Original article
Alkaline phosphatase velocity predicts overall survival and bone metastasis in patients with castration-resistant prostate cancer

https://doi.org/10.1016/j.urolonc.2017.02.001Get rights and content

Highlights

  • Previously, Alkaline Phosphatase Velocity (APV) has been shown to predict overall survival (OS) and bone metastasis free survival (BMFS) in castrate resistant prostate cancer (CRPC) patients.

  • The current study demonstrates additional evidence of the potential value of AP kinetics in patients with advanced CaP.

  • Prospective studies will be required to clarify these associations.

  • Given the restrictions on the current patient population, the findings are not inappropriately generalized to other men.

Abstract

Introduction and objectives

Identifying patients with prostate cancer (CaP) who will ultimately develop bone metastasis (BM) or die of disease is essential. Alkaline phosphatase velocity (APV) has been shown to predict overall survival (OS) and bone metastasis–free survival (BMFS) in an earlier study of an equal access military patient cohort of patients with castrate-resistant prostate cancer (CRPC). To confirm these findings, we examined a cohort of patients from a high-volume cancer center to validate a previous observation that faster alkaline phosphatase (AP) kinetics are predictive of OS and BMFS in this second cohort of patients.

Materials and methods

A retrospective cohort study was conducted of patients with CRPC treated at Memorial Sloan Kettering Cancer Center between 1989 and 2010. All patients who received androgen deprivation therapy (ADT) as primary treatment in response to a rising PSA after definitive surgery for CaP were eligible. For those who received primary ADT or surgery followed by ADT, CRPC was defined as one rising PSA value after a PSA nadir ≤4 ng/ml, and confirmed by a second rising PSA value, with concurrently documented testosterone levels <50 ng/dl. APV was computed as the slope of the linear regression line of all AP values (>2 values per patient) plotted against time. Study outcome included BMFS and OS. Univariable Kaplan-Meier analysis was used to examine time-to-event outcomes. Multivariable Cox proportional hazards regression analysis was used to model time to BMFS and OS.

Results

Of 89 patients with CRPC with evaluable data and CRPC, 17 (19%) experienced BM and 26 (29%) died. APV was dichotomized at the uppermost quartile split of all observed APV values:≥5.42 U/l/y vs. the lower 3 quartiles combined,<5.42 U/l/y. Patients with faster APV had significantly worse outcomes, including faster progression to BM and poorer OS when compared with those with slower APV (P = 0.0451 and P = 0.0109, respectively). There was strong correlation between PSA doubling time (PSADT) (<10,≥10 mo) and APV (≥5.42 U/l/y vs.<5.42 U/l/y) (P = 0.0289), preventing simultaneous evaluation of both factors in multivariable analysis. Kaplan-Meier analysis showed that PSADT was also predictive of BM and OS (log-rank P<0.0001). Separate multivariable Cox proportional hazards regression models were used to examine PSADT and APV, as predictors of each study outcome (BMFS and OS). Both PSADT and APV were strongly predictive of BMFS and OS (respectively).

Conclusions

APV and PSADT were predictors of BM and OS in patients with CRPC, respectively. These data are additional evidence of the potential value of AP kinetics in patients with advanced CaP. Prospective studies will be required to clarify these associations. However, given the restrictions on the current patient population in excluding metastatic disease within 12 months of ADT and a PSA nadir >4 ng/ml, the findings are not inappropriately generalized to other men.

Introduction

Despite recent controversy, prostate-specific antigen (PSA) remains the primary screening parameter for all stages of prostate cancer (CaP). Since its clinical application nearly 3 decades ago, patients present at an earlier stage with predominantly low-grade, organ-confined disease at younger age [1]. However, despite increased screening with PSA-based strategies, almost 4% of patients continue to be diagnosed with advanced-stage disease at the time of initial presentation [2], [3], [4]. More importantly, approximately 12% of the patients with organ-confined CaP at the time of initial presentation ultimately go on to develop bone metastases (BM) and less than 1% of those patients with BM have survival of 5 or more years [3], [4], [5].

Currently, metrics such as PSA doubling time (PSADT) and PSA velocity are the only relevant measures commonly used to evaluate the risk for disease progression and BM in men diagnosed with CaP [6]. Nevertheless, the efficacy of PSADT in predicting the onset of BM in patients with rising PSA is limited [7].

Alkaline phosphatase (AP) has been shown to be a nonspecific bone turnover marker that has been used to evaluate efficacy of treatment and to predict overall survival (OS) in men with castration-resistant prostate cancer (CRPC) [7], [8], [9], [10]. Historically, the clinical use of AP has been limited to detecting values above the upper limit of the reference range; only recently have AP kinetics been evaluated for clinical predictive value. A recently published study of a cohort of patients with CRPC demonstrated that alkaline phosphatase velocity (APV) has been shown to predict OS and bone metastasis–free survival (BMFS) [11].

It is well known that men who progress to metastatic CRPC have the highest probability of CaP-specific death compared with other stages of this disease. Furthermore, health care costs are significantly higher for patients who are diagnosed with this stage of disease [12], [13]. Subsequently, from the clinical perspective of improved patient care as well as from an economic perspective, better tools are needed to identify and treat patients at risk for metastatic CRPC. The primary aim of this study was to confirm a prior observation that APV is a useful predictor of PCa progression in the interval between achievement of CRPC status and metastasis.

Section snippets

Study population

Subjects of interest included those with biopsied-detected CaP between January 1, 1989 and December 31, 2010, who underwent androgen deprivation therapy (ADT) as primary CaP treatment or secondary to radical prostatectomy (RP) and provided written informed consent for study enrollment at Memorial Sloan Kettering Cancer Center (MSKCC). Patients with radiographic evidence of metastasis before or at the time of ADT initiation or within the first 12 months after ADT initiation were excluded from

Results

In total, 89 patients were identified who had 2 or more AP values, permitting an APV calculation. A flow diagram of patient selection and inclusion criteria is depicted in Fig. 1. Demographic and clinical characteristics are described in Table 1. Of the main cohort (n = 89), 17 developed BM (19.1%). Death was confirmed in 26 patients (29.2%); among the deceased, 9 (34.6%) patients had documented BM. Across kinetics measure categories, 60 patients (70%) had a PSADT≥10 months, whereas 26 patients

Discussion

In clinical practice, PSA is the most commonly accepted parameter used to evaluate patients with CaP for their risk of metastatic disease, CRPC, and PCSM [18]. This includes PSA kinetics, such as PSADT, PSA nadir, and PSA velocity [19]. The use of various biomarkers for bone turnover have long been used in conjunction with PSA kinetics. However, the clinical usage of biomarkers for bone turnover in patients with advanced CaP has not been established. Traditionally, single cut points of these

Conclusion

AP kinetics, specifically APV, appear to be predictive of BMFS and OS in a second cohort of patients with CRPC treated in a tertiary cancer center. PSADT is also strongly predictive of BMFS and OS. These data are additional evidence of the potential value of AP kinetics in an unique subset of patients with highly advanced CaP. Further, prospective data are needed to confirm these findings in geographically and racially diverse groups. APV should also be examined in larger study cohorts as a

Conflict of interest

The authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or nonfinancial interest (such as personal or professional relationships, affiliations, knowledge, or beliefs) in the subject matter or materials discussed

References (23)

  • Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res...
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