Phase 1 Study of Neoadjuvant Short-Course Radiotherapy Concurrent with Infusional 5-Fluorouracil for the Treatment of Locally Advanced Rectal Cancer

Abstract Purpose To assess the safety and feasibility of neoadjuvant short-course RT concurrent with continuous infusion 5-fluorouracil (5-FU) for the treatment of locally advanced rectal cancer. Methods and Materials Patients with cT3-4 or N+ rectal adenocarcinoma based on ultrasound or magnetic resonance imaging were prospectively enrolled in this study. Study treatment consisted of continuous infusion 5-FU combined with short-course RT (5Gy x 5 fractions) followed by 4 cycles of mFOLFOX, total mesorectal excision (TME), and 6 cycles of adjuvant mFOLFOX. To mitigate the potential added toxicity from concurrent 5-FU, intensity-modulated RT was used. Using the continual reassessment method, the dose of 5-FU was escalated from 100 to a maximum-tolerated dose of 200mg/m 2 /day. Results Fourteen patients were accrued. All patients completed continuous infusion 5-FU and short-course RT and the 5-FU dose was safely escalated to 200mg/m 2 /day with no dose-limiting toxicity. Thirteen patients completed the neoadjuvant mFOLFOX and only 1 patient went straight to surgery after chemoradiation. Clinical response was 22% complete, 64% partial, 14% stable disease, and no patients had progression. Three patients with cCR had negative biopsies and did not have TME. Pathologic response was 64% partial response and 14% stable disease. No patients had pathologic progression. Grade 4 toxicity was reported in 2 patients (cytopenia). The most common grade 1 and 2 toxicities were cytopenia, fatigue, diarrhea, and nausea. Conclusions Our findings suggest that concurrent chemotherapy with neoadjuvant short-course RT is feasible and can be safely given with concurrent continuous infusion 5-FU. This works adds to the growing evidence that short-course RT is not only equivalent to long-course RT but may provide additional benefits, such as allowing for a transition to full dose systemic therapy in the neoadjuvant setting, selective organ preservation in complete responders, and providing a more convenient and cost-effective way of delivering pelvic RT.