Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Blocker use During Stereotactic Body Radiation Therapy Associated with Decreased Pneumonitis: A Multi-center Analysis

Abstract

Radiation pneumonitis (RP) is a serious adverse effect associated with lung radiation therapy (RT). The use of angiotensin-converting enzyme inhibitors (ACEI) is associated with a lower risk of RP in the setting of conventional lung RT. However, whether ACEI use during stereotactic body radiation therapy (SBRT) has protective properties against RP is unknown. Similarly, the effect of angiotensin receptor blockers (ARB) use on the incidence of RP is not known. The purpose of this study is to examine the impact of ACEI and ARB use during lung SBRT treatment on the development of RP. Under an Institutional Review Board-approved protocol, the records of 252 consecutive patients from 2009 – 2015 at 4 related academic institutions with lung cancer treated with SBRT were reviewed. Presence of RP was determined using all available records, including follow-up data from radiation oncology, pulmonology, medical oncology, and hospitalizations, and graded using the Common Terminology Criteria for Adverse Events Version 4.0. Univariate and multivariate analysis was performed to identify factors associated with clinical outcomes. Kaplan-Meier methods were used to determine OS. A total of 208 patients were used for the analysis with a median follow-up time of 23 months. Median age was 71 years old. Median tumor size was 2.1cm, and 63% of the tumors were peripheral in location. 68% of the tumors were T1, 48% were T2, 7% were T3, and 2% were T4, 8% were node positive. 77 patients (37%) received either ACEI (26%) or ARB (11%) therapy during SBRT. 25 patients developed grade 1 pneumonitis (12%), 20 patients developed grade 2 pneumonitis (10%), 14 patients developed grade 3 pneumonitis (7%), 5 patients developed grade 4 pneumonitis (2%), and 2 patients developed grade 5 pneumonitis (1%). In total 32% of patients developed pneumonitis of any grade. Significantly fewer patients developed any grade of RP if ACEI or ARB were taken during SBRT compared to those who did not - 16.6% vs. 38.4% at 1 year, and 25.6% vs. 39.6% at 2 years (p<=0.005). ACEI or ARB use was associated with higher 5-year overall survival rates, 44.5% vs. 28.5% (HR 0.60, p=0.042). On subset univariate analysis in patients receiving either 3, 4 or 5 fraction SBRT, 5 fraction SBRT was associated with higher rates of any grade RP compared to those treated with 3 or 4 fraction SBRT (HR 2.15, p=0.029). On subset multivariable analysis ACEI/ARB use was significant for lower rates of any grade RP (HR 0.41, p=0.003), and; 5 fraction SBRT and age >65 years were associated with higher rates of any grade RP (HR 2.5, p=0.01, HR 1.92, p=0.049 respectively). ACEI or ARB use during SBRT was associated with significantly greater freedom from any grade RP, and higher likelihood of 5-year survival. ACEI or ARB use during SBRT should be prospectively evaluated.