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 Jan 1;8(1):e215445. doi: 10.1001/jamaoncol.2021.5445.
Emmanouil Fokas  1  2  3 ,  Anke Schlenska-Lange  4 ,  Bülent Polat  5 ,  Gunther Klautke  6 ,  Gerhard G Grabenbauer  7 ,  Rainer Fietkau  8 ,  Thomas Kuhnt  9 ,  Ludger Staib  10 ,  Thomas Brunner  11 ,  Anca-Ligia Grosu  12  13 ,  Simon Kirste  12  13 ,  Lutz Jacobasch  14 ,  Michael Allgäuer  15 ,  Michael Flentje  5 ,  Christoph-Thomas Germer  16 ,  Robert Grützmann  17 ,  Guido Hildebrandt  18 ,  Matthias Schwarzbach  19 ,  Wolf O Bechstein  20 ,  Heiko Sülberg  21 ,  Tim Friede  22 ,  Jochen Gaedcke  23 ,  Michael Ghadimi  23 ,  Ralf-Dieter Hofheinz  24 ,  Claus Rödel  1  2  3 ,  German Rectal Cancer Study Group
Affiliations
  • 1. Department of Radiotherapy and Oncology, University of Frankfurt, Frankfurt, Germany.
  • 2. German Cancer Research Center, German Cancer Consortium, Frankfurt, Germany.
  • 3. Frankfurt Cancer Institute, Frankfurt, Germany.
  • 4. Department of Haematology and Oncology, Barmherzige Brüder Hospital, Regensburg, Germany.
  • 5. Department of Radiation Oncology, University of Würzburg, Würzburg, Germany.
  • 6. Department of Radiation Therapy, Poliklinik Chemnitz GmbH, Chemnitz, Germany.
  • 7. Department of Radiation Oncology and Radiotherapy, DiaCura & Klinikum Coburg, Coburg, Germany.
  • 8. Department of Radiation Therapy, University of Erlangen-Nürnberg, Erlangen, Germany.
  • 9. Department of Radiation Therapy, University of Leipzig, Leipzig, Germany.
  • 10. Department of General and Visceral Surgery, Klinikum Esslingen, Germany.
  • 11. Department of Radiation Therapy, University of Magdeburg, Magdeburg, Germany.
  • 12. Department of Radiation Oncology, Medical Center University of Freiburg, Faculty of Medicine, Freiburg, Germany.
  • 13. German Cancer Research Center, German Cancer Consortium, Freiburg, Germany.
  • 14. Praxis of Haematology and Oncology, Dresden, Germany.
  • 15. Department of Radiotherapy, Barmherzige Brüder Hospital Regensburg, Regensburg, Germany.
  • 16. Department of General and Visceral Surgery, University of Würzburg, Würzburg, Germany.
  • 17. Department of General and Visceral Surgery, University of Erlangen-Nürnberg, Erlangen, Germany.
  • 18. Department of Radiotherapy and Oncology, University of Rostock, Rostock, Germany.
  • 19. Department of General and Visceral Surgery, Klinikum Frankfurt Höchst, Germany.
  • 20. Department of General and Visceral Surgery, University of Frankfurt, Frankfurt, Germany.
  • 21. X-act Cologne Clinical Research GmbH, Cologne, Germany.
  • 22. Department of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany.
  • 23. Department of General and Visceral Surgery, University Medical Center Göttingen, Göttingen, Germany.
  • 24. Department of Medical Oncology, University Hospital Mannheim, Mannheim, Germany.
PMID: 34792531 DOI: 10.1001/jamaoncol.2021.5445
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.

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