I RECENTLY asked a man named Norman Yang if he was chiefly responsible for inventing the test that has transformed the treatment of prostate cancer. Cancer of the prostate gland is astonishingly common. Estimates vary, but a typical assessment is that one out of ten men has the disease in some form by age fifty. In the natural order of things, though, most of those men will never know they have it, because prostate tumors are usually small and symptomless, and because most of the time they grow so slowly that their hosts die for some other reason before the condition causes trouble. The problem is that prostate cancer is so prevalent that the exceptions to the rule represent a lot of people. According to the American Cancer Society, the disease will kill 35,000 men this year -- putting it in the same ballpark as, though a bit behind, breast cancer.
In the past the lack of symptoms which allowed most men with prostate cancer to live undisturbed made timely detection of the bad cases extremely rare. Doctors looked for possible tumors by inserting a rubbergloved finger into a man's rectum and palpating for lumps in his prostate, an undignified and ineffective procedure avoided by patients and physicians alike. The Department of Health and Human Services has estimated that only one out of ten men in the appropriate age group has an annual rectal exam. As a consequence, more than half of all prostate carcinomas were discovered only after they had spread - by which point it was usually too late. Worse, such tumors frequently disperse to the bones, and even in the dark spectrum of untreatable diseases, bone cancer has a particularly grim hue: pain, long and intense, is a primary symptom. Treatments for advanced prostate cancer, which can include removal of the testicles, are not terribly effective.
In the 1970s Norman Yang was one of the scientists who identified prostatespecific antigen (PSA), a substance that the prostate, and only the prostate, releases into the blood. The researchers discovered that mouse antibodies in a test tube can react to the presence of PSA, that this reaction can be used to measure the level of PSA in human blood, and that a man's PSA level is like a thermometer reading: a sudden rise indicates that something is awry. The something is not always cancer - high PSA readings can also be caused by the ordinary swelling of the prostate that comes with old age. But they indicate cancer often enough that they can be regarded as a signal to perform more tests, usually a biopsy (in this case a sample extracted from the suspect area with a needle).
For many in the field the PSA test changed everything. Simple to perform, not hugely expensive, free of embarrassment and discomfort, it seemed to provide doctors with a way to detect prostate trouble early and accurately. If the PSA level jumped, the next step would be a biopsy - a more unpleasant and costly business, but one justified by the potential gravity of the situation. If the biopsy indicated cancer, a surgeon might be called in. The operation, called a radical prostatectomy, removes the prostate and thus the source of the problem. If performed before the carcinoma spreads, surgery is often successful, in that it ends the threat from cancer. But the procedure is dangerous - it may kill up to one out of a hundred patients outright - and fraught with possible side effects, such as impotence and incontinence. Even so, physicians reasoned, quick detection of prostate cancer would save thousands of people from awful deaths every year.
After PSA was identified, a company named Hybritech, in San Diego, jumped into the market with a testing kit. The Food and Drug Administration approved the Hybritech test in 1986, though solely for the purpose of tracking recurrent cancers; only last June did an FDA advisory panel formally recommend that it be used to detect early prostate cancer as well. (FDA approval for this use is expected in the relatively near future.) Doctors moved much faster. Today PSA measurements for older men are part of the furniture of American health care. According to John Wasson, the director of the Center for the Aging at the Dartmouth Medical School, who coheads the federally funded Prostate Patient Outcomes Research Team, in parts of the nation more than half of older men check their PSA annually. Some anxious types examine it monthly, like the balance in their checking account.
From 1988 to 1992 Hybritech sales rose from $74.7 million to $158.4 million, a rise that tapered slightly after the introduction of PSA tests by other firms, including Abbott Laboratories. (Hybritech itself was acquired in 1986 by another drug giant, Eli Lilly.) Statistics from the National Cancer Institute show that the number of prostate cancers detected rose 16 percent from 1989 to 1990; preliminary data indicate that it jumped another 30 percent from 1990 to 1991, the fastest rise in cancer detection ever recorded. Figures from last year are not available, but I have found no one who believes that the increase has stopped. The increase in diagnosis has been accompanied by an increase in treatment. Wasson estimates that the number of operations for prostate cancer in Medicare patients jumped sixfold, from about 2,600 in 1984, before the PSA test, to about 16,000 in 1990, the latest date for which statistics exist. Today, Wasson says, the number is still higher.
Not every scientist has a chance to affect the lives of so many people, and I wanted to ask Norman Yang how he had done it. Yang was hard to find. To his evident annoyance, he had somehow passed through the entrepreneurial 1980s without making a bundle on the discovery. He runs a biotech outfit in Bellevue, Washington, with five employees, including Yang and his wife, Fumei, in a small office building near a strip mall. When I telephoned the first time, I was not sure that he was the right Dr. Yang. Is this, I asked, the man who helped put together the test that is drastically changing the health prospects of the 28 million Americans who are male and more than fifty years old?
“Yes,” he said. “Unfortunately. If I had known what would happen, I would never have done the work.”
I was surprised at his vehemence but not at his sentiment. Even as Hybritech’s sales have risen, the medical establishment has been torn by a debate over whether the concomitant increase in early cancer detection and treatment is a good thing. The PSA test cannot distinguish between a prostate carcinoma that will never disturb its host and one that is ready to invade bone. The fear is that in the next few years tens of thousands of men will undergo needless operations, with an attendant rise in surgically induced impotence, incontinence, and death. For every surgeon who is full of enthusiasm, another medical professional paints the scary picture of a nation full of otherwise healthy retirees in diapers. Indeed, some critics argue that the dispute over prostate cancer is a case study in one of the American medical system's worst shortcomings - its propensity to embrace expensive treatments without considering their longterm social or medical impact.
Just ahead, these critics believe, are tests for Alzheimer's disease and several other types of cancer. All are common conditions with uncertain prospects for cure. Are we to follow the PSA pattern, and sentence the unfortunates who receive bad news to a round of medical intervention that may only increase their misery? Or, as proponents of the PSA test argue, can earlier, better diagnoses be only beneficial?
And what if - as may be the case with prostate cancer -- the benefits of quicker diagnosis and treatment are concentrated among relatively few people, whereas the costs, perhaps much larger, are spread over many more?
Yang is one of these critics. "It's gone out of control," he says. "People don't know what they're doing, and it's going to be a terrible mess. I feel sick about it. It's a disaster for the healthcare system - a horrible disaster. We've rushed ahead and created a nightmare."
The Troublesome Gland
At the center of the dispute is the prostate, a small gland that is frequently burdened in description with adjectives like "obscure," "inessential," and "dumb." Prostates vary considerably in size from man to man, but typical examples are said to be about the size of a walnut and to weigh almost an ounce. They are solid, as opposed to spongy, and are loosely attached to the bottom of the bladder. Their job is to concoct a chemical stew - PSA is one of the ingredients - and add it to semen just before ejaculation. Nobody understands what, precisely, the added compounds do, but they are thought to be important in reproduction.
From an evolutionary point of view, there is little reason for the prostate to keep functioning after the typical age of reproduction - and it doesn't. Indeed, the number of men who escape prostate trouble of any sort is small enough to put the likelihood of experiencing it just below that of death and taxes. No one knows why, though every researcher I have asked has a laundry list of speculations. "Perhaps it is exposed to carcinogens," says Donna Peehl, a specialist in prostate genetics at the Stanford University School of Medicine. "Perhaps the problem is its proximity to the urethra the channel carrying urine from the bladder], with all that urine leaking through. That explanation doesn't work particularly well, though. Perhaps it's a developmental thing, something about the biology of the prostate that is important to its normal behavior but that we don't know yet." Nobody knows, she says. "It's kind of an obscure little gland and yet it causes all this trouble."
The trouble comes in three varieties: prostatitis; benign prostatic hyperplasia (BPH); and prostatic carcinomaprostate cancer. All are diseases of old age, or at least middle age. Prostatitis is simply an infection or inflammation of the prostate. It is extremely common. Indeed, many men have chronic cases that they don't know about and don't need to know about, because the disease poses no longterm threat and in those men has no noticeable effects. In bad cases symptoms occur during urination: a sensation of burning, a need to urinate more often or more urgently than usual, or an inability to release more than a small amount of urine. The standard treatment is antibiotics of a class known as fluoroquinolones; the most common is ciprofloxacin (made by Miles, and sold as Cipro). A successful outcome is taken for granted.
Benign prostatic hyperplasia occurs when the inner portion of the prostate enlarges. The urethra tunnels through the middle of the prostate like a string through a bead. When the prostate swells, it becomes, in effect, a choke collar for the urethra, obstructing the flow of urine. Actually, it becomes a second collar; a band of muscle, the urethral sphincter, already rings one end of the prostate, preventing unwanted urination. That sphincter is under voluntary control; the BPHcaused sphincter is not. Symptoms of BPH include both trouble with urination and, paradoxically, its opposite, trouble with holding back urination, especially at night. By age sixtyfive about three quarters of all men will experience BPH - indeed, that is when some men first learn they own a prostate. The cause of BPH is unknown. It just seems to happen, along with wrinkles, hair on the shoulders and in the ears, and the other irritants of male aging.
BPH is "benign" only as doctors understand the word, which is to say that it is not malignant. ("Hyperplasia" is the unwanted growth of tissue.) It is almost always a bother and sometimes more than that, leading to infections of the urinary tract. If the symptoms are unpleasant enough, doctors recommend treatment. Until recently the most common treatment was transurethral resection of the prostate, or TURP. The surgeon threads a fiberoptic tube through the penis to the prostate, guided by a light at the tip of the tube. Bits of tissue bulge into a hole in the side of the tube, where they are snipped off by a tiny blade and sucked away. Repeated clippings eventually free up the passage. Descriptions of the procedure often include references to "RotoRootering." According to Patrick Walsh, the chairman of the urology department at the Johns Hopkins University School of Medicine, TURP is usually effective, although like all surgery, it is expensivethe full tab often runs to more than $5,000. Longterm difficulties with urinary control continue for about one out of every hundred patients, and fewer than one out of twenty, Walsh says, have subsequent problems with impotence.
One out of twenty sounds better to doctors than to patients, especially when it refers to sexual ability. Impotence and incontinence can usually be alleviated by further surgery, but for obvious reasons research into alternatives - that is, drugs - is vigorous. Unfortunately, BPH is linked to the presence of male hormones, especially testosterone, and male hormones are necessary to maintain interest in sex. Past efforts to treat the condition without surgery involved blocking the effects of testosterone, which risked eliminating a man's libido. Only recently was it discovered that not testosterone itself but rather some of the substances into which it is transformed by the prostate are directly responsible for BPH. First to take advantage of this finding was Merck & Company, a huge pharmaceutical firm that last year received FDA approval to market finasteride under the brand name Proscar. Finasteride blocks the action of 5-alphareductase, a compound secreted by the prostate which converts testosterone to dihydrotestosterone, one of the hormones that stimulates prostate growth. Like TURP, Proscar at least temporarily affects the sexual activity of some men, in this case about one out of twentyfive. Unlike surgery, though, its negative effects can be reversed easily - by throwing out the bottle of Proscar. From the point of view of a drug maker, Proscar is an ideal product: it costs more than $50 a month and must be taken forever. Unsurprisingly, Merck has widely advertised it in newspapers and magazines, including this one, though without mentioning Proscar by name.
Whether Proscar helps a particular man may depend on the makeup of his prostate. Dihydrotestosterone seems to affect the soft glandular part of the prostate to a greater degree than the hard muscular part. If a man's prostate is more glandular than muscular, he may be more likely to be helped. If it is the other way around, those men may need a TURP or perhaps some other, new treatment. One possibility for the latter is the class of drugs called alpha adrenergic blockers, which people with high blood pressure take to relax bloodvessel walls. The muscle in the prostate is similar to the muscle in blood vessels, and Patrick Walsh and others have told me that the analogy is promising. Alpha blockers have not been approved by the FDA for this purpose, but many doctors are already prescribing them on the basis of preliminary reports; among the most common is terazosin (brand name Hytrin, made by Abbott).
The third and most serious problem is prostate cancer, a medical oddity that is a long way from being understood. If all men lived to be ninety, almost all would harbor prostate cancer. It is especially widespread among African-Americans, who have the highest rates of death from prostate cancer in the world. According to John T. Isaacs, a medical oncologist at Johns Hopkins, data from autopsies suggest that about 11 million Americans have prostate cancer in some form. Lung cancer is thought to afflict about 300,000 Americans. The disparity in the prevalence of different types of cancer is baffling, and especially so when comparing prostate cancer with other kinds. "Cancer of the colon is extraordinarily common," says John McNeal, a pathologist in the department of urology at Stanford, "whereas cancer of the small intestine is very uncommon. How come? Here's two parts of the same organ, hooked together, and one appears to be quite susceptible to cancer and the other appears not to be." Yet more puzzling, he says, is the seminal vesicle, the small gland that produces most of the constituents of seminal fluid. "The seminal vesicle is attached to the prostate, and cancer of the seminal vesicle is, I would guess, the rarest of all human cancers, and it's only millimeters away from the organ that has one of the commonest cancers."
The American Cancer Society projects that no more than 165,000 prostate carcinomas will be discovered this year, whereas it expects 170,000 new cases of lung cancer and 182,000 of breast cancer. The difference is due in part to the relative newness of the PSA test, which for the first time makes diagnosis likely. But more important is the propensity for this cancer to lurk for years or even decades without apparent ill effects. As a rule it grows extremely slowly, taking four years or more to double in size. Breast carcinomas, in contrast, often double in less than three months; a tumor the size of a pinprick will fill a cubic centimeter in a couple of years and be ready to spread. According to McNeal, only about one out of five prostate carcinomas ever becomes clinically significant. The rest are sometimes called histologic carcinomas, meaning that tissue at the disease site fits the technical definition of cancer but no more. Many histologic carcinomas are microscopic; some are barely distinguishable from their surroundings. In some sense, he says, this dormancy is what one would expect. "A cancer so common as this would have to be very slowgrowing or it would have wiped out the population at the upper end," he points out. "It would not be something that people are just becoming aware of if it were like other cancers."
At present no one can distinguish at the outset between those carcinomas that will cause no trouble in a man's lifetime and thus should be ignored and those that will spread in time and thus should be treated, if at all possible. Scientists are not likely to solve this quandary in the near future. Cancer cells are generally thought to be created by a sequence of genetic mishaps. Every time a cell divides, there is a tiny chance -- typically one in a billion - that it will not copy its genetic material precisely and will instead produce a slightly abnormal daughter cell. (Such failures occur randomly, although their incidence can be increased by exposing the body to carcinogens, chemical compounds that in some way interfere with cell division.) In turn this imperfect daughter cell divides. There is a slight probability that it, too, will fail to copy itself exactly - actually, a slightly greater probability, because precancerous cells seem to be accidentprone. If the cell makes the "right" error, it will be one step further toward full malignancy. In colon cancer the mistakes usually occur in sequence. In prostate cancer, though, each mistake may be independent of the others, so that, say, step No. 4 could occur before step No. 2 and after step No. 6. All that matters is that over the years one cell or set of cells passes through every step. Nobody knows why this happens to one man rather than another, or why it happens especially often to AfricanAmericans.
The genetic material in a cell is deoxyribonucleic acid, or DNA, long, threadlike molecules twisted into forty-six bodies called chromosomes, which resemble the soft Hs in alphabet soup. Failures take place either when entire chunks of a chromosome snap off, fall away, or switch places, or when small bits of the strand get lost or mixed up. The former are easier to spot than the latter. For example, cancer of the colon is associated with gross chromosomal abnormalities, one reason that scientists have recently nailed down the sequence of events that leads to it. No such obvious changes have been spotted in prostatecancer cells, and hence the thinking is that the accidents involved are small and affect individual bits of DNA. If it were stretched out, the DNA in each human cell would be about six feet long; errors may involve snippets shorter than a millionth of an inch. The implication for researchers, unpleasant to contemplate, is a long period of slogging. Thus far the only clue is the possibility, turned up over the past three years by a group of researchers in Sweden and a second group at Johns Hopkins led by John Isaacs's brother William, that particular bits of chromosomes 8, 10, and 16 may be involved. Is a sudden clinical breakthrough possible? William Isaacs thinks it unlikely. "No one is going to shout 'Eureka!' on this one," he says. "The champagne is safe."
Imagine a blindfolded man with an unlimited supply of darts. He is standing before, say, six dart boards. (The exact number of steps necessary for prostate cancer to occur is unknown; colon cancer, as it happens, involves six major chromosomal changes, so I chose that number.) Blindly tossing away, he will eventually hit a bull'seye. That is equivalent to one of the "right" genetic accidents. After, say, two or more bull'seyes he will have histological cancer. After a long time he will probably hit all six bull'seyes. When he does, the cancer will be fully developed and ready to spread. The question is when treatment should occur. Surgery for prostate cancer involves the possibility of impotence, incontinence, and death. It also might not work: the cancer might already have spread, unnoticed, beyond the prostate. Considering these odds, the operation should take place immediately before he strikes the last bull'seye. But that's impossible. By definition, one can never predict when a random event will occur. A more realistic goal is needed. One of the bull'seyes - imagine that it is painted green - corresponds to the genetic change that triggers the propensity to spread that is cancer's most deadly feature. The other five bull'seyes can be hit without any real menace. The problem is that no one can say when a dart has struck the green bull'seye.
To be an ideal diagnostic test, the PSA would be positive only when the player has struck the green bull'seye. Instead it is like an alarm that rings when the player has hit two or more. It does not tell him which two bull'seyes he has hit; and because BPH, too, can increase the level of PSA, he may in fact have hit none at all. Are we better off for having installed this imperfect alarm nationwide? The answer depends on whether its use will lead to what social scientists call increased wellbeing. Everyone I have spoken with has an opinion on the use of the PSA test, favorable or un . But no one says that his or her opinion was empirically established, based on the sort of controlled data that biomedical researchers like. No scientific study has demonstrated that the PSA test saves lives, though it might seem logical to suppose it would. Indeed, none has shown definitively that surgery leaves people better off than doing nothing. As a result, John Wasson says, the United States is rapidly putting the cart before the horse. "We're using at an explosive rate a technology that has not proven itself," he says. "The Europeans at the international meetings I go to are aghast. They say, 'What are you people doing over there?"
A Better Surgical Outcome (Less Impotence)
FROM a surgeon's point of view, the big change in the prostate world began when one of Patrick Walsh's patients experienced no long-term impotence or incontinence after the operation Walsh had performed on him. Walsh was flabbergasted. He had removed the man's prostate, and doctors had known for decades that radical prostatectomy always had these side effects. It was a desperate operation for men in desperate circumstances, because it left most men impotent, incontinent, or both. "I congratulated him, of course," Walsh told me when I visited him recently. "But what I was thinking was, This man cannot be unique. If he could be spared these things, others could."
Then as now Walsh directed the James Buchanan Brady Urological Institute, at Johns Hopkins. Slight, usually softspoken, and possessed of slim, delicate hands, Walsh graduated from the Case Western Reserve University School of Medicine in 1964 and trained as a surgeon for seven years in Boston and Los Angeles before coming to Johns Hopkins. His specialty was urology, the treatment of the reproductive organs in men and the urinary tract in men and women (though most urological patients are men). Urologists work on kidneys, bladders, testicles, and other parts of the body, but they are most often called upon to assist in the treatment of prostate disease. Radical prostatectomy, often the only available treatment for prostate cancer, was a thoroughly unsatisfactory operation. "You were working blind," Walsh told me. "If you thought about it, it would scare you out of your wits." The incision caused so much bleeding from so many sources that the cavity filled faster than suction tubes could drain it. In addition to endangering patients, the blood "prevented you from seeing what on earth you were doing in there." Surgeons had to cut out the prostate by feel.
Johns Hopkins has long been a center of urological research. Hugh Hampton Young, one of the first important American urologists, pioneered radical prostatectomy there at the turn of the century, and was probably the first doctor to call for routine prostate screening. Walsh went to Johns Hopkins with the intention of building on the school's tradition. A central problem, he was convinced, was that the anatomy of the prostate region was poorly understood. Walsh worked out the location of the veins and figured out how to pinch them off during surgery. That accomplished, surgeons began to see what they were cutting apart. It was as if a whole new world had been revealed.
Halfway through the prostate, the urethra is joined by a second tunnel, the seminal duct, through which semen passes on its journey to the outside world. Small side tunnels carry the chemical products of the prostate to the urethra and the seminal duct. The whole structure is wrapped in what is called a capsule. One end of the capsule is ringed by the urethral sphincter, which surgeons had always sliced through - the principal cause of postoperative incontinence. Reducing the flow of blood let Walsh see well enough to cut out the prostate without damaging the sphincter.
The operation still resulted in impotence, but Walsh didn't think he could do much about that. Then he remembered the patient who had an entirely normal sex life after a prostatectomy. Walsh had been taught in medical school that the nerves controlling erection ran, like the urethra, through the prostate, and thus that impotence was an inevitable byproduct of removing it. The patient's experience sent Walsh back to his textbooks, which said little more than that the nerves were "small [and] difficult to follow." The medical profession had merely assumed that the nerves ran through the prostate.
Walsh looked for himself. The prostate was little studied, because it is surrounded by the kind of fatty tissue that does not survive embalming, and most anatomy research is performed on cadavers. In 1981 Walsh went to a medical convention in the Netherlands, where he met Pieter Donker, a retired urologist from Leiden. Donker had discovered that the ideal subjects for prostate dissection are stillborn infants, because their nerves are relatively large and the surrounding fatty tissue is thin. The two men spent an afternoon at the table. Walsh observed, to his excitement, that the nerve bundles were outside the prostate capsule, held in place by a thin, almost translucent sheet called the pelvic fascia. Scalpels had been blindly cutting through them. Lifting away the fascia like a blanket from a bed would give surgeons a clear path to the prostate. Walsh's first attempt at doing this, in April of 1982, was successful: the patient, a fiftytwoyearold man, was sexually active within a year.
Good surgeons operate often, to keep their touch. Using what has been called the nervesparing technique, Walsh performed more than 600 radical prostatectomies from 1982 to 1988. (Walsh has not assembled complete data on the longterm outcomes of the surgery he has performed since then.) Some 92 percent of his patients achieved complete urinary control; 68 percent of those who were potent preoperatively remained so, with the figure higher for younger men. (A hundred percent success is not to be expected; by the time of surgery, some cancers have spread to the sphincter or the nerves.) By the middle of this year Walsh had performed more than 1,300 radical prostatectomies; just two patients died, and about 70 percent seemed to be cured of cancer, Walsh says. Similar results have been reported by other pioneering urological surgeons, such as William Catalona, of the Washington University School of Medicine, in St. Louis, and Thomas Stamey, of Stanford.
Walsh was pleased, of course. And he was pleased that the arrival of the nervesparing technique roughly coincided with the arrival of the PSA test. The test, in his view, increased not only the likelihood of an accurate diagnosis but also the likelihood of diagnosis at all. Men as a group tend to avoid seeing their doctors, and even those who have annual checkups tend to refuse rectal exams. "Women have always had doctors poking at them," Walsh says. "It's unpleasant, but they recognize they have to do it. A middleaged man isn't used to it, and often won't do it." PSA testing suddenly made the job easier -- the doctor simply penciled in another X on the paperwork for the patient's blood tests. Walsh cautions, however, that one PSA reading is not enough to make a diagnosis. As many as a third of men with prostate cancer have low PSA readings, he says; a rectal examination is thus essential. Conversely, high PSA readings might not indicate cancer, and the test is often repeated over a period of months.
With the advent of moreeffective diagnosis and treatment, Walsh says, men finally began to talk about prostate cancer. They compared PSA levels over lunch. Celebrity victims emerged: Michael Milken, symbol of Wall Street; Frank Zappa, nosethumbing rock star. Jesse Helms on the right, Alan Cranston on the left. Robert Dole, whose cancer was discovered by a PSA test, endorsed a prostate advocacy group called Us Too. The King of Belgium discovered he had prostate cancer; Walsh operated on him. Billboards appeared in the United States, on which actors and sports personalities encouraged men over forty to see a doctor about prostate cancer. ScheringPlough, a drug company, distributed flyers about prostate trouble at doctors' offices and hospitals across the country. ("If you learn only one fact from this brochure," read a boldface paragraph, "let it be this: early detection of prostate cancer saves lives.") And Walsh himself, surgical mask at his throat like a cowboy bandanna, was featured in The New York Times in a fullpage advertisement placed by Johns Hopkins to extol its medical work.
Which may be why Walsh was so distressed when criticisms began to appear, first in the medical journals and then in the popular press. On the day I visited him, he took two calls from newspaper reporters, growing increasingly vexed as he answered their questions. It was possible to discern the surgeon's temper beneath his affability. He replaced the receiver with some vehemence. The criticisms, he said, were "misleading and biased." They were "really a step backward." They were "irresponsible." The press coverage was all too often "confused." Men are dying of this disease, he said, and many of them can be helped. "I can't believe they're suggesting that we do nothing," he said. His hand hovered over the desk as though he were thinking of banging it on the wood. "I find that incredible."
Clear Costs, Unclear Benefits
A test that lets surgeons treat a fatal disease - who could possibly object to such a thing? But that is precisely what a growing chorus is doing. The attack gained volume last May, when the Journal of the American Medical Association published two articles by the Prostate Patient Outcomes Research Team. Taking the PSA test, the team's John Wasson said, would be pointless if no effective treatment existed for the prostate cancer it diagnosed, or if the treatment were worse than the disease. A wellknown treatment for prostate cancer, radical prostatectomy, does exist; deciding whether it is effective turns out to be surprisingly complex. This means, Wasson argued, that the case for the widespread use of the test is muddy at best.
As any doctor knows, even the best treatment is not perfect. Aspirin, one of the safest and most effective drugs ever discovered, nonetheless managed to kill fortyfive Americans last year (at least twentyfive of the deaths, however, were suicides). The trick is to ensure that the benefit of the treatment outweighs the cost. In the case of aspirin the decision is obvious. If taken by the right people, this inexpensive drug could prevent perhaps a quarter of all first heart attacks, preventing thousands of premature deaths.
Radical prostatectomy for prostate cancer is a much harder call, because the cancer it removes may not be fatal, and because it takes a serious financial and personal toll: biopsy, surgery, hospitalization, possible major side effects, even death. A big, wellrun, randomized clinical trialthousands of people given surgery after a positive diagnosis, an equal number left untreated, the outcomes compared years laterwould go far toward resolving the issue. Nobody has completed such a trial, although the Department of Veterans Affairs is considering undertaking one and another has recently begun in Sweden and Finland. These studies will produce no results for at least a decade. Thus the critics are right: the increase in screening for prostate cancer means that this country is embarking on a vast experiment without being certain that the outcome will be beneficial.
In the absence of results from a clinical trial, researchers have tried to estimate the consequences of measuring the PSA of every eligible man in the country. The value of such projections is limited by the lack of data and the need for simplifying assumptions - for instance, that PSA tests are never given without an accompanying rectal exam. But they give an idea of how health professionals try to establish the desirability of medical procedures that may affect the lives of millions of people. According to the 1990 Census, there are about 23.4 million American men from fifty to seventyfive, a time of life that has been described as the optimal screening years. Not every one of these men should be screened for prostate cancer, because some have diseases that are likely to be fatal before prostate cancer would be, such as heart disease and other types of cancer. Figuring out how many men have such diseases is difficult, but one can make a rough approximation by looking at the most widespread of them - heart disease. A longterm study based in Framingham, Massachusetts, has by extrapolation shown that at least 2.8 million men aged fifty to seventyfive are afflicted with severe cardiac problems. Subtracting these people from the total number leaves 20.6 million potential candidates for screening.
To estimate the results of administering PSA tests to this many men, researchers have used data from pilot experiments. In the biggest screening project yet undertaken, William Catalona and three colleagues from Washington University tested the PSA levels of 9,629 older men, all at least fifty but some over seventyfive, whose physical characteristics were reasonably similar to those in the population at large (reasonably but not entirely similar - the researchers did not screen anyone with a history of prostatitis). Of these men, 9.4 percent had elevated PSA levels, suggesting a problem. Further diagnostic tests were performed on these men, and about one in three had cancer. If Catalona's findings could be extended to all 20.6 million eligible men, a nationwide PSA test would pick up almost two million people with high PSA levels. After biopsies about 1.3 million of them would be told not to worry (although some of them would have cancer that would be picked up on subsequent screening). About 640,000 would learn they had cancer. Of these, some 235,000 would have advanced cases that many doctors would regard as inoperable. Thus universal PSA screening would find, according to this rough estimate, about 405,000 cases of cancer treatable by prostatectomy.
In the past most of these smaller carcinomas would not have been discovered, and hence would have remained untreated. After ten years about two thirds of them would not have spread outside the prostate, if one is to believe the results of the largest study to date on the subject, in which six Swedish researchers tracked for an average of ten years 223 men with untreated early-stage prostate cancer. (This is standard practice in Sweden, where staterun medical programs are chary of procedures that have not been proved useful.) These results suggest that a significant proportion of the 405,000 tumors that would be detected in a national screening program would not spread in the patient's lifetime.
Because the individual patient cannot know whether he is one of the lucky men with a slowly progressing case, it is likely that most of those 405,000 men would undergo radical prostatectomy. What would happen? The conservative approach to this question is to find out the results obtained from operations in the past and project them into the future. According to the Prostate Patient Outcomes Research Team, which did just that using data on prostatectomies performed from 1981 to 1991, between 0.5 percent and two percent of all radical prostatectomies led to death within a month, with older men facing the most risk. More than five percent led to pulmonary embolism or some other serious complication in the hospital. At least 30 percent of the potent men who underwent prostatectomy in this period became impotent; seven percent lost all urinary control; many more had intermittent difficulties in both areas. And perhaps 20 percent were told that during surgery it was discovered that the tumor had already spread, and they would need further treatment (radiation, hormone therapy, or removal of the testicles). These figures imply that operating on all 405,000 men would result in 2,000 to 8,000 deaths, at least 20,000 cases of serious complications, at least 120,000 cases of surgeryinduced impotence, about 28,000 cases of surgery-induced total incontinence, and more than 80,000 cases of cancer requiring more treatment, along with many other cases of lesser problems. Meanwhile, men with elevated PSA levels but no sign of cancer would be likely to have biopsies again and again, because of the red flag in their blood - a process one doctor jokingly calls "prostatectomy by installment."
THE effort would be very expensive. PSA tests and rectal exams cost about $80 together; biopsies cost perhaps $350. If 20.6 million men had PSA tests and rectal exams and two million had biopsies, the bill would be in the neighborhood of $2.3 billion. The average cost of a prostatectomy is about $20,000, according to Kit Simpson, a healthpolicy specialist at the University of North Carolina at Chapel Hill; 405,000 of them would cost $8.1 billion. Treating the impotence or incontinence caused by surgery can cost $10,000 per patient. The total price of remedying such side effects would depend on how often they occurred, but in 1990 an economic study by a statistician and a urologist at the U.S. Army medical complex in Fort Sam Houston, Texas, projected that the extra expense for side effects might reach $2.1 billion. At the time, the two men pointed out, the national bill for prostate cancer was $255 million. An immediate nationwide program of screening all men in the proper age category, they said, would drive the price up to $28 billion - a hundredfold increase. To critics, such figures suggest that a screening program could sentence hundreds of thousands of people to immediate and costly suffering in the name of avoiding a disease that will kill only a small number of them many years in the future.
Nobody I have spoken with thinks that the United States could examine and treat 20.6 million men cheaply and painlessly. But proponents of mass PSA screening argue that estimates like these are based on inaccurate data. Claims that side effects from operations in the future will be at the level of those in the past ignores evidence from surgeons like Walsh and Catalona that the nervesparing technique is an important advance. Instead of a death rate of one in a hundred, these surgeons report death rates of zero to one in 600. Walsh and Catalona say that instead of seven out of a hundred becoming completely incontinent, and many more having problems, not one of their first 1,200 patients lost all urinary control, and only six to eight out of a hundred had any problems whatsoever with incontinence. Although these figures should not be taken as national averages, using them in calculating the cost of treating side effects would change the projections drastically. Indeed, it was the publication of the pessimistic estimate by the Prostate Patient Outcomes Research Team, which made little allowance for the improvement in surgical techniques, that caused the calls from the newspapers which so exercised Walsh during my visit.
Proponents also accuse critics of skewing their figures by overestimating the costs (such as saying that many seventyfiveyearolds will have the operation) and underestimating the benefits (failing to include the avoided years of pain from bone cancer, for instance). A prostatectomy today may cost $20,000, but treating that same cancer at a later, more advanced stage may cost $70,000. Most important, although many men diagnosed as having prostate cancer will never feel any effects from the disease, failing to treat the rest would sentence thousands of people to a death of rare awfulness. "Every fifteen minutes an American man dies of prostate cancer," Catalona says. "And when that happens, he's been through hell. None of them have a pleasant death. There's a long period of pain and agony with broken bones, urinary obstruction, constipation from all the morphine - it's horrible."
"The screeners say, How can you deprive all these people of a valuable treatment?" says Gerald Chodak, a urologist at the University of Chicago School of Medicine. "The other side says, How can you do all these things to people and not know if they really have any benefit?" It seems impossible to resolve the issue rationally, because the evidence is of such poor quality. The American Board of Urology and the American Urological Association have no idea, for instance, how many surgeons have been trained in Walsh's techniques. Surgeons like Catalona and Walsh assert that many of their colleagues know the new methods; outside observers like Wasson suspect that they don't.
Similar uncertainties dog the larger question of whether radical prostatectomy in fact saves lives. Most of the reports in favor of radical prostatectomy come from surgeons like Walsh and Catalona, who collect data on their patients. Alas, these articles suffer from "publication bias" - the tendency for people with good results to publish their data more often than those with bad results. "You won't see articles written by people with poor results," Chodak says. "They're put out by honest people who are superb surgeons, but the problem is that they may be such excellent doctors that they are totally unrepresentative of the average doctor that the average Joe is going to face." The rosy reports, he believes, may lead patients without access to topquality medical care to a falsely optimistic picture of the odds they face.
In the view of Brent Blumenstein, a medical statistician at the Fred Hutchinson Cancer Research Center, in Seattle, publication bias is merely part of a larger problem created by the lack of emphasis on research methodology during the surgicalresidency period. Unschooled, surgeons fall into many logical and statistical traps when they do research. Often, he says, they do not list the criteria they used in selecting patients for a study, invalidating their work from the outset. Several researchers have told me that data that call into question the use of surgery tend to come from studies with a disproportionately large number of old patients, who could be expected to have more side effects, and that data favoring it tend to come from studies with too many young patients. Carefully interpreted, such partial reports could be useful if they were put together with forethought. Unfortunately, they rarely are. Last May the Prostate Patient Outcomes Research Team reviewed more than 1,600 journal articles published since 1966 on the treatment of prostate cancer. Only 144less than a tenthwere detailed enough to permit independent reexamination of their data. Of these only one clearly described the patients' ages, to what point their cancers had progressed, and other medical conditions, and also gave the number of people who failed to attend followup appointments, although such information is supposed to be standard in medical research.
To be fair, determining the value of prostate surgery is a knotty matter. Because a majority of the men suffering from prostate cancer die of something else, the benefits of surgery, whatever they may be, for the most part accrue to the minority who would actually die of the disease. Even for them surgery may have little value. "If you have cancer that would kill you at sixty-nine, and you have treatment and then die at seventy of heart disease, you didn't gain much," Chodak says. Gains in lifespan are therefore most likely for younger, healthier patients - men under the age of sixty or seventy. Unfortunately, these are the very people who are most likely to live for many years without symptoms anyway. The benefits will show up only years later, assuming that the tumor would indeed have become lifethreatening.
One way of cutting through the fog of competing statistics is to estimate the overall benefit from PSA screening on the basis of the most optimistic assumptions about the use of radical prostatectomy. If it is small, one might question the value of the test. Kit Simpson presented such an analysis at the annual meeting of the American Urological Association last May. Unsurprisingly, she found that the benefits were unevenly distributed, with most of them accruing to the fifty to sixtyyearold men whose cancer would have spread quickly and whose lives would therefore presumably be lengthened by surgery.
Simpson tried to learn whether the gain for that group of people would be proportional to its price. When everything was added up, she concluded that a screening program would save society up to $3 billion over the lifetime of the present generation of older men.
"You get a little bit of life saved and a small amount of money saved per man screened," she told me recently, adding that benefits to individuals could of course be considerable.
I asked if that $3 billion savings merited investing in an enormous screening and treatment program for the whole country. Even in the most optimistic scenario the costs are high in the beginning, running to billions, and the benefits do not appear for years. "You'll spend more money each year until you find and treat all the cancers, and then you start saving money," she said. "The policy question is, can we afford to do that right now?"
What Men Should Do
IN some ways Simpson's question is moot. Although statistically each man obtains only a slight benefit from the test, those benefits are not distributed evenly - a man either receives them in full or he doesn't. The chances are quite good that if an otherwise healthy man who has just been diagnosed as having lowgrade prostate cancer ignores the news, his cancer will never trouble him and he will die of something else. Yet the penalty for guessing wrong is severe - and nobody plans to die of other causes. People focus on the problem at hand, and the argument that they should forget about prostate cancer because they might be felled by a stroke in five years carries little weight. As a result, men are willing to accept the possibility of deleterious side effects today to avoid an awful death in the future. Cost is rarely a factor to the individual, because his insurance will pick up most or all of the tab. On the broad societal level this may be the wrong choice, medically and fiscally. But the individual man doesn't care - his cancer will either stay dormant or kill him. As a result a de facto national screening program is taking place, good idea or no. Men are running pellmell to measure their PSA levels, and those with positive cancer diagnoses are submitting themselves to radical prostatectomy in record numbers. It is a perfect example of why healthcare costs are so difficult to control.
"What's good for the individual may not necessarily be good for the masses," Chodak told me. "It sounds like the moral of a Star Trek movie." Even William Catalona, a PSA enthusiast, would like to put some brakes on the prostatectomy express. Men over seventyfive should think twice about subjecting themselves to such a major surgical procedure as radical prostatectomy, he says. Even in the best of circumstances they are disproportionately likely to experience impotence and incontinence and to live no longer than they would have without the surgery. Therefore Catalona thinks the PSA test has considerably less utility for such men. Like every other researcher I have spoken with, he is dismayed by the recent explosion in prostate surgery in men older than seventyfive.
Fifty to sixtyyearolds, though, are a different matter. Both sides, pro and con, believe that if benefits accrue from treatment, they are concentrated among such men. These men, Catalona says, should have their PSA levels checked once or twice a year. If the level is high - above four nanograms per milliliter in the Hybritech test - they should have a rectal exam, an ultrasound exam, and a "quadrant" or "sextant" biopsy, which uses a computerassisted needle probe to image each part of the gland, obtaining samples from suspicious areas. Men should not have a biopsy if they suffer from prostatitis, because the biopsy may induce a dangerous infection. "Take the antibiotic and come back," Catalona says.
If a carcinoma is discovered, the patient should learn its location and size. Is it still confined within the prostate, or has it spread to the capsule? In the former case the disease is unlikely to have metastasized, and hence may be a candidate for surgery. In the latter case there is some chance that metastasis has already occurred and that it is too late for prostatectomy to do any good. Size is an important proxy measure of the likelihood that the carcinoma has passed through the genetic steps necessary to become dangerous: a widely but not universally accepted standard is that tumors less than half a cubic centimeter in volume are probably not old enough to have acquired the ability to grow rapidly and spread. Because tumor size is hard to determine precisely with a biopsy, surgeons also give considerable weight to the degree of differentiation, which describes, so to speak, the "cancerlike" qualities of the carcinoma. "Welldifferentiated" carcinomas are, despite the name, similar to the tissue surrounding them, and relatively unlikely to metastasize; "poorly differentiated" carcinomas are more likely to be advanced. All these factors play a role in determining the degree of threat. In general, surgeons consider poorly differentiated tumors that are still contained within the prostate to be the best candidates for immediate surgery.
Before submitting to a prostatectomy, Catalona says, men should choose their surgeon carefully. Ask surgeons if they know the nervesparing technique, how many prostatectomies they have performed, and at what rate their patients have experienced side effects. Avoid doctors who do not know the technique, who have performed fewer than 150 prostatectomies, or who have patients with higher rates of incontinence and impotence than those reported in journal articles by surgeons from major teaching hospitals. "If your surgeon can't tell you those rates," Catalona says, "that's grounds to think about trying another one."
Although such precautions will surely minimize the chance of an undesirable outcome on the individual level, they do nothing for the likelihood of an undesirable outcome on the collective level - that is, the possibility that the nation's healthcare spending will rise by billions to cover the cost of thousands of unnecessary operations. Indeed, as Kit Simpson says, "Surgery is expensive, justified or unjustified. The only truly cheap method of dealing with prostate cancer would be to prevent it."
Happily, prevention is what the National Cancer Institute is now examining. A number of laboratory reports suggest that prostate cancer is somehow linked to 5alphareductase, the enzyme that converts testosterone to dihydrotestosterone, the hormone that induces prostate swelling. The relation between the enzyme and the genetics of cancer is unknown, but it is known that finasteride (Proscar) stops the enzyme from functioning. Last month the NCI was scheduled to begin a clinical trial to examine whether finasteride can prevent cancer. The nationwide trial, which is headquartered in San Antonio, will randomly divide 18,000 healthy men into two groups. Half will take finastende for seven years; half will take a placebo. "It's a massive effort," says Brent Blumenstein, who assisted in designing the trial. "Whether this is the answer should come clear."
Blumenstein, like every statistician I have spoken with, is deeply skeptical of a national screening program. At fortynine he is rapidly approaching the age group most likely to be screened. What would he do, I asked, if he learned that he had a relatively large carcinoma in the center of his prostate? His answer came quickly. "Personally," he said, "I would start talking to the best surgeon I could find."