Risk Factor Analysis for Secondary Malignancy in Dexrazoxane-Treated Pediatric Cancer Patients / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Dexrazoxane has been used as an effective cardioprotector against anthracycline cardiotoxicity. This study intended to analyze cardioprotective efficacy and secondary malignancy development, and elucidate risk factors for secondary malignancies in dexrazoxane-treated pediatric patients. MATERIALS AND METHODS: Data was collected from 15 hospitals in Korea. Patients who received any anthracyclines, and completed treatment without stem cell transplantation were included. For efficacy evaluation, the incidence of cardiac events and cardiac event-free survival rates were compared. Data about risk factors of secondary malignancies were collected. RESULTS: Data of total 1,453 cases were analyzed; dexrazoxane with every anthracyclines group (D group, 1,035 patients) and no dexrazoxane group (non-D group, 418 patients). Incidence of the reported cardiac events was not statistically different between two groups; however, the cardiac event-free survival rate of patients with more than 400 mg/m2 of anthracyclines was significantly higher in D group (91.2% vs. 80.1%, p=0.04). The 6-year cumulative incidence of secondary malignancy was not different between both groups after considering follow-up duration difference (non-D, 0.52%±0.37%; D, 0.60%±0.28%; p=0.55). The most influential risk factor for secondary malignancy was the duration of anthracycline administration according to multivariate analysis. CONCLUSION: Dexrazoxane had an efficacy in lowering cardiac event-free survival rates in patients with higher cumulative anthracyclines. As a result of multivariate analysis for assessing risk factors of secondary malignancy, the occurrence of secondary malignancy was not related to dexrazoxane administration.

Avaliação econômica do uso de dexrazoxano na profilaxia de cardiotoxicidade em crianças em tratamento quimioterápico com antraciclinas / Economic assessment of dexrazoxane in prophylaxis of cardiotoxicity in children undergoing chemotherapy with anthracyclines / Evaluación económica del uso del dexrazoxano en la profilaxia de cardiotoxicidad en niños en tratamiento quimioterápico con antraciclinas

Resumo: O câncer em indivíduos de 0 a 19 anos é considerado raro, quando comparado à incidência em faixas etárias maiores, sendo estimado entre 2% e 3% de todos os tumores malignos registrados no Brasil. O uso de antraciclinas está frequentemente associado ao aparecimento de cardiotoxicidade e faz parte de aproximadamente 60% dos protocolos terapêuticos em oncologia pediátrica. Dentre as estratégias existentes para a prevenção de cardiotoxicidade, o dexrazoxano obteve resultados favoráveis pautados em desfechos intermediários (marcadores bioquímicos e medidas ecocardiográficas). Foi desenvolvida, neste trabalho, uma avaliação de custo-efetividade que compare o uso do dexrazoxano em diferentes populações, além de uma avaliação do impacto orçamentário causado pela possível incorporação da tecnologia. Foi utilizado o horizonte temporal de toda a vida do paciente e a perspectiva de análise do Sistema Único de Saúde. Uma análise de impacto orçamentário para cada tecnologia também foi construída. Após uma busca na literatura, foi desenvolvido um modelo de Markov capaz de comparar o uso do dexrazoxano em seis perfis de pacientes com risco de desenvolver cardiotoxicidade. Usar o medicamento nas crianças menores de cinco anos de idade se mostrou a alternativa mais custo-efetiva (razão de custo-efetividade incremental - RCEI de R$ 6.156,96), seguida de usar em todos os pacientes (RCEI de R$ 58.968,70). Caso o preço diminua a um valor menor que R$ 250,00 por frasco, a alternativa de usar em todas as crianças se torna a mais custo-efetiva. O impacto orçamentário ao final de cinco anos foi de R$ 30.622.404,81 para uso apenas nas crianças menores de cinco anos. Usar a tecnologia em todas as crianças produziria um impacto incremental de R$ 94.352.898,77.

Abstract: Cancer in individuals 0 to 19 years of age is considered rare when compared to incidence in older age brackets, and is estimated at 2% to 3% of all malignant tumors recorded in Brazil. The use of anthracyclines is frequently associated with cardiotoxicity, and these drugs are part of approximately 60% of treatment protocols in pediatric oncology. Among the existing strategies for the prevention of cardiotoxicity, dexrazoxane obtained favorable results based on intermediate outcomes (biochemical markers and echocardiographic parameters). This study was based on a cost-effectiveness assessment comparing the use of dexrazoxane in different populations, besides an assessment of the budget impact from the technology's potential incorporation. The patient's lifetime was used as the timeline, and the analysis was performed from the perspective of the Brazilian Unified National Health System (SUS). A budget impact analysis was also performed for each technology. After a literature search, a Markov model was developed, capable of comparing the use of dexrazoxane in six profiles of patients at risk of developing cardiotoxicity. Use of the drug in children under 5 years of age proved to be the most cost-effective alternative (incremental cost effectiveness ratio - ICER of BRL 6,156.96), followed by use in all patients (ICER of BRL 58,968.70). If the price decreased to less than BRL 250.00 per vial, the alternative of using the drug in all children would become the most cost-effective. The budget impact at 5 years was BRL 30,622,404.81 for use only in children under 5 years of age. Using the technology in all the children could produce an incremental impact of BRL 94,352,898.77.

Resumen: El cáncer en individuos de 0 a 19 años está considerado raro, cuando se compara la incidencia en franjas etarias mayores, estimándose entre 2% y 3% de todos los tumores malignos registrados en Brasil. El uso antraciclinas está frecuentemente asociado a la aparición de cardiotoxicidad y forma parte de aproximadamente un 60% de los protocolos terapéuticos en oncología pediátrica. Entre las estrategias existentes para la prevención de cardiotoxicidad, el dexrazoxano obtuvo resultados favorables pautados en desenlaces intermedios (marcadores bioquímicos y medidas ecocardiográficas). Se desarrolló en este trabajo, una evaluación de costo efectividad que compare el uso del dexrazoxano en diferentes poblaciones, además de una evaluación del impacto presupuestario causado por la posible incorporación de la tecnología. Se utilizó el horizonte temporal de toda la vida del paciente y la perspectiva de análisis del SUS. También se realizó un análisis del impacto presupuestario para cada tecnología. Tras una búsqueda en la literatura, se desarrolló un modelo de Markov capaz de comparar el uso del dexrazoxano en 6 perfiles de pacientes con riesgo de desarrollar cardiotoxicidad. Usar el medicamento en los niños menores de 5 años de edad se mostró la alternativa más costo-efectiva (relación costo-efectividad incremental - RCEI de BRL 6.156,96), seguido de usarlo en todos los pacientes (RCEI de BRL 58.968,7). En caso de que el precio disminuya a un valor inferior a BRL 250,00 por frasco, la alternativa de usarlo en todos los niños se convierte en la más costo-efectiva. El impacto presupuestario tras 5 años fue de BRL 30.622.404,81 para su uso exclusivo en niños menores de 5 años. Usar esta tecnología en todos los niños, tendría un impacto presupuestario incrementándolo hasta los BRL 94.352.898,77.

Cardioprotective Effect of Dexrazoxane in Patients with HER2-Positive Breast Cancer Who Receive Anthracycline Based Adjuvant Chemotherapy Followed by Trastuzumab / 한국유방암학회지

PURPOSE: We intended to determine whether dexrazoxane (DZR) is cardioprotective during administration of adjuvant anthracycline-based chemotherapy followed by a 1-year trastuzumab treatment. METHODS: The medical records of 228 patients who underwent surgical resection and received adjuvant chemotherapy with trastuzumab for human epidermal growth factor receptor type 2 (HER2)-positive breast cancer between January 2010 and December 2014 were reviewed. Approximately 25% of patients received DZR prior to each administration of doxorubicin during doxorubicin with cyclophosphamide (AC) chemotherapy. DZR was not administered during the 1-year trastuzumab maintenance period. Rates of cardiac events (reduction in left ventricular ejection fraction [LVEF] by 10% or more; reduction in absolute LVEF to <45%) and cardiac event-free duration (CFD) were examined. The trastuzumab interruption rate was also assessed. RESULTS: Twelve percent of patients experienced a cardiac event. Repeated-measures analysis of variance for ejection fraction revealed a significant main effect of time, and a significant group (DZR)×time interaction. The group treated with adjuvant chemotherapy and DZR experienced significantly lower frequencies of cardiac events than the adjuvant chemotherapy only group. In multivariate analysis, DZR administration was associated with significantly fewer cardiac events. Moreover, DZR administration was an independent good prognostic factor for CFD. Only one patient (2.3%) experienced early interruption of trastuzumab in the adjuvant chemotherapy with DZR group due to cardiac toxicity, whereas 10 patients (7.6%) experienced a trastuzumab stop event in the adjuvant chemotherapy only group. CONCLUSION: DZR is cardioprotective in HER2-positive breast cancer patients who received adjuvant chemotherapy with trastuzumab. A large cohort randomized trial is needed to determine if DZR has an effect on trastuzumab interruption and completion of 12-month trastuzumab. Because cardiac toxicity has a significant negative effect on trastuzumab maintenance and quality of life, DZR administration could be considered concomitantly with anthracycline-based adjuvant chemotherapy with trastuzumab.

Clinical Observation of the Reduction of Anthracycline-induced Cardiotoxicity in Patients with Breast Cancer by Dexrazoxane Combined with Shenmai Injection / 中国药房

OBJECTIVE:To observe therapeutic efficacy and safety of dexrazoxane combined with Shenmai injection in the treatment of anthracycline-induced cardiotoxicity in patients with breast cancer. METHODS:120 female breast cancer patients were randomly divided into group A,B,C and D with 30 cases in each group. Group A was given CAF chemotherapy plan(cyclophos-phamide 75 mg/m2+fluorouracil 500 mg/m2 + doxorubicin 60 mg/m2),ivgtt;group B was additionally given Shenmai injection 50 ml,qd,ivgtt,on the basis of CAF plan;group C was additionally given rapid intravenous of dexrazoxane 60 mg/m2 30 min before chemotherapy,on the basis of CAF;group D was additionally given constant dose of dexrazoxane combine with Shenmai injection on the basis of CAF plan. A treatment course lasted for 3 weeks,they were given 4 courses in total. The change of ECG,LVEF, cTnT and BNP and the incidence of bone marrow suppression were observed before and after chemotherapy. RESULTS:After treat-ment,the rate of abnormal ECG,LVEF value,cTnT value and BNP value of groups B,C and D were all decreased significant-ly,with statistical significance(P<0.05). Compared with group D,above index of groups B and C were decreased significantly, with statistical significance(P<0.05). The incidence of bone marrow suppression was in ascending order,group D

Clinical Study on Anthracycline Cardiotoxicity Reduction by Dexrazoxane Combined with cAMP / 中国药师

Objective:To compare the effects of a single dose of dexrazoxane or cAMP and their combined use on anthracycline cardiotoxicity in the multiple treatment course of patients with hematological malignancies to explore better alternatives for reducing an-thracycline cardiotoxicity. Methods: In the study, 80 patients were randomly divided into 4 groups with 20 cases each. Group A ( cAMP group) received cAMP 20 ml·d-1 for a week before every treatment course. Group B was treated with dexrazoxane and adria-mycin at a dosage ratio of 10∶1 via a fast intravenous drip 30 min before the application of anthracycline chemotherapy, and the 20 ml cAMP was given once a week before the chemotherapy session. Group C only received dexrazoxane. Anthracyclines was administered 30 min before each chemotherapy session. Groups A, B, and C were the experimental groups, and group D was designed as the blank control group. All groups received four complete cycles of chemotherapy. The ECG changes, echocardiography ( left ventricular ejection fraction, LVEF) and B-type brain natriuretic peptide ( BNP) values of all the groups were observed before and after the chemotherapy. Results:As for the ECG changes, group B and C had lower incidence rate of abnormal ECG than group A and D(P<0. 008 3). Sig-nificantly decreased LVEF and increased BNP values were observed in group A, B and C compared with those in the control group ( P<0. 05), and group B showed the most significant effect. Conclusion:All of the studied treatments can effectively reduce anthracy-cline chemotherapy-induced cardiotoxicity in cancer patients, and the combination of cAMP and dexrazoxane exhibits the best effect. Dexrazoxane has better protective effect on myocardial cells than cAMP.

Dexrazoxane for Preventing Anthracycline Cardiotoxicity in Children with Solid Tumors

This study attempted to assess the incidence and outcome of anthracycline cardiotoxicity and the role of dexrazoxane as a cardioprotectant in childhood solid tumors. The dexrazoxane group included 47 patients and the control group of historical cohort included 42. Dexrazoxane was given in the 10:1 ratio to doxorubicin. Fractional shortening and systolic and diastolic left ventricular diameters were used to assess the cardiac function. The median follow-ups were 54 months in the dexrazoxane group and 86 months in the control group. The mean cumulative doses of doxorubicin were 280.8+/-83.4 mg/m2 in the dexrazoxane group and 266.1+/-75.0 mg/m2 in the control group. The dexrazoxane group experienced significantly fewer cardiac events (27.7% vs. 52.4%) and less severe congestive heart failure (6.4% vs. 14.3%) than the control group. Thirteen cardiotoxicities including one cardiac death and 2 congestive heart failures occurred in the dexrazoxane group, and 22 cardiotoxicities including 2 cardiac deaths and 4 congestive heart failures, in the control group. Five year cardiac event free survival rates were 69.2% in the dexrazoxane group and 45.8% in the control group (P=0.04). Dexrazoxane reduces the incidence and severity of early and late anthracycline cardiotoxicity in childhood solid tumors.

Methodology of Sterility Test of Dexrazoxane for Injection / 中国药房

OBJECTIVE:To establish the method for sterility test of dexrazoxane for injection. METHODS: The relative procedures were conducted in accordance with the membrane-filter procedure included in sterility test specified in Chinese Pharmacopoeia (2005 edition),with Staphylococcus aureus,Pseudomonas aeruginosa,Bacillus subtilis,Clostridium sporogenes,Candida albicans and Aspergillus niger as test organisms,which were flushed with sodium chloride-peptone buffer solution (150 mL,250 mL,and 350 mL,respectively,pH 7.0) to evaluate the impact of three flushing doses on the results of sterility test. RESULTS: At a flushing dose of 150 mL,there was no growth of bacteria except Bacillus subtilis at 24～72 h;however,at a flushing dose of 250 mL or 350 mL,all bacteria strains had a good growth. CONCLUSION: The established method for sterility test of dexrazoxane for injection is accurate and reliable.

The Preventive Effect of Dexrazoxane and Pentoxifylline on Adriamycin Induced Cardiomyopathy / 소아과

PURPOSE: We hypothesized dexrazoxane (DXR) and pentoxifylline (PTX) may prevent myocardial damage in adriamycin (ADR) -induced cardiomyopathic rat model. We also investigated their effects on the myocardial apoptosis and fibrosis in ADR induced cardiomyopathy. METHODS: The six-week old female Spregue-Dawley rats were divided into control group (CNT, n= 4), ADR group (n=6), ADR+DXR group (DXR, n=5), ADR+PTX group (PTX, n=6), ADR+DXR+PTX group (DXPT, n=5). ADR (5 mg/week, twice) was administrated intravenously to rats except CNT group to induce cardiomyopathy. The PTX (50 mg/kg/day) was administered daily from day-0 to Day-21. The DXR (100 mg/kg) was administered 30 minutes before each ADR injection. On day 21, the rats were sacrificed and the degree of histopathologic changes of hypercontraction band necrosis, cytoplasmic vacuolar change and fibrosis were scored. Immunohistochemical staining for Bcl-2 expression and RT-PCR for TNF-alpha and CTGF were performed. RESULTS: Histopathological scores of myocardial damage were significantly higher in ADR rats than CNT rats (P< 0.05), and significantly lower in DXPT rats than ADR rats (P< 0.01). Myocardial fibrosis was prevented in both PTX rats and DXPT rats. The expression of Bcl-2 was weaker in ADR rats than that in CNT rats (P< 0.05), and stronger in both DXR and DXPT rats than that in ADR rats (P< 0.05). TNF-alpha concentration of ADR rats was not different from that of treated groups. CONCLUSION: DXR prevented myocyte apoptosis with increased Bcl-2 expression, and PTX prevented myocardial fibrosis in ADR induced cardiomyopathic rats. The combination therapy of DXR and PTX showed prevention of cardiomyopathy in ADR induced cardiomyopathy rat model.