Abstract
Purpose
The purpose of this study was to determine whether patients diagnosed with colorectal cancer and synchronous unresectable metastases (stage IV) can benefit from resection of the primary tumor in terms of an improvement in cancer-specific survival.
Methods
Stage IV colorectal cancer patients are eligible for inclusion in a randomized multicenter study carried out in 22 hospitals throughout Spain. Exclusion criteria are rectal tumors below 12 cm from the anal verge or locally advanced tumors, multiple bone or central nervous system metastases, and history of another primary cancer. The parallel design of the trial includes an arm of systemic chemotherapy alone versus an arm of resection of the primary tumor plus systemic chemotherapy after surgery. The primary endpoint of the study is cancer-specific survival that is assessed with a minimum follow-up of 24 months. Secondary endpoints are postoperative morbidity and mortality associated with resection of the primary tumor, complications and need of surgery in patients treated with systemic chemotherapy only, safety of systemic chemotherapy in both treatment strategies, and quality of life.
Conclusions
Confirmation of a survival benefit of surgical resection of the primary tumor in stage IV colorectal cancer patients not amenable to curative therapy is very relevant from a clinical and societal perspective, particularly considering the increase in the incidence and prevalence of colorectal cancer in developed countries.
ClinicalTrials.gov Identifier: NCT02015923.
Similar content being viewed by others
References
Poultsides GA, Paty PB (2011) Reassessing the need for primary tumor surgery in unresectable metastatic colorectal cancer: overview and perspective. Ther Adv Med Oncol 3:35–42. doi:10.1177/1758834010386283
Treatment of colon cancer, by stage. American Cancer Society. Available at: https://www.cancer.org/cancer/colon-rectal-cancer/treating/by-stage-colon.html. Accessed date: April 17, 2017
Gervaz P, Rubbia-Brandt L, Andres A, Majno P, Roth A, Morel P, Mentha G (2010) Neoadjuvant chemotherapy in patients with stage IV colorectal cancer: a comparison of histological response in liver metastases, primary tumors, and regional lymph nodes. Ann Surg Oncol 17:2714–2719. doi:10.1245/s10434-010-1056-6
Poultsides GA, Servais EL, Saltz LB, Patil S, Kemeny NE, Guillem JG, Weiser M, Temple LK, Wong WD, Paty PB (2009) Outcome of primary tumor in patients with synchronous stage IV colorectal cancer receiving combination chemotherapy without surgery as initial treatment. J Clin Oncol 27:3379–3384. doi:10.1200/JCO.2008.20.9817
Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, Findlay BP, Pitot HC, Alberts SR (2004) A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23–30
Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, Mitchell EP, Alberts SR, Schwartz MA, Benson AB 3rd (2007) Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25:1539–1544
Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzén F, Cassidy J (2008) Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26:2013–2019. doi:10.1200/JCO.2007.14.9930
Stillwell AP, Buettner PG, Ho YH (2010) Meta-analysis of survival of patients with stage IV colorectal cancer managed with surgical resection versus chemotherapy alone. World J Surg 34:797–807. doi:10.1007/s00268-009-0366-y
Stillwell AP, Ho YH, Veitch C (2011) Systematic review of prognostic factors related to overall survival in patients with stage IV colorectal cancer and unresectable metastases. World J Surg 35:684–692. doi:10.1007/s00268-010-0891-8
Sarela AI, Guthrie JA, Seymour MT, Ride E, Guillou PJ, O’Riordain DS (2001) Non-operative management of the primary tumour in patients with incurable stage IV colorectal cancer. Br J Surg 88:1352–1356
Scoggins CR, Meszoely IM, Blanke CD, Beauchamp RD, Leach SD (1999) Nonoperative management of primary colorectal cancer in patients with stage IV disease. Ann Surg Oncol 6:651–657
Stelzner S, Hellmich G, Koch R, Ludwig K (2005) Factors predicting survival in stage IV colorectal carcinoma patients after palliative treatment: a multivariate analysis. J Surg Oncol 89:211–217
Karoui M, Roudot-Thoraval R, Mesli F, Mitry E, Aparicio T, DesGuetz G, Luvet C, Landi B, Tiret E, Sobhani I (2011) Primary colectomy in patients with stage IV colon cancer and unresectable distant metastases improves overall survival: results of a multicentric study. Dis Colon rectum 54:930–938. doi:10.1097/DCR.0b013e31821cced0
Venderbosch S, de Wilt JH, Teerenstra S, Loosveld OJ, van Bochove A, Sinnige HA, Creemers GJM, Tesselaar ME, Mol L, Punt CJA, Koopman M (2011) Prognostic value of resection of primary tumor in patients with stage IV colorectal cancer: retrospective analysis of two randomized studies and a review of the literature. Ann Surg Oncol 18:3252–3260. doi:10.1245/s10434-011-1951-5
Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, de Jong RS, Rodenburg CJ, Vreugdenhil G, Loosveld OJ, van Bochove A, Sinnige HA, Creemers GJ, Tesselaar ME, Slee PH, Werter MJ, Mol L, Dalesio O, Punt CJ (2007) Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet 370:135–142
Tol J, Koopman M, Rodenburg CJ, Cats A, Creemers GJ, Schrama JG, Erdkamp FL, Vos AH, Mol L, Antonini NF, Punt CJ (2008) A randomised phase III study on capecitabine, oxaliplatin and bevacizumab with or without cetuximab in first-line advanced colorectal cancer, the CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG). An interim analysis of toxicity. Ann Oncol 19:734–738. doi:10.1093/annonc/mdm607
Frago R, Kreisler E, Biondo S, Salazar R, Dominguez J, Escalante E (2010) Outcomes in the management of obstructive unresectable stage IV colorectal cancer. Eur J Surg Oncol 36:1187–1194. doi:10.1016/j.ejso.2010.09.005
National Surgical Adjuvant Breast and Bowel Project (NSABP) 2010. Federally-Supported Clinical Trials: Protocol C-10,9/10 update. Available at: http://www.nsabp.pitt.edu/C10_Information.asp. Accessed date: April 17, 2017.
Chemotherapy with or without surgery in treating patients with metastatic colorectal cancer that cannot be removed by surgery. ClinicalTrials.gov Identifier: NCT01086618. Available at: https://clinicaltrials.gov/. Accessed date: April 17, 2017.
Miller AB, Hoogstraten B, Staquet M, Winkler A (1981) Reporting results of cancer treatment. Cancer 47:207–214
Arraras JI, Suárez J, Arias de la Vega F, Vera R, Asín G, Arrazubi V, Rico M, Teijeira L, Azparren J (2011) The EORTC Quality of Life questionnaire for patients with colorectal cancer: EORTC QLQ-CR29 validation study for Spanish patients. Clin Transl Oncol 13:50–56. doi:10.1007/s12094-011-0616-y
Nordlinger B, Van Cutsem E, Gruenberger T, Glimelius B, Poston G, Rougier P, Sobrero A, Ychou M (2009) Combination of surgery and chemotherapy and the role of targeted agents in the treatment of patients with colorectal liver metastases: recommendations from an expert panel. Ann Oncol 20:985–992. doi:10.1093/annonc/mdn735
Clancy C, Burke JP, Barry M, Kalady MF, Calvin Coffey J (2014) A meta-analysis to determine the effect of primary tumor resection for stage IV colorectal cancer with unresectable metastases on patient survival. Ann Surg Oncol 21:3900–3908. doi:10.1245/s10434-014-3805-4
Eisenberger A, Whelan RL, Negut AI (2008) Survival and symptomatic benefit from palliative primary tumor resection in patients with metastatic colorectal cancer: a review. Int J Color Dis 23:559–568
Rahbari NN, Lordick F, Fink C, Bork U, Stange A, Jäger D, Luntz S, Englert S, Rossion I, Koch M, Büchler M, Kieser M, Weitz J (2012) Resection of the primary tumor versus no resection prior to systemic therapy in patients with colon cancer and synchronous unresectable metastases (IUCC stage IV): SYNCHRONOUS—a randomised controlled trial (ISRCTN30964555). BMC Cancer 12:142
Acknowledgments
We thank Marta Pulido, MD, for editing the manuscript and editorial assistance and Bernat Miguel, project manager of the study.
The study is monitored by Scienco Klinico http://www.sciencoklinico.com/
Author information
Authors and Affiliations
Consortia
Corresponding author
Ethics declarations
The trial is conducted in accordance with the Declaration of Helsinki (7th revision) and the Spanish laws and regulations for biomedical research, with authorization from the Spanish Agency for Medicines and Medical Devices (Agencia Española del Medicamentos y Productos Sanitarios, AMPES). The trial protocol, patient information, and informed consent sheets have been approved by the competent Ethics Committees of all participating trial centers. The trial has been registered at the ClinicalTrials.gov database (NCT02015923; https://clinicaltrials.gov).
Funding
Instituto Carlos III, FIS PI12/02246 Ministry of Economy Industry and Competitiveness. Government of Spain.
Appendix
Appendix
CR4 Spanish study group:
Mercedes Villacampa, Instituto Catalan de Oncología
Eduardo Garcia-Granero Hospital La Fe
Laura Mora López, Corporació Sanitària Parc Taulí
Ignasi Camps, Hospital Germans Trias i Pujol
Miguel Pera, Hospital del Mar
Lorenzo Viso, Hospital Moisès Broggi
Elena Córdoba , Hospital Clínico Lozano Blesa
David Julià, Hospital Josep Trueta
Nieves Cáceres, Complejo Hospitalario de Vigo
Mario Álvarez, Hospital La Paz
José María Enríquez Navascués, Adelaida La Casta, Hospital Donostia
Fernando de la Portilla, Ana M García , Hospital Virgen del Rocío
Miguel Ángel Ciga, Hospital Virgen del Camino
José Luís Sánchez, Hospital Vall d’Hebron
Manuel Ferrer, Complejo Hospitalario Torrecárdenas
Jesús Abrisqueta, Hospital Virgen de la Arrixaca
Alberto Parajó, Complejo Hospitalario Ourense
Carlos Moreno, Complejo Hospitalario La Mancha Centro
Alejandro Espí, Hospital Clínico de Valencia
Rights and permissions
About this article
Cite this article
Biondo, S., Frago, R., Kreisler, E. et al. Impact of resection versus no resection of the primary tumor on survival in patients with colorectal cancer and synchronous unresectable metastases: protocol for a randomized multicenter study (CR4). Int J Colorectal Dis 32, 1085–1090 (2017). https://doi.org/10.1007/s00384-017-2827-3
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00384-017-2827-3