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Fokas, E; Schlenska-Lange, A; Polat, B; Klautke, G; Grabenbauer, GG; Fietkau, R; Kuhnt, T; Staib, L; Brunner, T; Grosu, AL; Kirste, S; Jacobasch, L; Allgäuer, M; Flentje, M; Germer, CT; Grützmann, R; Hildebrandt, G; Schwarzbach, M; Bechstein, WO; Sülberg, H; Friede, T; Gaedcke, J; Ghadimi, M; Hofheinz, RD; Rödel, C, , German, Rectal, Cancer, Study, Group.
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. 2022; 8(1): e215445 Doi: 10.1001/jamaoncol.2021.5445 [OPEN ACCESS]
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Brunner Thomas Baptist

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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: identifier: NCT02363374.
Find related publications in this database (using NLM MeSH Indexing)
Chemoradiotherapy - adverse effects, methods
Consolidation Chemotherapy - administration & dosage
Female - administration & dosage
Humans - administration & dosage
Male - administration & dosage
Middle Aged - administration & dosage
Neoadjuvant Therapy - adverse effects
Neoplasm Recurrence, Local - pathology
Neoplasm Staging - administration & dosage
Quality of Life - administration & dosage
Rectal Neoplasms - pathology

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