Multicenter phase II study of Neoadjuvant FOLFOXIRI Followed by Concurrent Chemoradiotherapy in Chinese Patients with High-Risk Rectal Cancer

BACKGROUND: We investigated the feasibility of adding neoadjuvant FOLFOXIRI to chemoradiotherapy (CRT) in Chinese patients with high-risk, locally advanced rectal adenocarcinoma (LARC) and examined the prognostic significance of IGF2 and L1CAM expression. METHODS: Eligible patients had non-metastatic, T3/T4 disease with or without nodal involvement, threatened circumferential resection margin (CRM) and/or sphincter involvement, received four cycles of a modified FOLFOXIRI regimen, followed by CRT, surgery, then adjuvant chemotherapy. Co-primary endpoints were objective response rate (ORR) and pathologic complete response rate (pCR). Secondary endpoints included overall survival (OS), relapse-free survival (RFS) and safety. Archival biopsies were analysed for IGF2 and L1CAM expression using immunostaining. RESULTS: Forty patients were enrolled with median age of sixty years and median follow up of 72.7 months. The ORR of FOLFOXIRI and CRT was 30.8% and 64.1%, respectively in 39 patients evaluated, 71.8% of them exhibiting TNM downstaging. For the entire cohort, the pCR rate was 20.5% and CRM was negative in 30 patients. The 3-year and 5-year OS were 79.5% and 59.5%, respectively. The 3-year RFS was 72.4%. Grade 3-4 toxicities to FOLFOXIRI were diarrhoea (13%), neutropenia (8%), vomiting (5%). Grade 3-4 toxicities to CRT were diarrhoea (3%), rectal haemorrhage (3%) and sexual dysfunction (3%). High IGF2 expression was negatively correlated with disease free survival (p = 0.0176), but not OS. CONCLUSIONS: Neoadjuvant modified FOLFOXIRI followed by concurrent capecitabine-RT and surgery was effective with manageable toxicities in Chinese patients with high risk LARC. Exploratory analyses showed that IGF2 expression may be a negative prognostic factor in LARC. (NCT01941641).