Faculty Bibliography

Objective: With the increasing age of the population, more elderly patients undergo gynecologic surgery. While multiple studies demonstrate the advantages of minimally invasive surgery (MIS), including reduced morbidity and hospital stay, there is a paucity of data in the elderly population, especially in patients older than 80 years. We sought to evaluate outcomes among elderly patients undergoing MIS by a gynecologic oncologist. Method: We reviewed the medical records of patients 65 years of age and older who underwent MIS (robotic, laparoscopic, or vaginal surgery) by a gynecologic oncologist at a single institution between 2009 and 2016. We compared outcomes among "younger-elderly" (65-79) and "older-elderly" (80 and older) patients. Results: A total of 298 patients underwent MIS by a gynecologic oncologist (younger-elderly, 268; older-elderly, 29). The median age was 69 years (range 65-79) in the younger-elderly and 83 years (range 80-93) in the older-elderly. The older-elderly had more medical comorbidity conditions (median Charlson index 7 vs 5, P b 0.001). There was no significant difference between the 2 groups with respect to surgical approach, underlying malignancy, conversion to laparotomy and hospital stay (Table 1). Two hundred and nineteen (81%) younger-elderly patients and 22 (76%) older-elderly patients had ambulatory surgery, defined as an admission of less than 24 hours (P = 0.31). Surgical complications were rare (8/298, 3%), and there was no difference between the younger-and olderelderly patients in rates of complications or 30-and 90-day readmissions. Conclusion: We found MIS with early discharge to be a safe approach in elderly patients undergoing surgery by gynecologic oncologists. While patients older than 80 years were poorer surgical candidates, there were no differences in surgical outcomes or hospital stay when compared to the younger-elderly group. Elderly age should not prohibit consideration of MIS with early hospital discharge

Objective: Borderline ovarian tumors (BOT) are not uncommon and affect a younger age group than epithelial ovarian cancers. The majority of BOT are stage I at presentation and have an excellent long-term prognosis; appropriately, fertility-sparing surgery is the norm. However, there is a wide variance in the reported rate of recurrence following fertility-sparing surgery, and the risk of reoperation secondary to increased surveillance has not been well reported. We sought to evaluate the rate of recurrence and reoperation among women with BOT. Method: Patients were identified using pathology results and electronic medical records from two medical centers. Demographic, clinical, and pathologic data were obtained from medical records. Comparative analyses were performed to determine the effects of histology and type of surgery on risk of recurrence and reoperation. Statistical tests were performed with R Studio v0.99.442. Results: Between January 1, 2005, and December 31, 2015, we identified 134 patients who underwent surgical management for BOT. Median age at diagnosis was 40, and 82% presented with stage I disease. The majority of index cases were either serous (70/134, 52%) or mucinous (46/134, 34%) BOT. Median follow-up was 22 months. Following initial surgery, 86 patients (65%) had at least 1 ovary in situ. Of these patients, 34 (40%) underwent additional ovarian surgery: 21/34 (64%) were diagnosed with BOT; 9/34 (27%) had benign disease; and 2/34 (6%) were diagnosed with cancer. Median time to the second surgery was 18 months following the initial surgery. Of the 86 patients with fertility-sparing surgery, 20 (23%) delivered a live infant. The risk of reoperation or recurrence was not influenced by histology (serous, mucinous, endometrioid) or type of surgery (unilateral oophorectomy, ovarian cystectomy). The risk of reoperation was increased with increasing stage of BOT: stage I = 23/90 (25%) versus stage III = 3/8 (37.5%) (P= 0.043). Conclusion: Patients who undergo fertility sparing surgery for BOT are at high risk of both recurrent disease and reoperation for benign lesions. There is no association between histology or type of surgery and risk of recurrence or reoperation. Patients should be counseled about these risks at the time of initial surgery

OBJECTIVES: To evaluate the efficacy and safety of irinotecan and bevacizumab in recurrent ovarian cancer. The primary objective was to estimate the progression free survival (PFS) rate at 6months. Secondary objectives included estimation of overall survival (OS), objective response rate (ORR), duration of response, and an evaluation of toxicity. METHODS: Recurrent ovarian cancer patients with no limit on prior treatments were eligible. Irinotecan 250mg/m2 (amended to 175mg/m2 after toxicity assessment in first 6 patients) and bevacizumab 15mg/kg were administered every 3weeks until progression or toxicity. Response was assessed by RECIST or CA-125 criteria every 2cycles. RESULTS: Twenty nine patients enrolled (10 were platinum-sensitive and 19 were platinum-resistant). The median number of prior regimens was 5 (range 1-12); 13 patients had prior bevacizumab and 11 prior topotecan. The PFS rate at 6months was 55.2% (95% CI: 40%-77%). The median number of study cycles given was 7 (range 1-34). Median PFS was 6.8months (95% CI: 5.1-12.1months); median OS was 15.4months (95% CI: 11.9-20.4months). In this study, no complete response (CR) was observed. The objective response rate (ORR; PR or CR) for all patients entered was 27.6% (95% CI: 12.7%-47.2%) and the clinical benefit rate (CR+PR+SD) was 72.4% (95% CI: 52.8%-87.3%); twelve patients experienced duration of response longer than 6months. In the 24 patients with measurable disease, a partial response (PR) was documented in 8 (30%) patients; 13 patients maintained stable disease (SD) at first assessment. The most common grade 3/4 toxicity was diarrhea. No treatment-related deaths were observed. CONCLUSIONS: Irinotecan and bevacizumab has activity in heavily pre-treated patients with recurrent ovarian cancer, including those with prior bevacizumab and topoisomerase inhibitor use.

OBJECTIVE: To determine factors influencing discharge patterns after laparoscopic hysterectomy for endometrial cancer and to evaluate the safety of same-day discharge during the 30-day postoperative period. METHODS: Using the American College of Surgeons' National Surgical Quality Improvement Project's database, patients who underwent hysterectomy for endometrial cancer from 2010 to 2014 were identified and categorized by their hospital length of stay. Statistical analyses were performed to assess the relationship between hospital stay and demographics, medical comorbidities, intraoperative surgical factors and postoperative outcomes. RESULTS: A total of 9020 patients had laparoscopic hysterectomies for endometrial cancer and of these, 729 patients (8.1%) were successfully discharged on the day of surgery. These patients were younger and had lower body mass indexes and fewer medical comorbidities than patients who were admitted after their procedure. The same-day discharge group underwent surgical procedures of less complexity than the hospital admission group based on shorter operative times and fewer relative value units (RVUs). There was a lower rate of surgical site infections in the same-day discharge group, and no difference in rates of other postoperative complications including hospital readmissions and reoperations. CONCLUSIONS: Rates of laparoscopic hysterectomy for endometrial cancer are gradually increasing but the rates of same-day discharge have increased at a much slower rate. Same-day discharge has been successful despite differences in preoperative demographics, medical comorbidities and intraoperative surgical complexity. Overall postoperative complication rates were equivalent despite length of hospital stay, demonstrating the safety and feasibility of same-day discharge after laparoscopic hysterectomy for endometrial cancer.

There is considerable interest in the clinical development of inhibitors of mTOR complexes mTORC1 and 2. Because mTORC1 and its downstream mRNA translation effectors may protect against genotoxic DNA damage, we investigated the inhibition of mTORC1 and mTORC1/2 in the ability to reverse platinum resistance in tissue culture and in animal tumor models of serous ovarian cancer. Cell survival, tumor growth, PI3K-AKT-mTOR pathway signaling, DNA damage and repair response (DDR) gene expression and translational control were all investigated. We show that platinum resistant OVCAR-3 ovarian cancer cells are re-sensitized to low levels of carboplatin in culture by mTOR inhibition, demonstrating reduced survival after treatment with either mTORC1 inhibitor everolimus or mTORC1/2 inhibitor PP242. Platinum resistance is shown to be associated with activating phosphorylation of AKT and CHK1, inactivating phosphorylation of 4E-BP1, the negative regulator of eIF4E, which promotes increased cap-dependent mRNA translation and increased levels of CHK1 and BRCA1 proteins. Animals with platinum resistant OVCAR-3 tumors treated with carboplatin plus mTORC1/2 inhibition had significantly longer median survival and strikingly reduced metastasis compared to animals treated with carboplatin plus everolimus which inhibits only mTORC1. Reduced tumor growth, metastasis and increased survival by mTORC1/2 inhibition with carboplatin treatment was associated with reduced AKT activating phosphorylation and increased 4E-BP1 hypo-phosphorylation (activation). We conclude that mTORC1/2 inhibition is superior to mTORC1 inhibition in reversing platinum resistance in tumors and strongly impairs AKT activation, DNA repair responses and translation, promoting improved survival in the background of platinum resistance.

Objectives: In June 2011, the Society of Gynecologic Oncology (SGO) endorsed the conclusion that physical examination and symptoms should be the primary surveillance methods in patients with endometrial cancer. We sought to evaluate adherence to these guidelines at an urban academic public hospital by evaluating the use of computed tomography (CT) scans, vaginal cuff cytology (Pap smears), and serum CA-125 measurements ordered for endometrial cancer surveillance before and after publication of these guidelines.Methods: We conducted a retrospective review of all patients undergoing surveillance for endometrial cancer at a single institution between June 2009 and June 2013. We assessed the number of patients without symptoms or abnormal physical examination findings who underwent surveillance CT scans, Pap smears, and/or CA-125 measurements during 2 years before and after SGO guideline publication.Results: Ninety-two patients (48 and 44 patients before and after June 2011, respectively) with endometrial cancer were followed in the gynecologic oncology clinic during the study period. The mean patient age was 58 years. Fifty-four patients had endometrioid histology and 38 had high-risk endometrial cancer subtypes. No significant differences were seen in age, ethnicity, body mass index, or disease grade or stage when comparing those under surveillance before and after the SGO guidelines. X² analysis showed a significant decline in patients under surveillance using CT scans after the SGO guidelines (n = 13 [27%] vs n = 4 [9%], P =.03). We similarly found a significant decline in those under surveillance using CA-125 (n = 14 [29%] vs n = 5 [11%], P =.035) and Pap smears (n = 34 [71%] vs n = 8 [18%], P <.001). No significant difference was noted in disease status at the last follow-up between the 2 groups. Using Medicare-allowable charges for surveillance interventions, we found a decrease in the cost of surveillance by more than $10,000 ($14,102 in the 2 years before guidelines, $3,055 in the 2 years after the guidelines).Conclusions: In a single urban academic public hospital after only 2 years, clinical adherence to the 2011 SGO endometrial cancer surveillance guidelines has resulted in a significant decline in the use of CT scans, CA-125, and Pap smears. This reduction does not appear to affect patient outcomes and led to an appreciable decrease in surveillance costs. This may have far-reaching significance for cost and resource allocation in endometrial cancer surveillance. (table present)

Objectives: Ovarian cancer is the most lethal gynecologic malignancy. Following the initial response to platinum drugs, most patients experience recurrence of resistant disease, necessitating development of durable new treatments. Resistance to treatment is centered on cancer stem (initiating) cells (CSCs) and the AKT pathway. AKT regulates mTOR complex (mTORC1/2), downstream mRNA translation, cell proliferation, survival, and angiogenesis in tumorigenesis. Rapalogs are clinically approved inhibitors of mTORC1 but have no effect on mTORC2. We investigate a clinical experimental dual mTORC1/2 inhibitor on platinum-resistant ovarian CSCs.Methods: Platinum-resistant ovarian OVCAR3 cells were treated with vehicle, carboplatin, or INK128/MLN128, (mTORC1/2 inhibitor). CSCs were identified with flow cytometry or isolated using fluorescence-activated cell sorting using CD133 +/CD44 +. The CSC population was quantified using non-adherent spheroid growth assays. Cell viability was determined by colony formation assays with spheroids for carboplatin re-sensitization by mTORC1 or mTORC1/2 inhibition. Doxycycline-inducible shRNA silencing cell lines were generated from OVCAR3 cells to inhibit Raptor (mTORC1) or Rictor proteins (mTORC2).Results: CSCs comprise 4.9% of untreated OVCAR3 cells, confirmed by stem cell markers Oct4 and Sox2, and AKT/mTORC1 activation by phosphorylated-4E-BP1. Surprisingly, INK128 treatment increased the platinum-resistant CSC population by 2-fold (Fig. 1, P <.005), whereas carboplatin alone had no effect. INK128-treated cells formed fewer colonies compared with vehicle controls (mean colony number 36.3 + 23.8 vs 83.3 + 32.1, P <.001) and smaller colonies (mean cell number 5,260 + 835.8 vs 6,907 + 702.4, P <.0002). NS- and Raptor-silenced cells were unchanged in all assays, whereas Rictor silencing reduced CSCs by half (Fig. 2, P <.002) and formed fewer colonies by approximately 5-fold (P <.03).Conclusions: The PI3K/AKT/mTOR pathway promotes platinum resistance in ovarian cancer cells, and supports the CSC population, but can be overcome by pharmacologic inhibition of mTORC1/2. Drugging mTORC1/2 does not selectively inhibit CD133 +/CD44 + ovarian CSCs, but appears to target non-CSCs and "stem-like" cells based on functional data. Targeting mTORC1/2 sensitizes the resistant CSC population and should be clinically explored. (figure present)

Purpose: This study evaluates the dosimetry of conformal boost to persistent gross recurrent disease in the vagina with a balloon based, multi-channel (MC) CapriTM vaginal brachytherapy applicator in patients with recurrent gynecologic cancer at the vagina following whole pelvis radiation. Materials and Methods: All patients had fiducial markers placed at the site of gross disease, and were treated with whole pelvis radiation to a dose of 45 Gy in 25 fractions. Following whole pelvis radiation, patients were treated with Ir-192 HDRvaginal brachytherapy. Patients underwent sizing using the balloon-based, MC CapriTM applicator (Varian Medical Systems, Palo Alto, CA, USA) expanded to maximum capacity with saline to a median volume of 69 cm3 (range, 45-81 cm3) in order to secure applicator position. A computed tomography CT scan was performed with applicator in place. Target volume was defined as the gross tumor volume delineated by fiducial markers and expanded by 3 mm to create the planning target volume (PTV). Using Brachytherapy Planning in the Eclipse treatment planning system (Varian, Palo Alto, CA, USA), dosimetry of the conformal boost plan was manually optimized to achieve 100% coverage of PTV coverage using a prescription of 4 Gy per fraction using the minimum number of catheters and dwell positions closest to the target volume. Maximum dose to 2 cm³ (D2cm³) to bladder and rectum, as well as vaginal mucosal surface points ipsilateral and contralateral to PTV 400 cGy and biologically equivalent dose in 2Gy equivalents (EQD2) for bladder and rectum were calculated using a prescription of 4Gy x 6 fractions with alpha/beta of 3. Results: Five plans were evaluated from 5 patients with vaginal cancer (2) and endometrial cancer (3) with vaginal cuff recurrences. PTV average dimensions, calculated from the vaginal surface, were 1.13 cm depth, 2.60 cm width and 2.37 cm height. The median number of loaded catheters used in each optimized plan was 3 (range, 2-4 catheters). The average GTV measured 1.3 cm³ (range, 1.0-1.8 cm³), and the PTV measured an average volume of 4.8 cm³ (range, 3.2-6.4 cm³). D99 to PTV for all 5 plans was 100%, average maximum dose to ipsilateral vaginal mucosa was 13.0 Gy (range, 11.8-14.2 Gy), average maximum dose to the contralateral vaginal mucosa was 2.6 Gy (range, 2-3.4 Gy), average D2cm³ to bladder was 3.2 Gy (range, 2.1-4.2 Gy), and average D2cm³ to rectum was 3.7 Gy (range, 3.1-4.8 Gy). Average EQD2 total for 45 Gy external beam and 6 fractions of 4Gy was 67.7 Gy for the bladder (range, 56.0-79.5 Gy) and 74.3 Gy for the rectum (range 67.6-88.1 Gy). Conclusions: Although ABS Consensus Guidelines for vaginal cancer suggest that lesions with a thickness exceeding 5 mm cannot be adequately treated with a vaginal cylinder, we demonstrate that with the Multichannel Balloon CapriTM applicator, PTV depths averaging 1cm from vaginal surface were able to prescribed using a multicatheter approach with clinically acceptable bladder, rectal and vaginal doses. Preliminary data suggests that the use of the Multicatheter CapriTM applicator may be an alternative approach to using an interstitial implant for selected patients with small vaginal recurrences, however, a larger cohort of patients with long-term follow-up is required to assess longterm clinical outcomes using this technical approach. Figure 1. PTV shown with fiducial markers located on right lateral vaginal wall for patient treated with CapriTM multichannel vaginal applicator demonstrating isodose lines of 12 Gy, 4 Gy and 2.5 Gy. (Figure Presented)