We report the safety data from the first multicenter phase I trial investigating the use of hypofractionated proton therapy with concurrent chemotherapy for patients with stage II or III non-small cell lung cancer (NSCLC).
From 2013 through 2018, patients with newly diagnosed stage II or III NSCLC were enrolled in a multicenter phase I clinical trial evaluating concurrent chemotherapy with increasing dose-per-fraction proton therapy. This was a stepwise 5+2 dose-intensification protocol with the following dose arms: (1) 2.5 GyRBE/fraction to 60 GyRBE; (2) 3.0 GyRBE/fraction to 60 GyRBE; (3) 3.53 GyRBE/fraction to 60.01 GyRBE; and (4) 4.0 GyRBE/fraction to 60 GyRBE. A dose arm was considered tolerable if no radiotherapy-attributable severe adverse event (SAE) occurred within 90 days of treatment among 5 patients enrolled on the arm or if 1 SAE occurred among 7 patients enrolled. Dose constraints to the heart, brachial plexus, and spinal cord were more conservative at higher doses per fraction.
The study closed early due to slow accrual and competing enrollment in NRG 1308 before accrual was met, with no maximum tolerated dose identified. Eighteen patients were treated, including 5 patients on arms 1 and 2, 7 patients on arm 3, and 1 patient on arm 4. Two SAEs occurred among 7 patients treated at 3.53 GyRBE/fraction; however, per outside expert review, both were attributed to chemotherapy and unrelated to radiotherapy.
Hypofractionated proton therapy delivered at 2.5-3.53 GyRBE/fraction to a dose of 60 GyRBEwith concurrent chemotherapy has an acceptable toxicity profile. Further exploration of this regimen is warranted on a phase II clinical trial.

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