SPCG-4

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Bill-Axelson A, et al. "Radical prostatectomy or watchful waiting in early prostate cancer". The New England Journal of Medicine. 2014. 370(10):932-942.
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Clinical Question

Among men with localized prostate cancer, does radical prostatectomy reduce mortality when compared to watchful waiting?

Bottom Line

Radical prostatectomy reduces mortality when compared to watchful waiting in men with localized prostate cancer. However, this benefit does not persist for men ≥65 years in age.

Major Points

The natural history of prostate cancer is one of slow growth. Radical prostatectomies are associated with significant morbidities including incontinence and impotence. As such, the optimal management of localized prostate cancer is unclear.

In a time before PSA screening for prostate cancer, the Scandinavian Prostate Cancer Group Study Number 4 (SPCT-4) randomized 695 Scandinavian men with localized prostate cancer to non-nerve-sparing radical prostatectomy or watchful waiting. The group has published its follow-up data every three years. The 2014 data was published by Bill-Axelson and colleagues when the population had an average follow-up of 23.2 years. Radical prostatectomy was associated with reduction in all-cause mortality (56.1% vs. 68.9%), prostate cancer mortality (17.7% vs. 28.7%), and distant metastatic disease (26.1% vs. 38.3%). However, all-cause and prostate cancer mortality lose significance for those enrolled at age ≥65 years.

Guidelines

Design

  • N=695 men with localized prostate cancer
    • Radical prostatectomy (n=347)
    • Watchful waiting (n=348)
  • Setting:
  • Enrollment: 1989-1999
  • Mean follow-up: 23.2 years (through 2012-12-31)
  • Analysis: Intention-to-treat
  • Primary outcomes:
    • All-cause mortality
    • Prostate cancer mortality
    • Distant metastatic disease

Population

Inclusion Criteria

  • Men age <75
  • Localized prostate cancer (T0d/T1b, T1, or T2 by the 1978 International Union Against Cancer staging; T1c tumors were included starting in 1994)
  • Well- or moderately-well differentiated by the WHO classification
  • PSA <50 ng/mL
  • Negative bone scan
  • Life expectancy >10 years
  • No other cancers

Exclusion Criteria

Baseline Characteristics

From the radical prostatectomy group.

  • Demographics: Age 64.6 years (<65 years old 45.2%)
  • PSA: 13.5 ng/mL
    • <4 ng/mL: 12.4%
    • 4-6.9 ng/mL: 17.3%
    • 7-10 ng/mL: 19.6%
    • 10.1-20 ng/mL: 28.8%
    • >20 ng/mL: 19.9%
    • Unknown: 0.9%
  • Disease:
    • Stage: T1b 9.5%, T1c 12.4%, T2 77.8%, unknown 0.3%
    • WHO grade: 1 48.4%, 2 51.3%, unknown 0.3%
    • Gleason score: 2-4 12.7%, 5-6 47.6%, 7 22.2%, 8-10 4.0%, unknown 13.5%
  • Detection: Opportunistic screening 5.2%, coincidental 25.1%, TURP 11.5%, symptoms 43.8%, other 14.1%, unknown 0.3%

Interventions

  • Randomization to a group:
    • Radical prostatectomy - If no nodal metastases on obturator fossa lymphadenectomy then a radical prostatectomy was performed
      • Radical excision of the tumor was given priority over nerve-sparing surgery
      • Androgen-deprivation if signs of recurrence
    • Watchful waiting - No immediate treatment
      • If obstructive voiding then TURP
      • Metastatic disease (or increasing PSA level after 2003) treated with androgen-deprivation therapy
  • Both groups following every 6 months for 2 years then annually with bone every 1-2 years

Outcomes

Presented as radical prostatectomy vs. watchful waiting. RR is relative risk. Subgroup analyses are included with primary outcomes for ease of reading.

Primary Outcome

All-cause mortality
56.1% vs. 68.9% (RR 0.71; 95% CI 0.59-0.86; P<0.001; NNT 8)
Age <65 years: 40.0% vs. 65.6% (RR 0.50; 95% CI 0.37-0.68; P<0.001)
Age ≥65 years: 69.8% vs. 71.7% (RR 0.92; 95% CI 0.73-1.18; P=0.52)
Low-risk tumor: 43.4% vs. 59.1% (RR 0.57; 95% CI 0.40-0.81; P=0.002)
Intermediate-risk tumor: 57.1% vs. 72.5% (RR 0.71; 95% CI 0.53-0.95; P=0.02)
High-risk tumor: 73.3% vs. 78.8% (RR 0.84; 95% CI 0.60-1.19; P=0.34)
Prostate cancer mortality
17.7% vs. 28.7% (RR 0.56; 95% CI 0.41-0.77; P=0.001; NNT 9)
Age <65 years: 18.3% vs. 34.1% (RR 0.45; 95% CI 0.29-0.69; P=0.002)
Age ≥65 years: 17.3% vs. 23.9% (RR 0.75; 95% CI 0.47-1.19; P=0.19)
Low-risk tumor: 10.2% vs. 14.0% (RR 0.54; 95% CI 0.26-1.13; P=0.17)
Intermediate-risk tumor: 15.1% vs. 39.3% (RR 0.38; 95% CI 0.23-0.62; P<0.001)
High-risk tumor: 33.1% vs. 35.7% (RR 0.87; 95% CI 0.52-1.46; P=0.84)
Distant metastatic disease
26.1% vs. 38.3% (RR 0.57; 95% CI 0.44-0.75; P<0.001; NNT 8)
Age <65 years: 28.7% vs. 44.5% (RR 0.49; 95% CI 0.34-0.71; P<0.001)
Age ≥65 years: 23.8% vs. 32.7% (RR 0.68; 95% CI 0.46-1.00; P=0.04)
Low-risk tumor: 13.6% vs. 24.2% (RR 0.40; 95% CI 0.21-0.73; P=0.006)
Intermediate-risk tumor: 25.0% vs. 44.9% (RR 0.49; 95% CI 0.32-0.74; P<0.001)
High-risk tumor: 45.9% vs. 50.8% (RR 0.81; 95% CI 0.52-1.26; P=0.39)

Secondary Outcomes

Androgen deprivation therapy
42.5% vs. 67.4% (RR 0.49; 95% CI 0.39-0.60; P<0.001)

Additional Analyses

Radical prostatectomy
84.7% vs. 8.3%
External radiotherapy
2.0% vs. 4.3%
Brachytherapy
0.6% vs. 2.3%

Adverse Events

 % vs. % (## HR; 95% CI ##-##; P=##; NNH=##)

Criticisms

Funding

Further Reading