Developing a fit-for-purpose composite symptom score as a symptom burden endpoint for clinical trials in patients with malignant pleural mesothelioma.

We developed a composite symptom score (CSS) representing disease-related symptom burden over time in patients with malignant pleural mesothelioma (MPM). Longitudinal data were collected from an open-label Phase IIB study in which 239 patients completed the validated MD Anderson Symptom Inventory for MPM (MDASI-MPM). A blinded, independent review committee of external patient-reported outcomes experts advised on MDASI-MPM symptoms to include in the CSS. Through iterative analyses of potential symptom-item combinations, 5 MPM symptoms (pain, fatigue, shortness of breath, muscle weakness, coughing) were selected. The CSS correlated strongly with the full MDASI-MPM symptom set (0.92-0.94) and the Lung Cancer Symptom Scale-Mesothelioma (0.79-0.87) at each co-administration of the scales. The CSS also had good sensitivity to worsening disease and global quality-of-life ratings. The MDASI-MPM CSS can be used as an outcome in MPM clinical trials, including in responder analyses and at the individual patient level. It is brief enough to administer frequently, including electronically, to better capture symptom trajectories during and after a trial and in clinical practice. As a single score, the CSS addresses multiplicity issues that can arise when several symptoms increase due to worsening disease. Our process can be adapted to produce a CSS for other advanced-cancer trials.

Time-to-event estimands and loss to follow-up in oncology in light of the estimands guidance.

Time-to-event estimands are central to many oncology clinical trials. The estimands framework (addendum to the ICH E9 guideline) calls for precisely defining the treatment effect of interest to align with the clinical question of interest and requires predefining the handling of intercurrent events (ICEs) that occur after treatment initiation and "affect either the interpretation or the existence of the measurements associated with the clinical question of interest." We discuss a practical problem in clinical trial design and execution, that is, in some clinical contexts it is not feasible to systematically follow patients to an event of interest. Loss to follow-up in the presence of intercurrent events can affect the meaning and interpretation of the study results. We provide recommendations for trial design, stressing the need for close alignment of the clinical question of interest and study design, impact on data collection, and other practical implications. When patients cannot be systematically followed, compromise may be necessary to select the best available estimand that can be feasibly estimated under the circumstances. We discuss the use of sensitivity and supplementary analyses to examine assumptions of interest.

Radium-223 in women with hormone receptor-positive bone-metastatic breast cancer receiving endocrine therapy: pooled analysis of two international, phase 2, randomized, double-blind, placebo-controlled trials.

BACKGROUND: Most women with advanced breast cancer have skeletal metastases. Radium-223 is an alpha-emitting radionuclide that selectively targets areas of bone metastases. METHODS: Two double-blind, placebo-controlled studies of radium-223 were conducted in women with hormone receptor-positive (HR+), bone-predominant metastatic breast cancer. All patients received endocrine therapy (ET), as a single agent of the investigator's choice (Study A) or exemestane + everolimus (Study B). Patients were randomized to receive radium-223 (55 kBq/kg) or placebo intravenously every 4 weeks for six doses. Accrual was halted following unblinded interim analyses per protocol amendments, and both studies were terminated. We report pooled analyses of symptomatic skeletal event-free survival (SSE-FS; primary endpoint), radiologic progression-free survival (rPFS) and overall survival (OS; secondary), and time to bone alkaline phosphatase (ALP) progression (exploratory). RESULTS: In total, 382 patients were enrolled, and 196 SSE-FS events (70% planned total) were recorded. Hazard ratios (95% confidence intervals) and nominal p values for radium-223 + ET versus placebo + ET were: SSE-FS 0.809 (0.610-1.072), p = 0.1389; rPFS 0.956 (0.759-1.205), p = 0.7039; OS 0.889 (0.660-1.199), p = 0.4410; and time to bone ALP progression 0.593 (0.379-0.926), p = 0.0195. Radium-223- or placebo-related treatment-emergent adverse events were reported in 50.3% versus 35.1% of patients (grade 3/4: 25.7% vs. 8.5%), with fractures/bone-associated events in 23.5% versus 23.9%. CONCLUSIONS: In patients with HR+ bone-metastatic breast cancer, numeric differences favoring radium-223 + ET over placebo + ET for the primary SSE-FS endpoint were suggestive of efficacy, in line with the primary outcome measure used in the underlying phase 2 studies. No similar evidence of efficacy was observed for secondary progression or survival endpoints. Adverse events were more frequent with radium-223 + ET versus placebo + ET, but the safety profile of the combination was consistent with the safety profiles of the component drugs. Clinical trial registration numbers Study A: NCT02258464, registered October 7, 2014. Study B: NCT02258451, registered October 7, 2014.

Anetumab ravtansine versus vinorelbine in patients with relapsed, mesothelin-positive malignant pleural mesothelioma (ARCS-M): a randomised, open-label phase 2 trial.

BACKGROUND: Few treatment options exist for second-line treatment of malignant pleural mesothelioma. We aimed to assess the antibody-drug conjugate anetumab ravtansine versus vinorelbine in patients with unresectable locally advanced or metastatic disease overexpressing mesothelin who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab. METHODS: In this phase 2, randomised, open-label study, done at 76 hospitals in 14 countries, we enrolled adults (aged ≥18 years) with unresectable locally advanced or metastatic malignant pleural mesothelioma, an Eastern Cooperative Oncology Group performance status of 0-1, and who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab. Participants were prospectively screened for mesothelin overexpression (defined as 2+ or 3+ mesothelin membrane staining intensity on at least 30% of viable tumour cells by immunohistochemistry) and were randomly assigned (2:1), using an interactive voice and web response system provided by the sponsor, to receive intravenous anetumab ravtansine (6·5 mg/kg on day 1 of each 21-day cycle) or intravenous vinorelbine (30 mg/m2 once every week) until progression, toxicity, or death. The primary endpoint was progression-free survival according to blinded central radiology review, assessed in the intention-to-treat population, with safety assessed in all participants who received any study treatment. This study is registered with ClinicalTrials.gov, NCT02610140, and is now completed. FINDINGS: Between Dec 3, 2015, and May 31, 2017, 589 patients were enrolled and 248 mesothelin-overexpressing patients were randomly allocated to the two treatment groups (166 patients were randomly assigned to receive anetumab ravtansine and 82 patients were randomly assigned to receive vinorelbine). 105 (63%) of 166 patients treated with anetumab ravtansine (median follow-up 4·0 months [IQR 1·4-5·5]) versus 43 (52%) of 82 patients treated with vinorelbine (3·9 months [1·4-5·4]) had disease progression or died (median progression-free survival 4·3 months [95% CI 4·1-5·2] vs 4·5 months [4·1-5·8]; hazard ratio 1·22 [0·85-1·74]; log-rank p=0·86). The most common grade 3 or worse adverse events were neutropenia (one [1%] of 163 patients for anetumab ravtansine vs 28 [39%] of 72 patients for vinorelbine), pneumonia (seven [4%] vs five [7%]), neutrophil count decrease (two [1%] vs 12 [17%]), and dyspnoea (nine [6%] vs three [4%]). Serious drug-related treatment-emergent adverse events occurred in 12 (7%) patients treated with anetumab ravtansine and 11 (15%) patients treated with vinorelbine. Ten (6%) treatment-emergent deaths occurred with anetumab ravtansine: pneumonia (three [2%]), dyspnoea (two [1%]), sepsis (two [1%]), atrial fibrillation (one [1%]), physical deterioration (one [1%]), hepatic failure (one [1%]), mesothelioma (one [1%]), and renal failure (one [1%]; one patient had 3 events). One (1%) treatment-emergent death occurred in the vinorelbine group (pneumonia). INTERPRETATION: Anetumab ravtansine showed a manageable safety profile and was not superior to vinorelbine. Further studies are needed to define active treatments in relapsed mesothelin-expressing malignant pleural mesothelioma. FUNDING: Bayer Healthcare Pharmaceuticals.

Economic benefits of substance abuse treatment: findings from Cuyahoga County, Ohio.

We estimated long-term economic benefits and treatment costs for a sample of substance abuse clients who received treatment in Cuyahoga County, Ohio, using health, criminal activity, and earnings data from the Persistent Effects of Treatment Studies. Clients were interviewed at baseline and 6, 12, 24, and 30 months following baseline. We find positive benefits from substance abuse treatment, almost of all of which were derived from reduced criminal activity and increased real earnings, with overall benefit-to-cost ratios ranging from 2.8 to 4.1. The reductions in costs to society were found to be persistent over the long-term, 30-month follow-up period. On average, treatment was found to be cost beneficial regardless of the number of times a client entered treatment in the baseline or follow-up periods. Clients who entered residential treatment and then step down to less intensive care showed greater treatment benefits than clients who only received residential treatment.

Estimating the mission-related costs of teaching hospitals.

Academic health centers and other teaching hospitals face higher patient care costs than nonteaching community hospitals face, because of their missions of graduate medical education (GME), biomedical research, and the maintenance of standby capacity for medically complex patients. We estimate that total mission-related costs were dollar 27 billion in 2002 for all teaching hospitals, with GME (including indirect and direct GME) and standby capacity accounting for roughly 60 and 35 percent of these costs, respectively. To assure their continued ability to perform important social missions in a competitive environment, it may be necessary to reassess the way in which these activities are financed.

Drivers of expenditure growth in outpatient care services.

OBJECTIVE: To identify and analyze drivers of costs for healthcare services delivered in outpatient settings. STUDY DESIGN: We estimated 2 regression models of state-level annual outpatient expenditures. The first model uses data on operating costs for hospital outpatient services from hospital cost reports. The second model uses outpatient claims data from a large, national, group health insurer, and covers all varieties of outpatient providers for a specific insured population. RESULTS: Several different cost drivers affected the growth of outpatient costs in the late 1990s. Foremost among the drivers is the change associated with demographics and general economic conditions, and economy-wide inflation, which together accounted for 60% of the growth in outpatient costs. Characteristics directly related to the healthcare sector had a smaller, but still significant role in cost growth. The supply of physicians and specialists accounted for 10% of cost growth, whereas supply and structure of outpatient facilities were responsible for an additional 5% of outpatient cost increase. The health status of the population was associated with 8% of expenditure growth; technology and treatment practices accounted for 7% of growth; and provider operating costs, such as wage levels, were linked to 9% of the growth. CONCLUSIONS: Some level of growth in outpatient care spending may be cost effective, because outpatient services can substitute for more expensive care in other settings. Strategies for limiting growth in the costs of outpatient care will be more effective if focused on enhancing cooperation between payers, providers, and other stakeholders in assuring an appropriate and cost-effective supply of outpatient care resources.

Drivers of healthcare expenditures associated with physician services.

OBJECTIVE: To identify and rank the key contributors to increases in healthcare costs for physician services. STUDY DESIGN: We performed regression analysis using state-level physician cost data from the state health expenditure accounts maintained by the Centers for Medicare and Medicaid Services (CMS) and a national, private (commercial) health insurer. RESULTS: We estimated that during 1990 to 2000, nominal physician expenditures per capita grew 4.7% annually. Forty-two percent of this growth was attributable to general price inflation measured by the gross domestic product price deflator. The category of general economic variables and demographics was the next largest contributor to growth at 17%, followed by physician supply and provider structure (12%) and technology and treatment patterns (11%). Operating costs, health status, healthcare regulation, and health insurance benefit and product design comprised the remaining 18% of the growth. CONCLUSIONS: Because physicians are central to the healthcare system in the United States, efforts to contain physician spending reverberate through all healthcare services. The combined effect of an increase in the number and proportion of specialty care physicians, the continued development of clinical approaches for the control of chronic disease, and an aging population requiring intensive medical care imply that the current increase in healthcare expenditures could continue unabated, unless effective cost-control devices are deployed. To be effective, emerging strategies for influencing the affordability of healthcare services are likely to require a greater level of partnership between payers, providers, and other stakeholders.