Total neoadjuvant therapy (TNT) is increasingly adopted for treating locally advanced rectal cancer (LARC) due to its potential to improve patient outcomes. TNT involves administering chemotherapy and chemoradiotherapy (CRT) before surgery, aiming to reduce locoregional failure and systemic relapse.
TNT Treatment Sequences
Various TNT treatment sequences are utilized, including short-course radiotherapy (SCRT) followed by chemotherapy, chemotherapy followed by SCRT, CRT followed by chemotherapy, and chemotherapy followed by CRT. TNT is now included in the National Comprehensive Cancer Network (NCCN) Guidelines as a treatment option for LARC.
Addressing Locoregional Failure and Systemic Relapse
The UNICANCER-PRODIGE 23 trial, a phase-III study, compared neoadjuvant chemotherapy with CRT to the standard approach of CRT followed by surgery and adjuvant chemotherapy. The experimental group received induction chemotherapy with FOLFIRINOX, CRT, and total mesorectal excision (TME) followed by six cycles of adjuvant FOLFOX. At a 7-year follow-up, the median disease-free survival (DFS) was greater in the TNT cohort (66.2 vs. 60.4 months, p = 0.048). The median metastasis-free survival (MFS) was also longer in the TNT cohort (69.3 vs. 62.1 months; p = 0.011). The pathological complete response (pCR) rates at surgery more than doubled in the TNT cohort compared to the standard cohort (27.8% vs. 12.1%, p < 0.001). An overall survival benefit of 4.37 months for the TNT arm was noted using restricted median survival time (RMST) (p = 0.033).
RAPIDO Trial Results
The RAPIDO trial randomized patients to either SCRT followed by CAPOX or the standard approach. At 3 years, the disease-related treatment failure (DRTF) was lower in the TNT arm (23.7%) compared to the standard approach (30.4%, p = 0.019). The pCR improved from 14.3% to 28.4% with TNT (p < 0.001). Distant metastases were also less frequent, with 20% at 3 years for the TNT cohort compared to 26.8% (p = 0.005). However, the locoregional failure rate (LRF) and local recurrence rate (LRR) were greater in the TNT group at the 5-year follow-up, with LRF at 12% vs. 8% (p = 0.07) and LRR at 10% vs. 6% (p = 0.027), respectively. This may be due to the enrollment of patients with higher-risk LARC in this study.
STELLAR Trial and Other Studies
The STELLAR trial, another phase-III study, aimed to determine whether SCRT followed by chemotherapy was non-inferior to CRT in treating LARC with distal and middle rectal tumors. The 3-year DFS for the experimental arm and CRT was 64.5% and 62.5%, respectively (p < 0.001 for non-inferiority). The 3-year OS was better in the experimental group (86.5% vs. 75.1%, p = 0.033). Results from an institutional database showed that at the 3-year follow-up, TNT improved DFS (83.5% vs. 71.4% CRT, p = 0.015), distant metastasis-free survival (DMFS, 84.3% vs. 75.2% CRT, p = 0.049), local recurrence-free survival (98.4% vs. 94.4% CRT, p = 0.048), and pCR rate (26.2% vs. 10% CRT, p < 0.001).
Considerations and Ongoing Research
While many TNT studies show improvement in outcomes, a phase-II randomized study (Grupo cancer de recto 3 study) found no difference in pCR, complete resection rates, downstaging, or tumor regression between neoadjuvant CRT with concurrent CAPOX and adjuvant CAPOX compared to induction chemotherapy with CAPOX and CRT with CAPOX. Further research is needed to optimize TNT strategies and identify which patients benefit most from this approach.
