Introduction

Jonathan S. Berek, MD, MMS
Stanford University School of Medicine
Editor-in-Chief, ASCO Connection

January 2011 issue: Two randomized trials of primary chemotherapy with bevacizumab ([Gynecologic Oncology Group] GOG 0218 and ICON7) were presented and discussed at the 2010 Annual Meetings of ASCO, the European Society for Medical Oncology (ESMO), and the International Gynecologic Cancer Society (ICGS). These trials demonstrate a modest progression-free survival advantage in patients treated with bevacizumab concurrently with standard carboplatin and paclitaxel chemotherapy and then as maintenance therapy. Overall survival data are not yet available.

Based on these data, targeting vascular endothelial growth factor (VEGF) in epithelial ovarian cancer is a valid strategy, and the development of other drugs that involve this pathway is important. The goal will be to discover similar agents that have an even better cost/benefit ratio and can be given by mouth. Drugs in this class will likely play an important role in the treatment of the disease.

Taken together, several questions should be considered. Do these results justify approval of the agent for this purpose? Does the cost vs. benefit of the drug warrant approval? If not, should the drug be approved for use in other situations, e.g., treatment of persistent or relapsed disease? My colleagues, Robert Burger, MD, and Maurie Markman, MD, discuss these issues.

Bevacizumab Should Be Available as Part of Standard Primary Treatment

Robert A. Burger, MD, FACS
Fox Chase Cancer Center

Strategies to target the fundamental processes of ovarian cancer disease progression are critical. Angiogenesis is one such process, and VEGF its central promoter. Bevacizumab, a VEGF neutralizing monoclonal antibody, has demonstrated single agent activity in phase II ovarian cancer trials.^1,2

Two positive international cooperative group phase III studies of bevacizumab in front-line therapy have been reported in 2010: GOG 0218 (doubleblind, placebo-controlled)^3-5 and ICON7 (open-label).^6,7 Both demonstrated that, in comparison to women randomized to six cycles of carboplatin/paclitaxel alone, those randomized to chemotherapy in combination with bevacizumab followed by bevacizumab maintenance up to a pre-specified number of cycles (16 and 12, respectively) conferred a statistically significant prolongation of progression-free survival, the primary endpoint. The majority of participants had advanced disease (all in GOG 0218, 82% in ICON7). The experimental regimens were well tolerated, with adverse events similar to previous phase III trials for metastatic non-gynecologic malignancies. Gastrointestinal perforation and fistula rates were less than 3% in the experimental groups. There was no apparent difference in the rates of febrile neutropenia, arterial thrombo-embolic events, or wound healing complications. The only cumulative effects were hypertension requiring treatment (23% and 18% for GOG 0218 and ICON7, respectively) and proteinuria (less than 1% grade 3); hypertension was manageable in the vast majority of cases.

Overall survival data have yet to mature—at this point there is no evidence of a benefit. For GOG 0218, unblinding to treatment assignment was permitted at the time of disease progression. The ultimate analysis of overall survival may be limited by a “cross-over” effect in the use of bevacizumab or other anti-VEGF agents for the management of recurrent disease.

The potential benefit
What is the potential clinical benefit to patients with advanced ovarian cancer? In GOG 0218 the hazard of disease progression was reduced by 28%, and for the 465 patients with stage III (residual tumor implants after initial surgery greater than 1 cm) or stage IV disease enrolled to ICON7, by 32%. This effect is consistent with results of previous advanced ovarian cancer phase III trials for which statistically significant improvements in overall survival were observed, but these trials were not vulnerable to a cross-over effect.^8-11

In June 2010, the Gynecologic Cancer Intergroup reiterated its consensus statement from 2005¹² that progression-free survival is “most often the preferred primary endpoint for front-line ovarian cancer clinical trials” (including maintenance trials) because of the potential impact of multiple recurrence regimens on overall survival, and indeed there are over a dozen preferred active therapies listed by the National Comprehensive Cancer Network¹³—including bevacizumab.

Those who argue against the incorporation of bevacizumab into front-line therapy often do so based on monetary cost. Although this is an important public health issue for patients with advanced ovarian cancer benefitting from prolonged therapy, our responsibility as oncologists is to offer the most clinically effective care available.

Is integration of bevacizumab into front-line therapy appropriate in all cases of advanced ovarian cancer? It is too early to tell. For example, there is no level I evidence for use in patients receiving intraperitoneal (IP) chemotherapy (although the current GOG phase III IP trial incorporates bevacizumab in all three regimens) or for use in patients receiving neo-adjuvant chemotherapy prior to surgical cytoreduction. Will all patients receiving bevacizumab in front-line therapy benefit? The answer is clearly “no,” but just as it is also “no” for platinum/taxane-based chemotherapy itself.

We clearly need to build on this experience, and there are many unanswered questions. Can molecular tumor or host characteristics predict benefit? What is the optimal duration of therapy in front-line treatment beyond a pre-specified number of cycles? For now, however, based on two independent lines of level I evidence, to deny the option of front-line bevacizumab to women with advanced ovarian cancer would be discriminatory.

References

1. Burger RA, Sill MW, Monk BJ, et al. J Clin Oncol. 2007;25:5165-71.
2. Cannistra SA, Matulonis UA, Penson RT, et al. J Clin Oncol. 2007;25:5180-6.
3. Burger RA, Brady MF, Bookman MA, et al. J Clin Oncol. 2010;28:18s (suppl; abstr LBA1).
4. Burger RA, Brady MF, Bookman MA, et al. Abstract Book of the 35th ESMO Congress. 2010;21 suppl 8:viii307 (978PD).
5. Burger RA, Brady MF, Fleming GF, et al. Phase III trial of bevacizumab in the primary treatment of advanced ovarian, primary peritoneal or fallopian tube cancer: a GOG study. Int J Gynecol Cancer. 2010;20 suppl 2. Accessible at: http://journals.lww.com/ijgc/Docume...Prague.pdf.
6. Perren T, Swart AM, Pfisterer J, et al. Abstract Book of the 35th ESMO Congress. 2010;21 suppl 8:viii2 (LBA4).
7. Pfisterer J, Perren T, Swart AM, et al. ICON7: A randomised controlled trial of bevacizumab in women with newly diagnosed epithelial ovarian, primary peritoneal or fallopian tube cancer. Int J Gynecol Cancer. 2010;20 suppl 2. Accessible at: http://journals.lww.com/ijgc/Docume...Prague.pdf.
8. McGuire WP, Hoskins WJ, Brady MF, et al. N Engl J Med. 1996;334:1-6.
9. Brady M. Personal communication with the author. 2010.
10. Armstrong DK, Bundy B, Wenzel L, et al. N Engl J Med. 2006;354:34-43.
11. Katsumata N, Yasuda M, Takahashi F, et al. Lancet. 2009;374:1331-8.
12. Thigpen T, Stuart G, du Bois A, et al. Ann Oncol. 2005;16 suppl 8:viii13-viii19.
13. Ovarian Cancer (Including Fallopian Tube Cancer and Primary Peritoneal Cancer), Version 2.2011. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Accessible at: http://www.nccn.org/professionals/p...varian.pdf.

Maurie Markman, MD
Cancer Treatment Centers of America, Eastern Regional Medical Center

Two well-designed and conducted phase II clinical trials have rather convincingly revealed that single-agent bevacizumab possesses considerable biological activity in recurrent and platinum-resistant ovarian cancer.^1,2 Further, one of these second-line studies demonstrated that, compared to a large and quite rationally selected “historical control population,” use of this agent provides at least as great an opportunity for an individual patient to experience a prolonged time to subsequent disease progression as associated with other drugs which might be employed in this specific setting.1 Additional reported phase II experiences support the overall conclusion that bevacizumab possesses an impressive degree of activity in the second-line management of epithelial ovarian cancer.^3,4

While the issue of defining clinical benefit was unfortunately not directly addressed in these studies (nor is such a critically relevant assessment a common practice in ovarian cancer clinical trials), it is clear that many women entered into the trials who exhibited a measurable tumor response also achieved a meaningful degree of improvement in cancer-related symptoms and quality-of-life. Thus, in the opinion of this commentator, the most appropriate question to be addressed in this current debate is not whether bevacizumab should be used as one potential standard-of-care option in the treatment of advanced ovarian cancer, but rather, when is the most rational time in the course of the malignancy to employ the agent in routine practice, with the very specific aim to favorably impact the individual woman’s clinical course and outcome (survival and cancer-related symptoms)?

Accepting the standard as being the specific treatment paradigm reported in the GOG trial would essentially require that all patients with advanced ovarian cancer receive 22 cycles of bevacizumab (assuming the absence of documented disease progression or unacceptable toxicity) to achieve a median improvement in progression-free survival of 3.8 months (with, to date, no statistically significant impact on median overall survival).⁵ Further, as these data actually relate to a population of individuals, the multiple cycles of this not-inexpensive and not-non-toxic drug will be delivered without any evidence that the particular patient is achieving any clinical benefit beyond that associated with the carboplatin plus paclitaxel (or a comparable platinum/taxane regimen) she is also receiving as a routine component of her treatment regimen.

However, if administered in the second-line (or later) setting as a single agent (or possibly as part of a regimen that includes a cytotoxic drug, assuming future evidence-based data support such a conclusion), formal assessment of the clinical utility of the approach (e.g., decrease in measurable tumor masses, reduction in pain or ascites, or a substantial reduction in the serum CA-125 level, etc.) can be undertaken after a limited number of bevacizumab cycles to determine if continuation of the agent (with its associated cost and toxicity) is medically warranted. Patients failing to achieve evidence of a meaningful objective or subjective (or both) measure of clinical benefit would have treatment with this agent stopped, while the demonstration of a favorable impact would certainly result in continuation of, and payment for, the drug.

It is reasonable to strongly argue that under this alternative scenario it would be far easier to justify the cost (and potential side effects) of this very important anti-neoplastic agent in the management of an individual patient with ovarian cancer, since after the initial one to three cycles only women exhibiting at least a modest documented degree of actual clinical benefit will be continuing to receive the drug.

References 

1. Burger RA, Sill MW, Monk BJ, et al. J Clin Oncol. 2007;25:5165-71.
2. Cannistra SA, Matulonis UA, Penson RT, et al. J Clin Oncol. 2007;25:5180-6.
3. Garcia AA, Hirte H, Fleming G, et al. J Clin Oncol. 2008;26:76-82.
4. Wright JD, Hagemann A, Rader JS, et al. Cancer. 2006;107:83-9.
5. Burger RA, Brady MF, Bookman MA, et al. J Clin Oncol. 2010;28:18s (suppl; abstr LBA1).

Current Controversies in Oncology is a forum for the exchange of views on topical issues in the field of oncology. The views and opinions expressed therein are those of the authors alone. They do not necessarily reflect the views or positions of the Editor or of the American Society of Clinical Oncology.