Randomized Trial of Hyperfractionation Versus Conventional Fractionation in T2 Squamous Cell Carcinoma of the Vocal Cord (RTOG 9512)

Abstract

Purpose To compare hyperfractionation versus standard fractionation for T2N0 vocal cord carcinoma in a randomized controlled trial. Methods and Materials Patients with T2 vocal cord cancer were stratified by substage (T2a vs. T2b) and randomly assigned to receive either hyperfractionation (HFX) to 79.2 Gy in 66 fractions of 1.2 Gy given twice a day, or standard fractionation (SFX) to 70 Gy in 35 fractions given once a day. The trial was designed to detect a 55% reduction in the local failure hazard rate with 80% statistical power. Results Between April 1996 and July 2003, 250 patients were enrolled. Of 239 patients analyzable for outcomes, 94% were male, 83% had KPS 90-100, and 62% had T2a tumor. Median follow-up for all surviving patients was 7.9 years (range: 0.6 – 13.1). The 5-year local control (LC) rate was 8 points higher (but not statistically significant: p=0.14) for HFX (78%) vs SFX (70%), corresponding to a 30% hazard rate reduction. Five-year disease-free survival (DFS) was 49% vs 40% (p=0.13) and overall survival (OS) 72% vs 63% (p=0.29). HFX had higher rates of acute skin, mucosal, and laryngeal toxicity. Grade 3-4 late effects were similar with 5-year cumulative incidence of 8.5% (3.4-13.6%) after SFX and 8.5% (3.4-13.5%) after HFX. Conclusions Five-year local control was modestly higher with HFX compared to SFX for T2 glottic carcinoma, but the difference was not statistically significant. These results are consistent with prior studies of hyperfractionation showing a benefit in local control. Substaging by T2a vs T2b carries prognostic value for DFS and OS. For cost and convenience reasons other altered fractionation schedules have been adopted in routine practice.

Role of radiotherapy fractionation in head and neck cancers (MARCH): an updated meta-analysis

“…The control group of a four-arm trial 4 was triplicated (ie, data for patients in the control group were copied twice to have three control arms to compare with each experimental arm), a 2 × 2 trial (EORTC 22962 45 ) included three relevant comparisons for the meta-analysis, and three three-arm trials 36,37,55 included two relevant comparisons. The 33 trials included in the analysis of fractionation schedules (comparison 1) were divided into four predefined subgroups, depending on the type of radiotherapy: hyperfractionation (eight comparisons, including the unpublished EORTC 22962 trial), 4,33,44,45,49,50,56 moderately accelerated radiotherapy (19 comparisons), 2,4,30,32,34–39,41,42,46,54,55,57–59 very accelerated radiotherapy (seven comparisons, including the unpublished CHARTWEL trial), 3,47,51–53,60 and moderately hypofractionated (dose per fraction between 2–2·5 Gy [two comparisons]; 31,40 appendix pp 17–18). After discussion with the steering committee, the moderately hypofractionated trials were included in the moderately accelerated radiotherapy group.…”

The DAHANCA 6 randomized trial: Effect of 6 vs 5 weekly fractions of radiotherapy in patients with glottic squamous cell carcinoma

“…A similar Korean trial of 156 patients with T1-T2 glottic scc substantiated the finding of improved disease control after accelerated hypofractionated radiotherapy compared to conventional fractionated radiotherapy [19]. In the RTOG 9512 study hyperfractionation with a 9.2 Gy dose increase and 0.5 week treatment time reduction increased local control 8% (78% vs 70%, p > 0.05) in T2N0 glottic cancer patients compared to conventional RT [20]. Overall, the evidence of a positive effect of reduced treatment time on loco-regional control is convincing.…”

Radiation Therapy Intensification for Solid Tumors: A Systematic Review of Randomized Trials

“…Several randomized studies have evaluated altered fractionation via gentle hypofractionation 17,18 or hyperfractionation 19 as a means to improve local tumor control in early-stage laryngeal cancer. All three studies demonstrated at least a trend favoring altered fractionation.…”