Analysis of Early Hypertension and Clinical Outcome With Bevacizumab: Results From Seven Phase III Studies

Abstract

Background. Hypertension is associated with antivascular endothelial growth factor treatment, but the clinical implications of hypertension are uncertain. To assess the prognostic and predictive value of bevacizumab-related hypertension, a comprehensive analysis of whether hypertension and efficacy outcomes are associated was conducted on seven companysponsored placebo-controlled phase III studies of bevacizumab. Methods. Patient-specific data were available from 6,486 patients with metastatic colorectal, breast, non-small cell lung, pancreatic, and renal cell cancers. Primary hypertension endpoint was a blood pressure (BP) increase of Ͼ20 mmHg systolic or Ͼ10 mmHg diastolic within the first 60 days of treatment. Additional endpoints included other predefined thresholds of change in BP and severity of hypertension graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events. To analyze the general prognostic importance of an early BP increase, multivariate Cox regression models were used to assess the correlation between BP changes and progression-free (PFS) and overall survival (OS) outcomes in the control groups. To analyze whether early BP increases could predict for benefit from bevacizumab, similar analyses were conducted in the bevacizumabtreated and control groups. Results. In six of seven studies, early BP increase was neither predictive of clinical benefit from bevacizumab nor prognostic for thecourseofthedisease.ForstudyAVF2107g,earlyincreasedBP was associated with longer PFS and OS times in the bevacizumab group but shorter OS time in the control group. Conclusions. Early treatment-related BP increases do not predict clinical benefit from bevacizumab based on PFS or OS outcomes. BP increases do not appear to have general prognostic importance for patients with advanced cancer. The Oncologist 2013;18:273-280 Implications for Practice: Treatment-related hypertension has been seen with multiple inhibitors of vascular endothelial growth factor (VEGF), including bevacizumab, when treating colorectal, non-small cell lung, renal cell, and brain cancers. Approximately 10%-20% of patients treated with bevacizumab develop grade 3 hypertension. While a qualitative association between hypertension and anti-VEGF therapy has been described, the clinical implications of this association have not been well studied. Current practice has no guidance on strategies related to maximizing hypertension as a strategy to increase patient benefit. There have been many speculations that patients should have their anticancer treatment adjusted to maximally increase blood pressure and/or that blood pressure should be left untreated. Here, a comprehensive analysis of hypertension and efficacy outcomes in seven large clinical studies involving 6,486 patients was performed to evaluate the prognostic and predictive value of bevacizumab-related hypertension. It was found that early treatment-related blood pressure increases do not predict clinical benefit from bevacizumab based on progression-fre...

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