Prostate ...

[Michael Scally MD]

Re: OnLine First

Testosterone Therapy (TRT) in Men With Untreated Prostate Cancer (PrCa)


Testosterone therapy has been shown to have a number of beneficial effects in men with testosterone deficiency, including improvement in symptoms of fatigue, decreased libido and sexual performance. However, a major concern has been that increased serum testosterone may cause growth of prostate cancer. This concern is based on the observations that androgen deprivation causes PrCa regression as reflected by decreased serum PSA, and that normalization of serum T in androgen deprived men causes an increase in PSA. Historically there has been an absolute prohibition against the use of TRT in men with any prior history of PrCa.

However, recent literature has called this traditional paradigm into question. A small series of retrospective studies have reported benign outcomes in men who underwent TRT following definitive treatment of localized PrCa. Of these studies 3, with a total population of 74 men, were of men with testosterone deprivation (TD) who had undergone radical prostatectomy for PrCa. None of the participants had biochemical recurrence with follow-up as long as 12 years. Another study reported no biochemical recurrence in 31 men who underwent TRT for a median of 4.5 years following brachytherapy for localized PrCa.

One explanation for the lack of biochemical recurrence is that men were cured of PrCa. Another is that a higher serum T concentration does not necessarily lead to greater PrCa growth. A global pooled collaborative analysis of 18 longitudinal studies of sex hormones and PrCa comprised of 3,886 men with PrCa and 6,438 age matched controls found no relationship between endogenous serum androgen concentrations and PrCa. In another study intraprostatic T and DHT concentrations were unchanged after 6 months of TRT in men with TD despite large changes in serum T concentrations. A saturation model has been proposed to account for the substantial prostatic changes observed with institution or cessation of androgen deprivation therapy and the relative indifference of prostate tissue to changes in serum T above the near castrate range.

Without large, randomized, long-term studies of TRT in men with TD it remains an unanswered question whether TRT may cause greater PrCa growth in this cohort. This question is of particular relevance to the increasing number of men who currently elect active surveillance for newly diagnosed PrCa, some of whom are symptomatic from T deficiency and desirous of TRT.

As new data have suggested a less risky relationship between T and PrCa than previously assumed, practitioners have become more open to the practice of offering TRT to men with a history of PrCa. A decrease in PSA was noted in an elderly man who received TRT during PrCa surveillance. In this study they report on prostate biopsy and PSA results in a group of symptomatic T deficient men who received TRT while undergoing active surveillance for untreated PrCa. The emergence of serial prostate biopsies as a critical component of active surveillance protocols in men with PrCa presents a new and unique opportunity to evaluate the effect of TRT on PrCa growth.


Morgentaler A, Lipshultz LI, Bennett R, Sweeney M, Avila D, Jr., Khera M. Testosterone Therapy in Men With Untreated Prostate Cancer. J Urol. Testosterone therapy in men with untreated prostat... [J Urol. 2011] - PubMed result

PURPOSE: A history of prostate cancer has been a longstanding contraindication to the use of testosterone therapy due to the belief that higher serum testosterone causes more rapid prostate cancer growth. Recent evidence has called this paradigm into question. In this study we investigate the effect of testosterone therapy in men with untreated prostate cancer.

MATERIALS AND METHODS: We report the results of prostate biopsies, serum prostate specific antigen and prostate volume in symptomatic testosterone deficient cases receiving testosterone therapy while undergoing active surveillance for prostate cancer.

RESULTS: A total of 13 symptomatic testosterone deficient men with untreated prostate cancer received testosterone therapy for a median of 2.5 years (range 1.0 to 8.1). Mean age was 58.8 years. Gleason score at initial biopsy was 6 in 12 men and 7 in 1. Mean serum concentration of total testosterone increased from 238 to 664 ng/dl (p <0.001). Mean prostate specific antigen did not change with testosterone therapy (5.5 +/- 6.4 vs 3.6 +/- 2.6 ng/ml, p = 0.29). Prostate volume was unchanged. Mean number of follow-up biopsies was 2. No cancer was found in 54% of followup biopsies. Biopsies in 2 men suggested upgrading, and subsequent biopsies in 1 and radical prostatectomy in another indicated no progression. No local prostate cancer progression or distant disease was observed.

CONCLUSIONS: Testosterone therapy in men with untreated prostate cancer was not associated with prostate cancer progression in the short to medium term. These results are consistent with the saturation model, ie maximal prostate cancer growth is achieved at low androgen concentrations. The longstanding prohibition against testosterone therapy in men with untreated or low risk prostate cancer or treated prostate cancer without evidence of metastatic or recurrent disease merits reevaluation.

 

[Michael Scally MD]

And for an ENTIRERLY different POV:


Morales A. Effect of testosterone administration to men with prostate cancer is unpredictable: a word of caution and suggestions for a registry. BJU International 2011;107(9):1369-73. Effect of testosterone administration to men with prostate cancer is unpredictable: a word of caution and suggestions for a registry - Morales - 2011 - BJU International - Wiley Online Library

What’s known on the subject? and What does the study add?

Very little is known on the effect of T in men with untreated PCa. There are only two small series (including the present one) available that comprise less than 25 men with PCs receiving TTh.

It raises a warning that testosterone administration to men with PCa is not always safe, that current precautions should be maintained, and that only an international registry would provide prompt answers to these issues. To assess the evidence for the concept that the androgen receptor of prostate cancer (PCa) cells becomes saturated when testosterone values exceed castrate levels, so that testosterone administration in hypogonadal men with untreated PCa does not stimulate tumour growth. To propose basic criteria for administration of testosterone to untreated patients with PCa and, as this is a rare clinical situation, to encourage the establishment of an international registry for these patients.

Men with a diagnosis of PCa and symptomatic testosterone deficiency received testosterone therapy (TTh). Patients were assessed quarterly. Prostate-specific antigen (PSA) velocity was used as the criterion to discontinue therapy and a return to nadir PSA levels allowed re-initiation of testosterone supplementation. The responses to testosterone supplementation were varied according to each individual and were unpredictable. While some men showed little change after years of treatment, others exhibited a rapid and significant increase in PSA levels. In others, the use of intermittent therapy resulted in synchronous changes in PSA levels. Interruption of TTh invariably translated into a decrease in PSA to pre-therapy levels. Available evidence regarding the effect of testosterone administration to hypogonadal men with untreated PCa is too limited to be considered reliable. In addition, the response to this treatment appears to be varied and unpredictable.

Hypogonadism associated with untreated PCa is not common, therefore, we propose the establishment of an international registry as the quickest way to establish the basic parameters for consideration of TTh in this situation and recommendations for follow-up. Until credible evidence becomes available, the current restrictions regarding the administration of testosterone to men with PCa should remain in place.

 

[Michael Scally MD]

Oncolytic Virus Initiated Protective Immunity Against Prostate Cancer

The primary mode of action for reovirus oncotherapy is the direct destruction of cancer cells. However, it is believed that antiviral immunological events initiated following administration of oncotherapy also assist in the development of beneficial antitumor immune responses. In a melanoma mouse model, reovirus oncotherapy invokes antitumor innate as well as adaptive immune components that aid in the tumor regression. However, whether reovirus or any other oncolytic virus-based therapy initiates such antitumor immune response during antiprostate cancer oncotherapy is presently unknown. Hence, this study focused on dissecting various oncolytic virus-initiated immunological events that may contribute toward the generation of antiprostate cancer immunity. Their data show that apart from its primary oncolytic activity, reovirus oncotherapy overrides tumor-associated immune evasion mechanisms. Furthermore, reovirus initiates antiprostate cancer T cell immune responses that protect against subsequent tumor challenge in an antigen-dependent manner without requiring a continued presence or an additional administration of reovirus. These anticancer immunotherapeutic activities initiated during reovirus therapy represent a clinically applicable treatment intervention for the efficient management of prostate cancer.


Gujar SA, Pan D, Marcato P, Garant KA, Lee PWK. Oncolytic Virus-initiated Protective Immunity Against Prostate Cancer. Mol Ther 2011;19(4):797-804. http://www.nature.com/mt/journal/v19/n4/abs/mt2010297a.html

Recently reovirus-based oncotherapy has been successfully implemented for the treatment of prostate cancer. In this report, we show that apart from its primary direct cancer-killing activity, reovirus oncotherapy overrides tumor-associated immune evasion strategies and confers protective antiprostate cancer immunity. Prostate cancer represents an ideal target for immunotherapies. However, currently available immune interventions fail to induce clinically significant antiprostate cancer immune responses, owing to the immunosuppressive microenvironment associated with this disease. We show here that during the process of oncolysis, reovirus acts upon prostate cancer cells and initiates proinflammatory cytokines and major histocompatibility complex (MHC) class I molecule expression. In an immunocompetent transgenic adenocarcinoma of mouse prostate (TRAMP) model, reovirus oncotherapy induces the homing of CD8+ T and NK cells in tumors and the display of tumor-associated antigens (TAAs) on antigen-presenting cells (APCs), and endows dendritic cells (DCs) with a capacity to successfully present TAAs to tumor-specific CD8+ T cells. These newly generated immunological events lead to the development of strong antiprostate cancer T cell responses, which restrict the growth of subsequently, implanted syngeneic tumor in an antigen-specific, but reovirus-independent manner. Such reovirus-initiated antiprostate cancer immunity represents a clinically valuable entity that can promote long-term cancer-free health even after discontinuation of the primary oncotherapy.

 

[Michael Scally MD]

[The following articles highlight the study above on the use of TRT in PrCa.]

Revisiting Testosterone Tx in Prostate Ca
Medical News: Revisiting Testosterone Tx in Prostate Ca - in Oncology, Prostate Cancer from MedPage Today

Men with low-risk prostate cancer and symptomatic hypogonadism had no evidence of cancer progression during long-term testosterone therapy, results of a small clinical trial showed.

Neither the mean PSA level nor prostate volume changed significantly during testosterone treatment that continued for as long as eight years, according to Abraham Morgentaler, MD, of Beth Israel Deaconess Medical Center in Boston, and colleagues.

Cancer biopsies in two men suggested cancer upgrading, but subsequent biopsy in one patient and radical prostatectomy in the other showed no evidence of progression.

The findings support the saturation hypothesis, which postulates that maximal prostate cancer growth occurs with low-level androgen stimulation, and higher levels elicit little or no additional growth, the researchers wrote in the April issue of the Journal of Urology.

"There has been a scare about testosterone for about 70 years that somehow it is a fuel for the fire in prostate cancer," Morgentaler said in an interview. "It's clear that's not the case.

"This study, although it's small, is the first time anyone has ever bothered to give testosterone and see what's happening in a prostate that has cancer."

Testosterone therapy has several beneficial effects in men with testosterone deficiency, including improvement in fatigue, libido, and sexual function. However, concern about potential stimulatory effects on prostate cancer has limited use of the hormonal therapy, Morgentaler and co-authors noted in the introduction to their findings.

The concern has its origin in observations that androgen deprivation slows prostate cancer progression, as reflected in decreased serum PSA, and that normalization of testosterone in androgen-deprived men raises PSA levels.

Though modest and circumstantial, the evidence has supported a traditional ban on testosterone therapy in men with a history of prostate cancer. When asked to write a review of the issue several years ago, Morgentaler and his co-authors were stunned to find no published clinical data to support a prohibition of testosterone in men with prostate cancer.

Subsequently, Morgentaler found a single article, published in 1941 by future Nobel Prize winner Charles Huggins and colleague Clarence Hodges of the University of Chicago (Cancer Res. 1941; 1: 293-297). The article detailed the effects of various interventions on acid phosphatase levels in men with metastatic prostate cancer, including three men who received testosterone injections.

Huggins and Hodges reported data for two of the three men, one of whom had been surgically castrated before getting testosterone.

"The general idea -- that adding testosterone to an otherwise relatively normal guy with or without prostate cancer will make the cancer grow -- is based on one individual," said Morgentaler.

More recently, results from several small studies have called into question the traditional paradigm of testosterone prohibition in men with prostate cancer. The studies, which collectively involved about 100 men with definitively treated prostate cancer and testosterone deficiency, showed no evidence of biochemical recurrence during treatment with testosterone for as long as 12 years.

With that clinical and scientific background, Morgentaler and co-authors examined the effects of testosterone therapy in 13 men with untreated prostate cancer undergoing active surveillance. The men had a mean age of 59, mean PSA value of 5.5 ng/mL, mean testosterone concentration of 238 ng/mL, and all but one had a biopsy Gleason score of 6 (one patient with Gleason 7).

After a median treatment duration of 2.5 years, the group's testosterone values averaged 664 ng/dL (P<0.001).

Mean PSA level declined to 3.6 ng/mL, which did not differ significantly from baseline. Prostate volume also did not change.

The men had an average of two prostate biopsies during follow-up, and 54% of specimens had no evidence of cancer.

Limitations of the study included its small size, retrospective design, inclusion of some men who had prostate cancer diagnosed after the start of testosterone therapy, and lack of generalizability to those with higher grade or higher volume disease.

On the basis of the results, the longstanding prohibition against testosterone therapy in men with untreated or low-risk prostate cancer merits re-evaluation, the authors wrote in conclusion.

Use of testosterone therapy by prostate cancer patients should be guided by an individual patient's testosterone level and any associated symptoms, said Morgentaler.

"To be a candidate for testosterone therapy, one needs to have symptoms and a low level of testosterone confirmed by blood testing," he said.

"In terms of giving it to men with a history of prostate cancer, the main impediment at this point is that there still are no large, long-term studies that can give us the bounds of safety data on this."

Before starting testosterone therapy, each of his patients must sign a consent form that spells out the unknown risks associated with the hormonal therapy, Morgentaler added.


Prognosis: Testosterone and Prostate Cancer
http://www.nytimes.com/2011/04/26/health/research/26prognosis.html?_r=1&partner=rss&emc=rss

By NICHOLAS BAKALAR

Doctors have long held that men with prostate cancer should not be given testosterone because the hormone might fuel tumor growth. But a small study adds to evidence that the fear may be overblown, at least in patients without evidence of recurrent or metastatic disease.

Researchers studied 13 men with scores of 6 or 7 on the 10-point Gleason scale, indicating mildly to moderately aggressive prostate cancer. They all initially chose watchful waiting rather than treatment for their cancers. All the men had low testosterone.

The men received testosterone therapy for an average of two and a half years, and had periodic prostate biopsies. None of their cancers progressed or spread to other organs. One subject whose score had increased to 7 from 6 had his prostate removed, but the final pathological exam found no aggressive disease.

The authors acknowledge that the study, published in the April issue The Journal of Urology, was small and retrospective. Still, it is the first to use biopsies to monitor the effects of testosterone in men with untreated, localized prostate cancer.

The lead author, Dr. Abraham Morgentaler, an associate clinical professor of surgery at Harvard, said that the findings of this and other recent studies suggest that the risks of testosterone therapy may have been exaggerated.

 

[Michael Scally MD]

[The following article by Morgenthaler set the stage for his later study on the use of TRT in PrCa.]

Shifting The Paradigm Of Testosterone And Prostate Cancer: The Saturation Model And The Limits Of Androgen-Dependent Growth

For >65 yr, it has been widely accepted that prostate cancer (PCa) growth is dependent on serum testosterone (T) concentrations, based on experiments by Huggins et al, and that castration caused PCa regression, whereas T administration caused more rapid PCa growth. Yet recent studies have shown little or no relationship between serum T concentrations and PCa, making the long-held belief in a T-dependent model of PCa problematic, if not untenable, and. We present here a simple yet critical refinement to the traditional view of T and PCa, namely, that there is a limit to the ability of T to stimulate PCa growth. The Saturation Model presented below is founded on basic biochemical principles of androgen action within the prostate, and it provides a robust framework for understanding the seemingly contradictory sets of results seen with T manipulation.

Defining the relationship between T and PCa is of considerable importance. Not only is androgen deprivation a mainstay of treatment for advanced PCa, but there is also growing interest in T therapy for hypogonadism. Although T therapy has been shown to improve sexual function, bone density, and body composition, none of these benefits might be worthwhile if T therapy increased the risk of PCa.

The Saturation Model has been introduced previously; in this paper, we present the model in full, together with supporting evidence from human and laboratory studies. In brief, the Saturation Model accounts for the key observation that PCa growth is exquisitely sensitive to variation in serum T concentrations at or below the near-castrate range and is insensitive to T variations above this concentration. This model postulates that physiologic concentrations of T provide an excess of T and its intracellular prostatic metabolite, 5?-dihydrotestosterone (DHT), for optimal prostatic growth requirements. However, reducing T concentration below a critical concentration threshold (the Saturation Point) creates an intracellular milieu in which the availability of androgen becomes the rate-limiting step governing prostate tissue growth. This model is based on evidence that binding of androgen to the androgen receptor (AR) follows a similar saturation curve. We believe this simple model has important ramifications for clinical medicine and basic science research.


Morgentaler A, Traish AM. Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth. Eur Urol 2009;55(2):310-20. http://www.europeanurology.com/article/S0302-2838(08)01124-X
http://www.landerurology.com/pdf/Shifting+the+Paradigm+of+Testosterone+and+Prostate+Cancer_+The+Saturation+Model+and+the+Limits+of+Androgen-Dependent+Growth.pdf

CONTEXT: The traditional belief that prostate cancer (PCa) growth is dependent on serum testosterone (T) level has been challenged by recent negative studies in noncastrated men.

OBJECTIVE: To provide an improved framework for understanding the relationship of PCa to serum T level that is consistent with current evidence and is based on established biochemical principles of androgen action within the prostate.

EVIDENCE ACQUISITION: A literature search was performed of publications dating from 1941 to 2008 that addressed experimental and clinical effects of androgens on prostate growth. Review of studies investigating the prostatic effects of manipulation of androgen concentrations in human and animal studies, and in PCa cell lines.

EVIDENCE SYNTHESIS: Prostate growth is exquisitely sensitive to variations in androgen concentrations at very low concentrations, but becomes insensitive to changes in androgen concentrations at higher levels. This pattern is consistent with the observation that androgens exert their prostatic effects primarily via binding to the androgen receptor (AR), and that maximal androgen-AR binding is achieved at serum T concentrations well below the physiologic range. A Saturation Model is proposed that accounts for the seemingly contradictory results in human PCa studies. Changes in serum T concentrations below the point of maximal androgen-AR binding will elicit substantial changes in PCa growth, as seen with castration, or with T administration to previously castrated men. In contrast, once maximal androgen-AR binding is reached the presence of additional androgen produces little further effect.

CONCLUSIONS: The evidence clearly indicates that there is a limit to the ability of androgens to stimulate PCa growth. A Saturation Model based on androgen-AR binding provides a satisfactory conceptual framework to account for the dramatic effects seen with castration as well as the minor impact of T administration in noncastrated men.


Tombal B. Editorial comment on: Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth. Eur Urol 2009;55(2):321. http://www.europeanurology.com/article/S0302-2838(08)01129-9

In Roman mythology, Janus was the god of gates and doors. He was usually depicted with two heads looking in opposite directions and was frequently used to symbolize changes and transitions, such as the progression from one vision to another. This idea perfectly illustrates the saturation model proposed by Morgentaler and Traish in the current issue of European Urology.

Indeed, many of us still regard testosterone through Charles Huggins's eyes and consider it to be a key promoter of prostate cancer progression only because its abrupt suppression induces metastatic prostate cancer to shrink. But is this view enough to sustain our common-sense understanding that testosterone promotes or even causes prostate cancer?

Although urologists still diabolize testosterone, endocrinologists, rheumatologists, and cardiologists attract more and more of our attention to its virtues, especially with regard to metabolic and cardiovascular health.

This paradigm is an interesting one for the physician counseling a man who was successfully treated for localized prostate cancer and who suffers from late-onset hypogonadism. What puts him more at risk: a high-testosterone-promoting cancer or a low-testosterone-promoting cardiovascular disease? Considering the extensive use of hormone therapy in early prostate cancer, it seems that urologists have some difficulties seeing the man around the prostate, although they should be aware of the lack of efficacy in that setting.

Morgentaler and Traish's saturation model provides a nice rational background in which to move away from our unwarranted fear of testosterone in prostate cancer. This article should help urologists to understand that treating middle-age men with localized disease requires getting rid of those fears and developing a holistic view of men's health that encompasses balancing the risks and benefits of adjusting testosterone to normal values.

 

[jonkobeck]

As someone who is newly diagnosed with Low T, and taking Androgel, I am concerned about possibly putting myself at risk for developing prostate cancer.
Is there any evidence that T replacement either via injections or via gel causes prostate cancer?
Does T replacement cause Benign Prostate Enlargement?

 

[cvictorg]

Men with high DHA levels may face risk of developing aggressive prostate cancer

Men with high DHA levels may face risk of developing aggressive prostate cancer

Omega 3: What is good for the heart may not be good for the prostate, study suggests

Serum Phospholipid Fatty Acids and Prostate Cancer Risk: Results From the Prostate Cancer Prevention Trial

The largest study ever to examine the association of dietary fats and prostate cancer risk has found what's good for the heart may not be good for the prostate.

Analyzing data from a nationwide study involving more than 3,400 men, researchers at Fred Hutchinson Cancer Research Center found that men with the highest blood percentages of docosahexaenoic acid, or DHA, an inflammation-lowering omega-3 fatty acid commonly found in fatty fish, have two-and-a-half-times the risk of developing aggressive, high-grade prostate cancer compared to men with the lowest DHA levels.

Conversely, the study also found that men with the highest blood ratios of trans-fatty acids - which are linked to inflammation and heart disease and abundant in processed foods that contain partially hydrogenated vegetable oils - had a 50 percent reduction in the risk of high-grade prostate cancer. In addition, neither of these fats was associated with the risk of low-grade prostate cancer risk. The researchers also found that omega-6 fatty acids, which are found in most vegetable oils and are linked to inflammation and heart disease, were not associated with prostate cancer risk. They also found that none of the fats were associated with the risk of low-grade prostate cancer.

 

[Michael Scally MD]

Men with high DHA levels may face risk of developing aggressive prostate cancer

Men with high DHA levels may face risk of developing aggressive prostate cancer

Omega 3: What is good for the heart may not be good for the prostate, study suggests

Serum Phospholipid Fatty Acids and Prostate Cancer Risk: Results From the Prostate Cancer Prevention Trial

The largest study ever to examine the association of dietary fats and prostate cancer risk has found what's good for the heart may not be good for the prostate.

Analyzing data from a nationwide study involving more than 3,400 men, researchers at Fred Hutchinson Cancer Research Center found that men with the highest blood percentages of docosahexaenoic acid, or DHA, an inflammation-lowering omega-3 fatty acid commonly found in fatty fish, have two-and-a-half-times the risk of developing aggressive, high-grade prostate cancer compared to men with the lowest DHA levels.

Conversely, the study also found that men with the highest blood ratios of trans-fatty acids - which are linked to inflammation and heart disease and abundant in processed foods that contain partially hydrogenated vegetable oils - had a 50 percent reduction in the risk of high-grade prostate cancer. In addition, neither of these fats was associated with the risk of low-grade prostate cancer risk. The researchers also found that omega-6 fatty acids, which are found in most vegetable oils and are linked to inflammation and heart disease, were not associated with prostate cancer risk. They also found that none of the fats were associated with the risk of low-grade prostate cancer.

Thanks for the contrarian article. This throws a wrench into the idea for a broad consensus on dietary recommendations, particularly before all of the evidence is available.

This large prospective investigation of inflammation-associated phospholipid fatty acids and prostate cancer risk found no support that omega-3 fatty acids reduce or trans-fatty acids increase prostate cancer risk. The findings are disconcerting as they suggest that omega-3 fatty acids, considered beneficial for coronary artery disease prevention, may increase high-grade prostate cancer risk, whereas trans-fatty acids, considered harmful, may reduce high-grade prostate cancer risk. These findings illustrate the complexity of research on nutrition and chronic disease risk, in which the effects of nutrients may differ across multiple diseases. A comprehensive understanding of the effects of nutrients on a broad range of diseases will be necessary before making recommendations for dietary changes or use of individual dietary supplements for disease prevention.

This is the article abstract referred to above:

Brasky TM, Till C, White E, et al. Serum Phospholipid Fatty Acids and Prostate Cancer Risk: Results From the Prostate Cancer Prevention Trial. American Journal of Epidemiology. Serum Phospholipid Fatty Acids and Prostate Cancer Risk: Results From the Prostate Cancer Prevention Trial

Inflammation may be involved in prostate cancer development and progression. This study examined the associations between inflammation-related phospholipid fatty acids and the 7-year-period prevalence of prostate cancer in a nested case-control analysis of participants, aged 55–84 years, in the Prostate Cancer Prevention Trial during 1994–2003. Cases (n = 1,658) were frequency matched to controls (n = 1,803) on age, treatment, and prostate cancer family history. Phospholipid fatty acids were extracted from serum, and concentrations of ?-3, ?-6, and trans-fatty acids (TFAs) were expressed as proportions of the total. Logistic regression models estimated odds ratios and 95% confidence intervals of associations of fatty acids with prostate cancer by grade. No fatty acids were associated with low-grade prostate cancer risk. Docosahexaenoic acid was positively associated with high-grade disease (quartile 4 vs. 1: odds ratio (OR) = 2.50, 95% confidence interval (CI): 1.34, 4.65); TFA 18:1 and TFA 18:2 were linearly and inversely associated with risk of high-grade prostate cancer (quartile 4 vs. 1: TFA 18:1, OR = 0.55, 95% CI: 0.30, 0.98; TFA 18:2, OR = 0.48, 95% CI: 0.27, 0.84). The study findings are contrary to those expected from the pro- and antiinflammatory effects of these fatty acids and suggest a greater complexity of effects of these nutrients with regard to prostate cancer risk.

 

[Michael Scally MD]

Daily intake of nutritional supplements, such as vitamin E, selenium, and soy, do not lower men's risk of prostate cancer, according to a study published online May 2 in the Journal of Clinical Oncology. The study included 303 men who were randomly assigned to a combination of the supplements or a placebo daily for three years. Notably, the findings confirm a larger, similar study published in 2008.


Fleshner NE, Kapusta L, Donnelly B, et al. Progression From High-Grade Prostatic Intraepithelial Neoplasia to Cancer: A Randomized Trial of Combination Vitamin-E, Soy, and Selenium. Journal of Clinical Oncology. Progression From High-Grade Prostatic Intraepithelial Neoplasia to Cancer: A Randomized Trial of Combination Vitamin-E, Soy, and Selenium

Purpose High-grade prostatic intraepithelial neoplasia (HGPIN) is a putative precursor of invasive prostate cancer (PCa). Preclinical evidence suggests vitamin E, selenium, and soy protein may prevent progression of HGPIN to PCa. This hypothesis was tested in a randomized phase III double-blind study of daily soy (40 g), vitamin E (800 U), and selenium (200 μg) versus placebo.

Patients and Methods Three hundred three men in 12 Canadian centers were analyzed. The main eligibility criterion was confirmed HGPIN in at least one of two biopsies within 18 months of random assignment. Treatment was administered daily for 3 years. Follow-up prostate biopsies occurred at 6, 12, 24, and 36 months postrandomization. The primary end point was time to development of invasive PCa. Kaplan-Meier plots and log-rank tests were used to compare two treatment groups for this end point.

Results For all patients, the median age was 62.8 years. The median baseline prostate-specific antigen (PSA; n = 302) was 5.41 ug/L; total testosterone (n = 291) was 13.4 nmol/L. Invasive PCa developed among 26.4% of patients. The hazard ratio for the nutritional supplement to prevent PCa was 1.03 (95% CI, 0.67 to 1.60; P = .88). Gleason score distribution was similar in both groups with 83.5% of cancers graded Gleason sum of 6. Baseline age, weight, PSA, and testosterone did not predict for development of PCa. The supplement was well tolerated with flatulence reported more frequently (27% v 17%) among men receiving micronutrients.

Conclusion This trial does not support the hypothesis that combination vitamin E, selenium, and soy prevents progression from HGPIN to PCa.

 

[Michael Scally MD]

Prostate Cancer Clinical Practice Guidelines in Oncology

In the late 1980s and early 1990s, the number of newly diagnosed prostate cancers in the United States increased dramatically, surpassing lung cancer as the most common cancer in men. Experts generally believe that these changes resulted from prostate-specific antigen (PSA) screening that detected many early-stage prostate cancers. For example, the percentage of patients with low-risk disease has increased (45.3% in 1999–2001 vs. 29.8% in 1989–1992; P < .0001). The incidence of prostate cancer increased 2.0% annually from 1995 to 2001 and has since declined. In 2009, an estimated 192,280 new cases were diagnosed and prostate cancer was expected to account for 25% of new cancer cases in men. Fortunately, the age-adjusted death rates from prostate cancer have also declined (–4.1% annually from 1994 to 2001). Researchers expect prostate cancer to account for 27,360 deaths in 2009. This comparatively low death rate suggests that, unless prostate cancer is becoming biologically less aggressive, increased public awareness with earlier detection and treatment of prostate cancer has begun to affect mortality from this prevalent cancer. However, early detection and treatment of prostate cancers that do not threaten life expectancy cause unnecessary side effects that impair quality of life, increase health care expenses, and decrease the value of PSA and digital rectal examination (DRE) as early detection tests.

To properly identify and manage patients with prostate cancer or any other malignancy, physicians must have an in-depth understanding of the natural history and diagnostic, staging, and treatment options. To this end, every year the NCCN convenes a panel of leading experts from the fields of urology, radiation oncology, and medical oncology at member institutions to review and update guidelines for the treatment of prostate cancer, which are available on the NCCN Web site (www.NCCN.org). The treatment algorithms and recommendations represent current evidence integrated with expert consensus regarding acceptable approaches to prostate cancer treatment rather than a universally prescribed course of therapy. Individual physicians treating individual patients with prostate cancer are expected to use independent judgment in formulating treatment decisions.


NCCN Categories of Evidence and Consensus

Category 1: The recommendation is based on high-level evidence (e.g., randomized controlled trials) and there is uniform NCCN consensus.

Category 2A: The recommendation is based on lower-level evidence and there is uniform NCCN consensus.

Category 2B: The recommendation is based on lower-level evidence and there is nonuniform NCCN consensus (but no major disagreement).

Category 3: The recommendation is based on any level of evidence but reflects major disagreement.


Mohler J, Bahnson RR, Boston B, et al. Prostate Cancer. Journal of the National Comprehensive Cancer Network 2010;8(2):162-200. Prostate Cancer

 

[Michael Scally MD]

Coffee May Reduce Risk of Lethal Prostate Cancer in Men
Coffee may reduce risk of lethal prostate cancer in men

ScienceDaily (May 17, 2011) — Men who regularly drink coffee appear to have a lower risk of developing a lethal form of prostate cancer, according to a new study led by Harvard School of Public Health (HSPH) researchers. What's more, the lower risk was evident among men who drank either regular or decaffeinated coffee.

The study was published May 17, 2011, in an online edition of the Journal of the National Cancer Institute.

"Few studies have specifically studied the association of coffee intake and the risk of lethal prostate cancer, the form of the disease that is the most critical to prevent. Our study is the largest to date to examine whether coffee could lower the risk of lethal prostate cancer," said senior author Lorelei Mucci, associate professor of epidemiology at HSPH. Lethal prostate cancer is cancer that causes death or spreads to the bones.

Prostate cancer is the most frequently diagnosed form of cancer and the second leading cause of cancer death among U.S. men, affecting one in six men during their lifetime. More than 2 million men in the U.S. and 16 million men worldwide are prostate cancer survivors.

"At present we lack an understanding of risk factors that can be changed or controlled to lower the risk of lethal prostate cancer. If our findings are validated, coffee could represent one modifiable factor that may lower the risk of developing the most harmful form of prostate cancer," said lead author Kathryn Wilson, a research fellow in epidemiology at HSPH.

The researchers chose to study coffee because it contains many beneficial compounds that act as antioxidants, reduce inflammation, and regulate insulin, all of which may influence prostate cancer. Coffee has been associated in prior studies with a lower risk of Parkinson's disease, type 2 diabetes, gallstone disease, and liver cancer or cirrhosis.

The study examined the association between coffee consumption and the risk of prostate cancer, particularly the risk for aggressive prostate cancer among 47,911 U.S. men in the Health Professionals Follow-Up Study who reported their coffee consumption every four years from 1986 to 2008. During the study period, 5,035 cases of prostate cancer were reported, including 642 fatal or metastatic cases.

Among the findings:

• Men who consumed the most coffee (six or more cups daily) had nearly a 20% lower risk of developing any form of prostate cancer.

• The inverse association with coffee was even stronger for aggressive prostate cancer. Men who drank the most coffee had a 60% lower risk of developing lethal prostate cancer.

• The reduction in risk was seen whether the men drank decaffeinated or regular coffee, and does not appear to be due to caffeine.

• Even drinking one to three cups of coffee per day was associated with a 30% lower risk of lethal prostate cancer.

• Coffee drinkers were more likely to smoke and less likely to exercise, behaviors that may increase advanced prostate cancer risk. These and other lifestyle factors were controlled for in the study and coffee still was associated with a lower risk.

The results from this study need to be validated in additional populations that have a range of coffee exposure and a large number of lethal prostate cancer cases. If confirmed, the data would add to the list of other potential health benefits of coffee. The authors currently are planning additional studies to understand specific mechanisms by which coffee may specifically lower the risk of lethal prostate cancer.


Wilson KM, Kasperzyk JL, Rider JR, et al. Coffee Consumption and Prostate Cancer Risk and Progression in the Health Professionals Follow-up Study. Journal of the National Cancer Institute. Coffee Consumption and Prostate Cancer Risk and Progression in the Health Professionals Follow-up Study

Background Coffee contains many biologically active compounds, including caffeine and phenolic acids, that have potent antioxidant activity and can affect glucose metabolism and sex hormone levels. Because of these biological activities, coffee may be associated with a reduced risk of prostate cancer.

Methods We conducted a prospective analysis of 47 911 men in the Health Professionals Follow-up Study who reported intake of regular and decaffeinated coffee in 1986 and every 4 years thereafter. From 1986 to 2006, 5035 patients with prostate cancer were identified, including 642 patients with lethal prostate cancers, defined as fatal or metastatic. We used Cox proportional hazards models to assess the association between coffee and prostate cancer, adjusting for potential confounding by smoking, obesity, and other variables. All P values were from two-sided tests.

Results The average intake of coffee in 1986 was 1.9 cups per day. Men who consumed six or more cups per day had a lower adjusted relative risk for overall prostate cancer compared with nondrinkers (RR = 0.82, 95% confidence interval [CI] = 0.68 to 0.98, Ptrend = .10). The association was stronger for lethal prostate cancer (consumers of more than six cups of coffee per day: RR = 0.40, 95% CI = 0.22 to 0.75, Ptrend = .03). Coffee consumption was not associated with the risk of nonadvanced or low-grade cancers and was only weakly inversely associated with high-grade cancer. The inverse association with lethal cancer was similar for regular and decaffeinated coffee (each one cup per day increment: RR = 0.94, 95% CI = 0.88 to 1.01, P = .08 for regular coffee and RR = 0.91, 95% CI = 0.83 to 1.00, P = .05 for decaffeinated coffee). The age-adjusted incidence rates for men who had the highest (?6 cups per day) and lowest (no coffee) coffee consumption were 425 and 519 total prostate cancers, respectively, per 100 000 person-years and 34 and 79 lethal prostate cancers, respectively, per 100 000 person-years.

Conclusions We observed a strong inverse association between coffee consumption and risk of lethal prostate cancer. The association appears to be related to non-caffeine components of coffee.

 

[HeadDoc]

Thanks for the contrarian article. This throws a wrench into the idea for a broad consensus on dietary recommendations, particularly before all of the evidence is available.




This is the article abstract referred to above:

Brasky TM, Till C, White E, et al. Serum Phospholipid Fatty Acids and Prostate Cancer Risk: Results From the Prostate Cancer Prevention Trial. American Journal of Epidemiology. Serum Phospholipid Fatty Acids and Prostate Cancer Risk: Results From the Prostate Cancer Prevention Trial

Inflammation may be involved in prostate cancer development and progression. This study examined the associations between inflammation-related phospholipid fatty acids and the 7-year-period prevalence of prostate cancer in a nested case-control analysis of participants, aged 55–84 years, in the Prostate Cancer Prevention Trial during 1994–2003. Cases (n = 1,658) were frequency matched to controls (n = 1,803) on age, treatment, and prostate cancer family history. Phospholipid fatty acids were extracted from serum, and concentrations of ?-3, ?-6, and trans-fatty acids (TFAs) were expressed as proportions of the total. Logistic regression models estimated odds ratios and 95% confidence intervals of associations of fatty acids with prostate cancer by grade. No fatty acids were associated with low-grade prostate cancer risk. Docosahexaenoic acid was positively associated with high-grade disease (quartile 4 vs. 1: odds ratio (OR) = 2.50, 95% confidence interval (CI): 1.34, 4.65); TFA 18:1 and TFA 18:2 were linearly and inversely associated with risk of high-grade prostate cancer (quartile 4 vs. 1: TFA 18:1, OR = 0.55, 95% CI: 0.30, 0.98; TFA 18:2, OR = 0.48, 95% CI: 0.27, 0.84). The study findings are contrary to those expected from the pro- and antiinflammatory effects of these fatty acids and suggest a greater complexity of effects of these nutrients with regard to prostate cancer risk.

An alternative analysis regarding omega 3 and prostate cancer.

? Food Journaling
The dangers of over-analyzing too much data in prostate study
Posted on May 11, 2011 by Dr. Barry Sears under Zone Health

In the last week there has been a constant buzz about an online pre-publication of a new research article that suggests that high concentrations of omega-3 fatty acids promote aggressive prostate cancer (1). Well, that really isn’t the case, in spite of the press reports. That’s why you have to carefully read the article before jumping to conclusions.

Prostate cancer, like all cancers, is driven by cellular inflammation. The level of cellular inflammation is defined by the AA/EPA ratio of isolated serum phospholipids. When you analyze the data correctly in that article, you find that there was no difference in the AA/EPA ratio between the low-aggressive, high- aggressive, or control group. In fact, all the groups had the same elevated AA/EPA ratio of 18.8. Since I like to have individuals try to maintain an AA/EPA ratio of less than 3, all of these groups could be considered to be inflamed.

Not surprisingly, when you look at either EPA or AA levels separately in each group, they are identical. It’s only when you look at the DHA levels, do you see a small difference statistically, but it’s meaningless clinically. There was a 2.5 percent increase in the DHA levels in the high-aggressive group compared to the control group. In the paper, authors state their error in measuring DHA is ± 2.4 percent. Call me crazy, but I don’t see the big difference between the reported results and their error measurements. To further cloud the results, the authors also find that the levels of trans-fatty acids are lower in the aggressive prostate cancer patients than the controls. So I guess if you wanted to take their data at face value, DHA makes prostate cancer more aggressive and trans-fatty acids found in junk foods make prostate cancer less aggressive.

I believe this is simply a case of over-interpretation of massive amounts of collected data. If you get enough data points, you can always make some type of correlation, but that’s all it is. At some point you also have to allow common sense to enter the final analysis.

Nonetheless, let’s say their data might be correct. How could excess DHA increase the aggressiveness of any cancer? Well, it might decrease the levels of dihomo gamma linolenic acid (DGLA) as I have explained in many of my books (2-5). DGLA is the building block for a powerful group of anti-inflammatory eicosanoids, and its formation is inhibited by DHA. Depressing DGLA levels would reduce the body’s ability to hold back the inflammation that drives the tumor. Unfortunately, with all the data they accumulated, they forgot to publish the changes in the DGLA levels in the various groups. Oops.

So even if there were not any changes in the AA/EPA ratio between groups, a depression of DGLA levels in the aggressive prostate cancer group would easily explain the clinical observation. Unfortunately, that interpretation requires an extensive background in understanding eicosanoid biochemistry, which is not easily found in academic clinical-research centers.

This is not the first time that the potential benefits of DHA are in question. In the largest cardiovascular intervention study ever done, it was demonstrated that adding high levels of EPA to the diet of Japanese patients with high cholesterol levels (who already with a very low AA/EPA ratio of 1.6), dramatically decreased their likelihood of future cardiovascular events (6). This reduction was only correlated with increases in EPA levels as well as with a decrease in the AA/EPA ratio from an already low 1.6 to an even lower 0.8 (7). The levels of DHA in these patients had no significance for predicting future cardiovascular events.

Likewise other studies using DHA alone to treatment post-partum depression, improve neurological functioning of children or treating Alzheimer’s have also been found to be negative (8,9).

It’s not that DHA is bad, it just doesn’t do much to reduce cellular inflammation. DHA does a lot of other useful things, but reducing cellular inflammation in not one of them.

References

1. Brasky TM, Till C, White E, Neuhouser ML, Song X, Goodman P, Thompson IM, King EB, Albanes D, and Kristal AR. “Serum phospholipid fatty acids and prostate cancer risk.” Amer J Epidem 173: doi 10:1093/aje/kwr9027 (2011)
2. Sears, B. “The Zone.” Regan Books. New York, NY (1995)
3. Sears, B. “The OmegaRx Zone.” Regan Books. New York, NY (2002)
4. Sears, B. “The Anti-inflammation Zone.” Regan Books. New York, NY (2005)
5. Sears, B. “Toxic Fat.” Thomas Nelson. Nashville, TN (2008)
6. Matsuzaki M, Yokoyama M, Saito Y, Origasa H, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, Shirato K, and Matsuzawa Y. “Incremental effects of eicosapentaenoic acid on cardiovascular events in statin-treated patients with coronary artery disease.” Circ J 73:1283-1290 (2009)
7. Itakura H, Yokoyama M, Matsuzaki M, Saito Y, Origasa H, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, Shirato K, and Matsuzawa Y. “Relationships between Plasma Fatty Acid Composition and Coronary Artery Disease.” J Atheroscler Thromb 18:99-107 (2011)
8. Makrides M, Gibson RA, McPhee AJ, Yelland L, Quinlivan J, and Ryan P. “Effect of DHA supplementation during pregnancy on maternal depression and neurodevelopment of young children: a randomized controlled trial.” JAMA 304; 1675-1683 (2010)
9. Quinn JF, Raman R, Thomas RG, Yurko-Mauro K, Nelson EB, Van Dyck C, Galvin JE, Emond J, Jack CR, Weiner M, Shinto L, and Aisen PS. “Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial.” JAMA 304: 1903-1911 (2010)

 

[cvictorg]

Coffee Consumption and Prostate Cancer Risk

Coffee Consumption and Prostate Cancer Risk and Progression in the Health Professionals Follow-up Study

Coffee Consumption and Prostate Cancer Risk and Progression in the Health Professionals Follow-up Study

http://www.hsph.harvard.edu/news/press-releases/2011-releases/prostate-cancer-coffee-mucci-wilson.html

The study was published May 17, 2011, in an online edition of the Journal of the National Cancer Institute. Read the abstract.

“Few studies have specifically studied the association of coffee intake and the risk of lethal prostate cancer, the form of the disease that is the most critical to prevent. Our study is the largest to date to examine whether coffee could lower the risk of lethal prostate cancer,” said senior author Lorelei Mucci, associate professor of epidemiology at HSPH. Lethal prostate cancer is cancer that causes death or spreads to the bones.

Prostate cancer is the most frequently diagnosed form of cancer and the second leading cause of cancer death among U.S. men, affecting one in six men during their lifetime. More than 2 million men in the U.S. and 16 million men worldwide are prostate cancer survivors.

“At present we lack an understanding of risk factors that can be changed or controlled to lower the risk of lethal prostate cancer. If our findings are validated, coffee could represent one modifiable factor that may lower the risk of developing the most harmful form of prostate cancer,” said lead author Kathryn Wilson, a research fellow in epidemiology at HSPH.

The researchers chose to study coffee because it contains many beneficial compounds that act as antioxidants, reduce inflammation, and regulate insulin, all of which may influence prostate cancer. Coffee has been associated in prior studies with a lower risk of Parkinson’s disease, type 2 diabetes, gallstone disease, and liver cancer or cirrhosis.

The study examined the association between coffee consumption and the risk of prostate cancer, particularly the risk for aggressive prostate cancer among 47,911 U.S. men in the Health Professionals Follow-Up Study who reported their coffee consumption every four years from 1986 to 2008. During the study period, 5,035 cases of prostate cancer were reported, including 642 fatal or metastatic cases.

Among the findings:

Men who consumed the most coffee (six or more cups daily) had nearly a 20% lower risk of developing any form of prostate cancer.

The inverse association with coffee was even stronger for aggressive prostate cancer. Men who drank the most coffee had a 60% lower risk of developing lethal prostate cancer.

The reduction in risk was seen whether the men drank decaffeinated or regular coffee, and does not appear to be due to caffeine.

Even drinking one to three cups of coffee per day was associated with a 30% lower risk of lethal prostate cancer.

Coffee drinkers were more likely to smoke and less likely to exercise, behaviors that may increase advanced prostate cancer risk. These and other lifestyle factors were controlled for in the study and coffee still was associated with a lower risk.

The results from this study need to be validated in additional populations that have a range of coffee exposure and a large number of lethal prostate cancer cases. If confirmed, the data would add to the list of other potential health benefits of coffee. The authors currently are planning additional studies to understand specific mechanisms by which coffee may specifically lower the risk of lethal prostate cancer.

 

[zkt]

Re: Coffee Consumption and Prostate Cancer Risk

WOO Hoo ! ONe less thing to worry about.
If ya wanna notch up the benefit even more add cocao and stevia. Then you get the antioxidant properties of high test chocolate too.

 

[LW64]

Re: Coffee Consumption and Prostate Cancer Risk

There's so much back and forth on this subject - one week it's beneficial, the next week it causes cancer - that I lost interest a long time ago. When the results are so divergent like that, it means nobody is doing any reproducible science and they've got their collective heads up their collective asses.

I like coffee. Very much.

I drink coffee. Very much.

coffee + chocolate (no/low sugar) = mocha (IIRC)

Yep, I like that too. Very much. No sugar or stevia is necessary for me.

 

[zkt]

Re: Coffee Consumption and Prostate Cancer Risk

Damn! You are hard core bro.
You understand I`m talkin baking cocao, the real deal, 100% bean dust! ?
A teaspoon of dust in a cup of strong coffee tends to pucker my asshole without the stevia.
[)]

 

[Michael Scally MD]

Researchers report here on the associations between use of 9 commonly used specialty supplements and prostate cancer risk after 6 yr of follow-up, among men in the VITAL cohort in western Washington state. Many men use these supplements because they believe that they have cancer-preventive properties; the results presented here may better inform these decisions.


Brasky TM, Kristal AR, Navarro SL, et al. Specialty Supplements and Prostate Cancer Risk in the VITamins And Lifestyle (VITAL) Cohort. Nutr Cancer 2011;63(4):573-82. Specialty Supplements and Prostate Cancer Risk in ... [Nutr Cancer. 2011] - PubMed result

Although there is evidence from studies of prostate cancer cell lines and rodent models that several supplements may have antiinflammatory, antioxidant, or other anticancer properties, few epidemiologic studies have examined the association between nonvitamin, nonmineral, "specialty" supplement use and prostate cancer risk. Participants, 50-76 yr, were 35,239 male members of the VITamins and Lifestyle (VITAL) cohort who were residents of western Washington state, and who completed an extensive baseline questionnaire in 2000-2002. Participants responded about their frequency (days/wk) and duration (yr) of specialty supplement uses. 1,602 incident invasive prostate cancers were obtained from the Surveillance, Epidemiology, and End Results registry. Multivariate-adjusted hazards ratios (HR) and 95% confidence intervals (95% CI) were estimated by Cox proportional hazards models. Any use of grapeseed supplements was associated with a 41% (HR 0.59, 95% CI: 0.40-0.86) reduced risk of total prostate cancer. There were no associations for use of chondroitin, coenzyme Q10, fish oil, garlic, ginkgo biloba, ginseng, glucosamine, or saw palmetto. Grapeseed may be a potential chemopreventive agent; however, as current evidence is limited, it should not yet be promoted for prevention of prostate cancer.

 

[Michael Scally MD]

Debate Continues on Use of PSA Testing for Early Detection of Prostate Cancer

Friedrich MJ. Debate Continues on Use of PSA Testing for Early Detection of Prostate Cancer. JAMA: The Journal of the American Medical Association 2011;305(22):2273-6. Debate Continues on Use of PSA Testing for Early Detection of Prostate Cancer, June 8, 2011, Friedrich 305 (22): 2273 — JAMA

Serum prostate-specific antigen (PSA) testing arrived on the scene more than 20 years ago, offering great promise for the early detection and treatment of prostate cancer. Yet even after 2 decades of experience with this seemingly simple blood test, debate continues to swirl over how and when—and if—it should be used.

Prostate cancer appears in a large percentage of men as they age, but is indolent most of the time. Critics emphasize that PSA testing is an imperfect screening tool because it does not differentiate clinically significant tumors from ones that would never cause harm, and the result is overdiagnosis and overtreatment. Others defend the use of PSA testing and say that a more rational, evidence-based approach to using it can help detect and treat prostate cancer early in men who would die of the disease.

 

[Michael Scally MD]

Biomarker Research In Prostate Cancer

Prostate cancer is the most common solid organ neoplasm in the Western world and a leading cause of cancer death. Prostate cancer death rates have declined, and widespread screening programs, leading to the earlier detection of prostate cancer, could cause mortality rates to fall even further. Advances in technologies such as proteomics, genomics and metabonomics, coupled with the enormous potential for clinical and commercial benefits of biomarker discovery, have resulted in an increase in biomarker discovery over recent years.

However, their translation into clinical utility has been limited, possibly due to the lack of suitable validation samples and the traditional single biomarker approach when, in fact, panels of biomarkers would be more useful. In addition, the constantly changing paradigms of prostate cancer diagnosis and management mean that many areas of need for biomarkers have not been properly described. Radiological imaging has become increasingly efficient, and the relative importance of clinical parameters and existing biomarkers has changed with the development of better statistical methods to predict for specific out¬comes (for example, nomograms and predictive tables). Studies that require long follow-up durations, such as prostate cancer recurrence studies, can be affected by these changes. For example, a study running from 1997 to 2007 would span three modifications to the Partin tables, as well as modification of the Gleason grading system, which could affect the conduct of the study.

Even among experts, it is difficult to establish a uniformly agreed treatment standard for prostate cancer, and practice differs significantly from region to region. If new biomarkers are to prove clinically useful, the initial step in their discovery should be the identification of a specific clinical question. To date, this is often not the case, and many studies have applied advanced ‘omics’ technologies to modest numbers of clinical samples without clearly defining the purpose of the study. For biomarkers to move from bench to bedside, the key clinical questions must originate from the bedside, which should direct the selection of the most appropriate sample type and technology for biomarker discovery.

In order to do this, identification of the most important areas of clinical need is vital. In this Review, they identify these areas of unmet need in prostate cancer through the generation of a clinical treatment ‘roadmap’.They suggest that through the rigorous adoption of this approach, biomarker discovery and validation efforts are more likely to reach clinical utility, both in prostate cancer and, by extension, to other medical conditions where there remains an urgent, as yet unmet, need for improved biomarkers.

The overall roadmap has been divided into the milestones typically experienced by patients with prostate cancer as they pass through the diagnostic phase to the treatment and recurrence phase of the disease. Each milestone asks a significant clinical question, and in itself represents an area of need for biomarker research. However, within each milestone, smaller questions also exist that may be equally amenable to biomarker discovery. The problems faced by clinicians in these areas are described, as are the existing tools available and their limitations. Finally the desirable information from potential new biomarkers, and how these might facilitate clinical practice, is considered.

Oon SF, Pennington SR, Fitzpatrick JM, Watson RWG. Biomarker research in prostate cancer - towards utility, not futility. Nat Rev Urol 2011;8(3):131-8. Access : Biomarker research in prostate cancer|[mdash]|towards utility, not futility : Nature Reviews Urology

The identification of an appropriate clinical question is critical for any biomarker project. Despite rapid advances in technology, few biomarkers have been forthcoming for prostate cancer. This could be because the clinical questions under investigation have not actually originated from clinical practice. These clinical questions are difficult to identify in the complex and heterogeneous pathogenesis of prostate cancer. In this Review, we have developed a prostate cancer 'roadmap' to identify the aspects of prostate cancer that may be amenable to biomarker discovery and serve as a guide for future projects in prostate cancer biomarker research.

 

[Michael Scally MD]

GTx Initiates Phase IIb Clinical Trial Evaluating Oral Capesaris(TM) Tablets Versus Lupron Depot(R) for First Line Treatment of Advanced Prostate Cancer
http://phx.corporate-ir.net/phoenix.zhtml?c=148196&p=irol-newsArticle&ID=1575339

GTx, Inc. (Nasdaq: GTXI), announced today that it initiated a Phase IIb clinical trial evaluating Capesaris(TM), a selective estrogen receptor alpha agonist, compared to Lupron Depot(R) (leuprolide acetate for depot suspension) for first line treatment of advanced prostate cancer.

"Acting selectively through estrogen receptor a, Capesaris has the potential to achieve medical castration without also causing several well documented problems of androgen deprivation therapy for prostate cancer such as hot flashes, bone loss and metabolic syndrome," said Thomas Keane, MD, Chairman and Professor of Urology at the Medical University of South Carolina, and lead investigator of the multicenter Capesaris Phase IIb clinical trial. "A new form of first line hormonal treatment that avoids some of the side effects of current ADT would be an important development."

"We are excited to have initiated the Phase IIb Capesaris clinical trial," said Ronald A. Morton, Jr., M.D., Chief Medical Officer of GTx. "Because of the tremendous interest to find a better ADT, we expect this trial to enroll quickly and to have primary efficacy results from the study in the fourth quarter 2011."

The Phase IIb clinical trial is an open label study comparing oral Capesaris tablets to Lupron Depot(R), a luteinizing hormone releasing hormone (LHRH) agonist. One hundred and fifty-six men with advanced prostate cancer will be randomized to receive one of two doses of Capesaris (2000 mg orally each day or 1000 mg orally each day) or Lupron Depot(R) injection every 3 months. The purpose of this study is to establish the dose of Capesaris required to maintain medical castration. The primary endpoint of the study is the proportion of patients that achieve castration by day 60. Secondary endpoints include maintenance of castration beyond 60 days, levels of free testosterone, sex hormone binding globulin (SHBG), luteinizing hormone, and prostate specific antigen (PSA), as well as safety endpoints of Capesaris compared to leuprolide such as hot flashes, libido changes, lipid profile, body composition, bone turnover markers, and bone mineral density.

"Now that we have an oral tablet that has been shown to achieve medical castration, the next step is to conduct dose finding studies to select the appropriate loading and maintenance doses to advance into Phase III clinical trials," said Mitchell Steiner, MD, Chief Executive Officer of GTx. "This Phase IIb clinical trial will help us answer the question of finding the lowest effective dose to maintain castration and to assess the clinical impact of avoiding estrogen deficiency by measuring the safety endpoints compared to Lupron."

GTx plans to initiate an additional Phase II study in advanced prostate cancer patients in second half of 2011 to determine the loading dose of Capesaris required to achieve medical castration in greater than 90% of patients within 28 days. In addition, GTx plans to advance Capesaris into a Phase II study for second line therapy for patients with castration resistant prostate cancer who have failed LHRH therapy.

About Capesaris(TM) (GTx-758)

The standard of care for men with advanced prostate cancer is androgen deprivation therapy (ADT) commonly achieved by surgical orchiectomy or medically by injection of a luteinizing hormone releasing hormone (LHRH) agonist or antagonist. These therapies can result in serious estrogen deficiency related side effects which include hot flashes, loss of libido, bone loss and increased risk of clinical fractures, metabolic syndrome, increased body fat, and increase in cardiovascular events.

As a selective estrogen receptor a agonist, Capesaris has the potential to achieve medical castration by feedback inhibition of the pituitary and hypothalamus with the potential to avoid these estrogen deficiency side effects. Capesaris also directly increases SHBG which has the potential to further lower serum free testosterone.

In 2010, GTx evaluated three doses (600 mg, 1000 mg and 1500 mg) of oral Capesaris solution in a Phase II pharmacokinetic and pharmacodynamic clinical trial. Patients receiving 1000 mg and 1500 mg of Capesaris achieved medical castration. In the 1500 mg cohort, 91% of treatment compliant subjects (10 of 11) met the endpoint of castration with a total serum testosterone <50ng/dL. In the 1000 mg dose group, 71% of treatment compliant subjects (10 of 14) achieved castration. Castration was not achieved in men treated with 600 mg of Capesaris. Capesaris was generally well tolerated in this study. The most common adverse events observed in the study were headache, upper respiratory tract infection, nipple pain, and nausea.