Bria Emilio, Cuppone Federica, Fornier Monica, Nisticò Cecilia, Carlini Paolo, Milella Michele, Sperduti Isabella, Terzoli Edmondo, Cognetti Francesco, Giannarelli Diana
Department of Medical Oncology, Regina Elena National Cancer Institute, Rome, Italy.
Breast Cancer Res Treat. 2008 May;109(2):231-9. doi: 10.1007/s10549-007-9663-z. Epub 2007 Jul 19.
In five randomized clinical trials (RCTs), adjuvant trastuzumab (T) for early stage breast cancer with human epidermal growth-factor receptor-2 over-expression/gene-amplification has shown to decrease the risk of both recurrence and death. The issue regarding the long-term safety profile of such drug is still open; in particular, questions remain about long-term cardiotoxicity, and specific patterns of relapse such as brain metastases (BM). In order to quantify the magnitude of these two risks, and then balance those with the survival outcome, a literature-based meta-analysis was performed.
All phase III trials were considered eligible. A literature-based meta-analysis was accomplished, and event-based relative risk ratios with 95% confidence interval were derived. A fixed- and a random-effect model according to the inverse variance and the Mantel-Haenzel method were applied. Heterogeneity test was applied as well. Absolute differences (AD) and the Number of patients Needed to Treat or to Harm (NNT/NNH) were calculated. Safety end-points were: (1) Chronic Heart Failure (CHF) grade III-IV rate, (2) Significant reduction of left-ventricular-ejection-fraction (L-FEV) rate and (3) BM rate. In order to quantify the magnitude of the significant benefit already found in the original RCTs, Efficacy end-points were: (1) disease-free survival (DFS) and (2) overall survival (OS).
Five RCTs were gathered (11,187 patients); at an average 2-years follow-up, all data was available for the safety and efficacy end-points, while three RCTs reported results for BM analysis (6,738 patients). When considering RCTs with trastuzumab administered for 1 year, a significant increased risk of grade III-IV Congestive Heart Failure (CHF) was found in the T-arm, with an AD of 1.61% (p < 0.00001), which translates into 62 treated patients required to harm one (NNH). When considering the asymptomatic L-FEV reduction, a significant increased risk of grade significant L-FEV reduction was found in the T-arm, although significantly heterogeneous, with an AD of 7.20% (p < 0.00001), which translates into 14 NNH. The incidence of BM was significantly higher in the T-arm, without significant heterogeneity, with an AD of 0.62 (p = 0.033), which translates into 161 NNH. The DFS, DDFS, and OS were significantly better in the T-arm, with an AD of 6.00, 4.80 and 1.96%, which translates into 16, 21 and 51 NNT, respectively.
The overall outcome results show that trastuzumab is one of the most important discoveries in oncology. Nevertheless, the biological activity of trastuzumab needs to be investigated more extensively to explore both long-term safety and specific relapse patterns.
在五项随机临床试验（RCT）中，辅助性曲妥珠单抗（T）用于治疗人类表皮生长因子受体2过表达/基因扩增的早期乳腺癌，已显示出可降低复发和死亡风险。关于此类药物长期安全性的问题仍未解决；特别是，长期心脏毒性以及脑转移（BM）等特定复发模式方面的问题依然存在。为了量化这两种风险的程度，然后将其与生存结果进行权衡，我们进行了一项基于文献的荟萃分析。
所有III期试验均被视为符合条件。完成了一项基于文献的荟萃分析，并得出了具有95%置信区间的基于事件的相对风险比。根据逆方差和Mantel-Haenzel方法应用了固定效应模型和随机效应模型。也进行了异质性检验。计算了绝对差异（AD）以及需要治疗或造成伤害的患者数量（NNT/NNH）。安全性终点为：（1）III-IV级慢性心力衰竭（CHF）发生率，（2）左心室射血分数（L-FEV）显著降低发生率，以及（3）BM发生率。为了量化在原始RCT中已发现的显著益处的程度，疗效终点为：（1）无病生存期（DFS）和（2）总生存期（OS）。
收集了五项RCT（11187例患者）；平均随访2年时，所有数据均可用于安全性和疗效终点分析，而三项RCT报告了BM分析结果（6738例患者）。当考虑接受曲妥珠单抗治疗1年的RCT时，在T组中发现III-IV级充血性心力衰竭（CHF）风险显著增加，AD为1.61%（p < 0.00001），这意味着每伤害1例患者需要治疗62例。当考虑无症状L-FEV降低时，在T组中发现显著L-FEV降低风险显著增加，尽管存在显著异质性，AD为（p < 0.00001），这意味着每伤害1例患者需要治疗14例。T组中BM发生率显著更高，无显著异质性，AD为0.62（p = 0.033），这意味着每伤害1例患者需要治疗161例。T组中的DFS、DDFS和OS显著更好，AD分别为6.00%、4.80%和1.96%，这意味着每治疗1例患者分别可使16例、21例和51例患者受益。
总体结果表明，曲妥珠单抗是肿瘤学领域最重要的发现之一。然而，需要更广泛地研究曲妥珠单抗的生物学活性，以探索其长期安全性和特定复发模式。
