Anthracycline-induced cardiotoxicity in children with cancer: strategies for prevention and management.
Anthracycline-induced cardiotoxicity in children with cancer: strategies for prevention and management.
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DOI：
10.2165/00148581-200507020-00001
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发表时间：
2005-01-01
期刊：
影响因子：
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通讯作者：
Calabro, Raffaele
中科院分区：
文献类型：
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作者：
Iarussi, Diana;Indolfi, Paolo;Calabro, Raffaele
蒽环类药物具有心脏毒性，严重缩小了其在肿瘤治疗中的治疗指标。心脏毒性风险随着累积剂量的增加而增加，并可能导致成人和儿童的充血性心力衰竭（CHF）和扩张性心肌病。预防蒽环类药物引起的心脏毒性对儿童尤其重要，因为他们的恶性肿瘤治愈后有望存活数十年。减少蒽环类药物心脏毒性的尝试方向是：(i)通过限制剂量和调整用药时间表来降低蒽环类药物及其代谢物的心肌浓度；（ii）开发对心脏毒性较小的类似物；（iii）同时使用心脏保护剂以减轻蒽环类药物对心脏的影响。至于时间表的修改，避免蒽环类药物的峰值水平可能会减少病理和临床心脏毒性，尽管这并不总是被观察到。阿霉素的类似物，如伊达柔比星和表柔比星，在给予等量的骨髓毒性时，具有与阿霉素相似的心脏毒性。脂质体蒽环类药物是一类新的药物，可能允许更具体的器官靶向，从而产生更少的全身和心脏毒性，但需要更多的研究来评估这些制剂与经典蒽环类药物相比的优势，如果有的话。心脏保护剂dexrazoxane是一种铁螯合剂，非常有效，对大多数接受含阿霉素的强化治疗的患者也能提供短期心脏保护。其长期效益仍有待确定。此外，数据仍然不足，无法就目前在儿童中使用dexrazoxane提出具体建议。据认为，与儿童期蒽环类药物治疗相关的细微异常可发展为更永久性的心肌疾病，导致心肌病，并可能发展为CHF。因此，关于蒽环类药物心脏毒性患者的治疗，必须考虑两种不同的情况：(i)如果患者出现心脏异常，例如超声心动图上的分步缩短减少，但没有心脏症状；（ii）如果患者患有慢性心力衰竭。在存在CHF的情况下，单独使用洋地黄-利尿剂治疗很少能恢复，对于有难治性血流动力学失代偿的患者，需要进行心脏移植。在CHF患者中，ACE抑制剂治疗可诱导左心室结构和功能的改善，但这种改善是短暂的。因此，需要随机临床试验来确定ACE抑制剂对轻中度左心室功能障碍的影响。在蒽环类药物引起的心力衰竭中，β -肾上腺素受体拮抗剂（β -受体阻滞剂）对心功能的有益作用似乎与在其他形式的心力衰竭合并收缩功能障碍中观察到的效果相当。许多药物可用于治疗因蒽环类药物治疗而患有CHF的儿童，但它们只是治标不治本的。
The fact that anthracyclines are cardiotoxic seriously narrows their therapeutic index in cancer therapy. The cardiotoxic risk increases with the cumulative dose and may lead to congestive heart failure (CHF) and dilated cardiomyopathy in adults and in children. The prevention of anthracycline-induced cardiotoxicity is particularly important in children who can be expected to survive for decades after being cured of their malignancy. Attempts to reduce anthracycline cardiotoxicity have been directed towards: (i) decreasing myocardial concentrations of anthracyclines and their metabolites by dose limitation and schedule modification; (ii) developing less cardio-toxic analogs; and (iii) concurrently administering cardioprotective agents to attenuate the effects of anthracyclines on the heart. As regards schedule modification, avoidance of anthracycline peak levels may reduce the pathologic and clinical cardiotoxicity, although this has not always been observed. The analogs of doxorubicin, such as idarubicin and epirubicin, have similar cardiotoxicity to that of doxorubicin when given in amounts of equivalent myelotoxicity. Liposomal anthracyclines are a new class of agents that may permit more specific organ targeting, thereby producing less systemic and cardiac toxicity, but more studies are required to assess the advantages, if any, of these preparations over classical anthracyclines. The cardioprotective agent, dexrazoxane, an iron chelator, is highly effective and provides short-term cardioprotection to most patients receiving even the most intensive doxorubicin-containing regimens. Its long-term benefits remain to be determined. In addition, data remain insufficient to make specific recommendations regarding current use of dexrazoxane in children. It is thought that subtle abnormalities, related to anthracycline treatment in childhood, can develop into more permanent myocardial disease resulting in cardiomyopathy, which may progress to CHF. As regards the therapy of patients with anthracycline cardiotoxicity, two different situations have, therefore, to be considered: (i) if the patient presents with cardiac abnormalities, such as a reduction in fractional shortening at echocardiogram, without cardiac symptoms; and (ii) if the patient has CHF. In the presence of CHF, recovery with digitalis-diuretic therapy alone seldom occurs, and in patients who have refractory hemodynamic decompensation, heart transplantation is indicated. In patients with CHF, therapy with ACE inhibitors induces improvement in left ventricular structure and function, but this improvement is transient. Randomized clinical trials are, therefore, necessary to determine the effects of ACE inhibitors in mild-to-moderate left ventricular dysfunction. The beneficial effects of beta-adrenoceptor antagonists (beta-blockers) on cardiac function in heart failure due to anthracyclines seem comparable with those observed in other forms of heart failure with systolic dysfunction. Many drugs are available to treat children with CHF due to anthracycline treatment, but they are only palliative.