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

• ClinicalTrials.gov Identifier: NCT01606098
• Recruitment Status: Active, not recruiting
• First Posted: May 25, 2012
• Last Update Posted: March 22, 2022
• Sponsor: Dutch Colorectal Cancer Group
• Collaborator: Hoffmann-La Roche
• Information provided by (Responsible Party): Dutch Colorectal Cancer Group

Tracking Information

• First Submitted Date: May 23, 2012
• First Posted Date: May 25, 2012
• Last Update Posted Date: March 22, 2022
• Actual Study Start Date: July 2012
• Estimated Primary Completion Date: June 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 22, 2016)

Overall survival [ Time Frame: Time from randomisation until death, assessed up to 5 years ]

Overall survival of the intent-to-treat population

Original Primary Outcome Measures (submitted: May 24, 2012)

Overall survival

Overall survival of the intent-to-treat population

Current Secondary Outcome Measures (submitted: January 22, 2016)

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

Original Secondary Outcome Measures (submitted: May 24, 2012)

• Progression-free survival
• Response to chemotherapy
  Response rate according to RECIST 1.1
• Systemic therapy related toxicity
  Adverse events graded according to NCI-CTC 4.0
• Surgery related morbidity and mortality [ Time Frame: 30 days ]
• Quality of life
• 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
  Overall survival in patients in treatment according to protocol was initiated

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: The Role of Surgery of the Primary Tumour in Patients With Synchronous Unresectable Metastases of Colorectal Cancer
• 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)
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Colon Cancer
• Primary Tumour
• Rectal Cancer

Intervention

• Procedure: Surgery of the primary tumour
  Surgical resection of the colon tumour
• 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 Name: Bevacizumab in combination with fluoropyrimidine-based schedules

Study Arms

• 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.
  Intervention: Drug: Systemic treatment
• 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
  Interventions:

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

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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: January 22, 2021): 206
• Original Estimated Enrollment (submitted: May 24, 2012): 360
• Estimated Study Completion Date: December 2022
• Estimated Primary Completion Date: June 2022 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Denmark, Netherlands

Administrative Information

• NCT Number: NCT01606098
• Other Study ID Numbers: CAIRO4
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Dutch Colorectal Cancer Group
• Original Responsible Party: Same as current
• Current Study Sponsor: Dutch Colorectal Cancer Group
• Original Study Sponsor: Same as current
• 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

• PRS Account: Dutch Colorectal Cancer Group
• Verification Date: March 2022