Concurrent chemotherapy and radiation therapy for advanced stage carcinoma of the nasopharynx.

For many years, radiation therapy (RT) provided the standard of care for carcinoma of the nasopharynx. However, the vast majority of nasopharyngeal carcinomas in the United States were (and still are) detected only after they reached an advanced stage and their associated 5-year survival rate was only 30–45%. Slightly more than two decades ago, some oncologists hypothesized that the addition of cisplatin (6 other drugs) to radiation therapy, either sequentially or concurrently, might improve the outcome of head and neck cancer. In one of its efforts to explore this concept, the Radiation Therapy Oncology Group (RTOG) designed and conducted a Phase II trial (RTOG 8117) testing the feasibility of concurrent cisplatin (CDDP) and radiation therapy in advanced-stage head and neck cancers. Fortunately, the trial demonstrated that concurrent therapy was feasible and, even better, that concurrent CDDP might boost the effectiveness of RT for advanced head and neck cancers in general, and nasopharyngeal cancer in particular (1). Spurred by these findings, Intergroup 0099 (also known as RTOG 8817) was designed as a prospective, randomized Phase III trial. (2) It tested three cycles of concurrent CDDP and conventional RT followed by three cycles of adjuvant CDDP and 5-fluorouracil (5-FU) compared with conventional RT alone for Stage III or IV carcinomas of the nasopharynx without detectable systemic metastases (American Joint Committee on Cancer [AJCC] 1988 definitions). The results of combined modality therapy were sufficiently better than those of radiation therapy alone (as measured by survival [78% vs. 47% at 3 years] or progression-free survival [69% vs. 24% at 3 years]) that the data activated an “early stopping rule.” Accrual to the trial was terminated by the Data and Safety Monitoring Committee and many physicians adopted combined modality therapy as their standard of practice for advanced nasopharyngeal carcinomas. But several issues remained before the Intergroup trial could rightfully be granted “landmark” status. First, we needed to be certain that the differences in outcome reflected an improvement resulting from combined modality therapy, rather than a statistic created by spuriously poor outcome of radiation therapy alone in the trial. Second, we needed a rational explanation to understand why the results of Intergroup 0099 seemed unique and chemotherapy failed to improve outcome consistently in other nasopharyngeal cancer trials. Third, we needed to know if the conclusions of the American Intergroup trial could be applied universally, particularly in Asian populations where nasopharyngeal carcinoma is far more common. Last, in the current era of evidence-based medicine, we needed additional independent confirmatory evidence. The article by Cheng et al. (3) included in this issue of the Journal responds to many of these issues. In a totally independent population in Taiwan, Cheng and colleagues demonstrate that concurrent radiation therapy and chemotherapy followed by adjuvant chemotherapy produces salutary treatment of advanced nasopharyngeal cancer: an 84% 5-year overall survival rate, a 74% disease-free survival rate, and a 90% locoregional control rate. The experience of Cheng et al., like my own (4), corroborates the Intergroup trial’s conclusion (2). Thus, it appears that the failure of multimodality therapy in other chemoradiation trials likely reflects the pattern of treatment, rather than a flaw in the concept, i.e., induction chemotherapy followed by radiation therapy alone is not the equal of concurrent therapy followed by chemotherapy alone for advanced nasopharyngeal cancer. Two other important concepts are raised by Cheng et al. (3). First, their data suggest that the precise manner in which the Intergroup trial prescribed chemoradiotherapy is not the only effective regimen. Cheng and coworkers used only 2 cycles of concurrent and 2 cycles of adjuvant chemotherapy (vs. the Intergroup’s 3 plus 3), but included 5-FU with cisplatin in all cycles (vs. the Intergroup’s use of cisplatin alone during radiation therapy). In addition, the numeric doses of chemotherapy are different (Table 1). Despite two-drug (albeit smaller CDDP dose, less frequent) concurrent therapy, Cheng et al. were able to deliver a far greater proportion of their planned doses. In fact, they delivered a greater proportion of their 4 intended total doses than the Intergroup could deliver for either of their 3 concurrent doses or three adjuvant doses (Fig. 1). Yet, the overall acute toxicity of the two regimens is of the same order of magnitude and the patterns of acute toxicity are sufficiently different that Int. J. Radiation Oncology Biol. Phys., Vol. 48, No. 5, pp. 1277–1279, 2000 Copyright © 2000 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/00/$–see front matter