Prostate ...

[Michael Scally MD]

Eapen RS, Herlemann A, Washington SL, 3rd, Cooperberg MR. Impact of the United States Preventive Services Task Force 'D' recommendation on prostate cancer screening and staging. Curr Opin Urol. http://journals.lww.com/co-urology/Abstract/publishahead/Impact_of_the_United_States_Preventive_Services.99309.aspx

PURPOSE OF REVIEW: In 2012, the United States Preventive Services Task Force (USPSTF) issued a grade 'D' recommendation against the use of routine prostate-specific antigen (PSA)-based screening for any men.

This recommendation reflects critical misinterpretations of the available evidence base regarding benefits and harms of PSA screening and has influenced the nationwide landscape of prostate cancer screening, diagnosis, and treatment.

RECENT FINDINGS: Following the USPSTF recommendation, a substantial decline in PSA screening was noted for all age groups. Similarly, overall rates of prostate biopsy and prostate cancer incidence have significantly decreased with a shift toward higher grade and stage disease upon diagnosis.

Concurrently, the incidence of metastatic prostate cancer has significantly risen in the United States. These trends are concerning particularly for the younger men with occult high-grade disease who are expected to benefit the most from early detection and definitive prostate cancer treatment.

SUMMARY: These emerging trends in PSA screening and prostate cancer incidence following the USPSTF recommendation may have significant public health implications. Due to the long natural history of the disease, a long-term follow-up is needed to provide a better understanding on the implications of such recommendations on disease progression and mortality rates in prostate cancer patients.

The future of US screening policy should reflect a targeted 'smarter' screening strategy rather than dichotomizing the decision between 'screen all' or 'screen none'.

 

[Michael Scally MD]

Chung SD, Kao LT, Lin HC, Xirasagar S, Huang CC, Lee HC. Patients receiving androgen deprivation therapy for prostate cancer have an increased risk of depressive disorder. PLoS One 2017;12(3):e0173266. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0173266
Androgen deprivation therapy (ADT) results in testosterone suppression, a hypothesized mechanism linking ADT to depressive symptoms.

This study investigated the relationship between ADT and the risk of subsequently being diagnosed with depressive disorder (DD) during a 3-year follow-up period.

The patient sample for this population-based, retrospective cohort study was retrieved from the Taiwan Longitudinal Health Insurance Database 2005.

We included all 1714 patients aged over 40 years with a first-time diagnosis of prostate cancer (PC) during 2001 to 2010 who did not have an orchiectomy.

Among them, we defined 868 patients who received ADT during the 3-year follow-up period as the study group, and 846 patients who did not receive ADT as the comparison group.

The incidence rates of DD per 1000 person-years were 13.9 (95% confidence interval (CI): 9.5~19.6) and 6.7 (95% CI: 3.7~11.0), respectively. Cox proportional hazard regressions showed that the adjusted hazard ratio for DD for ADT recipients was 1.93 (95% CI: 1.03~3.62) relative to the comparison group.

This study presents epidemiological evidence of an association between ADT and a subsequent DD diagnosis.

 

[Michael Scally MD]

Verges DP, Dani H, Sterling WA, et al. The Relationship of Baseline Prostate Specific Antigen and Risk of Future Prostate Cancer and Its Variance by Race. J Natl Med Assoc 2017;109(1):49-54. http://www.journalnma.org/article/S0027-9684(16)30088-8/abstract

PURPOSE: Several studies suggest that a baseline prostate specific antigen (PSA) measured in young men predicts future risk of prostate cancer. Considering recent recommendations against PSA screening, high-risk populations (e.g. black men, men with a high baseline PSA) may be particularly vulnerable in the coming years. Thus, we investigated the relationship between baseline PSA and future prostate cancer in a black majority-minority urban population.

MATERIALS AND METHODS: A retrospective analysis was performed of the prostate biopsy database (n = 994) at the Brooklyn Veterans Affairs Hospital. These men were referred to urology clinic for elevated PSA and biopsied between 2007 and 2014. Multivariate logistic regression was used to predict positive prostate biopsy from log-transformed baseline PSA, race (black, white, or other), and several other variables.

RESULTS: The majority of men identified as black (50.2%). Median age at time of baseline PSA and biopsy was 58.6 and 64.8, respectively. Median baseline PSA was similar among black men and white men (2.70 vs 2.91 for black men vs white men, p = 0.232).

Even so, black men were more likely than white men to be diagnosed with prostate cancer (OR 1.62, p < 0.0001). Black men less than age 70 were at particularly greater risk than their white counterparts.

Baseline PSA was not a statistically significant predictor of future prostate cancer (p = 0.101).

CONCLUSIONS: Black men were more likely to be diagnosed with prostate cancer than were white men, despite comparable baseline PSA. In our pre-screened population at the urology clinic, a retrospective examination of baseline PSA did not predict future prostate cancer.

 

[Michael Scally MD]

Llukani E, Katz BF, Agalliu I, et al. Low levels of serum testosterone in middle-aged men impact pathological features of prostate cancer. Prostate Int 2017;5(1):17-23. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5357970/

BACKGROUND: Serum testosterone deficiency increases with aging. Age is also a major risk factor for prostate cancer (PrCa) and PCa tumors are more frequently diagnosed among men >65 years old. We evaluated the relationship between preoperative serum testosterone and clinical/ pathological features of PrCa in middle-aged and elderly patients.

METHODS: A total of 605 PrCa patients who underwent robotic-assisted radical prostatectomy between September 2010 and January 2013 at the University of Pennsylvania, and who had serum testosterone levels measured using Elecsys Testosterone II Immunoassay were included in this IRB-approved protocol.

Androgen deficiency was determined as serum free testosterone (FT) <47 pg/ml and total testosterone (TT) <193 ng/dl. Demographic, clinical and tumor characteristics of men with low vs. normal TT or FT were compared using t-test or chi-square tests. Logistic regression was used to determine associations of clinical and pathological variables with FT or TT levels.

RESULTS: Among middle-aged men (45-64 years; n = 367), those with low FT and low TT had, on average, a higher BMI (29.7 vs. 27.4, P < 0.01; and 32.2 vs. 27.6; P < 0.01, respectively) and higher proportion of Gleason 8-10 PrCa (13.3% vs. 4.8%, P = 0.011; and 19.2% vs. 5.1%, P = 0.012) compared to men with normal FT and normal TT values.

Patients with low FT had also higher number of positive cores on biopsy (3.9 vs. 3.1 P = 0.019) and greater tumor volume (7.9 ml vs. 6.1 ml, P = 0.045) compared to those with normal FT. Among men >/=65 years (n = 135) there was no difference in prostatectomy specimens of PrCa between patients with low or normal FT or TT.

CONCLUSION: Among men aged 45-64 years low serum pretreatment FT and TT predicted more aggressive features of PrCa in prostatectomy specimens. In middle-aged patients low testosterone levels measured pre-operatively may indicate more aggressive disease parameters.

 

[Michael Scally MD]

Nead KT, Sinha S, Nguyen PL. Androgen deprivation therapy for prostate cancer and dementia risk: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. http://www.nature.com/pcan/journal/vaop/ncurrent/full/pcan201710a.html

Background: Androgen deprivation therapy (ADT) to treat prostate cancer may be associated with an increased risk of dementia, but existing studies have shown conflicting results. Here we synthesize the literature on the association of ADT for the treatment of prostate cancer with dementia risk.

Methods: We conducted a systematic review of articles reporting the outcome of dementia among individuals with prostate cancer in those exposed to ADT versus a lesser-exposed comparison group (for example, ADT versus no-ADT; continuous versus intermittent ADT) using PubMed (1966–present), Web of Science (1945–present), Embase (1966–present) and PsycINFO (1806–present). The search was undertaken on 4 December 2016 by two authors.

We meta-analyzed studies reporting an effect estimate and controlling for confounding. Random- or fixed-effects meta-analytic models were used in the presence or absence of heterogeneity per the I2 statistic, respectively. Small study effects were evaluated using Egger and Begg’s tests.

Results: Nine studies were included in the systematic review. Seven studies reported an adjusted effect estimate for dementia risk. A random-effects meta-analysis of studies reporting any dementia outcome, which included 50 541 individuals, showed an increased risk of dementia among ADT users (hazard ratio (HR), 1.47; 95% confidence interval (CI), 1.08–2.00; P=0.02).

We separately meta-analyzed studies reporting all-cause dementia (HR, 1.46; 95% CI, 1.05–2.02; P<0.001) and Alzheimer’s disease (HR, 1.25; 95% CI, 0.99–1.57; P=0.06). There was no evidence of bias from small study effects (Egger, P=0.19; Begg, P=1.00).

Conclusion: The currently available combined evidence suggests that ADT in the treatment of prostate cancer may be associated with an increased dementia risk. The potential for neurocognitive deficits secondary to ADT should be discussed with patients and evaluated prospectively.

 

[Michael Scally MD]

Tu H, Gu J, Meng QH, et al. Low serum testosterone is associated with tumor aggressiveness and poor prognosis in prostate cancer. Oncol Lett 2017;13(3):1949-57. https://www.spandidos-publications.com/10.3892/ol.2017.5616

Serum testosterone is a potential marker to distinguish between indolent and aggressive prostate cancer (PCa). The present study aimed to investigate whether low levels of total serum testosterone at diagnosis were associated with aggressive PCa and poor clinical outcomes.

In total, 762 non-Hispanic Caucasian men with previously untreated PCa were recruited from The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients were categorized into three groups based on their total serum testosterone levels according to clinical guidelines [low (<230 ng/dl), intermediate (230-350 ng/dl) and normal (>350 ng/dl)].

PCa aggressiveness (low-, intermediate- or high-risk, or metastatic) was compared using multinomial logistic regression. Rates of disease progression, mortality from any cause and PCa-specific mortality were compared using the multivariate Cox proportional hazards model.

Testosterone levels significantly decreased as PCa aggressiveness increased (P<0.001). Compared with the normal testosterone group, the low testosterone group had 2.9-fold (OR, 2.92; 95% CI, 1.74-4.90; P<0.001), 5.6-fold (OR, 5.63; 95% CI, 3.14-10.12; P<0.001) and 72.4-fold (OR, 72.40; 95% CI, 20.89-250.89; P<0.001) increased risks of having intermediate-risk, high-risk and metastatic PCa, respectively. Furthermore, low levels of testosterone were significantly associated with a 10.7-fold (HR, 10.68; 95% CI, 1.35-84.44; P=0.03) increased risk of PCa-specific mortality.

The results of the present study indicate that low levels of total serum testosterone at diagnosis are associated with aggressive PCa and predict poor PCa-specific survival.

 

[Michael Scally MD]

Testosterone Therapy on Active Surveillance and Following Definitive Treatment for Prostate Cancer

PURPOSE OF REVIEW: Previously considered an absolute contraindication, the use of testosterone therapy in men with prostate cancer has undergone an important paradigm shift. Recent data has changed the way we approach the treatment of testosterone deficiency in men with prostate cancer.

In the current review, we summarize and analyze the literature surrounding effects of testosterone therapy on patients being treated in an active surveillance protocol as well as following definitive treatment for prostate cancer.

RECENT FINDINGS: The conventional notion that defined the relationship between increasing testosterone and prostate cancer growth was based on limited studies and anecdotal case reports. Contemporary evidence suggests testosterone therapy in men with testosterone deficiency does not increase prostate cancer risk or the chances of more aggressive disease at prostate cancer diagnosis.

Although the studies are limited, men who received testosterone therapy for localized disease did not have higher rates of recurrences or worse clinical outcomes. Current review of the literature has not identified adverse progression events for patients receiving testosterone therapy while on active surveillance/watchful waiting or definitive therapies.

The importance of negative effects of testosterone deficiency on health and health-related quality of life measures has pushed urologists to re-evaluate the role testosterone plays in prostate cancer. This led to a paradigm shift that testosterone therapy might in fact be a viable option for a select group of men with testosterone deficiency and a concurrent diagnosis of prostate cancer.

Golla V, Kaplan AL. Testosterone Therapy on Active Surveillance and Following Definitive Treatment for Prostate Cancer. Curr Urol Rep 2017;18(7):49. https://link.springer.com/article/10.1007%2Fs11934-017-0695-6

 

[Michael Scally MD]

Association between Age-Related Reductions in Testosterone and Risk of Prostate Cancer - An Analysis of Patients' Data with Prostatic Diseases

The relationship between serum total testosterone and prostate cancer (PCa) risk is controversial. The hypothesis that faster age-related reduction in testosterone is linked with increased PCa risk remains untested.

We conducted this study at a tertiary-level hospital in southeast of the US, and derived data from the Medical Registry Database of individuals that were diagnosed of any prostate-related disease from 2001-2015. Cases were those diagnosed of PCa and had one or more measurements of testosterone prior to PCa diagnosis. Controls were those without PCa and had one or more testosterone measurements. Multivariable logistic regression models for PCa risk of absolute levels (one-time measure and 5-year average) and annual change in testosterone were respectively constructed.

Among a total of 1559 patients, 217 were PCa cases, and neither one-time measure nor 5-year average of testosterone was found to be significantly associated with PCa risk. Among the 379 patients with two or more testosterone measurements, 27 were PCa cases. For every 10 ng/dL increment in annual reduction of testosterone, the risk of PCa would increase by 14% [adjusted odds ratio, 1.14; 95% confidence interval (CI), 1.03-1.25]. Compared to patients with a relatively stable testosterone, patients with an annual testosterone reduction of more than 30 ng/dL had 5.03 [95% CI: 1.53, 16.55] fold increase in PCa risk.

This implies a faster age-related reduction in, but not absolute level of serum total testosterone as a risk factor for PCa. Further longitudinal studies are needed to confirm this finding. This article is protected by copyright. All rights reserved.

Wang K, Chen X, Bird VY, Gerke TA, Manini TM, Prosperi M. Association between Age-Related Reductions in Testosterone and Risk of Prostate Cancer - An Analysis of Patients' Data with Prostatic Diseases. Int J Cancer. http://onlinelibrary.wiley.com/doi/10.1002/ijc.30882/abstract

 

[Michael Scally MD]

Highlights
· Ninety-three per cent of men treated with 12 months of androgen deprivation therapy report hot flashes.
· Hot flashes began and reached peak frequency when testosterone levels were castrate.
· Hot flashes resolved a median of 8 months after the cessation of treatment.
· Cessation of hot flashes often preceded testosterone recovery.
· The median time to testosterone recovery was 9–18 months.

Dosani M, Morris WJ, Tyldesley S, Pickles T. The Relationship between Hot Flashes and Testosterone Recovery after 12 Months of Androgen Suppression for Men with Localised Prostate Cancer in the ASCENDE-RT Trial. Clin Oncol (R Coll Radiol). http://www.clinicaloncologyonline.net/article/S0936-6555(17)30284-4/abstract

AIMS: This study describes the proportion of men who experienced hot flashes (flashes), and the testosterone level at onset, peak frequency and cessation of flashes after 12 months of androgen deprivation therapy (ADT) in men undergoing curative-intent external beam radiation therapy (+/- brachytherapy boost). We also aimed to characterise testosterone recovery in this population.

MATERIALS AND METHODS: This was a pre-specified secondary analysis of the ASCENDE-RT clinical trial. Three hundred and ninety-eight men were randomised. All received 12 months of ADT. The presence and frequency of flashes were patient reported. Cessation of flashes was defined as the first date a patient reported resolution of this symptom. Testosterone recovery was defined as any single serum testosterone above the threshold of 5, 7.5 or 10 nmol/l.

RESULTS: The median age and follow-up were 68 years and 6.1 years. Flashes were reported in 93% of men. Flashes began and reached peak frequency at a median time of 4.0 months from the first luteinizing hormone-releasing hormone injection when testosterone levels had fallen to castrate.

The median time to cessation of flashes was 7.6 months after the cessation of ADT (last injection + 3 months), when the median testosterone had risen to 5.7 nmol/l. A resolution of flashes was reported in 99% of patients. Baseline testosterone was available in 338 patients (85%). The median baseline testosterone was 13.2 nmol/l.

The median (95% confidence interval) time of testosterone recovery to thresholds of 5 nmol/l, 7.5 nmol/l and 10 nmol/l were 9 (9-10) months, 13 (10-15) months and 18 (17-19) months from the cessation of ADT. At the time of censor, 96, 94 and 91% of patients had recovered testosterone to thresholds of 5, 7.5 and 10 nmol/l.

CONCLUSION: Flashes occur at castrate levels of testosterone, with cessation of hot flashes antedating full recovery of testosterone in most patients. Rates of testosterone recovery after 12 months of ADT exceed 90%, although it can be delayed.

 

[Michael Scally MD]

[OA] Lopez DS, Advani S, Tsilidis KK, Wang R, Canfield S. Endogenous and exogenous testosterone and prostate cancer: decreased-, increased- or null-risk? Transl Androl Urol 2017;6(3):566-79. http://tau.amegroups.com/article/view/15228/15466

For more than 70 years, the contention that high levels of testosterone or that the use of testosterone therapy (TTh) increases the development and progression of prostate cancer (PCa) has been widely accepted and practiced. Yet, the increasing and emerging evidence on testosterone research seems to challenge that contention.

To review literature on the associations of endogenous and exogenous testosterone with decreased-, increased-, or null-risk of PCa, and to further evaluate only those studies that reported magnitude of associations from multivariable modeling as it minimizes confounding effects.

We conducted a literature search to identify studies that investigated the association of endogenous total testosterone [continuous (per 1 unit increment and 5 nmol/L increment) and categorical (high vs. low)] and use of TTh with PCa events [1990-2016]. Emphasis was given to studies/analyses that reported magnitude of associations [odds ratio (OR), relative risk (RR) and hazard ratios (HRs)] from multivariable analyses to determine risk of PCa and their statistical significance. Most identified studies/analyses included observational and randomized placebo-controlled trials.

This review was organized in three parts:
(I) association of endogenous total testosterone (per 1 unit increment and 5 nmol/L increment) with PCa;
(II) relationship of endogenous total testosterone (categorical high vs. low) with PCa; and
(III) association of use of TTh with PCa in meta-analyses of randomized placebo-controlled trials.

The first part included 31 observational studies [20 prospective (per 5 nmol/L increment) and 11 prospective and retrospective cohort studies (per 1 unit increment)]. None of the 20 prospective studies found a significant association between total testosterone (5 nmol/L increment) and increased- or decreased-risk of PCa. Two out of the 11 studies/analyses showed a significant decreased-risk of PCa for total testosterone per 1 unit increment, but also two other studies showed a significant increased-risk of PCa. Remaining studies reported null-risks values.

Second part: eight of out of 25 studies reported an increased-risk of PCa for men with high levels of testosterone compared to low, but only four were statistically significant. However, 17 studies showed a decreased-risk of PCa after comparing high vs. low levels of testosterone, but 11 studies/analyses were statistically significant.

Third part: two meta-analyses of randomized placebo-controlled trials (n=8 and n=11, each) that investigated use of TTh with PCa reported not significant decreased-risks of PCa.

The contention that high levels of testosterone or that the use of TTh increases the risk of PCa doesn't seem to be supported from the literature. Yet, we still need a study with the adequate power, follow-up data, epidemiological, pathological and clinical data that can support the safety and beneficial effects of high levels of endogenous testosterone or use of TTh in the natural history of PCa and in men's health.

 

[Michael Scally MD]

Stamm AW, Banerji JS, Wolff EM, et al. A decision aid versus shared decision making for prostate cancer screening: results of a randomized, controlled trial. Can J Urol 2017;24(4):8910-7. http://www.canjurol.com/abstract.php?ArticleID=3146&PMID=&version=1.0

INTRODUCTION: Shared decision making (SDM) is widely encouraged by both the American Urological Association and Choosing Wisely for prostate cancer screening. Implementation of SDM is challenging secondary to time constraints and competing patient priorities. One strategy to mitigate the difficulties in implementing SDM is to utilize a decision aid (DA). Here we evaluate whether a DA improves a patient's prostate cancer knowledge and affects prostate-specific antigen (PSA) screening rates.

MATERIALS AND METHODS: Patients were randomized to usual care (UC), DA, or DA + SDM. Perception of quality of care was measured using the Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey. Outcomes were stratified by long term provider relationship (LTPR, > 3 years) versus short term provider relationship (STPR, < 3 years). Knowledge of prostate cancer screening and the decision regarding screening were assessed. Groups were compared using ANOVA and logistic regression models.

RESULTS: A total of 329 patients were randomized. Patients in the DA + SDM arm were significantly more likely to report discussing the implication of screening (33% DA + SDM, 22% UC, 16% DA, p = 0.0292) and answered significantly more knowledge questions correctly compared to the UC arm (5.03 versus 4.46, p = 0.046).

However, those in the DA arm were significantly less likely to report that they always felt encouraged to discuss all health concerns (72% DA, 78% DA + SDM, 87% UC, p = 0.0285). Interestingly, STPR patients in the DA arm were significantly more likely to undergo PSA-based prostate cancer screening (41%) than the UC arm (8%, p = 0.019). This effect was not observed in the LTPR group.

CONCLUSIONS: Providing patients a DA without a personal interaction resulted in a greater chance of undergoing PSA-based screening without improving knowledge about screening or understanding of the consequences of this decision.

This effect was exacerbated by a shorter term provider relationship. With complex issues such as the decision to pursue PSA-based prostate cancer screening, tools cannot substitute for direct interaction with a trusted provider.

 

[Michael Scally MD]

[OA] Song W, Soni V, Soni S, Khera M. Testosterone inhibits the growth of prostate cancer xenografts in nude mice. BMC Cancer 2017;17(1):635. https://bmccancer.biomedcentral.com/articles/10.1186/s12885-017-3569-x

BACKGROUND: Traditional beliefs of androgen's stimulating effects on the growth of prostate cancer (PCa) have been challenged in recent years. Our previous in vitro study indicated that physiological normal levels of androgens inhibited the proliferation of PCa cells.

In this in vivo study, the ability of testosterone (T) to inhibit PCa growth was assessed by testing the tumor incidence rate and tumor growth rate of PCa xenografts on nude mice.

METHODS: Different serum testosterone levels were manipulated in male nude/nude athymic mice by orchiectomy or inserting different dosages of T pellets subcutaneously. PCa cells were injected subcutaneously to nude mice and tumor incidence rate and tumor growth rate of PCa xenografts were tested.

RESULTS: The data demonstrated that low levels of serum T resulted in the highest PCa incidence rate (50%). This PCa incidence rate in mice with low T levels was significantly higher than that in mice treated with higher doses of T (24%, P < 0.01) and mice that underwent orchiectomy (8%, P < 0.001).

Mice that had low serum T levels had the shortest tumor volume doubling time (112 h). This doubling time was significantly shorter than that in the high dose 5 mg T arm (158 h, P < 0.001) and in the orchiectomy arm (468 h, P < 0.001).

CONCLUSION: These results indicated that low T levels are optimal for PCa cell growth. Castrate T levels, as seen after orchiectomy, are not sufficient to support PCa cell growth. Higher levels of serum T inhibited PCa cell growth.

 

[Michael Scally MD]

Inoue T, Mizowaki T, Kabata D, et al. Recovery of serum testosterone levels and sexual function in patients treated with short-term luteinizing hormone-releasing hormone antagonist as a neoadjuvant therapy before external radiotherapy for intermediate-risk prostate cancer: Preliminary prospective study. Clinical Genitourinary Cancer. Redirecting

Introduction/Background - External beam radiation therapy (EBRT) with short-term androgen deprivation therapy is a standard of care for intermediate-risk prostate cancer (PCa) patients. However, no study to date has evaluated the hormonal kinetics or sexual and hormonal function recovery after the cessation of short-term luteinizing hormone releasing hormone (LHRH)antagonist treatment.

Materials and Methods - Ten intermediate-risk PCa patients (mean age, 69.9 years) were included. All patients received 4 months of LHRH antagonist (degarelix) treatment followed by EBRT. Testosterone (T), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prostate-specific antigen levels were measured and Expanded Prostate Cancer Index Composite (EPIC) questionnaires were completed before the start of LHRH antagonist therapy at baseline; 1, 2, 3, and 4 months after the first injection of LHRH antagonist treatment; and every 2 months thereafter until 18 months.

Results - T levels were castration level at 1 month after the first LHRH antagonist injection. The median time to recover a normal T level (>7.2 nmol/L) was 7 months after the last LHRH antagonist administration. The LH and FSH levels decreased but increased more than twice above baseline at 15 months after the last LHRH antagonist injection. Sexual function and hormonal bother subdomain scores and sexual and hormonal domain scores decreased once after LHRH antagonist treatment but significantly recovered thereafter (p < 0.05).

Conclusions - In most patients, T level normalized within 9 months after the last administration. Sexual and hormonal function recovered after the short -term LHRH antagonist for neoadjuvant therapy before EBRT.

 

[MR10X]

I had this same exact treatment done. My TT dropped to 32. I used HCG and then Nolvadex to get mine back i took 2 cycles of Nolvadex to get it back to a goodnormal level. It has stayed in a good normal range since i did the treatment 5 years ago and my last PSA was 0.1.

 

[Michael Scally MD]

Stocking JJ, Fiandalo MV, Pop EA, Wilton JH, Azabdaftari G, Mohler JL. Characterization of Prostate Cancer in a Functional Eunuch. J Natl Compr Canc Netw 2017;14(9):1054-60. http://www.jnccn.org/content/14/9/1054.abstract

BACKGROUND: Eunuchs rarely, if ever, develop prostate cancer (CaP). This article reports on a 62-year-old functional eunuch from prepubertal mumps orchitis who developed clinically localized CaP.

METHODS: Serum and CaP and benign prostate tissue androgen levels were measured using a validated liquid chromatography-tandem mass spectrometry assay. The assay measures testosterone; dihydrotestosterone (DHT); the adrenal androgens, androstenedione and dehydroepiandrosterone; and the androgen metabolites, androsterone and androstanedione. Gene and protein expression levels of androgen metabolism enzymes, and androgen receptor and androgen-regulated genes were measured using quantitative reverse-transcription polymerase chain reaction and immunohistochemistry, respectively.

RESULTS: Intracrine androgen metabolism produced tissue DHT when serum and tissue testosterone levels were castrate and undetectable, respectively. Androgen receptor, androgen-regulated, and androgen metabolism enzyme genes were expressed but at lower levels in CaP than benign tissues.

CONCLUSIONS: DHT was synthesized using the primary backdoor androgen metabolism pathway and not using androstenedione or dehydroepiandrosterone via the frontdoor or secondary backdoor pathways.

 

[Michael Scally MD]

Ujike T, Uemura M, Kawashima A, et al. A novel model to predict positive prostate biopsy based on serum androgen level. Endocr Relat Cancer. http://erc.endocrinology-journals.org/content/early/2017/10/18/ERC-17-0134

Circulating levels of prostate-specific antigen (PSA) and testosterone are widely used for detection of prostate cancer prior to prostate biopsy; however both remain controversial. Effective screening strategies based on quantitative factors could help avoid unnecessary biopsies. Here, we sought to clarify the predictive value of free testosterone (FT) versus total testosterone (TT) in identifying patients likely to have positive biopsies. This study aims to develop a novel model for predicting positive prostate biopsy based on serum androgen levels. METHODS: this study included 253 Japanese patients who underwent prostate biopsy at our institution. TT and FT, %FT (=FT/TT), age, PSA, prostate volume (PV), and PSA density (PSAD=PSA/PV) were assessed for association with prostate biopsy findings.

RESULTS: of 253 patients, 145 (57.3%) had positive biopsies. Compared to the negative biopsy group, the positive biopsy group demonstrated higher age, PSA, and PSAD but lower PV, FT, and %FT by univariate analysis. Multivariate logistic regression analysis indicated PSA, PSAD and %FT were independent predictors of cancer detection. We developed a predictive model based on PSAD and %FT, for which the area under the curve was significantly greater than that of PSA (0.82 versus 0.66), a well-known predictor. Applying this analysis to the subset of patients with PSA <10ng/mL yielded similar results. We confirmed the utility of this model in another independent cohort of 88 patients.

CONCLUSION: lower %FT predicted a positive prostate biopsy. We constructed a predictive model based on %FT and PSAD, which are easily obtained prior to biopsy.

 

[Michael Scally MD]

Prostate Cancer Incidence and Severity in Testosterone-treated vs. Untreated Hypogonadal Men: Real-life Experience from more than 5500 Patients Years
SMSNA - SMSNA

Objectives: There is no evidence that testosterone therapy (TTh) in men with hypogonadism increases prostate cancer (PCa) incidence or severity. Canadian authors recently found that long-term TTh decreased the risk of PCa diagnosis (Wallis et al. Lancet Diab Endocrinol 2016; 4:498), confirmed by a German group (Yassin et al. Aging Male 2017;20:125) . We assessed incidence and severity of PCa in hypogonadal men on long-term TTh (T-group) in comparison to an untreated hypogonadal control group (CTRL).

Material and Methods: 400 men with testosterone ≤350 ng/dL and symptoms of hypogonadism received testosterone undecanoate 1000 mg every 3 months for up to 10 years. 376 hypogonadal men opted against TTh. Median follow-up: 8 years. Prostate volume (PV) and PSA were measured and digital rectal examination/ transrectal ultrasound performed before treatment initiation and then every 3-6 months in treated and every 12 months in untreated patients. Biopsies were performed when indicated according to EAU guidelines.

Results: In the T-group, 9 men (2.3%) were diagnosed with PCa. In CTRL, 26 (6.9%) were diagnosed with PCa. The incidence per 10,000 years was 31 in the T-group and 94 in CTRL. The mean baseline age of PCa patients was 65 years in the T-group and 64 in CTRL.

In the T-group, prostatectomy was performed in all men. All but 1 patient had a Gleason score ≤6, and all a predominant Gleason score of 3. Tumor grade was G2 in all 9 (100%), tumor stage T2 in all 9 patients (100%). In CTRL, prostatectomy alone was performed in 18 men, prostatectomy and radiation in 6, and radiation only in 2 men. Gleason score was >6 in all 26 patients. 2 men had a predominant Gleason score of 3, 20 had 4, and 4 had 5. Tumor grade was G2 in 6 (23%) and G3 in 20 patients (77%), tumor stage T2 in 1 (4%) and T in 25 patients (96%).

In the T-group, PCa was usually diagnosed within the first 1.5 years after initiation of TTh (minimum: 9, maximum: 21 months). In CTRL, PCa diagnosis was made at all times during the observation time (minimum: 24, maximum: 108 months).

Conclusions: In hypogonadal men, TTh may decrease PCa incidence compared to CTRL. PCa was less severe in the T-group.

 

[virginian]

So if I understand this correctly, it means TRT reduces the likelihood and severity of prostate cancer in men who had low testosterone. Or in other words, untreated low testosterone is bad with respect to prostate cancer.

 

[Michael Scally MD]

Murillo-Garzon V, Kypta R. WNT signalling in prostate cancer. Nature Reviews Urology 2017;14:683. WNT signalling in prostate cancer

Genome sequencing and gene expression analyses of prostate tumours have highlighted the potential importance of genetic and epigenetic changes observed in WNT signalling pathway components in prostate tumours — particularly in the development of castration-resistant prostate cancer. WNT signalling is also important in the prostate tumour microenvironment, in which WNT proteins secreted by the tumour stroma promote resistance to therapy, and in prostate cancer stem or progenitor cells, in which WNT–β-catenin signals promote self-renewal or expansion. Preclinical studies have demonstrated the potential of inhibitors that target WNT receptor complexes at the cell membrane or that block the interaction of β-catenin with lymphoid enhancer-binding factor 1 and the androgen receptor, in preventing prostate cancer progression. Some WNT signalling inhibitors are in phase I trials, but they have yet to be tested in patients with prostate cancer.

 

[Michael Scally MD]

Li R, Ravizzini GC, Gorin MA, et al. The use of PET/CT in prostate cancer. Prostate Cancer Prostatic Dis 2017. https://www.nature.com/articles/s41391-017-0007-8

BACKGROUND: Positron emission tomography/computed tomography (PET/CT) has recently emerged as a promising diagnostic imaging platform for prostate cancer. Several radiolabelled tracers have demonstrated efficacy for cancer detection in various clinical settings. In this review, we aim to illustrate the diverse use of PET/CT with different tracers for the detection of prostate cancer.

METHODS: We searched MEDLINE using the terms 'prostate cancer', 'PET', 'PET/CT' and 'PET/MR'). The current review was limited to (18)F-NaF PET/CT, choline-based PET/CT, fluciclovine PET/CT and PSMA-targeted PET/CT, as these modalities have been the most widely adopted.

RESULTS: NaF PET/CT has shown efficacy in detecting bone metastases with high sensitivity, but relatively low specificity. Currently, choline PET/CT has been the most extensively studied modality. Although having superior specificity, choline PET/CT suffers from low sensitivity, especially at low PSA levels. Nevertheless, choline PET/CT was found to significantly improve upon conventional imaging modalities (CIM) in the detection of metastatic lesions at biochemical recurrence (BCR). Newer methods using fluciclovine and PSMA-targeted radiotracers have preliminarily demonstrated great promise in primary and recurrent staging of prostate cancer. However, their superior efficacy awaits confirmation in larger series.

CONCLUSIONS: PET/CT has emerged as a promising staging modality for both primary and recurrent prostate cancer. Newer tracers have increased detection accuracies for small, incipient metastatic foci. The clinical implications of these occult PET/CT detected disease foci require organized evaluation. Efforts should be aimed at defining their natural history as well as responsiveness and impact of metastasis-directed therapy.