Perioperative risks of bevacizumab and other biologic agents for hepatectomy: theoretical or evidence based?

The management of hepatic colorectal cancer (CRC) metastases has undergone a dramatic change over the last decade. This is largely attributed to more accurate staging using innovative imaging technologies, improved surgical techniques, and more effective systemic therapies. Historically, palliative treatment of metastatic CRC with fluorouracil (FU) and leucovorin (LV) yielded response rates of only 10% to 20% with a median overall survival of less than 12 months. Tumor reduction permitting surgical resection was rare. However, the introduction of new chemotherapy and biologic agents including irinotecan, oxaliplatin, bevacizumab, cetuximab, and panitumumab has improved response rates and survival considerably. The improved activity seen with these multidrug regimens combined with liver resection may explain the results of recent series that report 5-year survival rates of almost 60%. The number of candidates for hepatectomy of previously unresectable metastases has also increased significantly. Oxaliplatin-based regimens have allowed resection in up to 20% of patients initially considered unresectable, with 5-year survival rates similar to that seen of initially resectable patients who undergo surgery without prior chemotherapy. The use of biologic agents such as vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) inhibitors has significantly improved the outcomes of patients with metastatic disease. Bevacizumab, a recombinant monoclonal antibody that inhibits VEGF-A, has rapidly been incorporated into the routine management of patients with metastatic CRC. The addition of bevacizumab to a regimen of irinotecan, FU, and LV demonstrated significantly prolonged survival, and the addition of bevacizumab to infusional FU and oxaliplatin significantly improved the survival in patients previously treated with irinotecan, FU, and LV. These encouraging results have generated enthusiasm for bevacizumabcontaining chemotherapy regimens as preoperative treatment for both resectable and unresectable liver metastases, though randomized trials evaluating bevacizumab are lacking in patients with potentially resectable disease. The anti-EGFR antibodies cetuximab and panitumumab have shown synergy with chemotherapy agents, leading to improved response rates and clinical benefit in the salvage. Furthermore, randomized trials have indicated improved resection rate of hepatic metastases compared with regimens not containing the anti-EGFR antibodies, sparking interest in the preoperative use of these agents. There are several theoretical advantages to a neoadjuvant approach. First, full-dose chemotherapy can be administered before any potential debilitation from surgery that might decrease the tolerance of chemotherapy, at a time when micrometastases are likely to be at their smallest. Second, it permits radiologic and pathologic assessment of the regimen’s efficacy that may guide the selection of postoperative chemotherapy. Third, it can reduce tumor burden and increase the likelihood of complete resection with negative margins. This is supported by the recently completed European Organisation for Research and Treatment of Cancer Intergroup prospective randomized phase III trial (EORTC 40983), which reported improved disease-free survival when FU and oxaliplatin was administered 3 months before and after surgical resection when compared with surgery alone. The downside of perioperative therapies are the potential for increased complications with liver resection. Cytotoxic agents such as fluoropyrimadines, oxaliplatin, and irinotecan can cause steatohepatitis and other liver abnormalities, which can make resection more difficult and increase complications. Biologic agents are also not without side effects and may have specific toxicities that could interfere with metastectomy. In initial clinical studies with bevacizumab, an increased incidence of bleeding, hypertension, GI perforations, and wound-healing complications was reported. Furthermore, in animal models, the inhibition of angiogenesis resulted in impaired wound healing, and it has been suggested that the inhibition of VEGF receptors on endothelial cells may regulate liver regeneration. The long circulating half-life of the antibody makes timing more difficult. For these reasons, a delay in elective surgery of at least 6 weeks after completion of bevacizumab, and a similar delay in restarting bevacizumab after liver surgery, has been recommended, though there is little supportive clinical evidence. EGFR may also play a role in liver regeneration, though there are no reports of increased surgical complications in patients on anti-EGFR antibodies. In this edition of the Journal of Clinical Oncology, Van Buren and colleagues report the effects of inhibition of VEGFR-2 and EGFR in a murine model of liver regeneration after resection. While most similar studies have targeted VEGFR ligands, this used inhibition of the receptor and found little inhibition of regeneration. In addition, JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 11 APRIL 1