Altered fractionation trials in head and neck cancer

Advancement in radiobiological concepts has led to the development of two classes of new fractionation schedules for the treatment of head and neck cancers. These altered fractionation regimens are referred to as hyperfractionation and accelerated fractionation schedules. Hyperfractionation exploits the difference in fractionation sensitivity between tumors and normal tissues manifesting late morbidity. In contrast, accelerated fractionations attempt to reduce tumor proliferation as a major cause of radiotherapy failure. Although there are many permutations in accelerating radiation treatment, the existing schedules can be conceptually grouped into two categories, pure accelerated fractionations and hybrid accelerated regimens, depending on whether there are concurrent changes in other fractionation parameters. The results of 10 completed phase III clinical trials addressing different types of altered fractionation schedules in head and neck carcinomas are examined and summarized in this review article. The data of trials on hyperfractionation regimens applying 10% to 15% total dose increment over the standard 66 to 70 Gy consistently revealed a 10% to 15% improvement in the local control rate of a subset of intermediate-stage carcinomas without an appreciable increase in the incidence of late complications. The available data on accelerated fractionation regimens showed that tumor clonogen proliferation is a major cause of radiation failure. Completed studies, however, revealed that a 1- to 1.5-week treatment acceleration without total dose reduction achieved by administering 2-Gy fractions 6 times per week or concomitant boost schedule yielded an approximately 15% higher tumor control rate without increasing late toxicity. Shortening the overall time to less than 2 weeks with an associated total dose reduction did not seem to improve tumor control rate, with an exception perhaps for a small subset of patients with laryngeal carcinomas, but might decrease some late normal tissue injury. A weekly dose accumulation rate of 14 Gy or greater, or delivery of 3 fractions of 1.6 Gy/d, with 6 hour intervals, without total dose reduction, was found to increase morbidity beyond the acceptable level. Further treatment refinements building on these findings are being pursued.