# Neoadjuvant FOLFOXIRI plus bevacizumab without radiotherapy for high-risk rectal cancer: multicentre phase II trial

## TL;DR

A chemotherapy regimen without radiotherapy showed good local control in high-risk rectal cancer patients, though with a modest complete response rate.

## Contribution

This study evaluates a chemotherapy-only neoadjuvant regimen for high-risk rectal cancer, avoiding radiotherapy while maintaining good local control.

## Key findings

- A 10% pathological complete response rate was observed in high-risk rectal cancer patients.
- Excellent R0 resection rate (97%) and low 3-year local recurrence rate (3%) were achieved.
- The regimen showed acceptable toxicity without gastrointestinal perforation.

## Abstract

The optimal neoadjuvant strategy for high-risk locally advanced rectal cancer (LARC) remains a matter of debate. This study evaluated the efficacy and safety of neoadjuvant FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, irinotecan) plus bevacizumab without radiotherapy in patients with magnetic resonance imaging-defined high-risk LARC.

A prospective, multicentre, single arm phase II trial was conducted in four Japanese Institutions between 2018 and 2024, enrolling patients with rectal adenocarcinoma and at least one high-risk criterion: clinical T4, lateral pelvic lymph node metastasis, mesorectal fascia involvement, or positive extramural vascular invasion. Patients received four cycles of FOLFOXIRI plus bevacizumab, followed by two cycles of FOLFOXIRI alone, before total mesorectal excision. The primary endpoint was pathological complete response (pCR); secondary endpoints included the R0 resection rate, local recurrence (LR), recurrence-free survival (RFS), overall survival (OS), and safety.

OF 50 eligible patients, 31 were enrolled before early trial closure due to a slow accrual (accrual rate 62%). All patients underwent surgery. The pCR rate was 10% (3 of 31) and R0 resection was achieved in 97% (30 of 31) of patients. The median follow-up was 36.7 months. The 3-year cumulative LR rate was 3%, with 3-year RFS and OS rates of 73 and 81%, respectively. Grade ≥ 3 neutropenia occurred in 29% of patients, with acceptable toxicity overall. No cases of gastrointestinal perforation were observed. Grade ≥ III postoperative complications occurred in seven patients (23%), with the most frequent events being anastomotic leakage in two patients (7%).

In this phase II trial, although recruitment was suboptimal, neoadjuvant FOLFOXIRI plus bevacizumab achieved good local control without radiotherapy in patients with high-risk LARC. Although the pCR rate was modest compared with radiotherapy-based regimens, this chemotherapy-only approach may represent a reasonable option for select patients who are not suitable candidates for pelvic radiotherapy. Registration number: UMIN000037367 (https://www.umin.ac.jp/english/).

This multicentre phase II study evaluated neoadjuvant FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, irinotecan) plus bevacizumab in patients with locally advanced low rectal cancer. Although the pathological complete response rate was modest, the regimen achieved favourable local control, with excellent R0 resection and low local recurrence rates, suggesting its potential efficacy in select high-risk patients.