PROSTATECTOMY OVER WATCHFUL WAITING

For some men with localized prostate cancer, radical prostatectomy significantly reduced mortality, according to the long-term follow-up results of a randomized study led by Swedish researchers.

Men aged under 65 years and those with intermediate-risk disease derived the most benefit from undergoing surgery, although it also reduced the risk for metastases and need for additional treatment in older men.

Compared with watchful waiting, prostatectomy provided "significant absolute reduction" not only in prostate cancer-related mortality, but in death from any cause. These benefits continued for up to 2 decades of follow-up, with no evidence that they diminished over time.

The Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) followed almost 700 men who had been randomly assigned to either surgery or watchful waiting. During the follow-up period of up to 23.2 years, 200 of 347 men in the surgery group and 247 of the 348 men in the watchful-waiting group died; of the deaths, 63 in the surgical arm and 99 in the watchful-waiting group were due to prostate cancer, with a relative risk of 0.56 (P = .001). The absolute difference for disease-specific death was 11.0 percentage points.

Earlier results from this study were published in 2011, andreported by Medscape Medical News at that time.

Now the latest findings continue to show that radical prostatectomy can not only improve survival, but can also reduce the burden of disease in terms of development of metastases and the need for palliative treatment, commented study coauthor Jennifer Rider, MPH, ScD, assistant professor in the department of epidemiology at Harvard School of Public Health and assistant professor of medicine, Brigham and Women's Hospital, Boston.

Still, active surveillance also provided a lot of men with effective, intervention-free outcomes.

"A large proportion of men in the trial still alive at 18 years did not require initial surgery or any subsequent therapy, pointing to the potential benefits of active surveillance strategies to limit overtreatment," she said in a statement.

The study is published in the March 6 issue of the New England Journal of Medicine.

Key to Understanding Results: Study Predates PSA Testing

"This report provides important additional long term findings that reaffirm several previous reports from this group — that in some men, especially those under the age of 65 and for those with non-PSA detected early stage prostate cancer, early treatment with surgery of clinically detected prostate cancer decreases all-cause and disease mortality, distant spread and use of other treatments," commented Timothy Wilt, MD, MPH, professor of medicine and core investigator, Minneapolis VA Center for Chronic Disease Outcomes Research, Minnesota.

"The absolute reduction is moderate and requires fairly long time to occur, although benefits increased with time," he told Medscape Medical News.

That said, many men treated with observation do not die from their disease or require any treatment and thus can be spared immediate and persistent side effects from treatment, explained Dr. Wilt, who was not involved in the study.

The Swedish study was initiated prior to the advent of prostate-specific antigen (PSA) testing, and the prostate cancers were clinically detected as opposed to being detected by screening. Conversely, the Prostate Cancer Intervention versus Observation Trial (PIVOT), which began with the advent of PSA testing, found that radical prostatectomy did not significantly reduce either all-cause or prostate-specific cancer mortality when compared with observation among men with localized disease.

Previous PSA screening studies have demonstrated that if any reduction in prostate cancer mortality exists, it is at most small through 10 to 15 years, and PSA screening does not reduce all-cause mortality, Dr. Wilt explained.

The majority of prostate cancers detected in US and reported in the PIVOT study were PSA-screen detected. In that trial, the absolute differences in mortality measures between the observation and surgery groups were less than 3 percentage points and were not statistically significant, explained Dr. Wilt, who was an investigator in that study.

"These men have an even better long term prognosis with observation or active surveillance," he said. "Many/most can be safely treated with observation or active surveillance, especially those with a life expectancy of less than 15 years or with low PSA or low risk disease — the majority currently diagnosed in US."

Mortality Benefit, Lower Metastases Rate

In the current study, 695 men from 14 centers in Sweden, Finland, and Iceland with localized prostate cancer were randomized to either radical prostatectomy or watchful waiting. Enrollment into the study took place between October 1989 and December 1999,

Men included in the study were younger than 75 years and had a life expectancy of more than 10 years, had no other known cancers, and had a localized tumor of stage T0d (later named T1b), T1, or T2, as defined by the 1978 criteria of the International Union against Cancer.

The mean age of the men in both groups was 65 years, and only 12% of the patients had nonpalpable T1c tumors when they entered the study. The mean PSA level was about 13 ng/ML.

The primary end points were death from any cause, death from prostate cancer, and the risk for metastases. Secondary end points included the initiation of androgen deprivation therapy.

By the end of 2012, 294 men in the radical prostatectomy group had undergone surgery while 294 of those in the watchful-waiting group had not received curative treatment.

In the surgical arm, 23 patients (16 patients in the high-risk group, 7 patients in the intermediate-risk group, and no patients in the low-risk group) had lymph node-positive disease and thus did not undergo radical prostatectomy.

The median follow-up time was 13.4 years, ranging from 3 weeks to 23.2 years.

Overall, younger men (< 65 years) appeared to derive the greatest benefit from surgery, as far as lowering the risk for prostate cancer-related death (relative risk, 0.45), as well as those with intermediate-risk disease (relative risk, 0.38). Surgery was also associated with a reduced risk for metastases among older men (relative risk, 0.68; P = .04).

A higher incidence of distant metastases was observed in the watchful-waiting group (89 men in the radical prostatectomy group vs 138 in the watchful-waiting group) and the cumulative incidence of distant metastases at 18 years of follow-up was 26.1% for the surgical arm and 38.3% for watchful waiting. This was a 12.2 difference in percentage points that corresponded to a relative risk of distant metastases in the radical prostatectomy group of 0.57 (P < .001).

When looking at palliative treatments, a higher number in the watchful-waiting group received androgen-deprivation therapy (235 vs 145). The cumulative incidence of the use of androgen-deprivation therapy at 18 years was 42.5% in the radical prostatectomy group and 67.4% in the watchful-waiting group (a difference of 25 percentage points, corresponding to a relative risk of the use of androgen-deprivation therapy in the radical prostatectomy group of 0.49; P < .001).

The study was supported by grants from the Swedish Cancer Society, the National Institutes of Health, the Karolinska Institutet, the Prostate Cancer Foundation, and the Percy Falk Foundation. No potential conflict of interest relevant to this article was reported.

N Engl J Med. 2014;370:932-941.