Numbere, Beade
(2016)
Can adrenergic blockers prevent or retard the progression of common cancers?
PhD thesis, University of Nottingham.
Abstract
Introduction
Significant developments have been made in the treatment and prevention of cancer. Despite these developments, a third of the population of the UK will get cancer in their lifetime and a quarter of the population are likely to die from it, making it a leading cause of death in the UK[1, 2]. There is an increase in the numbers of cancers being largely driven by the ageing and expanding population.[2, 3]Conventional anti-cancer and anti-metastatic approaches such as chemotherapy and radiotherapy are effective because these approaches mostly inhibit cell division in proliferating cancer cells or make the tissue environment hostile to cancer cell growth and migration. However, the non-selectiveness of these approaches often causes serious side effects leading to the damage of healthy tissue. Significant gains have been made through the development of targeted therapies and early detection with the benefit of personalising medicine for a specific target thereby minimising harm. However, there is a problem of drug resistance in about 50% of patients with these forms of treatment.
Progress in developing these treatments for disease remain slow, with traditional approaches inadequate and rational new therapies needed to tackle cancer. As a result, an alternative strategy for drug development such as using previously approved drugs for new medical indications is beginning to be explored.[4] This strategy will potentially remove substantial risks, costs and time from the pathway of drug development.[4] Recent evidence has shown the potential anti-neoplastic effects of some cheaper and safer medications. Among the best examples of this is the near 50% reduction in cancer specific mortality from colorectal cancer recently shown in those starting Aspirin after diagnosis[5], which has already led to a randomised controlled trial.[6]
In vitro and in vivo studies suggest a role for beta blockers and alpha blockers in inhibiting the proliferation and migration of cancer cells. A series of case-control and cohort studies was therefore conducted using the large population based Clinical Practice Research Datalink (CPRD) and associated datasets as the data source to explore the impact of beta and alpha blockers on cancer incidence and overall and cancer mortality.
Epidemiological studies on the effect of adrenergic blockers on cancer incidence have proved inconclusive with particularly limited evidence from large population based studies on cancer incidence. A case-control study was therefore conducted to assess the effect of adrenergic blockers upon incidence of cancers of the prostate, lung bowel and breast cancers. Additionally, epidemiological studies have examined the potential beneficial effects of adrenergic blocker on cancer survival, but these are still inconclusive with limited evidence from large population-based studies. Cohort studies were therefore carried out to examine the effect of beta and alpha blocker exposure post diagnosis on cancer specific and overall mortality. Furthermore, laboratory studies have demonstrated the effect of alphablockers in reducing induced angiogenesis and suppress metastasis in mouse models. A study was therefore conducted to examine in detail the effect of alpha blockers on mortality outcomes in a cohort of prostate cancer patients and additionally considering their indication of use. Finally observational studies have investigated the anti-proliferative effects of beta blocker use on survival outcomes but not specifically in those without metastases who might be most likely to benefit. This study therefore investigated the effect of adrenergic blockers on mortality outcomes in a large population based UK cohort of non-metastatic colorectal cancer patients.
The objectives of this thesis were:
To test the hypothesis that: β-blocker use is associated with a reduced incidence of breast, lung, prostate and colorectal cancer.
To test the hypothesis that: α-blocker use is associated with a reduced incidence of breast, lung and colorectal cancer.
To test the hypothesis that: α-blocker use is associated with a reduction in cancer specific and overall mortality in prostate cancer patients.
To test the hypothesis that: β-blocker &α-blocker use is associated with a reduction in cancer specific and overall mortality in patients with non-metastatic colorectal cancer.
To test the hypothesis that: β-blocker use is associated with a reduction in cancer specific and overall mortality in those diagnosed with prostate, breast, lung and colorectal cancer.
To test the hypothesis that: α-blocker use is associated with a reduction in cancer specific and overall mortality in those diagnosed with breast, lung and colorectal cancer.
To test the hypothesis that: β-blocker &α-blocker use is associated with a reduction in cancer specific and overall mortality in those diagnosed with non-metastatic breast, lung and prostate cancer.
Methods
A frequency matched case-control study was carried out using the Clinical Practice Research Datalink to assess the effect of adrenergic blockers upon incidence of prostate, lung, bowel and breast cancer. Amongst patients aged 18 years or older contributing at least 2 years of usable data between 01/01/1987 – 31/12/2012. Incident cases of relevant cancers and controls were selected and frequency matched 10:1 by age. Those with 2 or more prescriptions for alpha or beta blockers in the 2 years prior to cancer diagnosis were considered exposed and also assessed effect of the dose and duration of use. Logistic regression was used to adjust effect estimates for age, sex, smoking, alcohol use, and a number of potentially confounding co-morbidities and co-prescriptions.
A cohort study of colorectal, lung, breast and prostate cancer patients was conducted and selected from linked UK Clinical Practice Research Datalink, Hospital Episode Statistics and National Cancer Intelligence data between 1998 and 2010. Beta blocker and alpha blocker exposure were assessed in the 6 months post cancer diagnosis and its effect on all cause and cancer specific mortality was assessed. Data were analysed using cox proportional hazards modelling. Confounding by age, sex, cancer stage, grade and important comorbidities and co-prescriptions was adjusted for. The indication of use, dose and pre-diagnosis exposure was also examined. Additionally, from the linked data sources above, a cohort of 3164 non-metastatic colorectal cancer patients was selected and conducted a cohort study using similar methods but additionally considering the cardio-selectivity of beta blocker drugs.
Results
For the case-control study 18968 colorectal, 19082 lung, 21608 prostate and 29109 breast cancers were identified. There was no evidence of a protective effect of α or β blockade in lung and prostate cancer and found a slightly increased risk of colorectal and breast cancer in users. This was largely explained by the effects of confounding in a multivariate analyses with final OR estimates of lung, colorectal, breast and prostate cancer of 0.99, 95% CI [0.96-1.04]1.14, 95% CI [1.09 – 1.18]1.10, 95% CI [1.06 – 1.14]1.01, 95% CI [0.98-1.05] respectively for beta blocker exposure and 1.03, 95% CI [0.97 – 1.09]1.13, 95% CI [1.07 – 1.20]1.08, 95% CI [1.00 – 1.17] for alphablocker exposure. Stratification by dose and duration did not reveal any statistically significant findings.
For the cohort study of common solid cancers 15636 colorectal, 13646 lung, 23877 breast and 18654 prostate cancer patients were selected with a median follow up of 3.7, 0.6, 5.5 and 4.4 years respectively. There were no significant effects observed on all-cause mortality in any cancers and similarly no significant effects observed on cancer specific mortality in patients on betablockers compared to those who were not. For alphablocker exposure, there were no significant effects observed on all-cause mortality in any cancers and similarly no significant effect on cancer specific mortality except in prostate (HR0.874, 95% CI [0.781 – 0.978]) and colorectal(HR1.878, 95% CI [1.108 – 3.182]) cancer patients. There were no clear significant effects observed by dose or prediagnosis exposure.
For the cohort study of non-metastatic colorectal cancer patients during a median follow up time of 4 years no significant effects were observed on all-cause mortality (HR0.995, 95% CI [0.811 – 1.220]) or cancer specific mortality (HR1.153, 95% CI [0.868 – 1.530]) in patients on beta blockers compared to those who were not. Similar null findings were observed with alpha blockers: HR0.946, 95% CI [0.709 – 1.262] for all-cause mortality and (HR1.037, 95% CI [0.701 – 1.534]) for colorectal cancer mortality. Stratification by dose, prediagnosis exposure and cardio-selectivity showed no significant effects. For the cohort study of prostate cancer patients during a median follow up time of 4.4 years, alpha blocker exposure was associated with decreased all-cause mortality (HR: 0.839, 95% CI [0.776 – 0.908]) and cancer specific mortality (HR: 0.874, 95% CI [0.781 – 0.978]). Limiting analysis to those taking alpha blockers to treat hypertension rendered the effect on all-cause mortality non-significant (HR: 0.857, 95% CI [0.728 – 1.217], but a significant decrease in cancer specific mortality remained (HR: 0.692, 95% CI [0.534 – 0.897]). No modifying effects were observed by dose and pre-diagnosis exposure.
Conclusion
In these large population-based case-control and cohort studies investigating the impact of beta and alphablocker use on cancer incidence and mortality, limited evidence was found to suggest that adrenergic blocker use prevents the incidence of common cancers. Indeed, a slight increased risk of colorectal and breast cancer was found which may reflect residual confounding and health seeking behaviours. Furthermore, beta or alpha blocker use post diagnosis was not associated with a decreased risk of cancer-specific or all-cause mortality in colorectal, lung or breast cancer patients or in those with non-metastatic colorectal cancer. However, our results do provide evidence that alphablockers are associated with a decreased risk of prostate cancer.
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