Durvalumab plus tremelimumab in advanced or metastatic soft tissue and bone sarcomas: a single-centre phase 2 trial.

BACKGROUND: Few standard treatment options are available for patients with metastatic sarcomas. We did this trial to evaluate the efficacy, safety, and changes in the tumour microenvironment for durvalumab, an anti-PD-L1 drug, and tremelimumab, an anti-CTLA-4 drug, across multiple sarcoma subtypes. METHODS: In this single-centre phase 2 trial, done at The University of Texas MD Anderson Cancer Center (Houston, TX USA), patients aged 18 years or older with advanced or metastatic sarcoma with an Eastern Cooperative Oncology Group performance status of 0 or 1 who had received at least one previous line of systemic therapy were enrolled in disease subtype-specific groups (liposarcoma, leiomyosarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma, synovial sarcoma, osteosarcoma, alveolar soft-part sarcoma, chordoma, and other sarcomas). Patients received 1500 mg intravenous durvalumab and 75 mg intravenous tremelimumab for four cycles, followed by durvalumab alone every 4 weeks for up to 12 months. The primary endpoint was progression-free survival at 12 weeks in the intention-to-treat population (all patients who received at least one dose of treatment). Safety was also analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02815995, and is completed. FINDINGS: Between Aug 17, 2016, and April 9, 2018, 62 patients were enrolled, of whom 57 (92%) received treatment and were included in the intention-to-treat population. With a median follow-up of 37·2 months (IQR 1·8-10·1), progression-free survival at 12 weeks was 49% (95% CI 36-61). 21 grade 3-4 treatment-related adverse events were reported, the most common of which were increased lipase (four [7%] of 57 patients), colitis (three [5%] patients), and pneumonitis (three [5%] patients). Nine (16%) patients had a treatment related serious adverse event. One patient had grade 5 pneumonitis and colitis. INTERPRETATION: The combination of durvalumab and tremelimumab is an active treatment regimen for advanced or metastatic sarcoma and merits evaluation in specific subsets in future trials. FUNDING: AstraZeneca.

Lag3: From Bench to Bedside.

The introduction of immune checkpoint inhibitors represented a breakthrough treatment for metastatic melanoma, but the effect of these agents is not limited to a single cancer type. Promising results have been reported in various solid tumors, for example, lung cancer. The success of these drugs depends on the activation of tumor-infiltrating lymphocytes and primary and acquired resistance have been reported alongside a high rate of immune-related adverse events when agents targeting different immune checkpoints are given in combination. Numerous other targets have been investigated to overcome the resistance, improve the activity, and reduce the toxicity of checkpoint inhibitor therapy. Among these, the most promising is Lymphocyte-activation gene 3 (LAG-3), a transmembrane protein involved in cytokine release and inhibitory signaling in T cells. Preclinical data showed that LAG-3 is a negative regulator of both CD4+ T cell and CD8+ T cell and the activity on CD8+ T cell is independent of CD4+ activation. On the CD8+ T cell, LAG-3 activation abrogates the antigen presentation whereas on the CD4+ T cell, arrests the S phase of the cell cycle. The blockade of LAG-3 has been tested in several combination therapies, and recent clinical data showed a good safety profile and a synergistic effect with anti-PD-1, suggesting that this combination could become a standard treatment for metastatic melanoma. In this review, we report the available preclinical data and the new clinical data on LAG-3 blockade in different solid tumors, and we discuss LAG-3 as potential prognostic and predictive factor, together with possible future applications.

The efficacy of placebo for the treatment of cancer-related fatigue: a systematic review and meta-analysis.

PURPOSE: Cancer-related fatigue (CRF) is a common symptom among patients with cancer. The efficacy of placebo, however, was never the main objective of any meta-analysis. Predicting the efficacy of placebo may facilitate researchers in designing future clinical trials for the treatment of CRF. METHODS: We performed a systematic review searching for prospective clinical trials comparing any treatment versus placebo for the treatment of CRF. We included studies that enrolled patients with any primary site of neoplasia and any stage of cancer. We excluded all studies that assessed fatigue related to any treatment. The primary endpoint of this study is the mean effect of placebo on fatigue according to the Functional Assessment of Chronic Illness (FACIT-F) and Brief Fatigue Inventory (BFI) scales. The secondary endpoint was the proportion of patients who reported improvement in fatigue (response rate). RESULTS: We found 520 studies, and 29 studies with 3758 participants were included in the meta-analysis. Placebo had a mean effect of + 4.88 (95%CI + 2.45 to + 7.29) using the FACIT-F scale, although it was statistically worse than the interventions studied (p = 0.005). Using the BFI scale, placebo had an average effect of + 0.64 (95%CI + 0.02 to + 1.30), although it was also worse than the other interventions studied (p = 0.002). In terms of the response rate, 29% (95%CI 25-32%) of patients taking a placebo reported a significant improvement in CRF compared with 36% of patients treated with other interventions (p = 0.030). CONCLUSIONS: Placebo treatments had a significant effect on CRF, and predicting these effects may help design future studies for CRF.

Definitive chemoradiotherapy for squamous head and neck cancer: cisplatin versus carboplatin? A meta-analysis.

AIM: Concomitant chemoradiotherapy (with cisplatin or carboplatin) is an option of definitive treatment for squamous head and neck cancer. We aimed to perform a meta-analysis comparing those two platinum agents. MATERIALS & METHODS: We carried out a systematic search on English literature between 1990 and 17 April 2015 according to the Cochrane review guidelines. RESULTS: Five of 60 studies fulfilled inclusion criteria with 491 patients. There was no difference in response rate. Cisplatin tends to be more active systemically than carboplatin, without statistically significance; 5-year survival rate: 30 and 27%, respectively (p = 0.33). CONCLUSION: Despite the trend to improved outcomes in using cisplatin, carboplatin is also active and can be a reasonable option to treat patients.

Strategies for mitigating adverse events related to selective RET inhibitors in patients with RET-altered cancers.

The US Food and Drug Administration (FDA) approval of the selective RET inhibitors selpercatinib and pralsetinib has led to a paradigm change in the treatment of RET-altered lung and thyroid cancers through a higher response rate and a more tolerable safety and toxicity profile than multi-kinase inhibitors. Recently, selpercatinib has received a tissue-agnostic FDA approval for all RET-fusion-positive cancers, and pralsetinib has shown pan-cancer activity as well. Given the anticipated increase in the use of both drugs across multiple tumor types, it is crucial to recognize the possible side effects and approaches for their optimal management in order to maximize the clinical benefit for treated patients. In this review, we underscore potential toxicities associated with selective RET inhibitors and discuss strategies to mitigate them.

The immune landscape of undifferentiated pleomorphic sarcoma.

Introduction: Undifferentiated pleomorphic sarcoma (UPS) can be associated with a relatively dense immune infiltration. Immune checkpoint inhibitors (anti-PD1, anti-PDL1, and anti-CTLA4) are effective in 20% of UPS patients. We characterize the immune microenvironment of UPS and its association with oncologic outcomes. Material and methods: Surgically resected UPS samples were stained by immunohistochemistry (IHC) for the following: tumor-associated immune cells (CD3, CD8, CD163, CD20), immune checkpoints (stimulatory: OX40, ICOS; inhibitory: PD-L1, LAG3, IDO1, PD1), and the adenosine pathway (CD73, CD39). Sections were reviewed for the presence of lymphoid aggregates (LA). Clinical data were retrospectively obtained for all samples. The Wilcoxon rank-sum and Kruskal-Wallis tests were used to compare distributions. Correlations between biomarkers were measured by Spearman correlation. Univariate and multivariate Cox models were used to identify biomarkers associated with overall survival (OS) and disease-free survival (DFS). Unsupervised clustering was performed, and Kaplan-Meier curves and log-rank tests used for comparison of OS and DFS between immune clusters. Results: Samples analyzed (n=105) included 46 primary tumors, 34 local recurrences, and 25 metastases. LA were found in 23% (n=10/43), 17% (n=4/24), and 30% (n=7/23) of primary, recurrent, and metastatic samples, respectively. In primary UPS, CD73 expression was significantly higher after preoperative radiation therapy (p=0.009). CD39 expression was significantly correlated with PD1 expression (primary: p=0.002, recurrent: p=0.004, metastatic: p=0.001), PD-L1 expression (primary: p=0.009), and CD3+ cell densities (primary: p=0.016, recurrent: p=0.043, metastatic: p=0.028). In recurrent tumors, there was a strong correlation between CD39 and CD73 (p=0.015), and both were also correlated with CD163+ cell densities (CD39 p=0.013; CD73 p<0.001). In multivariate analyses, higher densities of CD3+ and CD8+ cells (Cox Hazard Ratio [HR]=0.33; p=0.010) were independently associated with OS (CD3+, HR=0.19, p<0.001; CD8+, HR= 0.33, p=0.010) and DFS (CD3+, HR=0.34, p=0.018; CD8+, HR=0.34, p= 0.014). Unsupervised clustering of IHC values revealed three immunologically distinct clusters: immune high, intermediate, and low. In primary tumors, these clusters were significantly associated with OS (log-rank p<0.0001) and DFS (p<0.001). Conclusion: We identified three immunologically distinct clusters of UPS Associated with OS and DFS. Our data support further investigations of combination anti-PD-1/PD-L1 and adenosine pathway inhibitors in UPS.

Identification of distinct immune landscapes using an automated nine-color multiplex immunofluorescence staining panel and image analysis in paraffin tumor tissues.

Immune profiling is becoming a vital tool for identifying predictive and prognostic markers for translational studies. The study of the tumor microenvironment (TME) in paraffin tumor tissues such as malignant pleural mesothelioma (MPM) could yield insights to actionable targets to improve patient outcome. Here, we optimized and tested a new immune-profiling method to characterize immune cell phenotypes in paraffin tissues and explore the co-localization and spatial distribution between the immune cells within the TME and the stromal or tumor compartments. Tonsil tissues and tissue microarray (TMA) were used to optimize an automated nine-color multiplex immunofluorescence (mIF) panel to study the TME using eight antibodies: PD-L1, PD-1, CD3, CD8, Foxp3, CD68, KI67, and pancytokeratin. To explore the potential role of the cells into the TME with this mIF panel we applied this panel in twelve MPM cases to assess the multiple cell phenotypes obtained from the image analysis and well as their spatial distribution in this cohort. We successful optimized and applied an automated nine-color mIF panel to explore a small set of MPM cases. Image analysis showed a high degree of cell phenotype diversity with immunosuppression patterns in the TME of the MPM cases. Mapping the geographic cell phenotype distribution in the TME, we were able to identify two distinct, complex immune landscapes characterized by specific patterns of cellular distribution as well as cell phenotype interactions with malignant cells. Successful we showed the optimization and reproducibility of our mIF panel and their incorporation for comprehensive TME immune profiling into translational studies that could refine our ability to correlate immunologic phenotypes with specific patterns of cells distribution and distance analysis. Overall, this will improve our ability to understand the behavior of cells within the TME and predict new treatment strategies to improve patient outcome.

Hypotensive activity of terpenes found in essential oils.

The cardiovascular activity of essential oils has been reported. Some studies showed that the main chemical components of these oils contribute to their pharmacological activity. Therefore, the cardiovascular activity of four monoterpenes and one sesquiterpene was evaluated in the present work. In non-anaesthetized normotensive rats, (+)-alpha-pinene, (-)-beta-pinene, (+/-)-citronellol and (+/-)-linalool (1, 5, 10, and 20 mg/kg, i.v.) induced hypotension [maximal effect: (-35 +/- 3)%, (-46 +/- 4)%, (-48 +/- 2)% and (-40 +/- 2)%, respectively; n=6] and tachycardia [maximal effect: (13 +/- 4)%, (16 +/- 7)%, (21 +/- 1)% and (19 +/- 3)%, respectively; n=6] while (-)-a-bisabolol (1, 5, 10, and 20 mg/kg, i.v.) induced hypotension [maximal effect: (-47 +/- 8)%, n=6] and bradycardia [maximal effect: (-57 +/- 3)%]. In conclusion, these results demonstrated that all terpenes tested had hypotensive activity in rats and that the pharmacological effect of the terpene alcohols was more effective than that of the terpene hydrocarbons.

In the Era of Cost-Effectiveness Analysis, Affordability Is a Limiting Factor for Patients' Access to Innovative Cancer Treatments.

BACKGROUND: Over the past 5 years, 55 new anticancer drugs have been launched worldwide. Considering the increasing costs of innovative treatments, both the number and the relevance of cost-effectiveness analyses have increased, meaningfully supporting decision making by stakeholders and policy makers. Notably, cost-effective treatments remain unavailable to patients because they are still unaffordable for a multitude of payers. OBJECTIVES: To discuss the differences between cost-effectiveness and affordability. METHODS: We reviewed the most relevant data on the divergences between cost-effectiveness and affordability. In addition, we included our recommendations to improve patients' access to innovative cancer therapies. RESULTS: The increasing costs of recently launched antineoplastic drugs, as high as $150 000 per year, represent a major barrier to patients' access to treatments globally. In Brazil, for example, patients' access to innovative treatments depends greatly on whether the individual has private health insurance. In the public health sector, patients' access to cost-effective innovative treatments varies according to the financial capacity of the facility, leading to inequalities within the same healthcare system. CONCLUSIONS: We conclude that because of the socioeconomic inequality mostly seen in lower and middle-income countries, it is difficult to define a cost-effectiveness threshold by region or a willingness-to-pay threshold affordable to the entire population. We consider that benchmark interventions might help to find an affordable willingness-to-pay threshold, and league table interventions might help policy makers, physicians, and the society to share the decision making.

Potential life years not saved due to lack of access to anti-EGFR tyrosine kinase inhibitors for lung cancer treatment in the Brazilian public healthcare system: Budget impact and strategies to improve access. A pharmacoeconomic study.

BACKGROUND: Lung cancer is the fourth most common cancer in Brazil. In the 2000s, better understanding of molecular pathways led to development of epidermal growth factor receptor (EGFR)-targeted treatments that have improved outcomes. However, these treatments are unavailable in most Brazilian public healthcare services (Sistema Único de Saúde, SUS). OBJECTIVE: To assess the potential number of years of life not saved, the budget impact of the treatment and strategies to improve access. DESIGN AND SETTING: Pharmacoeconomic study assessing the potential societal and economic impact of adopting EGFR-targeted therapy within SUS. METHODS: We estimated the number of cases eligible for treatment, using epidemiological data from the National Cancer Institute. We used data from a single meta-analysis and from the Lung Cancer Mutation Consortium (LCMC) study as the basis for assessing differences in patients' survival between use of targeted therapy and use of chemotherapy. The costs of targeted treatment were based on the national reference and were compared with the amount reimbursed for chemotherapy through SUS. RESULTS: There was no life-year gain with EGFR-targeted therapy in the single meta-analysis (hazard ratio, HR, 1.01). The LCMC showed that 1,556 potential life-years were not saved annually. We estimated that the annual budget impact was 125 million Brazilian reais (BRL) with erlotinib, 48 million BRL with gefitinib and 52 million BRL with afatinib. Their incremental costs over chemotherapy per life-year saved were 80,329 BRL, 31,011 BRL and 33,225 BRL, respectively. A drug acquisition discount may decrease the budget impact by 30% (with a 20% discount). A fixed cost of 1,000 BRL may decrease the budget impact by 95%. CONCLUSION: Reducing drug acquisition costs may improve access to EGFR-targeted therapy for lung cancer.

Cost-effectiveness analysis of abiraterone, docetaxel or placebo plus androgen deprivation therapy for hormone-sensitive advanced prostate cancer.

OBJECTIVE: To evaluate the cost-effectiveness of the addition of chemotherapy or abiraterone to androgen deprivation. METHODS: We developed an analytical model to determine the cost-effectiveness of the addition of docetaxel or abiraterone versus androgen deprivation therapy alone. Direct and indirect costs were included in the model. The effects were expressed in Quality-Adjusted Life Years adjusted for side effects. RESULTS: Compared to androgen deprivation therapy alone, the addition of chemotherapy and of abiraterone generated 0.492 and 0.999, respectively, in Quality-Adjusted Life Years. Abiraterone led to a Quality-Adjusted Life Years gain of 0.506 compared to docetaxel. The incremental costs per Quality-Adjusted Life Years were R$ 133.649,22 for docetaxel, R$ 330.828,70 for abiraterone and R$ 571.379,42 for abiraterone compared to docetaxel, respectively. CONCLUSION: The addition of chemotherapy to androgen deprivation therapy is more cost-effective than the addition of abiraterone to androgen deprivation therapy. However, discounts on abiraterone cost might improve cost-effectiveness.

A paradigm shift for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer: a review of CDK inhibitors.

In the last 3 years, a novel class of targeted therapy has been approved for patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer. There are currently three approved agents, which are oral cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. All of the approved drugs exhibit progression-free survival benefit when compared to standard of care and generally have less adverse events compared to traditional chemotherapeutic options. The treatment of HR+/HER2- advanced breast cancer is a continuously evolving landscape, and the addition of CDK4/6 inhibitors is the newest mechanism for treatment. In this review, we summarize all available data, highlight the unanswered questions, and discuss pharmacological differences between each CDK4/6 inhibitor.

Cost effectiveness of chemohormonal therapy in patients with metastatic hormone-sensitive and non-metastatic high-risk prostate cancer.

OBJECTIVE: To assess the cost-effectiveness of chemohormonal therapy in patients with metastatic hormone-sensitive and non-metastatic high-risk prostate cancer. METHODS: An analytical decision model was developed to determine the cost-effectiveness of chemohormonal therapy versus androgen deprivation therapy alone in patients with metastatic hormone-sensitive prostate cancer and patients with non-metastatic high-risk prostate cancer. The cost-effectiveness in metastatic patients with a high-volume disease was assessed separately. The model used data from randomized clinical trials and drug acquisition costs in Brazil. In addition, the costs of post-progression therapies have been included in this model. The benefits to health are expressed as the quality-adjusted life-years, and the incremental cost-effectiveness ratios were calculated. RESULTS: Chemohormonal therapy may be associated with improved quality-adjusted life-years for all patient. The improvement was more than six times greater for patients with high-volume metastatic disease. In these patients, the incremental cost-effectiveness ratios were up to 74% lower than the incremental cost-effectiveness ratios of patients with non-metastatic disease. CONCLUSION: Chemohormonal therapy has been more cost-effective in patients with high-volume metastatic disease.

Immune checkpoint inhibitors for advanced non-small cell lung cancer: emerging sequencing for new treatment targets.

Lung cancer is the leading cause of cancer-related deaths in the world. Immune checkpoint inhibitors (ICI) stimulate cytotoxic lymphocyte activity against tumour cells. These agents are available for the treatment of non-small cell lung cancer (NSCLC) after failure of platinum-based therapy. One recent study has demonstrated that ICI monotherapy was superior to platinum-based chemotherapy for first-line treatment. Nevertheless, this benefit was only for a minority of the population (30%) whose tumour programmed death receptor ligand-1 (PD-L1) expression was above 50%. Therefore, several strategies are under investigation. One option for patients with PD-L1 expression lower than 50% may be the combination of ICI with platinum-based chemotherapy or with ICIs against different targets. However, all of these combinations are at an early stage of investigation and may be very expensive or toxic, producing several harmful adverse events.

Potential life years not saved due to lack of access to anti-EGFR tyrosine kinase inhibitors for lung cancer treatment in the Brazilian public healthcare system: Budget impact and strategies to improve access. A pharmacoeconomic study

ABSTRACT BACKGROUND: Lung cancer is the fourth most common cancer in Brazil. In the 2000s, better understanding of molecular pathways led to development of epidermal growth factor receptor (EGFR)-targeted treatments that have improved outcomes. However, these treatments are unavailable in most Brazilian public healthcare services (Sistema Único de Saúde, SUS). OBJECTIVE: To assess the potential number of years of life not saved, the budget impact of the treatment and strategies to improve access. DESIGN AND SETTING: Pharmacoeconomic study assessing the potential societal and economic impact of adopting EGFR-targeted therapy within SUS. METHODS: We estimated the number of cases eligible for treatment, using epidemiological data from the National Cancer Institute. We used data from a single meta-analysis and from the Lung Cancer Mutation Consortium (LCMC) study as the basis for assessing differences in patients' survival between use of targeted therapy and use of chemotherapy. The costs of targeted treatment were based on the national reference and were compared with the amount reimbursed for chemotherapy through SUS. RESULTS: There was no life-year gain with EGFR-targeted therapy in the single meta-analysis (hazard ratio, HR, 1.01). The LCMC showed that 1,556 potential life-years were not saved annually. We estimated that the annual budget impact was 125 million Brazilian reais (BRL) with erlotinib, 48 million BRL with gefitinib and 52 million BRL with afatinib. Their incremental costs over chemotherapy per life-year saved were 80,329 BRL, 31,011 BRL and 33,225 BRL, respectively. A drug acquisition discount may decrease the budget impact by 30% (with a 20% discount). A fixed cost of 1,000 BRL may decrease the budget impact by 95%. CONCLUSION: Reducing drug acquisition costs may improve access to EGFR-targeted therapy for lung cancer.

Cost-effectiveness analysis of abiraterone, docetaxel or placebo plus androgen deprivation therapy for hormone-sensitive advanced prostate cancer / Análise de custo-efetividade da adição de abiraterona ou quimioterapia ao tratamento do câncer de próstata metastático hormônio-sensível

ABSTRACT Objective To evaluate the cost-effectiveness of the addition of chemotherapy or abiraterone to androgen deprivation. Methods We developed an analytical model to determine the cost-effectiveness of the addition of docetaxel or abiraterone versus androgen deprivation therapy alone. Direct and indirect costs were included in the model. The effects were expressed in Quality-Adjusted Life Years adjusted for side effects. Results Compared to androgen deprivation therapy alone, the addition of chemotherapy and of abiraterone generated 0.492 and 0.999, respectively, in Quality-Adjusted Life Years. Abiraterone led to a Quality-Adjusted Life Years gain of 0.506 compared to docetaxel. The incremental costs per Quality-Adjusted Life Years were R$ 133.649,22 for docetaxel, R$ 330.828,70 for abiraterone and R$ 571.379,42 for abiraterone compared to docetaxel, respectively. Conclusion The addition of chemotherapy to androgen deprivation therapy is more cost-effective than the addition of abiraterone to androgen deprivation therapy. However, discounts on abiraterone cost might improve cost-effectiveness.

RESUMO Objetivo Avaliar a relação custo-efetividade da adição de quimioterapia ou abiraterona à terapia de privação hormonal. Métodos Um modelo analítico foi desenvolvido para determinar a relação custo-efetividade da adição de docetaxel ou abiraterona comparada à terapia de privação hormonal isolada. Custos diretos e indiretos foram incluídos no modelo. Os efeitos foram expressos em Anos de Vida Ajustados para Qualidade corrigidos pelos efeitos colaterais de cada terapia. Resultados A adição de quimioterapia e de abiraterona à terapia de privação hormonal aumentou os Anos de Vida Ajustados para Qualidade em 0,492 e 0,999, respectivamente, em comparação à terapia de privação hormonal isolada. A abiraterona promoveu ganho de Anos de Vida Ajustados para Qualidade de 0,506 em relação ao docetaxel. O custo incremental por Anos de Vida Ajustados para Qualidade foi R$ 133.649,22 para o docetaxel, R$ 330.828,70 para a abiraterona e R$ 571.379,42 para a abiraterona comparada ao docetaxel. Conclusão A adição de quimioterapia à terapia de privação hormonal é mais custo-efetiva que a adição de abiraterona à terapia de privação hormonal. Contudo, descontos no custo da abiraterona poderiam tornar esse tratamento mais custo-efetivo.

Cost effectiveness of chemohormonal therapy in patients with metastatic hormone-sensitive and non-metastatic high-risk prostate cancer / Custo-efetividade da adição de quimioterapia ao tratamento hormonal do câncer de próstata metastático sensível a hormônio ou localizado de alto risco

ABSTRACT Objective To assess the cost-effectiveness of chemohormonal therapy in patients with metastatic hormone-sensitive and non-metastatic high-risk prostate cancer. Methods An analytical decision model was developed to determine the cost-effectiveness of chemohormonal therapy versus androgen deprivation therapy alone in patients with metastatic hormone-sensitive prostate cancer and patients with non-metastatic high-risk prostate cancer. The cost-effectiveness in metastatic patients with a high-volume disease was assessed separately. The model used data from randomized clinical trials and drug acquisition costs in Brazil. In addition, the costs of post-progression therapies have been included in this model. The benefits to health are expressed as the quality-adjusted life-years, and the incremental cost-effectiveness ratios were calculated. Results Chemohormonal therapy may be associated with improved quality-adjusted life-years for all patient. The improvement was more than six times greater for patients with high-volume metastatic disease. In these patients, the incremental cost-effectiveness ratios were up to 74% lower than the incremental cost-effectiveness ratios of patients with non-metastatic disease. Conclusion Chemohormonal therapy has been more cost-effective in patients with high-volume metastatic disease.

RESUMO Objetivo Avaliar a relação custo-efetividade da adição de quimioterapia hormonal em pacientes com câncer de próstata metastático sensível a hormônio ou localizado de alto risco. Métodos Um modelo de decisão analítico foi desenvolvido para determinar o custo-efetividade da adição de quimioterapia versus a monoterapia de privação de andrógeno para pacientes com câncer de próstata metastático hormônio-sensível e pacientes de alto risco com câncer de próstata não metastático. O custo-efetividade em pacientes metastáticos com um alto volume da doença foi verificado isoladamente. Os dados do modelo foram obtidos de ensaios clínicos randomizados utilizando custos de aquisição de medicamentos no Brasil. Os custos de terapias pós-progressão também foram incluídos no modelo. Os efeitos foram expressos em anos de vida ajustados por qualidade, e foram calculadas as razões de custo-efetividade incremental. Resultados A adição de quimioterapia levou a um ganho de anos de vida ajustados por qualidade para todos os doentes. Este incremento foi seis vezes maior para os pacientes com doença metastática de alto volume. Nestes pacientes, as taxas do custo incremental por anos de vida ajustados por qualidade foram até 74% mais baixos do que o aumento das taxas dos pacientes com doença não metastática. Conclusão A adição de quimioterapia foi mais custo-efetiva para pacientes com doença metastática de alto volume.

[Geographical distribution of leptospirosis in Aracaju, State of Sergipe from 2001 to 2007]. / Espacialização da leptospirose em Aracaju, Estado de Sergipe, no período de 2001 a 2007.

INTRODUCTION: Leptospirosis, a disease caused by pathogenic spirochetes of the genus Leptospira, is one of the most widespread zoonoses in the world and is considered an important public health problem. This paper aims to describe the spatial pattern of leptospirosis in the City of Aracaju from 2001 to 2007 in an effort to identify areas at risk for leptospirosis. METHODS: We used the ratio of Kernel, which represents the ratio between two surfaces, to visualize the surface of disease risk. The numerator corresponds to the number of cases geocoded to the census tract, and the denominator of the kernel corresponds to the population of these areas. Using this method, the areas with the highest density of cases were delineated and compared visually with socioeconomic factors, such as average income. RESULTS: The spatial pattern was different in periods of rain compared with periods of drought and did not coincide with the areas considered most at risk for the disease. This study revealed the importance of applying spatial analysis techniques in the field of public health. CONCLUSIONS: These findings indicate that the kernel is a useful tool for obtaining a comprehensive review of the epidemiology of leptospirosis in Aracaju, which supports the kernel's use by the municipal health departments and by the state.

Espacialização da leptospirose em Aracaju, Estado de Sergipe, no período de 2001 a 2007 / Geographical distribution of leptospirosis in Aracaju, State of Sergipe from 2001 to 2007

Introdução: A leptospirose, enfermidade causada por uma espiroqueta patogênica do gênero Leptospira, é uma das zoonoses mais difundidas no mundo, considerada um importante problema de saúde pública. Este trabalho tem como objetivo descrever o padrão espacial da leptospirose na Cidade de Aracaju, no período de 2001 a 2007, buscando identificar as áreas de risco para ocorrência da leptospirose. Métodos: Utilizou-se a razão de kernel, que consiste na criação de uma razão entre duas superfícies, para visualizar a superfície de risco da doença, onde no numerador coloca-se os casos, georreferenciados para setor censitário, e no denominador o kernel da população dessas áreas. Através deste método, foi possível delimitar áreas de maior densidade de casos, e compará-las visualmente com fator socioeconômico, como renda média. Resultados: Comparando os períodos de chuva com os períodos de seca, verificou-se que não ocorre a presença de padrão espacial semelhante nos dois períodos, não coincidindo com as áreas consideradas de maior risco para ocorrência da doença. Através dos parâmetros estabelecidos, neste estudo, foi permitido verificar a importância da aplicação de técnicas de análise espacial na área de saúde pública. Conclusões: O kernel se mostrou uma ferramenta útil na obtenção de uma análise global da situação epidemiológica da leptospirose em Aracaju, o que viabiliza sua utilização pelas secretarias de saúde municipal e estadual.

Espacialização da leptospirose em Aracaju, Estado de Sergipe, no período de 2001 a 2007 / Geographical distribution of leptospirosis in Aracaju, State of Sergipe from 2001 to 2007

INTRODUÇÃO: A leptospirose, enfermidade causada por uma espiroqueta patogênica do gênero Leptospira, é uma das zoonoses mais difundidas no mundo, considerada um importante problema de saúde pública. Este trabalho tem como objetivo descrever o padrão espacial da leptospirose na Cidade de Aracaju, no período de 2001 a 2007, buscando identificar as áreas de risco para ocorrência da leptospirose. MÉTODOS: Utilizou-se a razão de Kernel, que consiste na criação de uma razão entre duas superfícies, para visualizar a superfície de risco da doença, onde no numerador coloca-se os casos, georreferenciados para setor censitário, e no denominador o kernel da população dessas áreas. Através deste método, foi possível delimitar áreas de maior densidade de casos, e compará-las visualmente com fator socioeconômico, como renda média. RESULTADOS: Comparando os períodos de chuva com os períodos de seca, verificou-se que não ocorre a presença de padrão espacial semelhante nos dois períodos, não coincidindo com as áreas consideradas de maior risco para ocorrência da doença. Através dos parâmetros estabelecidos, neste estudo, foi permitido verificar a importância da aplicação de técnicas de análise espacial na área de saúde pública. CONCLUSÕES: O kernel se mostrou uma ferramenta útil na obtenção de uma análise global da situação epidemiológica da leptospirose em Aracaju, o que viabiliza sua utilização pelas secretarias de saúde municipal e estadual.

INTRODUCTION: Leptospirosis, a disease caused by pathogenic spirochetes of the genus Leptospira, is one of the most widespread zoonoses in the world and is considered an important public health problem. This paper aims to describe the spatial pattern of leptospirosis in the City of Aracaju from 2001 to 2007 in an effort to identify areas at risk for leptospirosis. METHODS: We used the ratio of Kernel, which represents the ratio between two surfaces, to visualize the surface of disease risk. The numerator corresponds to the number of cases geocoded to the census tract, and the denominator of the kernel corresponds to the population of these areas. Using this method, the areas with the highest density of cases were delineated and compared visually with socioeconomic factors, such as average income. RESULTS: The spatial pattern was different in periods of rain compared with periods of drought and did not coincide with the areas considered most at risk for the disease. This study revealed the importance of applying spatial analysis techniques in the field of public health. CONCLUSIONS: These findings indicate that the kernel is a useful tool for obtaining a comprehensive review of the epidemiology of leptospirosis in Aracaju, which supports the kernel's use by the municipal health departments and by the state.