Faculty Bibliography

Brachytherapy is well-established as an integral component in the standard of care for treatment of patients receiving primary radiotherapy for cervical cancer. A decline in brachytherapy has been associated with negative impacts on survival in the era of modern EBRT techniques. Conformal external beam therapies such intensity modulated radiation therapy (IMRT) or stereotactic body radiation therapy (SBRT) should not be used as alternatives to brachytherapy in patients undergoing primary curative-intent radiation therapy for cervical cancer. Computed tomography or magnetic resonance image-guided adaptive brachytherapy is evolving as the preferred brachytherapy method. With careful care coordination EBRT and brachytherapy can be successfully delivered at different treatment centers without compromising treatment time and outcome in areas where access to brachytherapy maybe limited.

High-grade serous ovarian cancer (HGSOC) is hallmarked by early onset of peritoneal dissemination, which distinguishes it from low-grade serous ovarian cancer (LGSOC). Here, we describe the aggressive nature of HGSOC ascitic tumor cells (ATCs) characterized by integrin α5^high (ITGA5^high) ATCs, which are prone to forming heterotypic spheroids with fibroblasts. We term these aggregates as metastatic units (MUs) in HGSOC for their advantageous metastatic capacity and active involvement in early peritoneal dissemination. Intriguingly, fibroblasts inside MUs support ATC survival and guide their peritoneal invasion before becoming essential components of the tumor stroma in newly formed metastases. Cancer-associated fibroblasts (CAFs) recruit ITGA5^high ATCs to form MUs, which further sustain ATC ITGA5 expression by EGF secretion. Notably, LGSOC is largely devoid of CAFs and the resultant MUs, which might explain its metastatic delay. These findings identify a specialized MU architecture that amplifies the tumor-stroma interaction and promotes transcoelomic metastasis in HGSOC, providing the basis for stromal fibroblast-oriented interventions in hampering OC peritoneal propagation.

BACKGROUND:A minimally invasive surgical approach has proven to decrease peri- and post-operative complications and shorten duration of hospital stay, however there is limited data evaluating the safety of robotic-assisted surgery and early hospital discharge in the elderly population. As age is a well-known, independent risk factor for peri-operative morbidity and gynecologists treat many elderly patients, this is an important area of study. OBJECTIVE:To evaluate discharge timing and surgical outcomes in elderly compared to younger patients undergoing robotic-assisted gynecologic surgery. STUDY DESIGN/METHODS:Retrospective cohort study of all patients who underwent robotic-assisted gynecologic surgery at a high volume, single institution from January 2013 - May 2016. Demographic information, discharge timing, and peri- and post-operative outcomes were compared for patients <65 years to those >65 years using univariate and multivariate analyses. RESULTS:), (28 vs. 26, P<0.001) and American Society of Anesthesia (ASA) classification (P<0.001). Elderly were more likely to have malignancy as the indication for surgery (68% vs. 11%, P<0.001) and to undergo hysterectomy (81% vs. 38%, P<0.001) or surgery with lymph node dissection (44.5% vs. 7.1%, P<0.001). Elderly patients had higher incidence of intra-operative complications (9% vs. 4.6%, P=0.002) and longer median hospital stay (17 vs. 7 hours, P<0.001) compared to younger patients. Same day discharge was more common in younger patients (76% vs. 45%, P<0.001) and elderly patients were more likely to have admissions lasting >23 hours (13% vs. 3%, P<0.001) on univariate and multivariate analysis. Analysis of post-operative outcomes included 2,023 patients with available post-operative data (80% of total population) (1,794 <65y, 229 > 65y). There were no differences between elderly and younger patients in overall post-operative complications, reoperations, intensive care unit admissions, emergency room visits, or hospital readmission within six weeks of surgery. CONCLUSIONS:Despite having more pre-operative risk factors and more surgically complex procedures, elderly patients undergoing robotic-assisted gynecologic surgery had similar post-operative complication rates and almost half of elderly patients were safely discharged the day of surgery. Our data suggest that robotic-assisted gynecologic surgery and early hospital discharge are safe in elderly patients.

We describe a case of the first successful treatment of platinum refractory clear cell ovarian cancer with secondary cytoreductive surgery and placement of Calypso transponders to facilitate post-operative volumetric arc radiation therapy. In the setting of both primary and recurrent disease, patients with clear cell ovarian cancer are less responsive to standard chemotherapy and those treated with radiation therapy may have improved outcomes compared to the use of other treatment modalities. Volumetric arc radiation therapy with implantable transponders is feasible, and allows for the targeted treatment of sites of metastatic disease while limiting toxicity to surrounding structures and can be considered for patients with recurrent ovarian cancer and oligometastatic disease.

OBJECTIVES/OBJECTIVE:Lynch syndrome (LS) accounts for the majority of inherited endometrial cancers (EC), and the identification of probands presents a unique opportunity to treat and prevent multiple cancers. The diagnosis of EC can provide the indication for women with specific risk factors to undergo genetic testing (GT). We sought to evaluate genetic counseling referrals (GCR) and subsequent GT rates in an ethnically diverse group of high-risk women. METHODS:All women diagnosed with EC between 2011 and 2016 were identified. Risk factors for LS including age, family and personal histories of Lynch-related cancers and loss of tumor mismatch repair (MMR) protein expression were identified from laboratory and medical records. Standard two-sided statistical tests were used. RESULTS:Of 583 women diagnosed with EC, 184 (31.6%) were found to have at least one high-risk characteristic for LS. Among these high-risk women, 58% were given GCR and resulting in only 35% undergoing GT. Ten of the 65 high-risk women who had GT (15.4%) were diagnosed with Lynch syndrome, and all ten met high-risk criteria. Two women of Asian race had tumors exhibiting retained MMR protein expression despite germline testing demonstrating Lynch syndrome. CONCLUSIONS:Many high-risk women do not receive GCR despite a high rate of germline mutations among these women. Improving GCR among high-risk women will lead to more subsequent GT to identify more Lynch syndrome families and prevent additional cancers. Among our ethnically diverse cohort, two women diagnosed with LS had retained MMR protein expression. GCR should be offered to women who possess high-risk characteristics despite normal MMR protein expression.

Purpose: There is limited data regarding how many cycles of chemotherapy are optimal prior to debulking surgery in metastatic ovarian cancer. Furthermore, early identification of non-responders would prompt discontinuation of chemotherapy and earlier surgical management. The purpose of our study was to investigate the performance of FDG PET, dynamic contrast-enhanced (DCE) and intra-voxel incoherent motion (IVIM) MR as early predictors of treatment response in ovarian cancer. Parametric images of molecular diffusion restriction (D), tissue perfusion (D[asterisk]), vascular volume fraction (F), blood->interstitium constant of transfer (Ktrans), interstitum->plasma constant of transfer (Kep), extravascular/extracellular volume % (Ve) and plasma volume % (Ve) were investigated along with routine measures of SUV and ADC. Materials & Methods: Five subjects with a new diagnosis of epithelial ovarian cancer enrolled in the study. All subjects underwent 3 cycles of standardized chemotherapy followed by cytoreduction (debulking surgery). FDG PET/MR including DCE and IVIM was performed at baseline (T1), after cycle 1 (T2) and after cycle 3 (T3) of chemotherapy. Final responses were categorized at T3 by RECIST 1.1. Olea 3.0 software was used to generate parametric images from the multi-B-value DWI and DCE-MR datasets at all three timepoints. Parametric DICOM images were then coregistered to anatomical datasets using MIMvista and fusion was manually adjusted to optimize co-registration of tumor lesions across the multiple datasets. VOIs were manually drawn on clearly visible solid tumor deposits on PET, DCE-MR and DWI MR images. The parametric images derived from IVIM and DCE-MR at T2 were analyzed as early predictors of final response. Results: Five subjects completed FDG PET and IVIM-MR, three of which underwent DCE-MR. All subjects were partial responders by RECIST at T3. SUV values were only available for 4/5 patients due to technical difficulties and DCE-MR was only available for 3/5. All 5 subjects had good IVIM data. At T2, the SUVmax decreased on average by -39% across all subjects (p<0.001) and the SUVmean decreased on average by -43% across all subjects (p<0.001). At T2, the ADCmean increased on average by +25% across all subjects (p<0.05). At T2, the molecular diffusion restriction (D) increased on average by +43% across all subjects, approaching statistical significance (p=0.058). Furthermore, D[asterisk], F, Kep, Ktrans, and Vp increased in some subjects and decreased in others, without any recognizable pattern. Ve decreased in 3/3 patients, however, not reaching statistical significance. Conclusions: In this current FDG PET/MR study of ovarian cancer, SUVmax and ADCmean values obtained after one cycle of chemotherapy were consistently associated with partial anatomical treatment responses at end of therapy. These findings are in agreement with pre-existing literature studying the value of SUV and ADC in early treatment response assessment. Only one of seven advanced perfusion/diffusion metrics (D; molecular diffusion restriction) was reliably associated with treatment response. This finding that D is associated with treatment response is not surprising given that it is based on ADC without the contribution of intravascular diffusion. Our current small dataset does not yet demonstrate the value of the remaining analyzed advanced DCE-MR and DWI parameters. Further study is required to determine the utility of DCE- and IVIM-derived parameters in early response assessment. Voxelwise correlative studies and other advanced data processing methods are underway to determine if these advanced quantitative parameters may provide further information in the early assessment of chemotherapy treatment response. (Table Presented)

PURPOSE/OBJECTIVE:To evaluate the outcomes of intraperitoneal chemotherapy (IP) compared with those of intravenous chemotherapy (IV) in patients with advanced ovarian cancer after neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS) or primary debulking surgery (PDS). METHODS:Patients with advanced epithelial ovarian carcinoma treated with PDS or NACT and IDS from 2006 to 2015 were identified. Comparative statistics were used to evaluate covariates, and survival rates were calculated using the Kaplan-Meier method and compared with log-rank tests. RESULTS:Sixty-six patients received NACT followed by IDS with residual disease of ≤ 1 cm; 42 of these patients (63.6%) received IP therapy; and 24 patients (36.3%) had IV therapy only after IDS. The median progression-free survival (PFS) was 16.0 months in the IP group and 13.5 months in the IV group (p = 0.13). The estimated median overall survival (OS) was 64.0 months with IP and 50.0 months with IV (p = 0.44). During the same study period, 149 patients underwent optimal PDS after which 93 patients (62.4%) received IP and 56 patients (37.6%) were given IV chemotherapy. Patients after IP demonstrated improved survival outcomes when compared to patients after IV therapy. The median PFS was 28.0 months after IP and 16.5 months after IV (p = 0.0006), and the median OS was not reached for IP and 50.0 months after IV (p < 0.0001). CONCLUSIONS:Although IP chemotherapy after PDS is associated with improved survival, IP therapy after NACT and IDS, despite high rates of completion, may not have the same degree of survival advantage over IV therapy.

Aims Niraparib (ZEJULATM) is a selective poly (ADP-ribose) polymerase (PARP) 1/2 inhibitor. The ENGOT-OV16/NOVA trial demonstrated the clinical efficacy of niraparib in patients with recurrent ovarian cancer (OC) who are in complete or partial response (CR or PR) to platinum-based chemotherapy, regardless of their germline BRCA mutation (gBRCAmut) or homologous recombination deficiency (HRD) status. The primary objective of this trial is to measure the efficacy of niraparib maintenance in patients with advanced OC with a CR or PR to front-line platinum-based chemotherapy. Method This multicenter international trial is enrolling =330 patients with ovarian, fallopian tube, or peritoneal cancer. Eligibility criteria includes all patients with stage IV disease, and patients with stage III disease who were treated with neoadjuvant chemotherapy followed by interval debulking surgery, or who have either inoperable disease or visible residual disease after primary debulking surgery. Patients must have had a PR or CR to front-line platinum-based chemotherapy. Stratification factors include neoadjuvant chemotherapy (yes/no), best response to platinum therapy (CR or PR), and HRD status (HRD positive, including the known deleterious BRCA mutations gBRCAmut or somatic BRCAmut, or HRD negative). Patients are randomized 2:1 to receive either oral niraparib (300 mg) or matched placebo once daily in 28-day cycles. Tumors are assessed every 12 weeks per RECIST v1.1. The primary endpoint is progression-free survival, assessed by RECIST criteria and clinical criteria using blinded central review. Secondary endpoints include overall survival, patient-reported outcomes, safety and tolerability, and time to progression on next therapy. Results In progress Conclusion In progress

Aims It's recommended that all women with OC undergo genetic counseling (GC) and consider testing (GT). Universal referral was endorsed by SGO in 2014. However, rates of referral to GC are 15-30%. Since 10/2015, women newly diagnosed at our institution have been offered GC through a facilitated referral pathway (FRP). Our objective is to examine differences in GC and GT since implementation of FRP. Method Patients with new diagnosis of OC were retrospectively evaluated from 2012-9/2015 and prospectively since. Through FRP, patients are contacted by a genetics-navigator to schedule GC and communication between patient, physician and genetic counselor are facilitated. Chi-square and Mann-Whitney tests were used. Results There were 216 women diagnosed with OC who hadn't undergone previous GT identified between 2/2012-10/2016, of which 61 (28%) were in FRP and 154 (72%) weren't. Patients in the FRP were significantly more likely to obtain GC than non-FRP patients, and similarly, GT was obtained more often in the FRP group. There were 10 (21%) patients in the FRP and 21 (23%) in the non-FRP group found to have at least one deleterious mutation (p=0.98). Conclusion Implementation of FRP has resulted in a significant increase in GT, with a rate >80% among women with newly diagnosed OC with similar mutation rates in both groups. Although historically uptake of GT has been low, this study highlights the effectiveness of FRP. The implications of increased GT are profound; targeted therapies are now FDA-approved for BRCA1/2 mutation carriers. GT can result in increased screening/risk-reducing measures and allows for cascade testing