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

Primary Purpose

Colon Cancer, Primary Tumour, Rectal Cancer

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Surgery of the primary tumour
Systemic treatment
Sponsored by
Dutch Colorectal Cancer Group
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Colon Cancer focused on measuring Surgery, Chemotherapy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University Hospital Aalborg
  • Rigshospitalet
  • Herlev Hospital
  • Regionshospital Herning
  • Roskilde hospital
  • Medisch Centrum Alkmaar
  • Ziekenhuisgroep Twente
  • Flevoziekenhuis
  • Ziekenhuis Amstelland
  • Academic Medical Centre
  • OLVG
  • VUMC
  • Gelre Ziekenhuis
  • Wilhelmina Ziekenhuis
  • Rode Kruis Ziekenhuis
  • Amphia Ziekenhuis
  • Jeroen Bosch
  • MC Haaglanden en Bronovo Nebo
  • Slingeland Ziekenhuis
  • Albert Schweitzer Ziekenhuis
  • Catharina Ziekenhuis
  • Maxima Medisch Centrum
  • St Annaziekenhuis
  • Groene Hart Ziekenhuis
  • Martini Ziekenhuis
  • UMCG
  • Spaarne Gasthuis
  • St Jansdal
  • Elkerliek Ziekenhuis
  • Spaarne Gasthuis
  • St Antonius Ziekenhuis
  • Radboudumc
  • Waterland Ziekenhuis
  • Laurentius Ziekenhuis
  • Maasstad Ziekenhuis
  • Erasmus MC
  • Fransicus Gastuis & Vlietland
  • Antonius Ziekenhuis
  • Ziekenhuis Rivierenland
  • Elisabeth-Tweesteden
  • Bernhoven Ziekenhuis
  • University Medical Centre Utrecht
  • Bernhoven Ziekenhuis
  • VieCuri Medisch Centrum
  • Zaans Medisch Centrum
  • Isala Klinieken

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Systemic treatment

Surgery followed by systemic treatment

Arm Description

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.

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

Outcomes

Primary Outcome Measures

Overall survival
Overall survival of the intent-to-treat population

Secondary Outcome Measures

Progression-free survival
Response to chemotherapy
Response rate according to RECIST 1.1
Systemic therapy related toxicity
Adverse events grade 3-4 according to NCI-CTC 4.0
Surgery related morbidity and mortality
Quality of life
EORTC QLQ-C30 and CR38
Interval between randomization and initiation of systemic treatment
Cost-benefit analyses
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
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

Full Information

First Posted
May 23, 2012
Last Updated
September 11, 2023
Sponsor
Dutch Colorectal Cancer Group
Collaborators
Hoffmann-La Roche
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1. Study Identification

Unique Protocol Identification Number
NCT01606098
Brief Title
The Role of Surgery of the Primary Tumour in Patients With Synchronous Unresectable Metastases of Colorectal Cancer
Acronym
CAIRO4
Official Title
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)
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Completed
Study Start Date
July 2012 (Actual)
Primary Completion Date
June 2022 (Actual)
Study Completion Date
December 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Dutch Colorectal Cancer Group
Collaborators
Hoffmann-La Roche

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Colon Cancer, Primary Tumour, Rectal Cancer
Keywords
Surgery, Chemotherapy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
206 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Systemic treatment
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Surgery followed by systemic treatment
Arm Type
Experimental
Arm Description
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
Intervention Type
Procedure
Intervention Name(s)
Surgery of the primary tumour
Intervention Description
Surgical resection of the colon tumour
Intervention Type
Drug
Intervention Name(s)
Systemic treatment
Other Intervention Name(s)
Bevacizumab in combination with fluoropyrimidine-based schedules
Intervention Description
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)
Primary Outcome Measure Information:
Title
Overall survival
Description
Overall survival of the intent-to-treat population
Time Frame
Time from randomisation until death, assessed up to 5 years
Secondary Outcome Measure Information:
Title
Progression-free survival
Time Frame
Time from randomisation until first progression or death whichever comes first, asessed up to 5 years
Title
Response to chemotherapy
Description
Response rate according to RECIST 1.1
Time Frame
Fist-line chemotherapy, assessed until progression
Title
Systemic therapy related toxicity
Description
Adverse events grade 3-4 according to NCI-CTC 4.0
Time Frame
Every 3 weeks during first-line treatment
Title
Surgery related morbidity and mortality
Time Frame
30 days
Title
Quality of life
Description
EORTC QLQ-C30 and CR38
Time Frame
Every 6 months from randomisation until first progression
Title
Interval between randomization and initiation of systemic treatment
Time Frame
Number of days between randomization and initiation of systemic treatment
Title
Cost-benefit analyses
Time Frame
Until end of first-line systemic treatment
Title
Patients requiring resection of the primary tumour in the non-resection arm
Description
Number of patients requiring resection of the primary tumour in the non-resection arm
Time Frame
Time from randomisation until death, assessed up to 5 years
Title
Overall survival in patients in whom treatment according to protocol was initiated
Description
Having received at least one cycle of systemic treatment in arm A and surgery in arm B
Time Frame
Time form randomisation until death, assessed up to 5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
M. Koopman, Prof MD PhD
Organizational Affiliation
UMC Utrecht
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
H. JW de Wilt, Prof MD PhD
Organizational Affiliation
Radboud University Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Hospital Aalborg
City
Aalborg
Country
Denmark
Facility Name
Rigshospitalet
City
Copenhagen
Country
Denmark
Facility Name
Herlev Hospital
City
Herlev
Country
Denmark
Facility Name
Regionshospital Herning
City
Herning
Country
Denmark
Facility Name
Roskilde hospital
City
Roskilde
Country
Denmark
Facility Name
Medisch Centrum Alkmaar
City
Alkmaar
Country
Netherlands
Facility Name
Ziekenhuisgroep Twente
City
Almelo
Country
Netherlands
Facility Name
Flevoziekenhuis
City
Almere
Country
Netherlands
Facility Name
Ziekenhuis Amstelland
City
Amstelveen
Country
Netherlands
Facility Name
Academic Medical Centre
City
Amsterdam
Country
Netherlands
Facility Name
OLVG
City
Amsterdam
Country
Netherlands
Facility Name
VUMC
City
Amsterdam
Country
Netherlands
Facility Name
Gelre Ziekenhuis
City
Apeldoorn
Country
Netherlands
Facility Name
Wilhelmina Ziekenhuis
City
Assen
Country
Netherlands
Facility Name
Rode Kruis Ziekenhuis
City
Beverwijk
Country
Netherlands
Facility Name
Amphia Ziekenhuis
City
Breda
Country
Netherlands
Facility Name
Jeroen Bosch
City
Den Bosch
Country
Netherlands
Facility Name
MC Haaglanden en Bronovo Nebo
City
Den Haag
Country
Netherlands
Facility Name
Slingeland Ziekenhuis
City
Doetinchem
Country
Netherlands
Facility Name
Albert Schweitzer Ziekenhuis
City
Dordrecht
Country
Netherlands
Facility Name
Catharina Ziekenhuis
City
Eindhoven
Country
Netherlands
Facility Name
Maxima Medisch Centrum
City
Eindhoven
Country
Netherlands
Facility Name
St Annaziekenhuis
City
Geldrop
Country
Netherlands
Facility Name
Groene Hart Ziekenhuis
City
Gouda
Country
Netherlands
Facility Name
Martini Ziekenhuis
City
Groningen
Country
Netherlands
Facility Name
UMCG
City
Groningen
Country
Netherlands
Facility Name
Spaarne Gasthuis
City
Haarlem
Country
Netherlands
Facility Name
St Jansdal
City
Harderwijk
Country
Netherlands
Facility Name
Elkerliek Ziekenhuis
City
Helmond
Country
Netherlands
Facility Name
Spaarne Gasthuis
City
Hoofddorp
Country
Netherlands
Facility Name
St Antonius Ziekenhuis
City
Nieuwegein
Country
Netherlands
Facility Name
Radboudumc
City
Nijmegen
ZIP/Postal Code
6542 KN
Country
Netherlands
Facility Name
Waterland Ziekenhuis
City
Purmerend
Country
Netherlands
Facility Name
Laurentius Ziekenhuis
City
Roermond
Country
Netherlands
Facility Name
Maasstad Ziekenhuis
City
Rotterdam
ZIP/Postal Code
3007 AC
Country
Netherlands
Facility Name
Erasmus MC
City
Rotterdam
Country
Netherlands
Facility Name
Fransicus Gastuis & Vlietland
City
Rotterdam
Country
Netherlands
Facility Name
Antonius Ziekenhuis
City
Sneek
Country
Netherlands
Facility Name
Ziekenhuis Rivierenland
City
Tiel
Country
Netherlands
Facility Name
Elisabeth-Tweesteden
City
Tilburg
Country
Netherlands
Facility Name
Bernhoven Ziekenhuis
City
Uden
Country
Netherlands
Facility Name
University Medical Centre Utrecht
City
Utrecht
Country
Netherlands
Facility Name
Bernhoven Ziekenhuis
City
Veghel
Country
Netherlands
Facility Name
VieCuri Medisch Centrum
City
Venlo
Country
Netherlands
Facility Name
Zaans Medisch Centrum
City
Zaandam
Country
Netherlands
Facility Name
Isala Klinieken
City
Zwolle
Country
Netherlands

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
34613339
Citation
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.
Results Reference
derived
PubMed Identifier
25277170
Citation
'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.
Results Reference
derived
Links:
URL
http://www.dccg.nl
Description
Dutch Colorectal Cancer Group

Learn more about this trial

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

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