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391
GYNECOLOGY FOR LESS-RESOURCED LOCATIONS
can also occur many months or even years after cisplatin alone given at a dose of 30 mg/m2 weekly
radiotherapy. during the administration of external beam radio-
therapy is the best option in low-resource settings.
The dosage of cisplatin is low, has minimal toxicity
Radiotherapy and chemo-radiation in cervical
and acts as a radiation sensitizer.
cancer
Early cervical cancer (stage I to IIA) may be treated Adjuvant postoperative radiotherapy
by surgery or radiotherapy with equivalent results
Adjuvant postoperative radiotherapy is indicated
although the complication rate may be higher with
following radical hysterectomy and pelvic node
radiotherapy (level of evidence 1)1. When surgery
dissection when there are positive pelvic nodes, the
for cervical cancer is not available, the patient
resection margins are close or positive and when
should be treated with radiotherapy.
there is evidence of microscopic parametrial spread.
Adjuvant pelvic chemo-radiation has shown a
Radical radiotherapy
survival benefit versus radiotherapy alone in this
Radical radiotherapy for cervical cancer is given by situation1,6,7.
both external beam radiotherapy and brachy- Patients found to have invasive cancer more
therapy. The target for the external beam radio- than stage IA1 after a simple hysterectomy for pre-
therapy in cervical cancer is the primary tumor sumed benign disease should be given postopera-
and pelvic nodes. A dose of 45–50.4 Gy is usually tive radiation therapy. In this situation pelvic
given over 25–28 fractions. Brachytherapy on the radiation alone in an increased dose of 48–51Gy
other hand involves giving high doses of radiation should be given. Chemotherapy is used con-
directly to the tumor using radioactive sources currently as in the previously described protocol.
such as Caesium137, Cobalt60 or Iridium192 either by
manual or remote after-loading techniques (i.e. Endometrial cancer
by introducing a device loaded with radioactive
The primary modality of treatment for endometrial
material into the vagina near the tumor).
cancer is surgery. Low-risk patients are those who
are stage IA grade 1 and 2 endometrioid adeno-
Combined chemo-radiation
carcinoma. These patients are at low risk of recur-
This has been shown to have superior survival rates rence and do not need adjuvant radiotherapy.
when compared with radiotherapy alone and is Intermediate-risk patients are those patients
currently the standard treatment for cancer of the with disease confined to the uterus but with risk
cervix bulky stage IB disease to stage IVA (level of factors of recurrence. These risk factors include
evidence 1)2–6. Thirty to fifty per cent improve- increased age, lymphovascular space invasion,
ments in response and survival rates have been moderate to poor differentiation and deep myo-
observed with this modality when compared to metrial invasion (see Table 3 in Chapter 29). Adju-
radiotherapy alone in randomized trials. Combined vant treatment for this group of patients remains
chemo-radiation is not difficult to administer pro- controversial. The preponderance of data suggests
vided there are adequate trained personnel to assess that external beam radiotherapy does not improve
and monitor patients, administer chemotherapy overall survival but provides a small improvement
according to the predetermined schedule as well as in local control. Vaginal brachytherapy appears
to treat the patient with radiotherapy. Every effort equally effective, with an improved quality of life
should be made to incorporate this modality of compared to external beam radiotherapy in the
treatment wherever possible because of the superior high-intermediate-risk group8.
survival rates. The side-effects of concurrent High-risk patients are those with papillary serous
chemo-radiation are usually not severe and easily and clear-cell histology and risk factors from the
managed in most situations. intermediate group (myometrial invasion >50%,
Prior to combined chemo-radiation, all patients stromal invasion of the cervix, lymphovascular
should have a normal blood count and normal renal space involvement) as well as those with advanced-
function. Although there are a number of options as stage disease (see Table 3 in Chapter 29). Radio-
far as the chemotherapeutic agents are concerned, therapy is recommended in this group of patients
392
Basic Oncology including Treatment in Less-resourced Locations
393
GYNECOLOGY FOR LESS-RESOURCED LOCATIONS
need chest wall irradiation after successful mastec- resourced settings application of 4% formalin has
tomy and regional lymph node irradiation depend- been found to be effective. The options that have
ing on intraoperative findings. Those who still been described are instilling four separate 20 cc
cannot be operated on after neoadjuvant systemic aliquots into the rectum with total mucosal contact
therapy should receive chest wall irradiation includ- of 20 min or performing a rigid sigmoidoscopy and
ing axillary and supraclavicular lymph nodes. applying a gauze soaked in 4% formalin in contact
with the mucosa for 4 min, repeating the procedure
Side-effects of radiotherapy until the bleeding stops9.
Patients with significant per rectal bleeding
Minor side-effects of radiotherapy are skin changes
should undergo endoscopic evaluation of the recto-
and fatigue. Anemia is an important cause of fatigue
sigmoid and descending colon to exclude other
and should be treated. Depression can exacerbate
causes of bleeding such as arterial venous malfor-
feelings of fatigue. Side-effects can occur during
mations, inflammatory bowel disease and malig-
radiation for pelvic malignancies due to the effects
nancy. A specific bleeding point if identified, can
of radiotherapy on the organs close to the areas
be coagulated.
being irradiated, namely colon and rectum (radia-
Rare complications of radiotherapy include sig-
tion proctitis), bladder (radiation cystitis) and small
moid stricture and vesico-vaginal or recto-vaginal
bowel (radiation enteritis). Lymphedema of the
fistulae. Patients with rectosigmoid stricture present
breast and arm, as well as lung and heart side-effects
with progressive bouts of constipation and in later
(radiation pneumonitis and fibrosis, dilatative
stages with abdominal pain, distention and vomit-
cardiomyopathy) can occur with radiation for
ing. When conservative measures fail, surgery is
breast cancer. Radiation-induced side-effects may
necessary.
be immediate, occurring during the treatment, or
Recto-vaginal fistulae presents with foul smelling
delayed, occurring months or even years later.
discharge or feces being discharged per vagina. The
surgical management of these complications requires
Managing side-effects of radiotherapy
considerable surgical judgment and an experienced
The most common side-effect encountered in surgeon should be involved in the assessment and
radiotherapy for genital cancers is due to radiation treatment of these problems as operating on irradia-
to the rectum and sigmoid colon. Patients present ted bowel is fraught with potential complications.
with symptoms of proctitis including bleeding per Radiation-induced small bowel damage is more
rectum and diarrhea. Most patients have mild symp- difficult to diagnose and manage. Patients may
toms that can be treated with simple measures. present with moderate to severe bowel symptoms,
Patients with diarrhea should be adequately and small bowel obstruction may sometimes occur.
hydrated by drinking at least 8–12 cups of clear The initial management will involve intravenous
fluids per day. Eating five to six small meals rather hydration and correction of electrolyte imbalance.
than three large meals is helpful. Foods that are low Nasogastric suction is useful in patients with nausea
in fiber, fat and lactose are recommended. Patients and vomiting and dilated small bowel loops. Con-
are also advised to avoid oily food, milk and dairy servative management may result in improvement
products and foods that cause production of gas like and resolution of partial obstruction in some
beans. patients. Good surgical judgment is important
Repeated episodes of diarrhea can cause irrita- when surgical intervention is contemplated and the
tion to the skin around the anal area. Toilet paper is treating surgeon must be experienced in managing
not recommended. Instead, squirting water after these problems.
bowel movements is advised to clean the anal area. Patients with radiation cystitis may present with
Warm water-sitting baths are soothing. Medication frequency, dysuria, hematuria and suprapubic pain.
that can be prescribed for diarrhea include diocta- The incidence has been reported as approximately
hedral smectite (Smecta®) 3 g 6-hourly or lopera- 6% with the majority of patients having minor
mide (Imodium®) daily or as necessary. symptoms. Most patients with minor degrees of
Rectal bleeding due to radiation proctitis can be hematuria resolve with antibiotics. Persistent hema-
treated with hydrocortisone enema 100 mg/60 ml turia will require cystoscopy to exclude recurrent
once to twice daily until the bleeding stops. In less- cancer or a second primary tumor. Severe bleeding
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Basic Oncology including Treatment in Less-resourced Locations
and the passage of clots will require insertion of a close attention to managing fluid balance and
large 3-way Foley’s catheter and performing con- electrolyte imbalances is important in this situation.
tinuous bladder irrigation. Monitoring the inflow The most frequent side-effects of radiotherapy
and outflow of infused fluids and maintaining in breast cancer are skin changes (i.e. redness, swell-
drainage is important as there are risks of bladder ing, which is called radiodermatitis or ulcera).
distention and rupture. When this occurs, it is important to instruct the
Rarely, hematuria does not respond to bladder patient to keep the area of radiation dry at all times.
irrigation and other measures may need to be con- Local measures for radiodermatitis include applica-
sidered. A 1% solution of Alum (50 g potassium tion of dexpanthenol ointment. If symptoms are
aluminum sulfate in 5 liters of distilled water) to severe, radiation might have to be temporarily
run intravesically at 3–5 ml/min and increasing to a stopped until radiodermatitis subsides. Lymph-
maximum of 10 ml/min if the returning fluid from edema of the breast and arm may cease on its own
the bladder is not clear is an option. The irrigation after 6–12 months, otherwise physiotherapy (i.e.
must be continued for 6 h after the bleeding has lymphatic drainage) might be needed. The patient
stopped. herself or a female family member can be taught
Formalin is effective in stopping intractable how to do that regularly.
hematuria but should only be used as a last resort as Other complications are more severe, but fortu-
there is a risk of complications including bladder nately rare, such as cardiomyopathy or pulmonary
contracture, ureteral fibrosis and delayed fistula fibrosis. Patients with chest wall irradiation, how-
formation. Ureteral reflux and bladder perforation ever, experience a higher rate of these complications.
must be excluded by cystogram prior to using
formalin. A 4% solution is used and the bladder is
CHEMOTHERAPY
filled to capacity for 23 min. As the procedure is
painful it should be conducted under general Cancer is characterized by unregulated growth.
anesthesia. This unregulated growth is caused by the loss of
Patients with cervical cancer and parametrial two cell control mechanisms that occur in normal
involvement may present with hydronephrosis and cells. Firstly, there is a loss of the normal cell cycle
sometimes complete obstruction and anuria due to regulation control and secondly there is failure of
blockage of the ureters by parametrial tumor exten- normal programmed cell death (apoptosis).
sion. Sometimes patients with a partially obstructed It is useful to have an understanding of the nor-
ureter may develop complete obstruction with the mal cell cycle. There are four phases as described
initiation of radiotherapy, as the radiotherapy can below (Figure 1).
cause tissue edema that completely blocks off
1. M-phase Chromosome division occurs (mito-
partially obstructed ureters.
sis) yielding two daughter cells.
In patients with hydronephrosis, the ideal
2. G-1 phase Specialized functions of cell types are
management is cystoscopy and stenting of the
fulfilled and the cell’s machinery is prepared for
ureters by a urologist or surgeon with the necessary
DNA synthesis. Cellular activities, protein and
experience. Ureteric stents can be expensive and
RNA synthesis and DNA repair occur in prep-
the necessary trained personnel to perform these
aration for cell division; G-1 cells can terminally
procedures are not always available. An alternative
differentiate into G-0 (non-cycling cells) or re-enter
is to perform a nephrostomy and drain the urine
the cell cycle after a period of quiescence.
percutaneously under ultrasound guidance. This
3. S-phase New DNA is synthesized (replication
procedure can salvage existing renal function while
of existing strand).
radiotherapy is initiated. If possible a retrograde
4. G-2 period A short phase when the cell’s
stenting of the ureter should be carried out with
nucleus is being organized for mitosis. The cell
radiological assistance at some stage later.
contains haploid number of chromosomes and
Sometimes radiotherapy will cause obstructed
twice the DNA of a normal cell; RNA and
ureters to ‘open up’ due to shrinkage of tumors.
protein are synthesized.
When this happens after complete obstruction, the
patient may go into a state of diuresis for many Normal and cancer cells are sensitive to chemo-
days. Intravenous hydration will be necessary and therapy during the active cell cycling period and
395
GYNECOLOGY FOR LESS-RESOURCED LOCATIONS
396
Basic Oncology including Treatment in Less-resourced Locations
commonly used chemotherapeutic agents used in Table 1 Dose adjustment for carboplatin–paclitaxel in
gynecological cancer. Toxicities may be classified leukopenia and thrombopenia (count at nadir)
according to the common toxicity criteria (CTC) Platelets WBC count
scale by the World Health Organization (WHO).
9
Specific conditions and symptoms may include bio- >2.5 × 10 <2.5 × 109
chemical laboratory values or descriptive comments ≥75 × 109/l 100% starting dose Delay 1 week and
for each level, but the general classification is: reduce AUC of
1. Mild carboplatin to 4, 75%
2. Moderate of paclitaxel dosage
<75 × 109/l Delay 1 week then Delay 1 week then
3. Severe
reduce AUC to 4, reduce AUC to 4,
4. Life-threatening paclitaxel 100% 75% of paclitaxel
5. Death. dosage
Further details can be obtained at: http://evs.nci.
nih.gov/ftp1/CTCAE/About.html WBC, white blood cell; AUC, area under the curve
397
GYNECOLOGY FOR LESS-RESOURCED LOCATIONS
398
Basic Oncology including Treatment in Less-resourced Locations
Table 4 Regimen with mesna and intravenous fluids to decrease the risk of hemorrhagic cystitis
399
GYNECOLOGY FOR LESS-RESOURCED LOCATIONS
Mucositis Hypersensitivity
Mucositis can occur with methotrexate, 5-fluoro- Hypersensitivity can occur with a number of
uracil, dactinomycin, doxorubicin, mitomycin C chemotherapeutic drugs like etoposide, cisplatin,
and vincristine. The onset of mucositis is 5–7 days carboplatin, doxorubicin, cyclophosphamide/
following administration and will usually resolve ifosfamide, melphalan, methotrexate, paclitaxel,
spontaneously within 2–3 weeks. Good oral 5-fluorouracil and bleomycin. Most patients will
hygiene is important. present with wheezing or rash. Rarely, serious
complications like angio-edema and hypotension
can occur. Hypersensitivity is treated by discon-
Extravasation
tinuing treatment at once, maintaining an IV line
Extravasation is a serious complication of a number with intravenous normal saline, antihistamines,
of chemotherapeutic agents. Skin necrosis can corticosteroids, vasopressors and bronchodilators.
occur with some drugs like doxorubicin, actino- The drug with the highest incidence of hyper-
mycin D, mitomycin C, etoposide and vincristine sensitivity is paclitaxel. It is now possible to greatly
when extravasation occurs. decrease the incidence of hypersensitivity to pacli-
Prevention is obviously best, and can be ensured taxel with prophylactic treatment with dexa-
by a number of simple measures. Firstly, choose methasone, diphenhydramine (antihistamine) and
large distal veins in the forearm, avoiding veins in cimetidine or ranitidine before administration of
the joints and antecubital fossa as well as veins in the drug.
which there has been access or attempted access Paclitaxel is often used together with carboplatin
in the preceding 24 h. Secondly, ensure that the as adjuvant treatment of ovarian cancer as well as
intravenous line is free flowing. Prior to adminis- some other gynecological cancers. The schedule
tering the chemotherapeutic drug, the IV lines below describes how this drug combination is
should be flushed slowly with 100 ml of normal administered with adequate pre-medication to
saline. Initial administration of the chemotherapeu- decrease paclitaxel hypersensitivity:
tic drug should be slow, at 1–2 cc per min paying
Carboplatin/paclitaxel regimen for epithelial ovarian cancer
attention to the patient’s complaints at the same
1. Dexamethasone 20 mg IV in 100 cc normal
time. While administering chemotherapy, the drip
saline (N/S) over 15 min
site must be continually monitored for redness,
2. Phenergan 12.5 mg IV over 30 min in N/S
swelling or leakage.
3. Ranitidine 50 mg slow bolus
When extravasation occurs, the chemothera-
4. Granisetron 3 mg IV bolus
peutic drug must be stopped at once. There are
5. Paclitaxel in 100 ml N/S to run over 3 h
specific antidotes for some drugs. For doxorubicin
175 mg/m2
extravasation, dilute hydrocortisone 100 mg per ml
6. Carboplatin in 500 ml N/S AUC of 5 to run
with 5 ml of saline and inject 1–2 ml through the
over 60 min
IV line and inject the remaining solution into the
extravasation site via 2 or 3 injections. Apply cold When hypersensitivity to a drug occurs, it is best
compress. not to use the same drug again. There are certain
For dactinomycin extravasation, prepare a solu- situations, however, where the drug in question
tion of sodium thiosulfate by mixing 4 ml of 10% may be the best option for an individual patient,
sodium thiosulfate with 6 ml of sterile water for in- due to reasons like a good response to treatment
jection. Inject 6 ml through the existing IV line and with that particular drug or lack of other good
inject 2 ml subcutaneously via multiple injections. alternatives. When this occurs, a careful assessment
The subcutaneous injection can be repeated hourly must be carried out of the benefits of the particular
over the next few hours. Apply cold compress. treatment causing hypersensitivity versus the risk of
For vincristine and etoposide extravasation, the hypersensitivity reaction. If it is felt that the drug
antidote is hyaluronidase; 1–6 ml of a 150 U/cc that has caused hypersensitivity is still the best
solution is injected subcutaneously via multiple option, desensitization may be carried out by
injections, repeating hourly over the next few administering SoluMedrol 100 mg IV every 6 h for
hours. A warm compress is advised in this situation. 24 h prior to paclitaxel administration.
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Basic Oncology including Treatment in Less-resourced Locations
401
GYNECOLOGY FOR LESS-RESOURCED LOCATIONS
chemotherapy with carboplatin and diagnosis of The best option in this situation is six courses of
recurrence. Patients should not be treated based on paclitaxel and carboplatin. If paclitaxel is not avail-
raised CA-125 alone in the absence of clinical or able, then carboplatin alone can be used. A dose
radiological evidence of recurrence. reduction of 80% of the calculated dose is used
If the platinum-free interval is ≤6 months, the when these patients are treated with second-line
patient is considered platinum resistant and the chemotherapy.
prognosis is poor. Patients are treated with single-
agent chemotherapy. There are a number of options Germ cell tumors
of chemotherapeutic agents available to treat patients
Germ cell tumors are generally chemosensi-
in this setting. Unfortunately, many of the drugs
tive. FIGO stage IA dysgerminoma and FIGO
used in this situation are expensive. In the low-
stage IA immature teratoma grade 1 do not need
resource setting, one of the options for platinum-
chemotherapy after surgery. All other germ cell
resistant disease is oral etoposide 50 mg twice a day
tumor histological types and stages will need
for 7 days every 21 days, increasing to 10 days and
chemotherapy.
then 14 days if toxicities are manageable10. The like-
The standard treatment is the BEP regimen14,15
lihood of response is in the region of 20–25%.
(bleomycin 30 units per week, etoposide 100 mg/
Another option is weekly paclitaxel at 80 mg/m2,
m2/day for days 1–5, cisplatin 20 mg/m2/day for
giving good palliation with manageable toxicity.
days 1–5 for 3–4 cycles. It is a toxic regimen. Blood
In platinum-sensitive disease, there is a direct
parameters need to be monitored closely and many
relationship between the duration of the platinum-
patients will need dose reduction. See Appendix 4
free interval and the response to further treatment,
of Chapter 28.
with a better response with longer platinum-
free interval. In platinum-sensitive disease (with
Sex cord stromal tumors
platinum-free interval ≥12 months), patients must
be carefully assessed clinically as well as radiologic- Adjuvant chemotherapy may be considered for
ally by CT scans. Selected patients may benefit high-risk stage I patients (stage IC, poorly differen-
with repeat surgery, a surgical procedure called tiated, heterologous elements as well as those with
secondary cytoreduction. This procedure will only more advanced disease). Chemotherapy with pacli-
benefit patients if the disease can be completely re- taxel and carboplatin in the standard fashion as des-
sected at surgery, therefore careful selection of suit- cribed previously is the currently preferred option.
able patients is necessary. The surgery should only
be undertaken by surgeons with the necessary Endometrial cancer
experience, expertise and skills. If complete re-
The role of chemotherapy in endometrial cancer is
section of the tumor is not achieved at an attempt
controversial and has been discussed earlier in this
at secondary cytoreduction, the patient will have
chapter as well as in the Chapter 29 on cancer of
the morbidity of the second surgery with no clini-
the uterine corpus. In addition to its role (contro-
cal benefit. There are additional criteria before em-
versial) in adjuvant disease, chemotherapy is also
barking on secondary cytoreductive surgery – the
used in the recurrent setting when metastatic
patient must have been optimally debulked at the
disease is present.
primary surgery, the recurrence should be isolated,
For recurrent disease, the preferred option is
with no evidence of carcinomatosis, and the sur-
paclitaxel/carboplatin administered in the same
geon should be confident that a complete resection
way as in ovarian cancer. When paclitaxel/carbo-
of the recurrent tumor could be achieved.
platin is not available, another option for chemo-
In recurrence of ovarian cancer in platinum-
therapy to consider is doxorubicin 60 mg/m2 plus
sensitive disease, the patient may be retreated with
cisplatin 50 mg/m2 every 3 weeks.
platinum-based chemotherapy. Patients who have
had secondary cytoreduction should receive the
Carcinosarcoma of the uterus
chemotherapy after recovery from the surgery.
Patients who are not candidates for secondary cyto- These are aggressive tumors which have a poor
reductive surgery should receive chemotherapy prognosis in spite of treatment. Following surgery,
when they have signs or symptoms of the recurrence. chemotherapy with paclitaxel and carboplatin is the
402
Basic Oncology including Treatment in Less-resourced Locations
first option to consider. Doxorubicin and ifos- • CMF and AC were equivalent in outcomes (re-
famide with mesna is another regimen that is used currence, mortality) and superior to no chemo-
in sarcomas of the uterus. therapy. They led to a reduction in mortality
rates by 20–25%.
• CEF and CAF had similar outcome rates and
Gestational trophoblastic disease
added an extra 15–20% reduction in mortality
Chemotherapy is very effective in gestational rates.
trophoblastic disease. Further details are given in • Taxanes added to anthracycline-based regimen
Chapter 27. improved outcomes slightly but significantly.
The classical regimen in breast cancer is CMF. It
Breast cancer has relatively few side-effects and the agents are
often available in resource-poor settings. Where
See Chapter 30 for the specific indications for
available anthracycline-based regimens should be
chemotherapy in breast cancer. The aim of treat-
used. Regimens with different dosages of anthra-
ment for patients with stage I–III disease is cure and
cyclines (e.g. FE100C) are used in different settings
they should be treated with combination therapy
but the EBCTCG trial showed no significant
even at the cost of toxicity. Patients with stage IV
difference in outcomes for regimens where only
disease are treated with as little therapy as needed
the anthracycline dose was increased.
since they cannot be cured and the aim of therapy
is solely to improve the quality of life of the patient 4-Weekly CMF 6 cycles
with as few side-effects as possible. Cyclophosphamide 500 mg/m2 IV days 1+8
Newly diagnosed stage I–III breast cancer may Methotrexate 40 mg/m2 IV days 1+8
be treated on an out-patient basis. The gold stan- 5-Fluorouracil 500 mg/m2 IV days 1+8
dard for early breast cancer is a taxane-based regi- 3-Weekly AC or EC 4 cycles
men, which is slightly superior to anthracycline-based Adriamycin 60 mg/m2 IV day 1/epi-
regimens for nodal-positive disease [relative risk rubicin 90 mg /m2 IV day 1
(RR) 0.86 for distant recurrence and 0.87 for mor- Cyclophosphamide 600 mg/m2 IV day 1
tality16] (level of evidence 1a). However, the former
may not be available in many resource-limited 4-Weekly CAF 6 cycles
settings. The Breast Health Global Initiative Cyclophosphamide 100 mg/m2 IV day 1
(BHGI) recommends their use only for areas with Adriamycin 30 mg/m2 IV day 1
an enhanced level of resources (see Chapter 30). 5-Fluorouracil 500 mg/m2 IV day 1
There are no well-designed studies on the best 4-Weekly CEF 6 cycles
drug regimen in low-resource settings. In many Cyclophosphamide 75 mg/m2 IV day 1
places the choice of regimen will depend on the Epirubicin 90 mg/m2 IV day 1
availability of drugs and associated toxicity. The 5-Fluorouracil 500 mg/m2 IV day 1
Early Breast Cancer Trialist Collaborative Group
(EBCTG) is carrying out meta-analyses on all ran- Patients with node-positive disease have additional
domized controlled trials (RCT) on adjuvant treat- benefit when taxanes are added.
ment since 1985. The latest update has included Docetaxel 75 mg/m2 IV day 1,
100,000 women in 123 RCT and compared the 3-weekly for 3 cycles
following16:
Neoadjuvant chemotherapy for patients with in-
• Taxane vs non-taxane-based regimens. operable findings should have an anthracycline
• Any anthracycline-based regimen vs CMF included if available. Including a taxane may even
(cyclophosphamide, methotrexate and 5-fluor- add further benefit. The following neoadjuvant
ouracil). regimen is suggested before surgery:
• Higher vs lower anthracycline dosage.
Adriamycin 60 mg/m2 IV day 1,
• Polychemotherapy vs no chemotherapy.
3-weekly for 4 cycles
The following results were produced for the Cyclophosphamide 600 mg/m2 IV day 1,
regimen quoted below16: 3-weekly for 4 cycles
403
GYNECOLOGY FOR LESS-RESOURCED LOCATIONS
In cases where taxanes are available this should be chemotherapy regimens (e.g. epithelial ovarian
followed by: cancer) due to its improved toxicity profile, causing
Docetaxel 75 mg/m2 IV day 1, less nausea, vomiting, renal as well as neuro- and
3-weekly for 4 cycles ototoxicity. Its main dose-limiting toxicity is hema-
tological. Approximately 70% is excreted un-
Stage IV disease Endocrine therapy should always be changed by glomerular filtration by the kidney.
considered first for a patient with stage IV disease Carboplatin is dosed according to the patient’s 24 h
(see Chapter 30). creatinine clearance as described under the section
In cases of resistance or high tumor load, a patient on ovarian cancer in this chapter.
who has not been treated with chemotherapy
before should receive an anthracycline as first-line 5-Fluorouracil
therapy. Single-agent therapy is preferred. The 5-Fluorouracil is an anti-metabolite. It blocks
number of cycles will depend on cumulative toxi- thymidine synthesis and thus DNA replication. It is
city (see below) and effects on the tumor load. The usually used intravenously but can also be applied
therapy should be given as long as the benefit out- topically. Its main side-effects are myelosuppression
weighs the side-effects. Weekly administration and gastrointestinal side-effects. Topical application
gives fewer side-effects, for example: can cause dermatitis. 5-Fluorouracil is only stable in
Epirubicin 30 mg/m2 IV day 1 the presence of folinic acid and should be given
together with leucovorin (however, through dif-
Common chemotherapeutic drugs used in ferent lines, as they don’t mix). Oral folinic acid
gynecological cancers may be used if leucovorin is not available but it is
less efficacious.
Cisplatin
This is an alkylating agent. It is used in low doses as
Paclitaxel, docetaxel
part of concurrent chemo-radiation in locally ad-
vanced cancer of the cervix. It is also used in higher Paclitaxel is metabolized in the kidney and biliary
doses as palliative chemotherapy in recurrent cancer excretion is important. Acute hypersensitivity was
of the cervix. In high doses it is a component of the the most important side-effect, but the incidence is
BEP regime for germ cell tumors of the ovary as well greatly reduced by adequate pre-mediation with
as part of the EMA/EP regime for choriocarcinoma. dexamethasone and anti-histamines and H1 and
Cisplatin acts through inhibition of DNA pre- H2 blockers. Neutropenia is the main dose-limiting
cursors, inter- and intra-strand alkylation and non- toxicity. The nadir occurs 8–11 days after adminis-
specific cell cycle phase activity. Administration is tration and recovery occurs within 20 days. Other
intravenous. Cisplatin is cleared by the kidneys side-effects are alopecia, peripheral neurotoxicity
mainly by glomerular filtration. Normal renal func- (mainly neurosensory), peri-treatment myalgia
tion must be ensured before administration. The which responds to simple analgesics, asymptomatic
most common toxicities are nausea, vomiting and bradycardia, mucositis and inflammation at the in-
renal dysfunction. Vomiting may be acute or jection site. Nausea and vomiting are uncommon.
delayed. The renal toxicity can be decreased by
ensuring rapid clearance of the drug by saline or Methotrexate
mannitol diuresis. This has been described under
This is a folate antagonist and acts by binding to
the section on side-effects. Adequate hydration and
dihydrofolate reductase. Cellular protein synthesis,
urinary output must be maintained during the 24 h
DNA and RNA production and cellular replica-
following infusion, maintaining a urinary output of
tion is affected. Leucovorin rescue is used 24 h after
at least 100 ml/h. Other toxicities are ototoxicity
administration of methotrexate to reduce the toxic
(irreversible) and peripheral sensory neuropathy.
effects of methotrexate. The drug is mostly excreted
by the kidney with a small amount through
Carboplatin
bile. Decreased renal function can result in toxi-
This is a platinum compound closely related to cis- city. Patients must be adequately hydrated and
platin. It has replaced cisplatin in many of the urine alkalinized to reduce renal side-effects.
404
Basic Oncology including Treatment in Less-resourced Locations
Myelosuppression occurs at about 7–10 days post- skin folds and creases, alopecia, anaphylactic re-
administration. Vomiting, diarrhea, stomatitis and actions and fever. The most serious toxicity is
mucositis can occur. Other side-effects are pulmo- interstitial pneumonitis and lung fibrosis.
nary, dermatologic and hepatic.
Doxorubicin, Adriamycin, epirubicin
Cyclophosphamide
These are anti-tumor antibiotics and their anti-
It is an alkylating agent and is largely metabolized cancer actions are by topoisomerase II inhibition,
in the liver into active compounds. It is excreted in DNA intercalation and free radical formation.
the urine. Myelosuppression occurs 8–14 days after Anthracyclines are the major cornerstones of
administration. Nausea and vomiting can be chemotherapy treatment in breast cancer. Doxo-
delayed, occurring 6–8 h after administration, so rubicin is used together with ifosfamide in one of
anti-emetic prophylaxis should be given for 24 h. the regimens for the treatment of uterine sarcoma.
Alopecia, skin and nail changes, increased liver It is metabolized in the liver. Most of the drug after
enzymes and rarely jaundice can occur. Hemor- metabolism is excreted in the bile with smaller
rhagic cystitis (adequate hydration decreases the amounts in the urine. Dose reductions are recom-
incidence) and secondary leukemia are other side- mended for hyperbilirubinemia (1.2–3 mg serum
effects described. bilirubin/100 ml, 50% of normal dose; >3 mg/100 ml
serum bilirubin, 25% of normal dose). Toxicities
Ifosfamide include myelosuppression, nausea, vomiting,
mucositis and stomatitis, alopecia, red or pink-
This is an alkylating agent and is activated in the
colored urine and hyperpigmentation. Extravasa-
liver and excreted in the urine. Myelosuppression
tion results in skin necrosis. Post chemotherapy
occurs 7–10 days after administration. Renal toxi-
anti-emetic prophylaxis should be given for 48 h.
city and hemorrhagic cystitis is common and mesna
Cardiomyopathy is a particular side-effect of
(an organosulfur compound) must be used as a con-
these drugs. The incidence of cardiomyopathy is
tinuous infusion of 4.5 g/m2/day and the patient
related to the cumulative dose of the drugs. A
must be adequately hydrated. Alopecia, skin and
maximum of dose of 900 mg/m2 epirubicin (3.3%
nail changes, increased liver enzymes may occur.
congestive heart failure) and a maximum of dose of
Neurological toxicities may manifest with, lethargy,
550 mg/m2 Adriamycin must not be exceeded in a
confusion, somnolence, disorientation, malaise and
patient’s lifetime! Always look for new shortness of
even coma.
breath or tachycardia in patients on anthracyclines
and do not start the drug if the patient already com-
Actinomycin D
plains about such symptoms.
This is an anti-tumor antibiotic and acts by inhibit- Pre-existing cardiac disease as well as prior media-
ing DNA transcription and RNA translation. It is stinal radiation may increase the incidence of cardiac
excreted through the urine and bile. Myelo- toxicity. An echocardiogram should be performed
suppression occurs 10–14 days after administration. prior to chemotherapy to confirm normal cardiac
Nausea and vomiting starts 1 h after administration function if facilities for this examination exist.
and can last for several hours. Mucositis, stomatitis,
diarrhea, alopecia, erythema and skin changes can Vinblastine and vincristine
occur. Extravasation can cause tissue necrosis. Se-
These are plant-derived anti-mitotic agents and act
vere skin sensitivity can occur in previously irradi-
by inhibiting microtubule assembly. They are
ated tissue (radiation recall).
mainly metabolized by the liver and excreted in the
bile. Potential side-effects are myelosuppression,
Bleomycin
abdominal cramps, alopecia, peripheral neuropathy
This is an anti-tumor antibiotic and causes DNA (dose limiting) and autonomic neuropathy. These
single-strand breaks as well as DNA degradation. It drugs can cause constipation, so laxatives should be
is excreted through the kidney by glomerular filtra- prescribed, Anaphylactic reactions, joint pains
tion. Myelosuppression, nausea and vomiting is especially the temporo-mandibular joint and
mild. Bleomycin can cause hyperpigmentation in SIADH (syndrome of inappropriate antidiuretic
405
GYNECOLOGY FOR LESS-RESOURCED LOCATIONS
hormone secretion) can occur. Extravasation can 6. Peters WA 3rd, Liu PY, Barrett RJ 2nd, Srock RJ, et al.
cause pain and necrosis. In addition, vincristine can Cisplatin, 5-flurouracil and radiation therapy are
superior to radiation therapy as adjunctive in high risk,
cause mild liver enzyme elevations and very rarely early stage carcinoma of the cervix: report of a phase III
cortical blindness. intergroup study. J Clin Oncol 2000;18:1606–13
7. Medenhall WM, Sombeck MD, Freeman DE, Morgan
Etoposide LS. Stage IB and IIA–B, carcinoma of the intact uterine
cervix; impact of tumor volume and the role of adjuvant
Etoposide can be given orally or IV. It is well hysterectomy. Semin Radiat Oncol 1994;4:16–22
absorbed through the gastrointestinal tract and is 8. Nout RA, Smit VT, Putter H, et al. Vaginal brachy-
mainly excreted in the urine unmetabolized. About therapy versus pelvic external beam radiotherapy for
patients with endometrial cancer of high-intermediate
10–15% is eliminated in the bile and passes in the risk (PORTEC-2): an open label, non-inferiority,
feces. The main dose-limiting side-effects are randomized trial. Lancet 2010;375:816–23
myelosuppression with the nadir at 7–14 days and 9. Tinger A, Waldron T, Peluso N, et al. Effective Pallia-
recovery by 20 days. Nausea and vomiting are tive Radiation Therapy in Advanced and Recurrent
common after oral administration. Alopecia, Ovarian Cancer. Int J Radiat Oncol Biol Phys 2001;51:
1256–63
anaphylaxis, and peripheral neuropathy are other 10. Bese NS, Kiel K, El-Gueddari BE, et al. Radiotherapy
potential side-effects. for breast cancer in countries with limited resources:
program implementation and evidence-based recom-
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