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

Abstract

Purpose: Although definitive chemoradiation therapy (CRT) with 5-fluorouracil (5-FU) and mitomycin-C (MMC) (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 patients with anal cancer treated with CRT using proton RT in 2 prospective pilot studies.

Methods and materials: Patients with stage I to III anal cancer treated with proton RT (pencil beam scanning or intensity modulated proton therapy) per Radiation Therapy Oncology Group (RTOG) 0529 dose schema with concurrent 5-FU/MMC (2 cycles) in 2 prospective, single-arm trials were followed. Locoregional failure, distant metastases, colostomy-free survival, disease-free survival, and overall survival were assessed. Physician-graded late toxicity (>90 days from CRT) was assessed per National Cancer Institute Common Terminology Criteria for Adverse Events version 4. Late toxicities were compared with RTOG 0529 via Fisher exact test. Patient-reported outcomes were analyzed.

Results: Between 2013 and 2020, 39 patients were treated; 37 (95%) patients completed treatment per protocol. The median follow-up was 63 months. The 5-year locoregional failure, distant metastases, colostomy-free survival, disease-free survival, and overall survival were 21%, 19%, 72%, 69%, and 75%, respectively. The worst late treatment toxicities were grade 1 in 38%, grade 2 in 24%, grade 3 in 19%, grade 4 in 3%, and no grade 5. Compared to RTOG 0529, rates of overall grade 2+ late toxicities were significantly lower (46% vs 75%, P = .01), attributed to lower dermatologic toxicities (0% vs 25%, P < .01), but there was no significant difference in overall grade 3+ toxicities (22% vs 20%, P = 1.00). No statistically significant correlations between organ-at-risk dosimetry and late toxicities were noted. Available patient-reported outcomes demonstrated that significant proportion of patients had persistent gastrointestinal symptoms at long term.

Conclusions: 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 minimize treatment toxicity and subsets of patients who are most likely to benefit from proton RT.