PSA Screening Updates – Use of Nomograms.

 

Feeding on a fish in Venice, Florida; BJ Gabrielsen photo.

 

As you may have heard, in 2011, the U.S. Preventative Services Task Force (USPSTF) issued a controversial recommendation to no longer recommend prostate-specific antigen  (PSA) screening for healthy men under the age of 75.  The USPSTF’s recommendations often guide physicians in their decisions as well as impact what tests Medicare and private insurers will pay for. This recommendation evoked considerable response from the medical community.

The Johns Hopkins Hospital is consistently rated as the nation’s #1 urology department according to the annual survey published in U.S. News and World Report.  They published a response in the Jan. 3rd, 2012 issue of their Health Alerts entitled “Should You Have a PSA  Screening Test? Johns Hopkins Responds to Recent USPSTF Recommendations.” I encourage you to read the linked article. They concluded that targeted PSA screening focused on men with greater risk and active surveillance for those not requiring immediate treatment could shift the benefit / risk ratio toward greater benefit. Screening should not be discontinued but focused on reducing harm.

It is agreed that it would be desirable to limit the number of unnecessary prostate biopsies and their resulting side effects. To this end, the Johns Hopkins Health Alerts (December 22, 2011) discussed the use of nomograms to address problems with using specific PSA values to ascertain the need for a biopsy. A nomogram considers multiple weighted factors to calculate risk of having biopsy-detectable prostate cancer. These factors include race, age, PSA level, family history, digital rectal exams (DRE) and results of previous biopsies and whether one has previously taken finasteride (Proscar).

Another important factor which could be used to identify candidates for biopsies is PSA density (PSAD). In a recent article published Dec. 12, 2011 in Medical News Today (a recommended source of prostate cancer information), Dr. Martin Sanda of Harvard Medical School wrote that PSA screening could be improved to identify only aggressive cancer requiring treatment by adjusting various factors like prostate size (volume, density, PSAD), obesity and family history. In my own case in 1995, my PSA values at the time of cancer detection averaged around 4 ng/ml.  I had undergone a routine biopsy in 1994 which revealed no cancer but concluded that my prostate gland itself was not enlarged. I therefore reasoned that my smaller prostate gland seemed to be producing a more significant amount of PSA (4.0) than it might under normal conditions. Following up with a second biopsy in October, 1995, the presence of cancer was revealed. Therefore I was using the concept of “PSA density” (PSAD) without knowing about it medically.  In his article, Dr. Sanda also recommended nomograms to predict aggressive cancers and identify candidates for biopsies. The use of two specific urine genetic biomarkers, TMPRSS2:ERG and PCA3, (see Sept.21, 2011 post) was also mentioned in the article entitled “PSA Testing Combined with Other Relevant Patient Data Can Reduce Unnecessary Prostate Biopsies.” The article was also cited in the January 10th, 2012 issue of the ZeroHour Newsletter (from Zero-The Project to End Prostate Cancer).

Lastly, WebMD is an illustrated internet resource that covers many medical issues. One can however choose those areas of specific interest such as prostate cancer. On Jan. 24th, 2012, the WebMD-Cancer published an illustrated introductory primer dealing with prostate cancer. WebMD-prostate cancer should be added to the list of medical resources.

 

 

Opting to Track Early Prostate Cancer.

A December 20th article by Associated Press medical writer Lauran Neergaard illustrated the difference between “watchful waiting” and “active surveillance” for men diagnosed with early-stage prostate cancer. Most of the 240,000 cases of prostate cancer diagnosed annually in the United States are in the “low-risk” category. Yet 90% of these men seek immediate treatment and its accompanying risks. For many of these men, “active surveillance” under the care of a urologist may have been a wiser choice. “Active surveillance” is much more aggressive than “watchful waiting”. It involves getting regular scans, blood tests and biopsies to monitor the tumor closely enough such that curative treatments could be administered if needed before symptoms would be observed. Men are urged to seek out treatment centers where such “active surveillance” is practiced. A panel from the National Institutes of Health (NIH) stated that men whose PSA level is less than ten (10) and whose Gleason score is six (6) or less would be candidates for such surveillance. A collaboration between two large active surveillance programs at Johns Hopkins University and Cedars Sinai Medical Center with the Prostate Cancer Foundation has been instituted to educate men about “active surveillance.” The program is entitled the National Proactive Surveillance Network- at http://www.npsn.net. Shortly an interactive section will be added to the site to link men with doctors who offer “active surveillance” and to track how these men fare over time. This represents an individualized approach to treatment as opposed to a one-size-fits-all approach.

Update on Government Panel Recommendation to Discontinue PSA Screening.

As discussed in this website blog posted on October 15th, a government medical panel, the United States Preventive Services Task Force, recently recommended that routine PSA testing in healthy men under the age of 75 be discontinued unless they have symptoms that are highly suspicious for prostate cancer. The panel claimed that such routine screening did not result in the overall saving of lives but instead led to an increase of  potentially harmful side effects. This controversial recommendation has produced considerable comment. The Johns Hopkins Health Alerts  posted an excellent review of this issue in their October 26th edition. I recommend reading the Johns Hopkins review of the current situation and the government panel’s rationale for their recommendation. Johns Hopkins’ advice was as follows. “Many leading cancer and patient groups and doctors agree that there is harm with PSA screening and the treatment that follows diagnosis. But a more targeted screening approach focusing on those at greatest risk of developing prostate cancer and active surveillance for those who don’t need immediate treatment, could shift the balance of benefit and harm toward benefit. PSA screening is the best test available for the detection of cancer cells in the prostate. Rather than discontinuing use of the only test available to detect the disease early and treat it successfully, efforts should focus on reducing harm.”

In addition, the November 1st edition of the ZeroHour Newsletter from the Project to End Prostate Cancer, cited an article published on October 28th in U.S. News and World Report, disclosing the results of a survey of urologists and internal medicine specialists’ responses to the government recommendation. “Virtually all responding urologists and more than 60 percent of internal-medicine specialists rejected the recent proposal by a high-level government advisory committee to end routine PSA testing.” About 95 percent of the responding urologists felt that doctors should continue to advise men starting at age 50, when testing typically begins, to have PSA screenings as part of a routine physical exam, contrary to the task force’s recommendation. There was however agreement that too many patients are encouraged to seek radical prostatectomy or radiation treatments and too few are informed about “watchful waiting”, in which periodic PSA tests, frequent physical exams, and biopsies are used to track a tumor’s growth and decide when, if ever, to pursue aggressive treatment.

URGENT ACTION NEEDED! Government Proposes Elimination of Prostate Cancer Testing. Does PSA Screening for Prostate Cancer Save Lives?

The United States Preventive Services Task Force (USPSTF), an independent panel appointed by the Federal cabinet-level Department of Health and Human Services (DHHS), is preparing a recommendation which would eliminate prostate cancer testing (PSA) for all men. The rationale cited by the government panel is that there is moderate or high certainty that PSA testing has no net benefit or that its harms outweigh its benefits. (It should be noted that the panel did not include a urologist nor a medical oncologist.) The basic question involved in this recommendation is whether or not routine PSA testing saves men’s lives. Prostate cancer patients, survivors and advocates are being urged to voice their opinion about this recommendation to their Senators and members of Congress. Additionally, the USPSTF is accepting public comments on the new recommendations for the next four weeks. Links to communicate your opinions can be found in the October 7th and October 12th ZeroHour Newsletter from Zero-the Project to End Prostate Cancer.

Two major conflicting medical studies, one American and the other a European study, are being cited as evidence for/against this recommendation. These studies and their conclusions have been summarized by Dr. Patrick Walsh from the James Buchanan Brady Urological Institute – Johns Hopkins University on its website.  (It should be noted that this institute at Johns Hopkins has been named the #1 choice for urology for the last 21 years consecutively by the annual survey in U.S. News and World Report. Dr. Walsh pioneered the development of the surgical nerve-sparing techniques whereby nerves controlling erections and urination are spared from damage during radical prostatectomies.) The European study was carried out in seven European countries involving 162,000 men who were randomized to PSA screening every four years versus no screening. After fourteen years of follow-up, “there was a 20% decrease in deaths from prostate cancer in the group of men assigned to screening.” Further examination of the data leads to a conclusion that the decrease in prostate cancer deaths could be as high as 27%.  According to Dr. Walsh, “this reduction in death from prostate cancer is similar to the 30% reduction in mortality from breast cancer in women who undergo mammography and the 33% reduction in prostate cancer mortality that occurred in the United States between 1994 and 2003 following the introduction of PSA screening. Thus, the results from the European study support other findings and unequivocally demonstrate that PSA testing can save lives.” The second trial was carried out in the United States and was half the size of the European trial. “It compared screening with PSA every year for six years with no screening thereafter versus no planned screening. It showed no improvement in prostate cancer mortality at 7 years.” The reader is encouraged to review Dr. Walsh’s comments on these trials at the Brady Urological Institute website.  He concludes that “if you are a healthy man age 55-69 who does not want to die from prostate cancer, the European trial provides conclusive evidence that PSA testing can save your life.”

What could occur if PSA screening was less accessible? What would be the options for a middle-aged man? A physician and close friend commented as follows. There are no specific symptoms whatsoever of the early stages of prostate cancer. The signs of early prostate cancer are indistinguishable from the signs of benign prostatic enlargement that commonly occurs as we age–namely, a weak or intermittent urinary stream, hesitancy (difficulty starting the flow of urine), straining, dribbling, having to get up at night to urinate, and the need to strain during urination.  More serious signs–that increase the odds of a cancer being present–include blood in the urine and bone pain especially in the pelvis, ribs, or back.  Any of the symptoms mentioned above in a man over 40 years old should prompt a visit to a physician. If cancer were present, blood in the urine and bone pain would seem to indicate the disease had advanced considerably by this point if more routine PSA screening had not been available.

As with any treatment, there are both benefits and risks. In the pre-PSA era, approximately 80% of patients who were diagnosed with prostate cancer, were already in advanced stages of the disease with metastatic cancer. Today, the number of patients who are diagnosed with metastatic disease at the time of initial diagnosis is around 20%. In the past 15 years, the prostate cancer death rate has been reduced from 42,000 annually to 33,000. On the other hand, according to the Prostate Cancer Foundation’s NewsPulse, PSA screening leads to biopsies wherein less than half of the patients who are biopsied each year are subsequently diagnosed with cancer.  In addition, recent studies show that approximately 7% of men over 65 who have prostate biopsies are hospitalized within 30 days of the procedure, primarily due to infections according to the October 4th issue of the National Cancer Institute Bulletin.

Treating men over 70 aggressively for prostate cancer when instead their cancers might never become life-threatening is a practice that needs to be reduced. Instead, concentrating treatment on younger prostate cancer patients should be encouraged.

Personally, at the age of 54, my own cancer was discovered by a biopsy which was dictated by a moderately-consistent PSA of 4-5 ng/ml. I underwent a radical prostatectomy in 1995 at Johns Hopkins which resulted in virtually none of the side effects such as incontinence and impotence. This is indicative of the Johns Hopkins surgical nerve-sparing skills. (This website tells my entire story and lessons learned.)

There are more positive recommendations that could be made in the case of prostate cancer screening. PSA screening in patients should be more selectively targeted thus reducing over-testing and risks from over-treatment. Annual PSA screening may be better utilized as a baseline test and a series of tests over time to determine the rate of change of the PSA values with time (PSA velocity). Another useful test is prostate density, which refers to the PSA divided by the estimated weight of the prostate. A PSA of 5 ng/ml in a small prostate is more likely to indicate a cancer than a PSA of 8 ng/ml in a very large prostate. Also, through joint public-private research partnerships, government scientists such as those at the National Cancer Institute (NCI) of the National Institutes of Health (NIH) could focus stronger efforts on better early detection tests of lethal prostate cancers.  Above all, validated biomarkers that are prevalent in most prostate cancers and could be detectible in urine or blood tests are sorely needed in order to detect and determine the aggressiveness of prostate cancers.  For example, the DNA markers TMPRSS2:ERG gene fusion and PCA3 (prostate cancer antigen DNA) are expressed at high levels in 95 percent of prostate cancers.  The gene fusion TMPRSS2:ERG occurs in 50 percent of prostate cancer patients. This two-gene DNA urine test is ultra-specific to prostate cancer and prostate cancer only.

Thank you for reading this most urgent blog. Please express your opinions on PSA screening to your senators and congressional representatives as well as to the USPSTF government panel.

Variations in Five Genes May Identify Lethal Varieties of Prostate Cancer.

Danger lurks in southwest Florida; bj gabrielsen photo

For years, the general practice used in the initial screening for prostate cancer is a blood test for prostate-specific antigen (PSA) in conjunction with a digital rectal examination. These tests are then used to determine whether or not to subject the patient to a prostate biopsy, inherent with its own side effects and hopefully negative results. If the biopsy reveals cancer, then the questions of whether or not to treat the cancer, what treatment(s) would be most effective while minimizing potential side effects, and the possibility of no treatment or “watchful waiting” must be addressed. It would be extremely useful if a blood or urine test could identify genetic biomarkers (genes and their products such as proteins) whereby physicians could determine not only the presence or absence of prostate cancer but be able to predict whether or not the cancer would require treatment and if so, should aggressive treatment be necessary. For the many cases of prostate cancer which are identified, ‘no one size of treatment fits all.’ Methods are sorely needed to determine the appropriate level of treatment, if any.

More than 25 genetic subtypes of prostate cancer have been already identified. Some of these cancers might never require treatment and a man could die of other causes while other cancers require immediate, aggressive treatment. A team of researchers from Seattle and Sweden have recently identified a set of variations in five (5) genes which may be signatures for lethal prostate cancer thereby requiring aggressive treatment. These genetic variants might serve as the basis for a new blood test that could be given on initial diagnosis in order to determine which patients need aggressive treatment versus “watchful waiting.” To discover the five “disease genes” implicated in lethal prostate cancers, researchers looked for genetic variants that prostate cancer patients share in common. These variants in genes are called single-nucleotide polymorphisms, or SNPs (pronounced “snips”). Genes can be depicted as chains of thousands of beads comprised of four-five basic colors all arranged in a specific sequence. An example of a SNP would be the substitution of one blue bead in a gene by a red bead at a specific location along the chain of thousands of colored beads. These inherited genetic variants are certain genes that may signal the development of fatal varieties of prostate cancer. The five SNPs that were identified were linked to five genes that may affect prostate cancer progression, namely LEPR, RNASEL, IL4, CRY1, and ARVCF.  It was of special interest to note that two of the five genes studied (IL4 and RNASEL) were associated with inflammation of the prostate, thereby suggesting a possible link between chronic inflammation of the prostate and the triggering of prostate cancer. The state of this research requires much more validation and development before it could be used as a diagostic test for aggressive prostate cancer. But it is a significant finding and indicative of the type of biomarker which would eventually relieve the uncertainties associated with PSA tests.

The research findings were published in the September issue of Cancer Epidemiology, Biomarkers and Prevention, and summarized in the September 2011 issue of NewsPulse from the Prostate Cancer Foundation.

Bone Scans for Metastatic Prostate Cancer

Sanibel, FL; photo BJ Gabrielsen

The most troubling thought for prostate cancer patients whose cancer has recurred after an initial radicalprostatectomy is the fact that there are PSA-producing cells located somewhere in our bodies. While subsequent treatments such as androgen deprivation (hormonal) therapy may keep these cells under control, there are undoubtedly micro-metastases somewhere in our bodies. When the controlling therapies are discontinued, the cells begin to multiply and PSA rises. Bone scans are generally prescribed to identify sites of metastases. The scans involve the injection of a small amount of a radioactive element, technetium-99 (as technetium Tc 99m medronate). Greater than 90% of the mild radiation produced is eliminated from the body in 24 hours. It is generally accepted that technetium Tc 99m medronate is deposited on the surface of hydroxyapatite crystals, a mineral form of calcium, which comprises up to 50% of bone. Rapidly dividing tumor cells require enhanced blood flow (a process called angiogenesis) in order to grow.  Enhanced blood flow and / or blood concentration is most important in the delivery of the technetium-99 reagent to sites of uptake. Therefore, actively dividing cancer cells in bone would be specifically targeted. In addition to areas of abnormal osteogenesis (bone formation) such as those that occur with metastatic bone disease, other non-cancerous conditions such as Paget’s disease, arthritic disease, osteomyelitis (bone infection), and fractures can also be identified in a bone scan. Bone scans may not always be recommended as long as a patient’s PSA levels are not increasing. In my own case, even though my PSA had remained at very low or at undetectable levels, my Johns Hopkins urologist recommended a bone scan since I had not had one in seven years. His rationale was that even though the likelihood of seeing bone metastases is small, nonetheless, the disease can progress on hormonal deprivation therapy even if the PSA is low. Small quiet progression, if it is found, is something to be noted and followed. Thank God, my bone scan showed no evidence of metastatic cancer but it “lit up like a Christmas tree” since it revealed areas of formerly-broken bones (ankle, wrist, ribs) and arthritis in my lower spine and right hip which had been replaced in 1991. Physicians may differ in their prescriptions for bone scans. Therefore this website commentary is for information purposes only and should be utilized only after discussion with your personal health care provider.  Since this blog was initially written, an excellent review article entitled “Imaging Studies for Prostate Cancer: What to Expect” was published in the October 20th, 2011 edition of the Johns Hopkins Prostate Disorders Health Alert. The article goes into more detail about when bone scans should be prescribed, ProstaScint scans for metastases to lymph nodes or small organs and the uses of computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) scans.

NewsPulse, a Medical Resource from the Prostate Cancer Foundation. Biomarkers in Urine for the Detection of Prostate Cancer.

Sources of current medical information concerning prostate cancer are listed on this website under the section Medical Resources.  Recently, a new August 2011 electronic newsletter entitled NewsPulse was received from the Prostate Cancer Foundation. The issue contained very current information on specific diagnostic methods, biomarkers for cancer detection, targeted therapies and drugs under development, nutrition and genetics. One example follows below. Their e mail address is info@pcf.org. I would strongly recommend a subscription.

Biomarkers in Urine for the Detection of Prostate Cancer.

Biomarkers are usually genes, gene products or proteins and are found in various body fluids (blood, urine, cerebrospinal fluid). Their presence, absence and quantities are measured and used to diagnose various diseases and their stages. An example is prostate-specific antigen or PSA used to detect prostate conditions. The availability of an easy-to-use urine test that is specific in identifying the presence of cancer has the potential to eliminate thousands of unnecessary prostate biopsies in the U.S. each year. Thus the benefits of such biomarker tests below include identifying which patients actually require biopsies.

The June 1st, 2011 issue of the Johns Hopkins Health Alerts and the August issue of NewsPulse both describe two new biomarkers found in urine which may potentially be useful in detecting prostate cancer as opposed to other non-cancerous prostate conditions such as BPH (benign prostatic hyperplasia or enlarged prostate). The two specific biomarkers are: a) prostate cancer antigen or PCA3, which is expressed at high levels in 95 percent of prostate cancer patients; and, b) the DNA marker TMPRSS2:ERG gene fusion, a hybrid gene made from two previously separate genes, specifically the ERG and TMPRSS2 genes. This DNA marker is present in 50 percent of prostate cancer patients. The presence of this gene fusion is “thought to promote the development of prostate cancer and possibly a more aggressive form of the disease.”

PCA3 is made by a specific gene that produces the protein in 60-100 times more abundance in prostate cancer cells as compared to non-cancerous ones. According to Johns Hopkins, in order to be most predictive, the test for PCA3 should be done in conjunction with a digital rectal examination. PCA3 testing would not replace the usual PSA blood test but would help to either confirm or rule out the prospect of cancer in men with elevated PSA levels.

Patients with high levels of these biomarkers have been shown to have a 70 percent chance of having cancer with a 40 percent of it being a high grade cancer. There is also an association between test results and the size of the tumor in patients who do have cancer. It will take some time before the combined urine-based assay is widely introduced into practice. However, NewsPulse reports that the “University of Michigan has been offering the PCA3 test alone since earlier this year. They expect to be offering it in combination with TMPRSS2:ERG by the end of this year under a license agreement with GenProbe. Another trial using the combined assay will soon be conducted in cooperation with the Early Detection Research Network (EDRN). EDRN, an initiative of the National Cancer Institute (NCI), brings together dozens of institutions to help accelerate the translation of biomarker information into clinical applications and to evaluate new ways of testing cancer in its earliest stages and for cancer risk.”

“Once the University of Michigan begins offering the combined TMPRSS2:ERG/PCA3 test, physicians can send urine samples for analysis until the combined test is more widely available. For more information on this, men with questions about prostate cancer screening should speak to their doctors or call the U-M Cancer AnswerLine at 800-865-1125.”

As previously stated, the contents of this website are intended solely for information and encouragement. All medical decisions and actions should be made in consultation with a physician or appropriate medical personnel.

PSA Velocity Does not Improve Prostate Cancer Detection

One of the major issues for men who are being screened for prostate cancer is whether or not to undergo a prostate needle biopsy. Factors considered in the standard risk model include prostate-specific antigen (PSA) level, digital rectal examination result, age, family history of prostate cancer and history of any prior prostate biopsies. The rate of change in PSA levels with time, referred to as PSA velocity, has also been used as one criterion for determining the need for a prostate biopsy. Clinical recommendations from two organizations, the National Comprehensive Cancer Network (NCCN) and the American Urology Association (AUA), suggest that men with a PSA velocity that exceeds a certain threshold value (0.35 ng/ml per year) should consider having a needle biopsy, even if their overall PSA levels are below the standard cutoff for the procedure and they have a normal result on a digital rectal examination. However, a recent study published online February 24 in the Journal of the National Cancer Institute concluded that a rapid increase in prostate-specific antigen (PSA) levels is not grounds for automatically recommending a prostate biopsy. This study was also summarized in the March 8th, 2011 issue of the National Cancer Institute (NCI) Cancer Bulletin. Researchers looked at whether a PSA velocity above the 0.35 ng/ml per year threshold—when added to a standard risk model that includes age, PSA level, DRE result, family history of prostate cancer, and history of a prior prostate biopsy—improved the model’s predictive accuracy. The authors concluded that “in all cases, the addition of PSA velocity yielded only a slight difference in the risk model’s predictive accuracy. In fact, the analysis indicated that lowering the PSA threshold for a biopsy from 4.0 ng/ml to 2.5 ng/ml would be a more effective means of directing prostate biopsies.”

As always, the content of this website is intended for information use only. All personal medical decisions and actions should be made only after consultation with established medical professionals.