Clinical Trials of Antiangiogenesis Therapy in Recurrent/Persistent and Metastatic Cervical Cancer

Gynecologic Oncology Clinical Trials of Antiangiogenesis Therapy in Recurrent/Persistent and Metastatic Cervical Cancer J ILL K. A LLDREDGE , K RISHNANSU S. T EWARI University of California, Irvine, Orange, California, USA Key Words. Uterine cervical neoplasms x Angiogenesis inhibitors x Biological markers x Clinical trials x Cervical cancer x Clinical trials x Antiangiogenesis therapy x Biomarkers A BSTRACT Background. Treatment options for women with metastatic, per- sistent, or recurrent cervical cancer are limited and thus the disease portends a poor prognosis. It is critical to understand the path- ophysiology of cervical cancer to better delineate therapeutic targets. The development of antiangiogenic therapies and their subsequent analysis in rigorous therapeutic trials have redefined current management strategies and is an exciting area of current exploration. Results. Translational trials have furthered the understand- ing of molecular determinants of angiogenesis. Phase II trials have shown promising trends with developing antiangiogenic therapies. A practice-changing phase III trial has recently been published. Given the potential benefits and different toxicity spectrum compared with standard cytotoxic chemotherapy, antiangiogenic options are under active investigation for this vulnerable patient population. Emerging data are promising for other antiangiogenic-directed therapeutics, as well as cervical cancer molecular biomarkers to guide diagnosis and treatment. Conclusion. Antiangiogenic therapies have evolved during the past 20 years and remain an exciting area of current exploration. The Oncologist 2016;21:576–585 Implications for Practice: Understanding of the angiogenic microenvironment has furthered understanding of tumor biology and management. Antiangiogenic therapies show promise for women with advanced cervical cancer. A review of the evolution of these biologic agents shows them to be an effective and tolerable management strategy for many patients in this vulnerable population, with exciting future potential. I NTRODUCTION On the global scale, numerically, cervical cancer remains the most lethal gynecologic malignancy, with 529,800 new cases and 275,100 deaths in 2011 [1]. Because of effective screening and early detection through the Papanicolaou test and improving dissemination of the human papilloma- virus (HPV) vaccine, cervical cancer is less prevalent in the U.S.; however, it continues to be a severe burden, with 12,990 new cases diagnosed and 4,120 deaths in 2016 alone [2]. A subset of these women will present with metastatic disease or develop recurrent disease after initial therapy. Unfortu- nately, treatment strategies for these patients are limited to palliation of symptoms, with most efforts to control disease progression and prolong life meeting with relatively poor success [3]. On the basis of several clinical trials, the backbone of therapy was established as cisplatin and paclitaxel [4]. Poor outcomes in this population despite chemotherapy have necessitated continued exploration into new therapeutic strategies. C ERVICAL C ANCER P ATHOGENIC M OLECULAR C ASCADE It is well-established that squamous cell carcinoma of the cervix is strongly associated with infection by high-risk sub- types of HPV [5]. Of these subtypes, HPV-16 and HPV-18 are responsible for 70% of invasive cervical cancer and 50% of high-grade cervical intraepithelial neoplasia [6, 7]. Specifically, it is dysregulation of the HPV E6 and E7 oncogenes that facili- tates transformation and maintenance of a dysplastic and sub- sequently malignant phenotype [8, 9]. Dysregulation of oncogene expression induces chromo- somal instability, promoting integration of the HPV genome into cellular chromosomes [10].This results in disruption of the E2 transcription regression factor, thereby causing enhanced E6 and E7 activity. E6 degrades the cellular tumor suppressor gene product, p53, leading to an arrest of DNA repair and apoptosis and thus continued cellular proliferation [11]. Con- versely, E7 inactivates another cellular tumor suppressor gene product, pRb, which results in upregulation of p53 and Correspondence: Krishnansu S. Tewari, M.D., University of California, Irvine, Medical Center, 101 The City Drive South, Building 56, Orange, CA 92868, USA. Telephone: 714-456-8020; E-Mail: ktewari@uci.edu Received September 30, 2015; accepted for publication December 1, 2015; published Online First on March 29, 2016. ©AlphaMed Press 1083-7159/2016/$20.00/0 http://dx.doi.org/10.1634/theoncologist.2015-0393 The Oncologist 2016;21:576–585 www.TheOncologist.com ©AlphaMed Press 2016