Treatment patterns and clinical outcomes with pazopanib in patients with advanced soft tissue sarcomas in a compassionate use setting: results of the SPIRE study.

BACKGROUND: A named patient program (NPP) was designed to provide patients with advanced soft-tissue sarcoma (aSTS) access to pazopanib, a multitargeted tyrosine kinase inhibitor. The SPIRE study was a retrospective chart review of participating patients. PATIENTS AND METHODS: Eligibility criteria for the NPP and SPIRE mirrored those of the pivotal phase-III study, PALETTE, which compared pazopanib with placebo in patients ≥18 years with aSTS and whose disease had progressed during or following prior chemotherapy or were otherwise unsuitable for chemotherapy. Outcomes of interest included treatment patterns, treatment duration, relative dose intensity, progression-free survival (PFS), overall survival (OS), clinical benefit rate, adverse events (AEs) and reasons for treatment discontinuation. RESULTS: A total of 211 patients were enrolled (median age 56 years; 60% female). Most patients received pazopanib in second- and third-line therapy (28.0% and 28.4%, respectively), followed by fourth line (19.0%) and ≥ fifth line (18.5%). The median duration of pazopanib treatment was 3.1 months (95% CI: 2.8-3.8), with a mean daily dose of 715 mg equating to 92% of recommended dose. Median OS was 11.1 months and clinical benefit rate was 46%. There was evidence of some clinical benefit across most histological subtypes. At study end, 40% of patients were alive and of these, 18% remained on pazopanib. Thirteen percent (13%) of patients discontinued pazopanib due to AEs. CONCLUSIONS: The SPIRE study demonstrated activity of pazopanib in heavily pretreated aSTS patients in a compassionate use setting. No new safety concerns were noted. Reassuringly, the relative dose intensity of pazopanib was 92%.

Health-related quality-of-life results from PALETTE: A randomized, double-blind, phase 3 trial of pazopanib versus placebo in patients with soft tissue sarcoma whose disease has progressed during or after prior chemotherapy-a European Organization for research and treatment of cancer soft tissue and bone sarcoma group global network study (EORTC 62072).

BACKGROUND: Health-related quality of life (HRQoL) was an exploratory endpoint in the PALETTE trial, a global, double-blind, randomized, phase 3 trial of pazopanib 800 mg versus placebo as second-line or later treatment for patients with advanced soft tissue sarcoma (N = 369). In that trial, progression-free survival was significantly improved in the pazopanib arm (median, 4.6 vs 1.6 months; hazard ratio, 0.31; P < .001), and toxicity of pazopanib consisted mainly of fatigue, diarrhea, nausea, weight loss, and hypertension. METHODS: HRQoL was assessed using the 30-item core European Organization for the Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire (EORTC QLQ-C30) at baseline and at weeks 4, 8, and 12 in patients who received treatment on protocol. The primary HRQoL endpoint was the EORTC QLQ-C30 global health status scale. RESULTS: Compliance with HRQoL assessments was good, ranging from 94% at baseline to 81% at week 12. Differences in scores on the EORTC QLQ-C30 global health status subscale between the 2 treatment arms were not statistically significant and did not exceed the predetermined, minimal clinically important difference of 10 points (P = .291; maximum difference, 3.8 points). Among the other subscales, the pazopanib arm reported significantly worse symptom scores for diarrhea (P < .001) loss of appetite (P < .001), nausea/vomiting (P < .001), and fatigue (P = .012). In general, HRQoL scores tended to decline over time in both arms. CONCLUSIONS: HRQoL did not improve with the receipt of pazopanib. However, the observed improvement in progression-free survival without impairment of HRQoL was considered a meaningful result. The toxicity profile of pazopanib was reflected in the patients' self-reported symptoms but did not translate into significantly worse overall global health status during treatment.

A retrospective chart review of drug treatment patterns and clinical outcomes among patients with metastatic or recurrent soft tissue sarcoma refractory to one or more prior chemotherapy treatments.

BACKGROUND: Limited clinical data on real-world practice patterns are available for patients with metastatic/relapsed soft tissue sarcomas (STS). The primary objective of this study was to evaluate treatment patterns in patients with metastatic/relapsed STS following failure of prior chemotherapy by examining data collected from 2000 to 2011 from a major tertiary academic cancer center in the United States. METHODS: Medical records, including community-based referral records, from a tertiary cancer center for adult patients with metastatic/relapsed STS with confirmed disease progression who commenced second-line treatment between January 1, 2000 and February 4, 2011, and with at least 3 months of follow-up data following second-line treatment initiation, were retrospectively reviewed. Overall survival, time to progression, and clinician-reported tumor response were collected. RESULTS: A total of 99 patients (leiomyosarcoma, n = 48; synovial cell sarcoma, n = 7; liposarcoma, n = 5; or other histological subtypes, n = 39) received an average of four lines of treatment (maximum of 10). No consistent or dominant regimens were used in each treatment line beyond the second line. Median second-line treatment duration was 4.1 months (95% confidence interval, 3.0-5.0). Overall, 72 of 99 patients (73%) discontinued second-line treatment due to progressive disease. Median progression-free survival from initiation of second-line treatment varied across regimens from 2.0 to 6.6 months (overall median, 5.4 months). CONCLUSIONS: Wide variations in treatment were evident, with no single standard of care for patients with metastatic/relapsed STS. Most patients discontinued second-line treatment due to progressive disease, often receiving additional systemic therapy with other drugs. These data suggest a high unmet need for more efficacious treatment options and improved data collection to guide practice among patients with relapsed/refractory STS.

Efficacy and safety of pharmacological interventions in second- or later-line treatment of patients with advanced soft tissue sarcoma: a systematic review.

BACKGROUND: Current guidelines recommend anthracycline-based chemotherapy primarily with doxorubicin either as monotherapy or in combination with ifosfamide as the first-line treatment for most advanced STS subtypes. Therapeutic options after failure of doxorubicin and/or ifosfamide are limited. This study aimed to comprehensively review available data on the activity and safety of interventions in second- or later-line treatment of advanced STS. METHODS: Electronic literature databases (Embase®, MEDLINE®, MEDLINE® In-Process, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews) were searched from 1980 to 01 March 2012 to identify randomised controlled trials (RCTs) and non-randomised studies (both prospective and retrospective) evaluating pharmacological interventions in patients with advanced STS pre-treated with anthracycline- and/or ifosfamide-based therapy. RESULTS: The review identified six RCTs (one phase III and five phase II trials) and 94 non-randomised studies. Based on the primary trial endpoints, RCTs demonstrated favourable efficacy for pazopanib over placebo (PFS: 4.6 months vs. 1.6 months), gemcitabine plus dacarbazine over dacarbazine monotherapy (3-month PFS rate: 54.2% vs. 35.2%), and trabectedin 3-weekly schedule over weekly schedule (TTP: 3.7 months vs. 2.3 months. The non-randomised studies demonstrated heterogeneity in efficacy and safety results. CONCLUSIONS: Across the RCTs, pazopanib over placebo, gemcitabine-dacarbazine over dacarbazine, and trabectedin 3-weekly over weekly regimen clearly demonstrated a PFS advantage in the second- and later-line treatment of advanced STS. With only one phase III trial in this setting, there is a clear need for additional comparative trials to better understand the risk: benefit ratios of available agents and combinations.

Epidemiology and Treatment of New-Onset and Established Rheumatoid Arthritis in an Insured US Population.

OBJECTIVE: To investigate the epidemiology and treatment of rheumatoid arthritis (RA) in a population broadly representative of employed adults in the US, using a retrospective cohort design. METHODS: Incident and prevalent RA cohorts were defined from a sample of 4.66 million adults with complete followup data from the period of January 2005 through September 2008 in the Pharmetrics medical claims database. Demographics, comorbidity, and medical therapies were summarized using descriptive statistics. RESULTS: Median duration in the database was 5.7 years. Age- and sex-adjusted incidence in 2006 was 0.71 per 1,000 persons at risk (n = 3,992) and prevalence in 2005 was 0.63% (n = 30,530). Within 12 months after diagnosis, 65%, 64%, and 20% of the incident cohort had been prescribed corticosteroids, nonbiologic disease-modifying antirheumatic drugs (DMARDs), and tumor necrosis factor (TNF) inhibitors, respectively. Median time to first anti-TNF prescription was 6 months; 31% switched to a second drug and 15% to a third. An aggressive subcohort (11% of incident patients) received more DMARDs (83%) and TNF inhibitors (43%), and was more likely to switch. Twenty-eight percent of incident patients received only symptomatic therapy over a minimum of 1.75 years of followup; these patients were older with more comorbidities and contraindications to methotrexate. CONCLUSION: In this insured population-based cohort, only two-thirds of newly diagnosed RA patients were prescribed a DMARD in year 1 and 28% received no antirheumatic therapy. Although limited by lack of clinical information and by left-censoring, administrative databases capture clinical practice and suggest that gaps exist in treatment options available to a significant number of patients.

Quantity determination and the distance effect with letters, numbers, and shapes: a functional MR imaging study of number processing.

BACKGROUND AND PURPOSE: The ability to quantify, or to determine magnitude, is an important part of number processing, and the extent to which language and other cognitive abilities are involved with number processing is an area of interest. We compared activation patterns, reaction times, and accuracy as subjects determined stimulus magnitude by ordering letters, numbers, and shapes. A second goal was to define the brain regions involved in the distance effect (the farther apart numbers are, the faster subjects are at judging which number is larger) and whether this effect depended on stimulus type. METHODS: Functional MR images were acquired in 19 healthy subjects. The order task required the subjects to judge whether three stimuli were in order according to their position in the alphabet (letters), position in the number line (numbers), or size (shapes). In the control (identify task), subjects judged whether one of the three stimuli was a particular letter, number, or shape. Each stimulus type was divided into near trials (quantity difference of three or less) and far trials (quantity difference of at least five) to assess the distance effect. RESULTS: Subjects were less accurate and slower with letters than with numbers and shapes. A distance effect was present with shapes and numbers, as subjects ordered the near trials slower than far trials. No distance effect was detected with letters. The occipital lobes and intraparietal sulci were active with all three stimuli. Shapes required no additional areas, although analysis of the distance effect revealed that near shapes involved other brain regions, including the frontal lobes. Letters activated a large network comprising the frontal lobes, the anterior cingulate gyrus, and basal ganglia, but few additional areas were engaged by the distance effect. Numbers involved a smaller network including the inferior and middle frontal gyri. The left supramarginal gyrus and both inferior frontal gyri were active in the distance effect with numbers. CONCLUSION: Numbers and letters, which are stimuli more associated with abstract symbolism compared with shapes, resulted in slower reaction times and an increased number of active brain regions. Shapes and numbers, but not letters, elicited a distance effect, indicating access to a mental continuum of quantity. The left supramarginal gyrus and both inferior frontal gyri were involved in the distance effect with numbers. The intraparietal sulci were important in determining stimulus magnitude for all stimuli.

Cost-effectiveness of pazopanib in advanced soft tissue sarcoma in the United kingdom.

In the phase III PALETTE trial, pazopanib improved progression-free survival (PFS) compared with placebo in patients with advanced/metastatic soft tissue sarcomas (mSTS) who had received prior chemotherapy. We used a multistate model to estimate expected PFS, overall survival (OS), lifetime STS treatment costs, and quality-adjusted life-years (QALYs) for patients receiving pazopanib, placebo, trabectedin, ifosfamide, or gemcitabine plus docetaxel as second-line mSTS therapies. The cost-effectiveness of pazopanib was expressed as the incremental costs per QALY gained. Estimates of PFS/OS, adverse events, and utilities for pazopanib and placebo were from the PALETTE trial. Estimates of relative effectiveness of the other comparators were from an unadjusted indirect comparison versus pazopanib. Costs were from published sources. Pazopanib is estimated to increase QALYs by 0.128 and costs by £7,976 versus placebo; cost per QALY gained with pazopanib versus placebo is estimated to be £62,000. Compared with the other chemotherapies, pazopanib provides similar QALYs at a lower cost. Pazopanib may not be cost-effective versus placebo but may be cost-effective versus the most commonly used active treatments, although this conclusion is uncertain. Given the unmet need for effective treatments for mSTS, pazopanib may be an appropriate alternative to some currently used medications in the United Kingdom.

Potential economic impact of increasing low dose aspirin usage on CVD in the US.

BACKGROUND: Cardiovascular disease (CVD) is a leading cause of death in the US and Western Europe, but regular use of preventive low-dose aspirin has proven effective in preventing CVD events. The purpose of this study was to explore the potential economic impact in the US if preventive aspirin usage were to be increased in line with clinical guidelines for primary and secondary prevention. METHODS: The risk profile of the US population was characterized using NHANES data, and Framingham cardiovascular risk equations were applied to calculate risk for myocardial infarction, angina and ischemic stroke according to age and gender. Primary and secondary patients were considered separately. Using publicly available unit costs, a budget impact model calculated the annual impact of increased preventive aspirin usage considering gastrointestinal bleeding and hemorrhagic stroke adverse events and diminishing aspirin adherence over a 10-year time horizon. RESULTS: In a base population of 1,000,000 patients, full implementation of clinical guidelines would potentially prevent an additional 1273 myocardial infarctions, 2184 angina episodes and 565 ischemic strokes in primary prevention patients and an additional 578 myocardial infarctions, and 607 ischemic strokes in secondary prevention patients. This represents a total savings of $79.6 million for primary prevention and $32.2 million for secondary and additional out-of-pocket expense to patients of $29.0 million for primary prevention and $2.6 million for secondary prevention for the cost of aspirin. CONCLUSIONS: This budgetary model suggests that there is a strong economic case, both for payers and society, to encourage aspirin use for patients at appropriate risk and per clinical guidelines. It also provides an example of how minimizing costs do not necessarily have to imply a rationing of care. Limitations include the exclusion of other CVD interventions in the analysis.

The cumulative burden of oral corticosteroid side effects and the economic implications of steroid use.

Oral corticosteroids (OCS) are a key part of therapy regimens for a diverse variety of conditions. Despite their efficacy, they are associated with a wide variety of adverse events. The purpose of this review was to identify the range of adverse events that have been reported to be related to oral corticosteroids, examine the factors that influence their incidence and estimate the economic burden caused by these adverse events. In 61 identified studies, 21 different categories of OCS related adverse events were reported with increased fracture risk being the category most frequently described. Most studies that examined factors linked to the incidence of OCS related adverse events found that dose, age, gender, duration of use, treatment history, smoking habits or cholesterol level were influential in determining risk. Additionally, a cumulative economic analysis of selected adverse events found the annual cost of treating these events in the UK to be at least 165 pounds per patient taking OCS. The clinical and economic burden of OCS related adverse events highlights the need for OCS sparing therapies to be developed.

Loss of interhemispheric inhibition in patients with multiple sclerosis is related to corpus callosum atrophy.

Axonal injury and loss in the corpus callosum (CC) is characteristic of the pathology of multiple sclerosis (MS). Functional magnetic resonance imaging (fMRI) potentially allows neurophysiological consequences of this interhemispheric axonal loss to be defined quantitatively. Here we have used 3T fMRI to study the activation in the contralateral primary sensorimotor cortex and deactivation (mediated by transcallosal tracts) in the homologous ipsilateral region in 14 patients with MS and in 14 matched healthy controls during a simple hand-tapping task. Both healthy controls and MS patients showed similar activation in the motor cortex contralateral to the hand moved, but the patients showed a significantly smaller relative deactivation in the ipsilateral motor cortex (P = 0.002). The difference was accounted for by the sub-group of MS patients who previously had impairment of motor function of the hand tested (MS-phd). The CC of the whole patient group was significantly thinner than for the controls (P = 0.001). Atrophy of the CC was correlated with loss of deactivation for the whole patient group (r = -0.50, P = 0.035), but particularly for MS-phd (r = -0.914, P = 0.004). Interhemispheric physiological inhibition thus is impaired in patients with MS, potentially contributing to impairment of motor control. This work suggests one way in which FMRI monitoring of the transcallosal interactions in motor cortex could become a tool for evaluation of therapies that may enhance function in reversibly impaired pathways.