Benefit for Prostatectomy in Localized Prostate Cancer

UPPSALA, Sweden—In a new study, radical prostatectomy reduced deaths due to prostate cancer but did not increase overall survival in men with newly diagnosed, early-stage disease. The Scandinavian Prostatic Cancer Study Group found that after a median 6.2 years of follow-up, there were no significant differences in overall survival, but patients randomized to radical prostatectomy were less likely to develop distant metastases than those randomized to watchful waiting.

The survival and quality-of-life analyses were reported in the September 12 New England Journal of Medicine. Lead author on the survival analysis is Lars Holmberg, MD, PhD. Lead author on the quality-of-life analysis is Gunnar Steineck, MD.

The study, which was initiated before the era of routine prostate-specific antigen (PSA) testing, enrolled 695 men with clinical stage T1b, T1c, or T2 disease. Anna Bill-Axelson, MD, who is co-author on the Holmberg paper, told ONI that the investigators were quite surprised to see a difference in disease-specific mortality emerge so early in the study.

"The most important clinical implication of our study is that radical prostatectomy reduces the risk of death from prostate cancer by 50%. The study was designed to detect a much smaller difference, and we were surprised that the difference was so prominent after such a short time," said Dr. Bill-Axelson, who is in the Department of Urology, University Hospital, Uppsala, Sweden.

The difference in disease-specific mortality first became apparent after 5 years of follow-up (4.6% with watchful waiting vs 2.6% with radical prostatectomy). At 8 years of follow-up, the prostate cancer death rate was 13.6% with watchful waiting and 7.1% with radical prostatectomy (relative hazard 0.5, 95% CI 0.27 to 0.91, P = .02).

"The relative risk reduction was 50%, which translates into a small absolute reduction, since the risk of death in both groups after this short time is small. We think that only longer follow-up can determine if there will be a benefit in overall survival. The difference at this time is too small to be significant," Dr. Bill-Axelson said.

In an interview with ONI, Eric A. Klein, MD, Section Head for Urologic Oncology, Cleveland Clinic Urological Institute, pointed out that 75% of prostate cancer diagnoses in the United States are in men with nonpalpable disease who have had biopsies because of elevated PSA levels, while only 10% of the patients in the Swedish study were diagnosed at this early stage.

Using data from the Physicians’ Health Study, Gann et al had previously estimated that the mean time between a PSA reading of 4 ng/mL (which typically triggers a biopsy) and progression to clinically apparent cancer (such as that in most patients in the Swedish study) is 5.5 years, so the conclusions of this trial are not immediately applicable to most newly diagnosed prostate cancer patients in the United States.

However, Dr. Klein emphasized that these papers establish two important points. "This is the first time that an advantage for prostatectomy compared with watchful waiting has been documented in a randomized, controlled clinical trial. A decrease in the risk of dying from prostate cancer is an important benefit in itself because this is a miserable way to die," Dr. Klein told ONI.

Quality-of-Life Findings

The trial showed also that, contrary to widely held assumptions, radical prostatectomy is not associated with worse quality of life than watchful waiting. "The surgery was associated with the well-known problems of erectile dysfunction and urinary leakage, but watchful waiting was associated with obstructed voiding and fecal leakage," Dr. Klein said. The study showed that 40% of men in the radical prostatectomy group and 45% in the watchful-waiting group reported low or only moderate subjective quality of life (difference not significant).

Overall Survival

Competing causes of death such as cardiovascular disease may be a factor in the absence of an overall survival benefit associated with radical prostatectomy at this relatively early time. "The lower rate of metastatic disease in the radical prostatectomy patients could be expected to produce an improvement in overall survival with longer follow-up. Men never die of prostate cancer unless they develop metastases," Dr. Klein said.

In an editorial that accompanied the research articles, Patrick C. Walsh, MD, of Johns Hopkins University, made the same prediction. "Given that the median survival of men with distant metastases is only 2 to 3 years, I anticipate that with longer follow-up, the difference in mortality found by Holmberg et al will increase," Dr. Walsh wrote.

On the difficult point of how to counsel an asymptomatic patient whose prostate cancer has been detected following PSA screening, Dr. Bill-Axelson said that age and comorbidity are important considerations and that younger, otherwise healthy men are most likely to benefit from prostatectomy. "It is important to remember that the patient must be aided to make an informed choice, since many men die with rather than from prostate cancer," she said.