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

BACKGROUND: Treatment options for women with metastatic, persistent, or recurrent cervical cancer are limited and thus the disease portends a poor prognosis. It is critical to understand the pathophysiology 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 understanding 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. 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.

Perineal body stretch during labor does not predict perineal laceration, postpartum incontinence, or postpartum sexual function: a cohort study.

INTRODUCTION AND HYPOTHESIS: The perineum stretches naturally during obstetrical labor, but it is unknown whether this stretch has a negative impact on pelvic floor outcomes after a vaginal birth (VB). We aimed to evaluate whether perineal stretch was associated with postpartum pelvic floor dysfunction, and we hypothesized that greater perineal stretch would correlate with worsened outcomes. METHODS: This was a prospective cohort study of primiparous women who had a VB. Perineal body (PB) length was measured antepartum, during labor, and 6 months postpartum. We determined the maximum PB (PBmax) measurements during the second stage of labor and PB change (ΔPB) between time points. Women completed functional questionnaires and had a Pelvic Organ Prolapse Quantification (POP-Q) system exam 6 months postpartum. We analyzed the relationship of PB measurements to perineal lacerations and postpartum outcomes, including urinary, anal, and fecal incontinence, sexual activity and function, and POP-Q measurements. RESULTS: Four hundred and forty-eight women with VB and a mean age of 24 ± 5.0 years with rare (5 %) third- or fourth-degree lacerations were assessed. During the second stage of labor, 270/448 (60 %) had perineal measurements. Mean antepartum PB length was 3.7 ± 0.8 cm, with a maximum mean PB length (PBmax) during the second stage of 6.1 ± 1.5 cm, an increase of 65 %. The change in PB length (ΔPB) from antepartum to 6 months postpartum was a net decrease (-0.39 ± 1.02 cm). PB change and PBmax were not associated with perineal lacerations or outcomes postpartum (all p > 0.05). CONCLUSIONS: PB stretch during labor is unrelated to perineal laceration, postpartum incontinence, sexual activity, or sexual function.

EZH2 inhibition in ARID1A mutated clear cell and endometrioid ovarian and endometrioid endometrial cancers.

Clear cell carcinoma and endometrioid adenocarcinoma are histologic subtypes of ovarian and uterine cancer that demonstrate unique clinical behavior but share common underlying genomic aberrations and oncogenic pathways. ARID1A mutations are more frequently identified in these tumors, in comparison to other gynecologic histologies, and loss of ARID1A tumor suppressor function is thought to be an essential component of carcinogenic transformation. Several therapeutic targets in ARID1A mutated cancers are in development, including EZH2 inhibitors. EZH2 facilitates epigenetic methylation to modulate gene expression, and both uterine and ovarian cancers show evidence of EZH2 over expression. EZH2 inhibition in ARID1A mutated tumors acts in a synthetically lethal manner to suppress cell growth and promote apoptosis, revealing a unique new therapeutic opportunity. Several phase 1 and 2 clinical trials of EZH2 inhibitors are ongoing currently and there is considerable promise in translational trials for utilization of this new targeted therapy, both to capitalize on ARID1A loss of function and to increase sensitivity to platinum-based adjuvant chemotherapies. This review will synthesize the molecular carcinogenesis of these malignancies and their unique clinical behavior, as a foundation for an emerging frontier of targeted therapeutics - the synergistic inhibition of EZH2 in ARID1A mutated cancers.