The Use of Bevacizumab in Treating Cervical Cancer

Nicole Kayatta, PharmD BCOP BCPS
Clinical Medical Oncology Specialist
Northside Hospital Cancer Institute
Atlanta, GA

The American Cancer Society estimates that about 12,820 new cases of invasive cervical cancer will be diagnosed and about 4,210 women will die from cervical cancer in the United States in 2017.¹ Despite primary prevention measures such as screening and human papillomavirus (HPV) vaccination, cervical cancer remains one of the most common cancers in women and is often diagnosed at advanced stages. Women with recurrent and metastatic cervical cancer have historically had extremely limited treatment options.²

It has been the standard of care since 1999 to consider the combination of chemotherapy and radiation for treating stages IB2 to IVA cervical cancer.³ However, the long-term complications from radiotherapy and poor control of micrometastases raised interest in investigating other approaches. Single-agent cisplatin was widely accepted as the standard for treating late-stage cervical cancer until 2005, when Long and colleagues demonstrated improved overall survival (OS) in patients treated with doublet chemotherapy versus cisplatin alone.⁴

In 2009, the Gynecologic Oncology Group (GOG) 204 study examined four cisplatin-based doublets to assess their efficacy and toxicities. This study found a trend favoring the cisplatin/paclitaxel regimen, although it was not statistically significant. Henceforward, cisplatin and paclitaxel has been considered the standard regimen for patients with stage IVB, recurrent, or persistent cervical carcinoma. However, the investigators in this study concluded that alternative regimens are reasonable and should be considered for individual patients, especially in the setting of pre-existing comorbidities or toxicities.⁵ Many patients unfortunately develop recurrence within the first 2 years of completing treatment, and their cases are often not salvageable. Survival for metastatic, recurrent, or persistent cervical cancer is about 12 months.²

Vascular endothelial growth factor (VEGF) has emerged as a target to inhibit angiogenesis in many solid tumors because the dysregulation of angiogenesis plays a role in tumor growth and metastasis. Vascularization and increased microvessel density are typically seen on colposcopy in women with invasive cervical cancer; thus, the VEGF receptor seemed a compelling potential target.⁶ Bevacizumab is a recombinant humanized monoclonal antibody that binds to VEGF A with potent anti-angiogenic action, and it has been approved for use in treating several types of solid tumors.⁷ In 2006, Wright and colleagues conducted a case series that suggested activity of bevacizumab in recurrent cervical cancer, demonstrating a progression-free survival (PFS) extended by 4.6 months.⁸ A subsequent phase-2 trial evaluated bevacizumab in patients with persistent or recurrent cervical cancer. This study found that median PFS was extended by 3.4 months and overall survival (OS) by 7.3 months, which compared favorably to historical data. As expected, hypertension, thromboembolism, anemia, cardiovascular side effects, vaginal bleeding, neutropenia, and gastrointestinal fistulas were identified as toxicities, but overall the treatment was considered to be well tolerated.⁹ This phase-2 study prompted the development of a phase-3 study with bevacizumab.

GOG 240 was a randomized, open-label phase-3 trial that included patients with metastatic, persistent, or recurrent cervical carcinoma.¹⁰ It included patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 and otherwise healthy patients with a very poor prognosis. Four hundred fifty-two patients were randomly assigned to treatment with either cisplatin plus paclitaxel, with or without bevacizumab, or the non-platinum-containing regimen paclitaxel plus topotecan, with or without bevacizumab. This trial sought to answer two questions: (1) whether bevacizumab was effective in addition to chemotherapy, and (2) whether the non-platinum-based chemotherapy doublet of topotecan/paclitaxel would be effective in circumventing platinum resistance. An interim analysis in 2014 demonstrated no difference in outcomes between the platinum and non-platinum chemotherapy regimens. However, adding bevacizumab to chemotherapy significantly prolonged OS (3.7 months) and PFS (2.3 months) and improved the overall response rate (48% vs. 36%).¹⁰ Primarily on the basis of this interim analysis, the FDA approved bevacizumab for women with advanced cervical cancer. This was the first new drug approved for the treatment of cervical cancer in more than 8 years. In addition to FDA approval, these results also led to the National Comprehensive Cancer Network guidelines listing of bevacizumab as a category 1 recommendation for patients with recurrent or metastatic cervical cancer in combination with either cisplatin/paclitaxel or topotecan/paclitaxel.¹¹

In July 2017, the final results from the GOG 240 trial were published. The overall survival curves showed stable separation with a 3.5-month improvement when bevacizumab was added to chemotherapy (16.8 months vs. 13.3 months, p = .007). Although this improvement may appear modest, it should be considered that most patients survive only about 12 months at this stage of disease. When the different chemotherapy arms (with and without bevacizumab) were compared, topotecan/paclitaxel was associated with a higher risk of disease progression over cisplatin/paclitaxel (median PFS 5.7 months vs. 7.6 months, p= .008), but there was no significant effect on OS (12.5 vs. 15 months, p= .88). Adding bevacizumab to the cisplatin/paclitaxel regimen reduced the hazard of death (OS 17.5 months vs. 15.0 months, p= .04), but this did not reach significance when added to topotecan/paclitaxel (16.2 vs. 12.0 months, p= .15). Interestingly, however, complete and partial responses to topotecan/paclitaxel were almost doubled when bevacizumab was added to the regimen (48% vs. 25%, p=.0004), an effect not seen with cisplatin/paclitaxel. Substituting topotecan for cisplatin did not circumvent drug resistance to platinum, which may suggest that cervical cancer does not exhibit platinum resistance specifically but instead may be resistant to chemotherapy in general. Using topotecan as a non-platinum-based alternative may be advantageous in patients with platinum hypersensitivity or renal insufficiency. After bevacizumab was discontinued, the researchers did not observe a negative rebound effect (i.e., a survival shorter after bevacizumab is stopped than after chemotherapy alone is stopped), which has been observed in other cancers.¹⁰

Across the literature, bevacizumab is associated with toxicities like hypertension (5%–18%), surgical and wound healing complications (3%–15%), gastrointestinal fistulas (2%–15%), thrombotic events (2.3%–10.6%), gastrointestinal perforation (.3%–3.2%), and nephrotic syndrome (less than 1%).¹² Of these, fistula formation, which occurred in 15% of all bevacizumab-assigned patients in GOG 240, is one of the most concerning toxicities. A clinically significant fistula (grade 3, requiring intervention) occurred in 6% (n= 13) of patients receiving bevacizumab, versus less than 1% (n= 1) in the chemotherapy-alone group.¹⁰ Of note, all patients were previously irradiated. Recurrent or persistent disease in the pelvis following chemoradiation appears to be a risk factor for fistula formation, potentially due to the damage incurred to the microvasculature.¹³

GOG 240 also developed a set of prognostic factors known as the Moore criteria, which identify negative prognostic risk factors that may be used to help guide therapy. Negative prognostic factors included African American race, performance status 1, pelvic disease, prior treatment with cisplatin, and a progression-free interval less than 365 days. Risk categories included low-risk (0–1 factors), mid-risk (2–3 factors), and high-risk (4–5 factors). Patients in the high-risk group obtain the greatest benefit from bevacizumab (hazard ratio [HR] .536) compared to patients in the mid-risk (HR .673) or low-risk (HR .96) groups. Additionally, in low-risk patients treated with chemoradiation prior to recurrence, these criteria can be used to argue against including bevacizumab because the fistula risk is 8.6% with a very small survival benefit.¹³

GOG has now completed nine phase-3 randomized trials over 30 years in the cervical cancer patient population. Although considerable progress has been made, the challenge remains to find tolerable treatments that can further increase survival. Bevacizumab increases the survival of patients with advanced cervical cancer, but significant progress must still be made to cure patients of this devastating disease.  

References

1. American Cancer Society. 2017. https://www.cancer.org/cancer/cervical-cancer/about/key-statistics.html. Accessed September 9, 2017.
2. Small W Jr., Bacon MA, Bajaj A, et al. Cervical cancer: a global health crisis. Cancer 2017; published online May 2.
3. Green JA, Kirwan JM, Tierney JF. Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: a systematic review and meta-analysis. Lancet. 2001;358:781-786.
4. Long HJ 3rd, Bundy BN, Grendys EC Jr., et al. Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group study. J Clin Oncol. 2005 Jul 20;23(21):4626-4633.
5. Monk BJ, Sill MW, McMeekin DS, et al. Phase III trial of four cisplatin-containing double combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2009;27:4649-4655.
6. Tewari KS, Monk BJ. New strategies in cervical cancer: from angiogenesis blockade to immunotherapy. Clin Cancer Res. 2014;20(21):5349-5358. doi:10.1158/1078-0432.CCR-14-1099. [Epub 2014 Aug 7.]
7. Ferrara N, Hillan KJ, Gerber HP, et al. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 2004 May;3(5):391-400.
8. Wright JD, Viviano D, Powell MA, et al. Bevacizumab combination therapy in heavily pretreated, recurrent cervical cancer. Gynecol Oncol. 2006;103:489-493.
9. Monk BJ, Sill MW, Burger RA, et al. Phase II trial of bevacizumab in the treatment of persistent or recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol. 2009 Mar 1;27(7):1069-1074.
10. Krishnansu TS, Tewari S, Sill MW, et al. Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240). Lancet. 2017;390(10103):1654-1663. http://dx.doi.org/10.1016/S0140-6736(17)31607-0 [Epub ahead of print 27 July 2017]
11. National Comprehensive Cancer Network. Cervical Cancer (Version 1.2017). https://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf. Accessed September 9, 2017.
12. Avastin [package insert]. Genentech, San Francisco, CA; 2016.
13. Tewari KS, Sill MW, Monk BJ, et al. Prospective validation of pooled prognostic factors in women with advanced cervical cancer treated with chemotherapy with and without bevacizumab: a NRG Oncology/ Gynecologic Oncology Group Study. Clin Cancer Res. 2015 Dec 15;21(24):5480-5487.