To Screen or Not to Screen? Two Major Studies on Prostate Cancer Leave Plenty of Questions Unanswered

Two studies that were expected to answer some long-standing questions about prostate cancer may have only further muddied the water.

At issue are two undeniable facts: screening for prostate cancer is up since the early 1990s, when doctors began placing an increased emphasis on the importance of early detection. And over the same period, the prostate cancer death rate has dropped. The big question, then, is whether that decline is largely due to increased screening, advances in treatment, or some combination of factors.

Two major, long-term trials — one American and one European — both aimed to determine whether screening, specifically with the prostate-specific antigen (PSA) blood test and traditional, digital rectal exams, makes a difference in mortality rates. The results clarify the issues somewhat, but are frustratingly lacking in solid answers.

Dr. Len Lichtenfeld, deputy chief medical officer of the American Cancer Society, wrote in his blog that he had eagerly awaited the results of the U.S. and European trials.

“In the meantime, millions of men continued to get tested and undergo treatment, even though no one could really say if we were saving lives, or just sending millions more men to unnecessary treatment with all sorts of side effects,” he wrote. “Well, my friends, the waiting is over. The day has arrived. And I don’t know that we now have any better idea whether or not prostate cancer screening actually works.”

The American study, dubbed the U.S. Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, was spearheaded by the National Cancer Institute. Researchers randomly assigned more than 76,600 men to two groups.

Participants in one group were given annual PSA tests for six years and digital rectal examinations every year for four years; the other group served as a control. The researchers found little difference in prostate cancer death rates between the two groups at seven years and again at 10 years of follow-up.

In the other trial, called the European Randomized Study of Screening for Prostate Cancer, researchers randomly assigned 182,000 men between the ages of 50 and 74 from seven different countries to either a control group or a screening group, which required the men to have a PSA screening, on average, every four years and a digital rectal exam every other year.

In following up, researchers found that screening reduced the rate of prostate cancer death by 20{06cf2b9696b159f874511d23dbc893eb1ac83014175ed30550cfff22781411e5}. But, according to the authors, “1,410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent one death from prostate cancer.”

And there’s the issue. Even when PSA and other tests find prostate cancer, they can’t tell how dangerous the cancer is. Some prostate cancers grow slowly and may never cause a man any problems, while others are more aggressive.

Because of a high PSA level, someone may choose to be treated, even though his cancer may never have manifested symptoms. Meanwhile, the treatment, which may include surgery, radiation, or other interventions, can have serious effects on quality of life. In a very real sense, the cure could be worse than the disease.

“When one considers all of the problems associated with treatment for prostate cancer — urine incontinence, impotence, pain, and bleeding, among others — that is a lot of men left with a lot of symptoms to save one life,” Lichtenfeld said.

Deadly … or Not

It’s an important topic, to judge solely by the numbers. An estimated 186,000 cases of prostate cancer were diagnosed in the U.S. in 2008, causing more than 28,000 deaths, according to the American Cancer Society. In addition, prostate cancer is the second-leading cause of cancer death in men — behind lung cancer — and accounts for 10{06cf2b9696b159f874511d23dbc893eb1ac83014175ed30550cfff22781411e5} of all cancer deaths. An American man has a 1 in 6 chance of being diagnosed with prostate cancer during his lifetime, with most of those diagnoses occurring at age 70 and older.

Importantly, however, only one in 34 men will die of the disease, and many live full lives without much disturbance.

“If you do a screening and your PSA is a little bit elevated, there’s a reasonable chance you might find cancer there,” said Dr. James Stewart, chief of Hematology and Oncology at Baystate Medical Center. “If so, then you have a big decision: do you have an operation to remove the prostate or get radiation? The downside of doing that is, you might not need to have it done.”

The studies, he said, “did see a very modest decrease in death rates. But you have to balance the positives against the harm — how many men are being overdiagnosed and overtreated?”

Dr. Otis Brawley, chief medical officer of the American Cancer Society, noted in a written statement that, “for several years, many experts had anticipated these studies would show a small number of men will benefit from prostate screening, but a large number of men will be treated unnecessarily. And that’s what these studies show.

“What we need to know is, what are benefits of prostate cancer screening, and are they large enough to outweigh the harms associated with it?” he continued. “And despite the release of this early data, we still cannot say whether the benefits outweigh the risk.”

For example, the studies had some important limitations. In the European trial, the countries used different study protocols, such as enrolling men of different age groups. And in the American trial, men in the control group weren’t barred from getting screening tests, and many of them ended up getting screened anyway; by the sixth year of the trial, 52{06cf2b9696b159f874511d23dbc893eb1ac83014175ed30550cfff22781411e5} of the men in the control group had undergone a PSA test, and 46{06cf2b9696b159f874511d23dbc893eb1ac83014175ed30550cfff22781411e5} a rectal exam.

Perhaps the most important topic being raised, Brawley said, is whether patients of average risk should be screened.

“For many years, people who suggested this was still an open question have been criticized as not supporting anti-cancer efforts,” he noted. “In some respects, over the last 20 years, many have been eager to promote widespread screening based on the assumption that finding cancer early is beneficial. Now as these reports have begun to come out, we see that the results may not be as favorable as many had hoped or even anticipated.”

Brawley added that he’s concerned that, if the information being reported from the dual studies is not interpreted appropriately by doctors, those covering the news, and by the general public, it could cause actual harm, by dissuading patients from approaching their doctors when actual symptoms arise.

“There is a group of men who should be getting screened but who, after hearing this week’s news, may begin to shy away from testing,” said Brawley. “There is no debate that men who have urinary symptoms, such as frequent or difficult urination, a weak stream, etc., ought to be getting exams, including PSA tests. That is not screening; screening is testing asymptomatic men for signs of cancer. Men who have symptoms should be getting tests.”

Into the Future

As for those without symptoms, well, the debate goes on, said Stewart.

“There are reasonable people on both side of this,” he said. “People might argue that the real benefits [of the studies] won’t be seen for 15 to 20 years, while skeptics would say the modest decline in mortality doesn’t compare to the side effects from all these treatments, that it’s not worth it.

“My recommendation is that, for significantly older men, if you’re 75 and up, you’re not likely to get any benefit,” Stewart said.

Dr. Mohammad Mostafavi, a urologist with the Urology Group of Western New England, agreed. “If a patient has prostate cancer in his 40s or 50s, that can probably become problematic,” he said. But if a patient in his 70s who has always had normal screenings suddenly has an abnormal one, it can force some tough — perhaps needlessly so — decisions.

“What if the PSA rises a little bit? You don’t want to create anxiety, and you don’t want to be too aggressive in treatment. At that age, the cancer is probably going to be insignificant. But you have to respect the patient’s wishes.”

The American Urologic Assoc. generally recommends screenings begin at age 50, but for high-risk groups, such as African-Americans and men with a family history of the disease, the recommended starting age is 40. Stewart argued, however, that no one should undertake a screening without a plan for what happens next.

“Before you go to get screened, you need to have a conversation with your doctor about what to do with the results,” he said. “If you haven’t had that conversation, you shouldn’t get screened.”

That’s because the treatment options can still be a major hindrance on quality of life — although modalities like robotics, cryotherapy, and brachytherapy are making it less invasive than ever before.

“The way we think about the disease is constantly evolving,” Mostafavi said. “How we practice today compared to 10 years ago is very different. The treatment options are different, and the way we think about the disease is always evolving.”

The only constant, it seems, are unanswered questions.

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