Faculty Bibliography

Ovarian cancer represents a significant challenge in women's health, with an estimated 21,980 new cases and 14,270 deaths in the United States in the year 2014. Despite excellent response rates to cytotoxic chemotherapy, the majority of patients will relapse within two to three years and extending the duration of their remission remains a priority. The development of novel treatment agents is therefore imperative. Poly (ADP-ribose) polymerase (PARP) inhibitors are a promising new class of targeted agents currently in clinical trials for ovarian cancer. PARP inhibitors were first studied in patients harboring BRCA1/2 mutations due to the known synthetic lethality of BRCA1/2-associated dysfunctional homologous recombination (HR) DNA repair and PARP inhibitor-associated loss of base excisional repair (BER) and non-homologous end rejoining. However, preclinical and emerging clinical data suggest that PARP inhibitors may benefit a broader patient population. While the initial studies of PARP inhibitors in ovarian cancer are encouraging, there remain many unanswered questions including the ideal timing of administration, whether to give these drugs as monotherapy or in combination with other antineoplastic agents and how to identify the patients most likely to respond. The focus of this review will be on the underlying mechanism of PARP inhibition in cancer, preclinical data, current clinical trials and the future of PARP inhibitors in the treatment of ovarian cancer.

OBJECTIVE: We aimed to compare access to gynecologic oncology care at a private and a city hospital, both of which closed for a period of time because of Hurricane Sandy. METHODS: This was a cross-sectional study of gynecologic oncology chemotherapy, radiotherapy, and surgical patients from October 29, 2012 (the eve of the storm), to February 7, 2013 (the reopening of the city hospital). New referrals during this time were excluded. Delays in chemotherapy, radiotherapy, and surgery were compared. RESULTS: Analysis included 113 patients: 59 private patients (52.2%) and 54 city patients (47.8%). Of the private patients, 33/59 received chemotherapy (55.9%), 1/59 received radiotherapy (1.7%), and 28/59 had planned surgery (47.5%). Of the city patients, 40/54 received chemotherapy (74.1%), 7/54 received radiotherapy (12.3%), and 18/54 had planned surgery (33.3%). The mean delay in chemotherapy was 7.6 days at the private hospital and 21.7 days at the city hospital (P=0.0004). The mean delay in scheduled surgery was 14.2 days at the private hospital and 22.7 days at the city hospital (P=0.3979). The mean delay in radiotherapy was 0.0 days at the private hospital and 25.0 days at the city hospital (P=0.0046). Loss to follow-up rates were 3/59 of the private patients (5.1%) and 3/54 of the city patients (5.6%). CONCLUSIONS: Gynecologic oncology care was maintained during a natural disaster despite temporary closure and relocation of services. Disparity in care was in access to chemotherapy. (Disaster Med Public Health Preparedness. 2015;0:1-4).

OBJECTIVE: We sought to compare robotic versus laparoscopic surgery in regards to patient reported post-operative pain and quality of life. STUDY DESIGN: This was a prospective study of patients who presented for treatment of a new gynecologic disease requiring minimally invasive surgical intervention. All subjects were asked to take the validated Brief Pain Inventory-Short Form (BPI-SF) at 3 time points to assess pain and its effect on quality of life. Statistical analyses were performed using Pearson x2 and Student's t test. RESULTS: One hundred eleven were included in the analysis of which 56 patients underwent robotic assisted surgery and 55 patients underwent laparoscopic surgery. There was no difference in post-operative pain between conventional laparoscopy and robotic assisted surgery for gynecologic procedures. There was a statistically significant difference found at the delayed postoperative period when evaluating interference of sleep, favoring laparoscopy (ROB 2.0 v LSC 1.0; p 0.03). There were no differences found between the robotic and laparoscopic groups of patients receiving narcotics (56 vs 53, p=0.24, respectively), route of administration of narcotics (47 vs 45, p=1.0, respectively), or administration of non-steroidal anti-inflammatory medications (27 vs 21, P=0.33, respectively). CONCLUSIONS: Our results demonstrate no difference in post-operative pain between conventional laparoscopy and robotic assisted surgery for gynecologic procedures. Furthermore, pain did not appear to interfere consistently with any daily activity of living. Interference of sleep needs to be further evaluated after controlling for BSO.

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.

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!

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!