Cochrane系统评价：曲妥珠单抗治疗晚期HER2阳性乳腺癌患者利大于弊

6月11日《Cochrane系统评价数据库》报告的据一项研究显示，曲妥珠单抗用于转移性HER2阳性乳腺癌女性治疗，与显著改善无进展生存期和总生存期相关，但以心衰和左心室射血分数（LVEF）降低等心脏毒性作为代价(Cochrane Database Syst. Rev. 2014 June 11 [doi:10.1002/14651858.CD006242.pub2]。

该系统评价纳入1,497例接受单纯曲妥珠单抗治疗或联合其他药物治疗的HER2阳性患者的7项随机对照试验，其中含曲妥珠单抗治疗组为752例，对照组为745例。结果显示，曲妥珠单抗延长死亡时间5~8个月，延长疾病进展时间2~12个月。

与对照组相比，曲妥珠单抗治疗可显著改善总生存期[风险比（HR），0.82；95%置信区间（CI）， 0.71~0.94；P =0.004]和无进展生存期（HR，0.61；95% CI， 0.54~0.70； P <0.00001）。

曲妥珠单抗用作一线治疗药物，对改善总生存期效果更加显著（HR， 0.79；95% CI ，0.67~0.94； P = 0.006），而在疾病进展后使用，未达到统计学显著差异水平。

与紫杉醇等紫杉烷类药物联用，也可显著改善总生存期（HR，0.80；95% CI，0.65~0.99；P = 0.04）和无进展生存期（HR，0.53；95% CI，0.42~0.68）。

意大利Cochrane中心统计学家Sara Balduzzi女士及其同事指出：“Meta分析显示，含有曲妥珠单抗的治疗方案可显著改善总生存期和无进展生存期，与进展后使用或以紫杉烷为基础的方案相比，曲妥珠单抗作为一线治疗效果可能更佳。”

对曲妥珠单抗治疗风险与获益的担忧促使研究者开展这项系统评价研究。

作者称：“现有支持曲妥珠单抗方案的证据大多基于替代终点指标，尽管有效性结果似乎支持该药物的使用，但有关其净获益方面的不确定性引发人们的关注，包括一过性心脏毒性和中枢神经系统转移长期风险增加。”

曲妥珠单抗组严重心脏事件发生率为4.7%，而对照组为1.1%，表明风险增加3倍[相对风险（RR），3.49；90% CI，1.88~6.47；P = 0.0009]。

与单纯接受蒽环类药物相比，曲妥珠单抗联合蒽环类药物可使严重心脏事件风险增加5倍（RR，5.43；90% CI，2.28~12.94；P = 0.001）。

在5项试验中，接受曲妥珠单抗治疗的478例女性中有28例（5.9%）出现LVEF降低，而在对照组460例女性中仅为9例（2%）（RR，2.65； 90% CI，1.48~4.74； P = 0.006）。

一项研究报告了有关脑转移的资料信息：含曲妥珠单抗组脑转移率为17.9%（42/235例），而对照组为9.0%（21/234例）（RR，1.99； 95% CI，1.32~3.01）。在另一项考察了已知脑转移患者病例的研究中，146例曲妥珠单抗治疗患者中有9例（6.2%）出现中枢神经系统进展，而接受单纯拉帕替尼治疗的145例患者中，有15例（10.3%）出现进展（RR，0.60；90% CI，0.31~1.16）。

研究者还观察到曲妥珠单抗治疗女性中性粒细胞减少性发热风险未见显著性增加。

一位作者声称为制药行业代言、担任顾问以及获得研究基金资助。无其他利益冲突披露。

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Trastuzumab therapy in women with metastatic HER2-positive breast cancer is associated with significant gains in progression-free and overall survival but at the expense of cardiac toxicities such as heart failure and reduced left ventricular ejection fraction, according to a Cochrane Review.

The review of seven randomized, controlled trials involving 1,497 HER2-positive patients treated with trastuzumab, alone or in combination with other therapies, found the drug extended the time to death between 5 and 8 months and extended time to disease progression by 2-12 months, as reported June 11 in Cochrane Database of Systematic Reviews.

Treatment with trastuzumab led to a statistically significant improvement in overall survival (hazard ratio, 0.82; 95% CI 0.71-0.94; P = .004), and in progression-free survival (HR, 0.61; 95% CI 0.54-0.70; P less than .00001), compared with the control groups.

Trastuzumab was significantly more effective at improving overall survival when used as a first-line treatment (HR, 0.79; 95% CI 0.67-0.94; P = .006) and failed to achieve statistical significance when used after disease progression.

Coadministration with taxanes such as paclitaxel also led to a statistically significant improvement in overall survival (HR, 0.80; 95% CI 0.65-0.99; P = .04) and in progression-free survival (HR, 0.53; 95% CI 0.42-0.68).

"The meta-analysis showed a significant improvement in overall survival and progression-free survival for trastuzumab-containing regimens, which is possibly greater when considering patients treated as first-line compared to its use beyond progression, or patients receiving taxane-based regimens," wrote Ms. Sara Balduzzi, a statistician with the Italian Cochrane Centre, and her colleagues.

The review was prompted by concerns about the risks vs. benefits of trastuzumab (Cochrane Database Syst. Rev. 2014 June 11 [doi:10.1002/14651858.CD006242.pub2]).

"The available evidence supporting trastuzumab regimens mostly relies upon surrogate endpoints and, although the efficacy results seem to support its use, other uncertainties have been raised about its net benefit in relation to transient cardiac toxicity and a long-term increased risk of metastasis to the central nervous system," the authors wrote.

The incidence of a severe cardiac event was 4.7% in the trastuzumab group, compared with 1.1% in the control group, reflecting a more than threefold increase in risk (relative risk, 3.49; 90% CI 1.88-6.47;P = .0009).

Coadministration with an anthracycline increased the risk of a severe cardiac event fivefold, compared with treatment with anthracycline alone (RR, 5.43; 90% CI 2.28-12.94; P = .001).

In five trials, there were also 28 cases (5.9%) of left ventricular ejection fraction (LVEF) decline in the 478 women treated with trastuzumab, compared with 9 cases out of 460 (2%) in the control group (RR, 2.65; 90% CI 1.48-4.74; P = .006).

One study reported information on brain metastases; There were 42 cases (17.9%) out of 235 in the trastuzumab-containing group and 21/234 (9.0%) in the control group (RR, 1.99; 95% CI 1.32-3.01). Another study, which allowed the accrual of patients with known brain metastases, reported that 9 (6.2%) out of the 146 patients treated with trastuzumab experienced central nervous system progression, whereas 15 patients (10.3) out of the 145 treated with lapatinib alone experienced progression while on the study (RR, 0.60; 90% CI 0.31-1.16), the authors reported.

Researchers also observed a nonsignificant increase in the risk of neutropenic fever among women treated with trastuzumab.

Overall, there were 752 women in the trastuzumab-containing arm and 745 controls.

One author declared speaking engagements, consultancies, and an institutional grant from the pharmaceutical industry. There were no other conflicts of interest declared.