As reported recently in Annals of Oncology, a retrospective study by Wang and colleagues showed that use of beta-adrenergic receptor antagonists (beta-blockers), typically used in treatment of hypertension and heart disease, was associated with significantly improved distant metastasis–free survival, disease-free survival, and overall survival in a large cohort of patients with non–small cell lung cancer (NSCLC) undergoing definitive radiation therapy at The University of Texas MD Anderson Cancer Center.¹ No significant prolongation of locoregional progression–free survival was observed.

Earlier Studies

Preclinical studies have shown that tumor cell migration is stimulated by norepinephrine in a process mediated by beta-adrenergic receptors, suggesting a potential mechanism for a beneficial effect of beta-blocker use. Other retrospective studies have indicated that beta-blockers may have antitumor activity, with reduced metastasis, tumor recurrence, and cancer-specific mortality being observed in breast cancer patients and increased survival being observed in melanoma patients.

Another recently reported retrospective cohort study assessing the effect of beta-blocker use in hypertensive patients with a variety of cancers showed no effect on survival among the 436 patients with lung cancer included in the analysis.² However, details on patient demographics and treatment regimens were not provided, making conclusions of the analysis less clear.

Patient Characteristics

The analysis by Wang and colleagues included 722 patients with newly diagnosed NSCLC undergoing definitive radiation therapy at MD Anderson Cancer Center between 1998 and 2010, of whom 155 had received beta-blocker treatment during radiation therapy. Of patients receiving beta-blockers, the majority received selective beta-blockers, with 85% receiving metoprolol or atenolol. Two-thirds of patients taking beta-blockers did so for treatment of hypertension, with the remainder most frequently receiving beta-blocker treatment for coronary heart disease.

There were significant baseline differences between the group receiving and the group not receiving beta-blockers. Patients receiving beta-blockers were significantly more likely to be older (P < .01, 66% vs 45% aged ≥ 65 years), have worse Karnofsky performance status (P = .04, 78% vs 69% with score ≤ 80), have less-advanced N category (P = .03; N0,1 in 22% vs 15% and N2,3 in 78% vs 85%), have lower-stage disease (P = .04; stage I, II, IIIA, and IIIB in 6%, 5%, 40%, and 49% vs 2%, 3%, 46%, and 49%), not have concurrent chemotherapy (P = .02, no concurrent chemotherapy in 23% vs 15%), have received a higher radiation dose (P < .01, > 63 Gy in 55% vs 43%), have hypertension (P < .01, 68% vs 36%), and be taking aspirin (P < .01, 42% vs 16%).

There were no differences between groups in sex (55% male in both), race (86% vs 85% Caucasian), T category (T3,4 in 46% vs 47%), histology (non–squamous cell in 66% vs 63%), gross tumor volume (≥ 119 cm in 45% vs 52%), or proportion with chronic obstructive pulmonary disease (28% vs 23%).

Univariate Analysis

Median follow up in surviving patients was 44 months (range, 1–155 months). On univariate analyses, Kaplan-Meier survival estimates indicated that beta-blocker use was associated with significantly improved distant metastasis–free, disease-free, and overall survival (all P ≤ .01). Cox proportional hazards analysis indicated that use of beta-blockers was associated with a 40% reduction in risk for distant metastasis (hazard ratio [HR] = 0.60, P < .01), a 32% reduction in risk for disease signs/symptoms (HR = 0.66, P < .01), and a 24% reduction in risk for death (HR = 0.76, P = .01). A nonsignificant 15% reduction in risk for locoregional progression was observed (HR = 0.85, P = .33).

Among other factors analyzed, stage T3,4 disease, stage N2,3 disease, and younger age were significantly associated with reduced distant metastasis–free and disease-free survival. Poorer performance status and more-advanced clinical disease stage were significantly associated with reduced overall survival. Concurrent chemotherapy was associated with significantly improved overall survival (P < .01).

Multivariate Analysis

On multivariate analysis adjusting for age, performance status, clinical disease stage, tumor histology, concurrent chemotherapy, radiation dose, gross tumor volume, hypertension, chronic obstructive pulmonary disease, and aspirin use, the use of beta-blockers was still associated with a significant 33% reduction in risk for distant metastasis (HR = 0.67, P = .01), a 26% reduction in risk for disease (HR = 0.74, P = .02), and a 22% reduction in risk for death (HR = 0.78, P = .02). Beta-blocker use was associated with a nonsignificant 9% reduction in risk for locoregional progression (HR = 0.91, P = .63).

Other factors significantly associated with survival outcomes on multivariate analysis included concurrent chemotherapy, which was associated with a 46% reduction in risk of death (HR = 0.54, P < .01); older age (≥ 65 vs < 65 years), associated with better disease-free survival (HR = 0.74, P < .01); better performance status (Karnofsky score > 80 vs ≤ 80), associated with improved distant metastasis–free survival (HR = 0.76, P = .03), disease-free survival (HR = 0.77, P = .02), and overall survival (HR = 0.72, P < .01); and more-advanced clinical stage (III vs I or II), associated with poorer distant metastasis–free survival (HR = 2.39, P = .01), disease-free survival (HR = 1.66, P = .04), and overall survival (HR = 1.97, P < .01).

In addition, non–squamous cell histology was associated with improved distant metastasis–free survival (HR = 0.68, P < .01), lower radiation dose (60–63 vs > 63 Gy) was associated with poorer locoregional progression–free survival (HR = 1.46, P < .01), and greater gross tumor volume (≥ 119 vs < 119 cm) was associated with significantly poorer distant metastasis–free survival (HR = 1.58, P < .01), disease-free survival (HR = 1.38, P < .01), and overall survival (HR = 1.61, P < .01). Aspirin use was associated with a borderline significant improvement in distant metastasis–free survival (HR = 0.74, P = .05).

Study Conclusion

The authors concluded, “This analysis demonstrated that the incidental use of beta-blockers in this group of patients with NSCLC was associated with improved [distant metastasis–free, disease-free, and overall survival]—but not with [locoregional progression–free survival]—after definitive treatment that included radiation therapy. These findings are concordant with those of previous preclinical studies, suggesting that beta-blockers have specific effects on the metastatic cascade. Future prospective trials are needed to validate these retrospective findings and establish whether the length and timing of beta-blocker use influence survival outcomes.” ■

References

1. Wang HM, Liao ZX, Komaki R, et al: Improved survival outcomes with the incidental use of beta-blockers among patients with non-small-cell lung cancer treated with definitive radiation therapy. Ann Oncol. January 8, 2013 (early release online).

2. Shah SM, Carey IM, Owen CG, et al: Does β-adrenoceptor blocker therapy improve cancer survival? Findings from a population-based retrospective cohort study. Br J Clin Pharmacol 72:157-161, 2011.