Population-Based Analysis of Patient Age and Other Disparities in the Treatment of Ovarian Cancer in Central Appalachia and Kentucky.

OBJECTIVES: Adherence to National Comprehensive Cancer Network (NCCN) guidelines for ovarian cancer treatment improves patient outcomes. The aim of this study was to assess disparities associated with ovarian cancer treatment in the state of Kentucky and central Appalachia. METHODS: Data on patients diagnosed as having ovarian cancer from 2007 through 2011 were extracted from administrative claims-linked Kentucky Cancer Registry data. NCCN compliance was defined by stage, grade, surgical procedure, and chemotherapy. Selection criteria were reviewed carefully to ensure data quality and accuracy. Descriptive analysis, logistic regression, and Cox regression analyses were performed to examine factors associated with guidelines compliance and survival. RESULTS: Most women were aged 65 years or older (62.5%) and had high-grade (65.9%) and advanced-stage (61.0%) ovarian cancer. Two-thirds of cases (65.9%) received NCCN-recommended treatment for ovarian cancer. The hazard ratio of death for women who did not receive NCCN-compliant care was 62% higher compared with the women who did receive NCCN-compliant treatment. Results from the logistic regression showed that NCCN-compliant treatment was more likely for women aged 65 to 74 years compared with women aged 20 to 49 years, late-stage compared with early-stage cancers, receipt of care at tertiary care hospitals, and privately insured compared with Medicaid or Medicare. CONCLUSIONS: When the treatment of ovarian cancer did not follow NCCN recommendations, patients had a significantly higher risk of death. Women were less likely to receive NCCN-compliant care if they were younger (20-49 years), had early-stage disease, did not have private insurance, or had care provided at a nontertiary care hospital.

Prospective validation of an intraoperative algorithm to guide surgical staging in early endometrial cancer.

OBJECTIVES: Prospectively validate an intraoperative surgical staging algorithm to stratify patients with early endometrial cancer by risk of lymph node metastasis. METHODS: Subjects with endometrial cancer clinically confined to the uterus were prospectively enrolled at an academic cancer center between Jan 2012 and Jun 2015. Study participants were stratified intraoperatively into two groups based on risk of nodal involvement using cell type, tumor grade, myometrial invasion, and tumor size in accordance with an established protocol from the Mayo Clinic. Low risk (LR) subjects received extrafascial hysterectomy with bilateral salpingo-oophorectomy; high risk (HR) patients received complete surgical staging including bilateral pelvic and para-aortic lymphadenectomy. RESULTS: Of the 200 subjects enrolled, 194 were eligible for analysis. The algorithm identified 132 (68%) HR and 62 (32%) LR cancers. Of the HR subjects, 126 had lymphadenectomy performed with 14 (11%) positive for nodal metastases. Five HR subjects experienced disease recurrence. Of the 62 LR cancers, two patients developed disease recurrence. Ten LR cancers were upgraded to HR on final pathology due to lesion size (6) and grade (4). None of these patients experienced disease recurrence. The algorithm demonstrated 90% sensitivity (18/20) and 36% specificity (62/174) as determined by positive lymph nodes and/or disease recurrence. CONCLUSIONS: Intraoperative assessment of early endometrial cancer can be used to determine the extent of surgical staging. The studied algorithm has low specificity and modifications are necessary to better match the surgical procedure to the risk of metastatic cancer.

Ultrasound follow up of an adnexal mass has the potential to save lives.

Ovarian cancer is among the most dreaded cancers since it is often found at a late stage where the opportunity for extended survival is poor. Ultrasound has been utilized in several ovarian cancer screening trials in asymptomatic women in order to detect ovarian cancer at early stages where survival rates are high. Efforts to improve screening for ovarian cancer are ongoing. While ovarian cancer screening in asymptomatic women is not recommended for clinical application currently, the care of women with adnexal masses found by ultrasound in clinical practice can benefit from close evaluation of the evidence obtained from large prospective ovarian cancer screening trials and by relating this evidence to recent advances in the understanding of different types of ovarian cancer. Post-menopausal women who have an adnexal mass discovered by ultrasound have a much higher risk of developing ovarian cancer than women with normal ultrasound. The preponderance of reported evidence indicates that ultrasound monitoring of an adnexal mass is safe, cost effective and can achieve an improved positive predictive value in detecting ovarian cancer when ovarian abnormalities resolve during surveillance. Proposals to arbitrarily discontinue ultrasound monitoring can negatively impact patient care and generate medical-legal actions, especially because there is no evidence to support safe discontinuation. In this review, we outline a rationale for continuing ultrasound surveillance of ovarian abnormalities.

Serial ultrasonographic evaluation of ovarian abnormalities with a morphology index.

OBJECTIVE: Transvaginal ultrasonography with tumor morphology index (MI) has been used to predict the risk of ovarian malignancy. Our objective was to analyze changes in serial MI scores for malignant and non-malignant ovarian tumors in a large and asymptomatic population. METHODS: Eligible subjects participated in the University of Kentucky Ovarian Cancer Screening Program and had abnormalities that included cysts, cysts with septations, complex cysts with solid areas, and solid masses. Analysis included: MI, change in MI (delta MI), delta MI per scan and per month, number and duration of scans. RESULTS: From 1987 to 2012, 38,983 women received 218,445 scans. Of the 7104 eligible subjects, 6758 tumors were observed without surgery and 472 were surgically removed. Eighty-six percent (5811) of observed tumors were resolved. There were 74 malignant and 272 non-malignant tumors. Eighty-five percent of malignancies had MI ≥5 at decision for surgery. The risk of malignancy based on MI was: MI=5 (3%), MI=6 (3.7%), MI=7 (12.6%), MI=8 (26.7%), MI=9 (27.8%), MI=10 (33.3%). The mean delta MI per month decreased for tumors that resolved (delta MI -1.0, p<0.001) or persisted without surgery (delta MI -0.7, p<0.001). For abnormalities surgically removed, the mean delta MI per month increased significantly more for malignancies than for benign tumors (delta MI +1.6 vs. +0.3, p<0.001). CONCLUSIONS: The mean MI for malignant ovarian tumors increases over time, while non-malignant tumors have a decreasing or stable MI. Serial MI analysis can improve the prediction of ovarian malignancy by reducing false-positive results, thereby decreasing the number of operations performed for benign abnormalities.

Apolipoprotein concentrations are elevated in malignant ovarian cyst fluids suggesting that lipoprotein metabolism is dysregulated in epithelial ovarian cancer.

SELDI-TOF MS analysis of ovarian cyst fluids revealed that peaks m/z 8696 and 8825 discriminate malignant, borderline, and benign tumors. These peaks correspond to isoforms of apoA2. ELISA demonstrates that apoA1, A2, B, C2, C3, and E cyst fluid concentrations are uncorrelated and higher in malignant ovarian tumors, but only apoA2, apoE, and age are independent classifiers of malignant ovarian tumors, yielding 55.1% sensitivity, 95% specificity, and 88.1% accuracy to discern malignant from benign and borderline tumors. These data suggest that lipoprotein metabolism is dysregulated in ovarian cancer and that apoA2 and apoE warrant further investigation as ovarian tumor biomarkers.

Ovarian cyst fluids are a cache of tumor biomarkers that include calgranulin A and calgranulin B isoforms.

SELDI-TOF MS analysis of cyst fluids identified 95 peaks that discriminate malignant, borderline, and benign ovarian tumors. Three prominent peaks, which correspond to calgranulin A (m/z 10847) and two isoforms of calgranulin B (m/z 12717 and 13294), have higher concentrations in borderline and malignant cyst fluids. Together, calgranulin A and B distinguish borderline and malignant tumors from benign tumors with 28.6% and 63.6% sensitivity for early stage disease, respectively, at 95% specificity and with 74.8% accuracy. Ovarian cyst fluids are useful for discovering discriminatory biomarkers, such as calgranulin, which may have utility for detecting, diagnosing, and biochemically classifying ovarian tumors.

Variables Associated With Resolution and Persistence of Ovarian Cysts.

OBJECTIVE: To estimate surveillance intervals of incident ovarian cysts, and describe variables associated with cyst resolution times. METHODS: The UK-OCST (University of Kentucky Ovarian Cancer Screening Trial) was a prospective cohort that enrolled 47,762 individuals over 30 years, including 2,638 individuals with incident cysts. Cyst diameter and structure and patient age, body mass index, use of hormone therapy (HT), family history of ovarian cancer, and menopausal status were examined as variables associated with cyst resolution using t tests, χ 2 test, Kaplan Meier, and Cox multiple regression. RESULTS: Of 2,638 individuals with incident cysts, 1,667 experienced resolution (63.2%) within 1.2 years, and 971 experienced persistence (36.8%). Within 1 year, unilocular and septated cysts had similar resolution rates (35.4% and 36.7%, respectively, P >.05), but time to resolution was shorter for unilocular cysts compared with septated cysts (mean 1.89 years vs 2.58 years, respectively, P <.001). Both unilocular and septated cysts smaller than 3 cm resolved faster than cysts larger than 6 cm ( P <.001). Variables associated with percent resolution included being of younger age, premenopausal status (but not for synchronous bilateral cysts), and those reporting a family history of ovarian cancer ( P <.05). Variables associated with a faster cyst resolution rate included being older than age 70 years and not using hormone therapy. Body mass index and family history were not associated with cyst resolution time. CONCLUSION: Different surveillance times may be appropriate depending on cyst structure and size and patient age and HT use. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov , NCT04473833.

Ovarian cancer screening--what women want.

BACKGROUND: The attitude of women with regard to the threat of ovarian cancer and toward screening for this disease is undefined. OBJECTIVE: To examine the 30-day moving results of a poll presented to women with a brief instructional component about ovarian cancer. METHODS: A poll was incorporated into the information page (http://ovarianscreening.info) used for recruitment of women into the University of Kentucky Ovarian Screening Research Program. Instructional information on ovarian cancer was included in the poll. The information page has received 26,055 unique visits, with 89.6% originating in the United States. Poll tabulation changes daily to cover the most current 30-day moving window. RESULTS: The current window (December 19, 2011) of poll results included views from 748 respondents. Ninety-seven percent of the respondents felt that ovarian cancer was a concern or threat to them. Only approximately 3% of women who felt that they were without risk factors and did not have any symptoms responded that they either did not want to participate in screening or were undecided, whereas only 2 women (<1%) with risk factors answered similarly. Ninety-one percent of the responders replied that their health insurance should pay $150 or more for screening, whereas 64% replied that they would pay $150 or more if their insurance would not. Only 1% replied that they would not want or need ovarian screening no matter what the cost, whereas 78% felt ovarian screening cost should be in line with other screening tests and be part of the standard of care. CONCLUSIONS: Women in the United States indicate in the ongoing poll that they are concerned about ovarian cancer and want screening to the extent that they express a willingness to pay for it from their own resources.

Ovarian cancer screening.

Annual screening of asymptomatic postmenopausal women using a combination of transvaginal sonography and serum Ca-125 has been evaluated in 4 major clinical trials as a means to facilitate earlier detection of ovarian cancer. In several trials, screening has caused a decrease in stage at detection. These ovarian cancer screening trials are reviewed. The effect of screening on ovarian cancer mortality varies in different trials and is the subject of further investigation.

Subsequent Ultrasonographic Non-Visualization of the Ovaries Is Hastened in Women with Only One Ovary Visualized Initially.

Because the effects of age, menopausal status, weight and body mass index (BMI) on ovarian detectability by transvaginal ultrasound (TVS) have not been established, we determined their contributions to TVS visualization of the ovaries when one or both ovaries are visualized on the first ultrasound exam. A total of 29,877 women that had both ovaries visualized on their first exam were followed over 202,639 prospective TVS exams and 9703 women that had only one ovary visualized on their first exam were followed over 63,702 ultrasonography exams. All images were reviewed by a physician. While non-visualization of both ovaries increased with age in women selected on the basis of the visualization of only one ovary on their first ultrasound exam, one or both ovaries could be visualized in two out of every three women at 80 years of age and more than 50% of women over 80 years of age. At each age, more non-visualizations were associated with women that had only one ovary visualized on their first visit. Having only one ovary visualized on the first exam advanced non-visualizations by an average of ~10 years across all ages and by >20 years in women under 40 years of age. Conclusions: Having only one ovary visualized on an initial ultrasound exam considerably hastens complete non-visualization for this population; however, in these women, ovaries can still be visualized well past menopause, and body habitus is not limiting to TVS ovarian imaging, thus TVS should be considered capable of capturing an ovarian image in two out of every three women at 80 years of age.

Ultrasonographic Visualization of the Ovaries to Detect Ovarian Cancer According to Age, Menopausal Status and Body Type.

Because the effects of age, menopausal status, weight and body mass index (BMI) on ovarian detectability by transvaginal ultrasound (TVS) have not been established, we determined their contributions to TVS visualization of the ovaries. A total of 29,877 women that had both ovaries visualized on their first exam were followed over 202,639 prospective TVS exams. All images were reviewed by a physician. While visualization of both ovaries decreased with age, one or both ovaries could be visualized in two of every three women over 80 years of age. Around 93% of pre-menopausal women and ~69% of post-menopausal women had both ovaries visualized. Both ovaries were visualized in ~72% of women weighing over 300 lbs. and in ~70% of women with a BMI over 40. Conclusions: Age had the greatest influence on the visualization of the ovaries. The ovaries can be visualized well past the menopause. Body habitus was not limiting to TVS ovarian imaging, and TVS should be considered capable of imaging one or both ovaries in two of every three women over 80 years of age. Thus, older and obese patients remain good candidates for TVS exams.

Significance of Pelvic Fluid Observed during Ovarian Cancer Screening with Transvaginal Sonogram.

The primary objective was to examine the role of pelvic fluid observed during transvaginal ultrasonography (TVS) in identifying ovarian malignancy. A single-institution, observational study was conducted within the University of Kentucky Ovarian Cancer Screening trial from January 1987 to September 2019. We analyzed true-positive (TP), false-positive (FP), true-negative (TN), and false-negative (FN) groups for the presence of pelvic fluid during screening encounters. Measured outcomes were the presence and duration of fluid over successive screening encounters. Of the 48,925 women surveyed, 2001 (4.1%) had pelvic fluid present during a TVS exam. The odds ratio (OR) of detecting fluid in the comparison group (TN screen; OR = 1) significantly differed from that of the FP cases (benign pathology; OR: 13.4; 95% confidence interval (CI): 9.1-19.8), the TP cases with a low malignant potential (LMP; OR: 28; 95% CI: 26.5-29.5), TP ovarian cancer cases (OR: 50.4; 95% CI: 27.2-93.2), and FN ovarian cancer cases (OR: 59.3; 95% CI: 19.7-178.1). The mean duration that pelvic fluid was present for women with TN screens was 2.2 ± 0.05 encounters, lasting 38.7 ± 1.3 months. In an asymptomatic screening population, free fluid identified in TVS exams was more associated with ovarian malignancy than in the control group or benign ovarian tumors. While pelvic free fluid may not solely discriminate malignancy from non-malignancy, it appears to be clinically relevant and warrants thoughtful consideration.

Suberoylanilide hydroxamic acid (SAHA) potentiates paclitaxel-induced apoptosis in ovarian cancer cell lines.

OBJECTIVES: To determine if SAHA, a histone deacetylase inhibitor, decreases ovarian cancer cell viability when combined with paclitaxel in vitro, and to explore molecular alterations of combined paclitaxel+SAHA treatment. METHODS: SKOV3 and Hey ovarian cancer cell lines were treated for 24 h with paclitaxel, then re-treated with SAHA or paclitaxel for an additional 48 h. Protein extracts were prepared at 48 h for western blot analysis. Cell viability was assessed at 72 h using the ApoAlert Annexin V Apoptosis Kit. RESULTS: SAHA causes G1 and G2 cell cycle arrest in ovarian cancer cell lines. Cell viability was significantly reduced by combined paclitaxel+SAHA treatment. In Hey cells, viability was reduced to 67% with paclitaxel, and to 48% with paclitaxel+SAHA (p<0.001). In the SKOV3 cell line, viability was reduced to 70% with continuous paclitaxel treatment, and was further reduced to 57% in the combined treatment group (p<0.05). Increased PARP cleavage was noted in the paclitaxel+SAHA groups. SAHA increased expression of p21cip1/waf1 and p27Kip1, down regulated cyclins A and B, and suppressed CDK1. Paclitaxel induced expression of survivin, an inhibitor of apoptosis protein, was reduced to baseline control levels with the addition of SAHA. The pro-apoptotic protein, Bad, was also increased with SAHA. CONCLUSIONS: Paclitaxel+SAHA reduces cell viability in excess of either agent alone in ovarian cancer cell lines. Cell death is mediated via several mechanisms including G1/G2 arrest from CDK1 downregulation, inhibition of paclitaxel-induced survivin accumulation, and from increased Bad expression.

Risk of malignancy in sonographically confirmed septated cystic ovarian tumors.

OBJECTIVE: To determine the risk of malignancy in septated cystic ovarian tumors. MATERIALS: 1319 (4.4%) of 29,829 women were identified by transvaginal sonography (TVS) as having a complex cystic ovarian tumor with septations without solid areas or papillary projections and were placed on long-term ultrasound surveillance for ovarian malignancy. RESULTS: These 1319 patients had a total of 2870 septated cystic ovarian tumors. 2288 tumors (79.7%) had a septal width <2 mm and 582 (20.3%) had a septal width >or=2 mm. 2286 tumors (79.6%) were <5 cm in diameter and 584 (20.4%) were>or=5 cm in diameter. 1114 septated cystic tumors (38.8%) resolved spontaneously (mean duration to resolution-12 months) and 1756 (61.2%) tumors persisted. 128 patients underwent surgical tumor removal within 3 months of ultrasound. Most common histopathology was: serous cystadenoma (75), mucinous cystadenoma (13), and endometrioma (10). One patient had an ovarian tumor of borderline malignancy (Stage IB). There were no cases of ovarian cancer. Patients were followed from 4 to 252 months (mean-77 months). One patient developed papillary morphology in the contralateral ovary 3.2 years after detection of a septated ovarian cyst and had epithelial ovarian cancer in that ovary and in the omentum (Stage IIIC disease). The remaining patients are all free of ovarian neoplasia after a total of 7642 follow-up years. CONCLUSIONS: Septated cystic ovarian tumors without solid areas or papillary projections have a low risk of malignancy and can be followed sonographically without surgery.

Assessing the Costs of Screening for Ovarian Cancer in the United States: An Evolving Analysis.

The primary objective of this study is to provide an updated analysis of the cost of screening for ovarian cancer in the United States. Here, we use updated information from the University of Kentucky Ovarian Cancer Screening Trial in conjunction with new modifying factors such as U.S. national estimates of the cost of care (Truven Health MarketScan Database), recently published estimates of earnings lost due to ovarian cancer death and estimates of federal income taxes paid on those earnings. In total, 326,998 screens were performed during the Kentucky trial from 1987 to 2019. At a cost of $56 per screen, we estimate that the total base cost to operate the program over the last 32 years is $18,311,888. When accounting for the surgical cost of 381 false-positive cases, the total cost of the screening program increases by $3,030,474. However, these costs are offset by the benefit of treating more early-stage ovarian cancer in the screened population, with a total cost advantage of $4,016,475 at our institution (Kentucky) or $1,525,050 ($725,700-$3,312,650) (U.S.) nationally. Additionally, program costs are offset by approximately $3,549,000 due to the potential earnings gained by the 26 women whose lives have been saved with screening. Furthermore, the cost of the program is offset by the federal tax dollars paid on the recovered earnings and amounts to $383,292. Ultimately, the net adjusted total cost of the Kentucky screening program is an estimated $13,393,595 at our institution or $15,885,020 ($13,978,068-$16,799,083) nationally. Thus, the adjusted cost per screen is an estimated $40.96 in Kentucky or $48.58 ($42.75-$51.37) nationally.

Disease-Specific Survival of Type I and Type II Epithelial Ovarian Cancers-Stage Challenges Categorical Assignments of Indolence & Aggressiveness.

Epithelial ovarian cancers (EOC) consist of several sub-types based on histology, clinical, molecular and epidemiological features that are termed "histo-types", which can be categorized into less aggressive Type I and more aggressive Type II malignancies. This investigation evaluated the disease-specific survival (DSS) of women with Type I and II EOC using histo-type, grade, and stage. A total of 200,658 EOC cases were identified in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) data. Kaplan-Meier survival analyses, one-factor ANOVA and Chi-square analyses were performed on 10-year DSS survivals. DSS strongly supported a 2-tiered classification (grade 1 vs. grade 2 & 3) for serous EOC. DSS of early stage serous EOC for grade 2 was significantly different from grade 3 indicating that a 2-tier classification for serous EOC applied only to late stage. DSS of Type I EOC was much better than Type II. However, DSS was 46-58% lower with late stage Type I than with early stage Type I indicating that Type I ovarian cancers should not be considered indolent. Early stage Type II EOC had much better DSS than late stage Type II stressing that stage has a large role in survival of both Type I and II EOC.

Clinical Factors Associated with Longer Hospital Stay Following Ovarian Cancer Surgery.

Background: Ovarian cancer (OC) is the leading cause of death from gynecologic malignancy and is treated with a combination of cytoreductive surgery and platinum-based chemotherapy. Extended length of stay (LOS) after surgery can affect patient morbidity, overall costs, and hospital resource utilization. The primary objective of this study was to identify factors contributing to prolonged LOS for women undergoing surgery for ovarian cancer. Methods: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was queried to identify women from 2012-2016 who underwent hysterectomy for ovarian, fallopian tube and peritoneal cancer. The primary outcome was LOS >50th percentile. Preoperative and intraoperative variables were examined to determine which were associated with prolonged LOS. Results: From 2012-2016, 1771 women underwent elective abdominal surgery for OC and were entered in the ACS-NSQIP database. The mean and median LOS was 4.6 and 4.0 days (IQR 0-38), respectively. On multivariate analysis, factors associated with prolonged LOS included: American Society of Anesthesiologists (ASA) Classification III (aOR 1.71, 95% CI 1.38-2.13) or IV (aOR 1.88, 95% CI 1.44-2.46), presence of ascites (aOR 1.88, 95% CI 1.44-2.46), older age (aOR 1.23, 95% CI 1.13-1.35), platelet count >400,000/mm3 (aOR 1.74, 95% CI 1.29-2.35), preoperative blood transfusion (aOR 11.00, 95% CI 1.28-94.77), disseminated cancer (aOR 1.28, 95% CI 1.03-1.60), increased length of operation (121-180 min, aOR 1.47, 95% CI 1.13-1.91; >180 min, aOR 2.78, 95% CI 2.13-3.64), and postoperative blood transfusion within 72 h of incision (aOR 2.04, 95% CI 1.59-2.62) (p < 0.05 for all). Conclusions: Longer length of hospital stay following surgery for OC is associated with many patient, disease, and treatment-related factors. The extent of surgery, as evidenced by perioperative blood transfusion and length of surgical procedure, is a factor that can potentially be modified to shorten LOS, improve patient outcomes, and reduce hospital costs.