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© 2003 American Society for Clinical Oncology Phase III Study of Concurrent Chemoradiotherapy Versus Radiotherapy Alone for Advanced Nasopharyngeal Carcinoma: Positive Effect on Overall and Progression-Free Survival
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. 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{at}mail.vghtc.gov.tw.
Purpose: Nasopharyngeal carcinoma (NPC) is a radiosensitive and chemosensitive tumor. This randomized phase III trial compared concurrent chemoradiotherapy (CCRT) versus radiotherapy (RT) alone in patients with advanced NPC. Patients and Methods: From December 1993 to April 1999, 284 patients with 1992 American Joint Committee on Cancer stage III to IV (M0) NPC were randomly allocated into two arms. Similar dosage and fractionation of RT was administered in both arms. The investigational arm received two cycles of concurrent chemotherapy with cisplatin 20 mg/m2/d plus fluorouracil 400 mg/m2/d by 96-hour continuous infusion during the weeks 1 and 5 of RT. Survival analysis was estimated by the Kaplan-Meier method and compared by the log-rank test.
Results: Baseline patient characteristics were comparable in both arms. After a median follow-up of 65 months, 26.2% (37 of 141) and 46.2% (66 of 143) of patients developed tumor relapse in the CCRT and RT-alone groups, respectively. The 5-year overall survival rates were 72.3% for the CCRT arm and 54.2% for the RT-only arm (P = .0022). The 5-year progression-free survival rates were 71.6% for the CCRT group compared with 53.0% for the RT-only group (P = .0012). Although significantly more toxicity was noted in the CCRT arm, including leukopenia and emesis, compliance with the combined treatment was good. The second cycle of concurrent chemotherapy was refused by nine patients and was delayed for Conclusion: We conclude that CCRT is superior to RT alone for patients with advanced NPC in endemic areas.
NASOPHARYNGEAL CARCINOMA (NPC) is a neoplasm of the head and neck that is rarely seen in the United States 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 radiosensitivity, 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 of locoregionally 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 chemotherapy 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 chemoradiotherapy (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 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/µL and platelet count greater than 100,000/µL; 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
Radiotherapy 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
Patient Assessment 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
Treatment for Relapse or Residual Disease
Patient Characteristics From December 1993 through April 1999, 284 eligible patients 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 arms—including age, sex, Karnofsky performance status, pathology, T stage, and N stage—were 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 Organization criteria are listed in Table 3 . No fatal toxicity related to planned treatment occurred in either group. A higher incidence 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 significant. 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 at 19 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
Survival Concurrent chemotherapy significantly improved overall survival 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), 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).
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 chemoradiotherapy. 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 comparing 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 overall 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 study’s 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 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 Group trial,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 chemotherapy 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 (neoadjuvant 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 suboptimal. 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 ominous 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 approaches to enhance the efficacy of RT, including radiosensitizers, 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 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 radiosensitizing 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 allocated 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 chemotherapy 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 encountered 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 completely eradicate micrometastases. Failure pattern analysis of our study revealed that distant metastases outnumbered local recurrence. 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.
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.
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ABSTRACT
INTRODUCTION
2 test was used for category or ordinal variables. Fisher’s exact test was used when a small sample size existed. Survival curves were estimated by the product-limit method.
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