Time to deterioration of patient-reported outcomes in non-small cell lung cancer: exploring different definitions.

PURPOSE: The clinical relevance of different time-to-deterioration (TTD) definitions for patient-reported outcomes were explored. METHODS: TTD definitions differing by reference score and deterioration event were used to analyse data from the phase 3 FLAURA trial of first-line osimertinib versus erlotinib or gefitinib in patients with EGFR-mutated advanced non-small cell lung cancer. Pre-specified key symptoms were fatigue, appetite loss, cough, chest pain and dyspnoea, scored using the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-LC13 questionnaires (≥ 10-point difference = clinically relevant). RESULTS: No significant treatment differences in TTD (distributions) were observed using definitions based on transient or definitive deterioration alone. TTD definitions based on definitive, sustained deterioration, with death not included as an event, yielded a significant treatment difference for dyspnoea (hazard ratio [HR] 0.71; P = 0.034) when baseline was the reference, and for cough (HR 0.70; P = 0.009) and dyspnoea (HR 0.71; P = 0.004) when best previous score was the reference. With death included as an event, treatment differences were significant for dyspnoea (HR 0.70; P = 0.025) when baseline was the reference, and for cough (HR 0.70; P = 0.011), dyspnoea (HR 0.71; P = 0.003) and chest pain (HR 0.71; P = 0.038) when best previous score was the reference. Irrespective of definition, TTD for appetite loss and fatigue did not differ significantly between arms. CONCLUSION: This exploratory work showed that different TTD definitions yield different magnitudes of treatment difference, highlighting the importance of pre-specifying TTD definitions upfront in clinical trials. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02296125.

Targeted literature review of the global burden of gastric cancer.

Gastric cancer (GC) and gastroesophageal junction cancers (GEJCs) are the third leading cause of cancer-related death worldwide. Although several studies have evaluated the epidemiology and management of GC and GEJC, to our knowledge, no global estimates of the economic burden of GC and GEJC have yet been reported. This targeted literature review was conducted to summarise the epidemiology and management of GC and GEJC and to estimate its global economic and humanistic burden. The incidence of GC and GEJC is highest in Eastern Asia, several South and Central American countries and Central and Eastern Europe and lowest in North America and Africa. Prognosis is generally poor; the global 5-year survival rate is 5%-10% in advanced stages. Patients with GC and GEJC have more severe symptoms compared with patients with other cancers, and health-related quality of life (HRQoL) worsens as the disease progresses. Given the rapid progression of GC and GEJC at advanced stages, chemotherapy, despite its toxicity, improves HRQoL compared with best supportive care. The costs of GC/GEJC are generally higher than for other cancers; in the US, the average annual cost per patient between 1998 and 2003 was 46,501 USD, compared with 29,609 USD and 35,672 USD for colorectal and lung cancer, respectively. Based on the 2012 incidence data and average costs per patient, estimates of the annual financial burden of GC and GEJC revealed great regional differences. Japan and Iran had the highest (8,492 million USD) and lowest (27 million USD) costs for 2017, respectively, while the estimate for the US was 3,171 million USD. The overall annual cost of GC and GEJC estimated for 2017 in a geographic area including Europe (France, Germany, Italy, Spain and the UK), Asia (Iran, Japan and China), North America (Canada and the US) and Australia was 20.6 billion USD.

Administration of intravenous morphine for acute pain in the emergency department inflicts an economic burden in Europe.

BACKGROUND: Acute pain is among the leading causes of referral to the emergency department (ED) in industrialized countries. Its management mainly depends on intensity. Moderate-to-severe pain is treated with intravenous (IV) administered opioids, of which morphine is the most commonly used in the ED. We have estimated the burden of IV administration of morphine in the five key European countries (EU5) using a micro-costing approach. SCOPE: A structured literature review was conducted to identify clinical guidelines for acute pain management in EU5 and clinical studies conducted in the ED setting. The data identified in this literature review constituted the source for all model input parameters, which were clustered as analgesic (morphine), material used for IV morphine administration, nurse workforce time and management of morphine-related adverse events and IV-related complications. FINDINGS: The cost per patient of IV morphine administration in the ED ranges between €18.31 in Spain and €28.38 in Germany. If costs associated with the management of morphine-related adverse events and IV-related complications are also considered, the total costs amount to €121.13-€132.43. The main driver of those total costs is the management of IV-related complications (phlebitis, extravasation and IV prescription errors; 73% of all costs) followed by workforce time (14%). CONCLUSIONS: IV morphine provides effective pain relief in the ED, but the costs associated with the IV administration inflict an economic burden on the respective national health services in EU5. An equally rapid-onset and efficacious analgesic that does not require IV administration could reduce this burden.

"De-escalation" strategy using micafungin for the treatment of systemic Candida infections: budget impact in France and Germany.

BACKGROUND: The incidence of azole-resistant Candida infections is increasing. Consequently, guidelines for treating systemic Candida infection (SCI) recommend a "de-escalation" strategy: initial broad-spectrum antifungal agents (e.g., echinocandins), followed by switching to fluconazole if isolates are fluconazole sensitive, rather than "escalation" with initial fluconazole treatment and then switching to echinocandins if isolates are fluconazole resistant. However, fluconazole may continue to be used as first-line treatment in view of its low acquisition costs. The aim of this study was, therefore, to evaluate the budget impact of the de-escalation strategy using micafungin compared with the escalation strategy in France and Germany. METHODS: A budget impact model was used to compare de-escalation to escalation strategies. As well as survival, clinical success (resolution/reduction of symptoms and radiographic abnormalities associated with fungal infection), was considered, as was mycological success (eradication of Candida from the bloodstream). Health economic outcomes included cost per health state according to clinical success and mycological success, and budget impact. A 42-day time horizon was used. RESULTS: For all patients with SCI, the budget impact of using de-escalation rather than escalation was greater, but improved rates of survival, clinical success and mycological success were apparent with de-escalation. In patients with fluconazole-resistant isolates, clinical success rates and survival were improved by ~72% with de-escalation versus escalation, producing cost savings of €6,374 and €356 per patient in France and Germany, respectively; improvements of ~72% in mycological success rates with de-escalation versus escalation did not translate into cost savings. CONCLUSION: Modeling provides evidence that when treating SCI in individuals at risk of azole-resistant infections, de-escalation from micafungin has potential cost savings associated with improved clinical success rates.

Economic Evaluation of Fidaxomicin for the Treatment of Clostridium Difficile Infection (C. difficile-associated diarrhoea) in Ireland.

Background: Clostridium difficile is associated with 20-30% of cases of antibiotic-associated diarrhoea. The incidence of C. difficile infection (CDI) is higher in Ireland than in other countries in Europe, and it is associated with considerable morbidity. Previously recommended standard therapeutic options were vancomycin and metronidazole, but the macrocyclic antibiotic fidaxomicin has recently been recommended for use in adults with CDI in Ireland. Objectives: To perform a cost-utility analysis of fidaxomicin compared to oral metronidazole (used to treat initial non-severe disease and first non-severe recurrence) and oral vancomycin (used to treat severe disease and any non-severe recurrence beyond the first) for the treatment of CDI. Methods: A Markov model was used to determine the cost-utility of fidaxomicin in the treatment of all adult CDI patients (base case), patients with severe CDI and patients with initial CDI recurrences, respectively. Patients enter the model in the CDI health state and are treated either with fidaxomicin or current standard of care (oral metronidazole for non-severe CDI; vancomycin for severe CDI) for 10 days. The time horizon was 1 year. Deterministic and probabilistic sensitivity analyses were performed. Health state utilities were derived from the literature. The perspective was that of the Irish Health Service Executive (HSE). Results: In the base case, fidaxomicin was dominant to current standard-of-care therapy, with cost savings of €2,904 and incremental quality-adjusted life year (QALY) gain of 0.031. The main drivers of costeffectiveness were recurrence rates and cost of hospitalization. Fidaxomicin was also dominant for all patient subgroups. The probability of fidaxomicin being cost-effective in all patients with CDI at a willingness to pay threshold of €45,000 per QALY gained was 82%. Conclusion: Fidaxomicin was dominant to the current standard-of-care therapy for CDI. Based on this analysis, fidaxomicin has received reimbursement for CDI treatment under the High Tech Drug Scheme in Ireland.

De-escalation from micafungin is a cost-effective alternative to traditional escalation from fluconazole in the treatment of patients with systemic Candida infections.

BACKGROUND: Systemic Candida infections (SCI) occur predominantly in intensive care unit patients and are a common cause of morbidity and mortality. Recently, changes in Candida epidemiology with an increasing prevalence of SCI caused by Candida non-albicans species have been reported. Resistance to fluconazole and azoles in general is not uncommon for non-albicans species. Despite guidelines recommending initial treatment with broad-spectrum antifungals such as echinocandins with subsequent switch to fluconazole if isolates are sensitive (de-escalation strategy), fluconazole is still the preferred first-line antifungal (escalation) in many clinical practice settings. After diagnosis of the pathogen, the initial therapy with fluconazole is switched to a broad-spectrum antifungal if a non-albicans is identified. METHODS: The cost-effectiveness of initial treatment with micafungin (de-escalation) vs fluconazole (escalation) in patients with SCI was estimated using decision analysis based on clinical and microbiological data from pertinent studies. The model horizon was 42 days, and was extrapolated to cover a lifetime horizon. All costs were analyzed from the UK NHS perspective. Several assumptions were taken to address uncertainties; the limitations of these assumptions are discussed in the article. RESULTS: In patients with fluconazole-resistant isolates, initial treatment with micafungin avoids 30% more deaths and successfully treats 23% more patients than initial treatment with fluconazole, with cost savings of £1621 per treated patient. In the overall SCI population, de-escalation results in 1.2% fewer deaths at a marginal cost of £740 per patient. Over a lifetime horizon, the incremental cost-effectiveness of de-escalation vs escalation was £15,522 per life-year and £25,673 per QALY. CONCLUSIONS: De-escalation from micafungin may improve clinical outcomes and overall survival, particularly among patients with fluconazole-resistant Candida strains. De-escalation from initial treatment with micafungin is a cost-effective alternative to escalation from a UK NHS perspective, with a differential cost per QALY below the 'willingness-to-pay' threshold of £30,000.