C. Nagel

Stage II uterine papillary serous carcinoma: Carboplatin/paclitaxel chemotherapy improves recurrence and survival outcomes

OBJECTIVES To determine recurrence patterns and survival outcomes of stage II uterine papillary serous carcinoma (UPSC) patients treated by various modalities with an emphasis on carboplatin/paclitaxel-based chemotherapy (CT)+/-radiotherapy (RT). METHODS A retrospective, multi-institution study of women with stage II UPSC diagnosed from 1992 to 2006 was performed. All patients underwent comprehensive surgical staging. Treatment included observation (OBS), RT (vaginal brachytherapy, whole pelvic and/or whole abdominal therapy), or >or=3 cycles carboplatin/paclitaxel alone or with RT. Recurrence and survival outcomes were determined. RESULTS We identified 55 subjects: 10 treated with OBS, 26 with RT alone and 19 with CT+/-RT. After a median follow-up of 33 mos (range, 10-119), 20 recurrences (36%) were observed. There was an overall difference in recurrence based upon treatment (p=.013). Specifically, all CT+/-RT treated patients had a lower risk of recurrence (11%) compared to patients treated by RT alone (50%) or OBS (50%). No patients treated with both CT+RT (n=12) experienced a recurrence. Treatment with CT was also associated with a decreased risk of recurrence on multivariate analysis (p=.015). Most recurrences were extra-pelvic (70%), occurred within 2 years (85%) and were not salvageable (84%). Five-year progression-free survival was 86% in chemotherapy-treated patients versus 41% in those not receiving chemotherapy (p=.010); overall survival was 88% in chemotherapy-treated patients versus 64% in those not receiving chemotherapy (p=.115). CONCLUSIONS Stage II UPSC patients have a significant risk for unsalvageable, extra-pelvic recurrence. However, treatment with platinum/taxane therapy+/-RT appears to reduce this risk and is associated with improved progression free survival outcomes.

A multi-institutional cohort study of adjuvant therapy in stage I–II uterine carcinosarcoma

OBJECTIVE To evaluate the impact of adjuvant post-operative therapy in women with early stage uterine carcinosarcoma. METHODS After IRB approval was obtained at all sites, a multi-center retrospective study of women with FIGO stage I-II uterine carcinosarcoma diagnosed from 1997 to 2007 was conducted. Post-operative treatment included observation (OBS), radiation (RT), chemotherapy (CT) alone or with RT (CT+RT). Data analyzed included demographic and pathologic factors, adjuvant therapy outcomes, and time-to-event information. The Kaplan-Meier method was used to estimate time-to-event functions. Cox regression modeling was used to examine the impact of selected covariates on progression free survival (PFS), and overall survival (OS). RESULTS 111 women were identified: 94 (85%) had stage I and 17 (15%) had stage II uterine carcinosarcoma. Forty-four women (40%) did not receive adjuvant therapy (OBS), 29 (26%) women had adjuvant CT, 23 (20%) women underwent RT and 15 (14%) women underwent RT+CT. Seventy-three patients were alive without disease and 38 had progressed or died at the close of data collection. In multivariate analysis, CT (p=0.003), LVSI (p<0.0001) and a pre-existing cancer (p=0.004) were most predictive of PFS. LVSI was predictive of shortened OS (p=0.01). CONCLUSIONS In women with FIGO stage I-II uterine carcinosarcoma, adjuvant chemotherapy is associated with improved PFS compared to radiation or observation alone. Ongoing clinical trials will clarify the role of chemotherapy in women with this disease.

Recurrence patterns and surveillance for patients with early stage endometrial cancer

INTRODUCTION To evaluate the recurrence patterns and the clinical and economic role of surveillance with vaginal cytology in women with low risk endometrial cancer. METHODS Patients undergoing primary surgery with final pathology consistent with a grade 1 endometrial cancer confined to the endometrium (FIGO 1988 stage IA) between 9/1997-12/2007 were retrospectively identified. Follow-up data for at least 2 years was also collected, including diagnosis of a recurrence, symptomatology at that time, and method of detection. Costs for vaginal cytology were estimated using Medicare charge-to-cost ratios adjusted to 2010 costs. RESULTS One hundred fifty-four patients met study inclusion criteria. The mean age was 54.4 years and the mean follow-up was 46.9 months. Four recurrences were detected, occurring 16-73 months after the initial diagnosis. During a scheduled visit, one patient was found to have an asymptomatic vaginal cuff recurrence, detected on physical examination. The remaining three cases were diagnosed at an unscheduled visit after the presence of symptoms (vaginal bleeding, abdominal pain, shortness of breath) prompted further evaluation. In all, cytology detected no cases of recurrence and the estimated cost associated with cytology alone for all patients over the study time frame was approximately

Nonsteroidal anti-inflammatory drugs and endometrial carcinoma mortality and recurrence

7,760 per year. CONCLUSIONS Patients with grade 1 endometrial cancer confined to the endometrium have a low risk of recurrence (2.6%) and were detected on clinical findings alone. Emphasis should be placed on counseling patients on symptoms of recurrence and performing a thorough physical examination. The elimination of vaginal cytology for this select group of patients may be appropriate and result in a significant reduction in health care costs.

The impact of body weight on ovarian cancer outcomes.

Background Recent data suggest that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) may be associated with reductions in endometrial cancer risk, yet very few have examined whether their use is related to prognosis among endometrial cancer patients. Methods Study subjects comprised 4374 participants of the NRG Oncology/Gynecology Oncology Group 210 Study with endometrial carcinoma who completed a presurgical questionnaire that assessed history of regular prediagnostic NSAID use and endometrial cancer risk factors. Recurrences, vital status, and causes of death were obtained from medical records and cancer registries. Fine-Gray semiproportional hazards regression estimated adjusted subhazard ratios (HRs) and 95% confidence intervals (CIs) for associations of NSAID use with endometrial carcinoma-specific mortality and recurrence. Models were stratified by endometrial carcinoma type (ie, type I [endometrioid] vs type II [serous, clear cell, or carcinosarcoma]) and histology. Results Five hundred fifty endometrial carcinoma-specific deaths and 737 recurrences occurred during a median of five years of follow-up. NSAID use was associated with 66% (HR = 1.66, 95% CI = 1.21 to 2.30) increased endometrial carcinoma-specific mortality among women with type I cancers. Associations were statistically significant for former and current users, and strongest among former users who used NSAIDs for 10 years or longer (HR = 2.23, 95% CI = 1.19 to 4.18, two-sided P trend = .01). NSAID use was not associated with recurrence or endometrial carcinoma-specific mortality among women with type II tumors. Conclusions In this study, use of NSAIDs was associated with increased endometrial carcinoma-specific mortality, especially in patients with type I tumors. Barring a clear biologic mechanism by which NSAIDs would increase the risk of cause-specific mortality, cautious interpretation is warranted.

The effect of age on the tolerability of intraperitoneal chemotherapy, complication rate, and survival in patients with ovarian cancer

Background Obesity is a known risk factor and poor prognostic factor for many comorbidities including cancer. However, the influence of body mass index (BMI) on ovarian cancer outcomes is inconclusive. Therefore, the objective of this study was to evaluate the impact of BMI and weight changes on survival in patients with advanced ovarian cancer after primary treatment. Methods All patients with a diagnosis of advanced epithelial ovarian cancer from January 2000 to December 2007 undergoing primary cytoreductive surgery and adjuvant chemotherapy were identified. Patients were divided into 3 categories: underweight/normal weight (BMI, <25 kg/m2), overweight (BMI, 25–30 kg/m2), and obese (BMI, >30 kg/m2). Adjusted hazard ratios for progression-free survival (PFS) and overall survival (OS) were calculated via Cox proportional hazards models. Results One hundred ninety-eight patients met the inclusion criteria. For all patients, the mean BMI was 26 kg/m2 (range, 16.4–49.1 kg/m2), with 43% of patients being classified as normal weight, 29% overweight, and 28% as obese. Median 5-year OS was 48.2 months (95% confidence interval, 16.4–49.1 months), and no differences in OS were noted between BMI groups. Unadjusted median PFS for patients with normal weight was 13.7 months, compared with 15.5 and 17.9 months for the overweight and obese groups. Adjusted analysis of BMI over time indicates a trend of increased risk for patients who gain weight in the 6 months after primary therapy on disease progression (hazard ratio, 1.68; 95% confidence interval, 0.87–3.26). Conclusions After adjustment for confounders, such as stage, grade, histology, age, and debulking status, data suggest a trend toward a shorter PFS in patients with a normal BMI. However, OS was not significantly related to BMI, and weight change in the 6 months after completion of treatment had no effect on PFS or OS. Further research should be directed at elucidating relationships between weight and cancer biology.

Effect of chemotherapy delays and dose reductions on progression free and overall survival in the treatment of epithelial ovarian cancer.

OBJECTIVE We sought to determine if patient age influenced chemotherapy completion rate, complication rate, or progression free survival (PFS) among patients who received intraperitoneal (IP) chemotherapy for epithelial ovarian, fallopian tube, or primary peritoneal cancers. METHODS Charts for patients receiving IP chemotherapy between January 2006 and September 2009 were reviewed at three institutions. Primary outcomes included completion rate of planned IP chemotherapy, complication rate, and PFS. Completion rates were categorized as 0-49%, 50-99%, or 100% of planned treatments were delivered. The tolerability of IP versus intravenous (IV) chemotherapy was also compared among patients ≥ 70 years. RESULTS One hundred nine patients receiving IP chemotherapy were identified, 86 were < 70 years and 23 were ≥ 70 years. All patients received IP cisplatin and paclitaxel in combination with IV paclitaxel or docetaxel. Patients ≥ 70 years old were less likely to complete all planned cycles of IP chemotherapy than the younger cohort (OR = 0.33, 95% CI 0.13-0.83, p = 0.01), but there was no significant association between age and complication rate or PFS (p = 0.82 and p = 0.68, respectively). Optimally debulked patients ≥ 70 years receiving IV chemotherapy completed more cycles than patients ≥ 70 receiving IP chemotherapy (p < 0.01). CONCLUSIONS Although elderly patients appear to tolerate fewer cycles of IP chemotherapy, they do not have higher objective complication rates or impaired PFS compared to younger patients. Age alone should not limit access to IP chemotherapy.

Uterine Neoplasms, Version 1.2018: Clinical practice guidelines in oncology

INTRODUCTION Hematologic, gastrointestinal, and neurologic complications are common side effects of the platinum and taxane-based chemotherapy used in the primary treatment of epithelial ovarian cancer (EOC). These side effects and the impact of the resultant chemotherapy dose modification on disease free interval have not been extensively studied. The goal of this study was to determine the effect of chemotherapy delays and dose reductions on progression free survival (PFS) and overall survival (OS). METHODS A review of patients with primary epithelial ovarian, peritoneal, and fallopian tube carcinoma treated between 1/2000 and 12/2007 was performed. Inclusion criteria were advanced stage disease and first line chemotherapy with a platinum and taxane regimen. Cox proportional hazard models were used to determine the effect of chemotherapy reductions and delays on PFS and OS. RESULTS One hundred and fifty seven patients met the inclusion criteria. Patients were divided into four groups: no delays or reductions (48%), delay only (27%), reduction only (8%), and both delay and reduction (18%). The mean number of delays/reductions per patient was 1.1 (range=0-5) and therapy was delayed a mean of 8 days. The most common reasons for delays/reductions were neutropenia (n=51), thrombocytopenia (n=45), and neuropathy (n=18). There were no differences detected in PFS or OS between groups. CONCLUSIONS There were no differences detected in survival between patients who required dose adjustments and treatment delays and those who did not. The lack of association between survival and chemotherapy alterations suggests that in specific circumstances patients with advanced ovarian cancer should have individualized treatment plans.

A genome-scale screen reveals context-dependent ovarian cancer sensitivity to miRNA overexpression

Endometrial carcinoma is a malignant epithelial tumor that forms in the inner lining, or endometrium, of the uterus. Endometrial carcinoma is the most common gynecologic malignancy. Approximately two-thirds of endometrial carcinoma cases are diagnosed with disease confined to the uterus. The complete NCCN Guidelines for Uterine Neoplasms provide recommendations for the diagnosis, evaluation, and treatment of endometrial cancer and uterine sarcoma. This manuscript discusses guiding principles for the diagnosis, staging, and treatment of early-stage endometrial carcinoma as well as evidence for these recommendations.

Randomized phase IIB evaluation of weekly paclitaxel versus weekly paclitaxel with oncolytic reovirus (Reolysin®) in recurrent ovarian, tubal, or peritoneal cancer: An NRG Oncology/Gynecologic Oncology Group study

Large‐scale molecular annotation of epithelial ovarian cancer (EOC) indicates remarkable heterogeneity in the etiology of that disease. This diversity presents a significant obstacle against intervention target discovery. However, inactivation of miRNA biogenesis is commonly associated with advanced disease. Thus, restoration of miRNA activity may represent a common vulnerability among diverse EOC oncogenotypes. To test this, we employed genome‐scale, gain‐of‐function, miRNA mimic toxicity screens in a large, diverse spectrum of EOC cell lines. We found that all cell lines responded to at least some miRNA mimics, but that the nature of the miRNA mimics provoking a response was highly selective within the panel. These selective toxicity profiles were leveraged to define modes of action and molecular response indicators for miRNA mimics with tumor‐suppressive characteristics in vivo. A mechanistic principle emerging from this analysis was sensitivity of EOC to miRNA‐mediated release of cell fate specification programs, loss of which may be a prerequisite for development of this disease.