THE MAN'S CANCER

By LEON JAROFF/SANTA MONICA

THREE YEARS AFTER HIS TRIUMPH IN THE GULF WAR, GENERAL H. Norman Schwarzkopf was feeling invincible. But in March 1994, uncomfortable with nagging tendinitis in one knee, he stopped by the MacDill Air Force Base Hospital in Tampa, Florida. While there, he decided to visit the base urologist for an exam. "I feel something not quite right," the doctor said, after making a routine rectal exam. "But if it's cancer, I can tell 90% of the time, and I don't think so."

Schwarzkopf, then 59, had reason to feel confident. He had recently undergone a PSA (prostate-specific antigen) test and registered a count of only 1.8, well below the level considered indicative of cancer. But to play it safe, the urologist performed an ultrasound exam ("It looks like a stone," he reassured the general), took a biopsy of the prostate gland and sent it off to a pathologist. Schwarzkopf left the hospital relaxed and optimistic. But a week later, the doctor called, paused and then said, "I don't know how to tell you this, but you have prostate cancer."

Shaken, and like most men woefully uninformed about prostate cancer, Schwarzkopf began devouring books and medical-journal articles. He overcame his squeamishness and started talking to friends and experts about this disease that seems to strike at the very core of masculinity. "For me, it was like war," he says. "First thing you do is learn about the enemy."

Schwarzkopf had little idea how formidable that enemy is. The American Cancer Society estimates that in 1996, 317,000 Americans will be told they have prostate cancer, more than the 184,000 new cases of breast cancer and nearly a quarter of all non-skin cancers expected this year. That figure represents a staggering increase over last year's 244,000 new prostate-cancer cases and the fewer than 85,000 recorded as recently as 1985. The acs predicts that deaths from prostate cancer in the U.S. will reach 41,400 this year, a number fast approaching the annual breast-cancer toll of 44,300. Says Dr. Nelson Stone, a urologist at Manhattan's Mt. Sinai Medical Center: "It sounds like an epidemic to me."

In a way, it is. The life-span of Americans is increasing, and because the disease most often strikes men who are in their 60s or 70s, more of them are now afflicted. When the baby-boom generation matures, the number will balloon. "As men live longer and do not succumb to heart disease and stroke, more will die from prostate cancer," says Dr. William Catalona, a urologist at Washington University in St. Louis, Missouri. "And it is not a nice death."

By far the biggest factor in the sharp rise of prostate-cancer diagnoses is the increasingly widespread use of the controversial PSA test, which in many cases can detect the disease early in its course, long before the tumor becomes palpable. By making early detection and treatment possible, the test could eventually reduce the number of prostate-cancer deaths. Paradoxically, it could also lead to a rise in premature or even unnecessary treatments.

Although 1 in 5 American men will develop prostate cancer in his lifetime, most are only vaguely aware of the disease, its treatment and its consequences. Unlike women, who usually talk freely among themselves about intimate health problems, most men shy away from exchanging information about any of their physical disorders, let alone problems involving a gland that produces seminal fluid and affects urinary flow. And they prefer not to undergo, or even think about, the traditional test for detecting prostate problems: the infamous digital rectal exam.

Still, says Dr. William Fair, head of the urology division at Manhattan's Memorial Sloan-Kettering Cancer Center, "prostate cancer is beginning to come out of the closet. Fifteen or 20 years ago, you couldn't even mention the word prostate in polite mixed company." Indeed, popular awareness of prostate cancer may now be at a stage similar to that of breast cancer two decades ago, after Betty Ford and Happy Rockefeller revealed publicly that they were victims of a cancer that until then had been discussed only in private, and urged women to have mammograms.

Their role is now being played by Schwarzkopf, who, after learning that his cancer had not metastasized, quickly decided on major and somewhat risky surgery--a radical prostatectomy--to excise the prostate gland. "I'm not a type-B personality who knows I have a cancer growing inside of me and can live with the knowledge," he says. "I go into a kung-fu attack position when I go through the door of a hospital." The position apparently worked. Schwarzkopf made a speedy recovery from the surgery, is now cancer free and, as spokesman for Prostate Cancer Awareness Week, lectures regularly, warning men over 50 about their risks.

In his crusade, Schwarzkopf has joined forces with an unlikely but powerful ally who has even more reason than the general to be motivated: Michael Milken, the famous junk-bond wizard of the 1980s.

For Milken, the world changed on a day in January 1993 that should have been a happy one. He had just been released from a halfway house after serving two years in prison for securities-law violations. Only 46, apparently in good health and eagerly anticipating his freedom, he called the doctor who had given him a physical exam the week before.

During that exam, Milken recalls, he asked for a PSA test. "Why bother?" the doctor responded. "You're too young." But Milken insisted, and now the results were in. "He told me that everything was perfect," says Milken, "except that I had a PSA score of 24." Two repeat PSA tests produced similar results, and a subsequent biopsy confirmed the worst: he did indeed have cancer.

"To say that the biopsy results were devastating would be an understatement," Milken says. "I remember lying in bed with my wife and talking about the Book of Job, wondering how many more challenges were coming my way. I was in a state of depression."

It didn't last long. Mustering the relentless drive that made him a Wall Street billionaire in his 30s, Milken declared a personal war on prostate cancer, vowing not only to fight his own illness but to help finance the larger scientific battle against the disease. "I decided that I had to change the course of history," he says. And he may just do that, for himself and for the millions of other men who have or will develop prostate cancer.

Like Schwarzkopf, Milken pored over the medical literature, conferred with experts and opted for a prostatectomy, relieved, he says, because "technology had improved and a lot of horror stories that you hear are related to surgeries from the past."

That relief was short-lived. Returning to his urologist for a diagnostic computer scan, Milken learned that his lymph nodes were swollen. A subsequent needle biopsy confirmed that the nodes were malignant. His cancer had metastasized, spread beyond the walls of his prostate; surgical removal of the gland would now really serve no purpose.

Milken was stunned. "I'd mentally got myself geared up to the realization that I had prostate cancer," he recalls. "I'd gotten over the 'Why me?' and spoken to a number of friends who had had successful surgery. That's where I was going to make my stand." Now what? Searching for an answer, he scheduled a bone-marrow test at M.D. Anderson Cancer Center in Houston to determine if the cancer had spread to his bones. If it had, his life expectancy would be measured in months, and he was hardly sanguine about the outcome. "I had not been successful in one test I'd taken," he recalls. "Every test I'd taken had turned out for the worst." This time, however, the word was good. Milken's cancer had not metastasized to his bones.

THE GROWTH OF PROSTATE-CANCER cells is stimulated by the male hormone testosterone, and to halt and possibly reverse the progress of Milken's malignancy, his doctors prescribed a hormone treatment that shuts down production of testosterone. "I began taking two pills three times a day," says Milken, and got a time-release shot once a month." The results were dramatic. His PSA level dropped from 24 to 15, then to 10, 5 and 3, and by August, when he began undergoing supplementary radiation therapy, it stood at zero. The computer scans were also encouraging; they showed that his swollen lymph nodes had shrunk back to normal size. Milken's cancer was, and still is, in remission.

Milken is back in business, running several of his family businesses and philanthropic enterprises and flying around the U.S. for meetings with top corporate officers. (He is also under investigation for possibly violating his parole in recent business dealings, including his consultations with the Turner Broadcasting System on its proposed merger with Time Warner.)

But Milken is realistic. He knows that in men who have undergone hormone therapy, the cancer cells eventually learn to thrive and multiply without testosterone, usually within a year or two. While Milken has reacted unusually well to the treatment, he is all too aware that he has not been cured. "We just don't know how long before it comes back," he says. "It's not that it's gone. It's how long."

For all of Milken's angst, however, he has never had an overt symptom of advanced prostate cancer, no pain in his bones, weight loss, chronic fatigue or problems with urination. "That's one of the things that's scary about this," he says. "Had I not had a PSA, I would not have known."

The PSA test, available since the 1980s and now administered to hundreds of thousands of men annually, measures the blood level of a protein produced by all prostate cells. In general, readings under a PSA count of 4 indicate that cancer is highly unlikely. The probability of cancer increases with a rising count between 4 and 22 and becomes highly likely over 22.

Usually in a man around age 50, the prostate begins to enlarge, and the growing number of cells contribute to what is generally a steady but slight rise in the PSA count. But if prostate cells become cancerous and begin multiplying, the PSA level jumps dramatically. Even if a rectal exam fails to detect any palpable evidence of cancer, an elevated PSA is most often warning enough to prompt the doctor to view the prostate with a transrectal ultrasound probe, and frequently to take needle biopsies from several regions of the gland.

Men whose prostate cancer is detected early have more choices than Milken did. Yet they may agonize even more before making a decision, because they face a painful dilemma: virtually all the therapies available to them can drastically affect their quality of life, and the only one that can virtually guarantee a cure--if the cancer has not metastasized--is the most forbidding of them all.

That one is radical prostatectomy, surgical removal of the entire prostate gland. If the cancer has not spread beyond the prostate wall and the gland is removed, the cancer is gone. Period. Three days after his surgery, at Walter Reed Army Medical Center, in Bethseda, Maryland, Schwarzkopf was visited by the chief of pathology, who said, "Good news. We looked at your cancer, and it was very slow-growing. We have 100% of your cancer in a jar."

Still, there are drawbacks. In performing a prostatectomy, the surgeon must reach the prostate by cutting through either the abdomen or the region behind the scrotum. This is major surgery, and the patient must undergo a hospital stay of at least several days and many weeks of recovery--attached all the while to a catheter. It can entail risks for anyone, but particularly for older men not in the best of health. Also, because the walnut-size prostate surrounds the urethra--the tube through which urine passes from the bladder--some of the sphincter muscle that controls the flow of urine may be cut away.

As a result, there is a substantial risk of incontinence. About 1% or 2% of prostatectomy patients will have complete lack of urinary control, according to Dr. Keith Light of Memorial Sloan-Kettering. From 20% to 50% will have partial control and stress incontinence--leakage caused by any kind of physical pressure--and more than half will have minimum leakage, only a few occasional drops. Many of these men will eventually regain control, but for some, pads or diapers will become essential wardrobe items. Schwarzkopf was fortunate. Within a day after he returned to the hospital to have his catheter removed, he says, "I had complete control." He attributes this to weeks of vigorous postoperative walks taken with catheter in tow.

A prostatectomy poses an even more intimate threat to a man's life-style. Because the two nerve bundles controlling erection run along the surface of the prostate, the operation until recently almost invariably rendered the patient impotent. Then in the early 1980s, Dr. Patrick Walsh of the Johns Hopkins Hospital in Baltimore, Maryland, pioneered a technique that enables the surgeon to move the nerve bundles out of the way before excising the prostate. After this nerve-sparing surgery, which Walsh practices only when it seems likely that the cancer does not lie close to those bundles, many patients are eventually able to have satisfactory erections. Walsh says as many as 90% of men under age 50 regain potency. Schwarzkopf? It's O.K., he says. The surgery has hardly slowed the general down in other physical activities. He was fly- fishing in Alaska two months after the operation and, a month later, climbing mountains during an African safari.

For men whose health is too fragile to withstand the rigors of a prostatectomy, and for those who want to avoid the week-long hospital stay, weeks-long dependence on a catheter, and extended recovery time associated with this surgery, external-beam radiation is often the therapy of choice. While it involves a series of exposures over several weeks to a finely focused X-ray beam, no hospital stay is required.

But radiation often fails to kill all the cancer cells. While the tumor shrinks significantly and PSA counts drop to low levels or even zero for several years, the cancer eventually returns. A study conducted by Dr. Thomas Stamey of Stanford University in California, concluded that nearly a decade after radiation therapy, 20% to 25% of the radiation patients had apparently been cured. But the remaining 75% to 80% showed "a steeply rising PSA," indicating a recurrence of the cancer. Also, as many as 50% of these patients became impotent within five years of treatment.

A completely different radiation technique, advanced by the late Dr. Willet Whitmore at Sloan-Kettering, places dozens of tiny radioactive palladium or iodine seeds directly in the prostate. Because the radiation emanates from each seed and affects only the immediate surrounding region of the prostate--instead of passing in a beam through the body to reach the gland--damage to nearby healthy tissue is minimized and a stronger dose can be delivered directly to the tumor. Though seeds remain permanently in the prostate, their radioactivity sinks to negligible levels after several months.

But even this relatively benign procedure--which can often be performed in an hour on an outpatient basis--poses some risks. Incontinence is common for weeks afterward and is permanent in about 5% of patients. Impotence occurs in about 15% of men under 70 and more often in older men. And while a five-year study from the Northwest Tumor Institute in Seattle shows that this method produces a lower rate of tumor recurrence than either prostatectomy or external-beam radiation, no longer-range studies have been published, and doctors can't say with any certainty that the cancers have been cured.

Yet another form of treatment, cryotherapy, involves pushing metallic probes into the prostate and circulating liquid nitrogen at -195 degrees F through them, forming an ice ball that freezes and kills the prostate cells. In the process, the overlying nerve bundles are usually frozen too, leaving more than 60% of patients impotent. Incontinence is seldom a problem, because a catheter is used to warm the urethra and keep it from freezing during the operation. One drawback to this strategy: prostatic tissue immediately adjacent to the catheter does not freeze, leaving the disturbing possibility that some cancer cells will survive to resume their attack.

While some doctors see promise in cryotherapy, especially for salvaging cases of recurrence after more conventional treatment, no studies have yet been conducted to gauge its long-range effectiveness. And hormone therapy, which Milken is now receiving, is at best a holding action; it is sometimes also used to shrink tumors before prostatectomies.

FACED WITH THIS BEWILDERING ARray of draconian treatments--and their humiliating side effects--many older men and some younger ones opt for "watchful waiting." This controversial nontreatment calls for frequent blood tests, rectal exams and an occasional biopsy but no intervention unless the cancer becomes more aggressive.

Who should be treated, and who is a candidate for watchful waiting? Because the average prostate cancer takes a decade to develop symptoms that seriously affect quality of life, Washington University's Dr. Catalona argues that any man whose life expectancy is 10 years or more should be treated. "Men with prostate cancer should have two goals," Catalona says. "One should be to live longer if they can, and the second should be to avoid dying of prostate cancer. A quick heart attack is far preferable." For these reasons, he supports widespread PSA screening to detect cancer early.

Yet experts at the National Cancer Institute (NCI) in Maryland, point out that PSA readings sometimes raise alarms that are misleading, fail to differentiate between fast-growing and less threatening prostate cancer and can lead to debilitating treatment that may not be necessary.

The fact is a few cancer cells are not necessarily that alarming. Oncologists estimate that by age 50, as many as 4 out of 10 men have at least some cancerous cells in their prostate, cells that are likely to result in higher PSA readings. Yet of these men, says Stanford's Dr. Stamey, only 8% will eventually develop symptoms that affect their quality of life, and only 3% will die of the cancer. "This is the only cancer that never really causes problems in a high proportion of men who develop it," says Dr. Otis Brawley, a senior investigator at the NCI, "and treating some patients may end up doing more harm than good."

The possibility that widespread PSA testing will lead to many cases of unnecessary treatment also disturbs Dr. Gerald Chodak, a University of Chicago urologist. "How many people is it O.K. to treat without benefit, and even with harm, in order to save one life?" he asks. "I find this issue very troublesome."

In his own practice, Chodak avoids either recommending or advising against a PSA test. "My approach," he says, "is informed consent. I tell my patients, 'If you want to see if you have cancer, then take the test. If you want to minimize your risk of undue harm, then don't take the test.'"

Much of the uncertainty could be eliminated, of course, if doctors could tell, while a prostate cancer is still small, if it is the lethally aggressive or relatively benign type. In other words, whether a man will die of it or merely with it. "The challenge," as the British Medical Journal editorializes, "is to separate the pussycats from the tigers and identify aggressive tumors."

Milken's millions may help meet that challenge. Three years ago, undoubtedly acting out of enlightened self-interest but with more universal goals also in mind, he set up a public charity, called CaP CURE, dedicated to finding a cure for prostate cancer, and pledged $25 million over the next five years to fund basic and clinical research, recruit scientists, sponsor scientific meetings and increase public awareness of the disease.

By last week, CaP CURE, with the help of a star-studded scientific advisory board, had awarded $22 million in grants to hundreds of researchers in the U.S. and abroad--making it the world's largest private source of funding for prostate-cancer research, second only to the NCI. Yet researchers complain that much more financing is needed. A CaP CURE brochure points out that while the number of deaths from prostate cancer is about the same as for aids and breast cancer, the Federal Government provides $1.3 billion for aids research and $313 million for breast cancer but only $59 million for prostate cancer.

Under the auspices of CaP CURE, Milken is financing the establishment of a prostate-cancer "virtual consortium," led by University of Washington molecular biologist Leroy Hood, that brings top U.S. researchers together via a computer network to facilitate communication.

Hood's immediate objective is to find biological markers that will characterize a tumor as essentially harmless or dangerous while it is still small--which would eliminate much of the uncertainty about decisions to treat, how to treat or not to treat prostate cancer. "A great many men who die in their their 70s and 80s have small prostate cancers that haven't done anything," Hood says, and wouldn't have benefited from treatment.

His strategy is to make use of the large bank of prostate tissue gathered by Washington University's Dr. Catalona and Dr. Paul Lange of the University of Washington, both members of the consortium. Researchers in Hood's lab plan to test every one of the consortium's variety of 600 tumor cells along with normal prostate cells collected at every stage of human development. Then they will use genetic-engineering techniques to produce markers that can identify tumors that are dangerous and those that are not. The same approach, he says, may eventually be used to identify many other kinds of cancer.

Hood's group is also trying to find its first prostate-cancer gene, perhaps before the end of the year. All told, researchers believe, there could be as many as 10 such genes. Once these genes are identified, scientists can develop tests for a man's susceptibility to prostate cancer and eventually, perhaps, use gene therapy to fight the disease. Long before that, however, identification of the genes may help doctors understand what environmental factors interact with the genes and contribute to the development of prostate tumors.

To achieve this goal, they need blood samples and pedigrees from volunteer families with at least three living members who have prostate cancer. They are currently working with 200 families recruited when Hood made an appeal during an appearance on cnn's Larry King Live, but many more are needed. (Interested families can call 800-777-3035 to volunteer.)

WHILE GENETICS PLAYS A MAjor role--black Americans, for example, have a 37% higher risk than whites of contracting the disease--environment is obviously involved. In such countries as China and Japan, where low-fat diets of vegetables and fish are the norm, the incidence of prostate cancer is extremely low. But prostate-cancer rates for first- and second-generation Japanese Americans are considerably higher than in Japan.

Those facts seem to point to an environmental factor, probably the change to a Western diet. In a test of that conjecture, researchers at Sloan-Kettering, led by Dr. William Fair and pharmacologist Warren Heston, discovered that tumors grew more rapidly in mice fed a high-fat diet than in those on a low-fat diet. And when the animals on high-fat diets were switched to low-fat ones, the growth of their tumors slowed.

Milken, for one, isn't waiting for confirmation of that theory. "You should feel comfortable knowing that everything we eat here is nonfat and vegetarian," he tells visitors to his Santa Monica, California, offices. A typical lunch, prepared by his private dietitian, consists of mushroom barley soup, a tofu egg-salad sandwich (the "egg" is actually tofu with mustard and spices ) with carrots and lettuce, and a black-bean-and-corn salad with a soy-based drink. One of Milken's favorites, an Egg McNothing, consists of a fat-free crumpet with soy cheese, vegetarian Canadian bacon and scrambled egg whites.

Why all the tofu and soy? Milken points to tests showing that soy products reduce tumors in rats. Impressed by other studies indicating that prostate-cancer rates are higher in northern climates, possibly because of less exposure to sunlight and a corresponding decrease in the production of vitamin D, he spends more time outside and at the beach. "Of course," he concedes, "we have to balance skin cancer with prostate cancer, I guess."

In an effort to dispel some of the guesswork about prevention and the choice of treatment, the NCI is conducting two large-scale prostate-cancer trials. One, called pivot (for Prostate Cancer Intervention Versus Observation Trial), is just getting under way, and will involve monitoring the progress over 15 years of 2,000 prostate-cancer patients in the Veterans Administration hospital system. The goal: to determine if radical prostatectomies save enough lives to justify choosing surgery over watchful waiting. The NCI's Dr. Richard Kaplan, who is supervising the trial, suspects that surgery "might not make a difference" for either low-grade or advanced, highly aggressive cancers. "Any real benefit," he says, "may be in the intermediate-grade group."

The other trial, organized in 1993, will eventually enroll 18,000 healthy men who are at least 55 years old and have a PSA level of 3 or less. Its aim is to determine if finasteride, a Merck drug, will help prevent prostate cancer. Every day for seven years, in a double-blind test, half the volunteers will take a finasteride tablet while the others take a placebo. Medical researchers suspect that finasteride may be effective because it reduces the level of a testosterone byproduct that promotes tumor growth. The NCI's Dr. Brawley, who is supervising the trial, anticipates that "those taking the drug will have a 25% lower incidence of cancer than those taking a placebo."

As important as these long-range trials may be, however, they hardly address the urgency felt by men with advanced prostate cancer. Milken is convinced that a massive, well-financed effort, making full use of available high technology and advances in genetics, can find "a cure or a permanent delaying action" for the disease not in decades but in a few years.

While most of the male prostate-cancer researchers are hardly that optimistic, they share the sense of urgency, all too aware that they also are vulnerable. "If I'm at all lucky, I won't be diagnosed with the disease," says Brawley. "But the odds that I'll get prostate cancer by the time I'm 70 are pretty good." For millions of other American men, that realization is beginning to hit home.

--With reporting by Hannah Bloch/Washington, Lawrence Mondi/New York, J. Madeleine Nash/Seattle and Martha Smilgis/Los Angeles

With reporting by HANNAH BLOCH/WASHINGTON, LAWRENCE MONDI/NEW YORK, J. MADELEINE NASH/SEATTLE AND MARTHA SMILGIS/LOS ANGELES