Phase I Study of Accelerated Hypofractionated Proton Therapy and Chemotherapy for Locally Advanced Non-Small Cell Lung Cancer

Purpose: Our purpose was to evaluate the maximum tolerated dose of hypofractionated proton beam radiation therapy with concurrent weekly carboplatin/paclitaxel in patients with stage II-III non-small cell lung cancer. Methods and Materials: A phase I trial was designed using the time-to-event continuous reassessment method. Maximum tolerated dose was defined as the dose associated with a 20% probability of Common Terminology Criteria for Adverse Events protocol-specified serious adverse events (SAEs). Starting dose was 3.5 Gy/fx for 15 fractions with 2 potential escalation and de-escalation levels in 0.25 Gy/fx increments. Chemotherapy was weekly concurrent carboplatin/paclitaxel with 2 cycles of optional consolidation carboplatin/paclitaxel. Results: From May 2015 to September 2016, 23 patients enrolled at a single institution. Of 20 evaluable, median age was 66.5 years (range, 54-89) and 12 were male (60%). Fourteen (70%) had squamous cell and 15 (75%) were stage IIIA. Nineteen (95%) completed all 3 cycles of concurrent chemotherapy, and 16 (80%) received at least 1 cycle of consolidation chemotherapy. Within the 6-month time-to-event continuous reassessment method assessment window, no SAEs were reported, and most patients were treated at the highest dose level. Dose level assignment was 52.5 Gy (n = 2), 56.25 Gy (n = 4), and 60 Gy (n = 14). The posterior probability of dose-limiting toxicity for 60 Gy was 5.3% (95% confidence interval, 1%-18.1%). Acute, nonserious AEs included grade 2 esophagitis in 7 patients (35%) and grade 2 pneumonitis in 1 patient (5%). At a median follow-up of 20.3 months for all and 44.9 months for living patients, there were no grade 4 or 5 AEs, though there were 3 (21% at 24 months) SAEs outside of the dose-escalation window. The 2-year overall survival, local, regional, and distant control rates were 48%, 84%, 77%, and 79%, respectively. Conclusions: Hypofractionated proton beam radiation therapy and chemotherapy up to 60 Gy in 15 fractions is acutely well tolerated, with high rates of locoregional control and overall survival, though late SAEs were noted.