This randomized phase II trial is designed to test the hypothesis that patients with LARC treated with TNT and TME, or NOM, will have improved 3-year DFS compared to patients treated with CRT, TME and ACT. This study investigates the efficacy of two neoadjuvant chemotherapy (NCT) schedules combined with CRT, in an effort to maximize the proportion of patients with LARC who may be cured without undergoing radical surgery. Patients with LARC who are considered candidates for a low anterior resection, a coloanal anastomosis (CAA) or abdominoperineal excision (APE) will be randomized to receive NCT, either a) before (Induction arm) or b) after (Consolidation arm) CRT. Those with incomplete tumor response will undergo TME. Patients with cCR will be observed, and only those showing signs of tumor relapse during follow-up will undergo TME. We have also put forth a novel regression schema to improve the uniformity of response assessment that will be tested and validated in a prospective fashion. To add value, we will measure QoL in patients treated with TNT and TME in comparison to patients treated with TNT alone. Additionally, we will compare induction chemotherapy (INCT) to consolidation chemotherapy (CNCT) with respect to organ preservation at 3 years, treatment compliance, adverse events and surgical complications.

Study design

This is a two-arm, randomized, multi-institutional phase II study investigating the efficacy of TNT and selective NOM in LARC patients. Patients with MRI-staged T2-3, N0 or T-any, N1,2 rectal cancer amenable to TME will be randomized to receive FOLFOX/CapeOx before or after 5-FU or capecitabine-based CRT. The study schema is presented in Fig. 1.

Trial schema. MSKCC-based multi-institutional, Phase II trial schema underway to test the feasibility of incorporating a NOM approach to the multimodality treatment of rectal cancer. This study will evaluate the 3-year DFS in LARC patients treated with CRT plus induction or consolidation chemotherapy and TME or NOM (

Study objectives

The primary objective of the study is to evaluate 3-year recurrence-free survival (RFS) in patients managed with INCT or CNCT, CRT and selective NOM, compared with standard historical controls managed with CRT and TME followed by CT. Secondarily, this study seeks to: a) compare outcomes between patients in the two study arms with respect to rates of organ preservation, compliance with the neoadjuvant protocol, and adverse events; and b) measure patient-reported functional outcomes and QoL in patients with LARC treated with NCT, CRT and NOM, and compare these to patients treated with TME.

Correlative studies will be completed to: a) investigate the diagnostic performance of conventional and diffusion-weighted magnetic resonance imaging (DW-MRI) in identifying patients with LARC who are treated with NCT and CRT, who may benefit from NOM; b) evaluate the feasibility of using circulating tumor DNA and micro-RNA (miRNA) profiles in plasma to monitor tumor response; c) profile rectal cancers Jaumo apk treated with NCT and CRT using next-generation sequencing; and d) investigate molecular mechanisms of tumor resistance to neoadjuvant therapy.

Trial organization

The majority of the rectal cancer consortium members (Fig. 2) were actively involved in a previous multicenter R01 NCI-funded project (1R01 CA090559-07): “The Timing of Rectal Cancer Response to Chemoradiation” (TIMING Trial; NIH NCT00335816; see recent work in The Lancet Oncology, PMID: 26187751) . Each of these sites has been actively involved in the study, and each site has a proven ability to accrue patients and treat them according to the protocol.

Nonoperative management trial contributors. A map of the United States is shown to demonstrate the multiple institutions involved in this described Phase II trial determining the feasibility of incorporating a NOM approach to the multimodality treatment of LARC patients