Toxicity and Survival Outcomes From Intensity Modulated Proton Therapy-Based Re-Irradiation in Patients With Non-Small Cell Lung Cancer

Abstract

<h3>Purpose/Objective(s)</h3> Cumulative radiation doses to organs-at-risk is the primary limiting factor when delivering thoracic reirradiation (reRT). Intensity-modulated proton therapy (IMPT) offers a unique dosimetric advantage allowing for dose-escalation while limiting normal tissue irradiation. Given the limited published data, we analyzed toxicity and survival outcomes of non-small cell lung cancer (NSCLC) patients with prior radiation history undergoing IMPT-based definitive reRT. <h3>Materials/Methods</h3> A single-institution retrospective IRB-approved analysis was conducted of 62 consecutive patients treated with IMPT-reRT between from 2016-2020. Median dose of prior RT was 60.2 Gy EQD2 (range 30-126 Gy EQD2). Median time between initial and reirradiation courses was 30 months (range 3.5 – 562 months). Median IMPT-reRT dose was 62.2 Gy (RBE) EQD2 (range 40.1 – 99.7 Gy RBE EQD2). Patients received conventionally fractioned (n=37), twice-daily (n=6), or hypofractionated (n=19) reirradiation. The majority had full overlap with the previous radiation field (N=49, 79%), were centrally located (N=42, 58%), and involved nodal irradiation (N=47, 76%). Concurrent chemotherapy was delivered in 27 (44%) patients. Treatment related toxicities were analyzed in relationship to re-RT dosimetric parameters in 30 patients whose initial RT plan was available. Kaplan-Meier method and Cox Proportional Hazard was used to estimate overall survival (OS) and freedom from local progression (FFLP) calculated from the start of reRT. <h3>Results</h3> Grade 3 acute toxicities were seen in 6 (9%) patients (pulmonary [N=3], esophageal/skin/fatigue [N=1 each]). With a median follow-up from the start of reirradiation of 12.5 months, 8 (13%) patients experienced a grade 3 late toxicity (esophageal [N=4], pulmonary [N=3] and cardiac [N=1]). Two (3%) grade 5 toxicities were observed. None of the analyzed dosimetric parameters (lung, heart, esophageal, target) correlated with grade 3 or more toxicity. CTV size greater than 150 cm³ exhibited a trend of association with grade 3+ toxicity HR = 3.2 (95% CI: 0.88 – 12.1; p=0.08). Median FFLP was not reached and median OS was 22.6 months (95% CI, 16.5 – 22.1 months). On univariate analysis variables associated with improved OS were higher reirradiation dose, cumulative radiation dose >135 Gy, and smaller CTV (< 150 cc). However, on MVA only CTV size retained statistical significance (HR = 3.56; 95% CI, 1.10 – 11.48; p=0.03). <h3>Conclusion</h3> This is the largest series to date reporting outcomes for NSCLC patients treated with IMPT-reRT which demonstrated acceptable risk (<15%) of grade 3 or higher late toxicity with durable local control and prolonged survival. In contrast to limited published literature, no specific dosimetric parameters were significantly correlated with risk of toxicity.