Prostate Cancer

The debate over whether to have  prostate check or not goes on. Here I present some of the arguments men should consider before having a PSA (prostate test).

Ann Intern Med. 2012 Jul 17;157(2):120-34.

Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement.

Abstract

DESCRIPTION:

Update of the 2008 U.S. Preventive Services Task Force (USPSTF) recommendation statement on screening for prostate cancer.

METHODS:

The USPSTF reviewed new evidence on the benefits and harms of prostate-specific antigen (PSA)-based screening for prostate cancer, as well as the benefits and harms of treatment of localized prostate cancer.

RECOMMENDATION:

The USPSTF recommends against PSA-based screening for prostate cancer (grade D recommendation).This recommendation applies to men in the general U.S. population, regardless of age. This recommendation does not include the use of the PSA test for surveillance after diagnosis or treatment of prostate cancer; the use of the PSA test for this indication is outside the scope of the USPSTF.

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More harm than good: rethinking routine prostate cancer screening

My offer for a public debate was accepted after I co-published opposing viewpoints about the high rates of over-diagnosis and over-treatment of early stage prostate cancer with leading urologist Professor Tony Costello in a Melbourne newspaper last year. The debate took place at a Melbourne conference…

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A diagnosis of early prostate cancer may end up doing more harm than good. Medical Office picture from Shutterstock

My offer for a public debate was accepted after I co-published opposing viewpoints about the high rates of over-diagnosis and over-treatment of early stage prostate cancer with leading urologist Professor Tony Costello in a Melbourne newspaper last year.

The debate took place at a Melbourne conference on prostate cancer last week. It received wide coverage in newspapers – here, here and here, television radio, and online. All of this is useful and important because it helps stimulate the very important debate about widespread PSA screening.

Prostate specific antigen (PSA) is an enzyme secreted in large amounts by normal as well as cancerous prostate cells. Only small amounts of PSA leak into circulation from a normal prostate, but this increases with any prostatic disease, benign or malignant.

PSA concentration is expressed as a number and its discovery in 1983 led to it being used as a screening blood test for early prostate cancer. A level below four is considered normal and men with abnormal results are usually sent for biopsies. It has been widely performed in Australian men for over ten years as part of a general health check but its ability to save lives is now being assessed and tested.

Ideal health

For years now, family physicians, the Urological Society of Australia and New Zealand and spokespeople for treatment advocacy groups, such as the Prostate Cancer Foundation of Australia have been telling men to have blood tests with a PSA as part of their regular health check up because early diagnosis may save their life.

The constant message is that men need to look closely for any signs of early prostate cancer by having a PSA and a digital rectal examination. This is because, up until recently, our belief and practice was that if the PSA was high, the patient should be referred to a urologist for a transrectal biopsy (a large and very unpleasant needle, inserted under local anaesthetic through the wall of the rectum up to 24 times, just above the anus). And if this biopsy showed prostate cancer, the man would usually be offered immediate radical treatment with surgery or radiation to cure the cancer.

But we’ve long known that prostate cancer is a disease that men can harbour for most of their lives without knowing. It is very commonly found during postmortem (even in very young men). We also now know that PSA is highly unreliable as a predictor of cancer.

False results and consequences

A major prospective prostate cancer trial actually found cancer in 15% of men with normal direct rectal examination results and PSA of less than the “normal” concentration of four (considered as the cut-off between “normal” and “abnormal”). It also found cancer in 25% of the participants with levels between three and four. This is similar to the rate of 25% of biopsies showing prostate cancers in men with so-called abnormal PSA. So you have an almost equal chance of having cancer found irrespective if your PSA is normal or abnormal!

Indeed, the false-positive and false-negative rates of PSA alone make it a useless screening test. Our current rate of PSA testing uptake threatens to diagnose up to 60,000 men a year in Australia, 25 times the number destined to die from it.

Prostate cancer appears to be two diseases, an uncommon one that can kill you (at an average age of 81 years) and a very common one that poses no risks. Even though prostate cancer is a leading cause of male mortality in Australia (with over 2000 deaths a year), it’s never been known whether radical treatment of early stage disease can alter the natural history of those cancers biologically destined to kill the patient or whether it only “cures” those cancers destined to remain indolent for many decades and not affect lifespan.

Man should be asked to provide informed consent for PSA tests. Man choosing his way from http://www.shutterstock.com

Some believe that the term “early stage prostate cancer” is misleading and a misnomer for most men, similar to the condition called chronic lymphocytic leukaemia, which sounds frightening but is usually a very indolent disease that lies dormant for decades and rarely ever needs treatment.

All harm, no help?

Recent evidence from several high-quality prospectively randomised clinical trials have shown two stunning results. The first two (here and here) showed that regular screening with PSA and treatment of detected cancers produces no overall survival benefit for the treated group, and only a tiny reduction in deaths due to prostate cancer. The third showed that radical treatment with surgery or radiation therapy provides no benefit for the vast majority of men who have been treated this way and causes very serious and long-lasting side-effects.

PSA screening of the male Australian population probably doesn’t save any lives at all, but leads to a lot of over-diagnosis of a condition called early prostate cancer that will not shorten the lives of the overwhelming majority of men. This creates serious harms, including toxicities from unnecessary and radical treatments and imposes vast financial and manpower costs on our health system.

The harms come from the transrectal biopsies (pain, infection and haemorrhage), and initial radical treatments. Then, there are penile implants and drugs to treat sexual impotence resulting from treatment and the cost of urethral sphincters (around $20,000 for every initial insertion and then replacement). Add to this the time of physiotherapists and nurses for urinary incontinence and the psychologists for the depression and associated relationship stresses.

Time to change

Following an extensive and detailed review of all the literature, an expert team from the US Preventative Services Taskforce has very recently issued the lowest possible recommendation for PSA screening because it’s highly likely that its harms significantly outweigh its benefits. And the test has been called a public health disaster by Dr Richard Ablin, who invented it. I clearly concur with him.

It’s time for family physicians to stop doing routine screening PSA tests of Australian men unless patients decide to proceed after being told about the latest research and indicate they understand the potential benefits and harms. Indeed, they should be asked to provide informed consent.

For those diagnosed with early prostate cancer, immediate and radical treatment is unnecessary for the vast majority and active surveillance or watchful waiting should be recommended. It’s now reasonable and preferable that all men be offered a second opinion before proceeding to radical treatment for early stage prostate cancer.

As with all advances in medical treatment over the last 350 years, we depend on constant clinical research comparing what we currently do with what we hope may be better by some measurable parameter. When the evidence changes, we must all revise our beliefs and practices.

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National Cancer Institute Fact Sheet

Prostate-Specific Antigen (PSA) Test

Key Points

  • Prostate-specific antigen (PSA) is a protein produced by cells of the prostate gland. The PSA test measures the level of PSA in the blood.
  • The U.S. Food and Drug Administration (FDA) has approved the use of the PSA test along with a digital rectal exam to help detect prostate cancer in men age 50 and older. The FDA has also approved the PSA test to monitor patients with a history of prostate cancer to see if the cancer has recurred (come back).
  • Doctors’ recommendations for PSA screening vary.
  • The higher a man’s PSA level, the more likely it is that cancer is present, but there are other possible reasons for an elevated PSA level.
  • Doctors take several factors into account for men who have a rising PSA level after treatment for prostate cancer.
  • The PSA test for screening has limitations and is still controversial.
  • Researchers are studying ways to validate and improve the PSA test and to find other ways of detecting prostate cancer early.
  1. What is the prostate-specific antigen (PSA) test?Prostate-specific antigen (PSA) is a protein produced by cells of the prostate gland. The PSA test measures the level of PSA in the blood. The doctor takes a blood sample, and the amount of PSA is measured in a laboratory. Because PSA is produced by the body and can be used to detect disease, it is sometimes called a biological marker or a tumor marker.It is normal for men to have a low level of PSA in their blood; however, prostate cancer or benign (not cancerous) conditions can increase a man’s PSA level. As men age, both benign prostate conditions and prostate cancer become more common. The most frequent benign prostate conditions are prostatitis (inflammation of the prostate) and benign prostatic hyperplasia (BPH) (enlargement of the prostate). There is no evidence that prostatitis or BPH causes cancer, but it is possible for a man to have one or both of these conditions and to develop prostate cancer as well.A man’s PSA level alone does not give doctors enough information to distinguish between benign prostate conditions and cancer. However, the doctor will take the result of the PSA test into account when deciding whether to check further for signs of prostate cancer.
  2. Why is the PSA test performed?The U.S. Food and Drug Administration (FDA) has approved the use of the PSA test along with a digital rectal exam (DRE) to help detect prostate cancer in men 50 years of age or older. During a DRE, a doctor inserts a gloved finger into the rectum and feels the prostate gland through the rectal wall to check for bumps or abnormal areas. Doctors often use the PSA test and DRE as prostate cancer screening tests; together, these tests can help doctors detect prostate cancer in men who have no symptomsof the disease.The FDA has also approved the use of the PSA test to monitor patients who have a history of prostate cancer to see if the cancer has recurred (come back). If a man’s PSA level begins to rise, it may be the first sign of recurrence. Such a “biochemical relapse” typically precedes clinical signs and symptoms of a relapse by months or years. However, a single elevated PSA measurement in a patient with a history of prostate cancer does not always mean the cancer has come back. A man who has been treated for prostate cancer should discuss an elevated PSA level with his doctor. The doctor may recommend repeating the PSA test or performing other tests to check for evidence of a recurrence. The doctor may look for a trend of rising PSA measurements over time rather than a single elevated PSA level.It is important to note that a man who is receiving hormone therapy for prostate cancer may have a low PSA level during, or immediately after, treatment. The low level may not be a true measure of the man’s PSA level. Men receiving hormone therapy should talk with their doctor, who may advise them to wait a few months after hormone treatment before having a PSA test.
  3. For whom might a PSA screening test be recommended?Doctors’ recommendations for screening vary. Some encourage yearly screening for men over age 50, and some advise men who are at a higher risk for prostate cancer to begin screening at age 40 or 45. Others caution against routine screening. Although specific recommendations regarding PSA screening vary, there is general agreement that men should be informed about the potential risks and benefits of PSA screening before being tested. Currently, Medicare provides coverage for an annual PSA test for all men age 50 and older.Several risk factors increase a man’s chances of developing prostate cancer. These factors may be taken into consideration when a doctor recommends screening. Age is the most common risk factor, with nearly 63 percent of prostate cancer cases occurring in men age 65 and older (1). Other risk factors for prostate cancer include family history, race, and possibly diet. Men who have a father or brother with prostate cancer have a greater chance of developing prostate cancer. African American men have the highest rate of prostate cancer, while Asian and Native American men have the lowest rates. In addition, there is some evidence that a diet higher in fat, especially animal fat, may increase the risk of prostate cancer.
  4. How are PSA test results reported?PSA test results show the level of PSA detected in the blood. These results are usually reported as nanograms of PSA per milliliter (ng/mL) of blood. In the past, most doctors considered a PSA level below 4.0 ng/mL as normal. In one large study, however, prostate cancer was diagnosed in 15.2 percent of men with a PSA level at or below 4.0 ng/mL (2). Fifteen percent of these men, or approximately 2.3 percent overall, had high-grade cancers (2). In another study, 25 to 35 percent of men who had a PSA level between 4.1 and 9.9 ng/mL and who underwent a prostate biopsy were found to have prostate cancer, meaning that 65 to 75 percent of the remaining men did not have prostate cancer (3).Thus, there is no specific normal or abnormal PSA level. In addition, various factors, such as inflammation (e.g., prostatitis), can cause a man’s PSA level to fluctuate. It is also common for PSA values to vary somewhat from laboratory to laboratory. Consequently, one abnormal PSA test result does not necessarily indicate the need for a prostate biopsy. In general, however, the higher a man’s PSA level, the more likely it is that cancer is present. Furthermore, if a man’s PSA level continues to rise over time, other tests may be needed.Because PSA levels tend to increase with age, the use of age-specific PSA reference ranges has been suggested as a way of increasing the accuracy of PSA tests. However, age-specific reference ranges have not been generally favored because their use may lead to missing or delaying the detection of prostate cancer in as many as 20 percent of men in their 60s and 60 percent of men in their 70s. Another complicating factor is that studies to establish the normal range of PSA values have been conducted primarily in white men. Although expert opinions vary, there is no clear consensus on the optimal PSA threshold for recommending a prostate biopsy for men of any racial or ethnic group.
  5. What if the screening test results show an elevated PSA level?A man should discuss an elevated PSA test result with his doctor. There can be different reasons for an elevated PSA level, including prostate cancer, benign prostate enlargement, inflammation, infection, age, and race.If no symptoms to suggest cancer are present, the doctor may recommend repeating DRE and PSA tests regularly to watch for any changes. If a man’s PSA level has been increasing or if a suspicious lump is detected during a DRE, the doctor may recommend other tests to determine if there is cancer or another problem in the prostate. A urine test may be used to detect a urinary tract infection or blood in the urine. The doctor may recommend imaging tests, such as a transrectal ultrasound (a test in which high-frequency sound waves are used to obtain images of the rectum and nearby structures, including the prostate), x-rays, or cystoscopy (a procedure in which a doctor looks into the urethra and the bladder through a thin, lighted tube that is inserted through the end of the penis; this can help determine whether urinary blockage is caused by an enlarged prostate). Medicine or surgerymay be recommended if the problem is BPH or an infection.If cancer is suspected, a biopsy is needed to determine whether cancer is present in the prostate. During a biopsy, samples of prostate tissue are removed, usually with a needle, and viewed under a microscope. The doctor may use ultrasound to view the prostate during the biopsy, but ultrasound cannot be used alone to tell if cancer is present.
  6. What if the test results show a rising PSA level after treatment for prostate cancer?A man should discuss rising PSA test results with his doctor. Doctors consider a number of factors before recommending further treatment. Additional treatment based on a single PSA test result is often not recommended. Rather, a rising trend in PSA test results over a period of time combined with other findings, such as an abnormal DRE, positive prostate biopsy results, or abnormal CT (computed tomography) scan results, may lead to a recommendation for further treatment.According to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Prostate Cancer (4), additional treatment may be indicated based on the following PSA test results:
    • For men who have been in the watchful waiting phase—their PSA level has doubled in fewer than 3 years or they have a PSA velocity (change in PSA level over time) of greater than 0.75 ng/mL per year, or they have a prostate biopsy showing evidence of worsening cancer (4).
    • For men who have had a radical prostatectomy (removal of the prostate gland)—their PSA level does not fall below the limits of detection after surgery or they have a detectable PSA level (> 0.3 ng/mL) that increases on two or more subsequent measurements after having no detectable PSA (4).
    • For men who have had other initial therapy, such as radiation therapy with or without hormonal therapy—their PSA level has risen by 2 ng/mL or more after having no detectable PSA or a very low PSA level (4).

    Please note that these are general guidelines. Prostate cancer is a complex disease and many variables need to be considered by each patient and his doctor.

  7. What are some of the limitations of the PSA test?
    • Detecting tumors does not always mean saving lives: When used in screening, the PSA test can detect small tumors. However, finding a small tumor does not necessarily reduce a man’s chances of dying from prostate cancer. PSA testing may identify very slow-growing tumors that are unlikely to threaten a man’s life. Also, PSA testing may not help a man with a fast-growing or aggressive cancer that has already spread to other parts of his body before being detected.
    • False-positive tests: False-positive test results (also called false positives) occur when the PSA level is elevated but no cancer is actually present. False positives may lead to additional medical procedures that have potential risks and significant financial costs and can create anxiety for the patient and his family. Most men with an elevated PSA test result turn out not to have cancer; only 25 to 35 percent of men who have a biopsy due to an elevated PSA level actually have prostate cancer (3).
    • False-negative tests: False-negative test results (also called false negatives) occur when the PSA level is in the normal range even though prostate cancer is actually present. Most prostate cancers are slow-growing and may exist for decades before they are large enough to cause symptoms. Subsequent PSA tests may indicate a problem before the disease progresses significantly.
  8. Why is the PSA test controversial in screening?Using the PSA test to screen men for prostate cancer is controversial because it is not yet known for certain whether this test actually saves lives. Moreover, it is not clear that the benefits of PSA screening outweigh the risks of follow-up diagnostic tests and cancer treatments. For example, the PSA test may detect small cancers that would never become life threatening. This situation, called overdiagnosis, puts men at risk of complicationsfrom unnecessary treatment.The procedure used to diagnose prostate cancer (prostate biopsy) may cause harmful side effects, including bleeding and infection. Prostate cancer treatments, such as surgery and radiation therapy, may cause incontinence (inability to control urine flow), erectile dysfunction (erections inadequate for intercourse), and other complications. For these reasons, it is important that the benefits and risks of diagnostic procedures and treatment be taken into account when considering whether to undertake prostate cancer screening.
  9. What research is being done to validate and improve the PSA test?The benefits of screening for prostate cancer are still being studied. The National Cancer Institute (NCI), a component of the National Institutes of Health, is currently conducting the Prostate, Lung, Colorectal, and Ovarian CancerScreening Trial, or PLCO trial, to determine whether certain screening tests can help reduce the number of deaths from these cancers. The PSA test and DRE are being evaluated to determine whether yearly screening to detect prostate cancer will decrease a man’s chances of dying from this disease.Initial results from the trial showed that annual PSA testing for 6 years and annual DRE testing for 4 years (performed in the same years as the first four PSA tests) did not reduce the number of deaths from prostate cancer through a median follow-up period of 11.5 years (range 7.2 to 14.8 years) (5). At 7 years of follow-up, a point in time when follow-up of the participants was essentially complete, 23 percent more cancers had been diagnosed in the screening group than in the control group. In the control group, men were randomly assigned to “usual care.”These results suggest that many men were diagnosed with, and treated for, cancers that would not have been detected in their lifetime without screening and, as a consequence, were exposed to the potential harms of unnecessary treatments, such as surgery and radiation therapy. Nevertheless, it remains possible that a small benefit from the earlier detection of these “excess” cancers could emerge with longer follow-up. Follow-up of the PLCO participants will continue, therefore, until all participants have been followed for at least 13 years.In contrast, initial results from another large randomized, controlled trial of prostate cancer screening, called the European Randomized Study of Screening for Prostate Cancer (ERSPC), found a 20 percent reduction in prostate cancer deaths associated with PSA testing every 4 years (6). At the time the results were reported, the participants had been followed for a median of 9 years. The average number of PSA tests per participant in ERSPC was 2.1. Most participating centers in this study used a lower PSA cutoff value as an indicator of abnormality than was used in the PLCO trial (3.0 ng/mL versus 4.0 ng/mL). As in the PLCO trial, many more cancers were diagnosed in the screening group than in the control group. The ERSPC researchers estimated that 1,410 men would have to be screened and 48 additional cancers would have to be detected to prevent one death from prostate cancer (6).Scientists are also researching ways to improve the PSA test, hopefully to allow cancerous and benign conditions, as well as slow-growing cancers and fast-growing, potentially lethal cancers, to be distinguished from one another. Some of the methods being studied include the following:
    • PSA velocity: PSA velocity is the change in PSA level over time. A sharp rise in the PSA level raises the suspicion of cancer and may indicate a fast-growing cancer. A 2006 study found that men who had a PSA velocity above 0.35 ng/mL per year had a higher relative risk of dying from prostate cancer than men who had a PSA velocity less than 0.35 ng/mL per year (7). More studies are needed to determine if a high PSA velocity more accurately detects prostate cancer early.
    • PSA density: PSA density considers the relationship between the level of PSA and the size of the prostate. In other words, an elevated PSA level might not arouse suspicion if a man has a very enlarged prostate. The use of PSA density to interpret PSA results is controversial because cancer might be overlooked in a man with an enlarged prostate.
    • Free versus attached PSA: PSA circulates in the blood in two forms: Free or attached to a protein molecule. The free PSA test is more often used for men who have higher PSA values. Free PSA may help tell what kind of prostate problem a man has. With benign prostate conditions (such as BPH), there is more free PSA, while cancer produces more of the attached form. If a man’s attached PSA level is high but his free PSA level is not, the presence of cancer is more likely. In this case, more testing, such as a prostate biopsy, may be done. Researchers are exploring additional ways of measuring PSA and comparing these measurements to determine whether cancer is present.
    • Alteration of PSA cutoff level: Some researchers have suggested lowering the cutoff levels used to determine whether a PSA measurement is normal or elevated. For example, a number of studies have used cutoff levels of 2.5 or 3.0 ng/mL (rather than 4.0 ng/mL). In such studies, PSA measurements above 2.5 or 3.0 ng/mL are considered elevated. Researchers hope that using these lower cutoff levels will increase the chance of detecting prostate cancer; however, this method may also increase overdiagnosis and false-positive test results and lead to unnecessary medical procedures. (See ERSPC trial results above.)
  10. What other methods are being studied to detect prostate cancer?Researchers are investigating several other ways to detect prostate cancer that could be used alone or together with the PSA test and DRE. Some of these include the following:
    • MicroRNA patterns: MicroRNAs are small, single-strand molecules of ribonucleic acid (RNA) that regulate important cellular functions. Researchers have found that the pattern of microRNAs in a cell can differ depending on the type of cell and between healthy cells and abnormal cells, such as cancer cells. Some research also suggests that the microRNA patterns in early-stage prostate cancer and late-stage prostate cancer may be different.
    • Non-mutation gene alterations: The activity of a gene can be altered in ways that do not involve a change (mutation) to its DNA code. This can occur by modifying the gene’s DNA through a process known as methylation or by modifying the proteins that bind to the gene and help control how it is configured in the chromosome on which it is located. These types of gene alterations are called epigenetic alterations. Research has already shown that certain genes become hypermethylated and inactivated during the development and progression of prostate cancer. Scientists hope to identify DNA methylation changes and protein modifications that will be able to identify prostate cancer early and help predict tumor behavior.
    • Gene fusions: Sometimes genes on different chromosomes can come together inappropriately and fuse to form hybrid genes. These hybrid genes have been found in several types of cancer, including prostate cancer, and may play a role in cancer development. The gene fusions found in prostate cancer involve members of the ETS family of oncogenes, which are genes that cause cancer when mutated or expressed at higher than normal levels. Researchers are investigating whether diagnostic or prognostic tests based on gene fusions can be developed.
    • PCA3: PCA3, also known as DD3, is a prostate-specific RNA that is reported to be expressed at high levels in prostate tumor cells. It does not appear to contain the genetic code for a protein. A urine test for this RNA, to be used in addition to current prostate cancer screening tests, has the potential to be useful and is under study.
    • Differential detection of metabolites: Molecules produced by the body’s metabolic processes, or metabolites, may be able to help distinguish between benign prostate tissue, localized prostate cancer, and metastatic prostate cancer. One such molecule, known as sarcosine, has been identified and may be associated with prostate cancer’s invasiveness and aggressiveness. Ongoing research is investigating whether a test based on sarcosine can be developed.
    • Proteo-imaging: Proteo-imaging is the ability to localize and follow changes at the molecular level, through imaging, of the protein distributions in specific tissues. Being able to see different patterns of protein expression in healthy prostate tissue versus abnormal prostate tissue may help classify early prostate changes that may one day lead to cancer.
    • Protein patterns in the blood: Researchers are also studying patterns of proteins in the blood to see if they can identify one or more unique patterns that indicate the presence of prostate cancer and allow more aggressive cancers to be distinguished from less aggressive ones.
Selected References
  1. Ries LAG, Melbert D, and Krapcho M, et al. SEER Cancer Statistics Review, 1975–2005. Bethesda, MD: National Cancer Institute, 2008. Available online at http://seer.cancer.gov/csr/1975_2005/index.html. Last accessed March 18, 2009.
  2. Thompson IM, Pauler DK, Goodman PJ, et al. Prevalence of prostate cancer among men with a prostate-specific antigen level < or = 4.0 ng per milliliter. New England Journal of Medicine 2004; 350(22):2239–2246.
  3. Smith DS, Humphrey PA, Catalona WJ. The early detection of prostate carcinoma with prostate specific antigen: The Washington University experience. Cancer 1997; 80(9):1853–1856.
  4. National Comprehensive Cancer Network (2009). NCCN Clinical Practice Guidelines in Oncology™: Prostate Cancer v.2.2009. Retrieved March 18, 2009, from http://www.nccn.org/professionals/physician_gls/PDF/prostate.pdf Exit Disclaimer.
  5. Andriole G, Crawford E, Grubb R, et al. Seven year mortality results and related findings from the prostate component of the PLCO randomized cancer screening trial. New England Journal of Medicine. Published online ahead of print March 18, 2009.
  6. Schröder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized European study. New England Journal of Medicine 2009; 360(13):1320–1328.
  7. Carter HB, Ferrucci L, Kettermann A, et al. Detection of life-threatening prostate cancer with prostate-specific antigen velocity during a window of curability. Journal of the National Cancer Institute 2006; 98(21):1521–152

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20 July 2012, 11.50am AEST

Surgery no better than observation for localised prostate cancer

Men with prostate cancer which has not spread have been found to live just as long as those who have had prostate-removal surgery.

It is becoming more common to monitor patients with regular tests, rectal exams, and biopsies to see if the cancer is becoming more of a threat as opposed to undergoing surgery early.

It is important that men discuss the possible risks and benefits of a prostate cancer screening with their doctor.

Here is the full article for those who are interested:

Original Article

Radical Prostatectomy versus Observation for Localized Prostate Cancer

Timothy J. Wilt, M.D., M.P.H., Michael K. Brawer, M.D., Karen M. Jones, M.S., Michael J. Barry, M.D., William J. Aronson, M.D., Steven Fox, M.D., M.P.H., Jeffrey R. Gingrich, M.D., John T. Wei, M.D., Patricia Gilhooly, M.D., B. Mayer Grob, M.D., Imad Nsouli, M.D., Padmini Iyer, M.D., Ruben Cartagena, M.D., Glenn Snider, M.D., Claus Roehrborn, M.D., Ph.D., Roohollah Sharifi, M.D., William Blank, M.D., Parikshit Pandya, M.D., Gerald L. Andriole, M.D., Daniel Culkin, M.D., and Thomas Wheeler, M.D. for the Prostate Cancer Intervention versus Observation Trial (PIVOT) Study Group

N Engl J Med 2012; 367:203-213July 19, 2012

Background

The effectiveness of surgery versus observation for men with localized prostate cancer detected by means of prostate-specific antigen (PSA) testing is not known.

Methods

From November 1994 through January 2002, we randomly assigned 731 men with localized prostate cancer (mean age, 67 years; median PSA value, 7.8 ng per milliliter) to radical prostatectomy or observation and followed them through January 2010. The primary outcome was all-cause mortality; the secondary outcome was prostate-cancer mortality.

Results

During the median follow-up of 10.0 years, 171 of 364 men (47.0%) assigned to radical prostatectomy died, as compared with 183 of 367 (49.9%) assigned to observation (hazard ratio, 0.88; 95% confidence interval [CI], 0.71 to 1.08; P=0.22; absolute risk reduction, 2.9 percentage points). Among men assigned to radical prostatectomy, 21 (5.8%) died from prostate cancer or treatment, as compared with 31 men (8.4%) assigned to observation (hazard ratio, 0.63; 95% CI, 0.36 to 1.09; P=0.09; absolute risk reduction, 2.6 percentage points). The effect of treatment on all-cause and prostate-cancer mortality did not differ according to age, race, coexisting conditions, self-reported performance status, or histologic features of the tumor. Radical prostatectomy was associated with reduced all-cause mortality among men with a PSA value greater than 10 ng per milliliter (P=0.04 for interaction) and possibly among those with intermediate-risk or high-risk tumors (P=0.07 for interaction). Adverse events within 30 days after surgery occurred in 21.4% of men, including one death.

Conclusions

Among men with localized prostate cancer detected during the early era of PSA testing, radical prostatectomy did not significantly reduce all-cause or prostate-cancer mortality, as compared with observation, through at least 12 years of follow-up. Absolute differences were less than 3 percentage points. (Funded by the Department of Veterans Affairs Cooperative Studies Program and others; PIVOT ClinicalTrials.gov number, NCT00007644.)

Supported by grants from the Department of Veterans Affairs Cooperative Studies Program, the National Cancer Institute, and the Agency for Healthcare Research and Quality.

Dr. Barry reports being employed by and serving as a board member of the Foundation for Informed Medical Decision Making, which receives royalties from Health Dialog. Dr. Wei reports serving on the board for Envisioneering, receiving consulting fees and grant support from Sanofi-Aventis, providing expert testimony for Genprobe concerning prostate-cancer detection, and serving as proctor for benign prostatic hyperplasia laser surgery for American Medical Systems. Dr. Andriole reports receiving consulting fees, payment for the development of presentations, and payment for travel, accommodation, and meeting expenses from Amgen; consulting fees, stock options, and payment for travel, accommodation, and meeting expenses from Augmenix; consulting fees and payment for travel, accommodation, and meeting expenses from Bayer; consulting fees and payment for travel, accommodation, and meeting expenses from Bristol-Myers Squibb; consulting fees, stock options, and payment for travel, accommodation, and meeting expenses from Cambridge Endo; consulting fees and payment for travel, accommodation, and meeting expenses from Caris; consulting fees and payment for travel, accommodation, and meeting expenses from GlaxoSmithKline; consulting fees and payment for travel, accommodation, and meeting expenses from Janssen Biotech; consulting fees and payment for travel, accommodation, and meeting expenses from Myriad Genetics; consulting fees and payment for travel, accommodation, and meeting expenses from Steba Biotech; consulting fees and payment for travel, accommodation, and meeting expenses from Ortho Clinical Diagnostics; consulting fees and stock options from Viking Medical; stock options from Envisioneering Medical; and grant support to his institution from Johnson & Johnson, Medivation, and Wilex; and being a member of an independent data monitoring committee for Amarex. Dr. Wheeler reports serving as a board member of Medscape; receiving consulting fees from GlaxoSmithKline; providing expert testimony for various law firms regarding medical malpractice, product liability, and toxic tort; receiving royalties from Metabolon; and receiving stock options from Digipath. No other potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article was updated on July 19, 2012, at NEJM.or

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Current Challenges in Prostate Cancer Management and the Rationale behind Targeted Focal Therapy

Abstract

Among men, prostate cancer has a high prevalence, with relatively lower cancer-specific mortality risk compared to lung and colon cancer. Prostate-specific antigen (PSA) screening has increased prostate cancer awareness since its implementation as a screening tool almost 25 years ago, but, due to the largely indolent course of this disease and the unspecific nature of the PSA test, increased incidence has largely been associated with cancers that would not go on to cause death (clinically insignificant), leading to an overdiagnosis challenge and an ensuing overtreatment consequences. The overtreatment problem is exacerbated by the high risk of side effects that current treatment techniques have, putting patients’ quality of life at risk with little or no survival benefit. The goals of this paper are to evaluate the rise, prevalence, and impact of the overdiagnosis and ensuing overtreatment problems, as well as highlight potential solutions. In this effort, a review of major epidemiological and screening studies, cancer statistics from the advent of prostate-specific antigen screening to the present, and reports on patient concerns and treatment outcomes was conducted to present the dominant factors that underlie current challenges in prostate cancer treatment and illuminate potential solutions.

1. Background

Accounting for 29% of all cancers in men, prostate cancer is the most common cancer among men behind nonmelanoma skin cancer and is the second highest cause of cancer death among men of all races [1, 2]. Over 2 million men currently alive in the United States have had prostate cancer, and it is estimated that 16.48% of men will be diagnosed with prostate cancer at some point during their lives [3]. Estimates of newly diagnosed prostate cancer cases hover near 240,000 for 2011 [4].

However prevalent, the incidence and mortality of prostate cancer present very differently. It is estimated that 1 in 6 men will be diagnosed with prostate cancer but only 1 in 36 are expected to die because of it [5]. This may be because it is predominantly diagnosed in more senior adults, and, with a generally favorable outlook, men usually die before any symptoms appear [1, 5]. To be sure, there are tens of thousands of individuals who suffer the symptoms of aggressive prostatic cancer, but, in terms of the larger picture of prostate cancer, these men are well in the minority. The question remains, why, for such a largely symptomless condition, do so many incidental or nonmortal cancers get diagnosed, and what does a diagnosis of cancer mean at this clinically insignificant stage? The purpose of this paper is to understand the trends that made such a predominantly hidden cancer become so noticeable, highlight the burden that this now markedly prevalent cancer places on healthcare, and illuminate current developments that may hold promise for easing that burden.

2. PSA Test Increases Incidence

The primary reason for such a high rate of diagnosis for so often a symptomless condition is most likely the result of prostate-specific antigen (PSA) screening practices which came about in the late 1980s following studies which seemed to demonstrate the value of PSA as a biomarker for prostate cancer [6–8]. The 1987 study by Stamey and colleagues was perhaps the most dominant one due to its citation prevalence in Medline [9, 10]. In 2004, however, Stamey and colleagues maintained that PSA was only an accurate reflection of prostate cancer circa 1985 and that it was only demonstrated a relation to benign prostate hyperplasia throughout the five years preceding their newer study [11]. Moreover, Thompson and colleagues demonstrated in 2005 that there was no single PSA cutoff that could yield both high sensitivity and specificity [12].

Nevertheless, early studies of PSA testing exhilarated the scientific community by offering the prospect of early detection of prostate cancer, a disease so often diagnosed late in its development due to its often symptomless progression [13, 14]. The use of PSA screening increased rapidly in the United States after 1987, resulting in a dramatic change in annual prostate cancer incidence and, in turn, a sharp increase in prostate cancer treatment both in the United States and abroad [15–17]. But while more cancers were being found and treated, the prostate cancer specific mortality rate only modestly decreased until 1993, after which little change was seen [15, 18]. Figure 1 from the National Cancer Institute shows this rising incidence of prostate cancer in contrast to the relatively unchanged mortality rate from 1975 to 2007. The disparity continues today, where the number of newly discovered prostate cancers is over seven times the number of prostate cancer related deaths [2].

Figure 1

Figure 1

Change in prostate cancer incidence and mortality from 1975 to 2007 documented by the National Cancer Institute. arates are age adjusted to the 2000 US Std Population (19 age groups—Census P25-1103). Regression lines and APCs are calculated using (more …)

3. PSA Test Creates Stage Migration

What may account for this is the fact that, while helping to discover mortal cancers, PSA testing also often led to the discovery of nonmortal cancers, or those which would never have been given notice in the absence of screening [19]. Given that 20–50% of asymptomatic men are found to harbor prostate cancer upon autopsy, it follows that the PSA test, with only a 24.1% positive predictive value, leads to a much greater detection of cancers, both mortal and nonmortal [20–23]. It is also possible that widespread PSA testing and treatment may have slowly weeded out the more dangerous prostate cancers from the population. Whether from increased testing, increased treatment of dangerous cancers, or some combination of the two, more cancers were being found at lower stages from 1986 to 1993, with tumors often being low grade, clinically localized, and/or organ confined. From 1993 to 2003, there was a 75% reduction in the proportion of metastatic diagnoses for prostate cancer [24]. The link between PSA testing and stage migration was documented in Austria during a large-scale PSA testing study and again later in the United States [24–26]. This seems to indicate that as PSA testing continues, prostate cancer will also continue to be diagnosed at clinically insignificant stages.

4. Overdiagnosis Ensues

Given the propensity of PSA testing to detect cancers both mortal and nonmortal, overdiagnosis was a probable outcome. Overdiagnosis due to PSA testing has been documented extensively through epidemiological studies and computerized models, at rates which range from 29% in specific regions to an estimated 80% should all men in the United States be screened [7, 27, 28]. Progress has been made in investigating different biomarkers and variations of PSA testing for early detection of mortal prostate cancer, but, despite its flaws, the PSA test still remains the best screening tool currently available, suggesting continued overdiagnosis [29–31].

5. Uncertainty Leads to Treatment

The corollary of the overdiagnosis problem is an overtreatment problem. While active surveillance (AS) might seem the best course of action for many due to the relatively low mortality rate and exceedingly high 15-year survival rates of prostate cancer, working against that is a lack of consensus on what the inclusion criteria should be for AS, what the optimal follow-up schedule should be, or even how to best define progression [32]. For instance, the Epstein criteria is one common method of establishing whether or not a cancer is clinically insignificant, and this relies on a third or less of biopsy cores being positive, 50% or less involvement of any 1 core, and a PSA density of less than 0.15 ng/mL. However, the D’Amico criteria, also widely used, calls for a Gleason score of six or less, a PSA of less than 10 ng/mL, and a T1 clinical stage. Studies have shown highly favorable results for certain criteria, like the 100% 10-year prostate cancer-specific survival rate documented by researchers who took patients off AS based on PSA doubling time [33]. Other studies suggest that PSA kinetics are not reliable for AS inclusion/exclusion criteria [34]. In yet another study, researchers found that prostate specimens fitting six different inclusion criteria for clinically insignificant disease would have been misclassified 14–27% of the time based on Gleason 8 findings [35]. Research continues to refine AS criteria, but a clear understanding of how to define clinically insignificant disease has not been reached.

The lack of consensus and the thought of harboring a cancer with an unpredictable progression leads to feelings of uncertainty in the patient, in turn arousing high levels of emotional distress, anxiety, and depression [36]. While support services can assist in ameliorating the psychological distress, men with prostate cancer tend to avoid disclosure and are unlikely to utilize health and psychological support services [37]. At the same time, doctors tend to underestimate the psychological morbidity of men with prostate cancer, leading to a lack of provider referral [38].

With a lack of social support, motivation to seek it out, or provider referrals to address the psychological discomfort associated with prostate cancer, most newly diagnosed men suffer the full psychological burden of living with an unpredictable cancer. This proves too much to bear, as rather than learning to live with what is most likely a nonmortal cancer, men elect various courses of treatment to escape the mental anguish of uncertainty. In a study of the reasons for undergoing various treatment types, Gwede et al. found that 44% of men chose radical prostatectomy primarily because they believed it to be their best chance to be cured [39].

Denberg et al. found that a group of men underwent surgery due to the belief that it was the most certain, expeditious, and tangible option and that, even though it might reveal that a tumor escaped the prostate, it would at least eliminate some uncertainty. These same men found no other option appealing because they dealt with acting on a hidden and unseen cancerous organ. Even those who did not choose surgery in the Denberg study were motivated by uncertainty, in their case, they were trying to avoid the uncertainties associated with surgery. It should also be noted that half of their patient sample avoided seeking second opinions due to delay, prolonged uncertainty, and feelings of increased anxiety [40]. Similar findings were reported in England, Scotland, and Whales, where a study of 50 men with early-stage prostate cancer found reasons for prostatectomy ranging from frustration with the lack of concrete information and consensus over what to do, to the explicit desire to fix the problem [41].

The uncertainty and anxiety of having prostate cancer are certainly a formidable driver for treatment instead of AS, and researchers have documented it as a valuable predictor of treatment receipt [42, 43]. Watchful waiting (often synonymous with AS) is often used in other countries but rarely in the United States, especially for younger men with early-stage prostate cancer for whom treatment is often advocated [44]. When briefed with specific cancer statistics and information on the side effects of treatment, most patients place little weight on side effects when there is even a chance of prolonged survival [45]. Mazur and Hickam showed that even when attempting to bias patients against surgical therapy by explicitly naming surgical complications and presenting rates of those complications higher than what was typically in the literature, most patients still preferred surgical treatment over AS for localized prostate cancer [46]. Research shows that, on the whole, only 18.5% forgo active treatment for watchful waiting, all in the face of a cancer that is lethal in only 1 in 32 cases [47].

6. Prevalence of Overtreatment

The amount of treatment received is certainly disproportional, and studies clearly indicate that a substantial proportion of treatments do not go on to prevent death from prostate cancer. The European Randomized Study for Prostate Cancer (ERSPC) reported, for instance, that 1410 men needed to be screened and 48 treated to prevent 1 cancer death [48]. Results from the Randomized Scandinavian Prostate Cancer Group Study show that an estimated 15 patients needed to be treated to avert one death at 15 years and that, for adjuvant radiation therapy, the number of patients needed to be treated to avert one death at 12.6 years was 9.1 [49]. Perhaps the most favorable results were found in Quebec, where out of an estimated 100 men with screen-detectable prostate cancer, an average of 16 could have their lives extended by surgery (should those men be found by way of extensive screening efforts) [50]. However, the most recent data comes from the Prostate Cancer Intervention versus Observation Trial (PIVOT), which reports that, after 12 years of followup, overall prostate cancer mortality was only 3% lower for men having radical prostatectomy. In fact, men with low-risk prostate cancer were actually shown to have a 2.4% better survival rate with watchful waiting than with surgery. PIVOT reports that, even when looking exclusively at cases of intermediate risk, radical prostatectomy still only achieves a 4.8% better survival rate [51].

The statistics from these studies also do not take into account the copious amounts of unnecessary biopsies that would have to be performed to find these cancers in the first place, as in order to detect even 83.4% of cancer cases by PSA testing, a calculated 61.1% of men without cancer would need to be subjected to prostate biopsy, a procedure that is in itself not without consequence to quality of life [12].

In an effort to quantify the amount of overtreatment stemming from prostate cancer, Welch and Albertsen used Surveillance Epidemiology and End Results (SEER) data from the National Cancer Institute and statistics from the US Census to estimate that from 1986 to 2005, 1,004,800 of an additional 1,305,600 overdiagnosed cancers received treatment, with 571,000 excess prostate-cancer-related surgeries, and 477,400 excess prostate-cancer-related radiation treatments [10].

7. Side Effects of Treatment

Excess treatment brings excess side effects, and, in the case of prostate cancer, they are not uncommon. Overtreated patients run several risks, especially when it comes to radical prostatectomy and/or radiation therapy, the most dominant treatment options. The US Preventative Services Task Forces reviewed the most common side effects of treatment from 1994 to 2002, bringing the problems associated with overtreatment to light. Long-term adverse effects of radical prostatectomy, for instance, were sexual dysfunction (20–70%) and urinary incontinence (15–50%). For electron beam radiation therapy, approximately 45% could expect erectile dysfunction, 2–16% urinary dysfunction, and 6–25% bowel dysfunction. For Androgen Deprivation Therapy (ADT), approximately half of patients who were sexually active beforehand were not sexually active afterward, 5–25% had breast swelling, and 50–60% had hot flashes along with other potential long-term complications like anemia and osteoporosis. For brachytherapy, a majority of men reported having distressing urinary symptoms, 21–36% reported decreased erectile function, 18% diarrhea, and 19% persistent rectal bleeding [52].

The primary concern of most men undergoing radical prostatectomy is preservation of potency, and, to that end, bilateral nerve sparing techniques in younger cohorts (median age 57) have yielded a potency rate as high as 86%, with more typical results hovering around 44–76% [53]. The second most dominant concern is urinary continence, but data on that is difficult to generalize given the changing definition of continence which various studies employ. When urinary continence is defined as not needing protection to keep outer garments dry, 93% of men followed for more than 18 months recovered continence, but, when using total urinary control as a benchmark, only 32% of men were continent at 24 months [53]. Among patients in the Rotterdam section of the ERSPC who underwent radical prostatectomy, as much as 80–90% reported erectile dysfunction and 39–49% reported urinary incontinence [54]. Studies analyzing even the most advanced minimally invasive prostatectomy techniques (robotic and/or laparoscopic) find continence ranging 68.0–94.7%, potency 33.3–65.3%, and progression-free survival 84.1–92.0% [55].

In more recent findings, these problems are still prevalent. In a comparison of 1938 men who received minimally invasive radical prostatectomy and 6899 men who received open retropubic radical prostatectomy, investigators found incontinence rates of 15.9 and 12.2 per 100 person-years, respectively. Sexual dysfunction was higher, however, with rates of 26.8 and 19.2 per 100 person-years, respectively [56]. Another large-scale study of 1,201 patients treated with surgery, brachytherapy, or EBRT found erectile dysfunction rates two years posttreatment of 57%, 31%, and 35%, respectively [57, 58].

8. Focal Therapy Offers a Solution

The aforementioned statistics indicate that the majority of these treatments will infer no survival benefit in the first place, so the amount of men who go on to suffer such side effects is certainly unwarranted. However, without an established and reliable way to distinguish mortal from nonmortal cancers and the overwhelming preference by both patients and providers to pursue treatment options in the face of such uncertainty, it seems treatment will continue to be the dominant option. Fortunately, focal therapy techniques developing since the 1990s are now showing promise as a method of treatment which is not associated with such arresting rates of side effects. These techniques avoid the costs that other techniques would require in order to reduce side effects to comparable levels while still being effective [59].

Clinical trials have demonstrated the feasibility of focal ablative methods using high-intensity focused ultrasound and cryosurgery [60], and focal techniques are expected to improve as imaging techniques allow for better pathological assessments [61–63]. Successful focal therapy demands stringent selection factors, and this requires an imaging modality which can accurately characterize the location, extent, and grade of a patient’s prostate cancer [64]. In this effort, a brachytherapy template-guided transperineal saturation biopsy technique (3DMB) was described and tested by Crawford et al. on prostate autopsy specimens in 2005, which demonstrated both feasibility and increased accuracy over sextant biopsies [65]. In evaluating the potential of 3DMB in vivo, Barqawi et al. compared previous TRUS results of 215 patients to those obtained using 3DMB, finding new cancer foci in 82 patients and higher Gleason scores in 49 patients, demonstrating a potentially significant improvement in the way prostate cancer can be evaluated [66]. While long-term results have not been disseminated as of yet, we are currently anticipating the publication of 5-year follow-up data on patients treated with focal cryoablation in conjunction with 3DMB.

While promising results continue to be seen, there are still hurdles to overcome, such as the issue of gland stabilization during treatment, or how to work around large prostates when employing 3DMB [67]. In addition, wide variability in patient selection, disease characterization, and treatment protocols still exist. A preferred ablative energy for focal therapy has also not been conferred (cryosurgery, high-intensity focused ultrasound, vascular-targeted photodynamic therapy, brachytherapy, radiotherapy, or tomotherapy), yet it seems that one of the dominant concern for those investigating this approach has to do with standardizing follow-up protocols and creating reliable and meaningful outcomes measures to evaluate it, as the PSA measurements so often relied on to assess other forms of treatment are not only unreliable as mentioned, but also tend to take on different meaning when larger portions of the organ are left intact, as is the case with focal therapy [68, 69]. While biochemical disease-free status using American Society of Therapeutic Radiation Oncology or Phoenix criteria seems to be the dominant means of evaluating focal treatment, standardized algorithms for determining success would be of significant benefit to researchers pursuing long-term follow-up studies on focal therapy. Standardization should be a primary focus of future follow-up studies and will serve greatly in conferring the efficacy of different methods and identifying areas for improvement.

9. Conclusion

While procedural advances and screening efforts continue to report improvements, the PSA test is still the best screening tool currently available, and this suggests a continuing trend of overdiagnosis based on historical data. Early detection of prostate cancer is possible, but early discrimination is not, leading to a great deal of uncertainty as to whether or not a particular patient’s prostate cancer will become aggressive. The psychological burden that comes with this uncertainty more often than not leads to treatment regardless of patients’ understanding of high risks of side effects and low survival benefit rates. Whether or not improved screening or imaging techniques will be able to better distinguish nonmortal from mortal cancers remains to be seen, as well as what role that will play in regards to the psychological distress that comes with being diagnosed with prostate cancer.

With overwhelming evidence, the root of overtreatment and the unnecessary side effects that ensue lie in the psychological burden of dealing with uncertainty and with the lack of emotional support or the motivation to seek it out, the vast majority of newly diagnosed men undergo serious treatment efforts regardless of the potential for harmful side effects. Solutions to the overtreatment problem may come from enhanced screening and imaging efforts or the delivery and implementation of psychological care for those diagnosed with localized cancer. More likely, solutions will come from improvements in treatment methodology. Focal therapy appears to be a promising avenue in this regard as it is noninvasive, has fewer side effects, and remains more cost-effective than side-effect reducing advanced radiation and robotic techniques. Moreover, focal therapy does not exclude the possibility of more radical options and does not necessarily replace traditional techniques. Enhanced methods to evaluate focal therapy and standardized protocols to assess outcomes measures will help progress this emerging practice as improvements in imaging modalities help practitioners realize its assumed potential.

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What the U.S. Preventive Services Task Force Missed in Its Prostate Cancer Screening Recommendation

  1. William J. Catalona, MD;
  2. Anthony V. D’Amico, MD;
  3. William F. Fitzgibbons, MD;
  4. Omofolasade Kosoko-Lasaki, MD;
  5. Stephen W. Leslie, MD;
  6. Henry T. Lynch, MD;
  7. Judd W. Moul, MD;
  8. Marc S. Rendell, MD; and
  9. Patrick C. Walsh, MD

+ Author Affiliations


  1. From Northwestern University Feinberg School of Medicine, Chicago, Illinois; Brigham and Women’s Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Creighton University School of Medicine, Omaha, Nebraska; Duke Cancer Institute and Duke University School of Medicine, Durham, North Carolina; and James Buchanan Brady Urologic Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland.

The U.S. Preventive Services Task Force (USPSTF), a panel that does not include urologists or cancer specialists, has just recommended against prostate-specific antigen (PSA)-based screening for prostate cancer, stating that “screening may benefit a small number of men but will result in harm to many others” (1). Recognizing that prostate cancer remains the second-leading cause of cancer deaths in men, we, an ad hoc group that includes nationally recognized experts in the surgical and radiological treatment of prostate cancer, oncologists, preventive medicine specialists, and primary care physicians, believe that the USPSTF has underestimated the benefits and overestimated the harms of prostate cancer screening. Therefore, we disagree with the USPSTF’s recommendation.

The USPTSF bases its recommendation, in large part, on the 2 largest published randomized clinical trials (2). The U.S. PLCO (Prostate, Lung, Colorectal, and Ovarian) Cancer Screening Trial randomly assigned 76 685 men ages 55 to 74 years to receive either annual screening for 6 years or “usual care” (3). By 2009, 57% of the men had been followed for at least 13 years. The cumulative incidence rate for prostate cancer was slightly higher in the screened group, and prostate cancer mortality did not differ significantly between groups (3). The ERSPC (European Randomized Study of Screening for Prostate Cancer) randomly assigned 162 243 men aged 55 to 69 years to either PSA screening once every 4 years or to an unscreened control group (4). After a median of 11 years of follow-up, the cumulative incidence of prostate cancer was 8.2% in the screened group and 4.8% in the control group. Prostate cancer death was reduced by 21% in the screened compared with the control group and 29% after adjustment for noncompliance (5). The Task Force concluded that this decrease in prostate cancer–specific mortality amounted to few lives saved and did not outweigh the harms of screening and diagnosis (false-positive results and associated anxiety and biopsy complications) and the harms related to the treatment of screen-detected cancer.

The Task Force’s evidence review (2) did acknowledge strong evidence that treatment of localized prostate cancer reduced mortality compared with observation alone, citing a Scandinavian randomized, controlled trial with 15 years of follow-up showing that radical prostatectomy resulted in a sustained 38% decrease in prostate cancer–specific mortality (15% vs. 21%; risk ratio, 0.62 [95% CI, 0.44 to 0.87]) and 25% reduction in all-cause mortality (risk ratio, 0.75 [CI, 0.61 to 0.92]) (6). It also acknowledged other trials of surgery and radiation therapy showing an approximate 35% decrease in mortality. However, the Task Force’s view was that perioperative events, urinary incontinence, and erectile dysfunction as complications of prostatectomy and bowel problems associated with radiation therapy must be considered, in addition to the mortality benefits of treatment.

In formulating its recommendation, we believe that the USPSTF either overlooked or misinterpreted the effect of significant methodological flaws in the 2 major clinical trials of screening. The most important flaws of the PLCO are the greater than 50% “contamination” rate by nonprotocol PSA measurements in the control group, prescreening of 40% of study participants before enrollment in the trial, and the fact that two thirds of patients with abnormal screening tests did not have prompt biopsy (7). These issues, in our opinion, impair the claim that the PLCO is a true screening trial. In the ERSPC, compared with the PLCO, participants were younger, the PSA cutoff was lower, there was only approximately 15% “contamination,” and prompt biopsy was done far more frequently after positive PSA values. A secondary analysis of data from the Rotterdam site of the ERSPC that corrected for failure of participants to have protocol-prescribed screening procedures as well as contamination showed that PSA screening reduced the risk for dying of prostate cancer by as much as 31% (8).

A further limitation of both trials was having only a median follow-up of roughly 10 years, which we believe is of inadequate duration for an often slowly progressive cancer such as prostate cancer. The Task Force gave little weight to the longer Göteborg Randomised Population-Based Prostate-Cancer Screening Trial, which had better protocol compliance and in which the interim 14-year median follow-up results showed a greater (44%) reduction in death from prostate cancer for the screened group (risk ratio, 0.56 [CI 0.39 to 0.82; P = 0.002]) (9).

In addition to misinterpreting the potential effect of the limitations of the 2 largest screening trails, we believe that the Task Force had other flaws in its reasoning. First, it overlooked the fact that diagnostic procedures and related complications occur in unscreened populations as well, and at a later stage of cancer discovery. In the ERSPC trial, higher-grade cancer (Gleason score ≥7) was more common in the control group (45.2%) versus the screened group (27.8%), with a 40% greater incidence of locally advanced and metastatic cancer (4). Undeniably, victims of advanced prostate cancer endure more invasive and harmful procedures than those with organ-confined disease. Second, the Task Force analysis focused on mortality and ignored the substantial illness associated with living with advanced cancer. Disseminated prostate cancer is characterized by painful bone metastases, pathologic fractures, and urinary tract obstruction. A comprehensive comparative analysis of benefits and harms in screened and control populations should consider the complications of advanced cancer, which could be more common in unscreened groups. Third, we believe that the Task Force recommendation lacks adequate consideration of high-risk populations, including men with a family history of prostate cancer and men of African descent, who have a 1.4-times higher risk for being diagnosed with and 2- to 3-times higher risk for dying of prostate cancer compared with European American men (10). Fourth, the USPSTF did not adequately emphasize epidemiologic data that shows that since the widespread use of PSA testing began in the early 1990s, there has been a 40% decrease in prostate cancer deaths and a 75% decrease in presentation with advanced disease at initial diagnosis, which is attributed, in large part, to PSA screening (11). A recent National Institutes of Health Consensus Development Conference concluded that “prior to the adoption of PSA screening, the majority of prostate cancer was detected because of symptoms of advanced cancer or a nodule found on digital rectal examination. The symptomatic tumors were usually high-grade, advanced, and often lethal” (12).

Finally, the Task Force recommendation opposes PSA testing regardless of age. The expected life span for a man aged 75 years is approximately 10 years but reaches 30 years for men at age 45 to 50 years. It is plausible that many men aged 75 years or older will die of other causes before developing metastatic prostate cancer, but the current recommendation, arguably to avoid adverse effects of screening, could result in delayed diagnosis of curable cancer in young men who may then present with advanced disease, illness, and death. The Task Force recommendation relies solely on mortality data from the PLCO and the ERSPC and early data from the Prostate Cancer Intervention Versus Observation Trial (1). We believe that studies with only a 10-year median follow-up are insufficient to dictate how a man with prostate cancer aged 50 to 60 years should be treated.

The recommendations of the USPSTF carry considerable weight with Medicare and other third-party insurers and could affect the health and lives of men at high risk for life-threatening disease. We believe that elimination of reimbursement for PSA testing would take us back to an era when prostate cancer was often discovered at advanced and incurable stages. At this point, we suggest that physicians review the evidence, follow the continuing dialogue closely, and individualize prostate cancer screening decisions on the basis of informed patient preferences.

Article and Author Information

  • Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-0991.

  • Requests for Single Reprints: Marc S. Rendell, MD, The Creighton Diabetes Center, 601 North 30th Street, Omaha, NE 68131; e-mail, Rendell@asndi.com.

  • Current Author Addresses: Dr. Catalona: 675 North St. Clair Street, Suite 20-150, Chicago, Illinois 60611.

  • Dr. D’Amico: Brigham and Women’s Hospital, 75 Francis Street #Asb1, Boston, MA 02115.

  • Dr. Fitzgibbons: Skyline Medical Center, 1908 North 203rd Street Suite 2, Elkhorn, NE 68022.

  • Dr. Kosoko-Lasaki: Health Sciences Office of Multicultural and Community Affairs, Hixson Lied Building, Suite L23, Creighton University, 2500 California Plaza, Omaha, NE 68178.

  • Dr. Leslie: Department of Surgery, Division of Urology, Suite 3700, 601 North 30th Street, Omaha, NE 68131.

  • Dr. Lynch: Hereditary Cancer Center and Department of Preventive Medicine, Creighton University, 2500 California Plaza, Omaha, NE 68178.

  • Dr. Moul: Division of Urologic Surgery, DUMC 3707-Room 1562 Duke South, Duke University Medical Center, Durham, NC 27705.

  • Dr. Rendell: The Creighton Diabetes Center, 601 North 30th Street, Omaha, NE 68131.

  • Dr. Walsh: Johns Hopkins Hospital, Park 224, Baltimore MD 21287.

  • Author Contributions: Conception and design: W.J. Catalona, W.F. Fitzgibbons, J.W. Moul, M.S. Rendell, P.C. Walsh.

  • Analysis and interpretation of the data: W.J. Catalona, A.V. D’Amico, S.W. Leslie, H.T. Lynch, M.S. Rendell, P.C. Walsh.

  • Drafting of the article: W.J. Catalona, A.V. D’Amico, S.W. Leslie, J.W. Moul, M.S. Rendell, P.C. Walsh.

  • Critical revision of the article for important intellectual content: W.J. Catalona, A.V. D’Amico, W.F. Fitzgibbons, S.W. Leslie, J.W. Moul, M.S. Rendell, P.C. Walsh.

  • Final approval of the article: W.J. Catalona, A.V. D’Amico, W.F. Fitzgibbons, O. Kosoko-Lasaki, S.W. Leslie, H.T. Lynch, J.W. Moul, M.S. Rendell, P.C. Walsh.

  • Administrative, technical, or logistic support: S.W. Leslie, M.S. Rendell.

  • Collection and assembly of data: W.J. Catalona, A.V. D’Amico, S.W. Leslie.

  • This article was published at www.annals.org on 22 May 2012.

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    Ganz PA, Barry JM, Burke W, Col NF, Corso PS, Dodson E, et al. National Institutes of Health State-of-the-Science Conference: Role of Active Surveillance in the Management of Men With Localized Prostate Cancer. Ann Intern Med. 2012;156:591-595. [PMID: 22351514]
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J Clin Oncol. 2011 February 1; 29(4): 464–467.
Published online 2010 December 28. doi:  10.1200/JCO.2010.30.6373
PMCID: PMC3058289

What Is the True Number Needed to Screen and Treat to Save a Life With Prostate-Specific Antigen Testing?

This article has been cited by other articles in PMC.

Abstract

Purpose

The European Randomized Study of Screening for Prostate Cancer (ERSPC) reported a 20% mortality reduction with prostate-specific antigen (PSA) screening. However, they estimated a number needed to screen (NNS) of 1,410 and a number needed to treat (NNT) of 48 to prevent one prostate cancer death at 9 years. Although NNS and NNT are useful statistics to assess the benefits and harms of an intervention, in a survival study setting such as the ERSPC, NNS and NNT are time specific, and reporting values at one time point may lead to misinterpretation of results. Our objective was to re-examine the effect of varying follow-up times on NNS and NNT using data extrapolated from the ERSPC report.

Materials and Methods

On the basis of published ERSPC data, we modeled the cumulative hazard function using a piecewise exponential model, assuming a constant hazard of 0.0002 for the screening and control groups for years 1 to 7 of the trial and different constant rates of 0.00062 and 0.00102 for the screening and control groups, respectively, for years 8 to 12. Annualized cancer detection and drop-out rates were also approximated based on the observed number of individuals at risk in published ERSPC data.

Results

According to our model, the NNS and NNT at 9 years were 1,254 and 43, respectively. Subsequently, NNS decreased from 837 at year 10 to 503 at year 12, and NNT decreased from 29 to 18.

Conclusion

Despite the seemingly simplistic nature of estimating NNT, there is widespread misunderstanding of its pitfalls. With additional follow-up in the ERSPC, if the mortality difference continues to grow, the NNT to save a life with PSA screening will decrease.

INTRODUCTION

Mortality from prostate cancer (PCa) has decreased substantially in the United States, coinciding with the initiation of widespread prostate-specific antigen (PSA) –based screening. From 1994 to 2006, mortality rates declined by an average of 4% per year, the most rapid decline observed for any cancer site.1 Mathematical models have estimated that the stage migration induced by screening likely accounts for 45% to 70% of the observed reduction in PCa mortality through 2000.2 Notably, a similar decline was observed in Tyrol, Austria after the introduction of a PSA screening program, compared with the rest of the country where screening and curative treatment were uncommonly performed.3

The European Randomized Study of Screening for Prostate Cancer (ERSPC) recently reported a 20% reduction in PCa mortality and a 41% reduction in metastatic disease at diagnosis in an intent-to-screen analysis conducted after a median follow-up time of 9 years.4 More recently, ERSPC estimated a mortality reduction of 31% after adjustment for noncompliance in the screening arm and contamination in the control arm.5 However, serious concerns were raised because the original ERSPC report included estimates indicating that a large number of men would have to be screened and treated to prevent one death from PCa.6 The number needed to treat (NNT) is a useful statistic to assess the balance of benefits and harms of an intervention.7 The goal of this study is to highlight some of the pitfalls in the calculation and interpretation of the NNT statistic and, in particular, to provide revised estimates of the NNT from the ERSPC trial accounting for the important effects of longer follow-up time.

Whether or not one accepts that PSA screening has a mortality benefit or at least reduces the incidence of metastatic disease, it must be acknowledged that screening programs engender costs at both the individual and societal level.8 Central to the debate over PSA screening are concerns regarding the diagnosis and treatment of tumors that may not cause harm.9 In the ERSPC trial, Schroder et al4 used the difference in cumulative mortality between the screening and control arms and the excess incidence of PCa in the screening arm to estimate a NNT of 48 to prevent one PCa death after a median follow-up time of 9 years. Because not every patient diagnosed with PCa will require treatment, NNT can be described more accurately in this context as the number needed to diagnose.10 The number needed to screen (NNS), which is simply the reciprocal of the absolute difference in cumulative mortality, was initially reported by ERSPC as 1,410 at the 9-year follow-up mark. This number can be reinterpreted as the number needed to be offered screening. The NNS was 1,068 when screening arm assignees who never underwent any screening were excluded.

Previous authors noted that the NNT statistic frequently has been used incorrectly in clinical trial reports in leading journals.11,12 NNT is easily understood when referring to proportions of patients assigned to each group at baseline but becomes more complex when dealing with differences in time-to-event data or event rates, which are based on actual person-time of observation. First, when rates, rather than proportions, are used as the basis for estimating NNT in the context of mortality, the NNT represents the amount of person-time (usually person-years), not the number of persons, that must be treated to prevent one death. Although this approach has been advocated as a way of standardizing the observation period and thus dealing with trials that have long and varying follow-up times for patients, the results are less intuitively appealing to clinicians, and their validity depends on the assumption that risk changes at a constant rate over time.12–14 Second, in almost all long-term trials such as ERSPC, some participants are removed from observation (ie, censored as a result of death or loss to follow-up) at varying points during follow-up, and the rates of censoring can also vary between treatment groups. Ignoring censoring, particularly differential censoring, can distort estimates of NNT that are based on simple proportions. This risk of distortion can be mitigated by instead calculating NNT based on the survival curves (or equivalent cumulative hazard functions [CHFs]) for each treatment group derived from common statistics such as the Kaplan-Meier or Nelsen-Aalen estimators, which account for variations in follow-up time among patients.15 Schroder et al4 appear to have used the Nelsen-Aalen CHF in estimating NNS and NNT. Because recalculation of the NNS and NNT using simple proportions based on the number of patients at baseline and the number of PCa deaths in each group yields nearly identical results, we assume that the pattern of censoring was approximately equivalent in each arm of the trial.

In the current analysis, however, we focused on another concern that we believe has a major effect on interpretation of NNT and NNS in the ERSPC, namely the fact that these statistics are time specific and will change as the risks for the treatment groups either converge or diverge over time. By extracting hazard rate estimates from the authors’ Nelsen-Aalen curves and applying those rates in an appropriate model, we calculated predicted NNS and NNT estimates for different periods of follow-up.

MATERIALS AND METHODS

We modeled the CHF of PCa-specific mortality for each treatment group using a piecewise exponential (PWE) model. The PWE model is a widely used approach to survival analysis that is particularly suited for situations involving nonproportional hazards (ie, those such as ERSPC where the relative hazards for PCa death and, therefore, the absolute mortality differences change over time).16,17 PWE models incorporate covariates into an actuarial life-table approach to survival analysis in much the way the Cox model incorporates covariates into a Kaplan-Meier approach. Unlike the Cox model, which does not specify any baseline hazard rate, the PWE model divides follow-up time into discrete, nonoverlapping intervals. The baseline hazard (ie, excluding the effects of covariates) can vary from one interval to the next but remains constant within the interval. The PWE and Cox models have been shown to yield nearly equivalent results for estimating covariate effects in many situations. However, the PWE model allows one to make predictions for individual patients based on covariate histories and, more to the point here, allows flexibility in defining the shape of the hazard function over time.16,18 This flexibility is important in situations such as PCa screening trials where the delayed emergence of a mortality benefit can be expected.

In our model, we assumed a constant hazard of 0.0002 for both the screening and control groups for years 1 to 7 of the trial. This is based on assuming the CHF to be 0.001 at 5 years based directly on the estimated CHF shown in Figure 2 of Schroder et al.4 Similarly, for years 8 to 12 of the trial, we assumed different constant rates of 0.00062 for the screening group (assuming a CHF of 0.0045 at 12 years) and 0.00102 for the control group (assuming a CHF of 0.0065 at 12 years), all based directly on Figure 2 of Schroder et al.4 Given this nonproportional hazards assumption, we computed PCa-free survival and cumulative hazard ratios over time as a function of the CHF. Annualized cancer detection and drop-out rates were also approximated based on the observed number of individuals at risk in published ERSPC data.4

RESULTS

Figure 1 compares the modeled CHFs to published data from the ERSPC. According to our model, the NNS and NNT at 9 years were 1,254 and 43, respectively (Table 1); these numbers are close to the published figures of 1,410 and 48, respectively. Our model also corresponds to a cumulative hazard ratio of 0.77, similar to the crude hazard ratio of 0.80 from the ERSPC report. Subsequently, the NNS decreased from 837 at year 10 to 503 at year 12, and the NNT decreased from 29 at year 10 to 18 at year 12, an estimate that is similar to the one determined by Welch et al9 using population data from the Surveillance, Epidemiology, and End Results program and by Bill-Axelson et al19 based on a randomized trial of surgery versus no treatment for PCa. Finally, Hugosson et al10 recently reported results from the Goteborg PCa screening trial, which was designed independently but included a subset of participants from the ERSPC. Using data from extended follow-up, these investigators calculated an NNS of 293 and NNT of 12 to prevent one PCa death at a median follow-up time of 14 years, suggesting that the estimates from our PWE model are highly plausible. We note that the NNS and NNT estimates from the Goteborg trial,10 unlike the ERSPC results, seem to have been based on simple proportions and may have been overestimated. The NNS calculated using the inverse of the difference (0.40%) in the Kaplan-Meier cumulative risk of PCa death is 250.

Fig 1.

Fig 1.

Modeled cumulative hazard functions assuming a piecewise exponential model. NNT, number needed to treat; NNS, number needed to screen; CHR, cumulative hazard ratio; HR, hazard ratio.
Table 1.

Table 1.

Modeled Results Assuming a Piecewise Exponential Model

DISCUSSION

Overall, our results demonstrate that NNS and NNT are highly sensitive to the time-dependent effects of the screening intervention on PCa mortality. Accordingly, estimates of NNS and NNT at a single time point during a survival study may be misleading. In addition to their dependence on time of follow-up and changes in the slopes of the hazard functions, NNS and NNT estimates from an intent-to-treat analysis may also be influenced by other features of a screening study, such as noncompliance and contamination. It is clear, based on both the CHF reported by Schroder et al4 and the estimated CHF using our PWE model (Fig 1), that the hazard rates for PCa mortality are not proportional over time and that there is a sharp increase in PCa-related deaths after 7 years that must be accounted for when estimating NNS and NNT as a function of time. Indeed, because of the long natural history of PCa, a follow-up time of more than 10 years is necessary to evaluate cancer-specific mortality.

Despite the seemingly simplistic nature of estimating NNT, there is widespread misunderstanding of its pitfalls among the medical community, the media, and the general public. Specifically, in the setting of a survival study such as the ERSPC, quoting one set of values for NNS and NNT at a single time point may be misleading. With additional follow-up in the ERSPC, the mortality difference between the screening and control arms will likely continue to grow, thus leading to further decreases in the NNT estimates.

Footnotes

See accompanying editorial on page 345 and article on page 355

Supported by the Urological Research Foundation, Prostate Specialized Programs of Research Excellence Grant No. P50 CA90386-05S2, Robert H. Lurie Comprehensive Cancer Center Grant No. P30 CA60553 (W.J.C.) and the Intramural Research Program of the National Institutes of Health, National Institute on Aging (E.J.M.).

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: William J. Catalona, Beckman Coulter (U), Ohmx (U) Stock Ownership: None Honoraria: William J. Catalona, Beckman Coulter, GlaxoSmithKline Research Funding: William J. Catalona, Beckman Coulter Expert Testimony: None Other Remuneration: None

AUTHOR CONTRIBUTIONS

Conception and design: Stacy Loeb, Edward F. Vonesh, E. Jeffrey Metter, H. Ballentine Carter, Peter H. Gann, William J. Catalona

Administrative support: Edward F. Vonesh, E. Jeffrey Metter, H. Ballentine Carter, William J. Catalona

Provision of study materials or patients: Stacy Loeb, Edward F. Vonesh, William J. Catalona

Collection and assembly of data: Stacy Loeb, Edward F. Vonesh, E. Jeffrey Metter, H. Ballentine Carter, Peter H. Gann, William J. Catalona

Data analysis and interpretation: Stacy Loeb, Edward F. Vonesh, E. Jeffrey Metter, H. Ballentine Carter, Peter H. Gann, William J. Catalona

Manuscript writing: Stacy Loeb, Edward F. Vonesh, E. Jeffrey Metter, H. Ballentine Carter, Peter H. Gann, William J. Catalona

Final approval of manuscript: Stacy Loeb, Edward F. Vonesh, E. Jeffrey Metter, H. Ballentine Carter, Peter H. Gann, William J. Catalona

REFERENCES

1. National Cancer Institute. Surveillance, Epidemiology and End Results (SEER) http://www.seer.cancer.gov.
2. Etzioni R, Tsodikov A, Mariotto A, et al. Quantifying the role of PSA screening in the US prostate cancer mortality decline. Cancer Causes Control. 2008;19:175–181. [PMC free article] [PubMed]
3. Bartsch G, Horninger W, Klocker H, et al. Tyrol Prostate Cancer Demonstration Project: Early detection, treatment, outcome, incidence and mortality. BJU Int. 2008;101:809–816. [PubMed]
4. Schröder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009;360:1320–1328. [PubMed]
5. Roobol MJ, Kerkhof M, Schröder FH, et al. Prostate cancer mortality reduction by prostate-specific antigen-based screening adjusted for nonattendance and contamination in the European Randomised Study of Screening for Prostate Cancer (ERSPC) Eur Urol. 2009;56:584–591. [PubMed]
6. Barry MJ. Screening for prostate cancer: The controversy that refuses to die. N Engl J Med. 2009;360:1351–1354. [PubMed]
7. Laupacis A, Sackett DL, Roberts RS. An assessment of clinically useful measures of the consequences of treatment. N Engl J Med. 1988;318:1728–1733. [PubMed]
8. Welch HG. Berkeley, CA: University of California Press; 2004. Should I Be Tested for Cancer? Maybe Not and Here’s Why.
9. Welch HG, Albertsen PC. Prostate cancer diagnosis and treatment after the introduction of prostate-specific antigen screening: 1986-2005. J Natl Cancer Inst. 2009;101:1325–1329. [PMC free article] [PubMed]
10. Hugosson J, Carlsson S, Aus G, et al. Mortality results from the Göteborg randomised population-based prostate-cancer screening trial. Lancet Oncol. 2010;11:725–732. [PubMed]
11. Suissa S. Calculation of number needed to treat. N Engl J Med. 2009;361:424–425. [PubMed]
12. Hildebrandt M, Vervölgyi E, Bender R. Calculation of NNTs in RCTs with time-to-event outcomes: A literature review. BMC Med Res Methodol. 2009;9:21. [PMC free article] [PubMed]
13. Lubsen J, Hoes A, Grobbee D. Implications of trial results: The potentially misleading notions of number needed to treat and average duration of life gained. Lancet. 2000;356:1757–1759. [PubMed]
14. Mayne TJ, Whalen E, Vu A. Annualized was found better than absolute risk reduction in the calculation of number needed to treat in chronic conditions. J Clin Epidemiol. 2006;59:217–223. [PubMed]
15. Altman DG, Andersen PK. Calculating the number needed to treat for trials where the outcome is time to an event. BMJ. 1999;319:1492–1495. [PMC free article] [PubMed]
16. Vonesh E, Schaubel DE, Hao W, et al. Statistical methods for comparing mortality among ESRD patients: Examples of regional/international variations. Kidney Int Suppl. 2000;54(suppl):S19–S27.
17. Holford TR. The analysis of rates and of survivorship using log-linear models. Biometrics. 1980;36:299–305. [PubMed]
18. Gann PH, Fought A, Deaton R, et al. Risk factors for prostate cancer detection after a negative biopsy: A novel multivariable longitudinal approach. J Clin Oncol. 2010;28:1714–1720. [PMC free article] [PubMed]
19. Bill-Axelson A, Holmberg L, Filén F, et al. Radical prostatectomy versus watchful waiting in localized prostate cancer: The Scandinavian Prostate Cancer Group-4 randomized trial. J Natl Cancer Inst. 2008;100:1144–1154. [PMC free article] [PubMed]
Articles from Journal of Clinical Oncology are provided here courtesy of American Society of Clinical Oncology

=======================================================

Screening for prostate cancer: the current evidence and guidelines controversy
Gomella G. Leonard ; Liu S. Xiaolong ; Trabulsi J. Edouard ; Kelly Kevin Wm. ; Myers Ronald ; Showalter Timothy ; Dicker Adam ; Wender Richard ; Department of Urology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
ARTICLE
Oct 2011 (Vol. 18, Issue 5, Pages( 5875 – 5883)
PMID: 22018148
PDF (141.9KB) Free

Abstract

Text-Size + –

  • INTRODUCTION: Prostate cancer presents a global public health dilemma. While screening with prostate specific antigen (PSA) has led to more men diagnosed with prostate cancer than in previous years, the potential for negative effects from over-diagnosis and treatment cannot be ignored. MATERIALS AND METHODS: We reviewed Medline for recent articles that discuss clinical trials, evidence based recommendations and guidelines from major medical organizations in the United States and worldwide concerning prostate cancer screening. RESULTS: Results from the European Randomized Screening for Prostate Cancer (ERSPC), the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, and Göteborg Swedish trials regarding prostate screening are controversial with the ERSPC and Göteborg showing a reduction in prostate cancer mortality and the PLCO trial showing no benefit. Recommendations from the American Urological Association (AUA), Japanese Urological Association (JUA), and National Comprehensive Cancer Network (NCCN) have recommended that all men obtain a baseline PSA beginning at age 40. The American Cancer Society (ACS) stratifies screening recommendations based on age and risk, but states that screening should take place only after an informed discussion between provider and patient. The United States Preventative Health Service Task Force (USPSTF) states that evidence is insufficient to assess the risks and benefits of prostate cancer screening in men younger than 75 years. Other major international health organizations offer a similar reserved approach or recommend against screening for prostate cancer. Most groups indicate that screening to determine who should undergo prostate biopsy typically includes both a serum PSA and digital rectal examination, with the latest ACS publications noting that the rectal exam is optional. A common theme from all groups is that an informed discussion with the patients is strongly recommended and that screening does increase the number of men diagnosed with non-metastatic, early disease. CONCLUSIONS: Prostate cancer screening guidelines vary widely between countries and between different medical organizations within individual countries including the United States. Further, the evidence for and against prostate cancer screening remains highly controversial. Longitudinal follow up of completed screening trials is ongoing and may yield additional findings as the time course of prostate cancer outcomes can be protracted. The literature controversy suggests that no standard of care exists for prostate cancer screening today. Until there is agreement in guidelines between major professional organizations who have weighed in on this topic, patients and physicians should be encouraged to consider engaging in shared and informed decision process concerning screening for prostate cancer.

=========================================================

N Engl J Med. 2012 Mar 15;366(11):981-90.

Prostate-cancer mortality at 11 years of follow-up.

Source

Department of Urology, Erasmus University Medical Center, Rotterdam, The Netherlands. secr.schroder@erasmusmc.nl

Abstract

BACKGROUND:

Several trials evaluating the effect of prostate-specific antigen (PSA) testing on prostate-cancer mortality have shown conflicting results. We updated prostate-cancer mortality in the European Randomized Study of Screening for Prostate Cancer with 2 additional years of follow-up.

METHODS:

The study involved 182,160 men between the ages of 50 and 74 years at entry, with a predefined core age group of 162,388 men 55 to 69 years of age. The trial was conducted in eight European countries. Men who were randomly assigned to the screening group were offered PSA-based screening, whereas those in the control group were not offered such screening. The primary outcome was mortality from prostate cancer.

RESULTS:

After a median follow-up of 11 years in the core age group, the relative reduction in the risk of death from prostate cancer in the screening group was 21% (rate ratio, 0.79; 95% confidence interval [CI], 0.68 to 0.91; P=0.001), and 29% after adjustment for noncompliance. The absolute reduction in mortality in the screening group was 0.10 deaths per 1000 person-years or 1.07 deaths per 1000 men who underwent randomization. The rate ratio for death from prostate cancer during follow-up years 10 and 11 was 0.62 (95% CI, 0.45 to 0.85; P=0.003). To prevent one death from prostate cancer at 11 years of follow-up, 1055 men would need to be invited for screening and 37 cancers would need to be detected. There was no significant between-group difference in all-cause mortality.

CONCLUSIONS:

Analyses after 2 additional years of follow-up consolidated our previous finding that PSA-based screening significantly reduced mortality from prostate cancer but did not affect all-cause mortality. (Current Controlled Trials number, ISRCTN49127736.)

==============================================================================================================


Sex after prostate cancer

The science of attraction is explored in <i>How to Get More Sex</i>.Erectile disfunction: Prostate cancer can lead to problems in the bedroom.

The media is full of articles about prostate cancer and just recently we had another scare when researchers at the Fred Hutchinson Cancer Research Centre in Seattle apparently found that men who take too many fish oil supplements or eat too much fatty fish may be likely to develop prostate cancer. Do we really need all these scare campaigns?

I rather would like to pay attention to the alarming fact that’s often overlooked when men learn they have prostate cancer.

Australia has one of the highest rates of prostate cancer diagnosis in the world, the result of regular testing.

Unfortunately, this means many men who are diagnosed receive unwarranted treatments that can leave them impotent, incontinent or both.

Advertisement

Men usually undergo needle biopsies when they have elevated levels of a blood test called prostate-specific antigen (PSA).

If the biopsy reveals cancer cells, a pathologist measures the severity in a range between one and 10. This is known as the Gleason score. Most prostate cancers score between six and seven. Several top urologists now agree that prostate cancer below a Gleason score of six should be watched but not treated.

At the Prostate Cancer World Congress in Melbourne last month, 14 opinion leaders agreed on a prostate cancer testing schedule. They believe that all men in their 40s should have a baseline PSA test to help predict their risk of developing prostate cancer.

Men who have a low risk won’t need to be tested again for five to seven years. Those who have a reading above the median for their age will be put under “active surveillance” with regular biopsies and blood tests. But they will have treatment only if the disease shows signs of progressing.

Testing should be decoupled from treatment which could have unwelcome outcomes for many men. Men with low-risk prostate cancer do not need aggressive treatment, which can leave them with sexual dysfunction or incontinence.

Until 1982 most men who had radical prostate surgery became impotent but then Patrick Walsh, a urologist at the Johns Hopkins Medical Institutions, performed the first deliberate nerve-sparing prostate surgery.

Nerve sparing is now widely available, but it remains a demanding operation to perform and it is difficult to assess if all the nerve fibres are spared.

The consensus is that when nerves can be preserved during surgery, they have the capacity to repair themselves and a man will not lose his potency.

But several urologists admit that even after a successful operation, there is no objective data to confirm what has been preserved and it is always possible that nerves have been injured.

If there is permanent nerve damage maintaining an erection will be difficult. But nerves can repair themselves slowly and it is therefore extremely important to start penile rehabilitation the day after surgery. This ensures that the tissues in the penis stay healthy while the spared nerves recover and that all the blood vessels are open to the blood flow that produces erections.

To encourage blood flow, the doctor often prescribes low doses of Viagra or Cialis for about three months, and may suggest using a vacuum device, penile injections or masturbation to keep the “machinery” running.

For some prostate treatment can lead to a psychological barrier to sex. Many men feel a loss of masculinity and sadness about their inability to sustain an erection. It’s therefore important for men to know they can seek help when they have problems with sex after their operations.

But it’s even better to be as informed as possible before starting treatment. I suggest to partners that they go together to see their sexual health physician and surgeon to get all the information they need. I also refer them to a physiotherapist who teaches special pelvic floor exercises before treatment, which can help to get rid of incontinence after surgery.

A new support program, PROSTMATE, funded by Australian Prostate Cancer Research will provide online intervention and self-management strategies after it starts in November.

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