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P h a s e I I I S t u d y o f C o n c u r r e n t C h e m o r a d i o t h e r a p y V e r s u sR a d i o t h e r a p y A l o n e f o r A d v a n c e d N a s o p h a r y n g e a l C a r c i n o m a :

P o s i t i v e E f f e c t o n O v e r a l l a n d P r o g r e s s i o n - F r e e S u r v i v a l

By Jin-Ching Lin, Jian-Sheng Jan, Chen-Yi Hsu, Wen-Miin Liang, Rong-San Jiang, and Wen-Yi Wang

Purpose: Nasopharyngeal carcinoma (NPC) is a radio-sensitive and chemosensitive tumor. This randomized phase

III trial compared concurrent chemoradiotherapy (CCRT) ver-sus radiotherapy (RT) alone in patients with advanced NPC.Patients and Methods: From December 1993 to April

1999, 284 patients with 1992 American Joint Committee onCancer stage III to IV (M0) NPC were randomly allocated intotwo arms. Similar dosage and fractionation of RT wasadministered in both arms. The investigational arm receivedtwo cycles of concurrent chemotherapy with cisplatin 20mg/m2/d plus fluorouracil 400 mg/m2/d by 96-hour con-tinuous infusion during the weeks 1 and 5 of RT. Survivalanalysis was estimated by the Kaplan-Meier method andcompared by the log-rank test.

Results: Baseline patient characteristics were compara-ble in both arms. After a median follow-up of 65 months,

26.2% (37 of 141) and 46.2% (66 of 143) of patients devel-oped tumor relapse in the CCRT and RT-alone groups, respec-

tively. The 5-year overall survival rates were 72.3% for theCCRT arm and 54.2% for the RT-only arm (P .0022). The5-year progression-free survival rates were 71.6% for theCCRT group compared with 53.0% for the RT-only group (P.0012). Although significantly more toxicity was noted in theCCRT arm, including leukopenia and emesis, compliance withthe combined treatment was good. The second cycle of con-current chemotherapy was refused by nine patients and wasdelayed for>1 week for another nine patients.There were notreatment-related deaths in either arm.

Conclusion: We conclude that CCRT is superior to RTalone for patients with advanced NPC in endemic areas.

J Clin Oncol 21:631-637. 2003 by AmericanSociety of Clinical Oncology.

NASOPHARYNGEAL CARCINOMA (NPC) is a neoplasmof the head and neck that is rarely seen in the UnitedStates and Western Europe. It is much more common, however,

among Southeast Asian, North African, and Eskimo populations.

NPC differs from other squamous cell carcinomas of the head

and neck with regard to epidemiology, histologic features,

treatment strategies, and response to therapy.1

Because of anatomic limitations and a high degree of radio-

sensitivity, NPC has traditionally been treated by radiotherapy

(RT) rather than surgery. The 5-year survival rates for RT alone

have been reported to be about 34% to 52%.2-9 Although

early-stage NPC is highly radiocurable, the treatment results oflocoregionally advanced NPC have been disappointing. NPC is

also a chemosensitive tumor, especially with cisplatin-based

regimens.10-15 Recently, a great deal of attention has focused on

combined RT and chemotherapy in the treatment of advanced

NPC. However, the choice of drug, timing of delivery, dosage,

and duration of therapy remain controversial. In general, three

different strategies have been employed to incorporate chemo-

therapy into the standard course of RT: before (neoadjuvant),

during (concurrent), and after (adjuvant) radiation therapy. Each

mode of combined therapy has advantages and disadvantages

and has been extensively investigated in the last few years.

Our previous studies have shown that concurrent chemoradio-therapy (CCRT) for locoregionally advanced NPC is both feasible

and effective, with acceptable toxic effects.16,17 On the basis of our

encouraging results and other similar studies,16-19 we conducted a

phase III randomized trial to compare the survival benefits and toxic

effects of CCRT versus RT alone for advanced NPC.

PATIENTS AND METHODS

Patients with biopsy-proven NPC and stage III to IV (M0) disease

according to the 1992 American Joint Committee on Cancer staging system20

were eligible for this trial. Patients could have no history of previous RT or

chemotherapy, and no history of previous cancer except for carcinoma-in-

situ of the cervix or nonmelanoma cancers of the skin. Other eligibility

criteria were Karnofsky performance status 60%; WBC count greater than

4,000/L and platelet count greater than 100,000/L; serum creatinine level

less than 1.6 mg/dL; normal liver function with total bilirubin less than 2.5

mg/dL; and no detectable distant metastasis. This study was performed after

approval from the institutional ethics committee. All patients were randomly

allocated and were required to provide written, informed consent before

treatment.

Pretreatment Evaluation

All patients underwent fiberoptic nasopharyngoscopy and biopsy to obtain

specimens for pathologic diagnosis. Pretreatment staging evaluations in-cluded clinical examination of the head and neck; computed tomography

(CT) scan or magnetic resonance imaging from the skull base to the whole

neck; chest radiography; whole-body bone scan; abdominal sonography;

complete blood count with differential count, platelet count, and biochemical

profile; and Epstein-Barr virus serology. Chest CT scan and bone marrow

biopsy were not routinely performed unless there were findings suspicious

for lung metastases on chest radiography or abnormal routine blood tests.

From the Departments of Radiation Oncology and Otorhinolaryngology,

Taichung Veterans General Hospital; Department of Public Health, China

Medical College; Department of Basic Medicine, Hung Kuang Institute of

Technology, Taichung; and Institute of Clinical Medicine, College of

Medicine, National Yang-Ming University, Taipei, Taiwan.Submitted June 27, 2002; accepted October 28, 2002.

Supported by grants from the National Science Council (NSC86-2314-B-

075A-022 and NSC87-2314-B-075A-002) and Taichung Veterans General

Hospital (TCVGH-887102C and TCVGH-897101C), Taiwan.

Address reprint requests to Jin-Ching Lin, MD, PhD, Department of

Radiation Oncology, Taichung Veterans General Hospital, Taiwan, No. 160,

Sec. 3, Taichung-Kang Rd., Taichung, 407 Taiwan, email: jclin@mail.

vghtc.gov.tw.

2003 by American Society of Clinical Oncology.

0732-183X/03/2104-631/$20.00

631Journal of Clinical Oncology,Vol 21, No 4 (February 15), 2003: pp 631-637DOI: 10.1200/JCO.2003.06.158

Downloaded from jco.ascopubs.org on December 27, 2013. For personal use only. No other uses without permission.Copyright 2003 American Society of Clinical Oncology. All rights reserved.

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Radiotherapy

Patients were initially treated with a telecobalt unit or a linear accelerator

of 6-MV photons. We used the source-axis distance technique with an

immobilized mask. All patients were treated in the supine position, usually

through bilateral parallel opposedfields to the primary tumor and upper neck

and a single anteriorfield to the lower neck with a central block. After 40 to

42 Gy, the primary boost field was changed to 10 MV photons delivered

from a linear accelerator via bilaterally opposed reduced portals. The bulky

nodal area was boosted using a posteroanterior neckfield of cobalt-60 or an

electron beam of appropriate energy. The total planned dose was 70 to 74Gy/7 to 8 weeks to the primary tumor and positive neck region and 50 to 60

Gy/5 to 6 weeks to the negative neck region. For patients with anterior

extension of the primary tumor, a three-field combination technique (bilateral

opposed and anterior portals) was administered.

The target volume was delineated by CT scan, and the field arrangement

was individualized. The superior margin of the primary field encompassed

2.0 cm beyond what was visible on CT scan and included the entire base of

the skull and the sphenoid sinus. Posteriorly, the field extended at least 2 cm

beyond the mastoid process and 2 cm beyond any palpable lymph nodes.

Anteriorly, the field included the posterior half of the maxillary sinus and

nasal cavity, or 2 cm beyond the limits of tumor involvement.

The fractionation was 1.8 to 2.0 Gy/d, Monday through Friday, for most

patients. During the initial period of this trial, a partially hyperfractionated

accelerated RT schedule (1.5 Gy/fraction, two fractions per day with at least

a 6-hour interfraction interval at weeks 1, 5, and 6; and 1.8 Gy/fraction, five

fractions per week at weeks 2 to 4 weeks) was delivered to 44 patients (20

in the CCRT group and 24 in the RT group).16

Concurrent Chemotherapy

Concurrent chemotherapy consisting of cisplatin 20 mg/m2/d mixed in

normal saline with fluorouracil (FU) 400 mg/m2/d was administered as a

96-hour continuous infusion during weeks 1 and 5 of RT. The chemotherapy

could be delivered using an ambulatory pump in the outpatient setting.

Patients were encouraged to drink large amounts offluid during chemother-

apy infusion. The second cycle of concurrent chemotherapy was delayed if

leukopenia persisted into week 5 or the patient experienced severe mucositis,

and was promptly resumed after recovery. No dose modi fications were made.

Patient Assessment

Tumor response and acute toxicity were assessed according to the World

Health Organization criteria.21 All patients were subjected to physical

examination, complete blood count, platelet count, and body weight deter-

mination during each week of therapy. Liver and renal function tests were

rechecked at the end of week 4. After completion of treatment, patients were

followed weekly until acute side effects resolved. Patients were then

evaluated every 2 months during thefirst year, every 3 months for the years

2 and 3, and every 6 months thereafter. CT scan, chest radiography,

abdominal sonography, whole-body bone scan, blood count, and biochem-

istry tests were routinely performed annually or at the time of clinical

suggestion of tumor relapse.

The primary end points of this study were progression-free survival and

overall survival. Progression-free survival was defined as the time from the

first day of treatment to the time of disease progression. Overall survival was

defined as the time from day 1 of treatment to date of death from any cause

or to last follow-up visit. Nasopharynx disease-free survival, neck disease-

free survival, and distant metastasis disease-free survival were also evaluated

and calculated from day 1 of treatment until the day of first occurrence of

primary, neck, or distant relapse or until the date of the last follow-up visit.

An intention-to-treat principle was applied to all patients in the analysis.

Statistical Considerations

Patient characteristics and other variables were compared as follows. A

Studentsttest was used for continuous variables between the two groups. A

2 test was used for category or ordinal variables. Fishers exact test was

used when a small sample size existed. Survival curves were estimated by the

product-limit method.22 Survival differences for treatment were analyzed

using the log-rank test.23 All statistical tests were two-sided, and aPvalue

0.05 was considered statistically significant. Analyses were performed by use

of the SAS program (Version 8.0; SAS Institute, Inc, Cary, NC).

Treatment for Relapse or Residual Disease

When possible, salvage treatments were given to patients after docu-

mented relapse or for persistent disease. The salvage treatments considered

appropriate by the attending physician included re-irradiation, chemotherapy,

and surgery.

RESULTS

Patient Characteristics

From December 1993 through April 1999, 284 eligible pa-

tients were entered onto the study. One hundred forty-one

patients were randomly allocated to the CCRT arm, and 143

patients were randomly allocated to the RT-alone arm. The

baseline characteristics of the two armsincluding age, sex,

Karnofsky performance status, pathology, T stage, and N

stagewere not significantly different (Table 1).

Response

The complete response rate, evaluated at 2 months after

completion of treatment, was 95.0% for the CCRT group and

85.3% for the RT-alone group (P .0497, Table 2). We

conclude that concurrent chemotherapy does enhance the effects

of radiation on tumor response.

Toxicity and Compliance

Acute toxic effects according to the World Health Organiza-

tion criteria are listed in Table 3. No fatal toxicity related to

planned treatment occurred in either group. A higher incidence

Table 1. Patient Characteristics

Characteristic

ConcurrentChemoradiotherapy

(n 141)Radiotherapy

Alone (n 143)

No. % No. %

Age, yearsRange 18-79 16-79Median 46 50Mean 45 48

SexMale 101 71.6 98 68.5Female 40 28.4 45 31.5

Karnofsky scale 80% 83 58.9 74 51.7

80% 58 41.1 69 48.3Pathology (WHO classification)

Type I 3 2.1 6 4.2Type II 103 73.0 105 73.4Type III 35 24.8 32 22.4

T stage (1992 AJCC)T1 to T2 51 36.2 66 46.2T3 to T4 90 63.8 77 53.8

N stage (1992 AJCC)N0 to N1 53 37.6 44 30.8

N2 to N3 88 62.4 99 69.2Overall stage (1992 AJCC)

III 34 24.1 22 15.4IV 107 75.9 121 84.6

Abbreviations: WHO, World Health Organization; AJCC, American Joint Com-mittee on Cancer.

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of leukopenia and emesis was observed in patients in the CCRT

arm (P .05). Grade 3 to 4 mucositis and adverse skin reactions

occurred more frequently in the CCRT group than in the

RT-alone group, but the difference was not statistically signifi-

cant. There was no liver or renal function impairment in either

arm. Alopecia caused by concurrent chemotherapy was not

observed for most patients, and only 5% of patients suffered

minimal hair loss (grade 1).

Two patients in the CCRT arm and three patients in the RT

arm did not complete the planned dose of RT. RT interruption

1 week occurred in 11 patients in the CCRT group and in 16

patients in the RT group. In the CCRT arm, the second cycle of

concurrent chemotherapy was refused by nine patients and was

delayed 1 week for another nine patients. Perforated peptic

ulcer with life-threatening acute peritonitis related to treatment

occurred in two patients receiving CCRT. They recovered

uneventfully after surgical correction. Boost RT was given to

four patients (two in each arm) for residual primary tumor (three

cases) or neck node (one case) within 3 months from the end

of initial (chemo)radiotherapy. In our experience, residual neck

nodes usually regress slowly or become fibrotic after several

months. Therefore, no planned neck dissections were performed

for 6 months in patients with residual neck disease. Two patients

with neck recurrence in the RT group received neck dissection at19 and 63 months, respectively. Salvage surgery for primary

recurrence was performed for three patients in the CCRT arm

and five patients in the RT arm at 14 to 28 months.

Patterns of Treatment Failure

After a median follow-up of 65 months (range, 36 to 100),

26.2% (37 of 141) and 46.2% (66 of 143) of patients in theCCRT and RT-alone groups developed tumor relapse, respec-

tively. The detailed distribution of the treatment failure pattern is

illustrated in Table 4. There were significant differences between

the two groups in primary and distant failures, but not in neck

recurrence.

Survival

Concurrent chemotherapy significantly improved overall sur-

vival and progression-free survival. The 5-year progression-free

survival rates were 71.6% for the CCRT group compared with

53.0% for the RT-alone patients (Fig 1, P .0012). The overall

survival rates at 5 years were 72.3% (CCRT group) and 54.2%(RT-alone group), respectively (Fig 2, P .0022). The survival

benefits of concurrent chemotherapy appear to be caused by its

radio-enhancing effects. The 5-year nasopharynx disease-free

survival rates were 89.3% for the CCRT group and 72.6% for the

RT-alone patients (Fig 3, P .0009). CCRT also had better

regional and distant control rates, but the difference did not reach

statistical significance. The 5-year neck disease-free survival

rates were 96.8% (CCRT group) and 92.1% (RT-alone group),

Table 2. Tumor Response

Response

Concurrent Chemoradiotherapy(n 141)

Radiotherapy Alone(n 143)

No. % No. %

Complete response 134 95.0 122 85.3Partial response

unevaluable7 5.0 21 14.7

Table 3. Acute Toxicity

Grade 0 (%) 1-2 (%) 3-4 (%)

Leukopenia

CCRT 52 (36.9) 83 (58.9) 6 (4.3)RT 87 (60.8) 56 (39.2)

AnemiaCCRT 100 (70.9) 37 (26.3) 4 (2.8)RT 107 (74.8) 36 (25.2)

ThrombocytopeniaCCRT 139 (98.6) 2 (1.4)RT 141 (98.6) 1 (0.7) 1 (0.7)

MucositisCCRT 2 (1.4) 75 (53.2) 64 (45.4)

RT 1 (0.7) 92 (64.5) 50 (35.0)Skin reaction

CCRT 4 (2.8) 94 (66.6) 43 (30.5)RT 3 (2.1) 103 (72.1) 37 (25.9)

VomitingCCRT 65 (46.1) 70 (49.6) 6 (4.3)RT 136 (95.1) 7 (4.9)

Weight lossCCRT 8 (5.7) 128 (90.8) 5 (3.5)RT 14 (9.8) 123 (86.1) 6 (4.2)

Abbreviations: CCRT, concurrent chemoradiotherapy; RT, radiotherapy.

Table 4. Patterns of Failure

Failure Site(s)

ConcurrentChemoradiotherapy

(n 141)

RadiotherapyAlone

(n 143) P

T 7 20N 0 1M 23 31T N 3 3T M 3 6

N

M 1 0T N M 0 5Total failure in T 13 (9.2%) 34 (23.8%) .0010Total failure in N 4 (2.8%) 9 (6.3%) .1634

Total failure in M 27 (19.1%) 42 (29.4%) .0446

Abbreviations: T, nasopharynx; N, neck; M, distant metastasis.

Fig 1. Comparison of progression-free survival curves between patientstreated by concurrent chemoradiotherapy () and radiotherapy alone ().

633CONCURRENT CHEMORADIOTHERAPY FOR ADVANCED NPC


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respectively (Fig 4, P .1716). The rates of distant metastasis

disease-free survival at 5 years were 78.7% (CCRT group) and

69.9% (RT-alone group) (Fig 5, P .0577).

DISCUSSION

Because NPC is a common cancer in Taiwan, we reviewed

more than 500 articles written in English regarding NPC during

the last few years. A SilverPlatter MEDLINE search (WinSpirs

version 4.01) was also conducted covering the years 1966 to

2002 to avoid missing relevant references. To the best of our

knowledge, there have been nine phase III randomized trials to

investigate the role of combined chemoradiotherapy in NPC.24-32

Table 5 summarizes the outcomes of these trials. Unfortunately,

most studies have shown no survival benefit. The most important

study was a United States Intergroup study,28 which is the only

randomized trial to show a survival benefit with chemoradiother-apy. However, its applicability to non-American NPC patients

has been criticized for differences in racial composition and

pathologic subtype distribution, as well as unexpected inferior

results in the RT-alone arm.

Because different staging systems, prognostic factors, drugs,

and schedules have been used in previous studies, it has been

difficult to determine which are optimal for the treatment of

NPC. Two trials explored the efficacy of postradiation adjuvant

chemotherapy. A trial conducted in Italy included more patients

with low risk for distant failure and used less active drug

combinations (vincristine, cyclophosphamide, doxorubicin).

This may account for the negative results obtained when com-

paring RT alone and RT plus six monthly cycles of adjuvant

chemotherapy.24 Using a weekly cisplatin, FU, and leucovorin

regimen of adjuvant chemotherapy for 9 weeks, the Taiwan

Cooperative Oncology Group demonstrated no benefit for over-

all or relapse-free survival.30 An unusually high incidence of

treatment-related deaths (six fatalities from toxicity) in the

combined treatment arm and a patient cohort that was primarily

at intermediate risk of relapse could explain this studys negative

findings. Four trials have evaluated the role of neoadjuvant

chemotherapy in the treatment of NPC. A Japanese trial32 failed

to demonstrate significant improvement in disease-free survival

or overall survival, but this outcome may have been caused by

the small sample size, the inclusion of patients with early-stage

disease (1988 American Joint Committee on Cancer stages I to

IV), as well as the relatively low dose-intensity of neoadjuvant

chemotherapy administered. Using a more active regimen of

neoadjuvant chemotherapy, the other three large, randomized

trials showed a positive tendency in the survival analysis of the

combined treatment arm.26,27,29 We re-evaluated why these

phase III randomized trials failed to demonstrate a significant

Fig 3. Comparison of nasopharynx disease-free survival curves betweenpatients treated by concurrent chemoradiotherapy () and radiotherapy alone ().

Fig 4. Comparison of neck disease-free survival curves between patientstreated by concurrent chemoradiotherapy () and radiotherapy alone ().

Fig 5. Comparison of distant metastasis disease-free survival curves betweenpatients treated by concurrent chemoradiotherapy () and radiotherapy alone ().

Fig 2. Comparison of overall survival curves between patients treated byconcurrent chemoradiotherapy () and radiotherapy alone ().

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survival benefit of neoadjuvant chemotherapy. Possible reasons

include a relatively lower dose of cisplatin (120 to 180 mg/m2/

person) in the Asian-Oceanian Clinical Oncology Association

trial,27 or an excess of chemotherapy-related deaths and RT

refusal in the International Nasopharynx Cancer Study Grouptrial,26 or the use of patient populations with less advanced stage

NPC.27,29 Indeed, subgroup analysis of patients with bulky neck

lymph nodes greater than 6 cm in the Asian-Oceanian Clinical

Oncology Association trial showed that neoadjuvant chemother-

apy improved 3-year relapse-free survival (63% v 28%, P

.026) and overall survival (73% v 37%, P .057).27

We think that adequate neoadjuvant chemotherapy followed

by RT may have the potential to improve survival for advanced

NPC. Two randomized trials from the same group in Hong Kong

reported no survival benefit of sandwich chemotherapy (neoad-

juvant chemotherapy plus RT plus adjuvant chemotherapy)25 or

concurrent weekly cisplatin chemotherapy.31 They used more

intensive RT (including parapharyngeal boost, brachytherapy,

and residual neck node boost), resulting in better locoregional

control in both arms. This increased control may have diluted

the effect of chemotherapy on survival in the RT-alone versus

the combined chemoradiotherapy group. In addition, their

chemotherapy dosage and schedule may have been subopti-

mal. On the basis of the above discussion, we believe that the

true benefit of combined chemoradiotherapy for advanced

NPC patients has yet to be fully determined.

The patterns of failure for advanced NPC are high rates of

both local recurrence and distant metastasis. Larger series

containing several hundred to a thousand patients have shown

distant metastases predominantly,4-8 but primary recurrence has

outnumbered distant failures in some reports.33-37 Regardless of

the major site of failure, locoregional control is by far most

important for patients with clinically localized disease and no

distant metastases. The locoregional failure rate for advanced

NPC is about 20% to 50% after treatment with RT alone.Locoregional recurrence has been demonstrated to be an omi-

nous sign of subsequent distant metastases in NPC patients.38

We believe that if locoregional control cannot be achieved, there

is no chance to improve survival. In general, no current therapies

have proved effective against the majority of solid tumors with

disseminated metastases, including NPC. Therefore, our first

goal was to determine the most effective treatment modality to

improve locoregional control of advanced NPC. Several ap-

proaches to enhance the efficacy of RT, including radiosensitiz-

ers, hyperbaric oxygen, radioprotectors, neutron beam therapy,

and hyperthermia have been tried for decades, with little or no

success. In contrast, altered fractionated RT or concurrent

chemotherapy in combination with RT has shown promising

results. When we started this trial in 1993, three-dimensional

conformal beam RT was not popular, and intensity-modulated

RT had not yet been fully developed.

Concurrent chemotherapy has many potential advantages,

including a possible additive or synergistic effect with RT, no

compromised blood supply, no time for development of cross-

resistance or accelerated repopulation triggered by neoadjuvant

chemotherapy, and no delay in primary treatment.39,40 For anal

cancer, CCRT as an alternative to conventional surgery has

resulted in improved survival and better quality of life through

preserved organ function. Furthermore, the concurrent use of

chemotherapeutic agents and RT has been shown to be effective

Table 5. Summary of Phase III Randomized Trials Comparing Combined Chemoradiotherapy versus Radiotherapy Alone in NPC

Study Group Entry Criteria Treatment EligibleCases

MedianFollow-up(months) Disease (%) Survival (%)

Italy 1978 UICC stage II-IV (M0) RT 116 43 56 (4-year RFS) 67 (4-year OS)RT VCA 6 113 58 59

Hong Kong Hos N3 or node 4 cm RT 40 28.5 72 (2-year DFS) 81 (2-year OS)PF 2 RT PF 4 37 68 80

INCSG 1987 UICC N2-3 RT 168 49 32 (3-year DFS*) 54 (3-year OS)

BEC

3

RT 171 52 60AOCOA Hos T3, N2-3 or node 3 cm RT 167 30 42 (3-year RFS) 71 (3-year OS)EP 2-3 RT 167 48 78

Intergroup 1988 AJCC/UICC stage III-IV RT 69 60 29 (5-year PFS*) 37 (5-year OS*)

CCRT PF 3 78 58 67 China 1992 Chinese stage III-IV RT 228 62 49 (5-year RFS) 56 (5-year OS)

PBF 2-3 RT 228 59 63TCOG 1988 AJCC/UICC stage IV RT 77 49.5 49.5 (5-year RFS) 60.5 (5-year OS)

RT PFL 9 weeks 77 54.5 54.5Hong Kong Hos N2-3 or node 4 cm RT 176 32.5 69 (2-year RFS) Not available

CCRT 174 76Japan 1988 AJCC/UICC stage I-IV RT 40 49 43 (5-year DFS) 48 (5-year OS)

PF 2 RT 40 55 60Taichung Veterans

General Hospital 1992 AJCC/UICC stage III-IV RT 143 65 53.0 (5-year PFS*) 54.2 (5-year OS*)

CCRT 141 71.6 72.3

*P.05.Abbreviations: INCSG, International Nasopharynx Cancer Study Group; AOCOA, Asian-Oceanian Clinical Oncology Association; TCOG, Taiwan Cooperative Oncology

Group; UICC, International Union Against Cancer; AJCC, American Joint Committee on Cancer; NPC, nasopharyngeal carcinoma; RT, radiotherapy; CCRT, concomitantchemoradiotherapy; VCA, vincristine, cyclophosphamide, doxorubicin; PF, cisplatin,fluorouracil; BEC, bleomycin, epirubicin, cisplatin; EP, epirubicin, cisplatin; PBF, cisplatin,bleomycin,fluorouracil; PFL, cisplatin,fluorouracil, leucovorin; RFS, relapse-free survival; DFS, disease-free survival; PFS, progression-free survival; OS, overall survival.



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in improving local control of carcinoma of the anus,41 head and

neck,42 esophagus,43 lung,44 cervix,45,46 and bladder.47

Cisplatin-based chemotherapy10-15 has been demonstrated to

have higher response rates in previously untreated, recurrent, or

metastatic NPC than do noncisplatin regimens.48-51 In this study,

we chose the combination of cisplatin and FU because both

chemotherapeutic agents have been shown to have radiosensi-

tizing effects. The dosage and schedule were based on previous

experience with careful consideration to reducing drug toxicity.First, we administered cisplatin 80 mg/m2/cycle by continuous

infusion over 4 days because high-dose cisplatin infusion in a

short period often causes severe emesis. Second, we selected a

relatively low dose of FU, 400 mg/m2/d, given by 96-hour

continuous infusion to reduce the severity of mucositis. Third, at

the doses administered, almost no hair loss was observed.

Finally, we mixed cisplatin and FU in normal saline for 96-hour

continuous infusion to simplify the delivery and provide the

option of outpatient treatment. Of note, the safety and efficacy of

mixing cisplatin and FU has been previously reported.52,53

Using our carefully designed CCRT protocol, we achieved

relatively good compliance. Nearly all patients randomly allo-cated to the CCRT and RT-alone arms completed their treatment.

Specifically, 93.6% (132 of 141) of patients randomly allocated

to the CCRT arm completed the planned concurrent chemother-

apy in our trial. This compliance is in contrast to the Intergroup

study, in which only 63% of patients who were to receive three

courses of concurrent cisplatin 100 mg/m2 by rapid intravenous

infusion and 55% of those to receive all three courses of adjuvant

chemotherapy completed their treatment.28 Both trials encoun-

tered similar acute toxicity during CCRT: a higher incidence of

leukopenia and emesis was observed in patients in the CCRT

arm (P .05). However, our CCRT protocol had less severe

grade 3 to 4 leukopenia (six of 141 patients 4.3%) and emesis

(six of 141 patients 4.3%) than the Intergroup trial (23 of 78

patients 29.5% and 11 of 78 patients 14.1%, respectively).

Both studies showed significant survival benefits with respect to

overall survival and progression-free survival, favoring the

CCRT arm. Our trial clearly demonstrates that the survival

benefit resulted from concurrent chemotherapy. Furthermore, the

survival benefit of our CCRT protocol appears to be mediated

through the radio-enhancing effects of concurrent chemotherapy

on the primary control of the tumor. In addition, the 5-year

nasopharynx disease-free survival rates were 89.3% for the

CCRT group and 72.6% for the RT-alone group (P .0009).

CCRT also had better regional and distant control rates, but the

difference did not reach statistical significance.

The results of our study strongly support the superior effect of

CCRT first described in the United States Intergroup trial. Our

study, however, is the first to demonstrate a positive effect of

adding chemotherapy to RT for NPC patients in an endemic area.

One area of concern regarding our treatment strategy is that two

cycles of concurrent chemotherapy may be inadequate to com-

pletely eradicate micrometastases. Failure pattern analysis of our

study revealed that distant metastases outnumbered local recur-

rence. The Intergroup study employed a schedule that included

an additional three courses of adjuvant chemotherapy following

RT. This strategy could be of benefit to our study population, and

could be incorporated easily into our current CCRT protocol. In

the future, we will consider adding more adjuvant or neoadjuvant

chemotherapy to our CCRT program in an attempt to further

reduce distant treatment failure rates.

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