Faculty Bibliography

Objective: Data regarding conservative treatment of endometrial neoplasia (EN) consist of case series and nonstandardized treatments. Prospective trial design for this regimen has been fraught with incongruity. We sought to design and implement a protocol for the conservative management of EN using a consistent treatment regimen, assessment of response, and endpoints. Methods: Women with atypical endometrial hyperplasia (AEH) or grade 1 and 2 endometrioid endometrial carcinoma (EC) with gynecologic pathologist- confirmed diagnoses, no evidence of myometrial invasion or extrauterine disease on imaging, and no contraindication to megestrol acetatewho desired conservative management of EN were enrolled on this phase 2 study. Women received 160 mg of megestrol daily. After 12 weeks of treatment, office endometrial biopsy (EMB) was performed. If EMB did not reveal negative endometrium or progression, patients could continue treatment. Those with negative EMB underwent dilation and curettage (D&C) to confirm response, and endpointwas described as pathologic complete response (pCR) on D&C. Patientswithout pCR orwith progression continued onmegestrol for an additional 12 weeks, after which they were similarly reassessed. There were no dose escalations or modifications. Treatment could continue if necessary for as long as 24 months. After pCR, patients were instructed to pursue fertility or start a lower-dose progestin-based maintenance agent. Under this 1-stage design, a sample size of 30 patients achieved 80% power to detect a difference of 0.25 between the H0 of 0.4 and the H1 of 0.65 using a 2-sided Z test. Results: Among 31 patients enrolled in the study, 30 underwent protocol-defined treatment. Ages ranged from 27 to 49 years, with a median age of 37.5 years. 42% of patients were not Caucasian. Median time on study was 210 days (range, 50-768 days). To date, 13/30 (43%) experienced pCR, 3/30 (10%) a partial response, 5/30 (17%) an unconfirmed complete response, 7/30 (23%) stable disease with 3 sti!

Objective: Irinotecan and bevacizumab have single-agent activity in both platinum- sensitive and -resistant recurrent ovarian cancer. We sought to evaluate the efficacy and safety of irinotecan in combination with bevacizumab in these patients. The primary end point of the study was to estimate the progression-free survival (PFS) rate at 6 months. Secondary objectives included overall survival, observed response rate, duration of response, and toxicity. Methods: Patients with recurrent ovarian cancerwho had received any number of prior regimens were eligible. Irinotecan 250 mg/m2 (amended to 175 mg/m2 after treatment-related toxicities in the first 6 patients) and bevacizumab 15 mg/kg every 3 weeks were administered until disease progression or toxicity. Response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) every 2 cycles and by CA-125 criteria for those patients without measurable disease. Results: Thus far, 25 of the planned 35 patients have been enrolled in the study. Themedian age was 61 years (range, 45-78 years). Seven patients were platinum-sensitive and 18 patients were platinum-resistant. The median number of prior regimens was 5 (range, 1-12), with 10 patients having received prior bevacizumab-containing therapies and 9 patients prior topotecan-containing therapies. The median number of study treatments received was 6 cycles (range, 1-25 cycles); 4 patients withdrew after only 1 cycle (3 due to toxicity and 1 due to physician discretion). Of the 19 patients assessable for response at this time, 5 patients experienced partial response (PR), 11 patientsmaintained stable disease (SD), and 3 patients had progressive disease. Eleven of the patients with PR/SD were platinum-resistant. The observed clinical benefit rate (PR+SD) was 68% (95% CI: 50%, 86%) for the 25 enrolled patients (intention to treat). Durable responses were observed, with 9 patients having longer than 24 weeks of sustained response. Themedian PFS was 8.1 months, and the median overall survival was!

Background Suppression of neoangiogenesis and pegylated liposomal doxorubicin (PLD) each contribute to the management of platinum-resistant/refractory ovarian cancer. The aim of this study is to test the combination of bevacizumab and PLD in women with resistant or refractory ovarian cancer. Methods Eligibility criteria were no more than two prior treatments with platinum-containing regimens and one additional regimen, without anthracyclines. Treatment was administered every 3 weeks (bevacizumab 15 mg/kg beginning on cycle 2 and PLD 30 mg/m(2)). The primary end point was progression-free survival (PFS) at 6 months; the secondary end points included side-effects, overall response rates (ORR) and survival (OS). Results Forty-six patients were enrolled. The average number of courses administered was 7. The median PFS was 6.6 months (range 1-24.6 months) according to Gynecologic Cancer Intergroup Committee (GCIC) criteria and 7.8 months (range 2-13.3 months) according to Response Evaluation Criteria in Solid Tumors (RECIST). The median OS was 33.2 months (range 3-37.5+ months). The ORR was 30.2% [95% confidence interval (CI) 17.2-46.1] and the clinical benefit rate (CBR) was 86.1% (95% CI 72.1-94.7). Adverse events included mucosal and dermal erosions (30% grade 3) and asymptomatic cardiac dysfunction. Additional toxic effects included hypertension, headache, renal dysfunction and proteinuria, wound healing delay, and one episode each of central nervous system (CNS) ischemia and hemolytic uremic syndrome. Conclusion PLD with bevacizumab has improved activity in recurrent ovarian cancer with increased toxicity.

Background: The majority of endometrial cancers present as early stage tumors, yet those that are advanced at diagnosis are associated with poor outcomes. The role of radical debulking surgery for endometrial cancer is not clear. However, the use of neoadjuvant chemotherapy is also unproven. We sought to evaluate if utilizing neoadjuvant chemotherapy for advanced endometrial cancer affected outcomes. Methods: A retrospective review from two hospitals served by one academic center from 2002 to 2011 was performed. All patients with stage 3 or 4 disease were identified. Patients with non-epithelial cell types, including carcinosarcoma, were excluded. Patients who received neoadjuvant treatment prior to surgery were identified. A case-control design was utilized matching patients 1:3 or 1:4 stratified by age, stage, grade, histology and performance status. Descriptive statistics and nonparametric analyses were utilized. Results: A total of 115 patients with advanced endometrial cancer were identified. 19 were excluded due to wrong cell type and 1 due to stage 3 disease based on positive cytology. 6 patients had a neoadjuvant treatment approach (NAs). 20 patients were identified as matched controls (CTRLs). The average age was 61 for the NAs, and 63 for the CTRLs. The average BMI was 26.9 for the NAs, and 27.4 for the CTRLs. NAs were more likely to have stage 4 disease-5/6 NAs versus 5/20 CTRLs. Both groups had a high proportion of grade 3 tumors-4/6 NAs versus 15/20 CTRLs. The performance status was similar in both groups. The median number of chemotherapy cycles was 11 in the NAs, and 4 in the CTRLs. 18/20 CTRLs received adjuvant treatment, and 17 included systemic chemotherapy. In the NAs, with a median follow-up of 17 months, 4 were alive with disease (AWD) and 2 were dead of disease (DOD). In the CTRLs, with a median follow-up of 14 months, 7 patients were NED, 8 were AWD, and 5 were DOD. Conclusions: Despite a small sample size, our results indicate that primary surgery remains the preferred s!

OBJECTIVE: : To identify patient characteristics associated with bilateral oophorectomy or removal of remaining ovary at the time of benign hysterectomy, and to estimate trends in the performance of oophorectomy from 2001 to 2006. METHODS: : This was a cross-sectional analysis using the New York State Department of Health Statewide Planning and Research Cooperative System. Women aged 18 years or older undergoing hysterectomies for benign gynecologic conditions were included. We evaluated factors associated with oophorectomy on both univariable and multivariable analyses and assessed for changes in performance of oophorectomy over the course of the study. RESULTS: : Forty-seven percent of 144,877 hysterectomies included oophorectomy. Women who underwent oophorectomy were older and were more likely to have a family history of breast or ovarian cancer, a personal history of breast cancer, ovarian cysts, or endometriosis. Women who underwent vaginal or laparoscopic hysterectomy or had uterine prolapse were less likely to undergo oophorectomy. Both race and insurance status were associated with performance of oophorectomy. From 2001 to 2006, there was an 8% absolute decrease in the performance of oophorectomy at the time of benign hysterectomy for women of all ages, with a 10.4% decrease in women aged younger than 55 (P for trend <.001). CONCLUSION: : Age, route of hysterectomy, and concomitant gynecologic diagnoses influence oophorectomy rate. From 2001 to 2006, a significant decrease in the performance of oophorectomy at the time of benign hysterectomy was noted in women aged younger than 55 years. Recent studies of complications of hormone therapy and prophylactic oophorectomy may have influenced patients' and physicians' decision-making, leading to lower oophorectomy rates. LEVEL OF EVIDENCE: : II

Epithelial ovarian cancer (EOC) patients with BRCA mutations (BRCA+) benefit from platinum-based treatment more than non-carriers. Impaired ability to repair DNA by homologous recombination increases their chemosensitivity. We investigated whether BRCA+ predicts for improved outcome following pegylated liposomal doxorubicin (PLD) for recurrence. Recurrent EOC patients receiving second- or third-line PLD from 1998 to 2009 in 4 institutions (Israel, Italy, NY) were subjected to retrospective comparisons between 40(25.8%) patients who were BRCA+, and 115(74.2%) deemed non-hereditary (NH). Median age was 59 years (range 31-83); 111(72%) had a platinum-free interval >6 months (PLD alone [n=65] and PLD plus platinum[n=90]); 104 received PLD in second-line and 51 in third-line. BRCA+ versus NH comparisons: median time to treatment failure (TTF) 15.8 months (95% CI 11.4-21.6) versus 8.1 months (95% CI 6.1-10.3;p=0.009); overall survival (OS) 56.8 months (95% CI 32.5-indeterminate) versus 22.6 months (95% CI 17.0-34.1;p=0.002). In multivariate Cox models BRCA status was significantly associated with TTF (HR=1.66; 95% CI 1.08-2.55;p=0.02) and OS (adjusted HR 2.07; 95% CI 1.18-3.60;p=0.01). Adjusted HR relating platinum sensitivity to OS was 1.58 (95% CI 0.93-2.68; p=0.09); no significant association found with age at diagnosis, line of PLD or combinations, or institution. In this retrospective analysis, recurrent EOC BRCA mutation carriers treated with PLD had an improved outcome, and this result appeared to be independent of platinum sensitivity. Tumors arising in a background of defective BRCA function are more sensitive than other epithelial ovarian cancers to DNA damaging agents such as PLD, even after acquiring platinum resistance