Prostate ...

[Michael Scally MD]

Miyoshi Y, Uemura H, Umemoto S, et al. High testosterone levels in prostate tissue obtained by needle biopsy correlate with poor-prognosis factors in prostate cancer patients. BMC Cancer 2014;14(1):717. http://www.biomedcentral.com/1471-2407/14/717/abstract

BACKGROUND: There is currently no consensus on the correlations between androgen concentrations in prostate tissue and blood and stage and pathological grade of prostate cancer. In this study, we used a newly-developed ultra-sensitive liquid-chromatography tandem mass spectrometry method to measure testosterone (T) and dihydrotestosterone (DHT) concentrations in blood and needle biopsy prostate specimens from patients with prostate cancer.

METHODS: We analyzed androgen levels in 196 men diagnosed with prostate cancer. All patients had undergone systematic needle biopsy, and an additional needle biopsy from the peripheral zone was conducted for the simultaneous determination of T and DHT. We analyzed the relationships between T and DHT levels in tissue and blood and Gleason score, clinical stage, and percentage of positive biopsy cores, using multivariate analysis.

RESULTS: The median T and DHT levels in blood were 3551.0 pg/mL and 330.5 pg/mL, respectively. There was a strong correlation between serum T and DHT. The median T and DHT levels in prostate tissue were 0.5667 pg/mg and 7.0625 pg/mg, respectively. In multivariate analysis, serum prostate-specific antigen and tissue T levels were significantly associated with poor prognosis; high T levels in prostate tissue were significantly related to high Gleason score (p = 0.041), advanced clinical stage (p = 0.002), and a high percentage of positive biopsy cores (p = 0.001).

CONCLUSIONS: The results of this study indicate that high T levels in prostate tissue are related to high Gleason score, advanced clinical stage, and a high percentage of positive biopsy cores in patients with prostate cancer. T level in needle biopsy specimens may therefore be a useful prognostic factor in prostate cancer patients.

 

[Michael Scally MD]

Klap J, Schmid M, Loughlin KR. The relationship between total testosterone levels and prostate cancer: A review of the continuing controversy. J Urol. http://www.jurology.com/article/S0022-5347(14)04490-5/abstract

PURPOSE: For many years it was believed that higher total testosterone levels (TT) contributed to prostate cancer (PCa) development and caused rapid cancer growth. International guidelines consider that adequate data are not available to determine whether there is any additional risk of PCa from testosterone replacement. Numerous studies with multiple designs and contradictory conclusions have investigated the relationship between TT and the development of PCa. To establish the current knowledge in this field, we reviewed the literature regarding TT and the subsequent risk of development of PCa as well as the safety of exogenous testosterone administration to patients with a past or current history of PCa.

MATERIALS AND METHODS: A literature search was conducted using the Pub Med database to identify the published English language articles related to the relationship between TT and PCa. The free-text search was extended by adding these keywords: prostate cancer, prostatic neoplasm, testosterone, hypogonadism, recurrence, prognosis, progression and incidence. All articles dated from 1994 to 2014 dealing with TT were examined by the authors. Emphasis was given to papers that were prospective, contained observational data or were randomized controlled trials. Case reports were excluded. Articles reporting safety of testosterone replacement were selected according to patient population (under active surveillance or with history of PCa).

We organized our results by the nature of the relationship between TT and PCa. First, the possible link between low TT and PCa; second, the effect of high levels, and third, the absence of any link. Finally, we summarized studies assessing the risk of the administration of exogenous testosterone in patients already diagnosed with PCa, treated or under active surveillance.

RESULTS: Forty-five articles studying the relationship between TT and PCa were selected. Eighteen reported a relationship to low TT, 17 to high TT and 10 found no relation. TT was defined according to the definition given in each article.

Contradictory findings were reported. This was due, to a large extent, to the disparate methodologies used in many of the studies. The majority of the studies did not adhere to the guidelines published by professional societies concerning TT measurements: 1 of 18 studies examining low TT and PCa adhered to published guidelines, none of the 17 reporting a relationship between high TT to PCa and only 1 of 10 that didn't identify a relationship between TT and PCa adhered to measurements guided by published guidelines.

Eleven papers were found examining the risk of the administration of exogenous testosterone in patients with history of PCa. Many of the studies were limited by the small size of the cohorts and duration of follow-up. However, in aggregate, this literature suggests that the risk of exogenous testosterone replacement in patients with PCa appears to be small.

CONCLUSIONS: The relationship between TT and PCa has been an area of interest among physicians for decades. Conflicting results regarding the relationship between TT and subsequent PCa have been reported. Much of this controversy appears to be based in conflicting study designs, definitions and methodologies. To date, no prospective study with sufficient power has been published to unequivocally resolve the issue.

The preponderance of studies examining the safety of exogenous testosterone administration in men with a history of PCa would suggest that there is little, if any risk, in such a circumstance. However, the risk has not been proven to be zero, so the most prudent course is to follow such men with regular PSAs and digital rectal exams.

 

[Michael Scally MD]

Zhao J, Zhu S, Sun L, et al. Androgen Deprivation Therapy for Prostate Cancer Is Associated with Cardiovascular Morbidity and Mortality: A Meta-Analysis of Population-Based Observational Studies. PLoS One 2014;9(9):e107516. http://www.plosone.org/article/info:doi/10.1371/journal.pone.0107516

BACKGROUND: There is no consensus regarding whether androgen deprivation therapy (ADT) is associated with cardiovascular disease (CVD) and cardiovascular mortality (CVM). The objective of this study was to determine the role of ADT for prostate cancer (PCa) in development of cardiovascular events (CVD and CVM).

METHODS AND FINDINGS: We performed a meta-analysis from population-based observational studies comparing ADT vs control aimed at treating PCa in patients with PCa, reporting either CVD or CVM as outcome. Publications were searched using Medline, Embase, Cochrane Library Central Register of observational studies database up to May 31th 2014, and supplementary searches in publications from potentially relevant journals.

6 studies were identified with a total of 129,802 ADT users and 165,605 controls investigating the relationship between ADT and CVD. The incidence of CVD was 10% higher in ADT groups, although no significant association was observed (HR = 1.10, 95%CIs: 1.00-1.21; P = 0.06).

For different types of ADT, CVD was related with gonadotropin-releasing hormone (GnRH) (HR = 1.19, 95%CIs: 1.04-1.36; P<0.001) and GnRH plus oral antiandrogen (AA) (HR = 1.46, 95%CIs: 1.03-2.08; P = 0.04), but not with AA alone or orchiectomy. For CVM, 119,625 ADT users and 150,974 controls from 6 eligible studies were included, pooled results suggested that ADT was associated with CVM (HR = 1.17, 95%CIs: 1.04-1.32; P = 0.01). Significantly increased CVM was also detected in GnRH and GnRH plus AA groups.

When patients received other treatments (e.g. prostatectomy and radiotherapy) were ruled out of consideration, more increased CVD (HR = 1.19, 95%CIs: 1.08-1.30; P<0.001) and CVM (HR = 1.30, 95%CIs: 1.13-1.50; P<0.001) were found in men treated with ADT monotherapy.

CONCLUSIONS: ADT is associated with both CVD and CVM. Particularly, GnRH alone and GnRH plus AA can significantly increase the incidence of cardiovascular events in patients with PCa.

 

[Michael Scally MD]

Taverna G, Tidu L, Grizzi F, et al. Highly-Trained Dogs' Olfactory System Detects Prostate Cancer in Urine Samples. J Urol. http://www.jurology.com/article/S0022-5347(14)04573-X/abstract

PURPOSE: To establish the diagnostic accuracy, in term of sensitivity and specificity at which a rigorously trained canine olfactory system can recognize prostate cancer (PC)-specific volatile organic compounds (VOCs) in urine samples.

MATERIALS AND METHODS: Two three-year old female German Shepherd Explosive Detection Dogs were trained to identify PC-specific VOCs in urine samples and tested on 902 subjects (362 with PC ranging from very-low risk to metastatic and 540 healthy, affected by non-neoplastic diseases or non-prostatic tumors control participants). This cross sectional design for diagnostic accuracy involved one large Italian teaching hospital and the Italian Ministry of Defense's, Military Veterinary Center.

RESULTS: The dogs achieved the following performances: Dog 1: sensitivity 100% (95%CI: 99.0-100.0%) and specificity 98.7% (95%CI: 97.3-99.5%). Dog 2: sensitivity 98.6% (95%CI: 96.8-99.6%) and specificity 97.6% (95%CI: 95.9-98.7%).

When only the adult men in the Control Group were considered, Dog 1 achieved a sensitivity of 100% and specificity of 98% (95%CI: 96-99.2%), while Dog 2 a sensitivity of 98.6% (95%CI: 96.8-99.6%) and specificity of 96.4% (95%CI: 93.9-98.1%).

Analysis of false positive cases did not reveal any consistent pattern in terms of participant demographics or tumor characteristics.

CONCLUSIONS: A trained canine olfactory system detects PC-specific VOCs in urine samples with high estimated sensitivity and specificity. Further studies will be necessary to investigate the potential predictive value of using this procedure for recognizing PC.

 

[Michael Scally MD]

Kosaka T, Miyajima A, Oya M. Is DHT Production by 5alpha-Reductase Friend or Foe in Prostate Cancer? Front Oncol 2014;4:247. http://journal.frontiersin.org/Journal/10.3389/fonc.2014.00247/full

The first advance in the history of studies on prostate cancer (PCa) and androgens was the development of treatment with castration and administration of estrogen by Charles B. Huggins, who won the Nobel Prize in Physiology and Medicine.

Since then, and for 70 years, androgen deprivation therapy has been the standard therapy for advanced PCa and the center of studies on PCa.

However, recent advances have shed light on the relationship between androgens and the development or the progression of PCa. The use of 5AR inhibitors to prevent progression of PCa continues to be widely discussed.

Discussion has been fueled by the findings of two large randomized, placebo-controlled trials: the Prostate Cancer Prevention Trial with finasteride and the Reduction by Dutasteride of Prostate Cancer Events trial.

Does the development of PCa or progression to castration-resistant PCa depend on dihydrotestosterone (DHT)?

Here, we summarize and discuss recent topics of local androgen production of DHT in PCa.

 

[Michael Scally MD]

Shtivelman E, Beer TM, Evans CP. Molecular pathways and targets in prostate cancer. Oncotarget 2014;5(17):7217-59. http://goo.gl/PUZMo5

Prostate cancer co-opts a unique set of cellular pathways in its initiation and progression. The heterogeneity of prostate cancers is evident at earlier stages, and has led to rigorous efforts to stratify the localized prostate cancers, so that progression to advanced stages could be predicted based upon salient features of the early disease.

The deregulated androgen receptor signaling is undeniably most important in the progression of the majority of prostate tumors.

It is perhaps because of the primacy of the androgen receptor governed transcriptional program in prostate epithelium cells that once this program is corrupted, the consequences of the ensuing changes in activity are pleotropic and could contribute to malignancy in multiple ways.

Following localized surgical and radiation therapies, 20-40% of patients will relapse and progress, and will be treated with androgen deprivation therapies.

The successful development of the new agents that inhibit androgen signaling has changed the progression free survival in hormone resistant disease, but this has not changed the almost ubiquitous development of truly resistant phenotypes in advanced prostate cancer.

This review summarizes the current understanding of the molecular pathways involved in localized and metastatic prostate cancer, with an emphasis on the clinical implications of the new knowledge.

 

[Michael Scally MD]

Kayali M, Balci M, Aslan Y, et al. The Relationship Between Prostate Cancer and Presence of Metabolic Syndrome and Late-onset Hypogonadism. Urology. http://www.goldjournal.net/article/S0090-4295(14)00717-1/abstract

OBJECTIVE: To investigate the relationship between prostate cancer (PCa), presence of metabolic syndrome (MetS), and late-onset hypogonadism (LOH).

MATERIALS AND METHODS: One hundred seventy patients who underwent transrectal ultrasonography-guided prostate needle biopsy were included in this study. For the diagnosis of MetS, American Heart Association/National Heart, Lung, and Blood Institute criteria were used.

For the diagnosis of LOH, Androgen Deficiency in Aging Males questionnaire and serum total and free testosterone levels were used.

Patients were divided into 4 groups according to the presence of MetS and LOH:
· group 1, MetS and LOH;
· group 2, with MetS but without LOH;
· group 3, with LOH but without MetS; and
· group 4, with neither MetS nor LOH.

RESULTS: The mean age of the patients was 63.7 +/- 7.2 years. In group 1, 12 patients (37.5%); in group 2, 5 patients (25%); in group 3, 11 patients (26.8%); and in group 4, 14 patients (18.2%) were diagnosed with PCa. Aggressive PCa was determined in 7 patients in group 1 (21.9%), 2 patients in group 2 (10%), 5 patients in group 3 (12.2%), and 5 patients in group 4 (6.5%).

There was a statistically significant difference only in between groups 1 and 4 in terms of detection of PCa (37.5% vs 18.2%, P = .031) and aggressive PCa (21.9% vs 6.5%, P = .019).

CONCLUSION: These results highlight the fact that coexistence of MetS and LOH increases the risk of PCa and aggressive PCa.

 

[Michael Scally MD]

Reis LO, Denardi F, Faria EF, Silva ED. Correlation Between Testosterone and PSA Kinetics in Metastatic Prostate Cancer Patients Treated With Diverse Chemical Castrations. Am J Mens Health. http://jmh.sagepub.com/content/early/2014/10/01/1557988314552468.abstract

To assess total testosterone and prostatic-specific antigen (PSA) kinetics among diverse chemical castrations, advanced-stage prostate cancer patients were randomized into three groups of 20:
Group 1, Leuprolide 3.75 mg;
Group 2, Leuprolide 7.5 mg; and
Group 3, Goserelin 3.6 mg.

All groups were treated with monthly application of the respective drugs. The patients' levels of serum total testosterone and PSA were evaluated at two time periods: before the treatment and 3 months after the treatment. Spearman's rank correlation coefficient was utilized to verify the hypothesis of linear correlation between total testosterone and PSA levels.

At the beginning the patients' age, stage, grade, PSA, and total testosterone were similar within the three groups, with median age 72, 70, and 70 years in Groups 1, 2, and 3, respectively.

Three months after the treatment, patients who received Leuprolide 7.5 mg presented significantly lower median total testosterone levels compared with Goserelin 3.6 mg and Leuprolide 3.75 mg (9.5 ng/dL vs. 20.0 ng/dL vs. 30.0 ng/dL, respectively; p = .0072), while those who received Goserelin 3.6 mg presented significantly lower PSA levels compared with Leuprolide 7.5 mg and Leuprolide 3.75 mg (0.67 vs. 1.86 vs. 2.57, respectively; p = .0067).

There was no linear correlation between total testosterone and PSA levels.

Overall, regarding castration levels of total testosterone, 28.77% of patients did not obtain levels </=50 ng/dL and 47.80% did not obtain levels </=20 ng/dL.

There was no correlation between total testosterone and PSA kinetics and no equivalence among different pharmacological castrations.

 

[MR10X]

I was on leuprolide 7.5 mg monthly for 6 months prior to seed implants. They never tested my test levels while i was on it but i felt like total shit...My test level before any treatments was TT 443. I ran nolvadex 20mg and clomid 25 mg daily for 1 month 5 months after my last leuprolide shot mainly because i had gyno after the ADT.My test levels after that were TT 32.FT 0.21,LH 2.0. My levels after my last test on june this year was TT 493,FT 4.7.and LH 16.1.....

 

[Michael Scally MD]

Nakonechnaya AO, Shewchuk BM. Growth hormone enhances LNCaP prostate cancer cell motility. Endocr Res 2014:1-9. http://informahealthcare.com/doi/abs/10.3109/07435800.2014.966383

Purpose: Prostate cancer cells are responsive to multiple hormones and growth factors that can affect cell function. These effects may include modulating cell proliferation and apoptosis, but the ability to impinge on the metastatic potential of prostate cancer cells by affecting cell motility should also be considered, as prostate tumor metastasis correlates with limited therapeutic options and poor prognosis.

Human growth hormone (hGH) can affect the growth and survival of prostate cancer cells, but the effect of hGH on prostate cancer cell motility is unknown. In the present study, the potential for exogenous and autocrine hGH to directly affect prostate cancer cell motility was addressed.

Materials and Methods: The effects of exogenous and autocrine hGH on the chemokinesis and chemotaxis of LNCaP prostate cancer cells were tested using cell monolayer wound healing and Boyden chamber invasion assays. The signaling pathways underlying these effects were resolved with chemical inhibitors and the correlation with cytoskeletal actin reorganization evaluated microscopically by staining cells with fluor-conjugated phalloidin.

Results: Both exogenous and autocrine hGH augmented the migration and invasion of LNCaP cells, and hGH itself acted as a chemoattractant. This activity was dependent upon the STAT5, MEK1/2 and PI3K signaling pathways, and was accompanied by an alteration in cellular actin organization.

Conclusions: hGH may enhance the metastatic potential of prostate cancer cells, both as a stimulant of cellular motility and invasiveness and as a chemoattractant.

 

[MR10X]

Just got back from my Oncologist and my PSA was down to 0.4 from my last 6 months test of 0.6...been almost 2 years since my seed implants and radiation treatments......Tetstosterone back to normal levels now.......I woundered about HGH and cancer,didnt seem like HGH was a good thing if you had cancer...

 

[Michael Scally MD]

The Problem With Prostate Screening
http://www.nytimes.com/2014/11/26/opinion/the-problem-with-prostate-screening.html

TUCSON — SCIENTIFIC data from clinical trials provides the foundation of medical decision making, from a doctor’s prescription pad to sweeping public health policies. Public trust that the data is accurate and unbiased is the glue that binds our $3 trillion health care system. I worry that this trust, particularly when it comes to American men and their physicians and screening programs for prostate cancer, is now at risk.

In 1970 I discovered the prostate-specific antigen, or PSA, which is now the most widely used tool in prostate screenings. But there has been a growing concern about whether the use of the PSA test has led to overdiagnosis and overtreatment, with millions of unnecessary surgeries, complications and deaths.

Nevertheless, the medical community has roundly embraced the results of a recent studyfinding that PSA screening reduced prostate cancer deaths by 20 percent. The study, the European Randomized Study of Screening for Prostate Cancer, joined another survey, the so-called Swedish Goteborg study (the results of which provided a basis for the European Randomized Study), which found an astounding 44 percent reduction.

But there’s a big problem with both of these studies: In March the Goteborg study’s http://1.usa.gov/11PE8Mo in the British Medical Journal that their data “are not available to outside investigators.”

That the researchers would block access to government- and charity-supported research is bad enough. Even worse, it calls into question why, if the data was strong, the researchers wouldn’t open it up to independent scrutiny.

As it turns out, there are some major concerns about the methodology and results of the studies, first raised last fall in the Journal of the National Cancer Institute by two Australian researchers.

The European Randomized Study reported results from seven countries, while Goteborg was a single-site study in Sweden. In both, men were divided into two groups: One underwent regular PSA tests, while the other was not screened. The results were published in The New England Journal of Medicine and the journal Lancet Oncology, respectively.

As the Australian researchers, Ian E. Haines and George L. Gabor Miklos, noticed, there was something strange about the data sets: A large amount of the data in the European Randomized Study came from a separately reported Finnish study, which showed no significant lifesaving benefits of PSA screening.

They found further red flags in terms of biased patient treatment. Many of the men who developed prostate cancer received excessive amounts of a treatment called hormonal monotherapy, which some research now indicates can actually accelerate cancer. Depending on which groups — screened and not screened — those men were in, the results of the study could be significantly compromised. And yet that information was missing from the published reports. When Drs. Haines and Miklos requested the European data to undertake independent analyses, researchers in both studies were unwilling to release it.

Even more troubling was that the European Randomized Study investigators transferred an astounding 60 percent of the data from the Swedish Goteborg study into their own data pool. Since the Goteborg study was alone among country-specific studies in showing an almost 50 percent reduction in prostate cancer deaths for screening recipients, such an overweighting of the data obviously tipped the balance in favor of lives saved. This is a bright-line ethical breach: Without this biased transfer, the lifesaving claims of PSA screening vanish.

Further bias was highlighted by Otis Brawley, the chief medical and scientific officer of the American Cancer Society, and by Paul Goldberg, the editor of the Cancer Letter. They pointed out that the nonscreened Swedish men who contributed to the two studies were not even informed that they were in a clinical trial, which introduced an unacceptable variable between them and the PSA-screened men, who were informed.

Finally, several senior authors of the European trials, and their American supporters, have potential conflicts of interest that relate to payments from companies involved in marketing PSA tests, or in holding patents in the PSA and prostate cancer diagnostic space — relationships documented by the International Committee of Medical Journal Editors, in the forms that accompany the PSA-study publications and in disclosures found in CA: A Cancer Journal for Clinicians.

As a result, those physicians who have not examined the data in depth are now treating patients on the basis of deeply flawed data. How flawed? That’s the real issue: Because the authors won’t release their data, we don’t know.

It is imperative that, as part of America’s continuing efforts at health care reform, we develop a declaration of principles about the need for data transparency. Our regulatory bodies must insist that clinical trials, and especially taxpayer-funded ones, be open to scrutiny by independent investigators who have no ties to industry. Hoarding data, especially flawed data, is unacceptable when lives are at stake.

Richard J. Ablin, a professor of pathology at the University of Arizona College of Medicine, the Arizona Cancer Center and the BIO5 Institute, is the author of “The Great Prostate Hoax: How Big Medicine Hijacked the PSA Test and Caused a Public Health Disaster.”

 

[Michael Scally MD]

Kaplan AL, Lenis AT, Shah A, Rajfer J, Hu JC. Testosterone Replacement Therapy in Men with Prostate Cancer: A Time-Varying Analysis. The Journal of Sexual Medicine. http://onlinelibrary.wiley.com/doi/10.1111/jsm.12768/abstract

Introduction The use of testosterone replacement therapy (TRT) in men with prostate cancer is controversial given concerns of androgen-related cancer progression. Although emerging evidence suggests that TRT may be safe in this setting, no study has investigated dose-related effects.

Aim We used time-varying analysis to determine whether increasing TRT exposure is associated with worse outcomes.

Methods Using linked Surveillance, Epidemiology, and End Results-Medicare data, we identified 149,354 men diagnosed with prostate cancer from 1991 to 2007. Subjects treated with TRT were stratified by duration of treatment. Weighted propensity score methods were used to adjust for differences between groups. A Cox proportional hazards model was constructed to assess the effect of injectable TRT exposure on outcomes.

Main Outcome Measure Overall mortality (OM), prostate cancer–specific mortality (PCSM), and use of salvage androgen deprivation therapy (ADT).

Results Men treated with TRT, regardless of duration, did not experience higher OM or PCSM (all hazard ratio

---

 < 1.0, all P ≤ 0.002). We found no difference in use of salvage ADT in the ≤30-day and 31–60 day groups compared with no-TRT (HR 1.23 and 1.05, P = 0.06 and 0.81, respectively), whereas it was lower for men on long-term TRT (HR 0.70, P = 0.04).

Conclusions TRT following prostate cancer diagnosis and treatment does not increase mortality or the use of salvage ADT. Using time-varying analysis, we demonstrate that longer duration of TRT is not associated with adverse mortality or greater need for ADT.

 

[BBC3]

Methods Using linked Surveillance, Epidemiology, and End Results-Medicare data, we identified 149,354 men diagnosed with prostate cancer from 1991 to 2007. Subjects treated with TRT were stratified by duration of treatment. Weighted propensity score methods were used to adjust for differences between groups. A Cox proportional hazards model was constructed to assess the effect of injectable TRT exposure on outcomes.

And you KNOW I found that ADMISSION interesting..

So what the article is saying, is that all men who have undergone hormonal blockade therapies in past were unduly tormented...?

Or are they saying that that some unknown MODE of conventional androgen blockade/deprivation is working, and that one should supp T replacement in addition to..???

 

[MR10X]

I had ADT when i was treated for PCa and i wouldnt do it again if i had to do it over.It fucked up my system and i felt like total shit while i was on it.Living like that was unbarable,and impossible to function....It took almost a year to get back to normal after stopping ADT............

 

[Michael Scally MD]

Vis AN, van der Sluis TM, Al-Itejawi HHM, van Moorselaar RJA, Meuleman EJH. Risk of disease flare with LHRH agonist therapy in men with prostate cancer: Myth or fact? Urologic Oncology: Seminars and Original Investigations 2014;33(1):7-15. http://www.urologiconcology.org/article/S1078-1439(14)00158-6/abstract

Objectives The traditional assumption of a linear relationship between serum testosterone and prostate cancer growth has been seriously challenged, as overwhelming evidence contradicts its basic principles. Luteinizing hormone–releasing hormone (LHRH) agonists are known to cause a peak in serum testosterone level in the initial weeks of treatment, and prevention of the clinical sequelae of testosterone flare by concomitant use of antiandrogens is recommended. Along the present biological concept that there appears to be a limit to the ability of androgens to stimulate prostate cancer growth, termed the saturation model, the use of antiandrogens to prevent this disease flare is questioned. The purpose of this review is to gain historical and modern evidence to provide an objective and up-to-date basis for clinical decision making.

Methods and Materials We performed a comprehensive research of the electronic databases PubMed and Embase until April 1, 2014. Studies with the subject of disease flare in men with prostate cancer on LHRH agonist therapy were included, as were studies that assessed the efficacy of antiandrogens to prevent this flare. Case reports were included as well.

Results Overall, 25 studies considering disease flare were included: 9 randomized clinical trials with an LHRH agonist and an LHRH agonist/antiandrogen arm, 14 observational studies evaluating LHRH agonists only, and 2 case reports. The incidence of disease flare was reported between 0% and 83% owing to a wide set of clinical, biochemical, and radiological factors evaluated. In some of the randomized clinical trials, a statistically significant reduction of the incidence of disease flare by concomitant use of antiandrogens was reported. Most of these historical studies report on subjective worsening of disease symptoms as outcome measure. More objective outcome measures such as the prostate-specific antigen level did not seem to increase to higher than the baseline values.

Conclusions At present, there is a lack of compelling data showing definite disease progression during the short period of testosterone flare after initiation of LHRH agonist therapy. Based on the saturation model, presence of disease flare and the need to prevent this flare by concomitant use of antiandrogens might well be a misconception.

 

[Michael Scally MD]

Chernichenko OA, Sakalo VS, Yakovlev PG, Sakalo AV, Zhylchuk YV, Zsolt A. Effect of androgen suppression on bone mineral density in patients with prostate cancer. Exp Oncol 2014;36(4):276-8. http://exp-oncology.com.ua/article/...eral-density-in-patients-with-prostate-cancer

The androgen-suppressive therapy (AST) in patients with prostate cancer (PC) may dramatically affect the bone mineral density (BMD), which puts patients at risk of severe adverse effects, such as weight-bearing bone fractures. AIM: To study the effect of AST on BMD in patients with non-metastatic hormone-sensitive PC treated with intermittent hormonal therapy, and effect of different total testosterone level on BMD.

MATERIALS AND METHODS: From 2011 to 2013 we treated 56 patients with non-metastatic hormone-naive PC. Intermittent hormonal treatment with flutamide at a dose of 250 mg 3 times per day with nine monthly injections of luteinizing gonadotropic releasing hormone (LGnRH) ["treatment" period] followed by period of observance ("no treatment") was administered.

We evaluated the BMD of lumbar spine and both proximal thighs by means of dual-energy x-ray densitometry at the end of "treatment" period and at the end of "no treatment" period.

RESULTS: During the first treatment period, 44 of 56 patients (78.6%) experienced the reduction in BMD in both lumbar spine and thighs. Total testosterone level in all patients dropped to castration level.

During the first period of "no treatment" there was an increase in BMD (p < 0.05) in 30 (68.2%) of 44 patients.

The median time to recovery of total testosterone level to the level > 50 ng/dl was 91 days (from 30 to 308 days), and > 100 ng/dl was 110 days (from 49 to 343 days).

The changes in BMD positively correlated with the changes in total testosterone level (correlation 0.18 [95% CI, 0.04-0.27], p = 0.009).

The decline in total testosterone level in serum was followed by the decline in BMD value in the studied areas, and vice versa.

CONCLUSIONS: The changes in BMD positively correlated with changes in total testosterone level. The BMD decreases during the androgen suppression and increases during the pause in the treatment. This demonstrates the benefit of intermittent AST in preventing osteoporosis, pathological bone fractures and possibly, bone metastases.

 

[Michael Scally MD]

Machioka K, Mizokami A, Yamaguchi Y, Izumi K, Hayashi S, Namiki M. Active Estrogen Synthesis and its Function in Prostate Cancer-derived Stromal Cells. Anticancer Res 2015;35(1):221-7. http://ar.iiarjournals.org/content/35/1/221.abstract

BACKGROUND: It remains unclear whether estrogen is produced in prostate cancer (PCa) and how it functions in PCa.

MATERIALS AND METHODS: To examine the production of estrogen in PCa cells, the concentration of estrogen in the medium in which LNCaP cells and PCa-derived stromal cells (PCaSC) were co-cultured, was measured by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS), while aromatase (CYP19) mRNA expression was confirmed by real-time polymerase chain reaction (RT-PCR) methods.

To verify whether estrogen is synthesized from testosterone in PCaSC functions, PCaSC were co-cultured with breast cancer MCF-7-E10 cells, which were stably-transfected with ERE-GFP, in the presence of testosterone. GFP expression was detected when PCaSCs could synthesize estrogen. The proliferation of PC-3 cells in the presence of PCaSC was determined by cell count.

RESULTS: PCaSC metabolized excessive testosterone to estrogen, which activated estrogen receptor in breast cancer cells. Moreover, estrogen synthesized from testosterone in PCaSC regulated the proliferation of PC-3 cell via repression of some unknown growth factors that were secreted from PCaSC.

CONCLUSION: A chimeric co-culture method between breast cancer cells and PCaSC revealed the production of active estrogen in PCaSC. High-dose testosterone therapy might introduce a new potential strategy to treat CRPC.

 

[Michael Scally MD]

Hongo H, Kosaka T, Oya M. Complete response to ethnylestradiol prolonged for almost two years in patients with castration-resistant prostate cancer. Can Urol Assoc J 2014;8(11-12):E921-3. http://journals.sfu.ca/cuaj/index.php/journal/article/view/2293

An 80-year-old man with an elevated prostate-specific antigen (PSA) level of 120 ng/mL) presented to the hospital in February 2011. A prostate needle biopsy was performed, and pathological examination revealed prostatic adenocarcinoma. The Gleason score was 4+5=9. Computed tomography revealed metastases of the pelvic lymph nodes. Combined androgen blockade was started. The PSA concentration decreased to 1.68 ng/mL, but started increasing again in August 2012 to 6.08 ng/mL. Although bicalutamide was discontinued due to antiandrogen withdrawal syndrome, the PSA concentration increased even more. The PSA concentration reached 21.62 ng/mL in September 2012, at which time ethnylestradiol was started. The PSA concentration decreased again and has remained below the limit of sensitivity for almost 2 years. To our knowledge, this is first case report describing a complete response to ethnylestradiol that lasted for almost 2 years in a patient with castration-resistant prostate cancer.

 

[Michael Scally MD]

We present the unusual case of a gentleman with prostate cancer with known biochemical recurrence after failure of local therapy, in which we found increasing levels of serum testosterone above the normal range, consistent with exogenous receipt of androgens.

The patient denied the use of androgens, and we discovered that his persistently high testosterone levels were due to the application of topical testosterone cream applied intravaginally by his wife.

Al-Marrawi MY, Cream LV, Mallon CA, et al. Effect of Topical Vaginal Androgens in a Woman on the Testosterone Levels of Her Sexual Partner With Prostate Cancer. Journal of Clinical Oncology. http://jco.ascopubs.org/content/early/2015/01/05/JCO.2014.59.7773.full