Further follow-up of a randomized trial comparing combined chemotherapy and radiotherapy with radiotherapy alone for inoperable squamous cell cancers of the head and neck confirms the trial's initial finding of greater efficacy for the combined treatment. The new analysis, performed after 5 years of follow-up, is reported in the Journal of the National Cancer Institute.
Marco Merlano, MD, and colleagues at the National Institute for Cancer Research, Genoa, Italy, followed 157 patients with untreated unresectable squamous cell head and neck cancers who were randomly assigned to receive either chemotherapy (four courses of cisplatin(Drug information on cisplatin) [Platinol] and fluorouracil(Drug information on fluorouracil) given daily for 5 consecutive days during weeks 1, 4, 7, and 10) alternating with radiotherapy (three courses of 20 Gy each, given in fractions of 2 Gy/d during weeks 2-3, 5-6, and 8-9) or radiotherapy alone (70 Gy total, given in fractions of 2 Gy/d 5 days per week) At total of 80 patients received the combined therapy, and 77 received radiotherapy alone.
After 5 years, although the frequency of overall response to treatment was similar between the treatment groups, the group receiving combined therapy showed a statistically significant increase in the number of complete responses (ie, disappearance of clinically detectable disease for at least 4 weeks). Including patients in both groups who were able to undergo surgery and become disease free following treatment, the complete response rate in the combined-therapy group reached 53%, as compared with 26% for the radiotherapy-only group.
The combined-therapy group also showed statistically significant increases, compared with the radiotherapy-only group, in locoregional disease control (64% vs 32% after 5 years), progression-free survival (21% vs 9% after 5 years), and overall survival (24% vs 10% at 5 years). Patients in the combined-treatment group, however, experienced a greater number of second primary tumors--a finding that the authors believe is explained by their longer survival. Importantly, the incidence and severity of treatment-related toxic effects, particularly mouth ulcers (mucositis), were similar in the two treatment groups; the authors conclude that the alternating, rather than simultaneous, chemotherapy and radiotherapy helped avoid the expected additive toxicity in the combined-therapy group.
The authors note that the findings must be considered with caution, since early termination of patient accrual to the study limited its statistical power. A total of 180 patient entries to the study had been planned originally, but enrollment was stopped after 157 patients because of the substantially higher complete response rate in the combined-therapy group.
Nonetheless, say Merlano and coworkers, the results confirm the superiority of an alternating regimen of chemotherapy and radiotherapy over radiotherapy alone in this series of patients. They conclude that improved local control of disease may underlie the observed improvements in progression-free and overall survival. But, they say, additional confirmatory trials must be conducted before the combined approach can be considered standard therapy for advanced, unresectable squamous cell carcinoma of the head and neck. They also believe that combined therapy may have implications for the management of earlier-stage disease, where it may prove to be a beneficial postoperative therapy or may enable organ preservation.
In an editorial accompanying the report, Bonnie S. Glisson, MD, and Waun Ki Hong, MD, of The University of Texas M.D. Anderson Cancer Center, Houston, underscore the possible study limitations outlined by Merlano and coworkers and concur that the combined-therapy approach cannot yet be recommended as standard therapy. Still, say Glisson and Hong, chemotherapy in conjunction with radiotherapy does appear to improve local control, the lack of which is the major cause of death among patients with unresectable cancer; combined therapy also appears to extend survival in these patients. They believe that the next steps are to further refine concomitant approaches with novel regimens and schedules that enhance tumor sensitivity while minimizing toxicity; explore additional chemotherapy approaches to eliminate micrometastases once lasting local control has been achieved; and involve long-term survivors in chemoprevention trials to address the problem of second primary cancers in these individuals.