Radical prostatectomy versus watchful waiting in localized prostate cancer: the Scandinavian prostate cancer group-4 randomized trial

Abstract

Background: The benefit of radical prostatectomy in patients with early prostate cancer has been assessed in only one randomized trial. In 2005, we reported that radical prostatectomy improved prostate cancer survival compared with watchful waiting after a median of 8.2 years of follow-up. We now report results after 3 more years of follow-up.

Methods: From October 1, 1989, through February 28, 1999, 695 men with clinically localized prostate cancer were randomly assigned to radical prostatectomy (n = 347) or watchful waiting (n = 348). Follow-up was complete through December 31, 2006, with histopathologic review and blinded evaluation of causes of death. Relative risks (RRs) were estimated using the Cox proportional hazards model. Statistical tests were two-sided.

Results: During a median of 10.8 years of follow-up (range = 3 weeks to 17.2 years), 137 men in the surgery group and 156 in the watchful waiting group died (P = .09). For 47 of the 347 men (13.5%) who were randomly assigned to surgery and 68 of the 348 men (19.5%) who were not, death was due to prostate cancer. The difference in cumulative incidence of death due to prostate cancer remained stable after about 10 years of follow-up. At 12 years, 12.5% of the surgery group and 17.9% of the watchful waiting group had died of prostate cancer (difference = 5.4%, 95% confidence interval [CI] = 0.2 to 11.1%), for a relative risk of 0.65 (95% CI = 0.45 to 0.94; P = .03). The difference in cumulative incidence of distant metastases did not increase beyond 10 years of follow-up. At 12 years, 19.3% of men in the surgery group and 26% of men in the watchful waiting group had been diagnosed with distant metastases (difference = 6.7%, 95% CI = 0.2 to 13.2%), for a relative risk of 0.65 (95% CI = 0.47 to 0.88; P = .006). Among men who underwent radical prostatectomy, those with extracapsular tumor growth had 14 times the risk of prostate cancer death as those without it (RR = 14.2, 95% CI = 3.3 to 61.8; P < .001).

Conclusion: Radical prostatectomy reduces prostate cancer mortality and risk of metastases with little or no further increase in benefit 10 or more years after surgery.

Figure 1

Trial flow diagram of the 695 men randomly assigned in the Scandinavian Prostate Cancer Group-4 study. RT = radiation therapy; RP = radical prostatectomy.

Figure 2

Cumulative incidence with 95% confidence intervals (CIs) at 4, 8, and 12 years of endpoints for all patients. A) Overall mortality: relative risk (RR) = 0.82, 95% CI = 0.65 to 1.03; P = .09. B) Prostate cancer (PC) death: RR = 0.65, 95% CI = 0.45 to 0.94; P = .03. C) Metastases: RR = 0.65, 95% CI = 0.47 to 0.88; P = .006. D) Local progression: RR = 0.36, 95% CI = 0.27 to 0.47; P < .001. E) Hormonal treatment: RR = 0.54, 95% CI = 0.44 to 0.68; P < .001. F) Other palliative treatment: RR = 0.63, 95% CI = 0.41 to 0.97; P = .04. P values (two-sided) were calculated using Gray's test.

Figure 3

Cumulative incidence of endpoints by age group. A) Overall mortality: Age < 65: Relative risk (RR) 0.59, 95% confidence interval (CI) = 0.41 to 0.85; P = .004. Age ≥ 65: RR = 1.04, 95% CI = 0.77 to 1.4; P = .81. B) Prostate cancer (PC) death. Age < 65: RR = 0.5, 95% CI = 0.3 to 0.84; P = .01. Age ≥ 65: RR = 0.87, 95% CI = 0.51 to 1.49; P = .55. C) Metastases. Age < 65: RR = 0.52, 95% CI = 0.34 to 0.81; P = .006. Age ≥ 65: RR = 0.8, 95% CI = 0.51 to 1.27; P = .28. P values (two-sided) were calculated using Gray's test.

Figure 4

Cumulative incidence of prostate cancer mortality among men who were randomly assigned to radical prostatectomy and underwent radical prostatectomy within 1 year after randomization. A) Mortality by extracapsular tumor growth. Relative risk (RR) = 0.05, 95% confidence interval (CI) = 0.01 to 0.22; P < .001. B) Mortality by Gleason score of radical prostatectomy specimens. Gleason score 7 vs Gleason score 8–10, RR = 0.24, 95% CI = 0.11 to 0.49; P < .001. Gleason score 2–6, RR was not estimated (no events). P values (two-sided) were calculated using Gray's test.