Questions We Should Be Asking About Bevacizumab for Cervical Cancer

May 15, 2015

There is good evidence that angiogenesis plays a central role in cervical cancer pathogenesis, suggesting a strong rationale for adding anti-angiogenesis agents to chemotherapeutic agents for the treatment of this disease.

Liu and colleagues here present an extensive overview of anti-angiogenesis therapy in gynecologic malignancies, with particular emphasis on the adjuvant role of bevacizumab in the treatment of advanced cervical cancer.[1] Bevacizumab is a humanized, anti–vascular endothelial growth factor (VEGF) monoclonal antibody. The authors present good evidence that angiogenesis plays a central role in cervical cancer pathogenesis, suggesting a strong rationale for adding anti-angiogenesis agents to chemotherapeutic agents for the treatment of this disease.

Let us consider, however, where cervical cancer most often occurs. The majority of cases of cervical cancer diagnosed in the world occur in developing countries (at least 86%, according to GLOBOCAN 2012),[2] where most women present with advanced, usually incurable disease, and where 85% of the deaths from cervical cancer are recorded. Standard of care for women with advanced cervical cancer involves concurrent platinum-based chemotherapy and pelvic radiotherapy, with expected cure rates of 0% to 40%[3] in low-resource settings and 60% to 80% in well-resourced settings, depending on Fedération Internationale de Gynécologie et Obstétrique (FIGO) stage.[4] These data from developing countries are from women who were lucky enough to receive any treatment at all. A recent review of radiotherapy capacity in low- and middle-income countries, which relied on data provided by the DIRAC (Directory of Radiation Centers), indicated that there are currently 160 radiation centers in Africa, with a total of 88 cobalt-60 machines and 189 linear accelerators, which together must serve a population of more than 1 billion people.[3,5] It should be noted, however, that 60% of the machines are located in South Africa and Egypt, and that 29 of the 54 countries in Africa have no radiation therapy resources at all. Thus there are 198 million people on the continent with extremely limited access to anticancer care.

Tewari et al[6] recently published an important study demonstrating improved survival with bevacizumab in women with advanced cervical cancer. Women with metastatic, persistent, or recurrent cervical cancer were eligible for the study, unless suitable for surgical exenteration. There were four regimens, repeated at 21-day intervals: The control treatment consisted of cisplatin plus paclitaxel, the non-platinum combination chemotherapy was topotecan plus paclitaxel, and each of these regimens was studied both with and without bevacizumab (at a dose of 15 mg/kg). Overall, 425 women were enrolled. At a median follow-up of 20.8 months, 271 deaths had occurred (60% of study participants). The data showed that the incorporation of bevacizumab significantly improved the median overall survival (OS) compared with chemotherapy alone (17.0 months vs 13.3 months; hazard ratio [HR] for death, 0.71 (98% confidence interval [CI] = 0.54–0.95). In addition, the response rate in those who received bevacizumab was significantly higher than the rate in those who did not receive the drug (28 vs 14 complete responses, respectively [P = .03]). However, a significantly higher proportion of women receiving bevacizumab had gastrointestinal fistulas (13 out of 220 women compared with 1 out of 219 women not treated with bevacizumab). Also, only 2% of women in the non-bevacizumab group developed hypertension compared with 25% in the bevacizumab-treated group. Further, these clinical data are supported by the mechanism by which anti-angiogenetic agents work, as explained by Tewari et al.[6]

Bevacizumab has also been studied in the primary treatment of ovarian cancer.[7] Burger et al published the result of a double-blind, placebo-controlled, phase III trial in which 1,873 women with advanced ovarian cancer were assigned to one of three regimens. Women in all three arms received carboplatin and paclitaxel; one arm received bevacizumab-initiated treatment, another received bevacizumab throughout treatment, and the third arm was the control. At the time of the analysis, 76.3% of the patients were alive, with no differences in OS among the three groups. The median progression-free survival (PFS) was 10.3 months in the control group, 11.2 months in the bevacizumab-initiation group, and 14.1 months in the bevacizumab-throughout group. The final conclusion was that up to 10 months after carboplatin and paclitaxel chemotherapy, the addition of bevacizumab prolonged PFS by 4 months. Perren et al[8] randomly assigned 1,528 women with ovarian cancer to standard carboplatin-paclitaxel chemotherapy or to this regimen plus bevacizumab (7.5 mg/kg), given concurrently. They reported an improved PFS for women with ovarian cancer who received bevacizumab (24.1 vs 22.4 months, respectively).

These clinical trials are important and may in fact become game changers in terms of what regimen is regarded as having the greatest therapeutic efficacy. However, there is much more to cancer control that improved survival. Among the issues to consider are those related to cost and cost-effectiveness. We need to critically evaluate sometimes minor benefits of proven interventions and whether these are worth the costs to individuals and to society. For example, should an intervention that has been shown to reduce tumor growth without improving OS or improving survival by only a few months (eg, 3.7 months with bevacizumab in cervical cancer) be regarded as ineffective, marginally effective, or clinically beneficial and therefore worth the cost? The answers to this question will vary according to medical context and culture, societal expectations, and budgetary constraints. Answering this question with regard to therapies used near the end of life is particularly challenging, especially for treatments that are associated with toxicity, that create a false sense of hope, that may be extremely expensive, and/or that may prevent patients from experiencing a “kinder death.”

Phippen et al[9] recently published a study on the cost-effectiveness of bevacizumab in recurrent, persistent, or advanced-stage carcinoma of the cervix. The authors used the Tewari study,[6] also known as Gynecologic Oncology Group (GOG) 240, as the basis for the construction of their decision analysis model. They found that the chemotherapy arm (carboplatin and paclitaxel), in which the median OS was 13.3 months, was the least costly, with an average regimen cost of $5,688. The chemotherapy-plus-bevacizumab arm, in which the OS was 17 months, had an average regimen cost of $53,784. The 3.7-month improvement in OS came at an Incremental Cost-Effectiveness Ratio (ICER) of $155,000 (the ICER is a numerical value comparing two regimens and indicating how much it would cost to gain a unit in effectiveness). Of note, when the dose of bevacizumab was reduced to 7.5 mg/kg, the cost decreased considerably, without discounting the cost of the drug. It is generally accepted that an ICER of over $100,000 is not cost-effective, so with an ICER of $155,000, chemotherapy plus bevacizumab is not cost-effective. Some countries, eg, the United Kingdom, use $50,000 as the threshold, and still others use a cut-off as low as $30,000.

There are many complexities to cost-effectiveness modeling, but the Phippen et al analysis is important for developing countries, where the most basic level of cancer care is extremely limited or nonexistent. Although innovation in healthcare should be encouraged and sometimes results in solutions that can be used in poor countries (one need simply think of vaccination), evidence of the value, the impact, the sustainability, and the cost-effectiveness of new medical interventions warrant rigorous scrutiny and must be of the highest quality.

Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Liu FW, Cripe J, Tewari KS. Anti-angiogenesis therapy in gynecologic malignancies. Oncology (Williston Park). 2015;29:350-60.

2. International Agency for Research on Cancer. GLOBOCAN 2012: Estimated cancer incidence, mortality, and prevalence worldwide in 2012. Available from: http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx.

3. Denny L, Anorlu R. Cervical cancer in Africa. Cancer Epidemiol Biomarker Prev. 2012;21:1434-8.

4. Monk BJ, Sill MW, McMeeking DS, et al. Phase III trial of four cisplatinum-containing doublet combinations in stage IVB, recurrent or persistent cervical carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol. 2009;27:4649-55

5. Grover S, Xu MJ, Yeager A, et al. A systematic review of radiotherapy capacity in low and middle income countries. Front Oncol. 2015;4-11.

6. Tewari KS, Sill MW, Long HJ, et al. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med. 2014:370:734-43.

7. Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365:26:2473-83.

8. Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365;26: 2482-96.

9. Phippen NT, Leath CA, Havrilesky LR, Barnett JC. Bevacizumab in recurrent, persistent, or advanced stage carcinoma of the cervix: Is it cost-effective? Gynecol Oncol. 2015; 136:43-7.