A randomized phase II trial of induction chemotherapy and low-dose fractionated radiation

Introduction: Squamous cell carcinoma of the head and neck (SCCHN) is a lethal disease with a high incidence in Kentucky, compared to the remainder of the United States. Treatment of locally advanced SCCHN provides an approximate 50% overall survival at 5 years; thus, innovative strategies are desperately needed. Synergy between radiation and chemotherapy is well established, but until recently low-doses of radiation were not thought to represent an effective therapeutic range. This proposal investigates the role of low-dose fractionated radiation (LDFRT) combined with chemotherapy as induction therapy in locally advanced SCCHN. Methods: Subjects with previously untreated, locally advanced SCCHN will be randomized receive induction chemotherapy with or without LDFRT for two cycles, followed by predefined definitive treatment. Correlative studies will evaluate the level of DNA damage and DNA repair kinetics in serial mucosal sampling within the irradiated fields in all subjects exposed to the different doses of radiation during this treatment paradigm. Statistical Design: The primary endpoint is primary site CR rate. Using a binomial test of two proportions with 2 planned interim analyses for futility (after 25% and 50% of total patient accrual), 34 subjects per group are needed for this phase II based on a one-side type I error rate of at most 5% and 80% power. Allowing for a 5% drop out rate, we plan to enroll 72 total patients; however, funding from this grant mechanism is only requested for the patients required to reach the first two interim analyses (n=34). Expected outcomes: Results of this randomized phase II trial will provide the evidence needed to test this treatment paradigm in a phase III trial. The evaluation of DNA damage will help to elucidate the mechanism of cell death when cells are exposed to radiation doses of less than 100 cGy compared to doses of 180 cGy, as well as to explore the mechanism of how LDFRT potentiates the effect of chemotherapy.