- More patients with locally-advanced rectal cancer treated with total neoadjuvant therapy (TNT) achieve a pathological complete response (pCR) if preoperative chemoradiotherapy (CRT) is administered prior to chemotherapy (CT), and not conversely.
Why this matters
- Optimal scheduling of preoperative CRT and CT has yet to be determined.
- This is the first trial to report safety and efficacy of TNT sequences.
- Results from this trial led to the selection of the TNT sequence for further phase 3 comparison with standard preoperative CRT.
- The multicentre, phase 2, “pick the winner” design, CAO/ARO/AIO-12 trial enrolled 311 patients with stage II-III rectal cancer.
- Patients were randomly assigned to induction CT prior to CRT (group A) or to consolidation CT following CRT (group B).
- CRT consisted of 50.4 Gy (28 fractions) plus infusional 5-fluorouracil (5-FU), and oxaliplatin.
- CT consisted of oxaliplatin (Ox), leucovorin, and infusional 5-FU (3 cycles).
- In both groups, surgery was scheduled on week 18.
- The primary endpoint was pCR.
- Compliance to CRT was higher in group B: full dose RT, 5-FU, Ox was received, respectively, by 91%, 78%, and 76% in group A and 97%, 87%, and 93% in group B.
- Compliance to CT was higher in group A: 92% vs 85% of patients in group A and B, respectively, completed the 3 cycles of Ox.
- CRT-related grade 3-4 toxicity was lower in group B (37% vs 27%); CT-related grade 3-4 toxicity was 22% in both groups.
- In the intention-to-treat population, a pCR was achieved in 17% (95% CI 12%-24%) in group A and in 25% (95% CI 18%-32%) in group B.
- Only group B (P=0.0002) but not group A (P=0.210) fulfilled the predefined statistical hypothesis that TNT can increase the pCR rate from 15% (expected after standard CRT) to 25%.