The slow clinical progression of prostate cancer after radical prostatectomy has necessitated the use of PSA recurrence as the primary end point for evaluating treatment outcome. However, PSA recurrence has a highly variable natural history and poses limited threat to the longevity of many patients. Hence, models that predict the risk of PCSM are needed. Ours is the first multi-institutional study of PCSM after radical prostatectomy for patients diagnosed in the era of widespread PSA screening. Hitherto poorly defined, the risk of death as a result of prostate cancer in a screened population is low, even for patients with adverse clinical features. Our nomogram accurately predicts the probability of PCSM using standard clinical parameters. Few contemporary patients had a predicted 15-year PCSM greater than 5%, highlighting the difficulty in identifying patients at substantially increased risk on the basis of clinical parameters alone. The need for novel markers specifically associated with the biology of lethal prostate cancer is evident.
Large, single-institution radical prostatectomy series have reported rates of PSA recurrence in approximately 25% of patients.10,14,15
Studies analyzing PCSM after radical prostatectomy were previously limited to cohorts diagnosed before the introduction of PSA.4,16–18
In our study, the overall 15-year PCSM was 12% for patients treated in the PSA era. Even for patients at the highest risk of PSA recurrence, the 10-year PCSM was only 15%, which compares favorably with the 50% to 70% PCSM reported for similar patients from unscreened populations who received no curative treatment.2
Currently, the vast majority of patients diagnosed in the United States (including 71% of our patients since 1998) are classified as good risk (clinical stage T1c or T2a, PSA < 10, and biopsy Gleason grade ≤ 6). Our results demonstrate the low lethality of these cancers after radical prostatectomy. Most of the decedents who were classified as good risk at diagnosis were clinically understaged or undergraded because they had pathologically advanced and/or high-grade cancers on examination of the radical prostatectomy specimen. Potentially, many of these patients may have had a similarly low risk of PCSM had they received no treatment. Comparative studies of patients treated without curative intent are limited to cohorts diagnosed before the PSA era.1–4
In the United States, only 2% of patients younger than 65 years choose active surveillance,19
and an estimated 73% of those who do ultimately opt for radical therapy within 4 years.20
The feasibility and safety of active surveillance in appropriately selected patients has been demonstrated, but it is not widely embraced because of concerns that clinical staging and grading underestimate the threat posed by the cancer.21
Currently, an international randomized trial is comparing active surveillance against radical treatment for good-risk cancer, but results are not expected for many years.
The discrepancy between the risk of PSA recurrence and PCSM may be explained by the variable natural history of PSA recurrence; only patients with a short PSA doubling time have a higher risk of PCSM relative to mortality from competing causes.22
Alternatively, this discrepancy may be related to the efficacy of secondary therapy: adjuvant radiation therapy and ADT have been shown to improve metastasis-free and overall survival.23,24
Lastly, the favorable impact of local disease control on the survival of women with breast cancer has been observed,25
and a similar effect in prostate cancer is suggested by the improved survival of patients with metastatic disease who received prior radical prostatectomy.26
Given the inadequacies of PSA recurrence as a valid surrogate end point, clinical trials in localized prostate cancer have focused on distant metastasis and PCSM as end points. The few contemporary patients with a predicted PCSM of greater than 5% has significant implications for clinical trial design. Any clinical trial in localized prostate cancer would require a sample size of thousands and a follow-up of 20 years to have sufficient power to detect a significant survival difference. There are few examples of successful clinical trials of this size in genitourinary oncology. Until molecular markers are discovered that identify a cohort of patients with lethal prostate cancer, future clinical trials may need to rely on PSA recurrence as the primary end point, despite its limitations.
PSA velocity has previously been reported to be associated with PCSM, although its predictive utility in models that include PSA, grade, and clinical stage has not been evaluated.27,28
In a recent study using data from the US prostate cancer screening trial, PSA velocity (when combined with standard clinical parameters) did not improve the accuracy of predicting poorly differentiated or pathologically advanced cancer.29
When combined with PSA, PSA velocity did not enhance the ability to predict the long-term risk of metastatic or locally advanced prostate cancer in a large, unscreened population.30
PSA velocity also did not significantly add to the accuracy of our nomogram. Though the timing of PSA measurements and the assays used were not standardized in our study, PSA velocity is not a clinically useful marker for the general population if these conditions must be satisfied. Although PSA velocity data were available for only 36% of our patients, this information was missing for 23% to 39% of patients in other studies, which argues against selection bias as an explanation for its lack of prognostic significance in our study.27,28
The failure of PSA velocity to improve the accuracy of our nomogram may be explained by its close correlation with PSA.31
We were also unable to identify an association between BMI and PCSM, despite its reported association with PSA recurrence in surgical series,32
and PCSM in population-based studies.33
More recent year of surgery has been reported to be associated with an improved risk of PSA recurrence.34
Year of surgery was also significantly associated with PCSM. Although the improved prognosis of contemporary patients may reflect improvements in surgical technique or changes in the tumor grading practices over time,13,35
it may be explained by the diagnostic lead time associated with PSA screening, which is estimated to be 11 years.5
The independent prognostic significance of year of surgery suggests that screen-detected cancers may have different biologic properties compared with similar cancers detected in the absence of screening. The favorable effect of year of surgery on PSA recurrence and PCSM appears to stabilize after 1998. Among the patients treated after 1998, only 4% had a 15-year PCSM probability of greater than 5% and less than 1% had a risk of greater than 30%.
Our study has several limitations worth noting. The nomogram predicts the probability of PCSM within 15 years, but patients seem to be at risk of PCSM for up to 20 years after treatment.17
A recent study of patients treated without curative intent in the pre-PSA era has suggested an acceleration in PCSM after 15 years,3
although a contradictory finding was reported in a separate study.1
The long-term risk of PCSM was low among patients in our study, but we do not know how these patients would have fared without radical therapy. Likewise, we are unable to compare the effectiveness of radical prostatectomy with other forms of treatment such as external-beam radiation therapy or brachytherapy. Our model considers only PCSM and does not consider health-related quality-of-life issues. All treatments for localized prostate cancer affect urinary, sexual, and bowel function to varying degrees, which the patient must also consider when formulating a treatment decision.36
An optimal nomogram would predict quality-adjusted survival. However, prospective, longitudinal quality-of-life data using validated instruments from patients with long-term follow-up are not available at this time. Lastly, our study consists of patients treated at high-volume, tertiary referral centers and thus the model presented here may not be as accurate for those treated in the community setting.
In summary, the long-term risk of PCSM among patients treated with radical prostatectomy in the era of widespread PSA screening is low, even for patients with adverse clinical features. This favorable prognosis may be related to the effectiveness of radical prostatectomy (with or without secondary therapy) or the low lethality of screen-detected cancers within 15 years of treatment. We have constructed and validated a nomogram that accurately predicts the 15-year PCSM, but few patients are predicted to have a substantially elevated risk on the basis of standard clinical parameters. Neither PSA velocity nor BMI were useful markers in our model. Our study is anticipated to provide important and useful information for patients and physicians regarding treatment decision making for localized prostate cancer.