Androgen Deprivation Therapy for Prostate Cancer and Neurocognitive Disorders: A Systematic Review and Meta-Analysis

doi:10.21203/rs.3.rs-3221041/v1

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Androgen Deprivation Therapy for Prostate Cancer and Neurocognitive Disorders: A Systematic Review and Meta-Analysis

https://doi.org/10.21203/rs.3.rs-3221041/v1

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Journal Publication

published 02 Jan, 2024

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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.

Health sciences/Medical research/Outcomes research

Health sciences/Diseases/Cancer/Urological cancer/Prostate cancer

Prostate cancer is the most common cancer in men and the second deadliest.¹ Treatment ranges from active surveillance to radical prostatectomy, radiotherapy, systemic therapy, and combinations of these.^2,3 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. 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.^4–8

Among their various functions, androgens play a crucial role in regulating the growth of prostatic tissue and the growth and proliferation of cancerous cells.⁹ 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.¹⁰ 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 which bind androgen receptors.¹⁰

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.¹¹ 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.^12,13 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.^13–15

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).

In December 2022, with prior PROSPERO registration (CRD42022297904, a systematic search for a systematic review was performed following the PRISMA criteria (eFigure 1). PubMed, EMBASE, Scopus, and Google Scholar were queried for the terms “Androgen Deprivation Therapy”, “Prostate Cancer”, AND “Dementia”, “new onset Dementia”, “Alzheimer’s Disease” and “Vascular Dementia” in title or abstract. The following search string was employed: “("Prostate Cancer"[Title/Abstract] AND ("Androgen Deprivation Therapy" [Title/Abstract] OR Orchiectomy[ Title/Abstract] OR "Anti-Androgen" [Title/Abstract] )) AND (Dementia [Title/Abstract] OR depression [Title/Abstract] OR "Vascular Dementia" [Title/Abstract] OR "Alzheimers d*" [Title/Abstract] OR Parkinson [Title/Abstract])”. No restrictions on publication date were applied; only English, Spanish, and Russian manuscripts were considered. Two independent (DEHG, AZ) reviewers screened returned results for inclusion and data extraction. Data conciliation was performed through consensus. In addition, related articles and a bibliography of identified studies were further screened for possible inclusion. This study was exempt from review by the institutional review board, and informed consent was not required because data were publicly available.

Study Inclusion

Included studies provided a time-dependent analysis confounder adjusted analysis reported in Hazard Ratios (HR) for risk of All-type dementia, Alzheimer’s dementia(AD), vascular dementia(VD), Parkinson’s disease(PD), and depression in patients with prostate cancer undergoing treatment with androgen deprivation therapy.

Data Extraction and Analysis

Data was extracted independently by two reviewers (DEHG, AZ). Relevant data for primary and secondary endpoints was HR for All-type dementia, Alzheimer’s dementia, vascular dementia, and depression. Further subgroup stratification was performed based on length of ADT duration, type of ADT used - bilateral orchiectomy, GnRH agonists or Antiandrogens, and patient age. Additional subgroup analysis was performed based on the continental distribution of patient populations, excluding overlapping cohorts (i.e., multiple publications using the same database over the same period) and by disease stage.

Data analysis was performed in Review Manager (RevMan) V 5.4.2 (Cochrane). Heterogeneity was assessed using Higgins I²%. Variables with over 50% I² were considered heterogeneous and were analyzed through a Random-Effects model. Otherwise, a Fixed-Effects model was used. Analysis was performed using the generic Inverse-Variance method, using RevMan’s built-in calculator to estimate the logarithmic function and standard error from provided HR and confidence intervals. HR was estimated for studies providing only survival curves but not HR using Tierney’s method.¹⁶ Values are expressed as HR with 95% confidence intervals. P values of 0.05 and less were considered statistically significant. Heterogeneity was explored through multiple subgroups and a one-by-one stepwise addition of studies to assess the impact and casuals of heterogeneity. The Newcastle-Ottawa criteria for cohort studies were utilized to perform quality evaluation. Each study was assigned a maximum of nine points, with 4 points for selection, 2 points for comparability, and 3 points for outcome assessment. Studies with scores ranging from 0 to 3, 4 to 6, and 7 to 9 were classified as low, moderate, and high quality, respectively. Primary outcomes were the HRs of dementia and AD. Secondary outcomes were HR of PD, depression, and VD.

Sensitivity Analysis for Heterogeneity

Subgroup analysis attempting to explore and adjust for variations noted during data extraction was performed further to clarify the impact of these variations in reported results. Subgroups were performed to stratify by ADT received (AA, GnRH Agonists, Orchiectomy), duration of therapy, patient age, and geographical region. Variations in results, when stratified by the characteristics, are narrated in the respective results section. Multiple studies queried the same database with overlapping periods. To adjust for possible duplication of patients, an additional sensitivity analysis was performed, excluding overlapping studies while only retaining the study with the largest population size.

A total of 28 studies were included in the analysis. Of these studies, only one did not report the number of patients. Among the remaining 27 studies, there were a total of 2 543 483 patients. Specifically, 900 994 patients had prostate cancer and received ADT, 1 262 905 patients had prostate cancer but did not receive ADT, and 334 682 patients did not have prostate cancer and did not receive ADT. Table 1 provides a summary of the variables analyzed and the quality assessment.

ADT and Dementia

The included studies analyzed the risk of various forms of cognitive decline associated with ADT, including dementia, Alzheimer's, and vascular dementia.

Dementia

The risk of dementia was analyzed in a total of 20 studies. The analysis revealed a statistically significant HR of 1.20 [1.11, 1.29], p < 0.00001, indicating an increased risk of dementia associated with ADT. Figure 1 displays these findings, and a comprehensive breakdown of the included studies can be found in eFigure 2.A.

Alzheimer’s Disease

Thirteen studies were included in the analysis of the risk of developing AD. The analysis of these studies concluded a statistically significant risk with a HR of 1.26 [1.10, 1.43], p < 0.00001, indicating an increased risk of AD in patients undergoing ADT. These findings are visually displayed in Fig. 1, and a detailed breakdown of the included studies can be found in eFigure 2.B.

Vascular Dementia

The risk of vascular dementia was assessed in 3 studies. The pooled analysis of these studies indicated a non-significant risk with a HR of 1.30 [0.97, 1.73], p < 0.00001. These findings are depicted in Fig. 1, and a comprehensive breakdown of the included studies can be found in eFigure 3.B.

Depression

The development of depression related to ADT was analyzed in a total of 7 studies. The analysis of these studies revealed a significant risk of depression in patients undergoing ADT, with a HR of 1.66 [1.40, 1.97], p < 0.00001. These findings are visually presented in Fig. 1, and a detailed breakdown of the included studies can be found in eFigure 3.A.

Parkinson’s Disease

The association between Parkinson's Disease and ADT was examined in 3 studies, and the pooled analysis demonstrated a significantly increased risk with a HR of 1.57 [1.31, 1.88], p < 0.00001. These findings are presented in Fig. 1, and a comprehensive breakdown of the included studies can be found in eFigure 3.C.

ADT Modality and Dementia

A subgroup analysis was conducted to stratify the risk of dementia or Alzheimer's disease (AD) based on different modalities of ADT, including orchiectomy, GnRH agonists/antagonists, and antiandrogens.

Dementia

The three therapies above, including bilateral orchiectomy, GnRH agonists/antagonists, and antiandrogens, were analyzed, and significant increases in risk were observed for all three forms of therapy. Among them, the highest risk was associated with bilateral orchiectomy, with a HR of 1.36 [1.17, 1.59], p < 0.0001. It is important to note that this subgroup had the lowest number of included studies (three). These findings are presented in Fig. 2, and a detailed breakdown of the included studies can be found in eFigure 4.A.

Alzheimer’s Disease

The analysis of various individual ADT modalities and the risk of AD indicates that orchiectomy and antiandrogens are associated with a significantly increased risk. These findings are depicted in Fig. 3, and a comprehensive breakdown of the included studies can be found in eFigure 4.B.

Treatment Duration

Studies that provided risk stratification based on treatment duration were included to analyze the impact of duration on the risk of ADT.

Dementia

Both therapies lasting less than 6–12 months and those lasting more than 6–12 months were associated with a significantly increased risk of dementia. However, the risk was higher in longer duration therapy, with a HR of 1.22 [1.10, 1.36], p < 0.0001. These findings are visually presented in Fig. 2, and a comprehensive breakdown of the included studies can be found in eFigure 5.A.

Alzheimer’s Disease

The analysis of treatment duration and the risk of developing Alzheimer's disease (AD) indicated an increased risk regardless of the duration of treatment. These findings are presented in Fig. 3, and a detailed breakdown of the included studies can be found in eFigure 5.B.

Age, ADT, and Dementia

Among the analyzed studies, only three examined subsets of patients based on age at initiation of ADT. In patients younger than 65, no significant risks were found. However, a significant risk was observed in patients aged 65 and older with a HR of 1.76 [1.30, 2.37], p = 0.0002. These findings are depicted in Fig. 2, and a comprehensive breakdown of the included studies can be found in eFigure 6.A.

The same two studies analyzed age subgroups and AD; however, in this case, the pooled analysis suggested an increased risk for AD regardless of age. These findings are displayed in Fig. 3 with a full breakdown of included studies in eFigure 6.B.

Regional Analysis

A subgroup analysis was conducted based on the continental geographic regions of the included cohorts.

Dementia

The geographical subgroup analysis revealed that only cohorts from America showed an increased risk of dementia with ADT, with a HR of 1.19 [1.08, 1.31], p < 0.0001. These findings are visually presented in Fig. 4, and a comprehensive breakdown of the included studies can be found in eFigure 7.A.

Alzheimer’s Disease

Geographical subgroup analysis revealed that American and Asian cohorts had an increased risk of dementia with ADT, with HR of 1.13 [1.00, 1.27], p < 0.00001) and 1.23 [1.05, 1.46], p = 0.01, respectively. These findings are displayed in Fig. 5, and a comprehensive breakdown of the included studies can be found in eFigure 7.B.

Sensitivity analysis suggests that, for the American subgroup, the main drivers of heterogeneity were Nead et al., Baik et al., and Deka et al. However, these studies did not significantly alter the results and exhibited high interstudy heterogeneity. Robinson et al. were the main drivers of heterogeneity in the European cohort. Partial exclusion of the antiandrogen and orchiectomy subgroups significantly increased risk, while the full exclusion of Robinson et al.'s cohort resulted in non-significant differences. In the Asian region, Kang was the main driver of heterogeneity, and its exclusion did not significantly alter the results.

In the geographical analysis of AD, Baik was identified as the main driver of heterogeneity for the American cohorts. However, excluding Baik did not significantly alter the results. In the Asian cohorts, Jhan and Kang et al. were identified as the main drivers of heterogeneity, but excluding them did not affect the results.

Localized and Adjusted Disease

Ten studies were included for analysis, which consisted of populations featuring only patients with localized prostate cancer or whose propensity scoring successfully adjusted for disease stage. The overall Hazard Ratio (HR) for dementia was 1.23 [1.03–1.38], with a p = 0.0009.

Overlapping Databases

The included studies examined large institutions such as Surveillance Epidemiology and End Results (SEER) and the Korean Health Insurance Information Service (KHIS). Therefore, there may be overlap in the analyzed populations across these studies. Upon excluding the overlapping studies, the HR was determined to be 1.15 [1.07, 1.24], p = 0.0002.

This meta-analysis presents the results of 28 analyzed studies. The findings suggest an increased risk of dementia, Alzheimer's disease (AD), Parkinson's disease (PD), and depression in patients undergoing androgen deprivation therapy (ADT) for prostate cancer. All analyzed treatment modalities showed an increased risk of dementia. Orchiectomy had the highest estimated risk; however, it is important to note that this treatment modality also had the least evidence. Furthermore, the employed methodology does not differentiate whether there are statistical differences between different types of ADT. Future studies should incorporate comparisons of treatment modalities into the results using network analysis or similar approaches.

Three included studies incorporated non-cancer cohorts into their analysis. These studies did not identify any significant differences in the risk of dementia between patients with prostate cancer not undergoing androgen deprivation therapy (ADT) and matched non-cancer cohorts. This finding strengthens the belief that ADT is the cause, rather than a confounder, of the established increased risk of various cognitive and neurodegenerative conditions observed in this analysis. This conclusion is further supported by prior evidence showing the influence of androgens on neuronal sustenance and plasticity.^12,13 A meta-analysis by Lv et al. found that cohorts with low testosterone levels are at an increased risk of developing dementia.¹⁷ Other studies have linked decreased bioavailability of testosterone in older men with dementia.¹⁸

The duration of treatment was found to increase the risk of dementia and AD. Although the risk appears to be higher with longer durations of ADT, the current methodology does not precisely quantify the differences or increases in risk. Previous studies have already established a connection between prolonged ADT and an increased risk of dementia.^{15, 19–30} Conversely, the age at which ADT is initiated may influence a patient's susceptibility to dementia. Only two studies showed that patients under 65 do not appear to be at an increased risk of dementia compared to those older than 65. However, when analyzing the relationship between age and AD, our analysis suggests an increased risk regardless of age. It is important to note that these findings are derived from limited evidence, and further studies would be beneficial to provide more comprehensive insights.

Race and socioeconomic factors have significantly impacted populations' risk of neurocognitive decline.^31,32 Regional analysis revealed that studies from American cohorts were the main contributors to the significant differences in risk observed, with increased risk of dementia in patients undergoing ADT. On the other hand, European studies did not show a significant increase in dementia risk associated with ADT. In terms of AD, both American and Asian cohorts showed an increased risk. It is worth noting that genetic and environmental factors may play a role in modifying the risk of cognitive decline in patients with prostate cancer. However, it is important to consider that the variations in risk observed could also stem from differences in the risk modeling, given that these studies utilized propensity matching. Furthermore, the diversity within some of the included databases limits the ability of regional analysis to discriminate between race-related risks adequately.

Disease severity and stage could also influence the risk of cognitive decline, either through additional treatments employed or through inherent biological processes.³³ Additional treatments such as chemotherapy have also been previously established to increase the risk of dementia.³⁴ Although additional studies have found conflicting evidence on the possible relationship between cancer and cognitive decline.³⁵

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. 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 meta-regression 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.

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.

Mohit Khera:

Consultant for AbbVie, Marius, Tolmar, Endo, Petros, Boston Scientific, Coloplast

Investor: Sprout

Other authors have no conflicts to disclose

Funding: None

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Kim YA, Kim SH, Joung JY, Yang MS, Back JH, Kim SH. The Insignificant Correlation between Androgen Deprivation Therapy and Incidence of Dementia Using an Extension Survival Cox Hazard Model and Propensity-Score Matching Analysis in a Retrospective, Population-Based Prostate Cancer Registry. Cancers. 2022;14(11):2705. doi:10.3390/cancers14112705

Table 1 is available in the Supplementary Files section.

Yes there is potential conflict of interest.

eFigure1.DisplaysPRISMAflowdiagram..pdf
eFigure 1. Displays PRISMA flow diagram.
eFigure2.DisplaysforestplotwithfullstudybreakdownforA.DementiaandB.AlzheimersDisease.png
eFigure 2. Displays forest plot with full study breakdown for A. Dementia and B. Alzheimers Disease
eFigure3.DisplaysforestplotwithfullstudybreakdownforA.DepressionB.VascularDementiaandC.ParkinsonXXXsDisease.png
eFigure 3. Displays forest plot with full study breakdown for A. Depression, B. Vascular Dementia, and C. Parkinson’s Disease
eFigure4.DisplaysforestplotwithfullstudybreakdownbytreatmentmodalityforA.DementiaandB.AlzheimerXXXsDisease.png
eFigure 4. Displays forest plot with full study breakdown by treatment modality for A. Dementia and B. Alzheimer’s Disease
eFigure5.DisplaysforestplotwithfullstudybreakdownbytreatmentdurationforA.DementiaandB.AlzheimerXXXsDisease.png
eFigure 5. Displays forest plot with full study breakdown by treatment duration for A. Dementia and B. Alzheimer’s Disease
eFigure6.DisplaysforestplotwithfullstudybreakdownbypatientageforA.DementiaandB.AlzheimerXXXsDisease.png
eFigure 6. Displays forest plot with full study breakdown by patient age for A. Dementia and B. Alzheimer’s Disease
eFigure7.DisplaysforestplotwithfullstudybreakdownbygeographicregionforA.DementiaandB.AlzheimerXXXsDisease.png
eFigure 7. Displays forest plot with full study breakdown by geographic region for A. Dementia and B. Alzheimer’s Disease
Table1ADT.docx
Table 1. Displays key summary data from included studies on population size, data origin, ADT employed, key findings, and quality rating.

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published 02 Jan, 2024

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You are reading this latest preprint version

Androgen Deprivation Therapy for Prostate Cancer and Neurocognitive Disorders: A Systematic Review and Meta-Analysis

Status:

Journal Publication

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Abstract

Background:

Methods:

Results:

Conclusion:

Figures

Introduction

Methods

Study Inclusion

Data Extraction and Analysis

Sensitivity Analysis for Heterogeneity

Results

ADT and Dementia

Dementia

Alzheimer’s Disease

Vascular Dementia

Depression

Parkinson’s Disease

ADT Modality and Dementia

Dementia

Alzheimer’s Disease

Treatment Duration

Dementia

Alzheimer’s Disease

Age, ADT, and Dementia

Regional Analysis

Dementia

Alzheimer’s Disease

Localized and Adjusted Disease

Overlapping Databases

Discussion

Conclusion

Declarations

References

Table 1

Additional Declarations

Supplementary Files

Status:

Journal Publication

Version 1