Faculty Bibliography

BACKGROUND:The American Society of Clinical Oncology recommends that patients with advanced cancer receive dedicated palliative care services early in their disease course. This investigation serves to understand how palliative care services are utilized for ovarian cancer patients in a tertiary referral center. METHODS:We conducted a retrospective review of women treated for ovarian cancer at our institution from 2010 through 2015. Clinical variables included presence and timing of palliative care referral. Data were correlated utilizing univariable and multivariable parametric and non-parametric testing, and survivals were analyzed using the Kaplan-Meier method and cox-proportional hazard models. RESULTS:We identified 391 women treated for ovarian cancer, of whom 68% were diagnosed with stage III or IV disease. Palliative care referral was utilized in 28% in the outpatient (42%) and inpatient (58%) settings. Earlier use of referral was observed in those who never underwent surgical cytoreduction or had interval cytoreductive surgery (p < 0.001). Palliative care referral was independently associated with advanced stage (OR 1.7, p = 0.02), recurrence (OR 2.0, p = 0.002) and hospice referral (OR 6.0, p < 0.001). In 38% of women referral occurred within 30 days of death, and 17% within one week of death. Outpatient initial consultation was associated with an unadjusted 1 year overall survival benefit (p < 0.01) compared to inpatient consultation. CONCLUSIONS:The outcomes in this study suggest a late use of palliative care that is reactionary to patient needs and not a routine component of ovarian cancer care as national guidelines recommend.

OBJECTIVES:To examine the relationship between volume of residual disease and oncologic outcomes among patients with advanced-stage epithelial ovarian/fallopian tube/primary peritoneal carcinoma undergoing primary debulking surgery (PDS). For patients that did not undergo a complete surgical resection (CSR), a surrogate for volume of residual disease was used to assess oncologic outcomes. METHODS:Medical records of patients with FIGO stage IIIC and IV epithelial ovarian/fallopian tube/primary peritoneal carcinoma undergoing PDS between January 2010 and November 2014 were reviewed. Patient demographics, operative characteristics, residual disease, anatomic site of residual disease and outcome data were collected. Among patients who did not undergo CSR, but had ≤1 cm of residual disease, the number of anatomic sites (single location vs. multiple locations) with residual disease was utilized as a surrogate for volume of residual disease. The effect of residual disease volume on progression-free survival (PFS) and overall survival (OS) was evaluated. RESULTS:Of 240 patients undergoing PDS, 94 (39.2%) had CSR, 41 (17.1%) had ≤1 cm of residual disease confined to a single anatomic location (≤1 cm-SL), 67 (27.9%) had ≤1 cm of residual disease in multiple anatomic locations (≤1 cm-ML) and 38 (15.8%) were sub-optimally (SO) debulked. Median PFS for CSR, ≤1 cm-SL, ≤1 cm-ML and SO-debulked were: 23, 19, 13 and 10 months, respectively (p < 0.001). Median OS for CSR, ≤1 cm-SL, ≤1 cm-ML and SO-debulked were: Not yet reached, 64, 50 and 49 months, respectively (p = 0.001). CONCLUSIONS:Following PDS, CSR and ≤ 1 cm-SL patients have the best prognosis. In contrast, despite being considered "optimally debulked", ≤1 cm-ML patients have survival similar to those SO-debulked.

OBJECTIVES/OBJECTIVE:The majority of hospital readmissions are unexpected and considered adverse events. The goal of this study was to examine the factors associated with unplanned readmission after surgery for vulvar cancer. METHODS:test and Student's t-test as appropriate for univariate analysis. Multivariate analysis was then performed. RESULTS:Of 363 eligible patients, 35.6% had in situ disease and 64.5% had invasive disease. Radical vulvectomy was performed in 39.1% and 23.4% underwent lymph node assessment. Seventeen patients (4.7%) were readmitted within 30days, with length of stay ranging 2 to 37days and 35% of these patients required a re-operation. On univariate analyses comorbidities, radical vulvectomy, nodal assessment, initial length of stay, and discharge to a post acute care facility (PACF) were associated with hospital readmission. On multivariate analysis, only discharge to a PACF was significantly associated with readmission (OR 6.30, CI 1.12-35.53, P=0.04). Of those who were readmitted within 30days, 29.4% had been at a PACF whereas only 6.6% of the no readmission group had been discharged to PACF (P=0.003). CONCLUSIONS:Readmission affected 4.7% of our population, and was associated with lengthy hospitalization and reoperation. After controlling for patient comorbidities and surgical radicality, multivariate analysis suggested that discharge to a PACF was significantly associated with risk of readmission.

BACKGROUND:Cervical cancer is the third most common gynecologic malignancy in the United States. Approximately 1-3% of cervical cancers will be diagnosed in pregnant and peripartum women; optimal management in the setting of pregnancy is not always clear. OBJECTIVE:We sought to describe the management of patients with cervical cancer diagnosed in pregnancy and compare their outcomes to nonpregnant women with similar baseline characteristics. STUDY DESIGN:We conducted a retrospective chart review of all patients diagnosed with cervical cancer in pregnancy and matched them 1:2 with contemporaneous nonpregnant women of the same age diagnosed with cervical cancer of the same stage. Patients were identified using International Classification of Diseases, Ninth Revision codes and the Dana-Farber/Massachusetts General Hospital Cancer Registry. Data were analyzed using Stata, Version 10.1 (College Station, TX). RESULTS:In all, 28 women diagnosed with cervical cancer during pregnancy were identified from 1997 through 2013. The majority were Stage IB1. In all, 25% (7/28) of women terminated the pregnancy; these women were more likely to be diagnosed earlier in pregnancy (10.9 vs 19.7 weeks, P = .006). For those who did not terminate, mean gestational age at delivery was 36.1 weeks. Pregnancy complications were uncommon. Complication rates in pregnant women undergoing radical hysterectomy were similar to those outside of pregnancy. Time to treatment was significantly longer for pregnant women compared to nonpregnant patients (20.8 vs 7.9 weeks, P = .0014) but there was no survival difference between groups (89.3% vs 95.2%, P = .08). Women who underwent gravid radical hysterectomy had significantly higher estimated blood loss than those who had a radical hysterectomy in the postpartum period (2033 vs 425 mL, P = .0064), but operative characteristics were otherwise similar. None of the pregnant women who died delayed treatment due to pregnancy. CONCLUSION:Gestational age at diagnosis is an important determinant of management of cervical cancer in pregnancy, underscoring the need for expeditious workup of abnormal cervical cytology. Of women who choose to continue the pregnancy, most delivered in the late preterm period without significant obstetric complications. For women undergoing radical hysterectomy in the peripartum period, complication rates are similar to nonpregnant women undergoing this procedure. Women who died were more likely to have advanced stage disease at the time of diagnosis. This information may be useful in counseling women facing the diagnosis of cervical cancer in pregnancy.

BACKGROUND:The objective of this investigation was to characterize the expression landscape of immune regulatory molecules programmed death-ligand-1 (PD-L1, B7-H1) and B7-H4 in a cohort of endometrial tumors across the spectrum of grade and histology. MATERIALS AND METHODS:With institutional review board approval, 70 endometrial tumors from patients with known clinical outcomes were identified representing a spectrum of grade and histology. Immunohistochemistry (IHC) was performed for PD-L1 and B7-H4 and scored. Microsatellite instability (MSI) status was assessed for endometrioid tumors using the institutional IHC assay for expression of the mismatch repair (MMR) genes, MLH1, MSH2, MSH6 and PMS2. RNA sequencing data from the Cancer Genome Atlas was queried for expression levels of CD274 (PD-L1 protein) and VTCN1 (B7-H4) across molecular subtypes of endometrial carcinoma and were correlated with a T cell infiltration index. RESULTS:We identified 40 low grade endometrioid tumors and a cohort of 30 high grade tumors. PD-L1 expression was observed in both high and low grade endometrial tumors (56% vs 35%, p=0.07). In the low grade tumors, PD-L1 expression was associated with MSI status (p<0.01). The high grade cohort had similar rates of PD-L1 expression compared to low grade MSI tumor (56% and 62% respectively), and both were distinct from low grade MSS tumors (22%, p<0.05). High (3+) B7-H4 positive cells were observed in both high and low grade carcinomas (33% and 31% respectively). RNA profiling data from confirmed highest CD274 expression in POLE and MSI tumors that was linearly correlated with T cell infiltration, while VTCN1 expression appeared consistent across molecular subtypes. CONCLUSIONS:While PD-L1 expression correlated with MSI and high grade tumors, B7-H4 expression was independent of grade, histology and immune cell infiltration. The development and testing of multi-agent therapeutics targeting PD-L1 and B7-H4 may be a novel strategy for endometrial tumors.

OBJECTIVE:To compare 3-year survival, length of hospitalization, perioperative mortality, risk of readmission, and residual disease associated with laparoscopic and laparotomic interval debulking surgery among women with epithelial ovarian cancer. METHODS:We used the National Cancer Database to identify a cohort of patients diagnosed with stage IIIC and IV epithelial ovarian cancer between 2010 and 2012 who underwent neoadjuvant chemotherapy and interval debulking surgery. We compared 3-year overall survival, duration of postoperative hospitalization, 90-day postoperative mortality, and residual disease status between women who underwent interval debulking by laparoscopy and by laparotomy. We used the Kaplan-Meier method and Cox regression models in survival analyses. At a significance of .05, this study had 80% power to detect an 8% difference in 3-year survival. The main analysis was intention to treat. RESULTS:We identified 3,071 women meeting inclusion criteria, of whom 450 (15%) underwent surgery initiated laparoscopically. There was no difference in 3-year survival between patients undergoing laparoscopy [47.5%; 95% confidence interval (CI) 41.4-53.5] and laparotomy (52.6%; 95% CI 50.3-55.0; P=.12). Survival did not differ after adjustment for demographic characteristics, facility type, presence of comorbidities, and stage (adjusted hazard ratio, 1.09; 95% CI 0.93-1.28; P=.26). Postoperative hospitalization was slightly shorter in the laparoscopy group (median 4 compared with 5 days, P<.001). Frequency of readmission (5.3% compared with 3.7%; P=.26), death within 90 days of surgery (2.8% compared with 2.9%, P=.93), and suboptimal debulking (20.6% compared with 22.6%, P=.29) did not differ between patients undergoing laparoscopy and laparotomy. CONCLUSION:Ovarian cancer patients selected for laparoscopic interval debulking surgery after neoadjuvant chemotherapy have 3-year survival rates similar to women who undergo interval debulking by laparotomy. Laparoscopy is associated with a modestly shorter postoperative hospitalization, whereas readmission rates and risk of perioperative death are similar for the surgeries.

STUDY OBJECTIVE:To assess outcomes of women with cervical cancer undergoing upfront radical hysterectomy (RH) via a minimally invasive surgery (MIS) or a traditional laparotomy (XL) approach at 2 large US academic institutions to determine whether the mode of surgery affects patient outcomes. DESIGN:Retrospective cohort study (Canadian Task Force classification II-1). SETTING:Two academic medical institutions in the United States. PATIENTS:Women undergoing upfront RH for cervical cancer between 2000 and 2013. INTERVENTION:Minimally invasive techniques (laparoscopic and robotic) for RH compared with XL. MEASUREMENTS AND MAIN RESULTS:) and a higher rate of perioperative blood transfusion (3.0% vs 26.2%; p < .001). Length of perioperative hospital stay was significantly shorter in the MIS group (1.9 days vs 4.9 days; p < .001). CONCLUSION:MIS RH does not compromise patient outcomes, including overall survival, rate of recurrence, and the frequency of pelvic lymph node dissection or positivity. Morbidity was decreased in the MIS group, including decreased EBL, fewer blood transfusions, and shorter hospital stay.

OBJECTIVE:The aim of this study was to review the experience with intraoperative radiation therapy (IORT) in the treatment of gynecologic cancers at the Massachusetts General Hospital. METHODS:From January 1, 1994 to December 31, 2011, 32 patients were treated with IORT at Massachusetts General Hospital. Hospital, pathology, and office medical records and radiation oncology records were reviewed. The Kaplan-Meier method was used to generate disease-free survival and overall survival (OS) data. RESULTS:In 27 patients (84.4), surgical resection margins were microscopically positive. In 5 patients (15.6%), margins were grossly positive. For patients with microscopic disease, 5-year disease-free survival was 40.9% (57 mo), compared with 9.1% (23 mo) for those with gross residual disease (P=0.001). Five-year OS was also statistically improved for patients with microscopic residual disease, when compared with OS among patients with gross residual disease, 77.3% (93 mo) and 54.5% (40 mo), respectively (P=0.001). The risk of distant metastases in patients with gross residual disease was 87%, compared with 28% in patients with microscopic disease (P=0.02). CONCLUSIONS:Volume of residual disease before IORT is an important prognostic indicator. Local recurrence and distant metastases were more common among patients with gross residual disease left in situ at time of IORT. Our institutional experience with IORT further supports the importance of complete surgical resection.

Ovarian, endometrial and cervical cancers are the most prevalent gynecologic cancers in the United States and account for significant mortality. Translational research into these cancers has highlighted the distinctive molecular and genomic profiles of these cancers finding that, even within a disease site, the landscapes and drivers of neoplasia are distinctive. Despite this molecular diversity, activation of the phosphatidylinositol-3-kinase (PI3K) pathway appears to be conserved in subsets of these tumors, suggesting that strategies that antagonize mediators in this signaling cascade could offer anti-tumor efficacy. Extensive pre-clinical and clinical data have demonstrated that single agent targeted therapies lead to modest single agent activity of generally limited duration, even in the setting of innate PI3K pathway activation via mutation or amplification. These findings in the laboratory and clinic have prompted investigations into resistance pathways following PI3K pathway inhibition in order to understand escape pathways and restore tumor cell sensitivity. A next generation of clinical trial investigations will focus on novel combinations in order to define how these important therapeutics can be used in the clinic. This review will present preclinical data that supports the role of the PI3K pathway in ovarian, endometrial and cervical cancers, in addition to discussing the reported clinical trial experience with PI3K pathway inhibition. A specific focus will be on the rationale behind ongoing clinical trials utilizing novel agents in concert with PI3K pathway inhibitors to reverse resistance in populations with and without gain of function alterations in this oncogenic signaling cascade.