Despite the introduction of screening and, latterly, vaccination programmes in the developed world, cervical cancer remains a significant global health problem. For those diagnosed with advanced or recurrent disease, even within resource-rich communities, prognosis remains poor with an overall survival (OS) of just over 12 months. New therapeutic interventions are urgently required. Advances in our understanding of the mechanisms underlying tumour growth and the downstream effects of human papilloma virus infection identified angiogenesis as a rational target for therapeutic intervention in cervical cancer. Anti-angiogenic agents showed promising activity in early-phase clinical trials culminating in a randomised phase III study of the humanised monoclonal antibody to vascular endothelial growth factor, bevacizumab, in combination with chemotherapy. This pivotal study, the Gynecologic Oncology Group (GOG) protocol 240, met its primary endpoint, demonstrating a significant improvement in OS. Bevacizumab became the first targeted agent to be granted regulatory approval by the US Food and Drug Administration for use alongside chemotherapy in adults with persistent, recurrent or metastatic carcinoma of the cervix. This review outlines the rationale for targeting angiogenesis in cervical cancer focusing on the current indications for the use of bevacizumab in this disease and future directions.
Angiogenesis, bevacizumab, recurrent and metastatic cervical cancer, target therapy, human papilloma virus
Ana Oaknin has served as a Consultant or advisory role for Roche, Astra-Zeneca and Clovis and as a speaker for Roche and Astra-Zeneca. Ana Oaknin has also received travel expenses from Roche, Astra-Zeneca and PharmaMar. Victor Rodriguez-Freixinos has nothing to disclose in relation to this article. No funding was received in the publication of this article.
This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit
October 07, 2015 Accepted:
November 19, 2015
Ana Oaknin, Hospital Universitario del Vall Hebrón, Vall d´Hebron Institute of Oncology (VHIO) Edificio Modulares Azules 1a planta Paseo Vall Hebrón 119-129, 08035 Barcelona, Spain. E: email@example.com
Worldwide, cervical cancer is the fourth most common cancer in women and seventh most common cancer overall. In 2012, approximately 528,000 new cervical cancer cases were diagnosed globally. Cervical cancer accounted for 7.5% of all female cancer deaths with approximately 266,000 deaths; the majority (87%) of these deaths occurred in developing countries.1,2 In Europe, the crude incidence of cervical cancer is 13.2/100,000 and the crude mortality rate is 5.9/100,000 women/year;3 in the US, according to the National Cancer Institute (NCI), a total of 12,900 and 4,100 women were estimated to be diagnosed and to have died from cervical cancer in 2015.4
The majority of invasive cervical cancers (70%) are caused by persistent infections with human papilloma virus (HPV) types 16 or 18. This has led to the development of vaccines against HPV16 and 18, which are available and recommended for girls from the age of 9 years, with catchup vaccination for women up to age 26. Although millions of doses have been provided to women and girls, the impact of the vaccine is still decades away.5 Between 80% and 90% of cervical carcinoma are squamous cell carcinomas. The second most common type is adenocarcinomas, which may be pure or mixed (adenosquamous carcinoma). While patients with the adenocarcinoma subtypes may have a poorer prognosis, the treatment recommendations for these subtypes are per the standard of care for cervical cancer as no other therapies have been defined, and these patients are included in all cervical cancer trials.
The Féderation Internationale de Gynécologie et d’Obstétrique (FIGO) cervical cancer staging (stage I–IV) is based on clinical examination, including tumour size (IA, B), vaginal or parametrial involvement (stage IIA–IIIB), bladder or rectum extension (stage IVA) and distant metastases (stage IVB). In its rules for clinical staging, FIGO states that palpation, inspection, colposcopy, endocervical curettage, hysteroscopy, cystoscopy, proctoscopy, intravenous urography and radiographic examination of the lungs and skeleton may be used for clinical staging. FIGO clinical staging criteria do not allow inclusion of computed tomography (CT) scan or magnetic resonance imaging (MRI) for the establishment of stage; however, the current standards of care consider patients with evidence of distant metastasis noted on these imaging modalities as having metastatic or stage IVB disease.
Early-stage cervical cancer is a potentially curable disease by surgery (FIGO stage IA/B1 disease); however, in locally advanced stage disease (FIGO stage II–IVA) the mainstay of primary treatment is combination radiation therapy and radiation sensitising platinum-based chemotherapy. These stages are usually characterised by large central pelvic tumours that are necrotic and often the cause of significant bleeding, as well as the involvement of adjacent pelvic organs (vagina, bladder, rectum, ureters). Up to 70% of patients with bulky primary or advanced disease will have a recurrence, which is generally considered incurable, particularly if distant metastases have developed. Patients with metastatic cancers and those with persistent or recurrent disease after platinum-based chemoradiotherapy not suitable for local control have poor outcomes, with 5-year survival rates between 5% and 15%.6 In this setting any treatment is palliative and the goals of care are to prolong survival but also, and perhaps more importantly, to maintain and/or improve quality of life (QoL).
Chemotherapy, though essentially palliative, is usually recommended for these patients, and although the optimal regimen for chemotherapy has not been defined, cisplatin combination therapy has been considered the standard of care for the last decade. Carboplatin or non platinum regimens (e.g., paclitaxel or topotecan) are options for patients who cannot tolerate cisplatin.5,7 Unfortunately, there are no standard second-line options for these women when their cancer progresses, therefore new therapeutic approaches are urgently required. Conducting clinical trials in cervical cancer patients pose particular difficulties due to their demographic characteristics. Most of the women diagnosed with advanced cervical cancer come from sections of society where, historically, engagement in clinical research has been low and where cost effectiveness and access to new treatments for those in need are major concerns issues.
Targeting angiogenesis is one of the most promising therapeutic strategies to emerge in recent years in the treatment of cervical cancer. Angiogenesis is a critical process in cervical carcinogenesis and tumour progression. Following the publication in 2014 of the randomised phase III study Gynecologic Oncology Group (GOG) 240, the US Food and Drug Administration (FDA) approved the first anti-angiogenic agent, bevacizumab (Avastin©, Genentech/Roche, California, United States), in combination with chemotherapy for use in women with advanced cervical cancer.8 This article will review the rationale for studying antiangiogenic therapy in cervical cancer, focus on the clinical use of bevacizumab and finally highlight potential future directions.
Unmet medical need in advanced cervical cancer and rationale for selection of chemotherapy agents
Improving overall survival (OS) has remained the primary endpoint for clinical trials in advanced cervical cancer, as the prognosis for women with persistent, recurrent or stage IVB cervical cancer remains poor with median durations of OS ≤12 months. In addition, OS has been selected as the primary endpoint because unlike what we see in other cancers, this population is not able to receive multiple lines of chemotherapy.
Over the past 3 decades, the GOG has studied the efficacy and tolerability of different cytotoxic regimens for metastatic and recurrent cervical cancer.9The studies GOG-169 and GOG-179 evaluated the clinical efficacy and safety of cisplatin-based doublets against singleagent cisplatin with paclitaxel or topotecan combinations displaying improvements in OS, progression free survival (PFS) and overall response rates (ORR) compared with cisplatin monotherapy. However, only the combination of cisplatin and topotecan achieved a statistically significant impact on ORR, PFS and OS (i.e., difference in median OS of 2.9 months [hazard ratio (HR) = 0.76; 95% confidence interval (CI):
0.593–0.979]).10,11 This study was the basis for the regulatory approval of the combination of topotecan and cisplatin for advanced/recurrent cervical cancer.11
As the use of cisplatin-based chemoradiation had become increasingly prevalent, the GOG analysed the response rates regarding the previous use of cisplatin in studies GOG-169 and GOG-179, only 27% of patients treated on GOG-169 received prior radiosensitising chemotherapy compared with 57% of patients on GOG-179, and noted that for those patients treated previously with cisplatin, the response rates for cisplatin and paclitaxel were superior compared with cisplatin and topotecan (32% versus 15%, respectively) (see Table 1).
1. Ferlay J, Soerjomataram I, Dikshit R, et al., Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012, Int J Cancer, 2015;136:E359–86.
2. World Cancer Research Fund International. Cervical cancer statistics. Available at: www.wcrf.org/int/cancer-facts-figures/ data-specificcancers/cervical-cancer statistics (accessed 29 December 2015).
3. Anttila A, von Karsa L, Aasmaa A, et al., Cervical cancer screening policies and coverage in Europe, Eur J Cancer, 2009;45:2649–58.
4. National Cancer Institute. SEER Stat Fact Sheets: Cervix Uteri Cancer Available at: http://seer.cancer.gov/statfacts/html/ cervix.html (accessed 29 December 2015).
5. Colombo N, Carinelli S, Colombo A, et al., Cervical cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Ann Oncol, 2012;23(Suppl. 7):vii27–vii32.
6. Waggoner SE, Cervical cancer, Lancet, 2003;361:2217–25.
7. Monk BJ, Sill MW, McMeekin DS, et al., Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study, J Clin Oncol, 2009;27:4649–55.
8. FDA News Release, FDA approves Avastin to treat patients with aggressive and late-stage cervical cancer. US Food and Drug Administration. Available at: www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ucm410121.htm (accessed 29 December 2015).
9. Tewari KS, Monk BJ, Gynecologic Oncology Group trials of chemotherapy for metastatic and recurrent cervical cancer, Curr Oncol Rep, 2005;7:419–34.
10. Moore DH, Blessing JA, McQuellon RP, et al., Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study, J Clin Oncol, 2004;22:3113–9.
11. Long HJ III, Bundy BN, Grendys EC Jr, et al.; Gynecologic Oncology Group Study, 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;23:4626–33.
12. Monk BJ, Sill MW, McMeekin DS, et al., Phase III trial of four cisplatin containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study, J Clin Oncol, 2009;27:4649–55.
13. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Cervical Cancer. Version 1.2014. NCCN org. Available at: www.nccn.org/professionals/ physician gls/pdf/ cervical.pdf (accessed 29 December 2015).
14. Kitagawa R, Noriyuki K, Shibata T, et al., Paclitaxel plus Carboplatin versus Paclitaxel plus Cisplatin in metastatic or recurrent cervical Cancer: The Open-Label Randomized Phase III Trial JCOG0505, J Clin Oncol, 2015;33:2129–35.
15. Moore DH, Tian C, Monk BJ, et al., Prognostic factors for response to cisplatin-based chemotherapy in advanced cervical carcinoma: a Gynecologic Oncology Group Study, Gynecol Oncol, 2010;116:44–9.
16. Symonds R, Davidson S, Chan S, et al., SCOTCERV: a phase II trial of docetaxel and gemcitabine as second-line chemotherapy in cervical cancer, J Clin Oncol (ASCO Annual Meeting Abstracts), 2007;25:Abstract 5548.
17. Tiersten AD, Selleck MJ, Hershman DL, et al., Phase II study of topotecan and paclitaxel for recurrent, persistent, or metastatic cervical carcinoma, Gynecol Oncol, 2004;92:635–8.
18. Tang N, Wang L, Esko J, et al., Loss of HIF-1α in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis, Cancer Cell, 2004;6:485–95.
19. Ferrara N, Gerber HP, LeCouter J, The biology of VEGF and its receptors, Nature Med, 2003;9:669–76.
20. Park JE, Chen HH, Winer J, et al., Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR, J Biol Chem, 1994;269:25646–54
21. Olofsson B, Korpelainen E, Pepper MS, et al., Vascular endothelial growth factor B (VEGF-B) binds to VEGF receptor-1 and regulates plasminogen activator activity in endothelial cells, Proc Natl Acad Sci U S A, 1998;95:11709–14.
22. Alitalo K, Tammela T, Petrova TV, Lymphangiogenesis in development and human disease, Nature, 2005;438:946–53.
23. Hellström M, Gerhardt H, Kalén M, et al., Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis, J Cell Biol, 2001;153:543–53.
24. Folkman J, Tumor angiogenesis: therapeutic implications, N Engl J Med, 1971;285:1182–6.
25. Jain RK, Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy, Science, 2005;307:58–62.
26. IARC monographs on the evaluation of carcinogenic risks to humans. Human papillomaviruses. Vol 64. Lyon (France): International Agency for Research on Cancer, 1995.
27. Ojesina AI, Lichtenstein L, Freeman SS, et al., Landscape of genomic alterations in cervical carcinomas, Nature, 2014;506:371–5.
28. Bosch FX, Lorincz A, Munoz N, et al., The causal relation between human papillomavirus and cervical cancer, J Clin Pathol, 2002;55:244–65.
29. Willmott LJ, Monk BJ, Cervical cancer therapy: current, future and anti-angiogensis targeted treatment, Expert Rev Anticancer Ther, 2009;9:895–903.
30. Nakamura M, Bodily JM, Beglin M, et al., Hypoxia-specific stabilization of HIF-1alpha by human papillomaviruses, Virology, 2009;387:442–8.
31. Bodily JM, Mehta KP, Laimins LA, et al., Human papillomavirus E7 enhances hypoxia-inducible factor 1-mediated transcription by inhibiting binding of histone deacetylases, Cancer Res, 2011;71:118–95.
32. Smith-McCune KK, Weidner N, Demonstration and characterization of the angiogenic properties of cervical dysplasia, Cancer Res, 1994;54:800–4.
33. Cooper RA, Wilks DP, Logue JP, et al., High tumor angiogenesis is associated with poorer survival in carcinoma of the cervix treated with radiotherapy, Clin Cancer Res, 1998;4:2795–800.
34. Peters WA III, Liu PY, Rolland J, et al., Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix, J Clin Oncol, 2000;1606–13.
35. Randall LM, Monk BJ, Darcy KM, et al., Markers of angiogenesis in high-risk, early-stage cervical cancer: a Gynecologic Oncology Group study, Gynecol Oncol, 2009;112:583–9.
36. Zijlmans HJ, Fleuren GJ, Hazelbag S, et al., Expression of endoglin (CD105) in cervical cancer, Br J Cancer, 2009;100:1617–26.
37. Dobbs SP, Hewett PW, Johnson IR, et al., Angiogenesis is associated with vascular endothelial growth factor expression in cervical intraepithelial neoplasia, Br J Cancer, 1997;76:1410–5.
38. Lebrecht A, Ludwig E, Huber A, et al., Serum vascular endothelial growth factor and serum leptin in patients with cervical cancer, Gynecol Oncol, 2002;85:32–5.
39. Loncaster JA, Cooper RA, Logue JP, et al., Vascular endothelial growth factor (VEGF) expression is a prognostic factor for radiotherapy outcome in advanced carcinoma of the cervix, Br J Cancer, 2000;83:620–5.
40. Grothey A, Galanis E, Targeting angiogenesis: progress with anti-VEGF treatment with large molecules, Nat Rev Clin Oncol, 2009;6:507–18.
41. Wright JD, Viviano D, Powell MA, et al., Bevacizumab combination therapy in heavily pretreated, recurrent cervical cancer, Gynecol Oncol, 2006;103:489–93.
42. 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;27:1069–74.
43. Weber DC, Skilling JH, A first course in the design of experiments A linear models approach, CRC, 2000.
44. Tewari KS, Sill MW, Monk BJ, et al., Phase III randomized clinical trial of cisplatin plus paclitaxel versus the nonplatinum chemotherapy doublet of topotecan plus paclitaxel in women with recurrent, persistent, or advanced cervical carcinoma: A Gynecologic Oncology Group study [SGO abstract 1], Gynecol Oncol, 2013;130:e2.
45. Eskandera RN, Javab J, Monk BJ, et al., Complete responses in the irradiated field following treatment with chemotherapy with and without bevacizumab in advanced cervical cancer: An NRG Oncology/Gynecologic Oncology Group study. SGO Women’s Health meeting 2014. Abstract 62, Gynecol Oncol, 2015;137:2–91.
46. Tewari KS, Sill M, Moore DH, et al., High-risk patients with recurrent/advanced cervical cancer may derive the most benefit from antiangiogenesis therapy: A Gynecologic Oncology Group (GOG) study. SGO Women’s Health meeting 2014. Abstract 144, Gynecol Oncol, 2014;133:2–207.
47. Willmott LJ, Java JJ, Monk BJ, et al., Fistulae in women treated with chemotherapy with and without bevacizumab for persistent, recurrent or metastatic cervical cancer in GOG- 240. International Gynecologic Cancer Society meeting; 8-11 November 2014; Melbourne, Australia 2014.
48. Cella D, Huang HQ, Monk BJ, et al., Health-related quality of life outcomes associated with four cisplatin-based doublet chemotherapy regimens for stage IVB recurrent or persistent cervical cancer: a Gynecologic Oncology Group study, Gynecol Oncol, 2010;119:531–7.
49. Penson RT, Huang HQ, Wenzel LB, et al., Bevacizumab for advanced cervical cancer: patient- reported outcomes of a randomised, phase 3 trial (NRG Oncology–Gynecologic Oncology Group protocol 240), Lancet Oncol, 2015;16:301–11.
50. FDA grants Genentech’s Avastin priority review for certain types of cervical cancer [press release] Genentech. Available at: www.gene.com/media/press-releases/ 14569/2014-07- 14/fda-grants-genentechs-avastin-priority-r (accessed: 29 December 2015).
51. EU approves Roche's Avastin plus chemotherapy for women with advanced cervical cancer [press release Roche. Available at: www.roche.com/media/store/releases/medcor- 2015-04-08.htm (accessed 29 December 2015).
52. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Cervical Cancer. Version 1.2014. NCCN org. Available at: www.nccn.org/professionals/ physician gls/pdf/ cervical.pdf (accessed 29 December 2015).
53. Tewari KS, Sill MW, Penson RT, et al., Final Overall Survival Analysis of the Phase III Randomized Trial of Chemotherapy with and without Bevacizumab for Advanced Cervical Cancer: A NRG Oncology-Gynecologic Oncology Group Study. ESMO Congress 2014. Abstract LBA26, Ann Oncol, 2014;25:1–41.
54. Tewari KS, Sill M, Monk BJ, et al., Impact of circulating tumor cells (CTCs) on overall survival among patients treated with chemotherapy plus bevacizumab for advanced cervical cancer: An NRG Oncology/Gynecologic Oncology Group study. SGO Women’s Health meeting 2014. Abstract 24, Gynecol Oncol, 2015;137:2–91.
55. Phippen NT, Leath CA 3rd, Havrilesky LJ, Barnett JC, Bevacizumab in recurrent, persistent, or advanced stage carcinoma of the cervix: is it cost-effective?, Gynecol Oncol, 2015;136:4–7.
56. Minion Le, Bai J, Monk BJ, et al., A Markov model to evaluate cost-effectiveness of antiangiogenesis therapy using bevacizumab in advanced cervical cancer, Gynecol Oncol, 2015;33:966.
57. Tewari KS, Sill MW, Long HJ III, et al., Improved survival with bevacizumab in advanced cervical cancer, N Engl J Med, 2014;370:734–43
58. Bonomi P, Blessing JA, Stehman FB, et al., Randomized trial of three cisplatin dose schedules in squamous-cell carcinoma of the cervix: a Gynecologic Oncology Group study, J Clin Oncol, 1985;3:1079–85.
59. Bloss JD, Blessing JA, Behrens BC, et al., Randomized trial of cisplatin and ifosfamide with or without bleomycin in squamous carcinoma of the cervix: a gynecologic oncology group study, J Clin Oncol, 2002;20:1832–7.
60. Aghajanian C, Blank SV, Goff BA, et al. OCEANS: A Randomized, Double-Blind, Placebo-Controlled Phase III Trial of Chemotherapy With or Without Bevacizumab in Patients With Platinum-Sensitive Recurrent Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer. J Clin Oncol. 2012;30:2039-2045.
61. Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365:2473-2483.
62. Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365:2484-2496.
63. Schefter T, Winter K, Kwon JS, et al., RTOG 0417: Efficacy of Bevacizumab in combination with definitive radiation therapy and cisplatin chemotherapy in untreated patients with locally advanced cervical carcinoma, Int J Radiat Oncol, 2014;88:101–5.
64. Monk BJ, Mas Lopez L, Zarba JJ, et al., Phase II, open-label study of pazopanib or lapatinib monotherapy compared with pazopanib plus lapatinib combination therapy in patients with advanced and recurrent cervical cancer, J Clin Oncol, 2010;28:3562–9.
65. Monk BJ, Pandite LN, Survival data from a phase II, open-label study of pazopanib or lapatinib monotherapy in patients with advanced and recurrent cervical cancer, J Clin Oncol, 2011;29:4845.
66. Mackay HJ, Tinker A, Winquist E, et al., A phase II study of sunitinib in patients with locally advanced or metastatic cervical carcinoma: NCIC CTG Trial IND.184, Gynecol Oncol, 2010;116:163–7.
67. Symonds P, Gourley C, Davidson S, et al., CIRCCA: a randomised double blind phase II trial of carboplatin paclitaxel plus cediranib versus carboplatin-paclitaxel plus placebo in metastatic/recurrent cervical cancer, Ann Oncol, 2014;25(Suppl. 4):LBA25-PR.
68. Basu P, Mehta AO, Jain MM, et al., ADXS11-001 immunotherapy targeting HPV-E7: final results from a phase 2 study in Indian women with recurrent cervical cancer, J Clin Oncol, 2014;32:5s (suppl;abstr 5610).
69. Hinrichs CS, Stevanovic S, Draper L, et al., HPV-targeted tumor-infiltrating lymphocytes for cervical cancer, J Clin Oncol, 2014;32:5s (suppl;abstr LBA3008).