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A phase III study of adjuvant chemotherapy in advanced nasopharyngeal carcinoma patients
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.,㛳 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 HospitalTaipei, Taipei, Taiwan; 㛳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 ⴝ 0.5) and 49.5% vs. 54.4% (p ⴝ 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 ⴝ 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 radiotherapy-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 Nasopharyngeal carcinoma (NPC) is a relatively common cancer in Taiwan. Most NPC patients in our study presented
pathologically as WHO (World Health Organization) Type II and III histology and presented clinically as Stage IV, M0 disease (UICC/AJCC 1992 staging). The observed 5-year 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., Taipei, 11217, Taiwan, Republic Of China. Tel: (886) 2-28757468; Fax: (886) 2-28749419; E-mail: [email protected] Acknowledgments—We are grateful to Cheng-Wen Wu, Jacqueline 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 WeiLien Feng and Mei-Suei Lin from the Taiwan Cooperative Oncology 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 HospitalTaipei; Shen-Yeh Lin, Kaohsiung Medical University; Chih-Jen Huang, Kaohsiung Medical University; Chien-Hsun Chen, Veterans General Hospital-Kaohsiung; Ming-Chih Chang, Mackay Memorial Hospital-Taipei; Yih-Chang Weng, Veterans General Hospital-Taichung; Tzeon-Jye Chiu, Veterans General HospitalTaipei; 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 HospitalTaipei during 1981–1996 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 decrease 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 (7–11). 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 metaanalysis excluded reports on NPC-only trials (12). Performing adjuvant chemotherapy after full-dose radiotherapy presents 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 markedly 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 radiotherapy. Therefore, since 1994 we have conducted a Phase III study comparing radiotherapy alone with radiotherapy followed by adjuvant chemotherapy; we have used weekly PFL to evaluate the role of cisplatin-based adjuvant chemotherapy in locally advanced NPC patients. METHODS AND MATERIALS Between November 1994 and March 1999, 157 newly diagnosed NPC patients were registered from nine institutions in the Taiwan Cooperative Oncology Group (TCOG). The eligibility criteria were as follows: biopsy-proven carcinoma of nasopharynx, Stage IV (UICC/AJCC 1992) disease (including T4N0 –1M0 and TN2–3M0), and performance status 0 –2 (WHO). Patients were required to have adequate bone marrow function (WBC [white blood cells] ⱖ4,000/ L, platelet count ⱖ100,000/L, hemoglobin ⱖ10.5 mg
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%), renal function (serum creatinine ⱕ1.5 mg/dL), and liver function (total bilirubin ⱕ2.0 mg/dL). Patients were allowed 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 serology evidence of hepatitis B surface antigen were excluded 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 institutional 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 Taipei. The randomization procedure was performed with the stratified permuted-block randomization method (with block size ⫽ 4). Radiotherapy All patients underwent mask immobilization with simulation 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 opposed 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 chemotherapy 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. Firstcycle chemotherapy was administered only if WBC ⱖ3,000/uL and platelet count ⱖ100,000/L. Chemotherapy was withheld on the day it was scheduled if WBC
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ⱕ2,000/L or platelet count ⱕ50,000/L; chemotherapy was delayed 1 week or more until WBC ⱖ3,000/L or platelet count ⱖ100,000/L. Weekly PFL chemotherapy was delayed 1 week until mucositis or diarrhea was Grade 0 –1. Doses were modified for significant mucositis or diarrhea: 5-FU was reduced 20% in subsequent cycles for Grade 3 or 4 mucositis or diarrhea; 5-FU was reduced 10% in subsequent cycles for Grade 2 mucositis or diarrhea. The next dose of cisplatin was stopped for patients who developed ⱖ Grade 2 neurotoxicity or progressive change in Lhermitte syndrome (ⱖ Grade 1). Cisplatin was stopped for creatinine ⬎2.0 mg/dL. Patient assessments The primary efficacy end point of this study was overall survival. The other efficacy end points were RFS, metastasis-free survival (MFS), and locoregional relapse-free survival (LRFS), including nodes. Complete response was defined as the complete disappearance of measurable or palpable tumors as confirmed by CT scan or MRI. The persistence of radiologic signs of nasopharyngeal mucosal thickening was scored as partial response. Progressive disease 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 lesions or the appearance of any new lesion or site. Patients who developed local or distant relapse after therapy could be treated by any means considered appropriate by the responsible physician. Statistical considerations We assume that the 5-year survival rate for advancedstage NPC patients who receive radiotherapy alone is 40% and for those who receive adjuvant PFL chemotherapy after radiotherapy is 60%. After adjusting for the 12% anticipated dropout rate, a total of 240 patients (120 patients per arm) is planned to ensure an 80% probability of detecting the difference between those two (5-year) survival rates at the one-sided 5% significance level. Differences between groups were evaluated by chi-square test or Fisher’s exact test for categoric variable. Overall survival (duration from the date of treatment to latest follow-up [event: death]), relapse-free survival (duration from the date of treatment to latest follow-up [event: relapse or death]), metastasis-free survival (duration from the date of treatment to latest follow-up [event: metastasis or death]), and local relapse-free survival (duration from the date of treatment to latest follow-up [event: locoregional relapse or death]) were analyzed by the Kaplan–Meier methods. Comparisons of survival were performed using the Cox regression model. Analyses were carried out on the intention-to-treat basis. Statistical significance was defined as p ⬍ 0.05. RESULTS Among the 157 patients enrolled in this study, 3 patients (2%) were considered ineligible. All 3 patients had meta-
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Table 1. Patients characteristics Assigned treatment
Age Median Range Gender Male Female Stratification I: T4, N0–1 II: Any T, N2 III: T1–3, N3 IV: T4-N3 Performance 0 1–2 Histology (WHO) I II III
RT (n ⫽ 77)
RT ⫹ CT (n ⫽ 77)
47 24–73
46 16–76
58 (75.3%) 19 (24.7%)
60 (77.9%) 17 (22.1%)
10 (13.0%) 52 (67.5%) 10 (13.0%) 5 (6.5%)
10 (13.0%) 50 (64.9%) 14 (18.2%) 3 (3.9%)
55 (71.4%) 22 (28.6%)
54 (70.1%) 23 (29.9%)
0 (0.0%) 46 (59.7%)
2 (2.6%) 41 (53.3%) 34 (44.2%)
31 (40.3%)
static disease (1 in bone, 1 in lung, and 1 in liver) before registration. The resulting 154 patients were evaluable for survival and toxicity analysis. Seventy-seven patients were randomized to radiotherapy plus chemotherapy, and 77 were randomized to radiotherapy alone. The patients’ characteristics in the two treatment groups are summarized in Table 1. The distributions of the patients’ main clinical characteristics were comparable between these two treatment groups. The median total dose delivered to the tumor was 70.2 Gy: 68.4 Gy to the upper neck and 54 Gy to the lower neck. There was no delay of allocation to the start of radiotherapy in all patients. All patients completed the treatment course with scheduled dose. Toxicity There were six fatal toxicities in the combined chemotherapy and radiotherapy group. One patient died of myocardial infarction before chemotherapy, one died of reactivation of hepatitis B after 4 cycles of weekly chemotherapy, one died of aspiration pneumonia after 4 cycles of weekly chemotherapy, one died of perforated gastric ulcer after the sixth cycle of weekly chemotherapy, one died of unknown cause after the full cycle of weekly chemotherapy, and one patient died of radiation myelitis 9 months after radiotherapy. In the radiotherapy-alone arm, one patient died of poor nutrition from Grade 4 oropharyngitis from radiotherapy. The most frequent toxicity from radiotherapy was mucositis. The mucositis (ⱖ Grade 2) occurred in 74.0% of patients randomized to the radiotherapy arm and in 84.4% of patients randomized to the combined arm. As shown in Table 2, the most frequent toxicity from adjuvant chemotherapy was myelotoxicity. Grade 3 and 4 leukopenia was observed in 31.4% and 2.0% of patients, respectively. The
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Table 2. Toxicity from CT (Grade ⱖ 2)
Hepatic Vomiting (51.0%) Nausea Diarrhea Mucosa Neurologic Ototoxicity Leukopenia Anemia Thrombocytopenia
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TCOG executive committee decided on the early termination of the T1394 trial.
Group B (RT ⫹ CT/ n ⫽ 51) Toxicity
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Grade 2
Grade 3
Grade 4
0 (0.0%) 26 (7.8%) 21 (41.2%) 7 (13.7%) 10 (19.6%) 1 (2.0%) 2 (3.9%) 21 (41.2%) 16 (31.4%) 1 (2.0%)
1 (2.0%) 4 (2.0%) 7 (13.7%) 2 (3.9%) 0
1 (2.0%) 1
0
0
1 (2.0%) 16 (31.4%) 9 (17.6%) 1 (2.0%)
0
0 0 0
1 (2.0%) 0 0
Abbreviations: CT ⫽ chemotherapy; RT ⫽ radiotherapy.
incidence of leukopenia (ⱖ Grade 3) occurred in 17 out of 819 (2.1%) weekly chemotherapy cycles. The incidence of nausea (ⱖ Grade 3) was 13.7%, and incidence of vomiting (ⱖ Grade 3) was 9.8%. Two patients (3.9%) developed diarrhea (ⱖ Grade 3). Remarkably, no patient developed moderate or severe mucositis (ⱖ Grade 3). Patient compliance to chemotherapy was poor, even though the toxicity profiles indicate that adjuvant weekly PFL chemotherapy is quite tolerable. Twenty-six patients (33.8%) randomized to receive adjuvant chemotherapy changed their minds after the completion of radiotherapy. Among the remaining 51 patients who intended to receive chemotherapy, 40 patients (78%) did complete the 9 weekly cycles of chemotherapy. Based on the slow accrual rate and the unexpected, serious adverse events, as well as on the interim analysis performed 4 years after patient accrual had begun, the Data and Safety Monitor Committee of TCOG suggested that there would be only a remote chance that the trial could reach its statistical goal within a reasonable time. The
Response and relapse patterns The median time to complete response was 6.08 months. Overall, 51 patients in the radiotherapy-alone arm (51/75 ⫽ 68.0%) achieved complete response, and 53 patients in the combined arm (53/73 ⫽ 72.6%) achieved complete response. The patterns of disease relapse are shown in Table 3. In the control group, 36.4% of patients (by adding distant and local ⫹ distant relapses) developed distant metastases, whereas in the combined treatment group, 19.5% developed distant metastases (p ⫽ 0.03). There was no statistically significant difference in the relapse rates between control and combined treatment groups based on the subgroup analysis of the four stratification groups (data not shown). Overall survival and relapse-free survival The median follow-up duration for the 154 randomized patients was 49.5 months. (range: 1.9 – 68.9⫹ months). Four patients were lost to follow-up; the follow-up rate was 97.4%. There was no statistical difference between the 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 (Fig. 1). The Cox regression analysis showed that the hazard rates ratio of combined treatment to RT alone was 0.673, with p ⫽ 0.232 and 95% confidence intervals of 0.352 and 1.288, respectively. Twenty-four patients in the radiotherapy-alone group died, 1 from treatment toxicity, whereas 26 patients in the combined treatment group died, 6 from treatment-related toxicities. The median RFS time was 38.7 months for the radiotherapy group and 40.4 months for the combined group (Fig. 2). The 5-year RFS rate, MFS rate, and LRFS rate was 54.4%, 59.6%, and 49.4%, respectively, for the combined group compared with 49.5%, 58.4%, and 51.3% for the RT-alone group. In the intention-to-treat analysis, there was no significant statistical difference (p ⫽ 0.376, 0.677, and 0.951, respectively) between the two treatment groups from those three survival end points. DISCUSSION Over the past two decades, attempts have been made to improve the results of radiotherapy for NPC treatment by
Table 3. Pattern of relapse Intent-to-treat Relapse pattern
RT (n ⫽ 77)
RT ⫹ CT (n ⫽ 77)
Total (n ⫽ 154)
Local recurrence Distant metastasis Local recurrence/distant metastasis Non–tumor-related death Non-relapse
8 (10.4%) 20 (26.0%) 8 (10.4%) 4 (5.2%) 37 (48.0%)
6 (7.8%) 13 (16.9%) 2 (2.6%) 10 (13.0%) 46 (59.7%)
14 (9.1%) 33 (21.4%) 10 (6.5%) 14 (9.1%) 83 (53.9%)
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Fig. 1. Overall survival curves (p ⫽ 0.5).
the incorporation of chemotherapy before, during, or after radiotherapy (15–17). Each type of integration has its advantages and disadvantages. Routinely incorporating chemotherapy into the treatment of NPC before the results of randomized trials on pure neoadjuvant, concomitant, or adjuvant chemotherapy have matured may result in overtreatment. 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).
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 adjuvant 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 European 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 chemoradiotherapy (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 chemotherapy 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 (3month 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 theoretically synergistic. Randomized trials of CCRT without adjuvant chemotherapy have achieved some improvement 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). Thirty-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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chemotherapy. The patients in the Intergroup trial suffered from Grade 3 mucositis (13%) and Grade 4 mucositis (8%) from a regimen of 3 cycles of PF once a week for 4 weeks (11). Our weekly PFL regimen produced no mucositis (ⱖ Grade 3). However, we need to improve the general nutrition/supportive care to reduce the treatment-related death rate, which was unfortunately too high in the early part of this study. Most of our patients were stratified into the N2-stage disease category. It was still unknown whether adjuvant chemotherapy had a greater impact on those with an intermediate risk of relapse, such as those at the TxN2 stage, because of the lack of statistical power from subgroup analysis of a small sample. On the other hand, neoadjuvant chemotherapy may benefit N3 disease more in regard to distant metastatic rate, as shown by the International Nasopharyx Cancer Study Group, which showed a better outcome in patients with ⱖ N2 stage given neoadjuvant therapy; the trial by the Asian-Oceanian Clinical Oncology Association, which studied the N3-stage subgroup, had a similar outcome (9, 10). CCRT theoretically may help more in the case of bulky disease, such as T4 and N3 disease. We agree with the hypotheses developed recently by Dr. Cooper, that early-stage NPC can be well treated by radiotherapy alone; NPC patients at intermediate risk stage can be treated by combined CCRT with adjuvant chemotherapy. The high-risk patients may need more aggressive neoadjuvant chemotherapy, followed by CCRT and adjuvant chemotherapy (23). In conclusion, overall survival benefit was not demonstrated in the current study with the addition of adjuvant chemotherapy after radiotherapy in patients with locally advanced NPC. Systemic relapse seems to be significantly reduced by adjuvant chemotherapy.
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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.,㛳 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 HospitalTaipei, Taipei, Taiwan; 㛳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 ⴝ 0.5) and 49.5% vs. 54.4% (p ⴝ 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 ⴝ 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 radiotherapy-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 Nasopharyngeal carcinoma (NPC) is a relatively common cancer in Taiwan. Most NPC patients in our study presented
pathologically as WHO (World Health Organization) Type II and III histology and presented clinically as Stage IV, M0 disease (UICC/AJCC 1992 staging). The observed 5-year 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., Taipei, 11217, Taiwan, Republic Of China. Tel: (886) 2-28757468; Fax: (886) 2-28749419; E-mail: [email protected] Acknowledgments—We are grateful to Cheng-Wen Wu, Jacqueline 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 WeiLien Feng and Mei-Suei Lin from the Taiwan Cooperative Oncology 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 HospitalTaipei; Shen-Yeh Lin, Kaohsiung Medical University; Chih-Jen Huang, Kaohsiung Medical University; Chien-Hsun Chen, Veterans General Hospital-Kaohsiung; Ming-Chih Chang, Mackay Memorial Hospital-Taipei; Yih-Chang Weng, Veterans General Hospital-Taichung; Tzeon-Jye Chiu, Veterans General HospitalTaipei; 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
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radiotherapy (RT) alone at the Veterans General HospitalTaipei during 1981–1996 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 decrease 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 (7–11). 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 metaanalysis excluded reports on NPC-only trials (12). Performing adjuvant chemotherapy after full-dose radiotherapy presents 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 markedly 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 radiotherapy. Therefore, since 1994 we have conducted a Phase III study comparing radiotherapy alone with radiotherapy followed by adjuvant chemotherapy; we have used weekly PFL to evaluate the role of cisplatin-based adjuvant chemotherapy in locally advanced NPC patients. METHODS AND MATERIALS Between November 1994 and March 1999, 157 newly diagnosed NPC patients were registered from nine institutions in the Taiwan Cooperative Oncology Group (TCOG). The eligibility criteria were as follows: biopsy-proven carcinoma of nasopharynx, Stage IV (UICC/AJCC 1992) disease (including T4N0 –1M0 and TN2–3M0), and performance status 0 –2 (WHO). Patients were required to have adequate bone marrow function (WBC [white blood cells] ⱖ4,000/ L, platelet count ⱖ100,000/L, hemoglobin ⱖ10.5 mg
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%), renal function (serum creatinine ⱕ1.5 mg/dL), and liver function (total bilirubin ⱕ2.0 mg/dL). Patients were allowed 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 serology evidence of hepatitis B surface antigen were excluded 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 institutional 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 Taipei. The randomization procedure was performed with the stratified permuted-block randomization method (with block size ⫽ 4). Radiotherapy All patients underwent mask immobilization with simulation 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 opposed 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 chemotherapy 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. Firstcycle chemotherapy was administered only if WBC ⱖ3,000/uL and platelet count ⱖ100,000/L. Chemotherapy was withheld on the day it was scheduled if WBC
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ⱕ2,000/L or platelet count ⱕ50,000/L; chemotherapy was delayed 1 week or more until WBC ⱖ3,000/L or platelet count ⱖ100,000/L. Weekly PFL chemotherapy was delayed 1 week until mucositis or diarrhea was Grade 0 –1. Doses were modified for significant mucositis or diarrhea: 5-FU was reduced 20% in subsequent cycles for Grade 3 or 4 mucositis or diarrhea; 5-FU was reduced 10% in subsequent cycles for Grade 2 mucositis or diarrhea. The next dose of cisplatin was stopped for patients who developed ⱖ Grade 2 neurotoxicity or progressive change in Lhermitte syndrome (ⱖ Grade 1). Cisplatin was stopped for creatinine ⬎2.0 mg/dL. Patient assessments The primary efficacy end point of this study was overall survival. The other efficacy end points were RFS, metastasis-free survival (MFS), and locoregional relapse-free survival (LRFS), including nodes. Complete response was defined as the complete disappearance of measurable or palpable tumors as confirmed by CT scan or MRI. The persistence of radiologic signs of nasopharyngeal mucosal thickening was scored as partial response. Progressive disease 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 lesions or the appearance of any new lesion or site. Patients who developed local or distant relapse after therapy could be treated by any means considered appropriate by the responsible physician. Statistical considerations We assume that the 5-year survival rate for advancedstage NPC patients who receive radiotherapy alone is 40% and for those who receive adjuvant PFL chemotherapy after radiotherapy is 60%. After adjusting for the 12% anticipated dropout rate, a total of 240 patients (120 patients per arm) is planned to ensure an 80% probability of detecting the difference between those two (5-year) survival rates at the one-sided 5% significance level. Differences between groups were evaluated by chi-square test or Fisher’s exact test for categoric variable. Overall survival (duration from the date of treatment to latest follow-up [event: death]), relapse-free survival (duration from the date of treatment to latest follow-up [event: relapse or death]), metastasis-free survival (duration from the date of treatment to latest follow-up [event: metastasis or death]), and local relapse-free survival (duration from the date of treatment to latest follow-up [event: locoregional relapse or death]) were analyzed by the Kaplan–Meier methods. Comparisons of survival were performed using the Cox regression model. Analyses were carried out on the intention-to-treat basis. Statistical significance was defined as p ⬍ 0.05. RESULTS Among the 157 patients enrolled in this study, 3 patients (2%) were considered ineligible. All 3 patients had meta-
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Table 1. Patients characteristics Assigned treatment
Age Median Range Gender Male Female Stratification I: T4, N0–1 II: Any T, N2 III: T1–3, N3 IV: T4-N3 Performance 0 1–2 Histology (WHO) I II III
RT (n ⫽ 77)
RT ⫹ CT (n ⫽ 77)
47 24–73
46 16–76
58 (75.3%) 19 (24.7%)
60 (77.9%) 17 (22.1%)
10 (13.0%) 52 (67.5%) 10 (13.0%) 5 (6.5%)
10 (13.0%) 50 (64.9%) 14 (18.2%) 3 (3.9%)
55 (71.4%) 22 (28.6%)
54 (70.1%) 23 (29.9%)
0 (0.0%) 46 (59.7%)
2 (2.6%) 41 (53.3%) 34 (44.2%)
31 (40.3%)
static disease (1 in bone, 1 in lung, and 1 in liver) before registration. The resulting 154 patients were evaluable for survival and toxicity analysis. Seventy-seven patients were randomized to radiotherapy plus chemotherapy, and 77 were randomized to radiotherapy alone. The patients’ characteristics in the two treatment groups are summarized in Table 1. The distributions of the patients’ main clinical characteristics were comparable between these two treatment groups. The median total dose delivered to the tumor was 70.2 Gy: 68.4 Gy to the upper neck and 54 Gy to the lower neck. There was no delay of allocation to the start of radiotherapy in all patients. All patients completed the treatment course with scheduled dose. Toxicity There were six fatal toxicities in the combined chemotherapy and radiotherapy group. One patient died of myocardial infarction before chemotherapy, one died of reactivation of hepatitis B after 4 cycles of weekly chemotherapy, one died of aspiration pneumonia after 4 cycles of weekly chemotherapy, one died of perforated gastric ulcer after the sixth cycle of weekly chemotherapy, one died of unknown cause after the full cycle of weekly chemotherapy, and one patient died of radiation myelitis 9 months after radiotherapy. In the radiotherapy-alone arm, one patient died of poor nutrition from Grade 4 oropharyngitis from radiotherapy. The most frequent toxicity from radiotherapy was mucositis. The mucositis (ⱖ Grade 2) occurred in 74.0% of patients randomized to the radiotherapy arm and in 84.4% of patients randomized to the combined arm. As shown in Table 2, the most frequent toxicity from adjuvant chemotherapy was myelotoxicity. Grade 3 and 4 leukopenia was observed in 31.4% and 2.0% of patients, respectively. The
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Table 2. Toxicity from CT (Grade ⱖ 2)
Hepatic Vomiting (51.0%) Nausea Diarrhea Mucosa Neurologic Ototoxicity Leukopenia Anemia Thrombocytopenia
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TCOG executive committee decided on the early termination of the T1394 trial.
Group B (RT ⫹ CT/ n ⫽ 51) Toxicity
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Grade 2
Grade 3
Grade 4
0 (0.0%) 26 (7.8%) 21 (41.2%) 7 (13.7%) 10 (19.6%) 1 (2.0%) 2 (3.9%) 21 (41.2%) 16 (31.4%) 1 (2.0%)
1 (2.0%) 4 (2.0%) 7 (13.7%) 2 (3.9%) 0
1 (2.0%) 1
0
0
1 (2.0%) 16 (31.4%) 9 (17.6%) 1 (2.0%)
0
0 0 0
1 (2.0%) 0 0
Abbreviations: CT ⫽ chemotherapy; RT ⫽ radiotherapy.
incidence of leukopenia (ⱖ Grade 3) occurred in 17 out of 819 (2.1%) weekly chemotherapy cycles. The incidence of nausea (ⱖ Grade 3) was 13.7%, and incidence of vomiting (ⱖ Grade 3) was 9.8%. Two patients (3.9%) developed diarrhea (ⱖ Grade 3). Remarkably, no patient developed moderate or severe mucositis (ⱖ Grade 3). Patient compliance to chemotherapy was poor, even though the toxicity profiles indicate that adjuvant weekly PFL chemotherapy is quite tolerable. Twenty-six patients (33.8%) randomized to receive adjuvant chemotherapy changed their minds after the completion of radiotherapy. Among the remaining 51 patients who intended to receive chemotherapy, 40 patients (78%) did complete the 9 weekly cycles of chemotherapy. Based on the slow accrual rate and the unexpected, serious adverse events, as well as on the interim analysis performed 4 years after patient accrual had begun, the Data and Safety Monitor Committee of TCOG suggested that there would be only a remote chance that the trial could reach its statistical goal within a reasonable time. The
Response and relapse patterns The median time to complete response was 6.08 months. Overall, 51 patients in the radiotherapy-alone arm (51/75 ⫽ 68.0%) achieved complete response, and 53 patients in the combined arm (53/73 ⫽ 72.6%) achieved complete response. The patterns of disease relapse are shown in Table 3. In the control group, 36.4% of patients (by adding distant and local ⫹ distant relapses) developed distant metastases, whereas in the combined treatment group, 19.5% developed distant metastases (p ⫽ 0.03). There was no statistically significant difference in the relapse rates between control and combined treatment groups based on the subgroup analysis of the four stratification groups (data not shown). Overall survival and relapse-free survival The median follow-up duration for the 154 randomized patients was 49.5 months. (range: 1.9 – 68.9⫹ months). Four patients were lost to follow-up; the follow-up rate was 97.4%. There was no statistical difference between the 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 (Fig. 1). The Cox regression analysis showed that the hazard rates ratio of combined treatment to RT alone was 0.673, with p ⫽ 0.232 and 95% confidence intervals of 0.352 and 1.288, respectively. Twenty-four patients in the radiotherapy-alone group died, 1 from treatment toxicity, whereas 26 patients in the combined treatment group died, 6 from treatment-related toxicities. The median RFS time was 38.7 months for the radiotherapy group and 40.4 months for the combined group (Fig. 2). The 5-year RFS rate, MFS rate, and LRFS rate was 54.4%, 59.6%, and 49.4%, respectively, for the combined group compared with 49.5%, 58.4%, and 51.3% for the RT-alone group. In the intention-to-treat analysis, there was no significant statistical difference (p ⫽ 0.376, 0.677, and 0.951, respectively) between the two treatment groups from those three survival end points. DISCUSSION Over the past two decades, attempts have been made to improve the results of radiotherapy for NPC treatment by
Table 3. Pattern of relapse Intent-to-treat Relapse pattern
RT (n ⫽ 77)
RT ⫹ CT (n ⫽ 77)
Total (n ⫽ 154)
Local recurrence Distant metastasis Local recurrence/distant metastasis Non–tumor-related death Non-relapse
8 (10.4%) 20 (26.0%) 8 (10.4%) 4 (5.2%) 37 (48.0%)
6 (7.8%) 13 (16.9%) 2 (2.6%) 10 (13.0%) 46 (59.7%)
14 (9.1%) 33 (21.4%) 10 (6.5%) 14 (9.1%) 83 (53.9%)
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Fig. 1. Overall survival curves (p ⫽ 0.5).
the incorporation of chemotherapy before, during, or after radiotherapy (15–17). Each type of integration has its advantages and disadvantages. Routinely incorporating chemotherapy into the treatment of NPC before the results of randomized trials on pure neoadjuvant, concomitant, or adjuvant chemotherapy have matured may result in overtreatment. 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).
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 adjuvant 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 European 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-
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ynx. Nevertheless, it has been concluded that the high survival rate results from concomitant chemoradiotherapy (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 chemotherapy 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 (3month 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 theoretically synergistic. Randomized trials of CCRT without adjuvant chemotherapy have achieved some improvement 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). Thirty-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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chemotherapy. The patients in the Intergroup trial suffered from Grade 3 mucositis (13%) and Grade 4 mucositis (8%) from a regimen of 3 cycles of PF once a week for 4 weeks (11). Our weekly PFL regimen produced no mucositis (ⱖ Grade 3). However, we need to improve the general nutrition/supportive care to reduce the treatment-related death rate, which was unfortunately too high in the early part of this study. Most of our patients were stratified into the N2-stage disease category. It was still unknown whether adjuvant chemotherapy had a greater impact on those with an intermediate risk of relapse, such as those at the TxN2 stage, because of the lack of statistical power from subgroup analysis of a small sample. On the other hand, neoadjuvant chemotherapy may benefit N3 disease more in regard to distant metastatic rate, as shown by the International Nasopharyx Cancer Study Group, which showed a better outcome in patients with ⱖ N2 stage given neoadjuvant therapy; the trial by the Asian-Oceanian Clinical Oncology Association, which studied the N3-stage subgroup, had a similar outcome (9, 10). CCRT theoretically may help more in the case of bulky disease, such as T4 and N3 disease. We agree with the hypotheses developed recently by Dr. Cooper, that early-stage NPC can be well treated by radiotherapy alone; NPC patients at intermediate risk stage can be treated by combined CCRT with adjuvant chemotherapy. The high-risk patients may need more aggressive neoadjuvant chemotherapy, followed by CCRT and adjuvant chemotherapy (23). In conclusion, overall survival benefit was not demonstrated in the current study with the addition of adjuvant chemotherapy after radiotherapy in patients with locally advanced NPC. Systemic relapse seems to be significantly reduced by adjuvant chemotherapy.
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