Total neoadjuvant approach with FOLFOXIRI plus bevacizumab followed by chemoradiotherapy plus bevacizumab in locally advanced rectal cancer: the TRUST trial

• Published in: European journal of cancer (1990) 2019-03, Vol.110, p.32-41
• Main Authors: Masi, Gianluca, Vivaldi, Caterina, Fornaro, Lorenzo, Lonardi, Sara, Buccianti, Piero, Sainato, Aldo, Marcucci, Lorenzo, Martignetti, Angelo, Luca Urso, Emanuele Damiano, Castagna, Maura, Fontanini, Gabriella, Bergamo, Francesca, Musettini, Gianna, Urbani, Lucio, Sensi, Elisa, Balestri, Riccardo, Montrone, Sabrina, Pasqualetti, Francesco, Cremolini, Chiara, Di Paolo, Antonello, Zagonel, Vittorina, Falcone, Alfredo
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bevacizumab; Bevacizumab - administration & dosage; Bevacizumab - adverse effects; Camptothecin - administration & dosage; Camptothecin - adverse effects; Camptothecin - analogs & derivatives; Cancer; Chemoradiotherapy; Chemoradiotherapy - methods; Chemoradiotherapy - mortality; Chemotherapy; Colorectal cancer; Colorectal carcinoma; Confidence intervals; Diarrhea; Disease control; Disease-Free Survival; Feasibility studies; Female; Fluorouracil - administration & dosage; Fluorouracil - adverse effects; FOLFOXIRI; Humans; Immunotherapy; Irinotecan; Leucovorin - administration & dosage; Leucovorin - adverse effects; Locally advanced rectal cancer; Male; Metastases; Middle Aged; Monoclonal antibodies; Neoadjuvant Therapy - methods; Neoadjuvant Therapy - mortality; Neutropenia; Organoplatinum Compounds - administration & dosage; Organoplatinum Compounds - adverse effects; Oxaliplatin; Patients; Proctitis; Radiation therapy; Radiotherapy; Rectal Neoplasms - mortality; Rectal Neoplasms - therapy; Rectum; Schedules; Surgery; Targeted cancer therapy; Toxicity; Treatment Outcome
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2019.01.006

Neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer (LARC) does not achieve effective control of distant metastases. Induction chemotherapy is a promising strategy, and bevacizumab (BV) could improve the results of CRT. 5-Fluorouracil, oxaliplatin and irinotecan (FOLFOXIRI) plus BV is a treatment option in metastatic colorectal cancer. We evaluate feasibility and efficacy of neoadjuvant treatment comprising induction FOLFOXIRI plus BV followed by CRT with fluoropyrimidines plus BV. In this phase II single-arm trial, patients node-positive or clinical T4 or high-risk T3 LARC underwent 6 cycles of induction FOLFOXIRI plus BV, followed by CRT (50.4 Gy plus concomitant capecitabine) and BV (5 mg/kg on days 1, 15 and 28). Surgery was planned 8 weeks after completion of CRT. Primary end-point was 2-year disease-free survival (DFS). We enrolled 49 patients: All but one (withdrewing consent after enrolment) were included in the per-protocol analyses. The study met its primary end-point: 36 patients were free of recurrence at 2 years (2-y DFS: 80.45%, 95% confidence interval [CI]: 78.79–82.10). Forty-four patients underwent surgery; pathologic complete response rate was 36.4%. Forty-six patients completed induction: neutropenia (41.6%) and diarrhoea (12.5%) were main G3/4 toxicities. Forty-five patients received CRT, but the protocol was amended and the capecitabine schedule during CRT was slightly modified after 13 patients due to the incidence of G3 hand-foot syndrome and proctitis (23.1%). After amendment, no severe events during CRT were reported. FOLFOXIRI plus BV followed by CRT plus BV is feasible and active. Results in terms of DFS suggest that this strategy may improve distant disease control in LARC. •This phase II trial met the primary end-point of improvement of disease-free survival.•An intensive preoperative regimen before chemoradiotherapy is safe.•This induction regimen results in meaningful clinical tumour responses (pCRs 36.4%).•This strategy may be of particular interest in locally advanced rectal cancer.