Preparation of the black rice starch-gallic acid complexes by ultrasound treatment: Physicochemical properties, multiscale structure, and in vitro digestibility.

This study aimed to investigate the multiscale structure, physicochemical properties, and in vitro digestibility of black rice starch (BRS) and gallic acid (GA) complexes prepared using varying ultrasound powers. The findings revealed that ultrasonic treatment disrupted BRS granules while enhancing the composite degree with GA. The starch granules enlarged and aggregated into complexes with uneven surfaces. Moreover, the crystallinity of the BRS-GA complexes increased to 22.73 % and formed V6-I-type complexes through non-covalent bonds. The increased short-range ordering of the complexes and nuclear magnetic resonance hydrogen (1H NMR) further indicated that the BRS and GA molecules interacted mainly through non-covalent bonds such as hydrogen bonds. Additionally, ultrasound reduced the viscoelasticity of the complexes while minimizing the mass loss of the complexes at the same temperature. In vitro digestion results demonstrated an increase in resistant starch content up to 37.60 % for the BRS-GA complexes. Therefore, ultrasound contributes to the formation of V-typed complexes of BRS and GA, which proves the feasibility of using ultrasound alone for the preparation of starch and polyphenol complexes while providing a basis for the multiscale structure and digestibility of polyphenol and starch complexes.

Achievement of the low-density lipoprotein cholesterol goal among patients with dyslipidemia in South Korea.

BACKGROUND: It is important to achieve the low-density lipoprotein cholesterol (LDL-C) goal recommended by clinical guidelines in managing the risk of cardiovascular (CV) events, however, the current management of LDL-C in actual clinical settings is suboptimal. We examined the LDL-C level among patients with dyslipidemia against the 2015 Korean guidelines, the crude rates of CV events based on LDL-C goal achievement, and the factors associated with LDL-C goal achievement. METHODS: This was a retrospective cohort study using the National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS) database from 2006 to 2013. Patients who had a health examination with LDL-C measurement between January 1, 2007, and December 31, 2011 were identified. Patients were required to have at least one diagnosis of dyslipidemia during the 1 year before the index date, defined as the first date of LDL-C measurement. The 2015 Korean guidelines were used to measure LDL-C goal achievement based on the CV risk level. Crude CV event rates were calculated for total and individual CV events as the number of events divided by person-years (PYs) during the follow-up period. CV events included acute coronary syndrome, ischemic stroke, peripheral artery disease, CV death, and all-cause death. Factors associated with LDL-C goal achievement were assessed using logistic regression. RESULTS: In the NHIS-HEALS database, 69,942 patients met the eligibility criteria: 36.7%, 22.5%, 20.1%, and 20.6% were among the very high-, high-, moderate-, and low-risk groups for the CV events, respectively, as defined by the 2015 Korean guidelines. Approximately half of the patients with dyslipidemia (47.6%) achieved their recommended LDL-C goal, but the achievement rates were substantially different across CV risk levels (17.6%, 47.2%, 66.9%, and 82.4% for very high-, high-, moderate-, and low-risk groups, respectively; P<0.0001). The crude event rate of total CV events during the follow-up period in the LDL-C goal non-achievers was higher than that in the LDL-C goal achievers (24.35/100 PYs vs. 11.93/100 PYs; P<0.0001). LDL-C goal achievement was significantly associated with patient characteristics, including age, sex, body mass index, lipid-modifying therapy, and CV risk level. CONCLUSIONS: In South Korea, LDL-C goal achievement among patients with very high or high CV risk was suboptimal. Patients who did not achieve the goal showed a higher rate of CV events during the follow-up period than patients who achieved the goal. LDL-C management strategies should be highlighted in dyslipidemia patients who are less likely to achieve the goal, such as female, overweight or obese patients, patients not adherent to statin, or patients with very high or high CV risk.

Treatment patterns of lipid-lowering therapies and possible statin intolerance among statin users with clinical atherosclerotic cardiovascular disease (ASCVD) or diabetes mellitus (DM) in Taiwan.

OBJECTIVES: To assess treatment patterns of statin and/or ezetimibe and possible statin intolerance among patients initiating statin or statin plus ezetimibe and with clinical atherosclerotic cardiovascular disease (ASCVD) or diabetes mellitus (DM) in Taiwan. METHODS: A retrospective cohort study using Taiwan's 2005 to 2013 National Health Insurance Research Database (NHIRD) was conducted. Patients with history of clinical ASCVD or DM (without previous clinical ASCVD) and initiating statin or statin plus ezetimibe therapy during 2006 to 2012 were identified. The treatment initiation date was defined as index date. Treatment patterns (including discontinuation, reinitiation, subtraction, switching, and augmentation), adherence (medication possession ratio [MPR]), persistence (gap no greater than 60 d) of statin and/or ezetimibe, and possible statin intolerance during 12-month follow-up from the index date were examined. RESULTS: Among patients initiating statin or statin plus ezetimibe, 11 092 patients with history of clinical ASCVD and 31 100 patients with DM but without clinical ASCVD were analysed. The discontinuation, reinitiation, and switching rates among patients with clinical ASCVD were 54.0%, 11.3%, and 25.7% during 12-month follow-up period, respectively. Among patients with DM, the rates were 57.5%, 14.2%, and 28.5%. The MPRs of statin among clinical ASCVD and DM cohorts were 0.62 and 0.60, respectively. As for ezetimibe, the MPRs were 0.56 and 0.59. Persistence to statin treatment was 46.1% among ASCVD patients and 42.6% among DM patients. Among the ASCVD and DM cohorts, possible statin intolerance was observed among 19.9% and 21.4% of patients, respectively. CONCLUSIONS: Large number of patients with either ASCVD or DM discontinued lipid-lowering therapies with suboptimal adherence and persistence among Taiwanese population. There is a large unmet medical need to provide safe and more effective therapies, which can be used in combination with statins or alone, to reduce the risk of CV events and improve outcomes in high-risk patients.

Characteristics of patients with dyslipidemia treated in routine care setting in China.

Objective: To describe characteristics of patients with dyslipidemia treated in routine care in China overall and stratified by diabetes and atherosclerotic cardiovascular disease (ASCVD). Methods: This study used data from a cross-sectional survey conducted in China in 2017 under the Dyslipidemia Disease Specific Programme (DSP). Each surveyed physician provided information including demographics, dyslipidemia diagnosis and treatment history, lab values on at least 8 patients currently treated for dyslipidemia with oversampling of patients with ASCVD or diabetes mellitus diagnosis at the time of survey. A related patient survey assessed treatment adherence and satisfaction. Results: This study included 195 physicians (40 endocrinologists, 75 internists, 80 cardiologists) who provided data on 1870 patients (852 with diabetes; 1018 patients without diabetes). Among patients with diabetes, 279 had ASCVD and 573 did not (non-ASCVD). In the diabetic population, patients with ASCVD were older (67.3 vs. 62.1 years), more often had caregiver support (34 vs. 14%), and had higher average LDL-C at diagnosis (172.4 vs. 167.4 mg/dL) compared to their non-ASCVD counterparts. Findings were similar for non-diabetic patients (ASCVD: 323 patients; non-ASCVD: 695) patients. In all four subgroups, 46-54% of patients reported low treatment adherence, and fewer than half expressed satisfaction with their cholesterol control, and 2-5% had LDL-C < 70 mg/dL at their most recent assessment. Conclusions: Among patients with dyslipidemia, those with ASCVD had higher LDL-C levels than patients without ASCVD, and many required caregiving. Low levels of treatment adherence, LDL-C control, and patient satisfaction suggest opportunities to improve care for Chinese patients with dyslipidemia.

The health and economic burden of osteoporotic fractures in Singapore and the potential impact of increasing treatment rates through more pharmacological options.

PURPOSE: This study aims to estimate the health and economic burden of osteoporosis in Singapore from 2017 to 2035, and to quantify the impact of increasing the treatment rate of osteoporosis. METHODS: Population forecast data of women and men aged 50 and above in Singapore from 2017 to 2035 was used along with prevalence rates of osteoporosis to project the osteoporosis population over time. The population projections by sex and age group were used along with osteoporotic fracture incidence rates by fracture type (hip, vertebral, other), and average direct and indirect costs per case to forecast the number of fractures, the total direct health care costs, and the total indirect costs due to fractures in Singapore. Data on treatment rates and effects were used to model the health and economic impact of increasing treatment rate of osteoporosis, using different hypothetical levels. RESULTS: Between 2017 and 2035, the incidence of osteoporotic fractures is projected to increase from 15,267 to 24,104 (a 57.9% increase) F 10,717 to 17,225 (a 60.7% increase) and M 4550 to 6878 (a 51.2% increase). The total economic burden (including direct costs and indirect costs to society) associated with these fractures is estimated at S$183.5 million in 2017 and is forecasted to grow to S$289.6 million by 2035. However, increasing the treatment rate for osteoporosis could avert up to 29,096 fractures over the forecast period (2017-2035), generating cumulative total cost savings of up to S$330.6 million. CONCLUSION: Efforts to improve the detection, diagnosis, and treatment of osteoporosis are necessary to reduce the growing clinical, economic, and societal burden of fractures in Singapore.

Estimating Years of Life Lost Due to Cardiovascular Disease in Japan.

BACKGROUND: In Japan, the burden associated with myocardial infarction (MI) and ischemic stroke as well as atherosclerotic cardiovascular disease (ASCVD) generally is high. One key element in measuring disease burden is years of life lost (YLL). The aim of this study was to understand the burden of these diseases by estimating YLL at an overall disease level and average person-YLL (PYLL), a measure of disease burden also used in prior studies. Methods and Results: Because calculation of YLL and PYLL involves inputs such as disease prevalence, disease-related mortality by age, and general population mortality by age and sex, we searched public databases of disease surveillance to identify comprehensive Japanese-specific inputs. For our reference analysis, disease-specific prevalence and mortality were taken from the Institute for Health Metrics and Evaluation Global Disease Burden study, and background mortality data were from the Japanese life tables published by the Ministry of Health, Labour and Welfare. The average age of patients with MI or stroke was 74 and 70 years, respectively. On average, men comprised 59% and 54% of the MI and stroke population, respectively. The disease-level burden of ASCVD (inclusive of MI, stroke, and peripheral artery disease) was 2,703,711 YLL in 2017. The patient-level burden was 11.99 PYLL for MI and 9.39 PYLL for stroke. CONCLUSIONS: The burden of ASCVD, MI, and stroke in terms of premature mortality is substantial in Japan, both on a population disease level and an individual patient level.

Utilization Patterns of Lipid-lowering Therapies in Patients With Atherosclerotic Cardiovascular Disease or Diabetes: A Population-based Study in South Korea.

PURPOSE: We aimed to study the utilization patterns of lipid-lowering treatment (LLT), including treatment modification, adherence, and possible statin intolerance, in patients with atherosclerotic cardiovascular disease (ASCVD) or diabetes using national claims data in South Korea. METHODS: A retrospective cohort study was conducted using data from the Korean Health Insurance Review & Assessment Service claims database. Patients aged ≥18 years with >1 outpatient pharmacy claim for a statin and/or ezetimibe dated January 1, 2012, to December 31, 2014, were identified and categorized into the following cohorts: patients with ASCVD, and patients with diabetes mellitus without ASCVD. LLT modification, adherence to index LLT, and possible statin intolerance were explored during the 12 months after the date of first prescription for a statin and/or ezetimibe. FINDINGS: Among 1,399,872 patients who met the eligibility criteria, 807,547 (57.7%) were patients with ASCVD and 592,325 (42.3%) were patients with diabetes without ASCVD. About half of the patients had no modification in their index treatment (46.2% in the ASCVD cohort and 48.9% in the diabetes cohort), and the most common modification was permanent discontinuation (19.6% in the ASCVD cohort and 21.4% in the diabetes cohort). The mean medication possession ratios were 0.77 in the ASCVD cohort and 0.73 in the diabetes cohort and showed a decreasing trend during the 12-month follow-up period. Among patients who initiated a statin and/or ezetimibe, possible statin intolerance was observed in 53,921 patients (6.7%) in the ASCVD cohort and 42,172 patients (7.1%) in the diabetes cohort. IMPLICATIONS: In South Korea, a high rate of permanent discontinuation of statin therapy in patients with ASCVD or diabetes places these patients at high risk for cardiovascular events in the future. A decreasing trend of adherence to LLT implies that more intensive education and management are required to improve therapeutic effect and reduce the risk for ASCVD. The high rate of possible statin intolerance highlights an unmet need in the prevention and management of ASCVD in South Korea.

Autoimmune comorbidities in patients with metastatic melanoma: a retrospective analysis of us claims data.

BACKGROUND: Immunotherapies have advanced the treatment of metastatic melanoma; however, they are associated with immune-related toxicities. Patients with pre-existing autoimmune comorbidities are commonly excluded from clinical trials investigating immunotherapies in metastatic melanoma. Since information on pre-existing autoimmune comorbidities in "real-world" patients with newly diagnosed metastatic melanoma is limited, we sought to estimate the prevalence of autoimmune comorbidities and its change over time. METHODS: Data were obtained from a large US claims database, MarketScan®, from 2004 to 2014. Records of patients with newly diagnosed metastatic or non-metastatic melanoma and of general population were analyzed. Autoimmune comorbidities were defined as presence of autoimmune disorders, which were obtained from the list of diseases at the American Autoimmune-Related Diseases Association web portal ( www.aarda.org ). The prevalence of pre-existing autoimmune comorbidities and its change over the 11-year period were calculated. Logistic regression analyses were performed to evaluate the relationship between clinical and demographic factors and pre-existing autoimmune comorbidities in patients with metastatic melanoma. RESULTS: This study assessed the prevalence and change of prevalence over a period of 11 years of 147 autoimmune comorbidities. Among 12,028 patients with newly diagnosed metastatic melanoma, the prevalence rate of pre-existing autoimmune comorbidities increased from 17.1% in 2004 to 28.3% in 2014 (P < 0.001). The prevalence rates of autoimmune comorbidities increased from 11.7% in 2004 to 19.8% in 2014 in patients with non-metastatic melanoma and 7.9% in 2004 to 9.2% in 2014 in the general population. In addition, patients with bone or gastrointestinal melanoma metastases, those with more comorbid diseases, or female patients, were found to have a higher risk of autoimmune comorbidities. CONCLUSIONS: The prevalence of pre-existing autoimmune comorbidities in patients with newly diagnosed metastatic melanoma was high, and increased over 11 years. In comparison, a lower prevalence of autoimmune comorbidities was seen in patients with newly diagnosed non-metastatic melanoma and in the general population. Increases in prevalence for these population groups were also observed over 11 years. Impact of autoimmune comorbidities on treatment decisions in patients with metastatic melanoma should be explored.

Durable response rate as an endpoint in cancer immunotherapy: insights from oncolytic virus clinical trials.

BACKGROUND: Traditional response criteria may be insufficient to characterize full clinical benefits of anticancer immunotherapies. Consequently, endpoints such as durable response rate (DRR; a continuous response [complete or partial objective response] beginning within 12 months of treatment and lasting ≥6 months) have been employed. There has not, however, been validation that DRR correlates with other more traditional endpoints of clinical benefit such as overall survival. METHODS: We evaluated whether DRR was associated with clinically meaningful measures of benefit (eg, overall survival [OS], quality of life [QoL], or treatment-free interval [TFI]) in a phase 3 clinical trial of an oncolytic virus for melanoma treatment. To evaluate the association between DRR and OS and to mitigate lead time bias, landmark analyses were used. QoL was evaluated using the FACT-BRM questionnaire (comprising the FACT-BRM Physical, Social/Family, Emotional, and Functional well-being domains, the Additional Concerns, Physical and Mental treatment-specific subscales, and the Trial Outcome Index [TOI]). TFI was defined as time from the last study therapy dose to first subsequent therapy dose (including any systemic anticancer therapy for melanoma after study therapy discontinuation). RESULTS: Four hundred thirty-six patients were included in the intent-to-treat population. Achieving DR was associated with a statistically significant improvement in OS in a landmark analysis at 9 months (HR = 0.07; P = 0.0003), 12 months (HR = 0.05, P < 0.0001), and 18 months (HR = 0.11; P = 0.0002) that persisted after adjusting for disease stage and line of therapy. Achieving a DR was associated with a longer median TFI (HR = 0.33; P = 0.0007) and a higher TOI improvement rate (58.1% versus 30.0%; P = 0.025). CONCLUSIONS: Achieving a DR was associated with clinical benefits such as improved OS and QoL and prolonged TFI, thus supporting the usefulness of DR as a meaningful immunotherapy clinical trial endpoint. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT00769704 ( https://clinicaltrials.gov/ct2/show/NCT00769704 ) October 7, 2008.

Patterns of use of systemic therapies among patients with metastatic melanoma: a retrospective claims database analysis in the United States.

OBJECTIVES: This retrospective analysis of the IMS PharMetrics Plus claims database aimed to describe the current real-world treatment patterns for metastatic melanoma in the USA. METHODS: Included patients (aged ≥18 years) had ≥1 prescription for ipilimumab, vemurafenib, temozolomide or dacarbazine between 1 January 2011 and 31 August 2013; diagnosis of melanoma and metastasis before first use (index date); no index drug use prior to the index date; continuous health plan enrollment for ≥6 months before and ≥3 months after index date. Proportion of days covered (PDC) was defined as days exposed to index therapy divided by continuously enrolled days between index date and last prescription date. RESULTS: Overall, 1043 patients were included (median age 57 years, 63% male), of whom 39% received the index drug ipilimumab, 35% vemurafenib, 19% temozolomide and 7% dacarbazine. Mean treatment duration (days) was 174 (vemurafenib), 100 (temozolomide) and 64 (dacarbazine). Mean PDC was 81% (vemurafenib), 67% (temozolomide) and 51% (dacarbazine). For patients receiving ipilimumab, 58% had the full 4 doses, 20% 3 doses, 14% 2 doses and 9% 1 dose only for the first induction course; 4% received re-induction, and none had a second re-induction. CONCLUSIONS: This study provides insights into the treatment patterns for metastatic melanoma, including newer agents, in real-world clinical practice.

Economic burden of toxicities associated with treating metastatic melanoma in eight countries.

BACKGROUND: Information on costs of managing adverse events (AEs) associated with current treatments in metastatic melanoma is limited. This study estimates costs of AEs in eight countries: Australia (AU), Canada (CA), France (FR), Germany (GE), Italy (IT), the Netherlands (NL), Spain (ES), and the UK. METHODS: A literature search was conducted to identify grade 3/4 AEs from product label, published trials, conference abstracts, and treatment guidelines. Resource utilization for the management of each type of AE was determined via interviews with 5 melanoma clinicians in each country. Outpatient and inpatient costs were estimated for each type of AE using country-specific tariffs or government/published sources. RESULTS: In outpatient settings, the most costly AEs per incident included cutaneous squamous cell carcinoma (CSCC) (€1063, £720; NL/UK), anemia (€1443, €1329, €1285; ES/IT/FR), peripheral neuropathy (€1289; ES), and immune-related diarrhea (AUS$1,121; AU). In inpatient settings, the most costly AEs per hospitalization included hypophysitis (€10,265; €5316; CAN$9735; AUS$7231: ES/FR/CA/AU), dyspnea (€9077; GE), elevated liver enzymes (€6913, CAN$8030, AUS$6594; FR/CA/AU), CSCC (CAN$8934; CA), peripheral neuropathy (€6977, €4144, CAN$9472; NL/ES/CA), and diarrhea (£4284, €4113; UK/ES). CONCLUSIONS: Costs of managing AEs can be significant, and thus effective treatments with lower rates of severe AEs would be valuable.

Relative Efficacy of Granulocyte-Macrophage Colony-Stimulating Factor, Dacarbazine, and Glycoprotein 100 in Metastatic Melanoma: An Indirect Treatment Comparison.

INTRODUCTION: Advances in the treatment of metastatic melanoma have been achieved in recent years: immunotherapies and targeted therapies have demonstrated survival benefits over older agents such as granulocyte-macrophage colony-stimulating factor (GM-CSF), dacarbazine, and glycoprotein peptide vaccine (gp100) in pivotal phase 3 trials. It is important to compare therapies to guide the treatment decision-making process, and establishing the relationship between older agents can strengthen the networks of evidence for newer therapies. We report the outcome of an indirect comparison of GM-CSF, dacarbazine, and gp100 in metastatic melanoma through meta-analysis of absolute treatment effect. METHODS: A systematic literature review identified trials for inclusion in the meta-analysis. A valid network meta-analysis was not feasible: treatment-specific meta-analysis was conducted. A published algorithm was used to adjust overall survival estimates from trials of GM-CSF, dacarbazine, and gp100 for heterogeneity in baseline prognostic factors. Survival estimates were compared in three patient groups: stage IIIB-IV M1c, stage IIIB-IV M1a, and stage IV M1b/c. RESULTS: One trial of GM-CSF, four of dacarbazine, and one of gp100 were included in the analysis. After adjusting for differences in baseline prognostic factors, median overall survival (OS) in all patient groups was longer for those receiving GM-CSF than for those receiving dacarbazine or gp100. The observed survival over time for GM-CSF was similar to the adjusted survival for dacarbazine and greater than for gp100 in all patient groups. CONCLUSION: The relative treatment effect of GM-CSF, dacarbazine, and gp100 has been reliably estimated by adjusting for differences in baseline prognostic factors. Results suggest that OS with GM-CSF is at least as good as with dacarbazine and greater than with gp100. Given the role of these agents as controls in phase 3 trials of new immunotherapies and targeted agents, these results can be used to contextualize the efficacy of newer therapies. FUNDING: Amgen Inc.

Economic Burden of Toxicities Associated with Treating Metastatic Melanoma in the United States.

BACKGROUND: Little has been reported on the costs of managing the adverse events (AEs) associated with current therapies for patients with regional or distant metastatic melanoma. OBJECTIVES: To identify treatment-related AEs in patients with metastatic melanoma and to estimate the associated costs of treating these AEs in the United States. METHODS: A cost-estimation study for AEs associated with treatment of metastatic melanoma was conducted from 2012 to 2013 by identifying grades 3 and 4 AEs through the use of a comprehensive search of drug labels and English-language, published phase 2/3 studies in PubMed, conference abstracts, and the National Comprehensive Cancer Network guidelines. Resource utilization for the management of each type of AE in the outpatient setting was obtained via interviews with 5 melanoma specialists in the United States. Unit costs for an AE associated with melanoma treatment in the outpatient setting were assigned using Medicare reimbursement rates to obtain these costs. Hospitalization and length-of-stay costs were estimated for each associated AE using the large national claims database Optum Clinformatics Data Mart for the period of July 1, 2004, to November 30, 2012. RESULTS: The most common AEs associated with chemotherapies used for melanoma were neutropenia, vomiting, and anemia. The most common AEs associated with vemurafenib were cutaneous squamous-cell carcinoma or keratoacanthoma, rash, and elevated liver enzymes; the most common AEs associated with dabrafenib were cutaneous squamous-cell carcinoma and pyrexia. Trametinib was most often associated with hypertension and rash. The most common AEs with ipilimumab were immune-related diarrhea or colitis, dyspnea, anemia, vomiting, and, less frequently, hypophysitis. The most common grade 3/4 AE with talimogene laherparepvec was cellulitis. The highest treatment costs for an AE in the outpatient setting were for neutropenia ($2092), headache ($609), and peripheral neuropathy ($539). The highest mean inpatient costs for an AE were for acute myocardial infarction, sepsis, and coma, which ranged from $31,682 to $47,069. Colitis or diarrhea, cutaneous squamous-cell carcinoma, thrombocytopenia, hyponatremia, oliguria or anuria, hypertension, anemia, and elevated liver enzymes were associated with mean costs for hospitalization ranging from $19,122 to $26,861. CONCLUSION: The costs of managing treatment-related AEs in patients with metastatic melanoma are substantial. Effective treatments with improved safety profiles may help to reduce these costs. Until real-world evidence for the costs associated with treatment toxicity is available in the outpatient and inpatient settings, the costs estimated in this study can help inform decision makers about the cost-effectiveness of managing patients with metastatic melanoma.

Indirect Treatment Comparison of Talimogene Laherparepvec Compared with Ipilimumab and Vemurafenib for the Treatment of Patients with Metastatic Melanoma.

INTRODUCTION: Few randomized controlled trials have compared new treatments for metastatic melanoma. We sought to examine the relative treatment effect of talimogene laherparepvec compared with ipilimumab and vemurafenib. METHODS: A systematic literature review of treatments for metastatic melanoma was undertaken but a valid network of evidence could not be established because of a lack of comparative data or studies with sufficient common comparators. A conventional adjusted indirect treatment comparison via network meta-analysis was, therefore, not feasible. Instead, a meta-analysis of absolute efficacy was undertaken, adjusting overall survival (OS) data for differences in prognostic factors between studies using a published algorithm. RESULTS: Four trials were included in the final indirect treatment comparison: two of ipilimumab, one of vemurafenib, and one of talimogene laherparepvec. Median OS for ipilimumab and vemurafenib increased significantly when adjustment was applied, demonstrating that variation in disease and patient characteristics was biasing OS estimates; adjusting for this made the survival data more comparable. For both ipilimumab and vemurafenib, the adjustments improved Kaplan-Meier OS curves; the observed talimogene laherparepvec OS curve remained above the adjusted OS curves for ipilimumab and vemurafenib, showing that long-term survival could differ from the observed medians. CONCLUSION: Even with limited data, talimogene laherparepvec, ipilimumab, and vemurafenib could be compared following adjustments, thereby providing a more reliable understanding of the relative effect of treatment on survival in a more comparable patient population. The results of this analysis suggest that OS with talimogene laherparepvec is at least as good as with ipilimumab and vemurafenib and improvement was more pronounced in patients with no bone, brain, lung or other visceral metastases. FUNDING: Amgen Inc.

Use Patterns and Costs of Isolated Limb Perfusion and Infusion in the Treatment of Regional Metastatic Melanoma: A Retrospective Database Analysis.

INTRODUCTION: Isolated limb perfusion and infusion (ILP/ILI) are therapies for regional metastatic melanoma that allow high doses of anticancer drugs to be delivered directly into the circulation of an affected limb, thereby minimizing systemic drug toxicity. This procedure can lead to high response rates and is recommended in patients with Stage III unresectable metastatic melanoma. However, limited information is available on patterns of use and costs. This study examined patterns of ILP/ILI use and associated costs in patients with melanoma in the United States (US). METHODS: Retrospective, observational study, using administrative claims data from the MarketScan(®) databases, was performed in patients with a diagnosis of melanoma (ICD-9-CM: 172.xx, V10.82) who underwent ILP/ILI (CPT-4: 36823) between January 1, 2002 and March 31, 2013. Patient characteristics, use patterns, length of hospital stay, and costs (per 2014 US $) of ILP/ILI were assessed. RESULTS: One hundred and thirteen patients met the study criteria and were included in the analysis. Mean age was 61.4 years (standard deviation [SD] 13.8) and 38.9% of patients were male; the mean baseline Charlson Comorbidity Index was 0.19; 34.5% of patients were Medicare beneficiaries. The majority of patients (87.6%) had melanoma of the lower limb, 11.5% of the upper limb, and 0.9% of both limbs; 60.2% had lymph node metastasis and 56.6% had skin metastasis. Four patients (3.5%) underwent multiple ILP/ILI. The mean (± SD) length of hospital stay was 5.6 (± 3.5) days and the mean (± SD) cost was US$36,758 (± 27,124) per ILP/ILI procedure. CONCLUSIONS: Isolated limb perfusion and infusion in patients with melanoma were associated with long hospital stays and high costs. These results provide useful source data for the economic evaluation of treatment options for regional metastatic melanoma. FUNDING: This study was funded by Amgen, Inc.

Estimating healthcare resource use associated with the treatment of metastatic melanoma in eight countries.

Objectives Studies reporting healthcare resourse use (HRU) for melanoma, one of the most costly cancers to treat, are limited. Using consistent, robust methodology, this study estimated HRU associated with the treatment of metastatic melanoma in eight countries. Methods Using published literature and clinician input, treatment phases were identified: active systemic treatment (pre-progression); disease progression; best supportive care (BSC)/palliative care; and terminal care. HRU elements were identified for each phase and estimates of the magnitude and frequency of use in clinical practice were obtained through country-specific Delphi panels, comprising healthcare professionals with experience in oncology (n = 8). Results Medical oncologists are the key care providers for patients with metastatic melanoma, although in Germany dermato-oncologists also lead care. During the active systemic treatment phase, each patient was estimated to require 0.83-2 consultations with a medical oncologist/month across countries; the median number of such assessments in 3 months was highest in Canada (range = 3.5-5) and lowest in France, the Netherlands and Spain (1). Resource use during the disease progression phase was intensive and similar across countries: all patients were estimated to consult with medical oncologists and 10-40% with a radiation oncologist; up to 40% were estimated to require a brain MRI scan. During the BSC/palliative care phase, all patients were estimated to consult with medical oncologists, and most to consult with a primary care physician (40-100%). Limitations Panelists were from centers of excellence, thus results may not reflect care within smaller hospitals; data obtained from experts may be less variable than data from broader clinical practice. Treatments for metastatic melanoma are continually emerging, thus some elements of our work could be superseded. Conclusions HRU estimates were substantial and varied across countries for some resources. These data could be used with country-specific costs to elucidate costs for the management of metastatic melanoma.

Years of life lost due to metastatic melanoma in 12 countries.

BACKGROUND: Regionally or distantly metastatic melanoma (stages IIIB/C and IV) place a high burden on society. To quantify this burden, this study estimated years of life lost (YLL) per patient for adults with metastatic melanoma in 12 countries in 2014. METHODS: General population growth and life expectancy were estimated from the Organization for Economic Co-operation and Development data and life tables for each country. Incidence of melanoma and mortality rates for the disease were based on GLOBOCAN and US registry data. The prevalence of metastatic melanoma was calculated using mortality rates and survival data from patients with melanoma. YLL per patient was estimated by the difference between the disease-free life expectancy and the life expectancy with metastatic melanoma. RESULTS: YLL per patient were as follows: Australia, men = 19.9 years, women = 22.7 years; Brazil, 16.3, 19.8; Canada, 19.4, 22.3; France, 18.8, 23.1; Germany, 18.3, 20.8; Italy, 19.3, 22.7; Mexico, 17.2, 19.0; the Netherlands, 18.5, 21.5; Spain, 19.2, 23.1; Sweden 19.4, 22.0; the UK, 18.7, 21.2; and the US, 17.9, 20.6. CONCLUSIONS: The burden of metastatic melanoma as measured by YLL is substantial in all 12 countries; although there is variation across countries and between men and women.

Overall survival in patients with metastatic melanoma.

INTRODUCTION: Patients with regionally or distantly metastatic melanoma have poor long-term prognosis. The objective of this analysis was to describe survival rates among patients diagnosed with unresectable stage IIIB/C or stage IV melanoma. METHODS: Using data from the Surveillance, Epidemiology, and End Results (SEER) database, patients diagnosed with unresectable stage IIIB/C and stage IV (M1a, M1b, M1c) melanoma between 2004 and 2009 were selected. Patients' demographic and clinical characteristics were reported at the time of diagnosis. The outcome of the analysis was time from melanoma diagnosis to death. Survival was presented as 1 year, 2 year, and 3 year survival rates, and median overall survival. RESULTS: A total of 1682 patients met the study criteria, with 4.4% at stage IIIB/IIIC, 12.6% at M1a, 17.4% at M1b, and 65.6% at M1c. The mean age was 64 years, 49.5% of patients were 64 years old or younger, 68.0% were male, and 91.7% were white. Patients at stage IIIB/IIIC had a median overall survival (OS) of 24.3 months, with a survival rate of 67.2% at 1 year, 42.9% at 2 years, and 32.1% at 3 years. For patients at stage M1a, the median OS was 22.3 months, 1 year, 2 year, and 3 year survival rates were 64.5%, 40.4%, and 26.4%, respectively; for patients at stage M1b, median OS was 11.2 months, 1 year, 2 year, and 3 year survival rates were 43.8%, 23.4%, and 13.8%, respectively; for patients at stage M1c, median OS was 5.1 months, and 1 year, 2 year, and 3 year survival rates were 22.3%, 8.9%, and 4.7%, respectively. CONCLUSIONS: Among patients diagnosed with unresectable metastatic melanoma from 2004 to 2009, patients at later stages had lower median overall survival and higher mortality rates than patients at earlier stages. Limitations of this analysis include the lack of information on disease progression, therapies used, and genetic factors.

Treatment patterns in patients with metastatic melanoma: a retrospective analysis.

Objective. To describe treatment patterns and factors influencing treatment in a real-world setting of US patients with metastatic melanoma (MM). Methods. This was a retrospective claims-based study among patients with MM diagnosed between 2005 and 2010 identified from MarketScan databases. Results. Of 2546 MM patients, 66.8% received surgery, 44.7% received radiation, 38.7% received systemic therapies, and 17.7% received all modalities. Patients with lung, brain, liver, or bone metastases were less likely to undergo surgery (all P < 0.0001); patients with lung (P = 0.04), brain (P < 0.001), or liver metastases (P = 0.03) were more likely to receive systemic therapies; patients with brain (P < 0.0001) or bone metastases (P < 0.0001) were more likely to receive radiation therapy. Oncologists were more likely to recommend systemic therapy (P < 0.0001) or radiation (P < 0.0001), while dermatologists were more likely to recommend surgery (P = 0.002). Monotherapy was the dominant systemic therapy (82.4% patients as first-line). Conclusions. Only 39% of MM patients received systemic therapies, perhaps reflecting efficacy and safety limitations of conventional systemic therapies for MM. Among those receiving systemic therapy, monotherapy was the most common approach. Sites of metastases and physician speciality influenced treatment patterns. This study serves as a baseline against which future treatment pattern studies, following approval of new agents, can be compared.

The impact of infusion reactions associated with monoclonal antibodies in metastatic colorectal cancer: a European perspective.

BACKGROUND AND OBJECTIVES: Published data on the clinical and economic impact of infusion reactions to monoclonal antibodies are limited. This study investigated oncologists' and oncology nurses' opinions about resource use associated with infusion reactions and the impact on patient management in Europe. METHODS: Eighty oncologists and nurses from Denmark, France, Germany, Greece, Italy, Spain, Sweden and the UK currently treating patients with metastatic colorectal cancer were interviewed by telephone using a 27-item questionnaire developed for this study. RESULTS: The mean estimated number of staff (physicians and nurses) involved in managing an infusion reaction was 1.97 for a grade 1, 2.35 for a grade 2, 3.6 for a grade 3 and 5.3 for a grade 4 reaction. In respondents' experiences, most patients with grade 3 infusion reactions (73.4%) were admitted to hospital for treatment; 82.5% of those with grade 4 infusion reactions were treated in intensive care. The estimated duration of hospital treatment was 13.3 ± 29 h for a grade 3 infusion reaction, increasing to 48.1 ± 43.7 h for a grade 4 infusion reaction. CONCLUSIONS: According to respondents, management of infusion reactions led to substantial resource use, which increased with the severity of the reaction. More severe reactions also led to anxiety in patients and distress to staff.