Breaking down the evidence for bevacizumab in advanced cervical cancer: past, present and future

Abstract

Despite the introduction of screening and, latterly, vaccination programs in the developed world, globally cervical cancer remains a significant 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 tumor growth and the downstream effects of human papilloma virus (HPV) 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 randomized phase III study of the humanized monoclonal antibody to vascular endothelial growth factor (VEGF), bevacizumab, in combination with chemotherapy. This pivotal study, the Gynecologic Oncology Group 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 United States 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.

A new marker based on risk stratification of human papillomavirus DNA and tumor size to predict survival of locally advanced cervical cancer

“…E5, E6, and E7 are the key HPV oncoproteins that induce cancer occurrence and progression. These oncoproteins can upregulate angiogenesis and increase the production of vascular endothelial growth factor, which is responsible for cancer recurrence and progression 27. In this study we found that lower HPV DNA load was associated with worse overall survival and distant metastasis-free survival, which concurs with research on populations of early-stage cervical cancer treated with surgery and later-stage patients with radiotherapy 8 9.…”

Cervical cancer – State of the science: From angiogenesis blockade to checkpoint inhibition

“…Molecularly, viral integration of oncogenic HPVs and expression of viral proteins E6 and E7 inhibit key cellular regulatory pathways governed by tumor suppressor gene products. Specifically, E6 increases p53 ubiquitination, and E7 inactivates retinoblastoma protein and induces hypoxia-inducible factor 1-alpha, ultimately leading to up-regulated VEGF expression which drives tumor angiogenesis [18–20].…”

The Incorporation of Immunotherapy and Targeted Therapy Into Chemoradiation for Cervical Cancer: A Focused Review

“…There is evidence that VEGF plays a role in human papilloma virus (HPV) mediated oncogenesis of cervical cancer, including through activity of oncoprotein E5 to upregulate the VEGF angiogenesis pathway ( 1 ). VEGF is a growth factor responsible for the proliferation, migration, and survival of endothelial cells.…”

“…Treatment options for early-stage cervical cancer include surgery or primary radiation with or without chemotherapy ( 1 ). Surgery in the form of radical hysterectomy is indicated for non-bulky and early stage disease although definitive radiotherapy has similar efficacy.…”