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DURHAM, N.C. -- Testing men for elevated levels of prostate-specific antigen (PSA) in the blood -- the gold standard screening test for prostate cancer -- may be biased against obese men, whose PSA levels tend to be deceptively low. And this bias may be creating more aggressive cancers in this population by delaying diagnosis, according to a new study led by investigators in the Duke Prostate Center and the Durham Veterans Affairs (VA) Medical Center.
"We know that obese men tend to have lower PSA values than their normal-weight counterparts, possibly caused by larger blood volumes which dilute the readings," said Stephen Freedland, M.D., a urologist at Duke and the Durham VA, and lead investigator on this study. "Now we know some of the real implications of this -- that these men are at a disadvantage in terms of prognosis compared to normal-weight men."
The researchers published their findings online in the journal BJU International. The study was funded by the United States Department of Veterans Affairs, the National Institutes of Health, the Georgia Cancer Coalition, the United States Department of Defense, the Prostate Cancer Research Program and the American Urological Association Foundation's Astellas Rising Star in Urology Award, given to Freedland.
"We used patient data to examine the association between body mass index, or BMI -- a measure of obesity -- and the amount of disease discovered after surgery to remove the prostate, " Freedland said. "We compared men who had their cancers detected by PSA screening to those who had an abnormal digital rectal exam, which may not confer the same bias against obese men."
The researchers looked at a total of nearly 3,400 men in the years since 2000, when PSA screening became the gold standard test for prostate cancer.
Obese patients whose cancer was diagnosed by PSA testing had more than twice the risk of cancer recurrence after surgery than their normal-weight counterparts, Freedland said. "In contrast, obese men with abnormal digital rectal exams had similar outcomes as normal-weight men," Freedland said.
Another Duke study published in the same issue of the journal provides further substantiation of the concern that obese men have poorer prognoses than normal-weight men. This study showed that obese men have a higher rate of positive surgical margins after surgery to remove the prostate, meaning that there was a higher chance cancer was left behind.
This suggests that prostate cancer surgery is technically more challenging in obese men, making complete tumor removal harder, according to Jayakrishnan Jayachandran, M.D., a urological oncology fellow at Duke and lead investigator on the second study.
"The aggressiveness of obese men's tumors, coupled with the fact that they may be more difficult to remove, is like a double whammy for being obese," Jayachandran said.
"The least we can do is find a way to level the playing field when it comes to diagnostic tools," Freedland said.
PSA screening has been the most common tool used to detect prostate cancer over the past eight to ten years; men are less commonly diagnosed based on digital rectal exam alone.
The researchers are hopeful that this data, coupled with the earlier data on which it builds, may be a catalyst to encourage alternative screening methods for obese men, or a lower threshold for worrisome PSA levels in obese men.
"Obesity is very common in the United States, so this potentially affects a lot of people," Freedland said. "We can't forget that when we use the term obese we are not just talking about very, very large men. A man who is 5 foot 9 and weighs 203 pounds would be considered obese."
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PSA and the Prostate
After a high PSA, the next step in diagnosis is a biopsy. A biopsy is painful and can lead to urinary obstruction, particularly in older men with an enlarged prostate.
Frequently, the biopsies find nothing. And they must be repeated. Some patients lose organs because of a biopsy that mistakenly breaks a vessel. Although doctors bet that the risk is small, nobody is willing to put a price on their “bet” on the patient.
Suppose the biopsy shows cancer. Depending on the type of cancer, studies suggest a certain life expectancy. But these average results are meaningless when applied to a specific case because treatment does not produce huge differences compared to no treatment. Moreover, there are many risks associated with treatment of prostate cancer. The risks have to increase with age because the body’s ability to recover decrease with age.
Treatment may increase life expectancy. Or it may not for people over 75 who likely have cardiovascular disease and other complications. Treatment may substantially decrease quality of life, and could shorten life.
If the PSA is extremely high, then the odds are high that there is prostate cancer. But if it is low, there could also be prostate cancer. There is also stress associated with the test. Once the test is high, there is psychological pressure on the physician and patient to have a biopsy. Or many biopsies. And if the biopsies are abnormal, there is pressure to have it treated. Although a few men may benefit from aggressive treatment, many more will suffer undesirable consequences.
Some men may benefit from having a PSA test. Men who have a history of PSA values to compare over time, or family history of severe prostate cancer. Or man who will have the PSA repeated every 4 to 12 months, depending on the results and physical condition. Men who have a biopsy when there is a substantial increase in PSA values (PSA velocity) given their prostate size. Men who are slim, exercise, don’t smoke, avoid unnecessary risks, eat very well, have excellent immune system, excellent healing, no bleeding abnormality, and have no known disease. These are the men that will likely live long and can withstand the adverse consequences of treatment (bleeding, fibrosis, decreased inmune system and susceptibility to infections, etc.).
Very few men meet these criteria. And the odds are high that even fewer have high PSAs. The vast majority of men are overweight, have abnormal cardiovascular disease, immune system and other abnormalities that makes them likely to suffer undesirable consequences from treatment (increased susceptibility to infection, etc.). These men will feel pressured to do something if the PSA is high, to have biopsies and proceed to treatment.
For them, the consequences of having a PSA test are far more likely to be undesirable than worthwhile. Moreover, once the chain starts, it is very difficult to stop (for legal, ethical and psychological reasons). From the high PSA we move to biopsies and then treatment.
Contrary to popular belief, it is practically impossible to make a rational decision. The necessary data does not exist. If the data existed, humans like the ability to make the multivariate probability calculations and cost/benefit analysis. Instead, decisions are almost random, and shifted towards aggressive therapy when the PSA is high.
Incidentally, there are several alternatives to conventional treatment. They are not followed because they are not profitable and there is no funding to evaluate them.
by Edward Siguel, MD, PhD (Clinical Pathologist)