Simple SummaryThe efficacy of carbon-ion radiotherapy (CIRT) alone vs. multimodality therapy, including surgery, chemoradiotherapy, and intraoperative radiotherapy for previously irradiated locally recurrent rectal cancer, has not been evaluated. A total of 85 patients receiving 70.4 Gy (RBE) in 16 fractions of CIRT were compared with 86 patients receiving 30 Gy in 15 fractions of chemoradiation, resection, and intraoperative electron radiotherapy. CIRT demonstrated improved two- and five-year overall survival (83.1% and 46.8% vs. 62.5% and 25.7% for CMT), with statistically equivalent local recurrence and disease progression, with reduced treatment toxicity and decreased patient cost. A prospective comparison is warranted.AbstractNo standard treatment paradigm exists for previously irradiated locally recurrent rectal cancer (PILRRC). Carbon-ion radiotherapy (CIRT) may improve oncologic outcomes and reduce toxicity compared with combined modality therapy (CMT). Eighty-five patients treated at Institution A with CIRT alone (70.4 Gy/16 fx) and eighty-six at Institution B with CMT (30 Gy/15 fx chemoradiation, resection, intraoperative electron radiotherapy (IOERT)) between 2006 and 2019 were retrospectively compared. Overall survival (OS), pelvic re-recurrence (PR), distant metastasis (DM), or any disease progression (DP) were analyzed with the Kaplan–Meier model, with outcomes compared using the Cox proportional hazards model. Acute and late toxicities were compared, as was the 2-year cost. The median time to follow-up or death was 6.5 years. Median OS in the CIRT and CMT cohorts were 4.5 and 2.6 years, respectively (p≤ 0.01). No difference was seen in the cumulative incidence of PR (p= 0.17), DM (p= 0.39), or DP (p= 0.19). Lower acute grade ≥ 2 skin and GI/GU toxicity and lower late grade ≥ 2 GU toxicities were associated with CIRT. Higher 2-year cumulative costs were associated with CMT. Oncologic outcomes were similar for patients treated with CIRT or CMT, although patient morbidity and cost were lower with CIRT, and CIRT was associated with longer OS. Prospective comparative studies are needed.