Stratification of High-risk Prostate Cancer into Prognostic Categories: A European Multi-institutional Study

doi:10.1016/j.eururo.2014.01.020

European Urology

Volume 67, Issue 1, January 2015, Pages 157-164

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Abstract

Background

High-risk prostate cancer (PCa) is an extremely heterogeneous disease. A clear definition of prognostic subgroups is mandatory.

Objective

To develop a pretreatment prognostic model for PCa-specific survival (PCSS) in high-risk PCa based on combinations of unfavorable risk factors.

Design, setting, and participants

We conducted a retrospective multicenter cohort study including 1360 consecutive patients with high-risk PCa treated at eight European high-volume centers.

Intervention

Retropubic radical prostatectomy with pelvic lymphadenectomy.

Outcome measurements and statistical analysis

Two Cox multivariable regression models were constructed to predict PCSS as a function of dichotomization of clinical stage (<cT3 vs cT3–4), Gleason score (GS) (2–7 vs 8–10), and prostate-specific antigen (PSA; ≤20 ng/ml vs >20 ng/ml). The first “extended” model includes all seven possible combinations; the second “simplified” model includes three subgroups: a good prognosis subgroup (one single high-risk factor); an intermediate prognosis subgroup (PSA >20 ng/ml and stage cT3–4); and a poor prognosis subgroup (GS 8–10 in combination with at least one other high-risk factor). The predictive accuracy of the models was summarized and compared. Survival estimates and clinical and pathologic outcomes were compared between the three subgroups.

Results and limitations

The simplified model yielded an R² of 33% with a 5-yr area under the curve (AUC) of 0.70 with no significant loss of predictive accuracy compared with the extended model (R²: 34%; AUC: 0.71). The 5- and 10-yr PCSS rates were 98.7% and 95.4%, 96.5% and 88.3%, 88.8% and 79.7%, for the good, intermediate, and poor prognosis subgroups, respectively (p = 0.0003). Overall survival, clinical progression-free survival, and histopathologic outcomes significantly worsened in a stepwise fashion from the good to the poor prognosis subgroups. Limitations of the study are the retrospective design and the long study period.

Conclusions

This study presents an intuitive and easy-to-use stratification of high-risk PCa into three prognostic subgroups. The model is useful for counseling and decision making in the pretreatment setting.

Introduction

Prostate cancer (PCa) patients with a prostate-specific antigen (PSA) >20 ng/ml, Gleason score (GS) 8–10, or clinical stage ≥T3 constitute a high-risk PCa group, recognized by international scientific organizations [1], [2]. Despite increased use of PSA as a screening tool, a fair proportion of patients still present with high-risk disease [3]. The management of locally advanced and high-risk PCa is one of the most compelling contemporary challenges. In the absence of a randomized trial comparing the true benefit of surgery, radiation therapy (RT), androgen deprivation therapy (ADT), or combinations of these, it is difficult to counsel patients properly on the optimal treatment. Radical prostatectomy (RP) combined with an extended pelvic lymph node dissection is a valid strategy accepted by international guidelines [1], [2]. The putative benefits of RP as first-line treatment are to achieve tumor volume reduction and optimal local control. Pathologic examination of the resection specimen allows for treatment individualization by carefully selecting patients who might benefit from adjuvant treatment. Prospective randomized trials have been conducted in that setting to provide insight into overall treatment strategies, yet the optimal one is far from definitive [4], [5], [6], [7], [8].

Most of the studies assessing outcomes of surgery, RT, or multimodality treatment in high-risk PCa have been confronted with two important problems: the lack of a standard definition of this disease stage and large heterogeneity within this group [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23]. Although most high-risk PCa patients seem to fare well after curative therapy, a subgroup of patients still succumbs despite treatment. Therefore, there is a need to revisit our classification system and attempt to better stratify patients within this heterogeneous high-risk PCa group. Research activity should then focus preferably on those patients at the highest risk of dying from their disease.

In the present study, we attempted to substratify surgically treated high-risk PCa patients in prognostic subgroups with homogeneous PCa-specific survival using combinations of accepted risk factors [2], [22], [23].

Section snippets

Patient population

We identified 1632 consecutive patients with high-risk PCa [1], [2] treated with RP between April 1987 and August 2009 at eight European tertiary centers. Of all patients, 205 who received neoadjuvant ADT and 67 for whom data on neoadjuvant ADT were not available were excluded, leaving 1360 patients available for final analysis.

Clinical stage was assigned according to the 2002 TNM system, prostate biopsies were performed under transrectal ultrasound (TRUS) guidance, and pretreatment PSA was

Study population

Table 1 presents the baseline characteristics. Mean follow-up was 65.5 mo (median: 60.0 mo; interquartile range: 29–95 mo), and 690 patients had follow-up beyond 5 yr. There were 171 deaths, 60 of which were from PCa. Figure 1 displays the PCSS for the entire cohort of high-risk PCa patients. The 5-yr and 10-yr estimated PCSS were 96.4% and 91.3%, respectively.

Univariable analysis

Gleason score was the most important predictor of PCSS (hazard ratio [HR]: 1.85; 95% confidence interval [CI], 1.47–2.32), followed by

Discussion

At diagnosis, PCa is usually classified into major risk categories based on TNM clinical stage, biopsy GS, and pretreatment PSA levels. It is generally assumed that high-risk patients are at an elevated risk of experiencing BCR, metastatic progression, and death from PCa [9], [10], [11], [12]. Interestingly, there is no definitive consensus on the definition of high-risk PCa, and not all patients classified as having high-risk PCa by common definitions have a uniformly poor prognosis after RP

Conclusions

This study presents a stratification of high-risk PCa patients into three demarcated prognostic subgroups. The model is easy to use and can help clinicians in counseling and investigators in selecting a patient population that could benefit from novel perioperative strategies.

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^†: Both authors contributed equally to the manuscript.

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Prostate CancerStratification of High-risk Prostate Cancer into Prognostic Categories: A European Multi-institutional Study

Abstract

Background

Objective

Design, setting, and participants

Intervention

Outcome measurements and statistical analysis

Results and limitations

Conclusions

Introduction

Section snippets

Patient population

Study population

Univariable analysis

Discussion

Conclusions

Eur Urol

Lancet

Lancet Oncol

J Urol

Eur Urol

J Urol

J Urol

J Urol

Eur Urol

J Urol

Eur Urol

Eur Urol

Int J Radiat Oncol Biol Phys

Screening and prostate-cancer mortality in a randomized European study

N Engl J Med

Predominant treatment failure in postprostatectomy patients is local: analysis of patterns of treatment failure in SWOG 8794

J Clin Oncol

Prostate Cancer
Stratification of High-risk Prostate Cancer into Prognostic Categories: A European Multi-institutional Study