In the 1930s, a diagnosis of prostate cancer was effectively a death sentence. Typically, the tumor was not identified until symptoms developed, and the primary treatment was surgical removal of the prostate. But because the cancer had nearly always metastasized to the bone or soft tissue, all the surgery did was buy the patient one or two years, often crippled by bone pain. For that, there was nothing but increasing doses of morphine.
Then, a young University of Chicago researcher named Charles Huggins made a discovery that would forever shape future prostate cancer care. New to urology, Huggins was studying dogs’prostates, with the aim of learning more about the human prostate, when he noticed that many of the elderly dogs had prostate tumors. At the same time, research into endocrinology—the area of medicine that focuses on hormones—was starting to expand, and the more Huggins learned, the more he began to think that hormones might be linked to prostate cancer. He began to explore the idea by neutering dogs that had prostate tumors, and he kept seeing the same result: After surgical removal of the testicles, the main source of the dog’s testosterone, the tumor shrank.
Huggins and his colleagues decided to try the same surgery on a few male patients, politely explaining that the procedure would “remove some gland.” (This was 30 years before research on human subjects was regulated.) The outcome was spectacular: Their first patient, a man with advanced metastases who'd been in agony and subsisting on toast and coffee, found himself pain-free and ravenous just hours after surgery. But surgery wasn't the only treatment Huggins tested. He and his colleagues also gave dogs, and then men, estrogen to see if it would slow tumor growth. The result of his treatments: Four of his original 21 patients lived an unheard-of 12 years after their surgery.
Huggins had discovered that prostate cancer cells need testosterone because cutting off their supply shrinks the tumor. The three papers Huggins and his colleagues published in 1941 on their findings indelibly changed the prostate cancer field. The basic tenet of this research—that cancer could be controlled with hormones—earned Huggins the 1966 Nobel Prize in Physiology or Medicine. His discovery also led to the use of Lupron (leuprolide acetate), which stops testosterone production, as a prostate cancer treatment and to the development of anti-androgen drugs like Casodex (bicalutamide) that attach to the androgen receptor, keeping out testosterone and other hormones that make up the androgen family.
These therapies have saved many men’s lives. Now, the challenge is not only inventing even better drugs but—in a development Huggins might not have anticipated—also finding ways to determine which men actually need to be treated.
A study published in the Aug. 15, 2013, issue of
Cancer Research suggests that less aggressive prostate cancers rarely, if ever, transform into more aggressive ones.
Kathryn Penney, an associate epidemiologist at Brigham and Women’s Hospital in Boston, and colleagues analyzed prostate cancers diagnosed in more than 1,000 men between 1982 and 2004, looking at each tumor’s stage as well as its Gleason grade—an indicator of its aggressiveness. They found that as the number of men being screened for prostate cancer increased, the proportion of late-stage cancers that were diagnosed dropped from about 20 percent between 1982 and 1993 to about 3 percent between 2000 and 2004. However, they saw a much smaller change in the proportion of high Gleason grade cancers that were diagnosed: The number only dropped from 25 percent to 18 percent.
These findings led Penney and her colleagues to conclude that prostate tumors begin as low grade or high grade—and don’t change. “Because of PSA screening, most prostate cancers are now diagnosed at an earlier stage”—which explains the decrease in late-stage tumors. If the Gleason score “increased over time and tracked with the stage of the cancer,” she says, “we would expect a similar decline in high-grade tumors.” Since the researchers didn’t see this decline, it suggests the Gleason grade is unlikely to change.
The findings also suggest, says Penney, that “men with low-grade disease at diagnosis should seriously consider talking with their doctors about active surveillance”—being monitored regularly and only considering treatment if tests show the tumor has become more aggressive.
Prostate cancer presents a peculiar challenge. On the one hand, many prostate cancers are harmless: They are so slow-growing that they never result in noticeable symptoms, let alone shorten a man's life. On the other hand, prostate cancer is the second most common type of cancer after non-melanoma skin cancer and the second biggest cause of cancer deaths after lung cancer among American men. The numbers are sobering: The American Cancer Society (ACS) estimated that in 2013 there would be nearly 240,000 men diagnosed with prostate cancer and almost 30,000 who would die of the disease.
“What I believe, and what many other oncologists are starting to think, is that—from a diagnostic perspective—prostate cancer is essentially two different diseases,” says Walter Stadler, a medical oncologist at the University of Chicago. “One is a low Gleason,” says Stadler, referring to the score pathologists use to describe how the tumor appears under a microscope. This low-grade and less-aggressive disease “doesn’t kill patients, and may rarely, if ever, transform into something nasty. For the most part it is just a warty growth. The other is a high Gleason: an aggressive, real-cancer type.”
The problem is how to tell the aggressive cancers from the harmless warty growths. In the early 1990s, the prostate-specific antigen (PSA) blood test, which had been used to monitor treatment response, began to be recommended for annual prostate cancer screening. The goal was to catch cancers early, when they were easier to treat. PSA screening has resulted in more cancers being found at an early stage. But it also has led to men who might have been fine without treatment being treated aggressively for low-grade tumors and forced to deal with long-term side effects like incontinence, impotence, bowel dysfunction and infection.
After weighing the risks and benefits of PSA screening, in 2012, the U.S. Preventive Services Task Force advised against PSA testing for men who were not experiencing prostate cancer symptoms. The aim was to reduce overtreatment, but the immediate result was controversy. Within a year, the ACS, the American College of Physicians and the American Urological Association each released guidelines recommending that doctors continue to offer PSA testing—albeit in the context of a discussion with patients about the risks and benefits of screening.
If a man decides to be tested and is found to have an elevated level of PSA in his blood, he is likely to be referred for a biopsy. Studying the cells obtained during the biopsy is the first step in determining if a man should be treated.
To Watch or to Treat?
Deciding not to treat a cancer may seem counterintuitive, but sometimes it makes sense. Men with a PSA-detected prostate cancer fall into one of three categories: those whose cancer will result in death despite early diagnosis and treatment, those who would have had good outcomes in the absence of screening, and those for whom early diagnosis and treatment will improve survival. Right now, nearly 90 percent of men diagnosed with a PSA-detected prostate cancer each year in the U.S. are treated with surgery, radiation or a drug that blocks the androgen hormones. Yet men have only about a 3 percent lifetime risk of dying from prostate cancer. This suggests that if every patient is treated aggressively “the sum total of harm done may well be greater than the sum total of good,” says Stadler. “But with thoughtful treatment, we could do more good than harm.”
To help guide decision-making, surgeons are improving how they perform prostate biopsies. Dynamic contrast-enhanced MRI, which uses advanced imaging and a contrast agent that's taken up by cancer cells and may be able to help determine the best place to biopsy, is being studied at large cancer programs like the University of Chicago, the Johns Hopkins Kimmel Cancer Center in Baltimore, and the University of Texas M. D. Anderson Cancer Center in Houston. “Right now, when we take biopsies, we are essentially blindly sticking needles into the prostate—so even if there’s significant cancer present, we could stick the wrong place and miss it,” says Stadler.” We and others are evaluating whether images can help us” find a cancer that is there.”
Scientists are also developing ways to more confidently determine whether the biopsy has found cells from a low-grade tumor that can be monitored or a high-grade tumor that can be deadly. Although a few new tests designed to predict if the tumor is likely to be aggressive have been introduced, cancer specialists say more studies are needed before those tests will be used with confidence in a clinical setting.
“A lot of research is being done on finding a better diagnostic test using genes and biomarkers, but to understand how well these newer tests ultimately predict outcomes will take several years to determine,” says Howard Scher, a medical oncologist at Memorial Sloan-Kettering Cancer Center in New York City.
Moving Treatment Forward
Huggins realized that the treatment he had developed could extend a man's life, but that it wasn't a cure. The tumor could still get hormones to fuel its growth from the adrenal glands, which sit on top of the kidneys. (More recently, researchers have learned that tumors can also make their own hormones.) But time and again, other therapies for treating patients with advanced metastatic prostate cancer proved unsuccessful. It wasn't until 2004 that Taxotere (docetaxel), which had been approved by the U.S. Food and Drug Administration (FDA) to treat other types of cancer, was approved for treating patients with advanced metastatic prostate cancer that no longer responded to hormone therapy. It was a step forward, but a small one: Even with that treatment few patients survived more than one or two years. The next significant advance came in 2010, when the chemotherapy drug Jevtana (cabazitaxel) was approved for use after tumors stopped responding to Taxotere.
Scientists have also begun to identify new ways to keep androgen from getting to the cancer cells. “Over the last few years, we’ve rediscovered the simple fact that the androgen receptor”—a protein testosterone binds to, triggering cancer cell growth—“is still the most important target in prostate cancer,” says Stadler. This renewed focus has resulted in two important new hormone-blocking prostate cancer treatments in the past three years: Zytiga (abiraterone acetate), which blocks androgen production in the testes, the adrenal glands and tumor cells, and Xtandi (enzalutamide), which blocks the androgen receptors. Studies are now underway testing the effectiveness of these drugs in combination with other treatments.
Another new option is the cancer vaccine Provenge (sipuleucel-T)—a therapy that trains the patient's immune cells to attack the cancer cells. It is currently approved only for patients who have metastatic disease that is no longer responsive to hormone therapy and who have few or no symptoms.
In yet another advance, in May 2013, the FDA approved Xofigo (radium Ra 223 dichloride) for treating prostate cancer that has spread to the bones. The drug is injected into a vein and taken up almost exclusively by cancerous bone cells, where a type of radiation called alpha particles kills the cells. It received FDA approval after interim results from a phase III trial, later published in the
New England Journal of Medicine, revealed that Xofigo had significantly improved overall survival by three months compared with a placebo.
Like Xofigo, all of the newer drugs have been found to extend life by on average a few months. But, says Stadler, this figure can be misleading. “There [will be people who respond] who may do quite well for much longer, as well as those who don’t respond at all,” he says.
The immediate aim is for researchers to learn the best way to take advantage of these new therapies. “The challenge now,” says Scher, “is figuring out how to use them most effectively” by looking for biological markers that indicate which tumors will respond to which drug. Also necessary, he adds, is determining if these new therapies are more effective—alone or in combination—when given to patients with less-advanced tumors.
It's easy to imagine that Huggins, who died in 1997, would have felt gratified by the explosion of research in the field. As he was fond of telling colleagues: “Don’t write books. Don’t teach hundreds of students. Discovery is our business. Make damn good discoveries.”
January 24, 2014