Long-Term Outcomes With Chemoradiotherapy Before vs After Chemotherapy in the Total Neoadjuvant Treatment of Locally Advanced Rectal Cancer

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Long-term results of a German phase II trial (CAO/ARO/AIO-12) reported in JAMA Oncology by Fokas et al showed similar disease outcomes, chronic toxicity, and quality of life with chemoradiotherapy before vs after chemotherapy in the total neoadjuvant treatment of patients with locally advanced rectal cancer.

The previously reported results from the trial showed that chemoradiotherapy followed by consolidation chemotherapy was associated with a better complete pathologic response rate (25% vs 17%). The current secondary analysis of the multicenter trial included 311 patients with cT3-4 or node-positive rectal adenocarcinoma recruited from the accrued CAO/ARO/AIO-12 trial population from June 2015 to January 2018. Patients were randomly assigned to receive a chemotherapy/ chemoradiotherapy sequence consisting of three cycles of fluorouracil, leucovorin, and oxaliplatin followed by fluorouracil/oxaliplatin chemoradiotherapy with radiotherapy at 50.4 Gy (n = 158) or chemoradiotherapy followed by chemotherapy (chemoradiotherapy/chemotherapy; n = 153). Total mesorectal excision was scheduled on day 123 after the start of total neoadjuvant therapy in both groups.

Long-Term Outcomes

A total of 306 patients were evaluable for outcomes, including 156 in the chemotherapy/chemoradiotherapy group and 150 in the chemoradiotherapy/chemotherapy group. Median follow-up was 43 months (range = 35–60 months).

At 3 years, for the chemotherapy/chemoradiotherapy vs chemoradiotherapy/chemotherapy groups: disease-free survival was 73% (95% confidence interval [CI] = 66%–80%) vs 73% (95% CI = 66%–80%; hazard ratio [HR] = 0.95, 95% CI = 0.63–1.45, P = .82); cumulative incidence of locoregional recurrence was 6% (95% CI = 2%–10%) vs 5% (95% CI = 1%–9%; HR = 0.81,  95% CI = 0.30–2.18, P = .67); cumulative incidence of distant metastasis was 18% (95% CI = 12%–24%) vs 16% (95% CI = 9%–22%; HR = 0.84, 95% CI = 0.50–1.43, P = .52); and overall survival was 92% (95% CI = 88%–97%) vs 92% (95% CI = 88%–97%, HR = 1.10, 95% CI = 0.53–2.27, P = .81).


  • No differences in long-term outcomes were observed with chemoradiotherapy before vs after chemotherapy in total neoadjuvant therapy.
  • No differences in chronic toxicity or quality of life were observed.

Chronic Toxicity and Quality of Life

Chronic grade 3 and 4 toxicity occurred in 18 (15.4%) of 117 patients in the chemotherapy/chemoradiotherapy group and 19 (17.4%) of 109 patients in chemoradiotherapy/chemotherapy group at 12 months and in 10 (11.8%) of 85 patients vs 8 (9.9%) of 66 patients at 3 years.

The combined global health status/quality-of-life score on the EORTC QLQ-C30 questionnaire decreased after total mesorectal excision and returned to pretreatment levels at 1 year after random assignment in both groups, with no between-group differences. As assessed by the Wexner stool incontinence score, stool incontinence deteriorated at 1 year after random assignment with a slight improvement at 3 years in both groups, but never returned to baseline levels.

The investigators concluded, “This secondary analysis of a randomized clinical trial showed that chemoradiotherapy followed by chemotherapy resulted in higher pathological complete response without compromising disease-free survival, toxicity, quality of life, or stool incontinence and is thus proposed as the preferred total neoadjuvant therapy sequence if organ preservation is a priority.”

Emmanouil Fokas, MD, DPhil, of the Department of Radiotherapy and Oncology, University of Frankfurt, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was supported by German Cancer Aid. For full disclosures of the study authors, visit

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