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© 2001 American Society for Clinical Oncology Results of a Prospective Randomized Trial Comparing Neoadjuvant Chemotherapy Plus Radiotherapy With Radiotherapy Alone in Patients With Locoregionally Advanced Nasopharyngeal CarcinomaFrom the Departments of Nasopharyngeal Carcinoma and Radiation Oncology, Cancer Center, Sun Yat-sen University of Medical Sciences, Guangzhou, People’s Republic of China. Address reprint requests to Jun Ma, MD, Department of Nasopharyngeal Carcinoma, Cancer Center, Sun Yat-sen University of Medical Sciences, 651 Dongfeng Road East, Guangzhou 510060, People’s Republic of China; email: Dr.MaJun{at}163.net
PURPOSE: A prospective randomized trial was performed to evaluate the contribution of neoadjuvant chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma. PATIENTS AND METHODS: Patients with locoregionally advanced nasopharyngeal carcinoma were treated either with radiotherapy alone (RT group) or neoadjuvant chemotherapy plus radiotherapy (CT/RT group). Neoadjuvant chemotherapy consisting of two to three cycles of cisplatin (100 mg/m2, day 1), bleomycin (10 mg/m2, days 1 and 5), and fluorouracil (5-FU; 800 mg/m2, days 1 through 5, continuous infusion) followed by radiotherapy was given to the CT/RT group. All patients were treated in a uniform fashion by definitive-intent radiation therapy in both groups. RESULTS: Between July 1993 and July 1994, 456 patients were entered onto the study, with 228 patients randomized to each treatment arm, and 449 patients (225 in the RT group and 224 in the CT/RT group) were assessable. All 456 patients were included in survival analysis according to the intent-to-treat principle. The 5-year overall survival (OS) rates were 63% for the CT/RT group and 56% for the RT group (P = .11). The median relapse-free survival (RFS) time was 50 months for the RT group and not reached for the CT/RT group. The 5-year RFS rate was 49% for the RT group versus 59% for the CT/RT group (P = .05). The 5-year freedom from local recurrence rate was 82% for the CT/RT group and 74% for the RT group (P = .04). There was no significant difference in freedom from distant metastasis between the two treatment groups (CT/RT group, 79%; RT group, 75%; P = .40). CONCLUSION: This randomized study failed to demonstrate any significant survival benefit with the addition of neoadjuvant chemotherapy for patients with locoregionally advanced nasopharyngeal carcinoma. Therefore, neoadjuvant chemotherapy for nasopharyngeal carcinoma should not be used outside of the context of a clinical trial.
AMONG HEAD AND neck carcinomas, nasopharyngeal carcinomas (NPC) have unique characteristics with regard to their epidemiology, histologic features, and response to radiotherapy (RT) and chemotherapy (CT). NPC also have specific therapeutic management. Radiotherapy is the primary treatment modality for all locally and regionally confined stages. Whereas the control of early-stage disease with radiotherapy is usually successful, the response of locally and regionally advanced NPC to radiation is poor because of local relapse and distant metastases.1-4 The highest incidence rates of NPC are found in Southern China and Hong Kong, followed by Singapore and U.S. Chinese. The incidence rates in whites are low. In China, the yearly incidence rate of NPC rises from the north (3 cases per 105 people) towards the south, where it varies between 25 and 50 cases per 105 people. Canton is the most affected area (as many as 2000 new cases of NPC per year in our center).5 Nearly 70% of the patients diagnosed with NPC will present with stage III or IV disease in Southern China and Hong Kong (International Union Against Cancer staging system).6,7 The 5-year survival rate reported for patients with stage III disease (Chinese 1992 staging system) treated by radiotherapy is 59%, and approximately 34% for stage IV.8 NPC is a highly chemosensitive tumor. The most active chemotherapeutic agents are cisplatin, carboplatin, epirubicin, bleomycin, methotrexate, and fluorouracil (5-FU).9-11 At the Institute Gustav Russy in Paris, France, between 1985 and 1991, three consecutive cisplatin-containing regimens were tested.12-15 Forty-one patients received cisplatin, bleomycin, and 5-FU (PBF); 44 patients received bleomycin, epirubicin, and cisplatin (BEC); and 46 patients received 5-FU, epirubicin, cisplatin, and mitomycin (FEP mito). In the PBF trial, three cycles of chemotherapy were given and the patients were observed; in the BEC trial, up to six cycles of chemotherapy were given; and in the FEP mito trial, a median of four cycles of chemotherapy was given. The best overall response rate, 75%, was obtained with the PBF regimen (22% complete response [CR], 53% partial response [PR]). The role of neoadjuvant chemotherapy in advanced NPC has been the subject of numerous investigations for many years. Although some retrospective and pilot studies have reported promising results,16-18 many have reported quite the opposite.19-20 The objective of the present study was to determine whether treatment outcomes for patients with locoregionally advanced NPC could be improved with the addition of cisplatin-based neoadjuvant chemotherapy (cisplatin, bleomycin, and 5-FU).
Eligibility Criteria Patients were evaluated using the Chinese 1992 staging system ( Table 1) and were eligible for this study if they met the following entry criteria: histologically proven NPC; stage III or IV disease; no evidence of systemic metastasis (M0); and World Health Organization (WHO) performance status of 0 to 2. There could be no history of radiotherapy or chemotherapy, and no history of prior malignancy except for nonmelanoma cancers of the skin or in situ cervical carcinoma. Patients were required to have adequate hematologic (leukocyte count  4,000/mm3, platelet count 100,000/mm3), hepatic (serum bilirubin level < 1.5 mg/dL), and renal (serum creatinine level < 1.5 mg/dL and/or 24-hour urinary creatinine clearance 60 mL/min) functions. A normal ECG was also required. Patients with a history of cardiac or renal disease were excluded. This study was performed after approval from the institutional ethics committee. All patients were randomized and were required to provide written informed consent before treatment.
Pretreatment Evaluation The initial examination included a medical history, a physical examination, a complete blood cell count with differentials, a full biochemical profile, and an ECG. All patients underwent fiberoptic endoscopy and biopsy of the nasopharynx and computed tomography (CT scan) of the nasopharynx and the upper neck for staging of the primary disease. Metastatic work-up included chest x-ray and imaging of liver by ultrasound or CT scan in all patients. Bone scan was performed in patients with bone pain, elevated serum alkaline phosphatase, or N2 to N3 disease.
Radiotherapy The en bloc technique was used for patients with upper cervical nodes, oropharyngeal involvement, or extensive parapharyngeal involvement. Forty grays were delivered with two lateral opposing faciocervical portals to irradiate the nasopharynx and the upper neck in one volume. An anterior field was used to treat the lower neck with a laryngeal block. Thereafter, 28 to 32 Gy were administered to the primary tumor by the shrinking-field technique (two lateral-opposed facial fields) to avoid excessive irradiation to the spinal cord. An anterior cervical field was used to treat the whole neck with a laryngeal block. The accumulated radiation dose to the primary tumor was 68 to 72 Gy. The accumulated dose to the involved areas of the neck was 60 to 62 Gy and 50 Gy to the uninvolved areas. The whole course of treatment was given by the split-field technique, which consisted of two lateral opposed facial fields, supplemented by an anterior field if necessary. This technique was used for patients with tumors confined to the nasopharynx. In cases of nasal or ethmoidal involvement, an anterior facial electron field was added. For patients with a residual tumor in the primary site (especially in the parapharyngeal space), after 70 Gy was delivered, the total dose could be boosted to 80 Gy with the cone-down technique. Boost doses of 10 to 14 Gy in five to seven fractions were delivered to the skull base in patients with involvement of skull base and intracranial extension. Intracavitary afterloading treatment with 192Ir was performed for local persistence 2 to 3 weeks after external radiotherapy (20 to 24 Gy in four to five fractions over 2 weeks to 1 cm above the midpoint of the 192Ir source). Any palpable residual nodes after external radiotherapy were boosted to 70 Gy at the 90% isodose level with an electron field (9 to 12 Mev). When possible, salvage treatments were given to patients after documented relapse or when disease was persistent. The salvage treatments included reirradiation, chemotherapy, and surgery.
Neoadjuvant Chemotherapy
Chemotherapy was delayed weekly in case of myelosuppression until leukocyte counts were greater than 3,000/mm3 and platelet counts were greater than 100,000/mm3. The dose of 5-FU was reduced by 25% if severe stomatitis or diarrhea developed. The dose of cisplatin was adjusted according to the value of creatinine after the last course. If serum creatinine was less than 1.5 mg/dL or if creatinine clearance was Early studies investigating neoadjuvant chemotherapy with two to three cycles of cisplatin-containing regimens given every 3 weeks before radical external radiotherapy demonstrated encouraging response rates to neoadjuvant chemotherapy of 75% to 98%. The toxicities were generally acceptable.17,20,23,24 In the present trial, the criteria used for giving two or three cycles of chemotherapy included the tumor response and the patient’s tolerance. At the end of two cycles, patients who tolerated chemotherapy well and had at least partial response were given one more cycle of chemotherapy followed by radiotherapy. Further chemotherapy was omitted for patients who did not satisfy these criteria.
Evaluation of Response and Toxicity The WHO scale25 was also used to record toxicity. Toxicity was assessed before each cycle of chemotherapy, and hematologic assessments were performed weekly to determine the toxicity at the nadir. For toxicity analysis, the worst data for each patient in all cycles of chemotherapy were used.
Follow-Up All local recurrences were diagnosed by fiberoptic endoscopy and biopsy and/or CT scan of the nasopharynx and the skull base showing progressive bone erosion and/or soft tissue swelling. Regional recurrences were diagnosed by clinical examination of the neck and, in doubtful cases, by fine needle aspiration or CT scan of the neck. Distant metastases were diagnosed by clinical symptom, physical examination, and imaging methods including chest x-ray, bone scan, CT scan, and abdominal sonography.
Statistical Analysis
SPSS 8.0 statistical software was used (SPSS Inc, Chicago, IL). The Kaplan-Meier product-limit method26 was used in the calculation of the OS, RFS, FLR, and FDM rates. Time was measured from the date of randomization until the time of first failure, or the most recent follow-up if no relapse was detected. OS was defined as the date of randomization to the date of death due to any cause. RFS was defined as the date of randomization to the date of the first observation of progressive disease or death due to any cause. For FLR analysis, the first local failure was scored. Patients who died of regional recurrence, distant metastases, or intercurrent illnesses without local recurrence were censored at the last follow-up. A similar definition was used for FDM analysis. Toxicity rates were compared using the Based on the previous data, the 5-year survival rate for the RT group was assumed to be 45%. To detect an increase from 45% to 60% in 5-year survival by combined modality at a significance of 5% and a power of 90%, a sample size of 190 patients per arm was anticipated.
Between July 1993 and July 1994, a total of 456 patients were entered onto this trial, with 228 patients randomized to each treatment arm. Seven patients were considered ineligible after review. Of these seven, four patients (two in the CT/RT group, two in the RT group) were ineligible based on pathology review (adenocarcinoma), and three patients (two in the CT/RT group, one in the RT group) had insufficient information (their scans were out of date). Thus, there were 449 assessable patients (224 patients in the CT/RT group, 225 in the RT group). In the CT/RT group, four patients refused chemotherapy, and one patient refused both the chemotherapy and radiotherapy. In the RT group, one patient had radiation treatment that was considered inadequate, two patients discontinued treatment during radiotherapy, and one patient died from a cerebrovascular accident before completion of radiotherapy. Thus, 219 patients (97.8%) in the CT/RT group and 221 patients (98.2%) in the RT group completed the treatment in accordance with the protocol. All 456 patients are included in survival analysis according to the intent-to-treat principle without exclusion of the seven ineligible patients. Two hundred nineteen patients were assessable for chemotherapy response and toxicity. Of these, 70 patients (32%) received three cycles of chemotherapy, and 149 patients (68%) received two cycles of chemotherapy. Pretreatment patient characteristics are listed in Table 2. There were no statistically significant differences in any of the patient characteristics between the two treatment arms (P > .05).
Treatment Response The responses to chemotherapy are listed in Table 3. After completion of two to three courses of neoadjuvant chemotherapy, there were 30 complete responses (30 of 219, 13.7%) and 151 partial responses (151 of 219, 68.9%) in the primary site, giving an overall local response rate of 82.6%. As assessed by palpation, there were 46 complete responses (46 of 180, 25.6%) and 110 partial responses (110 of 180, 61.1%) in cervical lymph nodes, giving an overall response rate of 86.7%.
Among the 180 patients with lymph node disease, an overall response rate of 85.6% in both the primary tumor and the cervical lymph nodes was observed, with a complete response rate of 14.5%.
Survival
Patterns of Treatment Failure The 5-year FLR rates were 82% for the CT/RT group and 74% for the RT group (P = .04, Fig 3). The 5-year FDM rates were 79% for the CT/RT group compared with 75% for the RT group (P = .40, Fig 4). The patterns of treatment failure are listed in Table 4. The pattern of distribution of distant metastases was similar in both arms with bone, lung, and liver being the sites of metastases in descending order of frequency.
Toxicity The toxicity of chemotherapy is reported in Table 5. There were no chemotherapy-related deaths. The main nonhematologic toxicities were nausea and vomiting; 28 patients (12.8%) had grade 3 or 4 nausea and vomiting. Hematologic toxicity was mild; only eight patients (3.7%) had grade 3 leukopenia and six patients (2.8%) had grade 3 or 4 anemia.
There was no significant difference in acute mucositis between the two groups during radiotherapy (P = .64). According to the Radiation Therapy Oncology Group (RTOG) grading system, grade 2 mucositis occurred in 18% of the patients in the CT/RT group compared with 15% of patients in the RT group. It should be noted that one patient in the RT group died of cerebrovascular accident, which may be a possible toxicity from the radiation therapy.
Patients with large primary tumors (T3 or T4) or nodal involvement (N2 to N3) but no systemic metastases have locoregionally advanced disease. These patients have traditionally been treated with radiotherapy alone. However, after radiotherapy, patients fail either locoregionally or systemically and long-term survival rates are unsatisfactory.1-4,6,8 NPC is a highly chemosensitive tumor.9-11 To improve survival rates, chemotherapy has been added to radiotherapy in various manners (concurrent, neoadjuvant, adjuvant).16-18
The International Nasopharynx Cancer Study Group27 has reported the preliminary results of a randomized trial comparing three cycles of neoadjuvant chemotherapy using bleomycin, epirubicin, and cisplatin plus radiotherapy versus radiotherapy alone in AJCC (American Joint Committee on Cancer) stage IV ( The main goal of neoadjuvant chemotherapy is to eradicate distant micrometastases. The drug dose and course necessary to achieve this aim are still unknown. In most modern protocols, drug doses equivalent to three courses or more are administered. Given the high distant failure rate associated with NPC, it is logical to expect a decline in distant failure with the use of neoadjuvant chemotherapy. In the present study, the 5-year FDM rates were 79% for the CT/RT group compared with 75% for the RT group (P = .40). There was no difference in distant metastases between the CT/RT and RT group. The present study showed that neoadjuvant chemotherapy was not effective in reducing distant metastasis. A possible explanation is that two to three cycles of neoadjuvant chemotherapy were not sufficient to eradicate all the distant micrometastases. Neoadjuvant chemotherapy is also aimed at decreasing the tumor burden in the nasopharynx before radiation. The 5-year FLR rates were 82% for the CT/RT group and 74% for the RT group. The incidence of local failure was of borderline statistical significance in the CT/RT group (P = .04). The enhancement of local control of the locally advanced NPC could be explained by the significant shrinkage of the primary tumor by the neoadjuvant chemotherapy, leading to an increased safety margin between the tumor volume and the radiation volume (for example, an improved dose-volume histogram for the tumor target).29 A trend of improved RFS favoring the CT/RT group was observed. The median RFS time for the RT group was 50 months and had not been reached for the CT/RT group. The 5-year RFS rate was 59% for the CT/RT group compared with 49% for the RT group (P = .05). The reduction in local relapses could have translated into an improvement in RFS. However, this gain did not translate into an overall survival benefit. Despite the possible advantage in RFS, there was not a significant improvement in OS in favor of the chemotherapy group. The possible explanation is that patients with local or regional recurrence may still be amenable to salvage treatment with either reirradiation or surgery. Furthermore, patients with locoregional disease tend to survive longer than those with distant failure, and a longer follow-up may be gained to show the poorer survival of the group in which locoregional relapse occurred more frequently. The negative result for neoadjuvant chemotherapy in this study agrees with the results of other prospective randomized trials that reported high response rates but no survival benefit.27,28 Different strategies of combined chemotherapy and radiotherapy were tested in some randomized trials. In NPC, the use of adjuvant chemotherapy has never been proven to be of benefit.30,31 The early results for concurrent chemoradiotherapy together with adjuvant chemotherapy reported by Al-Sarraf et al32 are highly encouraging, and further prospective randomized trials will determine whether this strategy is equally advantageous in endemic areas where NPC prevails.33,34 In a large randomized controlled trial, we failed to demonstrate a significant advantage from using neoadjuvant chemotherapy to treat locoregionally advanced NPC. A larger trial would be required to rule out smaller differences but a reasonable recommendation would be that such therapy should not be used outside the context of a well-designed clinical trial.
Supported by grant no. 85-914-02-06 from the Key Program of the Five-Year Plan of the National Committee for Science and Technology. We thank Peter M.L. Teo, MBBS, FRCR, DMRT, Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, for his assistance in English editing and recommendations. We also thank our patients and their families for their willingness to participate in this trial.
1. Perez CA, Devineni VR, Marciai-Vega V, et al: Carcinoma of the nasopharynx: Factors affecting prognosis. Int J Radiat Oncol Biol Phys 23: 271-280, 1992[Medline] 2. Zhang EP, Lian PG, Cai KL, et al: Radiation therapy of nasopharyngeal carcinoma: Prognostic factors based on a 10-year follow-up of 1302 patients. Int Radiat Oncol Biol Phys 16: 301-305, 1989 3. Qin D, Hu Y, Xu G, et al: Analysis of 1379 patients with nasopharyngeal carcinoma. Cancer 61: 1117-1124, 1988[Medline] 4. Lee AWM, Poon YF, Foo W, et al: Retrospective analysis of 5037 patients with nasopharyngeal carcinoma treated during 1976-1985: Overall survival and patterns of failure. Int J Radiat Oncol Biol Phys 23: 261-270, 1992[Medline] 5. Min HQ: Nasopharyngeal Carcinoma, in Gun GY (ed): Epidemiology. Beijing, China, People’s Medical Press, 1996, pp 280-285 6. Min HQ, Hong MH, Ma J, et al: A new staging system for nasopharyngeal carcinoma in China. Int J Radiat Oncol Biol Phys 30: 1037-1042, 1994[Medline] 7. Teo PML, Leung SF, Yu P, et al: A comparison of Ho’s, International Union Against Cancer, and American Joint Committee Stage Classifications for nasopharyngeal carcinoma. Cancer 67: 434-439, 1991[Medline] 8. Ma J, Hong MH, Min HQ, et al: A clinical verification of Chinese 1992 staging system for nasopharyngeal carcinoma. Chinese J Cancer 18: 44-55, 1998 9. Decker DA, Drelichman A, Al-Sarraf M: Chemotherapy for nasopharyngeal carcinoma: A ten-year experience. Cancer 52: 602-605, 1983[Medline] 10. Al-Sarraf M: Chemotherapeutic management of head and neck cancer. Cancer Metast Rev 6: 191-198, 1987 11. Yeo W, Leung TWT, Leung SF, et al: Phase II study of combination carboplatin and 5-fluorouracil in metastatic nasopharyngeal carcinoma. Cancer Chemother Pharmacol 38: 466-470, 1996[Medline] 12. Boussen H, Cvitkovic E, Wendling JL, et al: Chemotherapy of metastatic and/or recurrent undifferentiated nasopharyngeal carcinoma with cisplatin, bleomycin and fluorouracil. J Clin Oncol 9: 1675-1681, 1991[Abstract] 13. Mahjoubi R, Azli N, Bachouchi M, et al: Metastatic undifferentiated carcinoma of nasopharyngeal type treated with bleomycin (B), epirubicin (E), and cisplatin (C): Final report. Proc Am Soc Clin Oncol 11: 240, 1992 (abstr 772) 14. Cvikovic E, Mahjoubi R, Lianes P, et al: 5-Fluorouracil (FU), mitomycin (M), epirubicin (E), cisplatin (P) in recurrent and/or metastatic undifferentiated nasopharyngeal carcinoma (UCNT). Proc Am Soc Clin Oncol 10: 200, 1991 (abstr 664) 15. Altun M, Fandi A, Dupuis O, et al: Undifferentiated nasopharyngeal cancer (UCNT): Current diagnostic and therapeutic aspects. Int J Radiat Oncol Biol Phys 32: 859-877, 1995[Medline] 16. Al-Sarraf M, Pajak TF, Cooper JS, et al: Chemo-radiotherapy in patients with locally advanced nasopharyngeal carcinoma: A Radiation Therapy Oncology Group study. J Clin Oncol 8: 1342-1351, 1990[Abstract]
17.
Bachouchi M, Cvitkovic E, Azli N: High complete response in advanced nasopharyngeal carcinoma with bleomycin, epirubicin, and cisplatin before radiotherapy. J Natl Cancer Inst 82: 616-620, 1990 18. Dimery IW, Legha SS, Peters LJ, et al: Adjuvant chemotherapy for advanced nasopharyngeal carcinoma. Cancer 60: 943-949, 1987[Medline] 19. Peters LJ, Harrison ML, Dimery IW, et al: Acute and late toxicity associated with sequential bleomycin-containing chemotherapy regimens and radiation therapy in the treatment of carcinoma of the nasopharynx. Int J Radiat Oncol Biol Phys 14: 623-633, 1988[Medline]
20.
Tannock I, Payne D, Cummings B: Sequential chemotherapy and radiation for nasopharyngeal cancer: Absence of long-term benefit despite a high rate of tumor response to chemotherapy. J Clin Oncol 5: 629-634, 1987 21. Zhang EP, Luo W, Qian JY, et al: A study on improving the treatment technique of the radiotherapy in nasopharyngeal carcinoma: Part I. The dose distribution of target volume. Chinese J Cancer 14: 126-129, 1996 22. Luo W, Zhang EP, Tu MC, et al: A study on improving the treatment technique of the radiotherapy in nasopharyngeal carcinoma: Part II. Clinical results. Chinese J Cancer 15: 280-282, 1996 23. Clark JR, Norris CM, Dreyfuss AI, et al: Nasopharyngeal carcinoma: The Dana-Farber Cancer Institute experience with 24 patients treated with induction chemotherapy and radiotherapy. Ann Otol Rhinol Laryngol 96: 608-614, 1987[Medline] 24. Atichartakarn V, Kraiophibul P, Clongsusuek P, et al: Nasopharyngeal carcinoma: Result of treatment with cis-diamminedichloroplatinum II, 5 fluorouracil, and radiotherapy. Int J Radiat Oncol Biol Phys 14: 461-469, 1998 25. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47: 207-214, 1981[Medline] 26. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958
27.
International Nasopharynx Cancer Study Group: Preliminary results of a randomized trial comparing neoadjuvant chemotherapy (cisplatin, epirubicin, bleomycin) plus radiotherapy vs. radiotherapy alone in stage IV ( 28. Chua DTT, Sham JST, Choy D, et al: Preliminary report of the Asian-Oceanian Clinical Oncology Association randomized trial comparing cisplatin and epirubicin followed by radiotherapy versus radiotherapy alone in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma. Cancer 83: 2270-2283, 1998[Medline] 29. Teo PM, Chan AT, Lee WY, et al: Enhancement of local control in locally advanced node-positive nasopharyngeal carcinoma by adjunctive chemotherapy. Int J Radiat Oncol Biol Phys 43: 261-271, 1999[Medline]
30.
Rossi A, Molinari R, Boracchi P, et al: Adjuvant chemotherapy with vincristine, cyclophosphamide, and doxorubicin after radiotherapy in local-regional nasopharyngeal cancer: Results of a 4-year multicenter randomized study. J Clin Oncol 6: 1401-1410, 1988 31. Chan ATC, Teo PML, Leung TWT, et al: A prospective randomized study of chemotherapy adjunctive to definitive radiotherapy in advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 33: 569-577, 1995[Medline]
32.
Al-Sarraf M, LeBlanc M, Shanker Giri PG, et al: Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized intergroup study 0099. J Clin Oncol 16: 1310-1317, 1998 33. Chan ATC, Teo PML, Leung TWT, et al: The role of chemotherapy in the management of nasopharyngeal carcinoma. Cancer 82: 1003-1011, 1998[Medline] 34. Tan EH, Chua ET, Wee J, et al: Concurrent chemotherapy followed by adjuvant chemotherapy in Asian patients with nasopharyngeal carcinoma: Toxicities and preliminary results. Int J Radiat Oncol Biol Phys 45: 597-601, 1999[Medline] Submitted August 2, 2000; accepted November 14, 2000.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test. The statistical significance of differences among survival curves was analyzed using the log-rank test; a P value of .05 or less was considered statistically significant. Statistical tests were based on a two-sided significance level. 
