The Role of Surgery of the Primary Tumour in Patients With Synchronous Unresectable Metastases of Colorectal Cancer (CAIRO4)

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. A Study of the Dutch Colorectal Cancer Group (DCCG)

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.

Study Overview

• Status: Completed
• Conditions: Rectal Cancer; Colon Cancer; Primary Tumour
• Intervention / Treatment: Drug: Systemic treatment; Procedure: Surgery of the primary tumour

• Study Type: Interventional
• Enrollment (Actual): 206
• Phase: Phase 3

Contacts and Locations

Study Locations

• Denmark
  • Aalborg, Denmark
    • University Hospital Aalborg
  • Copenhagen, Denmark
    • Rigshospitalet
  • Herlev, Denmark
    • Herlev Hospital
  • Herning, Denmark
    • Regionshospital Herning
  • Roskilde, Denmark
    • Roskilde Hospital
• Netherlands
  • Alkmaar, Netherlands
    • Medisch Centrum Alkmaar
  • Almelo, Netherlands
    • Ziekenhuisgroep Twente
  • Almere, Netherlands
    • Flevoziekenhuis
  • Amstelveen, Netherlands
    • Ziekenhuis Amstelland
  • Amsterdam, Netherlands
    • Academic Medical Centre
  • Amsterdam, Netherlands
    • OLVG
  • Amsterdam, Netherlands
    • VUmc
  • Apeldoorn, Netherlands
    • Gelre Ziekenhuis
  • Assen, Netherlands
    • Wilhelmina ziekenhuis
  • Beverwijk, Netherlands
    • Rode Kruis Ziekenhuis
  • Breda, Netherlands
    • Amphia ziekenhuis
  • Den Bosch, Netherlands
    • Jeroen Bosch
  • Den Haag, Netherlands
    • MC Haaglanden en Bronovo Nebo
  • Doetinchem, Netherlands
    • Slingeland Ziekenhuis
  • Dordrecht, Netherlands
    • Albert Schweitzer Ziekenhuis
  • Eindhoven, Netherlands
    • Catharina Ziekenhuis
  • Eindhoven, Netherlands
    • Maxima Medisch Centrum
  • Geldrop, Netherlands
    • St Annaziekenhuis
  • Gouda, Netherlands
    • Groene Hart Ziekenhuis
  • Groningen, Netherlands
    • Martini Ziekenhuis
  • Groningen, Netherlands
    • UMCG
  • Haarlem, Netherlands
    • Spaarne Gasthuis
  • Harderwijk, Netherlands
    • St Jansdal
  • Helmond, Netherlands
    • Elkerliek Ziekenhuis
  • Hoofddorp, Netherlands
    • Spaarne Gasthuis
  • Nieuwegein, Netherlands
    • St Antonius Ziekenhuis
  • Nijmegen, Netherlands, 6542 KN
    • Radboudumc
  • Purmerend, Netherlands
    • Waterland Ziekenhuis
  • Roermond, Netherlands
    • Laurentius Ziekenhuis
  • Rotterdam, Netherlands
    • Erasmus MC
  • Rotterdam, Netherlands, 3007 AC
    • Maasstad Ziekenhuis
  • Rotterdam, Netherlands
    • Fransicus Gastuis & Vlietland
  • Sneek, Netherlands
    • Antonius Ziekenhuis
  • Tiel, Netherlands
    • Ziekenhuis Rivierenland
  • Tilburg, Netherlands
    • Elisabeth-TweeSteden
  • Uden, Netherlands
    • Bernhoven Ziekenhuis
  • Utrecht, Netherlands
    • University Medical Centre Utrecht
  • Veghel, Netherlands
    • Bernhoven Ziekenhuis
  • Venlo, Netherlands
    • VieCuri Medisch Centrum
  • Zaandam, Netherlands
    • Zaans Medisch Centrum
  • Zwolle, Netherlands
    • Isala Klinieken

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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.	Drug: 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); Other Names: Bevacizumab in combination with fluoropyrimidine-based schedules
Experimental: 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	Drug: 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); Other Names: Bevacizumab in combination with fluoropyrimidine-based schedules; Procedure: Surgery of the primary tumour; Surgical resection of the colon tumour

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Overall survival of the intent-to-treat population	Time from randomisation until death, assessed up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival		Time from randomisation until first progression or death whichever comes first, asessed up to 5 years
Response to chemotherapy	Response rate according to RECIST 1.1	Fist-line chemotherapy, assessed until progression
Systemic therapy related toxicity	Adverse events grade 3-4 according to NCI-CTC 4.0	Every 3 weeks during first-line treatment
Surgery related morbidity and mortality		30 days
Quality of life	EORTC QLQ-C30 and CR38	Every 6 months from randomisation until first progression
Interval between randomization and initiation of systemic treatment		Number of days between randomization and initiation of systemic treatment
Cost-benefit analyses		Until end of first-line systemic treatment
Patients requiring resection of the primary tumour in the non-resection arm	Number of patients requiring resection of the primary tumour in the non-resection arm	Time from randomisation until death, assessed up to 5 years
Overall survival in patients in whom treatment according to protocol was initiated	Having received at least one cycle of systemic treatment in arm A and surgery in arm B	Time form randomisation until death, assessed up to 5 years

Collaborators and Investigators

• Sponsor: Dutch Colorectal Cancer Group
• Collaborators: Hoffmann-La Roche
• Investigators: Principal Investigator: M. Koopman, Prof MD PhD, UMC Utrecht; Principal Investigator: H. JW de Wilt, Prof MD PhD, Radboud University Medical Center

Publications and helpful links

General Publications

• 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.
• '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.

Helpful Links

• Dutch Colorectal Cancer Group

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2012
• Primary Completion (Actual): June 1, 2022
• Study Completion (Actual): December 1, 2022

Study Registration Dates

• First Submitted: May 23, 2012
• First Submitted That Met QC Criteria: May 24, 2012
• First Posted (Estimated): May 25, 2012

Study Record Updates

• Last Update Posted (Actual): September 13, 2023
• Last Update Submitted That Met QC Criteria: September 11, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Surgery; Chemotherapy
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab
• Other Study ID Numbers: CAIRO4

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED