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Review Cervical Cancer Bevacizumab in the Treatment of Cervical Cancer – Current Evidence and Next Steps Ana Oaknin 1 and Victor Rodriguez-Freixinos 2 1. Medical Oncology Department, Gynecologic Oncology Cancer Division, Vall d’Hebron University Hospital and Vall d’Hebron Insitute of Oncology (VHIO), Barcelona, Spain; 2. Division of Medical Oncology and Hematology, Princess Margaret Hospital, University of Toronto, Canada Abstract 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. Keywords Angiogenesis, bevacizumab, recurrent and metastatic cervical cancer, target therapy, human papilloma virus Disclosure: 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. Open Access: 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. Received: 7 October 2015 Accepted: 19 November 2015 Citation: European Oncology & Haematology, 2016;12(1):32–43 Correspondence: 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: aoaknin@vhio.net 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 catch- up 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 32 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 TOU C H ME D ICA L ME D IA