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Change in PSA levels over time can help predict aggressive prostate cancer
By Dross at 2013-01-17 06:01
Change in PSA levels over time can help predict aggressive prostate cancer

Measurements taken over time of prostate specific antigen, the most commonly used screening test for prostate cancer in men, improve the accuracy of aggressive prostate cancer detection when compared to a single measurement of PSA, according to a Kaiser Permanente study published today in the British Journal of Urology International.

The retrospective study examined the electronic health records of nearly 220,000 men ages 45 and older over a 10-year period who had at least one PSA measurement and no previous diagnosis of prostate cancer. The study found that annual percent changes in PSA more accurately predicted the presence of aggressive prostate cancer when compared to single measurements of PSA alone, but only marginally improved the prediction of prostate cancer overall.

"The use of a single, elevated PSA level to screen for prostate cancer is considered controversial given the questionable benefits of PSA screening on prostate cancer mortality. The screening may also result in unnecessary prostate biopsies and subsequent treatments for localized prostate cancer, as it does not distinguish well between slow-growing and aggressive disease," said Lauren P. Wallner, PhD, MPH, study lead author and post-doctoral research fellow at Kaiser Permanente Southern California's Department of Research & Evaluation. "Our study demonstrates that repeated measurements of PSA over time could provide a more accurate – and much needed – detection strategy for aggressive forms of prostate cancer."

Men in the study were also found to experience a 2.9 percent change in PSA levels per year on average and that the rate of change in PSA increased modestly with age.

"The results of this study could provide clinicians with a better prostate cancer preventive strategy that could help differentiate between men with an aggressive form of the disease and those who have slow-growing, indolent cancer that may not necessarily merit treatment," said Wallner. "While we do not suggest that patients proactively seek out additional PSA measurements, men who already have had multiple PSAs may consider discussing the change in their PSA levels with their clinician when determining future treatment strategies."

The PSA test measures the level of prostate specific antigen, a substance made by the prostate, in a man's blood. It is one of the most commonly used tests to screen for prostate cancer, according to the Centers for Disease Control and Prevention. As a rule, the higher the PSA level in the blood, the more likely a prostate problem is present. But many factors, such as age, race, and non-cancerous conditions can affect PSA levels. The CDC and other federal agencies follow the prostate cancer screening recommendations set forth by the U.S. Preventive Services Task Force, which recommends against PSA-based screening for men who do not have symptoms. Kaiser Permanente guidelines include a recommendation that men age 40 and older should discuss the PSA test and rectal exam with their physician.

Aside from non-melanoma skin cancer, prostate cancer is the most common cancer among men in the United States, according to the CDC. In 2008 (the most recent year numbers are available), nearly 215,000 men in the United States were diagnosed with prostate cancer and more than 28,000 men died from the disease. Prostate cancer is the second most common cause of death from cancer among white, African American, American Indian/Alaska Native and Hispanic men, and is more common in African-American men than white men, according to the CDC.

4 comments | 2111 reads

by gdpawel on Mon, 2013-01-21 21:49
According to Badrinath Kontey, M.D., Professor and Chair of the Department of Urology at the University of Minnesota, the risk assessment of prostate cancer is based on a combination of factors such as the PSA level at the time of diagnosis, the Gleason grade of the cancer which represents its aggressiveness (can vary from a low score of 2 to a high score of 10) and how the cancer feels on digital examination of the prostate (whether a cancerous nodule can be felt and if so does it extend beyond the confines of the prostate).

High risk cancers are associated with a PSA > 20ng/ml, Gleason grade of 8-10 or a cancer that feels to be beyond the confines of prostate when felt with the finger in the rectum. Presence of any one of these characteristics renders a cancer to be high risk. The term high risk also connotes a high risk of recurrence of the cancer despite treatment.

A commentary in the British Journal of Urology International (BJUI) asked, “Should we really consider Gleason 6 prostate cancer?”

The National Cancer Institute defines the Gleason score as:

A system of grading prostate cancer tissue based on how it looks under a microscope. Gleason scores range from 2 to 10 and indicate how likely it is that a tumor will spread. A low Gleason score means the cancer tissue is similar to normal prostate tissue and the tumor is less likely to spread; a high Gleason score means the cancer tissue is very different from normal and the tumor is more likely to spread.

But on that spectrum of 2 to 10, different doctors draw different cut-off points for decision-making. The BJUI commentary stated:

“There is no doubt that prostate cancer kills, but only a minority of men who are given this diagnosis, die from prostate cancer. In the developed world we are now overdiagnosing and, more importantly, overtreating prostate cancer, a fact for which we will be criticized in generations to come. As well-intentioned urologists, we should have no trouble in justifying our radical therapy for pathologically moderate to high grade, Gleason 7 – 10 cancers. Despite the opinions of some urological luddites, careful active surveillance is slowly becoming the standard for Gleason 6, particularly for those with low volume disease associated with low serum PSA values, however, many patients with Gleason 6 still receive radical treatment. We (and others) would like to hypothesize, at least for the sake of discussion, that Gleason 6 pattern prostate pathology is not in itself a lethal prostate cancer, but rather can be associated with a higher risk of potentially lethal prostate cancer (e.g. Gleason 7 or higher) or, alternatively, is a precursor to such prostate cancer. This change in thinking would mean that patients with Gleason 6 scores would not be labelled with a ‘ lethal ’ cancer diagnosis and would be less anxious about the appropriate treatment plan of active surveillance. Many patients drop out of active surveillance and pursue radical treatment, not because of rising PSA levels, biopsy results or other forms of disease progression, but because of anxiety. There may be less morbidity (and cost) if patients were not given the ‘cancer-label ’ until they had Gleason 7 disease.

Whether Gleason 6 is really a cancer or not is a mute point, one that can only be debated, at this time. We continue to over-diagnose and subsequently over-treat unfortunate men who are labelled with a ‘lethal’ cancer, when in fact they will probably never die from it. It is a fact, however, that some men continue to die from prostate cancer, so we must try and direct our therapies to those men, a task that will only be possible through enlightened discussion coupled with basic and clinical research. We need to change our paradigm when dealing with Gleason 6 pattern diagnosis, whether it is a low-risk cancer, a benign disease associated with a high risk of developing real potentially lethal cancer, or a true prostate cancer precursor. Let ’s find a way to treat only those men who are destined to die from this serious cancer and relieve some of the psychological burden and significant morbidity from those men who should never have been labelled ashaving a lethal cancer in the first place. Let us make the case and put in the effort to develop improved prostate cancer screening for the higher grade prostate cancers,while at the same time relegating low volume Gleason 6 to the status of no more than a significant risk factor. Let us decide as a profession to stop the push for inappropriate, expensive, inopportune and perhaps even unethical radical therapies for a condition that by itself does not kill our patients.”

What to call certain abnormal cellular findings is increasingly becoming an issue for doctors.

In breast cancer, there’s been some discussion of re-naming ductal carcinoma in situ and removing the “carcinoma” from the diagnosis.

In cervical cancer, there are ASCUS cells – or “atypical squamous cells of unknown significance.”

Gleason 6 cells in the prostate cancer field have been called “adenosis.” They’ve been called IDLE – indolent lesions of epithelial origin.

Whatever these cells are called, one practical goal for now is to educate men about the harms of overdiagnosis and overtreatment and offer active surveillance as a treatment option.


Note: According to Dr. Matt Cooperberg, assistant professor at UCSF, active surveillance for prostate cancer means that based on the information available, the likelihood of cancer progressing in the short-term, while not zero, appears to be very low. Active surveillance does not mean the cancer will never need to be treated, but rather that it does not need treatment now. The "window of opportunity" for curing low risk prostate cancer is measurable in years in most cases, if not decades. In the meantime, men can avoid the risks and costs of surgery, radiation therapy and other interventions.

by gdpawel on Tue, 2013-01-29 06:43
Matthew Nielsen, M.D.
Assistant Professor of Surgery
Adjunct Assistant Professor of Epidemiology
Lineberger Comprehensive Cancer Center
University of North Carolina at Chapel Hill

The PSA test is a simple blood test, so getting the test is relatively straightforward, and the risks of the test have more to do with the potential downstream consequences than the test itself.

The results of the PSA test may suggest the indication for a prostate biopsy, which is the actual diagnostic test, though an abnormal PSA test can often be the result of causes other than prostate cancer (ie BPH, prostatitis, etc). A large screening study in the US found no significant difference in survival between men randomized to screening vs. no screening.

However, this population was already heavily pre-screened (many men had a PSA prior to enrolling in the study) and a large proportion of men randomized to "no screening" continued to have PSAs checked, so this study has significant limitations with regard to any conclusions that can be drawn about the effectiveness of PSA screening.

Another large study conducted over a similar time frame in Europe, where PSA screening was in general less commonly performed in the background of the study, found a significant reduction in prostate-cancer mortality as well as the proportion of men diagnosed with advanced disease among men randomized to screening, and a third study from Sweden found even more dramatic reductions in prostate cancer mortality among screened men, even with a large proportion of screen-detected cases undergoing active surveillance.

It is also important to note that prostate cancer mortality in the US has declined by 30-40% in the roughly two decades since PSA screening became widespread, and the proportion of men diagnosed with metastatic disease at first detection has declined dramatically over this period as well.

All that said, there are still legitimate concerns about something we call "overdiagnosis," particularly of low risk disease that would have never otherwise caused a man problems in his lifespan, and associated "overtreatment" if a large proportion of those "overdiagnosed" low-risk cases undergo aggressive treatment.

Notwithstanding these concerns, prostate cancer still has the potential to be a serious disease for many men, and despite the improvements in prostate cancer survival in the PSA era, it remains the second-leading cause of cancer death in US men, after lung cancer.

Recognizing the complex issues associated with PSA screening, an informed patient should understand the potential risks associated with the biopsy (bleeding, pain and infection) as well as potential risks associated with treatment (in particular side effects related to urinary, sexual and bowel function, as well as the possibility of finding a cancer for which active surveillance may be appropriate) as factors to consider when a decision is made to check a PSA and potentially embark down the path of further evaluation.

A great deal of research has been done in this area, providing physicians with tools to help patients understand the risk of a prostate cancer diagnosis based on PSA and other findings, and if that diagnosis is made, the potential risk of the affected patient's disease in light of their age and overall health to help them decide with their doctors if they want to pursue treatment, and if so, which type.

Active surveillance is an option for many men, as we have come to appreciate that, in addition to identifying cases with significant potential for causing harm, PSA testing often leads to the diagnosis of lower risk cases, which may not pose substantial risks to the patient's health and well-being in their lifetime.

The factors we consider in an individual case are the risk level of the patient’s prostate cancer diagnosis as well as the context of the man’s age, overall health, and estimated life expectancy.

In general, we risk-stratify prostate cancer cases on the basis of the Gleason Score (the grading system used to describe the microscopic appearance of prostate cancer on biopsy), the PSA level, and the clinical stage (whether or not there is an abnormality on the exam of the prostate, and if so, how extensive of a nodule). We typically divide cases into low, intermediate and high risk based on these variables.

The Gleason scoring system is perhaps the single most important variable. For practical purposes it is a scale of 6-10, with 6 being low risk, 7 intermediate, and 8-10 as a group being high risk. We also consider the proportion of biopsy tissue involved with cancer, in terms of the number of biopsy cores positive and the percentage of each positive core involved with cancer.

In terms of PSA, the absolute PSA value is similarly divided by less than 10, 10-20, and greater than 20, respectively. We can also gain more information if a man has PSA values over a number of years to look at what we call the “PSA velocity,” with faster rising PSAs being more concerning for potentially aggressive disease, and the PSA adjusted for prostate size (the “PSA density”), to attempt to account for the contribution of prostate enlargement (or BPH) to the PSA.

The clinical stage is based on whether there is a nodule felt on the prostate exam, and if so, how extensive. Based on these factors, we divide cases into the risk groups mentioned above, and for men with low risk disease, cases can be further substratified into a "very low risk" group.

For men with low or very-low risk disease, active surveillance is often a very reasonable consideration. For older men and/or men with significant other medical problems, surveillance may also be an option in select cases of intermediate risk disease.

It is important to appreciate that active surveillance is not synonymous with "doing nothing," as the approach entails a careful and systematic ongoing assessment of prostate cancer-related risk to identify signals suggesting the need for treatment while the window of opportunity for cure is still open.

A study published in the 1990s identified a set of criteria available at the time of diagnosis that had good predictive accuracy for identifying these cases. These features, often referred to as the "Epstein criteria," include low volume disease (defined by no greater than two biopsy cores involved, and no greater than 50% of an individual core involved with cancer) Gleason 6 only disease, a normal prostate exam (no nodule) and a PSA density (PSA level divided by prostate volume in cubic centimeters) of less than 0.15.

These were set as the inclusion criteria for the Johns Hopkins active surveillance program, a prospective research study that provides some of the best data available to help us understand the outcomes of men choosing active surveillance, and were also adopted by the National Comprehensive Cancer Network in the risk stratification scheme used in their prostate cancer treatment guidelines. A few studies have suggested that this group of cases represents somewhere on the order of 10-20% of new prostate cancer diagnoses in the US.

PCA3 (also referred to as DD3) is a urine test which can be performed after a digital rectal examination of the prostate. It is somewhat more specific for prostate cancer than PSA, which can be elevated both by cancer and benign prostate conditions. PCA3 has mostly been studied among men who have had a negative prostate biopsy but have a PSA which remains elevated or continues to rise. In this situation, it can help with decision-making about whether to proceed with a second biopsy.

Although PCA3 is typically reported as greater than or less than some threshold (usually 25 or 35), it is really a continuous variable just like PSA. When the PCA3 is very low, this is reassuring, and when it is very high, repeat indicated. In the intermediate range. the decision remains an individualized one. PCA3 may have a greater role going forward for men with an elevated PSA who have never had a biopsy, and potentially to help follow men on active surveillance for low risk prostate cancer.

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