Alliance A022104/NRG-GI010: The Janus Rectal Cancer Trial: a randomized phase II/III trial testing the efficacy of triplet versus doublet chemotherapy regarding clinical complete response and disease-free survival in patients with locally advanced rectal cancer

Abstract

Background: Recent data have demonstrated that in locally advanced rectal cancer (LARC), a total neoadjuvant therapy (TNT) approach improves compliance with chemotherapy and increases rates of tumor response compared to neoadjuvant chemoradiation (CRT) alone. They further indicate that the optimal sequencing of TNT involves consolidation (rather than induction) chemotherapy to optimize complete response rates. Data, largely from retrospective studies, have also shown that patients with clinical complete response (cCR) after TNT may be managed safely with the watch and wait approach (WW) instead of preemptive total mesorectal resection (TME). However, the optimal consolidation chemotherapy regimen to achieve cCR has not been established, and a randomized clinical trial has not robustly evaluated cCR as a primary endpoint. Collaborating with a multidisciplinary oncology team and patient groups, we designed this NCI-sponsored study of chemotherapy intensification to address these issues and to drive up cCR rates, to provide opportunity for organ preservation, improve quality of life for patients and improve survival outcomes.

Methods: In this NCI-sponsored multi-group randomized, seamless phase II/III trial (1:1), up to 760 patients with LARC, T4N0, any T with node positive disease (any T, N +) or T3N0 requiring abdominoperineal resection or coloanal anastomosis and distal margin within 12 cm of anal verge will be enrolled. Stratification factors include tumor stage (T4 vs T1-3), nodal stage (N + vs N0) and distance from anal verge (0-4; 4-8; 8-12 cm). Patients will be randomized to receive neoadjuvant long-course chemoradiation (LCRT) followed by consolidation doublet (mFOLFOX6 or CAPOX) or triplet chemotherapy (mFOLFIRINOX) for 3-4 months. LCRT in both arms involves 4500 cGy in 25 fractions over 5 weeks + 900 cGy boost in 5 fractions with a fluoropyrimidine (capecitabine preferred). Patients will undergo assessment 8-12 (± 4) weeks post-TNT completion. The primary endpoint for the phase II portion will compare cCR between treatment arms. A total number of 312 evaluable patients (156 per arm) will provide statistical power of 90.5% to detect a 17% increase in cCR rate, at a one-sided alpha = 0.048. The primary endpoint for the phase III portion will compare disease-free survival (DFS) between treatment arms. A total of 285 DFS events will provide 85% power to detect an effect size of hazard ratio 0.70 at a one-sided alpha of 0.025, requiring enrollment of 760 patients (380 per arm). Secondary objectives include time-to event outcomes (overall survival, organ preservation time and time to distant metastasis) and adverse event rates. Biospecimens including archival tumor tissue, plasma and buffy coat, and serial rectal MRIs will be collected for exploratory correlative research. This study, activated in late 2022, is open across the NCTN and had accrued 330 patients as of May 2024. Study support: U10CA180821, U10CA180882, U24 CA196171; https://acknowledgments.alliancefound.org .

Discussion: Building on data from modern day rectal cancer trials and patient input from national advocacy groups, we have designed The Janus Rectal Cancer Trial studying chemotherapy intensification via a consolidation chemotherapy approach with the intent to enhance cCR and DFS rates, increase organ preservation rates, and improve quality of life for patients with rectal cancer.

Trial registration: Clinicaltrials.gov ID: NCT05610163; Support includes U10CA180868 (NRG) and U10CA180888 (SWOG).

Keywords: Clinical complete response; Locally advanced rectal cancer; Organ preservation; Total neoadjuvant therapy; Watch and wait/active surveillance.

Fig. 1

The Janus Rectal Cancer Trial Schema. Key: Randomization = R; LCRT = long-course chemoradiation; Restaging determination = endoscopy, MRI and clinical exam 8–12 (± 4) weeks post-completion of assigned TNT regimen, LARC < = 12 cm, cT4N0, any T, N + ; T3N0 that would require APR or coloanal anastomosis

Fig. 2

Endoscopic response images. Baseline and post-TNT endoscopy images showing a clinical complete, near complete, and incomplete response for patients who have completed TNT

Fig. 3

Baseline and re-staging MRI of the rectum of patients with complete response (case 1), near complete response (case 2) and incomplete response (case 3) based on the MRI assessment is shown. The white arrows on baseline MRI rectum indicate the primary rectal tumor, which shows intermediate signal intensity (SI) on T2-weighted imaging (T2WI), with high SI on diffusion-weighted imaging (DWI), and low SI on the ADC map, indicating restricted diffusion within the primary tumor.  Re-staging MRI on case 1 shows clinical complete response (green box) which is characterized by normalized rectal wall or only fibrosis (low signal intensity on T2WI, green arrows on T2WI) and no areas of restricted diffusion on DWI and ADC map (green arrows on DWI and ADC map).  Re-staging MRI on case 2 shows near complete response (yellow box) defined as small area of intermediate SI on T2WI within the tumor bed fibrosis (yellow arrows on T2WI) and small areas of restricted diffusion (yellow arrows on DWI and ADC map).  Re-staging MRI on case 3 shows incomplete response (orange box) characterized as significant areas of viable tumor with intermediate SI on T2WI within the tumor bed (orange arrows on T2WI) with restricted diffusion (orange arrows on DWI and ADC map). Reviewing the baseline MRI is highly recommended, as it helps to localize the tumor bed and guide the MRI to the appropriate angulation for high-resolution axial oblique T2WI acquisition perpendicular to the tumor bed