Search

Background Falls in patients with cancer harbor potential for serious sequelae. Patients with brain metastases (BrM) may be especially susceptible to falls but supporting investigations are lacking. We assessed the frequency, etiologies, risk factors, and sequelae of falls in patients with BrM using 2 data sources. Methods We identified 42 648 and 111 patients with BrM utilizing Surveillance, Epidemiology, and End Results (SEER)-Medicare data (2008-2016) and Brigham and Women's Hospital/Dana-Farber Cancer Institute (BWH/DFCI) institutional data (2015), respectively, and characterized falls in these populations. Results Among SEER-Medicare patients, 10 267 (24.1%) experienced a fall that prompted medical evaluation, with cumulative incidences at 3, 6, and 12 months of 18.0%, 24.3%, and 34.1%, respectively. On multivariable Fine/Gray's regression, older age (≥81 or 76-80 vs 66-70 years, hazard ratio [HR] 1.18 [95% CI, 1.11-1.25], P <.001 and HR 1.10 [95% CI, 1.04-1.17], P <.001, respectively), Charlson comorbidity score of >2 vs 0-2 (HR 1.08 [95% CI, 1.03-1.13], P =.002) and urban residence (HR 1.08 [95% CI, 1.01-1.16], P =.03) were associated with falls. Married status (HR 0.94 [95% CI, 0.90-0.98], P =.004) and Asian vs white race (HR 0.90 [95% CI, 0.81-0.99], P =.03) were associated with reduced fall risk. Identified falls were more common among BWH/DFCI patients (N = 56, 50.4% of cohort), resulting in emergency department visits, hospitalizations, fractures, and intracranial hemorrhage in 33%, 23%, 11%, and 4% of patients, respectively. Conclusions Falls are common among patients with BrM, especially older/sicker patients, and can have deleterious consequences. Risk-reduction measures, such as home safety checks, physical therapy, and medication optimization, should be considered in this population. [ABSTRACT FROM AUTHOR]

Background Older patients with brain metastases (BrM) commonly experience symptoms that prompt acute medical evaluation. We characterized emergency department (ED) visits and inpatient hospitalizations in this population. Methods We identified 17 789 and 361 Medicare enrollees diagnosed with BrM using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database (2010-2016) and an institutional database (2007-2016), respectively. Predictors of ED visits and hospitalizations were assessed using Poisson regression. Results The institutional cohort averaged 3.3 ED visits/1.9 hospitalizations per person-year, with intracranial disease being the most common reason for presentation/admission. SEER-Medicare patients averaged 2.8 ED visits/2.0 hospitalizations per person-year. For patients with synchronous BrM (N = 7834), adjusted risk factors for ED utilization and hospitalization, respectively, included: male sex (rate ratio [RR] = 1.15 [95% CI = 1.09-1.22], P <.001; RR = 1.21 [95% CI = 1.13-1.29], P <.001); African American vs white race (RR = 1.30 [95% CI = 1.18-1.42], P <.001; RR = 1.25 [95% CI = 1.13-1.39], P <.001); unmarried status (RR = 1.07 [95% CI = 1.01-1.14], P =.02; RR = 1.09 [95% CI = 1.02-1.17], P =.01); Charlson comorbidity score >2 (RR = 1.27 [95% CI = 1.17-1.37], P <.001; RR = 1.36 [95% CI = 1.24-1.49], P <.001); and receipt of non-stereotactic vs stereotactic radiation (RR = 1.44 [95% CI = 1.34-1.55, P <.001; RR = 1.49 [95% CI = 1.37-1.62, P <.001). For patients with metachronous BrM (N = 9955), ED visits and hospitalizations were more common after vs before BrM diagnosis (2.6 vs 1.2 ED visits per person-year; 1.8 vs 0.9 hospitalizations per person-year, respectively; RR = 2.24 [95% CI = 2.15-2.33], P <.001; RR = 2.06 [95% CI = 1.98-2.15], P <.001, respectively). Conclusions Older patients with BrM commonly receive hospital-level care secondary to intracranial disease, especially in select subpopulations. Enhanced care coordination, closer outpatient follow-up, and patient navigator programs seem warranted for this population. [ABSTRACT FROM AUTHOR]

Background: Brain metastases are associated with considerable morbidity and mortality. Integration of hospice at the end of life offers patients symptom relief and improves quality of life, particularly for elderly patients who are less able to tolerate brain-directed therapy. Population-level investigations of hospice utilization among elderly patients with brain metastases are limited.Methods: Using the Surveillance, Epidemiology and End Results-Medicare database for primary cancer sites that commonly metastasize to the brain, we identified 50 148 patients (aged 66 years and older) diagnosed with brain metastases between 2005 and 2016. We calculated the incidence, timing, and predictors of hospice enrollment using descriptive techniques and multivariable logistic regression. All statistical tests were 2-sided.Results: The incidence of hospice enrollment was 71.4% (95% confidence interval [CI] = 71.0 to 71.9; P < .001), a rate that increased over the study period (P < .001). The odds of enrollment for black (odds ratio [OR] = 0.76, 95% CI = 0.71 to 0.82; P < .001), Hispanic (OR = 0.80, 95% CI = 0.72 to 0.87; P < .001), and Asian patients (OR = 0.52, 95% CI = 0.48 to 0.57; P < .001) were substantially lower than white patients; men were less likely to be enrolled in hospice than women (OR = 0.78, 95% CI = 0.74 to 0.81; P < .001). Among patients enrolled in hospice, 32.6% (95% CI = 32.1 to 33.1; P < .001) were enrolled less than 7 days prior to death, a rate that was stable over the study period.Conclusions: Hospice is used for a majority of elderly patients with brain metastases although a considerable percentage of patients die without hospice services. Many patients enroll in hospice late and, concerningly, statistically significant sociodemographic disparities exist in hospice utilization. Further investigations to facilitate targeted interventions addressing such disparities are warranted. [ABSTRACT FROM AUTHOR]

Historically, the gold standard for evaluation of cancer therapeutics, including medical devices, has been the randomized clinical trial. Although high-quality clinical data are essential for safe and judicious use of therapeutic oncology devices, class II devices require only preclinical data for US Food and Drug Administration approval and are often not rigorously evaluated prior to widespread uptake. Herein, we review master protocol design in medical oncology and its application to therapeutic oncology devices, using examples from radiation oncology. Unique challenges of clinical testing of radiation oncology devices (RODs) include patient and treatment heterogeneity, lack of funding for trials by industry and health-care payers, and operator dependence. To address these challenges, we propose the use of master protocols to optimize regulatory, financial, administrative, quality assurance, and statistical efficiency of trials evaluating RODs. These device-specific master protocols can be extrapolated to other devices and encompass multiple substudies with the same design, statistical considerations, logistics, and infrastructure. As a practical example, we outline our phase I and II master protocol trial of stereotactic magnetic resonance imaging-guided adaptive radiotherapy, which to the best of our knowledge is the first master protocol trial to test a ROD. Development of more efficient clinical trials is needed to promote thorough evaluation of therapeutic oncology devices, including RODs, in a resource-limited environment, allowing more practical and rapid identification of the most valuable advances in our field. [ABSTRACT FROM AUTHOR]

Background There are currently no circulating biomarkers used for clinical monitoring of clear cell renal cell carcinoma (ccRCC). Such a biomarker could facilitate individualized treatment decisions and minimize exposure to ineffective therapies. Prior studies have suggested that circulating KIM-1 is a potential minimally invasive biomarker for ccRCC, but the utility of KIM-1 for identifying early response to nivolumab therapy is not known. Methods CheckMate-009 was a prospective trial investigating nivolumab (every 3 weeks at 0.3, 2, or 10 mg/kg) in patients with metastatic clear cell RCC. We measured serum KIM-1 at baseline and after 3 weeks of treatment (prior to cycle 2) using a custom sandwich immunoassay using the R-PLEX platform. Human KIM-1 antibody (R&D systems, #AF1750) was used to prepare biotin conjugated antibodies and detection antibodies. The assay lowest limit of detection for KIM-1 was 4.88 pg/mL. We assessed the association between early changes in serum KIM-1 and treatment related clinical outcomes. Results Clinical data and serum KIM-1 was analyzed in 54 patients. KIM-1 was high in all patients at baseline (median serum KIM-1 5913 pg/mL, IQR 2137-25101 pg/mL). 25 patients (48%) had a decrease in KIM-1 at 3 weeks after a single dose of nivolumab. Decrease in KIM-1 at 3 weeks was associated with improved PFS (univariable HR 0.26, 95% CI 0.13-0.52; multivariable HR 0.22, 95% CI 0.097-0.50 after adjustment for sex, prior nephrectomy, nivolumab dose, and IMDC risk factors). Conclusions Serum KIM-1 is elevated in patients with metastatic ccRCC and is associated with clinical outcomes. Among patients treated with nivolumab in the CheckMate-009 trial, early decrease in KIM-1 from baseline to 3 weeks was predictive for PFS. CDMRP DOD Funding: yes [ABSTRACT FROM AUTHOR]

Abstract: Background: This study sought to determine the efficacy and safety profile of cabozantinib in patients with advanced Merkel cell carcinoma (MCC). Experimental Design: This prospective, phase II, single‐institution trial enrolled patients with platinum‐failure, recurrent/metastatic MCC to receive cabozantinib 60 mg orally daily until disease progression, withdrawal from study, or severe toxicity. The primary endpoint was disease control rate. Secondary endpoints included overall survival (OS), progression‐free survival (PFS), and toxicity. Immunohistochemistry for VEGFR‐2, MET, and HGF expression and next‐generation sequencing of tumor tissue were performed and correlated with outcome. Results: Eight patients were accrued from January 24, 2014, to June 8, 2016. The study was closed prematurely because of toxicity and lack of responses. The most frequent adverse events were grades 1 and 2 and included anorexia, fatigue, nausea, hypothyroidism, and dysgeusia. Two patients developed nonhealing, painful ulcers and tumor‐skin fistula. One patient had stable disease for 8 months. One patient withdrew from the study after 2 weeks of therapy because of adverse events. Three patients required dose reduction because of toxicity. Median PFS and OS were 2.1 and 11.2 months, respectively. No expression of MET, HGF, or VEGFR‐2 was identified in tumor cells by immunohistochemistry of patients’ tissue samples. Conclusion: Cabozantinib was poorly tolerated and did not demonstrate activity in patients with recurrent/metastatic, platinum‐failure MCC. It is unclear whether preselection of patients with the specific upregulation or genetic alteration in the targets for cabozantinib would have changed the results of this study. (Clinical trial identification number: NCT02036476) Implications for Practice: This phase II study demonstrated poor tolerability and lack of activity of cabozantinib in an unselected group of patients with advanced Merkel cell carcinoma. Although it is unclear whether preselection of patients with the specific upregulation and genetic alterations in targets for cabozantinib would have changed the results of this study, this would have likely led to an extremely rare patient population that would take many years to accrue. [ABSTRACT FROM AUTHOR]

Public health concerns over the occurrence of birth defects and developmental abnormalities that may occur as a result of prenatal exposure to drugs, chemicals and other environmental factors has led to an increasing number of developmental toxicity studies. Because fetal pups are commonly evaluated for multiple outcomes, data analysis frequently involves a joint modelling approach. We focus on modelling clustered binary and continuous outcomes in the setting where both outcomes are potentially observable in all offspring but, owing to practical limitations, the continuous outcome is only observed in a subset of offspring. The subset is not a simple random sample but is selected by the experimenter under a prespecified probability model. Although joint models for binary and continuous outcomes have been developed when both outcomes are available for every fetus, many existing approaches are not directly applicable when the continuous outcome is not observed in a simple random sample. We adapt a likelihood-based approach for jointly modelling clustered binary and continuous outcomes when the continuous response is missing by design and missingness depends on the binary trait. The approach takes into account the probability that a fetus is selected in the subset. Through the use of a partial likelihood, valid estimates can be obtained by a simple modification to the partial likelihood score. Data involving the herbicide 2,4,5-trichlorophenoxyacetic-acid are analysed. Simulation results confirm the approach. [ABSTRACT FROM AUTHOR]

We conduct a case-study evaluating the source-specific effects of particulate matter on respiratory function. Using a structural equation approach, we assess the effect of different receptor models on the estimated source-specific effects for univariate respiratory response. Furthermore, we extend the structural equation model by placing a factor analysis model on the response to represent the measured respiratory responses in terms of underlying respiratory patterns. We estimate the particulate matter source-specific effects on respiratory rate, accentuated normal breathing and airway irritation and find a strong increase in airway irritation that is associated with exposure to motor vehicle particulate matter. [ABSTRACT FROM AUTHOR]

The neurotoxic effects of chemical agents are often investigated in controlled studies on rodents, with multiple binary and continuous endpoints routinely collected. One goal is to conduct quantitative risk assessment to determine safe dose levels. Such studies face two major challenges for continuous outcomes. First, characterizing risk and defining a benchmark dose are difficult. Usually associated with an adverse binary event, risk is clearly definable in quantal settings as presence or absence of an event; finding a similar probability scale for continuous outcomes is less clear. Often, an adverse event is defined for continuous outcomes as any value below a specified cutoff level in a distribution assumed normal or log normal. Second, while continuous outcomes are traditionally analyzed separately for such studies, recent literature advocates also using multiple outcomes to assess risk. We propose a method for modeling and quantitative risk assessment for bivariate continuous outcomes that address both difficulties by extending existing percentile regression methods. The model is likelihood based; it allows separate dose–response models for each outcome while accounting for the bivariate correlation and overall characterization of risk. The approach to estimation of a benchmark dose is analogous to that for quantal data without the need to specify arbitrary cutoff values. We illustrate our methods with data from a neurotoxicity study of triethyl tin exposure in rats. [ABSTRACT FROM AUTHOR]

The authors evaluated the association between ventricular arrhythmias detected by implantable cardioverter defibrillators and ambient air pollution concentrations in the hours immediately before the arrhythmia. Patients given implantable cardioverter defibrillators at the New England Medical Center in Boston, Massachusetts, between mid-1995 and 1999 who lived within 40 km of a central monitoring site (n = 203) were followed until July 2002. The authors used a case-crossover design to study the association between ambient air pollution and up to 798 confirmed ventricular arrhythmias among 84 subjects. The authors found that interquartile range increases in 24-hour moving average particulate matter less than 2.5 μm in aerodynamic diameter and ozone were associated with 19% and 21% increased risks of ventricular arrhythmia, respectively. For each, there was evidence of a linear exposure response, and the associations appeared independent. These associations were stronger than associations with mean concentrations on the same calendar day and previous calendar days. The authors did not find associations with pollutant concentrations less than 24 hours before the arrhythmia. Cases with a prior ventricular arrhythmia within 72 hours had greater risk associated with air pollutants than did cases without a recent arrhythmia. These results confirm previous findings and suggest that matching of pollution periods to arrhythmias is important in detecting such associations. [ABSTRACT FROM AUTHOR]

The neurotoxicity of a substance is often tested using animal bioassays. In the functional observational battery, animals are exposed to a test agent and multiple outcomes are recorded to assess toxicity, using approximately 40 animals measured on up to 30 different items. This design gives rise to a challenging statistical problem: a large number of outcomes for a small sample of subjects. We propose an exact test for multiple binary outcomes, under the assumption that the correlation among these items is equal. This test is based upon an exponential model described by (1999, Environmetrics 10, 279–300) and extends the methods developed by (2001, Biometrics 57, 941–948) who developed an exact test for exchangeably correlated binary data for groups (clusters) of correlated observations. We present a method that computes an exact p-value testing for a joint dose–response relationship. An estimate of the parameter for dose response is also determined along with its 95% confidence bound. The method is illustrated using data from a neurotoxicity bioassay for the chemical perchlorethylene. [ABSTRACT FROM AUTHOR]

Background: Previous studies have demonstrated that African-Americans with colon cancer have worse overall and stage-specific survival rates than Caucasians. Such differences could reflect variation in access to health care, in tumor biology, or in treatment efficacy. Little is known about potential differences in chemotherapy-related toxicities between African-Americans and Caucasians. In this study, we examined survival and toxic effects among African-American and Caucasian patients enrolled in a large, randomized phase III trial of adjuvant chemotherapy for resected colon cancer.Methods: We analyzed data on 3380 patients (344 African-Americans and 3036 Caucasians) enrolled in a randomized trial of adjuvant 5-fluorouracil-based chemotherapy in patients with stage II (high risk) and stage III colon cancer to evaluate differences in outcomes and toxicity. We compared disease-free survival (DFS) and overall survival (OS) between African-Americans and Caucasians by the Kaplan-Meier method, computed Cox proportional hazards by multivariable analysis, and compared treatment-related toxicity rates by Fisher's exact test. All statistical tests were two-sided.Results: We found no differences in DFS or OS between African-American and Caucasian patients. Five-year DFS was 57% (95% confidence interval [CI] = 52% to 62%) for African-Americans and 58% (95% CI = 56% to 60%) for Caucasians (P =.15), and 5-year OS was 65% (95% CI = 60% to 70%) for African-Americans and 66% (95% CI = 64% to 68%) for Caucasians (P =.38). On multivariable analysis, no statistically significant difference in disease recurrence or death was detected between the racial/ethnic groups (hazard ratios for African-Americans versus Caucasians: disease recurrence = 1.1, 95% CI = 0.9 to 1.3; death = 1.1, 95% CI = 0.9 to 1.3). Treatment-related toxicity differed between the African-American and Caucasian patients, with African-Americans experiencing statistically significantly lower rates of diarrhea (P<.001), nausea (P<.001), vomiting (P =.01), stomatitis (P<.001), and overall toxicity (P =.005).Conclusions: In this study of patients with similar access to health care resources and treatment with adjuvant chemotherapy, we found similar 5-year DFS and OS in African-Americans and Caucasians with stage II and III colon cancer. The two groups derived similar benefits from adjuvant chemotherapy. Moreover, African-Americans appeared to experience less treatment-related toxicity. [ABSTRACT FROM AUTHOR]

The Functional Observational Battery (FOB) is a neurotoxicity screening assay composed of 25–30 descriptive, scalar, binary, and continuous endpoints. These outcomes have been grouped into six biologically logical domains as a means to interpret the neuroactive properties of tested chemicals (V. C. Moser, 1992, J. Am. Goll. Toxicol. 10(6), 661–669). However, no data-based exploration of these functional domains has been done. We investigated the degree to which experimental data correspond to the domain groupings by examining severity scores from 10 chemicals tested using a standardized protocol for acute exposure (V. C. Moser et al., 1995, J. Toxicol Environ. Health 45, 173–210) and identifying endpoint groupings (factors) that best describe the interrelationships in the data, allowing a statistical assessment of whether the FOB endpoints break into domains. We also used a standard measure of bivariate association to confirm the results of the factor analysis. Our results show that while there are clear relationships among variables that compose some domains, there is often substantial correlation among endpoints in different domains. In addition, we investigated a related issue concerning the relative power of the chosen endpoint groupings for identifying significant domain effects. Results from a randomization analysis of the 10 chemicals suggest that the neurophysiologic domain structuring may provide some degree of statistical efficiency for identifying effects. [ABSTRACT FROM PUBLISHER]

The Eastern Cooperative Oncology Group (ECOG) requires patient consent for the storage and future use of samples left over from its therapeutic cancer clinical trials. The ECOG consent instrument evolved from a simple statement requiring a signature to a more detailed three-question format. Between February 1998 and October 2000, more than 7000 patients were accrued to studies using one of the two consent forms. We analyzed our consent response data by consent type, demographic information, disease site, and institution type to determine the assent rates for future storage and research on biologic samples and to identify possible factors predicting patient refusal. The assent rate for the original banking consent statement was 89.4%, whereas that for the more detailed consent form was 93.7%. Higher assent rates were statistically significant for the detailed consent form versus the original consent form (P=.001), for community-based practices versus academic centers (P<.001), and for patients aged at least 65 years versus those younger (P=.002). The results show that increased patient protection does not result in decreased availability of biologic samples for future research purposes. [ABSTRACT FROM AUTHOR]