Study Questions Benefit of Surgery in Some Men with Early-Stage Prostate Cancer
Long-awaited results from a U.S. clinical trial indicate that, in men diagnosed with localized prostate cancer, surgery did not improve survival or decrease the risk of dying from prostate cancer. After 12 years of follow-up, there was no difference in overall or prostate cancer-specific survival between men randomly assigned to radical prostatectomy and those assigned to watchful waiting, observation with palliative treatment if the disease begins to progress.
Dr. Timothy Wilt of the Veterans Affairs Center for Chronic Disease Outcomes Research in Minneapolis, MN, presented the findings from the trial, called PIVOT, at the American Urological Association (AUA) annual meeting on May 17.
Several researchers cautioned that reaching firm conclusions will have to await publication of the results in a peer-reviewed journal, particularly when it comes to parsing any differences between patient subgroups. And because the trial was substantially smaller than originally planned, it may lack the statistical power to provide confidence in some of the findings, other experts said.
The trial began in 1994 and enrolled 731 men 75 years of age or younger who had been diagnosed with early-stage prostate cancer. The majority of the cancers were detected based on a PSA test, and all men in the trial had a life expectancy of at least 10 years.
Although overall survival and prostate cancer-specific survival were nearly the same in both groups, Dr. Wilt explained, both outcomes were slightly better in men who received surgery. The absolute differences between the two groups, however, were less than 3 percent.
The finding that surgery offered no survival benefit compared with observation was statistically strongest for men with a PSA level of 10 or less or whose cancer was classified as low risk based on factors that included PSA level, Gleason score, and disease stage. Less than 6 percent of these men died of prostate cancer, and men in the watchful waiting group had slightly better (but not statistically significant) overall and prostate cancer-specific survival than men in the surgery group.
—Dr. J. Erik Busby
“We need to do additional analyses, but we feel confident that our results, overall, show no significant difference in all-cause or prostate cancer-specific mortality in all men enrolled,” Dr. Wilt said in an interview. The research team was also confident, that surgery offers no survival benefit for men with low-risk disease or a PSA level of 10 or below, he continued.
Pouring through the Studies
The PIVOT results come on the heels of findings from two other studies of what has been one of the most contentious issues in oncology: whether men with early-stage prostate cancer should undergo some form of definitive treatment, usually surgery or radiation.
Earlier this month, results from a similar but smaller clinical trial conducted in three Scandinavian countries found that surgery improved survival in men with early-stage disease. Most of the men in that trial, however, had been diagnosed on the basis of symptoms, not PSA screening, which some experts said made the trial findings less relevant to patients in the United States. Meanwhile, recent findings from an observational study conducted at Johns Hopkins University showed excellent long-term survival in men with very low-risk prostate cancer who were treated with active surveillance, which is more aggressive than watchful waiting and entails regular check-ups and screening for disease progression with PSA tests and prostate biopsies.
“We know that we over treat a lot of patients with early-stage prostate cancer,” said Dr. J. Erik Busby of the University of Alabama at Birmingham School of Medicine and Comprehensive Cancer Center. “But we have to look carefully at the details of the various studies and try to ferret out which patients should be encouraged to have active surveillance and which should receive definitive treatment.”
For men with low-risk disease and a PSA score below 10, Dr. Peter Albertsen of the University of Connecticut Health Center said he believes the PIVOT trial results “strongly support active surveillance.”
“In the past,” he continued, “we would look to operate on patients with a PSA [score of] less than 10.”
Surgery did appear to improve survival in some subgroups based on PSA level and tumor-risk category but not those based on patient characteristics (e.g., age, race, other health conditions), Dr. Wilt noted. “But when you look at the different tumor-risk categories, it gets a bit muddier, and we have less confidence in any positive effect,” he cautioned.
The strongest case for a benefit from surgery was in men with a PSA score above 10 and, to a lesser extent, in men with high-risk disease, but only for prostate cancer-specific mortality.
Moving Forward with Caution
The PIVOT trial was initially designed to enroll 2,000 patients. Of the more than 5,000 men who were approached to participate in the trial, 4,300 declined—most, Dr. Wilt said, because they did not want their treatment determined by randomization. Even so, he stressed, PIVOT is the largest randomized trial ever conducted to compare surgery with watchful waiting.
—Dr. Julio Pow-Sang
The trial data have to be interpreted cautiously, said Dr. Bhupinder Mann of NCI’s Division of Cancer Treatment and Diagnosis. With inadequate sample sizes, the risks of false-positive and false-negative findings increase, he noted. The survival benefit from surgery suggested in the high-risk group, which accounted for 20 percent of the trial population, “is certainly conceivable,” Dr. Mann said, and is consistent with current clinical practices and guidelines. With more patients in the high-risk group, the possibility of demonstrating a benefit from treatment—if a benefit truly existed—would have been higher and more reliable, he added. But because of the study’s size, “it’s hard to have confidence” in either the positive or the negative results.
Based on the available data, as long as the men have a life expectancy of 10 years or greater, surgery or radiation would still be the preferred first-line treatment in most men with a PSA level higher than 10 or with high-risk disease, said Dr. Julio Pow-Sang of the H. Lee Moffitt Cancer Center and Research Institute in Tampa, FL.
But even in men for whom surgery is not the preferred first-line treatment, the situation is a bit murky. PIVOT and the recent Scandinavian trial compared surgery with watchful waiting, not with active surveillance. Based on the PIVOT results, Dr. Wilt said, “The data support watchful waiting rather than active surveillance or early intervention with surgery for most men with early-stage prostate cancer, particularly for men with PSA values of 10 or less and those with low-risk disease.”
In the United States, however, even active surveillance has been a tough sell to urologists and urologic oncologists for their patients with early-stage disease; many of these patients still undergo surgery after diagnosis. Given that backdrop, Drs. Albertsen and Busby agree, U.S. doctors are unlikely to recommend watchful waiting to many patients.
“Most of us are a bit nervous with this approach,” Dr. Albertsen said. “We do not yet have confidence that we have not missed higher-grade disease on biopsy.”
The bottom line, stressed Dr. Pow-Sang, is that treatment of early-stage prostate cancer must be individualized. “We know that intervention is good in selected men,” he said, “and that other men will do well without any intervention.”