The prostate cancer predicament

[ Winter 2013 ]

For many men diagnosed with prostate cancer, the treatment may be worse than the disease

To screen or not to screen? For prostate cancer—the second leading cause of cancer deaths in men, after lung cancer—that is the bedeviling question.

The dilemma springs the wide variation in the potential of prostate cancers to spread to the rest of the body. The vast majority of these malignancies, especially those discovered with the extensively used prostate-specific antigen, or PSA, test, are slow-growing tumors that are unlikely to cause a man any harm during his lifetime. Yet in 10 to 15 percent of cases, the cancer is aggressive and advances beyond the prostate, sometimes turning lethal.

Murky diagnoses

The dilemma has become more urgent in recent years as widespread screening with PSA in the U.S. and around the world has led to a sharp increase in the number of detected prostate cancers. Currently, there is no way to accurately determine at the time of diagnosis which cancers are likely to threaten a man’s health and which are not. As a result, almost all men with PSA-detected cancer opt for treatment, which can leave long-lasting physical and emotional scars.

lorelei mucci

“One of the biggest challenges in oncology is to distinguish men who have a potentially lethal form of prostate cancer from those with a more slow-growing disease.”
—Lorelei Mucci, ScD ’03, associate professor of epidemiology

Put simply: with prostate cancer, the cure may be worse than the disease. The dilemma was underscored in May 2012, when the U.S. Preventive Services Task Force (USPSTF) issued a strongly worded final recommendation against PSA-based screening for prostate cancer. According to the task force, “[M]any men are harmed as a result of prostate cancer screening and few, if any, benefit.” In a study of U.S. men who were randomly screened, the screening did not reduce prostate cancer death (though a similar study among European men did find a lower risk of cancer death). In any case, experts agree that prostate cancer has been vastly overdiagnosed as a result of screening.

So what should patients and doctors do? At Harvard School of Public Health, the prostate cancer epidemiology team—which includes more than 25 faculty, postdoctoral fellows, and student researchers—is developing the science to answer that question, identifying both the risk factors behind the deadliest variations of prostate cancer and the lifestyle changes that may lower the risk of aggressive disease.

“One of the biggest challenges in oncology is to distinguish men who have a potentially lethal form of prostate cancer from those with a more slow-growing disease,” says Lorelei Mucci, associate professor of epidemiology at HSPH. “Our research aims to directly address that question, as well as to find opportunities to reduce risk of dying from cancer after diagnosis.”

Aggressive or slow-growing?

When it became widely available in the late 1980s, the PSA screening test was hailed as a simple way to uncover possible malignancy. But PSA screening, which was adopted without evidence of its usefulness, turned out to be a poor indicator of cancer, in two ways. First, it creates false positives in men who may simply have elevated antigen levels from other conditions, such as benign enlargement of the prostate gland. These patients often endure subsequent invasive biopsies but never go on to develop prostate cancer. Second, even when the test correctly identifies prostate cancer, many of the diagnosed patients never develop the deadly form of the disease.

“PSA screening has been a disaster,” says Hans-Olov Adami, former chair and now adjunct professor of HSPH’s Department of Epidemiology, who has opposed the test for 20 years. “We overdiagnose many men who would die of other causes.” In fact, a multinational study of cancer registries published by Adami, Mucci, and other HSPH colleagues in July 2012 found that the most common causes of death among prostate cancer patients—65 percent of patients in Sweden and 84 percent in the U.S.—are heart disease, diabetes, stroke, or other cancers.

What may protect against advanced prostate cancer?

Yet these patients frequently underwent radical treatments for their prostate cancer—interventions such as radiation, surgery, and chemotherapy, which can produce severe side effects such as incontinence and erectile dysfunction. “While we are uncertain about the number of deaths that screening prevents,” says Adami, “we are certain that the price for any reduction in deaths from prostate cancer is very high.”

A study published in August 2012 in the New England Journal of Medicine found no difference in survival between men who had surgery for prostate cancer and those under “watchful waiting,” in which the doctor withholds treatment while carefully monitoring the progress of the cancer. “This is a very perplexing observation,” Adami says, “because screening reduces mortality only if treatment makes a difference in outcomes. This indicates there are still big question marks in how doctors and patients should respond to this diagnosis.” As the USPSTF noted last May, “[R]esearch is urgently needed to identify new screening methods that can distinguish nonprogressive or slowly progressive disease from disease that is likely to affect quality or length of life.”

“ Men with at least three hours of vigorous physcial activity a week had at least a 60 percent lower risk of prostate cancer death.” —Edward Giovannucci, professor of nutrition and epidemiology
“ Men with at least three hours of vigorous physical activity a week had at least a 60 percent lower risk of prostate cancer death.”
—Edward Giovannucci, professor of nutrition and epidemiology

Clues in diet and lifestyle

To clarify the prognosis for a tumor, HSPH researchers are homing in on other factors that might affect susceptibility to prostate cancer, especially the aggressive form of the disease. Edward Giovannucci, professor of nutrition and epidemiology, recently looked at nine diet and lifestyle factors. He found that smoking, obesity, and lack of physical activity raise the risk of developing a more virulent cancer. According to Giovannucci, “The question is whether there are two types of prostate cancer–an aggressive and nonaggressive form–or whether certain factors cause a nonaggressive form to become more aggressive.” Evidence provided by HSPH researchers suggests that an increase in insulin in the bloodstream, caused by obesity and physical inactivity, may encourage tumor growth.

Other investigations have linked dietary factors to the disease. A 2011 study by HSPH research associate Kathryn Wilson, together with Mucci and Giovannucci, professor of nutrition and epidemiology Meir Stampfer, and other colleagues, found that men who drank coffee had a notably lower risk of aggressive prostate cancer. Those who consumed six cups or more a day were 20 percent less likely to develop any form of the disease, and 60 percent less likely to develop a lethal disease; those who consumed one to three cups a day showed no difference in developing any form of the disease, but had a 30 percent lower risk of developing a lethal form.

Jennifer Rider, instructor inepidemiology at HSPH, has studied parasitic infection and prostate cancer.
Jennifer Rider, instructor in epidemiology at HSPH, has studied parasitic infection and prostate cancer.

Another, more surprising, study revealed that consuming tomato sauce was associated with a markedly lower risk of prostate cancer. In fact, men who had two or more servings of tomato sauce a week were about 20 percent less likely to develop prostate cancer, and about 35 percent less likely to die from the disease. A separate report in 2009 by Mucci and Giovannucci found that the overgrowth of blood vessels might be one of the most reliable indicators of whether a tumor will spread. After sifting through genetic and lifestyle factors that might lead to the growth of these vessels, they found that the antioxidant lycopene was the item most strongly associated with lower blood vessel formation.

Another factor that might determine the difference between a harmless and a lethal form of prostate cancer is the sexually transmitted parasitic infection Trichomonas vaginalis. By itself, the infection rarely produces symptoms in men (who are often treated only after their female partners show signs of infection). In a 2009 study, led by HSPH instructor in epidemiology Jennifer Rider, infected men had a much higher incidence of prostate cancer spreading to the bone or death from prostate cancer. “The good news is that if the association between the infection and lethal prostate cancer is confirmed, there is an effective antibiotic treatment,” Rider says.

To treat or not to treat?

“Up until now, with a few notable exceptions, doctors have myopically focused on treating prostate cancer,” says Adami. “They are willing to spend tens of thousands of dollars on chemotherapy that has minimal effects on cancer mortality, often with substantial side effects. But we ignore entirely the fact that large groups of prostate cancer patients die from other causes that actually are preventable.”

By focusing on lifestyle changes, he adds, men can achieve three goals simultaneously: diminishing the risk of dying from common conditions such as heart disease and diabetes, improving quality of life overall, and perhaps also improving the prognosis for prostate cancer. In particular, stopping smoking and increasing physical activity after diagnosis can substantially cut the risk of developing aggressive prostate cancer. “Men with at least three hours of vigorous physical activity a week had at least a 60 percent lower risk of prostate cancer death,” says Giovannucci. “It’s a strong association.”

Among older patients especially, that activity can take the form of vigorous walking. Recently, Mucci has spearheaded an intervention with Adami and other colleagues in Sweden, Iceland, and Ireland in which men walk in groups with a nurse three times a week. In a pilot study, researchers found improvements in just 12 weeks in body weight, blood pressure, sleep, urinary function, and mental health.

Scientists at HSPH are also searching for genetic and lifestyle markers that help predict how aggressive a patient’s prostate cancer will be. For example, an ongoing project led by Mucci and Adami draws on detailed cancer registries in Nordic countries, including an analysis of 300,000 twins, to tease out the relative contribution of different genes to prostate cancer incidence and survival.

Until all these associations come to light, doctors and patients will be confronted with weighty decisions about treatment. Surgery, radiation, or chemo might still be the wisest course of action in instances where the cancer has clearly already advanced, or when a patient is young and otherwise in good health. In situations where men are older or face a higher risk for other diseases, improvements in diet and lifestyle may be more effective not only in subduing the cancer but also in boosting general well-being. As Mucci puts it, “Our hope is that clinicians will use the prostate cancer diagnosis as a teachable moment to reflect on the global health of the patient.”

Michael Blanding is a Boston-based journalist and author of The Coke Machine: The Dirty Truth Behind the World’s Favorite Soft Drink.