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AzTrials

Colorectal CancerPhase 3CAIRO5NCT02162563

Treatment Strategies in Colorectal Cancer Patients With Initially Unresectable Liver-only Metastases

A Phase 3 study testing FOLFOX/ FOLFIRI with bevacizumab, FOLFOXIRI with bevacizumab and FOLFOX/ FOLFIRI with panitumumab in people with Colorectal Cancer and Liver Metastases, run by Dutch Colorectal Cancer Group at 56 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Colorectal Cancer, Liver Metastases
What is being tested?
FOLFOX/ FOLFIRI with bevacizumab, FOLFOXIRI with bevacizumab and FOLFOX/ FOLFIRI with panitumumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
530 participants
Where
56 sitesin 2 countries
Study dates
Jul 2014to Jan 2025
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 12Show fewer
  • 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

Who cannot join

  • 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
Show all 11Show fewer
  • 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.

Trial locations and contacts

56 sites in 2 countries.

56 sites in 2 countries

Netherlands55 sites

  • Jeroen Bosch Ziekenhuis

    's-Hertogenbosch, North Brabant

  • Medisch Centrum Alkmaar

    Alkmaar, North Holland

  • Flevoziekenhuis

    Almere Stad, Flevoland

  • Meander Medisch Centrum

    Amersfoort, Utrecht

  • Amsterdam UMC, location AMC

    Amsterdam, North Holland, 1105AZ

  • Amsterdam UMC, location VUMC

    Amsterdam, North Holland

  • Antoni van Leeuwenhoek

    Amsterdam, North Holland

  • BovenIJ Ziekenhuis

    Amsterdam, North Holland

  • OLVG, locatie Oost

    Amsterdam, North Holland

  • OLVG, locatie West

    Amsterdam, North Holland

  • Gelre Ziekenhuis

    Apeldoorn, Gelderland

  • Rijnstate ziekenhuis

    Arnhem, Gelderland

  • Bravis Ziekenhuis

    Bergen op Zoom, North Brabant

  • Amphia Ziekenhuis

    Breda, North Brabant

  • Reinier de Graaf

    Delft, South Holland

  • Deventer Ziekenhuis

    Deventer, Overijssel

  • Albert Schweitzer Ziekenhuis

    Dordrecht, South Holland

  • Ziekenhuis Nij Smellinghe

    Drachten, Provincie Friesland

  • Medisch Spectrum Twente

    Enschede, Overijssel

  • Admiraal de Ruyter ziekenhuis

    Goes, Zeeland

  • Martini Ziekenhuis

    Groningen, Provincie Groningen

  • UMC Groningen

    Groningen, Provincie Groningen

  • Spaarne Gasthuis

    Haarlem, North Holland

  • Sint Jansdal Ziekenhuis

    Harderwijk, Gelderland

  • Atrium Medical Center

    Heerlen, Limburg

  • Elkerliek Ziekenhuis

    Helmond, North Brabant

  • Ziekenhuisgroep Twente

    Hengelo, Overijssel

  • Tergooi

    Hilversum, North Holland

  • Spaarne ziekenhuis

    Hoofddorp, North Holland

  • Medisch Centrum Leeuwarden, loc. Zuid

    Leeuwarden, Provincie Friesland

  • LUMC

    Leiden, South Holland

  • Maastricht UMC+

    Maastricht, Limburg

  • Sint Antonius Ziekenhuis

    Nieuwegein, Utrecht

  • Radboud UMC

    Nijmegen, Gelderland

  • Waterlandziekenhuis

    Purmerend, North Holland

  • Laurentius Ziekenhuis

    Roermond, Limburg

  • Bravis Ziekenhuis

    Roosendaal, North Brabant

  • Erasmus MC

    Rotterdam, South Holland

  • Ikazia Ziekenhuis

    Rotterdam, South Holland

  • Maasstad Ziekenhuis

    Rotterdam, South Holland

  • Sint Franciscus Gasthuis

    Rotterdam, South Holland

  • Franciscus Vlietland

    Schiedam, South Holland

  • Orbis Medical Center

    Sittard, Limburg

  • Antonius Ziekenhuis

    Sneek, Provincie Friesland

  • Hagaziekenhuis

    The Hague, South Holland

  • Medisch Centrum Haaglanden, Westeinde

    The Hague, South Holland

  • Sint Elisabeth Ziekenhuis

    Tilburg, North Brabant

  • TweeSteden Ziekenhuis

    Tilburg, North Brabant

  • Bernhoven

    Uden, North Brabant

  • UMC Utrecht

    Utrecht, South Holland

  • Maxima Medisch Centrum, loc. Veldhoven

    Veldhoven, North Brabant

  • VieCuri Medisch Centrum

    Venlo, Limburg

  • Streekziekenhuis Koningin Beatrix

    Winterswijk, Gelderland

  • Zaans Medical Center

    Zaandam, North Holland

  • Isala Klinieken

    Zwolle, Overijssel

Other trials in Netherlands

Belgium1 site

  • Universitair ziekenhuis Antwerpen

    Antwerp

Other trials in Belgium

About this study

Official title: 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.

Read the 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.

Being tested
FOLFOX/ FOLFIRI with bevacizumab, FOLFOXIRI with bevacizumab, FOLFOX/ FOLFIRI with panitumumab
Keywords
Colorectal cancer, Chemotherapy, Anti-EGFR, Liver metastases, R0 R1 liver resection, Resectability of liver, Liver expert panel
Medical subject headings
Colorectal Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • FOLFOX/ FOLFIRI with bevacizumabDrug

    Also called - bevacizumab, - irinotecan, - leucovorin, - 5-fluorouracil

    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

  • FOLFOXIRI with bevacizumabDrug

    Also called - bevacizumab, - irinotecan, - oxaliplatin, - leucovorin

    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

  • FOLFOX/ FOLFIRI with panitumumabDrug

    Also called - panitumumab, - irinotecan, - leucovorin, - 5-fluorouracil

    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

Study groups in NCT02162563
Study groupRoleWhat they receive
Arm B: FOLFOXIRI & bevacizumab (inclusion completed)ExperimentalPatients with RAS or BRAF mutated and/or right-sided tumors will receive 5FU, irinotecan, oxaliplatin (FOLFOXIRI) and bevacizumab. Intervention: FOLFOXIRI with bevacizumab
Receives: Drug: FOLFOXIRI with bevacizumab
Arm A: FOLFOX/FOLFIRI & bevacizumab (inclusion completed)Active comparatorPatients 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
Receives: Drug: FOLFOX/ FOLFIRI with bevacizumab
Arm D: FOLFOX/FOLFIRI & panitumumabExperimentalPatients 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
Receives: Drug: FOLFOX/ FOLFIRI with panitumumab
Arm C: FOLFOX/ FOLFIRI & bevacizumabActive comparatorPatients 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
Receives: Drug: FOLFOX/ FOLFIRI with bevacizumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Progression-free survival (PFS)

    Time from registration until progression or death whichever comes first

    Measured: 2 years after last patient in study

Secondary outcomes (7)

  1. 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.

    Measured: 2 years after last patient in study

  2. Median overall survival

    From date of randomisation to death or last known to be alive

    Measured: 8 years after last patient in study

  3. Response rate

    Response according to RECIST 1.1

    Measured: 2 years after last patient in study

  4. Toxicity (AE)

    Patients will be evaluated for Adverse Events at the start of each treatment cycle according to CTCAE version 4.0.

    Measured: 2 years after last patient in study

  5. Pathological complete response rate (pCR)

    Pathological complete response rate (pCR) of the resected lesions

    Measured: 2 years after last patient in study

  6. Postoperative morbidity

    Patients will be evaluated for surgical morbidity during 2 months. Postoperative morbidity will be scored according 'Clavien Dindo Grade'.

    Measured: After surgery during two months

  7. 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).

    Measured: 2 years after last patient in study

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted12 Jun 2014 (estimated)
  2. Study startJul 2014
  3. Primary completionJul 2022
  4. Study completionJan 2025

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
530 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02162563
Sponsor's protocol ID
CAIRO5
Other IDs
2013-005435-24
Acronym
CAIRO5
Status last verified
Feb 2025
First submitted
5 Jun 2014
Last updated
6 Feb 2025
Results posted
No
Data monitoring committee
Yes
Individual data sharing
Yes: The data will be stored in the international ARCAD database which is available to other researchers.

Publications

  • Bond MJG, Bolhuis K, Loosveld OJL, de Groot JWB, Droogendijk H, Helgason HH, Hendriks MP, Klaase JM, Kazemier G, Liem MSL, Rijken AM, Verhoef C, de Wilt JHW, de Jong KP, Gerhards MF, van Amerongen MJ, Engelbrecht MRW, van Lienden KP, Hermans JJ, Molenaar IQ, Grunhagen DJ, de Valk B, Haberkorn BCM, Kerver ED, Erdkamp F, van Alphen RJ, Mathijssen-van Stein D, Komurcu A, May AM, Swijnenburg RJ, Punt CJA; Dutch Colorectal Cancer Group. First-Line Systemic Treatment for Initially Unresectable Colorectal Liver Metastases: Post Hoc Analysis of the CAIRO5 Randomized Clinical Trial. JAMA Oncol. 2025 Jan 1;11(1):36-45. doi: 10.1001/jamaoncol.2024.5174.

    PubMed 39570583

  • Wesdorp NJ, Zeeuw JM, Postma SCJ, Roor J, van Waesberghe JHTM, van den Bergh JE, Nota IM, Moos S, Kemna R, Vadakkumpadan F, Ambrozic C, van Dieren S, van Amerongen MJ, Chapelle T, 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, Marquering HA, Stoker J, Swijnenburg RJ, Punt CJA, Huiskens J, Kazemier G. Deep learning models for automatic tumor segmentation and total tumor volume assessment in patients with colorectal liver metastases. Eur Radiol Exp. 2023 Dec 1;7(1):75. doi: 10.1186/s41747-023-00383-4.

    PubMed 38038829

  • Bond MJG, Bolhuis K, Loosveld OJL, de Groot JWB, Droogendijk H, Helgason HH, Hendriks MP, Klaase JM, Kazemier G, Liem MSL, Rijken AM, Verhoef C, de Wilt JHW, de Jong KP, Gerhards MF, van Amerongen MJ, Engelbrecht MRW, van Lienden KP, Molenaar IQ, de Valk B, Haberkorn BCM, Kerver ED, Erdkamp F, van Alphen RJ, Mathijssen-van Stein D, Komurcu A, Lopez-Yurda M, Swijnenburg RJ, Punt CJA; Dutch Colorectal Cancer Study Group. First-line systemic treatment strategies in patients with initially unresectable colorectal cancer liver metastases (CAIRO5): an open-label, multicentre, randomised, controlled, phase 3 study from the Dutch Colorectal Cancer Group. Lancet Oncol. 2023 Jul;24(7):757-771. doi: 10.1016/S1470-2045(23)00219-X. Epub 2023 Jun 14.

    PubMed 37329889

  • 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.

    PubMed 35522139

  • 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.

    PubMed 25943574

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing FOLFOX/ FOLFIRI with bevacizumab, FOLFOXIRI with bevacizumab and FOLFOX/ FOLFIRI with panitumumab in people with Colorectal Cancer and Liver Metastases, run by Dutch Colorectal Cancer Group at 56 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 12 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 6 Feb 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 56 sites in Netherlands, Belgium. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Progression-free survival (PFS) (time frame: 2 years after last patient in study). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02162563, which also lists 5 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Feb 2025.

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