Marker Indicates Spread of Prostate Cancer

By William J. Cromie

Gazette Staff

Put yourself in the place of Bill C., who has been diagnosed with prostate cancer. It's a small tumor that apparently hasn't caused too much damage to his prostate gland. He has two choices: have the tumor removed immediately or wait and see if it grows dangerously larger.

Bill calls his friend Tom A., who was diagnosed with the cancer three years before. "My doctor says prostate tumors, especially small ones, grow very slowly," Tom tells him. "He points out that 85 to 90 percent of men diagnosed with prostate cancer die with the disease, not of it. More than half of those treated with surgery or radiation become impotent or incontinent, and some suffer both indignities. In other words, a lot of guys severely damage the quality of their lives when they may not have to."

Bill then calls John G. who had been diagnosed with prostate cancer a year ago. "I won't live with a malignancy in my body," John says firmly. "I had my prostate surgically removed as soon as I could schedule the operation."

Men have been struggling with this dilemma since the development of a blood test for prostate specific antigen (PSA) about 10 years ago. The test detects prostate cancer, but doesn't reveal if the cancerous cells are slow-growing and confined to a small area, or aggressive and likely to spread to the spine.

The confusion leaves a trail of scared and confused individuals whose number grows every day. Now, researchers at the Medical School believe they have found a potential solution, a protein that apparently distinguishes relatively benign tumor cells from those that spread quickly to other parts of the body and often are lethal.

"We found a protein, called thymosin beta 15, which is present in advanced prostate cancer but not in normal human cells," says Bruce Zetter, professor of surgery at Harvard-affiliated Children's Hospital. "Eight patients who tested positive for the protein two to five years ago have succumbed to metastatic [spreading] prostate cancer. Eight who tested negative have no evidence of the disease. Both groups had their tumors removed by surgery or radiation.

"This test may give us a potential to predict whether someone diagnosed with prostate cancer by their PSA level can afford the luxury of watchful waiting, or should start aggressive treatment as soon as possible."

Traveling Tumor Cells

Thymosin beta 15 apparently makes it easier for tumor cells to "drive" through the body. "Aggressive cancer cells are on the move and rely on their own internal . . . engines to wiggle their way out of their organs of origin and into distant metastatic sites," says Donald Coffey of the Johns Hopkins Hospital in Baltimore. "They can then proceed to produce their biological mayhem, which is so often devastating and fatal."

Prostate cancer cells usually travel to the spine. "It's a difficult journey," Zetter remarks. The cells must leave the tumor and invade blood vessels or the lymph system. Those that survive in the circulating fluids must then exit at their destination, the marrow of the spine in this case. They then grow into new tumors.

Zetter, Lere Bao, an instructor in surgery, and their colleagues have been able to prevent such malignant rovings in laboratory dishes by cutting off tumor-cell access to thymosin beta 15.

Outside of the laboratory, Zetter's team has been following 76 patients who underwent surgery or radiation two to five years ago. To date, 26 of these men have been examined. Of 13 who tested positive for thymosin beta 15, eight have died, one is suffering a recurrence of the disease, and four show no evidence yet of the cancer.

Four people showed partial evidence of thymosin beta 15, one has had a recurrence of his cancer, and three are cancer-free. Eight men who tested negative for the marker exhibit no sign of recurrence or metastasis.

"That's not enough people to claim that we can predict who will survive without treatment and who must be treated immediately," Zetter admits. "We need more patients and more markers."

His lab has found two more proteins that look promising as markers of metastasis. Other researchers have discovered a substance that acts as a roadblock to tumor-cell movement in rats with prostate cancer.

"We envision having a panel of different markers, some of which enhance and some of which suppress tumor cell mobility," Zetter says. "Let's say that someone's PSA level indicates he has cancer, but none or only one of seven or eight markers for metastasis is present. That would indicate a non-aggressive tumor and that man would be a candidate for watchful waiting. In other words, he might avoid expensive and painful treatments along with the high risks of impotence and incontinence."

According to Zetter and Coffey, the majority of tumors are of this slow-growing variety.

A score of five or six metastatic markers, however, would indicate that invasive cells could be creeping through the man's body, and treatment should be sought immediately.

During this year, the National Cancer Institute expects 334,000 new cases of prostate cancer. It is the second leading cause of male deaths in the U.S., after heart disease, and the cancer agency expects 42,000 to die of it in 1997.

"If anything good can be said about prostate cancer, it's that it takes a long time and a fairly large tumor before any cells leave the gland," Zetter notes. "If we can catch this process as it's beginning to show signs of mobility but is still confined to the prostate, that would be a terrific outcome."

Such markers may also find use in other types of cancers with a high percentage of non-aggressive tumors, such as breast cancer, Zetter speculates. But they would not be useful in lung, pancreatic, and other malignancies characterized by high populations of aggressive cells.

Choices Made

John, Tom, and Bill had to make their choices without the benefit of these markers.

John, a decisive executive, chose immediate treatment. Zetter points out, "In the U.S., many men want to be actively in control of their lives, and doctors often feel uncomfortable not doing something about a disease. Therefore, Americans, as compared to members of some other cultures, are more likely to treat the disease aggressively."

John suffered temporary incontinence after his surgery but recovered in a few months. He also became impotent but has been able to treat that successfully with regular injections of so-called vasoactive drugs into his penis.

Tom A. has no symptoms of the disease after five years without treatment. "I sometimes feel like the man who jumped off a 40-story building," he says. "As he was passing the 30th story, someone asked him how he was doing. He replied 'I'm OK, so far.' "

After agonizing about what to do for a year, Bill C. decided on radiation treatment, which is less likely than surgery to produce incontinence. He underwent daily irradiation for seven weeks, with its inevitable nausea, fatigue, and diarrhea, but dodged incontinence and is not impotent a year after treatment.

Bill also decided to participate in Zetter's study by submitting samples of tissue removed before the radiation.

"If the samples turn up negative for thymosin beta 15, then he has good cause for optimism," Zetter says. "If the results are positive, there were aggressive cells present at the time of treatment. Those cells might have been killed by radiation, or they might not have. It's something not everyone wants to know."