Elsevier

European Urology

Volume 59, Issue 6, June 2011, Pages 893-899
European Urology

Platinum Priority – Prostate Cancer
Editorial by Bertrand D. Guillonneau and Karim Fizazi on pp. 900–901 of this issue
Long-Term Risk of Clinical Progression After Biochemical Recurrence Following Radical Prostatectomy: The Impact of Time from Surgery to Recurrence

https://doi.org/10.1016/j.eururo.2011.02.026Get rights and content

Abstract

Background

The natural history of biochemical recurrence (BCR) after radical retropubic prostatectomy (RRP) is variable and does not always translate into systemic progression or prostate cancer (PCa) death.

Objective

To evaluate long-term clinical outcomes of patients with BCR and to determine predictors of disease progression and mortality in these men.

Design, setting, and participants

We reviewed our institutional registry of 14 632 patients who underwent RRP between 1990 and 2006 to identify 2426 men with BCR (prostate-specific antigen [PSA] levels ≥0.4 ng/ml) who did not receive neoadjuvant or adjuvant therapy. Median follow-up was 11.5 yr after RRP and 6.6 yr after BCR.

Intervention

RRP.

Measurements

Patients were grouped into quartiles according to time from RRP to BCR. Survival after BCR was estimated using the Kaplan-Meier method and compared using the log-rank test. Cox proportional hazard regression models were used to analyze clinicopathologic variables associated with systemic progression and death from PCa.

Results and limitations

Median systemic progression-free survival (PFS) and cancer-specific survival (CSS) had not been reached after 15 yr of follow-up after BCR. Cancer-specific mortality 10 yr after BCR was 9.9%, 9.3%, 7.8%, and 4.7% for patients who experienced BCR <1.2 yr, 1.2–3.1 yr, 3.1–5.9 yr, and >5.9 yr after RRP, respectively (p = 0.10). On multivariate analysis, time from RRP to BCR was not significantly associated with the risk of systemic progression (p = 0.50) or cancer-specific mortality (p = 0.81). Older patient age, increased pathologic Gleason score, advanced tumor stage, and rapid PSA doubling time (DT) predicted systemic progression and death from PCa. Limitations included retrospective design, varied utilization of salvage therapies, and the inclusion of few patients with positive lymph nodes.

Conclusions

Only a minority of men experience systemic progression and death from PCa following BCR. The decision to institute secondary therapies must balance the risk of disease progression with the cost and morbidity of treatment, independent of time from RRP to BCR.

Introduction

Despite the stage migration that has been noted in prostate cancer (PCa) over the prostate-specific antigen (PSA) era, biochemical recurrence (BCR) continues to be reported in up to 35% of men undergoing radical retropubic prostatectomy (RRP) [1], [2], [3], [4]. Although BCR does not always translate into clinical progression [1], [5], it does precede systemic relapse in the majority of cases, and patients with BCR have been shown to be at increased risk for subsequent metastases and mortality [6]. BCR has also been associated with the use of additional cancer treatments, as approximately a third of men who experience BCR receive a secondary therapy such as external-beam radiation therapy (RT) or androgen-deprivation therapy (ADT) [7].

Defining the natural history of patients with BCR after RRP is therefore relevant for patient counseling, clinical trial enrollment, and the judicious application of secondary therapies. Interestingly, reports to date have documented a relatively heterogeneous natural history of BCR [1], [5], [8], [9]. In addition, as men with PCa are generally >60 yr of age, it has been suggested that competing causes of mortality may obscure the ability of BCR to predict death from PCa [10]. In fact, men have been found to be as likely to die within 15 yr of BCR from competing causes as from PCa [11].

However, whether the outcomes from previous cohorts, which were largely composed of men treated during the pre-PSA and early PSA eras [1], [5], [8], can be extrapolated to the current PCa population has not been established. Moreover, the majority of patients from prior studies [5], [8], in contrast to common clinical practice [6], [7], [12], did not receive salvage therapy until the time of systemic progression. Therefore, the potential impact of secondary treatments on PCa mortality in men with BCR remains to be defined.

A further issue of contention in men with BCR following RRP has been the importance of the time interval from surgery to BCR. Although several series have noted that patients who experience BCR early after RRP are at higher risk for clinical progression and death from PCa [5], [8], [13], others have found that patients who experience BCR earlier after RRP are not at greater risk for subsequent adverse outcomes [1], [9]. Determining the prognostic impact of the disease-free interval after surgery is important, for example, when considering secondary treatments, as a shorter disease-free interval after RRP has been shown to predict receipt of salvage therapy [14]. Here, then, we evaluated long-term clinical outcomes in a large contemporary cohort of patients with BCR after RRP and determined predictors of disease progression and mortality in these men, including the importance of time from RRP to BCR and the impact of secondary cancer therapies.

Section snippets

Methods

After institutional review board approval was obtained, we reviewed our Prostatectomy Registry to identify 14 632 consecutive patients who underwent RRP at the Mayo Clinic between 1990 and 2006 (Table 1). Men who received neoadjuvant (n = 1625) or adjuvant (n = 1921) therapy were excluded from study, as were men who refused release of their records (n = 29) and 639 foreign patients without known follow-up.

Surgical procedures were performed by different surgeons using standardized techniques. The

Results

We identified 2426 men who experienced BCR following RRP and who did not receive neoadjuvant or adjuvant therapy (Table 1). Median age at surgery was 64 yr of age (IQR: 59–69), and median preoperative PSA was 7.9 ng/ml (IQR: 5.2–12.4). Approximately a third of patients had extraprostatic disease at RRP, and half had pathologic Gleason score ≥7 tumors. The fact that only a few men were included with positive lymph nodes (1.4%) reflects our common institutional practice of adjuvant treatment in

Discussion

We report that, at 15 yr following BCR, only 24% of patients had systemic progression, and 16% had died from PCa. In addition, we noted that although early BCR after RRP was associated with adverse clinicopathologic features, the time from surgery to BCR did not independently predict systemic progression or cancer-specific mortality. Instead, pathologic Gleason score, tumor stage, and PSA DT were significantly associated with systemic progression and death from PCa after BCR.

Our findings

Conclusions

Only a minority of men experience systemic progression and death from PCa following BCR after RRP for primarily lymph node–negative disease. Nevertheless, an increased interval from RRP to BCR is not independently associated with diminished risks of progression or mortality. Regardless of the timing of BCR, then, the decision to institute secondary therapies must balance the risk of disease progression based on clinical parameters—in particular, Gleason score, pathologic tumor stage, and PSA

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