MRC Biostatistics Unit, University of Cambridge, Cambridge, United Kingdom.
Winton Centre for Risk & Evidence Communication, Department of Pure Mathematics & Mathematical Statistics, University of Cambridge, Cambridge, United Kingdom.
PLoS One. 2022 Dec 1;17(12):e0275321. doi: 10.1371/journal.pone.0275321. eCollection 2022.
Trastuzumab is a valuable therapy option for women with ERBB2(HER2)+ breast cancer tumours, often used in combination with chemotherapy and alongside other therapies. It is known to have adverse effects, but these have proved difficult to separate from the effects of other concurrent therapies patients are usually taking. This study aims to assess the adverse effects specifically attributable to trastuzumab, and whether they vary by patient subgroup or concurrent therapies.
As registered on PROSPERO (CRD42019146541), we used previous systematic reviews as well as the clinicaltrials.gov registry to identify randomised controlled trials in breast cancer which compared treatment regimes with and without trastuzumab. Neoadjuvant, adjuvant and metastatic settings were examined. Data was extracted from those which had, as of July 2022, reported adverse events. Risk of bias was assessed using ROB2. Primary outcomes were adverse events of any type or severity (excluding death). A standard random-effects meta-analysis was performed for each outcome independently. In order to ascertain whether adverse effects differed by individual factors such as age or tumour characteristics, or by use of trastuzumab concurrently with hormone therapy, we examined individual-level patient data for one large trial, HERA.
79 relevant trials were found, of which 20 contained comparable arms of trastuzumab-containing therapy and corresponding matched therapy without trastuzumab. This allowed a comparison of 8669 patients receiving trastuzumab versus 9556 receiving no trastuzumab, which gave a list of 25 statistically and clinically significant adverse effects related to trastuzumab alone: unspecified pain, asthenia, nasopharyngitis, skin disorders (mainly rash), dyspepsia, paraesthesia, infections (often respiratory), increased lacrimation, diarrhoea, myalgia, oedema (limb/peripheral), fever, nose bleeds, cardiac events, insomnia, cough, back pain, dyspnoea, chills, dizziness or vertigo, hypertension, congestive heart failure, increased levels of aspartate aminotransferase, gastrointestinal issues and dehydration. Analysis of individual patient-level data from 5102 patients suggested that nausea is slightly more likely for women taking trastuzumab who are ER+ /also taking hormone therapy than for those who are ER-/not taking hormone therapy; no other potential treatment-subgroup interactions were detected. We found no evidence for significantly increased rates of neutropenia, anaemia or lymphopenia in patients on trastuzumab-containing regimes compared to those on comparable regimes without trastuzumab.
This meta-analysis should allow clinicians and patients to better identify and quantify the potential adverse effects of adding trastuzumab to their treatment regime for breast cancer, and hence inform their decision-making. However, limitations include serious risk of bias due to heterogeneity in reporting of the outcomes and the open-label nature of the trials.
曲妥珠单抗是一种有价值的治疗选择，适用于 ERBB2（HER2）+乳腺癌肿瘤的女性患者，通常与化疗联合使用，并与其他疗法联合使用。它已知具有不良反应，但这些不良反应很难与患者通常正在接受的其他同时进行的治疗的影响区分开来。本研究旨在专门评估曲妥珠单抗特有的不良反应，以及它们是否因患者亚组或同时进行的治疗而有所不同。
正如在 PROSPERO（CRD42019146541）上注册的那样，我们使用了以前的系统评价以及 clinicaltrials.gov 注册处，以确定比较了曲妥珠单抗治疗与无曲妥珠单抗治疗的乳腺癌随机对照试验。检查了新辅助、辅助和转移性环境。从截至 2022 年 7 月已报告不良事件的试验中提取数据。使用 ROB2 评估偏倚风险。主要结局是任何类型或严重程度的不良事件（不包括死亡）。为每个结局独立进行了标准的随机效应荟萃分析。为了确定不良反应是否因年龄或肿瘤特征等个体因素或曲妥珠单抗与激素治疗同时使用而有所不同，我们检查了一项大型试验 HERA 的个体水平患者数据。
发现了 79 项相关试验，其中 20 项包含了曲妥珠单抗治疗的可比臂和相应的无曲妥珠单抗治疗的可比臂。这允许比较 8669 名接受曲妥珠单抗治疗的患者和 9556 名未接受曲妥珠单抗治疗的患者，得出了 25 种与曲妥珠单抗单独相关的具有统计学和临床意义的不良反应：不明原因的疼痛、乏力、鼻咽炎、皮肤疾病（主要是皮疹）、消化不良、感觉异常、感染（常为呼吸道）、流泪增加、腹泻、肌痛、水肿（肢体/外周）、发热、鼻出血、心脏事件、失眠、咳嗽、背痛、呼吸困难、寒战、头晕或眩晕、高血压、充血性心力衰竭、天冬氨酸氨基转移酶水平升高、胃肠道问题和脱水。对来自 5102 名患者的个体患者水平数据的分析表明，与 ER-/未接受激素治疗的患者相比，接受曲妥珠单抗治疗且 ER+/同时接受激素治疗的女性患者发生恶心的可能性略高；未发现其他潜在的治疗亚组相互作用。我们发现，与无曲妥珠单抗治疗相比，接受曲妥珠单抗治疗的患者中性粒细胞减少症、贫血或淋巴细胞减少症的发生率没有明显增加。
这项荟萃分析应该使临床医生和患者能够更好地识别和量化添加曲妥珠单抗治疗乳腺癌的潜在不良反应，从而为他们的决策提供信息。然而，限制包括由于结局报告的异质性和试验的开放性标签性质而导致的严重偏倚风险。
