ASCO: Gene Test Predicts Prostate Cancer

ORLANDO, June 2 -- A set of six genes, measured in a blood test, can be used to tell whether a man has prostate cancer, a researcher said here.

In a case-control study, the six-gene panel outperformed a standard test -- age-adjusted prostate specific antigen -- in distinguishing between men with cancer and those without, according to Robert Ross, M.D., of Dana-Farber Cancer Institute in Boston.

When prostate specific antigen (PSA) levels were added to the group of genes, the performance of the test improved even more, Dr. Ross told attendees at the annual meeting of the American Society of Clinical Oncology.

The gold standard for diagnosing prostate cancer is a biopsy, he said, but 60% of biopsies in men thought to be at risk for the disease turn out to be negative.

The goal of this test is to avoid the "pain, discomfort, and anxiety" associated with biopsies, Dr. Ross said, by winnowing out the 60% of men who don't need the procedure.

Dr. Ross and his colleagues started with a set of 392 genes associated with inflammation, cancer, and the epidermal growth factor receptor, as well as some identified in other genetic studies of cancer.

In a training set of 76 healthy men and 76 with prostate cancer, six genes were significantly associated with disease. Of the six, five are less active in those with the disease and one has greater activity, the researchers found.

The finding was validated in a second cohort of 128 men with cancer and 94 without, he said.

In the second group, the six-gene test correctly detected 85.9% of the men with disease, compared with 69.5% detected by age-adjusted PSA, Dr. Ross said.

The six-gene test had a specificity of 83%, compared with 93.6% for PSA, he said.

When the researchers did both the six-gene test and measured PSA levels, the sensitivity and specificity improved -- to 87.5% and 92.6%, respectively.

The results are a "significant improvement" over the predictive value of PSA alone, Dr. Ross said.

"From a clinical hypothesis standpoint, this is great data," Dr. Ross said. But, he cautioned, "this is a case-control study (and) you'd like to see it validated prospectively."

He said his institution and several others are collaborating on a 1,000-patient prospective study -- dubbed PRECISE -- among men who meet the criteria for a biopsy, but have not yet had the test.

The goal will be to see if the test can predict the results of biopsy, he said.

Although the test is still in development, it will not be expensive, especially compared with the $2,000 it costs for a biopsy, said Karl Wassman, of Source MDx, the Boulder, Colo. company that has developed the test.

He said the blood test can be read by standard equipment, using a kit of primers and probes developed by Source MDx, so that the cost will be in the range of "a couple of hundred" dollars.

The various forms of PSA testing are "extremely valuable" in screening for prostate cancer, said Howard Sandler, M.D., of Cedars-Sinai Medical Center in Los Angeles, who was not involved in the study.
But the jury is out on whether screening and early detection have any benefit for patients, he said.

"If screening is beneficial, then better screening is important," he said, but there's no high-quality evidence that early detection is useful.

Dr. Sandler said the "weakness of this test" is that it doesn't answer the most important question about prostate cancer.

"The question is do you have clinically relevant prostate cancer or not?" he said. "Do you have potentially lethal cancer or do you have the cancer that will never kill you?"

Dr. Ross agreed that that question is important and said he and his colleagues have preliminary data that suggests it may be possible to use such a test to distinguish between types of cancer.

The study was supported by Source MDx, Dana Farber and the Harvard Cancer Center, the Gelb Center, and the Bing Sound Wong Fund.
Several researchers reported financial links with Source MDx.

Dr. Sandler reported financial links with sanofi-aventis, Genentech, Amgen, and AstraZeneca.

Primary source: Journal of Clinical Oncology
Source reference:
Ross RW, et al "Sensitivity and specificity of a whole-blood RNA transcript-based diagnostic test for the diagnosis of prostate cancer (CaP) compared with prostate-specific antigen (PSA) alone" J Clin Oncol 2009; 27(15S): Abstract 5052.

New Blood Test Greatly Reduces False-positives In Prostate Cancer Screening

ScienceDaily (May 28, 2009) — A new blood test used in combination with a conventional prostate-specific antigen (PSA) screening sharply increases the accuracy of prostate cancer diagnosis, and could eliminate tens of thousands of unneeded, painful, and costly prostate biopsies annually, according to a study led by researchers at Dana-Farber Cancer Institute.

At the annual meeting of the American Society of Clinical Oncology in Orlando, Fla., William K. Oh, M.D., and Robert W. Ross, M.D., will report that the six-gene molecular diagnostic test, when combined with a PSA test, accurately detected prostate cancer more than 90 percent of the time. Earlier studies suggest that the conventional PSA test is 60-70 percent accurate in detecting cancer. The findings will be discussed at a poster session on May 31.

Men who are found to have elevated levels of PSA in routine screening tests are often referred for a biopsy of the gland to check for tumors. Nearly two-thirds of biopsies performed -- a painful procedure with some risk of complications -- do not find any cancerous cells. This high rate of "false positive" PSA test results underscores the need for a more accurate method for detecting prostate cancer, said Oh, who is the clinical director of the Lank Center for Genitourinary Oncology at Dana-Farber.

The two-year study involved 484 participants. The group comprised 204 men with known prostate cancer, 110 men with benign prostatic hypertrophy (BPH), and 170 healthy men in a control group. (BPH can elevate PSA levels in the blood, which often leads to a biopsy to rule out prostate cancer.) These groups were split into age-matched training and validation sets.

The researchers sought to measure the accuracy of a six-gene whole blood RNA transcript-based diagnostic test developed by Source MDx in Boulder, Colo., both in terms of its sensitivity (the ability to detect prostate cancer) and specificity (the ability to identify people who don't have prostate cancer).

Source MDx researchers developed the test after initially working with a set of 174 candidate genes whose activity was compared in the different study groups. They narrowed the pool down to just six genes that, as a group, were highly sensitive in predicting which patients had prostate cancer and which were normal.

The study found that "the six-gene model was more accurate than PSA alone at predicting cancer if you had it and no cancer if you didn't," said Oh. The test's accuracy improved even more when PSA measurements were added. Combined, the two tests achieved a diagnostic accuracy of more than 90 percent in specificity and sensitivity and eliminated most of the false-positives yielded by the PSA test.

Based on these findings, the researchers are planning to conduct a larger, multicenter clinical trial involving approximately 1,000 men to determine if the findings remain valid.

"These findings are very encouraging and suggest that this new test could spare tens of thousands of men from undergoing an unnecessary biopsy," Oh said. "However, until we can verify our findings, it is important to recognize that the PSA test, despite its limitations, is still the best test available for diagnosing prostate cancer at this time."

The study was funded in part by Source MDx and a Prostate Cancer SPORE grant at Dana-Farber/Harvard Cancer Center.

Quick Test For Prostate Cancer

ScienceDaily (May 18, 2009) — A new 3-minute test could help in diagnosing prostate cancer, the most common cancer in men in the UK, according to scientists.

Researchers have developed the test by using light energy to measure the level of citrate in fluid samples from the prostate gland. The technique could provide the basis of a rapid means of detecting prostate cancer in the future. Almost a quarter of male cancers in the UK are diagnosed as prostate cancer and more than 10,000 men die from the disease each year.

Scientists, led by Prof David Parker from Durham University's Chemistry Department, have worked with experts from the University of Maryland, USA to develop the technique that measures the wavelength of light as it is shone through diluted samples of body fluids.

The research team, funded by the North East Proof of Concept Fund and the EPSRC, believe that the technique which can measure, with speed and accuracy, how citrate levels fall in the prostate gland as cancer develops, could also find use for the diagnosis of other medical conditions, associated with poor kidney function.

Prof Parker said: "Citrate provides a significant biomarker for disease that may provide a reliable method for screening and detecting prostate cancer, and for the monitoring of people with the disease. This technique could form the basis of a simple screening procedure for prostate cancer that could be used in outpatient departments at local hospitals."

His team have shone light into over 100 different chemical structures to see how they function and respond to the presence of certain important bioactive species. They have looked particularly closely at how citrate and lactate bind to luminescent structures within fluids.

Citrate and lactate are vital for our bodies' metabolism for normal function. Citrate provides energy for cells and the amount found in the prostate varies considerably due to an enzyme called m-aconitase which transforms it. This enzyme is very sensitive to zinc and, in prostate cancer sufferers, zinc levels are depressed and the enzyme switches on again.

Prof Leslie Costello from the University of Maryland said: "Citrate is formed in cell metabolism processes which alter as cancers grow. The analysis of the citrate concentration of prostatic fluid can provide an accurate way to screen and diagnose prostate cancer.

Since citrate concentrations decrease markedly early in malignancy, this technique makes it possible to analyse what's happening quickly in the early and treatable stage of prostate cancer. It shows much promise as a clinical tool."

The new test requires only a microlitre of fluid and the sample can be easily measured in an optical instrument. Using samples from male volunteers, the researchers have developed a portable instrument that can give results in 3 minutes.

The team's challenge has been how to accurately measure changes in the amount of citrate or lactate in fluid samples using the technique. The early results are promising and the team intends to look at the analysis of other body fluids. A possible way forward is to examine the citrate levels in seminal fluid samples, which are made up of 50% prostate fluid.

The University has launched a spin-out company called FScan Ltd to develop the technique and to seek commercial backing. The team has looked at 20 samples so far and verified the analysis in every case. The next stage is to work with a local hospital and examine samples from 200 volunteers to see whether the first Durham results correlate.

Prof Parker says: "It's been a complex process to develop the technique but we're very optimistic about it. Ultimately, this could provide an accurate method of screening for prostate cancer in men that could be carried out in 3-minutes once a biopsy has been obtained from the patient at a hospital outpatient department."

The discovery follows the invention in 2006 by Durham University Professor Douglas Newton of a Urine Flow Meter. The UFlow Meter helps men to assess if they have a restricted rate of urine flow - one of the warning signs of prostate problems.

The establishment of FScan Ltd is part of the University's aim to enhance the exploitation of the Intellectual Property generated by high quality research activities.

Tim Hammond, Head of Technology Transfer at Durham University, said: '"We quickly realised the potential of this research and have worked closely with Professor Parker and his team to secure initial proof of concept funding through NorthStar Equity Investors and the North East Proof of Concept Fund and to establish FScan Limited as the vehicle to validate and commercialise the technology."


Process for testing:

• Sample of prostatic fluid taken from patient in hospital using local anaesthetic 200 fold dilution of 1 microlitre of sample with a buffer solution into pre-coated disposable cuvettes.
• Optical spectroscopy on the sample, using a versatile bench top instrument with easy to use software.
• Reading of results after 3 min measurement cycle directly reading out actual citrate concentration.
• The sample is taken from the prostate gland – this is part of the biopsy procedure during clinical analysis in urology.

Scientists Find New Way to Identify Deadly Forms of Prostate Cancer

Researchers have discovered a new method to help doctors identify the most aggressive forms of prostate cancer.

A struggle for medical professionals in identifying prostate cancer is determining which forms are very aggressive and will require surgery and which forms are dormant and can be left untreated without risk.

Reporting in the British Journal of Cancer Research, scientists noted that bubbles of fat passed through the urine could provide new clues to deciding how to treat individuals with prostate cancer.

With about 34,000 new cases being found each year, prostate cancer is the most common form of cancer among men in the UK.

Doctors have previously used prostate specific antigen testing to screen patients for prostate cancer.

PSA testing can produce faulty results. Researchers have discovered that fatty capsules, called exosomes, come directly from the tumor and contain genetic information about they cancer.

“We hope that this innovative approach to studying prostate cancer will reveal new biomarkers for aggressive tumors,” said Dr Jonas Nilsson, at the VU University Medical Centre in Amsterdam.

“Tumor-derived RNA is preserved in these capsules and gives us an insight into the genetics of an individual’s tumor.”

But Matthew Shuford, urologist at Baylor University Medical Center at Dallas, said that PSA testing is still effective, and it saves lives.

“Keep in mind that it is only curable when caught early; it can only be caught early by screening; and the screening is a simple blood test that is cheap and easy.”

Approximately 90 percent of all prostate cancers are currently diagnosed at an early stage, according to the National Cancer Institute.

“Early diagnosis greatly increases a man’s chances of successful treatment,” said Dr. Shuford.

American Urological Association Counters Mainstream Recommendations With New Best Practice Statement On PSA Testing

ScienceDaily (Apr. 27, 2009) — The American Urological Association (AUA) has issued new clinical guidance – which directly contrasts recent recommendations issued by other major groups – about prostate cancer screening, asserting that the prostate-specific antigen (PSA) test should be offered to well-informed, men aged 40 years or older who have a life expectancy of at least 10 years.

The PSA test, as well as how it is used to guide patient care (e.g., at what age men should begin regular testing, intervals at which the test should be repeated, at what point a biopsy is necessary) is highly controversial; however, the AUA believes that, when offered and interpreted appropriately the PSA test may provide essential information for the diagnosis, pre-treatment staging or risk assessment and post-treatment monitoring of prostate cancer.

The new Best Practice Statement updates the AUA's previous guidance, which was issued in 2000. Major changes to the AUA statement include new recommendations about who should be considered for PSA testing, as well as when a biopsy is indicated following an abnormal PSA reading.

According to the AUA, early detection and risk assessment of prostate cancer should be offered to well-informed men 40 years of age or older who have a life expectancy of at least 10 years. The future risk of prostate cancer is closely related to a man's PSA score; a baseline PSA level above the median for age 40 is a strong predictor of prostate cancer.

Such testing may not only allow for earlier detection of more curable cancers, but may also allow for more efficient, less frequent testing. Men who wish to be screened for prostate cancer should have both a PSA test and a digital rectal exam (DRE).

The Statement also notes that other factors such as family history, age, overall health and ethnicity should be combined with the results of PSA testing and physical examination in order to better determine the risk of prostate cancer. The Statement recommends that the benefits and risks of screening of prostate cancer should be discussed including the risk of over-detection, detecting some cancers which may not need immediate treatment

"The single most important message of this statement is that prostate cancer testing is an individual decision that patients of any age should make in conjunction with their physicians and urologists. There is no single standard that applies to all men, nor should there be at this time," Dr. Carroll said. He also notes that the "panel carefully reviewed the most recently reported trials of PSA testing in both the United States and Europe before finalizing their guidelines. The strengths and limitations of these trials are reviewed in the guideline."

In regard to biopsy, a continuum of risk exists at all values, and major studies have demonstrated that there is no safe PSA value below which a man may be reassured that he does not have biopsy-detectable prostate cancer.

Therefore, the AUA does not recommend a single PSA threshold at which a biopsy should be obtained. Rather, the decision to biopsy should take into account additional factors, including free and total PSA, PSA velocity and density, patient age, family history, race/ethnicity, previous biopsy history and co-morbidities.

Additionally, the AUA statement emphasizes that not all prostate cancers require active treatment and that not all prostate cancers are life-threatening. The decision to proceed to active treatments is one that men should discuss in detail with their urologists to determine whether active treatment is necessary, or whether surveillance may be an option for their prostate cancer.

"Prostate cancer comes in many forms, some aggressive and some not," said Peter Carroll, MD, chair of the panel that developed the Statement. "But the bottom line about prostate cancer testing is that we cannot counsel patients about next steps for cancer that we do not know exist." He also notes that "the AUA is committed to the timely, expert and appropriate care for men either with or at risk of getting prostate cancer and is prepared to revise these guidelines continuously as new information becomes available."

Additionally, the Best Practice Statement clarifies a number of key points about the use of PSA in treatment selection and post-treatment follow up of prostate cancer patients:

• Serum PSA predicts the response of prostate cancer to local therapy.
• Routine use of a bone scan is not required for staging asymptomatic men with clinically localized prostate cancer when their PSA level is equal to or less than 20.0 ng/mL.
• Computed tomography or magnetic resonance imaging scans may be considered for the staging of men with high-risk clinically localized prostate cancer when the PSA is greater than 20.0 ng/mL or when locally advanced or when the Gleason score is greater than or equal to 8.
• Pelvic lymph node dissection for clinically localized prostate cancer may not be necessary if the PSA is less than 10.0 ng/mL and the Gleason score is less than or equal to 6.
• Periodic PSA determinations should be offered to detect disease recurrence.
• Serum PSA should decrease and remain at undetectable levels after radical prostatectomy.
• Serum PSA should fall to a low level following radiation therapy, high intensity focused ultrasound and cryotherapy and should not rise on successive occasions.
• PSA nadir (low point) after androgen suppression therapy predicts mortality.
• Bone scans are indicated for the detection of metastases following initial treatment for localized disease, but the PSA level that should prompt a bone scan is uncertain. Additional important prognostic information can be obtained by evaluation of PSA kinetics (velocity).
• The kinetics of PSA rise after local therapy for prostate cancer can help distinguish between local and distant recurrence.

The new AUA statement is based on panel review of all available professional literature, members' clinical experience and expert opinion.

Adapted from materials provided by American Urological Association, via EurekAlert!, a service of AAAS.

Drug Shows Activity In Men With Advanced Prostate Cancer

ScienceDaily (Apr. 8, 2009) — A new multi-center study shows that an experimental drug lowers prostate specific antigen (PSA) levels – a marker for tumor growth – in men with advanced prostate cancer for whom traditional treatment options have failed. The study, led by researchers at Memorial Sloan-Kettering Cancer Center (MSKCC), is published in Science Express, the online version of the journal Science.

Most men with metastatic prostate cancer eventually build up resistance to the drugs that lower or block male hormones and develop a more aggressive form of the illness called castration-resistant prostate cancer (CRPC), or hormone-refractory disease. According to the study's findings, investigators studied two novel compounds, RD162 and MDV3100, and not only gained an understanding of their novel mechanism of action, but found that these agents showed activity in CRPC cells in culture and in mice.

The study also reports on a Phase 1/2 trial of MDV3100 in 30 patients with advanced CRPC and found that 22 out of 30 men showed declining PSA levels, and 13 out of 30 men (43 percent) had PSA levels fall by more than half.

Several years ago, the senior author of the study, Charles Sawyers, MD, and his colleagues at the University of California, Los Angeles (UCLA), uncovered a potential reason why metastatic prostate cancer patients eventually relapse with CRPC. This insight was used to discover RD162 and MDV3100.

"It's gratifying to know that our hypotheses about why men develop resistance to currently available treatments are confirmed and, most importantly, that there are already patients who are benefiting from our research," said Dr. Sawyers, Chair of the Human Oncology and Pathogenesis Program at MSKCC and a Howard Hughes Medical Institute investigator.

Current treatments for men who have advanced prostate cancers inhibit the activity of male hormones that help drive tumor growth. Many of these drugs disrupt the androgen (male hormone) receptor, which helps regulate cell proliferation, but tumors eventually become resistant to the drugs by expressing higher levels of the receptor. Preclinical studies by Dr. Sawyers and others have demonstrated that CRPC cells have increased expression of the androgen receptor and that overexpression of this receptor may contribute to the progression of disease.

Based on this information, Dr. Sawyers initiated a collaboration with Michael Jung, PhD, Professor of Chemistry at UCLA, that led to the discovery of a number of nonsteroidal, small molecule antiandrogen compounds, including MDV3100, which has been shown to retain its anticancer activity, even when the receptor's expression is elevated.

"The discovery and initial development of this drug was a collaborative effort all done in the academic setting, without reliance on the engine of the pharmaceutical industry that typically drives drug development," said Dr. Sawyers.

Dr. Jung's group synthesized the compounds, which Dr. Sawyers' team then evaluated using prostate cancer mouse models engineered to highly express the androgen receptor, mimic progression to castration-resistant disease, and reflect the biology of clinical drug resistance.

According to the new study, the team of researchers tested various compounds to block the androgen receptor in CRPC cells. They chose to further evaluate the drug RD162 and a closely related compound, MDV3100. According to their findings, both drugs inhibit the androgen receptor function by impairing the receptor's ability to enter a CRPC cell's nucleus (called nuclear translocation), blocking it from binding to the DNA of its target genes, and preventing the cell from growing.

They found that both compounds worked well in cells in culture, shrank tumors in mice, maintained tumor shrinkage for months, and prevented the androgen receptor from activating additional genes later in the process, or "downstream." Other currently approved drugs cannot disable the receptor in such a way.

The biopharmaceutical company Medivation, Inc., licensed RD162 and MDV3100 from UCLA in 2006 and has already completed enrollment in the first human trial of oral MDV3100 – a Phase 1/2 clinical trial, which was led by investigators at MSKCC and conducted through the Prostate Cancer Clinical Trials Consortium.

The Consortium is sponsored by the Department of Defense and the Prostate Cancer Foundation. The trial enrolled men with metastatic, castration-resistant prostate cancer who relapsed after treatment with conventional hormone therapy and demonstrated anti-prostate cancer effects beginning with the first patient treated with MDV3100 at the lowest dose. Further positive results from an additional 110 patients who received the drug at higher doses were recently reported at the ASCO Genitourinary Cancers Symposium in February 2009.

"The declines in PSA levels observed thus far and the general tolerability of this treatment are encouraging," said Howard Scher, MD, a study co-author and Chief of the Genitourinary Oncology Service at MSKCC. "I am looking forward to continuing the study of this drug, which has the potential to be a powerful tool in a limited arsenal of treatments against this deadly form of the disease." A Phase 3 trial is planned to begin later this year.

The study was supported in part by the Prostate Cancer Foundation, the National Cancer Institute, and a Prostate Cancer Research Program Clinical Consortium Award.

Prostate cancer screenings: a second opinion

Doctors are rethinking the value of the tests because the disease is rarely a killer and the treatment can do serious harm. By H. Gilbert Welch - April 1, 2009.

I probably have prostate cancer.

There's no need to feel sorry for me -- so do about half the men my age (I'm in my mid-50s). We doctors have learned this from microscopic examinations of the prostates of men who are autopsied following an accidental death. And the older men get, the more likely it is that they have prostate cancer. Autopsies of men in their 70s have found that about 80% of them had the disease.

I almost certainly won't die from prostate cancer, however. The lifetime risk of prostate cancer death for American males is only about 3%. So, although the prevalence of the cancer may sound alarming, 97% of men will die from something else.

These two observations have forced doctors to rethink what it means to have this cancer. Some have envisioned the problem to be like an iceberg. In the past, we only saw the part of the iceberg above the waterline -- the cancers that caused disease and death. With early detection, we can see below the waterline -- and there are a lot more cancers there. Many of these will never cause problems. They would have been better off undiagnosed.

But doctors can't tell who is better off undiagnosed. We can't reliably distinguish between prostate cancers that will never cause symptoms and those that are deadly. So we tend to treat everyone. The bulk of men who are treated won't benefit from it, because there is nothing to fix. But many of them will be harmed. Treatment causes significant side effects in about 30% of those treated, most commonly a decline in sexual function, leaking urine and/or rectal irritation.

That's why prostate cancer screening is such a challenging issue. Yes, it may save some men's lives, but it will harm many others along the way.

Two weeks ago, we learned more. The results of two large, randomized trials of prostate cancer screening were published. The studies represented an enormous research effort: almost 20 years of work, involving more than a quarter of a million men and many millions of dollars.

Yet there is still some uncertainty whether screening saves any lives. The European study said yes; the U.S. study said no. That in itself tells you something: If there is a benefit, it is undoubtedly small. In contrast, researchers in the 1960s were able to convincingly demonstrate the benefit of treating very high blood pressure by studying about 150 men over a two-year period. Why were they able to do this with so few men so quickly? Because the benefit was huge.

I believe there probably is a benefit to prostate cancer screening. But it is accompanied by a substantial human cost. Let's assume the European study is right. Its data gives us some idea of the magnitude of the trade-off: For every man who avoids a prostate cancer death, about 50 are treated needlessly (some of my colleagues might say the number is closer to 30, others might say it's closer to 100).

Being 50 times more likely to be diagnosed and treated needlessly than being the one man who avoids a prostate cancer death doesn't strike me as a good gamble. To the extent I have control over my cause of death, avoiding a prostate cancer death isn't my top priority (I'm more concerned about a lingering cognitive decline in a long-term care facility.) And death is not the only outcome that matters to me. I place considerable value on not being medicalized and suffering the side effects of treatment any more than I need to.

But it doesn't matter what I think about the trade-off. What matters is what you think.

American men have been engaged in prostate cancer screening for almost two decades with relatively little effort given to communicating the trade-off between the benefit and the potential harm of unnecessary treatment. The time has come to make that trade-off clear. There are a lot of bad arguments out there for screening. They include:

* Doctors who tell you they don't want to go back to the era when all their prostate cancer patients had advanced disease. It is true that the typical prostate cancer patient in the past had advanced disease. But we now know that the primary reason these patients now seem so rare is that they are being diluted by the many new prostate cancer patients who would have never been diagnosed in the past -- the majority of whom had cancers that weren't destined to progress.

* Media messages that highlight the tremendous improvements in survival. It is true that over the last 50 years, the five-year survival for prostate cancer has increased more dramatically than any other cancer (from less than 50% to almost 100%). But we now know that these numbers too are largely an artifact of over-diagnosis -- diagnosing a lot of men with prostate cancer who were never destined to die from the disease.

* Friends, family, acquaintances or celebrities who "owe their life" to screening. There are now a lot of men who appear to be in this group. But once you understand the problem of over-diagnosis, you recognize an alternative explanation: They never needed treatment in the first place. Some have labeled this the popularity paradox of screening: The more over-diagnosis screening causes, the more people who feel they owe it their lives and the more popular screening becomes.

There is no imperative to be screened, or not screened, for prostate cancer. The only imperative is that men be informed about the consequences of either choice.

H. Gilbert Welch is a professor of medicine at the Dartmouth Institute of Health Policy and Clinical Practice. He is the author of "Should I Be Tested for Cancer? Maybe Not and Here's Why."

Digital rectal prostate exam a ritual of doctor-patient bonding, for good and bad

The practice, and its awkwardness, will come less often into play as U.S. Preventive Services Task Force guidelines now advise against it for men age 75 and over.

By Anna B. Reisman

November 3, 2008

In August, the U.S. Preventive Services Task Force, a government-sponsored panel of medical experts, issued new recommendations regarding prostate cancer screening: Men ages 75 and over should no longer be screened for prostate cancer with the PSA blood test or digital rectal exam.

An unexpected benefit may be an improvement in the doctor-patient relationship. The rectal exam can be one of the odder moments between a patient and his doctor. Not long ago, for example, I saw a 75-year-old for his routine annual visit. Things were not going well for him.

His wife's dementia was worsening daily. She would leave the stove on, accuse him of stealing her things, holler at him day and night. And yet he could not imagine putting her in a nursing home.

His eyes, usually sparkling with delight, were dull. As I examined his heart and lungs, neck and belly, ankles and feet, he heaved a long sigh. I felt gloomy about his wretched situation.

I must have been preoccupied, because when it was time for the rectal exam, I bumbled my words. I asked him to lower his pants, but instead of saying "Lie on the table," I told him to lie on the floor. The patient and I burst out laughing.

Still chuckling, I stepped out of the room so he could get ready. To be sure, my bumble had brought levity to a traditionally awkward moment -- but why, I asked myself, did this encounter have to end with an examination of his anus?

I was drawn to primary-care medicine by the human connection that comes with the white coat and stethoscope, the prospect of people willing to share their everyday thoughts and deepest secrets, and their expectation that I would use this information to help them.

What I didn't fully grasp was that this intimacy also had a critical physical component -- one that came gloved and lubed.

I'd never imagined that performing rectal exams would become a daily reality. Most of my patients are men over 50, which means that I ask them if they'd like to be screened for prostate cancer.

Some inquire whether the PSA (prostate-specific antigen) blood test alone will suffice. I explain that it's most informative to have both the PSA and the digital exam: Some cancers hide in prostate nodules in men whose PSA readings are normal.

So for men under 75 and over 50 (earlier for higher-risk men) who wish to be screened, just as important as the PSA is the old-fashioned, low-tech way with a pair of rubber gloves, a foil packet of lubricating jelly and an index finger.

For years I didn't feel confident in my ability to do a good rectal exam. In medical school, we spent about two months learning the heart exam, maybe one month on the lungs. The rectal exam was granted a single session.

Not surprising: It's one thing for a parade of students to line up, stethoscopes ready, at the bedside of a chatty patient with a heart murmur; it's quite another to find a patient willing to roll over and endure a series of rectal exams by unskilled, anonymous fingers. The result: a culture of squeamishness.

During residency, I did a lot of rectal exams and tried to get a sense of the prostate's normal size and consistency. But often I wasn't sure of myself. Was a slight asymmetry a normal variant or something worrisome?

I probably sent too many patients to urologists earlier in my career because of my self-doubt, but that was better, I suppose, than missing something.

And although plenty of men will hop onto the exam table without hesitation, there's no shortage of reluctant and nay-saying patients, of awkward silences followed by excuses.

One patient I recall stole a glance at my hands, the muscles in his face relaxing ever-so-slightly when he looked at my fingers. "My old doctor," he said, "had thick fingers, like sausages."

Another said, "My other doctor did one a few months ago, I think." And another, "Next time, I promise." Many opt for the PSA without the rectal exam.

Back in my exam room, the patient lay on the exam table in a fetal position, pants down, buttocks exposed, testicles dangling.

I examined his rectal area for internal hemorrhoids, the subtle edge of an anal fissure, the flat cauliflower of an anal wart, and found none.

I touched the precise spot of the anal skin that elicits the mischievously named "anal wink reflex," a test of nerve function. I dabbed my finger with the jelly and eased it in against the muscular resistance until I touched the prostate.

To feel the whole prostate and distinguish between its two lobes, I bent my knees, turned my arm upside down and swiveled my finger to reach the other side of the gland. It was the size of an apricot, smooth and rubbery.

As usual, I grimaced: The rectum has muscles that clench and unclench at the slightest sensation, and it always feels odd to have my finger locked in that tight embrace. It doesn't get more intimate than this.

Then I closed my eyes and focused on all of the nerve endings packed closely in my fingertip. As my finger swept the prostate gland, I felt its normal consistency, its symmetry and, to my relief, not a single nodule.

It was almost a Zen moment: worlds of otherwise hidden information uncovered through careful probing -- earlier, via conversation; now, via a digit.

I wiped my finger on the stool-sample card and discarded my gloves. The old man looked over his shoulder from the table, the twinkle in his eyes returned. "Does this mean we're friends?"

There's nothing like an awkward joke to defuse an awkward moment. But thanks to the U.S. Preventive Services Task Force, there may now be fewer of both.

Prostate Cancer Patients Pick Treatments That May Worsen Quality of Life

Men with early-stage prostate cancer frequently choose treatments that worsen problems they already have, according to a new study published in Cancer.

Researchers from Boston University School of Public Health, Dana-Farber Cancer Institute, Harvard Medical School, Harvard Radiation Oncology Program, and Massachusetts General Hospital found that of 438 men who completed the study, 389 (89%) reported pre-existing urinary, bowel, or sexual problems, yet more than one-third opted for treatments that made them more vulnerable in those areas.

"Prostate cancer patients experience the same fears and hard decisions as all cancer patients do, but prostate cancer treatment directly affects very personal things that most people aren't comfortable talking about—urinary, bowel, and sexual function," lead researcher James Talcott, MD, SM, of the Center for Outcomes Research at Massachusetts General Hospital (MGH) Cancer Center, said in a statement. "In this case, however, having that information matters because the 3 major treatments available to patients have different patterns of potential side effects. Knowing if patients already have problems in these areas should help guide treatment options."


A High Degree of Mismatch

The 3 most common active treatments for prostate cancer -- brachytherapy, external beam radiation therapy, and radical prostatectomy -- have been shown to be about equally effective in clinical trials. But each has its own unique set of urinary, bowel, and sexual side effects that need to be taken into consideration when choosing a treatment.

A man with urinary irritation or difficulty passing urine, for example, might be advised against brachytherapy because it can make these symptoms worse. Likewise, men with bowel problems would likely be discouraged from external beam radiation therapy because it can affect the rectum as well as the prostate. Nerve-sparing radical prostatectomy is typically done in an effort to preserve sexual function. In some cases, though, this approach might reduce the chance that a surgeon can remove the entire tumor, so for men who already have erectile dysfunction, the risks of this procedure might outweigh any quality-of-life benefits.

The men in the study were recruited from Boston-area multi-specialty treatment centers. They answered questions about their urinary, bowel, and sexual function before they underwent treatment.

The researchers then classified the men into 4 groups. The first 2 groups had a urinary, bowel, or sexual problem that would likely make 1 of the 3 most common prostate cancer treatments inappropriate. The inappropriate treatment was more clear-cut for men in Group I than those in Group II. Patients in Group III had problems in several areas, but were felt to have at least one "appropriate" treatment option. Men who had problems that would be further aggravated by all of the treatments fell into Group IV.

The researchers found a surprising number of mismatched treatments among the study participants, regardless of the clinical complexity of their cases. About 34% of Group I patients received a treatment that might have worsened a pre-existing problem, compared to 37% in Group II and 40% in Group III.

Not surprisingly, choosing a mismatched treatment had negative effects. More men who had bowel problems prior to external beam radiation therapy reported diarrhea, pain with bowel movements, bowel urgency, and rectal bleeding. Patients who had urinary problems prior to brachytherapy were more likely to report painful urination. They also reported more need to urinate at night, though the difference did not reach statistical significance. Nearly all men with sexual dysfunction continued to have trouble in that regard after radical prostatectomy, regardless of whether a nerve-sparing procedure was used.


Emphasizing Quality-of-Life Concerns

The authors offer several hypotheses to explain why many men didn't seem to take these problems into account as part of their treatment decision-making. Some men may make decisions hurriedly and base their decisions on anecdotes and misconceptions (see "Fear, Anecdotes Often Trump Facts When Men Make Prostate Treatment Decisions.")

Another explanation is that men might have a hard time talking to their doctors about sensitive issues, making it harder for physicians to determine the extent of any dysfunction. Talcott and his co-authors suggest physicians consider using questionnaires to get more candid responses to sensitive quality-of-life questions.

The authors also note that there are other factors that might legitimately enter into treatment decisions. For example, some men might not consider external beam radiotherapy if radiotherapy centers are not close enough for daily treatments to be practical.

Mark S. Litwin, MD, professor of urology at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA), and the UCLA School of Public Health and a researcher at UCLA's Jonsson Comprehensive Cancer Center, calls this a "great study that provides real opportunities for quality improvement." He agrees that there's a real need for a standardized pre-consultation questionnaire. "We should use any tool we can to better understand and better inform our patients," says Litwin, who was not involved in the research.

But Litwin sees the problem in a slightly different light: "It's not that men don't tell their doctors about their pre-existing problems, but that they have a skewed perspective of them, and as a result, of their treatment outcomes. We in medicine need to do a better job of sitting down with our patients and explaining how these treatments are going to affect quality of life."

Only around 5% of the men in each group chose "watchful waiting," or "active surveillance," a percentage Litwin and the researchers suggest reflects the tendency in the United States to over-treat prostate cancer in some cases. "We need to lay out the quality-of-life compromises associated with active treatment and help guide patients who should embrace active surveillance," Litwin said.



Citation: "Treatment 'Mismatch' in Early Prostate Cancer." Published online Nov. 26, 2007, and in the Jan 2008 issue of Cancer (Vol. 112, No.1). First author: James Talcott, MD, SM, Center for Outcomes Research at Massachusetts General Hospital (MGH) Cancer Center.

Radiation Therapy - Week THREE

DAY FIVE

Today I received the results of my liver function test - courtesy of Nurse Judy! I had no sooner asked if she could contact the doctor for me and request them on my behalf; when PRESTO! There was Nurse Judy approaching me with a 'printout' of the results in her hot little hand!

Never one to disappoint, Nurse Judy had simply 'taken over the NUM's office'; used his computer to look up the results and sent them off to the nearby printer. That easy! I had been waiting 4 days for the doctor to contact me! There's nothing like knowing the 'go to person' for getting things done!!

Now after all that ... there was nothing outstanding about the results; so that's another one for the good guys!

The Radiation Treatment went well again today - no hiccups. The staff and I are becoming more like friends than a strictly professional, patient to health professional relationship.



I must admit I really enjoy their company and it certainly makes the daily treatment much more tolerable. In fact, all of the 'hands on' staff have been amazing; from the front desk (reception) to the Linear Accelerator team.

Testing for Prostate Cancer

The following is excerpt from the Prostate Cancer Foundation's website. I have reproduced the information here, but encourage all readers to visit the above website.

Caught in its early stages prostate cancer can be cured especially when the cancer is still confined within the prostate gland. Testing through a blood test - the Prostate Specific Antigen (PSA ) or DRE (digital rectal examination) offers the best opportunity to determine the presence of cancer.

Early detection is the key to enabling better outcomes and potential cure of prostate cancer. Accordingly, it is recommended that men at 50 with no family history of prostate cancer, and men at 40 with a family history, should seek voluntary annual assessments in the form of a Prostate Specific Antigen (PSA) blood test together with a Digital Rectal Examination (DRE). It can be life threatening to wait for symptoms before seeking assessment.


What are the common reasons to get tested

Most men will seek testing for prostate cancer for the following reasons:

(1) As part of a general check up - usually after 50 years of age.

(2) Due to a recent experience with a relative or friend who has suffered from prostate cancer.

(3) A family history of prostate cancer.

(4) A recent onset of urinary symptoms

Some men, when enquiring about prostate cancer, may be confused by conflicting views expressed about methods of diagnosing and treating the disease. Perhaps the most controversial is the view, that it would be better for men not to know whether they have the disease and therefore they should not be tested be treated.


The thinking behind this is...

(1) Because the disease can be relatively slow to develop, most men would die
with, rather than of, the disease.

(2) Because treatment has potentially serious side effects such as impotence and incontinence, treatment may be worse than the disease. It as the right of all men to make decisions for themselves about whether to be tested. It is your choice.


What Test Could I Have?

The PSA

The PSA blood test looks for the presence in the blood of a protein that is produced specifically by prostate cells called Prostate Specific Antigen.

The result of a PSA test needs expert evaluation by an experienced doctor but the following provides a guide in regards to PSA levels.

* Below a PSA of 4 the chance of prostate cancer being confined to the prostate gland is 65%.

* Between 4 and 10, the chance is 50%.

* Between 10 and 20, 35% and,

* Beyond 20, 20% and less.

Once the PSA is above 30, it is very likely the cancer has spread beyond the prostate and therefore cannot be cured surgically. If your test reveals a slightly elevated PSA, your doctor may recommend the test be repeated from time to time to establish the rate of change, if any, before recommending a biopsy.


The DRE

About 90% of all prostate cancers arise in the outer part of the prostate where they may be detected by a digital rectal exam (DRE), which is the simplest and most widely-performed screening procedure. The doctor inserts a gloved and lubricated finger into the patient's rectum and feels the prostate for bumps or other abnormalities. The exam is quick and painless but some men find it embarrassing. It is not very accurate in detecting early cancers, but studies indicate that regular DREs still save lives.

Biopsy

A Biopsy is a small tissue sample taken with a spring loaded needle. This normally conducted by a urologist. A small probe containing an ultrasound generator and sampling needles (known as Trans Rectal Ultra Sound or TRUS) is inserted in the anus. The ultrasound generates an image of the prostate on a computer screen and guides the doctor to insert the sampling needles into selected areas of the prostate. Your doctor may recommend an anaesthetic for the procedure and a course of antibiotics before or afterwards.

The biopsy samples will be analysed by a pathologist to determine the stage and grade of the cancer. If cancer is detected, two further assessments will be made:


Biopsy outcomes

There are four likely results...

* The tissue is normal benign prostate tissue.

* A condition called atypia or dyspalasia where the cells do not look typical of either normal or cancerous cells.

* Prostatic interpitelial neoplasia (PIN) where the cells appear to be in the transitional stage between normal and cancer.

* Prostate cancer - which are currently graded on a numerical scoring system call the Gleason Score and the Stage of cancer.

Gleason Score

Utilising the 'Gleason Grade', the Urologist rated the two most common types of cancer cells present in the samples, numbering each type from 1 for the least affected up to 5 for the most affected.


Gleason Score Agressiveness of prostate cancer

2-4 Low
5-6 Moderate
7 Intermediate
8-10 High

A score of 2 to 5 indicates the cancer is relatively slow growing and probably not very agressive. A score from 5 to 7 indicates the cancer is faster growing and moderately aggressive. A score of 8 or higher indicates an aggressive cancer.


Stage - how far the cancer has developed.

Stage 1 - The cancer is small and contained within the prostate.

Stage 2 - The cancer is larger and may be in both lobes of the prostate, but is still confined to the organ.

Stage 3 - The cancer has spread beyond the prostate and may have invaded the adjacent lymph glands or seminal vesicles.

Stage 4 - The cancer has spread to other organs, or to bone.

Note:

Each stage has up to 4 sub-groupings (a, b, c, & d) for more accurate definition. Frequently the letter “T” (for tumour) is placed before the stage number, which then appears, for example, as T2(c), or similar. If in doubt, ask your doctor to explain the meaning to you fully. It is vital information for you to understand.

If you have the misfortune to be diagnosed, be sure to ask your doctor for the exact grade and stage of your cancer and discuss their meaning and implications. Be sure to note this information for future reference, as stage and grade are important indicators when choosing treatment. Your doctor may call for additional tests like a bone scan, CT scan and a MRI to check the extent of the disease.