|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 25, No 33 (November 20), 2007: pp. 5150-5152 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.6150
Bevacizumab for the Treatment of Epithelial Ovarian Cancer: Will This Be Its Finest Hour?Royal Marsden Hospital and Institute of Cancer Research, Sutton, Surrey, United Kingdom Few would argue that one of the key success stories of the modern era of molecular targeted therapy for cancer has been the demonstration that an antiangiogenic approach confers therapeutic benefit in several adult malignancies. If one had been asked 5 years ago to predict the tumors in which this would be most likely to be seen, there is no doubt that epithelial ovarian cancer would be very high on most lists. The reason relates to the biology of the disease. Angiogenesis, which is controlled by a range of pro-angiogenic factors, particularly including those in the vascular endothelial growth factor (VEGF) family of proteins, plays a central role in the physiological function of the healthy ovary. It could therefore be anticipated that the abnormal angiogenesis that characterizes malignancy would be especially relevant in this disease.1 Preclinical studies with appropriate models have indeed indicated the potential for an anti-VEGF strategy in preventing tumor progression and reducing the formation of malignant effusions.2 In addition, numerous studies indicate a direct correlation between angiogenic factors and disease extent and progression.3 It is, therefore, no surprise to read in two reports in this issue of the Journal of Clinical Oncology4,5 that bevacizumab, the humanized anti-VEGF monoclonal antibody, does indeed possess significant single-agent activity in patients with relapsed epithelial ovarian cancer. It is instructive to compare these data with clinical experience in other tumors. Bevacizumab possesses minimal single-agent activity in more common epithelial cancers such as colorectal, non–small-cell lung, and breast cancers. Nevertheless, large-scale combination studies in which bevacizumab is administered together with various cytotoxic regimens have revealed significant improvements in outcome in those diseases,6-8 leading to registration and widespread usage. Ovarian cancer has had to take its turn as a less common cancer, but the drug's potential impact in this disease should not be underestimated. As a single agent, bevacizumab possesses more single-agent activity in epithelial ovarian cancer than in any other epithelial cancer, apart from renal cancer, where the vascular biology is specifically relevant to this therapeutic approach. The two studies presented herein convincingly demonstrate this efficacy. Both involve relapsed ovarian cancer and both used a regimen of 15 mg/kg of bevacizumab every 21 days, but they have various points of difference. The study by Burger et al (Gynecology Oncology Group [GOG] study 170D)4 recruited 62 cases and was restricted to patients who had received only one or two prior chemotherapy regimens. It was open to patients with both platinum-sensitive disease (> 6-month platinum-free interval, 26 cases) and platinum-resistant disease (< 6-month interval, 36 cases). The second study, by Cannistra et al,5 sponsored by Genentech Inc (South San Francisco, CA), recruited a total of 44 patients, all of whom were platinum-resistant, as well as resistant to either topotecan or liposomal doxorubicin. Patients could have received up to three prior chemotherapy regimens. Despite these differences, bevacizumab clearly demonstrated single-agent activity in both studies, with objective response rates of 21% and 16%, respectively. Additionally, 32 (52%) and 27 (64%) of cases, respectively, achieved stable disease with median progression-free survival of 4.4 and 4.5 months. Both studies underwent changes as data accumulated, but for different reasons. GOG 170D was initially designed to evaluate efficacy primarily utilizing progression-free survival, because measurable tumor shrinkage was not anticipated; however, the primary end point was changed after objective responses were observed, and the study was extended at that point. By contrast, the Genentech study closed earlier than initially planned, because of concern over toxicity, specifically the rate of spontaneous bowel perforation (11%). The complication of bowel perforation is now well documented with bevacizumab, with an incidence of up to 4% documented by the manufacturers across all studies. There were no perforations in GOG 170D; by contrast, a total of five patients developed GI perforation in the Genentech study, and this was fatal in one case. As a result, this trial was closed to recruitment after 44 of the initially planned total of approximately 120 cases had been treated. Other manifestations of bevacizumab toxicity also appeared more frequently in the Genentech trial, especially arterial-thrombotic events (three cases [fatal in one] compared with no cases in GOG 170D) and also grade 3/4 hypertension (four cases). In terms of overall toxicity, particularly in GOG 170D, bevacizumab was well tolerated. The reasons for the difference in toxicity, especially the bowel perforation rate, are not clear and the numbers are too small to draw definitive conclusions, but the differences in patient characteristics are likely to be relevant. Patients in the Genentech study were more heavily pretreated (48% having received three prior regimens) and all had platinum-resistant disease. The investigators conducted a careful analysis of risk factors for perforation, and prior therapy with three regimens emerged as the only significant factor. Of the radiographic factors, it is tempting to conclude that even though the increased risk associated with bowel obstruction or bowel wall thickening was not statistically significant, it was clinically relevant. It would be interesting to compare the extent of pretreatment bowel wall involvement in the two trials; other small series of ovarian cancer patients treated with bevacizumab for recurrent disease in different combination schedules also report significant bowel perforation rates of two of 13 (in combination with erlotinib)9 and two of 23 (in combination with chemotherapy).10 Pre-existing small bowel obstruction, and platinum-resistant disease, may have been predisposing factors. No bowel perforations have been reported so far in two studies when bevacizumab has been combined with chemotherapy as part of first-line therapy after definitive surgery.11,12 These, therefore, are the key questions that need to be answered as bevacizumab enters detailed evaluation in ovarian cancer: (a) Will bevacizumab find a role in both first-line treatment and in recurrent disease? (b) Is a combination approach likely to be more effective than single-agent treatment? (c) Can the risk factors for bowel perforation be accurately identified? (d) Is 15 mg/kg every 3 weeks the appropriate dose, or is a lower dose just as effective? (e) Can the patients most likely to benefit from bevacizumab be identified pretreatment? Answers to all these questions are likely to emerge in due course from ongoing trials. The major focus for these is in first-line treatment; and there are two similar randomized trials now underway, incorporating most of the major cooperative groups worldwide. In the United States, GOG 218 (activated in October 2005) aims to randomly assign 2,000 patients in a three-arm placebo-controlled trial in which patients with stage III and IV disease receive paclitaxel and carboplatin, with or without bevacizumab (15 mg/kg every 21 days) for six courses, with a third arm continuing bevacizumab for an additional 48 weeks. The Gynecological Cancer Intergroup (GCIG) trial (ICON 7), activated in October 2006, has similar entry criteria, although mandates that patients should not be candidates for further interval debulking or delayed primary surgery. It is non–placebo controlled, uses a smaller dose of bevacizumab (7.5 mg/kg every 21 days) and is a smaller, two-arm trial (1,520 patients) in which patients receive either conventional paclitaxel plus carboplatin (six cycles) or the same treatment plus bevacizumab every 3 weeks during chemotherapy and continuing for an additional 36 weeks. Despite the differences, it will be important to examine the potential for a pooled analysis of these two trials. A key question not addressed by the previous randomized combination trials in other disease types is, what are the separate contributions to any observed therapeutic benefit for bevacizumab when administered together with chemotherapy, as opposed to bevacizumab as a single agent? GOG 158 will be the first trial that will help to define this essential distinction. It is particularly important to emphasize this point in epithelial ovarian cancer. In addition to the potential for enhancing the efficacy of chemotherapy, bevacizumab—and indeed other antiangiogenic approaches—may have a real role to play either as single-agent therapy, or potentially as part of a combined antiangiogenic regimen excluding chemotherapy. In this context, early experience in which bevacizumab has been combined with the multitargeted tyrosine kinase inhibitor sorafenib has yielded promising efficacy data, albeit at reduced doses compared with single-agent treatment because of additive toxicity.13 Other antiangiogenic agents, including VEGF-TRAP,14 as well as small molecule anti-VEGF receptor (VEGFR) tyrosine kinase inhibitors such as pazopanib,15 are now being reported as having single-agent activity in relapsed ovarian cancer. The potential for exploiting these observations with combined antiangiogenic regimens is considerable. This is not to downplay the potential for bevacizumab in combination with chemotherapy in ovarian cancer. Given the positive data in other tumor types, it would be disappointing if the combination with paclitaxel plus carboplatin in this disease did not lead to a positive result, potentially through the mechanism of normalization of tumor vasculature as demonstrated both in animal models and in the clinic.16 The key point is to recognize that combination treatments with chemotherapy and antiangiogenic treatments in their own right are not mutually exclusive; indeed, both may be necessary at different stages to achieve optimal benefit in ovarian cancer. It is conceivable that the risks of this approach may be slightly higher in this disease than in other cancers, particularly when it is being used in the context of bulky abdominal disease involving the bowel. However, further experience is very likely to reduce these risks, with appropriate caution being exercised in patients anticipated to need further surgery. Although it is clear that the first-line trials are of major importance, it would certainly be important to retain the potential use of bevacizumab-containing treatment in recurrent ovarian cancer. As an illustration of the improvements in management of relapsed ovarian cancer, patients with ovarian cancer can now expect to live longer after their first disease relapse than before it. In the next few years, the hope is that antiangiogenic treatment, incorporating bevacizumab or other VEGF-targeted agents, in various ways including maintenance schedules can lead to further improvements. In this respect, both GOG and the GCIG investigators are initiating important randomized trials in patients with platinum-sensitive relapsed ovarian cancer, receiving treatment with paclitaxel plus carboplatin. GOG 213 will recruit 1,600 patients in a two-arm trial examining the role of concurrent and maintenance bevacizumab, whereas ICON 6 will recruit 2,000 patients in a three-arm trial assessing the role of the small molecule VEGFR inhibitor AZD 2171, both as concurrent and maintenance treatment. As new targeted treatments of this type increasingly become part of our armamentarium, the logical question to address—not least for pharmacoeconomic reasons—is whether robust methods can be developed to accurately predict which patients will benefit from treatment. These may involve early assessments of treatment efficacy by noninvasive imaging, changes in key serum markers, or decreases in circulating endothelial cells. As the momentum builds towards combinations of novel targeted agents, this will be a major challenge for the future. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Martin L, Schilder R: Novel approaches in advancing the treatment of epithelial ovarian cancer: The role of angiogenesis inhibition. J Clin Oncol 25:2894-2901, 2007 2. Byrne AT, Ross L, Holash J, et al: VEGF-trap decreases tumor burden, inhibits ascites and causes dramatic vascular remodeling in an ovarian cancer model. Clin Cancer Res 9:571-5728, 2003 3. Alvarez AA, Krigman HR, Whitaker RS, et al: The prognostic significance of angiogenesis in epithelial ovarian carcinoma. Clin Cancer Res 5:587-591, 1999 4. Burger RA, Sill MW, Monk BJ, et al: Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: A Gynecologic Oncology Group study. J Clin Oncol 25:5165-5171, 2007 5. Cannistra SA, Matulonis UA, Penson RT, et al: Phase II study of bevacizumab in patients with platinum resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol 25:5180-5186, 2007 6. 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 7. Miller KD: E2100: A phase III trial of paclitaxel versus paclitaxel/bevacizumab for metastatic breast cancer. Clin Breast Cancer 3:421-422, 2003[Medline] 8. Sandler A, Gray R, Perry MC, et al: Paclitaxel-carboplatin alone or with bevacizumab for non small cell lung cancer. N Engl J Med 355:2542-2550, 2006 9. Friberg G, Oza AM, Morgan RJ, et al: Bevacizumab (B) plus erlotinib (E) for patients (pts) with recurrent ovarian (OC) and fallopian tube (FT) cancer: Preliminary results of a multi-center phase II trial. J Clin Oncol 24:260s, 2006 (suppl; abstr 5018) 10. Wright JD, Hagemann A, Rader JS, et al: Bevacizumab combination therapy in recurrent platinum-refractory, epithelial ovarian carcinoma: A retrospective analysis. Cancer 107:83-89, 2006[CrossRef][Medline] 11. Micha JP, Goldstein BJ, Rettebnauer N, et al: Phase II study of outpatient first-line paclitaxel, carboplatin and bevacizumab for advanced stage epithelial ovarian, peritoneal and fallopian tube cancer. In J Gyn Cancer 17:771-776, 2007[CrossRef] 12. Campos S, Dizon D, Cannistra S, et al: Safety of maintenance bevacizumab after first-line chemotherapy for advanced ovarian and mullerian cancers. J Clin Oncol 25:278s, 2007 (suppl; abstr 5517) 13. Azad NS, Annunziata C, Barrett T, et al: Dual targeting of vascular endothelial growth factor with sorafenib and bevacizumab: Clinical and translational results. J Clin Oncol 25:148s, 2007 (suppl; abstr 3542) 14. Tew WP, Colombo N, Ray-Coquard A, et al: VEGF-Trap for patients with recurrent platinum-resistant epithelial ovarian cancer: Preliminary results of a randomized multicentre phase II study. J Clin Oncol 25:276s, 2007 (suppl; abstr 5508) 15. Friedlander M, Hancock KC, Benigno B, et al: Pazopanib is active in women with advanced epithelial ovarian, fallopian tube and peritoneal cancers: Initial results in a phase II study. J Clin Oncol 25:289s, 2007 (suppl; abstr 5561) 16. Jain RK: Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy. Science 307:58-62, 2005 Related Articles
Related Correspondence
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
