Sixty-Day Mortality of Patients With Metastatic Colorectal Cancer Randomized to Systemic Treatment vs Primary Tumor Resection Followed by Systemic Treatment: The CAIRO4 Phase 3 Randomized Clinical Trial

doi:10.1001/jamasurg.2021.4992

Clinical Trial

. 2021 Dec 1;156(12):1093-1101.

doi: 10.1001/jamasurg.2021.4992.

Sixty-Day Mortality of Patients With Metastatic Colorectal Cancer Randomized to Systemic Treatment vs Primary Tumor Resection Followed by Systemic Treatment: The CAIRO4 Phase 3 Randomized Clinical Trial

Collaborators, Affiliations

Collaborators

CAIRO4 Working Group:
Gijs J D van Acker, Rahim Altaf, Kees van Arkel, Coen I M Baeten, Sandra D Bakker, Frank C den Boer, Marien O den Boer, Koop Bosscha, Edwin A van Breugel, Rebecca P M Brosens, Huib A Cense, Esther C J Consten, Geert-Jan Creemers, Hester van Cruijsen, Wendy M van der Deure, Joyce M van Dodewaard, Anne-Lene G Fromm, A J Hans Gelderblom, Michael F Gerhards, Marie-José de Gier, Eelco J R de Graaf, W M U Helma van Grevenstein, Jan Willem B de Groot, Brigitte C M Haberkorn, Jamal Oulad Hadj, Paul Hamberg, Erwin van der Harst, Helgi H Helgason, Mathijs P Hendriks, Daniël A Hess, Ignace H J T de Hingh, R Hoekstra, Joost A B van der Hoeven, M J van Hoogstraten, Henrik L Jakobsen, Felix E de Jongh, Emile D Kerver, Monica L Kjær, Bart C Kuenen, Philomeen Kuijer, Sophie Kurk, Wouter K G Leclercq, Lobke L van Leeuwen-Snoeks, Jeroen W A Leijtens, Gabor I Liposits, Olaf J L Loosveld, Martijn F Lutke Holzik, Peter Nieboer, Jesper D Nielsen, Koen C M J Peeters, Lone N Petersen, Apollo Pronk, Bareld B Pultrum, Koen Reijnders, J M G H Anne-Marie Van Riel, Ron C Rietbroek, George P van der Schelling, W H Hermien Schreurs, Nis H Schlesinger, Heidi Schut, Michael Seiersen, Lieke H J Simkens, Dirkje W Sommeijer, Pieter J Tanis, Mehmet Temizkan, Marc W A van Tilburg, Marija Trajkovic, Anthony W H van de Ven, Henk M W Verheul, Mareille Verseveld, Jeroen Vincent, Wouter J Vles, F J Jeroen Vogelaar, Aad I de Vos, Allert H Vos, Ronald J C L M Vuylsteke, Wim A Bleeker, Dareczka Wasowicz-Kemps, Johannes A Wegdam, Henderik L van Westreenen, Louise M de Widt-Levert, A J Yes van de Wouw, Mette K Yilmaz, Peter van Duijvendijk

Affiliations

¹ Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
² Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
³ Department of Research and Development, Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, the Netherlands.
⁴ Department of Surgery, Radboud University Medical Center, Nijmegen, the Netherlands.
⁵ Clinical Research Department, Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, the Netherlands.

PMID: 34613339
PMCID: PMC8495602
DOI: 10.1001/jamasurg.2021.4992

Clinical Trial

Sixty-Day Mortality of Patients With Metastatic Colorectal Cancer Randomized to Systemic Treatment vs Primary Tumor Resection Followed by Systemic Treatment: The CAIRO4 Phase 3 Randomized Clinical Trial

Dave E W van der Kruijssen et al. JAMA Surg. 2021.

. 2021 Dec 1;156(12):1093-1101.

doi: 10.1001/jamasurg.2021.4992.

Collaborators

CAIRO4 Working Group:
Gijs J D van Acker, Rahim Altaf, Kees van Arkel, Coen I M Baeten, Sandra D Bakker, Frank C den Boer, Marien O den Boer, Koop Bosscha, Edwin A van Breugel, Rebecca P M Brosens, Huib A Cense, Esther C J Consten, Geert-Jan Creemers, Hester van Cruijsen, Wendy M van der Deure, Joyce M van Dodewaard, Anne-Lene G Fromm, A J Hans Gelderblom, Michael F Gerhards, Marie-José de Gier, Eelco J R de Graaf, W M U Helma van Grevenstein, Jan Willem B de Groot, Brigitte C M Haberkorn, Jamal Oulad Hadj, Paul Hamberg, Erwin van der Harst, Helgi H Helgason, Mathijs P Hendriks, Daniël A Hess, Ignace H J T de Hingh, R Hoekstra, Joost A B van der Hoeven, M J van Hoogstraten, Henrik L Jakobsen, Felix E de Jongh, Emile D Kerver, Monica L Kjær, Bart C Kuenen, Philomeen Kuijer, Sophie Kurk, Wouter K G Leclercq, Lobke L van Leeuwen-Snoeks, Jeroen W A Leijtens, Gabor I Liposits, Olaf J L Loosveld, Martijn F Lutke Holzik, Peter Nieboer, Jesper D Nielsen, Koen C M J Peeters, Lone N Petersen, Apollo Pronk, Bareld B Pultrum, Koen Reijnders, J M G H Anne-Marie Van Riel, Ron C Rietbroek, George P van der Schelling, W H Hermien Schreurs, Nis H Schlesinger, Heidi Schut, Michael Seiersen, Lieke H J Simkens, Dirkje W Sommeijer, Pieter J Tanis, Mehmet Temizkan, Marc W A van Tilburg, Marija Trajkovic, Anthony W H van de Ven, Henk M W Verheul, Mareille Verseveld, Jeroen Vincent, Wouter J Vles, F J Jeroen Vogelaar, Aad I de Vos, Allert H Vos, Ronald J C L M Vuylsteke, Wim A Bleeker, Dareczka Wasowicz-Kemps, Johannes A Wegdam, Henderik L van Westreenen, Louise M de Widt-Levert, A J Yes van de Wouw, Mette K Yilmaz, Peter van Duijvendijk

Affiliations

¹ Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
² Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
³ Department of Research and Development, Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, the Netherlands.
⁴ Department of Surgery, Radboud University Medical Center, Nijmegen, the Netherlands.
⁵ Clinical Research Department, Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, the Netherlands.

PMID: 34613339
PMCID: PMC8495602
DOI: 10.1001/jamasurg.2021.4992

Abstract

Importance: The role of primary tumor resection (PTR) in synchronous patients with metastatic colorectal cancer (mCRC) who had unresectable metastases and few or absent symptoms of their primary tumor is unclear. Studying subgroups with low postoperative mortality may identify patients who potentially benefit from PTR.

Objective: To determine the difference in 60-day mortality between patients randomized to systemic treatment only vs PTR followed by systemic treatment, and to explore risk factors associated with 60-day mortality.

Design, setting, and participants: CAIRO4 is a randomized phase 3 trial initiated in 2012 in which patients with mCRC were randomized to systemic treatment only or PTR followed by systemic treatment with palliative intent. This multicenter study was conducted by the Danish and Dutch Colorectal Cancer Group in general and academic hospitals in Denmark and the Netherlands. Patients included between August 2012 and December 2019 with histologically proven colorectal cancer, unresectable metastases, and a primary tumor with few or absent symptoms were eligible.

Interventions: Systemic treatment, consisting of fluoropyrimidine-based chemotherapy with bevacizumab vs PTR followed by fluoropyrimidine-based chemotherapy with bevacizumab.

Main outcomes and measures: The aim of the current analysis was to compare 60-day mortality rates in both treatment arms. A secondary aim was the identification of risk factors for 60-day mortality in the treatment arms. These aims were not predefined in the study protocol.

Results: A total of 196 patients were included in the intention-to-treat analysis (112 [57%] men; median [IQR] age, 65 [59-70] years). Sixty-day mortality was 3% (95% CI, 1%-9%) in the systemic treatment arm and 11% (95% CI, 6%-19%) in the PTR arm (P = .03). In a per-protocol analysis, 60-day mortality was 2% (95% CI, 1%-7%) vs 10% (95% CI, 5%-18%; P = .048). Patients with elevated serum levels of lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, and/or neutrophils who were randomized to PTR had a significantly higher 60-day mortality than patients without these characteristics.

Conclusions and relevance: Patients with mCRC who were randomized to PTR followed by systemic treatment had a higher 60-day mortality than patients randomized to systemic treatment. Especially patients randomized to the PTR arm with elevated serum levels of lactate dehydrogenase, neutrophils, aspartate aminotransferase, and/or alanine aminotransferase were at high risk of postoperative mortality. Final study results on overall survival have to be awaited.

Trial registration: ClinicalTrials.gov Identifier: NCT01606098.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr van der Kruijssen reported a grant from Dutch Cancer Society and an unrestricted grant from Hoffmann-La Roche Ltd during the conduct of the study. Dr Vink reported grants from Servier, Merck, Pierre Fabre, Sirtex, Bristol Myers Squibb, and Bayer and nonfinancial support from PGDx outside the submitted work. Dr de Wilt reported a grant from Dutch Cancer Society and an unrestricted grant from Hoffmann-La Roche Ltd during the conduct of the study and grants from Dutch Cancer Society, Bergh in het Zadel Foundation, ZonMw, and Medtronic outside the submitted work. Dr Koopman reported a grant from Dutch Cancer Society and an unrestricted grant from Hoffmann-La Roche Ltd during the conduct of the study; grants from Bayer, Bristol Myers Squibb, Hoffmann-La Roche Ltd, Merck, Servier, and Pierre Fabre paid to their institution outside the submitted work; and paid advisory roles for Nordic Pharma, Merck Serono, Pierre Fabre, Servier, and MSD outside the submitted work. No other disclosures were reported.

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Comment in

Primary Tumor Resection and Patients With Asymptomatic Colorectal Cancer and Nonresectable Metastases: Results of Recent Randomized Trials.
Fong Y. Fong Y. JAMA Surg. 2021 Dec 1;156(12):1101-1102. doi: 10.1001/jamasurg.2021.5023. JAMA Surg. 2021. PMID: 34613343 No abstract available.
Comments on the CAIRO4 Trial Secondary Outcomes Report-Reply.
van der Kruijssen DEW, Elias SG, de Wilt JHW. van der Kruijssen DEW, et al. JAMA Surg. 2022 Jun 1;157(6):551-552. doi: 10.1001/jamasurg.2021.7585. JAMA Surg. 2022. PMID: 35171236 No abstract available.
Comments on the CAIRO4 Trial Secondary Outcomes Report.
Hammett F, Perin G, Balasubramanian S. Hammett F, et al. JAMA Surg. 2022 Jun 1;157(6):551. doi: 10.1001/jamasurg.2021.7584. JAMA Surg. 2022. PMID: 35171238 No abstract available.
Patient with unresectable colorectal liver metastases and asymptomatic primary tumor: end of the debate!
Allard MA, Adam R. Allard MA, et al. Hepatobiliary Surg Nutr. 2022 Jun;11(3):412-414. doi: 10.21037/hbsn-22-176. Hepatobiliary Surg Nutr. 2022. PMID: 35693410 Free PMC article. No abstract available.

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References

1. Ruo L, Gougoutas C, Paty PB, Guillem JG, Cohen AM, Wong WD. Elective bowel resection for incurable stage IV colorectal cancer: prognostic variables for asymptomatic patients. J Am Coll Surg. 2003;196(5):722-728. doi:10.1016/S1072-7515(03)00136-4 - DOI - PubMed
1. Matsumoto T, Hasegawa S, Matsumoto S, et al. . Overcoming the challenges of primary tumor management in patients with metastatic colorectal cancer unresectable for cure and an asymptomatic primary tumor. Dis Colon Rectum. 2014;57(6):679-686. doi:10.1097/DCR.0000000000000025 - DOI - PubMed
1. Seo GJ, Park JW, Yoo SB, et al. . Intestinal complications after palliative treatment for asymptomatic patients with unresectable stage IV colorectal cancer. J Surg Oncol. 2010;102(1):94-99. doi:10.1002/jso.21577 - DOI - PubMed
1. Verhoef C, de Wilt JHW, Burger JWA, Verheul HMW, Koopman M. Surgery of the primary in stage IV colorectal cancer with unresectable metastases. Eur J Cancer. 2011;47(suppl 3):S61-S66. doi:10.1016/S0959-8049(11)70148-4 - DOI - PubMed
1. Benson AI, Venook AP, Cederquist L, et al. Colon cancer. Oxford Case Histories in Oncology. Oxford University Press; 2017. doi:10.1093/med/9780199664535.003.0012 - DOI

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[1] Ruo L, Gougoutas C, Paty PB, Guillem JG, Cohen AM, Wong WD. Elective bowel resection for incurable stage IV colorectal cancer: prognostic variables for asymptomatic patients. J Am Coll Surg. 2003;196(5):722-728. doi:10.1016/S1072-7515(03)00136-4 - DOI - PubMed

[2] Ruo L, Gougoutas C, Paty PB, Guillem JG, Cohen AM, Wong WD. Elective bowel resection for incurable stage IV colorectal cancer: prognostic variables for asymptomatic patients. J Am Coll Surg. 2003;196(5):722-728. doi:10.1016/S1072-7515(03)00136-4 - DOI - PubMed

[3] Matsumoto T, Hasegawa S, Matsumoto S, et al. . Overcoming the challenges of primary tumor management in patients with metastatic colorectal cancer unresectable for cure and an asymptomatic primary tumor. Dis Colon Rectum. 2014;57(6):679-686. doi:10.1097/DCR.0000000000000025 - DOI - PubMed

[4] Matsumoto T, Hasegawa S, Matsumoto S, et al. . Overcoming the challenges of primary tumor management in patients with metastatic colorectal cancer unresectable for cure and an asymptomatic primary tumor. Dis Colon Rectum. 2014;57(6):679-686. doi:10.1097/DCR.0000000000000025 - DOI - PubMed

[5] Seo GJ, Park JW, Yoo SB, et al. . Intestinal complications after palliative treatment for asymptomatic patients with unresectable stage IV colorectal cancer. J Surg Oncol. 2010;102(1):94-99. doi:10.1002/jso.21577 - DOI - PubMed

[6] Seo GJ, Park JW, Yoo SB, et al. . Intestinal complications after palliative treatment for asymptomatic patients with unresectable stage IV colorectal cancer. J Surg Oncol. 2010;102(1):94-99. doi:10.1002/jso.21577 - DOI - PubMed

[7] Verhoef C, de Wilt JHW, Burger JWA, Verheul HMW, Koopman M. Surgery of the primary in stage IV colorectal cancer with unresectable metastases. Eur J Cancer. 2011;47(suppl 3):S61-S66. doi:10.1016/S0959-8049(11)70148-4 - DOI - PubMed

[8] Verhoef C, de Wilt JHW, Burger JWA, Verheul HMW, Koopman M. Surgery of the primary in stage IV colorectal cancer with unresectable metastases. Eur J Cancer. 2011;47(suppl 3):S61-S66. doi:10.1016/S0959-8049(11)70148-4 - DOI - PubMed

[9] Benson AI, Venook AP, Cederquist L, et al. Colon cancer. Oxford Case Histories in Oncology. Oxford University Press; 2017. doi:10.1093/med/9780199664535.003.0012 - DOI

[10] Benson AI, Venook AP, Cederquist L, et al. Colon cancer. Oxford Case Histories in Oncology. Oxford University Press; 2017. doi:10.1093/med/9780199664535.003.0012 - DOI

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Sixty-Day Mortality of Patients With Metastatic Colorectal Cancer Randomized to Systemic Treatment vs Primary Tumor Resection Followed by Systemic Treatment: The CAIRO4 Phase 3 Randomized Clinical Trial

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Sixty-Day Mortality of Patients With Metastatic Colorectal Cancer Randomized to Systemic Treatment vs Primary Tumor Resection Followed by Systemic Treatment: The CAIRO4 Phase 3 Randomized Clinical Trial

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