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A phase III study of adjuvant chemotherapy in

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 Int. J. Radiation Oncology Biol. Phys., Vol. 52, No. 5, pp. 1238 1244, 2002
Copyright 2002 Elsevier Science Inc.
Printed in the USA. All rights reserved
0360-3016/02/$see front matter

PII S0360-3016(01)02781-X

CLINICAL INVESTIGATION Head and Neck

A PHASE III STUDY OF ADJUVANT CHEMOTHERAPY IN ADVANCED

NASOPHARYNGEAL CARCINOMA PATIENTS

KWAN-HWA CHI, M.D.,* YUE-CUNE CHANG, PH.D., WAN-YAO GUO, M.D.,

MEIN-JUNG LEUNG, M.D.,* CHENG-YIN SHIAU, M.D.,* SHENG-YU CHEN, M.D.,*
LING-WEI WANG, M.D.,* YUEN-LIANG LAI, M.D., MAU-MIN HSU, M.D., SHI-LONG LIAN, M.D.,
CHING-HSIUNG CHANG, M.D.,# TSANG-WU LIU, M.D.,** YUNG-HSIN CHIN, R.N.,**
SANG-HUE YEN, M.D.,* CHENG-HWANG PERNG, PH.D., AND KUANG Y. CHEN, M.D., PH.D.*
*Cancer Center and Department of Radiology, Veterans General Hospital-Taipei, National Yang-Ming University, Taipei, Taiwan;

Department of Mathematics, Tamkang University, Taipei, Taiwan; Department of Radiation Oncology, Mackay Memorial Hospital-
Taipei, Taipei, Taiwan; Department of Otolaryngology, National Taiwan University Hospital, National Taiwan University, Taipei,
Taiwan; Department of Radiation Oncology, Kaohsiung Medical University, Kaohsiung, Taiwan; #Department of Radiation Oncology,
Veterans General Hospital-Kaohsiung, Kaohsiung, Taiwan; **Taiwan Cooperative Oncology Group, National Health Research Institutes,
Taipei, Taiwan

Purpose: To evaluate the role of adjuvant chemotherapy in locally advanced nasopharyngeal carcinoma (NPC)
patients, we conducted a randomized Phase III trial comparing radiotherapy (RT) followed by adjuvant
chemotherapy to RT alone in patients with advanced NPC.
Methods and Materials: Between November 1994 and March 1999, 157 patients with Stage IV, M0 (UICC/AJCC,
1992) advanced NPC disease were randomized to receive standard radiotherapy, as follows: 35 40 fractions,
1.8 2.0 Gy/fraction/day, 5 days/week, to a total dose 70 72 Gy with or without 9 weekly cycles of 24-h infusional
chemotherapy (20 mg/m2 cisplatin, 2,200 mg/m2 5-fluorouracil, and 120 mg/m2 leucovorin) after RT. Of 157
patients enrolled, 154 (77 radiotherapy, 77 combined therapy) were evaluable for survival and toxicity analysis.
Results: With a median follow-up of 49.5 months, the 5-year overall survival and relapse-free survival rates were
60.5% vs. 54.5% (p 0.5) and 49.5% vs. 54.4% (p 0.38) for the radiotherapy-alone group and the combined
radiotherapy and adjuvant chemotherapy group, respectively. The Cox regression showed that the hazard rates
ratio of combined treatment to RT alone was 0.673 (p value 0.232); the 95% confidence interval was 0.352 and
1.288, respectively. Patients who received combined treatment had a lower systemic relapse rate than radiother-
apy-alone patients, according to relapse pattern analysis. The incidence of leukopenia (> Grade 3) occurred in
17 out of 819 (2.1%) cycles of weekly chemotherapy. No patient developed moderate to severe mucositis (> Grade
3).
Conclusions: We conclude that adjuvant chemotherapy after RT for patients with advanced NPC has no benefit
for overall survival or relapse-free survival. 2002 Elsevier Science Inc.

Nasopharyngeal carcinoma, Adjuvant chemotherapy, Radiotherapy, Chemotherapy.

INTRODUCTION pathologically as WHO (World Health Organization) Type

II and III histology and presented clinically as Stage IV, M0
Nasopharyngeal carcinoma (NPC) is a relatively common disease (UICC/AJCC 1992 staging). The observed 5-year
cancer in Taiwan. Most NPC patients in our study presented survival rate for 1,125 Stage IV, M0 NPC patients treated by

Reprint requests to: Kwan-Hwa Chi, M.D., Cancer Center,
Veterans General Hospital-Taipei, #201, sec. 2 Shih-Pai Rd., Tai-
pei, 11217, Taiwan, Republic Of China. Tel: (886) 2-28757468;
Fax: (886) 2-28749419; E-mail: khchi@vghtpe.gov.tw
AcknowledgmentsWe are grateful to Cheng-Wen Wu, Jacque-
line Whang-Peng, and Gi-Ming Lai for support from the Taiwan
Cooperative Oncology Group (TCOG) and the National Health
Research Institute. We are very grateful for help throughout the
study with data management and statistical assistance from Wei-
Lien Feng and Mei-Suei Lin from the Taiwan Cooperative Oncol-
ogy Group and the National Health Research Institute, Taiwan. We
also thank the members of TCOG who contributed to this clinical
trial but who are not in the authorship list, as follows: Yu-Ming
Liu, Veterans General Hospital-Taipei; Wen-San Liu, Veterans
General Hospital-Kaohsiung; Jian-Sheng Jan, Veterans General
Hospital-Taichung; Meng-Hao Wu, Mackay Memorial Hospital-
Taipei; Shen-Yeh Lin, Kaohsiung Medical University; Chih-Jen
Huang, Kaohsiung Medical University; Chien-Hsun Chen, Veter-
ans General Hospital-Kaohsiung; Ming-Chih Chang, Mackay Me-
morial Hospital-Taipei; Yih-Chang Weng, Veterans General Hos-
pital-Taichung; Tzeon-Jye Chiu, Veterans General Hospital-
Taipei; I-Cheng Lai, Mackay Memorial Hospital-Taipei; Kou-Hwa
Chang, Mackay Memorial Hospital-Taipei; and Jeng-Yuh Ko,
National Taiwan University Hospital. The authors also thank Dr.
Wing-Kai Chan for his advice on preparing the manuscript.
Received Jul 19, 2001, and in revised form Nov 5, 2001.
Accepted for publication Nov 12, 2001.

1238
 Adjuvant chemotherapy in NPC patients
radiotherapy (RT) alone at the Veterans General Hospital-
Taipei during 19811996 was 46% (1). Because of the high
incidence of locoregional and/or systemic relapse in patients
with locally advanced NPC treated with RT alone, the
addition of chemotherapy had been a strategy in various
studies (2 6). These protocols consisted of neoadjuvant
adjuvant concomitant chemotherapy. The neoadjuvant
chemotherapy in theory may decrease the bulky tumor and
facilitate the radiotherapy given subsequently and may de-
crease the chance of micrometastases before radiotherapy.
The concomitant chemotherapy usually aims at increasing
the efficacy of radiation. The use of adjuvant chemotherapy
after radiotherapy is generally believed to decrease the
chance of distant metastases.
Five prospective randomized Phase III trials investigating
various combinations of chemotherapy and RT have been
reported (711). Rossi et al. have reported on the only
adjuvant chemotherapy trial in which NPC patients received
six cycles of cyclophosphamide, adriamycin, and oncovin
after radiotherapy (7). No significant difference in overall or
relapse-free survival (RFS) was observed. One possible
explanation may be that the non-cisplatin chemotherapy
was ineffective. The role of adjuvant chemotherapy using a
cisplatin-containing regimen is unknown in NPC. Although
there are other studies that have not shown an effectiveness
for adjuvant chemotherapy in head-and-neck cancers as
shown in meta-analysis, the trials included in the meta-
analysis excluded reports on NPC-only trials (12). Perform-
ing adjuvant chemotherapy after full-dose radiotherapy pre-
sents the problem of toxicities from chemotherapy,
especially mucositis. We have developed in NPC treatment
an active but relatively nontoxic chemotherapy combination
regimen, PFL, with cisplatin, 5-fluorouracil (5-FU), and
leucovorin (13). The weekly PFL chemotherapy may mark-
edly reduce the oral mucositis rate while maintaining its
anticancer effect, as compared with its counterpart regimen
of 4-day infusional PFL (14). We believe that the weekly
PFL regimen may be an ideal candidate for the adjuvant
chemotherapy of NPC patients after a full course of radio-
therapy.
Therefore, since 1994 we have conducted a Phase III
study comparing radiotherapy alone with radiotherapy fol-
lowed by adjuvant chemotherapy; we have used weekly
PFL to evaluate the role of cisplatin-based adjuvant chemo-
therapy in locally advanced NPC patients.
METHODS AND MATERIALS
Between November 1994 and March 1999, 157 newly
diagnosed NPC patients were registered from nine institu-
tions in the Taiwan Cooperative Oncology Group (TCOG).
The eligibility criteria were as follows: biopsy-proven car-
cinoma of nasopharynx, Stage IV (UICC/AJCC 1992) dis-
ease (including T4N0 1M0 and TN23M0), and performance
status 0 2 (WHO). Patients were required to have adequate
bone marrow function (WBC [white blood cells] 4,000/
L, platelet count 100,000/L, hemoglobin 10.5 mg
K.-H. CHI et al. 1239
%), renal function (serum creatinine 1.5 mg/dL), and liver
function (total bilirubin 2.0 mg/dL). Patients were al-
lowed no previous history of chemotherapy or radiotherapy.
Pretreatment evaluation included a complete history and
physical examination, complete blood count, and blood
chemistry analysis. Staging evaluations included a CT scan
or MRI of the nasopharynx and base of skull and neck, chest
X-ray, bone scan, and liver sonography. Patients with se-
rology evidence of hepatitis B surface antigen were ex-
cluded from the study after October 1997 by protocol
amendment, because chemotherapy-induced reactivation of
hepatitis B had been found to be a serious adverse event in
one patient. Dental care and an audiogram were performed
before radiotherapy. The study was approved by the insti-
tutional review board. All patients gave written informed
consent before registration. Patients fulfilling enrollment
criteria were centrally randomized by fax at the central
office of the Taiwan Cooperative Oncology Group in Tai-
pei. The randomization procedure was performed with the
stratified permuted-block randomization method (with
block size 4).
Radiotherapy
All patients underwent mask immobilization with simu-
lation and CT-based planning. Six-megavolt photons were
used along with electrons, when indicated. The nasopharynx
and the upper neck were initially treated by bilateral op-
posed fields. The lower neck and supraclavicular regions
were treated by single anterior field with or without a
posterior beam. At the dose level of 40 Gy from the initial
opposed lateral fields, a spinal cord block was introduced in
the upper-neck field. The posterior neck under the spinal
cord block was treated with electron beam. The primary and
neck boost fields were given separately after 50 Gy. The
infraorbital two-wedge angle portals, three-field technique,
or three-dimensional conformal treatment techniques were
used. In the absence of a palpable upper-neck node, the
lower neck was prophylactically treated on the side to 50
Gy. A daily dose to gross tumor sites of 1.8 Gy to 2.0 Gy per
fraction, 5 fractions per week to a total dose 70 72 Gy was
used in this study.
Chemotherapy
Patients were randomized to receive adjuvant PFL che-
motherapy or radiotherapy alone. Adjuvant chemotherapy
was started 4 weeks after completion of radiotherapy; the
PFL chemotherapy consisted of 9 weekly cycles of cisplatin
(P), 5-fluorouracil (F), and leucovorin (L) in the following
dose: 20 mg/m2 cisplatin, 2,200 mg/m2 5-fluorouracil, and
120 mg/m2 leucovorin in a 24-h infusion. The regimen can
be administered to an outpatient with a portable infusion
pump or to an inpatient with an i.v. infusion pump, using a
500-mL normal saline. Patients were instructed to drink at
least 3,000 mL/day while on outpatient treatment. First-
cycle chemotherapy was administered only if WBC
3,000/uL and platelet count 100,000/L. Chemotherapy
was withheld on the day it was scheduled if WBC
1240 I. J. Radiation Oncology Biology Physics Volume 52, Number 5, 2002

2,000/L or platelet count 50,000/L; chemotherapy Table 1. Patients characteristics

was delayed 1 week or more until WBC 3,000/L or
Assigned treatment
platelet count 100,000/L. Weekly PFL chemotherapy
was delayed 1 week until mucositis or diarrhea was Grade RT RT CT
0 1. Doses were modified for significant mucositis or diar- (n 77) (n 77)
rhea: 5-FU was reduced 20% in subsequent cycles for Grade
Age
3 or 4 mucositis or diarrhea; 5-FU was reduced 10% in Median 47 46
subsequent cycles for Grade 2 mucositis or diarrhea. The Range 2473 1676
next dose of cisplatin was stopped for patients who devel- Gender
oped Grade 2 neurotoxicity or progressive change in Male 58 (75.3%) 60 (77.9%)
Lhermitte syndrome ( Grade 1). Cisplatin was stopped for Female 19 (24.7%) 17 (22.1%)
Stratification
creatinine 2.0 mg/dL. I: T4, N01 10 (13.0%) 10 (13.0%)
II: Any T, N2 52 (67.5%) 50 (64.9%)
Patient assessments III: T13, N3 10 (13.0%) 14 (18.2%)
The primary efficacy end point of this study was overall IV: T4-N3 5 (6.5%) 3 (3.9%)
survival. The other efficacy end points were RFS, metasta- Performance
0 55 (71.4%) 54 (70.1%)
sis-free survival (MFS), and locoregional relapse-free sur- 12 22 (28.6%) 23 (29.9%)
vival (LRFS), including nodes. Complete response was Histology (WHO)
defined as the complete disappearance of measurable or I 0 (0.0%) 2 (2.6%)
palpable tumors as confirmed by CT scan or MRI. The II 46 (59.7%) 41 (53.3%)
persistence of radiologic signs of nasopharyngeal mucosal III 34 (44.2%)
31 (40.3%)
thickening was scored as partial response. Progressive dis-
ease was defined as the growth of any measurable lesion,
according to CT or MRI, by more than 25% of the sum of
two perpendicular diameters, or as the presence of palpable static disease (1 in bone, 1 in lung, and 1 in liver) before
lesions or the appearance of any new lesion or site. Patients registration. The resulting 154 patients were evaluable for
who developed local or distant relapse after therapy could survival and toxicity analysis. Seventy-seven patients were
be treated by any means considered appropriate by the randomized to radiotherapy plus chemotherapy, and 77
responsible physician. were randomized to radiotherapy alone. The patients char-
acteristics in the two treatment groups are summarized in
Statistical considerations Table 1. The distributions of the patients main clinical
We assume that the 5-year survival rate for advanced- characteristics were comparable between these two treat-
stage NPC patients who receive radiotherapy alone is 40% ment groups. The median total dose delivered to the tumor
and for those who receive adjuvant PFL chemotherapy after was 70.2 Gy: 68.4 Gy to the upper neck and 54 Gy to the
radiotherapy is 60%. After adjusting for the 12% anticipated lower neck. There was no delay of allocation to the start of
dropout rate, a total of 240 patients (120 patients per arm) is radiotherapy in all patients. All patients completed the treat-
planned to ensure an 80% probability of detecting the dif- ment course with scheduled dose.
ference between those two (5-year) survival rates at the
one-sided 5% significance level. Differences between Toxicity
groups were evaluated by chi-square test or Fishers exact There were six fatal toxicities in the combined chemo-
test for categoric variable. Overall survival (duration from therapy and radiotherapy group. One patient died of myo-
the date of treatment to latest follow-up [event: death]), cardial infarction before chemotherapy, one died of reacti-
relapse-free survival (duration from the date of treatment to vation of hepatitis B after 4 cycles of weekly chemotherapy,
latest follow-up [event: relapse or death]), metastasis-free one died of aspiration pneumonia after 4 cycles of weekly
survival (duration from the date of treatment to latest fol- chemotherapy, one died of perforated gastric ulcer after the
low-up [event: metastasis or death]), and local relapse-free sixth cycle of weekly chemotherapy, one died of unknown
survival (duration from the date of treatment to latest fol- cause after the full cycle of weekly chemotherapy, and one
low-up [event: locoregional relapse or death]) were ana- patient died of radiation myelitis 9 months after radiother-
lyzed by the KaplanMeier methods. Comparisons of sur- apy. In the radiotherapy-alone arm, one patient died of poor
vival were performed using the Cox regression model. nutrition from Grade 4 oropharyngitis from radiotherapy.
Analyses were carried out on the intention-to-treat basis. The most frequent toxicity from radiotherapy was mucosi-
Statistical significance was defined as p 0.05. tis. The mucositis ( Grade 2) occurred in 74.0% of pa-
tients randomized to the radiotherapy arm and in 84.4% of
patients randomized to the combined arm. As shown in
RESULTS
Table 2, the most frequent toxicity from adjuvant chemo-
Among the 157 patients enrolled in this study, 3 patients therapy was myelotoxicity. Grade 3 and 4 leukopenia was
(2%) were considered ineligible. All 3 patients had meta- observed in 31.4% and 2.0% of patients, respectively. The
 Adjuvant chemotherapy in NPC patients K.-H. CHI et al. 1241

Table 2. Toxicity from CT (Grade 2) TCOG executive committee decided on the early termina-
tion of the T1394 trial.
Group B (RT CT/ n 51)

Toxicity Grade 2 Grade 3 Grade 4 Response and relapse patterns

The median time to complete response was 6.08 months.
Hepatic 0 1 1 Overall, 51 patients in the radiotherapy-alone arm (51/75
(0.0%) (2.0%) (2.0%)
Vomiting 26 4 1 68.0%) achieved complete response, and 53 patients in the
(51.0%) (7.8%) (2.0%) combined arm (53/73 72.6%) achieved complete re-
Nausea 21 7 0 sponse. The patterns of disease relapse are shown in Table
(41.2%) (13.7%) 3. In the control group, 36.4% of patients (by adding distant
Diarrhea 7 2 0 and local distant relapses) developed distant metastases,
(13.7%) (3.9%)
Mucosa 10 0 0 whereas in the combined treatment group, 19.5% developed
(19.6%) distant metastases (p 0.03). There was no statistically
Neurologic 1 0 0 significant difference in the relapse rates between control
(2.0%) and combined treatment groups based on the subgroup
Ototoxicity 2 1 0 analysis of the four stratification groups (data not shown).
(3.9%) (2.0%)
Leukopenia 21 16 1
(41.2%) (31.4%) (2.0%) Overall survival and relapse-free survival
Anemia 16 9 0 The median follow-up duration for the 154 randomized
(31.4%) (17.6%) patients was 49.5 months. (range: 1.9 68.9 months). Four
Thrombocytopenia 1 1 0 patients were lost to follow-up; the follow-up rate was
(2.0%) (2.0%)
97.4%. There was no statistical difference between the
Abbreviations: CT chemotherapy; RT radiotherapy. 5-year overall survival rate of 54.5% for the combined
radiotherapy and adjuvant chemotherapy group and the
5-year overall survival rate of 60.5% for the RT-alone group
incidence of leukopenia ( Grade 3) occurred in 17 out of (Fig. 1). The Cox regression analysis showed that the hazard
819 (2.1%) weekly chemotherapy cycles. The incidence of rates ratio of combined treatment to RT alone was 0.673,
nausea ( Grade 3) was 13.7%, and incidence of vomiting with p 0.232 and 95% confidence intervals of 0.352 and
( Grade 3) was 9.8%. Two patients (3.9%) developed 1.288, respectively. Twenty-four patients in the radiothera-
diarrhea ( Grade 3). Remarkably, no patient developed py-alone group died, 1 from treatment toxicity, whereas 26
moderate or severe mucositis ( Grade 3). patients in the combined treatment group died, 6 from
Patient compliance to chemotherapy was poor, even treatment-related toxicities. The median RFS time was 38.7
though the toxicity profiles indicate that adjuvant weekly months for the radiotherapy group and 40.4 months for the
PFL chemotherapy is quite tolerable. Twenty-six patients combined group (Fig. 2). The 5-year RFS rate, MFS rate,
(33.8%) randomized to receive adjuvant chemotherapy and LRFS rate was 54.4%, 59.6%, and 49.4%, respectively,
changed their minds after the completion of radiotherapy. for the combined group compared with 49.5%, 58.4%, and
Among the remaining 51 patients who intended to receive 51.3% for the RT-alone group. In the intention-to-treat
chemotherapy, 40 patients (78%) did complete the 9 weekly analysis, there was no significant statistical difference (p
cycles of chemotherapy. 0.376, 0.677, and 0.951, respectively) between the two
Based on the slow accrual rate and the unexpected, seri- treatment groups from those three survival end points.
ous adverse events, as well as on the interim analysis
performed 4 years after patient accrual had begun, the Data
DISCUSSION
and Safety Monitor Committee of TCOG suggested that
there would be only a remote chance that the trial could Over the past two decades, attempts have been made to
reach its statistical goal within a reasonable time. The improve the results of radiotherapy for NPC treatment by

Table 3. Pattern of relapse

Intent-to-treat

RT RT CT Total
Relapse pattern (n 77) (n 77) (n 154)

Local recurrence 8 (10.4%) 6 (7.8%) 14 (9.1%)

Distant metastasis 20 (26.0%) 13 (16.9%) 33 (21.4%)
Local recurrence/distant metastasis 8 (10.4%) 2 (2.6%) 10 (6.5%)
Nontumor-related death 4 (5.2%) 10 (13.0%) 14 (9.1%)
Non-relapse 37 (48.0%) 46 (59.7%) 83 (53.9%)
1242 I. J. Radiation Oncology Biology Physics
Fig. 1. Overall survival curves (p 0.5).
the incorporation of chemotherapy before, during, or after
radiotherapy (1517). Each type of integration has its ad-
vantages and disadvantages. Routinely incorporating che-
motherapy into the treatment of NPC before the results of
randomized trials on pure neoadjuvant, concomitant, or
adjuvant chemotherapy have matured may result in over-
treatment.
This study is the second randomized trial that was
unable to demonstrate the benefit of adjuvant chemother-
Fig. 2. Relapse-free survival curves (p 0.376).
Volume 52, Number 5, 2002
apy after standard RT. This is the first randomized trial
using a cisplatin-based chemotherapy regimen that failed
to demonstrate a survival benefit in locally advanced
NPC patients. Adjuvant chemotherapy may still be of
benefit in reducing the incidence of systemic relapse from
36.4% of patients in the control group to 19.5% of
patients in the combined treatment group (p 0.03), as
assessed from relapse pattern analysis. However, the
RFS, MFS, and LRFS analysis should regard all causes of
death as events, and none of the survival parameters
reported in this study are statistically different between
the two treatment arms.
The Head and Neck Intergroup 0099 trial is the only
trial to date that has shown an improvement in overall
survival (11). It tested three cycles of concurrent cisplatin
and conventional RT followed by three cycles of adju-
vant PF chemotherapy with RT alone. The trial differs
from all others in that the chemotherapy was given during
and after radiotherapy. The results showed a significant
improvement in 3-year overall survival (47% vs. 78% at
3 years, p 0.005) in favor of the combined treatment
group. The major criticism of this study is the relatively
low overall survival rate of patients receiving RT alone
compared to the survival rate in most Asian and Euro-
pean trials, including the current Taiwan Cooperative
Oncology Group trial, which shows a 3-year overall
survival rate of 68.4% with RT alone. The difference may
result from including a large proportion of patients with
WHO Type I squamous cell carcinoma of the nasophar-
 Adjuvant chemotherapy in NPC patients
ynx. Nevertheless, it has been concluded that the high
survival rate results from concomitant chemoradiother-
apy (CCRT), and the benefit of adjuvant chemotherapy is
further supported by others (17). To understand why the
results of the Intergroup 0099 trial seemed unique, data
on individual modalities of NPC treatment, adjuvant che-
motherapy or CCRT, need to be recorded separately.
Comparing the Intergroup study with this one, the dose
intensity and duration of the weekly PFL chemotherapy
used here (9-week cycle) is no less than that in the
adjuvant chemotherapy part of the Intergroup study (3-
month cycle). When we compare our results with that of
the Intergroup study, the role of CCRT seems more
important than that of adjuvant chemotherapy. There is a
randomized trial ongoing in Hong Kong comparing
CCRT vs. radiotherapy alone in locally advanced NPC
patients (18). The preliminary results show a significantly
better 2-year progression-free survival in the CCRT arm
(78% vs. 62%) (p 0.013), but the overall survival rate
has not yet been mentioned. Unless the data for CCRT
alone prove a dramatic survival benefit in the near future,
CCRT followed by adjuvant chemotherapy is theoreti-
cally synergistic. Randomized trials of CCRT without
adjuvant chemotherapy have achieved some improve-
ment in the overall survival rate in lung cancers, cervix
cancers, and head-and-neck cancers compared to their
radiotherapy-alone counterparts (12, 19 21). NPC may
prove to be another example.
Poor compliance to adjuvant chemotherapy has always
been reported in head-and-neck cancer trials (11, 22). Thir-
ty-three percent of patients refused to receive chemotherapy
in the Intergroup study, as did 33.8% in our patient group.
One of the major concerns regarding toxicity from adjuvant
chemotherapy after full-dose radiotherapy in head-and-neck
patients was the fear of re-experiencing mucositis from
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