Chemoradiotherapy (CRT) followed by chemotherapy was found to be the optimal sequence for the treatment of locally advanced rectal cancer. These findings were published in JAMA Oncology.

The Randomized Phase 2 Trial of Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer (CAO/ARO/AIO-12) was a multicenter randomized trial conducted between 2015 and 2018 ( Identifier: NCT02363374). Patients (N=306) with rectal adenocarcinoma £12 cm above the anal verge based on rigid rectoscopy were randomly assigned to receive chemotherapy before or after CRT. Chemotherapy consisted of 3 cycles of fluorouracil, leucovorin, and oxaliplatin and CRT included fluorouracil/oxaliplatin (50.4 Gy). Safety and efficacy of treatment timing were assessed.

Patients who received chemotherapy before (n=156) and after (n=150) CRT were aged mean 60 (SD, 11) and 62 (SD, 10) years, 68% and 67% were men, 20% and 32% were Eastern Cooperative Oncology Group performance status 1, and 31% and 22% had mesorectal fascia involvement, respectively.

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The study investigators previously reported an improved pathological complete response with the CRT before chemotherapy treatment.

After a median follow-up of 43 (range, 35-60) months, 3-year disease-free survival was 73% among both cohorts (hazard ratio [HR], 0.95; 95% CI, 0.63-1.45; P =.82). There were no group differences for 3-year cumulative incidence of locoregional recurrence (HR, 0.81; 95% CI, 0.30-2.18; P =.67), distant metastasis (HR, 0.84; 95% CI, 0.50-1.43; P =.52), or overall survival (HR, 1.10; 95% CI, 0.53-2.27; P =.81).

Rates of chronic toxicity grades 3 to 4 were 15.4% for chemotherapy before and 17.4% for after CRT at 12 months and 11.8% and 9.9% at 36 months, respectively. Oxaliplatin-induced grade 3 to 4 neurotoxicity was reduced from 9.4% and 9.2% at 12 months to 1.2% and 2.5% at 36 months, respectively.

Patient-reported outcome completion rates, global health status/quality of life, and stool incontinence did not differ between the 2 cohorts. Global health status/quality of life scores decreased after total mesorectal excision and returned to baseline at 1 year. Neither group returned to baseline for stool incontinence levels.

This study was limited by utilizing a design that didn’t support detection of long-term oncologic outcomes.

The study authors concluded that in addition to the previously reported improved pathological complete response, CRT before chemotherapy did not compromise disease-free survival, toxicity, quality of life, or stool incontinence and should be considered the preferred sequence for the treatment of locally advanced rectal cancer.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.


Fokas E, Schlenska-Lange A, Polat B, et al. 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 Oncol. Published online November 18, 2021. doi:10.1001/jamaoncol.2021.5445