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

Abstract

Importance: Total neoadjuvant therapy has been increasingly adopted for multimodal rectal cancer treatment. The optimal sequence of chemoradiotherapy (CRT) and chemotherapy needs to be established.

Objective: To report the long-term results of the secondary end points prespecified in the Randomized Phase 2 Trial of Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy (CAO/ARO/AIO-12 trial) for Locally Advanced Rectal Cancer.

Design, setting, and participants: This secondary analysis of a randomized clinical trial included 311 patients who were recruited from the accrued CAO/ARO/AIO-12 trial population from June 15, 2015, to January 31, 2018, from 18 centers in Germany. Patients with cT3-4 and/or node-positive rectal adenocarcinoma were included in the analysis. Data were analyzed from June 15, 2015, to January 31, 2018. The follow-up analysis was conducted between January 31, 2018, and November 30, 2020.

Interventions: Patients were randomly assigned to group A for 3 cycles of fluorouracil, leucovorin, and oxaliplatin before fluorouracil/oxaliplatin CRT (50.4 Gy), or to group B for CRT before chemotherapy. Total mesorectal excision was scheduled on day 123 after the start of total neoadjuvant therapy in both groups.

Main outcomes and measures: The end points assessed in this secondary analysis included long-term oncologic outcomes, chronic toxicity, patient-reported outcome measures for global health status (GHS) and quality of life (QoL), and the Wexner stool incontinence score.

Results: Of the 311 patients enrolled, 306 were evaluable, including 156 in group A (mean [SD] age, 60 [11] years; 106 men [68%]) and 150 in group B (mean [SD] age, 62 [10] years; 100 men [67%]). After a median follow-up of 43 months (range, 35-60 months), the 3-year disease-free survival was 73% in both groups (hazard ratio, 0.95; 95% CI, 0.63-1.45, P = .82); the 3-year cumulative incidence of locoregional recurrence (6% vs 5%, P = .67) and distant metastases (18% vs 16%, P = .52) were not significantly different. Chronic toxicity grade 3 to 4 occurred in 10 of 85 patients (11.8%) in group A and 8 of 66 patients (9.9%) in group B at 3 years. The GHS/QoL score decreased after total mesorectal excision but returned to pretreatment levels 1 year after randomization with no difference between the groups. Stool incontinence deteriorated 1 year after randomization in both groups and only improved slightly at 3 years, but never reached baseline levels.

Conclusions and relevance: This secondary analysis of a randomized clinical trial showed that CRT followed by chemotherapy resulted in higher pathological complete response without compromising disease-free survival, toxicity, QoL, or stool incontinence and is thus proposed as the preferred total neoadjuvant therapy sequence if organ preservation is a priority.

Trial registration: ClinicalTrials.gov identifier: NCT02363374.

Figure 1.. Consolidated Standards of Reporting Trials (CONSORT) Diagram

Patients who were disease-free after protocol-specified treatment as well as patients with clinical complete response (cCR) who rejected surgery (S) and had nonoperative management were included in the assessment of toxicity and quality of life (QoL) assessment. For the assessment of stool incontinence, patients who were disease-free and stoma-free as well as patients with cCR who rejected surgery and had nonoperative management were included. CRT indicates chemoradiotherapy; DFS, disease-free survival; OS, overall survival; TNT, total neoadjuvant therapy.

Figure 2.. Long-term Oncologic Outcomes

A, Disease-free survival; B, cumulative incidence of locoregional recurrence after R0-1 resection; C, cumulative incidence of distant metastases; D, overall survival. HR indicates hazard ratio.

Figure 3.. Quality of Life (QoL) and Incontinence Changes Over Time in Both Treatment Groups

A, Global health status (GHS)/QoL score, assessed by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire in the 2 groups, as indicated. B, Stool incontinence, assessed by the Wexner score. The Wexner score postoperatively and at 6 mo after randomization is not shown as most patients still had a protective ileostomy at this time point. A higher score represents worse incontinence status. OP indicates operation. ^aOf note, only disease-free patients were included in the analysis, whereas patients who refused surgery due to clinical complete response were excluded (data shown separately in eFigures 4A and B in Supplement 1). ^bData are shown as mean (SD) score. A higher mean score represents a better level of GHS/QoL status. ^cBaseline patient numbers for the Wexner score are lower compared with those for GHS/QoL score in Figure 3A as patients who initially received a protective ileostomy were excluded from the stool incontinence analysis. Similarly, patients with cCR were excluded (data shown separately in eFigures 4C and D in Supplement 2).