Disease Control and Late Toxicity in Adaptive Dose Painting by Numbers Versus Nonadaptive Radiation Therapy for Head and Neck Cancer: A Randomized Controlled Phase 2 Trial

PURPOSE: Local recurrence remains the main cause of death in stage III-IV nonmetastatic head and neck cancer (HNC), with relapse-prone regions within high 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET)-signal gross tumor volume. We investigated if dose escalation within this subvolume combined with a 3-phase treatment adaptation could increase local (LC) and regional (RC) control at equal or minimized radiation-induced toxicity, by comparing adaptive 18F-FDG-PET voxel intensity-based dose painting by numbers (A-DPBN) with nonadaptive standard intensity modulated radiation therapy (S-IMRT). METHODS AND MATERIALS: This 2-center randomized controlled phase 2 trial assigned (1:1) patients to receive A-DPBN or S-IMRT (+/-chemotherapy). Eligibility: nonmetastatic HNC of oral cavity, oro-/hypopharynx, or larynx, needing radio(chemo)therapy; T1-4N0-3 (exception: T1-2N0 glottic); KPS ≥ 70; ≥18 years; and informed consent. PRIMARY OUTCOMES: 1-year LC and RC. The dose prescription for A-DPBN was intercurrently adapted in 2 steps to an absolute dose-volume limit (≤1.75 cm3 can receive >84 Gy and normalized isoeffective dose >96 Gy) as a safety measure during the study course after 4/7 A-DPBN patients developed ≥G3 mucosal ulcers. RESULTS: Ninety-five patients were randomized (A-DPBN, 47; S-IMRT, 48). Median follow-up was 31 months (IQR, 14-48 months); 29 patients died (17 of cancer progression). A-DPBN resulted in superior LC compared with S-IMRT, with 1- and 2-year LC of 91% and 88% versus 78% and 75%, respectively (hazard ratio, 3.13; 95% CI, 1.13-8.71; P = .021). RC and overall survival were comparable between arms, as was overall grade (G) ≥3 late toxicity (36% vs 20%; P = .1). More ≥G3 late mucosal ulcers were observed in active smokers (29% vs 3%; P = .005) and alcohol users (33% vs 13%; P = .02), independent of treatment arm. Similarly, in the A-DPBN arm, significantly more patients who smoked at diagnosis developed ≥G3 (46% vs 12%; P = .005) and ≥G4 (29% vs 8%; P = .048) mucosal ulcers. One arterial blowout occurred after a G5 mucosal toxicity. CONCLUSIONS: A-DPBN resulted in superior 1- and 2-year LC for HNC compared with S-IMRT. This supports further exploration in multicenter phase 3 trials. It will, however, be challenging to recruit a substantial patient sample for such trials, as concerns have arisen regarding the association of late mucosal ulcers when escalating the dose in continuing smokers.