VA Study Urging Watchful Waiting for Early Prostate Cancer Sparks Controversy

by U.S. Medicine

September 6, 2012

By Brenda L. Mooney

MINNEAPOLIS — New research out of the Minneapolis VAMC finds that radical prostatectomy does not significantly reduce the risk of death in prostate cancer patients, when compared to observation over more than a decade. While that study confirms other major research on the topic, the controversy about how to treat early-stage prostate cancer continues.


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The results came from the Prostate Cancer Intervention Versus Observation Trial (PIVOT), partially funded by VA and led by Timothy J. Wilt, MD of the Minneapolis VAMC. PIVOT, which began enrolling patients in 2004, looked at men with early-stage prostate tumors detected by PSA screening and compared the relative benefits of prostate cancer surgery soon after diagnosis to observation.

Study results, published recently in the New England Journal of Medicine, found that most men did not benefit from the surgery by reductions in mortality from prostate cancer or other causes.

“Our data show that observation provides equivalent length of life, with no difference in death from prostate cancer, and avoids the harms of early surgical treatment,” Wilt said in a VA press release.

VA Study Urging ‘Watchful Waiting’ for Early Prostate Cancer Sparks Controversy

Few Younger Patients

Andriole also noted in a news release that fewer than 10% of men in the study were in their 40s and 50s, not enough to determine whether surgery would lower mortality in that group.

“While the study demonstrates that some men with low-grade disease may not benefit from surgical intervention, it does not add to our understanding of who exactly these men are,” Penson added. “This is due in no small part to the fact that only 10% of the men in PIVOT were under age 60, and only half of the patients (55%) had no other co-morbid conditions. Given that the median follow-up in PIVOT was only 10 years and the real possibility that patients with low-grade prostate cancer and longer life-expectancies may garner some benefit from surgical treatment with longer follow-up, younger, healthier patients with low-grade prostate cancer should still strongly consider surgical treatment for their disease.”

Despite objections from the urology group, PIVOT’s findings support the results of the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer-screening trial, which to date has shown that most cancers detected by repeated PSA screening are low risk and that annual prostate cancer screening does not reduce mortality.

“The findings of these two studies should be reassuring to men with low-risk prostate cancer,” said Andriole, who also serves as chairman of the PLCO’s prostate cancer committee. “PSA screening commonly results in the discovery of cancers that are generally not a threat to life. This ‘overdiagnosis’ of nonlethal cancers is concerning in and of itself and becomes especially problematic if men with such low-risk cancers are ‘overtreated,’ since they are unlikely to benefit from the treatment and may experience side effects like incontinence and impotence.”

Overall, deaths from prostate cancer occurred infrequently during the study period. Only 5.8% of those treated with surgery died of prostate cancer or treatment, compared with 8.4% of those under observation — not a statistically significant difference.

In recently assigning PSA screening a Grade D recommendation and discouraging its use, the U.S. Preventative Services Task Force considered results of both the PLCO and PIVOT studies.

Andriole suggested a middle ground for many men with low-risk prostate cancer detected by PSA screening.

“Active surveillance is apt to be better than observation or immediate treatment in most low-risk patients,” he said. “We watch the PSA very closely and biopsy men periodically, so, if a tumor starts growing or becomes more aggressive, we can still successfully treat it.”

Penson, meanwhile, said the inability to conclusively determine whether prostate cancer is low- or high-risk makes it difficult to discourage treatment in patients who want it.

He said the data about “positive findings in the high-risk patients underscore a strong need for reliable, effective biomarkers that allow us to distinguish low-risk disease from high-risk disease, so we can prescribe treatment accordingly. Until we are able to distinguish between indolent and aggressive disease, some men with low-risk prostate cancer will desire treatment; this is appropriate in the absence of a certainty that they will die with prostate cancer, not of prostate cancer.VA Study Urging ‘Watchful Waiting’ for Early Prostate Cancer Sparks Controversy

The study reported that, “among men with localized prostate cancer detected during the early era of PSA testing, radical prostatectomy did not significantly reduce all-cause or prostate-cancer mortality, as compared with observation, through at least 12 years of follow-up. Absolute differences were less than 3 percentage points.”

Two subgroups of participants, those with PSA levels greater than 10 ng/mL and those with more aggressive tumors, demonstrated some longevity benefit from surgery.

“For most men with low-risk prostate cancer, there is no evidence they need immediate treatment,” said study co-author Gerald Andriole, MD, of the Washington University School of Medicine in St. Louis. “But the data suggest that men with high PSA levels and those with more aggressive tumors likely benefit from early surgery, and these men should undergo treatment, because their tumors are more likely to be lethal, if left alone.”

The study group included 731 men, averaging 67 years old, with tumors limited to the prostate. Participants were randomly assigned to surgery or observation.

During the follow-up period — a median of 10 years with some patients tracked for as long as 12 years — 71 of 364 men (47%) assigned to radical prostatectomy died, compared with 183 of 367 (49.9%) assigned to observation.

Of those who received surgery, 5.8% died from prostate cancer or treatment, compared with 8.4% assigned to observation. Adverse events within 30 days after surgery occurred in 21.4% of men, including one death.

The study’s conclusions were not universally accepted, however.

“Though, on the surface, these new data from PIVOT may imply that radical prostatectomy did not significantly reduce mortality in men with localized prostate cancer, when compared with observation, the data do show a demonstrated positive effect in prostate cancer-specific mortality [as well as a trend in overall mortality] in high-risk patients,” said David F. Penson, MD, MPH of Vanderbilt University in Nashville, TN, the health policy chair at the American Urological Association (AUA).

“This trend is evident, despite the fact that PIVOT is an undersized study [its enrollment of 731 men is not large enough to give an adequate confidence interval] and suffers from other flaws that impact its ability to fully assess the effects of treatment. Had study enrollment been larger, this trend would be even more significant,” Penson added in a statement released by AUA.

When preliminary results of the study were presented to the AUA annual meeting in 2011, Wilt said more than 5,000 men across multiple centers were approached to participate in the trial, but 4,300 declined, usually because they did not want their treatment determined by randomization.

He noted, however, that PIVOT is the largest randomized trial ever conducted to compare surgery with watchful waiting.

According to the study, of men with PSA levels greater than 10 ng/mL, 5.6% in the surgery group died, compared with 12.8% of those in the observation group. Fewer deaths from prostate cancer also occurred among men treated with surgery who had high-risk prostate cancer, classified as a PSA level above 20 ng/mL and a score of 8-10 on the Gleason scale, a measure of tumor aggressiveness. In this subgroup, 9.1% of men who had surgery died, compared with 17.5% for observation.

In addition to its size, the PIVOT study also is criticized because it began gathering data early in the PSA era, when testing was less universal and more likely to be prompted by symptoms. In fact, only 40% of men in the PIVOT study had low-risk prostate tumors, defined as a PSA level of less than 10 ng/mL or a Gleason score of less than 7. Currently, more than two-thirds of prostate cancers detected by PSA tests are considered low-risk.

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