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

NCT ID: NCT01606098

Last Updated: 2023-09-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 206 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-07-31
• Study Completion Date: 2022-12-31

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Systemic treatment

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.

Group Type: ACTIVE_COMPARATOR

Systemic treatment

Intervention Type: 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)

Surgery followed by systemic treatment

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

Group Type: EXPERIMENTAL

Surgery of the primary tumour

Intervention Type: PROCEDURE

Surgical resection of the colon tumour

Systemic treatment

Intervention Type: 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)

Interventions

Surgery of the primary tumour

Surgical resection of the colon tumour

Intervention Type: PROCEDURE

Systemic treatment

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)

Intervention Type: DRUG

Other Intervention Names

Bevacizumab in combination with fluoropyrimidine-based schedules

Eligibility Criteria

Inclusion Criteria

• 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

Exclusion Criteria

• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: collaborator

Dutch Colorectal Cancer Group

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

M. Koopman, Prof MD PhD

Role: PRINCIPAL_INVESTIGATOR

UMC Utrecht

H. JW de Wilt, Prof MD PhD

Role: PRINCIPAL_INVESTIGATOR

Radboud University Medical Center

Locations

University Hospital Aalborg

Aalborg, , Denmark

Rigshospitalet

Copenhagen, , Denmark

Herlev Hospital

Herlev, , Denmark

Regionshospital Herning

Herning, , Denmark

Roskilde hospital

Roskilde, , Denmark

Jeroen Bosch

's-Hertogenbosch, , Netherlands

Medisch Centrum Alkmaar

Alkmaar, , Netherlands

Ziekenhuisgroep Twente

Almelo, , Netherlands

Flevoziekenhuis

Almere Stad, , Netherlands

Ziekenhuis Amstelland

Amstelveen, , Netherlands

Academic Medical Centre

Amsterdam, , Netherlands

OLVG

Amsterdam, , Netherlands

VUMC

Amsterdam, , Netherlands

Gelre Ziekenhuis

Apeldoorn, , Netherlands

Wilhelmina Ziekenhuis

Assen, , Netherlands

Rode Kruis Ziekenhuis

Beverwijk, , Netherlands

Amphia Ziekenhuis

Breda, , Netherlands

Slingeland Ziekenhuis

Doetinchem, , Netherlands

Albert Schweitzer Ziekenhuis

Dordrecht, , Netherlands

Catharina Ziekenhuis

Eindhoven, , Netherlands

Maxima Medisch Centrum

Eindhoven, , Netherlands

St Annaziekenhuis

Geldrop, , Netherlands

Groene Hart Ziekenhuis

Gouda, , Netherlands

Martini Ziekenhuis

Groningen, , Netherlands

UMCG

Groningen, , Netherlands

Spaarne Gasthuis

Haarlem, , Netherlands

St Jansdal

Harderwijk, , Netherlands

Elkerliek Ziekenhuis

Helmond, , Netherlands

Spaarne Gasthuis

Hoofddorp, , Netherlands

St Antonius Ziekenhuis

Nieuwegein, , Netherlands

Radboudumc

Nijmegen, , Netherlands

Waterland Ziekenhuis

Purmerend, , Netherlands

Laurentius Ziekenhuis

Roermond, , Netherlands

Maasstad Ziekenhuis

Rotterdam, , Netherlands

Erasmus MC

Rotterdam, , Netherlands

Fransicus Gastuis & Vlietland

Rotterdam, , Netherlands

Antonius Ziekenhuis

Sneek, , Netherlands

MC Haaglanden en Bronovo Nebo

The Hague, , Netherlands

Ziekenhuis Rivierenland

Tiel, , Netherlands

Elisabeth-Tweesteden

Tilburg, , Netherlands

Bernhoven Ziekenhuis

Uden, , Netherlands

University Medical Centre Utrecht

Utrecht, , Netherlands

Bernhoven Ziekenhuis

Veghel, , Netherlands

VieCuri Medisch Centrum

Venlo, , Netherlands

Zaans Medisch Centrum

Zaandam, , Netherlands

Isala Klinieken

Zwolle, , Netherlands

Countries

Denmark; Netherlands

References

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.

Reference Type: DERIVED

PMID: 38852675 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34613339 (View on PubMed)

'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.

Reference Type: DERIVED

PMID: 25277170 (View on PubMed)

Related Links

http://www.dccg.nl

Dutch Colorectal Cancer Group

Other Identifiers

CAIRO4

Identifier Type: -

Identifier Source: org_study_id