Rethinking Prostate Cancer Treatments

In an outcome likely to raise broad questions about aggressive prostate cancer treatment, a randomized study of 1,643 British men found that, roughly 10 years after a prostate cancer diagnosis, the vast majority of participants had survived the cancer regardless of whether they were treated with radiation, had their prostates surgically removed, or were simply monitored by their physicians.

While the study provided some of the longest follow-up in prostate cancer research to date, a decade remains a fairly limited window, and further study will be needed to determine whether the men’s lifespans would ultimately be shortened without these therapies.

Still, while surgery and radiation did more to reduce the risk of the cancer’s progression, the risk of disease progression in the entire group over the course of the trial period was quite small. And quality-of-life feedback collected directly from study participants revealed that surgery and radiation therapy had left many of the men with serious side effects, including impotence, and bowel and urinary incontinence, the researchers report.

The findings were presented in two papers — one addressing cancer-related outcomes, and another taking up the patients’ self-reported outcomes. Both were published Wednesday in the New England Journal of Medicine.

“Men don’t need to rush to make a decision about what to do with a diagnosis of localized prostate cancer [and select] what treatment to choose,” said Freddie Hamdy, the trial’s lead investigator and head of the Nuffield Department of Surgery at the University of Oxford. “With an equivalent and extremely low ten-year death rate no matter what you do, you can think very carefully before you choose what to do.”

Ian Thompson, director of the Cancer Therapy and Research Center and a urologic oncologist at the University of Texas Health Science Center in San Antonio who was not involved with the study, viewed the findings more cautiously — and warned against interpretations suggesting it would be safe for men with prostate cancer not to be treated. “It would be a mistake, Thompson said, “if you assumed that all prostate cancers are toothless lions that you don’t need to treat.”

The U.K. ProtecT (Prostate Testing for cancer and Treatment) trial screened more than 82,000 men aged 50 to 69 across the United Kingdom. Of those men, 1,643 who were diagnosed with cancer that had not spread outside of the prostate were randomized to one of three treatment protocols: radiation therapy (545 men), prostate removal (553 men), and active monitoring (545 men), which entails regular blood testing and clinical review to permit changing tack and pursuing aggressive treatment if deemed necessary.

Notably, the research team solicited quality-of-life feedback from study participants, who provided self-reported updates on both psychological and physical outcomes, including instances of depression or anxiety, and urinary, bowel, or sexual dysfunction. Patients completed questionnaires before diagnosis, at six and 12 months after randomization, and then annually after that.

Previous prostate cancer research has had a dearth of high-quality patient-reported quality-of-life data, and follow-up periods have been far shorter, leaving patients feeling excluded from the research process. But most of the patients in the new trial remained involved throughout the follow-up period, the researchers suggest, and want to participate going forward.

“It’s a beautifully conducted, high quality trial,” said Anthony L. Zietman, associate director of the Harvard Radiation Oncology Residency Program at Massachusetts General Hospital, who served on the trial’s steering committee.

Jenny Donovan of the University of Bristol, who led the patient-reported outcomes part of the research, said the research team worked to build community involvement among participants from the beginning. “Before we launched the trial, we did a systematic review of everything on quality-of-life and patient-reported outcomes that had been done and we realized much more work needed to be done,” Donovan said.

“Our research is the first time that head-to-head results have been reported for all patient-reported outcomes,” she added.

Among the key findings: Surgery to remove the prostate, known as a radical prostatectomy, resulted in urinary incontinence far more than radiation or monitoring. Radiation therapy and active monitoring were not associated with any urinary side effects. Radiation therapy resulted in more bowel problems than surgery or active monitoring. In terms of anxiety, depression, and overall quality of life, there were no differences across treatments. Half of the men in the active monitoring group remained on active surveillance for a full 10 years, while others eventually began more radical therapy if monitoring picked up worrisome findings, or if they became too anxious to continue with surveillance.

The survival rate for all participants was 90 percent, though this includes patients who died of other causes. But just 1 percent of participants had died of prostate cancer over the course of the study, regardless of the treatment assigned. That rate is “considerably lower than was anticipated when the trial commenced,” the researchers noted. 

The results underscore concerns about aggressive screening and interventions with certain cancers adopted across the board — a trend that began in the early 1990s in the United States with the advent of prostate-specific antigen, or PSA testing. The blood tests were considered revolutionary for a disease that affected millions of men. The National Institutes of Health puts the number of American men currently living with prostate cancer at about 3 million, with an estimated 181,000 new diagnoses expected this year. More than 65 percent of all prostate cancer in the U.S. is diagnosed in men older than 65, according to the Prostate Cancer Foundation, with the average age at diagnosis being 69 years.

But the overuse of PSA tests among healthy men to diagnose prostate cancer — which many medical experts came to recommend against — led to a cascade of prostate biopsies and widespread use of radical prostatectomies. Radiation therapy provided an alternative, but surgery dominated.

“We became obsessed with screening and treatment and became so bullheaded,” said Otis Brawley, chief medical officer for the American Cancer Society. “There was a frenzy that was not very scientific.”

Of course, doctors believed they were saving men from disease progression and early death. But the findings of the new study suggest that may not always have been the case. “What have we been doing all these years with low-risk disease?” Zietman said. “This adds up to millions of men over three decades.”

In recent years, many doctors have begun moving away from immediate and aggressive treatment regimens, and researchers say they hope the new study will further dissuade men with low-risk disease from rushing into a quick treatment that they may live to regret. “I am not sure if this will alter the thinking on treating men ages 50 to 70,” said Peter Albertsen, another member of the trial’s steering committee and Chief of Urology at University of Connecticut Health. “It will probably alter thinking beyond age 70.”

Regarding younger men, while they certainly don’t need to rush a decision, the jury is still out on which interventions make sense, and on what timeline. But researchers hope that the focus shifts from aggressive treatment of all prostate cancers, to finding better ways to identify those men whose lives are truly threatened by the disease. “We don’t yet have good biomarkers and genetic information on who is likely to have lethal disease,” said Hamdy.

That’s why Thompson, the Texas urologist, favors a tempered interpretation of the study. He noted that the U.K. trial took all comers, suggesting that low-risk men may have been disproportionally represented among the study population. And in any case, Thompson said, while active surveillance is safe in low-risk men, not all prostate cancers are low-risk. Although the U.K. research team thinks that the trial might lead to fewer older men going into treatment, Thompson warned that an across-the-board, do-not-treat approach with older men would be hazardous.

“What’s really important is the grade and volume of the tumor as measured through biopsy,” Thompson said. “To say that treatment is unimportant for high-risk men would put many high-risk men at risk for death from prostate cancer,” he added. “If you take a 75-year-old man with high-volume, high-grade disease, he has a 75 percent risk of dying of prostate cancer in 15 years. That involves bone pain, loss of appetite, and treatment with expensive drugs. Moreover, if a man is caring for a spouse, it’s a horrible way to go.”

Zietman, a radiation oncologist himself, does not disagree, noting that the new study only suggests that low-risk men are likely being over-diagnosed and treated, and that physicians can safely stop rushing them into more aggressive treatments right away.

“We don’t want the pendulum to swing from overtreatment to undertreatment,” Zietman said. “There are certainly some men who do need, and benefit from, treatment. The rate of men with metastases at 10 years — although very low for men managed with surveillance — was even lower for those who had treatment.”