Astro plenary: Interfraction interval is a major determinant of late effects, with hyperfractionated radiation therapy of carcinomas of upper respiratory and digestive tracts: Results from radiation therapy oncology group protocol 8313

Abstract

A prospective, randomized, multi-institutional, Phase I LE II trial of HFX was conducted by the RTOG between 1983 and 1987. Patients with histologically proven, inoperable squamous cell carcinoma of the upper respiratory and digestive tracts stratified by site, nodal status, and performance status, were assigned to one of three arms, 67.2 Gy, 72.0 Gy, or 76.8 Gy. Fractions of 1.2 Gy were given twice daily, 5 days per week: intervals of 4 to 8 hours were permitted between fractions. After acceptable rates of acute normal tissue effects were found, the randomization was changed to evaluate a new higher total dose, 81.6 Gy. Of 479 patients entered, 447 were analyzed, 63 on 67.2 Gy, 129 on 72.0 Gy, 117 on 76.8 Gy, and 138 on 81.6 Gy. The treatment arms were well balanced with respect to pretreatment characteristics. Acute reactions consisted almost entirely of pseudomembranous inflammation. “Severe” (Grade 3) acute reactions were reported in 33% to 41% and grade 4 reactions were found in 0 to 3% of patients, with no differences in frequencies among the four arms. Toxicities that developed or persisted beyond 90 days after the first treatment (408 patients evaluable >90 days) did not differ among arms: grade 3+ reactions occurred in 10% to 14%, and grade 4+ effects (necroses) were reported in 5% at 67.2 Gy, 3% at 72.0 Gy, 7% at 76.8 Gy, and 2% at 81.6 Gy. Grade 3+ acute reactions occurred in 40% of patients when the interfraction interval was ≤4.5 hours versus 31% with >4.5 hours ( p = .03). Interfraction intervals ≤ 4.5 hours were associated with higher frequencies of grade 4+ late effects in all four arms, 8% of 197 patients with ≤4.5 hours versus 1% of 211 patients with >4.5 hours. Estimates of late toxicity at 1, 2, and 3 years were 5.5%, 9.8%, and 15.4% with intervals ≤ 4.5 hours, versus 1.7% at all three periods for >4.5 hours ( p = .006). Local-regional control at 2 years was 25% for the assigned dose of 67.2 Gy compared to 43% to 45% for the three higher doses ( p = .01), but a similar comparison for survival showed no significant difference ( p = .35). There was no evidence for an effect of interfraction interval on either local-regional control ( p = .38) or survival ( p = .28). The sparing of normal tissues associated with HFX using interfraction intervals > 4.5 hours despite the high total doses achieved, and the dissociation of acute effects and tumor control from late effects support the comparison of 81.6 Gy HFX, using longer interfraction intervals, with standard fractionation in a Phase III trial.