Custo-efetividade do pazopanibe comparado ao sunitinibe para câncer renal metastático na perspectiva de um hospital do Sistema Único de Saúde / Cost-effectiveness between pazopanib and sunitinib for metastatic renal cancer from the perspective of the Brazilian Unified National Health System / Costo-efectividad entre el pazopanib y el sunitinib para el cáncer renal metastásico desde la perspectiva del Sistema Único de Salud

Resumo: O câncer renal é a 13ª neoplasia mais frequente no mundo. Entre 2012 e 2016, representou 1,48% das mortes por câncer no Brasil. A terapia de escolha para o tratamento de câncer renal metastático são os inibidores de tirosina quinase (ITK), sunitinibe e pazopanibe. Este artigo avalia o custo-efetividade do pazopanibe comparado ao sunitinibe no tratamento de câncer renal metastático. Foi realizada uma análise de custo-efetividade sob a perspectiva de um hospital federal do Sistema Único de Saúde. No modelo de árvore de decisão foram aplicados os desfechos de efetividade e segurança dos ITK. Os dados clínicos foram extraídos de prontuários e os custos diretos consultados em fontes oficiais do Ministério da Saúde. O custo de 10 meses de tratamento, englobando o valor dos ITK, procedimentos e manejo de eventos adversos, foi de R$ 98.677,19 para o pazopanibe e R$ 155.227,11 para o sunitinibe. Os medicamentos apresentaram efetividade estatisticamente equivalente e diferença estatisticamente significativa para o desfecho de segurança, no qual o pazopanibe obteve o melhor resultado. O pazopanibe, nesse contexto, é a tecnologia dominante quando os custos de tratamento são associados aos de manejo de eventos adversos.

Abstract: Renal cancer is the 13th most frequent neoplasm in the world. From 2010 to 2014, renal cancer accounted for 1.43% of cancer deaths in Brazil. The treatment of choice for metastatic renal cancer is tyrosine kinase inhibitors (TKI) sunitinib and pazopanib. This article assesses cost-effectiveness between pazopanib and sunitinib in the treatment of metastatic renal cancer. A cost-effectiveness study was performed from the perspective of a federal hospital under the Brazilian Unified National Health System (SUS). TKI effectiveness and safety outcomes were applied to the decision tree model. Clinical data were extracted from patient charts, and direct costs were consulted from official Ministry of Health sources. The cost of 10 months of treatment, including the costs of the TKI, procedures and management of adverse events, was BRL 98,677.19 for pazopanib and BRL 155,227.11 for sunitinib. The drugs displayed statistically equivalent effectiveness and statistically different safety outcomes, with pazopanib displaying better results. In this setting, pazopanib is the dominant technology when the treatment costs are analyzed together with the costs of managing adverse events.

Resumen: El cáncer renal es la 13ª neoplasia más frecuente en el mundo. Entre 2010 y 2014, representó un 1,43% de las muertes por cáncer en Brasil. La terapia de elección para el tratamiento de cáncer renal metastásico son los inhibidores de tirosina quinasa (ITK), sunitinib y pazopanib. Este artículo evalúa el costo-efectividad entre pazopanib y sunitinib en el tratamiento de cáncer renal metastásico. Se realizó un análisis de costo-efectividad desde la perspectiva de un hospital federal del Sistema Único de Salud. En el modelo de árbol de decisión se aplicaron los desenlaces de efectividad y seguridad de los ITK. Los datos clínicos se extrajeron de registros médicos, y los costos directos consultados en fuentes oficiales del Ministerio de Salud. El costo de 10 meses de tratamiento, englobando el valor de los ITK, procedimientos y gestión de eventos adversos, fue de BRL 98.677,19 con el pazopanib y BRL 155.227,11 con el sunitinib. Los medicamentos presentaron efectividad estadísticamente equivalente y diferencia estadísticamente significativa para el desenlace de seguridad, en el que el pazopanib obtuvo el mejor resultado. El pazopanib, en este contexto, es la tecnología dominante cuando los costes de tratamiento están asociados a los de la gestión de eventos adversos.

Treatment with dasatinib or nilotinib in chronic myeloid leukemia patients who failed to respond to two previously administered tyrosine kinase inhibitors - a single center experience

OBJECTIVE: To evaluate hematological, cytogenetic and molecular responses as well as the overall, progression-free and event-free survivals of chronic myeloid leukemia patients treated with a third tyrosine kinase inhibitor after failing to respond to imatinib and nilotinib/dasatinib. METHODS: Bone marrow karyotyping and real-time quantitative polymerase chain reaction were performed at baseline and at 3, 6, 12 and 18 months after the initiation of treatment with a third tyrosine kinase inhibitor. Hematologic, cytogenetic and molecular responses were defined according to the European LeukemiaNet recommendations. BCR-ABL1 mutations were analyzed by Sanger sequencing. RESULTS: We evaluated 25 chronic myeloid leukemia patients who had been previously treated with imatinib and a second tyrosine kinase inhibitor. Nine patients were switched to dasatinib, and 16 patients were switched to nilotinib as a third-line therapy. Of the chronic phase patients (n=18), 89% achieved a complete hematologic response, 13% achieved a complete cytogenetic response and 24% achieved a major molecular response. The following BCR-ABL1 mutations were detected in 6/14 (43%) chronic phase patients: E255V, Y253H, M244V, F317L (2) and F359V. M351T mutation was found in one patient in the accelerated phase of the disease. The five-year overall, progression-free and event-free survivals were 86, 54 and 22% (p<0.0001), respectively, for chronic phase patients and 66%, 66% and 0% (p<0.0001), respectively, for accelerated phase patients. All blast crisis patients died within 6 months of treatment. Fifty-six percent of the chronic phase patients lost their hematologic response within a median of 23 months. CONCLUSIONS: Although the responses achieved by the third tyrosine kinase inhibitor were not sustainable, a third tyrosine kinase inhibitor may be an option for improving patient status until a donor becomes available for transplant. Because the long-term outcome ...

Cost-Effectiveness of High, Moderate and Low-Dose Statins in the Prevention of Vascular Events in the Brazilian Public Health System / Efetividade de Estatinas em Dose Alta, Moderada e Baixa na Prevenção de Eventos Vasculares no SUS

Background: Statins have proven efficacy in the reduction of cardiovascular events, but the financial impact of its widespread use can be substantial. Objective: To conduct a cost-effectiveness analysis of three statin dosing schemes in the Brazilian Unified National Health System (SUS) perspective. Methods: We developed a Markov model to evaluate the incremental cost-effectiveness ratios (ICERs) of low, intermediate and high intensity dose regimens in secondary and four primary scenarios (5%, 10%, 15% and 20% ten-year risk) of prevention of cardiovascular events. Regimens with expected low-density lipoprotein cholesterol reduction below 30% (e.g. simvastatin 10mg) were considered as low dose; between 30-40%, (atorvastatin 10mg, simvastatin 40mg), intermediate dose; and above 40% (atorvastatin 20-80mg, rosuvastatin 20mg), high-dose statins. Effectiveness data were obtained from a systematic review with 136,000 patients. National data were used to estimate utilities and costs (expressed as International Dollars - Int$). A willingness-to-pay (WTP) threshold equal to the Brazilian gross domestic product per capita (circa Int$11,770) was applied. Results: Low dose was dominated by extension in the primary prevention scenarios. In the five scenarios, the ICER of intermediate dose was below Int$10,000 per QALY. The ICER of the high versus intermediate dose comparison was above Int$27,000 per QALY in all scenarios. In the cost-effectiveness acceptability curves, intermediate dose had a probability above 50% of being cost-effective with ICERs between Int$ 9,000-20,000 per QALY in all scenarios. Conclusions: Considering a reasonable WTP threshold, intermediate dose statin therapy is economically attractive, and should be a priority intervention in prevention of cardiovascular events in Brazil. .

Fundamento: Estatinas tem eficácia comprovada na redução de eventos cardiovasculares, mas o impacto financeiro de seu uso disseminado pode ser substancial. Objetivo: Conduzir análise de custo-efetividade de três esquemas de doses de estatinas na perspectiva do SUS. Métodos: Foi desenvolvido modelo de Markov para avaliar a razão de custo-efetividade incremental (RCEI) de regimes de dose baixa, intermediária e alta, em prevenção secundária e quatro cenários de prevenção primária (risco em 10 anos de 5%, 10%, 15% e 20%). Regimes com redução de LDL abaixo de 30% (ex: sinvastatina 10mg) foram considerados dose baixa; entre 30-40% (atorvastatina 10mg, sinvastatina 40mg), dose intermediária; e acima de 40% (atorvastatina 20-80 mg, rosuvastatina 20 mg), dose alta. Dados de efetividade foram obtidos de revisão sistemática com aproximadamente 136.000 pacientes. Dados nacionais foram usados para estimar utilidades e custos (expressos em dólares internacionais - Int$). Um limiar de disposição a pagar (LDP) igual ao produto interno bruto per capita nacional (aproximadamente Int$11.770) foi utilizado. Resultados: A dose baixa foi dominada por extensão nos cenários de prevenção primária. Nos cinco cenários, a RCEI da dose intermediária ficou abaixo de Int$10.000 por QALY. A RCEI de dose alta ficou acima de Int$27.000 por QALY em todos os cenários. Nas curvas de aceitabilidade de custo-efetividade, dose intermediária teve probabilidade de ser custo-efetiva acima de 50% com RCEIs entre Int$9.000-20.000 por QALY em todos os cenários. Conclusões: Considerando um LDP razoável, uso de estatinas em doses intermediárias é economicamente atrativo, e deveria ser intervenção prioritária na redução de eventos cardiovasculares no Brasil. .

Efeito da revascularização renal sobre a evolução da disfunção renal na nefropatia isquêmica aterosclerótica / Effect of renal revascularization on the development of renal dysfunction in atherosclerotic ischemic nephropathy

A doença renal crônica (DRC) é caracterizada por uma perda progressiva da função renal e suas principais causas são hipertensão arterial (HA) e diabete melito. Entre as causas de HA, podemos destacar a doença renal aterosclerótica (DRA). O desenvolvimento de DRC nos pacientes com DRA parece ser decorrente não apenas do acometimento das artérias renais principais, mas também da microcirculação renal, o que pode justificar o fato de o sucesso do procedimento não garantir uma melhora da evolução da DRC. Até o presente momento, não existe evidência de benefício da angioplastia em relação ao tratamento clínico exclusivo nos pacientes com DRA. O presente trabalho analisa os estudos mais significantes sobre os desfechos renais em pacientes portadores de DRA submetidos à revascularização ou ao tratamento clínico exclusivo.

Chronic kidney disease (CKD) is characterized by a progressive loss of renal function and its main causes are hypertension and diabetes mellitus. Among the causes of hypertension is atherosclerotic renal disease (ARD). The development of CKD in patients with ARD appears to be due not only to the involvement of the main renal arteries, but also of the renal microcirculation, which may explain the fact that the success of the procedure does not guarantee an improvement in the progression of CKD. To date there is no evidence of benefit of angioplasty compared to medical treatment alone in patients with ARD. The present paper analyzes the most significant studies on renal outcomes in patients with ARD undergoing revascularization or medical treatment alone.

Preoperative imatinib for patients with primary unresectable or metastatic/recurrent gastrointestinal stromal tumor

OBJECTIVES: Despite its rising popularity, reports on the use of preoperative imatinib mesylate (IM) in patients with advanced gastrointestinal stromal tumor (GIST) are limited. This study aims to explore the clinical efficacy of preoperative IM in patients with primarily unresectable or metastatic/recurrent GIST. METHODS: Between September 2009 and February 2014, patients with primarily unresectable or metastatic/recurrent GIST treated by a single medical team were recruited and considered for preoperative IM therapy. Re-examination was conducted regularly and abdominal enhanced CT data, blood biochemistry and responses to IM were recorded. RESULTS: A total of 18 patients were enrolled, including 13 with a primary tumor (7 stomach, 3 small bowel, 2 rectal and 1 pelvic tumor) and 5 with recurrent or metastatic GIST (2 with liver metastasis, 2 with anastomotic recurrence and 1 with pelvic GIST). The median follow-up time was 9.5 months (range of 3-63). The median tumor sizes before and after initiation of IM treatment were 9.1 cm and 6.0 cm (p = 0.003) based on the CT findings, respectively. All patients showed a decrease in tumor burden and the median tumor size reduction was 35%. Sixteen of the 18 patients showed a partial response to IM and two possessed stable disease. Nine of the 18 patients (50%) underwent surgical resection of primary or metastatic/recurrent tumors, with a median of 7 months of IM therapy. One case each of multivisceral resection and tumor recurrence were noted. CONCLUSIONS: IM as a preoperative therapy is feasible and safe for unresectable or metastatic/recurrent GIST that can effectively decrease tumor size, facilitating resection. .

Resultados del tratamiento quirúrgico de los tumores del estroma gastrointestinal (GIST) en la IV Región de Chile / Surgical outcomes of gastrointestinal stromal tumors (GIST)

Background: Despite that current knowledge regarding the pathology and treatment of Gastrointestinal Stromal Tumors (GIST) is widely available; most patients in the developing world and mainly in rural areas of developing countries have limited access to diagnostic technology and modern specific therapy such as imatinib. Objective: To review the management and outcomes of GISTs treated at the hospitals of the IV Region of Chile. Patients and Methods: This retrospective, observational and descriptive study was performed with data obtained from the medical records of 3 community hospitals were all surgical practice of the IV Region is performed. During the study period, 24 consecutive patients with GISTs at different localizations of the gastrointestinal tract were treated. Results: Five patients were operated on with the preoperative diagnostic of GIST, in 19 patients the diagnostic of GIST was suspected during the operation and confirmed by histology and immunohistochemistry. Most patients were operated on emergency grounds. Of 10 patients requiring imatinib therapy, only 2 are currently receiving the medication sponsored by an international foundation. Conclusions: There were no disparities in the standard surgical care of our patients. The main differences with published series from Chile and developed countries are the available technology to perform a preoperative diagnosis and the availability of imatinib for the treatment of metastatic and recurrent disease.

Introducción: A pesar de que el conocimiento actual sobre la patología y tratamiento de los tumores del estroma gastrointestinal (GIST) se encuentra ampliamente disponible, la mayoría de los pacientes en los países en desarrollo, principalmente en las áreas rurales, tienen un limitado acceso a la tecnología diagnóstica moderna y a tratamientos específicos como el imatinib. Objetivo: Revisión del manejo y resultados de los GIST tratados en los hospitales de la IV Región de Chile. Pacientes y Métodos: Estudio retrospectivo, observacional y descriptivo de la información obtenida de las fichas clínicas de 3 hospitales tipo 2 en los cuales se realiza toda la práctica quirúrgica de la IV Región. Durante el período estudiado, 24 pacientes consecutivos con GISTs en diferentes localizaciones fueron tratados quirúrgicamente. Resultados: Cinco pacientes fueron operados con el diagnóstico preoperatorio de GIST, en los otros 19 pacientes el diagnóstico se sospechó durante la cirugía y fue confirmado por histología e inmunohistoquímica. La mayoría de los pacientes fueron operados de urgencia. Diez pacientes fueron candidatos a tratamiento con imatinib, sólo 2 pacientes se encuentran actualmente en tratamiento gracias a una fundación internacional. Conclusiones: El tratamiento quirúrgico de nuestros pacientes es similar a las publicaciones nacionales e internacionales. Las diferencias se presentan en la disponibilidad de estudios de imagen para el diagnóstico preoperatorio y en la disponibilidad de imatinib para el tratamiento de las recurrencias y metástasis.

Five-year follow-up of patients treated with imatinib mesylate for chronic myeloid leukaemia in Trinidad and Tobago / Pacientes con cinco años de seguimiento tratados con imatinib mesilato por leucemia mieloide crónica en Trinidad y Tobago

OBJECTIVE: Data on the use of Imatinib (IM) in developing countries remain limited. A retrospective study was done to assess the efficacy and toxicity of IM in treating chronic myeloid leukaemia (CML) in Trinidad and Tobago. METHODS: Patients in all phases of CML who started IM therapy between February 2001 and February 2004 were included. All had received other previous therapy. They were assessed for haematological, cytogenetic and molecular response, overall survival (OS), event free survival (EFS) and adverse effects (AE). RESULTS: Twenty-five patients were followed-up for a median 61 months. At initiation ofIM, 18 were in the chronic phase (CP), 3 in accelerated phase (AP), 3 in blast crisis (BC) and one in myelofibrotic transformation (MF). Overall, 96% of patients achieved complete haematological remission (CHR). Among CP patients, 67% attained a major cytogenetic response (MCR) and 44% a complete cyto genetic response (CCR). Overall survival and event free survival in the CP group were 82% and 76% respectively. Overall survival for advanced phase patients was 14% at 61 months The adverse effects of IM were the same as previously described and generally tolerable. No patient opted to discontinue IM because ofside effects. CONCLUSION: After 5 years of follow-up, IM was found to induce favourable and durable survival responses with an acceptable side effect profile in CP-CML patients who had received prior treatment with alternative agents.

OBJETIVO: Los datos sobre el uso de imatinib (IM) en los países en vías de desarrollo, siguen siendo limitados. Se hizo un estudio retrospectivo con el fin de evaluar la eficacia y toxicidad de IM en el tratamiento de la leucemia mieloide crónica (LMC) en Trinidad y Tobago. MÉTODOS: Se incluyeron todos los pacientes -en todas las fases de LMC - que empezaron la terapia de IM entre febrero de 2001 y febrero de 2004. Todos habían recibido otra terapia previamente. Se les evaluó con respecto a su respuesta hematológica, citogenética y molecular, supervivencia global (SG), supervivencia libre de eventos (SLE), y efectos adversos (EA). RESULTADOS: Veinticinco pacientes tuvieron seguimiento por espacio de 61 meses como promedio. En la iniciación de IM, 18 estaban en fase crónica (FC), 3 en la fase acelerada (FA), 3 en crisis blástica (CB) y uno en transformación mielofibrótica (MF). En general, 96% de los pacientes lograron la remisión hematológica completa (RHC). Entre los pacientes de CF, 67% lograron una repuesta citogénica mayor (RCM) y 44% una respuesta citogénica completa (RCC). La supervivencia global (SG) y la supervivencia libre de eventos (SLE) en el grupo FC fueron 82% y 76% respectivamente. La supervivencia global para los pacientes en fase avanzada fue de 14% en 61 meses. Los EA de IM fueron los mismos previamente descritos, y eran generalmente tolerables. Ningún paciente optó por discontinuar IM debido a efectos adversos. CONCLUSIÓN: Después de 5 años de seguimiento, se halló que IM induce respuestas de supervivencia favorables y duraderas en los pacientes de LMC-FC previamente tratados, con un perfil aceptable de efectos colaterales.

Positive response to imatinib mesylate therapy for childhood chronic myeloid leukemia

Chronic myeloid leukemia (CML) is rare in the pediatric population, accounting for 2-3 percent of childhood leukemia cases, with an annual incidence of one case per million children. The low toxicity profile of imatinib mesylate has led to its approval as a front-line therapy in children for whom interferon treatment has failed or who have relapsed after allogeneic transplantation. We describe the positive responses of 2 children (case 1 - from a 7-year-old male since May 2005; case 2 - from a 5-year-old female since June 2006) with Philadelphia-positive chromosome CML treated with imatinib (300 mg/day, orally) for up to 28 months, as evaluated by morphological, cytogenetic, and molecular approaches. Our patients are alive, are in the chronic phase, and are in continuous morphological complete remission.

Influence of late treatment on how chronic myeloid leukemia responds to imatinib

INTRODUCTION: In Brazil, patients with chronic myeloid leukemia (CML) in the chronic phase were not given first-line imatinib treatment until 2008. Therefore, there was a long period of time between diagnosis and the initiation of imatinib therapy for many patients. This study aims to compare the major molecular remission (MMR) rates of early versus late imatinib therapy in chronic phase CML patients. METHODS: Between May 2002 and November 2007, 44 patients with chronic phase CML were treated with second-line imatinib therapy at the Hematology Unit of the Ophir Loyola Hospital (Belém, Pará, Brazil). BCR-ABL transcript levels were measured at approximately six-month intervals using quantitative polymerase chain reaction. RESULTS: The early treatment group presented a 60 percent probability of achieving MMR, while the probability for those patients who received late treatment was 40 percent. The probability of either not achieving MMR within one year of the initiation of imatinib therapy or losing MMR was higher in patients who received late treatment (79 percent), compared with patients who received early treatment (21 percent, odds ratio=5.75, P=0.012). The probability of maintaining MMR at 30 months of treatment was 80 percent in the early treatment group and 44 percent in the late treatment group (P=0.0005). CONCLUSIONS: For CML patients in the chronic phase who were treated with second-line imatinib therapy, the probability of achieving and maintaining MMR was higher in patients who received early treatment compared with those patients for whom the time interval between diagnosis and initiation of imatinib therapy was longer than one year.

Efecto de un inhibidor tirosina kinasa (imatinib) en pacientes con tumores estromales gastrointestinales metastásicos: Experiencia preliminar / Treatment of metastatic gastrointestinal stromal tumors with Imatinib: Report of four cases

Gastrointestinal stromal tumors (GIST) have mutations of the tyrosine kinase receptor. When they are localized, the treatment of choice is surgical excision, but advanced tumors have a limited response to chemo or radiotherapy. Imatinib (STI571 or Glivec®) is a selective inhibitor or tyrosine kinase proteins that has been used successfully in the treatment of advanced GIST. We report four patients (two women) with a metastatic GIST that were treated with Imatinib 400 mg day and followed for 40 months. The disease tumor stabilized in three patients and in one it had an initial reduction and progressed at the end of follow up. Therefore Imatinib can be a therapeutic alternative in patients with metastatic GIST.

Differential molecular response of the transcripts B2A2 and B3A2 to imatinib mesylate in chronic myeloid leukemia

Chronic myeloid leukemia (CML) originates from the hematopoietic stem cell and is characterized by the reciprocal translocation t(9;22)(q34;q11), which results in the BCR-ABL fusion gene on chromosome 22q-, also known as the Philadelphia chromosome. This chimeric gene codes for a cytoplasmic protein with constitutive tyrosine-kinase activity, responsible for cellular transformation and leukemogenesis in CML. The aim of this observational cohort study was to discriminate and quantify BCR-ABL transcripts in the peripheral blood of patients with CML who were treated with imatinib mesylate (Glivec, Novartis). Twenty-two patients were followed for six months during treatment. Quantitative real time polymerase chain reaction was performed before treatment and after 3 and 6 months from treatment initiation. As compared with the third month, there was a significant decrease in BCR-ABL expression in the sixth month of treatment (P = 0.0002). At the sixth month, there was a significant difference in the levels of the two major transcripts of BCR-ABL, B2A2 and B3A2 (P = 0.0347), indicating that B2A2 may be more sensitive to imatinib. The results of our study indicate that imatinib is able to modify the natural history of CML, and raise the hypothesis that patients who express the B2A2 transcript may have a better prognosis.