Multi-Institutional Comparison of SC-TNT and LC-TNT for Rectal Cancer Non-Operative Management.

PURPOSE/OBJECTIVE(S): Recent data support the use of total neoadjuvant therapy (TNT) for treatment of locally advanced rectal cancer (LARC), although the optimal TNT regimen and therapy sequence is unclear for non-operative management (NOM). We performed a multi-institutional comparison of short-course radiation (SCRT) followed by consolidation chemotherapy (SC-TNT) versus long-course chemoradiation (CRT) preceded by induction chemotherapy (LC-TNT), after adoption of NOM at both institutions.

MATERIALS/METHODS: The records of 187 patients with cT2-4N0-2 rectal cancer treated between 2016-2020 with TNT at two academic institutions were reviewed under an IRB-approved protocol. The SC-TNT cohort (institution 1) included 85 patients treated with SCRT (25-30 Gy in 5 fx) followed by FOLFOX/CAPOX (n = 82) or capecitabine (n = 3). The LC-TNT cohort (institution 2) included 102 patients treated with FOLFOX/CAPOX followed by CRT (45-56 Gy at 1.8-2 Gy/fx) with concurrent fluoropyrimidine-based chemotherapy. Patients with a clinical complete response (cCR) were offered NOM. The rates of cCR were compared between SC- and LC-TNT. Disease-free survival (DFS) was compared using the log-rank test. To account for any differences in NOM selection between institutions, local-only tumor regrowth was censored from DFS if salvaged with R0 resection, and the overall complete response (CR) rate, defined as cCR + pCR rate for patients undergoing surgery, was assessed. Multivariate analysis (MVA) was performed with logistic and Cox regression to determine factors associated with CR and DFS, respectively.

RESULTS: The median age at diagnosis was 60 and 54 years for SC-TNT and LC-TNT cohorts, respectively (P = 0.002). All other characteristics including performance status, tumor location, and clinical stage were balanced. The median duration of neoadjuvant FOLFOX/CAPOX chemotherapy was 105 vs 98 days for the SC-TNT and LC-TNT cohorts, respectively (P = 0.001). The median follow-up was 27 months. The cCR rate was higher in the SC-TNT cohort (44/85, 52.8% vs 21/102, 20.6%, P < 0.001), with a trend for improved CR rate for SC-TNT (54.1% vs 40.2%, P = 0.057). On MVA, use of SC-TNT was associated with improved CR (HR = 2.24, 95% CI: 1.13-4.45, P = 0.021). Among patients undergoing NOM, 33/39 patients (84.6%) in the SC-TNT group and 10/17 patients (58.8%) in the LC-TNT group (P = 0.27) were free from local recurrence at 1 year. Two-year DFS was 93.4% and 95.4% for the SC-TNT and LC-TNT cohorts with improved DFS on log-rank test for LC-TNT (P = 0.023), but no DFS difference on MVA between SC-TNT and LC-TNT (HR = 2.29, 95% CI: 0.8-6.51, P = 0.121).

CONCLUSION: SC-TNT demonstrated a greater rate of cCR compared to LC-TNT, without DFS difference on MVA. Although future studies are warranted to compare SC-TNT with a CRT and consolidative chemotherapy TNT approach, our data support SC-TNT as a suitable regimen for LARC NOM.