Resection vs no Resection of the Primary in Colorectal Cancer With Unresectable Metastases (CCRe-IV)

Multicenter Randomized Study in Patients With Colorectal Cancer With Unresectable Metastases. Impact of Resection vs no Resection of the Primary Tumour as a Survival Factor

Main outcome: Assess the impact of cancer-related survival at 2 years in patients with unresectable metastatic colorectal cancer treated with chemotherapy alone versus surgery followed by chemotherapy. To assess overall survival. To evaluate postoperative morbidity and mortality in patients treated with resection of the primary tumor. Assess complications and meed for surgery in patients treated with systemic chemotherapy only during the course of the disease. Identify and describe the complications related to chemotherapy and toxicity in the short and medium term systemic treatment. Assessing the quality of life questionnaire QLQ-C30 and QLQ-CR29. To study prognostic survival factors.

Method: multicenter randomized clinical trail (22 hospitals). Two parallel group in which to evaluate two therapeutic strategies for colorectal cancer metastasis unresectable stage IV: chemotherapy alone versus primary tumor resection plus chemotherapy.

Subjects: patients with unresectable nonmetastatic colorectal cancer. Hypothesis:Surgical resection of the primary tumor in stage IV colorectal patients with unresectable synchronous metastases increases by 14% overall survival compared to patients receiving systemic treatment with chemotherapy without resection of the primary tumor (survival of 34% vs 20%).

Study Overview

• Status: Terminated
• Conditions: Colonic Cancer; Unresectable Metastasis Originating in Colonic Cancer
• Intervention / Treatment: Procedure: Colonic resection; Drug: Chemotherapy- scheme

Detailed Description

Intervention: Arm B (control): chemotherapy alone, regimen according to each center. Arm A (experimental): surgery (complete tumoral resection; R0) followed by chemotherapy, regimen according to each center. Statistical Analysis: A power analysis showed that to assure a significance level of 0,05 and a beta error 0.20. 168 patients are necessary in each arm. It has been estimated a loss rate of up to 10%.

Differences between groups will be analyzed by t, U, X2, exact test and survival will be assessed according to Kaplan and Meier method. Evaluation of safety of the trial will be made in the middle of the study statistically

• Study Type: Interventional
• Enrollment (Actual): 107
• Phase: Phase 4

Contacts and Locations

Study Locations

• Spain
  • Almería, Spain
    • Complejo Hospitalario Torrecárdenas
  • Barcelona, Spain
    • Hospital del Mar
  • Barcelona, Spain
    • Hospital de la Santa Creu i Sant Pau
  • Barcelona, Spain
    • Hospital Univesitari Vall d'Hebron
  • Donostia, Spain
    • Hospital Universitario Donostia
  • Girona, Spain
    • Hospital Universitari de Girona DrJosep Trueta
  • Madrid, Spain
    • Hospital Univerisitario La Paz
  • Murcia, Spain
    • Hospital Clínico Universitario Virgen de la Arrixaca
  • Ourense, Spain
    • Complejo Hospitalario Universitario de Orense
  • Sevilla, Spain
    • Hospital Universitario Virgen del Rocío
  • Valencia, Spain
    • Hospital Clinico Universitario de Valencia
  • Valencia, Spain
    • Hospital General de Valencia
  • Valencia, Spain
    • Hospital Universitari i Politecnic La Fe
  • Zaragoza, Spain
    • Hospital Clínico Univeristario "Lozano Blesa"
  • Araba
    • Vitoria/Gasteiz, Araba, Spain
      • Hospital Universitario Araba
  • Barcelona
    • Badalona, Barcelona, Spain
      • Hospital Universitari Germans Trias I Pujol
    • L'Hospitalet de Llobregat, Barcelona, Spain, 08709
      • Hospital Universitari de Bellvitge
    • Sabadell, Barcelona, Spain
      • Corporacio Sanitaria Parc Tauli
    • Sant Joan Despí, Barcelona, Spain
      • Hospital Moisés Broggi
  • Ciudad Real
    • Alcazar de San Juan, Ciudad Real, Spain
      • Complejo Hospitalario La Mancha Centro
  • Navarra
    • Pamplona, Navarra, Spain
      • Complejo Hospitalario de Navarra
  • Pontevedra
    • Vigo, Pontevedra, Spain
      • Complejo Hospitalario Universitario de Vigo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• colorectal cancer above to 12 cm from the anal verge
• unresectable synchronous metastases
• no contraindications for chemotherapy
• absence of peritoneal carcinomatosis, central nervous system o bone metastasis.
• performance status ECOG ≤ 2 (Eastern Cooperative Oncology Group)
• uncontrolled concomitant medical conditions that may compromise to chemotherapy
• significant symptomatic cardiac disease
• not pregnancy or breastfeeding

Exclusion Criteria:

• Cases of rectal tumours below 12cm from anal verge, or locally advanced tumours invading blood vessels, nerves or bone.
• Multiple bone metastasis or central nervous system metastasis
• Other neoplastic disease in the 5 previous years, except squamous or basal cell skin carcinoma or cervical "in situ" carcinoma
• Significant heart disease (chronic congestive heart failure, symptomatic coronary disease) or myocardial infarction in the previous 6 months
• Peripheral neuropathy
• Patients who do not give informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Health Services Research
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: colonic resection; Arm A (experimental): surgery (complete tumoral resection; R0) followed by chemotherapy, regimen according to each center.	Procedure: Colonic resection; Colonic cancer resection, R0 No surgical intervention on metastasis; Drug: Chemotherapy- scheme; Chemotherapy, specified in each center with or without biological drugs; Other Names: FOLFOX-4; FOLFIRI; CAPOX; FOLFOXIRI; FOLFOX-6; CETUXIMAX / BEVACIZUMAB/PANITUMUMAB
Active Comparator: Chemotherapy; Arm B (control): chemotherapy alone, regimen according to each center	Procedure: Colonic resection; Colonic cancer resection, R0 No surgical intervention on metastasis; Drug: Chemotherapy- scheme; Chemotherapy, specified in each center with or without biological drugs; Other Names: FOLFOX-4; FOLFIRI; CAPOX; FOLFOXIRI; FOLFOX-6; CETUXIMAX / BEVACIZUMAB/PANITUMUMAB

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess the impact of overall survival in patients with unresectable metastatic colorectal cancer treated with chemotherapy alone vs surgery followed by chemotherapy.	The percentage of patients who are still alive for follow-up at 2 years after randomization.	up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postoperative morbidity and mortality.	Postoperative complications were classified according to the Dindo-Clavien classification. Mortality within 30 days after surgery	30 days postoperatively
Complications in patients treated with systemic chemotherapy	The toxicity will be evaluated and documented according to the CTCAE version 4.0.	up to 2 years
Questionnaire Quality of life CR29	Specific questionnaire for colon cancer	up to 2 years
Study of possible survival factors	Identify factors that may influence patient survival before applying any treatment (demographics, clinicals and analitycal factors, tumor characteristics; ...)	up to 2 years

Collaborators and Investigators

• Sponsor: Hospital Universitari de Bellvitge
• Collaborators: Instituto de Salud Carlos III
• Investigators: Study Chair: Sebastiano Biondo, Sponsor, Hospital Universitari de Bellvitge; Principal Investigator: Javier Vaqué, Hospital Universitario La Fe; Principal Investigator: Juan García Armengol, Hospital General Universitario de Valencia; Principal Investigator: Laura Mora, Corporacion Parc Tauli; Principal Investigator: Ignasi Camps Ausàs, Hospital Universitari Gemans Tiras i Pujol; Principal Investigator: Miguel Pera Román, Hospital Univesitari del Mar; Principal Investigator: Eduardo Targarona Soler, Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau; Principal Investigator: Lorenzo Viso Pons, Hospital de Sant Joan Despí Moisès Broggi; Principal Investigator: José Manuel Ramírez Rodríguez, Hospital Clínico Univeristario "Lozano Blesa"; Principal Investigator: David Julià Bergkvist, Hospital Universitari de Girona DrJosep Trueta; Principal Investigator: Teresa García Martínez, Complejo Hospitalario Universitario de Vigo; Principal Investigator: Mario Álvarez Gallego, Hospital Univerisitario La Paz; Principal Investigator: José María Enríquez Navascués, Hospital Universitario Donostia; Principal Investigator: Fernando de la Portilla de Juan, Hospitales Universitarios Virgen del Rocío; Principal Investigator: Miguel Angel Ciga, Complejo Hospitalario de Navarra; Principal Investigator: Eloy Espín Basany, Hospital Universitari de la Vall d'Hebron; Principal Investigator: Manuel Ferrer Márquez, Complejo Hospitalario Torrecárdenas; Principal Investigator: Jesús Abrisqueta Carrión, Hospital Clínico Universitario Virgen de la Arrixaca; Principal Investigator: José Errasti Alustiza, Hospital Universitario Araba; Principal Investigator: Alberto Parajó Calvo, Complejo Hospitalario Universitario de Orense; Principal Investigator: Carlos Moreno Sanz, Complejo Hospitalario La Mancha Centro; Principal Investigator: Alejando Espí Macías, Hospital Clinico Universitario de Valencia; Principal Investigator: Ricard Frago Montanuy, Hospital Universitari de Bellvitge

Publications and helpful links

General Publications

• Biondo S, Frago R, Kreisler E, Espin-Basany E; Spanish CR4 Group. 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. 2017 Jul;32(7):1085-1090. doi: 10.1007/s00384-017-2827-3. Epub 2017 May 11.

Study record dates

Study Major Dates

• Study Start: December 1, 2013
• Primary Completion (Actual): June 1, 2019
• Study Completion (Actual): February 1, 2020

Study Registration Dates

• First Submitted: November 28, 2013
• First Submitted That Met QC Criteria: December 13, 2013
• First Posted (Estimate): December 19, 2013

Study Record Updates

• Last Update Posted (Actual): March 16, 2021
• Last Update Submitted That Met QC Criteria: March 12, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Metastasis; Colonic cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Neoplastic Processes; Colorectal Neoplasms; Neoplasm Metastasis; Colonic Neoplasms; Antineoplastic Agents; Antineoplastic Agents, Immunological; Panitumumab
• Other Study ID Numbers: 01CCRe-IV; 2013-001688-22 (EudraCT Number)