Phase IV, Multicenter, Randomized Study to Evaluate the Correlation of Overall Objective Response According to RECIST Criteria Evaluated by Conventional Imaging Techniques, Morphologic Response by CT, and Histopathologic Response in Patients With Resectable Hepatic Metastasis Secondary to Colorectal Cancer Treated With Bevacizumab in Combination With XELOX
1. Written informed consent.
2. Age ≥ 18 years.
3. ECOG 0-1.
4. Life expectancy of at least 12 weeks.
5. Histologic confirmation of adenocarcinoma of the colon or rectum, according to the
7th edition of the TNM classification, with evidence of liver metastases according to
RECIST v 1.1 criteria (Annex V). Patients with the diagnosis of liver metastasis
presenting synchronically or after a disease-free interval. The primary tumor shall
have been resected previously although the inverse approach may be acceptable if the
tumor is not very symptomatic. Patients in whom combined surgery of the primary tumor
and metastases is planned are not eligible.
6. Availability of a tumor sample for KRAS gene determination.
7. No prior chemotherapy treatment for metastatic CRC.
8. Patients with resectable hepatic metastases of colorectal carcinoma who satisfy the
- ≤ 4 metastases
- Size < 10 cm
- Technically feasible R0 resection, with a residual liver volume of no less than
NOTE: Patients with bilateral metastases may be enrolled if they satisfy the above
criteria (<4 metastases and size <10 cm).
9. Adequate bone marrow, liver and kidney function, defined as:
- Hemoglobin ≥ 9.0 g/dl (a transfusion can be given before treatment).
- Platelet count ≥ 100 × 109/L.
- Absolute neutrophil count (ANC) ≥ 1.5 × 109/L.
- Serum bilirubin ≤ 1.5 times higher than the upper limit of normality (ULN).
- Alkaline phosphatase, ALT (SGPT) and AST (SGOT) ≤ 5 × ULN.
- Serum creatinine < 1.5 x ULN or creatinine clearance ≥ 50 ml/min according to
Cockcroft and Gault formula (Annex VII).
- INR < 1.5 within the 7 days prior to the start of study treatment. aPTT < 1.5 ×
ULN within 7 days prior to the start of study treatment. Exception: Patients
treated with complete doses of anticoagulants due to venous thromboembolism
usually must have an INR value within the established range (usually 2-3). The
patient must be receiving a stable dose of anticoagulant treatment before
enrollment in the study.
- Urine strip for proteinuria < 2+. If the result of the reactive strip in urine
is ≥ 2+, the 24-hour urine sample must demonstrate ≤ 1 g protein in 24 hours in
order to include the patient.
10. Women of childbearing potential must have a negative pregnancy test in serum or urine
in the 7-day period before entering the study. Postmenopausal women must have been
amenorrheic during at least 12 months. Likewise, both the men and the women who
participate in this study must use effective contraceptive methods (e.g., abstinence,
intrauterine device, oral contraceptives, a double barrier method or surgical
sterility), beginning upon signing the informed consent form and for at least 6
months after the end of treatment or the last dose, whichever occurs first.
11. The subject must have the capacity, in the opinion of the investigator, to comply
with all the procedures and examinations of study follow-up.
1. Patients with non-resectable hepatic metastases at the time of enrollment.
2. Previous systemic or local treatment of metastatic disease.
3. Presence of metastatic extrahepatic disease.
4. Neo-adjuvant or adjuvant chemotherapy/radiotherapy in the 6 months prior to entering
5. Use of any investigational drug in the 4 weeks before starting the study treatment.
6. Current or recent (in the 10 days prior to the first administration of the study
treatment) use of acetylsalicylic acid (> 325 mg/day) or clopidogrel (75 mg/day).
7. Current presence of peripheral neuropathy = 1 (CTCAE).
8. Hypertension not properly controlled (defined as systolic pressure > 150 mm Hg and/or
diastolic pressure > 100 mm Hg in repeated measurements), despite optimal medical
9. Previous history of hypertensive episodes or hypertensive encephalopathy.
10. CHF class II or higher of the NYHA classification.
11. History of myocardial infarction or unstable angina within the 6 months prior to
starting the study treatment.
12. Significant vascular disease (e.g., aortic aneurysm requiring surgery, pulmonary
embolism or recent peripheral arterial thrombosis) in the 6 months prior to the start
of the study treatment.
13. History of hemoptysis (equivalent to = ½ teaspoon of red-colored blood per episode)
in the month prior to the study treatment.
14. Major surgery, open surgical biopsy or significant trauma in the 4 weeks prior to the
start of study treatment. Thick-needle biopsy of a major organ in the 7 days prior to
entering the study. Insertion of a vascular access > 3 days before entering the study
15. Tests or history of significant hemorrhagic diathesis or coagulation disorder (in the
absence of anticoagulation).
16. History of abdominal fistula or gastrointestinal perforation in the 6 months prior to
the start of study treatment.
17. Intra-abdominal acute inflammatory process.
18. Serious unhealed wounds, active ulcer or untreated bone fracture.
19. History of another neoplastic disease aside from colorectal cancer in the last 2
years prior to the start of study treatment, with the exception of basal cell or
squamous cell carcinoma of the skin or carcinoma in situ of the cervix treated
20. Human immunodeficiency virus infection or chronic infection by the hepatitis B or C
virus or presence of uncontrolled intercurrent infections, or other severe
uncontrolled concomitant diseases.
21. Current grade ≥ 2 infection (CTCAE).
22. Pregnant or breast-feeding women.
23. Known allergy, suspicion of allergy, or hypersensitivity to any of the study drugs
(bevacizumab, oxaliplatin, capecitabine) and/or iodide contrast agents.
24. Incapacity for oral intake.
25. Any important and uncontrolled medical, psychological, psychiatric or social problem
that can interfere in the subject's participation in the study or the evaluation of
the study results or represents and increased risk of complications related to the
26. Patients in whom combined surgery of the primary tumor and metastases is planned are
27. Venous Cava invasion and 2 or more hepatic venous invasion Both portal venous
invasion Remanent future minor to 40% Use of portal embolization previous to