The RAPIDO trial [8] compared the short-course radiation therapy followed by consolidation chemotherapy with standard long-course nCRT. The standard nCRT group received long-course CRT (either 50.4 Gy with 28 fractions or 50.0 Gy with 20 fractions) with capecitabine (twice daily oral capecitabine 825 mg/m² during the radiation period) followed by TME within 6 to 10 weeks after CRT was completed. Postoperative adjuvant chemotherapy is either 8 cycles of CAPOX (capecitabine and oxaliplatin; capecitabine 1,000 mg/m² orally twice daily on days 1–14 and oxaliplatin 130 mg/m² intravenously on day 1) or 12 cycles of FOLFOX4 (fluorouracil, leucovorin, and oxaliplatin; oxaliplatin 85 mg/m² intravenously on day 1, leucovorin 200 mg/m² intravenously on days 1 and 2, followed by bolus fluorouracil 400 mg/m² intravenously and fluorouracil 600 mg/m² intravenously for 22 hours on days 1 and 2) administered within 6 to 8 weeks after surgery. The experimental group received short-course radiation therapy followed by either 6 cycles of CAPOX or 9 cycles of FOLFOX4. Surgery was performed after 2 to 4 weeks after the completion of chemotherapy. The primary endpoint was a 3-year disease-related treatment failure defined as the first occurrence of locoregional failure, distant metastasis, a new primary colorectal tumor, or treatment-related death.

Among the 920 enrolled patients, 912 were eligible for the analysis (462 in the experimental group and 450 in the standard group). The 3-year disease-related treatment failure rate was 23.7% in the experimental group, whereas 30.4% in the standard group, showing a statistically significant difference (P=0.019) with a median follow-up of 4.6 years. This promising result supported TNT can be considered a new standard treatment of rectal cancer, especially for high-risk locally advanced rectal cancers defined as cT4 or N2 disease, CRM-threatening, extramural vascular invasion–positive, and lateral pelvic node enlargement, and ugly rectal cancers.

The PRODIGE 23 trial [9] compared the triplet induction chemotherapy followed by long-course CRT and TME with standard nCRT followed by TME. The standard nCRT group received long-course CRT with capecitabine (twice daily oral capecitabine 825 mg/m² during the radiation period) followed by mandatory TME within 6 to 8 weeks after CRT was completed postoperative adjuvant chemotherapy is either 8 cycles of capecitabine (capecitabine 1,250 mg/m² orally twice daily on days 1–14) or 12 cycles of FOLFOX6 (oxaliplatin 85 mg/m² intravenously on day 1, leucovorin 400 mg/m² intravenously on days 1 and 2, followed by bolus fluorouracil 400 mg/m² intravenously and fluorouracil 2,400 mg/m² intravenously for 46 hours) administered within 5 to 12 weeks after surgery. The experimental group received the triplet induction chemotherapy with FOLFIRINOX (oxaliplatin 85 mg/m² intravenously, irinotecan 180 mg/m², leucovorin 400 mg/m², and fluorouracil 2,400 mg/m² intravenously every 14 days for 6 cycles) followed by CRT (50 Gy for 5 weeks and 800 mg/m² concurrent oral capecitabine twice daily for 5 days per week), TME, and adjuvant chemotherapy either 6 cycles of modified FOLFOX6 or oral capecitabine. The primary endpoint was 3-year disease-free survival (DFS).

A total of 461 patients were randomly assigned to either the experimental induction chemotherapy group (n=231) or standard group (n=230). The 3-year DFS rate was 75.5% in the experimental induction chemotherapy group and 68.5% in the standard nCRT group, showing a statistically significant difference (P=0.034), with a median follow-up of 46.5 months. Although the triplet induction chemotherapy group had slightly more high serious adverse events than the standard group (27% vs. 22%, respectively), these differences were not statistically significant.

The CAO/ARO/AIO-12 German trial [10, 11] compared 3 cycles of induction chemotherapy with FOLFOX (oxaliplatin 100 mg/m², leucovorin 400 mg/m² intravenously followed by fluorouracil 2,400 mg/m² intravenously for 46 hours) followed by nCRT adding fluorouracil and oxaliplatin (continuous infusion of 250 mg/m² of fluorouracil on days 1–14 and days 25–35 of radiotherapy and 2-hour infusion of 50 mg/m² oxaliplatin on day 1, 8, 22, and 29 of radiotherapy) with nCRT adding fluorouracil and oxaliplatin and 3 cycles of consolidation chemotherapy with same FOLFOX. Mandatory TME was scheduled approximately at the 18th week after TNT initiation in both groups. The primary aim of the trial was to identify the most promising TNT sequence which can increase pCR to 25% from 15% after conventional nCRT using a pick-the-winner design.

The pCR rates achieved in 17% and 25% of the induction and consolidation chemotherapy groups, respectively. When clinical complete response (cCR) was included in both groups, combined complete response was increased to 21% for the induction and 28% for the consolidation group. However, the 3-year DFS rate was 73% in both groups after a median follow-up of 43 months [11].

The OPRA trial [12] was also a head-to-head comparison of induction and consolidation chemotherapy with long-course radiation therapy and either TME or watch-and-wait on the basis of tumor response and aimed at comparing the 3-year DFS and TME-free survival. Both groups received the same 8 cycles of FOLFOX or 5 cycles of CAPOX chemotherapy as a TNT strategy. Patients received radiation therapy of up to 50.6 Gy with either infusional fluorouracil or oral capecitabine. The primary endpoint of the OPRA trial was 3-year DFS. Unlikely the other studies, after the completion of TNT, the investigators restaged the patients for approximately 8 weeks to confirm the cCR for organ preservation purposes. Once the patients achieved cCR or near cCR, they followed a watch-and-wait strategy.

The 3-year DFS rate was identical in both groups (76%). The TME-free survival was significantly better in the consolidation group (53%) than in the induction group (41%).