Financial toxicity in ovarian cancer.

Ovarian cancer is the most costly and deadly of the gynecologic malignancies. Financial toxicity from out-of-pocket costs for direct care and medications as well as indirect costs from lost income is a growing challenge in oncology. The aim of this review is to focus on recent financial toxicity literature in the gynecologic oncology sphere and highlight specific issues and challenges regarding financial toxicity in ovarian cancer. Treatment options for ovarian cancer lead to variable costs for patients, and there are risk factors for high financial toxicity unique to gynecologic oncology patients. Identification and prompt intervention for those most at risk can help alleviate financial distress from ovarian cancer care.

Uterine leiomyosarcoma: A review of the literature and update on management options.

Uterine leiomyosarcoma is the most common type of uterine sarcoma. It is an extremely aggressive malignancy associated with a poor overall prognosis. Women affected may vary in age, but are most often diagnosed in their perimenopausal years. Presenting symptoms may be vague and mimic other benign uterine conditions. Preoperative diagnosis of leiomyosarcoma is difficult and often only made at time of surgical resection. These rare mesenchymal tumors are characterized by cytologic atypia, a high mitotic index, and tumor necrosis on histologic inspection. Management of early stage disease entails hysterectomy and complete surgical resection of gross tumor, though routine oophorectomy or lymph node dissection do not appear to confer much clinical benefit. Adjuvant therapy for early stage disease remains controversial as multiple clinical trials have failed to demonstrate benefit on overall survival. Recently, progress has been made in regards to therapy for advanced and recurrent disease. Novel chemotherapeutics, targeted therapies such as olaratumab and pazopanib, and new immunotherapies such as nivolumab and pembrolizumab have demonstrated promise in these previously difficult drug-resistant patients. In this article, we provide a detailed review of uterine leiomyosarcoma including epidemiology, clinical presentation, diagnosis, and pathologic characteristics. We then go on detail management strategies, including options for adjuvant therapy, and highlight new and developing regimens in the field.

Obesity and Endometrial Cancer: A Lack of Knowledge but Opportunity for Intervention.

OBJECTIVE: The causal link between obesity and endometrial cancer is well established; however obese women's knowledge of this relationship is unknown. Our objective was to explore patients' understanding of this relationship and assess the acceptability of a technology-based weight loss intervention. METHODS/MATERIALS: Obese women with Type I endometrial cancer/hyperplasia were surveyed about their assessment of their body mass, knowledge of the relationship of obesity and endometrial cancer, and eating and activity habits. Interest in participation in an intervention also was assessed. RESULTS: Eighty-one women with early stage (71.6% stage I) and grade (41.7% grade 1) disease completed the survey. The median BMI was 35.4 kg/m2 (IQR 32.2-43.5 kg/m2) and the average age was 59.3 (SD 11.1) yr. 76.25% of women were unable to categorize their BMI correctly and 86.9% of those incorrectly underestimated their BMI category. One-third (35.9%) were unaware of any association between obesity and endometrial cancer and 33.3% responded that obesity decreased or did not significantly increase the risk of endometrial cancer. 59% expressed interest in a weight loss intervention. CONCLUSIONS: Endometrial cancer survivors with obesity underestimated their obesity and lacked knowledge regarding the link between obesity and endometrial cancer. However, the majority expressed interest in electronically delivered weight loss interventions.

Opportunities and Challenges: Human Papillomavirus and Cancer.

Mucosal exposure to human papillomavirus (HPV) can lead to anogenital and head and neck (H&N) cancer. Vaccination at a young age can be almost 100% effective in preventing HPV infection with the viral subtypes in both men and women, at least for disease in the anogenital tract. Therapeutic strategies targeting HPV in cervical dysplasia and cancer are showing promise as well in regressing dysplasia and controlling disease. That HPV-positive H&N cancer is a different disease from HPV-negative disease, with different molecular and clinical features and prognosis, is becoming better appreciated. At this time, however, the NCCN Guidelines for H&N Cancers do not distinguish between the types. This is expected to change.

The use of novel technology-based weight loss interventions for obese women with endometrial hyperplasia and cancer.

OBJECTIVE: Obesity significantly increases the risk of the development of both endometrial hyperplasia and cancer. Our objective was to assess the feasibility of two technology-based weight loss interventions in this patient population. METHODS: Women with obesity (BMI≥30kg/m(2)) and endometrial hyperplasia or Type I endometrial cancer were randomized 1:1 to a technology-based 6month lifestyle intervention via either telemedicine or text messaging. The telemedicine arm received weekly phone calls, with weights tracked online using Withings© Wi-Fi scales. The text arm received 3-5 personalized messages daily via Text4Diet™. Participants maintained a 1200-1800calorie/day diet, self-monitored food intake and received exercise goals. Biomarkers (IGFBP-1, adiponectin, VEGF, IL1-beta, IL2, IL6, and IL7) were assessed pre- and post-treatment. RESULTS: Twenty women were randomized (Telemedicine: n=10, Text4Diet: n=10), and 90% lost weight. Many were early stage (70%) and grade (43.8%) disease with a median age of 60.5years. We observed a statistically greater weight loss in the Telemedicine arm [median loss: 9.7kg (range: 1.6-22.9kg)] versus 3.9kg (range: 0.3-11.4kg) in the Text4Diet arm (p=0.0231). Similarly, percent weight loss was greater in the Telemedicine (7.6%) as compared to the Text4Diet arm (4.1%, p=0.014). Mean serum levels of IL-2 were significantly (27.15pg/mL vs. 5.18pg/mL, p=0.0495) lower at intervention end as compared to baseline. CONCLUSIONS: A technology-based weight loss intervention is feasible in women with Type I endometrial cancer/hyperplasia. Both interventions produced weight loss, although more person-to-person contact produced more significant outcomes. Reductions in expression of IL-2 were related to weight loss.

Effectiveness and safety of expanded perioperative thromboprophylaxis in complex gynecologic surgery.

OBJECTIVE: To determine the effectiveness and safety of an expanded perioperative venous thromboembolism (VTE) prophylaxis strategy in women undergoing complex gynecologic surgery. METHODS: We performed a cohort study of 527 patients undergoing major surgery at a single institution over a thirty-month interval during which the gynecologic oncology service implemented an expanded approach to VTE prophylaxis. We compared rates of VTE pre- and post-intervention as well as bleeding and infectious complications. RESULTS: Prior to the intervention, there were 23 VTE events in 345 patients (rate of 6.67%): 8 deep vein thromboses (DVTs) and 15 pulmonary emboli (PEs). Post-intervention, there were 5 VTE events in 182 patients (2.7%): 3 DVTs and 2 PEs (RR=0.4, p=0.056). Time-to-event analysis showed a significantly higher incidence of VTE events in the pre-intervention time frame compared to the post-intervention period (p=0.049). There were no significant differences in bleeding or infection complications between groups. CONCLUSIONS: Implementation of a perioperative VTE prophylaxis protocol was safe, feasible and resulted in a clinically significant reduction in symptomatic VTE. Preoperative single-dose unfractionated heparin for all patients, combined with two weeks of thromboprophylaxis in gynecologic cancer patients, may decrease VTE events without increasing bleeding or infection.

Physical activity, daily walking, and lower limb lymphedema associate with physical function among uterine cancer survivors.

PURPOSE: We sought to quantify the proportion of uterine cancer survivors who self-report poor physical function. We then sought to quantify the association of poor physical function with physical activity (PA), walking, and lower limb lymphedema (LLL), among women with a history of uterine cancer. METHODS: Physical function was quantified using the Medical Outcomes Study 12-Item Short-Form Health Survey (SF-12) questionnaire. PA, walking, and LLL were measured using self-report questionnaire. PA was calculated using metabolic equivalent hours per week (MET-h week(-1)), and walking was calculated using blocks per day (blocks day(-1)). Logistic regression estimated odds ratios (OR) and 95 % confidence intervals (95 % CI). RESULTS: Among the 213 uterine cancer survivors in our survey (43 % response rate), 35 % self-reported poor physical function. Compared to participants who reported <3.0 MET-h week(-1) of PA, participants who reported ≥18.0 MET-h week(-1) of PA were less likely to have poor physical function (OR 0.03, 95 % CI 0.01-0.10; P trend < 0.0001). Compared to participants who reported <4.0 blocks day(-1) of walking, participants who reported ≥12.0 blocks day(-1) of walking were less likely to have poor physical function (OR 0.07, 95 % CI 0.03-0.19; P trend < 0.0001). Compared to participants who did not have LLL, participants with LLL were more likely to have poor physical function (OR 5.25, 95 % CI 2.41-11.41; P < 0.0001). CONCLUSION: Higher levels of PA and walking associate with a lower likelihood of reporting poor physical function. The presence of LLL associates with a higher likelihood of reporting poor physical function. These findings are hypothesis-generating and should be evaluated in future prospective studies.

Metastatic cholangiocarcinoma to the ovary: a case series.

Metastases to the ovary can be a challenging diagnostic dilemma as they often present similarly to a primary ovarian cancer, and there are many potential sites of origin. We present a case series of 5 patients with known cholangiocarcinoma recurrent in the ovary after completion of initial multimodality therapy including surgical resection of the primary tumor followed by adjuvant chemotherapy.

Bevacizumab-induced perforation of the gastrointestinal tract: clinical and radiographic findings in 11 patients.

AIM: To present the gastrointestinal (GI) complications associated with bevacizumab therapy and their findings on abdominal imaging studies. METHODS: A computerized search identified 11 patients with GI complications of bevacizumab therapy on abdominal CT (n = 11) and fluoroscopic GI contrast studies (n = 4) who met our study criteria (including five patients with ovarian cancer, five with colon cancer, and one with cervical cancer). The medical records and imaging studies were reviewed to determine the clinical and radiographic findings in these patients. RESULTS: All 11 patients had findings of GI perforation on CT, or CT and GI contrast studies. CT revealed a localized extraluminal collection containing gas, fluid, and/or contrast material in eight patients (73%) with focal perforation, and free abdominal air and fluid in three (27%) with free perforation The imaging studies also revealed seven fistulas, including two colovaginal, one rectovaginal, one enterocutaneous, one colocutaneous, one gastrocolic, and one colorectal fistula. Eight (73%) of the 11 patients died within 1 year of the development of GI perforation, and the perforation was felt to be the cause of death in four patients (36%). CONCLUSION: Abdominal CT and fluoroscopic GI contrast studies are useful imaging tests for the diagnosis of potentially life-threatening GI perforation as a complication of bevacizumab therapy. When GI perforation is detected on abdominal imaging studies, treatment with bevacizumab should immediately be discontinued.

Starting the Conversation: randomized pilot trial of an intervention to promote effective clinical communication about sexual health for gynecologic cancer survivors.

PURPOSE: Gynecologic cancer survivors often hesitate to raise sexual health concerns with their clinicians. We pilot tested Starting the Conversation (STC), a theory-guided intervention aimed at facilitating survivors' clinical communication about sexual health. METHODS: Survivors (N = 32) were randomized 2:1 to STC (23-min video and accompanying workbook grounded in social cognitive theory that provides information and skills training for communicating with providers about sexual concerns, and resource guide) or control (resource guide only). Feasibility was assessed through enrollment, retention, and intervention completion rates (benchmarks: 60%, 80%, 70%); acceptability was assessed through post-intervention program evaluations (benchmark: 75%). Preliminary effects were assessed for sexual health communication (self-reported after next clinic encounter), self-efficacy for clinical communication about sexual health (post-intervention and 2-month follow-up), and sexual activity and anxiety/depressive symptoms (2-month follow-up). RESULTS: All feasibility/acceptability benchmarks were surpassed; 76% enrolled, 97% retained, ≥ 95% used intervention materials, and 100% endorsed STC as acceptable. Positive STC effects were seen for increases in self-efficacy (Cohen's d's = 0.45 at post-intervention; 0.55 at follow-up). In STC, 35% and 45% of women raised or asked about sexual health concerns during the post-intervention clinic visit, respectively, versus 0 and 27% in the control arm. Other measures showed little change. CONCLUSIONS: Data support the STC intervention as feasible and acceptable, with promising effects for gynecologic cancer survivors' communication about sexual health concerns. Because sexual health communication is relevant across the treatment trajectory, we included both on-treatment and post-treatment survivors. While this may be a limitation, it could also enhance sample generalizability. A larger trial is needed to determine efficacy. IMPLICATIONS FOR CANCER SURVIVORS: Communication about sexual health is important yet lacking for cancer survivors. Patient-focused interventions may help address concerns and improve survivors' health outcomes.

Perceived importance of weight loss and exercise among endometrial cancer survivors with overweight or obesity: Implications for lifestyle modification interventions.

Objective: Type 1 endometrial cancer (EC) survivors who are overweight or obese are at increased risk of comorbidities and reduced quality of life. Lifestyle modification interventions (e.g., healthy eating, exercise) may help these women reduce excess weight and improve their quality of life. However, existing interventions have shown limited success. Guided by Self-Determination Theory, the proposed study sought to identify factors associated with perceived importance of weight loss and exercise as well as interest in lifestyle modification interventions (components of extrinsic and intrinsic motivation) among EC survivors with overweight or obesity to inform future intervention development. Methods: One hundred type 1 EC survivors [body mass index (BMI) ≥ 25 kg/m2] completed a cross-sectional survey assessing sociodemographics, medical factors, exercise, risk perceptions and provider communication, quality of life, barriers to dieting and exercise, perceived importance of healthy lifestyles, and desired intervention content. Results: EC survivors who were aware obesity is a risk factor for EC were significantly more likely to perceive weight loss as important and were interested in weight loss programs and receiving information about exercise (ps < 0.05). Additionally, EC survivors who reported their provider discussed the importance of a healthy weight after their diagnosis were significantly more likely to perceive exercise as important and were interested in receiving dieting information. Conclusions: EC survivors expressed interest in lifestyle modification interventions. Increasing awareness about the risk of obesity and provider discussions about healthy weight during routine appointments may motivate EC survivors to engage in lifestyle modification interventions.

Phase I/II randomized trial of dendritic cell vaccination with or without cyclophosphamide for consolidation therapy of advanced ovarian cancer in first or second remission.

PURPOSE: In spite of increased rates of complete response to initial chemotherapy, most patients with advanced ovarian cancer relapse and succumb to progressive disease. Immunotherapy may have potential for consolidation therapy. EXPERIMENTAL DESIGN: This randomized open-label phase I/II trial evaluated responses of patients with advanced ovarian cancer in remission for vaccination with monocyte-derived dendritic cells (DC) loaded with Her2/neu, hTERT, and PADRE peptides, with or without low-dose intravenous cyclophosphamide. All patients also received pneumococcal vaccine and were randomized to cyclophosphamide 2 days prior to first vaccination. Blood samples were analyzed by ELISPOT and flow cytometry. RESULTS: Of 11 patients, 2 recurred during vaccination. Nine received all 4 doses: 3 patients recurred at 6, 17, and 26 months, respectively, and 6 have no evidence of disease at 36 months. No grade 3/4 vaccine-related toxicities were noted. The 3-year overall survival was 90%. Patients receiving cyclophosphamide showed a non-significant improvement in survival over controls. Patients receiving cyclophosphamide had a transient reduction in neutrophils, but no change in total lymphocytes or regulatory T cells. Modest T-cell responses to Her2/neu and hTERT were seen post-vaccine by IFN-γ ELISPOT. Patients demonstrated below normal responses to the diphtheria conjugate protein CRM197, a component of the pneumococcal vaccine. CONCLUSIONS: In this setting, peptide-loaded DC vaccination elicits modest immune responses, but survival is promising. Pneumococcal vaccination revealed substantial immune suppression, even in patients in remission. Rational design of consolidative strategies for ovarian cancer will need to overcome tolerance and immunosuppression.

Reversible paraneoplastic encephalitis in three patients with ovarian neoplasms.

Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis is a recently described potentially lethal but treatable disorder that often occurs as a paraneoplastic manifestation of ovarian teratomas. We report three women with this disorder who presented with subacute onset of delirium, seizures and autonomic instability. Anti-NMDA receptor antibodies were detectable in the serum or cerebrospinal fluid of each patient. Ovarian masses were detected in two patients, and subsequently excised. In the third patient, an empirical bilateral salpingo-oophorectomy was performed and revealed a microscopic neoplasm. All patients experienced slow reversal of the neurological symptoms following surgery and immunotherapy. Our experience suggests that prompt syndrome recognition followed by tumor removal and immunotherapy usually results in neurological recovery.

Non-Gestational Ovarian Choriocarcinoma: A Rare Ovarian Cancer Subtype.

Non-Gestational Ovarian Choriocarcinoma (NGOC) is an extremely rare ovarian tumor, with an incidence of less than 0.6% of malignant ovarian germ cell tumors. Its close pathologic resemblance to Gestational Ovarian Choriocarcinoma (GOC), however, requires special attention as the treatments differ greatly. NGOC typically affects patients in late adolescence or early reproductive years. As a result, NGOCs are often misdiagnosed as ectopic pregnancies due to their common presentation of bleeding, abdominal pain, adnexal mass, and positive serum beta-HCG. On pathologic examination, the tumor is indistinguishable from GOC, and only after review of tissue for paternal genetic components can the diagnosis of NGOC be made. Imaging studies often show highly vascular lesions with further investigation with computer topography (CT) sometimes showing metastatic lesions in the lungs, pelvis, vagina, and liver. These lesions are often hemorrhagic and can lead to catastrophic bleeding. Treatment is vastly different from GOC; NGOC requires treatment with both surgical resection and chemotherapy, with Bleomycin, Etoposide, and Cisplatin (BEP) being the most used regimen. With correct diagnosis and treatment, patients can often receive fertility sparing treatment with long term survival.

Clinical predictors of bevacizumab-associated gastrointestinal perforation.

OBJECTIVES: Bevacizumab is a generally well-tolerated drug, but bevacizumab-associated gastrointestinal perforations (BAP) occur in 0 to 15% of patients with ovarian carcinoma. Our goal was to evaluate the clinical predictors of BAP in order to identify factors, which may preclude patients from receiving treatment. METHODS: We conducted a review of patients with recurrent epithelial ovarian carcinoma treated with bevacizumab between 2006 and 2009. Demographic and treatment data were collected for statistical analysis. RESULTS: Eighty-two patients were identified; perforation occurred in 8 (9.76%). Among patients with perforation, a significantly higher incidence of prior bowel surgeries (p=0.0008) and prior bowel obstruction or ileus (p<0.0001) were found compared to non-perforated patients. The median age at onset of bevacizumab in the perforated group was 3 years younger (60 vs. 63 years, p=0.61). The incidence of thromboembolic events, GI comorbidities, number of prior chemotherapies, and body mass index were similar between the groups. None of the patients in the perforated group developed grade 3 or 4 hypertension, compared to a 32.4% incidence among the non-perforated patients (p=0.09). Upon multivariate analysis, when controlled for age greater or less than 60, prior bowel surgery, obstruction/ileus, and grade 3 or 4 hypertension, only the presence of obstruction/ileus was noted to be a significant predictor of perforation (p=0.04). CONCLUSIONS: Predicting BAP remains a challenge. Bowel obstruction or ileus appears to be associated with increased risk of BAP.

Risk of occult malignancy in morcellated hysterectomy: a case series.

Uterine morcellation is performed only when significant neoplasia is not anticipated. In this study, we aimed to determine the prevalence of unexpected pathology in a series of low-risk morcellated hysterectomies. We reviewed a series consisting of all patients undergoing hysterectomy with morcellation at a tertiary-care hospital over a 4-yr period (n=101). Patient records were reviewed to retrieve demographics, details of preoperative evaluation (Pap smear, endometrial biopsy, imaging), and surgical pathology diagnoses. The median number of blocks submitted for histology was 6. On final pathology, endometrium was detected in 99% of all cases. No endometrial, myometrial, or cervical neoplasia other than leiomyoma (numerous cases) was present in the morcellated uteri, but in 1 case an atypical trophoblastic nodule with necrosis and myometrial infiltration, suspected to represent epithelioid trophoblastic tumor, was inadvertently morcellated. From this series, the prospective risk of occult malignancy in a low-risk population undergoing morcellation is estimated at 1% (95% confidence interval, <0.01%-5.94%). A subgroup analysis of patients who participated in what we propose as a complete preoperative workup, consisting of nonconcerning Pap smear, endometrial biopsy, and ultrasound or magnetic resonance imaging, showed no significant findings on final histology. Even with a complete workup, however, morcellation of occult uterine malignancy remains a possibility. This risk should be discussed as part of informed consent before morcellation.

Two sisters with Mayer-Rokitansky-Küster-Hauser syndrome and serous adenocarcinoma of the ovary.

BACKGROUND: Mayer-Rokitansky-Küster-Hauser syndrome is a rare entity with proposed genetic underpinnings. Ovarian carcinoma has well-described genetic associations and syndromes, although much of the etiology of the disease remains unknown. CASES: Two sisters present in the 1970s with primary amenorrhea, 46, XX karyotypes, and absent uteri consistent with MRKH syndrome. In the 2010s, both sisters again present for care. Case 1 presents one sister with stage IIIC serous ovarian adenocarcinoma and negative BRCA panel. Case No 2 presents the other sister with stage IIIC serous ovarian adenocarcinoma and a negative panel for 32 genetic variants associated with ovarian carcinoma. CONCLUSION: The familial association of two rare diseases and negative genetic workup could point to a new genetic understanding of reproductive structure development and ovarian carcinogenesis.

Peritumoral lymphatic vessel density and vascular endothelial growth factor C expression in early-stage squamous cell carcinoma of the uterine cervix.

PURPOSE: Lymphatic invasion and nodal metastasis plays a major role in the spread of cervical cancer; however, little is known about the mechanisms whereby tumor cells enter the lymphatic system. EXPERIMENTAL DESIGN: We examined the intra- and peritumoral lymphatic vessel density (LVD) using D2-40 immunohistochemistry in 111 cervical squamous cell carcinomas and correlated them with vascular endothelial growth factor (VEGF)-C expression, clinicopathologic tumor features, and outcome. RESULTS: Compared with benign cervix, intratumoral and peritumoral LVD was significantly increased (P < 0.0001). Peritumoral LVD was significantly higher than intratumoral LVD (P = 0.009). High peritumoral, but not intratumoral, LVD showed significant correlation with high tumor stage, lymphatic invasion, and nodal metastasis. VEGF-C showed increased expression at the invasive edge compared with the center of tumors (P < 0.0001) and correlated with high peritumoral LVD, lymphatic invasion, and nodal metastasis. High peritumoral LVD and VEGF-C expression at the invasive edge of tumors were associated with poor overall and recurrence-free survival in univariate analysis. In multivariate analysis, peritumoral LVD was the only independent term predictive of overall survival. CONCLUSIONS: Our findings suggest a potential role for VEGF-C in tumor-induced lymphangiogenesis represented by high peritumoral LVD, which may be one of the mechanisms leading to lymphatic invasion and metastatic spread. High peritumoral LVD may be an independent prognostic factor in early-stage cervical cancer.

Screening for ovarian cancer in the general population.

Screening for ovarian cancer in the general population presents several unique challenges. Without a clearly identified premalignant state, efforts have focused on detection of early stage disease. Towards this end, investigators have focused on the use of serum markers and transvaginal ultrasound. CA125 determination is the most reliable serum marker in use, and utilization of serial measurements to calculate risk of cancer appears to have greater utility than evaluation of a single value. Multimodality screening focuses on combining serial CA125 measurement with transvaginal ultrasound follow-up for those with abnormal values. Large prospective trials, such as the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), are currently underway to assess the impact of various screening strategies on mortality, and to evaluate feasibility, acceptability, and morbidity of screening. Future research efforts will undoubtedly focus on promising techniques to examine the serum proteosome for patterns to identify early ovarian cancer.

Multiple initial culture conditions enhance the establishment of cell lines from primary ovarian cancer specimens.

To increase the efficiency of stable cell line establishment from primary ovarian cancer specimens, we simultaneously initiated cultures under multiple conditions, varying extracellular matrices and the inclusion of supplements (e.g., serum or serum albumin), while minimizing exposure to xenogeneic antigens (e.g., fetal calf serum). Primary cultures were initiated from 30 specimens; cell lines were established from 10 of these for a success rate of 33%. In some instances, multiple cell lines were established from the same specimen. Five lines were characterized extensively with respect to growth properties, antigen expression, and genomic alterations. Although these lines are all low-passage, marked heterogeneity was observed, even between lines derived from the same specimen. The culture approach outlined herein will facilitate generation of reagents useful for many aspects of ovarian cancer biology.