Faculty Bibliography

Ovarian cancer is the deadliest among gynecologic cancers. Hereditary cancer related to BRCA1/2 gene mutations account for approximately 10%-12% of ovarian cancers. The BRCA1/2 proteins are important in homologous recombination (HR) repair of DNA. Patients with BRCA1/2 mutations have been reported to have improved chemosensitivity to platinum agents, longer disease-free intervals, and longer survivals than nonhereditary counterparts. Recent interest in poly(ADP-ribosyl) polymerase (PARP) proteins which are key components of base excision repair, has led to the development of PARP inhibitors; tumors arising in BRCA1/2 mutation carriers and/or with HR deficiency (HRD) are particularly sensitive to the action of these drugs. As 60%-80% of all advanced ovarian cancers are high-grade serous type, exhibiting HRD in at least 50% (referred as BRCAness) future antitumor strategies may depend on identifying these defects through molecular testing. Once HRD becomes amenable to routine testing, a larger group of ovarian cancer patients than are currently considered for PARP inhibitor trials, may benefit from such targeted therapy.

BACKGROUND: Phase 2 trials suggest that prolonged intravenous (IV) infusion of the topoisomerase 1 inhibitor topotecan may be less toxic than when given by standard IV bolus 5-day administration. Oxaliplatin exhibits efficacy in platinum-pretreated disease and shows preclinical synergy with topoisomerase 1 inhibitors. We sought to determine the efficacy and safety of oxaliplatin plus infusion topotecan in recurrent platinum-pretreated ovarian cancer. METHODS: Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancers previously treated with 1 to 2 prior regimens including platinum and taxane received oxaliplatin (85 mg/m day 1 and day 15) and topotecan (0.4 mg/m per day) by continuous IV infusion over 14 days every 4 weeks. The primary objective of the trial was to estimate the objective response rate in platinum-resistant disease (stratum 1) and in platinum-sensitive disease (stratum 2). Toxicities were assessed in all patients. RESULTS: Thirty-eight patients received 144 cycles of therapy (median, 4; range, 1-6). The most common grade 3 and grade 4 toxicities included thrombocytopenia (grade 3, 37%; and grade 4, 19%), neutropenia (grade 3, 37%; grade 4, 11%), and anemia (grade 3, 15%). Response occurred in 4 of 19 patients in stratum I (21%; 95% confidence intervals, 6%-46%) and 9 of 19 patients in stratum 2 (47%; 95% CI, 24%-71%). Three in each stratum had lengthy complete responses. CONCLUSIONS: Biweekly oxaliplatin plus a 14-day continuous IV infusion of topotecan, given monthly, is an active regimen in platinum-pretreated ovarian cancer and merits additional evaluation.

Objective: Risk-reducing BSO (RRBSO), or prophylactic removal of the adnexae in women at increased genetic risk of ovarian cancer, diminishes ovarian cancer risk. While many general gynecologists (GG) perform these procedures, some argue that they should be performed exclusively by gynecologic oncologists (GO). Crucial aspects of the procedure include attention to removing all adnexal tissue, systematic methods and processing to detect occult disease, and communication between surgeon and pathologist. After compiling a "best practices" protocol for performing RRBSO, we sought to identify how often these practices were followed and whether surgeons' training affected implementation. Methods: All cases of RRBSO from 2006 to 2010 at a single institution were identified.We abstracted data from the medical record, including type of surgeon and year of procedure. We reviewed operative reports to determine if pelvic washings were obtained; whether the upper abdomen, and peritoneal surfaces were inspected; and whether a retroperitoneal approach was used to skeletonize the infundibulopelvic (IP) ligament and maximize length of this pedicle. The pathology report was used to determine if the applicable preoperative diagnosis was noted and whether the entirety of the fallopian tubes and ovaries was sectioned or if only representative sections were reviewed. Fisher's exact test and chi-square were used as appropriate to compare differences between groups (InStat, LaJolla, CA). Results: Among 290 RRBSOs, 26 were performed by GGs and 264 by GOs. When performed by GOs, the ovaries and fallopian tubes were more likely to be completely sectioned compared with GG cases: 231/264 (88%) vs. 17/26 (65%) (P =0.003). GOs were more likely to perform pelvic washings 228/264 (86%) when compared to GGs 13/ 26 (50%) (P < 0.0001). GOs were more likely to use a retroperitoneal approach to skeletonize the IP ligaments 172/264 (65%) when compared to GGs 6/26 (23%) (P < 0.0001). GOs were more likely to include a description of t!

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: PARP1 inhibition enhances the effects of DNA-damaging agents such as doxorubicin. We sought to investigate PK of PLD in a phase I study of veliparib (ABT-888, V) and PLD in patients (pts) with recurrent ovarian, fallopian tube, and primary peritoneal, and triple negative breast cancers. No prior PK interactions have been described in V clinical trials. Methods: Complete blood samples on day (D) 1 (pre-PLD and 1 hr post PLD), D 8, D 22 on cycle 1 and 2 of treatment in pts receiving PLD 40 mg/m2, day (D) 1 and V D1-14 at varying dose levels of 50,100,150, 200, 300, 350 mg twice daily, were collected in 25 of 31 pts enrolled to a previously reported dose finding phase I study of V and PLD (SGO2012). Plasma PLD levels were measured by HPLC methodology detailed by Gabizon et al Cancer Chemo Pharmacol 2008, 61:695. PK parameter estimates were obtained using non-linear modeling programs available in Winnonlin Ver 5.3. Affect of V dose on PK parameters was estimated with linear regression analysis. Due to a higher degree of GI toxicity with V dosages > 200 mg, we utilized a cut-off of 200 mg for V. PK parameters in the group with dosages greater than or equal to 200 mg (high V, n=18) and those less than 200 mg (low V, n=7) were compared, utilizing an unpaired, 2 sided t-test. Results: PLD clearance (CL) was reduced, half-life (hL) was increased, and AUC/mg was increased with higher dosages of V when compared to historical published data. We noted a positive correlation of the auc/mg dose, p=0.001 and a negative correlation with the CL, p=0.001 and increasing V dose. When analyzed as low and high V groups, the mean +/- SEM hL (hrs) was significantly lower in the low V when compared to the high V group, 83.2 +/- 11.7 vs 108.6 +/- 6.0(p =0.042) , and the mean PLD clearance (ml/h)was greater in the low V versus the high V group 35.9 +/- 5.6 vs 14.2 + 1.0, P<.0001. Similarly the AUC/mg dose (mg x h/L) was significantly lower in the low vs high V groups, 35.0 +/-5.2 vs 74.9 +/- 4.4, P<0.0001. Con!

The decision to undergo major palliative surgery in end-stage gynecologic cancer is made when severe disease symptoms significantly hinder quality of life. Malignant bowel obstruction, unremitting pelvic pain, fistula formation, tumor necrosis, pelvic sepsis, and chronic hemorrhage are among the reasons patients undergo palliative surgeries. This review discusses and summarizes the literature on surgical management of malignant bowel obstruction and palliative pelvic exenteration in gynecologic oncology.

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.