Concomitant and Subsequent Chemotherapy Enhances Responses to Advanced Nasophary
June 1, 1998
Concomitant and Subsequent Chemotherapy Enhances Responses to Advanced Nasopharyngeal Cancer
ABSTRACT & COMMENTARY
Synopsis: The Southwest Oncology Group coordinated an intergroup study of initial treatment for stage III and IV disease in a randomized, prospective trial comparing radiation alone vs. combined radiation therapy and chemotherapy. The radiation approach was the same in both arms of the study. For those receiving chemotherapy, cisplatin was administered three times during the radiation course and subsequently with 5-fluorouracil in three monthly cycles (adjuvant). Progression-free survival and overall survival were significantly better for the combined treatment group.
Source: Al-Sarraf M, et al. J Clin Oncol 1998;16: 1310-1317.
Although nasopharyngeal carcinomas are sensitive to both radiation therapy and chemotherapy, a distinct advantage to using the two modalities concomitantly had not been established in a randomized, prospective trial. One reason for this is that the tumor is relatively uncommon in the United States and Western Europe, although it is common in other parts of the world, including Asia and Africa. Thus, the Southwest Oncology Group coordinated an intergroup phase III study involving participating centers from the Radiation Therapy Oncology Group (RTOG) and the Eastern Cooperative Oncology Group (ECOG) to determine if concomitant therapy was as good or better than radiation therapy alone for advanced (stage III and IV) nasopharyngeal cancers.
Radiation therapy was administered to all patients with the same dose and schedule: 1.8-2.0 Gy/d, five days a week to a total dose of 70 Gy (35-39 fractions). Patients on the investigational arm also received chemotherapy-cisplatin 100 mg/m2 on days 1, 22, and 43 of radiation therapy. Furthermore, the chemotherapy was continued for three monthly cycles upon completion of radiation therapy. For this adjuvant part of the treatment, patients received cisplatin 80 mg/m2 on day 1 and 5-fluorouracil 1000 mg/m2/d by continuous infusion on days 1-4 of each monthly cycle.
Of the 193 patients entered on study, 147 were evaluable with regard to survival and toxicity. The median progression-free survival (PFS) was 15 months for the radiation therapy alone arm and was not reached for the combined therapy arm. The three-year PFS rate was 24% for radiation therapy alone and 69% for the combined modality arm (P < 0.001). The three-year survival rate was 47% for radiation therapy alone and 76% for combined modality therapy (P < 0.001). Thus, Al-Sarraf and colleagues conclude that the combined therapy was the superior approach for patients with advanced nasopharyngeal malignancies.
Nevertheless, the toxicity was substantial in the combined modality group, with 19 of 78 patients (24%) dropping off the program because of toxicity or unspecified refusal.
COMMENTARY
Nasopharyngeal carcinomas are sensitive to radiation therapy, and, in general, this has become the favored approach to initial management. In one large series of patients presenting with advanced disease (stages III and IV) and treated with radiation therapy alone,1 the five-year survival was 41%. Thus, the 76% overall survival at three years observed in this study for those on the combined modality arm looks favorable compared to historical experience as well as in comparison to the control arm of this study.
Nasopharyngeal carcinomas are also sensitive to chemotherapy, especially cisplatin-based regimens, and the idea of combining the two approaches is not especially novel. In fact, several pilot or phase II studies have demonstrated remarkable results.2-4
In a European cooperative phase III trial, chemotherapy was used as initial therapy followed by radiation therapy (vs radiation therapy alone).5 In this study, overall response rate was improved in those receiving the combined modality treatment but no survival advantage was seen. This may have been because of the schedule, the choice of drugs, or the fact that there was a high incidence of treatment-related deaths in the combined modality treatment arm (9%). The Intergroup protocol included both concomitant and subsequent (adjuvant) chemotherapy and included drugs with demonstrated activity against nasopharyngeal cancer. Toxicity was moderate. Yet, despite the relatively high dropout, there was significant survival advantage to the combined modality approach.
It is interesting to note that patients as old as 81 years were entered into the study. However, no comments were made regarding the incidence of toxicity or the effectiveness of therapy as a function of age. This might be important because patients enrolled in research protocols tend to be younger and have less comorbid illness than those observed in the community.6 Indeed, the median age for patients in this report was around 51 years, a decade younger than the mean age for nasopharyngeal cancer in the United States.7
A final point worth mentioning is that this important research was only possible because of a large collaborative effort involving three cooperative groups and multiple institutions. Progess in the treatment of rarer entities critically depends on the successful conduct of large-scale collaborations such as this.
References
1. Qin D, et al. Cancer 1988;61:1117-1124.
2. Al-Kourainy K, et al. Am J Clin Oncol 1988;11: 553-557.
3. Atichartakan V, et al. Int J Radiat Oncol Biol Phys 1988;14:461-469.
4. Bachouchi M, et al. J Natl Cancer Inst 1990;82: 616-620.
5. Eschwege F, et al. Int J Radiat Oncol Biol Phys 1995;32:192 (abstract).
6. Newcomb P, et al. J Natl Cancer Inst 1993;85: 1580-1584.
7. Ries LAG, et al. SEER Data. NIH. Bethesda, MD: US PHS, 1996.
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