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

NCT ID: NCT02162563

Last Updated: 2025-02-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 530 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-07-31
• Study Completion Date: 2025-01-31

Brief 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.

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.

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.

Conditions

Colorectal Cancer; Liver Metastases

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: EXPERIMENTAL

FOLFOXIRI with bevacizumab

Intervention Type: DRUG

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

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

Group Type: ACTIVE_COMPARATOR

FOLFOX/ FOLFIRI with bevacizumab

Intervention Type: DRUG

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

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

Group Type: EXPERIMENTAL

FOLFOX/ FOLFIRI with panitumumab

Intervention Type: DRUG

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

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

Group Type: ACTIVE_COMPARATOR

FOLFOX/ FOLFIRI with bevacizumab

Intervention Type: DRUG

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

Interventions

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

Intervention Type: 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

Intervention Type: 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

Intervention Type: DRUG

Other Intervention Names

- bevacizumab; - irinotecan; - leucovorin; - 5-fluorouracil; - oxaliplatin; - bevacizumab; - irinotecan; - oxaliplatin; - leucovorin; - 5-fluorouracil; - panitumumab; - irinotecan; - leucovorin; - 5-fluorouracil; - oxaliplatin

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Dutch Colorectal Cancer Group

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

C.J.A. Punt, Prof. dr.

Role: PRINCIPAL_INVESTIGATOR

University Medical Center, Utrecht NL

R.J. Swijnenburg, Dr.

Role: PRINCIPAL_INVESTIGATOR

Academic Medical Center, Amsterdam NL

Locations

Universitair ziekenhuis Antwerpen

Antwerp, , Belgium

Flevoziekenhuis

Almere Stad, Flevoland, Netherlands

Gelre Ziekenhuis

Apeldoorn, Gelderland, Netherlands

Rijnstate ziekenhuis

Arnhem, Gelderland, Netherlands

Sint Jansdal Ziekenhuis

Harderwijk, Gelderland, Netherlands

Radboud UMC

Nijmegen, Gelderland, Netherlands

Streekziekenhuis Koningin Beatrix

Winterswijk, Gelderland, Netherlands

Atrium Medical Center

Heerlen, Limburg, Netherlands

Maastricht UMC+

Maastricht, Limburg, Netherlands

Laurentius Ziekenhuis

Roermond, Limburg, Netherlands

Orbis Medical Center

Sittard, Limburg, Netherlands

VieCuri Medisch Centrum

Venlo, Limburg, Netherlands

Jeroen Bosch Ziekenhuis

's-Hertogenbosch, North Brabant, Netherlands

Bravis Ziekenhuis

Bergen op Zoom, North Brabant, Netherlands

Amphia Ziekenhuis

Breda, North Brabant, Netherlands

Elkerliek Ziekenhuis

Helmond, North Brabant, Netherlands

Bravis Ziekenhuis

Roosendaal, North Brabant, Netherlands

Sint Elisabeth Ziekenhuis

Tilburg, North Brabant, Netherlands

TweeSteden Ziekenhuis

Tilburg, North Brabant, Netherlands

Bernhoven

Uden, North Brabant, Netherlands

Maxima Medisch Centrum, loc. Veldhoven

Veldhoven, North Brabant, Netherlands

Medisch Centrum Alkmaar

Alkmaar, North Holland, Netherlands

Amsterdam UMC, location AMC

Amsterdam, North Holland, Netherlands

Amsterdam UMC, location VUMC

Amsterdam, North Holland, Netherlands

Antoni van Leeuwenhoek

Amsterdam, North Holland, Netherlands

BovenIJ Ziekenhuis

Amsterdam, North Holland, Netherlands

OLVG, locatie Oost

Amsterdam, North Holland, Netherlands

OLVG, locatie West

Amsterdam, North Holland, Netherlands

Spaarne Gasthuis

Haarlem, North Holland, Netherlands

Tergooi

Hilversum, North Holland, Netherlands

Spaarne ziekenhuis

Hoofddorp, North Holland, Netherlands

Waterlandziekenhuis

Purmerend, North Holland, Netherlands

Zaans Medical Center

Zaandam, North Holland, Netherlands

Deventer Ziekenhuis

Deventer, Overijssel, Netherlands

Medisch Spectrum Twente

Enschede, Overijssel, Netherlands

Ziekenhuisgroep Twente

Hengelo, Overijssel, Netherlands

Isala Klinieken

Zwolle, Overijssel, Netherlands

Ziekenhuis Nij Smellinghe

Drachten, Provincie Friesland, Netherlands

Medisch Centrum Leeuwarden, loc. Zuid

Leeuwarden, Provincie Friesland, Netherlands

Antonius Ziekenhuis

Sneek, Provincie Friesland, Netherlands

Martini Ziekenhuis

Groningen, Provincie Groningen, Netherlands

UMC Groningen

Groningen, Provincie Groningen, Netherlands

Reinier de Graaf

Delft, South Holland, Netherlands

Albert Schweitzer Ziekenhuis

Dordrecht, South Holland, Netherlands

LUMC

Leiden, South Holland, Netherlands

Erasmus MC

Rotterdam, South Holland, Netherlands

Ikazia Ziekenhuis

Rotterdam, South Holland, Netherlands

Maasstad Ziekenhuis

Rotterdam, South Holland, Netherlands

Sint Franciscus Gasthuis

Rotterdam, South Holland, Netherlands

Franciscus Vlietland

Schiedam, South Holland, Netherlands

Hagaziekenhuis

The Hague, South Holland, Netherlands

Medisch Centrum Haaglanden, Westeinde

The Hague, South Holland, Netherlands

UMC Utrecht

Utrecht, South Holland, Netherlands

Meander Medisch Centrum

Amersfoort, Utrecht, Netherlands

Sint Antonius Ziekenhuis

Nieuwegein, Utrecht, Netherlands

Admiraal de Ruyter ziekenhuis

Goes, Zeeland, Netherlands

Countries

Belgium; Netherlands

References

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.

Reference Type: DERIVED

PMID: 39570583 (View on PubMed)

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.

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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.

Reference Type: DERIVED

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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.

Reference Type: DERIVED

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Related Links

http://www.dccg.nl

Website Dutch Colorectal Cancer Group

Other Identifiers

2013-005435-24

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CAIRO5

Identifier Type: -

Identifier Source: org_study_id