Randomized Phase III Study Post Radical Resection of Liver Metastasis of Colorectal Cancer: Bevacizumab in Combination With XELOX as Adjuvant Chemotherapy vs XELOX Alone
18 Years
N/A
Both
Colorectal Cancer, Liver Metastases
Trial Information
Randomized Phase III Study Post Radical Resection of Liver Metastasis of Colorectal Cancer: Bevacizumab in Combination With XELOX as Adjuvant Chemotherapy vs XELOX Alone
The primary therapy of colorectal cancer is surgical resection, but more than half of all
colorectal cancer patients eventually die of metastatic disease. Although the introduction
of new anticancer agents with efficacy in metastatic colorectal cancer, e.g.: oxaliplatin
and irinotecan, and the targeted agents cetuximab and bevacizumab has changed therapeutic
nihilism, chemotherapy alone has failed to cure these patients.
It is estimated that 15-20 % of colorectal cancer patients present with synchronous liver
metastases and approximately 50% of the patients with colorectal tumors will develop liver
metastases at some point during the course of their disease. In almost one third of the
cases, the liver was shown at autopsy to be the only site of cancer spread. This is in
accordance with the 20% - 45 % five-year survival obtained with surgical resection of
hepatic metastases.
Previous studies have not shown a clear benefit of adjuvant chemotherapy after
metastatectomy of liver metastases. However, most of these studies have been performed with
5-fluorouracil with or without other older cytostatic drugs. Since new effective agents have
been developed (e.g.: capecitabine, oxaliplatin and bevacizumab), adjuvant combination
treatment with these agents might be more effective. These drugs have proven activity as
first line palliative treatment of recurrent metastases. This raises the question if this
new effective treatment is of value as an adjuvant treatment after metastatectomy.
As mentioned before, a two-arm EORTC study: neoadjuvant and adjuvant FOLFOX vs no
chemotherapy in resectable liver metastases of colorectal cancer is almost completed
(Nordlinger et al). It is expected that this study will show a 10% 3 year DFS benefit in
favour of th treatment arm. Definitive data of this trial will be released at the end of
2006, and will most probably lead to adjuvant treatment post metastasectomy as a standard of
care. In the HEPATCIA trial we anticipate on this by using adjuvant XELOX as the control
arm.
As mentioned earlier, the 3-year disease free survival in patients post metastatectomy of
liver metastases is approximately 25%. There is no data available on the effectivity of the
XELOX regimen as adjuvant treatment after metastatectomy of colorectal cancer metastases.
The EORTC study was designed to demonstrate a 10% improvement in 3y DFS. Assuming that this
study is positive, 3 year DFS would be 35% in the control arm (XELOX post liver resection).
Since bevacizumab inhibits angiogenesis, which is required for growth of metastases, this
drug may be valuable in the adjuvant setting. Several studies investigate the value of this
drug in combination with fluoropyrimidines as an adjuvant regimen after resection of primary
colorectal cancers. However, at this moment there is no mature data available of these
studies. Therefore, we assume an increase in 3-year disease free survival of 10%, to 45% in
the XELOX and bevacizumab treatment arm.
This study will therefore evaluate patients with resectable liver metastasis without
extra-hepatic disease, investigating whether the capecitabine, oxaliplatin and bevacizumab
regimen is superior to capecitabine and oxaliplatin alone applied as adjuvant treatment, in
order to extent disease free and overall survival.
Inclusion Criteria:
- Signed written informed consent obtained prior to any study-specific procedures.
- Age ≥ 18 years.
- Liver metastases radically resected (R0 resection).
- Study medication started ≥4 and ≤ 8 weeks post liver surgery.
- Histologically confirmed liver metastasis of colorectal cancer after surgery.
- ECOG performance status 0 or 1.
- Adequate hematology: ANC ≥1.5 x 109/L, platelets ≥100 x 109/L, Hb ≥5.5 mmol/L, INR ≤
1.5, APTT < 1.5 X UNL.
- Adequate biochemistry: total bilirubin ≤1.5 UNL, ASAT and ALAT ≤2.5 x UNL, alkaline
phosphatase ≤2.5 x UNL, serum creatinin ≤1.5 UNL.
- Urine dipstick <2+ for protein.
Exclusion Criteria:
- Extrahepatic metastatic disease.
- Prior adjuvant chemotherapy given <6 months prior to detection of the liver
metastases.
- Prior non colorectal malignancies.
- Bleeding diathesis or coagulation disorders or the need for full-dose
anticoagulation.
- Major surgical procedure <4 weeks prior to start of study treatment.
- Females with a positive pregnancy test (within 14 days before treatment start) .
- Lactating women.
- Fertile women (<2 years after last menstruation) and women of childbearing potential
not willing to use effective means of contraception.
- History of psychiatric disability judged by the investigator to be clinically
significant, precluding informed consent or interfering with compliance for oral drug
intake.
- Clinically significant (i.e. active) cardiovascular disease e.g. cerebrovascular
accidents (≤6 months prior to randomization), myocardial infarction (≤1 year prior to
randomization), uncontrolled hypertension while receiving chronic medication,
unstable angina, New York Heart Association (NYHA) Grade II or greater congestive
heart failure, or serious cardiac arrhytmia requiring medication.
- Lack of physical integrity of the upper gastro-intestinal tract, malabsorption
syndrome, or inability to take oral medication.
- Known peripheral neuropathy, including oxaliplatin induced neuropathy > grade Absence
of deep tendon reflexes as the sole neurological abnormality does not render the
patient ineligible.
- Organ allografts requiring immunosuppressive therapy.
- Serious, non-healing wound, ulcer, or bone fracture.
- Current or recent (within 10 days prior to study treatment start) use of full-dose
oral or parenteral anticoagulants or thrombolytic agent for therapeutic purposes.
- Chronic, daily treatment with high-dose asprin (> 325 mg/day) or nonsteroidal
anti-inflammatory medications (those known to inhibit platelet function at doses used
to treat chronic inflammatory diseases). Patients can be rendered eligible by
changing the treatment to COX II inhibitors.
- Chronic treatment with corticosteroids (dose of ≥ 10 mg/day methylprednisolone
equivalent excluding inhaled steroids).
- Serious intercurrent infections (uncontrolled or requiring treatment).
- Current or recent (within the 28 days prior to randomization) treatment with another
investigational drug or participation in another investigational study.
- Patients with known allergy to Chinese hamster Ovary cell proteins or other
recombinant human or humanized antibodies or to any excipients of bevacizumab
formulation, platinum compounds or to any other component of the study drugs.
Type of Study:
Interventional
Study Design:
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
3-year disease free survival, defined as the percentage of disease free patients 3 year after randomisation.
Outcome Time Frame:
study duration
Safety Issue:
No
Principal Investigator
Richard van Hillegersberg, MD PhD
Investigator Role:
Principal Investigator
Investigator Affiliation:
Universitair Medisch Centrum Utrecht
Authority:
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Study ID:
HEPATICA
NCT ID:
NCT00394992
Start Date:
December 2006
Completion Date:
December 2013
Related Keywords:
- Colorectal Cancer
- Liver Metastases
- Colorectal cancer
- Liver metastasis
- Radical resection
- Adjuvant therapy
- Bevacizumab
- Capecitabine
- Oxaliplatin
- Hepatica
- Colorectal Neoplasms
- Neoplasm Metastasis
- Neoplasms, Second Primary
- Liver Neoplasms
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