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Radical Prostatectomy or Watchful Waiting: 29-Year Follow-up of Scandinavian Trial


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AS REPORTED in The New England Journal of Medicine by Anna Bill-Axelson, MD, PhD, Lars Holmberg, MD, PhD, both of Uppsala University Hospital, and and colleagues, the 29-year follow-up of the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) trial has shown that radical prostatectomy is associated with a lower risk of prostate cancer–specific mortality vs watchful waiting in men with clinically detected localized prostate cancer.1 As stated by the investigators, “Radical prostatectomy reduces mortality among men with clinically detected localized prostate cancer, but evidence from randomized trials with long-term follow-up is sparse.”

Anna Bill-Axelson, MD, PhD

Anna Bill-Axelson, MD, PhD

Lars Holmberg, MD, PhD

Lars Holmberg, MD, PhD

Study Details

IN THE TRIAL, 695 men with localized disease from 14 centers in Sweden, Finland, and Iceland were randomly assigned to radical prostatectomy or watchful waiting between October 1989 and February 1999. Follow-up data were collected through 2017. The cumulative incidence and the relative risks for death from any cause, death from prostate cancer, and metastasis were estimated, as were the numbers of years of life gained. The median follow-up was 23.6 years; the maximum observed follow-up time was 28.0 years, and the maximum potential follow-up time was 29.3 years.

By December 31, 2017, 294 men in the radical prostatectomy group (85%) had undergone a radical prostatectomy, and 52 men in the watchful waiting group (15%) had undergone curative treatment.

Treatment Outcomes

BY DECEMBER 31, 2017, a total of 261 of the 347 men in the radical prostatectomy group and 292 of the 348 men in the watchful waiting group had died in the intention-to-treat population. Prostate cancer was the cause of death in 71 vs 110 patients. In the intent-to-treat analysis, the cumulative incidence of death from prostate cancer was 19.6% with radical prostatectomy and 31.3% with watchful waiting (absolute difference = 11.7 percentage points) at 23 years, with the relative risk for the complete follow-up period being 0.55 (P < .001) in favor of radical prostatectomy. The mean years of life gained in the radical prostatectomy group at 23 years was 2.9 years.

The cumulative incidence of death from any cause at 23 years was 71.9% in the radical prostatectomy group and 83.8% in the watchful waiting group (absolute difference = 12.0 percentage points), with the relative risk for the complete follow-up period being 0.74 (P < .001). The number needed to treat to avert 1 death from any cause was 8.4.

“Men with clinically detected, localized prostate cancer and a long-life expectancy benefited from radical prostatectomy, with a mean of 2.9 years of life gained.”
— Anna Bill-Axelson, MD, PhD, and colleagues

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Distant metastases were diagnosed in 92 men in the radical prostatectomy group and 150 men in the watchful waiting group. The cumulative incidence of distant metastases at 23 years was 26.6% vs 43.3% (absolute difference = 16.7 percentage points), with the relative risk based on data from the complete follow-up period being 0.54 (P < .001).

The beneficial effect of radical prostatectomy was greater among men younger than age 65 vs 65 years of age or older at diagnosis, with the risk of overall mortality being 15.0 percentage points lower, prostate cancer mortality being 15.1 percentage points lower, and distant metastasis being 18.6 percentage points lower in the radical prostatectomy group than in the watchful waiting group. Among men 65 years of age or older, between-group differences were smaller for all 3 outcomes.

A per-protocol analysis was performed involving all patients who survived at least 1 year and based on treatments given during the first year. In this analysis, for radical prostatectomy vs watchful waiting, the relative risks were 0.70 (95% confidence interval [CI] = 0.59–0.83) for death from any cause, 0.45 (95% CI = 0.33–0.61) for prostate cancer death, and 0.43 (95% CI = 0.33–0.57) for distant metastases.

RADICAL PROSTATECTOMY VS WATCHFUL WAITING

  • Compared with watchful waiting, radical prostatectomy was associated with a reduced risk of prostate cancer–specific mortality.
  • Radical prostatectomy was associated with improved overall survival and a reduced risk of distant metastasis.

Among the men who underwent radical prostatectomy, a factor predictive of poorer prostate cancer survival was extracapsular extension (relative risk = 5.21, 95% CI = 2.42–11.22). Compared with a Gleason score of 3 to 6, the risk of prostate cancer mortality was increased in men with a Gleason score of 3 + 4 (relative risk = 5.73, 95% CI = 1.59–20.67) and among men with a Gleason score of 8 or 9 (no patient had a score of 10; relative risk = 10.63, 95% CI = 3.03–37.30).

A positive surgical margin was associated with a poorer prognosis in a model adjusting for age alone; however, after adjustment was made for extracapsular extension, prostate-specific antigen level, and Gleason score, the relative risk of death from prostate cancer for positive vs clear margins was no longer statistically significant (1.16, 95% CI = 0.62–2.15).

The investigators concluded: “Men with clinically detected, localized prostate cancer and a long-life expectancy benefited from radical prostatectomy, with a mean of 2.9 years of life gained. A high Gleason score and the presence of extracapsular extension in the radical prostatectomy specimens were highly predictive of death from prostate cancer.”

DISCLOSURE: The study was funded by the Swedish Cancer Society and others. For full disclosures of the study authors, visit www.nejm.org. 

REFERENCE

1. BillAxelson A, Holmberg L, Garmo H, et al: Radical prostatectomy or watchful waiting in prostate cancer—29-year follow-up. N Engl J Med 379:2319- 2329, 2018.


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