Surgical resection after downsizing of colorectal liver metastasis in the era of bevacizumab.

During the last 5 years, numerous publications have demonstrated the potential value of chemotherapy in downstaging patients with hepatic metastasis from colorectal cancer (CRC). Improvements in fluorouracil (FU) -based chemotherapy by the addition of irinotecan or oxaliplatin has led to resectability rates of 12% to 22% in those patients who were initially deemed unresectable. Patients who subsequently undergo resection can achieve a respectable 5-year survival rate (30% to 35%). The addition of bevacizumab, a monoclonal antibody to vascular endothelial growth factor A (VEGF-A), and other targeted therapies (such as cetuximab) to cytotoxic chemotherapy improves response rates further, and it certainly is possible that this could increase the rate of resection. However, this brings one to question the effect of targeted therapies, with or without cytotoxic chemotherapy, on wound healing and hepatic regeneration in patients who undergo liver resection after neoadjuvant therapy. Well-designed preclinical studies have demonstrated that inhibition of angiogenesis can inhibit wound healing. Interestingly, there are no published studies examining the effect of anti-VEGF therapy on liver regeneration. One of the reasons for this lack of data is the fact that studies on liver regeneration in murine models cannot be done with bevacizumab because this antibody specifically recognizes the human form of VEGF and not murine VEGF. It must be remembered that VEGF-A binds to both VEGF receptor 2 (VEGFR2) and VEGFR1, which mediate distinct functions on endothelial cells and other cell types. Bevacizumab, therefore, theoretically can inhibit the activity of both receptors that likely play a role in liver regeneration. In the pivotal phase III clinical trial comparing bolus FU/leucovorin/irinotecan with or without bevacizumab as first-line therapy of advanced CRC, patients who underwent surgery while receiving bevacizumab had a slightly higher (yet not statistically significant) complication rate than those receiving chemotherapy alone (six of 39 v one of 25). A subsequent analysis of pooled data confirmed the increased incidence of complications in patients undergoing surgery while receiving bevacizumab-containing regimens for metastatic CRC. Although these numbers are small, one must recognize the fact that anti-VEGF therapy does inhibit wound healing. Potential inhibition of normal hepatic regeneration becomes even more important when patients are being considered for hepatic resection after downstaging while receiving, or shortly after being treated with bevacizumab-containing regimens. VEGF plays a critical role in liver regeneration after partial hepatectomy or chemical injury. VEGF not only regulates angiogenesis in the regenerating liver, but also mediates a paracrine pathway by which other cytokines can be upregulated in liver sinusoidal endothelial cells. For example, activation of VEGFR1 on liver sinusoidal endothelial cells leads to induction of hepatocyte growth factor that, in turn, mediates liver repair. Interestingly, in regenerating livers in animals with hepatic steatosis, the angiogenic response is impaired. Cytotoxic chemotherapy drugs can induce hepatic steatosis. In patients with CRC metastases who undergo downstaging of their disease by chemotherapy, hepatic steatosis can be present in up to 45% of patients. Therefore, in patients who undergo hepatic resection after treatment with bevacizumab-containing regimens, one must be cognizant of the fact that hepatic regeneration may be impaired due to several mechanisms. Regardless of the mechanism of impaired hepatic regeneration, it is critical to determine the appropriate timing of surgery in patients presenting with CRC metastases who are being considered for liver resection after being treated with bevacizumab-containing chemotherapeutic regimens. In contrast to standard chemotherapeutic agents, the half-life of bevacizumab is relatively long. In pharmacokinetic studies, the mean half-life of bevacizumab is approximately 20 days, but the range varies between 11 and 50 days. Males and patients with large tumor burden seem to JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 23 NUMBER 22 AUGUST 1 2005