Trends in guideline-adherent chemoradiation therapy for locally advanced cervical cancer before and after the affordable care act.

OBJECTIVE: To assess trends in guideline-adherent chemoradiation therapy (GA-CRT) for locally advanced cervical cancer relative to Patient Protection and Affordable Care Act (ACA) implementation. METHODS: National Cancer Database patients treated with chemoradiation for locally advanced cervical cancer (FIGO 2018 Stage IB3-IVA) from 2004 to 2016 were included. GA-CRT was defined according to NCCN guidelines and included: 1) delivery of external beam radiation, 2) brachytherapy, and 3) chemotherapy, 4) no radical hysterectomy. Logistic regression was used to determine trends in GA-CRT relative to the ACA. Survival was also estimated using Kaplan-Meier analysis. RESULTS: 37,772 patients met inclusion criteria (Pre-ACA:16,169; Post-ACA:21,673). A total of 33,116 patients had squamous cell carcinoma and 4626 patients had other histologies. Forty-five percent of patients had lymph node-positive disease. A total of 14.6% of patients had Stage I disease, 41.8% had Stage II disease, 36.4% had Stage III disease, and 7.9% had Stage IVA disease. On multivariable analysis, medicare insurance (OR 0.91; 95%CI: 0.84-0.99 compared to commercial insurance), non-squamous histology (OR 0.83; 95%CI: 0.77-0.89 for adenocarcinoma) and increasing Charlson-Deyo score were associated with decreased odds of receiving GA care. Increasing T-stage was associated with greater receipt of GA-CRT. The percentage of the population that received guideline adherent care increased post-ACA (Pre-ACA 28%; Post-ACA 34%; p < 0.001). Adherence to treatment guidelines increased 2-year survival by 15% (GA 76%; Not GA 61%; p < 0.001). Increased 2-year survival was seen in the post-ACA cohort (Pre-ACA 62%; Post-ACA 69%; p < 0.001). CONCLUSIONS: Implementation of the ACA was associated with improved GA-CRT and survival in patients with locally advanced cervical cancer.

Standardization of lower extremity quantitative lymphedema measurements and associated patient-reported outcomes in gynecologic cancers.

Practice changing standardization of lower extremity lymphedema quantitative measurements with integrated patient reported outcomes will likely refine and redefine the optimal risk-reduction strategies to diminish the devastating limb-related dysfunction and morbidity associated with treatment of gynecologic cancers. The National Cancer Institute (NCI), Division of Cancer Prevention brought together a diverse group of cancer treatment, therapy and patient reported outcomes experts to discuss the current state-of-the-science in lymphedema evaluation with the potential goal of incorporating new strategies for optimal evaluation of lymphedema in future developing gynecologic clinical trials.

Trends in guideline-adherent fertility-sparing surgery for early-stage cervical cancer before and after the Affordable Care Act.

OBJECTIVE: To assess trends in guideline-adherent fertility-sparing surgery (GA-FSS) for early-stage cervical cancer relative to Patient Protection and Affordable Care Act (ACA) implementation. METHODS: National Cancer Database patients treated for Stage IA1-IB1 cervical cancer from 2004 to 2016 were included. Multivariable logistic regression was used to determined trends in GA-FSS relative to the ACA and identify patient factors independently associated with GA-FSS. RESULTS: Odds of GA-FSS increased in the post- compared to pre-ACA cohort (aOR = 1.65; 95%CI: 1.34-2.03). Decreasing age, Asian/Pacific Islander race, higher education and income levels, more recent treatment year, and lower clinical stage were independently associated with increased odds of receiving GA-FSS. In the pre- and post-ACA samples, decreasing age (per 1 year age increase; pre-ACA aOR = 0.87, 95%CI:0.85-0.90; post-ACA aOR = 0.85, 95%CI:0.83-0.87), higher education level (top vs. lowest education quartile; pre-ACA aOR = 2.08, 95%CI:1.19-3.65; post-ACA aOR = 2.00, 95%CI:1.43-2.80), and lower clinical stage (stages IA2 [pre-ACA aOR = 0.19, 95%CI:0.09-0.41; post-ACA aOR = 0.29, 95%CI:0.19-0.45] and IB1 [pre-ACA aOR = 0.06, 95%CI:0.06-0.16; post-ACA aOR = 0.16, 95%CI: 0.12-0.20] relative to stage IA1) were independently associated with increased odds of GA-FSS receipt. After the ACA, Asian/Pacific Islander race (aOR = 2.81, 95%CI: 1.81-4.36) and more recent treatment year (Spearman's ρ = 0.0348, p-value = 0.008) were also independently associated with increased odds of GA-FSS receipt. When adjusted for the pre- vs. post-ACA treatment periods, Medicaid patients were less likely to undergo GA-FSS than privately-insured patients (aOR = 1.65; 95%CI:1.34-2.03). CONCLUSIONS: Patients were more likely to receive GA-FSS post-ACA. Though the proportion of publicly-insured women increased after ACA implementation, women on Medicaid remained less likely to receive GA-FSS than women with private insurance.

Combining DNMT and HDAC6 inhibitors increases anti-tumor immune signaling and decreases tumor burden in ovarian cancer.

Novel therapies are urgently needed for ovarian cancer, the deadliest gynecologic malignancy. Ovarian cancer has thus far been refractory to immunotherapies that stimulate the host immune system to recognize and kill cancer cells. This may be because of a suppressive tumor immune microenvironment and lack of recruitment and activation of immune cells that kill cancer cells. Our previous work showed that epigenetic drugs including DNA methyltransferase inhibitors and histone deacetylase 6 inhibitors (DNMTis and HDAC6is) individually increase immune signaling in cancer cells. We find that combining DNMTi and HDAC6i results in an amplified type I interferon response, leading to increased cytokine and chemokine expression and higher expression of the MHC I antigen presentation complex in human and mouse ovarian cancer cell lines. Treating mice bearing ID8 Trp53-/- ovarian cancer with HDAC6i/DNMTi led to an increase in tumor-killing cells such as IFNg+ CD8, NK, and NKT cells and a reversal of the immunosuppressive tumor microenvironment with a decrease in MDSCs and PD-1hi CD4 T cells, corresponding with an increase in survival. Thus combining the epigenetic modulators DNMTi and HDAC6i increases anti-tumor immune signaling from cancer cells and has beneficial effects on the ovarian tumor immune microenvironment.

A pilot study of lower extremity lymphedema, lower extremity function, and quality of life in women after minimally invasive endometrial cancer staging surgery.

OBJECTIVE: The primary aim of this study was to pilot the use of an objective measurement technique to prospectively evaluate the incidence of lower extremity lymphedema (LEL) after minimally invasive staging surgery for endometrial cancer. Secondary objectives included observation of changes in lower extremity function and quality of life in this patient population. METHODS: A prospective evaluation of LEL was performed in 97 women who underwent minimally invasive staging surgery for endometrial cancer using comparative circumferential volume measurements. Postoperative changes in lower extremity function and global quality of life were also assessed using patient-reported outcome measures. RESULTS: Ninety-seven patients were included for lymphedema analysis. The rate of LEL was 25% at 4-6 weeks, 19% at 6-9 months, and 27% at 12-18 months postoperatively. The presence of LEL was associated with a significant worsening from baseline Lower Extremity Functional Scale (LEFS) scores at 4-6 weeks (-27.0% vs -3.7%, p = 0.02) and 6-9 months (-13.0% vs 0%, p = 0.01). LEL was not associated with a change in patient-reported global quality of life. CONCLUSIONS: Up to one in four women experience lymphedema following surgical staging for endometrial cancer, and its presence is associated with diminished lower extremity function. Larger, prospective trials using the objective methodology piloted in this study should better clarify risk factors and long-term outcomes of this morbidity.

Epigenetic therapy for ovarian cancer: promise and progress.

Ovarian cancer is the deadliest gynecologic malignancy, with a 5-year survival rate of approximately 47%, a number that has remained constant over the past two decades. Early diagnosis improves survival, but unfortunately only 15% of ovarian cancers are diagnosed at an early or localized stage. Most ovarian cancers are epithelial in origin and treatment prioritizes surgery and cytoreduction followed by cytotoxic platinum and taxane chemotherapy. While most tumors will initially respond to this treatment, recurrence is likely to occur within a median of 16 months for patients who present with advanced stage disease. New treatment options separate from traditional chemotherapy that take advantage of advances in understanding of the pathophysiology of ovarian cancer are needed to improve outcomes. Recent work has shown that mutations in genes encoding epigenetic regulators are mutated in ovarian cancer, driving tumorigenesis and resistance to treatment. Several of these epigenetic modifiers have emerged as promising drug targets for ovarian cancer therapy. In this article, we delineate epigenetic abnormalities in ovarian cancer, discuss key scientific advances using epigenetic therapies in preclinical ovarian cancer models, and review ongoing clinical trials utilizing epigenetic therapies in ovarian cancer.

Rates of regression of cervical dysplasia between initial biopsy and excisional procedure in routine clinical practice.

PURPOSE: To determine rates and factors associated with regression of cervical intraepithelial neoplasia (CIN) 2 + between colposcopic biopsy and therapeutic excisional procedure in standard practice. METHODS: A retrospective chart review was performed for women undergoing a cervical excisional procedure for CIN 2 + at clinics at three academic institutions over a 3-year period. Cytology, histology, patient age and time-to-excision were analyzed to determine factors influencing rates of regression. RESULTS: Of 356 women undergoing excision for CIN 2 + on colposcopic biopsy, 91 (25.3%) of final pathology diagnoses displayed clinically significant regression. Age and time-to-excision were not associated with regression, but referral cytology and severity of initial biopsy histology were, with ASC-H (aOR 0.1, CI 0.03, 0.8) and CIN 3/AIS (aOR 0.4, CI 0.2, 0.7) being less likely to regress than less severe lesions. CONCLUSIONS: Disease severity by referral cytology or diagnostic biopsy, as opposed to age or length of time-to-excision, is likely the most relevant factor in determination of regression for cervical intraepithelial neoplasia in women undergoing excisional treatment for biopsy-confirmed CIN2 +.

Predicting 6- and 12-Month Risk of Mortality in Patients With Platinum-Resistant Advanced-Stage Ovarian Cancer: Prognostic Model to Guide Palliative Care Referrals.

OBJECTIVE: Predictive models are increasingly being used in clinical practice. The aim of the study was to develop a predictive model to identify patients with platinum-resistant ovarian cancer with a prognosis of less than 6 to 12 months who may benefit from immediate referral to hospice care. METHODS: A retrospective chart review identified patients with platinum-resistant epithelial ovarian cancer who were treated at our institution between 2000 and 2011. A predictive model for survival was constructed based on the time from development of platinum resistance to death. Multivariate logistic regression modeling was used to identify significant survival predictors and to develop a predictive model. The following variables were included: time from diagnosis to platinum resistance, initial stage, debulking status, number of relapses, comorbidity score, albumin, hemoglobin, CA-125 levels, liver/lung metastasis, and the presence of a significant clinical event (SCE). An SCE was defined as a malignant bowel obstruction, pleural effusion, or ascites occurring on or before the diagnosis of platinum resistance. RESULTS: One hundred sixty-four patients met inclusion criteria. In the regression analysis, only an SCE and the presence of liver or lung metastasis were associated with poorer short-term survival (P < 0.001). Nine percent of patients with an SCE or liver or lung metastasis survived 6 months or greater and 0% survived 12 months or greater, compared with 85% and 67% of patients without an SCE or liver or lung metastasis, respectively. CONCLUSIONS: Patients with platinum-resistant ovarian cancer who have experienced an SCE or liver or lung metastasis have a high risk of death within 6 months and should be considered for immediate referral to hospice care.

Choriocarcinoma with brain, lung and vaginal metastases successfully treated without brain radiation or intrathecal chemotherapy: A case report.

•There is no consensus on optimal treatment for GTN and brain metastases.•Brain metastasis treated with craniotomy and intravenous, EMA-CO chemotherapy•Intravenous high-dose methotrexate may be adequate to treat brain metastases.

Cost Comparison of Genetic Testing Strategies in Women With Epithelial Ovarian Cancer.

PURPOSE: The advent of multigene panels has increased genetic testing options for women with epithelial ovarian cancer (EOC). We designed a decision model to compare costs and probabilities of identifying a deleterious mutation or variant of uncertain significance (VUS) using different genetic testing strategies. METHODS: A decision model was developed to compare costs and outcomes of two testing strategies for women with EOC: multigene testing (MGT) versus single-gene testing for BRCA1/2. Outcomes were mean cost and number of deleterious mutations and VUSs identified. Model inputs were obtained from published genetic testing data in EOC. One-way sensitivity analyses and Monte Carlo probabilistic sensitivity analyses were performed. RESULTS: No family history model: MGT cost $1,160 more on average than BRCA1/2 testing and identified an additional 3.8 deleterious mutations for every 100 women tested. For each additional deleterious mutation identified, MGT cost $30,812 and identified 5.4 additional VUSs. Family history model: MGT cost $654 more on average and identified an additional 7.0 deleterious mutations for every 100 women tested. For each additional deleterious mutation identified, MGT cost $9,909 and identified 2.6 additional VUSs. CONCLUSION: MGT was associated with a higher additional cost per deleterious mutation identified and a higher ratio of VUS burden to actionable information in women with no family history as compared with women with a family history. Family history should be considered when determining an initial genetic testing platform in women with EOC.

Performance of sentinel lymph node biopsy in high-risk endometrial cancer.

OBJECTIVE: To determine the rate and performance of sentinel lymph node (SLN) mapping among women with high-risk endometrial cancers. METHODS: Patients diagnosed between 2012 and 2015 with uterine cancer of grade 3 endometrioid, clear cell, serous or carcinosarcoma histology and who underwent SLN mapping prior to full pelvic lymph node dissection were included. Subjects underwent methylene blue or ICG injection for laparoscopic (N = 16) or robotic-assisted laparoscopic (N = 20) staging. Outcomes included SLN mapping rates, SLN and non-SLN positive rates, false negative SLN algorithm rate, and the negative predictive value (NPV) of the SLN algorithm. Fisher's exact test was used to compare mapping and node positivity rates. RESULTS: 9/36 (25%) patients with high-risk uterine cancer had at least one metastatic lymph node identified. Successful mapping occurred in 30/36 (83%) patients. SLN mapped to pelvic nodes bilaterally in 20 (56%), unilaterally in 9 (25%), and aortic nodes only in 1 (3%). Malignancy was identified in 14/95 (15%) of all sentinel nodes and 12/775 (1.5%) of all non-sentinel nodes (p < 0.001). The false negative rate of SLN mapping alone was 2/26 (7.7%); the NPV was 92.3%. When the SLN algorithm was applied retrospectively the false negative rate was 0/31 (0%); the NPV was 100%. CONCLUSION: SLN mapping rates for high-risk cancers are slightly lower than in prior reports of lower risk cancers. The NPV of the SLN mapping alone is 92% and rises to 100% when the SLN algorithm is applied. Such results are acceptable and consistent with larger subsets of lower risk endometrial cancers.

Dasatinib (BMS-35482) potentiates the activity of gemcitabine and docetaxel in uterine leiomyosarcoma cell lines.

BACKGROUND: To explore the activity of dasatinib alone and in combination with gemcitabine and docetaxel in uterine leiomyosarcoma (uLMS) cell lines, and determine if dasatinib inhibits the SRC pathway. METHODS: SK-UT-1 and SK-UT-1B uLMS cells were treated with gemcitabine, docetaxel and dasatinib individually and in combination. SRC and paxcillin protein expression were determined pre- and post-dasatinib treatment using Meso Scale Discovery (MSD) multi-array immunogenicity assay. Dose-response curves were constructed and the coefficient of drug interaction (CDI) and combination index (CI) for drug interaction calculated. RESULTS: Activated phosphorylated levels of SRC and paxillin were decreased after treatment with dasatinib in both cell lines (p < 0.001). The addition of a minimally active concentration of dasatinib (IC25) decreased the IC50 of each cytotoxic agent by 2-4 fold. The combination of gemcitabine-docetaxel yielded a synergistic effect in SK-UT-1 (CI = 0.59) and an antagonistic effect in SK-UT-1B (CI = 1.36). Dasatinib combined with gemcitabine or docetaxel revealed a synergistic anti-tumor effect (CDI < 1) in both cell lines. The triple drug combination and sequencing revealed conflicting results with a synergistic effect in SK-UT-1B and antagonistic in SK-UT-1. CONCLUSION: Dasatinib inhibits the SRC pathway and yields a synergistic effect with the two-drug combination with either gemcitabine or docetaxel. The value of adding dasatinib to gemcitabine and docetaxel in a triple drug combination is uncertain, but may be beneficial in select uLMS cell lines. Based on our pre-clinical data and known activity of gemcitabine and docetaxel, further evaluation of dasatinib in combination with these agents for the treatment of uLMS is warranted.

Cost-effectiveness of early palliative care intervention in recurrent platinum-resistant ovarian cancer.

OBJECTIVE: To determine if early palliative care intervention in patients with recurrent, platinum-resistant ovarian cancer is potentially cost saving or cost-effective. METHODS: A decision model with a 6 month time horizon evaluated routine care versus routine care plus early referral to a palliative medicine specialist (EPC) for recurrent platinum-resistant ovarian cancer. Model parameters included rates of inpatient admissions, emergency department (ED) visits, chemotherapy administration, and quality of life (QOL). From published ovarian cancer data, we assumed baseline rates over the final 6 months: hospitalization 70%, chemotherapy 60%, and ED visit 30%. Published data from a randomized trial evaluating EPC in metastatic lung cancer were used to model odds ratios (ORs) for potential reductions in hospitalization (OR 0.69), chemotherapy (OR 0.77), and emergency department care (OR 0.74) and improvement in QOL (OR 1.07). The costs of hospitalization, ED visit, chemotherapy, and EPC were based on published data. Ranges were used for sensitivity analysis. Effectiveness was quantified in quality adjusted life years (QALYs); survival was assumed equivalent between strategies. RESULTS: EPC was associated with a cost savings of $1285 per patient over routine care. In sensitivity analysis incorporating QOL, EPC was either dominant or cost-effective, with an incremental cost-effectiveness ratio (ICER) <$50,000/QALY, unless the cost of outpatient EPC exceeded $2400. Assuming no clinical benefit other than QOL (no change in chemotherapy administration, hospitalizations or ED visits), EPC remained highly cost-effective with ICER $37,440/QALY. CONCLUSION: Early palliative care intervention has the potential to reduce costs associated with end of life care in patients with ovarian cancer.

Palliative and hospice care in gynecologic cancer: a review.

Despite the increasing availability of palliative care, oncology providers often misunderstand and underutilize these resources. The goals of palliative care are relief of suffering and provision of the best possible quality of life for both the patient and her family, regardless of where she is in the natural history of her disease. Lack of understanding and awareness of the services provided by palliative care physicians underlie barriers to referral. Oncologic providers spend a significant amount of time palliating the symptoms of cancer and its treatment; involvement of specialty palliative care providers can assist in managing the complex patient. Patients with gynecologic malignancies remain an ideal population for palliative care intervention. This review of the literature explores the current state of palliative care in the treatment of gynecologic cancers and its implications for the quality and cost of this treatment.

Timing of end-of-life care discussion with performance on end-of-life quality indicators in ovarian cancer.

OBJECTIVES: (1) To describe the prevalence, timing and setting of documented end-of-life (EOL) discussions in patients with advanced ovarian cancer; and (2) to assess the impact of timing and setting of documented end-of-life discussions on EOL quality care measures. METHODS: A retrospective study of women who died of ovarian cancer diagnosed between 1999 and 2008 was conducted. The following are the EOL quality measures assessed: chemotherapy in the last 14 days of life, >1 hospitalization in the last 30 days, >1 ER visit in the last 30 days, intensive care unit (ICU) admission in the last 30 days, dying in an acute care setting, admitted to hospice ≤3 days. RESULTS: One hundred seventy-seven (80%) patients had documented end-of-life discussions. Median interval from EOL discussion until death was 29 days. Seventy-eight patients (44%) had EOL discussions as outpatient and 99 (56%) as inpatient. Sixty-four out of 220 (29%) patients' care did not conform to at least one EOL quality measure. An EOL discussion at least 30 days before death was associated with a lower incidence of: chemotherapy in the last 14 days of life (p=0.003), >1 hospitalization in the last 30 days (p<0.001), ICU admission in the last 30 days (p=0.005), dying in acute care setting (p=0.01), admitted to hospice ≤3 days (p=0.02). EOL discussion as outpatient was associated with fewer patients hospitalized >1 in the last 30days of life (p<0.001). CONCLUSIONS: End-of-life care discussions are occurring too late in the disease process. Conformance with EOL quality measures can be achieved with earlier end-of-life care discussions.

Primary radiation therapy for medically inoperable patients with clinical stage I and II endometrial carcinoma.

OBJECTIVE: To determine the outcomes associated with primary radiation therapy for medically inoperable, clinical stage I and II, endometrial adenocarcinoma (EAC). METHODS: A multi-institution, retrospective chart review from January 1997 to January 2009 was performed. Overall survival (OS), disease-specific survival (DSS), progression-free survival (PFS) and time to progression (TTP) were assessed using the Kaplan-Meier method. Disease-specific survival was analyzed using a competing risks approach. RESULTS: Seventy-four patients were evaluable. The median age and BMI were 65 years (range 36-92 years) and 46 kg/m(2) (range 23-111 kg/m(2)), respectively. 85.1% had severe systemic disease, most frequently cardiopulmonary risk and morbid obesity. With a mean follow-up of 31 months, 13 patients (17.6%) experienced a recurrence. The median PFS and OS were 43.5 months and 47.2 months, respectively. Overall, 35 women died, including 4 women who died of unknown cause. Of the remaining 31 women, 7 patients (9.5%) died of disease, while 24 died of other causes (32.4%). The hazard ratio comparing the risk of death due to other causes to the risk of death due to disease was 3.4 (95% CI 1.4-9.4, p=0.003). Among patients who are alive three years after diagnosis, 14% recurred and the conditional recurrence estimate did not exceed 16%. CONCLUSIONS: Primary radiation therapy for clinical stage I and II EAC is a feasible option for medically inoperable patients and provides disease control, with fewer than 16% of surviving patients experiencing recurrence.