Long-term Outcomes of Definitive Chemoradiation with Proton Therapy for Treatment of Carcinoma of the Anal Canal: Combined Analysis of Two Prospective Trials.

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While definitive chemoradiation (CRT) with 5-FU/MMC remains the standard of care for localized anal cancer, treatment is associated with significant acute and late toxicity. Proton radiation therapy (RT) may potentially reduce such toxicity. Here, we assess the long-term outcomes of anal cancer patients treated with CRT using proton RT in two prospective pilot studies. Patients with stage I-III anal cancer treated with proton RT (pencil beam scanning or intensity modulated proton therapy) per RTOG 0529 dose schema with concurrent 5-FU/MMC (2 cycles) in two prospective, single-arm trials were followed. Loco-regional failure (LRF), distant metastases (DM), colostomy-free survival (CFS), disease free survival (DFS), and overall survival (OS) were assessed. Physician-graded late toxicity (>90 days from CRT) was assessed per CTCAE v4.0. Late toxicities were compared with RTOG 0529 via Fisher's exact test. Patient-reported outcomes (PROs) were analyzed. Between 2013-2020, 39 patients were treated. 37 (95%) patients completed treatment per protocol. Median follow-up was 63 months. 5-year LRF, DM, CFS, DFS, and OS were 21%, 19%, 72%, 69%, and 75%, respectively. Worst late treatment toxicities were G1 in 38%, G2 in 24%, G3 in 19%, G4 in 3%, and no G5. Compared to RTOG 0529, rates of overall G2+ late toxicities were significantly lower (46% vs 75%, p=0.01), attributed to lower dermatologic toxicities (0% vs 25%, p<0.01), but there was no significant difference in overall G3+ toxicities (22% vs 20%, p=1.00). No statistically significant correlations between organ-at-risk dosimetry and late toxicities were noted. Available PROs demonstrated significant proportion of patients had persistent gastrointestinal symptoms at long-term. Definitive CRT with proton RT with concurrent 5-FU/MMC for the treatment of anal cancer resulted in comparable long-term disease control and grade 3+ late toxicities compared to RTOG 0529. Future studies should evaluate additional measures to minimizing treatment toxicity and subsets of patients who are most likely to benefit from proton RT.