Treatment Strategies in Colorectal Cancer Patients with Initially Unresectable Liver-only Metastases (CAIRO5)

Treatment Strategies in Colorectal Cancer Patients with Initially Unresectable Liver-only Metastases CAIRO5 a Randomized Phase 3 Study of the Dutch Colorectal Cancer Group (DCCG)

Colorectal cancer patients with initially unresectable liver-only metastases may be cured after downsizing of metastases by neoadjuvant systemic therapy. However, the optimal neoadjuvant induction regimen has not been defined, and no consensus exist on criteria for resectability.

In this study colorectal cancer patients with initially unresectable liver-only metastases, as prospectively confirmed by an expert panel according to predefined criteria, will be tested for RAS and BRAF tumor mutation status and selected by location of primary tumor. Patients with RAS or BRAF mutant and/or right sided tumors will be randomised between doublet chemotherapy (FOLFOX or FOLFIRI) plus bevacizumab (schedule 1), and triple chemotherapy (FOLFOXIRI) plus bevacizumab (schedule 2). Patients with RAS AND BRAF wildtype AND left-sided primary tumors will be randomized between doublet chemotherapy (FOLFOX or FOLFIRI) plus either bevacizumab (schedule 1) or panitumumab (schedule 3). Patient imaging will be reviewed for resectability by a central panel, consisting of at least one radiologist and three surgeons every assessment. Central panel review will be performed prior to randomization as well as during treatment, as described in the protocol.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer; Liver Metastases
• Intervention / Treatment: Drug: FOLFOXIRI with bevacizumab; Drug: FOLFOX/ FOLFIRI with bevacizumab; Drug: FOLFOX/ FOLFIRI with panitumumab

Detailed Description

Patients will be stratified for resectability of liver metastases (potentially resectable versus permanently unresectable), serum lactate dehydrogenase (LDH) (normal versus abnormal), BRAF mutation status (wildtype versus mutated), type of neoadjuvant chemotherapy (FOLFIRI versus FOLFOX) and hospital of registration.

Patients with RAS and BRAF wildtype and left-sided primary tumors will be randomised between FOLFOX or FOLFIRI plus either bevacizumab or panitumumab. The choice between FOLFOX or FOLFIRI is to the discretion of the local investigator, however, the treatment is restricted to regimens that are specified in the protocol. Patients with RAS or BRAF mutated and/or right-sided primary tumors will be randomized between FOLFOX/ FOLFIRI (investigator choice) plus bevacizumab or 5FU, irinotecan, oxaliplatin (FOLFOXIRI) plus bevacizumab.

Patients will be evaluated every 8 weeks by CT scan for disease status. The assigned systemic treatment should be continued for at least 6 months or earlier in case of resectability, progression of disease, unacceptable toxicity, or patient refusal. If after 6 months the panel concludes that the patient is still not resectable, it is highly unlikely that resectability will be achieved at all. Therefore the chemotherapy regimen may be reconsidered after 6 months of treatment. These patients should continue with the targeted drug in combination with chemotherapy, but the chemotherapy may be altered into a less toxic schedule such as fluoropyrimidine monotherapy. The targeted drug should be continued until progression or unacceptable toxicity. In patients who will become resectable and undergo secondary surgery of liver metastases, the total duration of preoperative and postoperative treatment together should be 6 months, with the chemotherapy schedule being administered according to the assigned treatment arm. However in these patients the targeted drug (bevacizumab or panitumumab) should not be continued after surgery.

• Study Type: Interventional
• Enrollment (Actual): 530
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Antwerpen, Belgium
    • Universitair Ziekenhuis Antwerpen
• Netherlands
  • Groningen, Netherlands
    • Martini Ziekenhuis
  • Groningen, Netherlands
    • UMC Groningen
  • Flevoland
    • Almere, Flevoland, Netherlands
      • Flevoziekenhuis
  • Friesland
    • Drachten, Friesland, Netherlands
      • Ziekenhuis Nij Smellinghe
    • Leeuwarden, Friesland, Netherlands
      • Medisch Centrum Leeuwarden, loc. Zuid
    • Sneek, Friesland, Netherlands
      • Antonius Ziekenhuis
  • Gelderland
    • Apeldoorn, Gelderland, Netherlands
      • Gelre Ziekenhuis
    • Arnhem, Gelderland, Netherlands
      • Rijnstate Ziekenhuis
    • Harderwijk, Gelderland, Netherlands
      • Sint Jansdal Ziekenhuis
    • Nijmegen, Gelderland, Netherlands
      • Radboud UMC
    • Winterswijk, Gelderland, Netherlands
      • Streekziekenhuis Koningin Beatrix
  • Limburg
    • Heerlen, Limburg, Netherlands
      • Atrium Medical Center
    • Maastricht, Limburg, Netherlands
      • Maastricht UMC+
    • Roermond, Limburg, Netherlands
      • Laurentius Ziekenhuis
    • Sittard, Limburg, Netherlands
      • Orbis Medical Center
    • Venlo, Limburg, Netherlands
      • VieCuri Medisch Centrum
  • Noord Holland
    • Amsterdam, Noord Holland, Netherlands
      • OLVG, locatie Oost
  • Noord-Brabant
    • 's Hertogenbosch, Noord-Brabant, Netherlands
      • Jeroen Bosch Ziekenhuis
    • Bergen op Zoom, Noord-Brabant, Netherlands
      • Bravis ziekenhuis
    • Breda, Noord-Brabant, Netherlands
      • Amphia ziekenhuis
    • Helmond, Noord-Brabant, Netherlands
      • Elkerliek Ziekenhuis
    • Roosendaal, Noord-Brabant, Netherlands
      • Bravis ziekenhuis
    • Tilburg, Noord-Brabant, Netherlands
      • TweeSteden Ziekenhuis
    • Tilburg, Noord-Brabant, Netherlands
      • Sint Elisabeth Ziekenhuis
    • Uden, Noord-Brabant, Netherlands
      • Bernhoven
    • Veldhoven, Noord-Brabant, Netherlands
      • Maxima Medisch Centrum, loc. Veldhoven
  • Noord-Holland
    • Alkmaar, Noord-Holland, Netherlands
      • Medisch Centrum Alkmaar
    • Amsterdam, Noord-Holland, Netherlands, 1105AZ
      • Amsterdam UMC, location AMC
    • Amsterdam, Noord-Holland, Netherlands
      • Amsterdam UMC, location VUmc
    • Amsterdam, Noord-Holland, Netherlands
      • Antoni van Leeuwenhoek
    • Amsterdam, Noord-Holland, Netherlands
      • BovenIJ ziekenhuis
    • Amsterdam, Noord-Holland, Netherlands
      • OLVG, locatie Oost
    • Amsterdam, Noord-Holland, Netherlands
      • OLVG, locatie West
    • Haarlem, Noord-Holland, Netherlands
      • Spaarne Gasthuis
    • Hilversum, Noord-Holland, Netherlands
      • Tergooi
    • Hoofddorp, Noord-Holland, Netherlands
      • Spaarne Ziekenhuis
    • Purmerend, Noord-Holland, Netherlands
      • Waterlandziekenhuis
    • Zaandam, Noord-Holland, Netherlands
      • Zaans Medical Center
  • Overijssel
    • Deventer, Overijssel, Netherlands
      • Deventer Ziekenhuis
    • Enschede, Overijssel, Netherlands
      • Medisch Spectrum Twente
    • Hengelo, Overijssel, Netherlands
      • Ziekenhuisgroep Twente
    • Zwolle, Overijssel, Netherlands
      • Isala Klinieken
  • Utrecht
    • Amersfoort, Utrecht, Netherlands
      • Meander Medisch Centrum
    • Nieuwegein, Utrecht, Netherlands
      • Sint Antonius Ziekenhuis
  • Zeeland
    • Goes, Zeeland, Netherlands
      • Admiraal De Ruyter Ziekenhuis
  • Zuid-Holland
    • Delft, Zuid-Holland, Netherlands
      • Reinier de Graaf
    • Den Haag, Zuid-Holland, Netherlands
      • HagaZiekenhuis
    • Den Haag, Zuid-Holland, Netherlands
      • Medisch Centrum Haaglanden, Westeinde
    • Dordrecht, Zuid-Holland, Netherlands
      • Albert Schweitzer Ziekenhuis
    • Leiden, Zuid-Holland, Netherlands
      • LUMC
    • Rotterdam, Zuid-Holland, Netherlands
      • Erasmus MC
    • Rotterdam, Zuid-Holland, Netherlands
      • Maasstad Ziekenhuis
    • Rotterdam, Zuid-Holland, Netherlands
      • Ikazia Ziekenhuis
    • Rotterdam, Zuid-Holland, Netherlands
      • Sint Franciscus Gasthuis
    • Schiedam, Zuid-Holland, Netherlands
      • Franciscus Vlietland
    • Utrecht, Zuid-Holland, Netherlands
      • UMC Utrecht

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
• Initially unresectable metastases confined to the liver according to CT scan, obtained ≤3 weeks prior to registration. Unresectability should be confirmed by the liver expertpanel. Patients with small (≤ 1 cm) extrahepatic lesions that are not clearly suspicious of metastases are eligible
• Known mutation status of RAS and BRAF
• WHO performance status 0-1 (Karnofsky performance status ≥ 70)
• Age ≥ 18 years
• No contraindications for liver surgery
• In case of primary tumor in situ: tumor should be resectable
• In case of resected primary tumor: adequate recovery from surgery
• Adequate organ functions, as determined by normal 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 ≤ 5x ULN)
• Life expectancy > 12 weeks
• Expected adequacy of follow-up
• Written informed consent

Exclusion Criteria:

• Extrahepatic metastases, with the exception of small (≤ 1 cm) extrahepatic lesions that are not clearly suspicious of metastases
• Unresectable primary tumor
• Serious comorbidity or any other condition preventing the safe administration of study treatment (including both systemic treatment and surgery)
• Major cardiovascular events (myocardial infarction, severe/unstable angina, congestive heart failure, CVA) within 12 months before randomisation
• Uncontrolled hypertension, or unsatisfactory blood pressure control with ≥3 antihypertensive drugs
• Previous systemic treatment for metastatic disease; previous adjuvant treatment is allowed if completed ≥ 6 months prior to randomisation
• Previous surgery for metastatic disease
• Previous intolerance of study drugs in the adjuvant setting
• Pregnant or lactating women
• 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, or second primary colorectal cancer.
• Any concomitant experimental treatment.

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

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm B: FOLFOXIRI & bevacizumab (inclusion completed); Patients with RAS or BRAF mutated and/or right-sided tumors will receive 5FU, irinotecan, oxaliplatin (FOLFOXIRI) and bevacizumab. Intervention: FOLFOXIRI with bevacizumab	Drug: FOLFOXIRI with bevacizumab; FOLFOXIRI + bevacizumab Bevacizumab 5 mg/kg in 15-30 minutes i.v., followed by irinotecan 165 mg/m2 i.v. in 60 minutes, followed by oxaliplatin 85 mg/m2 i.v. together with leucovorin 400 mg/m2 i.v. in 120 minutes, followed by continuous infusion of 5-fluorouracil 3200 mg/m2 in 46 hours, every 2 weeks; Other Names: - bevacizumab; - irinotecan; - leucovorin; - 5-fluorouracil; - oxaliplatin
Active Comparator: Arm A: FOLFOX/FOLFIRI & bevacizumab (inclusion completed); Patients with RAS or BRAF mutated and/or right-sided tumors will receive doublet fluoropyrimidine-containing chemotherapy (FOLFOX or FOLFIRI), plus bevacizumab. Intervention: FOLFOX/FOLFIRI with bevacizumab	Drug: FOLFOX/ FOLFIRI with bevacizumab; FOLFIRI + bevacizumab Bevacizumab 5 mg/kg in 15-30 minutes i.v., followed by irinotecan 180 mg/m2 i.v. in 60 minutes together with leucovorin 400 mg/m2 i.v. in 120 minutes, followed by bolus 5-fluorouracil 400 mg/m2 within 4 minutes, all on day 1, followed by continuous infusion of 5-fluorouracil 2400 mg/m2 in 46 hours, every 2 weeks FOLFOX6 + bevacizumab Bevacizumab 5 mg/kg in 15-30 minutes i.v., followed by oxaliplatin 85 mg/m2 i.v. together with leucovorin 400 mg/m2 i.v. in 120 minutes, followed by bolus 5FU 400 mg/m2 within 4 minutes, all on day 1, followed by continuous infusion of 5-fluorouracil 2400 mg/m2 in 46 hours, every 2 weeks; Other Names: - bevacizumab; - irinotecan; - leucovorin; - 5-fluorouracil; - oxaliplatin
Experimental: Arm D: FOLFOX/FOLFIRI & panitumumab; Patients with RAS and BRAF wildtype and left-sided tumors will receive doublet fluoropyrimidine-containing chemotherapy (FOLFOX or FOLFIRI), plus panitumumab. Intervention: FOLFOX/FOLFIRI with panitumumab	Drug: FOLFOX/ FOLFIRI with panitumumab; FOLFIRI + panitumumab Panitumumab 6 mg/kg i.v. (1st dose in 60 minutes, if well tolerated subsequent doses in 30 minutes), followed by irinotecan 180 mg/m2 i.v. in 60 minutes together with leucovorin 400 mg/m2 i.v. in 120 minutes, followed by bolus 5-fluorouracil 400 mg/m2 within 4 minutes, all on day 1, followed by continuous infusion of 5-fluorouracil 2400 mg/m2 in 46 hours, every 2 weeks FOLFOX6 + panitumumab Panitumumab 6 mg/kg i.v. (1st dose in 60 minutes, if well tolerated subsequent doses in 30 minutes), followed by oxaliplatin 85 mg/m2 i.v. together with leucovorin 400 mg/m2 i.v. in 120 minutes, and bolus 5FU 400 mg/m2 within 4 minutes, all on day 1, followed by continuous infusion of 5-fluorouracil 2400 mg/m2 in 46 hours, every 2 weeks; Other Names: - irinotecan; - leucovorin; - 5-fluorouracil; - oxaliplatin; - panitumumab
Active Comparator: Arm C: FOLFOX/ FOLFIRI & bevacizumab; Patients with RAS and BRAF wildtype and left-sided tumors will receive doublet fluoropyrimidine-containing chemotherapy (FOLFOX or FOLFIRI), plus bevacizumab. Intervention: FOLFOX/FOLFIRI with bevacizumab	Drug: FOLFOX/ FOLFIRI with bevacizumab; FOLFIRI + bevacizumab Bevacizumab 5 mg/kg in 15-30 minutes i.v., followed by irinotecan 180 mg/m2 i.v. in 60 minutes together with leucovorin 400 mg/m2 i.v. in 120 minutes, followed by bolus 5-fluorouracil 400 mg/m2 within 4 minutes, all on day 1, followed by continuous infusion of 5-fluorouracil 2400 mg/m2 in 46 hours, every 2 weeks FOLFOX6 + bevacizumab Bevacizumab 5 mg/kg in 15-30 minutes i.v., followed by oxaliplatin 85 mg/m2 i.v. together with leucovorin 400 mg/m2 i.v. in 120 minutes, followed by bolus 5FU 400 mg/m2 within 4 minutes, all on day 1, followed by continuous infusion of 5-fluorouracil 2400 mg/m2 in 46 hours, every 2 weeks; Other Names: - bevacizumab; - irinotecan; - leucovorin; - 5-fluorouracil; - oxaliplatin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)	Time from registration until progression or death whichever comes first	2 years after last patient in study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
R0/1 secondary resection rate	R0/1 secondary resection rate in each of the 4 study arms upon neoadjuvant treatment with chemotherapy plus targeted therapy.	2 years after last patient in study
Median overall survival	From date of randomisation to death or last known to be alive	8 years after last patient in study
Response rate	Response according to RECIST 1.1	2 years after last patient in study
Toxicity (AE)	Patients will be evaluated for Adverse Events at the start of each treatment cycle according to CTCAE version 4.0.	2 years after last patient in study
Pathological complete response rate (pCR)	Pathological complete response rate (pCR) of the resected lesions	2 years after last patient in study
Postoperative morbidity	Patients will be evaluated for surgical morbidity during 2 months. Postoperative morbidity will be scored according 'Clavien Dindo Grade'.	After surgery during two months
Correlation of evaluation by the panel with outcome	CT-scans will be reviewed for liver resectability by expert panel before randomisation and during neo-adjuvant treatment (every 8 weeks).	2 years after last patient in study

Collaborators and Investigators

• Sponsor: Dutch Colorectal Cancer Group
• Investigators: Principal Investigator: C.J.A. Punt, Prof. dr., University Medical Center, Utrecht NL; Principal Investigator: R.J. Swijnenburg, Dr., Academic Medical Center, Amsterdam NL

Publications and helpful links

General Publications

• Wesdorp NJ, Kemna R, Bolhuis K, van Waesberghe JHTM, Nota IMGC, Struik F, Oulad Abdennabi I, Phoa SSKS, van Dieren S, van Amerongen MJ, Chapelle T, Dejong CHC, Engelbrecht MRW, Gerhards MF, Grunhagen D, van Gulik TM, Hermans JJ, de Jong KP, Klaase JM, Liem MSL, van Lienden KP, Molenaar IQ, Patijn GA, Rijken AM, Ruers TM, Verhoef C, de Wilt JHW, Swijnenburg RJ, Punt CJA, Huiskens J, Stoker J, Kazemier G; Dutch Colorectal Liver Expert Panel. Interobserver Variability in CT-based Morphologic Tumor Response Assessment of Colorectal Liver Metastases. Radiol Imaging Cancer. 2022 May;4(3):e210105. doi: 10.1148/rycan.210105.
• Huiskens J, van Gulik TM, van Lienden KP, Engelbrecht MR, Meijer GA, van Grieken NC, Schriek J, Keijser A, Mol L, Molenaar IQ, Verhoef C, de Jong KP, Dejong KH, Kazemier G, Ruers TM, de Wilt JH, van Tinteren H, Punt CJ. Treatment strategies in colorectal cancer patients with initially unresectable liver-only metastases, a study protocol of the randomised phase 3 CAIRO5 study of the Dutch Colorectal Cancer Group (DCCG). BMC Cancer. 2015 May 6;15:365. doi: 10.1186/s12885-015-1323-9.

Helpful Links

• Website Dutch Colorectal Cancer Group

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2014
• Primary Completion (Actual): July 1, 2022
• Study Completion (Actual): January 1, 2025

Study Registration Dates

• First Submitted: June 5, 2014
• First Submitted That Met QC Criteria: June 10, 2014
• First Posted (Estimated): June 12, 2014

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 4, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: Colorectal cancer; Chemotherapy; Liver metastases; Anti-EGFR; R0 R1 liver resection; Resectability of liver; Liver expert panel
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Neoplastic Processes; Colorectal Neoplasms; Neoplasm Metastasis; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Micronutrients; Topoisomerase I Inhibitors; Topoisomerase Inhibitors; Protective Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Antidotes; Vitamin B Complex; Vitamins; Oxaliplatin; Bevacizumab; Irinotecan; Panitumumab; Fluorouracil; Leucovorin; Levoleucovorin
• Other Study ID Numbers: CAIRO5; 2013-005435-24 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The data will be stored in the international ARCAD database which is available to other researchers.
• IPD Sharing Time Frame: As of 2023
• IPD Sharing Access Criteria: Member of ARCAD
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR