In our previous analyses, which were based on a median of 8.2 years of follow-up (4
), we found relative reductions of 40% in risk of metastases, 44% in risk of prostate cancer mortality, and 26% in overall mortality in favor of radical prostatectomy. After added follow-up, now to a median of 10.8 years, we found a relative reduction of 35% in risk of metastases, 35% in prostate cancer death, and 18% in overall mortality in favor of radical prostatectomy. These relative risks correspond to absolute risk reductions at 12 years of 6.7%, 5.4%, and 7.1%, respectively. Contrary to our predictions based on shorter follow-up (5
), the absolute difference in cumulative incidence of distant metastasis and prostate cancer death did not further increase after 7–9 years of follow-up. The relative risk of disease-specific mortality increased after 3 more years of follow-up from 0.50 (5)
, to 0.56 at a median follow-up of 8 years (4
), to 0.65 in the present analysis. The relative reduction in all-cause mortality following radical prostatectomy also decreased over time and was no longer statistically significant after 12 years of follow-up. In the present analysis, we could add data from the radical prostatectomy specimens following a complete central review, and a key finding is that almost all men in the radical prostatectomy group who died from prostate cancer had tumor growth outside the prostate capsule.
Strengths of our study include its randomized design, complete follow-up, standardized histopathologic review, and use of clinically relevant outcomes, which were assessed blindly with regard to randomization group. Compliance with recommended treatment was high despite the drastic difference between the two interventions. Furthermore, a large proportion of patients in this trial belonged to a group with clinically significant disease who might benefit from radical local treatment.
A critical question is whether our results are generalizable to settings in which the majority of prostate cancers are detected by means of PSA testing among asymptomatic men, a situation that prevails in the United States and in a growing number of Western countries. Radical local treatment can by definition convey no survival benefit to those who are overdiagnosed because such men have a nonlethal disease. It is unlikely that the high risk of overdiagnosis and the long lead times estimated in screening (3
) will be substantially offset by the proportion of men who are cured due to early treatment. In settings with a large proportion of PSA-detected tumors, the relative reduction in risk of death following radical prostatectomy might be somewhat larger or similar to that in our study, but the absolute reduction would be smaller. An absolute risk reduction of 5.4% implies a number needed to treat of 19 at 12 years in our patient population. However, estimates built on the SPCG-4 study and the current clinical situation (14
) suggest that the number needed to treat might be up to five times higher. This perspective further underlines the importance of trials testing active surveillance in patient groups for whom the estimated cost utility of radical prostatectomy is low, or even negative.
As expected from the literature, Gleason score and PSA level at diagnosis were prognostic factors, as also shown in our previous analyses (15
). However, we found that men with high Gleason score (≥7) or PSA level (≥10 ng/mL) had similar relative benefits from radical prostatectomy as men with low Gleason score or PSA less than 10 ng/mL, although the absolute benefits will differ by prognostic subgroup (15
). These findings regarding outcome after radical prostatectomy by subgrouping the men by Gleason score and PSA level at diagnosis is potentially important for clinical decision making. However, our study was not powered to analyze the effect modification of different prognostic variables, and we could have missed moderate but clinically relevant interactions. The absence of strong interactions indicates, however, that our estimate of the effect of radical prostatectomy is generalizable to other settings without screening but with a different distribution of these prognostic factors. Further evidence regarding the generalizability of our findings might come from the Prostate Cancer Intervention Versus Observation Trial in the United States (16
) and the Prostate Testing for Cancer and Treatment study (ProtecT) in the United Kingdom (17
). Until the results of those studies are available, our study provides the only evidence from a randomized trial for the benefit of radical prostatectomy.
Local recurrence and/or progression was much lower in the radical prostatectomy group than in the watchful waiting group, as was the use of hormonal and other palliative treatments. Because local recurrence or progression could not be assessed uniformly in the study arms and because indications for palliative treatment could not be followed in detail, the quantitative estimates of the effect of radical prostatectomy on these endpoints are difficult to interpret. However, the more frequent use of hormonal therapy and palliative treatments in the watchful waiting arm reflects symptom burden and has consequences for the patients’ quality of life. Androgen deprivation has been shown in two studies (18
) to decrease general health and quality of life, with more fatigue, loss of energy, emotional distress, change in body image, and worries about cancer and dying. The quality of life of patients with hormone-refractory prostate cancer has also shown to be reduced, likely from both the palliative care and the knowledge of having an incurable disease (20
). The higher cumulative incidence of all palliative interventions in the watchful waiting arm corresponds well with our previous finding (21
) that the symptom burden in the watchful waiting group seems to outweigh the side effects of surgery, as measured by self-estimated global well-being.
The use of hormonal therapy and other palliative measures followed the pattern of risk of progression and metastatic disease regarding both quantitative levels of use and timing. Thus, these factors cannot explain the better prognosis in the group randomized to surgery. If anything, our data imply that the difference in time to progression may be underestimated because the occurrence of metastatic disease was in absolute terms 6.7% more common even though use of hormonal therapies was 19.3% more common in the watchful waiting arm at 12 years.
Evidence of extracapsular tumor growth in radical prostatectomy specimens was a strong predictor of metastases and prostate cancer death. Indeed, among patients with extracapsular growth, 26 of 132 (20%) died during follow-up. Thus, these men should be considered for postoperative radiotherapy (22
However, because most men with extracapsular extension did not die during this follow-up, a substantial proportion of them may have benefited from surgery. Positive surgical margins did not carry prognostic information independent of extracapsular growth in multivariable analyses. This finding is in contrast with those of other studies (23
) that used PSA recurrence, rather than death, as an endpoint. In our study, no men who underwent radical prostatectomy and had specimen Gleason scores of 2–6 died from prostate cancer.
The subgroup analyses by age showed that the benefit of radical prostatectomy was limited to younger men. However, we caution that the study was not designed to look at age groups separately and, as for any of our subgroup analyses, all results should be interpreted cautiously. The age 65 cutoff was chosen because this was the mean age of the participants. However, we have no underlying empirical data to judge whether this cutpoint is biologically relevant. Other studies are needed to validate both the finding itself and whether the cutpoint is clinically relevant. In our data, the age-related difference in benefit could not be attributed to selection bias or confounding by any of the measured prognostic factors, and age per se is not an important prognostic factor in the source population for this study (25
). One possible interpretation of our findings is that in elderly patients all tumors with a potentially lethal phenotype have already metastasized at the time of diagnosis and cannot be cured by local treatment alone.
This is the third time an analysis of the main outcomes of this trial has been presented, and multiple statistical tests have been done with the risk of finding one or more randomly statistically significant results. However, our interpretation does rely mainly on stable long-term quantitative estimates as manifested in the cumulative incidence curves. The results of the subgroup analyses should be viewed as hypothesis generating rather than informing clinical action.
We conclude that radical prostatectomy results in a reduction in distant metastases and disease-specific death among patients with clinically localized prostate cancer not detected by PSA screening. Longer follow-up is needed to document whether this reduction is mainly restricted to the first decade of follow-up. The benefits of surgery radical prostatectomy have to be weighed against side effects, but in our study this was not a straightforward balance between years of life gained and side effects (21
). Watchful waiting also has side effects, and men face two different scenarios of symptoms and distress. We caution that this balance may look quite different if radical prostatectomy were to be compared with active surveillance. The finding that almost all prostate cancer deaths following radical prostatectomy occurred among patients with extracapsular tumor growth appears clinically relevant when searching for those who can be cured only with the addition of adjuvant treatment. Finally, the finding that radical prostatectomy conveys benefit chiefly to younger patients needs to be applied cautiously in the management of clinically localized prostate cancer. Although the finding was statistically robust, it was from a subgroup analysis, and the possible biologic underpinning of this observation is still enigmatic.