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Journal of Clinical Oncology, Vol 23, No 22 (August 1), 2005: pp. 4853-4855 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.23.754
Surgical Resection After Downsizing of Colorectal Liver Metastasis in the Era of BevacizumabDepartments of Surgical Oncology and Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and Division of Medical Oncology, Mayo Clinic, Rochester, MN 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.1-5 Patients who subsequently undergo resection can achieve a respectable 5-year survival rate (30% to 35%).1,2 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.6-8 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.9 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,10 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).11 A subsequent analysis of pooled data confirmed the increased incidence of complications in patients undergoing surgery while receiving bevacizumab-containing regimens for metastatic CRC.12 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.13-19 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.16 Interestingly, in regenerating livers in animals with hepatic steatosis, the angiogenic response is impaired.18 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.2 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.20 Males and patients with large tumor burden seem to have a higher clearance rate of the drug (bevacizumab package insert). Even a relatively low dose of bevacizumab (0.3 mg/kg) can lead to undetectable levels of free VEGF in the systemic circulation.20 At present, the dose of bevacizumab approved by the US Food and Drug Administration in patients with metastatic CRC is 5 mg/kg every 2 weeks. Waiting two half-lives (ie, about 6 weeks) would leave the equivalence of a dose of 1.25 mg/kg in the circulation—a dose far above the level of bevacizumab that has been shown to remove free VEGF from the circulation.20 However, it is unknown if circulating VEGF levels are the correct predictor for the biologic effects of a molecule that exerts its effects largely via paracrine mechanisms in the tumor microenvironment. Thus, how long should one wait before performing hepatic resection following neoadjuvant chemotherapy plus bevacizumab? Unfortunately, we do not have any preclinical or clinical data to make definitive recommendations. With conventional agents, one would typically wait a period of two half-lives before assuming that there is an ineffective drug concentration remaining. However, in the case of bevacizumab, as noted above, waiting only two half-lives would theoretically allow a dose of circulating bevacizumab that would still be above the threshold for neutralization of free circulating VEGF. Recently, a group of medical oncologists, surgical oncologists, diagnostic radiologists, and research experts met to develop a therapeutic decision-making model for patients with CRC liver metastases. A RAND/University of California, Los Angeles (Los Angeles, CA) appropriateness method was used to assess timing, sequence, and appropriateness of chemotherapeutic and surgical treatment options in patients with a variety of presentations of CRC liver metastases.21-23 The model that was developed is called the OncoSurge decision model.23 Although this model may be useful in helping medical oncologists and surgical oncologists determine the appropriateness and timing of multidisciplinary treatment of patients with CRC liver metastases, it does not provide assistance in the timing of liver resection after regimens containing bevacizumab because the only chemotherapy combinations considered in the OncoSurge model are FU/leucovorin (LV), FU/LV plus oxaliplatin, FU/LV plus irinotecan, or FU/LV plus oxaliplatin and irinotecan.23 Before any elective surgical procedure is performed, it would be optimal if one could wait for a time period after which free circulating VEGF could again be detected. Unfortunately, with standard enzyme-linked immunosorbent assays (none of which are approved for clinical use) one cannot differentiate free circulating VEGF from VEGF bound to bevacizumab (H.-P. Gerber, personal communication, April 2005). Alternatively, one could assay serum bevacizumab levels to determine when such levels are undetectable. However, this research assay likewise is unavailable for clinical use. Therefore, we can only make recommendations based on extrapolation of our knowledge of risk factors for hepatic resection and pharmacokinetics/dynamics of bevacizumab clearance. At present, the authors recommend waiting 8 weeks after the last dose of bevacizumab before performing an elective hepatic resection. During this waiting period, in principle, one could administer another course of cytotoxic chemotherapy without bevacizumab to maximize response to the prior regimen. However, it may be warranted to give patients a complete drug holiday (8 weeks without any chemotherapy) to minimize hepatic steatosis, chemical hepatitis, and risks of postoperative hepatic insufficiency (G.J. Poston, personal communication, April 2005). This is certainly more important in those patients undergoing resection of more than 30% of their baseline liver volume (given that this is the threshold for the regenerative response) and in patients with chemotherapy-induced or pre-existing hepatic dysfunction. Until we gain more experience with hepatic resection after downstaging of liver metastasis in patients who have received bevacizumab, it is imperative for investigators to collect plasma just before surgical resection for future analysis of free VEGF or bevacizumab levels. Increases in surgical complication or hepatic insufficiency rates after liver resection may correlate with bevacizumab-related inhibition of hepatic regeneration. Although the issue of wound healing after elective surgery may not be an issue with the use of tyrosine kinase inhibitors to VEGF receptors such as vatalanib (PTK 787/ZK222584), sorafenib (BAY 43-9006), or sutent (SU11248) due to their short half-life, none of the VEGFR tyrosine kinase inhibitors have been proven to be efficacious (or are not yet approved by the US Food and Drug Administration) in CRC at the time of this writing. However, cetuximab, another targeted agent that has shown activity alone or in combination with other agents in metastatic CRC, does not appear to increase the complication rate of surgery.24 The half-life of cetuximab is approximately 10 days because of its chimeric structure. There is no current evidence that epidermal growth factor receptor inhibitors impair wound healing or liver regeneration. In addition, early reports on the combination of active cytotoxic regimens such as infusional FU/LV plus oxaliplatin, or the combination of folinic acid, FU, and irinotecan plus cetuximab as first-line therapy in metastatic CRC have shown impressive response rates that theoretically could facilitate downsizing of liver metastases as a neoadjuvant approach.25,26 Although the era of targeted therapies has provided us with new opportunities, we are also confronted with new challenges. It is critical for surgeons and oncologists to understand biologic principles of targeted therapies if we are to maximize treatment efficacy while minimizing morbidity. Authors' Disclosures of Potential Conflicts of Interest Although all authors have completed the disclosure declaration, the following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
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5. Tournigand C, Andre T, Achille E, et al: FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomized GERCOR study. J Clin Oncol 22: 229-237, 2004 6. Howdieshell TR, Callaway D, Webb WL, et al: Antibody neutralization of vascular endothelial growth factor inhibits wound granulation tissue formation. J Surg Res 96: 173-182, 2001[CrossRef][Medline] 7. Zhang F, Lei MP, Oswald TM, et al: The effect of vascular endothelial growth factor on the healing of ischaemic skin wounds. Br J Plast Surg 56: 334-341, 2003[CrossRef][Medline] 8. Roman CD, Choy H, Nanney L, et al: Vascular endothelial growth factor-mediated angiogenesis inhibition and postoperative wound healing in rats. J Surg Res 105: 43-47, 2002[CrossRef][Medline]
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10. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350: 2335-2342, 2004 11. Hurwitz H, Fehrenbacher L, Cartwright T, et al: Wound healing/bleeding in metastatic colorectal cancer patients who undergo surgery during treatment with bevacizumab. J Clin Oncol 22: 294, 2004 (suppl; abstr 3702) 12. Scappaticci FA, Fehrenbacher L, Cartwright T, et al: Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab. J Surg Oncol (in press) 13. Assy N, Spira G, Paizi M, et al: Effect of vascular endothelial growth factor on hepatic regenerative activity following partial hepatectomy in rats. J Hepatol 30: 911-915, 1999[CrossRef][Medline] 14. Furnus CC, Inda AM, Andrini LB, et al: Chronobiology of the proliferative events related to angiogenesis in mice liver regeneration after partial hepatectomy. Cell Biol Int 27: 383-386, 2003[CrossRef][Medline] 15. Kraizer Y, Mawasi N, Seagal J, et al: Vascular endothelial growth factor and angiopoietin in liver regeneration. Biochem Biophys Res Commun 287: 209-215, 2001[CrossRef][Medline]
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20. Gordon MS, Margolin K, Talpaz M, et al: Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol 19: 843-850, 2001 21. Brook RH, Chassin MR, Fink A, et al: A method for the detailed assessment of the appropriateness of medical technologies. Int J Technol Assess Health Care 2: 53-63, 1986[Medline] 22. Fitch K, Bernstein SJ, Aguilar MD, et al: The RAND/UCLA Appropriateness Users' Manual. Santa Monica, CA, RAND, 2001 23. Haller DG, Alberts S, Adam R, et al: OncoSurge: A therapeutic decision model to optimize the management of colorectal liver metastases. Proceedings of the 2005 Gastrointestinal Cancers Symposium, Hollywood, FL, January 27-29, 2005
24. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351: 337-345, 2004 25. Rougier P, Raoul J-L, Van Laethem J-L, et al: Cetuximab+FOLFIRI as first-line treatment for metastatic colorectal cancer. J Clin Oncol 22: 248, 2004 (suppl; abstr 3513)[CrossRef] 26. Tabernero JM, Van Cutsem E, Sastre J, et al: An international phase II study of cetuximab in combination with oxaliplatin/5-fluorouracil (5-F&)/folinic acid (FOLFOX-4) in the first-line treatment of patients with metastatic colorectal cancer expressing epidermal growth factor receptor (EGFR): Preliminary results. J Clin Oncol 22: 248, 2004 (suppl; abstr 3512)
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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