Difference Engine: Blissful ignorance
Three out of four men in America aged 50 or older have had a PSA test, often unbeknown to themselves during a routine check-up. The test measures the amount of prostate-specific antigen floating around in the blood. PSA is a protein made in the prostate gland to help sperm do its job. The test, which has nothing directly to do with a man's reproductive capacity, is carried out solely to screen for prostate cancer.
So, what is wrong with that? For a start, while elevated levels of PSA in the blood can indicate the presence of cancer cells in the prostate, higher levels than normal can also be caused by an enlarged prostate (common in older men), infection, inflammation, irritation, head-ache pills like ibuprofen, and whether the person concerned recently had sex. Even a doctor's digital rectal examination (“thumb up the bum”) can raise a patient's PSA level.
The widely used PSA test has been criticised for giving too many false-positive results, which, in turn, lead to over-treatment of cancers that might never have caused harm. Among men with PSA levels in the warning zone (between four and ten nanograms of PSA per millilitre of blood), biopsies show that over two-thirds of them had no trace of prostate cancer. Meanwhile, one in six men with PSAs in the normal zone (below 4ng/mL) were subsequently found to have been harbouring cancer cells in their prostate glands.
Usually a family doctor will refer a patient to a urologist if his PSA level is above 4ng/mL—or if the level rises by more than 0.35ng/mL over the course of a year. Because of the vagaries of the PSA blood test, many urologists confronted with borderline cases have started using a biomarker in the urine that focuses on a gene called PCA3. Comparing the activity level of the PCA3 gene with that of the PSA gene can be twice as accurate as relying on a PSA test alone. Based on such findings, the urologist may recommend a biopsy.
But that has problems, too. Tissue cores are taken from various parts of the prostate using an instrument with a dozen hollow needles that is inserted via the rectum. The sampling covers only a minuscule part of the prostate, making it easy to miss regions where cancerous cells may lurk. The procedure is not painless and can cause infection, fever, bleeding, problems with urination, and other conditions requiring hospitalisation.
In the laboratory, a pathologist slices the cylindrical biopsy samples taken from the patient's prostate and examines them under a microscope. A grade is assigned, first, to the most common tumour pattern and, second, to the next most common pattern. The two grades, each with ranges 1 to 5, are added together to give what is called a Gleason score ranging from 2 to 10. For a Gleason score of 7, the combination 4+3 denotes a more aggressive cancer than 3+4.
With a Gleason score of 6 or less, the urologist may advise active surveillance rather than surgery or radiation. “Watchful waiting” involves tracking the PSA level every three months or so and having an annual biopsy. That may be the best advice the patient will ever receive. But it does require that the person is content to live with the knowledge that he has cancer and has chosen not to have it treated. Most men find that daunting—and opt for treatment, even though medically it may not be warranted.
Even in cases where a biopsy proves positive, the majority of cancer cells found are likely to be localised and to grow so slowly as never to cause even the symptoms of prostate cancer, let alone death. The condition has been likened to a handful of tortoises crawling around the bottom of a well. In the vast majority of instances, they remain trapped at the bottom. But, once in a while, a tortoise manages to crawl up the side and escape into the surroundings.
In the majority of cases, men who do nothing about cancer cells found in their prostates will most likely die in old age of something else—heart attack, stroke, lung cancer, pneumonia or whatever—long before they would have succumbed to prostate cancer. In other words, they will die with the disease, not from it. The same goes for the vast majority of men who live in blissful ignorance, having never had a PSA test. Autopsies show that three out of four men who reached the age of 85 had prostate cancer but died of other causes.
Yet, the urgency to treat any detected cancer—whether aggressive or not—can be immense. The pressure to do so can come as much from the patient himself (“Get that thing out of me!”) as from a medical professional (“To be on the safe side, we advise surgery or radiation.”). Such screening can cause serious stress and anxiety. Researchers at Harvard and Brigham & Women's Hospital in Boston have found that just being diagnosed with prostate cancer doubles the risk of dying from heart attack or suicide.
If over-detection resulting from PSA screening and biopsies has its risks, over-treatment involves even bigger ones. None of the treatments—and there are half a dozen or so different ones to chose from—is benign.
Among men who opt to have their prostates removed—often to treat cancers that would never have harmed them—0.5% die within a month due to complications from the surgery. Up to 7% have serious problems but survive. And between 20% and 30% of those treated with surgery or radiation finish up with erectile dysfunction, urinary incontinence and other disabilities. Of those who use chemotherapy to suppress the hormones that feed cancerous cells in the prostate, 40% become impotent.
If truth be told, the PSA test can cause more grief than relief. There is no evidence that the test provides any advantages, even to men who turn out to have the fast-growing version of the disease. The first sign of the invasive form of prostate cancer occurs too late for it to be treated successfully. No amount of screening will prevent those destined to develop the deadly, untreatable form of the disease from doing so. In the final analysis, PSA screening has allowed more prostate cancers to be detected, but it has not lowered the death rate from the disease.
Even the scientist who discovered PSA over 40 years ago has argued vociferously for routine testing of prostate-specific antigen levels to be abandoned. Richard Ablin, professor of immunobiology and pathology at the University of Arizona, has called the test based on his work “a public health disaster” that is little better than the toss of a coin. So why is it still used? “Because drug companies continue peddling the tests and advocacy groups [encourage] men to get screened,” Dr Ablin wrote in the New York Times.
Two years ago, the United States Preventive Services Task Force, an independent panel of medical experts empowered to evaluate cancer testing, recommended against PSA screening for men over 75 years of age. Being older and frailer, such men were viewed as unlikely to benefit from having surgery, radiation and other treatments that were unlikely to prolong their lives, but could well cause incontinence and impotence. At the time, the panel made no change in its recommendation for younger men.
Having reviewed the findings of leading studies in Europe and America, the Task Force has now downgraded its previous recommendation on prostate-cancer screening for younger men. In an announcement on October 7th, the panel noted that for men 50 to 69 years old the reduction in death caused by prostate cancer ten years after screening “is small to none”. In other words, the PSA test does not save lives, and is not needed by healthy men showing no symptoms of the disease. The risks it causes outweigh any benefits it may bestow.
But even Dr Ablin admits PSA testing has a place. “After treatment for prostate cancer, for instance, a rapidly rising [PSA] score indicates a return of the disease,” he wrote in his Op-Ed piece last year. And men with a family history of prostate cancer should probably get a regular PSA test. At present, PCA3 screening looks a better bet, but it could turn out eventually to have similar drawbacks as PSA.
The real problem with prostate-cancer screening—whatever the test employed—is the over-treatment that ensues. If that could be eliminated, even the PSA test might do more good than harm. Ultimately, what is needed, of course, is a way of identifying the odd tortoise that escapes from the well, while ignoring all the other critters that will never do any harm. That is something science has yet to deliver.