By Catherine Grillo

Every year in the United States more than 180‚000 men are diagnosed with prostate cancer. Thanks to the discovery of prostate–specific antigen (PSA)‚ the vast majority of these cancers are detected at a very early stage‚ before cancerous cells have had an opportunity to spread. But in a few cases—around 6%—diagnosis does not come until the cancer has traveled well beyond the prostate‚ into the lymph system‚ bones‚ or distant organs.

In April of 2001‚ Donald Lavallee of Pompano Beach‚ Florida‚ became one of that select group. “I knew it was something bad because I had to urinate very often with very little coming out‚” says Lavallee. “It got to a point where my bladder was really big and I couldn’t urinate at all.”

Lavallee had not been to a physician in more than 30 years—a by product of several traumatic medical experiences during his childhood. By the time his wife‚ Claire‚ persuaded him to see a doctor about his problems‚ he had been unable to urinate or move his bowels for nearly five days. The doctors at his local emergency room were taken aback‚ and the final diagnosis was not encouraging: advanced prostate cancer with a Gleason grade of 9.4‚ a PSA of 1‚ 193‚ and bone metastases of his hip and skull. “The first urologist we saw said he wouldn’t live past June‚” recalls Claire.

A New Look at Advanced Prostate Cancer
Not long ago‚ the urologist’s original prediction might well have proved accurate. But recent research on the nature and causes of prostate cancer has changed the face of prostate cancer treatment and given new hope to patients whose cancer has advanced beyond the prostate gland and spread to other parts of their bodies.

“Even when cancer has spread beyond the prostate‚ there are a variety of treatment options available‚” explains A. Oliver Sartor‚ MD‚ director of the Stanley S. Scott Cancer Center‚ New Orleans. “These newer treatments provide possibilities for disease control that may turn this particular cancer into more of a chronic illness‚ even when it is not curable.”

The Basics
Prostate cancer is most common among older men‚ affecting one in eight between the ages of 60 and 79. According to the American Cancer Society‚ prostate cancer is the second most common type of cancer in men‚ and the second leading cause of cancer death in men.

Although common‚ prostate cancer is less lethal than most cancers. While more than 180‚000 men are diagnosed with prostate cancer each year‚ fewer than 40‚000 a year die of the disease. Contrast that with lung cancer‚ which afflicts more than 90‚000 men a year and kills nearly 89‚000‚ or with colon cancer‚ which is diagnosed in about 20‚000 men annually‚ and takes the lives of several thousand.

“The fact is‚ only about a third of patients with prostate cancer ever die of it‚” notes Ian Tannock‚ MD‚ PhD‚ Princess Margaret Hospital‚ University of Toronto. “You’ve got a lot of competing causes of mortality as most patients are elderly men with other medical problems.”

Dr. William K. Oh‚ Dana Farber Cancer Institute‚ Boston‚ points out that studies indicate that as many as a third of all patients will recur after local treatment for prostate cancer.

“So‚ there are a substantial proportion of men who are diagnosed early but still progress‚” he says.

Hormone–Based Treatments
Because complete eradication of the cancer is not an option in men with advanced prostate cancer‚ treatment is focused on stopping cancer’s spread and relieving symptoms. As prostate cancer cells need testosterone to grow‚ the first line of treatment is usually removal of testosterone from the body. This can be accomplished through surgical removal of the testicles—a procedure known as orchiectomy—or by administering drugs called luteinizing hormone–releasing hormone (LHRH) agonists‚ which stop the testicles from producing testosterone. LHRH agonists such as Lupron® (leuprolide) and Zoladex® (goserelin) are generally given by injection‚ either monthly or every three months. Two other LHRH agonists have recently been approved by the FDA‚ Eligard™ (leuprolide acetate) and Trelstar™ (triptorelin pamoate).

Small amounts of testosterone are also produced by the adrenal glands‚ so some physicians also prescribe anti–androgens such as Eulexin® (flutamide)‚ Casodex® (bicalutamide)‚ and Nilandron® (nilutamide) to block the effects of residual testosterone. These medications occupy androgen receptors on cancer cells‚ so stray testosterone molecules are unable to latch on. Unlike Lupron and Zoladex‚ antiandrogens are taken as pills‚ one to three times a day. Another less common approach is the use of drugs that shut down testosterone at the level of the adrenal glands‚ such as Nizoral® (ketoconazole) and Cytadren® (aminoglutethamide).

“Hormonal therapy is associated with untoward side effects‚” admits Dr. Oh. “But when you consider what we have for other forms of advanced cancer‚ this is one of the most effective therapies available. We’re talking about a 90% response rate that lasts years in patients with cancer that has already spread to their bones‚ with relatively minor side effects. That’s a very‚ very good therapy.”

The other problem with hormonal therapy is that it does not work forever. At some point the cancer becomes hormone resistant (or hormone refractory) and resumes its advance. “The generally accepted theory is that there are a small percentage of refractory cells present from the very start‚” explains Dr. Oh. “If you don’t remove those cells by radiation or surgery‚ or if those cells have a chance to spread before you can operate or irradiate‚ then that small percentage can continue to grow and proliferate over time. Eventually they predominate‚ since hormonal therapy is unable to control their growth‚ unlike hormone–sensitive cells‚ which are either killed or kept under control as long as you continue the hormonal treatment.

Prior to the discovery of PSA‚ the first hint doctors had that a cancer had become hormone refractory was the presence of additional tumors or an increase in symptoms such as bone pain. Now‚ physicians can monitor PSA levels‚ and change the treatment plan as soon as PSA starts to rise.
The time it takes for prostate cancer to become hormone refractory differs from patient to patient. Hormonal treatment typically works for a year and a half to two years‚ but some men respond for much longer. “I’ve had patients respond to hormones for up to 10 years or longer‚” notes Dr. Oh. “So you can actually control metastatic disease for quite a while.”

“There is a subset of patients who may respond for a long time to initial hormonal treatments‚” agrees Dr. Sartor. “The rough rule of thumb is that maybe as many as 10% of patients will respond for 10 years. Now that’s a minority‚ but nevertheless it is a measurable number.”

Researchers and practitioners are looking at several ways to prevent‚ or at least delay‚ the development of hormone–refractory prostate cancer. One technique most commonly used in advanced patients who are not showing symptoms such as bone pain is intermittent hormonal therapy. “You treat the patient for a while‚ get the cancer under control‚ and then stop‚” says Dr. Oh. “From a quality–of–life perspective‚ if a patient is off hormones‚ even for six months out of the year‚ then‚ at least for part of the time‚ he will feel better. And there are preclinical data that suggest this approach may delay the time that cancers become hormone refractory.”

This technique is being studied in a large randomized clinical trial sponsored by the National Cancer Institute‚ which is comparing continuous and intermittent hormonal therapy.

Occasionally‚ men whose cancers have become hormone refractory may respond to stopping hormone therapy. When treatment is stopped‚ their PSA levels either drop or become stable. This is particularly true of patients treated with anti–androgens like Casodex or Eulexin.

“Among patients who receive anti–androgens‚ an occasional patient‚ maybe even as many as 20%‚ will have no progression of the disease for a year after withdrawal of the drug‚” says Dr. Sartor. “The most likely explanation appears to be that in some patients‚ the cancer cells undergo a mutation in response to antiandrogen treatment‚ so that instead of blocking cancer growth the antiandrogens begin to stimulate growth. In these patients‚ withdrawal of the antiandrogen results in a response because now you’re dealing with a mutant variety instead of the original type of cancer cell.”

Conventional Chemotherapy
Only two decades ago‚ patients who developed hormone–refractory prostate cancer had few options beyond waiting for death. The chemotherapeutic agents that helped other cancers seemed to have no effect on the progression of prostate cancer‚ so the best physicians could offer was radiation therapy to ease the pain of bone metastases. Then‚ two critical changes occurred. First‚ Dr. Tannock and colleagues looked beyond tumor shrinkage to evaluate how chemotherapy made patients feel. They discovered that the combination of prednisone and the chemotherapeutic drug Novantrone® (mitoxantrone) significantly relieved pain in patients with bone metastases‚ with relatively few side effects.

“Mitoxantrone plus prednisone is an extremely non–toxic therapy‚” notes Dr. Tannock. “And we’ve shown fairly convincingly that‚ overall‚ the quality of life improves while on treatment.” In 1996‚ the FDA approved Novatrone as a treatment for the pain of advanced prostate cancer‚ making it the first chemotherapy specifically approved for prostate cancer.

Next came the introduction of the taxanes‚ Taxol® (paclitaxel) and Taxotere® (docetaxel). Among other things‚ these drugs interfere with a protein called Bcl–2‚ which is thought to prevent cancer cells from dying‚ and which is overexpressed in approximately two thirds of hormone–refractory prostate cancers.

By inhibiting the effects of Bcl–2‚ Taxotere makes it possible for cancer cells to die. In clinical studies‚ the combination of Taxotere plus the chemotherapeutic agent Emcyt® (estramustine) lowered PSA levels in up to 75% of patients with advanced prostate cancer‚ and shrank tumors in up to 30%. The Taxotere and Emcyt combination is widely prescribed‚ and clinical trials are ongoing.

New Horizons: Targeted Therapies
Chemotherapy for advanced prostate cancer is a promising development‚ but still carries the risk of undesirable side effects‚ ranging from mild to severe. “When considering treatment options‚ the real question is not only do they improve survival‚ but do they improve survival enough to put up with greater toxicity?” says Dr. Tannock. “Most patients want to live longer‚ and they also want to live better. If you have a treatment that does both of those things‚ then there’s no conflict. But sometimes you may have a treatment that does things in opposite directions. You then have to make judgment calls about the relative benefits of treatment.”

These considerations are particularly important in prostate cancer‚ as patients with advanced disease often live far longer than patients with other cancers. “Advanced prostate cancer is not curable‚ but it is a disease patients may have to live with—often for many years‚” explains Dr. Oh. “This puts a premium on quality of life.”

The need for therapies that combine improved efficacy with an acceptable quality of life is one of the driving forces behind the search for so–called “targeted therapies.” These are drugs designed to home in on the specific molecular pathways that become abnormal in cancers. “The idea is that instead of a one–size–fits–all approach—which may have toxic effects because the drug affects all cells that may be growing fast—you target cells that have the specific molecular abnormality that leads to the cancer‚” explains Dr. Oh. “As you can imagine‚ the more complex the cancer is‚ the harder it is to find one switch that’s involved in cancer development.” Prostate cancer is indeed complex‚ but there are several targeted therapies currently in use or in development that may prove useful.

Making Choices
Today‚ men with advanced prostate cancer have treatment options that were unheard of a mere 25 years ago. These treatments offer a great deal of hope‚ but also present physicians and patients with a wide range of decisions concerning how best to deal with the cancer. “Treatment is a balancing act of side effects versus palliative effect‚” says Dr. Sartor. “Our goal is to control the cancer to the greatest extent possible using therapies that are minimally toxic whenever possible.”

The choice and timing of prostate cancer treatment requires an ongoing dialogue between patient and physician‚ coupled with regular monitoring of the cancer’s status. “One of the elements that I consider to be central to the management of patients with hormone–refractory disease is a rapidly alternating change in therapies until you find one that works. When that therapy fails to work‚ then you rotate on to the next option‚” Dr. Sartor says. “The key is to rotate options until success is achieved.”

For Donald Lavallee‚ combined hormone therapy has worked well. More than a year after being told he would die within two months‚ his PSA was 3.5 and he remained pain free.

“It helps me to realize I’m one of the worst ones‚ and I don’t feel any pain‚” says Lavallee. “At the meetings I hear these other men whose cancers aren’t as bad as mine‚ and they’re already dealing with pain.”

When the time comes for a shift in treatment strategies‚ Lavallee has no doubt about what he will do. Now free of the fear that kept him away from doctors for 30 years‚ he has no intention of giving in to prostate cancer just yet.
“Sometimes when my wife is talking to people‚ she’ll say I’ve got terminal cancer‚ and I’ll say‚ ‘Claire‚ everyone’s got terminal something‚’” he says.
“I mean‚ why even use that word? You don’t hear anybody saying you’ve got terminal heart attack. When you have a disease like this‚ your priorities change a little bit. I thank my lucky stars every day.”