Upfront chemoradiotherapy (CRT) followed by consolidation chemotherapy (CT) may be a feasible strategy for total neoadjuvant therapy (TNT) for patients with rectal cancer, according to data presented at the ESMO 21st World Congress on Gastrointestinal Cancer.

“TNT presents a new paradigm for rectal cancer treatment,” said Ralf Hofheinz (University Hospital Mannheim, Germany), who presented the study results. He cited benefits including better compliance with chemotherapy and lower toxicity compared with the adjuvant setting.

“Furthermore, TNT can potentially improve control of micrometastases through early administration of systemic treatment,” he said.

Still, optimal scheduling of preoperative CRT and CT remains to be established.

Dr Hofheinz and his colleagues in Germany conducted a multicenter, randomized, phase 2 trial using a “pick the winner” design to compare two exploratory regimens: induction CT using 3 cycles of fluorouracil, leucovorin, and oxaliplatin prior to fluorouracil/oxaliplatin CRT to 50 x 4 Gy (CT/CRT/S), versus consolidation CT following CRT (CRT/CT/S).

The study design was based on the hypothesis of an increased pathological complete response rate (pCR) of 25% after TNT compared with standard 15% after preoperative CRT. A total of 304 patients with stage II-III rectal cancer were assigned to 1 of the 2 treatment arms.

Dr Hofheinz emphasized that the trial was not designed to demonstrate any significant difference between the TNT sequences, but rather to select the better TNT sequence for further investigation.

Secondary endpoints of the trial included toxicity, chemotherapy compliance, and incidence of surgical complications. This is the first randomized trial to report safety and efficacy of different TNT sequences, Dr Hofheinz noted.

Of the 311 patients enrolled, 306 patients were evaluable (156 in the CT/CRT/S group, and 150 in the CRT/CT/S group). Only 142 patients in each arm proceeded to surgery.

CRT-related grade 3-4 toxicity was lower in the CRT/CT/S group compared with the CT/CRT/S group (37% vs 27%). Additionally, compliance to CRT was higher in the CRT/CT/S group: 97%, 87%, and 93% of patients received full-dose radiotherapy, concomitant fluorouracil, and concomitant oxaliplatin, respectively, vs 91%, 78%, and 76% in the CT/CRT/S group, respectively. However, more patients completed all induction/consolidation CT cycles in the CT/CRT/S group compared with the CRT/CT/S group (92% vs 85%).

The CRT/CT/S group had a longer interval between completion of CRT and surgery than the CT/CRT/S group as per the trial design (median 90 days vs 45 days), though this did not increase surgical morbidity.

In the intention-to-treat population, a pCR was achieved in 17% of patients in the CT/CRT/S group (95% CI [12%; 24%]; P < .210) and in 25% of patients in the CRT/CT/S group (95% CI [18%; 32%]; P < .0002). Thus, only the latter fulfilled the predefined statistical hypothesis.

The study results suggest that upfront CRT followed by consolidation CT is not only feasible but also resulted in better compliance to CRT, though worse compliance to CT, compared with CT followed by CRT.

“This TNT sequence has now been selected for comparison with standard preoperative CRT in the ACO/ARO/AIO-18.1 phase 3 trial,” Dr Hofheinz concluded.—Kara Rosania

Hofheinz R, Fokas E, Polat B, et al. Randomized phase 2 trial of chemoradiotherapy plus induction or consolidation chemotherapy as total neoadjuvant therapy for locally advanced rectal cancer: CAO/ARO/AIO-12.

This article is a news release from ESMO 21st World Congress on Gastrointestinal Cancer Meeting. Read the original here.