Organ Preservation in Rectal Adenocarcinoma: a phase II randomized controlled trial evaluating 3-year disease-free survival in patients with locally advanced rectal cancer treated with chemoradiation plus induction or consolidation chemotherapy, and total mesorectal excision or nonoperative management

Abstract

Background: Treatment of patients with non-metastatic, locally advanced rectal cancer (LARC) includes pre-operative chemoradiation, total mesorectal excision (TME) and post-operative adjuvant chemotherapy. This trimodality treatment provides local tumor control in most patients; but almost one-third ultimately die from distant metastasis. Most survivors experience significant impairment in quality of life (QoL), due primarily to removal of the rectum. A current challenge lies in identifying patients who could safely undergo rectal preservation without sacrificing survival benefit and QoL.

Methods/design: This multi-institutional, phase II study investigates the efficacy of total neoadjuvant therapy (TNT) and selective non-operative management (NOM) in LARC. Patients with MRI-staged Stage II or III rectal cancer amenable to TME will be randomized to receive FOLFOX/CAPEOX: a) before induction neoadjuvant chemotherapy (INCT); or b) after consolidation neoadjuvant chemotherapy (CNCT), with 5-FU or capecitabine-based chemoradiation. Patients in both arms will be re-staged after completing all neoadjuvant therapy. Those with residual tumor at the primary site will undergo TME. Patients with clinical complete response (cCR) will receive non-operative management (NOM). NOM patients will be followed every 3 months for 2 years, and every 6 months thereafter. TME patients will be followed according to NCCN guidelines. All will be followed for at least 5 years from the date of surgery or--in patients treated with NOM--the last day of treatment.

Discussion: The studies published thus far on the safety of NOM in LARC have compared survival between select groups of patients with a cCR after NOM, to patients with a pathologic complete response (pCR) after TME. The current study compares 3-year disease-free survival (DFS) in an entire population of patients with LARC, including those with cCR and those with pCR. We will compare the two arms of the study with respect to organ preservation at 3 years, treatment compliance, adverse events and surgical complications. We will measure QoL in both groups. We will analyze molecular indications that may lead to more individually tailored treatments in the future. This will be the first NOM trial utilizing a regression schema for response assessment in a prospective fashion.

Trial registration: NCT02008656.

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 (https://clinicaltrials.gov/ct2/show/NCT02008656?term=NCT02008656&rank=1)

Fig. 2

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

Fig. 3

Clinical complete response. Endoscopic and T2-weighted MRI images, both pre- and post-treatment, are shown for a patient who has achieved a clinical complete response. Images displayed were taken from endoscopic and MRI views of an 85 year-old man who underwent capecitabine CRT followed by consolidation chemotherapy with CapeOx and was determined to achieve cCR both clinically and radiologically. In the post-treatment T2-weighted MRI image shown, the green arrow points to the prior site of the tumor

Fig. 4

Near-complete response. Endoscopic and T2-weighted MRI images both pre- and post-treatment are shown for a patient who has achieved a near complete response. This is a 74-year-old man who underwent 8 cycles of induction FOLFOX followed by CRT, and achieved a near-cCR. A biopsy obtained in surveillance was determined to contain residual cancer; therefore, the patient was referred for TME

Fig. 5

. Incomplete response. Endoscopic and T2-weighted MRI images both pre- and post-treatment are shown for a patient who experienced no significant response to induction chemotherapy followed by CRT. This is a 45-year-old woman who underwent 8 cycles of induction FOLFOX followed by CRT with minimal or no response. The patient was therefore referred for TME