Excel l ent Di sease Cont rol and Survi val i n Pat i ent s Wi t h

Advanced Nasopharyngeal Cancer Treat ed Wi t h

Chemoradi at i on
By Danny Rischin, June Corry, Jennifer Smith, Josephine Stewart, Peter Hughes, and Lester Peters
Purpose: To determine the efcacy and safety of
epirubicin, cisplatin, and infusional uorouracil (5-FU)
chemotherapy followed by radiation with concurrent
cisplatin in patients with locally and/or regionally ad-
vanced nasopharyngeal cancer.
Patients and Methods: Thirty-ve patients were
treated with three cycles of induction chemotherapy
with epirubicin 50 mg/m
2
and cisplatin 75 mg/m
2
combined with continuous-infusion 5-FU 200 mg/m
2
daily for 9 weeks, followed by concurrent chemoradia-
tion of 60 Gy in 2-Gy fractions with cisplatin 20 mg/m
2
daily for 5 days in weeks 1 and 6.
Results: Median age was 43 years, 74% had World
Health Organization type III histology, and 91% had
stage IV disease (International Union Against Cancer,
ed 4). All patients received three cycles of induction
chemotherapy, and 97% completed chemoradiation.
The estimated 4-year progression-free survival rate
was 81% (95% CI, 59% to 93%), and the estimated
4-year overall survival rate was 90% (95% CI, 74% to
97%). Only two patients have had a locoregional re-
lapse by the close-out date despite the use of only 60
Gy. Induction chemotherapy was well tolerated, with
11% grade 3 or 4 stomatitis, 26% grade 3 vomiting,
and no episodes of febrile neutropenia. Acute toxicities
of chemoradiation were as follows: 23% grade 3 or 4
vomiting, 6%febrile neutropenia, 31%grade 3 mucosi-
tis, and 23% grade 3 skin toxicity. The most prevalent
grade 3 late effects were xerostomia and hearing loss.
Conclusion: This regimen was well tolerated, can be
delivered as planned, and has resulted in excellent
locoregional disease control and survival in patients
with locally advanced nasopharyngeal cancer.
J Clin Oncol 20:1845-1852. 2002 by American
Society of Clinical Oncology.
N
ASOPHARYNGEAL CANCER has traditionally been
treated with radiation alone. However, high rates of
both locoregional recurrence and distant metastases have
been reported in patients with locally advanced nasopha-
ryngeal cancer treated with radiation alone.
1-3
The poor
results in patients with locally advanced disease, with 5-year
survival of 15% to 50%, has led to the investigation of the
benet of adding chemotherapy to the primary treatment of
nasopharyngeal cancer. Nasopharyngeal cancer is a rela-
tively chemosensitive disease,
4
hence the rationale for using
induction or adjuvant chemotherapy to decrease distant
metastases. Furthermore, there is increasing evidence that
concurrent chemoradiation in a variety of malignancies may
improve locoregional control and overall survival.
5-7
The
Intergroup trial demonstrated a marked improvement in
progression-free and overall survival from the addition of
concurrent cisplatin during radiation followed by three
cycles of cisplatin and uorouracil (5-FU).
8
Although the
results of this trial altered practice in many centers, other
investigators have expressed concern that the high propor-
tion of patients with World Health Organization (WHO)
stages I and II histology casts doubt on the relevance of the
results to populations with predominantly undifferentiated
nasopharyngeal carcinomas.
9
Moreover, the practicality of
the Intergroup regimen has been questioned: on the chemo-
radiation arm, only 73% patients completed treatment as
planned, with 63% receiving all three cycles of concurrent
chemotherapy and 55% receiving the three planned cycles
of adjuvant chemotherapy.
In this trial, we set out to investigate an induction and
concurrent chemoradiation regimen with the radiation dose
limited to 60 Gy, that we postulated may be feasible to
deliver in a high proportion of patients with acceptable
toxicity. We chose to study the epirubicin/cisplatin/5-FU
(ECF) regimen, with a higher cisplatin dose, in the induc-
tion phase of the treatment program, as this regimen has
demonstrated impressive activity in a number of malignan-
cies,
10,11
good tolerability, and includes three drugs with
proven activity in nasopharyngeal cancer.
PATIENTS AND METHODS
Eligibility
Patients were required to have histologically proven carcinoma of
the nasopharynx (any WHO type), International Union Against Cancer,
From the Division of Hematology and Medical Oncology, Division
of Radiation Oncology, and Statistical Center, Peter MacCallum
Cancer Institute, Melbourne, Australia.
Submitted September 5, 2001; accepted January 2, 2002.
Address reprint requests to Danny Rischin, MD, Division of Hema-
tology and Medical Oncology, Peter MacCallum Cancer Institute,
Locked Bag No 1, ABeckett St, Melbourne 8006, Australia; email:
drischin@petermac.unimelb.edu.au.
2002 by American Society of Clinical Oncology.
0732-183X/02/2007-1845/$20.00
1845 Journal of Clinical Oncology, Vol 20, No 7 (April 1), 2002: pp 1845-1852
10.1200/JCO.2002.07.011
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Copyright 2002 American Society of Clinical Oncology. All rights reserved.
ed 4 (UICC, ed 4), stage III or IV disease, and no systemic metastatic
disease (M0) on staging. Other eligibility criteria were age 16 years,
WHO performance status 0 to 2, absolute neutrophil count 2.0
10
9
/L, platelet count 100 10
9
/L, creatinine clearance or glomerular
ltration rate 1.0 mL/sec, serum bilirubin 1.5 times upper limit
of normal, and left ventricular ejection fraction measured by gated
cardiac scan within the normal range. Written informed consent was
obtained from all patients, and the Institutional Ethics Committee
approved the protocol.
Patients were excluded from the trial for any of the following: prior
chemotherapy or radiotherapy, prior malignancy apart from nonmela-
noma skin cancer or carcinoma-in-situ of the cervix, signicant
hearing impairment unless attributable to nasopharyngeal cancer,
pre-existing motor or sensory neurotoxicity WHO grade 2, active
uncontrolled infection, unstable cardiac disease requiring treatment,
contraindication to insertion of a suitable indwelling venous cathe-
ter, and pregnancy or lactation.
Pretreatment and Follow-Up Evaluations
Before enrollment, all patients underwent a full history, physical
examination, complete blood count (CBC) with differential, electro-
lytes, liver function tests, 24-hour urinary creatinine clearance, mag-
netic resonance imaging (MRI) and/or computed tomography (CT)
scans of the head and neck, chest x-ray, liver imaging, and bone scan.
While on induction chemotherapy, patients were clinically assessed
weekly for toxicity and CBC including differential. Electrolytes, serum
creatinine, and liver function tests were performed every 3 weeks.
During radiotherapy, patients were clinically assessed weekly for
toxicity, and CBC including differential, electrolytes, serum creatinine,
and liver function tests were performed before each cycle of chemo-
therapy. Assessment of tumor response by clinical examination was
performed after every cycle during induction chemotherapy, and every
2 months after completion of treatment. MRI or CT scanning took place
after completion of induction chemotherapy and 2 months after
completion of radiotherapy. Thereafter, imaging was based on clinical
indications only.
Systemic toxicity from treatment was graded according to WHO
criteria. Mucous membrane radiation toxicity was graded according to
the European Organization for Research and Treatment of Cancer
Radiation Therapy Oncology Group (RTOG) toxicity criteria. Antitu-
mor activity was assessed according to the WHO response criteria.
Nonpalpable, nonnecrotic lymph nodes less than 1 cm seen on
pretreatment MRI or CT scans were not considered to be signicant.
Similarly, nonpalpable, nonnecrotic nodes less than 1 cm seen on
follow-up scans were not deemed to be signicant.
Treatment Plan
Three cycles of epirubicin and cisplatin were administered at 3-week
intervals. Infusional 5-FU was commenced on day 1 and was continued
for 9 weeks, stopping 24 hours before the commencement of radiation
(Fig 1). Epirubicin was given 5 to 30 minutes before cisplatin on day
1 of each cycle. Hydration with cisplatin was according to our standard
protocol with 1 L of normal saline and 400 mL of 10% mannitol before
cisplatin, and 2 L of normal saline after cisplatin. All patients had an
indwelling central venous catheter device, and the 5-FU was delivered
via an ambulatory infusion pump. The doses were epirubicin 50 mg/m
2
,
cisplatin 75 mg/m
2
, and 5-FU 200 mg/m
2
/d.
During radiation, cisplatin was administered daily at a dose of 20
mg/m
2
for 5 days in weeks 1 and 6, and given approximately 15 to 45
minutes before radiation on those days. Antiemetics, including a
5-hydroxytryptamine antagonist and 8 mg of dexamethasone, were
given daily on days cisplatin was administered. Prophylactic recombi-
nant granulocyte colony-stimulating factor support was not permitted.
Radiation Therapy
Planned radiation therapy consisted of 60 Gy in 30 fractions over 6
weeks to all known sites of disease and 50 Gy to sites of potential
spread including the uninvolved neck. The treatment volume was
determined on the basis of the extent of disease at presentation and was
not inuenced by the response to chemotherapy. The maximum spinal
cord dose was 45 Gy; the maximum brainstem dose was 54 Gy. In
seven patients, the upper level of the eld was reduced in the last week
of treatment so as to limit the optic chiasm dose to 54 Gy as permitted
in the protocol, and one other patient with very extensive intracranial
disease received 54 Gy to the whole volume. Seventeen patients were
treated by parallel opposed photon elds junctioned at the level of the
thyroid notch to an anterior neck eld with 20-mm spinal cord
shielding to a dose of 40 Gy. Thereafter, the lateral elds were reduced
off cord and inferiorly to the level of the mandible and junctioned to
anteroinferior neck elds for the last 10 Gy (uninvolved neck) or 20 Gy
(involved neck). Eighteen patients were treated with parallel opposed
photon elds to 36 Gy in 18 fractions; then, the nal 24 Gy was given
via two asymmetric arc elds. These elds were junctioned with a
50-Gy (uninvolved neck) or 60-Gy (involved neck) bilateral anterior
photon eld, with spinal cord shielding. The total dose of 60 Gy was
chosen on the basis of previous experience in our own institution using
concurrent cisplatin and radiotherapy and the difculty, if not impos-
sibility, of achieving a minimum tumor dose of 70 Gy to the full
planning target volume (PTV) in many cases of advanced nasopharyn-
geal cancer using then-available technology.
Dose Modication for Toxicity
During induction chemotherapy, grade 4 neutropenia lasting 7
days, febrile neutropenia, or grade 3 or 4 thrombocytopenia required a
25% dose reduction of all drugs. Grade 3 or 4 mucositis or diarrhea
required discontinuation of 5-FU for at least 1 week, and then it could
be restarted with a 25% dose reduction of 5-FU and epirubicin. Other
grade 3 or 4 nonhematologic toxicity required a 25% dose reduction of
all drugs. If the glomerular ltration rate (GFR) decreased to less than
0.9 mL/sec, carboplatin targeting an area under the curve of 5 (Calvert
formula) was to be substituted for cisplatin. Grade 2 peripheral
neuropathy also required changing to carboplatin, whereas grade 3 or 4
neuropathy required cessation of chemotherapy. Before giving cisplatin
and epirubicin on day 1 of each cycle, the neutrophil count had to be
1.5 10
9
/L and the platelet count had to be 100 10
9
/L.
Between cycles, 5-FU was to be discontinued for 1 week if grade 4
neutropenia or grade 3 or 4 thrombocytopenia developed. 5-FU could
be recommenced if the neutrophil count was 1.0 10
9
/L and the
Fig 1. Treatment schedule. E, epirubicin 50 mg/m
2
; C, cisplatin 75
mg/m
2
when administered with epirubicin and 20 mg/m
2
/d when given
during RT.
1846 RISCHIN ET AL
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Copyright 2002 American Society of Clinical Oncology. All rights reserved.
platelet count was 75 10
9
/L. During radiation, if carboplatin
needed to be substituted for cisplatin, the dose was to target an area
under the curve of 4 according to the Calvert formula, divided into ve
equal doses.
Statistical Methods
Overall survival, progression-free survival, and time to develop
grade 3 or 4 late effects from commencement of induction chemother-
apy were estimated using the Kaplan-Meier (product-limit) method,
with condence intervals calculated using the logit transformation. The
potential follow-up time for each patient was the time from treatment
start to the close-out date for all analyses (February 5, 2001, or the date
of last contact for two patients lost to follow-up). For overall survival,
all deaths were counted regardless of cause, and survival times for
living patients were censored at the close-out date. For progression-free
survival, the rst progression at any site or death without progression
was counted as an event, and times were censored at the close-out date
for patients who were alive at that date without progression.
Late effects were recorded if they occurred or persisted for more than
6 months after completing chemoradiation and were graded using the
RTOG criteria, except for peripheral neuropathy and ototoxicity, which
were graded by National Cancer Institute common toxicity criteria. For
estimating time to develop grade 3 or 4 late effects, the rst grade 3 or
4 late effect was counted as an event and times were censored for
patients who did not develop any grade 3 or 4 late effect before the
close-out date. The date of censoring was the date of death for one
patient who died before completing chemoradiation, the date of last
assessment for patients who progressed or died more than 6 months
after chemoradiation, and the close-out date for the remaining patients.
RESULTS
Patient Characteristics
From September 1995 to February 1999, 35 patients were
enrolled onto this study. Patients had predominantly undif-
ferentiated carcinomas (WHO type 3), with the details of
patient characteristics listed in Table 1. According to the
original staging criteria stipulated in the protocol (UICC, ed
4, 1992) three patients (9%) had stage III disease, and 32
(91%) had stage IV disease (Table 2). During the conduct of
the trial, new staging criteria (UICC criteria, ed 5, 1997)
became available (Table 3). Under the new staging system,
skull base or clivus invasion is classied as T3 rather than
T4. Also, only N3 nodal disease (not N2) counts as stage IV
under the new system. These changes in classication
reduced the number of patients in stage IV to 40%.
However, it is noteworthy that of these, six had documented
intracranial extension and eight had large-volume and/or
supraclavicular lymphadenopathy. Thirty-two patients
(91%) had a baseline MRI scan of head and neck, with the
remaining 9% having a CT scan only. All patients had a
baseline chest x-ray and bone scan, and 34 (97%) had a liver
CT scan or ultrasound.
Efcacy
After completion of induction chemotherapy, 30 (86%)
of 35 patients (95% condence interval [CI], 70% to 95%)
achieved a response on clinical and MRI/CT examination,
with two achieving a complete response and 28 a partial
response. After completion of chemoradiation, all 34 assess-
able patients were in complete response, on the basis of
clinical examination alone, but eight had a residual abnor-
mality on imaging and hence were deemed to be in partial
response. The median potential follow-up time from com-
mencing treatment to the close-out date was 43 months
(range, 23 to 65 months). Thirty patients remained alive and
in remission at the close-out date. One patient died of
unrelated causes (scleroderma) while in complete remis-
sion, and one patient died after a sagittal sinus thrombosis
while on treatment. One patient died after developing local
recurrence and distant metastases 21.2 months after com-
mencing treatment. This was one of the patients who had the
Table 1. Patient Characteristics
Characteristic
No. of Patients
(N 35)
Age, years
Median 43
Range 17-63
WHO performance status
0 27
1 7
2 1
WHO histology
1 5
2 4
3 26
Ethnicity
White 6
Chinese/Southeast
Asian
23
Mediterranean 6
Table 2. Tumor Stage Versus Node Stage (UICC, ed 4, 1992)
Stage T1 T2 T3 T4 Total
N1 0 1 2 0 3
N2 6 8 3 11 28
N3 2 0 1 1 4
Total 8 9 6 12 35
Table 3. Tumor Stage Versus Node Stage (UICC, ed 5, 1997)
Stage T1 T2 T3 T4 Total
N1 5 4 1 0 10
N2 6 2 3 6 17
N3 3 3 2 0 8
Total 14 9 6 6 35
1847 CHEMORADIATION FOR NASOPHARYNGEAL CANCER
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upper level of their treatment eld reduced to limit the dose
to the optic chiasm to 54 Gy. Another two patients relapsed
but remained alive at the close-out date; one developed
distant metastases 3.3 months after commencing treatment,
and another had a regional nodal recurrence 47.9 months
after commencing treatment. The regional nodal recurrence
occurred at a site that had previously received 50 Gy, as it
was below the level of his known nodal disease at initial
diagnosis. Progression-free and overall survival curves are
shown in Figs 2 and 3. The 4-year progression-free survival
rate was estimated to be 81% (95% CI, 59% to 93%), and
the 4-year overall survival rate was estimated to be 90%
(95% CI, 74% to 97%).
Toxicity
Induction chemotherapy was generally well tolerated
(Table 4). Grade 3 or 4 neutropenia occurred in 11 patients
(31%) during induction chemotherapy but was not compli-
cated by febrile neutropenia. Seven patients had central
venous catheterrelated infections. Grade 3 or 4 5-FU
related stomatitis occurred in four patients (11%), and nine
patients (26%) experienced grade 3 vomiting after receiving
cisplatin and epirubicin. During induction chemotherapy, all
patients developed grade 2 or worse toxicity and 21 patients
(60%) developed at least one grade 3 or 4 toxicity, exclud-
ing alopecia. All patients received three cycles of induction
chemotherapy. Five patients (14%) had a dose reduction of
cisplatin and/or epirubicin. Sixteen patients (46%) had a
dose delay of 5 days, most commonly because of delayed
neutrophil recovery. Nine patients (26%) had a dose reduc-
tion of 5-FU, most commonly because of stomatitis. Five
days after the third cycle of induction chemotherapy while
still on 5-FU, a 50-year-old woman had a syncopal episode
with a subsequent seizure and evidence of watershed cere-
bral infarcts on MRI. She made a complete recovery over a
period of several days. She was presumed to have been
hypotensive during the syncopal episode, to account for the
watershed cerebral infarcts. The cause of the syncopal
episode and possible associated hypotension is not known,
but one possibility was a 5-FUrelated cardiac arrhythmia.
Her 5-FU was ceased and she proceeded with chemoradia-
tion, and completed treatment successfully.
Toxicities during and after chemoradiation are listed in
Table 5. All patients developed grade 2 or worse toxicity
and 28 (80%) developed at least one grade 3 or 4 toxicity,
excluding alopecia. Grade 3 or 4 neutropenia occurred in six
(17%) patients and was complicated by febrile neutropenia
in two patients. Another two patients had chest infections
not associated with neutropenia. Grade 3 or 4 nausea and
vomiting caused by the cisplatin occurred in eight (23%).
There was one death while on treatment. A 46-year-old man
developed a sagittal sinus thrombosis at the end of the
second week of radiotherapy, which was subsequently
complicated by a massive cerebral hemorrhagic infarct. His
Fig 2. Progression-free survival (censored times are indicated as tick
marks on the curves).
Fig 3. Overall survival (censored times are indicated as tick marks on the
curves).
Table 4. Toxicity During Induction Chemotherapy
WHO Grade (% of 35 patients)
0 1 2 3 4
Hemoglobin 74 26 0 0 0
Neutrophils 3 26 40 17 14
Platelets 97 3 0 0 0
Oral 34 23 31 9 3
Nausea and vomiting 3 23 49 26 0
Diarrhea 66 20 11 3 0
Cutaneous 86 11 3 0 0
Alopecia 9 6 54 31
1848 RISCHIN ET AL
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condition continued to deteriorate and he died 2 weeks later.
It was thought that he may have had a septic thrombosis, but
all cultures were negative. He was not neutropenic, and his
peripherally inserted central venous catheter remained in the
correct position and there was no clinical evidence of
infection. He had no past history of thrombosis. He had
achieved an excellent partial response to induction chemo-
therapy and was very well until his acute presentation with
the sagittal sinus thrombosis.
Acute radiation toxicity was as expected, with 31% and
23% patients experiencing grade 3 mucositis and skin
toxicity, respectively (Table 5). The median duration of
acute mucositis RTOG grade 2 was 9 weeks (range, 0 to
30 weeks). Thirteen patients (37%) required enteral feeding
via a percutaneous endoscopic gastrostomy or nasogastric
tube. The median weight loss within 90 days of commenc-
ing chemoradiation as a percentage of weight on commenc-
ing radiotherapy was 11% (range, 2% to 22%). The median
duration of WHO grade 2 skin reaction was 4 weeks
(range, 0 to 19 weeks). Thirty-three patients (94%) received
the protocol-specied radiation dose of 60 Gy to the
primary tumor and involved neck. One patient received a
planned dose of 54 Gy in 30 fractions, as permitted in the
protocol, owing to the intracranial extent of his disease,
which precluded administration of a higher dose. The
patient who died during treatment received 20 Gy before
cessation of treatment. In the 34 patients who completed
radiation, the duration of radiotherapy was 39 to 44 days
(protocol-specied, 42 days). The 34 patients who com-
pleted treatment all received two cycles of chemotherapy
during radiation. One patient received carboplatin in the rst
week because of a decrease in his GFR to 0.8 mL/min. An
additional three patients received carboplatin in week 6
because of a reduction in GFR in two cases and severe
emesis with prior cisplatin in the other patient. One patient
had a dose reduction of cisplatin in week 6 because of
febrile neutropenia after the previous cycle. The patient who
had received carboplatin in week 1 only received 2 days of
carboplatin in week 6, as he developed grade 3 neutropenia
on the second day.
The late toxicities of combined treatment are listed in
Table 6. Apart from hearing loss and peripheral neuropathy,
these were similar to those reported with radiation alone for
nasopharyngeal cancer. Seventeen patients (50%) experi-
enced ear or hearing difculties beyond 6 months after
radiotherapy. Five patients had mild or moderate otitis
externa; 12 patients had middle ear effusions or infections
that resulted in some hearing impairment, with one being
graded as severe; and seven patients had hearing impair-
ment resulting from inner ear problems, with two being
graded as severe. These patients had no clinically apparent
hearing impairment before treatment, although baseline
audiometry was not performed on this trial. During and after
treatment, 16 patients (46%) developed symptoms of pe-
ripheral neuropathy, which persisted beyond 6 months after
treatment in eight patients, grade 2 in one instance but grade
1 in the others. All 34 patients who survived at least 6
months after completing radiotherapy developed grade 2 or
worse late effects. The estimated actuarial risk of grade 3
late effects at 4 years was 35% (95% CI, 20% to 53%), and
no grade 4 late toxicity was observed.
DISCUSSION
In this phase II trial, we have demonstrated that a regimen
of induction chemotherapy with epirubicin, cisplatin, and
continuous-infusion 5-FU, followed by radiation with con-
current cisplatin in weeks 1 and 6 in patients with locally
advanced nasopharyngeal cancer, is well tolerated and
results in excellent 4-year progression-free and overall
survival rates.
The U.S. Intergroup trial, which demonstrated the supe-
riority of chemoradiation followed by three cycles of
cisplatin and 5-FU chemotherapy compared with radiation
alone, reported 3-year progression-free and overall survival
rates of 69% and 78%, respectively, in the chemoradiation
arm, with a median follow-up of 32 months.
8
Our 4-year
results of 81% and 90% with a median follow-up of 43
Table 5. Acute Toxicity Caused by Chemoradiation
WHO Grade (% of 35 patients)
0 1 2 3 4
Hemoglobin 37 54 6 3 0
Neutrophils 49 23 11 14 3
Platelets 86 6 9 0 0
Nausea and vomiting 11 29 37 20 3
Infection 69 20 3 6 3
Alopecia 3 6 31 60
Skin (in the radiation eld) 3 29 46 23 0
Mucosa* 0 6 63 31 0
*Mucositis graded according to RTOG acute toxicity criteria.
Table 6. Late Toxicity
RTOG/NCI-CTC Grade (% of 34 patients)
0 1 2 3 4
Skin 38 53 9 0 0
Subcutaneous tissue 32 59 3 6 0
Mucous membrane 9 47 41 3 0
Salivary glands 0 0 76 24 0
Ear/hearing* 50 9 32 9 0
Peripheral neuropathy* 76 21 3 0 0
Abbreviation: NCI-CTC, National Cancer Institute common toxicity criteria.
*Graded according to NCI-CTC acute toxicity criteria.
1849 CHEMORADIATION FOR NASOPHARYNGEAL CANCER
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months compare favorably, but such comparisons between
trials need to be interpreted with caution. The results for
both trials are derived from relatively short follow-up for
nasopharyngeal cancer, and further relapses are inevitable
with time. There were signicant differences in patient
populations and treatment regimens in the two trials. Al-
though the stage distribution was similar, there was a higher
proportion of patients with undifferentiated carcinomas
(WHO type 3) in our trial. We administered induction rather
than adjuvant chemotherapy, as administration of chemo-
therapy after radiation for head and neck cancer has proven
difcult to deliver in previous trials. This is borne out by the
Intergroup trial, in which only 55% of patients received all
three planned cycles of adjuvant chemotherapy and 33% did
not receive any adjuvant chemotherapy.
8
In contrast, 100%
of patients on our trial received all three cycles of induction
chemotherapy. The chemotherapy regimens differed, with
our regimen containing epirubicin, and the 5-FU was
administered as a continuous infusion over 9 weeks rather
than as three cycles of infusional 5-FU for 96 hours every 4
weeks. The cisplatin doses were similar, but were adminis-
tered every 3 weeks in our trial and every 4 weeks in the
Intergroup trial. The radiation dose in the Intergroup trial
was 70 Gy, whereas we administered 60 Gy. Both trials
gave concurrent cisplatin during radiation. In the Intergroup
trial, there were three planned cycles of 100 mg/m
2
in weeks
1, 4, and 7 of radiation, whereas in our regimen there were
two planned cycles of 20 mg/m
2
/d for 5 days in weeks 1 and
6. All our patients completed chemoradiation (apart from
the patient who died during treatment), but in the Intergroup
trial 27% patients did not complete chemoradiation. Impor-
tantly, in our trial the prior administration of induction
chemotherapy did not compromise the delivery of chemo-
radiation. The design of the Intergroup trial does not permit
one to determine the relative contributions of concurrent
versus adjuvant chemotherapy to the improved outcome
compared with radiation alone. Similarly, with the excellent
results achieved in our phase II trial, it is not possible to
determine the relative contributions of the induction in
addition to the concurrent chemotherapy, the administration
of each concurrent cisplatin cycle in ve divided doses
rather than as a single dose, or the use of sophisticated
radiation treatment planning techniques.
Reported response rates to induction chemotherapy and
to chemoradiation are quite variable. Most reports of induc-
tion chemotherapy in nasopharyngeal cancer have reported
clinical assessment of response rates without any imaging
assessments. In such trials, response rates of 65% to 91%
have been reported, with complete response rates of 5% to
47%.
9,12,13
In our trial, the equivalent clinical response rate
after induction chemotherapy was 89%, with a 40% com-
plete response (CR) rate. With the incorporation of imaging,
predominantly MRI, into the assessment of response, the
response rate in our trial remains high at 86%, but the CR
rate drops to 6%. Assessment of response after radiation/
chemoradiation has more often incorporated CT ndings,
with CR rates of 49% to 55% reported.
8,12
In our trial, the
response rate after chemoradiation was 97%, with a 74%
CR rate. Twenty-three percent had a residual abnormality
on MRI of uncertain signicance, with no patient having
any evidence of residual disease on clinical assessment. The
relevance of residual abnormalities on MRI is uncertain, as
only two patients had experienced a locoregional relapse by
the close-out date.
The primary rationale for induction or adjuvant chemo-
therapy in nasopharyngeal cancer has been to decrease the
risk of developing distant metastases. The three large trials
of induction without concurrent chemotherapy have not
demonstrated improved overall survival compared with
radiation alone.
9,12,14
The International Nasopharynx Can-
cer Study Group trial demonstrated improved disease-free
survival, but not improved overall survival.
12
In that trial,
which was restricted to patients with N2 or N3 undifferen-
tiated carcinomas and used an induction regimen of three
cycles of bleomycin, epirubicin, and cisplatin, signicant
toxicity and 8% treatment-related mortality was reported. In
the Asian-Oceanian Clinical Oncology Association Trial,
which was restricted to patients with Hos T3 or N2 or N3
or any stage with node size greater than 3 cm and poorly or
undifferentiated carcinomas, no difference in relapse-free or
overall survival was reported.
9
Subset analyses in assessable
patients and in patients with nodes greater than 6 cm
favored the chemotherapy arm. The chemotherapy regimen
was two to three cycles of epirubicin (110 mg/m
2
) and
cisplatin (60 mg/m
2
). In a recently reported trial performed
in Guangzhou, China, no difference in overall survival was
seen, although there was a signicant difference in relapse-
free survival.
14
In this trial, the chemotherapy regimen
consisted of two to three cycles of cisplatin (100 mg/m
2
),
bleomycin (10 mg/m
2
on days 1 and 5), and 5-FU (800
mg/m
2
continuous infusion on days 1 to 5), with only 32%
receiving three cycles and 68% receiving two cycles. The
chemotherapy regimens used in these three trials may not
have been optimal, with the bleomycin, epirubicin, and
cisplatin regimen having unacceptable toxicity, a relatively
low dose of cisplatin in the Asian-Oceanian trial, and
difculty in administering the protocol-specied chemo-
therapy in the Guangzhou trial. The combination of cispla-
tin and 5-FU is the standard regimen for patients with
metastatic nasopharyngeal carcinoma and the one adminis-
tered in the Intergroup trial. We chose to base our regimen
around this combination, but altered the 5-FU schedule to
1850 RISCHIN ET AL
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continuous infusion and added epirubicin. The ECF regi-
men has impressive activity, is well tolerated in other
malignancies,
10,11
and contains three drugs active in naso-
pharyngeal cancer. However, we used a higher dose of
cisplatin than in the standard ECF regimen.
As already discussed, one advantage of induction com-
pared with adjuvant chemotherapy is the greater ability to
administer full-dose chemotherapy as planned. Another
potential advantage of induction over adjuvant chemother-
apy is the reduction in tumor bulk juxtaposed to vital
dose-limiting structures before radiation. In our trial, PTVs
were not reduced on the basis of chemotherapy-induced
response; however, the tumor bulk reduction after induction
chemotherapy increased the probability that gross residual
disease received the full radiation dose. Although random-
ized trials of induction chemotherapy without concurrent
chemotherapy have not demonstrated any signicant differ-
ences in overall survival, these trials do suggest that
induction chemotherapy may improve locoregional con-
trol.
9,12,14
In the International Cancer Study Group trial, the
improved disease-free survival was attributable to a de-
crease in both locoregional relapses and distant metastases
as sites of rst failure.
12
In the Asian-Oceanian Clinical
Oncology Association Trial, the subgroup analysis in pa-
tients with bulky neck nodes showed a signicant difference
in relapse-free survival that was attributable to improved
local control in the induction chemotherapy arm, without
any difference in incidence of distant metastases as the site
of rst failure.
9
Similarly, in the Guangzhou trial there was
a signicant difference in relapse-free survival that was
attributable to improved local control.
14
Recently, a large
retrospective series from Hong Kong has been reported
demonstrating improved local control in patients who re-
ceived two cycles of induction chemotherapy compared
with patients treated with radiation alone for locally ad-
vanced node-positive nasopharyngeal carcinoma.
15
Multi-
variate analysis identied administration of chemotherapy
as being of independent signicance in determining the
local failure rate.
The role of concurrent chemotherapy alone (without
induction or adjuvant chemotherapy) has not been studied in
depth for nasopharyngeal cancer. In a preliminary report of
a randomized trial of concurrent cisplatin conducted in
Hong Kong, there was a borderline signicant improvement
in progression-free survival compared with radiation
alone.
16
It seems likely, on the basis of the available
randomized trial data and our own results, that both induc-
tion or adjuvant chemotherapy and concurrent chemother-
apy are required to achieve a signicant improvement in
overall survival in patients with locally advanced nasopha-
ryngeal cancer. Although it is anticipated that concurrent
chemotherapy will improve locoregional control, and hence
its major impact would be in patients with advanced
T-stage disease,
17
it is possible that induction chemother-
apy may also contribute to locoregional control in these
patients, as well as being potentially benecial in patients
with advanced N-stage or low-neck disease, the group
most at risk for distant metastases.
18
The excellent locoregional control achieved in our trial
with the moderate radiation dose of 60 Gy is noteworthy,
especially because most recent trials have used higher doses
of around 70 Gy.
8,9,12,14,16
Two factors warrant discussion
in this regard. First, a positive contribution of chemotherapy
to locoregional control of nasopharyngeal cancer is much
more convincing than for other head and neck cancers.
Nasopharyngeal cancer is a chemosensitive tumor, and by
analogy with tumors such as lymphomas and certain child-
hood cancers, it is not unreasonable to expect that high rates
of locoregional control can be achieved with combined-
modality treatment, using lower radiation doses than would
be required with radiotherapy alone.
Second, using standard radiotherapy techniques, the nom-
inal dose administered to patients with advanced nasopha-
ryngeal cancer is often greater than the actual dose to parts
of the PTV, because of technical limitations to radiation
dose delivery. In this trial, we used sophisticated treatment
planning and delivery techniques to ensure that the specied
tumor dose of 60 Gy was in fact received by a PTV
encompassing all gross disease, unless the PTV included the
optic chiasm (when a superior eld reduction was made at
54 Gy). In cases where the disease had bilateral high
posterolateral parapharyngeal extension and/or bilateral
high posterior lymphadenopathy, this involved the use of
asymmetric arc elds. With the advent of intensity-modu-
lated radiation therapy, the technical constraints on dose
delivery are reduced and it would now be possible to
undertake dose escalation if necessary. On the other hand, if
the results we have reported are maintained with longer
follow-up, there may be no need to use a higher radiation
dose for WHO type 3 disease when treated with induction
and concurrent chemotherapy. However, a randomized trial
conrming at least equivalent locoregional control would be
required before it could be recommended that a radiation
dose of 60 Gy rather than 70 Gy be widely adopted.
The corollary of using a lower radiation dose is that the
probability of late radiation toxicity should be less than with
regimens using a tumor dose of 70 Gy. Our data would
appear to bear out this prediction in that there have been to
date no grade 4 late toxicities observed and no CNS
toxicities of any grade. Nonetheless, late toxicity is still of
some concern. In addition to xerostomia, which occurred to
a moderate to severe degree in nearly all patients, we did
1851 CHEMORADIATION FOR NASOPHARYNGEAL CANCER
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Copyright 2002 American Society of Clinical Oncology. All rights reserved.
encounter troublesome ototoxicity affecting the external,
middle, and inner ear. The relative contribution of radiation
and cisplatin to the incidence of sensorineural hearing loss
is unclear. Ototoxicity is poorly documented in most reports
on nasopharyngeal cancer treated by radiotherapy alone,
probably because it is not included in the RTOG late
toxicity criteria, but it is likely more common than generally
believed. As discussed in regard to tumor dose escalation,
new technologies such as intensity-modulated radiation
therapy allow much more elegant dose distributions to be
obtained than has hitherto been possible. In the context of
treatment-related morbidity, reduced doses to the salivary
glands and auditory apparatus would have signicant ben-
et. Ototoxicity could also be reduced by development of
less cisplatin-intensive chemotherapy regimens. Both these
approaches are now under investigation.
In summary, we have achieved excellent rates of locore-
gional control and survival in a series of patients with
disease at least as advanced anatomically as those in the
Intergroup trial. A phase III trial comparing the two strate-
gies would seem indicated.
ACKNOWLEDGMENT
We thank Alan McKenzie for reviewing the MRI and CT scans of
all patients treated on this trial and Paul Harari for critically
reviewing the manuscript.
REFERENCES
1. Petrovich Z, Cox JD, Middleton R, et al: Advanced carcinoma of
the nasopharynx: 2. Pattern of failure in 256 patients. Radiother Oncol
4:15-20, 1985
2. Qin D, Hu Y, Yan J, et al: Analysis of 1379 patients with
nasopharyngeal carcinoma treated by radiation. Cancer 61:1117-1124,
1988
3. Lee AWM, Poon YF, Foo W, et al: Retrospective analysis of
5037 patients with nasopharyngeal carcinoma treated during 1976-
1985: Overall survival and patterns of failure. Int J Radiat Oncol Biol
Phys 23:261-270, 1992
4. Boussen H, Cvitkovic E, Wendling JL, et al: Chemotherapy of
metastatic and/or recurrent undifferentiated nasopharyngeal carcinoma
with cisplatin, bleomycin, and uorouracil. J Clin Oncol 9:1675-1681,
1991
5. Brizel DM, Albers ME, Fisher SR, et al: Hyperfractionated
irradiation with or without concurrent chemotherapy for locally ad-
vanced head and neck cancer. N Engl J Med 338:1798-1804, 1998
6. 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 340:1137-1143, 1999
7. Schaake-Koning C, Van Den Bogaert W, Dalesio O, et al: Effects
of concomitant cisplatin and radiotherapy on inoperable non-small cell
lung cancer. N Engl J Med 326:524-530, 1992
8. Al-Sarraf M, LeBlanc M, Giri PGS, et al: Chemoradiotherapy
versus radiotherapy in patients with advanced nasopharyngeal cancer:
Phase III randomized Intergroup study 0099. J Clin Oncol 16:1310-
1317, 1998
9. Chua DTT, Sham JST, Choy D, et al: Preliminary report of the
Asian-Oceanian Clinical Oncology Association randomized trial com-
paring cisplatin and epirubicin followed by radiotherapy versus radio-
therapy alone in the treatment of patients with locoregionally advanced
nasopharyngeal carcinoma. Cancer 83:2270-2283, 1998
10. Webb A, Cunningham D, Scarffe JH, et al: Randomized trial
comparing epirubicin, cisplatin and uorouracil versus uorouracil,
doxorubicin, and methotrexate in advanced esophagogastric cancer.
J Clin Oncol 15:261-267, 1997
11. Jones AL, Smith IE, OBrien MER, et al: Phase II study of
continuous infusion uorouracil with epirubicin and cisplatin in pa-
tients with metastatic and locally advanced breast cancer: An active
new regimen. J Clin Oncol 12:1259-1265, 1994
12. International Nasopharynx Cancer Study Group: Preliminary
results of a randomized trial comparing neoadjuvant chemotherapy
(cisplatin, epirubicin, bleomycin) plus radiotherapy vs radiotherapy
alone in stage IV ( N2, M0) undifferentiated nasopharyngeal carci-
noma: A positive effect on progression-free survival. Int J Radiat Oncol
Biol Phys 35:463-469, 1996
13. Chan ATC, Teo PML, Leung TWT, et al: A prospective
randomized study of chemotherapy adjunctive to denitive radiother-
apy in advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol
Phys 33:569-577, 1995
14. Ma J, Mai H-Q, Hong M-H, et al: Results of a prospective
randomized trial comparing neoadjuvant chemotherapy plus radiother-
apy with radiotherapy alone in patients with locoregionally advanced
nasopharyngeal carcinoma. J Clin Oncol 19:1350-1357, 2001
15. Teo PML, Chan ATC, Lee WY, et al: Enhancement of local
control in locally advanced node-positive nasopharyngeal carcinoma
by adjunctive chemotherapy. Int J Radiat Oncol Biol Phys 43:261-271,
1999
16. Chan AT, Teo PM, Ngan RK, et al: A phase III randomized trial
comparing concurrent chemotherapy-radiotherapy with radiotherapy
alone in locoregionally advanced nasopharyngeal carcinoma. Proc Am
Soc Clin Oncol 19:415a, 2000 (abstr 1637)
17. Sanguineti G, Geara FB, Garden AS, et al: Carcinoma of the
nasopharynx treated by radiotherapy alone: Determinants of local and
regional control. Int J Radiat Oncol Biol Phys 37:985-996, 1997
18. Geara FB, Sanguineti G, Tucker SL, et al: Carcinoma of the
nasopharynx treated by radiotherapy alone: Determinants of distant
metastasis and survival. Radiother Oncol 43:53-61, 1997
1852 RISCHIN ET AL
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