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
neoadjuvant therapy 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 (11), 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 296 evaluable
patients (148 per
arm)
will provide statistical
power of 90.5% to detect an 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 effects. Biospecimens including archival
tumor tissue,
plasma and buffy coat in
EDTA tubes, and serial rectal MRIs
will be collected for exploratory correlative
research. This study, activated in late 2022, is open across the NCTN and has a current accrual of 312. Support U10CA180821, U10CA180882, U24 CA196171; https//acknowledgments.alliancefound.org .
Discussion:
Building off of data from modern day
rectal cancer trials and
patient input from national advocacy groups, we have designed the current 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).