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Transl Oncol. Oct 2013; 6(5): 539–545.
Published online Oct 1, 2013.
PMCID: PMC3799196

Exposure to ACEI/ARB and β-Blockers Is Associated with Improved Survival and Decreased Tumor Progression and Hospitalizations in Patients with Advanced Colon Cancer1

Abstract

BACKGROUND: Advanced colon cancer is associated with weight loss and decreased survival. Studies suggest that angiotensin and β-adrenergic blockade decrease colon cancer progression and ameliorate weight loss. This study aims to determine whether exposure to β-adrenoceptor blockers (BBs), angiotensin-converting enzyme inhibitors (ACEIs), or angiotensin receptor blockers (ARBs) is associated with decreased mortality, tumor progression, number of hospitalizations, or weight loss in colorectal cancer. METHODS: Retrospective chart review included patients with advanced colorectal cancer. Survival, stage, hospitalization, cancer progression, cancer treatment, and body weight history were collected. RESULTS: Two hundred sixty-two of 425 new stage III to IV colorectal cancer cases reviewed met the study criteria. Those exposed to ACEI/ARB, BB, or both were more likely to have diabetes, hypertension, and stage III colorectal cancer. Adjusting for age, presence of hypertension and diabetes, and stage, ACEI/ARB + BB exposure was associated with decreased mortality compared to unexposed individuals [hazard ratio (HR) = 0.5, confidence interval (CI) = 0.29–0.85; Cox regression, P = .01]. Fewer total and cancer-related hospitalizations and decreased cancer progression in the ACEI/ARB + BB group versus the unexposed group (HR = 0.59, CI = 0.36–0.99, P = .047) were seen. Exposure did not affect weight changes; furthermore, body weight changes from both prediagnosis and at diagnosis to 6, 12, 18, and 24 months postdiagnosis predicted survival. CONCLUSIONS: We have observed an association between exposure to a combination of ACEI/ARB + BB and increased survival, decreased hospitalizations, and decreased tumor progression in advanced colorectal cancer. Future studies will be needed to replicate these results and generalize them to broader populations. Determination of causality will require a randomized controlled trial.

Introduction

Colorectal cancer is the third most prevalent cancer in America with more than 143,000 people newly diagnosed with this disease each year. Although several treatments are available for advanced colorectal cancer, novel therapies are needed, given that this cancer is one of the leading causes of death in the western world and it usually takes a toll on these patients' quality of life [1].

Recent studies suggest that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may modulate the development and progression of cancer [2]. ACEIs reduce the production of angiotensin II, whereas ARBs selectively block the activation of angiotensin II type 1 receptors. Both result in a suppression of the renin-angiotensin system. Angiotensin II, through activation of vascular endothelial growth factor (VEGF) and VEGF receptor 2 expression in endothelial cells, stimulates neovascularization [3–5]. The angiotensin II type 2 receptor is a G protein-coupled receptor that regulates signal transducer and activator of transcription 3 (STAT3) [6]. These heterotrimeric G proteins and STAT3 have recently been established as novel therapeutic targets for both lung and colon cancers [7]. Angiotensin II also acts as an antiapoptotic agent and growth factor, stimulating cell replication through the epidermal growth factor receptor transactivation/extracellular signal-regulated kinase (ERK) signaling pathway. In vitro, the growth of cultured cancer cells is retarded by ACEI [8]. Moreover, they inhibit angiogenesis and growth of induced cancer in rats [9,10]. There are also data to suggest that blocking angiotensin II may decrease muscle proteolysis, prevent cachexia, and improve the host's function [11].

The β-adrenergic receptor has also been implicated as a potential therapeutic target for cancer. Circulating norepinephrine and epinephrine bind to β-adrenergic receptors and subsequently stimulate macro-phages and cancer cells to produce angiogenic factors, including VEGF [12]. β-Adrenoceptor blockers (BBs) are believed to downregulate the rapidly accelerated fibrosarcoma (RAF)-mitogen-activated protein kinase (MAPK) pathway and, consequently, inhibit angiogenesis. Moreover, studies have shown that blockade of adrenergic activity and subsequent decline in resting energy expenditure (REE) in tumor-bearing animals and patients with cancer may prevent cancer cachexia.

Given that a large number of individuals receive ACEI, ARB, or BB as part of the treatment for hypertension, we sought to determine whether exposure to these agents is associated with decreased tumor progression, mortality, weight loss, or number of hospitalizations in patients with advanced colorectal cancer.

Materials and Methods

This was a retrospective chart review of patients diagnosed with advanced colorectal cancer at the Michael E. DeBakey Veterans Affairs (VA) Medical Center (Houston, TX) between January 2000 and July 2009. Inclusion criteria were men and women older than 18 years with stage III and IV colorectal cancer. Exclusion criteria were medical conditions associated with weight loss or that would benefit from BB and/or ACEI/ARB for other reasons, including New York Heart Association class III or IV congestive heart failure (CHF), end-stage liver disease or liver function tests more than three times the normal limits, renal failure defined with creatinine ≥ 3 mg/dl, hyperthyroidism, or human immunodeficiency virus infection. Other conditions that would affect weight, such as significant edema, use of anabolic agents such as testosterone, growth hormone, orexigenic agents (i.e., Megestrol), or research medications were excluded. Patients with known medication noncompliance were not included in this study.

Data collected included survival, hospitalization, gender, cancer progression, cancer treatment, body weight history (at 6–12 months prediagnosis, at time of diagnosis, and every 6 months postdiagnosis for 24 months), albumin, creatinine, medications, and stage. All survival data were collected until 15 December 2011 or until death, whichever occurred first. Subjects were followed for a maximum of 4364 days. Hospitalization and death events were categorized as cancer related or not cancer related. To account for differences in time at risk for being hospitalized, we calculated total hospitalization and cancer-related hospitalization ratios as follows: Total (or cancer-related) hospitalizations/years survived.

Exposure groups for ACEI, ARB, and BB were defined as prescription use ≥6 months per any year in the observation period (1 year before cancer diagnosis to 3 years postdiagnosis). A secondary analysis was also performed, categorizing subjects on the basis of exposure to these drugs on the year before diagnosis to account for a potential immortal time bias [13] and including only subjects that survived at least 6 months after diagnosis to account for the potential influence of medications being withdrawn before death. Compliance with medications was established by prescription use for ≥6 months with patient-initiated medication refills. Cancer progression was determined by increasing tumor size on serial imaging or the oncologist's documentation in progress notes. ACEIs and ARBs were combined into one group because there were no differences in relevant outcomes between the two groups and because of the similar mechanism of action. Individuals were categorized into one of these four mutually exclusive exposure groups: 1) unexposed to BB, ACEI, or ARB (control group), 2) exposed to ACEI and/or ARB only, 3) exposed to BB only, or 4) exposed to both ACEI/ARB and BB.

All statistical analyses were performed using SPSS software (SPSS 17.0; IBM, Somers, NY). Variables were summarized descriptively by group using N , mean, and standard error or by median and interquartile range for continuous variables and by frequencies (%) for nominal or ordinal variables. Analysis of variance (ANOVA) was used to analyze normally distributed continuous variables, and non-parametric tests were used for non-normally distributed variables. Statistical comparisons for categorical data were performed using the Fisher exact test or χ2 test. Statistical significance was assigned to each comparison for P < .05, and appropriate post hoc tests were used when needed during ANOVA. It was anticipated that cancer stage may be highly associated with survival. The association between drug exposure or weight change and survival and tumor progression was measured by a Cox proportional hazards model to determine which variables, in addition to cancer stage, were significant predictors of mortality or progression of disease. The measure of association was given by the hazard ratio (HR) and confidence intervals (CIs), with time to event (death or progression) being the outcome of interest. For preliminary stepwise regression analyses used to determine significant cofactors for predicting survival or weight change percent, α for excluded variables was set at 0.10.

Role of the Funding Source

The Department of Veterans Affairs and the National Institutes of Health did not play a role in study design, in the collection, analysis, and interpretation of data, in the writing of the report, and in the decision to submit the paper for publication.

Results

Of the 425 charts reviewed, 163 patients were excluded (Figure 1). Of the 262 patients that met the criteria, patients that were exposed to ACEI/ARB, BB, or both were most likely to have diabetes, hypertension, and stage III colorectal cancer. This is likely due to the fact that these medications are used to treat hypertension and complications of diabetes. Furthermore, there may be a physician bias to not prescribe these medications to their more ill, stage IV, patients. Diabetes, hypertension, and stage were included as covariates in all analyses. Body weight was significantly lower for the unexposed group than for the exposed group. There was no significant difference in age, gender, chemotherapy regimen, or radiation therapy between groups (Table 1). The study patients were predominantly elderly, white males, as expected in a VA hospital setting.

Figure 1
Overview of study selection. CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; tx, treatment.
Table 1
Baseline Characteristics by Exposure Groups.

Exposure to ACEI, ARB, or BB and Survival

Exposure to ACEI/ARB + BB combination was associated with decreased mortality compared to unexposed individuals even after adjusting for age, presence of diabetes and hypertension, and stage (Table 2 and Figure 2). Exposure to BB or ACEI/ARB alone did not significantly improve survival compared to the unexposed group. The majority of deaths in all groups was cancer related [100% (109 of 109) in unexposed, 94.4% (34 of 36) in ACEI/ARB only, 100% (22 of 22) in BB only, and 100% (16 of 16) in ACEI/ARB + BB]. The survival benefit of exposure to ACEI/ARB + BB combination persisted on the secondary analysis performed, categorizing subjects on the basis of exposure to these drugs on the year before diagnosis and including only subjects that survived at least 6 months after diagnosis [odds ratio = 0.27 (CI = 0.09–0.85) compared to unexposed, P = .03].

Figure 2
Exposure and survival—HR compared to unexposed subjects. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, β-adrenoceptor blocker.
Table 2
Survival by Exposure.

Exposure to ACEI, ARB, or BB and Tumor Progression and Hospitalizations

Exposure to BB or ACEI/ARB alone did not significantly change the rate of tumor progression compared to the unexposed group. However, subjects receiving ACEI/ARB + BB combination had decreased risk of tumor progression. Tumor progression was not predicted by hypertension, but it was predicted by the presence of diabetes. Nevertheless, exposure to ACEI/ARB and BB remained a significant predictor of tumor progression even after adjusting for the presence of diabetes and stage (HR = 0.59, CI = 0.36–0.99, P = .05; Figures 3 and and44).

Figure 3
Exposure and tumor progression. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, β-adrenoceptor blocker. P value was obtained using χ2 test, comparing ACEI/ARB + BB to unexposed group.
Figure 4
Exposure and tumor progression—HR compared to unexposed subjects. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, β-adrenoceptor blocker.

Hospitalizations were evaluated as the ratio of number of hospitalizations (total or cancer related) per year survived and were analyzed by ANOVA adjusting for multiple comparisons. Diabetes and hypertension were not found to be associated with these outcomes on regression analyses. There was a significant decrease in total (P = .004) as well as cancer-related (P = .006) hospitalizations in the ACEI/ARB + BB group compared to the unexposed group (Figure 5). BBs or ACEI/ARB alone did not affect the rate of hospitalizations.

Figure 5
Total and cancer-related hospitalizations. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, β-adrenoceptor blocker. P values were compared to unexposed. Hospitalization ratio was calculated as the ratio of ...

Exposure to ACEI, ARB, or BB and Weight

Body weights at 6 to 12 months prediagnosis and at the time of diagnosis were lower for the unexposed group compared to the ACEI/ARB and BB + ACEI/ARB groups (Table 1). Hence, body weights were analyzed as change from baseline to account for these differences. Body weight changes from 6 to 12 months prediagnosis or at the time of diagnosis to 6, 12, 18, or 24 months postdiagnosis were not significantly different between groups (Figure 6). Neither diabetes nor hypertension was associated with weight change from prediagnosis or baseline to all other time points.

Figure 6
Exposure and weight change. BMI, body mass index; dx, diagnosis; mo, months; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, β-adrenoceptor blocker.

Body Weight and Survival

Body weights at 6 to 12 months prediagnosis or at the time of diagnosis were not predictive of survival on Cox regression analysis adjusted for stage (HR = 0.99, CI = 0.97–1.03, P = .84 and HR = 0.99, CI = 0.96–0.10, P = .42, respectively). Body weight changes from 6 to 12 months prediagnosis to 6, 12, 18, and 24 months post-diagnosis were significant predictors of survival even after adjusting for stage (Figure 7). Moreover, body weight changes from diagnosis to 6, 12, 18, and 24 months postdiagnosis were also significant predictors of survival after adjusting for stage (HR = 0.97, CI = 0.95–0.99, P = .01; HR = 0.97, CI = 0.95–0.99, P = .001; HR = 0.87, CI = 0.81–0.94, P = .001; HR = 0.82, CI = 0.76–0.88, P < .001, respectively).

Figure 7
Weight change and survival—HR; predx, prediagnosis; DX, diagnosis; mo, month.

Discussion

Our data suggest that exposure to a combination of BB and ACEI/ARB is associated with decreased tumor progression, decreased hospitalizations, and increased survival in patients with advanced colorectal cancer even after adjusting for cancer stage. This is potentially very relevant because this disease is very prevalent and it usually affects quality of life and survival greatly in these patients.

Several mechanisms have been proposed for angiotensin or β-adrenergic receptor blockade to improve these outcomes in patients with colon cancer. BBs and ACEI/ARB are associated with decreased mortality in the setting of CHF [14,15]. Although it is possible that the decrease in mortality was due to these well-known cardiovascular effects, this is unlikely in this setting given that almost all deaths were cancer related. In addition, angiotensin and β-adrenergic receptor blockade are thought to have antiproliferative effects in tumors. Angiotensin II mediates induction of VEGF, resulting in angiogenesis [16,17]. Furthermore, it can activate multiple mitogenic signaling pathways, such as protein kinase C, phosphatidylinositol-3-kinase-protein kinase B (PI3K-AKT), MAPK, and STAT3, leading to cancer proliferation [18]. Yasumaru et al. showed that angiotensin II blockade also enhances the antitumor effect of cycloxygenase-2 (COX-2) inhibitors through the insulin-like growth factor-1 (IGF-1) receptor pathway [19]. Lastly, several groups have shown that angiotensin blockade can mitigate the cardiac toxicity associated with some chemotherapy regimens, thereby enhancing tolerability of these drugs and allowing more effective doses of these agents to be delivered [20].

Other reports are in agreement with our findings. For instance, Lever and colleagues showed recently that long-term use of ACEI can protect against certain types of cancers, including colorectal, lung, and breast cancers. Compared with controls, the relative risk of developing cancer was 0.72 (95% CI = 0.55–0.92) in that report [21]. Long-term use of lisinopril has also been associated with decreased incidence of advanced adenomatous colon polyps and decreased tumor metastasis in non-small cell lung cancer [22].

BBs have also been considered as potential novel therapies for cancer. In 2004, a cohort study of 839 patients followed prospectively for an average of 10 years showed a reduced cancer risk with BB usage [23]. Furthermore, population-based studies have suggested that inhibition of β2-adrenergic signaling pathway could reduce breast cancer progression and mortality [12]. In 2008, propranolol was shown to inhibit the growth of hemangiomas [24] and the proliferation of human umbilical vein endothelial cells [25]. These data suggest that β-blockade results in inhibition of angiogenesis. It is hypothesized that this is the result of down-regulation of VEGF and basic fibroblast growth factor genes through the inhibition of the RAF-MAPK pathway. Adrenaline directly stimulates colon cancer cell growth through β-adrenoceptors [26] and has been shown to stimulate HT-29 cell proliferation and expression of COX-2 and VEGF. This may be relevant because COX-2 is overexpressed in colon cancer and may play a role in cancer progression [27]. Animal experiments have shown that carvedilol reduces the expression of hypoxia-inducible factor 1α, which plays a major role in regulating tumor angiogenesis [28]. Moreover, propranolol inhibits the secretion of matrix metalloproteinases, which are significantly increased during tumor progression and thought to play a key role in angiogenesis [29].

Increased cancer progression was noted in the unexposed group compared to the ACEI/ARB + BB exposed group. Furthermore, when observing the number of hospitalizations adjusted for the time survived, there was a clear decrease in total and cancer-related hospitalizations in the group exposed to ACEI/ARB + BB. These findings further support the hypothesis that these agents have a beneficial effect in this setting. The fact that the majority of the hospitalizations were cancer related also suggests that the mechanisms mediating these effects were cancer related rather than cardiovascular.

Moreover, ACEI/ARB and BBs may prevent cachexia in the setting of cancer, and this could also contribute to their positive effect on survival. ACEI/ARB inhibit muscle proteolysis through inhibition of the suppressor of cytokine signaling-3 (SOCS3) pathway [11]. β-Blockade decreases REE and subsequently inhibits lipolysis [30]. Elevated REE in patients with cancer contributes to progressive weight loss and is largely related to the increased adrenergic activity and sensitivity. It is thought that this could be an adaptive response to systemic inflammation and partial starvation. Previous studies have shown a significant reduction in whole-body REE in patients with solid tumors after 5 days of BB therapy [30]. Nevertheless, our data do not support a role of angiotensin or β-adrenergic blockade in preventing cachexia or muscle wasting given that we failed to show an association between overall weight changes and exposure to these drugs. More studies are needed to test this hypothesis directly.

Mortality was significantly decreased in the group exposed to both drugs but not to the individual drugs. Given that these drugs work through mechanisms that could be complementary (such as modifying tumor vascularization through VEGF), there may be an additive effect of these medications on survival. In addition, it is possible that a larger sample size may have resulted in a significant difference in these individual groups, although our data do not support this because the HRs for tumor progression or survival were indistinguishable between the BB or ACEI/ARB group and the unexposed group.

Body weights at prediagnosis and at diagnosis or weight loss history at the time of diagnosis was not predictive of survival; however, changes in body weight from both prediagnosis or at diagnosis to all time points were predictive. This is consistent with the work of several groups including ours [31] showing the predictive value of weight changes on survival in the setting of cancer. It was particularly interesting to see how the predictive value of weight changes increased with a longer follow-up. This suggests that clinicians should continue to evaluate weight changes beyond the diagnostic stages and may use these as a prognostic indicator.

Strengths of this study include the relatively homogeneous population studied. The potential for confounding by factors such as socioeconomic status or gender is greatly decreased because patients within the VA system are more likely to be males of similar socioeconomic status and all subjects have access to the same level of care. In addition, all patients were treated by the same group of oncologists following current guidelines of treatment. The long-term follow-up enabled a sufficient number of cancer outcomes and accurate survival data to be obtained. The clinical data were retrieved from the detailed electronic medical record and, thus, not subject to recall bias.

Limitations of this study include the lack of female patients, given the predominance of men in the VA system. In addition, the retrospective analysis of medical record data makes it difficult to determine causality of the associations found or to confirm medication compliance. Nevertheless, within the VA system, medications are not mailed unless the patient requests them in person or by phone, increasing the accuracy of our medical record system. Multiple other retrospective studies relying on our VA electronic medical record have been published [32]. We did not correlate mortality with drug frequency or length of use. However, most individuals who are prescribed with these drugs are likely to take them for long periods of time. While there were significantly more patients with diabetes and hypertension in the exposed groups, this would have likely resulted in an increased, not decreased, mortality.

In summary, we show here that patients with advanced colon cancer receiving ACEI/ARB and BBs have increased survival and decreased tumor progression and hospitalization rate. Although the mechanisms underlying these observations could not be elucidated from this study, further studies may be warranted to determine if angiotensin and/or adrenergic blockade will improve outcomes in patients with advanced colon cancer.

Footnotes

1This material is based on the work supported by the Michael E. DeBakey Veterans Affairs Medical Center (Houston, TX), Department of Veterans Affairs (MERIT awards BX000507 and CX000174), and the National Institutes of Health (AG040583) to J.M.G. The authors report no conflicts of interest.

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