Disease control and late toxicity in Adaptive Dose Painting by Numbers vs. non-adaptive radiotherapy for head and neck cancer: a randomized controlled phase II trial.

Local recurrence remains the main cause of death in stage III-IV non-metastatic head-and-neck cancer (HNC) with relapse-prone regions within high F-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 F-FDG-PET-voxel-intensity-based dose-painting-by-numbers (A-DPBN) with non-adaptive standard intensity-modulated radiotherapy (S-IMRT). This two-center randomized controlled phase II trial assigned (1:1) patients to receive A-DPBN or S-IMRT (+/-chemotherapy). Eligibility: non-metastatic 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. 1-year LC and RC. The dose prescription for A-DPBN was intercurrently adapted in two steps to an absolute dose-volume limit (≤1.75cm can receive >84Gy and normalized isoeffective dose >96Gy) as a safety measure during the study course after 4/7 A-DPBN patients developed ≥G3 mucosal ulcers. Ninety-five patients were randomized (A-DPBN: 47; S-IMRT: 48). Median follow-up amounts 31 months (IQR: 14-48 months); 29 patients died (17 of cancer progression). A-DPBN results in superior LC compared to S-IMRT with 1- and 2-year LC of 91% and 88% vs. 78% and 75%, respectively (hazard ratio, 3.13; 95% confidence interval, 1.13-8.71; p=0.021). RC and overall survival are comparable between arms, as is overall grade (G) ≥3 late toxicity (36% vs. 20%, p=0.1). More ≥G3 late mucosal ulcers are observed in active smokers (29% vs. 3%, p=0.005) and alcohol users (33% vs. 13%, p=0.02), independent of treatment arm. Similarly, in the A-DPBN arm, significantly more patients that smoked at diagnosis developed ≥G3 (46% vs. 12%, p=0.005) and ≥G4 (29% vs. 8%, p=0.048) mucosal ulcers. One arterial blowout occurred following a G5 mucosal toxicity. A-DPBN resulted in superior 1- and 2-year LC for HNC compared to S-IMRT. This supports further exploration in multicenter phase III trials. It will however be challenging to recruit a substantial patient sample for such trials as concerns have arisen on the association of late mucosal ulcers when escalating the dose in continuing smokers.