC: Compatibility of antineoplastic, antibiotic and corticosteroid drugs in
intravenous admixtures. Am J Hosp Pharm 1976; 33:1010-1013.
555. Trissel LA: Handbook on Injectable Drugs, 5th. American Society of Hospital Pharmacists,
Bethesda, MD, 1988.
556. Brammer MK, Chan P, Heatherly K, et al: Compatibility of doripenem with other drugs during
simulated Y-site administration. Am J Health Syst Pharm 2008; 65(13):1261-1265.
557. Cohen MH, Johnston-Early A, Hood MA, et al: Drug precipitation within IV tubing: a potential
hazard of chemotherapy administration. Cancer Treat Rep 1985; 69(11):1325-1326.
Bethesda, MD, 1988.
559. King JC: 5-Fluorouracil and methotrexate sodium: an admixture incompatibility?. Am J Hosp
Pharm 1978; 35:18.
560. Vyas HM, Baptista RJ, Mitrano FP, et al: Drug stability guidelines for a continuous infusion
chemotherapy program. Hosp Pharm 1987; 22(7):685-687.
561. Wang DP, Chang LC, & Lee DKT: Stability of fluorouracil-metoclopramide hydrochloride
admixture. Am J Health Syst Pharm 1995; 52:98-99.
hazard of chemotherapy administration. Cancer Treat Rep 1985; 69:1325-1326.
563. Trissel LA, Williams KY, & Gilbert DL: Compatibility screening of linezolid injection during
simulated Y-site administration with other drugs and infusion solutions. J Am Pharm Assoc (Wash)
2000; 40(4):515-519.
312/317
25/10/12
564. Dorr RT, Peng YM, & Alberts DS: Bleomycin compatibility with selected intravenous medications.
J Med 1982; 13:121-130.
566. Xu QA, Trissel LA, & Martinez JF: Stability and compatibility of fluorouracil with morphine sulfate
and hydromorphone hydrochloride. Ann Pharmacother 1996; 30:756-761.
567. Trissel LA, Gilbert DL, & Martinez JF: Compatibility of propofol injectable emulsion with selected
drugs during simulated Y-site administration. Am J Health-Syst Pharm 1997; 54:1287-1292.
570. Vyas HM, Baptista RJ, Mitrano FP, et al: Drug stability guidelines for a continuous infusion
chemotherapy program. Hosp Pharm 1987; 22(7):685-687.
hazard of chemotherapy administration. Cancer Treat Rep 1985; 69(11):1325-1326.
572. Woloschuk DM, Wermeling JR, & Pruemer JM: Stability and compatibility of fluorouracil and
mannitol during simulated Y-site administration. Am J Hosp Pharm 1991; 48:2158-2160.
573. Trissel LA, Martinez JF, & Xu QA: Incompatibility of fluorouracil with leucovorin calcium or
levoleucovorin calcium. Am J Health Syst Pharm 1995; 52:710-715.
574. Xu QA, Trissel LA, & Martinez JF: Stability and compatibility of fluorouracil with morphine sulfate
and hydromorphone hydrochloride. Ann Pharmacother 1996; 30:756-761.
575. Trissel LA & Martinez JF: Visual, turbidimetric, and particle-content assessment of compatibility
of vinorelbine tartrate with selected drugs during simulated Y-site injection. Am J Hosp Pharm 1994;
51:495-499.
577. Lober CA & Dollard PA: Visual compatibility of gallium nitrate with selected drugs during
simulated Y-site injection. Am J Hosp Pharm 1993; 50:1208-1210.
578. Trissel LA & Martinez JF: Compatibility of piperacillin sodium plus tazobactam with selected
drugs during simulated Y-site injection. Am J Hosp Pharm 1994; 51:672-678.
579. Salamone FR & Muller RJ: Intravenous admixture compatibility of cancer chemotherapeutic
agents. Hosp Pharm 1990; 25:567-570.
313/317
25/10/12

sites of intravenous administration sets: Part 2. Am J Hosp Pharm 1981; 38:380-381.
Bethesda, MD, 1988.
585. Personal Communication: Kim M Murray, PharmD, Senior Professional Services Associate.
Immunex Corp, Seattle, WA, February, 1996.
589. Trissel LA, Tramonte SM, & Grilley BJ: Visual compatibility of ondansetron hydrochloride with
selected drugs during simulated Y-site injection. Am J Hosp Pharm 1991b; 48:988-992.
590. Product Information: Zofran(R), ondansetron. Glaxo Inc, Research Triangle Park, NC, 1996.
591. Trissel LA & Bready BB: Turbidimetric assessment of the compatibility of taxol with selected
other drugs during simulated Y-site injection. Am J Hosp Pharm 1992; 49:1716-1719.
592. Product Information: ELOXATIN(R) intravenous injection, oxaliplatin intravenous injection.
Sanofi-Aventis U.S. LLC, Bridgewater, NJ, 2008.
593. Product Information: Platinol(R)/Platinol-AQ(R), cisplatin. Bristol-Myers Oncology Division,
Evansville, IN, 1990.
594. Stewart CF & Fleming RA: Compatibility of cisplatin and fluorouracil in 0.9% sodium chloride
injection. Am J Hosp Pharm 1990; 47:1373-1377.
314/317
25/10/12
597. Trissel LA & Martinez JF: Compatibility of amifostine with selected drugs during simulated Y-site
administration. Am J Health Syst Pharm 1995; 52:2208-2212.
598. McRae MP & King JC: Compatibility of antineoplastic, antibiotic, and corticosteroid drugs in
599. Product Information: Zofran(R), ondansetron. Glaxo Inc, Research Triangle Park, NC, 1999.
600. Leak RE & Woodford JD: Pharmaceutical development of ondansetron injection. Eur J Cancer Clin
Oncol 1989; 25(suppl 1):S67-S69.
601. Salamone FR & Muller RJ: Intravenous admixture compatibility of cancer chemotherapeutic
602. Trissel LA & Martinez JF: Compatibility of filgrastim with selected drugs during simulated Y-site
administration. Am J Hosp Pharm 1994; 51:1907-1913.
603. Ogawa GS, Young R, & Munar M: Dispensing-pin problems (letter). Am J Hosp Pharm 1985;
42:1042-1043.
604. Trissel LA & Martinez JF: Compatibility of allopurinol sodium with selected drugs during
simulated Y-site administration. Am J Hosp Pharm 1994; 51:1792-1799.
606. McRae MP & King JC: Compatibility of antineoplastic, antibiotic, and corticosteroid drugs in
607. Trissel LA, Bready BB, Kwan JW, et al: Visual compatibility of sargramostim with selected
antineoplastic agents, anti-infectives, or other drugs during simulated Y-site injection. Am J Hosp
Pharm 1992; 49:402-406.
609. Horton JK & Stevens MFG: Search for drug interactions between the antitumor agent DTIC and
other cytotoxic agents. J Pharm Pharmacol 1979; 31(suppl):64P.
610. Horton JK & Stevens MFG: Search for drug interactions between the antitumor agent DTIC and
other cytotoxic agents. J Pharm Pharmacol 1979; 31(suppl):64P.
611. Trissel LA, Parks NPT, & Santiago NM: Visual compatibility of fludarabine phosphate with
antineoplastic drugs, anti-infectives, and other selected drugs during simulated Y-site injection. Am J
315/317
25/10/12
Hosp Pharm 1991a; 48:2186-2189.

612. Trissel LA & Martinez JF: Compatibility of aztreonam with selected drugs during simulated Y-site
administration. Am J Health Syst Pharm 1995; 52:1086-1090.
613. Mayron D & Gennaro AR: Stability and compatibility of granisetron hydrochloride in iv solutions
and oral liquids and during simulated Y-site injection with selected drugs. Am J Health Syst Pharm
1996; 53:294-304.
614. Benvenuto JA, Anderson RW, Kerkof K, et al: Stability and compatibility of antitumor agents in
glass and plastic containers. Am J Hosp Pharm 1981; 38:1914-1918.
615. Biondi L & Nairn JG: Stability of 5-fluorouracil and flucytosine in parenteral solutions. Can J Hosp
Pharm 1986; 39:60-66.
Bethesda, MD, 1990.
617. Athanikar N, Boyer B, Deamer R, et al: Visual compatibility of 30 additives with a parenteral
nutrient solution. Am J Hosp Pharm 1979; 36:511-513.
618. Hardin TC, Clibon U, Page CP, et al: Compatibility of 5-fluorouracil and total parenteral nutrition
solutions. J Parenter Enteral Nutr 1982; 6:163-165.
Bethesda, MD, 1988.
620. Trissel LA, Gilbert DL, Martinez JF, et al: Compatibility of parenteral nutrition solutions with
selected drugs during simulated Y-site administration. Am J Health Syst Pharm 1997; 54:1295-1300.
Bethesda, MD, 1990.
622. US Food and Drug Administration: Potential signals of serious risks/new safety information
identified by the Adverse Event Reporting System (AERS) January - March 2008. US Food and Drug
Administration. Rockville, MD. 2008. Available from URL:
http://www.fda.gov/Cder/aers/potential_signals/potential_signals_2008Q1.htm.
DEFINITIONS
Strength of Recommendation
Class I - Recommended
The given test or treatment has been proven to be useful, and should be performed or administered.
Class IIa - Recommended, In Most Cases
316/317
25/10/12
The given test, or treatment is generally considered to be useful, and is indicated in most cases.
Class IIb - Recommended, In Some Cases
The given test, or treatment may be useful, and is indicated in some, but not most, cases.
Class III - Not Recommended
The given test, or treatment is not useful, and should be avoided.
Class Indeterminate - Evidence Inconclusive
Strength of Evidence
Category A
Category A evidence is based on data derived from: Meta-analyses of randomized controlled trials
with homogeneity with regard to the directions and degrees of results between individual studies.
Multiple, well-done randomized clinical trials involving large numbers of patients.
Category B
Category B evidence is based on data derived from: Meta-analyses of randomized controlled trials
with conflicting conclusions with regard to the directions and degrees of results between individual
studies. Randomized controlled trials that involved small numbers of patients or had significant
methodological flaws (e.g., bias, drop-out rate, flawed analysis, etc.). Nonrandomized studies (e.g.,
cohort studies, case-control studies, observational studies).
Category C
Category C evidence is based on data derived from: Expert opinion or consensus, case reports or
case series.
No Evidence
Last Modified: August 24, 2012
COPYRIGHT 1974-2012 Thomson Reuters. All rights reserved.
317/317

5 - Fluorouracilo Ficha Tecnica

Загружено:

Сведения о документе

Оригинальное название

Авторское право

Доступные форматы

Поделиться этим документом

Поделиться или встроить документ

Параметры публикации

Этот документ был вам полезен?

Это неприемлемый материал?

Авторское право:

Доступные форматы

5 - Fluorouracilo Ficha Tecnica

Загружено:

Авторское право:

Доступные форматы

25/10/12

dose 1 g/week [1]

Drug details - MICROMEDEX 2.0

Drug details - MICROMEDEX 2.0

4) Colorectal cancer, Palliative

Storage and Stability

Drug details - MICROMEDEX 2.0

a) Dilution is not required before fluorouracil IV administration [203].

Drug details - MICROMEDEX 2.0

Drug details - MICROMEDEX 2.0

Drug details - MICROMEDEX 2.0

b) Maintenance therapy may be considered in patients tolerating fluorouracil

mg/m(2) = milligrams/square meter

Drug details - MICROMEDEX 2.0

2) In the clinical trial, granulocyte-colony stimulating factor (G-CSF) was

Drug details - MICROMEDEX 2.0

Oral and intravenous administration of fluorouracil 15 milligrams/kilogram/week was

Drug details - MICROMEDEX 2.0

obese patients with appropriate dosing; however, comorbidities must be considered.

Drug details - MICROMEDEX 2.0

2) Colorectal cancer, mean steady state concentration (Css): 94 ng/mL [380].

Cmax value for the fluorouracil 370

Drug details - MICROMEDEX 2.0

Drug details - MICROMEDEX 2.0

B) Total Body Clearance

Drug details - MICROMEDEX 2.0

Drug details - MICROMEDEX 2.0

however, transthoracic echocardiography showed an abnormal left ventricle with

Drug details - MICROMEDEX 2.0

with an ejection fraction of 7%; hemodynamic parameters also indicated cardiogenic

Drug details - MICROMEDEX 2.0

Drug details - MICROMEDEX 2.0

Drug details - MICROMEDEX 2.0

x-ray revealed pulmonary edema. ST elevations and ANTEROLATERAL ISCHEMIA

of neutropenia and hand-foot

Drug details - MICROMEDEX 2.0

Drug details - MICROMEDEX 2.0

1) A case of malignant hypercalcemia was reported in a 36-year-old female with

Drug details - MICROMEDEX 2.0

ANOREXIA and DIARRHEA

Drug details - MICROMEDEX 2.0

ESOPHAGOPHARYNGITIS, NAUSEA, VOMITING, ANOREXIA and DIARRHEA

toxicity included a poor

Drug details - MICROMEDEX 2.0

Drug details - MICROMEDEX 2.0

observed from 4 to 20 days after starting therapy [271].

Drug details - MICROMEDEX 2.0

receiving fluorouracil as a one-hour infusion. Nine (41%) patients receiving fluorouracil

Drug details - MICROMEDEX 2.0

6) In patients with dihydropyrimidine dehydrogenase (DPD) enzyme deficiency

Drug details - MICROMEDEX 2.0

disease in this patient is unclear [274].

Drug details - MICROMEDEX 2.0

Dexamethasone 16 milligrams/day for 28 days then tapered off led to improvement.

Drug details - MICROMEDEX 2.0

Drug details - MICROMEDEX 2.0

Drug details - MICROMEDEX 2.0

Drug details - MICROMEDEX 2.0

5) Postoperative subconjunctival injections of fluorouracil (5-FU) following

Drug details - MICROMEDEX 2.0

1) A case of noninfectious crystalline keratopathy is described in a 69-year-old female

by hepatic infusion for 3 weeks.

Drug details - MICROMEDEX 2.0