Association of pazopanib-induced toxicities with outcome of patients with advanced soft tissue sarcoma; a retrospective analysis based on the European Organisation for Research and Treatment of Cancer (EORTC) 62043 and 62072 clinical trials

<b>Background:</b> There is an unmet need for markers predicting the outcome of patients with advanced soft tissue sarcoma (STS) treated with pazopanib. Since toxicity might be related to the anti-tumor activity of the drug, the aim of this study was to determine whether pazopanib-induced proteinuria, hypothyroidism and cardiotoxicity grade 3-4 were associated with outcome. <b>Methods:</b> The combined results of the EORTC 62043 and 62072 trials were retrospectively assessed and used in a landmark analysis to evaluate the effect of the toxicities on progression-free survival (PFS) and overall survival (OS), using the Kaplan-Meier method and Cox regression models. <b>Results:</b> Of the 333 eligible patients, 259 patients were included in the analyses, for which a landmark time point of 60 days after randomization/registration was selected. Proteinuria occurred in 25.1%, hypothyroidism in 22.0% and cardiotoxicity grade 3–4 in 5.8% of the patients (any grade in 41.7%). There was no effect of the occurrence of proteinuria (6-months PFS 35.4% for patients with vs. 38.3% for patients without proteinuria, HR 1.01, <i>p</i> = .953), hypothyroidism (41.2% vs. 36.5%, HR 0.82, <i>p</i> = .210) or cardiotoxicity grade 3–4 (26.7% vs. 38.2%, HR 0.97, <i>p</i> = .897) on PFS. Nor was there an effect of proteinuria (6-months OS 63.2% for patients with vs. 74.4% for patients without proteinuria, HR 1.22, <i>p</i> = .196), hypothyroidism (76.2% vs. 70.5%, HR 0.75, <i>p</i> = .093) or cardiotoxicity grade 3–4 (80.0% vs. 77.2%, HR 0.93, <i>p</i> = .801) on OS. <b>Conclusion:</b> There was no association between the occurrence of pazopanib-induced proteinuria, hypothyroidism and cardiotoxicity and outcome. Therefore, these toxicities cannot be used as predictors for pazopanib activity in patients with advanced STS.

**背景：** 目前临床仍存在未被满足的临床需求，即缺乏针对接受帕唑帕尼（pazopanib）治疗的晚期软组织肉瘤（soft tissue sarcoma, STS）患者的预后预测标志物。由于药物毒性可能与该药物的抗肿瘤活性相关，本研究旨在探讨帕唑帕尼诱导的蛋白尿、甲状腺功能减退及3~4级心脏毒性是否与患者预后存在关联。
**方法：** 本研究对欧洲癌症研究与治疗组织（EORTC）62043与62072两项临床试验的合并数据进行回顾性分析，并采用界标分析（landmark analysis）方法，结合Kaplan-Meier法与Cox回归模型，评估上述毒性反应对患者无进展生存期（progression-free survival, PFS）及总生存期（overall survival, OS）的影响。
**结果：** 在333例符合入组标准的患者中，最终有259例纳入本次分析，本研究选取随机入组/登记后60天作为界标时间点。结果显示，患者中蛋白尿发生率为25.1%，甲状腺功能减退发生率为22.0%，3~4级心脏毒性发生率为5.8%；任意级别毒性反应的总发生率为41.7%。上述三种毒性反应的发生均未对患者PFS产生显著影响：伴蛋白尿患者的6个月PFS率为35.4%，未伴者为38.3%（风险比（hazard ratio, HR）=1.01，p=0.953）；伴甲状腺功能减退患者的6个月PFS率为41.2%，未伴者为36.5%（HR=0.82，p=0.210）；伴3~4级心脏毒性患者的6个月PFS率为26.7%，未伴者为38.2%（HR=0.97，p=0.897）。同样，上述毒性反应也未对患者OS产生显著影响：伴蛋白尿患者的6个月OS率为63.2%，未伴者为74.4%（HR=1.22，p=0.196）；伴甲状腺功能减退患者的6个月OS率为76.2%，未伴者为70.5%（HR=0.75，p=0.093）；伴3~4级心脏毒性患者的6个月OS率为80.0%，未伴者为77.2%（HR=0.93，p=0.801）。
**结论：** 本研究结果显示，帕唑帕尼诱导的蛋白尿、甲状腺功能减退及心脏毒性的发生与晚期STS患者的预后无显著关联。因此，上述毒性反应无法作为预测晚期STS患者接受帕唑帕尼治疗疗效的标志物。