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The incidence of prostate cancer (PCa) is steadily increasing worldwide [1]. This is largely due to the adoption of widespread prostate-specific antigen (PSA) screening, which allows diagnosing more tumours at an earlier stage. To date, optimal management of men with low-risk, clinically localized prostate cancer remains controversial. Among all the available therapeutic alternatives, two such options are radical prostatectomy (RP) and watchful waiting (WW). Watchful waiting involves providing no initial treatment and monitoring the patient with the intention of providing palliative treatment if there is evidence of disease progression. In this context, these options were compared in two major randomized controlled trials (RCTs): the Scandinavian Prostate Cancer Group (SPCG)-4 trial [2] and the Prostate Intervention Versus Observation Trial (PIVOT) [3]. According to their results, the SPCG-4 trial showed a definite survival advantage for surgery over WW at a median follow-up of 12.8 years [2]. Conversely, the PIVOT trial showed that RP did not significantly reduce PCa-specific or overall mortality after 12 years, and highlighted that the benefit from surgery might be confined to intermediate- and highrisk tumours [3].
The recently published updated work from Bill-Axelson et al. has shed light on the dilemma. After the longest period of follow-up in the SPCG-4 trial (23.2 years), the cumulative incidence of all-cause mortality at 18 years was 56.1% in the RP group and 68.9% in the WW group (a difference of 12.7 percentage points; 95% confidence interval [CI], 5.1–20.3), corresponding to a relative risk for death in the RP group of 0.71 (95% CI, 0.59–0.86; p<0.001). The cumulative incidence of PCa-specific mortality at 18 years was also lower in the RP than the WW group: 17.7% in the RP group and 28.7% in the WW group (a difference of 11.0 percentage points; 95% CI, 4.5–17.5), corresponding to a relative risk for death in the RP group of 0.56 (95% CI, 0.41–0.77; p=0.001).
In addition, the cumulative incidences of distant metastasis and disease progression were lower in the RP group than the WW group: 26.1% in the RP group and 38.3% in the WW group (a difference of 12.2 percentage points; 95% CI, 5.1–19.3), corresponding to a relative risk for distant metastases in the RP group of 0.57 (95% CI, 0.44–0.75; p<0.001); and 42.5% in the RP group and 67.4% in the WW group (a difference of 25.0 percentage points; 95% CI, 17.7–32.3), corresponding to a relative risk for the use of androgen-deprivation therapy in the RP group of 0.49 (95% CI, 0.39–0.60; p<0.001), respectively.
A subgroup analysis of the latest SPCG-4 trial results suggests that effects of RP may vary according to age. In men under 65 years at diagnosis, RP was associated with statistically significant reductions in the cumulative incidences of all-cause mortality, PCa-specific mortality, and distant metastases. However, for men aged 65 years and older, any differences between RP and WW did not reach statistical significance. However, among men older than 65 years of age who underwent RP, there was a significantly decreased risk for metastases and need for palliative treatment. All this indicates that RP prevented deaths from tumours over a wide range of growth rates.
However, as observing patients carries its own risk for disease progression, RP is itself not innocuous. Assessment of quality of life at a mean of 12.4 years showed a prevalence of erectile dysfunction of 84% in the RP group and 80% in the WW group; urinary leakage was reported in 41% and 11%, respectively. Distress from these symptoms was reported as being significantly greater in men assigned to RP than WW.
The weakest aspect of this trial is probably related to the low numbers in each subgroup, which may hamper results extrapolation to larger populations. However, the strengths of the study are reflected by the study's good methodological quality, its randomized nature, the completeness of an extended follow-up, the high adherence to the assigned regimen, and the independent and blinded evaluation of the results.
It is expected that awaited results of ongoing RCTs may provide more information on the comparative effectiveness of different treatment modalities in the near future [4] (Prostate Testing for Cancer and Treatment [ProtecT] trial; Phase III Study of Active Surveillance Therapy Against Radical Treatment in Patients Diagnosed With Favourable Risk Prostate Cancer [START] trial).
In conclusion, the important message we must retain from this manuscript is the fact that RP provides a definite survival advantage over WW, and indicates that RP prevents deaths from tumours over a wide range of growth rates.
From our perspective, factors other than survival should be considered when counseling men with localized PCa, which will ultimately reflect on their quality of life and perception of the disease: on one hand, the risk for metastases and ensuing palliative treatments; on the other hand, the post-operative functional results.