以较长时间输注Anthracyclines降低心脏损伤

　　November 29, 2006 — 根据一项新的Cochrane回顾性文章，以较长anthracycline可能降低这些药物的心脏毒性。
　　
　　作者表示，以6个小时以上的输注时间注射anthracycline，可以降低发生临床心脏衰竭的风险，而且似乎可以降低亚临床心脏损伤的风险。
　　
　　主要作者荷兰阿姆斯特丹Emma 儿童医院Elvira van Dalen医师表示，Anthracycline类药物引起的心脏毒性显然与最高血中浓度有关，且其抑制肿瘤效力与组织中浓度有关；她表示，较长的输注时间可以降低anthracycline浓度，使心脏毒性降低，且维持抗肿瘤活性。
　　
　　【显著降低临床心脏衰竭】
　　作者进行一项收纳6个随机分派临床试验的综合分析，共有625位病患；主要的病患为罹患不同形式固体肿瘤的成人，使用的药物包括doxorubicin、daunorubicin与epirubicin。
　　
　　收集五项临床数据（共有557位）显示，接受持续输注6个小时以上的病患发生临床心脏衰竭风险，相较于输注时间较短病患（少于1个小时）低，接受较长时间输注病患相较于较短输注时间风险大约下降75%（相对风险为0.27；95%信赖区间为0.09－0.81）。
　　
　　根据两项各自临床试验，输注时间较长也降低亚临床心脏损伤，举例来说，以无症状病患的心脏超音波来诊断不同心脏异常。
　　
　　作者表示，输注时间显然不会影响抑制肿瘤活性或是整体存活率。
　　
　　作者的结论是，延长输注时间超过6个小时可能适用于高心脏损伤风险病患、或是需要高累积剂量化学疗法病患；然而，van Dalen医师向Medscape表示，临床治疗的建议应该由医师权衡所有目前的证据，而不是仅根据心脏毒性，还要兼顾抑制肿瘤活性与其他不良反应。
　　
　　【未来需要儿童的研究】
　　作者强调，这些研究中大部分的病患是罹患进展性固体肿瘤的成人，仅有少数儿童病患；由于儿童相关数据并不多，且因为成人病患数据不能延伸应用在儿童身上，应该针对儿童病患进行不同anthracycline输注时间的研究。
　　
　　van Dalen医师表示，目前并没有足够罹患固体肿瘤儿童病患的资料，虽然有两项白血病儿童研究；但她表示，这两项研究中，不同输注时间引起的心脏损伤并没有差异，且没有相关抑制肿瘤活性资料。
　　
　　【不同Anthracycline类药物之间的差异】
　　同样一群作者的另一篇Cochrane回顾性文章中，研究anthracycline相似物在心脏损伤方面是否有差异。
　　
　　她表示，有部份意见表示epirubicin引起临床心脏衰竭的风险比doxorubicin低，虽然其差异并不显著；这项研究根据五项临床试验，共有1036位病患，作者的结论是，当以同样剂量投予时，我们并不能决定epirubicin或是doxorubicin孰优孰劣。
　　
　　他们表示，然而，证据显示，微脂粒包覆之doxorubicin比传统doxorubicin，使用于罹患固体肿瘤成人病患身上，发生心脏损伤的风险较低；在一项分析两项临床试验，共521位病患的研究中显示，微脂粒包覆的doxorubicin相较于传统产品，发生临床心脏衰竭的比例显著较低（相对风险为0.20；95%信赖区间为0.05－0.75）。

Longer Infusion Times for Anthracyclines Reduce Cardiac Damage

By Zosia Chustecka
Medscape Medical News

November 29, 2006 ??Using a longer infusion time for anthracycline administration may reduce the cardiotoxicity of these drugs, suggests a new Cochrane review.

"An anthracycline infusion duration of 6 hours or longer reduces the risk of clinical heart failure, and it seems to reduce the risk of subclinical cardiac damage," the authors conclude.

Anthracycline-induced cardiotoxicity appears to be related to the peak plasma drug concentration, while the antitumor activity depends on tissue concentration over time, lead researcher Elvira van Dalen, MD, from the Emma Children's Hospital, in Amsterdam, the Netherlands, explained to Medscape. Prolonging the infusion time reduces the peak anthracycline concentration, with potentially less cardiotoxicity, while maintaining the antitumor activity, she said.

Significant Reduction in Clinical Heart Failure

The authors conducted a meta-analysis of 6 randomized clinical trials, involving a total of 625 patients. The majority of patients were adults with different types of solid tumors, and the drugs used were doxorubicin, daunorubicin, and epirubicin.

Results from 5 trials (n = 557) showed that patients who received an infusion over a 6-hour period or longer had a significantly lower rate of clinical heart failure than patients who received infusions of shorter duration (lasting 1 hour or less). The risk was around 75% lower in patients receiving the longer infusions compared with the shorter infusions (relative risk, 0.27; 95% CI 0.09 ??0.81).

Results from 2 individual trials suggest that the longer infusion time also reduces the risk of subclinical cardiac damage ??the various cardiac abnormalities diagnosed with, for example, echocardiography in asymptomatic patients.

The duration of the infusion did not appear to affect either tumor response or overall survival, the researchers report.

The prolonged infusion of 6 hours or more might be justified in patients who are at high risk of cardiac damage or patients who need a high cumulative dose of chemotherapy, the authors conclude. However, in comments to Medscape, Dr. van Dalen added: "Recommendations for clinical practice should be made by clinicians who should weigh all the available evidence, not only on cardiotoxicity but also on antitumor efficacy and other adverse effects."

Further Studies in Children Needed

The researchers emphasize that most of the patients in these studies were adults with advanced solid tumors, and very few children were included. "Since there is only a small amount of data for children and because data obtained in adults cannot be extrapolated to children, different anthracycline infusion durations should be evaluated further in children," they comment.

No adequate studies in children with solid tumors are available, Dr. van Dalen noted, although there are 2 trials in children with leukemia. In these 2 trials, no difference was seen in the cardiac damage with different infusion durations, and there was no information on antitumor efficacy, she said.

Differences Between Anthracycline Derivatives

A second Cochrane review by the same group of authors investigated whether the anthracycline derivatives differed in their potential for cardiotoxicity.

There is some suggestion of a lower rate of clinical heart failure with epirubicin compared with doxorubicin, they comment, although the difference was not significant. This analysis was based on 5 trials involving 1036 patients. "We are not able to favor either epirubicin or doxorubicin when given at the same dose," they conclude.

However, there is evidence to favor liposomal-encapsulated doxorubicin over conventional doxorubicin in adults with solid tumors, they note. In an analysis of 2 trials involving 521 patients, the liposomal-encapsulated drug was associated with a significantly lower rate of clinical heart failure than the conventional product (RR, 0.20; 95% CI, 0.05 ??0.75).

Cochrane Database Syst Rev. 2006;(4):CD005008, CD005006.