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BACKGROUND: Peritoneal carcinomatosis (PC) is common in patients with advanced gynecologic and gastrointestinal cancers. Frequently, patients with PC undergo palliative surgery or procedures to manage disease-related complications and side effects. However, there are limited data regarding patients' and family caregivers' decision-making processes about these procedures. Thus, we sought to describe the decision-making experiences of patients with PC who elect to pursue palliative surgical procedures and their family caregivers. METHODS: We conducted a secondary analysis of qualitative data collected during a pilot randomized controlled trial of BOLSTER, a nurse-led telehealth intervention for patients with PC and their caregivers after an acute hospitalization and palliative procedure. Participants in both study arms described their experiences in semi-structured interviews. We re-analyzed coded qualitative data with a focus on understanding decision-making experiences surrounding palliative surgery and procedures using conventional content analysis. RESULTS: Interviews from 32 participants, 23 patients and 9 caregivers, were analyzed. Participants reported their decision-making was complicated by illness uncertainty and a desire for clear, effective communication with surgical and medical oncology teams. Participants requested more information about the impact of palliative procedures on their daily life. Several also noted that, without improved understanding, a misalignment between patient and family caregiver goals and palliative procedures may inadvertently increase suffering. CONCLUSION: Discussions related to patients' goals and preferences can improve the quality of treatment decision-making in patients with PC and their caregivers. Future research should test interventions to improve advanced cancer patients' illness understanding and decision-making surrounding palliative surgery and procedures.
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OBJECTIVE: Patients with advanced gynecologic (GYN) and gastrointestinal (GI) cancers frequently develop peritoneal carcinomatosis (PC), which limits prognosis and diminishes health-related quality of life (HRQoL). Palliative procedures may improve PC symptoms, yet patients and caregivers report feeling unprepared to manage ostomies, catheters, and other complex needs. Our objectives were to (1) assess the feasibility of an efficacy trial of a nurse-led telehealth intervention (BOLSTER) for patients with PC and their caregivers; and (2) assess BOLSTER's acceptability, potential to improve patients' HRQoL and self-efficacy, and potential impact on advance care planning (ACP). METHODS: Pilot feasibility RCT. Recently hospitalized adults with advanced GYN and GI cancers, PC, and a new complex care need and their caregivers were randomized 1:1 to BOLSTER or enhanced discharge planning (EDP). We defined feasibility as a ≥ 50% approach-to-consent ratio and acceptability as ≥70% satisfaction with BOLSTER. We assessed patients' HRQoL and self-efficacy at baseline and six weeks, then compared the proportion experiencing meaningful improvements by arm. ACP documentation was identified using natural language processing. RESULTS: We consented 77% of approached patients. In the BOLSTER arm, 91.0% of patients and 100.0% of caregivers were satisfied. Compared to EDP, more patients receiving BOLSTER experienced improvements in HRQoL (68.4% vs. 40.0%) and self-efficacy for managing symptoms (78.9% vs. 35.0%) and treatment (52.9% vs. 42.9%). The BOLSTER arm had more ACP documentation. CONCLUSIONS: BOLSTER is a feasible and acceptable intervention with the potential to improve patients' HRQoL and promote ACP. An efficacy trial comparing BOLSTER to usual care is underway. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03367247; PI: Wright.
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BACKGROUND: Patients with peritoneal carcinomatosis (PC) frequently undergo palliative procedures, yet these patients and their caregivers report being unprepared to manage ostomies, drains, and other complex care needs at home. The purpose of this study was to characterize the unique needs of these patients and their caregivers during care transitions. METHODS: Patients completed measures of health status and advance care planning, caregivers completed measures of preparedness and burden, and all participants completed measures of depression and anxiety. Participants detailed their experiences in individual, semi-structured interviews. We analyzed data using descriptive statistics and conventional content analysis. RESULTS: Sixty-one patients and 39 caregivers completed baseline measures. Twenty-four (39.3%) patients acknowledged their terminal illness and seven (11.5%) had discussed end-of-life care preferences with clinicians. Most (26/39, 66.7%) caregivers provided daily care. Among caregivers who managed symptoms, few were taught how to do so (6/20, 30%). Seven patients (11.5%) and seven caregivers (17.9%) met case criteria for anxiety, while 15 patients (24.6%) and two caregivers (5.1%) met case criteria for depression. Interview participants described a diagnosis of PC as a turning point for which there is no road map and identified the need for health systems change to minimize suffering. CONCLUSION: Patients with PC and their caregivers are highly burdened by symptoms and care needs. Patients' prognostic understanding and advance care planning are suboptimal. Interventions that train patients with PC and their caregivers to perform clinical care tasks, facilitate serious illness conversations, and provide psychosocial support are needed.
Subject(s)
Hospice Care , Peritoneal Neoplasms , Terminal Care , Humans , Caregivers/psychology , Palliative Care/methods , Peritoneal Neoplasms/therapy , Terminal Care/methodsABSTRACT
Background: Family caregivers are often inexperienced and require information from clinic visits to effectively provide care for patients. Despite reported deficiencies, 68% of health systems facilitate sharing information with family caregivers through the patient portal. The patient portal is especially critical in the context of serious illnesses, like advanced cancer and dementia, where caregiving is intense and informational needs change over the trajectory of disease progression. Objective: The objective of our study was to analyze a large, nationally representative sample of family caregivers from the National Study of Caregiving (NSOC) to determine individual characteristics and demographic factors associated with patient portal use among family caregivers of persons living with dementia and those living with cancer. Methods: We conducted a secondary data analysis using data from the 2020 NSOC sample of family caregivers linked to National Health and Aging Trends Study. Weighted regression analysis by condition (ie, dementia or cancer) was used to examine associations between family caregiver use of the patient portal and demographic variables, including age, race or ethnicity, gender, employment status, caregiver health, education, and religiosity. Results: A total of 462 participants (representing 4,589,844 weighted responses) were included in our analysis. In the fully adjusted regression model for caregivers of persons living with dementia, Hispanic ethnicity was associated with higher odds of patient portal use (OR: 2.81, 95% CI 1.05-7.57; P=.04), whereas qualification lower than a college degree was associated with lower odds of patient portal use by family caregiver (OR 0.36, 95% CI 0.18-0.71; P<.001. In the fully adjusted regression model for caregivers of persons living with cancer, no variables were found to be statistically significantly associated with patient portal use at the .05 level. Conclusions: In our analysis of NSOC survey data, we found differences between how dementia and cancer caregivers access the patient portal. As the patient portal is a common method of connecting caregivers with information from clinic visits, future research should focus on understanding how the portal is used by the groups we have identified, and why.
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Dementia , Neoplasms , Patient Portals , Humans , Caregivers , Dementia/epidemiology , Regression Analysis , Neoplasms/therapyABSTRACT
OBJECTIVE: Our objective was to obtain perspectives from ovarian cancer patients on job demands, cancer demands, and workplace or cancer resources and strategies to manage the cancer-work interface using the cancer-work management conceptual framework. METHODS: We recruited ovarian cancer patients receiving systemic therapy who screened positive for financial distress using Comprehensive Score for Financial Toxicity <26. Interviews were conducted with participants about their costs of care, including employment concerns. Interviews were recorded, transcribed verbatim, and analyzed by three researchers using an inductive thematic analysis. RESULTS: Of 22 participants, the average age was 57 years old, 36% were Black, 68% had income <$40,000, 41% had public insurance, and 68% were being treated for recurrent disease. Job demands included decreased productivity, inability to return to work, and worry about losing a job or employer-based health insurance coverage. Cancer demands included physical and cognitive limitations due to cancer treatment and reliance on caregivers, especially for transportation. Workplace resources/strategies including having a supportive employer, modifying job responsibilities, and utilizing family medical leave. Cancer care resources/strategies included planning appointments ahead of time and utilizing resources, such as disability. CONCLUSIONS: Cancer care teams should consider screening patients for employment concerns; streamline care to minimize the side effects, time, and transportation demands of treatment on patients and caregivers; maximize utilization of available resources; and proactively communicate with employers to accommodate patients and caregivers who want or need to work.
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Disabled Persons , Ovarian Neoplasms , Carcinoma, Ovarian Epithelial/therapy , Employment/psychology , Female , Humans , Middle Aged , Ovarian Neoplasms/therapy , Qualitative Research , Workplace/psychologyABSTRACT
OBJECTIVE: Distress screening and management is a recommended component of oncology care. Our objective was to evaluate distress rate, sources, and compliance with psychosocial follow-up among ovarian cancer patients receiving chemotherapy. METHODS: We reviewed patient distress surveys completed by ovarian cancer patients receiving chemotherapy from 10/2017-6/2019. Lay or nurse navigators conducted screening with the NCCN Distress Thermometer from 0 (none) to 10 (highest distress). A distress score ≥ 4 (moderate/severe) was considered a positive screen. A recommendation for psychosocial follow-up was automatically generated in the treatment care plan based upon a yes response to any depression-related concern, independent of distress score. Documentation of referral to a mental health professional or social worker for counseling was considered compliant with psychosocial follow-up. We performed descriptive statistics and bivariate analyses. RESULTS: 97/211 (46%) ovarian cancer patients screened positive for distress. Average score was 6.1 for those who screened positive and 3.3 for the entire cohort (range 0-10). Unmarried status (p < 0.01) was associated with positive screen, whereas non-white race (p = 0.26) and recurrent disease (p = 0.21) were not. Median age was older for patients with a positive distress screen (p < 0.01). Among screened patients, the most frequent sources of distress were: cognitive/physical (87%), psychosocial (62%), practical (84%), and family concerns (40%). Of 50 patients recommended to have psychosocial referral, 4 (8%) patients had documented psychiatric follow-up and 19 (38%) patients had documented psychosocial counseling by a social worker. CONCLUSIONS: Nearly half of ovarian cancer patients screened positive for moderate/severe distress. Cancer/treatment-related cognitive/physical symptoms were the most frequent sources. Improved methods of symptom monitoring and management during treatment and resources to address psychosocial concerns are needed to improve distress management of ovarian cancer patients.
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Neoplasms , Ovarian Neoplasms , Carcinoma, Ovarian Epithelial/complications , Female , Humans , Mass Screening , Medical Oncology , Neoplasms/therapy , Ovarian Neoplasms/complications , Ovarian Neoplasms/therapy , Referral and Consultation , Stress, Psychological/diagnosis , Stress, Psychological/etiology , Stress, Psychological/psychologyABSTRACT
BACKGROUND: Both incidence and mortality of uterine cancer are on the rise and mortality is higher for African American women. The aim of our study was to evaluate how Next Generation Sequencing (NGS) may facilitate identification of and intervention for treatment disparities when integrated into clinical workflows. RESULTS: Our cohort included 159 uterine cancer patients with recurrent/progressive and newly diagnosed advanced stage and/or high-risk histology. The most common tumor histological subtypes included EEC (n = 67), SEC (n = 34), UCS (n = 20), and mixed (n = 14). Black patients were most likely to present with aggressive histology: (SEC, 34.0%) and carcinosarcoma (UCS, 14.0%). The four most common mutations across all subtypes were TP53, PIK3CA, PTEN, and ARID1A. There was racial disparity between Black versus non-Black patients who were initiated on targeted therapy (28.2% vs. 38.2%, respectively) and clinical trial (15% vs. 22.6%, respectively). Compared to non-Black patients, Black patients had a significantly higher percentage TP53 mutations (p < 0.05) and a significantly lower percentage ARID1A mutations (p < 0.05). CONCLUSIONS: NGS for uterine malignancies provides actionable information for targetable mutations and/or clinical trial enrollment in most patients; further investigation is necessary to identify potentially modifiable factors contributing to current disparities that may improve targeted therapy uptake and clinical trial participation.
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High-Throughput Nucleotide Sequencing/methods , Molecular Targeted Therapy , Mutation , Uterine Neoplasms/drug therapy , Adult , Black or African American , Aged , Aged, 80 and over , DNA-Binding Proteins/genetics , Female , Genes, p53 , Humans , Middle Aged , Prospective Studies , Transcription Factors/genetics , Uterine Neoplasms/diagnosis , Uterine Neoplasms/geneticsABSTRACT
Ovarian cancer is the second most common gynecologic malignancy in the United States and the most common cause of gynecologic cancer-related death. The majority of ovarian cancers ultimately recur despite excellent response rates to upfront platinum- and taxane-based chemotherapy. Maintenance therapy after frontline treatment has emerged in recent years as an effective tool for extending the platinum-free interval of these patients. Maintenance therapy with PARP inhibitors (PARPis), in particular, has become part of standard of care in the upfront setting and in patients with platinum-sensitive disease. Homologous recombination deficient (HRD) tumors have a nonfunctioning homologous recombination repair (HRR) pathway and respond well to PARPis, which takes advantage of synthetic lethality by concomitantly impairing DNA repair mechanisms. Conversely, patients with a functioning HRR pathway, that is, HR-proficient tumors, can still elicit benefit from PARPi, but the efficacy is not as remarkable as what is seen in HRD tumors. PARPis are ineffective in some patients due to HR proficiency, which is either inherent to the tumor or potentially acquired as a method of therapeutic resistance. This review seeks to outline current strategies employed by clinicians and scientists to overcome PARPi resistance-either acquired or inherent to the tumor.
Subject(s)
Drug Resistance, Neoplasm , Homologous Recombination , Neoplasms/drug therapy , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Recombinational DNA Repair/drug effects , Animals , Humans , Neoplasms/genetics , Neoplasms/pathologyABSTRACT
INTRODUCTION: The Wnt/beta-catenin pathway is a complex signaling pathway known to be dysregulated in several cancers; Dickkopf-1 (Dkk1) is an inhibitor of canonical Wnt signaling via negative feedback. Elevated Dkk1 is associated with a poor prognosis in several cancers, including gynecologic and gastroesophageal malignancies. This review focuses on the potential therapeutic benefit of targeting Dkk1 with the IgG4 monoclonal antibody, DKN-01. AREAS COVERED: We highlight current treatment approaches for advanced gynecologic and esophageal malignancies highlighting the need for more effective therapies, specifically improved immune-modulating agents and combinations. Our discussion of DKN-01 addresses the rationale for targeting Dkk1, available safety, pharmacokinetic and efficacy data. EXPERT OPINION: DKN-01 presents an interesting therapeutic consideration in advanced gynecologic and gastroesophageal malignancies. It has been especially promising in patients with high-Dkk1-expressing tumors or known Wnt mutations. We postulate that the complementary mechanisms, limited adverse effects and emerging biomarker data position DKN-01 as a promising agent for combination therapy in patients with advanced malignancies. Specifically, we believe this occurs through an immuno-modulatory effect, primarily acting through the innate arm of the immune system. This highlights the possibility for addressing innate immune resistance and expanding the portion of patients who may benefit, possibly in a biomarker-selected manner.
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Antibodies, Monoclonal/pharmacology , Intercellular Signaling Peptides and Proteins/immunology , Neoplasms/therapy , Animals , Humans , Immunotherapy/methods , Neoplasms/immunology , Prognosis , Wnt Signaling Pathway/immunologyABSTRACT
OBJECTIVE: Report final results of a phase I/II study of VB-111, a targeted anti-cancer gene therapy with a dual mechanism: anti angiogenic/vascular disruption and induction of an anti-tumor directed immune response, in combination with paclitaxel in patients with platinum-resistant ovarian cancer. METHODS: Study NCT01711970 was a prospective, open label, dose escalation study assessing combination treatment of VB-111 and weekly paclitaxel. In the Phase I part of the study, patients were treated with escalating doses of intravenous VB-111 and paclitaxel. In Phase 2, patients were treated with therapeutic doses of VB-111 and paclitaxel 80 mg/m2. Assessments included safety, overall survival (OS), progression free survival (PFS), and tumor response (CA-125 and RECIST). RESULTS: 21 patients with recurrent platinum-resistant ovarian cancer were enrolled. 17/21 received the therapeutic dose. Patients had a median of 3 prior lines of therapy. Half of the subjects were platinum refractory, and half were previously treated with antiangiogenics. No DLTs were observed. VB-111 was well tolerated and associated with mild flu-like symptoms. In the therapeutic dose cohort, a 58% CA-125 GCIG response rate was seen in evaluable patients. The median OS was 16.6 months in patients treated with therapeutic dose compared to 5.8 months in sub-therapeutic dose (p = 0.028). Tumor specimens taken after treatment demonstrated tumor infiltrated with cytotoxic CD8 T-cells in regions of apoptotic cancer cells. CONCLUSIONS: Treatment with VB-111 in combination with paclitaxel was safe and well tolerated. Favorable tumor responses and overall survival outcomes were associated with induction of an immunotherapeutic effect.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Immunotherapy/methods , Ovarian Neoplasms/drug therapy , Aged , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Bleomycin/pharmacology , Bleomycin/therapeutic use , Cisplatin/pharmacology , Cisplatin/therapeutic use , Female , Humans , Middle Aged , Vinblastine/pharmacology , Vinblastine/therapeutic useABSTRACT
OBJECTIVES: Wnt pathway mutations are a hallmark of endometrioid and clear cell subtypes of epithelial ovarian carcinoma (EOC). However, no drugs targeting the Wnt pathway in EOC are FDA-approved. Dickkopf-related protein 1 (DKK1), a modulator of the Wnt pathway, has emerged as a promising therapeutic target. We aimed to examine the role of DKK1 and the effects of a monoclonal antibody against DKK1 (DKN-01) in vivo and in a murine model of ovarian cancer. METHODS: We examined in vitro the role of DKK1 and the effects of DKK1 inhibition in EOC cell lines. We then studied in vivo the role of DKN-01 and DKK1 overexpression on tumor burden and anti-tumor immune cell populations using the ID8 syngeneic mouse model. RESULTS: DKN-01 did not phenotypically alter ES2 cells in vitro; however, DKK1 inhibition promoted Wnt signaling. Tumor burden and immune populations were unchanged in ID8 challenged mice treated with mDKN01. Mice challenged with ID8 cells overexpressing DKK1 had tumor burden similar to controls (p = 0.175). However, the overexpression of DKK1 decreased CD45+ leukocyte infiltration into the peritoneum (p = 0.008) and omentum (p = 0.032), reducing both natural killer (NK) and CD8 T cells, and reducing interferon-gamma (IFNγ) expression on activated CD8 T cells. CONCLUSIONS: Our results suggest that DKK1 inhibition does not affect tumor growth in the ID8 ovarian cancer model. DKK1 overexpression alters anti-tumor immune populations within the tumor microenvironment. Thus, our findings confirm DKK1 as a new therapeutic target in EOC and suggest that DKK1 inhibition may function best in a combinatorial, immune-modulatory therapy.
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In ovarian cancer, upregulation of the Wnt/ß-catenin pathway leads to chemoresistance and correlates with T cell exclusion from the tumor microenvironment (TME). Our objectives were to validate these findings in an independent cohort of ovarian cancer subjects and determine whether inhibiting the Wnt pathway in a syngeneic ovarian cancer murine model could create a more T-cell-inflamed TME, which would lead to decreased tumor growth and improved survival. We preformed RNA sequencing in a cohort of human high grade serous ovarian carcinoma subjects. We used CGX1321, an inhibitor to the porcupine (PORCN) enzyme that is necessary for secretion of WNT ligand, in mice with established ID8 tumors, a murine ovarian cancer cell line. In order to investigate the effect of decreased Wnt/ß-catenin pathway activity in the dendritic cells (DCs), we injected ID8 cells in mice that lacked ß-catenin specifically in DCs. Furthermore, to understand how much the effects of blocking the Wnt/ß-catenin pathway are dependent on CD8+ T cells, we injected ID8 cells into mice with CD8+ T cell depletion. We confirmed a negative correlation between Wnt activity and T cell signature in our cohort. Decreasing WNT ligand production resulted in increases in T cell, macrophage and dendritic cell functions, decreased tumor burden and improved survival. Reduced tumor growth was found in mice that lacked ß-catenin specifically in DCs. When CD8+ T cells were depleted, CGX1321 treatment did not have the same magnitude of effect on tumor growth. Our investigation confirmed an increase in Wnt activity correlated with a decreased T-cell-inflamed environment; a relationship that was further supported in our pre-clinical model that suggests inhibiting the Wnt/ß-catenin pathway was associated with decreased tumor growth and improved survival via a partial dependence on CD8+ T cells.