Clinical trial NCT02162563: Treatment Strategies in Colorectal Cancer Patients With Initially Unresectable Liver-only Metastases
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Colorectal Cancer
Liver Metastases
Keywords: Colorectal cancer
Chemotherapy
Anti-EGFR
Liver metastases
R0 R1 liver resection
Resectability of liver
Liver expert panel
Lead sponsor: Dutch Colorectal Cancer Group
Sponsor class: OTHER
First posted: 2014-06-12
Enrollment: 530
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Progression-free survival (PFS)
timeFrame: 2 years after last patient in study
Secondary outcomes:
measure: R0/1 secondary resection rate
timeFrame: 2 years after last patient in study
measure: Median overall survival
timeFrame: 8 years after last patient in study
measure: Response rate
timeFrame: 2 years after last patient in study
measure: Toxicity (AE)
timeFrame: 2 years after last patient in study
measure: Pathological complete response rate (pCR)
timeFrame: 2 years after last patient in study
measure: Postoperative morbidity
timeFrame: After surgery during two months
measure: Correlation of evaluation by the panel with outcome
timeFrame: 2 years after last patient in study
Other outcomes:
Locations:
city: Antwerpen
country: Belgium
facility: Universitair ziekenhuis Antwerpen
city: Almere
country: Netherlands
facility: Flevoziekenhuis
state: Flevoland
city: Drachten
country: Netherlands
facility: Ziekenhuis Nij Smellinghe
state: Friesland
city: Leeuwarden
country: Netherlands
facility: Medisch Centrum Leeuwarden, loc. Zuid
state: Friesland
city: Sneek
country: Netherlands
facility: Antonius Ziekenhuis
state: Friesland
city: Apeldoorn
country: Netherlands
facility: Gelre Ziekenhuis
state: Gelderland
city: Arnhem
country: Netherlands
facility: Rijnstate ziekenhuis
state: Gelderland
city: Harderwijk
country: Netherlands
facility: Sint Jansdal Ziekenhuis
state: Gelderland
city: Nijmegen
country: Netherlands
facility: Radboud UMC
state: Gelderland
city: Winterswijk
country: Netherlands
facility: Streekziekenhuis Koningin Beatrix
state: Gelderland
city: Heerlen
country: Netherlands
facility: Atrium Medical Center
state: Limburg
city: Maastricht
country: Netherlands
facility: Maastricht UMC+
state: Limburg
city: Roermond
country: Netherlands
facility: Laurentius Ziekenhuis
state: Limburg
city: Sittard
country: Netherlands
facility: Orbis Medical Center
state: Limburg
city: Venlo
country: Netherlands
facility: VieCuri Medisch Centrum
state: Limburg
city: Amsterdam
country: Netherlands
facility: OLVG, locatie Oost
state: Noord Holland
city: 's Hertogenbosch
country: Netherlands
facility: Jeroen Bosch Ziekenhuis
state: Noord-Brabant
city: Bergen op Zoom
country: Netherlands
facility: Bravis Ziekenhuis
state: Noord-Brabant
city: Breda
country: Netherlands
facility: Amphia Ziekenhuis
state: Noord-Brabant
city: Helmond
country: Netherlands
facility: Elkerliek Ziekenhuis
state: Noord-Brabant
city: Roosendaal
country: Netherlands
facility: Bravis Ziekenhuis
state: Noord-Brabant
city: Tilburg
country: Netherlands
facility: Sint Elisabeth Ziekenhuis
state: Noord-Brabant
city: Tilburg
country: Netherlands
facility: TweeSteden Ziekenhuis
state: Noord-Brabant
city: Uden
country: Netherlands
facility: Bernhoven
state: Noord-Brabant
city: Veldhoven
country: Netherlands
facility: Maxima Medisch Centrum, loc. Veldhoven
state: Noord-Brabant
city: Alkmaar
country: Netherlands
facility: Medisch Centrum Alkmaar
state: Noord-Holland
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC, location AMC
state: Noord-Holland
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC, location VUMC
state: Noord-Holland
city: Amsterdam
country: Netherlands
facility: Antoni van Leeuwenhoek
state: Noord-Holland
city: Amsterdam
country: Netherlands
facility: BovenIJ Ziekenhuis
state: Noord-Holland
city: Amsterdam
country: Netherlands
facility: OLVG, locatie Oost
state: Noord-Holland
city: Amsterdam
country: Netherlands
facility: OLVG, locatie West
state: Noord-Holland
city: Haarlem
country: Netherlands
facility: Spaarne Gasthuis
state: Noord-Holland
city: Hilversum
country: Netherlands
facility: Tergooi
state: Noord-Holland
city: Hoofddorp
country: Netherlands
facility: Spaarne ziekenhuis
state: Noord-Holland
city: Purmerend
country: Netherlands
facility: Waterlandziekenhuis
state: Noord-Holland
city: Zaandam
country: Netherlands
facility: Zaans Medical Center
state: Noord-Holland
city: Deventer
country: Netherlands
facility: Deventer Ziekenhuis
state: Overijssel
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente
state: Overijssel
city: Hengelo
country: Netherlands
facility: Ziekenhuisgroep Twente
state: Overijssel
city: Zwolle
country: Netherlands
facility: Isala Klinieken
state: Overijssel
city: Amersfoort
country: Netherlands
facility: Meander Medisch Centrum
state: Utrecht
city: Nieuwegein
country: Netherlands
facility: Sint Antonius Ziekenhuis
state: Utrecht
city: Goes
country: Netherlands
facility: Admiraal de Ruyter ziekenhuis
state: Zeeland
city: Delft
country: Netherlands
facility: Reinier de Graaf
state: Zuid-Holland
city: Den Haag
country: Netherlands
facility: Hagaziekenhuis
state: Zuid-Holland
city: Den Haag
country: Netherlands
facility: Medisch Centrum Haaglanden, Westeinde
state: Zuid-Holland
city: Dordrecht
country: Netherlands
facility: Albert Schweitzer Ziekenhuis
state: Zuid-Holland
city: Leiden
country: Netherlands
facility: LUMC
state: Zuid-Holland
city: Rotterdam
country: Netherlands
facility: Erasmus MC
state: Zuid-Holland
city: Rotterdam
country: Netherlands
facility: Ikazia Ziekenhuis
state: Zuid-Holland
city: Rotterdam
country: Netherlands
facility: Maasstad Ziekenhuis
state: Zuid-Holland
city: Rotterdam
country: Netherlands
facility: Sint Franciscus Gasthuis
state: Zuid-Holland
city: Schiedam
country: Netherlands
facility: Franciscus Vlietland
state: Zuid-Holland
city: Utrecht
country: Netherlands
facility: UMC Utrecht
state: Zuid-Holland
city: Groningen
country: Netherlands
facility: Martini Ziekenhuis
city: Groningen
country: Netherlands
facility: UMC Groningen
Study officials:
affiliation: University Medical Center, Utrecht NL
name: C.J.A. Punt, Prof. dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Academic Medical Center, Amsterdam NL
name: R.J. Swijnenburg, Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.