The Role of Surgery of the Primary Tumour in Patients With Synchronous Unresectable Metastases of Colorectal Cancer

NCT01606098 | Completed Phase 3 DMC

• 1 other identifier: CAIRO4
• Study Type: interventional
• Target: 206
• Locations: 2 countries
• Sites: 46

Brief Summary

The clinical benefit of resection of the primary tumour in patients with synchronous unresectable metastases is not known. In the literature studies usually describe retrospective selected patients with synchronous metastases treated with or without resection of the primary tumour. All these studies are biased in patient selection and there are no prospective randomized studies on this topic. In patients with few or absent symptoms of the primary tumour, arguments both in favour and against initial resection have been presented, and therefore a randomized trial is warranted. Although recent publications suggest that resection of the primary tumour in synchronous metastasized colon cancer patients might not be necessary, this appears to be based on feasibility and not on clinical outcome. Several studies comparing large groups of patients with or without resection of the primary tumour suggest an improved survival when the primary tumour is resected. A potential benefit of resection of the primary tumour is to prevent complications of the primary tumour during chemotherapy treatment or during later stages of the disease. A recent analysis of the CAIRO and CAIRO2 data showed that metastatic colon cancer patients who had a resection of the primary tumour prior to study entry, had an improved survival compared to patients without a resection of the primary tumour. However, these patients were selected after the primary tumour was resected and therefore these results are not corrected for surgical morbidity and mortality. The investigators here propose a randomized trial in order to demonstrate that resection of the primary tumour does improve overall survival.

Conditions

Colon Cancer; Primary Tumour; Rectal Cancer

Keywords

Surgery; Chemotherapy

Outcome Measures

Primary Outcomes (1)

• Overall survival

  Overall survival of the intent-to-treat population

  Time from randomisation until death, assessed up to 5 years

Secondary Outcomes (9)

• Progression-free survival

  Time from randomisation until first progression or death whichever comes first, asessed up to 5 years

• Response to chemotherapy

  Fist-line chemotherapy, assessed until progression

• Systemic therapy related toxicity

  Every 3 weeks during first-line treatment

• Surgery related morbidity and mortality

  30 days

• Quality of life

  Every 6 months from randomisation until first progression

Study Arms (2)

Systemic treatment

ACTIVE COMPARATOR

First-line fluoropyrimidine-based chemotherapy with bevacizumab initiated within 4 weeks of randomization, followed by salvage therapy upon progression at the discretion of the local investigator. Surgery of primary tumour will be performed only when indicated by local signs or symptoms.

Drug: Systemic treatment

Surgery followed by systemic treatment

EXPERIMENTAL

Surgery within 4 weeks of randomization followed by fluoropyrimidine-based chemotherapy with bevacizumab until progression or unacceptable toxicity, followed by salvage therapy upon progression at the discretion of the local investigator

Procedure: Surgery of the primary tumour; Drug: Systemic treatment

Interventions

Surgery of the primary tumour PROCEDURE

Surgical resection of the colon tumour

Surgery followed by systemic treatment

Systemic treatment DRUG

First line fluoropyrimidine-based chemotherapy with bevacizumab. The chemotherapy regimen is to the discretion of the local investigator, who may choose between: 5FU/LV or capecitabine or capecitabine + oxaliplatin(CAPOX)or 5FU + oxaliplatin(FOLFOX 4 or FOLFOX 7)or 5FU + irinotecan (FOLFIRI) or capecitabine + irinotecan(CAPIRI)

Also known as: Bevacizumab in combination with fluoropyrimidine-based schedules

Surgery followed by systemic treatment; Systemic treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histological proof of colorectal cancer
• Resectable primary tumour in situ with unresectable distant metastases
• No indication for neo-adjuvant (chemo)radiation
• No severe signs or symptoms related to the primary tumour (i.e. severe bleeding, obstruction, severe abdominal pain) that require immediate surgery or other symptomatic treatment (e.g. stenting)
• No prior systemic treatment for advanced disease
• Age ≥ 18 years
• WHO performance status 0-2
• Laboratory values obtained ≤ 4 weeks prior to randomization: Adequate bone marrow function (Hb ≥ 6.0 mmol/L, absolute neutrophil count ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L), renal function (serum creatinine ≤ 1.5x ULN and creatinine clearance, Cockroft formula, ≥ 30 ml/min), liver function (serum bilirubin ≤ 2 x ULN, serum transaminases ≤ 3 x ULN without presence of liver metastases or ≤ 5x ULN with presence of liver metastases)
• Expected adequacy of follow-up
• Written informed consent
• CT scan abdomen and CT thorax/X-thorax performed ≤ 4 weeks prior to randomization

You may not qualify if:

• Pregnancy, lactation
• Unresectable primary tumour (i.e. neurovascular encasement, substantial ingrowth in pancreatic head), or any condition preventing the safety or feasibility of resection of the primary tumour, i.e. massive ascites or extensive peritoneal disease
• Requirement of neoadjuvant (chmo)radiation therapy
• Second primary malignancy within the past 5 years with the exception of adequately treated in situ carcinoma of any organ or basal cell carcinoma of the skin
• Any medical condition that prevents the safe administration of systemic treatment
• Previous intolerance of fluoropyrimidines, known dihydropyrimidine dehydrogenase (DPD) deficiency
• Planned radical resection of all metastatic disease
• Uncontrolled hypertension, i.e. values consistently \> 150/100 mmHg
• Use of ≥ 3 antihypertensive drugs
• Significant cardiovascular disease \< 1 yr before randomization (symptomatic congestive heart failure, myocardial infarction, unstable angina pectoris, serious uncontrolled cardiac arrhythmia, cerebro vascular event)
• Chronic active infection
• Concurrent treatment with any other anti-cancer therapy as described per protocol

Sponsors & Collaborators

• Dutch Colorectal Cancer Group: lead
• Hoffmann-La Roche: collaborator

Study Sites (46)

University Hospital Aalborg

Aalborg, Denmark

Location

Rigshospitalet

Copenhagen, Denmark

Location

Herlev Hospital

Herlev, Denmark

Location

Regionshospital Herning

Herning, Denmark

Location

Roskilde hospital

Roskilde, Denmark

Location

Jeroen Bosch

's-Hertogenbosch, Netherlands

Location

Medisch Centrum Alkmaar

Alkmaar, Netherlands

Location

Ziekenhuisgroep Twente

Almelo, Netherlands

Location

Flevoziekenhuis

Almere Stad, Netherlands

Location

Ziekenhuis Amstelland

Amstelveen, Netherlands

Location

Academic Medical Centre

Amsterdam, Netherlands

Location

OLVG

Amsterdam, Netherlands

Location

VUMC

Amsterdam, Netherlands

Location

Gelre Ziekenhuis

Apeldoorn, Netherlands

Location

Wilhelmina Ziekenhuis

Assen, Netherlands

Location

Rode Kruis Ziekenhuis

Beverwijk, Netherlands

Location

Amphia Ziekenhuis

Breda, Netherlands

Location

Slingeland Ziekenhuis

Doetinchem, Netherlands

Location

Albert Schweitzer Ziekenhuis

Dordrecht, Netherlands

Location

Catharina Ziekenhuis

Eindhoven, Netherlands

Location

Maxima Medisch Centrum

Eindhoven, Netherlands

Location

St Annaziekenhuis

Geldrop, Netherlands

Location

Groene Hart Ziekenhuis

Gouda, Netherlands

Location

Martini Ziekenhuis

Groningen, Netherlands

Location

UMCG

Groningen, Netherlands

Location

Spaarne Gasthuis

Haarlem, Netherlands

Location

St Jansdal

Harderwijk, Netherlands

Location

Elkerliek Ziekenhuis

Helmond, Netherlands

Location

Spaarne Gasthuis

Hoofddorp, Netherlands

Location

St Antonius Ziekenhuis

Nieuwegein, Netherlands

Location

Radboudumc

Nijmegen, 6542 KN, Netherlands

Location

Waterland Ziekenhuis

Purmerend, Netherlands

Location

Laurentius Ziekenhuis

Roermond, Netherlands

Location

Maasstad Ziekenhuis

Rotterdam, 3007 AC, Netherlands

Location

Erasmus MC

Rotterdam, Netherlands

Location

Fransicus Gastuis & Vlietland

Rotterdam, Netherlands

Location

Antonius Ziekenhuis

Sneek, Netherlands

Location

MC Haaglanden en Bronovo Nebo

The Hague, Netherlands

Location

Ziekenhuis Rivierenland

Tiel, Netherlands

Location

Elisabeth-Tweesteden

Tilburg, Netherlands

Location

Bernhoven Ziekenhuis

Uden, Netherlands

Location

University Medical Centre Utrecht

Utrecht, Netherlands

Location

Bernhoven Ziekenhuis

Veghel, Netherlands

Location

VieCuri Medisch Centrum

Venlo, Netherlands

Location

Zaans Medisch Centrum

Zaandam, Netherlands

Location

Isala Klinieken

Zwolle, Netherlands

Location

Related Publications (3)

• van der Kruijssen DEW, Elias SG, van de Ven PM, van Rooijen KL, Lam-Boer J', Mol L, Punt CJA, Sommeijer DW, Tanis PJ, Nielsen JD, Yilmaz MK, van Riel JMGH, Wasowiz-Kemps DK, Loosveld OJL, van der Schelling GP, de Groot JWB, van Westreenen HL, Jakobsen HL, Fromm AL, Hamberg P, Verseveld M, Jaensch C, Liposits GI, van Duijvendijk P, Oulad Hadj J, van der Hoeven JAB, Trajkovic M, de Wilt JHW, Koopman M; CAIRO4 Working Group. Upfront resection versus no resection of the primary tumor in patients with synchronous metastatic colorectal cancer: the randomized phase III CAIRO4 study conducted by the Dutch Colorectal Cancer Group and the Danish Colorectal Cancer Group. Ann Oncol. 2024 Sep;35(9):769-779. doi: 10.1016/j.annonc.2024.06.001. Epub 2024 Jun 7.

  PMID: 38852675 DERIVED

• van der Kruijssen DEW, Elias SG, Vink GR, van Rooijen KL, 't Lam-Boer J, Mol L, Punt CJA, de Wilt JHW, Koopman M; CAIRO4 Working Group. 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. JAMA Surg. 2021 Dec 1;156(12):1093-1101. doi: 10.1001/jamasurg.2021.4992.

  PMID: 34613339 DERIVED

• 't Lam-Boer J, Mol L, Verhoef C, de Haan AF, Yilmaz M, Punt CJ, de Wilt JH, Koopman M. The CAIRO4 study: the role of surgery of the primary tumour with few or absent symptoms in patients with synchronous unresectable metastases of colorectal cancer--a randomized phase III study of the Dutch Colorectal Cancer Group (DCCG). BMC Cancer. 2014 Oct 2;14:741. doi: 10.1186/1471-2407-14-741.

  PMID: 25277170 DERIVED

Related Links

• Dutch Colorectal Cancer Group

MeSH Terms

Conditions

Colonic Neoplasms; Rectal Neoplasms

Interventions

Neoadjuvant Therapy; Bevacizumab

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Combined Modality Therapy; Therapeutics; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• M. Koopman, Prof MD PhD

  UMC Utrecht

  PRINCIPAL INVESTIGATOR

• H. JW de Wilt, Prof MD PhD

  Radboud University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 23, 2012
• First Posted: May 25, 2012
• Study Start: July 1, 2012
• Primary Completion: June 1, 2022
• Study Completion: December 1, 2022
• Last Updated: September 13, 2023

Record last verified: 2023-09

Locations

DK (5); NL (41)