Prostate Cancer: Influence of Screening and Intervention on Mortality
Abstract & Commentary
By William B. Ershler, MD
Synopsis: Two recent reports provide supportive evidence for current strategies in the management of prostate cancer. The first, from Finland, is a report of the marginal value of PSA screening in terms of long-term prostate cancer survival. And, from a cooperative observational cohort in the United States, there is suggestive evidence that radical prostatectomy provides a somewhat more favorable survival outcome when compared to external beam radiotherapy. Both studies include cohorts from the early- to mid-1990s with valuable and instructive long-term outcomes, but modern approaches have evolved such that specific translation to current practice is limited.
Sources: Klipelainen TP, et al. Prostate cancer mortality in the Finnish randomized screening trial. J Natl Cancer Inst 2013;105:719-725.
Hoffman RM, et al. Mortality after radical prostatectomy or external beam radiotherapy for localized prostate cancer. J Natl Cancer Inst 2013;105:711-718.
Two articles published in the current issue of the Journal of the National Cancer Institute relate to prostate cancer mortality. The first is a report from the European Randomized Study of Screening for Prostate Cancer describing the findings from the Finnish Prostate Cancer Screening Trial, for which the primary endpoint was prostate cancer-specific mortality. In this study of 80,144 men identified from a population registry, individuals were randomized to either a screening arm (SA) or a control arm (CA). Those randomized to the SA were asked to have a serum prostate-specific antigen (PSA) determination up to three times within a 4-year interval (between 1996-1999) and referred for biopsy if the PSA concentration were ≥ 4.0 ng/mL or 3.0-3.99 ng/mL with a free/total PSA ratio ≤ 16%. Men in the CA received usual care. All men were followed for up to 12 years after randomization and hazard ratios (HRs) were estimated for incidence and mortality using Cox proportional hazard model.
At the time of analysis, prostate cancer had occurred in 8.8 per 1000 person-years in the SA and 6.6 in the CA (HR, 1.34; 95% confidence interval [CI], 1.27-1.40). The incidence of advanced prostate cancer was lower in the SA vs CA arm (1.2 vs 1.6, respectively; HR, 0.73; 95% CI, 0.64 to 0.82; P < 0.001). For prostate cancer mortality, no statistically significant difference was observed between the SA and CA (HR, 0.85; 95% CI, 0.69-1.04). Thus prostate cancer-specific mortality was not significantly influenced at 12 years by the institution of a relatively conservative screening protocol. There was, however, a trend toward reduced mortality. The authors calculated that to avoid one prostate cancer death, approximately 1200 men would need to be screened and that this would come at the inherent costs of overdiagnosis.
The second report examining a cohort from approximately the same time period (1994-1995) compared prostate cancer and overall mortality in the context of primary therapy received: radical prostatectomy (RP) vs external beam radiotherapy (EBRT). Acknowledging that there has been no randomized trial comparing RP and EBRT as definitive primary treatment for localized prostate cancer, Hoffman and colleagues report observational data derived from the population-based Prostate Cancer Outcomes Study, which included men aged 55-74 years diagnosed with localized PC between October 1994 and October 1995 who underwent either RP (n = 1164) or EBRT (n = 491) within 1 year of diagnosis. Patients were followed until death or study end (December 31, 2010). After 15 years of follow-up, there were 568 deaths, including 104 from prostate cancer. RP was associated with statistically significant advantages for overall (HR, 0.60; 95% CI, 0.53-0.70; P<.0001 and disease-specific mortality ci>P < 0.0001). By using propensity scores to adjust for potential treatment selection confounders (demographics, comorbidities, and tumor characteristics) and subgroup analyses based on age, tumor characteristics, and comorbidity, the mortality benefit for RP remained apparent.
Thus, there are two current reports supporting, but not proving conventional wisdom regarding prostate cancer screening and initial therapy. Among more than 80,000 Finnish men randomized to receive PSA screening or “usual care,” those formally screened were found over 12 years to have a more frequent diagnosis of prostate cancer but a less frequent occurrence of advanced prostate cancer. However, even with this large sample size, there was no significant impact on prostate cancer mortality. The PSA screening undertaken was rather modest (up to three samples over the initial 4-year period) and it is possible a more aggressive screening strategy might have been more successful in ultimately reducing PC mortality. Similarly, although no significant difference was observed at 12 years, it remains possible that future analyses of this cohort will prove a positive mortality benefit from the modest screening undertaken.
In the mid-1990s, definitive treatment for localized PC was either RP or EBRT, and the commonly held notion was that clinical outcomes were comparable. Inasmuch as no randomized trial has compared the two, the population-based observational data reported from the Prostate Cancer Outcomes Study are of value. In fact, there have been other observational or retrospective reports with comparable findings of improved outcomes for patients treated by RP.1-3 Of course, there is substantial concern that selection bias would be at play (e.g., patients with greater comorbidities would be more likely to receive EBRT), despite efforts to minimize this bias by using propensity scoring to control for variations. Yet, even with such an approach, imbalances are likely to be present.
However, an even larger concern with regard to current applicability of this finding is that the data reflect treatment standards almost 2 decades old. Currently, low-risk patients might have comparable survival with initial therapy being neither radiotherapy or surgery but active surveillance. For patients with locally advanced, high-risk disease, survival with EBRT followed by androgen deprivation therapy is known to exceed survival with EBRT alone.4,5 As pointed out by Madan and colleagues in an accompanying editorial, modern management for locally advanced prostate cancer is becoming more personalized with technical improvements in pretreatment imaging and the incorporation of multimodality, personalized management that often may involve surgery, radiation, hormonal, and other systemic approaches in a manner not all that different than the management of breast cancer.6 Although it is unlikely we will ever see a randomized trial comparing RP with EBRT, reports such as that from Hoffman and colleagues are useful in framing modern treatment strategies.
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2. D’Amico AV, et al. J Clin Oncol 2003;21:2163-2172.
3. Kibel AS, et al. J Urol 2012;187:1259-1265.
4. Horwitz EM, et al. J Clin Oncol 2008;26:2497-2504.
5. Pilepich MV, et al. Int J Radiat Oncol Biol Phys 2005;61:1285-1290.
6. Madan RA, et al. J Natl Cancer Inst 2013;105:683-685.