Department of Oncology, Università degli Studi di Torino, Turin, Italy; Phase 1 Unit, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome.
Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy; Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.
Cancer Treat Rev. 2022 Feb;103:102326. doi: 10.1016/j.ctrv.2021.102326. Epub 2021 Dec 23.
Retrospective series suggest that bevacizumab-induced hypertension (HTN) is a prognostic and potentially predictive biomarker of efficacy of the antiangiogenic drug in the upfront treatment of metastatic colorectal cancer (mCRC) patients. The immortal-time bias and the effect of pre-existing HTN might affect these findings. We conducted a pooled, post hoc analysis of 2 prospective randomized trials of chemotherapy plus bevacizumab in mCRC, and performed a systematic review of the available literature focusing on how the immortal-time bias was taken into account and how pre-existing HTN potentially requiring the use of antihypertensive drugs was managed.
The pooled-analysis included patients enrolled in the phase III TRIBE and TRIBE-2 studies that compared upfront FOLFOXIRI + bevacizumab to FOLFIRI or FOLFOX + bevacizumab, respectively. Association between HTN and survival outcomes was assessed by incorporating a time-dependent Cox regression model to consider the time-dependency of the probability of HTN onset during the treatment. The systematic review was conducted according to PRISMA guidelines.
The systematic review retrieved 14 eligible and highly heterogeneous studies. A positive prognostic impact of bevacizumab-induced HTN was reported in the 58% of the analyses reporting Progression Free Survival (PFS) and in the 54% of the analyses reporting Overall Survival (OS) data. Immortal-time bias was incorporated in 4 studies (28%). In TRIBE and TRIBE-2 study populations (N = 1175), patients experiencing ≥ G2 HTN during first-line bevacizumab administration showed longer PFS (median: 14.7 versus 10.3 months, p < 0.001) and OS (median: 31.7 versus 24.2 months, p < 0.001). The association with OS retained statistical significance after correction for time-dependency (p = 0.003) and was confirmed in the multivariable model including HTN as a time-dependent variable (p = 0.02). Moreover, in patients with pre-existing HTN, no difference in terms of PFS and OS was observed compared with the subgroup of patients who never experienced ≥G2 HTN (HR 1.01, p = 0.86 and HR 1.02, p = 0.78 respectively.
Bevacizumab-induced HTN during the first-line treatment of mCRC is an independent prognostic factor, also adopting a time-dependency correction. Toxicity should be interpreted as a time-dependent variable when exploring its association with clinical outcome.
回顾性研究表明，贝伐珠单抗引起的高血压（HTN）是抗血管生成药物在转移性结直肠癌（mCRC）一线治疗中疗效的预后和潜在预测生物标志物。可能存在起始时间偏倚和预先存在的 HTN 的影响。我们对两项化疗联合贝伐珠单抗治疗 mCRC 的前瞻性随机试验进行了汇总、事后分析，并对现有文献进行了系统回顾，重点关注如何考虑起始时间偏倚以及如何管理潜在需要使用降压药物的预先存在的 HTN。
汇总分析包括分别比较 FOLFOXIRI+贝伐珠单抗与 FOLFIRI 或 FOLFOX+贝伐珠单抗的 III 期 TRIBE 和 TRIBE-2 研究中的入组患者。通过纳入时间依赖性 Cox 回归模型来评估 HTN 与生存结果之间的关联，以考虑治疗期间 HTN 发生概率的时间依赖性。系统评价按照 PRISMA 指南进行。
系统评价检索到 14 项符合条件且高度异质性的研究。在报告无进展生存期（PFS）的分析中，有 58%报告了贝伐珠单抗诱导的 HTN 具有阳性预后影响，在报告总生存期（OS）数据的分析中，有 54%报告了贝伐珠单抗诱导的 HTN 具有阳性预后影响。4 项研究（28%）纳入了起始时间偏倚。在 TRIBE 和 TRIBE-2 研究人群（N=1175）中，在一线贝伐珠单抗治疗期间发生≥G2 HTN 的患者 PFS（中位数：14.7 个月与 10.3 个月，p<0.001）和 OS（中位数：31.7 个月与 24.2 个月，p<0.001）更长。在考虑时间依赖性后，与 OS 的相关性仍具有统计学意义（p=0.003），并在包括 HTN 作为时间依赖性变量的多变量模型中得到证实（p=0.02）。此外，在预先存在 HTN 的患者中，与从未经历过≥G2 HTN 的亚组相比，PFS 和 OS 无差异（HR 1.01，p=0.86 和 HR 1.02，p=0.78）。
在 mCRC 的一线治疗中，贝伐珠单抗诱导的 HTN 是一个独立的预后因素，同时采用了时间依赖性校正。在探索其与临床结果的相关性时，应将毒性解释为时间依赖性变量。
