Phase II Study of a Radiotherapy Total Dose Increase in Hypoxic Lesions Identified by 18F-Misonidazole PET/CT in Patients with Non-Small Cell Lung Carcinoma (RTEP5 Study)

This multicenter phase II study investigated a selective radiotherapy dose increase to tumor areas with significant F-18-misonidazole (F-18-FMISO) uptake in patients with non-small cell lung carcinoma (NSCLC). Methods: Eligible patients had locally advanced NSCLC and no contraindication to concomitant chemoradiotherapy. The F-18-FMISO uptake on PET/CT was assessed by trained experts. If there was no uptake, 66 Gy were delivered. In F-18-FMISO-positive patients, the contours of the hypoxic area were transferred to the radiation oncologist. It was necessary for the radiotherapy dose to be as high as possible while fulfilling dose-limiting constraints for the spinal cord and lungs. The primary endpoint was tumor response (complete response plus partial response) at 3 mo. The secondary endpoints were toxicity, disease-free survival (DFS), and overall survival at 1 y. The target sample size was set to demonstrate a response rate of 40% or more (bilateral alpha = 0.05, power 1-beta = 0.95). Results: Seventy-nine patients were preincluded, 54 were included, and 34 were F-18-FMISO-positive, 24 of whom received escalated doses of up to 86 Gy. The response rate at 3 mo was 31 of 54 (57%; 95% confidence interval [CI], 43%-71%) using RECIST 1.1 (17/34 responders in the F-18-FMISO-positive group). DFS and overall survival at 1 y were 0.86 (95% CI, 0.77-0.96) and 0.63 (95% CI, 0.49-0.74), respectively. DFS was longer in the F-18-FMISO-negative patients (P = 0.004). The radiotherapy dose was not associated with DFS when adjusting for the F-18-FMISO status. One toxic death (66 Gy) and 1 case of grade 4 pneumonitis (> 66 Gy) were reported. Conclusion: Our approach results in a response rate of 40% or more, with acceptable toxicity. F-18-FMISO uptake in NSCLC patients is strongly associated with poor prognosis features that could not be reversed by radiotherapy doses up to 86 Gy.