Chemotherapy before or after preoperative chemoradiotherapy and surgery for locally advanced rectal cancer: 5-year results of the CAO/ARO/AIO-12 trial - a general pairwise comparison.

Background: Total neoadjuvant treatment (TNT) has been increasingly adopted for multimodal rectal cancer treatment. Here, we present the 5-year results of our CAO/ARO/AIO-12 randomized phase II trial that compared two TNT sequences.

Patients And Methods: Patients were initially randomized 1 : 1 to arm A (induction chemotherapy followed by chemoradiotherapy) or arm B (chemoradiotherapy followed by consolidation chemotherapy) followed by total mesorectal excision surgery. This report on the 5-year results involved a general pairwise comparison (GPC) of the following parameters, ranked as indicated: overall survival, incidence of locoregional recurrence, incidence of distant metastasis, rate of pathological/clinical complete remission, long-term quality of life (at least 24 months after randomization) based on global health assessed by the European Organisation For Research And Treatment Of Cancer Quality of Life Questionnaire Core 30 questionnaire, and incidence of toxicity, ranked by grade, during follow-up.

Results: A total of 306 patients were eligible for this analysis. After a median follow-up of 60 months (interquartile range 58-62 months), we found that long-term oncological outcome was comparable in both arms [e.g. 5-year overall survival 85.8% (95% confidence interval 80.2% to 91.8%) in arm A and 84.2% (95% confidence interval 78.2% to 90.5%) in arm B], regardless of whether patients received induction chemotherapy and chemoradiotherapy or chemoradiotherapy and consolidation chemotherapy. The GPC showed no clinically meaningful overall treatment benefit (-1.38%) or win ratio difference (0.97) between the two treatment sequences. The incidence of pathological or sustained clinical complete remission remained higher in patients treated with consolidation chemotherapy after adjusting for long-term outcome between both arms (11% versus 6.5%).

Conclusions: Our 5-year GPC confirmed the 3-year findings that chemoradiotherapy followed by consolidation chemotherapy resulted in higher rates of pathological complete remission without compromising oncological outcome, toxicity, or quality of life. The TNT sequence chemoradiotherapy/chemotherapy may be preferred for organ preservation strategies.