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
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.
| Errataetall: |
CommentIn: JAMA Oncol. 2022 May 1;8(5):781-782. - PMID 35357411 |
|---|---|
| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:8 |
|---|---|
| Enthalten in: |
JAMA oncology - 8(2022), 1 vom: 01. Jan., Seite e215445 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Fokas, Emmanouil [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Clinical Trial, Phase II |
|---|
| Anmerkungen: |
Date Completed 14.03.2022 Date Revised 19.11.2022 published: Print-Electronic ClinicalTrials.gov: NCT02363374 CommentIn: JAMA Oncol. 2022 May 1;8(5):781-782. - PMID 35357411 Citation Status MEDLINE |
|---|
| doi: |
10.1001/jamaoncol.2021.5445 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM333301285 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM333301285 | ||
| 003 | DE-627 | ||
| 005 | 20231225221359.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1001/jamaoncol.2021.5445 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1110.xml |
| 035 | |a (DE-627)NLM333301285 | ||
| 035 | |a (NLM)34792531 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Fokas, Emmanouil |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Chemoradiotherapy Plus Induction or Consolidation Chemotherapy as Total Neoadjuvant Therapy for Patients With Locally Advanced Rectal Cancer |b Long-term Results of the CAO/ARO/AIO-12 Randomized Clinical Trial |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 14.03.2022 | ||
| 500 | |a Date Revised 19.11.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT02363374 | ||
| 500 | |a CommentIn: JAMA Oncol. 2022 May 1;8(5):781-782. - PMID 35357411 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02363374 | ||
| 650 | 4 | |a Clinical Trial, Phase II | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Randomized Controlled Trial | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 700 | 1 | |a Schlenska-Lange, Anke |e verfasserin |4 aut | |
| 700 | 1 | |a Polat, Bülent |e verfasserin |4 aut | |
| 700 | 1 | |a Klautke, Gunther |e verfasserin |4 aut | |
| 700 | 1 | |a Grabenbauer, Gerhard G |e verfasserin |4 aut | |
| 700 | 1 | |a Fietkau, Rainer |e verfasserin |4 aut | |
| 700 | 1 | |a Kuhnt, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Staib, Ludger |e verfasserin |4 aut | |
| 700 | 1 | |a Brunner, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Grosu, Anca-Ligia |e verfasserin |4 aut | |
| 700 | 1 | |a Kirste, Simon |e verfasserin |4 aut | |
| 700 | 1 | |a Jacobasch, Lutz |e verfasserin |4 aut | |
| 700 | 1 | |a Allgäuer, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Flentje, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Germer, Christoph-Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Grützmann, Robert |e verfasserin |4 aut | |
| 700 | 1 | |a Hildebrandt, Guido |e verfasserin |4 aut | |
| 700 | 1 | |a Schwarzbach, Matthias |e verfasserin |4 aut | |
| 700 | 1 | |a Bechstein, Wolf O |e verfasserin |4 aut | |
| 700 | 1 | |a Sülberg, Heiko |e verfasserin |4 aut | |
| 700 | 1 | |a Friede, Tim |e verfasserin |4 aut | |
| 700 | 1 | |a Gaedcke, Jochen |e verfasserin |4 aut | |
| 700 | 1 | |a Ghadimi, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Hofheinz, Ralf-Dieter |e verfasserin |4 aut | |
| 700 | 1 | |a Rödel, Claus |e verfasserin |4 aut | |
| 700 | 0 | |a German Rectal Cancer Study Group |e verfasserin |4 aut | |
| 700 | 1 | |a Imhoff, Detlef |e investigator |4 oth | |
| 700 | 1 | |a Woeste, Guido |e investigator |4 oth | |
| 700 | 1 | |a Habbe, Nils |e investigator |4 oth | |
| 700 | 1 | |a Pession, Ursula |e investigator |4 oth | |
| 700 | 1 | |a Hansmann, Martin-Leo |e investigator |4 oth | |
| 700 | 1 | |a Wild, Peter |e investigator |4 oth | |
| 700 | 1 | |a Falk, Stephan |e investigator |4 oth | |
| 700 | 1 | |a Hödl, Petra |e investigator |4 oth | |
| 700 | 1 | |a Serebrennikov, Andre |e investigator |4 oth | |
| 700 | 1 | |a Schmeck, Sanja |e investigator |4 oth | |
| 700 | 1 | |a Paolucci, Vittorio |e investigator |4 oth | |
| 700 | 1 | |a Sahm, Stephan |e investigator |4 oth | |
| 700 | 1 | |a Eichel, Martin |e investigator |4 oth | |
| 700 | 1 | |a Römer, Giovanna |e investigator |4 oth | |
| 700 | 1 | |a Bank, Wolfgang |e investigator |4 oth | |
| 700 | 1 | |a Moosmann, Nicolas |e investigator |4 oth | |
| 700 | 1 | |a Braess, Jan |e investigator |4 oth | |
| 700 | 1 | |a Piso, Popiliu |e investigator |4 oth | |
| 700 | 1 | |a Wiesinger, Heinrich |e investigator |4 oth | |
| 700 | 1 | |a Kappl, Peter |e investigator |4 oth | |
| 700 | 1 | |a Germer, Elisabeth |e investigator |4 oth | |
| 700 | 1 | |a Warmuth-Metz, Monika |e investigator |4 oth | |
| 700 | 1 | |a Kunzmann, Volker |e investigator |4 oth | |
| 700 | 1 | |a Krajinovic, Katica |e investigator |4 oth | |
| 700 | 1 | |a Rosenwald, Andreas |e investigator |4 oth | |
| 700 | 1 | |a Bley, Thorsten |e investigator |4 oth | |
| 700 | 1 | |a Stölzel, Ulrich |e investigator |4 oth | |
| 700 | 1 | |a Dörne, Manfred |e investigator |4 oth | |
| 700 | 1 | |a Renziehausen, Lutz |e investigator |4 oth | |
| 700 | 1 | |a Boese-Land, Joachim |e investigator |4 oth | |
| 700 | 1 | |a Meißner, Dietrich |e investigator |4 oth | |
| 700 | 1 | |a Burchert, Dagmar |e investigator |4 oth | |
| 700 | 1 | |a Dirsch, Olaf |e investigator |4 oth | |
| 700 | 1 | |a Habeck, Jörg Olaf |e investigator |4 oth | |
| 700 | 1 | |a Kirchhof, Klaus |e investigator |4 oth | |
| 700 | 1 | |a Lamberti, Christof |e investigator |4 oth | |
| 700 | 1 | |a Leibl, Bernhard |e investigator |4 oth | |
| 700 | 1 | |a Gschwendtner, Andreas |e investigator |4 oth | |
| 700 | 1 | |a Lahmer, Godehard |e investigator |4 oth | |
| 700 | 1 | |a Lang-Welzenbach, Marga |e investigator |4 oth | |
| 700 | 1 | |a Hohenberger, Werner |e investigator |4 oth | |
| 700 | 1 | |a Kuhnt, Thomas |e investigator |4 oth | |
| 700 | 1 | |a Papsdorf, Kirsten |e investigator |4 oth | |
| 700 | 1 | |a Wittekind, Christian |e investigator |4 oth | |
| 700 | 1 | |a Volkheimer, Christine |e investigator |4 oth | |
| 700 | 1 | |a Wenz, Frederik |e investigator |4 oth | |
| 700 | 1 | |a Merx, Kirsten |e investigator |4 oth | |
| 700 | 1 | |a Post, Stefan |e investigator |4 oth | |
| 700 | 1 | |a Gaiser, Timo |e investigator |4 oth | |
| 700 | 1 | |a Attenberger, Ulrike |e investigator |4 oth | |
| 700 | 1 | |a Geißler, Michael |e investigator |4 oth | |
| 700 | 1 | |a Sträter, Jörn |e investigator |4 oth | |
| 700 | 1 | |a Gnann, Helmut |e investigator |4 oth | |
| 700 | 1 | |a Krämer, Stefan |e investigator |4 oth | |
| 700 | 1 | |a Henke, Michael |e investigator |4 oth | |
| 700 | 1 | |a Schäfer, Henning |e investigator |4 oth | |
| 700 | 1 | |a Manegold, Philipp |e investigator |4 oth | |
| 700 | 1 | |a Neeff, Hannes Philipp |e investigator |4 oth | |
| 700 | 1 | |a Bronsert, Peter |e investigator |4 oth | |
| 700 | 1 | |a Schmiegel, Wolff |e investigator |4 oth | |
| 700 | 1 | |a Pohl, Michael |e investigator |4 oth | |
| 700 | 1 | |a Möllecken, Christian |e investigator |4 oth | |
| 700 | 1 | |a Adamietz, Irenäus |e investigator |4 oth | |
| 700 | 1 | |a Viehbahn, Richard |e investigator |4 oth | |
| 700 | 1 | |a Tannapfel, Andrea |e investigator |4 oth | |
| 700 | 1 | |a Freiberg-Richter, Jens |e investigator |4 oth | |
| 700 | 1 | |a Jacobi, Thorsten |e investigator |4 oth | |
| 700 | 1 | |a Wendt, Wolfgang |e investigator |4 oth | |
| 700 | 1 | |a Holzweißig, Klaus |e investigator |4 oth | |
| 700 | 1 | |a Kittner, Thomas |e investigator |4 oth | |
| 700 | 1 | |a Graeven, Ullrich |e investigator |4 oth | |
| 700 | 1 | |a Lange, Christiane |e investigator |4 oth | |
| 700 | 1 | |a Kania, Ulrich |e investigator |4 oth | |
| 700 | 1 | |a Rösler, Elisabeth |e investigator |4 oth | |
| 700 | 1 | |a Ortloff, Harold |e investigator |4 oth | |
| 700 | 1 | |a Müller-Leisse, Christoph |e investigator |4 oth | |
| 700 | 1 | |a Folprecht, Gunnar |e investigator |4 oth | |
| 700 | 1 | |a Ubbelohde, Ulrike |e investigator |4 oth | |
| 700 | 1 | |a Baretton, Gustavo |e investigator |4 oth | |
| 700 | 1 | |a Kölbl, Oliver |e investigator |4 oth | |
| 700 | 1 | |a Steger, Felix |e investigator |4 oth | |
| 700 | 1 | |a Hofstädter, Ferdinand |e investigator |4 oth | |
| 700 | 1 | |a Schlitt, Hans Jürgen |e investigator |4 oth | |
| 700 | 1 | |a Stroszczynski, Christian |e investigator |4 oth | |
| 700 | 1 | |a Binnebösel, Marcel |e investigator |4 oth | |
| 700 | 1 | |a Eble, Michael J |e investigator |4 oth | |
| 700 | 1 | |a Lüdde, Tom |e investigator |4 oth | |
| 700 | 1 | |a Knüchel-Clarke, Ruth |e investigator |4 oth | |
| 700 | 1 | |a Bruners, Philipp |e investigator |4 oth | |
| 700 | 1 | |a Küchenmeister, Ute |e investigator |4 oth | |
| 700 | 1 | |a Klar, Ernst |e investigator |4 oth | |
| 700 | 1 | |a Erbesdolber, Andreas |e investigator |4 oth | |
| 700 | 1 | |a Halm, Ulrich |e investigator |4 oth | |
| 700 | 1 | |a Zachäus, Markus |e investigator |4 oth | |
| 700 | 1 | |a Schneider, Eckhardt |e investigator |4 oth | |
| 700 | 1 | |a Schmidt, Thomas |e investigator |4 oth | |
| 700 | 1 | |a Köhne, Claus-Henning |e investigator |4 oth | |
| 700 | 1 | |a Rosin, Bernd |e investigator |4 oth | |
| 700 | 1 | |a Willborn, Kay C |e investigator |4 oth | |
| 700 | 1 | |a Henke, Rolf-Peter |e investigator |4 oth | |
| 773 | 0 | 8 | |i Enthalten in |t JAMA oncology |d 2015 |g 8(2022), 1 vom: 01. Jan., Seite e215445 |w (DE-627)NLM250070588 |x 2374-2445 |7 nnns |
| 773 | 1 | 8 | |g volume:8 |g year:2022 |g number:1 |g day:01 |g month:01 |g pages:e215445 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1001/jamaoncol.2021.5445 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 8 |j 2022 |e 1 |b 01 |c 01 |h e215445 | ||