Behavioural economic interventions to embed palliative care in community oncology (BE-EPIC): study protocol for the BE-EPIC randomised controlled trial.

INTRODUCTION: Palliative care (PC) is a medical specialty focusing on providing relief from the symptoms and stress of serious illnesses such as cancer. Early outpatient specialty PC concurrent with cancer-directed treatment improves quality of life and symptom burden, decreases aggressive end-of-life care and is an evidence-based practice endorsed by national guidelines. However, nearly half of patients with advanced cancer do not receive specialty PC prior to dying. The objective of this study is to test the impact of an oncologist-directed default PC referral orders on rates of PC utilisation and patient quality of life. METHODS AND ANALYSIS: This single-centre two-arm pragmatic randomised trial randomises four clinician-led pods, caring for approximately 250 patients who meet guideline-based criteria for PC referral, in a 1:1 fashion into a control or intervention arm. Intervention oncologists receive a nudge consisting of an electronic health record message indicating a patient has a default pended order for PC. Intervention oncologists are given an opportunity to opt out of referral to PC. Oncologists in pods randomised to the control arm will receive no intervention beyond usual practice. The primary outcome is completed PC visits within 12 weeks. Secondary outcomes are change in quality of life and absolute quality of life scores between the two arms. ETHICS AND DISSEMINATION: This study has been approved by the Institutional Review Board at the University of Pennsylvania. Study results will be disseminated in peer-reviewed journals and scientific conferences using methods that describe the results in ways that key stakeholders can best understand and implement. TRIAL REGISTRATION NUMBER: NCT05365997.

Corneal endothelial cell density in patients receiving chemotherapy.

PURPOSE: This study aimed to determine if the corneal endothelium was affected by chemotherapy. METHODS: Chemotherapy patients were recruited to undergo specular microscopy before treatment and again at 1- and 2-year follow-up visits. One eye per patient, per follow-up, was selected for comparison to baseline. RESULTS: Forty-six volunteers completed baseline and at least one follow-up assessment. From 51 eyes, there was no significant change in endothelial cell density for 41 eyes assessed at one year (MD = 0.73%, 95% CI -1.33 to 2.78%) and 18 eyes at two years (MD = 0.31%, 95% CI -3.53 to 4.15%). CONCLUSION: Although other studies have shown that chemotherapy can adversely affect the corneal epithelium, this study showed no measurable change in endothelial cell density.

Implementation of a Palliative Oncology Tumor Board.

CONTEXT: The integration of palliative care into standard oncologic care has been shown to improve multiple outcomes in patients with advanced cancer. Ideal methods for integrating these disciplines is an ongoing area of discussion. One method of integration is a palliative oncology tumor board (POTB). OBJECTIVES: To describe the implementation of a POTB in a community cancer center as a method of integrating oncology and palliative care by providing a forum for multidisciplinary discussion of complex cases. METHODS: During development of the POTB, multiple influencing factors and barriers were considered including the setting of implementation, culture prior to implementation, design elements, engagement of stakeholders, and evaluation of implementation. The focus of this POTB was to address the identified communication gap between inpatient and outpatient care teams. Two complex hospitalized oncology patients were selected to be discussed weekly. RESULTS: Conferences were attended by an average of 23 individuals. The highest proportion of attendees were members of oncology support services (including nurse navigators, social workers, chaplains, dietitians, financial counselors; OSS; 31%), followed by medical oncology (25%). The most common theme of discussion was methods of communication with patient and/or family (68% of cases). Thirty days after presentation, a total of 50 new referrals were placed to inpatient palliative care, OSS, and outpatient palliative care and 11 new advance care plans were documented in the electronic medical record. CONCLUSION: This paper describes a sustainable method to implement a POTB in a community cancer center setting, which is one method of integrating palliative care into standard oncologic care.

Implementation of the Institute of Medicine Treatment Plan in Oncology Practice.

Participation in the Centers for Medicare & Medicaid Services (CMS) value-based payment reform, the Oncology Care Model (OCM), requires that every beneficiary has a documented 13-point Institute of Medicine treatment plan (TP) when commencing antineoplastic therapy. The intent is to enhance shared decision-making between the patient and care team by providing transparent treatment recommendations and engaging patients and caregivers in meaningful discussion. There is limited discussion in the literature about how to adapt the CMS recommendations to diverse practice settings while maintaining fidelity to the intent of the TP. Here, the authors compare how 3 clinically and geographically unique OCM participating institutions implemented the TP in their respective institutions within the domains of the Consolidated Framework for Implementation Research. Similar themes in implementation are identified, including engaging stakeholders, leveraging information technology, and considering scalability. Adaptations that are unique to the culture and setting of each site are also described.

Anticancer Therapy at the End of Life: Lessons From a Community Cancer Institute.

INTRODUCTION: Studies have shown aggressive cancer care at the end of life is associated with decreased quality of life, decreased median survival, and increased cost of care. This study describes the patients most likely to receive systemic anticancer therapy at the end of life in a community cancer institute. MATERIALS AND METHODS: We performed a retrospective cohort study of 201 patients who received systemic anticancer therapy in our institution and died between July 2016 and April 2017. Data collected included primary malignancy, hospice enrollment, healthcare utilization, Oncology Care Model (OCM) enrollment, and clinical assessments at last office visit prior to a treatment decision before death. We defined our outcome variable as the receipt of anticancer treatment in the last 14 days of a patient's life. We evaluated 20 clinical exposure variables with respect to the outcome classes. Risk ratios along with their associated confidence intervals and P values were calculated. Significance was determined using the Benjamini-Hochberg procedure to account for multiple testing. RESULTS: Of the 201 patients who died of cancer, 36 (17%) received anticancer therapy within the last 14 days of life. Several risk factors were significantly positively associated with receiving anticancer therapy at the end of life including hospitalization within 30 days of end of life, number of hospitalizations per patient (≥2), death in hospital, enrollment in OCM, and a diagnosis of hematologic malignancy. CONCLUSION: Our findings demonstrate those enrolled in the OCM and those with hematologic malignancies have a higher risk of receiving anticancer therapy in the last 14 days of life. These observations highlight the need for better identifying the needs of high-risk patients and providing good quality care throughout the disease trajectory to better align end-of-life care with patients' wishes.

Patterns of Support Service, Emergency Department, and Hospital Utilization in Patients with Advanced Cancer: A Descriptive Study.

CONTEXT: Palliative care in oncology provides multiple benefits, however access to specialty palliative clinicians is limited in community cancer centers. Individual support services are more often available, but little is known on the utilization and impact of these services. OBJECTIVES: To describe the utilization of outpatient support services in the advanced cancer population and the association with ED and hospital use in a community setting. METHODS: A retrospective chart review of 314 patients with advanced cancer of lung, gastrointestinal, genitourinary, and gynecologic origin was conducted. Data collected included demographics, descriptive data, type and number of support services (symptom management, nurse navigator, social worker, nutrition, financial counselor, chaplain, and oncology clinical counselor) within 90 days of diagnosis and descriptions of ED visits/hospitalizations within 12 months of diagnosis. Support services were available to patients by referral. RESULTS: 29.6% of patients were deceased within 6 months and were considered to have severe disease. Patients with severe disease had a significantly greater mean number of support services than patients with non-severe disease (8.9 vs 6.0, p=0.001) and had a greater mean number of visits per year to the ED (6.4 vs 1.8, p<0.001). A greater proportion of patients with severe disease had palliative consultations (48.9% vs 21.7%, p<0.001), but 65.5% of palliative consultations occurred after an ED or hospital visit. CONCLUSION: Our data demonstrated that advanced cancer patients with severe disease had increased healthcare utilization in all areas measured. Despite high utilization, outpatient support services used in a reactive manner were not effective in reducing ED or hospital visits.

Models of Outpatient Palliative Care Clinics for Patients With Cancer.

PURPOSE: Early integration of outpatient palliative care (OPC) benefits patients with advanced cancer and also the health care systems in which these patients are seen. Successful development and implementation of models of OPC require attention to the needs and values of both the patients being served and the institution providing service. SUMMARY: In the 2016 clinical guideline, ASCO recommended integrating palliative care early in the disease trajectory alongside cancer-directed treatment. Despite strong endorsement and robust evidence of benefit, many patients with cancer lack access to OPC. Here we define different models of care delivery in four successful palliative care clinics in four distinct health care settings: an academic medical center, a safety net hospital, a community health system, and a hospice-staffed clinic embedded in a community cancer center. The description of each clinic includes details on setting, staffing, volume, policies, and processes. CONCLUSION: The development of robust and capable OPC clinics is necessary to meet the growing demand for these services among patients with advanced cancer. This summary of key aspects of functional OPC clinics will enable health care institutions to evaluate their specific needs and develop programs that will be successful within the environment of an individual institution.

Illness Understanding of Oncology Patients in a Community-Based Cancer Institute.

PURPOSE: Several studies have demonstrated that patients have a poor understanding of prognosis, survival, and effectiveness of chemotherapy, particularly in the setting of advanced cancer. This study examines oncology patients' understanding of their illness based on accurate reporting of stage at diagnosis and knowledge of cancer status (ie, free of cancer or in remission v active disease). MATERIALS AND METHODS: Two hundred eight patients with cancer previously treated at our large community-based cancer institute participated in the Consumer-Based Cancer Care Value Index field survey. Electronic medical record documentation of stage at diagnosis and cancer status was compared with patients' self-reported responses. Concordance of responses and variables influencing discordance were evaluated. RESULTS: In 51.0% of patients, self-reported cancer stage matched the abstracted stage, with the highest concordance in patients with advanced cancer (72%) versus patients with stage I to III disease (36.4% to 61.5%). Unexpectedly, discordance was lower among patients with advanced cancer compared with patients with stage I to III cancer ( P = .0528). Patients who were concordant for cancer stage at diagnosis were significantly more likely to be female ( P = .001), be younger than age 65 years ( P = .01), have an income > $60,000 ( P = .03), and have more education ( P = .02). In 64.4% of patients, self-reported cancer status (ie, free of cancer or in remission v active disease) matched the abstracted status. Nearly 30% of patients were not sure about their status, even when they were free of cancer or in remission. CONCLUSION: Our findings confirm that more than one quarter of patients with advanced cancer have poor illness understanding and highlight that an even greater number of patients with early stage I to III cancer have poor illness understanding. These observations highlight the need to improve illness understanding for patients across the entire cancer continuum.

An analysis of the clinical trial landscape for cutaneous melanoma.

Recognizing current trends and obstacles in melanoma clinical trial development is critical to future progress in this field. This article examines the melanoma research enterprise to identify changing trends and potential barriers to success. All trials registered at ClinicalTrials.gov after September 2005 were evaluated for possible inclusion. A total of 777 interventional trials designed specifically for cutaneous melanoma patients were included. Geographic trial distribution as well as disease state and type of intervention were analyzed and compared among each group. ClinicalTrials.gov is an invaluable tool to study the research enterprise. Further studies are needed on prevention and early detection of melanoma in the curative setting, a critical role for dermatologists.

Reporting quality of abstracts in phase III clinical trials of systemic therapy in metastatic solid malignancies.

BACKGROUND: Manuscript abstracts represent a critical source of information for oncology practitioners. Practitioners may utilize the information contained in abstracts as a basis for treatment decisions particularly when full-text articles are not accessible. In 2007, the Consolidated Standards of Reporting Trials (CONSORT) extension statement for abstracts provided a minimum list of elements that should be included in abstracts. In this study we evaluate the degree of adherence to these recommendations and accessibility of full text publications in oncology publications. METHODS: A systematic review of abstracts of randomized, controlled, phase III trials in metastatic solid malignancies published between January 2009 and December 2011 in PubMed, Medline, and Embase was completed. Abstracts were assigned a completeness score of 0-18 based on the number of CONSORT-recommended elements. Accessibility through open access was recorded. RESULTS: 174 abstracts with data for 95,956 patients were reviewed. The median completeness score was 9 (range, 3-17). Open access to full text articles was available for 80 % of abstracts. The remaining 20 % (35 out of 174) had a median cost of 38 USD (range: $22-49.95). The least frequently reported elements were: trial design description (20 %), participant allocation method (13 %), blinding (24 %), trial enrollment status (22 %), registration and name of trial (26 %) and funding source (18 %). The most frequently reported elements were eligibility criteria (98 %), study interventions (100 %), and primary endpoint (87 %). CONCLUSION: There is poor adherence to the CONSORT recommendations for abstract reporting in publications of randomized cancer clinical trials which could negatively impact clinical decision-making. Full-text articles are frequently available through open access.

Defining the role of CD2 in disease progression and overall survival among patients with completely resected stage-II to -III cutaneous melanoma.

BACKGROUND: Accurate assessment of prognosis remains clinically challenging in stage II to III cutaneous melanoma. Studies have implicated CD2 in immune surveillance, T-cell activation, and antitumor immunity, but its role in melanoma progression warrants further investigation. OBJECTIVE: We sought to investigate the prognostic role of CD2 in primary cutaneous melanoma. METHODS: Patients with American Joint Committee on Cancer stage II and III cutaneous melanoma were identified by retrospective review of dermatopathology databases from 2001 to 2010 at Mount Sinai Medical Center and Geisinger Medical Center. Additional patients were provided by New York University Medical Center based on retrospective review and tissue availability. Immunohistochemistry was performed on tumors from 90 patients with known recurrence status and documented follow-up. RESULTS: Primary tumors from patients who developed recurrent disease had fewer CD2(+) cells (P = .0003). In multivariable analyses including standard clinicopathologic predictors, CD2 was an independent predictor of disease recurrence (P = .008) and overall survival (P = .007). CD2 count correlated with characterization of tumor-infiltrating lymphocytes (P = .0004). Among the intermediate prognosis group of patients with nonbrisk tumor-infiltrating lymphocytes, CD2 count was predictive of disease recurrence (P = .0006) and overall survival (P = .0318). LIMITATIONS: Our retrospective design may have resulted in incomplete representation of patients lacking documented follow-up. CONCLUSIONS: CD2 may be an independent predictor of disease recurrence and overall survival among patients with primary cutaneous melanoma.

Dissection of immune gene networks in primary melanoma tumors critical for antitumor surveillance of patients with stage II-III resectable disease.

Patients with resected stage II-III cutaneous melanomas remain at high risk for metastasis and death. Biomarker development has been limited by the challenge of isolating high-quality RNA for transcriptome-wide profiling from formalin-fixed and paraffin-embedded (FFPE) primary tumor specimens. Using NanoString technology, RNA from 40 stage II-III FFPE primary melanomas was analyzed and a 53-immune-gene panel predictive of non-progression (area under the curve (AUC)=0.920) was defined. The signature predicted disease-specific survival (DSS P<0.001) and recurrence-free survival (RFS P<0.001). CD2, the most differentially expressed gene in the training set, also predicted non-progression (P<0.001). Using publicly available microarray data from 46 primary human melanomas (GSE15605), a coexpression module enriched for the 53-gene panel was then identified using unbiased methods. A Bayesian network of signaling pathways based on this data identified driver genes. Finally, the proposed 53-gene panel was confirmed in an independent test population of 48 patients (AUC=0.787). The gene signature was an independent predictor of non-progression (P<0.001), RFS (P<0.001), and DSS (P=0.024) in the test population. The identified driver genes are potential therapeutic targets, and the 53-gene panel should be tested for clinical application using a larger data set annotated on the basis of prospectively gathered data.

Adverse event reporting in cancer clinical trial publications.

PURPOSE: Reporting adverse events is a critical element of a clinical trial publication. In 2003, the Consolidated Standards of Reporting Trials (CONSORT) group generated recommendations regarding the appropriate reporting of adverse events. The degree to which these recommendations are followed in oncology publications has not been comprehensively evaluated. METHODS: A review of citations from PubMed, Medline, and Embase published between Jan 1, 2009 and December 31, 2011, identified eligible randomized, controlled phase III trials in metastatic solid malignancies. Publications were assessed for 14 adverse event-reporting elements derived from the CONSORT harms extension statement; a completeness score (range, 0 to 14) was calculated by adding the number of elements reported. Linear regression analysis identified which publication characteristics associated with reporting completeness. RESULTS: A total of 175 publications, with data for 96,125 patients, were included in the analysis. The median completeness score was eight (range, three to 12). Most publications (96%) reported only adverse events occurring above a threshold rate or severity, 37% did not specify the criteria used to select which adverse events were reported, and 88% grouped together adverse events of varying severity. Regression analysis revealed that trials without a stated funding source and with an earlier year of publication had significantly lower completeness scores. CONCLUSION: Reporting of adverse events in oncology publications of randomized trials is suboptimal and characterized by substantial selectivity and heterogeneity. The development of oncology-specific standards for adverse event reporting should be established to ensure consistency and provide critical information required for medical decision-making.

Pulmonary complications with the use of mTOR inhibitors in targeted cancer therapy: a systematic review and meta-analysis.

Mammalian target of rapamycin (mTOR) inhibitors have gained regulatory approval for use in several cancer types. Pulmonary adverse events associated with mTOR inhibitors are well recognized but their frequency has varied considerably among trials. PubMed and ASCO abstracts were searched to identify clinical trials of mTOR inhibitors in solid tumors. Twenty-two eligible trials on which 4,242 patients were treated met the criteria for inclusion in this systematic review and meta-analysis. Adverse event data were extracted and used to determine the incidence rate and incidence rate ratio for pneumonitis, dyspnea, and cough. The incidence rate of any grade pneumonitis in patients with solid tumors treated with mTOR inhibitors was 0.11 (95% confidence interval (CI), 0.06-0.17) per patient, while the incidence of grade 3-4 pneumonitis was 0.03 (95% CI, 0.01-0.04) per patient. The incidence rate ratio (IRR) of any grade pneumonitis with mTOR inhibitors relative to controls was 19.0 (95% CI, 6.5-55.4), and for grade 3-4 pneumonitis was 8.0 (95% CI, 2.6-24.1). The incidence rate for any grade and grade 3-4 cough was 0.23 (95% CI, 0.20-0.27) per patient and 0.01 (95% CI, 0.00-0.01) per patient, respectively. The incidence rate for any grade and grade 3-4 dyspnea was 0.15 (95% CI, 0.10-0.21) per patient and 0.03 (95% CI, 0.02-0.04) per patient, respectively. Compared to control, treatment with mTOR inhibitors were associated with a significant increase in any grade cough [IRR = 1.9 (95% CI, 1.6-2.4)] and grade 3-4 dyspnea [IRR = 2.0 (95% CI, 1.2-3.3)]. This study provides an estimation of the risk of pulmonary adverse events in solid tumor patients treated with mTOR inhibitors. While pulmonary adverse events are relatively common with mTOR inhibitors, most are low grade and asymptomatic.

Metabolic complications with the use of mTOR inhibitors for cancer therapy.

BACKGROUND: mTOR inhibitors are now approved by regulatory agencies for the treatment of a variety of malignancies. The risk of metabolic complications with these agents is not well characterized. METHODS: PubMed was searched for articles published from 2001 until 2011. Eligible studies included prospective randomized trials evaluating temsirolimus, everolimus, and ridaforolimus in patients with all solid tumor malignancies. Sixteen eligible phase II clinical trials and 8 randomized controlled clinical trials were included in a systematic review and meta-analysis and the number of metabolic related AEs (hyperglycemia, hypercholesterolemia, and hypertriglyceridemia) was extracted. Incidence rates and incident rate ratios were calculated. FINDINGS: Twenty-four trials, including 4261 patients, were included in the calculation of the incidence rate. The average incidence rate of all grade metabolic related events was 0.70 (95% CI, 0.47, 0.93). The average incidence rate of serious (grade 3 and 4) metabolic related adverse events was 0.11 (95% CI, 0.08, 0.15). The incidence rate ratio (IRR) of a metabolic adverse event with mTOR inhibitor therapy compared with control was 2.93 (95% CI, 2.33, 3.70) and of serious grade 3 and 4 metabolic adverse events was 4.58 (95% CI, 2.86, 7.34). The IRR of all grade hyperglycemia was 2.95 (95% CI, 2.14, 4.05) and of grade 3-4 hyperglycemia was 5.25 (95% CI, 3.07, 9.00). The IRR of all grade hypertriglyceridemia was 2.49 (95% CI, 1.76, 3.52) and of grade 3-4 hypertriglyceridemia was 2.01 (95% CI, 0.65, 6.27). The IRR of all grade hypercholesterolemia was 3.35 (95% CI, 2.17, 5.18) and of grade 3-4 hypercholesterolemia was 6.51 (95% CI, 1.48, 28.59). These findings suggest a statistically significant increase in the risk of hyperglycemia, hypercholesterolemia (all grades and grade 3 and 4), and all grade hypertriglyceridemia associated with mTOR therapy when compared with control. INTERPRETATION: The risk of all grade and grade 3-4, hyperglycemia, hypercholesterolemia, and hypertriglyceridemia, are increase in patients treated with mTOR inhibitors compared with control.

Oncolytic virus therapy for cancer.

The use of oncolytic viruses to treat cancer is based on the selection of tropic tumor viruses or the generation of replication selective vectors that can either directly kill infected tumor cells or increase their susceptibility to cell death and apoptosis through additional exposure to radiation or chemotherapy. In addition, viral vectors can be modified to promote more potent tumor cell death, improve the toxicity profile, and/or generate host antitumor immunity. A variety of viruses have been developed as oncolytic therapeutics, including adenovirus, vaccinia virus, herpesvirus, coxsackie A virus, Newcastle disease virus, and reovirus. The clinical development of oncolytic viral therapy has accelerated in the last few years, with several vectors entering clinical trials for a variety of cancers. In this review, current strategies to optimize the therapeutic effectiveness and safety of the major oncolytic viruses are discussed, and a summary of current clinical trials is provided. Further investigation is needed to characterize better the clinical impact of oncolytic viruses, but there are increasing data demonstrating the potential promise of this approach for the treatment of human and animal cancers.

Treatment-related mortality with vascular endothelial growth factor receptor tyrosine kinase inhibitor therapy in patients with advanced solid tumors: a meta-analysis.

BACKGROUND: Several vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKI) are now approved by regulatory agencies and are important in the treatment of solid tumor malignancies. The risk of fatal adverse events (FAEs) with these agents is not well characterized. METHODS: PubMed was searched for articles published from 2001 until 2011. Eligible studies included prospective randomized trials evaluating sunitinib, sorafenib, pazopanib, and vandetanib in patients with all malignancies. Thirteen eligible randomized controlled trials were included in a meta-analysis and the number of FAEs (defined by the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) criteria) was extracted and study quality was calculated. Incidence rates and relative risks were calculated for all thirteen studies as well as for the subset of patients with renal cell carcinoma. RESULTS: Analysis of the 5164 patients across 13 RCTs revealed that the relative risk was 1.64 (95% CI, 1.16, 2.32; P=0.01; incidence 2.26% vs. 1.26%) for the association of a VEGFR TKI with FAEs using a random-effects model. All exploratory subgroup analyses indicated a trend toward an increase risk of FAEs with VEGFR TKI treatment, though the subgroup analyses reached statistical significance for renal carcinoma studies, studies utilizing placebo as the control arm, and studies evaluating sorafenib. INTERPRETATION: This analysis suggests that VEGFR TKIs are associated with a significant increase in the risk of FAEs in patients with advanced solid tumors.

Treatment of Langerhans cell histiocytosis bone lesions with zoledronic acid: a case series.

Langerhans cell histiocytosis (LCH) is a rare disease caused by a clonal proliferation of specialized dendritic (Langerhans) cells. Although uncommon, it is potentially fatal and carries significant morbidity. Bone involvement is particularly destructive and to date, no standard of care exists for management of both the disease and the significant bone pain as many of these patients experience. In the literature, 12 patients who had previously been heavily pretreated for their disease had their bone pain treated with a bisphosphonate as extrapolated from the cancer literature. Interestingly, these patients had a complete or near complete resolution of their pain, return of functional status and in 75% of cases radiographic evidence of reduction or regression of disease. Only 6 of these patients were treated with a newer generation bisphosphonate, zoledronic acid. In this paper, we report a case series of 2 patients with LCH bone involvement who received 4 mg of intravenous zoledronic acid monthly for 1 year with complete resolution in their bone pain. In addition, both patients demonstrated reduction in tumor burden after bisphosphonate treatment. Uniquely, our first case is the only reported case in the literature using a bisphosphonate as first line therapy in the treatment of LCH. This case demonstrates the potential role of zoledronic acid therapy in the first line setting for disease stabilization and symptomatic control in patients unable to receive conventional therapy.