Upfront chemoradiotherapy (CRT) followed by consolidation chemotherapy may be the optimal order of total neoadjuvant therapy (TNT) in patients with locally advanced rectal cancer, according to research published in JAMA Oncology.1

Researchers found that CRT followed by chemotherapy — when compared with chemotherapy followed by CRT — resulted in a higher pathological complete response (pCR) rate without compromising disease-free survival (DFS) or increasing toxicity.

These results come from the phase 2 CAO/ARO/AIO-12 trial (Clinicaltrials.gov identifier: NCT02363374). The trial included 306 evaluable patients with cT3-4 and/or node-positive rectal adenocarcinoma.

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Patients were divided into 2 groups:

  • In group A, 156 patients were assigned to induction chemotherapy (3 cycles of fluorouracil, leucovorin, and oxaliplatin) followed by CRT (fluorouracil/oxaliplatin plus a radiotherapy dose of 50.4 Gy).
  • In group B, 150 patients were assigned to CRT followed by consolidation chemotherapy.

In both groups, 143 patients went on to total mesorectal excision surgery on approximately day 123 after starting TNT.

Prior results from this study showed that compliance was better in group B, and the pCR rate was higher in group B than in group A — 25% and 17%, respectively.2

The current analysis, with a median follow-up of 43 months, showed no significant differences between the groups with regard to locoregional recurrence, DFS, or overall survival (OS).

The 3-year cumulative incidence of locoregional recurrence was 6% in group A and 5% in group B (hazard ratio [HR], 0.81; 95% CI, 0.30-2.18; P =.67).

The 3-year DFS rate was 73% in both groups (HR, 0.95; 95% CI, 0.63-1.45, P =.82), and the OS rate was 92% in both groups (HR, 1.10; 95% CI, 0.53-2.27; P =.81).

The rate of grade 3-4 chronic toxicity at 12 months was 15.4% in group A and 17.4% in group B. At 36 months, the rate of grade 3-4 chronic toxicity was 11.8% and 9.9%, respectively.

There were no significant differences between the groups in quality of life scores or stool incontinence.

Given these and prior results, the researchers concluded that upfront CRT followed by consolidation chemotherapy “is the preferred sequence for total neoadjuvant therapy if organ preservation is a priority.”

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


  1. Fokas E, Schelenska-Lange A, Polat B. Chemoradiotherapy plus induction or consolidation chemotherapy as total neoadjuvant therapy for patients with locally advanced rectal cancer: Long-term results of the CAO/ARO/AIO-12 randomized clinical trial. JAMA Oncology. Published online on November 18, 2021.  doi:10.1001/jamaoncol.2021.5445
  2. Fokas E, Allgäuer M, Polat B, et al. Randomized phase II trial of chemoradiotherapy plus induction or consolidation chemotherapy as total neoadjuvant therapy for locally advanced rectal cancer: CAO/ARO/AIO-12. J Clin Oncol. 2019;37(34):3212-3222. doi:10.1200/JCO.19.00308