Prostate ...

[Michael Scally MD]

[OA] Questioning the Evidence Behind the Saturation Model for Testosterone Replacement Therapy in Prostate Cancer

Published in 2009, the Saturation Model suggested that there were limits to which androgen encouraged growth of the prostate. This was, in particular, applied to prostate cancer, where conventional wisdom since Huggins has considered it almost taboo for a patient being treated with cancer to receive testosterone replacement therapy (TRT).

Since then, several studies began to investigate the application of TRT in, at first, mild and stable prostate cancer patients. While early reports seem promising, the validity of the Saturation Model had not been addressed. The current review investigates the evidence synthesis behind the Saturation Model, based on its original publication where it was presented. The evidence reviewed includes in vitro, in vivo and clinical studies that were referenced as the basis when the model was presented.

Despite promising associations, the evidence employed were troublingly taken out of context in many cases and applied freely in cases where it would be unwise to do so. In light of some shortcomings in evidence synthesis, we advise some caution when applying the Saturation Model in prostate cancer.

Kim JW. Questioning the evidence behind the Saturation Model for testosterone replacement therapy in prostate cancer. Investig Clin Urol. 2020;61(3):242‐249. doi:10.4111/icu.2020.61.3.242 Questioning the evidence behind the Saturation Model for testosterone replacement therapy in prostate cancer

 

[Michael Scally MD]

MRI in Early Detection of Prostate Cancer

Purpose of review: The use of MRI in the early detection of prostate cancer (PCa) is increasing rapidly. In the last couple of years, there have been a number of key publications that have led to its adoption in the UK and European guidelines.

Recent findings: PROMIS showed that standard biopsy missed up to half of clinically significant disease, compared with 5 mm template mapping biopsy. Three studies then compared the standard transrectal ultrasound (TRUS) pathway with an MRI with or without targeted biopsy pathway. These showed that MRI-targeted biopsies detect more clinically significant disease and reduce overdetection of indolent disease whilst allowing between one-third to one half of men to avoid an immediate biopsy. Cost-effectiveness data show that using MRI to determine who gets a biopsy and how that biopsy is done is a cost-neutral approach when men at lowest risk do not undergo biopsy.

Summary: Prostate MRI is a useful and cost-effective tool for early detection of PCa that minimizes the impact of overdetection and overtreatment whilst maximizing the detection of PCa, which could benefit from treatment. The next challenge is to ensure that centres offering MRI are able to offer high-quality MRI acquisition and reporting.

Giganti F, Moore CM. MRI in early detection of prostate cancer. Curr Opin Urol. 2019;29(6):563‐568. doi:10.1097/MOU.0000000000000668 MRI in early detection of prostate cancer : Current Opinion in Urology

 

[Michael Scally MD]

Prostate Cancer Incidence 5 Years After US Preventive Services Task Force Recommendations Against Screening

Background: Previous studies reported that prostate cancer incidence rates in the United States (US) declined for local-stage disease and increased for regional- and distant-stage disease following the US Preventive Services Task Force recommendations against prostate-specific antigen-based screening for men aged ≥75 in 2008 and for all men in 2012. It is unknown, however, whether these patterns persisted through 2016.

Methods: Based on the US Cancer Statistics Public Use Research Database, we examined temporal trends in invasive prostate cancer incidence from 2005-2016 in men aged ≥50 years stratified by stage (local, regional, and distant), age group (50-74 and ≥75), and race/ethnicity (all races/ethnicities, non-Hispanic whites, and non-Hispanic blacks) with joinpoint regression models to estimate annual percent changes. Tests of statistical significance are two-sided, P < 0.05.

Results: For all races/ethnicities combined, incidence for local-stage disease declined beginning in 2007 in men aged 50-74 and ≥75 years though the decline stabilized during 2013-2016 in men aged ≥75 years. Incidence decreased by 6.4% (95%CI, 4-9%-7.9%) per year from 2007-2016 in men aged 50-74 years and by 10.7% (95%CI, 6.2%-15.0%) per year from 2007-2013 in men aged ≥75 years. In contrast, incidence for regional- and distant-stage disease increased in both age groups during the study period. For example, distant-stage incidence in men aged ≥75 years increased by 5.2% (95%CI, 4.2%-6.1%) per year from 2010-2016.

Conclusions: Regional- and distant-stage prostate cancer incidence continue to increase in the US in men aged ≥50 years, and future studies are needed to identify reasons for the rising trends.

Jemal A, Culp MB, Ma J, Islami F, Fedewa SA. Prostate Cancer Incidence 5 Years After US Preventive Services Task Force Recommendations Against Screening [published online ahead of print, 2020 May 20]. J Natl Cancer Inst. 2020;djaa068. doi:10.1093/jnci/djaa068 https://academic.oup.com/jnci/advance-article-abstract/doi/10.1093/jnci/djaa068/5837113?redirectedFrom=fulltext

 

[Michael Scally MD]

Tadalafil Improves Nocturia and Nocturia-Related Quality of Life in Patients with Benign Prostatic Hyperplasia

Introduction: Tadalafil improves lower urinary tract symptoms (LUTS) including nocturia. However, the effect of tadalafil on the nocturia-related quality of life (QoL) is still unknown.

Objective: The effects of tadalafil on nocturia and nocturia-related QoL were evaluated prospectively in patients with benign prostatic hyperplasia (BPH) as a multicenter study.

Methods: Eligible men were ≥40 years with nocturia ≥2 and a prostate volume ≥20 mL. Patients were asked to complete a self-report questionnaire on the International Prostate Symptom Score (IPSS), the Nocturia Quality of Life questionnaire (N-QoL) and the International Index of Erectile Function 5 (IIEF5). Urinary frequency volume charts (FVCs) were also evaluated. These measures were evaluated at baseline, and after 4, 8, and 12 weeks of tadalafil administration (5 mg once daily).

Results: Thirty-one patients with a mean age of 74 years, a mean prostate volume of 31 mL, and a mean prostate-specific antigen level of 2.8 ng/mL were included. Treatment with tadalafil significantly improved their nocturia after 4 weeks, and these improvements were maintained for the 12-week treatment period. Total N-QoL score in new patients and several N-QoL items (inadequate sleep at night and overall bother) in all patients improved significantly after tadalafil treatment. FVCs revealed a significant improvement in the number of hours of undisturbed sleep (HUS) after treatment with tadalafil. No serious adverse events were observed.

Conclusions: This study indicates that tadalafil 5 mg once daily improves nocturia, nocturia-related QoL, and HUS in BPH patients with nocturia. These results suggest that tadalafil can offer a clinically meaningful treatment option for BPH patients with nocturia.

Takahashi R, Sumino Y, Miyazato M, et al. Tadalafil Improves Nocturia and Nocturia-Related Quality of Life in Patients with Benign Prostatic Hyperplasia (KYU-PRO Study) [published online ahead of print, 2020 Jun 2]. Urol Int. 2020;1‐7. doi:10.1159/000506489 Tadalafil Improves Nocturia and Nocturia-Related Quality of Life in Patients with Benign Prostatic Hyperplasia (KYU-PRO Study)

 

[Michael Scally MD]

[OA] Pharmacology of The Lower Urinary Tract: Update on LUTS Treatment

The number of compounds used in the pharmacological treatment of lower urinary tract symptoms (LUTS) of patients who do not respond to conservative measures has been relatively stable during the last decade, with the exception of the introduction of the new class of β3 adrenoceptor agonists. However, different combinations have been investigated, and the long-term use of these compounds has raised new concerns about adherence and safety.

This review summarizes the current state of pharmacology for LUTS, and presents a thorough discussion of the possible challenges concerning their future use. In this narrative review, we analyze the most recent articles related to LUTS pharmacotherapy, after an initial review of mechanisms of bladder function relevant in present clinical practice.

The main problems with pharmacotherapy in LUTS are associated with its moderate efficacy, low persistence on treatment, and the incidence of short- and long-term adverse events (AE) associated with some compounds. The long-term AE, such as cognitive impairment in the elderly vulnerable patients associated with antimuscarinic drugs or persistent erectile dysfunction in sexually active men after treatment with 5-α-reductase inhibitors (5-ARI), are some of the problems addressed in this review. Combination therapy taking advantage of the synergistic mechanisms of action between some classes of compounds may overcome AE associated with dose escalation.

LUTS pharmacotherapy offers moderate results to most patients but not a full cure. The use of combination drugs to achieve better clinical results, reduce AE and improve both efficacy and adherence, will be used more frequently in the future. The recently raised concern on potential long-term irreversible AE associated with some of these drugs, like antimuscarinics and 5-ARI, are critically important and require further investigation.

Abreu-Mendes P, Silva J, Cruz F. Pharmacology of the lower urinary tract: update on LUTS treatment. Ther Adv Urol. 2020;12:1756287220922425. Published 2020 May 13. doi:10.1177/1756287220922425 https://journals.sagepub.com/doi/10.1177/1756287220922425

 

[Michael Scally MD]

Hormonal Prostate Cancer Therapies and Cardiovascular Disease

Therapeutic intervention for prostate cancer mostly relies on eliminating circulating androgen or antagonizing its effect at the cellular level. As the use of endocrine therapies grows, an under-reported incidence of cardiovascular toxicities occurs in prostate cancer patients.

In this review, we summarize data of clinical studies, investigating the cardiovascular and metabolic alterations associated with the use of old and new endocrine drugs (gonadotropin-releasing hormone [GnRH] agonists and antagonists, androgen receptor inhibitors, 17α-hydroxylase/c-17,20-lyase [CYP17] inhibitor) in prostate cancer.

To date, studies looking for links between cardiovascular complications and hormone-mediated therapies in prostate cancer have reached conflicting results. Several confounding factors, such as age of patients and related cardiovascular liability, other comorbidities, and use of concomitant drugs, have to be carefully evaluated in future clinical trials.

Further research is needed given the continuous advancements being made in prostate cancer treatment.

Cereda V, Falbo PT, Manna G, et al. Hormonal prostate cancer therapies and cardiovascular disease: a systematic review [published online ahead of print, 2020 Jun 4]. Heart Fail Rev. 2020;10.1007/s10741-020-09984-2. doi:10.1007/s10741-020-09984-2 Hormonal prostate cancer therapies and cardiovascular disease: a systematic review

 

[Michael Scally MD]

Cardiovascular Risks and Toxicity - The Achilles Heel of Androgen Deprivation Therapy

Highlights
· Androgen deprivation therapy (ADT) causes various adverse effects, including increased risk of cardiovascular events
· Improved life span and novel androgen receptor inhibitors further extend the risk of cardiovascular disease among cancer survivors
· Among various ADT agents, gonadotropin releasing hormone agonists are associated with higher cardiotoxicity
· The underlying molecular mechanisms of ADT-induced cardiotoxicity is still limited

Androgen deprivation therapy (ADT) is the primary systemic therapy for treating locally advanced or metastatic prostate cancer (PCa). Despite its positive effect on PCa patient survival, ADT causes various adverse effects, including increased cardiovascular risk factors and cardiotoxicity.

Lifespans extension, early use of ADT, and second-line treatment with next-generation androgen receptor pathway inhibitors would further extend the duration of ADT and possibly increase the risk of ADT-induced cardiotoxicity. Meanwhile, information on the molecular mechanisms underlying ADT-induced cardiotoxicity and measures to prevent it is limited, mainly due to the lack of specifically designed preclinical studies and clinical trials.

This review article compiles up-to-date evidence obtained from observational studies and clinical trials, in order to gain new insights for deciphering the association between ADT use and cardiotoxicity. In addition, potential cardioprotective strategies involving GnRH receptors and second messenger cGMP are discussed.

Muniyan S, Xi L, Datta K, et al. Cardiovascular risks and toxicity - The Achilles heel of androgen deprivation therapy in prostate cancer patients [published online ahead of print, 2020 Jun 11]. Biochim Biophys Acta Rev Cancer. 2020;188383. doi:10.1016/j.bbcan.2020.188383 Cardiovascular risks and toxicity - The Achilles heel of androgen deprivation therapy in prostate cancer patients - ScienceDirect

 

[Michael Scally MD]

Serum Testosterone and Obesity in Prostate Cancer Biology

Making healthy lifestyle choices in men to combat obesity and metabolic syndrome must be promoted, not only for the known benefits of improvements in cardiovascular and general male health, but also within the realm of prostate cancer prevention. At the same time, total testosterone serum levels (TTsl) monitoring should be considered in the assessment of the general health status of middle-aged men, as well as for its possible role in PCa biology. In late onset hypogonadal males, a careful substitutive therapy, after accurate screening for PCa, should be advised as useful to approach low TTsl effects without an increased risk of PCa development.

Scientific communities should strongly influence the social policies to favor healthy alimentation and life style regimes. Hormonal screening should be encouraged to promote actions finalized to keep TTsl into the normal range. Importantly, such initiatives could provide a large amount of data of routine testosterone serum levels, improving the knowledge on the relation between hormonal asset and PCa.

Tafuri A, Porcaro AB, Shakir A, et al. Serum testosterone and obesity in prostate cancer biology: a call for health promotion in the ageing male [published online ahead of print, 2020 Jun 17]. Aging Clin Exp Res. 2020;10.1007/s40520-020-01625-w. doi:10.1007/s40520-020-01625-w Serum testosterone and obesity in prostate cancer biology: a call for health promotion in the ageing male

 

[Michael Scally MD]

Basal Total Testosterone Serum Levels Predict Biopsy and Pathological ISUP Grade Group in A Large Cohort of Caucasian Prostate Cancer Patients Who Underwent Radical Prostatectomy

Aims: - The study aimed to evaluate associations of preoperative total testosterone (TT) with the risk of aggressive prostate cancer (PCA).

Materials & methods: - From 2014 to 2018, basal TT levels were measured in 726 consecutive PCA patients. Patients were classified according to the International Society of Urologic Pathology (ISUP) system. Aggressive PCA was defined by the detection of ISUP > 2 in the surgical specimen. The logistic regression model evaluated the association of TT and other clinical factors with aggressive PCA.

Results: - On univariate analysis, there was a significant association of basal TT with the risk of aggressive PCA as well as age, prostate-specific antigen (PSA), percentage of biopsy positive cores (BPC), tumor clinical stage (cT), and biopsy ISUP grade groups.

On multivariate analysis, two models were considered. The first (model I) excluded biopsy ISUP grading groups and the second (model II) included biopsy ISUP grade groups.

Multivariate model I, revealed TT as well as all other variables, was an independent predictor of the risk of aggressive disease [odds ratio (OR) = 1.585; 95% confidence interval (CI): 1.113–2.256; p = 0.011]. Elevated basal PSA greater than 20 µg/dl was associated with the risk of aggressive PCA.

Multivariate model II revealed that basal TT levels maintain a positive association between aggressive PCA, whereas age, BPC, and clinical stage cT3 lost significance. In the final adjusted model, the level of risk of TT did not change from univariate analysis (OR = 1.525; 95% CI: 1.035–2.245; p = 0.011).

Conclusion: - Elevated preoperative TT levels are associated with the risk of aggressive PCA in the surgical specimen. TT may identify patients who are at risk of aggressive PCA in the low and intermediate European Association of Urology (EAU) risk classes.

Tafuri A, Sebben M, Rizzetto R, et al. Basal total testosterone serum levels predict biopsy and pathological ISUP grade group in a large cohort of Caucasian prostate cancer patients who underwent radical prostatectomy. Therapeutic Advances in Urology 2020;12:1756287220929481. https://doi.org/10.1177/1756287220929481

 

[Michael Scally MD]

Event-Free Survival, a Prostate-Specific Antigen–Based Composite End Point, Is Not a Surrogate for Overall Survival in Men With Localized Prostate Cancer Treated With Radiation

PURPOSE - Recently, we have shown that metastasis-free survival is a strong surrogate for overall survival (OS) in men with intermediate- and high-risk localized prostate cancer and can accelerate the evaluation of new (neo)adjuvant therapies. Event-free survival (EFS), an earlier prostate-specific antigen (PSA)–based composite end point, may further expedite trial completion.

METHODS - EFS was defined as the time from random assignment to the date of first evidence of disease recurrence, including biochemical failure, local or regional recurrence, distant metastasis, or death from any cause, or was censored at the date of last PSA assessment. Individual patient data from trials within the Intermediate Clinical Endpoints in Cancer of the Prostate–ICECaP–database with evaluable PSA and disease follow-up data were analyzed.

We evaluated the surrogacy of EFS for OS using a 2-stage meta-analytic validation model by determining the correlation of EFS with OS (patient level) and the correlation of treatment effects (hazard ratios [HRs]) on both EFS and OS (trial level). A clinically relevant surrogacy was defined a priori as an R2 ≥ 0.7.

RESULTS - Data for 10,350 patients were analyzed from 15 radiation therapy–based trials enrolled from 1987 to 2011 with a median follow-up of 10 years. At the patient level, the correlation of EFS with OS was 0.43 (95% CI, 0.42 to 0.44) as measured by Kendall’s tau from a copula model. At the trial level, the R2 was 0.35 (95% CI, 0.01 to 0.60) from the weighted linear regression of log(HR)-OS on log(HR)-EFS.

CONCLUSION - EFS is a weak surrogate for OS and is not suitable for use as an intermediate clinical end point to substitute for OS to accelerate phase III (neo)adjuvant trials of prostate cancer therapies for primary radiation therapy–based trials.

Xie W, Regan MM, Buyse M, et al. Event-Free Survival, a Prostate-Specific Antigen–Based Composite End Point, Is Not a Surrogate for Overall Survival in Men With Localized Prostate Cancer Treated With Radiation. Journal of Clinical Oncology 2020:JCO.19.03114. https://doi.org/10.1200/JCO.19.03114

 

[Michael Scally MD]

[OA] A Risk Calculator To Inform The Need For A Prostate Biopsy

Background: Prostate cancer (PCa) represents a significant healthcare problem. The critical clinical question is the need for a biopsy. Accurate risk stratification of patients before a biopsy can allow for individualised risk stratification thus improving clinical decision making. This study aims to build a risk calculator to inform the need for a prostate biopsy.

Methods: Using the clinical information of 4801 patients an Irish Prostate Cancer Risk Calculator (IPRC) for diagnosis of PCa and high grade (Gleason ≥7) was created using a binary regression model including age, digital rectal examination, family history of PCa, negative prior biopsy and Prostate-specific antigen (PSA) level as risk factors.

The discrimination ability of the risk calculator is internally validated using cross validation to reduce overfitting, and its performance compared with PSA and the American risk calculator (PCPT), Prostate Biopsy Collaborative Group (PBCG) and European risk calculator (ERSPC) using various performance outcome summaries. In a subgroup of 2970 patients, prostate volume was included. Separate risk calculators including the prostate volume (IPRCv) for the diagnosis of PCa (and high-grade PCa) was created.

Results: IPRC area under the curve (AUC) for the prediction of PCa and high-grade PCa was 0.6741 (95% CI, 0.6591 to 0.6890) and 0.7214 (95% CI, 0.7018 to 0.7409) respectively. This significantly outperforms the predictive ability of cancer detection for PSA (0.5948), PCPT (0.6304), PBCG (0.6528) and ERSPC (0.6502) risk calculators; and also, for detecting high-grade cancer for PSA (0.6623) and PCPT (0.6804) but there was no significant improvement for PBCG (0.7185) and ERSPC (0.7140).

The inclusion of prostate volume into the risk calculator significantly improved the AUC for cancer detection (AUC = 0.7298; 95% CI, 0.7119 to 0.7478), but not for high-grade cancer (AUC = 0.7256; 95% CI, 0.7017 to 0.7495). The risk calculator also demonstrated an increased net benefit on decision curve analysis.

Conclusion: The risk calculator developed has advantages over prior risk stratification of prostate cancer patients before the biopsy. It will reduce the number of men requiring a biopsy and their exposure to its side effects. The interactive tools developed are beneficial to translate the risk calculator into practice and allows for clarity in the clinical recommendations.

Jalali A, Foley RW, Maweni RM, et al. A risk calculator to inform the need for a prostate biopsy: a rapid access clinic cohort. BMC Med Inform Decis Mak. 2020;20(1):148. Published 2020 Jul 3. doi:10.1186/s12911-020-01174-2 A risk calculator to inform the need for a prostate biopsy: a rapid access clinic cohort

 

[Michael Scally MD]

A discussion on controversies and ethical dilemmas in prostate cancer screening.

Prostate cancer (PCa) is one of the the most common cancers in men. A blood test called prostate-specific antigen (PSA) has a potential to pick up this cancer very early and is used for screening of this disease. However, screening for prostate cancer is a matter of debate.

Level 1 evidence from randomised controlled trials suggests a reduction in cancer-specific mortality from PCa screening. However, there could be an associated impact on quality of life due to a high proportion of overdiagnosis and overtreatment as part of the screening.

The US Preventive Services Task Force (USPSTF) in 2012 recommended that PSA-based PCa screening should not to be offered at any age. However, considering the current evidence, USPSTF recently revised its recommendation to offer the PSA test to men aged 55-69 years with shared decision-making, in line with earlier guidelines from the American Cancer Society and the American Urological Association.

A shared decision making is necessary since the PSA test could potentially harm an individual. However, the literature suggests that clinicians often neglect a discussion on this issue before ordering the test.

This narrative discusses the main controversies regarding PCa screening including the PSA threshold for biopsy, the concept of overdiagnosis and overtreatment, the practical difficulties of active surveillance, the current level 1 evidence on the mortality benefit of screening, and the associated pitfalls. It offers a detailed discussion on the ethics involved in the PSA test and highlights the barriers to shared decision-making and possible solutions.

Mishra SC. A discussion on controversies and ethical dilemmas in prostate cancer screening [published online ahead of print, 2020 Jul 6]. J Med Ethics. 2020;medethics-2019-105979. doi:10.1136/medethics-2019-105979 https://jme.bmj.com/content/early/2020/07/05/medethics-2019-105979

 

[Michael Scally MD]

[OA] Testosterone Replacement Therapy in Men with Untreated or Treated Prostate Cancer: Do We Have Enough Evidences?

Purpose: To investigate the oncologic safety of testosterone replacement therapy (TRT) in men with untreated or treated prostate cancer.

Materials and methods: We systematically searched PubMed, Embase, and Cochrane library database from January 1941 to March 2019.

Results: In total, 36 articles met the eligibility criteria for this systematic review. They included a total of 2,459 TRT-treated patients, with a median of 20 patients per study (range: 1-1,142). Except for four studies, all were single-armed studies with poor quality scores (median MINOR, 9 of 24).

Of the 36 studies, prostate cancer was managed through active surveillance (AS), in 5 studies; radical prostatectomy, in 11 studies; radiation therapy, in 5 studies; multiple intervention modalities, in 5 studies; and systemic therapy, in 9 studies.

In comparison with TRT-treated and untreated patients, the pooled risk ratio (RR) was not significantly higher than one in comparisons of risk for disease progression (pooled RR, 0.83; 95% confidence interval, 0.57-1.21).

The results of systematic review implied that TRT might be harmful in men with advanced disease (progression rate: 38.5%-100.0%), who undergo AS (15.4%-57.1%), and who successfully treated but having high-risk disease (0.0%-50.0%).

Conclusions: Compared to TRT-untreated patients, TRT-treated patients may not have increased risks for disease progression in prostate cancer. However, the quality of currently available evidence is extremely poor. TRT may be harmful in men with advanced disease burden, in those with untreated prostate cancer undergoing AS, and in those with successfully treated prostate cancer but having high-risk disease.

Kim M, Byun SS, Hong SK. Testosterone Replacement Therapy in Men with Untreated or Treated Prostate Cancer: Do We Have Enough Evidences? [published online ahead of print, 2020 Jun 25]. World J Mens Health. 2020;10.5534/wjmh.190158. doi:10.5534/wjmh.190158 https://wjmh.org/DOIx.php?id=10.5534/wjmh.190158

 

[Michael Scally MD]

[OA] Androgen deprivation therapy and side effects: are GnRH antagonists safer?

Androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) agonists and antagonists is the mainstay of advanced prostate cancer treatment. Both drug classes decrease levels of luteinizing hormone and follicle-stimulating hormones (FSH), thereby lowering testosterone to castrate levels. This is associated with adverse events (AEs), including cardiovascular (CV) disorders, bone fractures, metabolic dysfunction, and impaired cognitive function.

This literature review discusses these AEs, with a focus on CV and bone-related events. A hypothesis-generating meta-analysis of six clinical trials showed a potentially increased risk for CV disorders with GnRH agonists versus the GnRH antagonist degarelix. While no study has directly compared GnRH agonists versus antagonists with a primary CV outcome, one hypothesis for this observation is that GnRH agonists lead to initial surges in FSH that may negatively impact CV health, whereas antagonists do not.

GnRH agonists are associated with metabolic and cognitive AEs and while data are lacking for GnRH antagonists, no differences in risk are predicted. Other common AEs with ADT include injection site reactions, which are much more common with degarelix than with GnRH agonists, which may reflect differing administration and injection techniques.

Future studies are needed to further evaluate and compare the safety profiles of GnRH agonists and antagonists, especially in patients with pre-existing CV disease and other co-morbidities. Physicians should carefully evaluate benefits and risks when prescribing ADT and ensure that side effects are well managed.

Freedland SJ, Abrahamsson PA. Androgen deprivation therapy and side effects: are GnRH antagonists safer? [published online ahead of print, 2020 Jul 10]. Asian J Androl. 2020;10.4103/aja.aja_22_20. doi:10.4103/aja.aja_22_20 Androgen deprivation therapy and side effects: are GnRH antagonists safer? Freedland SJ, Abrahamsson PA, - Asian J Androl

 

[Michael Scally MD]

The Response of Prostate Cancer Cell Lines to Exogenous Testosterone

Introduction & Objectives: There is debate in the urological community regarding the proliferative response of the prostate to testosterone (T). The androgen-dependent model states that prostate cell proliferation is directly proportional to T concentration.

Conversely, the saturation model argues that T stimulates proliferation up to a certain point, at which androgen receptors become saturated and growth plateaus. However, there is limited in vitro evidence underpinning this.

Therefore, the objective of this study was to investigate the proliferative response of both malignant (LNCaP and PC3) and benign (PNT2/C2) prostate cells to T in vitro and see if this sheds any light on observed clinical behaviours.

Materials & Methods: LNCaP (androgen-sensitive cancer), PC3 (androgen-insensitive cancer) and PNT2/C2 (benign) cells were seeded at a concentration of 1x105 viable cells into separate 96-well plates using trypan blue exclusion assay. Cells were seeded in foetal bovine serum. Exogenous T was titrated down each 96-well plate using doubling dilutions starting at 230nmol/L and reaching 0.11 nmol/L.

The residual viable biomass of each cell line was calculated by MTT assay. Incubation intervals for each cell line was derived from standard urological molecular biology protocols in peer reviewed journals. The data was statistically analysed using the paired sample t tests between testosterone concentrations.

Results: Androgen-sensitive prostate cells, LNCaP and PNT2/C2, showed an inverted ″U″ biphasic response, with reduced cell growth at T concentrations below 1.00 nmol/L (p<0.05) and above 57.50 nmol/L (p<0.05) (see fig). Androgen-insensitive PC3 cells showed little response to T below 57.50 nmol/L, however between 57.50 and 230.00 nmol/L growth was reduced (p<0.05).

Conclusions: These data suggest that the response to T of both malignant and benign androgen-sensitive cell lines is not saturation dependent, but instead biphasic. These findings are consistent with clinical observations that:1.

Prostate cancer (PC) is inhibited at both castrate and supra- physiological concentrations of T 2. PC and BPH both increase with age as T levels decline 3. Failure to supress T adequately (<1 nmol/L) will reduce PC response.4. T replacement above T concentrations of 1.8 nmol/L does not promote PC or BPH epithelial proliferation.

Birch BRP, Hald O. 13 - The response of prostate cancer cell lines to exogenous testosterone: Lessons for clinical practice. European Urology Open Science 2020;19:e121-e2. The response of prostate cancer cell lines to exogenous testosterone: Lessons for clinical practice - ScienceDirect

 

[Michael Scally MD]

Use of Testosterone Replacement Therapy after Radical Prostatectomy Might Kill Two Birds with One Stone from the Perspective of Men’s Health and Disease Control

Testosterone plays an important role in promoting the differentiation and stimulation of prostate epithelial cells. Adding to the basic physiology of testosterone, several studies led to the dissemination of the historical androgen hypothesis that higher circulating androgen levels promote prostate cancer cell growth and make the tumor more aggressive. Whereas, the prostate saturation model accounted for the androgen sensitivity of testosterone stimulation in the prostate up to a saturation point, which occurred near the level of castration.

Testosterone is related to prostate cancer metabolism in a complex manner; however, within the reference range, high or normal testosterone levels are expected to maintain benign and malignant prostate cells in a differentiated state. Accumulating evidence has suggested that testosterone replacement therapy (TRT) might prevent the development of prostate cancer and even reduce prostate cancer risk. There is no change in the clinical guidelines to be followed when considering TRT in patients with a history of prostate cancer, but it is necessary for the physician to inform patients of the positive effects of TRT on male health and prostate cancer.

Nam JK, Lee KS, Kim TN. Use of Testosterone Replacement Therapy after Radical Prostatectomy Might Kill Two Birds with One Stone from the Perspective of Men’s Health and Disease Control. J Men’s Health [Internet]. 2020Jul.11 [cited 2020Jul.17];16(SP1):e52-e56. Available from: https://www.jomh.org/index.php/JMH/article/view/271

 

[Michael Scally MD]

[OA] Letter to the editor: Questioning the evidence behind the Saturation Model for testosterone replacement therapy in prostate cancer.

We are honored by Dr. Kim's detailed review [1] of our paper, titled, “Shifting the paradigm of testosterone and prostate cancer: The Saturation Model and the limits of androgen-dependent growth,” [2] and grateful for his generous comments. However, we feel obligated to address several inaccurate comments by Dr. Kim.

It has now been 11 years since publication of this article, and over that time we have been gratified by the wealth of published research confirming all key elements of the Saturation Model. The introduction of the Saturation Model revolutionized concepts regarding the relationship of androgens and prostate growth, benign and malignant, and has served as the theoretical framework for major changes in clinical practice, including the use of testosterone (T) therapy in men with prostate cancer (PCa).

It is important for younger readers to understand that, prior to introduction of the Saturation Model, the universally held belief was the “Androgen Hypothesis”, which held that higher androgen concentrations caused proportionally greater growth of prostate tissue, and that higher serum T meant greater PCa risk and aggressiveness.

The saturation model provided a radically different view, one that resolved an awkward paradox in which androgen deprivation clearly lowered prostate-specific antigen (PSA), yet raising T in hormonally intact men had little effect on PSA or prostate size. In one swoop, the Saturation Model assembled a messy assortment of clinical observations and experimental results into a coherent picture.

Simply, the Saturation Model holds that prostate tissue is exquisitely sensitive to changes in serum androgens at low concentrations, and little to no sensitivity once a saturation point is reached. Clinical data indicate the saturation point for serum T is approximately 250 ng/dL [3, 4, 5].

The mechanisms underlying the Saturation Model include the following observations:

a) T or its derivative, 5α-dihydrotestosterone (5α-DHT), mediate prostatic cellular function by binding to the androgen receptors (AR).

b) There is a finite number of AR binding sites per cell, and

c) once AR sites are fully occupied with T or 5α-DHT, a saturation state is achieved, beyond which increasing circulating T or 5α-DHT cannot elicit additional biological activity via this mechanism [2].

Other mechanisms are possible [6], yet this relationship of androgens with AR is adequate to explain observed phenomena over a wide range of experimental data.

Morgentaler A, Traish AM. Letter to the editor: Questioning the evidence behind the Saturation Model for testosterone replacement therapy in prostate cancer. Investigative and clinical urology 2020;61:452-4. https://icurology.org/DOIx.php?id=10.4111/icu.2020.61.4.452

 

[Michael Scally MD]

Implications from Autopsy Studies of Latent Prostate Cancer

Autopsy studies of latent prostate cancer provide important information for understanding the disease and, crucially, for addressing overdiagnosis. Further autopsy studies with standardized methods are needed to drive progress in this field, and studying the differences between latent and clinically significant prostate cancer might be a promising direction for future research.

Chen, Y., Yan, W. Implications from autopsy studies of latent prostate cancer. Nat Rev Urol 17, 428–429 (2020). https://doi.org/10.1038/s41585-020-0327-7

 

[Michael Scally MD]

Association Between Dihydrotestosterone and Long-Term Risk for Prostate Cancer Mortality

Background: The androgen metabolism plays an important role in the progression of prostate cancer. Contradictory to what one might assume given the androgenic potency of dihydrotestosterone (DHT) there are indications that high DHT levels protect from prostate cancer. We want to determine whether there is a long-term association between baseline levels of DHT and death from prostate cancer.

Method: During the years 1988 and 1989, 1782 men out of 2400 invited were screened for prostate cancer. The invited men were randomly selected from a background population of more than 27 000 men. Serum levels of DHT were analyzed for all 65 men diagnosed in the trial and 130 controls from the same cohort without any signs of prostate cancer.

In this study we evaluate outcomes for the whole cohort (n = 195), the men without clinical signs of prostate cancer at beginning of follow up (n = 130) and men with screening detected cancer (n = 65). The cohort was followed up after 30 years and data from the Swedish Cause of Death Registry and the Swedish Cancer Registry were extracted. Hazard ratios (HRs) were calculated using Cox regression models.

Result: High DHT levels were positively correlated to a lower risk for prostate cancer death in the entire cohort: HR = 0.44 (0.25-0.77 95% confidence interval [CI]). The positive correlation remained significant for the subgroup analysis. HR for the men enrolled in the study without any clinical signs of prostate cancer was 0.25 (0.07-0.88 95% CI) and for the men with a prostate cancer diagnosis at time of inclusion: HR = 0.50 (0.26-0.94 95% CI).

Conclusion: DHT is negatively associated with long-term prostate cancer death regardless of clinical presentation at time of inclusion.

Lundgren PO, Kjellman A, Norming U, Gustafsson O. Association between dihydrotestosterone and long-term risk for prostate cancer mortality: A prospective cohort study. Prostate. 2020;80(10):777-781. doi:10.1002/pros.23991 Error - Cookies Turned Off

 

[Michael Scally MD]

[OA] Cardiovascular Risks of Androgen Deprivation Therapy for Prostate Cancer

Androgen deprivation therapy (ADT) is the gold standard treatment in patients with locally advanced or metastatic prostate cancer (PC). Emerging evidence has documented a tight association between ADT and body composition, along with metabolic profile impairment. These alterations might underpin the observed ADT-related increase in cardiovascular (CV) and thromboembolic (venous thromboembolism, VTE) mortality and morbidity.

However, the specific mechanisms underlying these associations have not yet been completely elucidated. In the present review we summarize and discussed the available evidence linking ADT to increased cardio-metabolic risk, using both preclinical and clinical data. When possible, meta-analytic studies were preferred.

Preclinical evidence, using a rabbit model of gonadotrophin-releasing hormone analogue-induced hypogonadism, indicates that the induced condition is associated with a dramatic increase in visceral adiposity and with an impairment of acetylcholine induced vascular relaxation, along with an increased propensity towards fatty liver.

This suggests a direct role of ADT in inducing a worsened metabolic profile. In contrast, available clinical data are not sufficient to clarify a direct pathogenic link between reduced testosterone (T) and altered metabolism.

In fact, although T deprivation is associated with an altered metabolism, it is possible that the association between ADT and CV or VTE risk could simply be the result of a selection bias, related to the poor health status of patients with advanced PC. Despite the aforementioned considerations, all patients who are candidates for ADT should be screened for CV risk factors at baseline and monitored during the therapy. Life-style modifications and physical exercise are strongly encouraged.

Corona G, Filippi S, Bianchi N, et al. Cardiovascular Risks of Androgen Deprivation Therapy for Prostate Cancer [published online ahead of print, 2020 Aug 18]. World J Mens Health. 2020;10.5534/wjmh.200109. doi:10.5534/wjmh.200109 Cardiovascular Risks of Androgen Deprivation Therapy for Prostate Cancer