Prostate ...

[Michael Scally MD]

Gen-Probe seeks FDA approval of prostate cancer test
Gen-Probe seeks FDA approval of prostate cancer test - SignOnSanDiego.com

BY KEITH DARCÉ
TUESDAY, SEPTEMBER 21, 2010 AT 2:53 P.M.

San Diego medical diagnostics maker Gen-Probe said it submitted a premarket approval application to the Food and Drug Administration for its Progensa PCA3 test, which screens urine samples for a gene tied to prostate cancer.

The PCA3 gene is present at abnormally high levels in 90 percent of men with prostate cancer, the company said. The new test is designed for patients who have had a negative biopsy test. A negative PCA3 test result would avoid putting the patient through another biopsy.
Gen-Probe President and Chief Executive Officer Carl Hull said the company plans to submit premarket approval applications for two additional tests by the end of the year.


PROGENSA® PCA3 Assay
http://www.gen-probe.com/pipeline/
PCA3.org - Helping you to decide when prostate biopsy is right

In Europe, Gen-Probe's PROGENSA PCA3 assay received marketing clearance in 2006. The assay detects the overexpression of a gene called PCA3 in urine. Studies have shown that PCA3 is highly over-expressed in the vast majority of prostate cancers, indicating that PCA3 may be a useful biomarker for the disease.

Preliminary data show that the PCA3 assay is more specific to prostate cancer than the traditional serum prostate specific antigen (PSA) test, thus decreasing the likelihood of false positive results. PSA is produced by both cancerous and non-cancerous prostate cells. Non-cancerous conditions can therefore cause elevated serum PSA levels that must be investigated, resulting in unnecessary medical procedures and patient anxiety.

The PROGENSA PCA3 assay remains under development in the United States, and has not been approved for marketing by the FDA.

 

[HeadDoc]

good news. Especially if this allows one to avoid biopsies otherwise indicated by PSA values.

 

[zkt]

Its about time.

 

[BBC3]

I hear it all, but I am wondering. Do I really want to cut out my prostate, end my sex life, my ability to get one (my favorite), be incontinent for while at least, and wonder?

So, I am assuming prostates removed per test results and no positive biopsy will all find a cancer there (except 10%). Perhaps they can just lie to those few and make them feel better.[)]

Its all good and not bashing. So I am wondering what the primary reason for negative biopsies is? Obviously tumors begin usually isolated, and you hope to hell its the perimeter type, not centrally/nervous involved. But what is the predominant reason for inaccurate biopsy or missed digital diagnosis. It it because the tumor/cancer activity is on the front side of the prostate and not readily accessible persay?[/B] Or really what is the reason? I am sure the doc can find an angle to biopsy about 85% of the area without damaging the honeyhole, but he doesn't really know where to look if its on the front. Even if they run some kind of camera, or ultrasound down the uretha, its not going to match up to the "Golden Digit"...

 

[Michael Scally MD]

Simplifying the Decision for a Prostate Screening
Simplifying the Decision for a Prostate Screening - NYTimes.com

September 27, 2010
By TARA PARKER-POPE

One of the most difficult decisions a man makes about prostate cancer happens long before the diagnosis. Should he get a regular blood test to screen for the disease?

Screening for early detection of cancersounds like a no-brainer, but it’s not an easy choice for men considering regular P.S.A.tests, which measure blood levels of prostate-specific antigen and are used to detect prostate cancer. Though use of the test is widespread, studies show that the screening saves few, if any, lives.

While the test helps find cellular changes in the prostate that meet the technical definition of cancer, they often are so slow-growing that if left alone they will never cause harm. But once cancer is detected, many men, frightened by the diagnosis, opt for aggressive surgical and radiation treatments that do far more damage than their cancers would have, leaving many impotent and incontinent.

As a result, major health groups don’t advise men one way or the other on regular P.S.A. screenings, saying it should be a choice discussed between a man and his doctor.

So how does a man decide whether to get P.S.A. screening or not? Finally, some new research offers simple, practical advice — at least for men 60 and older.

Researchers at Memorial Sloan-Kettering Cancer Center in New York and Lund University in Sweden have found that a man’s P.S.A. score at the age of 60 can strongly predict his lifetime risk of dying of prostate cancer, according to a new report in the British medical journal BMJ.

The findings also suggest that at least half of men who are now screened after age 60 don’t need to be, the study authors said.

The researchers followed 1,167 Swedish men from the time they were 60 years old until they died or reached 85. During that time, there were 43 cases of advanced prostate cancer and 35 deaths in the group. The researchers found that having had a P.S.A. score of 2.0 or higher at the age of 60 was highly predictive of developing advanced prostate cancer, or dying of the disease, within the next 25 years.

About one in four men will have a P.S.A. score of 2.0 or higher at the age of 60, and most of them will not develop prostate cancer, said the study’s lead author, Andrew Vickers, associate attending research methodologist at Memorial Sloan-Kettering. But the score does put them in a higher-risk group of men who have more to gain from regular screening, he concluded.

The higher the score at age 60, the greater the long-term risk of dying from prostate cancer, Dr. Vickers and his colleagues found. Men with a score of 2.0 or higher at age 60 were 26 times more likely to eventually die of the disease than 60-year-old men with scores below 1.0.

Still, the absolute risks for men with elevated scores were lower than might be expected. A 60-year-old man with a P.S.A. score just over 2.0 had an individual risk of dying from prostate cancer during the next 25 years of about 6 percent, the researchers found. A 60-year-old man with a P.S.A. score of 5 had about a 17 percent risk.

“Most of those men are going to be absolutely fine,” said Dr. Vickers. “But they can be told they are at high risk and they need screening.”

Men with a P.S.A. score of 1.0 or lower at age 60 had a very low individual risk of death from prostate cancer over the next 25 years, the study found: just 0.2 percent.

“They can be reassured that even if they have prostate cancer or get it, it’s unlikely to become life-threatening,” said Dr. Vickers. “There’s a strong case that they should be exempted from screening.”

The advice is less clear for men with scores between 1.0 and 2.0 at the age of 60. They still have a very low individual risk of dying from prostate cancer, judging from the new data. The long-term risk of dying from prostate cancer ranged from about 1 percent to 3 percent for these men, and the decision to screen may depend on their personal views and family histories, Dr. Vickers said.

While the findings don’t answer all of the questions associated with P.S.A. screening, they should give peace of mind to sizable numbers of men who decide not to continue regular testing. The results also will reassure men who decide to continue with regular screenings that the benefits most likely outweigh the risks.

Dr. Eric A. Klein, chairman of the Glickman Urological and Kidney Institute at the Cleveland Clinic, said that he would like to see the findings of the new study independently confirmed, but that other studies also have suggested that the risk of cancer is low in men whose P.S.A. levels remain below 1.5 in their 50s and 60s.

“We are in the midst of a paradigm shift in screening and risk assessment that no longer relies on a simple P.S.A. cutoff to determine who should be biopsied,” Dr. Klein said.

P.S.A. screening is already not advised for those 75 and older, because the slow-moving nature of the disease means that a vast majority of men at that age are likely to die from something other than a newly detected prostate cancer. A major study last year confirmed that P.S.A. testing is not helpful for men with 10 years or less of life expectancy.

But the advice continues to be murky for younger men. In a large European study reported last year, 50- to 54-year-olds didn’t benefit from screening. But men ages 55 to 69 who had annual P.S.A. testing were slightly less likely to die from prostate cancer than those who weren’t screened.

The researchers who conducted the latest study also have investigated whether a man’s P.S.A. score at 50 can predict his long-term risk. In a 2008 report of 21,000 men published in the journal BMC Medicine, the researchers found that two-thirds of the advanced cancer cases that developed over 25 years were in men who had a P.S.A. score of 0.9 or higher at the age of 50.

Those findings can help younger men decide how intensely they want to screen for the disease. A man whose P.S.A. test shows him to be at low risk at age 50 may decide not to be retested again until the age of 60. A man with a higher score may want to do more frequent testing.

“We haven’t solved every single problem with screening,” Dr. Vickers noted. “We need to screen fewer people, screen the right people, and we don’t have to treat every cancer we catch.”


Vickers AJ, Cronin AM, Bjork T, et al. Prostate specific antigen concentration at age 60 and death or metastasis from prostate cancer: case-control study. BMJ 2010;341. Prostate specific antigen concentration at age 60 and death or metastasis from prostate cancer: case-control study -- Vickers et al. 341 -- bmj.com

Objective To determine the relation between concentrations of prostate specific antigen at age 60 and subsequent diagnosis of clinically relevant prostate cancer in an unscreened population to evaluate whether screening for prostate cancer and chemoprevention could be stratified by risk.

Design Case-control study with 1:3 matching nested within a highly representative population based cohort study.

Setting General population of Sweden taking part in the Malmo Preventive Project. Cancer registry at the National Board of Health and Welfare.

Participants 1167 men aged 60 who provided blood samples in 1981 and were followed up to age 85. Main outcome measures Metastasis or death from prostate cancer.

Results The rate of screening during the course of the study was low. There were 43 cases of metastasis and 35 deaths from prostate cancer. Concentration of prostate specific antigen at age 60 was associated with prostate cancer metastasis (area under the curve 0.86, 95% confidence interval 0.79 to 0.92; P<0.001) and death from prostate cancer (0.90, 0.84 to 0.96; P<0.001). The greater the number for the area under the curve (values from 0 to 1) the better the test. Although only a minority of the men with concentrations in the top quarter (>2 ng/ml) develop fatal prostate cancer, 90% (78% to 100%) of deaths from prostate cancer occurred in these men. Conversely, men aged 60 with concentrations at the median or lower (≤1 ng/ml) were unlikely to have clinically relevant prostate cancer (0.5% risk of metastasis by age 85 and 0.2% risk of death from prostate cancer).

Conclusions The concentration of prostate specific antigen at age 60 predicts lifetime risk of metastasis and death from prostate cancer. Though men aged 60 with concentrations below the median (</=1 ng/ml) might harbour prostate cancer, it is unlikely to become life threatening. Such men could be exempted from further screening, which should instead focus on men with higher concentrations.

 

[Michael Scally MD]

Early prostate test study gives hope for accuracy
Early prostate test study gives hope for accuracy | Reuters

By Kate Kelland
LONDON | Tue Sep 28, 2010 3:10pm EDT

(Reuters) - British scientists say they have developed a lab test that can accurately distinguish prostate cancer from healthy tissue and other prostate conditions -- a finding that may in future help men avoid unnecessary treatment. http://www.ogt.co.uk/documents/ACCRMedia/Poster_AACR_Prostate_240910.pdf

Researchers at a genetics and diagnostics firm Oxford Gene Technology (OGT) say the set of biological signals, or biomarkers, they have identified was able to distinguish healthy tissue and benign prostate disease from prostate cancer with 90 percent accuracy in initial laboratory sample tests.

A full test for use in doctors' clinics is likely to be at least five years off, they said, but their pilot study testing around 130 samples showed encouraging results in a disease area where more accurate diagnostic tests are sorely needed.

Prostate cancer killed an estimated 258,000 people in 2008 and is the second most common cause of cancer death in men in the United States.

The most effective screening tests currently available are based on a single biomarker called prostate specific antigen (PSA). But PSA testing is problematic because it has low specificity, which generates high false positive rates and leads to unnecessary surgical and radiotherapy treatment.

A U.S. study published last year found that routine PSA prostate screening has resulted in more than one million American men being diagnosed with tumors who might otherwise have suffered no ill effects from them.

"There is a real need for a test that is very sensitive, i.e. something that will pick up prostate cancer -- but also something very specific i.e. that it won't get confused by other diseases or conditions that men in that age group may suffer from," John Anson, vice president of biomarker discovery at OGT, said in a telephone interview.

"Our pilot test was encouraging because we were able to discriminate between samples from those who were known to have prostate cancer, the benign prostate conditions and the healthy ones, with levels of accuracy and specificity that were much better than the conventional clinical test."

Anson, who presented his findings at a conference on cancer diagnostics in the United States on Tuesday, said the test was designed to detect so-called autoantibodies -- antibodies produced by the immune system to attack the body's own proteins.

Although they are more commonly linked to autoimmune diseases such as lupus or Type 1 diabetes, the immune system also produces autoantibodies in response to other diseases, including cancer, because of changes that occur in proteins during the course of the disease.

"Our screening test...is looking at the prevalence of these autoantibodies as early indicators of disease," Anson said.

He said this not only suggested the test could work as a very early warning system for prostate cancer, but could also have potential as an early test for other forms of cancer too.

The researchers said they were now using testing their findings on 1,700 samples taken from prostate cancer patients, people with no cancer, patients with other cancers and patients with other prostate diseases. They are also doing tests on bowel cancer and a type of cancer called non-small cell lung cancer.

 

[Michael Scally MD]

Factors Identified for Bone Risk in Men on ADT

By Charles Bankhead, Staff Writer, MedPage Today
Published: October 08, 2010

Androgen deprivation therapy (ADT) leads to decay of bone microarchitecture and is a predisposing factor in bone fragility and fracture in prostate cancer patients, Australian researchers reported.

Using high-resolution peripheral quantitative computed tomography (HR-pQCT), Emma Hamilton, MD, of the University of Melbourne, and colleagues found that 12 months of ADT resulted in significant loss of cortical and trabecular bone mineral density (BMD).

Loss of the two types of bone resulted in a significant decrease in total volumetric bone density, averaging 4% to 5% at the distal tibia, they reported online in the Journal of Clinical Endocrinology and Metabolism.

Continue Reading: Medical News: Factors Identified for Bone Risk in Men on ADT - in Oncology/Hematology, Prostate Cancer from MedPage Today


Hamilton EJ, Ghasem-Zadeh A, Gianatti E, et al. Structural Decay of Bone Microarchitecture in Men with Prostate Cancer Treated with Androgen Deprivation Therapy. J Clin Endocrinol Metab:jc.2010-0902. Structural Decay of Bone Microarchitecture in Men with Prostate Cancer Treated with Androgen Deprivation Therapy -- Hamilton et al., 10.1210/jc.2010-0902 -- Journal of Clinical Endocrinology & Metabolism

Context: Androgen deprivation therapy (ADT) used in the treatment of prostate cancer reduces bone mineral density (BMD) and predisposes to fractures. The structural basis of the BMD deficit and bone fragility is uncertain.

Objective and Patients: We investigated changes in bone microarchitecture in 26 men (70.6 {+/-} 6.8 yr) with nonmetastatic prostate cancer during the first year of ADT using the new technique of high-resolution peripheral quantitative computed tomography.

Design and Setting: We conducted a 12-month prospective observational study in the setting of a tertiary referral center.

Results: After 12 months of ADT, total volumetric density decreased by 5.2 {+/-} 5.4% at the distal radius and 4.2 {+/-} 2.7% at the distal tibia (both P < 0.001). This was due to a decrease in cortical volumetric BMD (by 11.3 {+/-} 8.6% for radius and 6.0 {+/-} 4.2% for tibia, all P < 0.001) and trabecular density (by 3.5 {+/-} 6.0% for radius and 1.5 {+/-} 2.3% for tibia, all P < 0.01), after correcting for trabecularization of cortical bone. Trabecular density decreased due to a decrease in trabecular number at both sites (P < 0.05). Total testosterone, but not estradiol, levels were independently associated with total and corrected cortical volumetric BMD at the tibia.

Conclusions: Sex steroid deficiency induced by ADT for prostate cancer results in microarchitectural decay. Bone fragility in these men may be more closely linked to testosterone than estradiol deficiency.

 

[Michael Scally MD]

Drug Extends Survival in Prostate Cancer
Medical News: ESMO: Drug Extends Survival in Prostate Cancer - in Meeting Coverage, ESMO from MedPage Today

By Ed Susman, Contributing Writer, MedPage Today
Published: October 11, 2010

MILAN -- Prostate cancer patients with castration-resistant metastatic disease appeared to benefit from an experimental drug that counteracts the tumor's ability to create growth-sustaining hormones, researchers reported here.

Treatment with abiraterone acetate led to a 35% reduction in the risk of death (HR=0.65; 95% CL: 0.54-0.77; P<0.0001) that translated into a 36% increase in median survival, according to a presentation at the European Society for Medical Oncology meeting.

The patients on the combination of abiraterone and steroids achieved a median 14.8 month survival compared with 10.9 months for patients who received steroids and placebo.

"Abiraterone has the potential to meet a significant unmet need so this news will be incredibly important to prostate cancer patients and their families," said lead investigator Johann de Bono, MD, PhD, of the Institute of Cancer Research at Royal Marsden Hospital in London.

De Bono and colleagues enrolled 1,195 men whose advanced cancer had proved refractory to hormonal therapy and taxane-containing chemotherapy.

"The patients in this study represent the sickest of the sick patients -- the castration-resistant prostate cancer [patients]," said Fortunato Ciardiello, MD, professor of Second University in Naples, Italy, who moderated the press briefing at which the trial results were presented. "What we see here is that one of three of these patients who have no treatment options can be helped by this drug," he told MedPage Today.

In a statement, drugmaker Janssen Pharmaceutical said that it plans to file marketing applications for abiraterone in the U.S. and Europe by the end of the year.

"This has been a remarkable year for prostate cancer patients," de Bono toldMedPage Today, noting the approval in the U.S. of cabazitaxel (Jevtana) and sipuleucel-T (Provenge). "If abiraterone is approved I can see it and the other new drugs being used sequentially to try and make advanced prostate cancer more of a chronic disease."

The randomized, double-blind, placebo-controlled phase III study included recruitment through 147 centers in 13 countries. De Bono said 787 patients were randomized to receive abiraterone 1,000 mg once a day as an oral medication, plus prednisone/prednisolone 5 mg twice daily. The remaining 398 patients were assigned to placebo and the same dose of steroids.

In addition to meeting the primary endpoint of overall survival, de Bono said the time to disease progression was 10.2 months among those on abiraterone and 6.6 months for the placebo patients (P<0.0001).

About 38% of the abiraterone patients experienced a response to treatment that favorably affects levels of prostate specific antibody (PSA) compared with 10% of the patients on placebo plus steroids.

Adverse effects of the drug included fluid retention and hypokalemia.

"I anticipate that this drug will provide a helpful option for these very sick patients and because it is an oral drug it may be of greater help than the vaccine or intravenous treatments," Ciardiello suggested.

 

[Michael Scally MD]

In 2003, Medicare paid out about $1 billion for gonadotropin-releasing hormone (GnRH) agonists used in the treatment of prostate cancer. By 2005, the payout for these drugs, known as androgen-deprivation therapy (ADT), was reduced to about $400 million.

A study published in the November 4 issue of the New England Journal of Medicine reveals that this steep cut in expenditures over a 2-year period did not come at the expense of prostate cancer patients.

Instead, investigators from the University of Michigan in Ann Arbor found that, during this period, "the rate of inappropriate use of ADT declined substantially," and that "there was no decrease in the appropriate use of adjuvant ADT." In short, the reduction in expenditure was accompanied by a more disciplined use of ADT by clinicians.

"The guys who really needed the therapy still received it," lead author Vahakn B. Shahinian, MD, told Medscape Medical News.

The story of ADT and massive cost savings by the federal government is a "case study that has implications for healthcare reform," said Dr. Shahinian, who is from the University of Michigan's Department of Internal of Medicine. He suggested that the journal probably published the study with this object lesson in mind.

"It's possible to manipulate reimbursement to maintain appropriate treatment while at the same time reducing inappropriate treatment," he said.


Shahinian VB, Kuo Y-F, Gilbert SM. Reimbursement Policy and Androgen-Deprivation Therapy for Prostate Cancer. New England Journal of Medicine 2010;363(19):1822-32.

BACKGROUND
The Medicare Modernization Act led to moderate reductions in reimbursement for androgen-deprivation therapy (ADT) for prostate cancer, starting in 2004 and followed by substantial changes in 2005. We hypothesized that these reductions would lead to decreases in the use of ADT for indications that were not evidence based.

METHODS
Using the Surveillance, Epidemiology, and End Results (SEER) Medicare database, we identified 54,925 men who received a diagnosis of incident prostate cancer from 2003 through 2005. We divided these men into groups according to the strength of the indication for ADT use. The use of ADT was deemed to be inappropriate as primary therapy for men with localized cancers of a low-to-moderate grade (for whom a survival benefit of such therapy was improbable), appropriate as adjuvant therapy with radiation therapy for men with locally advanced cancers (for whom a survival benefit was established), and discretionary for men receiving either primary or adjuvant therapy for localized but high-grade tumors. The proportion of men receiving ADT was calculated according to the year of diagnosis for each group. We used modified Poisson regression models to calculate the effect of the year of diagnosis on the use of ADT.

RESULTS
The rate of inappropriate use of ADT declined substantially during the study period, from 38.7% in 2003 to 30.6% in 2004 to 25.7% in 2005 (odds ratio for ADT use in 2005 vs. 2003, 0.72; 95% confidence interval [CI], 0.65 to 0.79). There was no decrease in the appropriate use of adjuvant ADT (odds ratio, 1.01; 95% CI, 0.86 to 1.19). In cases involving discretionary use, there was a significant decline in use in 2005 but not in 2004.

CONCLUSIONS
Changes in the Medicare reimbursement policy in 2004 and 2005 were associated with reductions in ADT use, particularly among men for whom the benefits of such therapy were unclear. (Funded by the American Cancer Society.)

 

[Michael Scally MD]

Review of prostate cancer drug Provenge renews medical cost-benefit debate
Review of prostate cancer drug Provenge renews medical cost-benefit debate

By Rob Stein

Washington Post Staff Writer
Monday, November 8, 2010; 7:52 AM

Federal officials are conducting an unusual review to determine whether the government should pay for an expensive new vaccine for treating prostate cancer, rekindling debate over whether some therapies are too costly.

The Centers for Medicare & Medicaid Services, which dictate what treatments the massive federal health-insurance program for the elderly will cover, is running a "national coverage analysis" of Provenge, the first vaccine approved for treating any cancer. The treatment costs $93,000 a patient and has been shown to extend patients' lives by about four months.

Although Medicare is not supposed to take cost into consideration when making such rulings, the decision to launch a formal examination has raised concerns among cancer experts, drug companies, lawmakers, prostate cancer patients and advocacy groups.

Provenge, which was approved for advanced prostate cancer in April, is the latest in a series of new high-priced cancer treatments that appear to eke out only a few more months of life, prompting alarm about their cost.

"This absolutely is the opening salvo in the drive to save money in the health-care system," said Skip Lockwood, who heads Zero - the Project to End Prostate Cancer, a Washington-based lobbying group. "If the cost wasn't a consideration, this wouldn't even be under discussion."

Those concerns have been heightened because the review comes after the bitter health-care reform debate, which was marked by accusations about rationing and "death panels." The appointment of Donald M. Berwickto head Medicare only intensified anxieties. President Obama sidestepped a Senate battle by naming Berwick, who has advocated for scrutinizing costs, when Congress was in recess in July.

Because men tend to be elderly when they get diagnoses of advanced prostate cancer, Medicare's decision will have a major effect on Provenge's availability. Regional Medicare providers paying for Provenge would have to stop. Private insurers also tend to follow Medicare's lead.

Medicare officials, who are convening a panel of outside advisers to vet the issue at a public hearing Nov. 17, say Provenge's price tag isn't an issue. But Berwick and other officials declined to discuss the rationale for the review.

"Certainly no one in the Medicare program would publicly state that the price tag would have anything to do with Medicare looking at it. But they are human beings, too. They notice things like that," said Sean Tunis, director of the Center for Medical Technology Policyand a former chief medical officer at Medicare. Tunis said, though, that other factors, such as the special nature of the therapy and lingering questions about its effectiveness, were probably playing a more crucial role.

The review comes as the Food and Drug Administration considers withdrawing an approval for another expensive cancer treatment- Avastin for metastatic breast cancer - which triggered a similar debate even though the FDA too is not supposed to factor costs into its analyses.

Medicare usually covers new cancer drugs once they have been approved by the FDA. The decision in June to scrutinize Provenge prompted several members of Congress to question the action. Supporters have inundated the agency with hundreds of thousands of comments.

"I don't want to blame Obamacare, but it just kind of figures that people are taking a look at what the cost-benefit ratios are and all that sort of stuff," said David Dykes, 69, of Lorton, a retired federal employee who was hoping to try Provenge. "That may sound pretty good to the people who want to cut costs, but it doesn't sound too good to me. This is something that could extend my life. I'd like to give that a shot."

Some fear the move will discourage pharmaceutical companies from developing new cancer drugs.

"It is extremely chilling if, after spending a huge sum of money, time and effort to get a drug through FDA approval, you'll then have to go through it all again to see if CMS will pay for it," said Allen S. Lichter, head of the American Society of Clinical Oncology. "Firing a shot across the bow like this is not the way to have an intelligent and meaningful discussion about how we start to address the complex issue of drug costs."

Provenge has long been the center of controversy. The FDA delayed Provenge's approval in 2007. The rejection triggered outrage among patients, advocates and investors in Dendreon, the Seattle company that developed Provenge. The campaign to win Provenge's approval included anonymous death threats, accusations of conflicts of interest, protests, congressional lobbying and vitriolic Internet postings.

Prostate cancer strikes 192,000 men in the United States each year and kills about 27,000. The only therapies are surgery, radiation, hormones and the chemotherapy drug Taxotere.

Unlike standard vaccines, which are given before someone gets sick to stimulate their immune system to fight off infections, Provenge is a "therapeutic vaccine," designed to attack cancer cells in the body.

To produce Provenge, doctors remove immune system cells from patients, expose the cells in the laboratory to a protein found on most prostate cancer cells and an immune system stimulator, and infuse the cells back into the patient in a month-long series of three treatments. In a study involving 512 patients with advanced prostate cancer, Provenge increased median survival from 21.7 months to 25.8 months.

"To charge $90,000 for four months, which comes out to $270,00 for a year of life, I think that's too expensive," said Tito Fojo of the National Cancer Institute. "A lot of people will say, 'It's my $100,000, and it's my four months.' Absolutely: A day is worth $1 million to some people. Unfortunately, we can't afford it as a society."

Others agreed, especially given the modest benefit.

"I'd like to think cost doesn't need to come up when it's a slam dunk," said H. Gilbert Welchof the Dartmouth Institute for Health Policy and Clinical Practice. "But when it's a close call like this, it certainly has to be a factor. That's $100,000 Medicare can't spend elsewhere."

But such commentary has caused widespread alarm among patients and advocates.

"The men most impacted by prostate cancer are African American men. If CMS doesn't approve this, then this treatment becomes an exclusive kind of treatment for men who can afford it out of pocket," said Thomas Farrington, president of the Prostate Health Education Network.

Others stressed that many men live far longer on the treatment and that even four months is extremely valuable to some.

"Whenever you are faced with a disease where you can lose your life, you really would like to extend it as much as you can," said Leibel B. Harelik, 61, a prostate cancer patient who is executive director of the Prostate Cancer Resource Center in Austin.

Company officials say the cost is not out of line with that of other cancer drugs. Each treatment with Provenge, which the company estimates cost nearly $1 billion to develop, is tailored to each patient.

"Because of that, we have higher costs associated with this product," said Mitchell H. Gold, Dendreon's chief executive. "Provenge is a unique new medicine that prolongs the lives of patients with late-stage prostate cancer. These patients need access to innovative new medicines."

Whatever the outcome on Provenge, many on both sides agreed that more debate over other new high-tech therapies was likely to come.

"At some point, if we keep paying these very high prices for treatments that provide very limited benefit, we're going to reach the point where we can no longer afford health care," said Alan Garber, a professor of medicine and economist at Stanford University. "Some say we're living through that right now."

 

[Michael Scally MD]

In Small Test, Experimental Prostate Drug Shows Promise
http://www.nytimes.com/2010/11/18/health/18prostate.html

November 18, 2010
By ANDREW POLLACK

An experimental drug is showing what some experts say is intriguing effectiveness in treating a major cause of death and disability for men with prostate cancer — tumors that have spread to the bone.

The results of early testing of the drug, to be presented at a cancer conference in Berlin on Thursday, would be another piece of good news this week for men with the disease. On Wednesday, a federal advisory committee said there was adequate evidence that the already marketed prostate cancer drug Provenge, developed by Dendreon, prolongs lives.

That makes it more likely that Medicare will pay for the drug, which costs $93,000 a patient and has long been the focus of a passionate debate. Some prostate cancer patients, doctors and investors in Dendreon saw Medicare’s review of Provenge as the beginning of a federal crackdown on expensive drugs.

The experimental drug, XL184, is the lead drug candidate of Exelixis, a biotechnology company in South San Francisco, Calif.

In very early testing, 19 of 20 patients showed an improvement in the scans used to determine whether cancer has spread to the bone. In some cases, the bone scans could no longer detect any cancer, and the men were able to stop taking the narcotics they were using to control bone pain. To be sure, the results are from very few patients and there was no control group. It is still not known if XL184 prolongs life or how long the improvement in bone scans will last.

“There’s really no precedent for another drug that does this,” said Dr. Matthew R. Smith, a prostate cancer specialist at the Massachusetts General Hospital.

Also, bone scans actually measure bone formation, not the presence of cancer itself. So it cannot be completely ruled out that XL184 somehow stopped bone growth without killing the cancer. However, Dr. Smith said he doubted that was the case because there were signs the drug also controlled tumors outside the bones.

Drugs now used to treat advanced prostate cancer, like Taxotere, do not have much affect on bone scans, Dr. Smith said. Bone drugs like Zometa from Novartis and denosumab from Amgen can protect cancerous bones from fractures, but have not been shown to fight the cancer itself.

Another investigator in the trial, Dr. David C. Smith of the University of Michigan, said he could not believe it when the bone scan of one patient, who previously had widespread cancer in his bones, came back completely clean.

“I thought they had scanned the wrong person,” said Dr. Smith, who is not related to the doctor in Massachusetts. “I’ve never seen anything like this.”

Exelixis will now add many prostate cancer patients to the midstage clinical trial from which the results were drawn, said Michael M. Morrissey, the company’s chief executive. A late-stage trial could begin as early as next year, he said.

XL184 is believed to block the formation of blood vessels that feed tumors and also inhibits a protein called MET that helps spur tumor growth.

Provenge from Dendreon, by contrast, trains the patient’s immune system to attack the tumor. The drug was approved by the Food and Drug Administration in April after a clinical trial showed that those getting the drug had a median survival of about 26 months, four months longer than those in a control group.

Some critics say Medicare would not be doing a review of a drug already approved by the F.D.A. were it not for its high cost.

“One has to wonder if today’s meeting is about something other than science, namely the cost,” Brad Loncar, an investor in Dendreon whose grandfather died of prostate cancer, told the Medicare Coverage Advisory Committee on Wednesday.

Dr. Louis Jacques, director of the coverage and analysis group at the Centers for Medicare and Medicaid Services, said cost was not a factor and that the agency had reviewed products approved by the F.D.A. in the past.

Dr. Jacques said he ordered the review after being contacted by federal lawmakers questioning why their constituents could not get the drug. He realized that reimbursement by regional Medicare contractors was inconsistent, so he decided the agency should have a uniform national policy.

The Medicare Coverage Advisory Committee, which met in Baltimore, did not discuss the cost of Provenge or make a coverage recommendation. It reviewed the clinical trial data and then rated the strength of the data on a scale of 1 to 5.

The 10 voting members, mainly doctors and health policy experts, averaged 3.6 on the question of how much confidence they had that there was adequate evidence to conclude that Provenge significantly prolongs survival.

That is between 3, which is intermediate confidence and 5, which is high confidence. But some analysts said that should be enough for reimbursement. Trading in Dendreon shares, halted during regular market hours, rose 6 percent after hours.

However, the panel gave very low scores to evidence that the drug would help prostate cancer patients other than the type who participated in the clinical trial, which were men with advanced cancer, but no or minimal symptoms. That could give Medicare grounds for denying payment when the drug is used off-label, as cancer drugs often are.

Medicare is scheduled to put a proposed decision out for comment by March 30, with a final decision around the end of June.

Provenge has stirred passions since the F.D.A. initially declined to approve it in 2007. Some Dendreon investors and prostate cancer patients staged protests and advertising campaigns and sued the F.D.A. Two doctors who had spurred investor wrath by voting against the drug’s approval at an advisory committee meeting attended a major cancer conference accompanied by bodyguards.

Medicare’s review has drawn hundreds of comments, mostly in favor of coverage. One criticism of the drug was filed by a law firm, Willkie Farr & Gallagher, on behalf of a client who the law firm said wanted to remain anonymous because of the “public vilification of anyone that questions Provenge.”

 

[Michael Scally MD]

No Routine PSA Screen for U.K. Men
Medical News: No Routine PSA Screen for U.K. Men - in Oncology, Prostate Cancer from MedPage Today

The United Kingdom's National Screening Committee has recommended against routine screening for prostate cancer risk with prostate specific antigen (PSA) testing.

The U.K. screening committee concluded that the PSA test's potential harms -- including worry and anxiety due to the reported high number of false positives -- outweigh any potential benefits.

The panel noted that benign enlargement of the prostate or a urinary infection can also lead to elevated serum PSA levels.

Still, the committee recommended giving a PSA test to any patient who requests one.

"The 'informed choice' program should ensure men receive clear and balanced information about the advantages and disadvantages of the PSA test and treatment for prostate cancer," the committee wrote in its review documents.

The screening committee's findings were based on evidence from three clinical trials -- the European Randomized Study on Screening for Prostate Cancer (ERSPC), the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), and the Prostate Testing for Cancer and Treatment Trial (ProtecT).

The U.K. panel began its review in March 2009, after a new analysis from the ERSPC found a 20% mortality benefit from prostate cancer screening (albeit with a "great deal of 'over diagnosis,' " the committee noted).

Subsequent models by the School of Health and Related Research in Sheffield, England, found that a single screen at age 50 has little effect on age-specific incidence of prostate cancer, and found little benefit for annual or biannual screens.

The committee's main conclusions included the determination that PSA is "a poor test for prostate cancer and a more specific and sensitive test is needed," and that the test is "unable to correctly identify those cancers which will progress and those which ... may be safely watched."

The panel also emphasized that data related to incidence, prevalence, and treatments are poor and "renders planning very difficult."

The policy will be reviewed again in three years unless there is "significant new peer-reviewed evidence," the committee added.

 

[HeadDoc]

Ultrasound to detect prostate cancer

Public release date: 8-Dec-2010
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Contact: Ivo Jongsma
i.l.a.jongsma@tue.nl
31-402-472-110
Eindhoven University of Technology
Accurate diagnosis of prostate cancer with ultrasound



IMAGE: Massimo Mischi, Ph.D., of Eindhoven University of Technology developed a new technology to accurately diagnose prostate cancer.
Click here for more information.




Prostate cancer is the most common type of cancer among men, but its diagnosis has up to now been inaccurate and unpleasant. Researchers at Eindhoven University of Technology (TU/e), in cooperation with AMC Amsterdam, have developed an imaging technology that can accurately identify tumors. The technology is based on ultrasound, and also has the potential to assess how aggressive tumors are. This can lead to better and more appropriate treatment, and to cost savings in health care.

About 11% of men who die of cancer in the western world do so as a result of prostate cancer. Each year 200,000 men are diagnosed with the disease in the US alone. But diagnosis is still rudimentary. After determining the PSA (prostate-specific antigen) level in the blood-, biopsies are performed to see if there are tumors in the prostate. However the PSA level is not a very good indicator: two-thirds of all biopsies turn out to afterwards to have been unnecessary.

The biopsies also have disadvantages; for example they are not targeted, but instead tissue is sampled randomly using 6 to 12 needles. The chance that the needles will miss a tumor is high, causing a false negative result. In around one-third of cases with negative biopsies, tumors are later found to be present. Furthermore doctors often operate after a positive biopsy, but find a tumor so small that it would have been better not to operate.

The new technology uses the injection of microbubbles of a contrast agent with no side-effects. The response of the tiny bubbles to ultrasound is different from that of human tissue or blood. This makes the bubbles traceable from the outside, right into the smallest blood vessels. The pattern of blood vessels in tumors is different from that in healthy tissue. The researchers can recognize this pattern from advanced analysis of the bubble concentrations. And because tumors need blood – and hence new blood vessels – to grow, the researchers expect to be able to see how aggressive the cancer is from the pattern of the blood vessels.

The technology has been tested on four patients from whom the affected prostate was removed, dr.ir. Massimo Mischi of the TU/e department of Electrical Engineering explains. The location and size of the tumors turned out to match accurately with the images produced using the new technology. Mischi presented these first, promising results at a recent conference in Chicago.

Next year the research team will carry out a pilot with biopsies guided by images made using the new technology. This allows the biopsies to be targeted, and therefore more effective. In a later phase the ultrasound technology will be used to decide whether biopsies are required, which will reduce the number of biopsies carried out. The researchers expect their technology to be available in hospitals within five years. The ultimate goal is for doctors to be able to determine if an operation is necessary, and if so what kind of operation, based on the images produced, without the need for biopsies.

All in all doctors will eventually be able to intervene much more accurately, expects prof.dr.ir. Hessel Wijkstra, head of urology research at AMC Amsterdam. Wijkstra was appointed part-time professor of Hemodynamic Contrast Sonography at TU/e last month. Furthermore he believes that there will be less unnecessary operations. In some cases doctors may decide to leave small, non-aggressive tumors untouched and monitor these tumors, in cases where a tumor is not causing any symptoms and is not impairing the health of the patient. In these cases the health effects of surgery are worse than those of the tumor itself. A further positive effect of this new approach is that the total costs will be reduced.

As well as TU/e and the AMC Amsterdam, the Catharina Hospital in Eindhoven and a number of ultrasound companies are also involved in the research. Dr.ir. Massimo Mischi received a Vidi grant worth eur 800,000 from the NWO (Netherlands Organisation for Scientific Research) last year for this research. The research also receives financial support from the Cure for Cancer Foundation.

###

 

[Michael Scally MD]

Study: Gene markers may aid prostate cancer test


(AP) – 17 hours ago

WASHINGTON (AP) — Scientists have taken a first step toward improving those problematic PSA tests for prostate cancer, by mixing in some genetic information that might help tell which men really need a biopsy.

The widely used blood tests measure a protein named PSA that only sometimes signals prostate cancer is brewing. It can be high for other reasons, but doctors order a biopsy to check for a tumor whenever PSA reaches a certain level.

Now scientists have discovered a set of genetic variants that show those cutoffs may be skewed for some men because their normal PSA level is naturally much higher than the average that PSA testing was based on.

That means "you end up biopsying a lot of prostates that did not need any biopsy," said Dr. Kari Stefansson, chief executive officer of deCODE Genetics in Iceland.

His team reported the findings Wednesday in the journal Science Translational Medicine.

Stefansson said he plans to develop a test for those genetic markers, perhaps later next year, in hopes that doctors could use the information to customize how they read and react to their patient's PSA test results.

This genetic approach makes sense but "I don't think that this test is ready for prime time" without more research to confirm the findings, cautioned Dr. Otis Brawley, chief medical officer of the American Cancer Society, who wasn't part of the study.

"It's important, but it's a small step in the long road ahead" for better prostate cancer detection, he said.

Making a PSA test more accurate solves only part of the problem, Brawley stressed. Screening often detects small prostate tumors that will prove too slow-growing to be deadly, but there's no sure way to tell in advance who needs aggressive therapy.

"What we desperately need is some type of test ... that tells us, 'This is the kind of prostate cancer that kills' versus the kind of cancer that doesn't kill," he said.

More than 190,000 cases of prostate cancer will be diagnosed this year in American men, and it will kill about 27,000. But routine screening is highly controversial: While most men over 50 have had at least one PSA test, many major medical groups don't recommend them, worried they may do more harm than good. The cancer society, for instance, advises that men be told of the pros and cons and decide for themselves.

Among the problems: More than a third of men with PSA levels of 10 or more have no evidence of prostate cancer at biopsy, and many doctors order a tumor check at levels lower than that, around 4. Conversely, some men with very low PSA levels wind up with cancer.

Stefansson's team discovered a set of genetic variants that alters how much PSA, or prostate specific antigen, men naturally produce.

The team reported that men who bear any of three of those variants had PSA levels about 40 percent higher than average men. When they examined the records of nearly 4,000 men in Iceland and Britain who underwent prostate biopsies, those high-PSA producers were more likely to have had an unnecessary biopsy.

Conversely, men with a fourth variant had PSA levels about 40 percent lower than average. Roughly 5 percent of men fall into each category, Stefansson said.

What does that mean? If a doctor usually orders a biopsy for a PSA of 4, a high-PSA producer might not need one until reaching almost 6, Stefansson said. But a low-PSA producer might need one sooner.


Gudmundsson J, Besenbacher S, Sulem P, et al. Genetic Correction of PSA Values Using Sequence Variants Associated with PSA Levels. Science Translational Medicine 2010;2(62):62ra92. Genetic Correction of PSA Values Using Sequence Variants Associated with PSA Levels — Sci TM

Measuring serum levels of the prostate-specific antigen (PSA) is the most common screening method for prostate cancer. However, PSA levels are affected by a number of factors apart from neoplasia. Notably, around 40% of the variability of PSA levels in the general population is accounted for by inherited factors, suggesting that it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects.

To search for sequence variants that associate with PSA levels, we performed a genome-wide association study and follow-up analysis using PSA information from 15,757 Icelandic and 454 British men not diagnosed with prostate cancer. Overall, we detected a genome-wide significant association between PSA levels and single-nucleotide polymorphisms (SNPs) at six loci: 5p15.33 (rs2736098), 10q11 (rs10993994), 10q26 (rs10788160), 12q24 (rs11067228), 17q12 (rs4430796), and 19q13.33 [rs17632542 (KLK3: I179T)], each with Pcombined <3 × 10?10.

Among 3834 men who underwent a biopsy of the prostate, the 10q26, 12q24, and 19q13.33 alleles that associate with high PSA levels are associated with higher probability of a negative biopsy (odds ratio between 1.15 and 1.27). Assessment of association between the six loci and prostate cancer risk in 5325 cases and 41,417 controls from Iceland, the Netherlands, Spain, Romania, and the United States showed that the SNPs at 10q26 and 12q24 were exclusively associated with PSA levels, whereas the other four loci also were associated with prostate cancer risk.

We propose that a personalized PSA cutoff value, based on genotype, should be used when deciding to perform a prostate biopsy.


Witte JS. Personalized Prostate Cancer Screening: Improving PSA Tests with Genomic Information. Science Translational Medicine 2010;2(62):62ps55. Personalized Prostate Cancer Screening: Improving PSA Tests with Genomic Information — Sci TM

The use of a prostate-specific antigen (PSA) test to screen for prostate cancer is controversial because of its modest predictive value and the potential overdiagnosis and over-treatment of the disease. A research article in this issue of Science Translational Medicine describes single-nucleotide polymorphisms (SNPs) in or near six genes that are independently associated with serum PSA concentrations and that help to explain interindividual PSA variation. Three of these SNPs are also associated with prostate biopsy outcomes. These findings are an important step toward incorporating genetic markers into PSA screening, with the ultimate goal of devising personalized PSA tests for use in the clinic.

 

[cvictorg]

Is a Decreased Serum Testosterone Level a Risk Factor for Prostate Cancer?

Is a Decreased Serum Testosterone Level a Risk Factor for Prostate Cancer? A Cohort Study of Korean Men

Conclusions

Patients with lower levels of serum testosterone had a higher risk of prostate cancer than did patients with high serum testosterone. Even though a lower serum testosterone level was a predictor of prostate cancer risk, it was not associated with an increased risk of high-grade prostate cancer.

 

[Michael Scally MD]

Study Knocks Diagnostic Value of PSA Velocity
Medical News: Study Knocks Diagnostic Value of PSA Velocity - in Oncology/Hematology, Prostate Cancer from MedPage Today

If prostate biopsy is based on PSA velocity alone, the number of unnecessary biopsies would be almost four times the number of additional cancers diagnosed, data from a large clinical trial showed.

In the absence of other predictive factors, PSA velocity would have identified 115 prostate cancers at a cost of 433 unnecessary biopsies, according to Andrew Vickers, PhD, of Memorial Sloan-Kettering Cancer Center in New York City and colleagues.

If used as sole justification for a biopsy, PSA velocity would trigger about one of every seven prostate biopsies, they reported online in the Journal of the National Cancer Institute.

Moreover, adding PSA velocity to a multifactor model resulted in minuscule improvement in diagnostic accuracy, particularly for high-grade cancers.

The findings have implications for clinical guidelines that include PSA velocity in criteria for prostate biopsy, including recommendations from the American Urological Association (AUA) and the National Comprehensive Cancer Network (NCCN).

"We found no reason to believe that implementation of the guideline would improve patient outcomes; indeed, its use would lead to a large number of unnecessary biopsies," Vickers and co-authors wrote in conclusion.

"We therefore recommend that organizations issuing policy statements related to PSA and prostate cancer detection remove references to PSA velocity."

The authors did acknowledge that current clinical guidelines for prostate cancer have a strong evidentiary base for many aspects of diagnosis, evaluation, and treatment; in particular, use of PSA and free PSA levels to diagnose cancer.

However, they noted, inclusion of PSA velocity in clinical recommendations has questionable support.

The NCCN guidelines, for example, recommend prostate biopsy in men who have a PSA velocity greater than 0.35 ng/mL-1 y-1. In support of the recommendation, the guideline authors cited a single study showing that PSA velocity predicted diagnosis of fatal prostate cancer 10 to 15 years later.

"It is unclear why a marker that predicts aggressive prostate cancer many years in the future should be used to suggest immediate biopsy to patients," Vickers and colleagues wrote. "Moreover, PSA velocity was not demonstrated to add predictive accuracy to PSA alone."

To examine the predictive value of PSA velocity, the authors analyzed data from the Prostate Cancer Prevention Trial, which included an end-of-trial prostate biopsy for all study participants (N Engl J Med 2003; 349: 215-224). The analysis included 5,519 men from the placebo arm of the trial.

Vickers and colleagues constructed a linear regression model that incorporated various predictors of prostate cancer on biopsy. They compared results in models with and without PSA velocity. They also performed an analysis that limited the definition of prostate cancer to high-grade disease (Gleason score 7 to 10).

In a univariate analysis, PSA velocity had a significant association with biopsy outcome (P<0.001). As a component of a multivariable prediction model, however, the association was substantially diminished.

Varying the definition of PSA velocity, the authors found marginally significant associations with log(PSA) values one year before diagnosis (OR 0.74, P=0.037) and annualized velocity (OR 0.98, P=0.047).

Receiver operating characteristic analysis showed minimal improvement in the area under the curve (AUC) when PSA velocity was added to other predictors of prostate cancer risk (AUC 0.702 versus AUC 0.709).

Even less improvement in predictive accuracy was observed for detection of high-grade or clinically significant cancers.

"There was little evidence that PSA velocity adds an important level of predictive accuracy to either standard predictors or to PSA alone," the authors wrote.

"Superior risk stratification can be achieved simply by choosing a different PSA cut point, especially for the endpoints of high-grade cancer or clinically significant cancer," they added.

The Prostate Cancer Prevention Trial used a PSA cutoff of 4.0 ng/mL as a biopsy trigger, resulting in a biopsy rate of approximately one in 20 with no appreciable loss in diagnostic accuracy, Siu-Long Yao, PhD, and Grace L. Lu-Yao, PhD, of the University of Medicine and Dentistry of New Jersey, wrote in an accompanying editorial.

The study by Vickers et al. serves as a reminder that "the use of PSA as a screening tool leaves much to be desired," wrote Yao and Lu-Yao. "Indeed, after more than 20 years of PSA screening, it has been estimated that approximately one million men may have been unnecessarily treated for clinically insignificant prostate cancer."

"The shortcomings of PSA testing also remind us that there is still much art to the diagnosis and treatment of prostate cancer.”


Vickers AJ, Till C, Tangen CM, Lilja H, Thompson IM. An Empirical Evaluation of Guidelines on Prostate-specific Antigen Velocity in Prostate Cancer Detection. Journal of the National Cancer Institute. An Empirical Evaluation of Guidelines on Prostate-specific Antigen Velocity in Prostate Cancer Detection — J. Natl. Cancer Inst.

Background The National Comprehensive Cancer Network and American Urological Association guidelines on early detection of prostate cancer recommend biopsy on the basis of high prostate-specific antigen (PSA) velocity, even in the absence of other indications such as an elevated PSA or a positive digital rectal exam (DRE).

Methods To evaluate the current guideline, we compared the area under the curve of a multivariable model for prostate cancer including age, PSA, DRE, family history, and prior biopsy, with and without PSA velocity, in 5519 men undergoing biopsy, regardless of clinical indication, in the control arm of the Prostate Cancer Prevention Trial. We also evaluated the clinical implications of using PSA velocity cut points to determine biopsy in men with low PSA and negative DRE in terms of additional cancers found and unnecessary biopsies conducted. All statistical tests were two-sided.

Results Incorporation of PSA velocity led to a very small increase in area under the curve from 0.702 to 0.709. Improvements in predictive accuracy were smaller for the endpoints of high-grade cancer (Gleason score of 7 or greater) and clinically significant cancer (Epstein criteria). Biopsying men with high PSA velocity but no other indication would lead to a large number of additional biopsies, with close to one in seven men being biopsied. PSA cut points with a comparable specificity to PSA velocity cut points had a higher sensitivity (23% vs 19%), particularly for high-grade (41% vs 25%) and clinically significant (32% vs 22%) disease. These findings were robust to the method of calculating PSA velocity.

Conclusions We found no evidence to support the recommendation that men with high PSA velocity should be biopsied in the absence of other indications; this measure should not be included in practice guidelines.

 

[Michael Scally MD]

Many Elderly Men Are Undergoing Unnecessary PSA Screenings, Researchers Find
Many elderly men are undergoing unnecessary PSA screenings, researchers find

ScienceDaily (Mar. 28, 2011) — A new study on the use of prostate-specific antigen (PSA)-based prostate cancer screening in the United States found that many elderly men may be undergoing unnecessary prostate cancer screenings. Using data from surveys conducted in 2000 and 2005, researchers report that nearly half of men in their seventies underwent PSA screening in the past year -- almost double the screening rate of men in their early fifties, who are more likely to benefit from early prostate cancer diagnosis and treatment. Further, men aged 85 and older were screened just as often as men in their early fifties.

Because prostate cancer tends to be slow-growing, data show that many men -- particularly those in their seventies and older -- will die of other causes before prostate cancer becomes a problem that requires medical attention. Published in theJournal of Clinical Oncology, the new findings underscore a long-standing concern that overuse of PSA screening and PSA-based treatment decisions may lead to unnecessary treatment of many older men and potential complications such as incontinence, impotence and bowel dysfunction.

"Our findings show a high rate of elderly and sometimes ill men being inappropriately screened for prostate cancer. We're concerned these screenings may prompt cancer treatment among elderly men who ultimately have a very low likelihood of benefitting the patient and paradoxically can cause more harm than good," said senior author Scott Eggener, MD, assistant professor of surgery at the University of Chicago. "We were also surprised to find that nearly three-quarters of men in their fifties were not screened within the past year. These results emphasize the need for greater physician interaction and conversations about the merits and limitations of prostate cancer screening for men of all ages."

While large declines in prostate cancer metastases and death rates in the last 20 years coincide with widespread use of PSA-based screening, questions remain about its use. Data have been unclear about when men should be considered for PSA screening and when screening should stop, and recent studies have provided conflicting evidence on whether routine PSA screening in the general population of men actually reduces the risk of dying from prostate cancer. Based on these concerns, major organizations such as the American Cancer Society now encourage men who expect to live at least 10 years to talk with their doctor about the risks and benefits of screening, starting at age 50 for men with an average risk or at age 45 for men with a higher risk.

In this study, the researchers examined results from health surveys of randomly selected households conducted in 2000 and 2005 as part of the federal government-sponsored National Health Interview Survey. In addition to reviewing survey data, which included information on age, smoking, mass-body index, underlying medical conditions and other factors, the investigators calculated the estimated five-year life expectancy of each man over 40 who had received a PSA test.

They divided survey results of men age 70 and older into five-year age groups (70 to 74, 75 to 79, 80 to 84, and 85 years and older). In all, 2,623 men ages 70 and older were included in the analysis, while nearly 12,000 men between the ages of 40 and 69 served as controls.

The overall PSA screening rate within the past year for men aged 40 and older was 23.7 percent in 2000 and 26.0 percent in 2005. The PSA screening rate was lowest in the 40 to 44 age group (7.5 percent). Researchers found that the PSA screening rate was 24.0 percent in men ages 50 to 54, increasing with age until a peak of 45.5 percent in ages 70 to 74. Screening rates then declined with age, with 24.6 percent of men 85 or older reporting being screened.

Among men who were 70 or older, the investigators did find that PSA screening was more common in men with a greater estimated five-year life expectancy. For example, approximately 47.3 percent of men who were unlikely to die in five years (an estimated chance of 15 percent or less) were screened, 39.2 percent of men with an intermediate chance (16 to 48 percent probability) of dying received screening, and 30.7 percent of those with the highest probability of death (48 percent or greater) in five years were screened.

Eggener offered some possible explanations for the results, noting that screening rates may reflect how frequently men visit primary care physicians. Older men tend to have more health problems that require doctor visits, and this may in turn result in more frequent PSA testing than younger men, who see their doctors less. The authors suggest that physicians should be more selective in recommending PSA testing for older men, particularly those with a limited life expectancy, and consider more routinely screening younger, healthier men who are most likely to benefit from early prostate cancer diagnosis and related treatment. Men are encouraged to talk with their doctor about their individual risk for prostate cancer, and about the risks and benefits of prostate cancer screening.


Drazer MW, Huo D, Schonberg MA, Razmaria A, Eggener SE. Population-Based Patterns and Predictors of Prostate-Specific Antigen Screening Among Older Men in the United States. Journal of Clinical Oncology. http://jco.ascopubs.org/content/early/2011/03/28/JCO.2010.31.9004.full.pdf

Purpose For patients who elect to have prostate cancer screening, the optimal time to discontinue screening is unknown. Our objective was to describe rates and predictors of prostate-specific antigen (PSA) screening among older men in the United States.

Methods Data were extracted from the population-based 2000 and 2005 National Health Interview Survey (NHIS). PSA screening was defined as a PSA test as part of a routine exam within the past year. Demographic, socioeconomic, and functional characteristics were collected, and a validated 5-year estimated life expectancy was calculated. Age-specific rates of PSA screening were determined, and sampling weight-adjusted multivariate regressions were fitted to determine predictors of screening among men age 70 years or older.

Results The PSA screening rate was 24.0% in men age 50 to 54 years, and it increased steadily with age until a peak of 45.5% among age 70 to 74 years. Screening rates then gradually declined by age, and 24.6% of men age 85 years or older reported being screened. Among men age 70 years or older, screening rates varied by estimated 5-year life expectancy: rates were 47.3% in men with high life expectancies (≤ 15% probability of 5-year mortality), 39.2% in men with intermediate life expectancies (16% to 48% probability), and 30.7% in men with low life expectancies (> 48% probability; P < .001). In multivariate analysis, estimated life expectancy and age remained independently associated with PSA screening (P < .001 for each).

Conclusion Rates of PSA screening in the United States are associated with age and estimated life expectancy, but excessive PSA screening in elderly men with limited life expectancies remains a significant problem. The merits and limitations of PSA should be discussed with all patients considering prostate cancer screening.

 

[Michael Scally MD]

The favorable outcome after radical surgery shown in a Scandinavian study comparing radical prostatectomy with watchful waiting has stimulated the debate on early detection of prostate cancer, in particular by testing for prostate specific antigen. The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial and the European Randomized Study of Screening for Prostate Cancer (ERSPC) were expected to provide final evidence for or against screening as a method to reduce mortality from prostate cancer. These two large studies, however, did not show unequivocal benefit from prostate specific antigen screening. The ERSPC trial showed a significant improvement in cancer specific survival for men in the screened group but with a high risk of overdiagnosis and overtreatment. The Gothenburg randomized population based prostate cancer screening trial, from one of the centers included in the ERSPC trial, found a risk ratio for prostate cancer specific death similar to that found in the ERSPC trial. The PLCO trial, on the other hand, did not show any benefit from screening, probably because of a large degree of crossover contamination. Follow-up in the PLCO might also have been too short to provide reliable data on mortality.

In 1987, a randomized controlled trial on screening for prostate cancer was started in Norrköping, Sweden. The study was started before prostate specific antigen testing was established as a method of screening so at the first two screening sessions only digital rectal examination was used. From 1993, this was combined with a prostate specific antigen test. The feasibility of a screening program for prostate cancer has previously been reported. Researchers have also previously presented data on the reliability of digital rectal examination, the cost effectiveness of screening for prostate cancer, and the clinical consequences of screening. Here they report on mortality 20 years after the start of study.


Sandblom G, Varenhorst E, Rosell J, Lofman O, Carlsson P. Randomised prostate cancer screening trial: 20 year follow-up. BMJ 2011;342:d1539. http://www.bmj.com/content/342/bmj.d1539.full.pdf

OBJECTIVE: To assess whether screening for prostate cancer reduces prostate cancer specific mortality.

DESIGN: Population based randomised controlled trial. SETTING: Department of Urology, Norrkoping, and the South-East Region Prostate Cancer Register.

PARTICIPANTS: All men aged 50-69 in the city of Norrkoping, Sweden, identified in 1987 in the National Population Register (n=9026).

INTERVENTION: From the study population, 1494 men were randomly allocated to be screened by including every sixth man from a list of dates of birth. These men were invited to be screened every third year from 1987 to 1996. On the first two occasions screening was done by digital rectal examination only. From 1993, this was combined with prostate specific antigen testing, with 4 microg/L as cut off. On the fourth occasion (1996), only men aged 69 or under at the time of the investigation were invited.

MAIN OUTCOME MEASURES: Data on tumour stage, grade, and treatment from the South East Region Prostate Cancer Register. Prostate cancer specific mortality up to 31 December 2008.

RESULTS: In the four screenings from 1987 to 1996 attendance was 1161/1492 (78%), 957/1363 (70%), 895/1210 (74%), and 446/606 (74%), respectively. There were 85 cases (5.7%) of prostate cancer diagnosed in the screened group and 292 (3.9%) in the control group. The risk ratio for death from prostate cancer in the screening group was 1.16 (95% confidence interval 0.78 to 1.73). In a Cox proportional hazard analysis comparing prostate cancer specific survival in the control group with that in the screened group, the hazard ratio for death from prostate cancer was 1.23 (0.94 to 1.62; P=0.13). After adjustment for age at start of the study, the hazard ratio was 1.58 (1.06 to 2.36; P=0.024).

CONCLUSIONS: After 20 years of follow-up the rate of death from prostate cancer did not differ significantly between men in the screening group and those in the control group.

 

[Michael Scally MD]

Crosstalk Between The Androgen Receptor And The Liver X Receptor

Whilst cardiovascular disease has been the main focus for research into cholesterol regulation, there is now renewed interest in the relationship between cholesterol and prostate cancer (PCa). Epidemiological evidence associates PCa risk with high-fat diets and lipid accumulation, whilst taking cholesterol-lowering drugs (e.g., statins) correlates with reduced PCa risk. Studies at the cellular level have led to the general observation that the ageing prostate and PCa have elevated intracellular cholesterol levels. This could contribute to PCa development by providing a raw material for membrane synthesis, androgen production, and other signaling pathways.

Within the cell, cholesterol levels are regulated by uptake, synthesis, and efflux. A major homeostatic mechanism occurs at the transcriptional level, governed by the transcription factors sterol-regulatory element binding protein 2 (SREBP-2) and liver X receptor (LXR; NR1H2/NR1H3). SREBP-2 upregulates a suite of genes involved in cholesterol uptake (e.g., low-density lipoprotein receptor [LDLR]) and synthesis (e.g., HMG-CoA reductase [HMGCR]), promoting cholesterol accumulation. In contrast, as a heterodimer with the retinoid X receptor (RXR), LXR downregulates genes involved in cholesterol synthesis and increases those involved in efflux, such as the ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1). Combined with promoting the degradation of the LDLR, LXR thus prevents cholesterol accumulation. Consequently, it is possible that PCa cells have increased SREBP-2 activity and reduced LXR activity, thus leading to elevated cholesterol levels.

These researchers previously investigated cholesterol homeostasis in two PCa laboratory cell-lines, PC-3 and LNCaP, in the context of SREBP-2. Although SREBP-2 responded to altered cholesterol status in both cell-lines, PC-3 cells had higher basal SREBP-2 activity. Here, they began by further exploring how these cell-lines vary, and subsequently observed that a critical difference between these two cell-lines, namely androgen receptor (AR; NR3C4) activity, influences LXR. This adds another level of complexity to cholesterol regulation in a PCa setting, and given the role of the AR in both PCa development and treatment, this has implications for PCa therapy.


Krycer JR, Brown AJ. Crosstalk between the androgen receptor and the liver X receptor: Implications for cholesterol homeostasis. J Biol Chem. http://www.jbc.org/content/early/2011/04/13/jbc.M111.227082.full.pdf

High cholesterol levels are associated with prostate cancer development. Androgens promote cholesterol accumulation by activating the sterol-regulatory element binding protein isoform 2 (SREBP-2) transcription factor. However, SREBP-2 is in balance with the liver X receptor (LXR; NR1H2/NR1H3), a transcription factor that prevents cholesterol accumulation. Here, we show that LXR activity is downregulated by the androgen receptor (AR; NR3C4). In turn, this reduces LXR target gene expression. This antagonism on LXR is also exerted by other steroid hormone receptors, including the estrogen, glucocorticoid, and progesterone receptors. This suggests a generalizable mechanism, but the AR does not affect LXR mRNA levels, protein degradation, or DNA-binding. We also found that the AR does not require protein synthesis to influence LXR, suggesting a direct antagonism. However, the AR does not directly bind LXR. The AR N-terminal domain (involved in transactivation), but not its DNA-binding domain, was required to suppress LXR activity, suggesting coactivator competition.

Overall, this androgen-mediated antagonism of LXR complements SREBP-2 activation, providing a more complete picture as to how androgens increase cellular cholesterol levels in a prostate cancer setting. Given the crosstalk between other steroid hormone receptors and LXR, hormonal regulation of cholesterol via LXR may occur in a variety of cellular contexts.

 

[Michael Scally MD]

While it is acknowledged that PC is a multifactorial disease, no precise proven cause has been adduced. Although, an enviromental effect on the development of PC is assumed, an important, possibly predominant role is played by genetic predisposition. Differences between PC incidence and mortality in white and Afro-American men for example, testify to this (156 resp. 25 in white vs. 248 resp. 59 in Afro-American men /100 000 men).

Enviromental factors include animal fat, alcohol, history of vasectomy, smoking, obesity, statin and nonsteroid anti-inflammatory drug medication, vitamin D and E and mineral intake (calcium, selenium, zinc) and sexual activity. However, the conclusions of a large number of studies on these causative risk factors as either protective or detrimental differ. Androgens, estrogens, insulin, IGF (insulin-like growth factor) and other hormones lie on the borderline of enviromental and genetic factors – levels can vary according to individual genetic predisposition and external conditions (hormone substitution, obesity, comorbidities).

Generally, oncological disease is caused by multiple gene mutations occurring during cell senescence (due to physical, chemical or biological mutagens). These mutations happen at several levels simultaneously. Such changes are common in healthy cells and do not necessarily lead into malignant transformation. Only if the reparation processes are unable to eliminate the existing malignant cells, does unregulated growth and proliferation take place where among other processes, apoptosis is suppressed. If such cell change or damage occurs in a germ cell, the changed information is transferred onto descendants in a direct line. Apart from mutation theory, current emphasis is on stem cell theory as explanatory of the pathogenesis of a number of diseases and not only cancer.

Prostate cancers can be divided for practical purposes into three groups – hereditary, familial and sporadic. More than 85% of all prostate cancers are sporadic and only 10–15 per cent cancers are genetically determined. We are able to establish genetic factors with varying degrees of probability. In analysis of population studies, a higher incidence of PC was found in first line relatives. The appearance of a high risk disposition allele for PC is more frequent in men with cancers that were diagnosed at a younger age (43% of men younger than, 34% of men younger than 70 and 9% of men younger than 85). Sporadic prostate cancers occur in men with a negative family history. Familial PC affects two or more men in one family while true hereditary prostate cancers affect three or more men in one family in three subsequent generations or two men aged 55 or younger.


Kral M, Rosinska V, Student V, Grepl M, Hrabec M, Bouchal J. Genetic determinants of prostate cancer: a review. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2011;155(1):3-9. http://mefanet.upol.cz/BP/2011/1/3.pdf

Background. In prostate cancer, early detection and appropriate treatment remain key approaches. But given the constantly increasing incidence, prostate cancer ethiopathogenetic determinants are a current focus of attention. Although the development of this cancer is influenced by both environmental and genetic factors which are as yet ill-defined, genetic studies have revealed gene abnormalities which may be specifically associated with the risk of prostate cancer: changes in genes for the androgen receptor, RNAseL, ELAC2, MSR1, BRCA 1 and 2, HPCX, KLF6, HPC20 and fusion genes, e.g. TMPRSS2-ERG). Despite differing research results from molecular biological studies, these techniques can assist in earlier diagnosis enabling timely initiation of treatment.

Methods. Methods and literature: MEDLINE search was performed to collect both original and review articles addressing prostate cancer and genetic risk factors using key words genetics, prostate cancer and risk.

Conclusions. A number of potential genetic risk factors/markers has been identified which may in near future contribute to earlier diagnosis of prostate cancer so that earlier treatment can be started. Despite many promising data we have found differing results and therefore we suppose further research should be conducted to achieve more precise conclusion. This review focuses on current knowledge of the genetic factors affecting the development of prostate cancer.