Faculty Bibliography

OBJECTIVE:Surgical cytoreduction has been postulated to affect survival by increasing the efficacy of chemotherapy in ovarian cancer. We hypothesized that women with high-grade serous ovarian cancer, which usually responds to chemotherapy, would derive greater benefit from complete cytoreduction than those with histologic subtypes that are less responsive to chemotherapy, such as mucinous and clear cell carcinoma. METHODS:We conducted a retrospective cohort study of patients who underwent primary cytoreductive surgery and adjuvant chemotherapy for stage IIIC or IV epithelial ovarian cancer from 2011 to 2013 using data from the National Cancer Database. We constructed multivariable models to quantify the magnitude of associations between residual disease status (no residual disease, ≤1cm, or >1cm) and all-cause mortality by histologic type among women with clear cell, mucinous, and high-grade serous ovarian cancer. Because 26% of the sample had unknown residual disease status, we used multiple imputations in the primary analysis. RESULTS:We identified 6,013 women with stage IIIC and IV high-grade serous, 307 with clear cell, and 140 with mucinous histology. The association between residual disease status and mortality hazard did not differ significantly among histologic subtypes of ovarian cancer (p for interaction=0.32). In covariate adjusted models, compared to suboptimal cytoreduction, cytoreduction to no gross disease was associated with a hazard reduction of 42% in high-grade serous carcinoma (hazard ratio [HR]=0.58, 95% confidence interval [CI]=0.49-0.68), 61% in clear cell carcinoma (HR=0.39, 95% CI=0.22-0.69), and 54% in mucinous carcinoma (HR=0.46, 95% CI=0.22-0.99). CONCLUSIONS:We found no evidence that surgical cytoreduction was of greater prognostic importance in high-grade serous carcinomas than in histologies that are less responsive to chemotherapy.

PURPOSE/OBJECTIVE:The aim of this study was to determine factors associated with the adoption of minimally invasive surgery (MIS) compared with laparotomy in the treatment of endometrial cancer and to compare surgical outcomes and survival between these two surgical modalities. METHODS:We utilized the National Cancer Data Base (NCDB) to identify women diagnosed with presumed early-stage endometrial cancer between 2010 and 2012. We also identified factors associated with the performance of MIS and utilized propensity score matching to create a matched cohort of women who underwent minimally invasive staging surgery or laparotomy for surgical staging. RESULTS:Overall, 20,346 women were eligible for inclusion in the study; 12,604 (61.9%) had MIS, while 7742 (38.1%) had a laparotomy. African American race (odds ratio [OR] 0.54, 95% confidence interval [CI] 0.49-0.60], Hispanic ethnicity (OR 0.70, 95% CI 0.61-0.80), Charlson score >2 (OR 0.79, 95% CI 0.69-0.91), high-grade histology (OR 0.63, 95% CI 0.59-0.68), presumed clinical stage II disease (OR 0.53, 95% CI 0.46-0.60), and surgery at a community cancer program (OR 0.46, 95% CI 0.39-0.55) or in the Midwest region (OR 0.70, 95% CI 0.64-0.76) were associated with a decreased likelihood of having MIS, while private insurance (OR 1.69, 95% CI 1.45-1.97) and highest quartile median household income (OR 1.13, 95% CI 1.03-1.24) were associated with an increased likelihood of having MIS. After propensity score matching, there was no association between minimally invasive staging surgery and 3-year overall survival (hazard ratio 1.03, 95% CI 0.92-1.16). CONCLUSION/CONCLUSIONS:There are notable racial, ethnic, socioeconomic, and geographic variations in the utilization of MIS for endometrial cancer staging in the US. After controlling for the aforementioned factors, MIS had a similar 3-year survival compared with laparotomy in women undergoing staging surgery for endometrial cancer.

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.

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.

OBJECTIVE:The objective of this study is to review existing data regarding the feasibility, diagnostic performance, and oncologic outcomes of sentinel lymph node biopsy (SLNB) versus lymphadenectomy (LND) in endometrial cancer. MATERIALS AND METHODS:A PubMed search identified studies on different staging strategies in endometrial cancer, including routine LND, predictive models of selective nodal dissection, and SLNB. RESULTS:There is ongoing controversy over the risk-benefit ratio of LND in assessing nodal involvement in presumed early-stage endometrial cancer. Current experience with sentinel node biopsy suggests high detection rates and low false-negative rates across most series, as well as the increased detection of occult metastatic disease overlooked by conventional pathology. Although data on the long-term oncologic outcomes of sentinel node biopsy in this setting are limited, short-term follow-up shows no immediate impairment of disease-free survival or overall survival rates when compared with LND. CONCLUSIONS:SLNB holds promise as a less-morbid and more accurate alternative to LND for determining nodal spread in early-stage endometrial cancer. Further studies are necessary to understand how lymph node status will guide postoperative management and impact survival of women with nodal metastases.

OBJECTIVE:To assess if referral of patients with molar pregnancy who then developed postmolar gestational trophoblastic neoplasia (PMGTN) is associated with different outcomes when compared to referral of patients already with a diagnosis of PMGTN. STUDY DESIGN/METHODS:The records of the New England Trophoblastic Disease Center (NETDC) were queried for all patients with molar pregnancy or PMGTN from 1993-2013. Retrospective chart review was performed to extract relevant clinical and demographic data. Parametric and nonparametric tests were utilized to compare variables. RESULTS:From 1993-2013, 429 women with molar disease were evaluated at the NETDC. Of those, 68% were referred with molar pregnancy and 32% were referred with PMGTN. Comparing women with PMGTN who were referred with a molar pregnancy versus referred with PMGTN, the women were of equivalent stage and World Health Organization (WHO) score. Additionally, referral with molar pregnancy or PMGTN did not associate with time to persistence, time to remission, or number of lines of chemotherapy administered. CONCLUSION/CONCLUSIONS:In this trophoblastic disease specialty center in the United States, referral at the time of PMGTN as opposed to at diagnosis of molar pregnancy did not appear to affect the stage or WHO score at diagnosis, the need for multiple chemotherapy lines, or time to remission.

OBJECTIVE:To investigate racial disparities with respect to adjuvant treatment and survival in patients presenting with malignant ovarian germ cell tumors (OGCT). METHODS:The National Cancer Database (NCDB) was used to identify women diagnosed with OGCT. Demographic data were abstracted, including stratification by race and histology. Standard univariate and multivariate analyses using logistic regression were performed to describe predictors of adjuvant treatment. Kaplan-Meier and Cox proportional hazards survival methods were used to evaluate racial differences in survival between African American (AA) and white (W) women. RESULTS:The study population included 2196 patients, with 1654 (75.3%) W and 328 (14.9%) AA women. Histologic distribution varied significantly by race (p<0.0001), but neither age nor stage at presentation showed racial differences (p=0.086 and p=0.209, respectively). AA received more chemotherapy than W (W: 54.6%, AA: 65.5%, p=0.008), but in multivariate analysis there was no statistically significant difference in any adjuvant treatment modality. Despite similar treatment, and independent of histology, survival varied significantly by race with 91% (CI 0.89-0.93) five year survival in W patients compared to 84% five year survival in AA (CI 0.8-0.89) (p=0.02). These disparities were most pronounced in advanced stage disease, with 5 year survival of 84% (CI 0.79-0.89) in W compared to 61% (CI 0.48-0.78) for AA in stage III (p=0.0002), and 54% (CI 0.42-0.68) compared to 14% (CI 0.03-0.71) for stage IV (p=0.05). CONCLUSIONS:AA with OGCT have significantly worse 5 year survival when compared to W patients despite similar rates and modalities of adjuvant treatment.

OBJECTIVE:To describe trends in the use of lymphadenectomy for endometrioid adenocarcinoma of the endometrium between 1998 and 2012. METHODS:A time-trend analysis was conducted using a population-based cancer registry covering 28% of the population of the United States. To quantify differences over the study period time, the frequency of lymphadenectomy and nodal metastasis among women who underwent surgical treatment of endometrioid endometrial adenocarcinoma was compared among consecutive 3- to 4-year periods. Biannual frequency of lymphadenectomy was modeled with Joinpoint regression to identify when potential changes in trends occurred and calculate annual percentage change. RESULTS:A total of 74,365 women who underwent surgery between 1998 and 2012 were analyzed. Frequency of lymphadenectomy increased by 4.2% annually (95% confidence interval [CI] 3.7-4.6) from 1998 to 2007, after which the frequency declined by 1.6% per year (95% CI 0.9-2.2). Between 1998-2000 and 2007-2009, the frequency of lymphadenectomy rose from 48.7% to 65.5% (risk difference 16.8%, 95% CI 15.4-18.1), the proportion of women found to have nodal metastasis increased by 1.1% (95% CI 0.4-1.7), and the frequency of negative lymphadenectomy increased by 15.7% (95% CI 14.3-17.1). The decline in frequency of lymphadenectomy after 2007 was associated a 3.1% (95% CI 2.1-4.1) decline in the rate of negative lymphadenectomy, but no change in the proportion of women found to have nodal metastasis (P=.17). CONCLUSION/CONCLUSIONS:The frequency of lymphadenectomy in the surgical treatment of endometrioid endometrial cancer increased by 4.2% annually from 1998 to 2007 and decreased by 1.6% annually from 2007 to 2012. LEVEL OF EVIDENCE/METHODS:II.

OBJECTIVE:Evaluate rates of chemotherapy and radiotherapy delivery in the treatment of uterine serous carcinoma, and compare clinical outcomes of treated and untreated patients. METHODS:The National Cancer Database was queried to identify patients diagnosed with uterine serous carcinoma between 2003 and 2011. The impact of chemotherapy on survival was analyzed using the Kaplan-Meier method. Factors predictive of outcome were compared using the Cox proportional hazards model. RESULTS:A total of 13,752 patients met the study eligibility criteria. Stage I, II, III, and IV disease accounted for 4355 (31.7%), 1023 (7.4%), 3484 (25.3%), and 2451 (17.8%) of the study population, respectively. 2439 (17.7%) women had unknown stage. Chemotherapy was administered in 4290 (35.4%) patients, radiotherapy to 1673 (12.2%), adjuvant chemo-radiation to 2915 (21.2%), and 4874 (35.4%) of women did not receive adjuvant therapy during the study period. Utilization of chemotherapy became more frequent over time. Over the entire study period, after adjusting for age, period of diagnosis, race, facility location, facility type, insurance provider, socioeconomic status, comorbidity index, lymph node dissection, treatment modality, and stage, there was an association between treatment modality and survival, with the lowest hazard ratio in patients that received chemo-radiation. After adjusting for the same factors in women with stages I and II, chemo-radiation was associated with improved survival compared to patients that received no treatment. Radiotherapy or chemotherapy alone was not associated with improved survival. CONCLUSION/CONCLUSIONS:Utilization of chemotherapy is increased in this population over the study period from 2003-2012 and more importantly that survival, particularly in advanced stage patients, is improving.

UNLABELLED:Endometrial cancer is the most common gynecologic cancer in the United States, diagnosed in more than 50,000 women annually. While the majority of women present with low-grade tumors that are cured with surgery and adjuvant radiotherapy, a significant subset of women experience recurrence and do not survive their disease. A disproportionate number of the more than 8,000 annual deaths attributed to endometrial cancer are due to high-grade uterine cancers, highlighting the need for new therapies that target molecular alterations specific to this subset of tumors. Numerous correlative scientific investigations have demonstrated that the HER2 (ERBB2) gene is amplified in 17%-33% of carcinosarcoma, uterine serous carcinoma, and a subset of high-grade endometrioid endometrial tumors. In breast cancer, this potent signature has directed women to anti-HER2-targeted therapies such as trastuzumab and lapatinib. In contrast to breast cancer, therapy with trastuzumab alone revealed no responses in women with recurrent HER2 overexpressing endometrial cancer, suggesting that these tumors may possess acquired or innate trastuzumab resistance mechanisms. This review explores the literature surrounding HER2 expression in endometrial cancer, focusing on trastuzumab and other anti-HER2 therapy and resistance mechanisms characterized in breast cancer but germane to endometrial tumors. Understanding resistance pathways will suggest combination therapies that target both HER2 and key oncogenic escape pathways in endometrial cancer. IMPLICATIONS FOR PRACTICE/CONCLUSIONS:This review summarizes the role of HER2 in endometrial cancer, with a focus on uterine serous carcinoma. The limitations to date of anti-HER2 therapy in this disease site are examined, and mechanisms of drug resistance are outlined based on the experience in breast cancer. Potential opportunities to overcome inherent resistance to anti-HER2 therapy in endometrial cancer are detailed, offering opportunities for further clinical study with the goal to improve outcomes in this challenging disease.