Elucidating the role of incidental use of beta-blockers in patients with metastatic brain tumors in controlling tumor progression and survivability
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.152625
Source of Support: None, Conflict of Interest: None
Background: Beta-adrenergic antagonists have demonstrated beneficial effects in tumor progression and survivability in patients with various cancers by inhibiting norepinephrine-induced tumor cell migration. However, little is known about their effects on the outcomes of metastatic brain tumors (MBTs). This study was undertaken to evaluate the effects of beta-blockers, if any, on the outcome of MBTs, and their possible role in controlling tumor progression and survivability.
Keywords: Beta-blockers; gamma knife radiosurgery; metastatic brain tumors; tumor progression
Metastatic brain tumors (MBTs) are the most common intracranial neoplasms in adults, with an increasing worldwide incidence. ,, They usually develop as a resultant metastasis from primary tumors including, but not limited to the neoplasms of the lung, breast, colon, skin, and the kidney.  Recent evidence suggests the critical role of ligands to G-protein- coupled receptors in the control of cancer cell migration.  Among the different ligands, neurotransmitters are the stimulators of migration of various cancer cells.  Of these, norepinephrine is considered as being the most potent stimulator of different cancer cell migration by its predominant action in activating beta -adrenergic receptors. ,,, However, norepinephrine-induced tumor cell migration can be inhibited by beta-blockers as suggested by evidence on cancer cell lines and experimental mice. ,,, Moreover, beta-blockers inhibit the progression of tumors and improve survivability in patients affected with cancer in systemic organs. ,, However, to our knowledge, no information is available in the literature till date regarding the potential effects of beta-blockers on the outcome of MBTs and their possible role in controlling the progression of the tumor. Hence, this retrospective analysis was undertaken to explore the effects of beta-blockers, if any, on the outcomes of MBTs, and their possible role in controlling the tumor progression and survivability.
Study protocol and patient population
A retrospective cohort analysis of 298 patients identified as having MBTs presenting to our institution from 2001 through 2013 was conducted as a part of the study evaluating the long-term outcomes of gamma knife radiosurgery (GKRS) for MBTs  at the Louisiana State University Health Sciences Center, Shreveport. Institutional review board approval was obtained.
Patient population and data extraction
A total of 225 patients with MBTs who were treated with GKRS and having pre-existing hypertension that fulfilled the inclusion criteria were included for analysis. Information relating to demographics, clinical and radiological characteristics, medications for pre-existing hypertension, clinical outcomes, and follow-ups was extracted from the electronic patient records. Patients on concomitant multiple antihypertensive medications and those with inadequate follow-up with neuroimaging and data on clinical condition, were excluded. To ensure completeness, accuracy, and reliability of the data, two authors (SCB and PB) independently reviewed patients' case notes, follow-up charts, and radiological reports. Stringent quality assurance measures were followed at various stages of data handling. Potential conflicts arising upon any clinical characteristic or variables were resolved by discussion and consensus. Patients were categorized into three groups for analysis: Group A comprised hypertensive patients on beta-blockers only as their antihypertensive medication (40, 18%), Group B consisted of hypertensive patients on antihypertensive medications other than beta-antagonists (65, 29%), and Group C comprised normotensives (120, 53%). All outcomes were compared using the data on pre-and post-GKRS for these groups.
All statistical analyses were performed using the Statistical Package for Social Sciences (SPSS) software, version 21.0 (IBM Corp., Armonk, NY).  The data were analyzed for descriptive and inferential statistics. Descriptive statistics was conducted for frequencies, percentages, and proportions. All values are expressed as mean ± standard deviation. One-way analysis of variance (ANOVA) was used to compare the radiological and clinical outcomes in the different patient groups (Group A vs groups B and C). Cox regression model was used to demonstrate prognostic factors for the outcome in patients having different primaries. Overall survival period was analyzed using the Kaplan-Meier test. The log-rank (Mantel-Cox) test was used to analyze the survival difference in the cases. P < 0.05 was considered as significant.
Patient demographics and tumor characteristics
The baseline demographic and clinical characteristics of the MBT patients are presented in [Table 1]. The mean age of the patients was 57.34 ± 10.98 years (range: 30-87 years) and 43% were males. Approximately 70% of the cohort comprised Caucasian ethnic group, whereas 30% were African Americans. A vast majority (130, 58%) of patients with MBT had their primary tumor source in the lung with frontal lobe being the most commonly affected (80, 35.5%). Approximately 53% patients were normotensives, whereas 47% were hypertensives and on antihypertensive medications. Among the cohort of hypertensive patients, 40 patients received beta-blockers, whereas 65 patients received non--beta-blocker medications [Table 1].
Tumor characteristics and outcomes
Presence of a single MBT was significantly higher in Group A as compared to groups B and C (50% vs 37 and 37.5%; P = 0.023), whereas multiple MBTs were observed to be significantly lower in Group A as compared to groups B and C (50% vs 63 and 62.5%; P = 0.043). Extracranial metastasis (15% vs 61 and 57%; P ≤ 0.0001), recurrence of tumor (17.5% vs 49 and 62%; P ≤ 0.0001), and distant intracranial metastasis (12.5% vs 42 and 48%; P ≤ 0.0001) were observed to be statistically lower in Group A as compared to groups B and C [Table 2].
Tumor response following incidental beta-blockers use
Tumor response with regards to control and progression following GKRS is depicted in [Table 2]. The mean and median size of the MBTs before treatment were 2.07 and 2 cm, respectively (range 0.8-4 cm). Recent follow-up imaging demonstrated control of tumor size in approximately 78% of patients in Group A vs 55% in Group B and 56% in Group C, and was statistically significant (P = 0.001). Tumor progression was also significantly lower in Group A as compared to groups B and C (18% vs 42 and 44%; P = 0.0005) [Table 2].
The overall mean survival period in our series was 29 months for Group A as compared to 18 months each for groups B and C [Figure 1] and [Figure 2]. The recorded number of deaths in Group A was significantly lower than those observed in groups B and C (47% vs 59 and 65%; P ≤ 0.046). The mean survival time in patients with MBTs derived from breast cancer as a primary source was 62.6 months in contrast to 14 months in patients with MBTs from other tumor sources (lungs, skin, colon, and renal). The log-rank test demonstrated the difference in mean survival time between primary sources (breast cancer vs others) to be of statistical significance with P = 0.043 [Figure 3].
In the present study, hydrocephalus developed in two patients from groups B and C only. A total of 26 (21.7%), 16 (24.6%), and 3 (7.5%) patients underwent salvage therapy in groups C, B, and A, respectively. The requirement of salvage therapy was significantly lower in Group A as compared to Groups B and C (P = 0.032).
Prognostic factors of survival
Cox regression was performed to identify the predictors of survival in patients with MBTs who were treated with beta-blockers. Primary tumors were the covariate included in the model. Among the primary tumors, tumors originating from the breasts were identified as prognostic factors of survival (P = 0.049).
The present study retrospectively assessed the role of beta-adrenergic antagonists on the clinical outcomes of MBTs and evaluated their possible role in controlling tumor progression and survivability. Recent evidence has highlighted the role of beta-adrenergic blockers in inhibiting tumor activity, reducing metastasis, and recurrence, thus providing survival benefits for the patients with primary tumors in different organs. ,,, Despite significant advances in the conventional treatment strategies like surgical resections, whole brain radiation therapy (WBRT), and stereotactic radiosurgery for patients with MBTs, the prognosis of MBTs is far from satisfactory.  It is critical to explore better therapeutic options to suppress tumor growth and subsequent progression of micrometastases in these patients. Our preliminary findings suggested statistically significant reduction in the number of MBTs, metastasis (both extracranial and distant intracranial), and recurrence of the tumor in hypertensive patients on beta-adrenergic blockers in contrast to hypertensive patients not on beta-blockers and normotensives. Our findings are consistent with the results of previous preclinical studies looking at cancers in different organs and the effect of beta-blockers in their control. ,,,, These results are coherently supported by beta-adrenergic signaling mechanism that regulates various cellular processes of cancer cell growth and development including tumor cell proliferation; extracellular matrix invasion and cell migration; matrix metalloproteinase activation; expression of angiogenic growth factors; and angiogenesis in several types of tumor, including those from lung, breast, colon, melanoma, prostate, pancreas, etc. ,,,
Control of local tumor growth is critical in the management of neoplasms. Our data demonstrated that local tumor growth control was achieved in significantly higher number of patients in the beta-blocker group as compared to those in groups B and C [Table 2]. The overall survival period was markedly higher in the beta-blockers group compared to that in the control groups. Similar to our findings, Wang et al. showed improved overall survival period with incidental use of beta-blockers in the patients with non-small cell lung cancer.  Similarly, Botteri et al. found that the overall survival period was improved with the use of beta-blockers in the patients with breast cancer.  The primary source of MBTs in our cohort was from the primary in the lungs, breasts, colon, skin (melanoma), and kidneys (renal cell cancer). We observed primary source of MBTs to influence the long-term survival benefits of beta-blockers in these patients. MBTs originating from breast cancers were found to positively affect the survival rate (62 vs 14 months) as compared to other systemic primaries, implying that the use of beta-blockers may be more beneficial for the hypertensive patients with MBTs derived from breast cancer. Moreover, complications such as hydrocephalus were markedly lower in the beta-blocker group compared to others. Likewise, the need for salvage therapy (those on beta-blockers, 7.5% vs non--beta-blockers, 24.6% vs nonhypertensives, 21.7%) was also significantly lower in the group being administered beta-blockers when compared to the other groups.
The major drawback of the study is its retrospective design and relatively small sample cohort. Furthermore, lower volume of patients in the beta-blocker group (Group A) as compared to others (groups B and C) could serve as a potential confounding factor.
Concomitant use of beta-blockers as an antihypertensive medication with conventional therapy may offer potential benefit to hypertensive patients developing MBTs by ameliorating tumor progression and conferring a survival advantage. This effect was most notable in patients with primary tumors originating in the breast. Our study is limited in size and design; molecular and prospective studies, and randomized controlled trials are warranted to further explore this promising effect.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]