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Journal of Clinical Oncology, Vol 24, No 16 (June 1), 2006: pp. 2592-2593 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.2910
Neoadjuvant Therapy With BevacizumabDepartment of General Surgery, Medical University of Vienna, Vienna, Austria
Department of Oncology, Medical University of Vienna, Vienna, Austria
Department of Oncology, Medical University of Vienna, Vienna, Austria To the Editor: Two recent editorials have addressed issues relating to surgical resection of liver metastases in patients with colorectal cancer.1,2 Chong and Cunningham1 illustrate that patients presenting with colorectal cancer and synchronous liver metastases are a poor prognostic group who may benefit from perioperative chemotherapy and resection of all disease sites. They also conclude that patient selection criteria must be standardized so that appropriate therapy can be delivered and trials can be designed to investigate new regimens; perioperative treatment regimens designed to increase the likelihood of liver resectability must be improved, partly because current chemotherapy regimens (particularly the most effective, oxaliplatin-based regimens) cause hepatic toxicity and may increase the risk of postoperative complications; and surgical techniques must be improved. Both Chong and Cuningham1 and Ellis et al2 address the potential of novel biologic agents, such as bevacizumab and cetuximab, to improve outcomes for patients with initially unresectable liver metastases. Both studies discuss the use of the humanized anti-vascular endothelial growth factor monoclonal antibody bevacizumab. Specific issues include the impact of bevacizumab on postsurgical-wound healing, potentially causing delayed surgery after bevacizumab administration; the impact of bevacizumab on hepatic regeneration following surgery, based on the role of vascular endothelial growth factor in this process; and the absence of data for patients with colorectal cancer undergoing resection after bevacizumab-containing therapy.1-3 Phase II/III clinical trials in patients with metastatic colorectal cancer have demonstrated that the addition of bevacizumab to fluoropyrimidine-based chemotherapy regimens significantly improves response rates, overall survival, and progression-free survival compared with chemotherapy alone.4-6 The improved response rate should result in a higher proportion of patients with respectable tumors; however, resection rates in these trials were low, probably because of clinical practice in the participating hospitals. These trials did show that bevacizumab therapy is associated with a low but increased incidence of wound-healing complications in patients who undergo emergency surgery while on therapy, but not in those who receive bevacizumab therapy at least 4 weeks after surgery.7 Based on the pharmacokinetics of bevacizumab, Ellis et al2 recommend waiting at least 8 weeks after the last dose of this agent before performing hepatic resection. At our clinic, we have been evaluating the use of neoadjuvant chemotherapy to treat patients with colorectal cancer and resectable liver metastases. In these trials, neoadjuvant chemotherapy improved response, reduced the extent of surgery, and possibly extended survival.8-10 In a review of current practice for treatment of colorectal cancer with liver metastases, we concluded that a multidisciplinary and multimodality approach maximizes patient benefit.11 We recently commenced a pilot series examining the potential of neoadjuvant bevacizumab in combination with capecitabine plus oxaliplatin (XELOX or CAPOX) in colorectal cancer patients with potentially resectable liver metastases. Our experience indicates that this regimen is feasible and provides data that address some of the issues raised by Ellis et al2 and Chong and Cunningham.1 We enrolled 13 patients, nine of whom are currently assessable. Selected patients were at high risk for early recurrence, with synchronous liver metastases; primary, nonoptimally resectable disease; metastatic disease developed within a year after primary resection; or lymph node-positive primary tumors. The assessable patients received combination chemotherapy consisting of bevacizumab 5 mg/kg every 2 weeks and XELOX (capecitabine 3,500 mg/m2/d on days 1 through 7 plus oxaliplatin 85 mg/m2 on day 1 of a 2-week cycle) for six cycles (3 months). The sixth cycle of therapy did not include bevacizumab, providing a gap of 5 weeks between the last bevacizumab dose and surgery. Between the last oxaliplatin and capecitabine doses and surgery, there was a gap of 3 and 2 weeks, respectively. Eight of the nine patients underwent liver resection, with synchronous primary tumor resection in three patients. One patient had explorative laparotomy with intended liver resection but was not resected, because of extrahepatic disease. Seven patients stayed in the intensive care unit overnight, which is routine practice at the Medical University of Vienna (Vienna, Austria); the median length of postoperative hospitalization for all patients was 6 days (± 1.871 days). Therapy with bevacizumab plus XELOX was restarted 5 weeks after surgery for another six cycles. Peri- and postoperative events were consistent with our previous studies evaluating chemotherapy alone; increased bleeding did not occur, and no blood transfusions or further surgery were required. Notably, postoperative liver function and regeneration were normal in all patients. The only postoperative complication observed was a wound infection after synchronous liver and primary bowel resection. This patient received bevacizumab plus XELOX as scheduled 5 weeks after surgery, at which time the wound had recovered fully with conservative management. These data suggest that bevacizumab can be administered before liver resection in patients with colorectal cancer without increasing the rate of surgical or wound-healing complications or the severity of bleeding in a selected group of patients. Furthermore, rather than the 8-week gap between the end of bevacizumab therapy and surgery recommended by Ellis et al,2 a 5-week gap was allowed in this trial. Willett et al,12,13 have also shown that neoadjuvant bevacizumab therapy can be administered less than 8 weeks before surgery, in patients with rectal cancer, with no apparent effects on wound healing or bleeding. Our data are the first to indicate that neoadjuvant bevacizumab therapy does not affect hepatic regeneration following resection. A growing number of studies demonstrate that bevacizumab can be administered as part of neoadjuvant and adjuvant regimens without appearing to adversely affect surgical wound healing, bleeding, or hepatic regeneration. However, patients with potentially curative metastatic colorectal disease must be treated by an experienced multidisciplinary team, and liver surgery must be performed by a surgeon qualified in dealing with chemotherapy-altered livers. Further research is required before definitive recommendations are made, but evidence indicates that elective surgery 5 weeks after the last bevacizumab dose, and emergency surgery with an even shorter delay after bevacizumab therapy, is possible and generally safe in most patients. Several palliative studies using bevacizumab are ongoing, and further knowledge on optimal delay before surgery is eagerly awaited. Currently, we would favor a shorter delay in future trials, because timing of chemotherapy removal and surgery are constantly set at 3 weeks in similar settings. Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following authors or their immediate family members 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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
REFERENCES
1. Chong G, Cunningham D: Improving long term outcomes for patients with liver metastases from colorectal cancer. J Clin Oncol 23:9063-9066, 2005 2. Ellis LM, Curley SA, Grothey A: Surgical resection after downsizing of colorectal liver metastasis in the era of bevacizumab. J Clin Oncol 23:4853-4855, 2005 3. Taniguchi E, Sakisaka S, Matsuo K, et al: Expression and role of vascular endothelial growth factor in liver regeneration after partial hepatectomy in rats. J Histochem Cytochem 49:121-130, 2001 4. 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 5. Kabbinavar FF, Hambleton J, Mass RD, et al: Combined analysis of efficacy: The addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol 23:3706-3712, 2005 6. Giantonio BJ, Catalano PJ, Meropol NJ, et al: High-dose bevacizumab in combination with FOLFOX4 improves survival in patients with previously treated advanced colorectal cancer: Results from the Eastern Cooperative Oncology Group (ECOG) study E3200. J Clin Oncol 23:1S, 2005 (suppl; abstr 2)[CrossRef][Medline] 7. Scappaticci F, Fehrenbacher L, Cartwright T, et al: Analysis of wound healing and bleeding post-surgery in metastatic colorectal cancer patients treated with bevacizumab. J Clin Oncol 22:252S, 2004 (suppl; abstr 3530) 8. Gruenberger T, Schuell B, Kornek G, et al: Neoadjuvant chemotherapy for resectable colorectal cancer liver metastases: Impact on magnitude of liver resection and survival. J Clin Oncol 22:269S, 2004 (suppl; abstr 3598) 9. Gruenberger T, Schuell B, Kornek G, et al: Elderly patients do benefit from oxaliplatin based neoadjuvant chemotherapy in resectable colorectal cancer liver metastases. J Clin Oncol 23:271S, 2005 (suppl; abstr 3601) 10. Nordlinger B, Sorbye H, Debois M, et al: Feasibility and risks of pre-operative chemotherapy (CT) with Folfox 4 and surgery for resectable colorectal cancer liver metastases (LM). Interim results of the EORTC Intergroup randomized phase III study 40983. J Clin Oncol 23:253S, 2005 (suppl; abstr 3528) 11. Gruenberger T, Schuell B, Puhalla H, et al: Changes in liver surgery for colorectal cancer liver metastases under neoadjuvant treatment strategies. Acta Med Austriaca 36:317-321, 2004 12. Willett CG, Boucher Y, di Tomaso E, et al: Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10:145-147, 2004[CrossRef][Medline] 13. Willett CG, Boucher Y, Duda DG, et al: Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: Continued experience of a phase I trial in rectal cancer patients. J Clin Oncol 23:8136-8138, 2005
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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