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
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
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.
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
3-year disease free survival, defined as the percentage of disease free patients 3 year after randomisation.
Richard van Hillegersberg, MD PhD
Universitair Medisch Centrum Utrecht
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)