Chemoradiotherapy Before Chemotherapy the Optimal Treatment Sequence for Locally Advanced Rectal Cancer

Investigators aimed to determine the optimal treatment order of chemoradiotherapy and chemotherapy for patients with locally advanced rectal cancer.

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.

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