Below the Belt
- Understanding the predisposition, progression
and treatment of prostate cancer is making this common malignancy
a little less deadly.
- by Alicia Di Rado
Yankees manager Joe Torre got the diagnosis. So did New York Mayor Rudy Giuliani. Archbishops Roger Mahony and Desmond Tutu also heard the dreaded words:
Prostate cancer.
More than 198,000 American men got the same medical news last year. Most of them never made headlines, but they all shared one thing in common: a poorly understood disease that is the second-leading cause of cancer death among men. And even when men survive it, they are often left with a lower quality of life.
USC researchers and doctors, though, want to change that. Whether striking at the roots of prostate cancer, better comprehending how prostate cancer treatment affects men, or offering options to deal with the side effects of treatment, physicians are attacking prostate cancer from all directions.
Cancer Growth
One of the enigmas of prostate cancer is how it progresses from its earliest stages into full-blown cancer. That mystery forms the basis of a $2.2 million Prostate Cancer Center Initiation Award granted to researchers at the Keck School of Medicine of USC by the U.S. Department of Defense.
Research dollars support a USC team leading a three-pronged investigation into the genetics of prostate cancer.
The American Cancer Society estimates that one in five men will be diagnosed with the cancer during his lifetime. Yet, some men who have initial seeds of the cancer never end up with a tumor, while other men develop aggressive cancer, says Ronald K. Ross, M.D., professor and chair of preventive medicine and project coordinator. No one is sure why.
"If you took 1,000 men who are 60 years old, pathologists would say that 50 percent of them or more have occult, or very early stage, prostate cancer," Ross says. "Yet only a fraction of those progress and become invasive. Occult disease is common, but clinical disease is much less common."
Another unknown: why progression seems to follow racial lines. Among racial and ethnic groups, the rate of very early stage prostate lesions is about the same, but rates of actual prostate cancer incidence and death is higher in some than in others. It is highest in African-American men and lowest in Asian-American men.
"What we really need is to be able to say that we know which lesions will progress, and which will not," Ross says.
That is where Gerhard Coetzee, Ph.D., associate professor of urology, and Juergen Reichardt, Ph.D., associate professor of biochemistry and molecular biology, come in.
Coetzee is looking into the role of the androgen receptor gene, and Reichardt is investigating the importance of the steroid 5-alpha-reductase type 2 gene. Both genes are involved in the activity of androgens, male hormones that are critical to normal and abnormal prostate growth.
Somehow, genes mutate during the cancer process, but no one has yet been able to find a roadmap of consecutive genetic changes that lead to cancer. To help find an answer, the researchers look at whether the two genes mutate often during prostate cancer progression, and examine how that affects the genes' function.
Reichardt's target, the steroid 5-alpha-reductase type 2 gene, encodes an enzyme that converts testosterone to dihydrotestosterone (DHT), the most potent androgen in the human body. Androgens appear to drive the growth of many prostate cancers, much like estrogen drives many breast cancers.
In 1999, Reichardt and colleagues showed that African-American and Latino men who carried a simple germline, or inherited, mutation in the gene face five times the risk of developing prostate cancer than those without the mutation.
The Department of Defense grant will allow him to examine somatic changes in the gene to see how they affect the way a tumor progresses. Somatic changes are mutations in genes that are not inherited from parents, but rather, are wrought by environmental factors. "Someone may have a germline mutation that makes them predisposed to the cancer, but other mutations have to happen to produce prostate cancer," Reichardt says.
In the future, Reichardt hopes that tests for genetic markers will lead to personalized medicine to battle prostate cancer, more effective or customized drugs and more individualized dosages.
Coetzee, meanwhile, looks for the type and frequency of somatic mutations in the androgen receptor gene in the prostate and their relation to the stages of prostate cancer. The androgen receptor, Coetzee's line of research for the last six years, is a protein within prostate cells that attracts and binds the male hormone, and sends the message to make prostate cells proliferate. If the receptor works more efficiently in one man than another, or in one prostate cell than another, the individual (or cell) may be exposed to an increased effect of androgen. That, in turn, can increase susceptibility to cancer development.
Coetzee's lab was the first to demonstrate how variations of this gene affect predisposition to prostate cancer. New research will lead to further understanding of how the protein works during prostate cancer's progression-not just in predisposition to the disease. This, in turn, will lead to more precise diagnoses and development of targeted treatments.
And today's patients need targeted treatments, especially those whose cancer is in later stages.
In most cases, doctors treating advanced prostate cancer focus on counteracting the effects of male hormones such as testosterone. This so-called "hormone therapy" can shut down the effects of testosterone, effectively slamming the brakes on cancer growth-at least at first.
The problem is that the therapy tends to lose effectiveness over time. Coetzee and his fellow scientists believe mutations in the androgen receptor gene may contribute to the cancer becoming resistant to the hormone therapy by somehow enabling cancer cells to overcome the treatment. Better understanding of the mutations may lead to ways to overcome resistance.
Richard Cote, M.D., leads the third part of the project, which delves into a series of new cellular and molecular markers with potential for predicting prostate cancer progression. The markers will be examined in tumor tissues from men in the Hawaii-Los Angeles Multiethnic Cohort Study, spearheaded at USC by Brian Henderson, M.D., the Kenneth T. Norris, Jr. Chair in Cancer Prevention.
Tumor tissues come from African-American, Asian-American, Latino and white patients in the study. Researchers hope to establish which of these potential markers are associated with more advanced tumors, and whether differences exist in these markers among prostate tumors from men in various racial and ethnic groups. "The idea is to get leads on promising areas for future research," Ross says.
Difficult Decisions
Men diagnosed with prostate cancer face an uneasy choice when it comes to treatment. Is surgery the best option, or is radiation the way to go? Some men even wonder whether to be treated at all.
When doctors detect cancer early, both radiation and surgery leave patients with a comparable, positive outlook for survival-so patients are left to consider other issues when deciding on treatment.
Results from the Prostate Cancer Outcomes Study, or PCOS, might help them in making these tough choices. Through the 3,500-man study, researchers from USC and five other universities-as well as the National Cancer Institute-have analyzed what happens to prostate cancer patients after their treatments. The lasting effects of surgery and radiation in patients' daily lives, years after their treatment, form just one portion of their extensive, ground-breaking investigation.
Faculty members deeply involved in the research since it began in 1994 are Dennis M. Deapen, Dr.P.H., associate professor and director of the Cancer Surveillance Program, Ann S. Hamilton, Ph.D., assistant professor of preventive medicine, and Frank D. Gilliland, M.D., Ph.D., associate professor of preventive medicine.
Writing in the Journal of the National Cancer Institute, the research team reported that men who had surgery for prostate cancer, or prostatectomy, were more likely than men who received radiation to suffer from impotence and urinary incontinence after treatment. In contrast, men receiving radiotherapy had greater trouble controlling their bowels than did men who had prostatectomies.
"This study gives people a fair picture of what their risks are with these treatments," Gilliland says. "They can use it in decision-making."
Of course, other factors also are involved in making the decision on treatment, including the stage of the disease and the age and underlying health of the patient, the researchers noted.
In looking at the after-effects of treatment, the team compared 1,591 men from 55 to 74 years old who were diagnosed with cancer confined to the prostate from 1994 to 1995 and who either had a radical prostatectomy or external beam radiation. After two years, 80 percent of those who chose surgery had lost sexual function, compared to 62 percent of those who received radiation.
Also, among men who chose surgery, 10 percent suffered from some degree of urinary incontinence, compared to 4 percent of the patients who chose radiation.
But men who had surgery reported that they recovered some of their urinary and sexual function the second year after treatment, while men who received radiation did not report any improvement and, in fact, may further deteriorate over time.
On top of that, men who had radiation reported more bowel problems. They were more than twice as likely as surgery patients to report bowel urgency (nearly 36 percent for the radiation group, compared to less than 15 percent for surgery patients) and more of them had diarrhea, as well.
Otherwise, researchers saw no clear difference in physical, emotional and mental health between men who had surgery and men who had radiation. And if given the option to go back in time, most men would have made the same treatment choice. Notes Hamilton: "It's important to remember these men had early stage disease, and were pleased that their cancer could be treated effectively."
PCOS also explores other areas, including: the higher risk African-Americans face for being diagnosed with advanced-stage prostate cancer; factors that may predict whether a patient's cancer has spread outside the prostate; the effects of hormone therapy on quality of life, and the effectiveness of treatments for sexual dysfunction after prostate cancer. (Information is available online at www-dccps.ims.nci.nih.gov/ARP/PCOS)
Gilliland says understanding previous patients' experiences will help future patients more realistically gauge the problems that might arise after treatment.
"For a lot of men, the idea of just getting the cancer out is really important," he says. "But there may be quality of life issues he should consider when making his choice, after discussing his options with his doctor."
Combating Side Effects
Hundreds of men in the PCOS study reported problems with urinary incontinence. With more men getting treatment for prostate cancer, Keck School doctors have seen a renewed interest in methods for dealing with this common problem.
One of those is the artificial urinary sphincter.
Although the artificial sphincter has been used for 25 years, "so many men have resigned themselves to leakage when they don't have to, simply because no one talked to them about the problem," says Stuart D. Boyd, M.D., professor of urology. Experts believe that fewer than one in 10 people with urinary incontinence are ever treated.
But one of Boyd's patients, prostate cancer survivor John Gorman, is enjoying a renewed sporting life thanks to the device. After four years without racing, he has returned to running marathons. The 63-year-old is also playing golf again, another endeavor he had put behind him after a prostatectomy in 1995.
Before getting the artificial sphincter last year, Gorman remembers having lots of "embarrassing moments."
"You are always embarrassed to leave a wet spot on somebody's couch," he recalls. "I found I was cutting back on the amount of liquids I'd drink." He tried running marathons, but even with pads he developed debilitating rashes.
Then Boyd told him of the artificial urinary sphincter, a small silicone device implanted entirely within the body. It mimics natural sphincter function, enabling the patient to control voiding. A cuff squeezes the urethra closed, and when a patient squeezes an implanted pump, the cuff deflates and allows urination.
"Men are very relieved to hear this is something you can take charge of and get corrected," says Boyd, who specializes in such urological problems.
For Gorman, the device meant a new start. "I'm so happy I don't have to deal with those problems anymore," he says.
The sphincter adds to the arsenal of alternatives available to men to improve life after prostate cancer; among others, nerve-sparing surgeries with high-tech probes to reduce the chance of impotence and maintain sexual function.
"If men knew these options were available, they might be more likely to get help," says Boyd. "And if that meant more men were comfortable with being screened for cancer, many more cases would be caught early-saving patients' lives."
For more information about prostate cancer research and treatment, or to learn more about The Doctors of USC, call 1-800-USC-CARE (1-800-872-2273).
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