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Journal of Clinical Oncology, Vol 26, No 11 (April 10), 2008: pp. 1786-1788 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.6380
Perioperative Risks of Bevacizumab and Other Biologic Agents for Hepatectomy: Theoretical or Evidence Based?California Oncology Research Institute; University of California Los Angeles David Geffen School of Medicine, Los Angeles, CA
University of California Los Angeles David Geffen School of Medicine, Los Angeles, CA 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.1,2 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.1-11 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%.1,3,4 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.4-6 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,7 and the addition of bevacizumab to infusional FU and oxaliplatin significantly improved the survival in patients previously treated with irinotecan, FU, and LV.8 These encouraging results have generated enthusiasm for bevacizumab-containing 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.9,10 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.11 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),12 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.13 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.7,8 Furthermore, in animal models, the inhibition of angiogenesis resulted in impaired wound healing,14,15 and it has been suggested that the inhibition of VEGF receptors on endothelial cells may regulate liver regeneration.14 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 colleagues16 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, anti-EGFR therapy had no effect. Since the regenerating liver depends on both of these growth factors, these data are intriguing and may be of relevance as anti-VEGF–and anti-EGFR–containing regimens are introduced into the neoadjuvant setting. It is important to recognize, however, that the current anti-EGFR and anti-VEGF antibodies approved for the treatment of metastatic CRC only recognize human antigens and cannot be used in animal models. Furthermore, the relatively minor impairment of liver regeneration seen in the Van Buren study may not be clinically relevant. Of more importance will be reports of hepatic resection after the use of anti-VEGF and anti-EGFR agents in humans. Gruenberger and colleagues17 report a prospective single-institution phase II trial that evaluated the impact of bevacizumab on surgical complications and hepatic regeneration following resection for hepatic CRC liver metastases. Fifty-six patients received bevacizumab, capecitabine, and oxaliplatin, and the bevacizumab was held 5 weeks before surgery. There was no increase in surgical complications, bleeding, or decreased hepatic function compared with historic controls. A robust preoperative objective response rate of 73% was obtained. Shortcomings of the study include relatively small numbers and evaluation of hepatic regeneration defined by CT appearance and liver functions only 3 months after surgery, a period too short to evaluate the full regenerative capacity of the liver. Nevertheless, these data suggest that bevacizumab can be safely administered preoperatively. Other studies have also confirmed the practicality of preoperative bevacizumab. In a recent report by D'Angelica et al,18 there were no significant differences in perioperative morbidity or delayed complications in patients treated with bevacizumab compared with a set of matched controls. Reddy et al19 also showed no increase in the morbidity of hepatic resection in patients receiving bevacizumab and chemotherapy compared with chemotherapy alone in a retrospective analysis of 96 patients, though there was a trend toward fewer complications if the bevacizumab was held for more than 8 weeks prior to surgery. The results of an international phase IV trial from 41 countries (First BEAT) were recently presented at the 2007 European Cancer Conference in Barcelona, Spain.21 This nonrandomized registry trial of 1,965 patients receiving first-line bevacizumab recorded 215 surgeries of curative intent and showed only a 4% incidence of wound-healing complications.21 These studies are extremely encouraging and suggest that bevacizumab can safely and effectively be administered preoperatively in combination with any fluoropyrimidine-based regimen. However, this should still be tempered with caution since the optimal neoadjuvant regimen is unknown, the potential toxicity in major hepatectomies is unclear, and the interval needed between cessation of bevacizumab before hepatectomy is not standardized. The First BEAT study included a variety of bevacizumab-containing regimens, and the extent of hepatectomy is not well defined. In the Gruenberger study, only one third of patients underwent a major hepatectomy. It is unlikely that any impairment of regeneration in a patient undergoing a segmental or minor resection will impact hepatic function, with or without bevacizumab. This is particularly relevant as the indications for hepatectomy expand, leading to larger and more complex hepatectomies.2 As previously mentioned, another concern is the regenerative capacity of a liver compromised by prolonged exposure to chemotherapy. Both oxaliplatin- and irinotecan-based regimens can induce hepatotoxicity,13 which can have a profound effect on hepatic function after a standard liver resection. It is possible that the additional benefit of bevacizumab may reduce the dose of neoadjuvant chemotherapy needed to obtain an optimal response, but this remains to be determined. Conversely, the combination may have an additive adverse effect. Neoadjuvant therapy is rapidly gaining popularity and is likely to become the standard of care for "resectable" and "borderline resectable" patients with metastatic CRC. The integration of novel effective cytotoxic biologic therapies with advanced surgical procedures has transformed the treatment of patients with colorectal cancer metastatic to the liver. In nonrandomized trials, the preoperative administration of regimens containing chemotherapy in combination with biologic agents appears to be both effective and safe. Further studies, however, are needed to evaluate the optimal duration that these agents, bevacizumab in particular, should be held before surgery and to also evaluate whether this can be modified based on the extent of hepatectomy planned. This is a potential window of opportunity for shorter-acting agents such as small-molecule VEGFR inhibitors, though there is no clear evidence of their activity in this disease.22 Until more prospective data is available, we recommend that bevacizumab be stopped earlier than the cytotoxic chemotherapy with which it is given (a minimum of 4 to 6 weeks) and withheld for the first few weeks of postoperative chemotherapy. Even less is known about the best ways to utilize anti-EGFR inhibitors before surgery. As treatment paradigms evolve, early coordination between the medical and surgical oncologist with regular evaluation of the patient for resectability is essential to optimize the chance for cure. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Manuscript writing: Anton J. Bilchik, J. Randolph Hecht Final approval of manuscript: Anton J. Bilchik, J. Randolph Hecht REFERENCES
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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