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Revolution in Advanced Prostate Cancer


Revolution in Advanced Prostate Cancer

Michael Carducci and Mario Eisenberger:
Elegant, highly specific new drugs are remarkable for their relative lack of side effects. Many are aimed at containing prostate cancer, rather than eradicating it.

There have never been so many promising drugs being developed for prostate cancer, and never before have doctors been so hopeful about their ability to help men with advanced disease -- cancer that either has spread beyond the prostate, or cancer that has returned after surgery or radiation.

Not only has research in advanced prostate cancer exploded with whole new classes of innovative, cancer-fighting drugs and treatments targeted at various stages of the disease -- perhaps even more exciting, scientists are rethinking their strategies for giving these drugs.

Armed with revolutionary guidelines (see What Happens if PSA Comes Back After Surgery) that -- for the first time -- allow doctors and patients to predict what will happen if a man's PSA returns after surgery, Hopkins oncologists and urologists are working together to go after prostate cancer when it is still relatively young and vulnerable, hitting it hard, and hoping to change the course of disease.

Traditionally, oncologists have begun chemotherapy in men with advanced diseases only after other treatment -- surgery or radiation, followed ( somethimes even several years afterward, when men developed symtoms of advanced cancer) by hormone therapy -- has failed to control the cancer. But over the last few years -- in breast and colon cancer, as well as prostate cancer -- there has been a seachange in scientific thinking: "Why should we wait until it's a last-ditch effort?" says oncologist Mario Eisenberger, M.D., a pioneer in developing and refining drugs to treat prostate cancer. "Why not go all-out first?"

In the past, oncologists have been unwilling to take a man who is, for all practical purposes, healthy -- who has steadily increasing PSA levels, but no other symptoms of disease -- and make him sick. Chemotherapy drugs have been notorious for their side effects, which often include vomiting, hair loss, and debilitating fatigue. Similarly, physicians have been reluctant to start a man on hormone therapy before he really needs it because of that treatment's undesirable side effects -- including loss of libido, hot flashes, and osteoporosis -- and because there is no definitive medical evidence in favor of starting hormones early.

But the latest generations of drugs are remarkable for their relative lack of side effects: They're smarter, more specific, and many of them are aimed at containing prostate cancer, rather than eradicating it . "These are all relatively nontoxic, outpatient oral medications that have different approaches" says Hopkins oncologist Michael A. Carducci, M.D., who is leading several studies of new drugs, and working to develop others. "Our laboratoy models suggest that they can help stabilize the disease and inhibit growth -- so ideally if you use them in men with minimal disease, they may delay further progression of cancer, and thus the development of symptoms. And if you use them in folks with more advanced disease who are well, they may stay well for a longer period of time."

Hopkins oncologists, led by Mario Eisenberger and Michael A. Carducci, M.D., have targeted key groups of men with advanced rate cancer, all of whom have different needs and who probably respond best to different drugs:

  • Men who have undergone surgery, who have been identified as having a high risk of cancer recurrence
  • Men who have undergone surgery and/or radiation, who have a detectable PSA level, but no other evidence; that the cancer has spread;
  • Men with a with metastatic disease, in whom hormone therapy has lost its effectiveness (this is also called "hormone-refractory" cancer)

Most of the drugs have traditionally been developed and tested in this last of men, says Carducci. "But increasingly, the drugs are showing few or limited side effects, and laboratory models suggest that they work best in patients who have hardly any diseases." In fact, he and colleagues are even testing one drug, recently approved by the FDA as a treatment for arthritis, on men before radical prostatectomy. In a placebo-controlled trial, they will give the drug during the period after diagnosis and before surgery -- usually about eight weeks -- "to see if there's any effect on the primary cancer,on blood vessel growth, cell proliferation" and other aspects of cancer. For men at high risk of a recurrence of cancer, Carducci, Eisenberger and colleagues will be testing a drug called exisulind. "In studies across the country, it has lowered men's PSAs in early disease," says Carducci. "Now we're going to see if we can delay the time until PSA rises."

For men with rising PSA levels but no other evidence of diseseas, there is a "cancer vaccine" (Click here for more on this story..), and a drug called marimastat. "This is in the class of drugs that make biologic sense," Carducci explains, an anti-metastatic" drug that inhibits invasion, angiogenesis ( development of new blood vessels to supply the cancer), and cancer cell growth. It's designed to keep cancer confined, and stop it from growing. Marimastat also inhibits "matrix metal loproteinases" -- enzymes that transport cells and blood vessels, and help them grow. When a man nicks his chin shaving, for example, white blood cells and wound-healing cells called fibroblasts charge in on these enzymes to save the day. Marimastat is a new drug , wich has just completed Phase I trials ( designed to make sure that the drug is safe, and to find a effective dose), led by Eisenberger and Carducci, who hope marimastat will slow down the cancer, and slow down the PSA rise indefinitely.

There are several studies involving the drug phenylbutyrate, for men with hormone-refractory prostate cancer. Phenylbutyrate is a "differentiating agent," which works by putting cancer's growth, or proliferation, in slow-motion. Carducci, with Hopkins colleagues John Isaacs, Ph.D., and Roberto Pili, have shown that together with Vitamin A (which slows down cancer's growth; low levels of Vitamin A are believed to increase a man's susceptibility to prostate cancer), phenylbutyrate can hamper the growth of new blood vessels, and can shrink tumors and prevent them from progressing. In another study, phenylbutyrate will be combined with azacytidine, a drug that can reverse some of cancer's expedient genetic changes. "Cancers turn off certain genes that can inhibit cancer growth," says Carducci. "Azacytidine can turn those genes back on, and when you combine that with phenylbutyrate, you increase the likelihood that these genes will stay on, and give men a better chance to fight the cancer."

Eisenberger and Carducci will also be studying drugs in the taxane family (which includes the drug taxol, shown to help women with ovarian cancer). One of them, taxotere, is being studied in combination with emcyt -- an estrogen- related drug known to diminish testosterone and kill cancer cells, but which has caused undesirable side effects including nausea, heart problems, and a higher risk of blood clots. "Virtually all studies using the combination of taxotere and emcyt have shown a consistent response in patients with widespread disease, ranging between 30 and 70 percent," says Eisenberger, "But the side effects of emcyt are very prominent, because men have to take it daily." Eisenberger developed a new protocol, in which emcyt is given for one day only in five divided doses, along with taxotere. "This abbreviated exposure to emcyt has substantially improved the tolerance of this combination," Eisenberger says. Emcyt and taxotere are repeated every three weeks, for a total of six times. "Were observing a high response rate, about 50 percent, and our next objective is to build on that." In some patients, results been dramatic: PSA levels have dropped by at least 50 percent, pain has decreased significantly, and metastases -- even in the lymph nodes and liver -- have shrunk.

FURTHER READING: Carducci, M.A., Nelson, J.B., Chan-Tack, K et al, "Phenylbutyrate Induces Apoptosis in Human Prostate Cancer and Is More Potent Than Phenylacetate." Clinical Cancer Research, 2: 379-285, 1985.
Carducci M.A., Deweese, T.L., Nelson, WG., Simons, J.W, Sinibaldi, V., Eisenberger, M.A., "Prostate Cancer Treatment Strategies Based On Tumor- Specific Biological Principals." Seminars in Oncology, 23:56-62,1996.

The Flutamide Disappointment

Kill all androgens! Don't stop at shutting down the testes, the body's main testosterone-making factory: eliminate every single one, even weak male hormones produced in tiny amounts by the adrenal glands -- anything that could possibly affect the prostate. This is the concept of "total" androgen blockade, combining surgical or medical castration with LHRH-agonist drugs (castration deprives the prostate of its chief hormone, testosterone, causing the prostate cancer cells that are hormone-controlled to die) with an anti-androgen drug called flutamide.

The idea was that this one-two punch would be far more successful than either approach alone, and it became a huge issue in prostate cancer treatment in the late 1980s. Scientists around the world conducted trials of flutamide; oncologist Mario Eisenberger, M.D., conducted two of them, with about 2,000 patients. "The first trial we did was marginally positive, a six-month difference in survival" in favor of the group of men randomly assigned to receive total androgen blockade versus the men who took LHRH agonists alone. Eisenberger's results were good enough for the FDA to approve the drug in 1989.

"The problem," Eisenberger says, "is that the issue continued to be controversial. There were two more positive trials, and everybody focused on those three trials," despite the fact that in one of them, the difference in survival was only about three months. "There were 24 other trials, all negative. This included my second trial -- the largest ever done, with close to 1,400 patients. In the end, close to 8,000 patients were entered in 27 clinical trials, and only three of the trials were marginally positive." Eisenberger estimates that more than $1 billion has been spent in clinical research on total androgen blockade. The sum could be justified, he adds, "if it generated something that would consistently be shown to improve the survival of our patients." But that didn't happen. The 24 negative trials didn't receive nearly as much attention as the three marginally positive ones. Combining LHRH agonists or surgical castration with anti-androgens "became a standard treatment, and added substantially to the cost of prostate cancer treatment." Antiandrogens cost about $300 a month. The negative result of Eisenberger's second trial, reported in the New England Journal of Medicine, confirmed what he had suspected: "Men with prostate cancer don't really need an anti-androgen. Antiandrogens provide what we consider a clinically insignificant advantage." Worse, in another trial designed to look at patients' quality of life, Eisenberger found that flutamide caused men to have more hot flashes (side effects of hormonal therapy in general), cramps, diarrhea, nausea, vomiting and depression.

These results, Eisenberger concludes, show that men with advanced prostate cancer don't need an anti-androgen together with castration. By not taking it, they're saving money, not affecting their quality of life, and not losing anything." Anti-androgens are best used as a "backup" to surgical or medical castration, he adds. "For patients treated with castration who demonstrate a rising level of PSA in the blood, anti-androgens represent an option. About 20 percent of patients will get a second response." Over the last two years, Carducci and endocrinologist Adrian Dobs, M.D., have also found decreasing bone and muscle mass in men on hormone therapy -- another reason for delaying therapy. When hormone treatment is necessary, they advocate monotherapy.

Eisenberger, M., Blumenstein, B., et al. "Bilateral Orchiectomy With or Without Flutamide for Metastatic Prostate Cancer." New England Journal of Medicine, 1998; 339: 1036-1043.



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