madman
Super Moderator
BACKGROUND
Prostate cancer is a prevalent disease that urgently needs to address its treatment-related complications. By examining existing evidence on the association between Androgen Deprivation Therapy (ADT) and dementia, this study contributes to the understanding of potential risks. We sought to analyze the currently available evidence regarding the risk of dementia, Alzheimer’s disease (AD), vascular dementia, and Parkinson’s disease (PD) in patients undergoing ADT.
METHODS
A systematic search of PubMed, EMBASE, Scopus, and Google Scholar was performed to identify studies published from the databases’ inception to April 2023. Studies were identified through systematic review to facilitate comparisons between studies with and without some degree of controls for biases affecting distinctions between ADT receivers and non-ADT receivers. This review identified 305 studies, with 28 meeting the inclusion criteria. Heterogeneity was assessed using Higgins I2%. Variables with an I2 over 50% were considered heterogeneous and analyzed using a random effects model. Otherwise, a Fixed-Effects model was employed.
RESULTS
A total of 28 studies were included for analysis. Out of these, only 1 study did not report the number of patients. From the remaining 27 studies, there were a total of 2,543,483 patients, including 900,994 with prostate cancer who received ADT,1,262,905 with prostate cancer who did not receive ADT, and 334,682 patients without prostate cancer who did not receive ADT. This analysis revealed significantly increased Hazard Ratios (HR) of 1.20 [1.11, 1.29], p < 0.00001 for dementia, HR 1.26 [1.10, 1.43],p = 0.0007 for Alzheimer’s Disease, HR 1.66 [1.40, 1.97], p < 0.00001 for depression, and HR 1.57 [1.31, 1.88], p < 0.00001 for Parkinson’s Disease. The risk of vascular dementia was HR 1.30 [0.97, 1.73], p < 0.00001.
CONCLUSION
Based on the analysis of the currently available evidence, it suggests that ADT significantly increases the risk of dementia, AD, PD, and depression.
INTRODUCTION
Prostate cancer is the most common cancer in men and the second deadliest [1]. Approximately 12.9% of men will receive a prostate cancer diagnosis during their lifetime, contributing to a prevalence of 3,343,976 men currently living with the disease in the United States [2]. Treatment ranges from active surveillance to radical prostatectomy, radiotherapy, systemic therapy, and combinations of these [3, 4]. Androgen Deprivation Therapy (ADT) is a widely used treatment for prostate cancer, with approximately half of all patients with prostate cancer estimated to undergo ADT as part of their treatment [5]. This treatment approach encompasses various scenarios, including adjuvant therapy for high-risk patients undergoing radiotherapy for localized disease, locally advanced disease, post-radical prostatectomy in node-positive disease, and metastatic disease [6–10].
Among their various functions, androgens play a crucial role in regulating the growth of prostatic tissue and the growth and proliferation of cancerous cells [11]. Huggins and Hodges first described ADT in 1941; they won a Nobel Prize in 1967 for their work on ADT in managing symptomatic metastatic prostate cancer [12]. Androgen deprivation can be achieved surgically through bilateral orchiectomy, nearly depleting the body’s androgen synthetic capacity, or medically through GnRH/LHRH agonists, decreasing the synthesis of androgens through downstream inhibition or antiandrogens that bind androgen receptors [12].
While the use of ADT is associated with improved outcomes and survival in prostate cancer, it is important to note that it is also linked to significant morbidity. The side effects of ADT encompass a wide range, including osteoporosis, metabolic syndrome, cardiovascular disorders, sexual dysfunction, and cognitive decline[13]. Androgens have been proposed to play a crucial role in the neuronal microenvironment through various mechanisms associated with maintaining synaptic density, degrading beta-amyloid, and promoting neuronal plasticity [14, 15]. The link between ADT and dementia has been proposed for over 20 years, and recently it has been the subject of epidemiological studies. However, the evidence from these studies has yielded mixed results, indicating a need for further investigation and research in this area [15–17].
This study analyzes the currently available evidence regarding the risk of dementia, Alzheimer’s disease (AD), vascular dementia, and Parkinson’s disease in patients undergoing Androgen Deprivation Therapy (ADT).
This study faces various limitations. Methodological variation between included studies, as well as unaccounted confounders in the different regions, races, and ethnicities included, may impact results. Additionally, propensity matching algorithms are prone to interstudy variation, and thus adjustment of confounders might be unequal. The high heterogeneity observed even within subgroups suggests the presence of other factors influencing the results. Although subgroup analysis provides additional insights, it does not allow for quantitative analysis of observed differences. More precise methods, such as metaregression or network comparison of different interventions, would be beneficial in quantifying the variations in risk. Another limitation is that the included studies also had variations in clinical stage and treatment employed, which could be potential confounders that were not adequately accounted for. However, sub-analysis focusing on localized prostate cancer patients still showed significant results. Furthermore, including studies with stratified data by type of ADT may introduce bias due to the particular offering of certain ADT types based on disease stage.
CONCLUSION
Available evidence suggests that ADT significantly increases the risk of dementia, AD, PD, and depression. The increased risk of dementia is observed regardless of the treatment modality and duration; however, quantitative analysis is needed to assess the differences between treatment modalities and durations accurately. It is important to note that some studies may have used similar databases and overlapping patient cohorts, which could introduce potential bias or duplicate data in this analysis. Clinicians should be vigilant in monitoring prostate cancer patients undergoing ADT for symptoms of cognitive decline and other neurodegenerative disorders.
Prostate cancer is a prevalent disease that urgently needs to address its treatment-related complications. By examining existing evidence on the association between Androgen Deprivation Therapy (ADT) and dementia, this study contributes to the understanding of potential risks. We sought to analyze the currently available evidence regarding the risk of dementia, Alzheimer’s disease (AD), vascular dementia, and Parkinson’s disease (PD) in patients undergoing ADT.
METHODS
A systematic search of PubMed, EMBASE, Scopus, and Google Scholar was performed to identify studies published from the databases’ inception to April 2023. Studies were identified through systematic review to facilitate comparisons between studies with and without some degree of controls for biases affecting distinctions between ADT receivers and non-ADT receivers. This review identified 305 studies, with 28 meeting the inclusion criteria. Heterogeneity was assessed using Higgins I2%. Variables with an I2 over 50% were considered heterogeneous and analyzed using a random effects model. Otherwise, a Fixed-Effects model was employed.
RESULTS
A total of 28 studies were included for analysis. Out of these, only 1 study did not report the number of patients. From the remaining 27 studies, there were a total of 2,543,483 patients, including 900,994 with prostate cancer who received ADT,1,262,905 with prostate cancer who did not receive ADT, and 334,682 patients without prostate cancer who did not receive ADT. This analysis revealed significantly increased Hazard Ratios (HR) of 1.20 [1.11, 1.29], p < 0.00001 for dementia, HR 1.26 [1.10, 1.43],p = 0.0007 for Alzheimer’s Disease, HR 1.66 [1.40, 1.97], p < 0.00001 for depression, and HR 1.57 [1.31, 1.88], p < 0.00001 for Parkinson’s Disease. The risk of vascular dementia was HR 1.30 [0.97, 1.73], p < 0.00001.
CONCLUSION
Based on the analysis of the currently available evidence, it suggests that ADT significantly increases the risk of dementia, AD, PD, and depression.
INTRODUCTION
Prostate cancer is the most common cancer in men and the second deadliest [1]. Approximately 12.9% of men will receive a prostate cancer diagnosis during their lifetime, contributing to a prevalence of 3,343,976 men currently living with the disease in the United States [2]. Treatment ranges from active surveillance to radical prostatectomy, radiotherapy, systemic therapy, and combinations of these [3, 4]. Androgen Deprivation Therapy (ADT) is a widely used treatment for prostate cancer, with approximately half of all patients with prostate cancer estimated to undergo ADT as part of their treatment [5]. This treatment approach encompasses various scenarios, including adjuvant therapy for high-risk patients undergoing radiotherapy for localized disease, locally advanced disease, post-radical prostatectomy in node-positive disease, and metastatic disease [6–10].
Among their various functions, androgens play a crucial role in regulating the growth of prostatic tissue and the growth and proliferation of cancerous cells [11]. Huggins and Hodges first described ADT in 1941; they won a Nobel Prize in 1967 for their work on ADT in managing symptomatic metastatic prostate cancer [12]. Androgen deprivation can be achieved surgically through bilateral orchiectomy, nearly depleting the body’s androgen synthetic capacity, or medically through GnRH/LHRH agonists, decreasing the synthesis of androgens through downstream inhibition or antiandrogens that bind androgen receptors [12].
While the use of ADT is associated with improved outcomes and survival in prostate cancer, it is important to note that it is also linked to significant morbidity. The side effects of ADT encompass a wide range, including osteoporosis, metabolic syndrome, cardiovascular disorders, sexual dysfunction, and cognitive decline[13]. Androgens have been proposed to play a crucial role in the neuronal microenvironment through various mechanisms associated with maintaining synaptic density, degrading beta-amyloid, and promoting neuronal plasticity [14, 15]. The link between ADT and dementia has been proposed for over 20 years, and recently it has been the subject of epidemiological studies. However, the evidence from these studies has yielded mixed results, indicating a need for further investigation and research in this area [15–17].
This study analyzes the currently available evidence regarding the risk of dementia, Alzheimer’s disease (AD), vascular dementia, and Parkinson’s disease in patients undergoing Androgen Deprivation Therapy (ADT).
This study faces various limitations. Methodological variation between included studies, as well as unaccounted confounders in the different regions, races, and ethnicities included, may impact results. Additionally, propensity matching algorithms are prone to interstudy variation, and thus adjustment of confounders might be unequal. The high heterogeneity observed even within subgroups suggests the presence of other factors influencing the results. Although subgroup analysis provides additional insights, it does not allow for quantitative analysis of observed differences. More precise methods, such as metaregression or network comparison of different interventions, would be beneficial in quantifying the variations in risk. Another limitation is that the included studies also had variations in clinical stage and treatment employed, which could be potential confounders that were not adequately accounted for. However, sub-analysis focusing on localized prostate cancer patients still showed significant results. Furthermore, including studies with stratified data by type of ADT may introduce bias due to the particular offering of certain ADT types based on disease stage.
CONCLUSION
Available evidence suggests that ADT significantly increases the risk of dementia, AD, PD, and depression. The increased risk of dementia is observed regardless of the treatment modality and duration; however, quantitative analysis is needed to assess the differences between treatment modalities and durations accurately. It is important to note that some studies may have used similar databases and overlapping patient cohorts, which could introduce potential bias or duplicate data in this analysis. Clinicians should be vigilant in monitoring prostate cancer patients undergoing ADT for symptoms of cognitive decline and other neurodegenerative disorders.
