Early Detection of Anthracycline-Induced Cardiotoxicity in Long-Term Survivors of Acute Lymphoblastic Leukemia Treated with Low Cumulative Dose

We investigated the left ventricular (LV) function, using for the first time strain (S) and strain rate (SR) imaging, in long-term survivors affected by acute lymphoblastic leukemia treated with a low cumulative dose of anthracyclines, and in presence of a normal global LV systolic and diastolic function. A total of 21 were enrolled in the study. The mean cumulative dose of anthracylines was 180 mg/m² (range: 120-210 mg/m²). As control group 21 age-sex matched healthy subjects were included. Radial S (17 ± 3% vs. 55 ± 6%, P < 0.0001) and SR (2.1 ± 0.3 vs. 3.0 ± 0.8 1\s, P < 0.0001), assessed on the midsegment of the posterior wall from the parasternal views were significantly reduced when compared with controls. Conversely, myocardial performance index was not able to discriminate between patients and controls. In this preliminary study, the myocardial deformation indices appear to be a more sensitive noninvasive technique for detecting subclinical LV dysfunction than other echocardiographic measurements.     

乳腺癌中TOP2A与蒽环类药物关系的研究进展

目的探讨拓扑异构酶ⅡA（TOP2A）与人表皮生长因子受体2（HER2/neu）的关系,以及TOP2A对蒽环类药物在乳腺癌中疗效的预测价值。方法检索Cochrane、Medline、Embase、PubMed、中国知网及万方数据库以获得TOP2A与蒽环类药物相关研究的文献并进行综述。结果 TOP2A基因与HER2基因共同位于17q21,是HER2的下游基因。HER2与TOP2A基因异常有一定的关系,关于HER2与TOP2A对含蒽环类药物治疗方案的反应存在争议,目前普遍认为,根据TOP2A基因状态来预测患者对含蒽环类药物治疗方案的疗效可能更为准确。TOP2A的基因扩增与过表达表现出不一致性,是两个不同的生物学行为,它们有可能代表不同分子亚型的特点。目前,足量的临床研究可以说明TOP2A是蒽环类药物治疗的一个重要靶点,但蒽环类药物可以通过多种机制诱导细胞的凋亡,因此在乳腺癌中蒽环类药物杀死肿瘤细胞的机制不一定只是通过抑制TOP2A,可能比预测的更为复杂。结论 TOP2A是蒽环类药物治疗的一个重要靶点,但只是通过观察TOP2A来预测蒽环类药物的疗效似乎比较局限。     

Topoisomerase II-alfa gene as a predictive marker of response to anthracyclines in breast cancer

Amplification or deletion of the topoisomerase IIα (TOP2A) gene in breast cancer has been related with responsiveness to anthracyclines-based chemotherapy. The purpose of this study was to evaluate the predictive value of TOP2A gene for the efficacy of neo-adjuvant anthracycline in a population with locally advanced breast cancer. Sixty-two patients were included, and the status of TOP2A gene was determined by in situ hybridization method. Treatment efficacy was determined by clinical and pathological response and overall survival. TOP2A gene alterations were found in 22.6% (21.0% of cases with amplification and 1.6% with deletion), and these tumors were biologically more aggressive, with higher nuclear grade, more frequently with HER2 amplification and inflammatory type. Also in these tumors response to chemotherapy appeared to be increased. There was a higher clinical and pathological response rate (complete pathological response of 21.4% vs. 8.3%), a trend toward longer progression-free survival (82.51 vs. 63.12 months) and a trend to increased overall survival (92.08 months; 95% CI 82.81–101.35 vs. 73.40 months; 95% CI 63.44–83.36; p = 0.113). These results corroborate that the TOP2A gene alterations may play an important role in determining anthracycline sensitivity in breast cancer.     

多西紫杉醇联合卡培他滨治疗蒽环类耐药性晚期乳腺癌的疗效观察

目的 观察多西紫杉醇联合卡培他滨治疗蒽环类耐药性晚期乳腺癌的疗效和不良反应.方法 43例经病理证实的蒽环类耐药性晚期乳腺癌患者,采用多西紫杉醇联合卡培他滨方案化疗.多西紫杉醇75 mg/m<'2>、静脉滴注、dl,卡培他滨1600 mg/d、分2次口服、dl～14,21 d为1个周期,化疗周期数为3～6个周期,中位周期数4个,直至病情进展或不良反应无法耐受.结果 43例患者中,完全缓解9例(20.9%),部分缓解19例(44.2%),稳定9例(20.9%),疾病进展6例(14.0%),有效率为65.1%.中位肿瘤进展时间为7.5个月,中位生存期为15个月,1年生存率为62.8%,2年生存率为41.9%.不良反应主要为胃肠道反应、骨髓抑制和手足综合征,患者均可耐受.结论 多西紫杉醇联合卡培他滨治疗蒽环类耐药性晚期乳腺癌的疗效显著,不良反应可以耐受,可作为蒽环类耐药的晚期乳腺癌的有效解救治疗方案.     

Early detection of doxorubicin and daunorubicin cardiotoxicity by echocardiography: Diastolic versus systolic parameters

Doxorubicin and daunorubicin are effective anticancer agents in children, however, their therapeutic value is limited by myocardial cardiotoxicity. In 14 children (median age 5,0 years, range 3–12) prospective studies were performed using pulsed Doppler echocardiography to assess the changes in left ventricular systolic and diastolic filling dynamics. None of these children developed cardiomyopathy. M-mode echocardiographic systolic parameters and Doppler transmitral flow velocities were analysed at baseline, after a cumulative anthracycline dose of 138±26 mg/m² (second examination) and after 240±15 mg/m² (third examination). At the second examination the acceleration time/ejection time ratio was significantly reduced (P<0.01), but this was no longer evident at the third examination. There was no significant change of peak velocity over aortic valve, preejection period and change of velocity over time. In contrast, three diastolic parameters changed significantly; the late over early inflow velocity (P<0.05), mitral valve late time velocity integral (P<0.01 at the second andP<0.05 at the third examination) and the ratio A-TVI/TVI (P<0.025 andP<0.01). At the third examination the velocity of the A wave was also significantly increased.Conclusion In anthracyline treated children left ventricular diastolic function deteriorates before systolic function. Diastolic function parameters should be used rather than systolic parameters to monitor these patients.     

多西紫杉醇对蒽环类耐药性晚期乳腺癌的疗效分析

目的观察国产多西紫杉醇(Taxotere,TXT)为主的联合化疗方案治疗蒽环类耐药的晚期乳腺癌的疗效与安全性。方法晚期乳腺癌患者46例,其中21例给予多西紫杉醇联合顺铂(TXT DDP)方案化疗,17例给予多西紫杉醇联合吡喃阿霉素(TXT THP)方案化疗,8例给予多西紫杉醇联合米托蒽醌(TXT MIT)方案化疗。21天为1周期,2周期后评价疗效,有效患者治疗4周期以上。结果46例均可评价疗效,完全缓解(CR)4例(8.7%),部分缓解(PR)22例(47.9%),稳定(SD)18例(39.1%),进展(PD)2例(4.3%),总有效率(CR PR)为56.6%,中位肿瘤进展时间(TTP)为7.5个月。结论以多西紫杉醇为主的联合化疗可以作为治疗蒽环类耐药性晚期乳腺癌的补救方案。     

Phase I study of liposomal annamycin

Annamycin is a highly lipophilic anthracycline with the ability to bypass the MDR-1 mechanism of cellular drug resistance. In this phase I study, annamycin entrapped in liposomes was administered by a 1- to 2-h intravenous infusion at 3-week intervals. Thirty-six patients with relapsed solid tumors were treated and 109 courses were administered at doses ranging from 3 to 240 mg/m². The dose-limiting toxicity was thrombocytopenia. Five patients had a probable allergic reaction, requiring discontinuation of treatment in one. Treatment was well tolerated otherwise. No cardiac toxicity was seen on endomyocardial biopsy of four patients studied. There was limited gastrointestinal toxicity and no alopecia. No objective tumor responses were observed. Pharmacokinetic studies at 24, 120 and 240 mg/m² showed a biexponential plasma concentration-versus-time profile. There was a linear relationship between the dose and the maximal plasma concentration with relatively constant plasma clearance values. The maximum tolerated dose (MTD) for liposomal annamycin defined in this study is 210 mg/m². Because of a subsequent change in the formulation of the drug, future studies will use 190 mg/m² as the MTD. Received: 28 December 1999 / Accepted: 29 June 2000     

Long-term serial echocardiographic examination of late anthracycline cardiotoxicity and its prevention by dexrazoxane in paediatric patients

The authors conducted an 8-year prospective non-randomised study to determine whether dexrazoxane (ICRF-187) would reduce late anthracycline-induced cardiotoxicity in patients treated in childhood for haematological malignancy. The authors examined prospectively 75 patients (40 male/35 female) aged 2–17 years (median 6.5 years) at the time of diagnosis. The cardioprotection was given to 53 patients (26 male/17 female) and the standard protocol was used in 22 patients (14 male/8 female). The prospective echocardiographic evaluation was done before and after the chemotherapy and every year during the follow-up period. Dynamic stress echocardiography (DSE) was assessed in the final year. The clinical cardiotoxicity was not diagnosed. Higher cumulative doses of anthracycline were given in the dexrazoxane group (234±58 mg/m², median 240 mg/m² versus 203±86 mg/m², median 210 mg/m², P <0.04) and a significantly higher percentage of patients received cumulative doses >240 mg/m² of anthracycline ( P <0.05). During the follow-up period, the fractional shortening (FS) declined in the no-dexrazoxane group only in the 8th year and was significantly lower compared to the dexrazoxane group ( P <0.05). The pathological decrease in FS was present in 24% of patients; 41% in the no-dexrazoxane and 17% in the dexrazoxane groups, respectively ( P <0.05). DSE demonstrated lower rest EF and cardiac index (CI) in the no-dexrazoxane group ( P <0.05); however, neither the response of EF and CI to the stress echocardiography nor the exercise tolerance significantly differed between sub-groups. A higher number of patients in the dexrazoxane group had very good exercise tolerance (ET) >3 Watts/kg ( P <0.05) and a lower number responded with a decreased ET <2 Watts/kg ( P <0.05) compared to the no-dexrazoxane group. Conclusion:Dexrazoxane seems to reduce the risk of late subclinical cardiotoxicity. Dexrazoxane-treated patients revealed better exercise tolerance; however the haemodynamic response to the stress was no different in both sub-groups.     

治疗乳腺癌所致的心脏毒性及评价

在乳腺癌治疗中,蒽环类药物、紫杉类药物和靶向治疗药物曲妥单抗均具有心脏毒性,第三代芳香化酶抑制剂会增加冠状动脉粥样硬化性心脏病(冠心病)的风险,放疗也会引起心脏毒性。尤其以蒽环类化疗药物及其联合化疗方案的心脏毒性最为突出。因此,早期心脏毒性的检测对于预防和治疗心脏损害至关重要,心脏毒性的评价方法有多种,如心电图、心肌活检、超声心动图等,常规超声心动图是最常用的方法,超声心动图及其新技术的应用对心脏毒性的检测有重要价值。