Prostate ...

[Michael Scally MD]

Pastuszak AW, Khanna A, Badhiwala N, Morgentaler A, Hult M, et al. Testosterone Therapy after Radiation Therapy for Low, Intermediate, and High Risk Prostate Cancer. J Urol. https://www.sciencedirect.com/science/article/pii/S0022534715040811

INTRODUCTION: Limited literature regarding the safety of testosterone (T) therapy (TTh) in men treated for prostate cancer (CaP) exists. Here we present multiinstitutional data for TTh in hypogonadal men with CaP treated with radiation therapy (RT).

METHODS: A retrospective review of hypogonadal men treated with TTh after RT for CaP at four institutions was performed. Serum testosterone, free T (FT), estradiol (E), sex hormone-binding globulin (SHBG), prostate specific antigen (PSA), PSA velocity, and prostate biopsy findings were analyzed.

RESULTS: There were 98 men treated with RT, with median age 70.0 years (range 63.0-74.3) at initiation of TTh. Baseline T levels were 209 (152-263) ng/dL and PSA 0.08 (0.00-0.33) ng/mL. The cohort comprised 3 (3.1%) men with Gleason score (Gl) 5, 44 (44.9%) men with Gl 6, 28 (28.6%) with Gl 7, 7 (7.1%) with Gl 8, and 4 (4.1%) with Gl 9 tumors. Median duration of follow-up was 40.8 months (range 1.5-147). Serum T increased to 420 ng/dl (231-711) (p<0.001) during follow-up. Overall, a non-significant increase in mean PSA from 0.08 ng/mL at baseline to 0.09 ng/mL (p=0.05) was observed. Among high-risk patients, PSA increased from 0.10 ng/mL to 0.36 ng/mL (p=0.018). Six (6.1%) men met criteria for biochemical recurrence (BCR).

CONCLUSIONS: TTh in men following radiation therapy for CaP was associated with a minor increase in serum PSA and a low rate of BCR.

 

[Michael Scally MD]

Liu LH, Kang R, He J, Zhao SK, Li FT, et al. Vasectomy and risk of prostate cancer: a systematic review and meta-analysis of cohort studies. Andrology. http://onlinelibrary.wiley.com/doi/10.1111/andr.12040/abstract

The results of published literature focusing on the association between vasectomy and the incidence of prostate cancer are often inconsistent. We conducted a meta-analysis to provide a quantitative assessment of the association between vasectomy and the risk of prostate cancer.

We identified all cohort studies by searching the PubMed, Embase, and Cochrane Library before August 2014. The quality of the studies was evaluated using the Newcastle-Ottawa Scale checklist. Summary effect estimates with 95% confidence intervals (CI) were derived using a fixed or random effects model, depending on the heterogeneity of the included studies.

Nine cohort studies that spanned across two continents involving 1 127 096 participants (ages 20–75) with 7539 cases of prostate cancer cases were included in the meta-analysis. The overall combined relative risks for men with the reference group were 1.08 (95% CI: 0.87–1.34) in a random effects, however, the association was not statistically significant (p = 0.48).

Estimates of total effects were generally consistent in the sensitivity and subgroup analyses. No evidence of publication bias was observed.

This meta-analysis indicated that vasectomy may not contribute to the risk of prostate cancer. The conclusion might have a far-reaching significance for the public health, especially in countries with high prevalence rates of vasectomy.

 

[Michael Scally MD]

Neuzillet Y, Raynaud JP, Lebret T, Pichon A, Radulescu C, et al. Obesity and hypogonadism are associated with an increased risk of predominant Gleason 4 pattern on radical prostatectomy specimen. Horm Mol Biol Clin Investig. 2015;22(3):101-9. http://www.degruyter.com/view/j/hmbci.2015.22.issue-3/hmbci-2015-0005/hmbci-2015-0005.xml?format=INT

PURPOSE: To compare histological features of prostate cancer according to both obesity, defined by a body mass index (BMI) >/=30 kg/m2, and androgenic status in patients who underwent radical prostatectomy.

MATERIALS AND METHODS: Between March 2007 and September 2013, clinical, pathological and biological data were prospectively collected for patients referred for radical prostatectomy in a single European center.

Preoperative total testosterone (TT) and bioavailable testosterone (bioT) serum determinations were performed. The threshold for hypogonadism was set at TT <3 ng/mL. The preoperative PSA value was registered.

Gleason score (GS) and predominant Gleason pattern (PrdGP) were determined in prostate tissue specimens, and crosschecked by two uro-pathologists. Statistical analyzes were done for PrdGP4 risk assessment.

RESULTS: A total of 937 consecutive patients were included. One hundred and thirty-five filled the criterion for obesity (14.4%), out of which 42 had TT <3 ng/mL (31.1%), while in non-obese patients, only 97 had TT <3 ng/mL (12.0%). In prostate specimens, mean GS was 6.8+/-0.5: 291 patients (31.1%) had a PrdGP4.

The incidence of PrdGP4 was higher (p<0.001) in the 135 obese patients [50% when hypogonadal (p<0.02) or 42% when eugonadal (p<0.005)] than in non-obese patients (28.9% and 27.1%, respectively). In multivariable analyzis for PrdGP4 risk, obesity, TT <3 ng/mL, PSA, and age were independent risk factors.

CONCLUSIONS: Both obesity and hypogonadism are independent risk factors for PrdGP4 in patients who underwent radical prostatectomy and should be taken into account in localized prostate cancer management, to improve the therapeutic choice, especially when prostate sparing approach is considered.

 

[Michael Scally MD]

Taplin M, Balk SP. Has the Time Arrived for Biomarker-Directed Therapy in Castration-Resistant Prostate Cancer?. JAMA Oncol. Published online June 04, 2015. http://oncology.jamanetwork.com/article.aspx?articleID=2300757

Men with advanced prostate cancer live for years while receiving sequential cancer treatments that are costly and associated with morbidity. The mainstay of systemic treatment is androgen deprivation therapy aimed at abrogating critical androgen receptor (AR) directed growth, but it invariably leads to the development of castration-resistant prostate cancer (CRPC).

There are 7 approved therapies for metastatic CRPC (mCRPC) but no prospective validated data to guide individualized treatment or the sequence of treatments. Many men with CRPC respond to secondary hormonal treatments such as CYP17A1 inhibitors (abiraterone) or to a more potent AR antagonist (enzalutamide), but responses are not durable.

One mechanism that contributes to resistance is alternative splicing of the AR to generate AR variants (AR-Vs) that lack the ligand-binding domain and therefore no longer require androgen; AR variant 7 (AR-V7) is the most commonly expressed AR-V.1

Studies evaluating AR-V7 reported by Antonarakis et al first in the context of abiraterone and enzalutamide therapy and in this issue of JAMA Oncology with taxane therapy provide promise for AR-V7 as the first predictive biomarker in CRPC.


Antonarakis ES, Lu C, Luber B, et al. Androgen Receptor Splice Variant 7 and Efficacy of Taxane Chemotherapy in Patients With Metastatic Castration-Resistant Prostate Cancer. JAMA Oncol. Published online June 04, 2015. http://oncology.jamanetwork.com/article.aspx?articleid=2300763

Importance We previously showed that detection of androgen receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs) from men with castration-resistant prostate cancer (CRPC) was associated with primary resistance to enzalutamide and abiraterone therapy, but the relevance of AR-V7 status in the context of chemotherapy is unknown.

Objective To investigate whether AR-V7–positive patients would retain sensitivity to taxane chemotherapy and whether AR-V7 status would have a differential impact on taxane-treated men compared with enzalutamide- or abiraterone-treated men.

Design, Setting, and Participants We examined CTCs for AR-V7 mRNA using a reverse-transcription polymerase chain reaction assay. From January 2013 to July 2014, we prospectively enrolled patients with metastatic CRPC initiating taxane chemotherapy (docetaxel or cabazitaxel) at a single academic institution (Johns Hopkins). Our prespecified statistical plan required a sample size of 36 taxane-treated men.

Main Outcomes and Measures We evaluated associations between AR-V7 status and prostate-specific antigen (PSA) response rates, PSA progression-free survival (PSA PFS), and clinical and/or radiographic progression-free survival (PFS). After incorporating updated data from our prior study of 62 patients treated with enzalutamide or abiraterone, we also investigated the interaction between AR-V7 status (positive or negative) and treatment type (taxane vs enzalutamide or abiraterone).

Results Of 37 taxane-treated patients enrolled, 17 (46%) had detectable AR-V7 in CTCs. Prostate-specific antigen responses were achieved in both AR-V7–positive and AR-V7–negative men (41% vs 65%; P = .19). Similarly, PSA PFS (hazard ratio

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, 1.7, 95% CI, 0.6-5.0; P = .32) and PFS (HR, 2.7, 95% CI, 0.8-8.8; P = .11) were comparable in AR-V7–positive and AR-V7–negative patients. A significant interaction was observed between AR-V7 status and treatment type (P < .001). Clinical outcomes were superior with taxanes compared with enzalutamide or abiraterone therapy in AR-V7–positive men, whereas outcomes did not differ by treatment type in AR-V7–negative men. In AR-V7–positive patients, PSA responses were higher in taxane-treated vs enzalutamide- or abiraterone-treated men (41% vs 0%; P < .001), and PSA PFS and PFS were significantly longer in taxane-treated men (HR, 0.19 [95% CI, 0.07-0.52] for PSA PFS, P = .001; HR, 0.21 [95% CI, 0.07-0.59] for PFS, P = .003).

Conclusions and Relevance Detection of AR-V7 in CTCs from men with metastatic CRPC is not associated with primary resistance to taxane chemotherapy. In AR-V7–positive men, taxanes appear to be more efficacious than enzalutamide or abiraterone therapy, whereas in AR-V7–negative men, taxanes and enzalutamide or abiraterone may have comparable efficacy. Circulating tumor cell–based AR-V7 detection may serve as a treatment selection biomarker in CRPC.

 

[Michael Scally MD]

Drazer MW, Huo D, Eggener SE. National Prostate Cancer Screening Rates After the 2012 US Preventive Services Task Force Recommendation Discouraging Prostate-Specific Antigen - Based Screening. Journal of Clinical Oncology. http://jco.ascopubs.org/content/early/2015/06/08/JCO.2015.61.6532.abstract

Purpose In 2012, the US Preventive Services Task Force (USPSTF) discouraged prostate-specific antigen (PSA) –based prostate cancer screening. Previous USPSTF recommendations did not appreciably alter prostate cancer screening. Therefore, we designed a trend analysis to determine the population-based impact of the 2012 recommendation.

Methods The nationally representative National Health Interview Survey was used to estimate the proportion of men age 40 years and older who saw a physician and were screened for prostate cancer in 2013. An externally validated 9-year mortality index was used to analyze screening rates based on remaining life expectancy. Screening rates from 2005, 2010, and 2013 were compared using logistic regression.

Results PSA-based screening did not significantly change from 2010 to 2013 among 40- to 49-year-old men (from 12.5% to 11.2%; P = .4). Screening rates significantly declined in men age 50 to 59 years (from 33.2% to 24.8%; P < .01), age 60 to 74 years (from 51.2% to 43.6%; P < .01), and age 75 years or older (from 43.9% to 37.1%; P = .03). A large percentage of men were screened for prostate cancer despite a high risk (> 52%) of 9-year mortality, including approximately one third of men older than age 75 years. Approximately 1.4 million men age 65 years or older with a high risk (> 52%) of 9-year mortality were screened in 2013.

Conclusion Prostate cancer screening significantly declined among men older than age 50 years after the 2012 USPSTF guideline discouraging PSA-based screening. A significant proportion of men continue to be screened despite a high risk of 9-year mortality, including one third of men age 75 years and older.

 

[Michael Scally MD]

Baillargeon J, Kuo YF, Fang X, Shahinian VB. Long-Term Exposure to Testosterone Therapy and the Risk of High-Grade Prostate Cancer. J Urol. https://www.sciencedirect.com/science/article/pii/S0022534715041488

PURPOSE: No population-based studies have examined whether long-term exposure to testosterone therapy is associated with an increased risk of high-grade prostate cancer. In this study, we examined whether exposure to testosterone over a 5-year period was associated with an increased risk of high-grade prostate cancer and whether this risk increased in a dose-response fashion with cumulative number of testosterone injections.

MATERIALS AND METHODS: Using SEER-Medicare linked data, we identified 52,579 men who were diagnosed with incident prostate cancer between January 1, 2001 and December 31, 2006 and who had a minimum of 5 years continuous enrollment in Medicare before their cancer diagnosis. We excluded patients who were diagnosed at death or after autopsy, enrolled in a health maintenance organization in the 60 months before diagnosis, or had unknown tumor grade or tumor stage. In the 5 years before their diagnosis, 574 men had a history of testosterone use and 51,945 did not.

RESULTS: Using logistic regression adjusting for demographic and clinical characteristics, exposure to testosterone therapy was not associated with an increased risk of high-grade prostate cancer (OR 0.84, 95% CI 0.67-1.05) or receipt of primary ADT following diagnosis (OR 0.97, 95% CI 0.74-1.30). In addition, the risk of high-grade disease did not increase according to total number of testosterone injections (OR 1.00, 95% CI 0.98-1.01).

CONCLUSIONS: Our finding that testosterone therapy was not associated with an increased risk of high-grade prostate cancer may provide important information regarding the risk-benefit assessment for men with testosterone deficiency considering treatment.

 

[Michael Scally MD]

Azoulay L, Eberg M, Benayoun S, Pollak M. 5α-Reductase Inhibitors and the Risk of Cancer-Related Mortality in Men With Prostate Cancer. JAMA Oncol. 2015;1(3):314-320. http://oncology.jamanetwork.com/article.aspx?articleid=2212207

Importance 5α-Reductase inhibitors (5-ARIs) are widely used in the treatment of benign prostatic hyperplasia. However, randomized clinical trials have raised concerns that their use may be associated with an increased risk of high-grade prostate cancer tumors that would ultimately lead to worse prostate cancer outcomes. To date, few observational studies have addressed this important safety concern.

Objective To determine whether the use of 5-ARIs before prostate cancer diagnosis is associated with an increased risk of cancer-specific and all-cause mortality in men with a new diagnosis of prostate cancer in the real-world setting.

Design, Setting, and Participants A retrospective cohort study was conducted in a cohort of 13 892 men with a new diagnosis of prostate cancer between January 1, 1999, and December 31, 2009, who were followed up until October 1, 2012. Patients were individually linked across 4 databases from the United Kingdom: National Cancer Data Repository, Clinical Practice Research Datalink, Hospital Episodes Statistics database, and Office for National Statistics database.

Main Outcomes and Measures Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% CIs of prostate cancer–specific and all-cause mortality associated with prediagnostic use of 5-ARIs. For each outcome, 2 models were constructed, one adjusted for predefined covariates (conventional model) and another adjusted for high-dimensional propensity score (HD-PS) deciles.

Results During a mean (SD) of 4.5 (3.1) years, 5001 deaths occurred, including 2429 from prostate cancer (crude incidence rate of 3.86 per 100 person-years [95% CI, 3.71-4.02]). In the conventional model, use of 5-ARIs before prostate cancer diagnosis was not associated with an increased risk of prostate cancer–specific mortality (crude incidence rates, 3.76 [95% CI, 3.04-4.59] [use] vs 3.87 [95% CI, 3.71-4.03] [nonuse] per 100 person-years; adjusted hazard ratio [aHR], 0.86 [95% CI, 0.69-1.06]) and all-cause mortality (crude incidence rates, 8.42 [95% CI, 7.32-9.64] [use] vs 7.93 [95% CI, 7.71-8.16] [nonuse] per 100 person-years; aHR, 0.87; 95% CI, 0.75-1.00). Similar results were observed with the HD-PS adjusted model (prostate cancer–specific mortality: aHR, 0.90 [95% CI, 0.73-1.13]; and all-cause mortality: aHR, 0.92 [95% CI, 0.80-1.07]).

Conclusions and Relevance The use of 5-ARIs was not associated with an increased risk of prostate cancer–specific and all-cause mortality in men with a new diagnosis of prostate cancer. While these results provide reassurance, additional studies are needed to replicate these findings.


Figg WD, Thompson IM. Effect of 5α-Reductase Inhibitor Use on Mortality From Prostate Cancer. JAMA Oncol. 2015;1(3):321-322. http://oncology.jamanetwork.com/article.aspx?articleID=2212205

The role of 5-ARIs as chemopreventive agents for prostate cancer remains uncertain. On the one hand, reduction of low-grade tumor incidence is unlikely to translate to a reduction in prostate cancer mortality; on the other hand, such a reduction could reduce disease overdetection and overtreatment, a serious concern that led the US Preventive Services Task Force to recommend against PSA screening.10 The study by Azoulay et al suggests that 5-ARI use is unlikely to increase prostate cancer mortality in men receiving them for BPH, reassuring those men on the symptom relief they may provide.

 

[Michael Scally MD]

Park J, Cho SY, Jeong SH, Lee SB, Son H, et al. Low testosterone level is an independent risk factor for high-grade prostate cancer detection via biopsy. BJU Int. http://onlinelibrary.wiley.com/doi/10.1111/bju.13206/abstract

OBJECTIVES: To investigate the relationship between low testosterone level and prostate cancer detection risk in a biopsy population.

PATIENTS AND METHODS: A total of 681 men who underwent initial 12-core transrectal prostate biopsy at our institution were included in this retrospective study. Patients were divided into groups with low (< 300 ng/dL) and normal testosterone levels (>/= 300 ng/dL). Clinical and pathological data were analyzed.

RESULTS: Among 681 men, 86 men (12.6%) showed low testosterone level, 143 (32.7%) had a positive biopsy, and 99 (14.5%) were revealed to have high-grade prostate cancer.

Mean age, prostate-specific antigen (PSA), PSA density (PSAD), body mass index (BMI), the numbers of abnormal digital rectal examination (DRE) findings and diabetes mellitus (DM) history were significantly different between the low and normal testosterone groups.

A low testosterone level was significantly associated with a higher risk of detection of overall prostate cancer than a normal testosterone level in univariate analysis (odds ratio [OR] = 2.545, P = 0.001), but not in multivariate analysis adjusting for parameters such as age, PSA, prostate volume, BMI, abnormal DRE findings and DM (OR = 1.583, P = 0.277).

Meanwhile, the low testosterone level was significantly related with a higher rate of high-grade prostate cancer compared to the normal testosterone level in univariate (OR = 3.324, P < 0.001) and multivariate analysis adjusting for other parameters (OR = 2.138, P = 0.035).

CONCLUSIONS: Low testosterone level is an independent risk factor for high-grade prostate cancer detection via biopsy. Therefore, checking testosterone levels could help to determine whether prostate biopsy should be carried out.

 

[Michael Scally MD]

Tivesten A, Pinthus JH, Clarke N, Duivenvoorden W, Nilsson J. Cardiovascular risk with androgen deprivation therapy for prostate cancer: Potential mechanisms. Urol Oncol. https://www.sciencedirect.com/science/article/pii/S1078143915002744

Androgen deprivation therapy (ADT) is frequently used for the treatment of advanced prostate cancer. ADT is associated with numerous side effects related to its mode of action, namely the suppression of testosterone to castrate levels.

Recently, several large retrospective studies have also reported an increased risk of diabetes and cardiovascular disease in men receiving ADT, although these risks have not been confirmed by prospective randomized trials.

We review the literature to consider the risk of cardiovascular disease with different forms of ADT and examine in detail potential mechanisms by which any such risk could be mediated.

Mechanisms discussed include the metabolic syndrome resulting from low testosterone level and the potential roles of testosterone flare, gonadotropin-releasing hormone receptors outside the pituitary gland, and altered levels of follicle-stimulating hormone.

Finally, the clinical implications for men prescribed ADT for the treatment of advanced prostate cancer are considered.

 

[Michael Scally MD]

Lee JK, Byun SS, Lee SE, Hong SK. Preoperative Serum Sex Hormone-Binding Globulin Level Is an Independent Predictor of Biochemical Outcome After Radical Prostatectomy. Medicine (Baltimore). 2015;94(28):e1185. http://www.ncbi.nlm.nih.gov/pubmed/26181566

To investigate the significance of preoperative serum sex hormone-binding globulin (SHBG) level regarding the postoperative biochemical outcome in patients who were followed up for relative longer periods after undergoing radical prostatectomy (RP).

Preoperative serum levels of testosterone (T), free T, and SHBG level were prospectively analyzed in 307 consecutive patients who underwent RP at our institution between January 2006 and July 2007. We analyzed potential associations of sex hormones with postoperative biochemical recurrence (BCR)-free survival via multivariate Cox proportional regression analysis.

Mean postoperative follow-up duration for 307 total patients was 72.1 +/- 19.6 months. Kaplan-Meier curve demonstrated that BCR-free survival was significantly worse in patients with higher (>/= 40 ng/mL) SHBG level than others (P < 0.001). Serum T (P = 0.280) and free T (P = 0.606) levels showed no significant association with biochemical outcome.

In multivariate analysis encompassing postoperative variables along with PSA, T, and free T, SHBG level (HR 1.825, 1.061-3.138; P = 0.030) was observed to be independently associated with BCR-free survival. Addition of SHBG level to the multivariate model for prediction of BCR-free survival resulted in increased accuracy (83.5% vs. 82.2%; P = 0.164).

Our study of patients who were followed up for relative longer periods after RP shows that preoperative serum SHBG level, but not T, is an independent predictor of postoperative BCR-free survival. According to our findings, SHBG measurement may be useful in the selection of candidates for adjuvant treatment following RP.

 

[Michael Scally MD]

Is Prostate Screening Worthless? The Icon Box Speaks.
http://econlog.econlib.org/archives/2015/08/is_prostate_scr.html

[An icon box brings transparency into health care. It can be used to communicate facts about screening, drugs, or any other treatment. The alternative treatments are placed directly next to each other in columns and both benefits and harms are shown. Most important, no misleading statistics such as survival rates and relative risks are allowed to enter the box. All information is given in plain frequencies.]

Statistically speaking, prostate cancer screening is worthless. Over the course of ten years, 1-in-100 men dies of prostate cancer regardless of screening. 20-in-100 die for any reason, regardless of screening.

The only difference: 2-in-100 screened men - and screened men alone - endure hellish treatments, and another 18-in-100 endure milder torments and a false alarm.

 

[Michael Scally MD]

Prostate Cancer Screening

The US Preventive Services Task Force (USPSTF) recommends against PSA-based screening for prostate cancer due to moderate or high certainty that the test has no net benefit or the harms outweigh the benefits (grade D).

The American Urological Association (AUA) recommends shared decision making for men aged 55 to 69 years; for men electing to be screened, an interval of 2 years or more may be preferable to annual screening. The AUA recommends against PSA screening in men younger than 40 years, against routine screening between ages 40 and 54 years for men at average risk, and against routine screening in men older than 70 years or any man with less than a 10- to 15-year life expectancy.


Eggener SE, Cifu AS, Nabhan C. Prostate Cancer Screening. JAMA. 2015;314(8):825-826. http://jama.jamanetwork.com/article.aspx?articleid=2429697

PSA screening is an area of contentious debate within the medical literature and popular press.

Opponents of screening maintain that the population-based risk of harm outweighs the modest benefit and, therefore, that PSA screening should be uniformly discouraged.

Proponents argue that screening is responsible for approximately 45% to 70% of the decline in age-adjusted prostate cancer mortality observed in the United States over the past 2 decades.


Strategies are being evaluated to supplement PSA testing. Any acceptable prostate cancer screening test must minimize overdetection by reducing the number of false-positive results, limiting the number of biopsies, and more accurately identifying higher-grade (Gleason score ≥7) cancers.

These novel approaches include the PCA3 (RNA-based urine test), prostate health index, and 4K score (serum tests) as well as multiparametric magnetic resonance imaging.

Novel approaches to shared decision making are needed because a thorough discussion of this complex decision is not always practical within the workflow of a primary care clinic.

Strategies designed to minimize overtreatment include active surveillance of most low-grade and some intermediate-grade cancers, genomic profiling of diagnostic biopsy tissue, and ablative treatment targeting the cancer rather than the entire prostate (focal therapy).

 

[Michael Scally MD]

[Open Access] Can Testosterone Therapy Be Offered To Men On Active Surveillance (AS) For Prostate Cancer?

The data presented here indicate that T therapy may not increase the oncologic aggressiveness of low to intermediate risk prostate cancer over the short- to medium-term.

Given the small number of men in this study that received T therapy while undergoing AS, these data must be regarded as preliminary and these results should not influence treatment decisions regarding the use of T in men on AS.

However, these results have potentially important clinical implications. Men may develop symptomatic T deficiency while on AS, and men who are already on T therapy may be diagnosed with low-risk PCa and be candidates for AS.

Historically, T therapy was contraindicated in these men due to the belief that such treatment would cause rapid PCa growth or more aggressive disease, even though systematic reviews of the literature have not supported this view.

Although there is minimal published experience with T therapy in men on AS, and such treatment may seem risky based on traditional beliefs regarding the biological relationship of T and PCa, it should be considered that approximately one in seven T-deficient men with PSA <4.0 ng ml−1 will have PCa identified if those men were subjected to biopsy, meaning that clinicians already provide T therapy to substantial numbers of men with untreated, albeit clinically undiagnosed, PCa. Treatment of these men has not been shown to increase PCa rates.

The preliminary data presented here suggest that T administration does not cause short-term biopsy progression or rapid PCa growth in men undergoing AS, contradicting the long-held belief that higher androgen concentrations necessarily cause rapid PCa growth.

For men with T deficiency, T therapy can lead to improvement in energy, libido, and sexual function and may also improve metabolic function, bone density, and overall quality of life.

Given the large numbers of men who are candidates for AS, and who may also be symptomatic from T deficiency, there is a need for prospective controlled studies of T therapy in these men to assess safety and benefits.

Kacker R, Mariam H, San Francisco IF, Conners WP, Rojas PA, et al. Can testosterone therapy be offered to men on active surveillance for prostate cancer? Preliminary results. Asian J Androl. http://www.ajandrology.com/preprintarticle.asp?id=160270

This report presents our experience with T therapy in a cohort of T-deficient men on active surveillance (AS) for Gleason 3 + 3 and Gleason 3 + 4 prostate cancer (PCa).

A retrospective chart review identified 28 men with T deficiency who underwent T therapy (T group) for at least 6 months while on AS for PCa. A comparison group of 96 men on AS for PCa with untreated T deficiency (no-T group) was identified at the same institution.

The AS protocol followed a modified Epstein criteria and allowed inclusion of men with a single core of low-volume Gleason 3 + 4 PCa. Mean age was 59.5 and 61.3 years, and mean follow-up was 38.9 and 42.4 months for the T and no-T groups, respectively.

Of all 28 men in the T group, 3 (10.7%) men developed an increase in Gleason score while on AS.

Of 22 men in the T group with Gleason 3 + 3 disease, 7 (31.8%) men developed biopsy progression including 3 men (13.6%) who developed Gleason 3 + 4 PCa.

Of 6 men with Gleason 3 + 4 disease at baseline, 2 (33.3%) men developed an increase in tumor volume, and none developed upgrading beyond Gleason 3 + 4.

All 96 men in the no-T group had Gleason 3 + 3 disease at baseline and, 43 (44.7%) developed biopsy progression, including 9 men (9.38%) with upgrading to Gleason 7 (3 + 4).

Biopsy progression rates were similar for both groups and historical controls. Biopsy progression in men on AS appears unaffected by T therapy over 3 years.

Prospective placebo-controlled trials of T therapy in T-deficient men on AS should be considered given the symptomatic benefits experienced by treated men.

 

[Michael Scally MD]

Intermediate and Longer-Term Outcomes From a Prospective Active-Surveillance Program for Favorable-Risk Prostate Cancer

Purpose To assess long-term outcomes of men with favorable-risk prostate cancer in a prospective, active-surveillance program.

Methods Curative intervention was recommended for disease reclassification to higher cancer grade or volume on prostate biopsy. Primary outcomes were overall, cancer-specific, and metastasis-free survival. Secondary outcomes were the cumulative incidence of reclassification and curative intervention. Factors associated with grade reclassification and curative intervention were evaluated in a Cox proportional hazards model.

Results A total of 1,298 men (median age, 66 years) with a median follow-up of 5 years (range, 0.01 to 18.00 years) contributed 6,766 person-years of follow-up since 1995.

Overall, cancer-specific, and metastasis-free survival rates were 93%, 99.9%, and 99.4%, respectively, at 10 years and 69%, 99.9%, and 99.4%, respectively, at 15 years.

The cumulative incidence of grade reclassification was 26% at 10 years and was 31% at 15 years; cumulative incidence of curative intervention was 50% at 10 years and was 57% at 15 years.

The median treatment-free survival was 8.5 years (range, 0.01 to 18 years).

Factors associated with grade reclassification were older age (hazard ratio

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, 1.03 for each additional year; 95% CI, 1.01 to 1.06), prostate-specific antigen density (HR, 1.21 per 0.1 unit increase; 95% CI, 1.12 to 1.46), and greater number of positive biopsy cores (HR, 1.47 for each additional positive core; 95% CI, 1.26 to 1.69).

Factors associated with intervention were prostate-specific antigen density (HR, 1.38 per 0.1 unit increase; 95% CI, 1.22 to 1.56) and a greater number of positive biopsy cores (HR, 1.35 for one additional positive core; 95% CI, 1.19 to 1.53).

Conclusion Men with favorable-risk prostate cancer should be informed of the low likelihood of harm from their diagnosis and should be encouraged to consider surveillance rather than curative intervention.

Tosoian JJ, Mamawala M, Epstein JI, Landis P, Wolf S, et al. Intermediate and Longer-Term Outcomes From a Prospective Active-Surveillance Program for Favorable-Risk Prostate Cancer. Journal of Clinical Oncology. http://jco.ascopubs.org/content/early/2015/08/31/JCO.2015.62.5764.abstract

 

[Michael Scally MD]

Elshafei A, Chevli KK, Moussa AS, Kara O, Chueh SC, et al. PCA3-based nomogram for predicting prostate cancer and high grade cancer on initial transrectal guided biopsy. Prostate. http://onlinelibrary.wiley.com/doi/10.1002/pros.23096/abstract

BACKGROUND: To develop a validated prostate cancer antigen 3 (PCA3) based nomogram that predicts likelihood of overall prostate cancer (PCa) and intermediate/high grade prostate cancer (HGPCa) in men pursuing initial transrectal prostate biopsy (TRUS-PBx).

METHODS: Data were collected on 3,675 men with serum prostate specific antigen level (PSA) </= 20 ng/ml who underwent initial prostate biopsy with at least 10 cores sampling at time of the biopsy. Two logistic regression models were constructed to predict overall PCa and HGPCa incorporating age, race, family history (FH) of PCa, PSA at diagnosis, PCA3, total prostate volume (TPV), and digital rectal exam (DRE).

RESULTS: One thousand six hundred twenty (44%) patients had biopsy confirmed PCa with 701 men (19.1%) showing HGPCa.

Statistically significant predictors of overall PCa were age (P < 0.0001, OR. 1.51), PSA at diagnosis (P < 0.0001, OR.1.95), PCA3 (P < 0.0001, OR.3.06), TPV (P < 0.0001, OR.0.47), FH (P = 0.003, OR.1.32), and abnormal DRE (P = 0.001, OR. 1.32). While for HGPCa, predictors were age (P < 0.0001, OR.1.77), PSA (P < 0.0001, OR.2.73), PCA3 (P < 0.0001, OR.2.26), TPV (P < 0.0001, OR.0.4), and DRE (P < 0.0001, OR.1.53).

Two nomograms were reconstructed for predicted overall PCa probability at time of initial biopsy with a concordance index of 0.742 (Fig. 1), and HGPCa with a concordance index of 0.768 (Fig. 2).

CONCLUSIONS: Our internally validated initial biopsy PCA3 based nomogram is reconstructed based on a large dataset. The c-index indicates high predictive accuracy, especially for high grade PCa and improves the ability to predict biopsy outcomes.

 

[Michael Scally MD]

[Open Access] Penson DF. Re: Relationship between Male Pattern Baldness and the Risk of Aggressive Prostate Cancer: An Analysis of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. J Urol. 2015;194(4):990-1.
http://www.jurology.com/article/S0022-5347(15)04351-7/fulltext

Editorial Comment

This large secondary analysis of the prostate component of PLCO (Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial) generated a lot of media attention when it was released earlier in this year. http://jco.ascopubs.org/content/33/5/419.long [Our analysis indicates that frontal plus moderate vertex baldness at age 45 years is associated with an increased risk of aggressive prostate cancer and supports the possibility of common pathophysiologic mechanisms.]

This focus, in turn, led balding male patients to come into my office (and I suspect into yours), worrying about their risk of prostate cancer. When I see large secondary epidemiology studies of this type, I always approach them with a healthy degree of skepticism. In this case it is probably justified.

This study classifies men into 5 groups in worsening degree of baldness “severity,” ie no baldness, frontal baldness only, frontal and mild vertex baldness, frontal and moderate vertex baldness, and frontal and severe vertex baldness.

The study failed to show any association between baldness (regardless of type) and overall risk of incident prostate cancer in PLCO. However, it revealed a relationship between risk of aggressive prostate cancer and frontal plus moderate vertex baldness only. This relationship was not noted in the more severe form of baldness, where the presumed etiology of the association (changes in endogenous hormone levels) would be more pronounced.

This outcome is a red flag to me.

If this finding were real, I would expect to see some sort of trend. However, none is there.

The authors attribute this lack of trend to limitations in study design but I am inclined to blame a statistically spurious positive finding in the moderate vertex baldness group. Therefore, you can tell your balding patients to rest easy when it comes to their hairline and prostate cancer (although you may want to remind them to use sunscreen or wear a hat if they are going to be out in the sun).

 

[Michael Scally MD]

Pichon A, Neuzillet Y, Botto H, et al. Preoperative low serum testosterone is associated with high-grade prostate cancer and an increased Gleason score upgrading. Prostate Cancer Prostatic Dis. http://www.nature.com/pcan/journal/vaop/ncurrent/abs/pcan201544a.html

BACKGROUND: To compare histological feature of prostate cancer (PCa) according androgenic status in patients who underwent radical prostatectomy (RP).

METHODS: Between March 2007 and September 2013, we prospectively analysed 937 patients who were referred to our centre for RP. Clinical, pathological and biological data have been prospectively collected. Preoperative total testosterone (TT) and bioavailable testosterone (BT) serum determinations were carried out.

The threshold for low serum testosterone was set at TT<3 ng/ml. Preoperative PSA value was registered. Gleason score (GS) and predominant Gleason pattern were determined in prostate biopsies and in prostate tissue specimens, crosschecked by two uro-pathologists.

RESULTS: Nine hundred and thirty-seven consecutive patients were included. In all, 14.9% patients had low TT in the population. An exact match between biopsy and prostate specimens in GS grading was observed for 50.6% patients (n=474). Also, 40.9% of all patients were upgraded (n=383): 45.3% (n=63) in low serum testosterone patients and 40.1% (n=320) in normal serum testosterone patients.

For prostate specimens, the proportion of patients with predominant Gleason pattern 4 was higher in patients with low TT compared with normal TT (41.7% vs 29.1%, P=0.0029). In all, 20.1% were upgraded from predominant Gleason pattern 3 on biopsies specimen to predominant Gleason 4 pattern on the prostate specimen in patients with low TT, whereas 11.6% were upgraded for normal TT patients (P=0.002).

CONCLUSIONS: Low serum testosterone is an independent risk factor for predominant Gleason pattern 4 on prostate specimen after RP and for upgrading from low- to high-grade cancer between prostate needle biopsies and RP specimen. This observation should be taken into account in localised PCa management, especially for active surveillance or when a nerve-sparing approach is considered.

 

[Michael Scally MD]

Shiota M, Takeuchi A, Sugimoto M, et al. Low Serum Testosterone But Not Obesity Predicts High Gleason Score at Biopsy Diagnosed as Prostate Cancer in Patients with Serum PSA Lower than 20 ng/ml. Anticancer Res 2015;35(11):6137-45. http://ar.iiarjournals.org/content/35/11/6137.abstract

BACKGROUND/AIM: The impact of testosterone or obesity on the pathological grade of prostate cancer remains controversial. Therefore, in this study, we investigated the relationship of serum testosterone and body mass index (BMI) to Gleason score at biopsy.

PATIENTS AND METHODS: This study included 128 Japanese patients diagnosed with prostate cancer from 2000 through 2012 whose serum testosterone level and BMI were measured before treatment. Associations between clinical parameters, including pre-treatment serum testosterone level and BMI, and Gleason score at biopsy were examined.

RESULTS: The median serum testosterone and BMI were 434 ng/dl (interquartile range=362-542 ng/dl) and 23.5 kg/m(2) (interquartile range=21.7-25.4 kg/m(2)), respectively. Gleason score at biopsy was <7, 7 and >7 for 58 patients (45.3%), 52 patients (40.6%) and 18 patients (14.1%), respectively.

On univariate analysis, positive finding at digital rectal examination (DRE), high prostate-specific antigen level at diagnosis and low serum testosterone level, but not BMI, were correlated with high Gleason score at biopsy. Multivariate analysis identified positive finding at DRE and low serum testosterone level as significant predictors of a high Gleason score at prostate biopsy. By combining these parameters, the predictive ability of a high Gleason score was improved.

CONCLUSION: This study showed that positive finding at DRE and a low pre-treatment serum testosterone level, but not obesity, may be factors predictive of aggressive prostate cancer, indicating the diagnostic value of serum testosterone, as well as DRE findings, in risk assessment.

 

[Michael Scally MD]

[Open Access] Di Zazzo E, Galasso G, Giovannelli P, et al. Prostate cancer stem cells: the role of androgen and estrogen receptors. Oncotarget. http://www.impactjournals.com/oncot...page=article&op=view&path[]=6220&path[]=15731

Prostate cancer is one of the most commonly diagnosed cancers in men, and androgen deprivation therapy still represents the primary treatment for prostate cancer patients. This approach, however, frequently fails and patients develop castration-resistant prostate cancer, which is almost untreatable.

Cancer cells are characterized by a hierarchical organization, and stem/progenitor cells are endowed with tumor-initiating activity. Accumulating evidence indicates that prostate cancer stem cells lack the androgen receptor and are, indeed, resistant to androgen deprivation therapy. In contrast, these cells express classical (alpha and/or beta) and novel (GPR30) estrogen receptors, which may represent new putative targets in prostate cancer treatment.

In the present review, we discuss the still-debated mechanisms, both genomic and non-genomic, by which androgen and estradiol receptors (classical and novel) mediate the hormonal control of prostate cell stemness, transformation, and the continued growth of prostate cancer.

Recent preclinical and clinical findings obtained using new androgen receptor antagonists, anti-estrogens, or compounds such as enhancers of androgen receptor degradation and peptides inhibiting non-genomic androgen functions are also presented. These new drugs will likely lead to significant advances in prostate cancer therapy.

 

[MR10X]

Did the ADT for 3 months before seed implants and radiation therapy and would do the ADT again.Felt absolutely horrible and found it hard to function in daily activities.They said the ADT would shrink the prostrate,which it probably would and make treating the cancer easier,they also said it would slow down the cancer progression ,which sounds like is probably not true if the cancer have no androgen receptors in them....