Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Patients With Locally Advanced Rectal Cancer
Authors: Emmanouil Fokas, Anke Schlenska-Lange, Bülent Polat, Gunther Klautke, Gerhard G. Grabenbauer, Rainer Fietkau, Thomas Kuhnt, Ludger Staib, Thomas Brunner, Anca-Ligia Grosu, Simon Kirste, Lutz Jacobasch, Michael Allgäuer, Michael Flentje, Christoph-Thomas Germer, Robert Grützmann, Guido Hildebrandt, Matthias Schwarzbach, Wolf O. Bechstein, Heiko Sülberg, Tim Friede, Jochen Gaedcke, Michael Ghadimi, Ralf-Dieter Hofheinz, Claus Rödel, Detlef Imhoff, Guido Woeste, Nils Habbe, Ursula Pession, Martin-Leo Hansmann, Peter Wild, Stephan Falk, Petra Hödl, Andre Serebrennikov, Sanja Schmeck , Vittorio Paolucci, Stephan Sahm, Martin Eichel, Giovanna Römer, Wolfgang Bank, Nicolas Moosmann, Jan Braess, Popiliu Piso, Heinrich Wiesinger, Peter Kappl, Elisabeth Germer, Monika Warmuth-Metz, Volker Kunzmann, Katica Krajinovic, Andreas Rosenwald, Thorsten Bley, Ulrich Stölzel, Manfred Dörne, Lutz Renziehausen, Joachim Boese-Land, Dietrich Meißner, Dagmar Burchert, Olaf Dirsch, Jörg Olaf Habeck, Klaus Kirchhof, Christof Lamberti, Bernhard Leibl, Andreas Gschwendtner, Godehard Lahmer, Marga Lang-Welzenbach, Werner Hohenberger, Thomas Kuhnt, Kirsten Papsdorf, Christian Wittekind, Christine Volkheimer, Frederik Wenz, Kirsten Merx, Stefan Post, Timo Gaiser, Ulrike Attenberger, Michael Geißler, Jörn Sträter, Helmut Gnann, Stefan Krämer, Michael Henke, Henning Schäfer, Philipp Manegold, Hannes Philipp Neeff, Peter Bronsert, Wolff Schmiegel, Michael Pohl, Christian Möllecken, Irenäus Adamietz, Richard Viehbahn, Andrea Tannapfel, Jens Freiberg-Richter, Thorsten Jacobi, Wolfgang Wendt, Klaus Holzweißig, Thomas Kittner, Ullrich Graeven, Christiane Lange, Ulrich Kania, Elisabeth Rösler, Harold Ortloff, Christoph Müller-Leisse, Gunnar Folprecht, Ulrike Ubbelohde, Gustavo Baretton, Oliver Kölbl, Felix Steger, Ferdinand Hofstädter, Hans Jürgen Schlitt, Christian Stroszczynski, Marcel Binnebösel, Michael J. Eble, Tom Lüdde, Ruth Knüchel-Clarke, Philipp Bruners, Ute Küchenmeister, Ernst Klar, Andreas Erbesdolber, Ulrich Halm, Markus Zachäus, Eckhardt Schneider, Thomas Schmidt, Claus-Henning Köhne, Bernd Rosin, Kay C. Willborn, Rolf-Peter Henke, Frank Griesinger, Hagen Flach
Journal: JAMA Oncology (2021)

Total neoadjuvant therapy has been increasingly adopted for multimodal rectal cancer treatment. The optimal sequence of chemoradiotherapy (CRT) and chemotherapy needs to be established. 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. 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. 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. 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. 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. 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. ClinicalTrials.gov identifier: NCT02363374.