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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)

  • Clinical Study Protocol
  • Published:
International Journal of Colorectal Disease Aims and scope Submit manuscript

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.

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References

  1. 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

    Article  PubMed  PubMed Central  Google Scholar 

  2. 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

  3. 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

    Article  PubMed  Google Scholar 

  4. 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

    Article  PubMed  PubMed Central  Google Scholar 

  5. 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

    Article  CAS  PubMed  Google Scholar 

  6. 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

    Article  CAS  PubMed  Google Scholar 

  7. 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

    Article  CAS  PubMed  Google Scholar 

  8. 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

    Article  CAS  PubMed  Google Scholar 

  9. 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

    Article  PubMed  Google Scholar 

  10. 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

    Article  CAS  PubMed  Google Scholar 

  11. 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

    Article  CAS  PubMed  Google Scholar 

  12. 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

    Article  PubMed  Google Scholar 

  13. 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

  14. 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

    Article  PubMed  PubMed Central  Google Scholar 

  15. 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

    Article  CAS  PubMed  Google Scholar 

  16. 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

    Article  CAS  PubMed  Google Scholar 

  17. 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

    Article  CAS  PubMed  Google Scholar 

  18. 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.

  19. 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.

  20. Miller AB, Hoogstraten B, Staquet M, Winkler A (1981) Reporting results of cancer treatment. Cancer 47:207–214

    Article  CAS  PubMed  Google Scholar 

  21. 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

    Article  PubMed  Google Scholar 

  22. 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

    Article  CAS  PubMed  Google Scholar 

  23. 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

    Article  PubMed  Google Scholar 

  24. 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

    Article  Google Scholar 

  25. 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

    Article  PubMed  PubMed Central  Google Scholar 

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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

  1. Department of General and Digestive Surgery, Colorectal Unit, Bellvitge University Hospital, University of Barcelona and IDIBELL, C/ Feixa Llarga s/n, L’Hospitalet de Llobregat, 08907, Barcelona, Spain

    Sebastiano Biondo, Ricardo Frago & Esther Kreisler

  2. Department of General and Digestive Surgery, Colorectal Unit, Vall d’Hebron University Hospital, Autonomic University of Barcelona, Barcelona, Spain

    Eloy Espin-Basany

Authors
  1. Sebastiano Biondo
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  2. Ricardo Frago
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  3. Esther Kreisler
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  4. Eloy Espin-Basany
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Consortia

the Spanish CR4 Group

  • Sebastiano Biondo
  • , Eloy Espin Basany
  • , Lorenzo Viso Pons
  • , Jesús Abrisqueta Carrion
  • , Elena Córdoba Díaz de Laspra
  • , Fernando de la Portilla de Juan
  • , Miguel Pera Román
  • , Alberto Parajó Calvo Parajó Calvo
  • , Jose María Enríquez Navascués
  • , Carlos Moreno Sanz
  • , Manuel Ferrer Márquez
  • , Miguel Ángel Ciga Lozano
  • , Ignasi Camps Ausàs
  • , Mario Álvarez Gallego
  • , Antoni Codina Cazador
  • , Alejandro Espí Macías
  • , Laura Mora López
  •  & Nieves Cáceres Alvarado

Corresponding author

Correspondence to Sebastiano Biondo.

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

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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

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  • DOI: https://doi.org/10.1007/s00384-017-2827-3

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