• FOLFOXIRI plus bevacizumab
• locally advanced rectal cancer
• neoadjuvant treatment

Background: Neoadjuvant fluoropyrimidine-based chemoradiotherapy (CRT) followed by surgery represents the standard of care in locally advanced rectal cancer (LARC).This approach has led to significantly reduced rates of local recurrences, but has does not achieved effective control of distant metastases. Induction chemotherapy (CT) followed by CRT is a promising strategy in LARC. Bevacizumab (BV) has shown to improve results of fluoropyrimidine-based CRT. FOLFOXIRI plus BV is an effective treatment option in metastatic colorectal cancer.
Methods: This is a phase 2 multicentric single-stage single-arm trial. Patients with LARC at <12 cm from the anal verge, with node (N) positive or clinical (c) T4 or high risk clinical T3 stage (Magnetic Resonance Imaging criteria), underwent 6 cycles of induction therapy with the GONO FOLFOXIRI plus BV regimen (BV 5 mg/kg day 1; irinotecan 165 mg/m2 day 1; oxaliplatin 85 mg/m2 day1; folinate 200 mg/m2 day 1; 5FU 3200 mg/m2 48h continuous infusion starting on day 1), followed by CRT (50.4 Gy + 5FU 225 mg/m2/day or capecitabine 825 mg/m2/bid continuously) plus BV (5 mg/kg on days 1, 15, 28). Surgery was planned 8 weeks after CRT. Primary endpoint was 2-year disease-free survival (DFS).
Results: We enrolled 49 patients. One patient withdrew consent after enrollment and received conventional neoadjuvant CRT: hence, 48 patients are considered in the per-protocol analyses. Main patients characteristics were: median age, 53 years (30-74); T3/T4, 64.6%/35.4%; cN0/N+, 16.7%/83.3%; distance from anal verge 0-5/5-10/>10 cm, 50%/43.7%/6.3%. Forty-six patients completed induction therapy; 2 patients prematurely stopped treatment: 1 bowel perforation and sepsis resulting in death and 1 acute kidney injury recovered without sequelae. Main grade (G) 3/4 toxicities during induction CT were: neutropenia (41.6%), febrile neutropenia (4.2%) and diarrhea (12.5%). After induction therapy 45 patients started CRT and 1 underwent surgery. After the first 13 patients, the protocol was amended and the schedule of capecitabine slightly modified (800 mg/m2/bid 5 days/week) due to an excessive rate of G3 hand-foot syndrome (23.1%) and proctitis (23.1%). After amendment, all patients completed CRT with acceptable toxicity: no G3-4 toxicities were reported, with the exception of proctitis (6.2%). After CRT 44 patients underwent surgery (1 died due to early progression after CRT): low anterior (88.6%), abdomino-perineal (7%) resection or other (4.4%). R0 resection was achieved in 97.8% resected patients. Early post-surgical complication rate was 32%, with a rate of 18% of anastomotic dehiscences (all solved). Pathologic complete response (pCR) rate was 36.4%. At a median follow up of 32.3 months, 12 patients experienced disease progression (2 local relapse, 8 distant spreading, 4 both distant and local recurrence) and the estimated 2-year DFS is 80.3%.
Conclusions: Induction therapy with FOLFOXIRI plus BV followed by CRT plus BV is feasible, but a careful patient selection is needed because of the overall safety profile. Results in terms of pCR and preliminary DFS data are promising.