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

  • STATUS
    Recruiting
  • participants needed
    564
  • sponsor
    Dutch Colorectal Cancer Group
Updated on 8 November 2020
Investigator
A.E.M. Smals, dr.
Primary Contact
St. Anna Ziekenhuis (3.0 mi away) Contact
+47 other location
ct scan
cancer
systemic therapy
BRAF
metastasis
neutrophil count
panitumumab
bevacizumab
primary tumor
folfox regimen
folfiri regimen
liver surgery

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.

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.

Details
Treatment FOLFOX/ FOLFIRI with bevacizumab, FOLFOXIRI with bevacizumab, FOLFOX/ FOLFIRI with panitumumab
Clinical Study IdentifierNCT02162563
SponsorDutch Colorectal Cancer Group
Last Modified on8 November 2020

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Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age greater than or equal to 18 yrs?
Gender: Male or Female
Do you have any of these conditions: Liver Metastases or Colorectal Cancer?
Histologically proven colorectal cancer
Unresectable metastases confined to the liver according to CT scan, obtained 2 weeks prior to registration. Unresectability will be confirmed by the panel. Patients with small ( 1 cm) extrahepatic lesions that are not clearly suspicious of metastases are eligible
Adequate tumor tissue available for assessment of RAS/BRAF mutation status
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 lesionsthat 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 registration
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 registration
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
Any concomitant experimental treatment
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