Serum alpha-fetoprotein surge after the initiation of chemotherapy for non-seminomatous testicular cancer has an adverse prognostic significance.

It has been recognized that the tumour markers alpha-fetoprotein (AFP) and human chorionic gonadotrophin (HCG) may show a transient elevation after the initiation of chemotherapy in non-seminomatous testicular cancer. We investigated the prognostic importance of these so-called marker surges in a cohort of patients treated with cisplatin combination chemotherapy between 1983 and 1991. A total of 669 patients were studied. Of 352 patients who had an elevated AFP at the start of treatment and for whom we had data at both day 1 and day 8, 101 (29%) had a surge. Of 317 patients for whom we had data for HCG, 80 patients (25%) had a surge. It was found that an AFP surge was a strong adverse prognostic factor for progression [hazard ratio (HR) 2.28, P=0.005]. There was no statistically significant difference in survival (HR 1.65, P=0.13). There was no prognostic significance of a HCG surge, either for progression or for survival. To investigate whether a surge was an independent prognostic factor for progression and survival, multivariate Cox regression models were fitted using the independent prognostic factors for progression and survival and the surge/decline variable. An AFP surge was retained in the final model for progression. A HCG surge was of no prognostic importance for progression or survival. We conclude that an AFP surge has an adverse prognostic significance, independent of pretreatment characteristics

Systematic Review and Quality Appraisal of Cost-Effectiveness Analyses of Pharmacologic Maintenance Treatment for Chronic Obstructive Pulmonary Disease:Methodological Considerations and Recommendations

Worldwide, chronic obstructive pulmonary disease (COPD) is a highly prevalent chronic lung disease with considerable clinical and socioeconomic impact. Pharmacologic maintenance drugs (such as bronchodilators and inhaled corticosteroids) play an important role in the treatment of COPD. The cost effectiveness of these treatments has been frequently assessed, but studies to date have largely neglected the impact of treatment sequence and the exact stage of disease in which the drugs are used in real life. We aimed to systematically review recently published articles that reported the cost effectiveness of COPD maintenance treatments, with a focus on key findings, quality and methodological issues. We performed a systematic literature search in Embase, PubMed, the UK NHS Economic Evaluation Database (NHS-EED) and EURONHEED (European Network of Health Economics Evaluation Databases) and included all relevant articles published between 2011 and 2015 in either Dutch, English or German. Main study characteristics, methods and outcomes were extracted and critically assessed. The Quality of Health Economic Studies (QHES) instrument was used as basis for quality assessment, but additional items were also addressed. The search identified 18 recent pharmacoeconomic analyses of COPD maintenance treatments. Papers reported the cost effectiveness of long-acting muscarinic antagonist (LAMA) monotherapy (n = 6), phosphodiesterase (PDE)-4 inhibitors (n = 4), long-acting beta agonist/inhaled corticosteroid (LABA/ICS) combinations (n = 4), LABA monotherapy (n = 2) and LABA/LAMA combinations (n = 2). All but two studies were funded by the manufacturer, and all studies indicated favourable cost effectiveness; however, the number of quality-adjusted life-years (QALYs) gained was small. Less than half of the studies reported a COPD-specific outcome in addition to a generic outcome (mostly QALYs). Exacerbation and mortality rates were found to be the main drivers of cost effectiveness. According to the QHES, the quality of the studies was generally sufficient, but additional assessment revealed that most studies poorly represented the cost effectiveness of real-life medication use. The majority of studies showed that pharmacologic COPD maintenance treatment is cost effective, but most studies poorly reflected real-life drug use. Consistent and COPD-specific methodology is recommended

Tumour marker concentration at the start of chemotherapy is a stronger predictor of treatment failure than marker half-life: a study in patients with disseminated non-seminomatous testicular cancer.

We investigated the prognostic value of the serum half-life of human chorionic gonadotrophin (HCG) and alpha-fetoprotein (AFP) during induction chemotherapy and the relative prognostic importance of initial marker concentrations and marker half-life. Marker half-lives were calculated using two abnormal values observed between day 8 and day 22 of the first chemotherapy cycle. Moreover, analyses were carried out using day 43 as the second measurement point. Treatment failure at any time was chosen as the end point. The relative prognostic influence of marker half-lives and initial marker concentrations was tested in univariate and multivariate analyses. Half-lives were considered to be prolonged if > 3 days for HCG and > 6 days for AFP. In addition, we separated patients into those with half-lives > 6 days for HCG and those with half-lives > 10 days for AFP to examine whether these long half-lives were associated with a poor prognosis. A group of 669 patients treated with cisplatin combination chemotherapy was studied. Forty-two per cent of the patients had normal HCG and 37% had normal AFP at the start of chemotherapy. At day 22, HCG was still elevated in 138 patients and AFP in 211. At day 43, the numbers of these patients were 35 and 80 respectively. Based on the measurements obtained on day 8 and day 22, a half-life of HCG > 3 days or > 6 days and/or a half-life AFP > 6 days or > 10 days did not accurately predict treatment failure (P=0.413 and P=0.851, respectively; values obtained using tests for trend). However, initial marker concentrations of HCG and/or AFP > 1000 IU l(-1) were highly significant prognosticators for treatment failure (P=0.001 and P < 0.001 respectively), independent of half-life values. Half-lives calculated with the values obtained on day 43 did not contribute to the accuracy of the prediction of treatment failure. We conclude that half-lives of HCG and AFP during induction chemotherapy are inaccurate parameters for the prediction of treatment failure. In contrast, initial serum concentrations of HCG and AFP are highly significant in the prediction of unfavourable treatment outcome

A novel doxorubicin-glucuronide prodrug DOX-GA3 for tumour-selective chemotherapy: distribution and efficacy in experimental human ovarian cancer

The doxorubicin (DOX) prodrug N -[4-doxorubicin- N -carbonyl (oxymethyl) phenyl] O -β-glucuronyl carbamate (DOX-GA3) was synthesised for specific activation by human β-glucuronidase, which is released in necrotic areas of tumour lesions. This novel prodrug was completely activated to the parent drug by human β-glucuronidase with V max= 25.0 μmol min–1mg–1and K m= 1100 μM. The pharmacokinetics and distribution of DOX-GA3 in nude mice bearing human ovarian cancer xenografts (OVCAR-3) were determined and compared with DOX. Administration of DOX at 8 mg kg–1i.v. (maximum tolerated dose, MTD) to OVCAR-3-bearing mice resulted in a peak plasma concentration of the drug of 16.4 μM (t = 1 min). A 7.6-times lower peak plasma concentration of DOX was measured after injection of DOX-GA3 at 250 mg kg–1i.v. (50% of MTD). In normal tissues the prodrug showed peak DOX concentrations that were up to 5-fold (heart) lower than those found after DOX administration. DOX-GA3 activation by β-glucuronidase in the tumour yielded an almost 5-fold higher DOX peak concentration of 9.57 nmol g–1(P< 0.05) than the peak concentration of only 2.14 nmol g–1observed after DOX. As a consequence, the area under the curve of DOX calculated in tumour tissue after DOX-GA3 (13.1 μmol min–1g–1) was 10-fold higher than after DOX (1.31 μmol min–1g–1). The anti-tumour effects of DOX-GA3 and DOX were compared at equitoxic doses in OVCAR-3 xenografts at a mean tumour size of 125 mm3. The prodrug given i.v. at 500 mg kg–1weekly × 2 resulted in a maximum tumour growth inhibition of 87%, while the standard treatment with DOX at a dose of 8 mg kg–1i.v. weekly × 2 resulted in a maximum tumour growth inhibition of only 56%. Treatment with DOX-GA3 was also given to mice with larger tumours containing more necrosis. For tumours with a mean size of 400 mm3the specific growth delay by DOX-GA3 increased from 2.7 to 3.9. Our data indicate that DOX-GA3 is more effective than DOX and suggest that the prodrug will be specifically advantageous for treatment of advanced disease. © 2001 Cancer Research Campaign http://www.bjcancer.co

Long-term cost-effectiveness of digital inhaler adherence technologies in difficult-to-treat asthma

BACKGROUND: Digital inhalers can monitor inhaler usage, support difficult-to-treat asthma management and inform step-up treatment decisions yet their economic value is unknown, hampering wide-scale implementation.OBJECTIVE: We aimed to assess the long-term cost-effectiveness of digital inhaler-based medication adherence management in difficult-to-treat asthma.METHODS: A model-based cost-utility analysis was performed. The Markov model structure was determined by biological and clinical understanding of asthma and was further informed by guideline-based assessment of model development. Internal and external validation was performed using the AdViSHE tool. The INCA Sun randomized clinical trial data were incorporated into the model to evaluate the cost-effectiveness of digital inhalers. Several long-term clinical case scenarios were assessed (reduced number of exacerbations, increased asthma control, introduction of biosimilars [25% price-cut on biologics]).RESULTS: The long-term modelled cost-effectiveness based on a societal perspective indicated 1-year per-patient costs for digital inhalers and usual care (i.e., regular inhalers) of €7,546 and €10,752, respectively, reflecting cost savings of €3,207 for digital inhalers. Using a 10-year intervention duration and time horizon resulted incost savings of €26,309 for digital inhalers. In the first year, add-on biologic therapies accounted for 69% of the total costs in the usual care group, and for 49% in the digital inhaler group. Scenario analyses indicated consistent cost savings ranging from €2,287 (introduction biosimilars) to €4,581 (increased control, decreased exacerbations).CONCLUSION: In patients with difficult-to-treat asthma, digital inhaler based interventions can be cost-saving on the long-term by optimizing medication adherence and inhaler technique and reducing add-on biologic prescriptions.</p

Long-term cost-effectiveness of digital inhaler adherence technologies in difficult-to-treat asthma

BACKGROUND: Digital inhalers can monitor inhaler usage, support difficult-to-treat asthma management and inform step-up treatment decisions yet their economic value is unknown, hampering wide-scale implementation.OBJECTIVE: We aimed to assess the long-term cost-effectiveness of digital inhaler-based medication adherence management in difficult-to-treat asthma.METHODS: A model-based cost-utility analysis was performed. The Markov model structure was determined by biological and clinical understanding of asthma and was further informed by guideline-based assessment of model development. Internal and external validation was performed using the AdViSHE tool. The INCA Sun randomized clinical trial data were incorporated into the model to evaluate the cost-effectiveness of digital inhalers. Several long-term clinical case scenarios were assessed (reduced number of exacerbations, increased asthma control, introduction of biosimilars [25% price-cut on biologics]).RESULTS: The long-term modelled cost-effectiveness based on a societal perspective indicated 1-year per-patient costs for digital inhalers and usual care (i.e., regular inhalers) of €7,546 and €10,752, respectively, reflecting cost savings of €3,207 for digital inhalers. Using a 10-year intervention duration and time horizon resulted incost savings of €26,309 for digital inhalers. In the first year, add-on biologic therapies accounted for 69% of the total costs in the usual care group, and for 49% in the digital inhaler group. Scenario analyses indicated consistent cost savings ranging from €2,287 (introduction biosimilars) to €4,581 (increased control, decreased exacerbations).CONCLUSION: In patients with difficult-to-treat asthma, digital inhaler based interventions can be cost-saving on the long-term by optimizing medication adherence and inhaler technique and reducing add-on biologic prescriptions.</p

Long-term cost-effectiveness of digital inhaler adherence technologies in difficult-to-treat asthma

BACKGROUND: Digital inhalers can monitor inhaler usage, support difficult-to-treat asthma management and inform step-up treatment decisions yet their economic value is unknown, hampering wide-scale implementation.OBJECTIVE: We aimed to assess the long-term cost-effectiveness of digital inhaler-based medication adherence management in difficult-to-treat asthma.METHODS: A model-based cost-utility analysis was performed. The Markov model structure was determined by biological and clinical understanding of asthma and was further informed by guideline-based assessment of model development. Internal and external validation was performed using the AdViSHE tool. The INCA Sun randomized clinical trial data were incorporated into the model to evaluate the cost-effectiveness of digital inhalers. Several long-term clinical case scenarios were assessed (reduced number of exacerbations, increased asthma control, introduction of biosimilars [25% price-cut on biologics]).RESULTS: The long-term modelled cost-effectiveness based on a societal perspective indicated 1-year per-patient costs for digital inhalers and usual care (i.e., regular inhalers) of €7,546 and €10,752, respectively, reflecting cost savings of €3,207 for digital inhalers. Using a 10-year intervention duration and time horizon resulted incost savings of €26,309 for digital inhalers. In the first year, add-on biologic therapies accounted for 69% of the total costs in the usual care group, and for 49% in the digital inhaler group. Scenario analyses indicated consistent cost savings ranging from €2,287 (introduction biosimilars) to €4,581 (increased control, decreased exacerbations).CONCLUSION: In patients with difficult-to-treat asthma, digital inhaler based interventions can be cost-saving on the long-term by optimizing medication adherence and inhaler technique and reducing add-on biologic prescriptions.</p

Long-term cost-effectiveness of digital inhaler adherence technologies in difficult-to-treat asthma

BACKGROUND: Digital inhalers can monitor inhaler usage, support difficult-to-treat asthma management and inform step-up treatment decisions yet their economic value is unknown, hampering wide-scale implementation.OBJECTIVE: We aimed to assess the long-term cost-effectiveness of digital inhaler-based medication adherence management in difficult-to-treat asthma.METHODS: A model-based cost-utility analysis was performed. The Markov model structure was determined by biological and clinical understanding of asthma and was further informed by guideline-based assessment of model development. Internal and external validation was performed using the AdViSHE tool. The INCA Sun randomized clinical trial data were incorporated into the model to evaluate the cost-effectiveness of digital inhalers. Several long-term clinical case scenarios were assessed (reduced number of exacerbations, increased asthma control, introduction of biosimilars [25% price-cut on biologics]).RESULTS: The long-term modelled cost-effectiveness based on a societal perspective indicated 1-year per-patient costs for digital inhalers and usual care (i.e., regular inhalers) of €7,546 and €10,752, respectively, reflecting cost savings of €3,207 for digital inhalers. Using a 10-year intervention duration and time horizon resulted incost savings of €26,309 for digital inhalers. In the first year, add-on biologic therapies accounted for 69% of the total costs in the usual care group, and for 49% in the digital inhaler group. Scenario analyses indicated consistent cost savings ranging from €2,287 (introduction biosimilars) to €4,581 (increased control, decreased exacerbations).CONCLUSION: In patients with difficult-to-treat asthma, digital inhaler based interventions can be cost-saving on the long-term by optimizing medication adherence and inhaler technique and reducing add-on biologic prescriptions.</p