소아 Anthracycline 심독성의 추적 관찰

권혁주,송영환,강수정,강형진,최형수,배은정,신희영,노정일,윤용수,안효섭,Kwon, Hyok Joo,Song, Young Hwan,Kang, Soo Jung,Kang, Hyoung Jin,Choi, Hyoung Soo,Bae, Eun Jung,Shin, Hee Young,Noh, Chung Il,Yun, Yong Soo,Ahn, Hyo Seop 대한소아청소년과학회 2003 Clinical and Experimental Pediatrics (CEP) Vol.46 No.3

Purpose : We studied the relationship between anthracycline cumulative dose and anthracycline cardiotoxicity in childhood cancer and followed up 40 children with anthracycline cardiotoxicity. Methods : A retrospective study was performed in 154 children who received anthracycline chemotherapy between January 1995 to December 2000. Cardiotoxicity was defined when the left ventricular fractional shortening(FS) was below 26%; it was divided into two groups, mild and severe cardiotoxicity, according to the FS. We followed up survivors with cardiotoxicity, and checked their present cardiac function by physical activity, echocardiography, electrocardiography(EKG) and chest X-ray. Results : Of the 154 children treated with anthracyclines, forty(26.0%) were diagnosed as cardiotoxicity. The incidence of cardiotoxicity increased in exponential fashion with increases in the cumulative dose of anthracyclines. There was minimal increase of incidence until a dose of $300mg/m^2$ after which the incidence increased rapidly. After mean $3.8{\pm}1.8year$ follow-up of 23 survivors with cardiotoxicity, FS increased significantly. EKG and chest X-rays were not helpful for the diagnosis of cardiotoxicity because of their low sensitivity and specificity. Conclusion : Although convenient, non-invasive and inexpensive, EKG and chest X-rays were not helpful for the follow-up of anthracycline cardiotoxicity. Almost all survivors with anthracycline cardiotoxicity have improved in both physical activity and echocardiographic findings after discontinuation of anthracyclines. 목 적 : 항암치료 중 anthracycline을 사용한 환아들에 대한 후향적 조사를 통해 anthracycline의 축적량과 anthracycline 심독성과의 관계를 알고자 했고 심독성 환아들에 대한 추적 조사를 통해 anthracycline 심독성 환아의 예후를 알고자 하였다. 방 법 : 1995년 1월부터 2000년 12월까지 서울대학교병원 소아과에서 anthracycline을 포함한 항암치료를 시작한 환아를 대상으로 과거 anthracycline 축적량과 심장 초음파 검사 소견, 심독성 발생 유무 등을 조사하였다. 심독성은 좌심실 수축분율이 26% 이하로 감소한 경우로 정하였고 이들을 다시 좌심실 수축분율이 20%가 넘는 경증 심독성과 20% 미만인 중증 심독성으로 분류하였다. Anthracycline 심독성이 발생한 환아들에게 운동 능력과 심장 초음파, 심전도 검사, 흉부 방사선 촬영 등의 추적 검사를 시행하였다. 결 과 : 총 조사대상 환아는 154명이었다. 이 중에서 40명(26.0%)의 anthracycline 심독성이 발생하였으며 경증 심독성이 27명(17.5%), 중증 심독성이 13명(8.4%)이었다. 심독성의 발생률은 anthracycline의 축적량이 증가함에 따라 서서히 증가하다가 축적량이 $300mg/m^2$ 이상부터 갑자기 지수적으로 증가하는 양상을 보였다. 심독성 환아 40명 중 12명이 추적조사 이전에 사망하였고 생존한 환아 중 23명에 대해 추적검사를 시행하였다. Anthracycline의 사용을 중단한 후 평균 $3.6{\pm}1.8$년의 추적검사 결과 심독성 환아들의 좌심실 수축분율은 유의하게 증가하였다(P<0.01). 흉부 방사선 촬영이나 심전도 검사는 심독성의 진단을 위해 민감도와 특이도가 매우 낮은 검사였다. 결 론 : 일반적으로 anthracycline 심독성 환아의 추적검사로 시행하는 심전도 검사나 흉부 방사선 촬영은 심독성의 추적 조사에 도움이 되지 않는다. 심독성 환아들은 일단 생존하여 항암치료를 마치고 약 2-5년 정도 경과하면 심부전 증상이나 심장초음파 검사상 대부분 호전을 보인다.

Vascular endothelial dysfunction after anthracyclines treatment in children with acute lymphoblastic leukemia

장우정,최덕영,전인상 대한소아청소년과학회 2013 Clinical and Experimental Pediatrics (CEP) Vol.56 No.3

Purpose: Anthracyclines have been utilized in the treatment of children with acute lymphoblastic leukemia (ALL). Recent studies have shown that anthracyclines may induce toxicity in the vascular endothelium. This study was performed using brachial artery reactivity (BAR) to evaluate vascular endothelial function in ALL patients who were treated with anthracycline chemotherapy. Methods: We included 21 children with ALL who received anthracycline chemotherapy and 20 healthy children. The cumulative dose of anthracyclines in the ALL patients was 142.5±18.2/m2. The last anthracycline dose was administered to the patients 2 to 85 months prior to their examination using BAR. The diameter of the brachial artery was measured in both groups using echocardiography, and BAR was calculated as the percentage change in the arterial diameter after release of the cuff relative to the baseline vessel diameter. Results: In the anthracycline-treated group, BAR was observed to be 3.4%±3.9%, which was significantly lower than that observed in the control group (12.1%±8.0%, P<0.05). The time elapsed after the last anthracycline treatment and the age at the time of treatment did not affect the change in BAR (P =0.06and P =0.13, respectively). Conclusion: These results provided evidence that treatment of ALL patients with anthracycline results in endothelial dysfunction. A larger cohort study and a longer follow-up period will be required to clarify the relationship between endothelial dysfunction resulting from anthracycline treatment for childhood ALL and occurrence of cardiovascular diseases later in life.

Vascular endothelial dysfunction after anthracyclines treatment in children with acute lymphoblastic leukemia

Jang, Woo Jung,Choi, Duk Yong,Jeon, In-Sang The Korean Pediatric Society 2013 Clinical and Experimental Pediatrics (CEP) Vol.56 No.3

Purpose: Anthracyclines have been utilized in the treatment of children with acute lymphoblastic leukemia (ALL). Recent studies have shown that anthracyclines may induce toxicity in the vascular endothelium. This study was performed using brachial artery reactivity (BAR) to evaluate vascular endothelial function in ALL patients who were treated with anthracycline chemotherapy. Methods: We included 21 children with ALL who received anthracycline chemotherapy and 20 healthy children. The cumulative dose of anthracyclines in the ALL patients was $142.5{\pm}18.2/m^2$. The last anthracycline dose was administered to the patients 2 to 85 months prior to their examination using BAR. The diameter of the brachial artery was measured in both groups using echocardiography, and BAR was calculated as the percentage change in the arterial diameter after release of the cuff relative to the baseline vessel diameter. Results: In the anthracycline-treated group, BAR was observed to be $3.4%{\pm}3.9%$, which was significantly lower than that observed in the control group ($12.1%{\pm}8.0%$, P<0.05). The time elapsed after the last anthracycline treatment and the age at the time of treatment did not affect the change in BAR (P =0.06 and P =0.13, respectively). Conclusion: These results provided evidence that treatment of ALL patients with anthracycline results in endothelial dysfunction. A larger cohort study and a longer follow-up period will be required to clarify the relationship between endothelial dysfunction resulting from anthracycline treatment for childhood ALL and occurrence of cardiovascular diseases later in life.

Are Biomarkers Predictive of Anthracycline-Induced Cardiac Dysfunction?

Malik, Abhidha,Jeyaraj, Pamela Alice,Calton, Rajneesh,Uppal, Bharti,Negi, Preety,Shankar, Abhishek,Patil, Jaineet,Mahajan, Manmohan Kishan Asian Pacific Journal of Cancer Prevention 2016 Asian Pacific journal of cancer prevention Vol.17 No.4

Background: The early detection of anthracycline- induced cardiotoxicity is very important since it might be useful in prevention of cardiac decompensation. This study was designed with the intent of assessing the usefulness of cardiac troponin T (cTnT) and NT- Pro BNP estimation in early prediction of anthracycline induced cardiotoxicity. Materials and Methods: In this prospective study histologically proven breast cancer patients who were scheduled to receive anthracycline containing combination chemotherapy as a part of multimodality treatment were enrolled. Baseline cardiac evaluation was performed by echocardiography (ECHO) and biomarkers like cardiac troponin T (cTnT) and N terminal- pro brain natriuretic peptide (NT- Pro BNP). All patients underwent cTnT and NT- Pro BNP estimation within 24 hours of each cycle of chemotherapy and were followed up after 6 months of initiation of chemotherapy. Any changes in follow up ECHO were compared to ECHO at baseline and cTnT and NT- Pro BNP levels after each cycle of anthracycline-based chemotherapy. Results: Initial data were obtained for 33 patients. Mean change in left ventricular diastolic diameter (LVDD) within 6 months was $0.154{\pm}0.433cms$ (p value=0.049). Seven out of 33 patients had an increase in biomarker cTnT levels (p value=0.5). A significant change in baseline and follow up LVDD was observed in patients with raised cTnT levels (p value=0.026) whereas no change was seen in ejection fraction (EF) and left atrial diameters (LAD) within 6 months of chemotherapy. NT- Pro BNP levels increased in significant number of patients (p value ${\leq}0.0001$) but no statistically significant change was observed in the ECHO parameters within 6 months. Conclusions: Functional monitoring is a poorly effective method in early estimation of anthracycline induced cardiac dysfunction. Estimation of biomarkers after chemotherapy may allow stratification of patients in various risk groups, thereby opening window for interventional strategies in order to prevent permanent damage to the myocardium.

Gemcitabine and Vinorelbine Combination Chemotherapy in Anthracycline- and Taxane-pretreated Advanced Breast Cancer

김혜진,김진수,서명덕,오소연,오도연,김지현,이세훈,김동완,임석아,김태유,허대석,방영주 대한암학회 2008 Cancer Research and Treatment Vol.40 No.2

Purpose: Anthracycline and taxanes are effective agents in advanced breast cancer and prolong survival times. Some patients achieve prolongation of life with capecitabine, gemcitabine, or vinorelbine, even after failure of both anthracycline and taxanes. We analyzed the efficacy and toxicity of gemcitabine and vinorelbine combination chemotherapy in anthracycline- and taxane-pretreated advanced breast cancer. Materials and Methods: The medical records of anthracycline- and taxane-pretreated metastatic breast cancer patients who received gemcitabine and vinorelbine combination chemotherapy at the Seoul National University Hospital were reviewed. Gemcitabine (1,000 mg/m²) and vinorelbine (25 mg/m²) were administered intravenously on days 1 and 8 every 3 weeks. Results: Between 2000 and 2006, 57 patients were eligible (median age, 45 years), and the median number of previous chemotherapy regimens was 3 (range, 1∼5). The overall response rate was 30% (95% CI, 18.1∼ 41.9), and the disease control rate was 46% (PR, 30%; SD, 16%). The median duration of follow-up was 33.4 months, the median time-to-progression (TTP) was 3.9 months, and the median overall survival was 10.8 months. None of thepatients with patients with anthracycline and taxane primary resistance showed a response and the median TTP for these patients was significantly shorter than that of other patients (1.9 vs. 4.4 months; p=0.018). Although the efficacy was unsatisfactory in patients with both anthracycline and taxane primary resistance, gemcitabine and vinorelbine combination chemotherapy showed comparable efficacy in anthracyclineand/ or taxane-sensitive patients and the patients with secondary resistance, even after failure of second-line therapy. Grade 3/4 hematologic toxicities included neutropenia (18.1%) and febrile neutropenia (0.3%), and non-hematologic toxicities were tolerable. Conclusion: Gemcitabine and vinorelbine combination chemotherapy in anthracycline- and taxane-pretreated advanced breast cancer was effective and tolerable.

Comparing Role of Two Chemotherapy Regimens, CMF and Anthracycline-Based, on Breast Cancer Survival in the Eastern Mediterranean Region and Asia by Multivariate Mixed Effects Models: a Meta-Analysis

Ghanbari, Saeed,Ayatollahi, Seyyed Mohammad Taghi,Zare, Najaf Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.14

Purpose: To assess the role of two adjuvant chemotherapy regimens, anthracycline-based and CMF on disease free survival and overall survival breast cancer patients by meta-analysis approach in Eastern Mediterranean and Asian countries to determine which is more effective and evaluate the appropriateness and efficiency of two different proposed statistical models. Materials and Methods: Survival curves were digitized and the survival proportions and times were extracted and modeled to appropriate covariates by two multivariate mixed effects models. Studies which reported disease free survival and overall survival curves for anthracycline-based or CMF as adjuvant chemotherapy that were published in English in the Eastern Mediterranean region and Asia were included in this systematic review. The two transformations of survival probabilities (Ln (-Ln(S)) and Ln(S/ (1-S))) as dependent variables were modeled by a multivariate mixed model to same covariates in order to have precise estimations with high power and appropriate interpretation of covariate effects. The analysis was carried out with SAS Proc MIXED and STATA software. Results: A total of 32 studies from the published literature were analysed, covering 4,092 patients who received anthracycline-based and 2,501 treated with CMF for the disease free survival and in order to analyze the overall survival, 13 studies reported the overall survival curves in which 2,050 cases were treated with anthracycline-based and 1,282 with CMF regimens. Conclusions: The findings illustrated that the model with dependent variable Ln (-Ln(S)) had more precise estimations of the covariate effects and showed significant difference between the effects of two adjuvant chemotherapy regimens. Anthracycline-based treatment gave better disease free survival and overall survival. As an IPD meta-analysis in the Italy the results of Angelo et al in 2011 also confirmed that anthracycline-based regimens were more effective for survival of breast cancer patients. The findings of Zare et al 2012 on disease free survival curves in Asia also provided similar evidence.

Clinical Correlation between Brain Natriutetic Peptide and Anthracyclin-induced Cardiac Toxicity

이호섭,손창배,신성훈,김양수 대한암학회 2008 Cancer Research and Treatment Vol.40 No.3

Purpose: Anthracycline can effectively treat hematologic malignancies, but has significant risk of cardiotoxicity. We measured the clinical correlation between brain natriuretic peptide (BNP) and anthracycline-induced cardiotoxicity. Materials and Methods: Between March 2005 and March 2007, 86 patients with acute leukemia, malignant lymphoma, or multiple myeloma receiving systemic chemotherapy with anthracycline were enrolled in the Department of Hemato-oncology, Kosin University Gospel Hospital. We investigated the relationship between BNP level and cardiotoxicity through echocardiography, electrocardiography, BNP levels, and symptoms of heart failure at each chemotherapy cycle. Results: Of the 86 participants (mean age, 48.5 years; range 20∼65 years), cardiotoxicity developed in 21 patients (24.4%), with 2 patients showing arrhythmia only, 17 patients with transient aspects of heart failure, and 2 patients with chronic heart failure. Cardiotoxicity related to serum BNP level, age, cumulative dose of anthracycline, accompanying chronic disease, and elevated level of troponin-I. Heart failure was more common if BNP levels reached 100 pg/ml at least once. Conclusions: The clinical correlation between BNP and cardiotoxicity was significant in patients with systemic anthracycline chemotherapy. A prospective clinical trial will be needed to identify the causal relationship between serum BNP level and cardiotoxicity.

혈액종양 : Anthracycline 기반 항암화학요법에 반응을 한 염증성 근섬유모세포종

김달용 ( Dal Yong Kim ),박한승 ( Han Seung Park ),김선목 ( Sun Mok Kim ),박지현 ( Ji Hyun Park ),홍용상 ( Yong Sang Hong ),이재련 ( Jae Lyun Lee ),서철원 ( Cheok Won Suh ) 대한내과학회 2012 대한내과학회지 Vol.82 No.6

An inflammatory myofibroblastic tumor (IMT) is a rare disease entity, and the clinical characteristics range from indolent to aggressive forms. No established management for patients with unresectable or aggressive IMT is available. We report on a 62-year-old patient with aggressive IMT who achieved a durable partial response lasting 12 months after anthracycline-containing cytotoxic chemotherapy without corticosteroids. The patient was admitted for an evaluation of progressive weight loss and lower abdominal pain lasting for 2 weeks. Abdominopelvic computed tomography revealed a 10 cm sized heterogeneous mass in the mesentery that encased the superior mesenteric artery and a liver metastasis. The diagnosis of IMT was confirmed by percutaneous core needle biopsy of the mesenteric mass. Systemic chemotherapy was performed after confirming disease progression during a 1 month observation period. A partial response was obtained after two cycles of chemotherapy. Anthracycline-containing cytotoxic chemotherapy could be a treatment option for patients with aggressive IMT.

Phase II Study of Gemcitabine plus Cisplatin in Patients with Anthracycline- and Taxane- Pretreated Metastatic Breast Cancer

김정환,오성용,권혁찬,이수이,김성현,김대철,이진화,이형식,조세헌,김효진 대한암학회 2008 Cancer Research and Treatment Vol.40 No.3

Purpose: Metastatic breast cancer patients are usually exposed to taxane and anthracycline as neoadjuvant, adjuvant and palliative chemotherapeutic agents. This study was designed to determine the efficacy and safety of the use of a gemcitabine and cisplatin (GP) combination treatment in patients with metastatic breast cancer that were pretreated with anthracycline and taxane. Materials and Methods: We evaluated the use of a GP regimen (1,000 mg/m² gemcitabine administered on days 1 and 8 plus 60 mg/m² cisplatin administered on day 1 every 3 weeks) in 38 breast cancer patients who had received prior chemotherapy with anthracycline and taxane as an adjuvant or neoadjuvant therapy, or as a palliative therapy. Results: The median patient age was 49 years (age range, 35∼69 years). The overall response rate was 28.9% in 11 patients (95% confidence interval [CI], 14∼44%). The median time to progression was 5.2 months (95% CI, 3.6∼6.8 months). Median survival was 19.5 months (95% CI, 11.2∼27.8 months). Major grade 3/4 hematological toxicity was due to leukopenia (36 of 157 cycles, 23.1%). Non-hematological toxicity was rarely severe; grade1/2 nausea and vomiting were observed in 37.8% of the patients. There were no treatment related deaths. Conclusions: Our results suggest that the use of gemcitabine plus cisplatin appears to be effective and has an acceptable toxicity profile in patients with advanced breast cancer that have been pretreated with anthracycline and taxane.

새로운 Anthracycline계 항암제 DA-125의 일반약리작용

김명석,박종완,김영훈,김순회,신명수,김원배,양중익,Kim, Myung-Suk,Park, Jong-Wan,Kim, Young-Hoon,Kim, Soon-Hoe,Shin, Myeong-Soo,Kim, Won-Bae,Yang, Junn-Ick 대한약리학회 1994 대한약리학잡지 Vol.30 No.2

The general pharmacological effects of a new anthracycline anticancer agent, DA-125 $[7-0-(2,\;6-dideoxy-2-fluoro-{\alpha}-L-talopyranosyl)-adriamycinone-14-{\beta}-alaninate{\cdot}HCI]$ were investigated in mice, rats, guinea pigs, rabbits and dogs. Intravenous administration of DA-125 presented no significant effects on the central and peripheral nervous systems of ICR mice except a decrease in the numbers of acetic acid-induced writhing response at a dose of 10 mg/kg. In anesthetized rats and dogs, DA-125 produced a transient depression of blood pressure and an increase in heart rate, but did not affect the peripheral blood flow in the isolated ear vessels of rabbits and the mechanical functions of the isolated hearts of guinea pigs. No significant effects were observed on the gastrointestinal functions and the contractilities of smooth muscle preparations obtained from guinea pig trachea, rabbit ileum, pregnant and non-pregnant uterus and vas deferens of rats. DA-125 Increased the contractility of the isolated ileum of guinea pigs in a dose range of $10^{-6}{\sim}10^{-9}g/ml$, and also increased, but weaker than adriamycin, the vascular permeability in rat skin. DA-125 had no effect on the kallikrein-induced increase in permeability and the permeability of the visceral organs. DA-125 did not adversely affect the liver function and the blood coagulation system, and did not induce hemolysis in vitro. It is concluded from the results that the general pharmachological effects of DA-125 are similar to or weaker than those of adriamycin, and that little adverse effects are anticipated with a therapeutic dose range.