Angiotensin-converting enzyme inhibitors decrease the risk of radiation pneumonitis after stereotactic body radiation therapy

Abstract

Purpose

Although angiotensin-converting enzyme (ACE) inhibitor use during conventionally fractionated radiation therapy has been associated with a decreased risk of radiation pneumonitis (RP), a similar effect has not been demonstrated in stereotactic body radiation therapy (SBRT). The purpose of this study was to examine the impact of ACE inhibitor use during SBRT on the risk of symptomatic (grade ≥ 2) RP.

Methods and materials

Patients with at least 1 follow-up treated with SBRT for primary lung cancer were included. ACE inhibitors, angiotensin receptor blockers, statins, nonsteroidal anti-inflammatory drugs, and glucocorticoids were examined. RP was determined from all available medical records, including follow-up appointments with radiation oncology, pulmonology, medical oncology, and hospitalizations. It was scored with the Common Terminology Criteria for Adverse Events, version 4.0. Analysis was performed with Kaplan-Meier and Cox proportional hazards modeling.

Results

A total of 257 patients met inclusion criteria. Seventy (27.2%) used an ACE inhibitor during SBRT. The overall rates of grade ≥ 2 and ≥ 3 RP were 19.1% (n = 49) and 7.0% (n = 18), respectively. ACE inhibitor users experienced greater freedom from symptomatic RP on univariate (vs nonusers, 89.8% vs 76.3% at 12 months, P = .029) and multivariate analysis (hazard ratio 0.373, 95% confidence interval 0.156-0.891, P = .026). The volume of normal lung tissue receiving ≥ 5 Gy, %, ≥ 10 Gy, ≥ 20 Gy, and mean lung dose were also significantly associated with RP on univariate and multivariate analysis. ACE inhibitor use was not associated with overall survival. Angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs, glucocorticoids, and statin administration were not associated with symptomatic RP or survival.

Conclusions

ACE inhibitor use during SBRT was associated with significantly greater freedom from grade ≥ 2 RP, even after adjusting for pulmonary dose. Given the data on their protective effect in human and animal models, a prospective evaluation is warranted.

Introduction

Despite the established safety of stereotactic body radiation therapy (SBRT) for inoperable early-stage lung cancers, radiation pneumonitis (RP) remains a significant concern for patients with poor pulmonary reserve. Reported rates of grade ≥ 2 RP after SBRT range from 10% to 29%.[1], [2], [3], [4], [5], [6] Reducing incidental radiation to the uninvolved pulmonary tissue is a major concern during treatment planning and may limit radiation therapy in those with tenuous baseline function or multifocal disease. (See Fig. 1.)

Much research has therefore focused on the prediction and mitigation of pulmonary toxicity. Treatment plans are generally tailored to meet an acceptable mean lung dose (MLD) and volume of normal lung tissue receiving ≥ 20 Gy (V20), both of which predict for RP.¹ Although the use of dose-volume histograms has become a required part of planning, no biomarkers or medical interventions aimed at prevention have been adopted into standard practice. Studies of angiotensin-converting enzyme (ACE) inhibitors in irradiated animal models have revealed antifibrotic effects with corresponding decreases in RP.[7], [8], [9] Similarly, their use in patients undergoing conventionally fractionated radiation therapy (CFRT) has also been associated with lower rates of pulmonary toxicity.¹⁰

A similar protective effect of ACE inhibitors against pulmonary toxicity after SBRT has yet to be demonstrated.¹¹ The purpose of this study was to analyze the impact of ACE inhibitor use during SBRT on the risk of symptomatic (grade ≥ 2) radiation pneumonitis.