D12 - TRUST: phase II trial of induction chemotherapy (CT) with FOLFOXIRI plus bevacizumab (BV) followed by chemo-radiotherapy (CRT) plus BV and surgery in locally advanced rectal carcinoma (LARC)

Abstract

Background: Induction CT followed by CRT is a promising strategy in LARC. FOLFOXIRI plus BV is an effective treatment in metastatic colorectal cancer. Materials and methods: This is a phase II multicentric single-stage single-arm trial (EUDRACT 2011-003340-45). Patients (pts) with LARC at <12 cm from the anal verge, staged cN+ or cT4 or high risk cT3 (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 48 pts. Main pts characteristics were: median age, 53 years (30-74); cT2/T3/T4, 4%/60%/36%; cN0/N +, 4%/96%; distance from anal verge 0-5/5-10/ > 10 cm, 56%/38%/6%. 46 pts completed induction therapy; 2 pts 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 were: neutropenia (42%), febrile neutropenia (4.2%) and diarrhea (12.5%). After induction therapy 45 pts started CRT and 1 underwent surgery. After the first 13 pts, 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%) and proctitis (23%). After amendment, all pts completed CRT with acceptable toxicity: no G3-4 toxicities were reported, with the exception of proctitis (6.2%). After CRT 44 pts underwent surgery (1 died due to early progression after CRT): low anterior (89%) or abdomino-perineal (7%) resection. R0 resection was achieved in 98% resected pts. Early post-surgical complication rate was 32%, with a rate of 18% of anastomotic dehiscences (all solved). Pathologic complete response (pCR) rate was 36%. At a median follow up of 25.1 months, 11 pts experienced disease progression (3 local recurrences) and the estimated 2-year DFS is 78.8%. 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.