The appropriate treatment of men with clinically localized prostate cancer diagnosed in the PSA era has been a subject of great controversy. For the majority of older men (aged ≥65 years) who are diagnosed with localized disease, randomized clinical trial data have not been able to demonstrate a survival benefit for surgery,3
or any other approach compared to conservative management.21
Despite these data raising the possibility that conservative management may be a reasonable treatment choice, little data exist that describe outcomes following conservative management in the contemporary PSA era.22-25
To address this lack of data, we examined 14,516 men with localized T1/T2 prostate cancer without initial attempted curative therapy and found that ten-year prostate cancer specific mortality declined by more than 60% compared to previous studies (). We also found that for the majority of men managed without initial attempted curative therapy (ie., those >65 years old with moderately-differentiated cancer), only a limited proportion (4-11%) used palliative radiation therapy, chemotherapy, or treatments for spinal cord compression over the ensuing 10 years following diagnosis. In contrast, use of androgen deprivation therapy was quite common.
The substantial improvement in survival we observed in our study compared with previous reports10, 11, 26
might be explained, in part, by additional lead time, overdiagnosis related to PSA testing, or grade migration, among other factors.27
PSA testing identifies disease 6-13 years before it presents clinically.28
Contemporary patients identified through such testing would be expected to live at least 6-13 years longer because of this lead time.28
In addition, previously documented systematic upgrading of modern tumors compared to earlier eras29
makes more recently graded tumors appear to have a more benign course, resulting in longer survivals.27
Finally, it is also possible that advancements in medical care might have led to improved outcomes. The net overall effect is that outcomes following conservative management are now significantly better than those reported in previous eras; therefore, physicians and their patients may need to reconsider this management option, particularly in light of randomized trial data from the pre-PSA era suggesting little if any benefit to more aggressive intervention.
Our documentation of a major improvement in conservative management outcomes is important, not only because it provides updated information for physicians and patients, but also because the results may color the interpretation of maturing randomized clinical trials. For example, in the widely cited Scandinavian randomized study of prostatectomy vs. conservative management, disease-specific survival in the conservative management arm (~85% at 10-years)3
was found to be very similar to that documented in several observational cohort studies of conservative management from the same pre- or early PSA era (~87%,26
). The use of radical prostatectomy resulted in a ~5.3% absolute percentage point increase (to ~90%) in cancer-specific survival in this study.
The results of our study, however, demonstrated that 10-year cancer-specific survival with conservative management has now increased from ~83-87% in the pre- or early PSA era to ~94% in the PSA era, which is now beyond the ~90% 10-year cancer-specific survival rate for a similar population of men treated with prostatectomy in the pre- or early PSA era Scandinavian trial (ie., those aged 66-74 years with moderately-differentiated cancer) (). The room available for additional improvement when 10-year cancer-specific survival is already ~94% with conservative management may be limited, and the absolute benefit of surgery in the Scandinavian trial may be difficult to reproduce in similar studies like the U.S. Prostate Cancer Intervention Versus Observation Trial (PIVOT), where most men were diagnosed through PSA screening.32
Nonetheless, the only true way to determine if this will be the case is to await the results of contemporary randomized studies like PIVOT, and it is not our intent to suggest that benefit for the majority of men with localized prostate cancer (ie., those ≥65 years old) can be excluded based on our results and those of the Scandinavian study.3
On the other hand, for men with poorly-differentiated disease managed conservatively, the 10-year cancer-specific survival was substantially lower (~58-74%) than reported in the Scandinavian trial and, therefore, the potential for benefit with attempted curative therapy may be greater in these men.
Our study had some limitations. The men in our study, like the majority of prostate cancer patients, were ≥65 years of age and our results might not apply to younger patients. In addition, we were limited to data available in the SEER registries. For example, PSA values at diagnosis were not collected during the study period and Gleason 5, 6, and 7 tumors were grouped together as moderately-differentiated disease. Consequently, the results for moderately-differentiated disease as a whole may overestimate survival for Gleason 7 tumors and underestimate survival for Gleason 5 tumors. In addition, there may be unmeasured patient or disease characteristics beyond age, tumor stage and tumor grade, unique to patients selecting conservative management that impact results so that they may not apply to patients with more aggressive disease characteristics not captured in the database. Another limitation is the length of follow-up. Because of the protracted nature of the disease, longer follow-up data are needed for men with a life expectancy greater than 10 years.
Finally, as in other observational and randomized trials and studies, the secondary endpoints were supportive, exploratory, and less robust than the primary endpoints. For example, although the Medicare database is generally able to capture the initiation of secondary therapy accurately (surgery, radiation, ADT, and chemotherapy, etc.), the actual accuracy may vary somewhat from procedure to procedure and, therefore, comparisons between rates of secondary therapies may be less exact.12, 16, 33
In addition, the Medicare database does not consistently capture the use of oral agents, such as the antiandrogens, that may be used for ADT. In the case of antiandrogens, however, data from the CaPSURE database34
have shown that the use of antiandrogens as sole treatment for localized prostate cancer is uncommon (~2%) and, therefore, it is unlikely that the use of hormonal therapy would be significantly underestimated. Irrespective of the strengths and limitations of each secondary endpoint, however, it is important to recognize that the purpose of these additional analyses was to provide additional insight and context for the interpretation of the primary endpoints of cancer-specific and overall survival, and not necessarily for these endpoints to stand alone as definitive conclusions.
In addition to the study’s limitations, there were also some important strengths. The study was population-based, and all-inclusive in the regions studied, rather than limited to specific institutions or networks. Consequently, the results are more likely to apply more broadly. In addition, the study was much larger than previous studies and, therefore, provided more stable estimates on which to base future clinical decisions. In particular, conservative management is often an especially relevant treatment choice for men aged ≥75 years. However, data on this older population are rare and this group is often excluded or underrepresented in randomized trials. Our study, with more than 10,000 men aged ≥75 years, provided crucial information to fill this important knowledge gap.
In summary, our findings suggest that outcomes following conservative management of contemporary PSA era patients with localized prostate cancer are substantially more favorable than in studies from earlier eras, and patients with well- or moderately-differentiated disease managed conservatively are generally even more likely to die of causes other than prostate cancer.9, 10, 26, 30
Considering favorable 10-year outcomes following conservative management, men with a life expectancy less than 10-years may wish to consider an active surveillance/watchful waiting protocol as an alternative to immediate attempted curative therapy.10, 25, 26, 30, 35