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Prostate Cancer, Redefined

The determination that not every prostate cancer is life-threatening is changing treatment. By Jocelyn Selim
​Photos © Christopher Robbins / Digital Vision / Thinkstock; Carme Balcells / iStock / Thinkstock; Kevin Peterson / Thinkstock; Gave Palmer / Hermera / Thinkstock; Ostill / iStock / Thinkstock.
​Photos © Christopher Robbins / Digital Vision / Thinkstock; Carme Balcells / iStock / Thinkstock; Kevin Peterson / Thinkstock; Gave Palmer / Hermera / Thinkstock; Ostill / iStock / Thinkstock.

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.

A Set Path
A recent study in Cancer Research suggests that less aggressive prostate cancers rarely, if ever, transform into more aggressive ones.
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.

Diagnosis Dilemma
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.


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