Economic impact of olaparib on maintenance treatment of patients with BRCA-mutation positive, platinum-sensitive relapsing high-grade serous epithelial ovarian cancer in Spain / Impacto económico de olaparib en el tratamiento de mantenimiento de mujeres con cáncer de ovario epitelial seroso de alto grado en recaída, platino sensibles y con mutación BRCA en España

Objective: To estimate the economic impact of the introduction of olaparib in the Spanish National Health System as maintenance monotherapy in patients with BRCA-mutation positive high-grade serous ovarian cancer. Method: A budget impact model was developed from the Spanish NHS perspective and a time horizon of 5 years for four treatment lines. The model included prevalent and incident patients estimated according to Spanish epidemiological data. Patients moved between treatment lines according to the progression-free survival and overall survival curves obtained from the respective clinical trials. Only direct costs (Euros 2017) were considered: pharmacological, administration, adverse effects and genetic tests. The robustness of the model was verified by a univariate sensitivity analysis. Results: The use of olaparib meant that, after 5 years, 6% fewer patients progressed to later lines compared to scenario without olaparib, remaining longer in the second line and delaying the initiation of subsequent lines. The total estimated budgetary impact ranged between Euros 1.6 and Euros 5.4 million (1-5 years). The economic impact associated to the introduction of olaparib is partially offset by the lower cost of chemotherapy, related adverse events, and palliative care in patients with olaparib than in patients without it. Conclusions: Olaparib as maintenance treatment in patients with BRCA-mutation positive high-grade serous ovarian cancer increases progression-free survival and delays the use of subsequent chemotherapy, with an budgetary impact for the Spanish National Health System of 5.4 million euros after 5 years

Objetivo: Estimar el impacto económico de la introducción de olaparib en el Sistema Nacional de Salud como monoterapia de mantenimiento en pacientes con cáncer de ovario seroso de alto grado y mutación BRCA. Método: Se desarrolló un modelo de impacto presupuestario desde la perspectiva del Sistema Nacional de Salud y un horizonte temporal de cinco años a lo largo de cuatro líneas de tratamiento. El modelo incluye pacientes prevalentes e incidentes estimadas a partir de datos epidemiológicos españoles. Las pacientes se mueven entre las líneas de tratamiento en función de las curvas de supervivencia libre de progresión y supervivencia global obtenidas de los respectivos ensayos clínicos. Solo se consideraron costes directos (Euros 2017): farmacológicos, de administración, efectos adversos y test genéticos. La robustez del modelo se ha comprobado a través de un análisis de sensibilidad univariante. Resultados: El uso de olaparib conllevó que, tras cinco años, un 6% menos de pacientes progresaran a líneas posteriores, en comparación al escenario sin olaparib, permaneciendo más tiempo en segunda línea y retrasando el inicio de líneas subsiguientes. El impacto presupuestario total estimado osciló entre 1,6 y 5,4 millones de euros (1-5 años). Este impacto económico se ve parcialmente compensado por los costes de la quimioterapia, el manejo de sus efectos adversos y los cuidados paliativos, los cuales producen ahorros para el Sistema Nacional de Salud. Conclusiones: Olaparib como tratamiento de mantenimiento en pacientes con cáncer de ovario seroso de alto grado y mutación del gen BRCA aumenta la supervivencia libre de progresión y retrasa la utilización de quimioterapia posteriores, con un impacto presupuestario para el Sistema Nacional de Salud de 5,4 millones de euros tras 5 años

Economic impact of olaparib on maintenance treatment of patients with BRCA-mutation positive, platinum-sensitive relapsing high-grade serous epithelial ovarian cancer in Spain.

OBJECTIVE: To estimate the economic impact of the introduction of olaparib in  the Spanish National Health System as maintenance monotherapy in patients  with BRCA-mutation positive high-grade serous ovarian cancer. METHOD: A budget impact model was developed from the Spanish NHS perspective and a time horizon of 5 years for four treatment lines. The model included prevalent and incident patients estimated according to Spanish epidemiological data. Patients moved between treatment lines according to the progression-free survival and overall survival curves  obtained from the respective clinical trials. Only direct costs (€ 2017) were considered: pharmacological, administration, adverse effects and genetic tests. The robustness of the model was verified by a univariate  sensitivity analysis. RESULTS: The use of olaparib meant that, after 5 years, 6% fewer patients progressed to later lines compared to scenario without olaparib,  remaining longer in the second line and delaying the initiation of subsequent lines. The total estimated budgetary impact ranged between € 1.6  and € 5.4 million (1-5 years). The economic impact associated to the  introduction of olaparib is partially offset by the lower cost of chemotherapy, related adverse events, and palliative care in patients with  olaparib than in patients without it. CONCLUSIONS: Olaparib as maintenance treatment in patients with BRCA-mutation positive high-grade serous ovarian cancer increases progression-free  survival and delays the use of subsequent chemotherapy, with an budgetary  impact for the Spanish National Health System of 5.4 million euros after 5 years.

Objetivo: Estimar el impacto económico de la introducción de olaparib en el  Sistema Nacional de Salud como monoterapia de mantenimiento en pacientes  con cáncer de ovario seroso de alto grado y mutación BRCA.Método: Se desarrolló un modelo de impacto presupuestario desde la  perspectiva del Sistema Nacional de Salud y un horizonte temporal de cinco años a lo largo de cuatro líneas de tratamiento. El modelo incluye pacientes  prevalentes e incidentes estimadas a partir de datos epidemiológicos españoles.  Las pacientes se mueven entre las líneas de tratamiento en función de las curvas de supervivencia libre de progresión y supervivencia global obtenidas de los  respectivos ensayos clínicos. Solo se consideraron costes directos (€ 2017):  farmacológicos, de administración, efectos adversos y test genéticos. La  robustez del modelo se ha comprobado a través de un análisis de sensibilidad  univariante.Resultados: El uso de olaparib conllevó que, tras cinco años, un 6% menos de  pacientes progresaran a líneas posteriores, en comparación al escenario sin  olaparib, permaneciendo más tiempo en segunda línea y retrasando el inicio de  líneas subsiguientes. El impacto presupuestario total estimado osciló entre 1,6 y  5,4 millones de euros (1-5 años). Este impacto económico se ve parcialmente  compensado por los costes de la quimioterapia, el manejo de sus efectos  adversos y los cuidados paliativos, los cuales producen ahorros para el Sistema  Nacional de Salud.Conclusiones: Olaparib como tratamiento de mantenimiento en pacientes con  cáncer de ovario seroso de alto grado y mutación del gen BRCA aumenta la  supervivencia libre de progresión y retrasa la utilización de quimioterapia  posteriores, con un impacto presupuestario para el Sistema Nacional de Salud de  5,4 millones de euros tras 5 año.

Effects of free leucine supplementation and resistance training on muscle strength and functional status in older adults: a randomized controlled trial.

OBJECTIVE: To assess the effect of free leucine supplementation combined with resistance training versus resistance training only on muscle strength and functional status in older adults. METHODS: This was a randomized, double-blind, placebo-controlled, parallel study with two intervention groups. Thirty older adults were randomly assigned to receive either 10 g leucine/day (leucine group [LG], n=15) or a placebo (control group [CG], n=15), plus resistance training over a 12-week period. Maximal overcoming isometric leg strength, functional status, nutritional status, body composition, health-related quality of life, depression, and dietary intake were assessed at 4 and 12 weeks. Missing data at 12 weeks were handled using mixed models for repeated measurements for data imputation. RESULTS: Twenty-four subjects completed the 4-week assessment and eleven completed the 12-week intervention. Clinically significant gains were found in isometric leg strength at both assessment time points. Analysis of the effect size also showed how participants in LG outperformed those in CG for chair stands and the timed up and go test. No significant changes were observed for the rest of the outcomes. CONCLUSION: Our combined analysis showed moderate changes in isometric leg muscle strength and certain components of functional status. The magnitude of changes found on these outcomes should be qualified as a positive effect of the concomitant intervention.

Randomized phase II study comparing gemcitabine plus dacarbazine versus dacarbazine alone in patients with previously treated soft tissue sarcoma: a Spanish Group for Research on Sarcomas study.

PURPOSE: To assess the activity and toxicity of the combination of gemcitabine plus dacarbazine (DTIC) in patients with advanced soft tissue sarcoma (STS) in a randomized, multicenter, phase II study using DTIC alone as a control arm. PATIENTS AND METHODS: Patients with previously treated advanced STS were randomly assigned to receive either fixed-dose rate gemcitabine (10 mg/m2/min) at 1800 mg/m2 followed by DTIC at 500 mg/m2 every 2 weeks, or DTIC alone at 1200 mg/m2 every 3 weeks. The primary end point of the study was progression-free rate (PFR) at 3 months. RESULTS: From November 2005 to September 2008, 113 patients were included. PFR at 3 months was 56% for gemcitabine plus DTIC versus 37% for DTIC alone (P = .001). Median progression-free survival was 4.2 months versus 2 months (hazard ratio [HR], 0.58; 95% CI, 0.39 to 0.86; P = .005), and median overall survival was 16.8 months versus 8.2 months (HR, 0.56; 95% CI, 0.36 to 0.90; P = .014); both favored the arm of gemcitabine plus DTIC. Gemcitabine plus DTIC was also associated with a higher objective response or higher stable disease rate than was DTIC alone (49% v 25%; P = .009). Severe toxicities were uncommon, and treatment discontinuation for toxicity was rare. Granulocytopenia was the more common serious adverse event, but febrile neutropenia was uncommon. Asthenia, emesis, and stomatitis were the most frequent nonhematologic effects. CONCLUSION: The combination of gemcitabine and DTIC is active and well tolerated in patients with STS, providing in this phase II randomized trial superior progression-free survival and overall survival than DTIC alone. This regimen constitutes a valuable therapeutic alternative for these patients.

Activity of a multitargeted chemo-switch regimen (sorafenib, gemcitabine, and metronomic capecitabine) in metastatic renal-cell carcinoma: a phase 2 study (SOGUG-02-06).

BACKGROUND: Maximum tolerated dose (MTD) chemotherapy followed by metronomic chemotherapy (low doses given on a frequent schedule) acts on tumour vascular endothelial cells by increasing the anti-tumour effect of anti-angiogenic agents. This multicentre, phase 2 study investigated the effectiveness of MTD gemcitabine combined with metronomic capecitabine plus the multikinase inhibitor sorafenib for the treatment of metastatic renal-cell carcinoma (RCC). METHODS: Patients were enrolled at eight centres across Spain between Dec 13, 2006, and April 17, 2008. Patients were aged 18 years or older, had confirmed metastatic RCC with clear-cell histology, had an Eastern Cooperative Oncology Group performance status of 0 or 1, had not undergone previous therapy, and were unsuitable for, or intolerant to, immunotherapy. Treatment consisted of intravenous gemcitabine 1000 mg/m(2) (days 1 and 8), oral capecitabine 500 mg/m(2) twice a day (final dose after adjustment, days 1-14), and oral sorafenib 400 mg twice a day (days 1-21), for six cycles, followed by sorafenib monotherapy (at the investigator's discretion if clinical benefit was maintained). The primary endpoint was median progression-free survival (PFS) analysed in a population of all patients who received treatment. The trial is registered with ClinicalTrials.gov, number NCT00496301. FINDINGS: 44 patients enrolled in the study, 40 of whom received treatment. Median PFS for these patients was 11.1 months (95% CI 7.9-17.1). A partial response was achieved in 20 patients, and stable disease in 17 patients. Most adverse events were grade 1 or 2. Grade 3 adverse events were fatigue or asthenia (n=9), hand-foot skin reaction (n=11), mucositis (n=3), diarrhoea (n=2), infection (n=2), and allergic reaction, hypertension, and rash (all n=1). Grade 3 haematological toxicity was noted in nine patients. One death due to pulmonary embolism was reported as grade 5 dyspnoea possibly related to study drug. INTERPRETATION: PFS and response rates were greater than those previously observed with gemcitabine and capecitabine or sorafenib monotherapy in patients with metastatic RCC. Adverse events were manageable in most patients. These findings provide preliminary confirmation of the synergistic activity of the chemo-switch concept seen in preclinical studies, and merit further exploration. FUNDING: Spanish Oncology Genitourinary Group (SOGUG).

Efficacy of sequential high-dose doxorubicin and ifosfamide compared with standard-dose doxorubicin in patients with advanced soft tissue sarcoma: an open-label randomized phase II study of the Spanish group for research on sarcomas.

PURPOSE: To assess the progression-free survival (PFS) and antitumor response to standard-dose doxorubicin compared with sequential dose-dense doxorubicin and ifosfamide in first-line treatment of advanced soft tissue sarcoma. PATIENTS AND METHODS: Patients with measurable advanced soft tissue sarcoma, Eastern Cooperative Oncology Group (ECOG) performance status (PS) < 2, between the ages 18 and 65 years, and with adequate bone marrow, liver, and renal function were entered in the study. The stratifications were: ECOG PS (0 v 1), location of metastases, and potentially resectable disease. Patients were randomly assigned to either doxorubicin 75 mg/m(2) given as a bolus injection every 3 weeks for 6 cycles (arm A) or doxorubicin at 30 mg/m(2) per day for 3 consecutive days once every 2 weeks for 3 cycles followed by ifosfamide at 12.5 g/m(2) delivered by continuous infusion over 5 days once every 3 weeks for 3 cycles with filgastrim or pegfilgastrim support (arm B). RESULTS: Between December 2003 and September 2007, 132 patients were entered onto the study. Febrile neutropenia, asthenia, and mucositis were more frequent in the arm B. The interim preplanned analysis for futility allowed the premature closure. Objective responses were observed in 23.4% of assessable patients in arm A and 24.1% in arm B. PFS was 26 weeks in the arm A and 24 weeks in arm B (P = .88). Overall survival did not differ between the two therapeutic arms (P = .14). CONCLUSION: Single-agent doxorubicin remains the standard treatment in fit patients with advanced soft tissue sarcoma.

Phase II study of weekly Kahalalide F in patients with advanced malignant melanoma.

This phase II clinical trial evaluated the antitumour response of Kahalalide F (KF) 650 microg/m(2) given as a 1-h weekly infusion in advanced malignant melanoma patients, both untreated and those who relapsed or progressed after one line of systemic therapy. Of 24 enrolled patients (median age, 55 years; range, 28-89), 14 patients had been previously treated with chemotherapy or biological therapy. No RECIST responses occurred; five chemotherapy-naïve patients with cutaneous melanoma had disease stabilisation for > or = 3 months; median progression-free survival was 1.7 months (95% CI, 1.2-1.9 months); and median overall survival was 10.8 months (95% CI, 5.0-upper limit not reached). The most common laboratory toxicities were non-cumulative increase of transaminases (ALT/AST) and gamma-glutamyltransferase (GGT). No patients experienced leukopenia and thrombocytopenia during the study. KF was a well-tolerated and safe chemotherapy regimen. Despite a favourable safety profile, this trial was closed after the first stage because of the lack of objective response in patients with malignant melanoma.