Original article
Role of ultrasensitive prostate-specific antigen in the follow-up of prostate cancer after radical prostatectomy

https://doi.org/10.1016/j.urolonc.2014.10.010Get rights and content

Abstract

Objective

Prostate-specific antigen (PSA) is an important tool in the follow-up of prostate cancer after radical prostatectomy (RP). However, the relevance of ultrasensitive PSA (uPSA) after RP is not well defined. The aim of this study was to investigate the value of uPSA in follow-up after RP and to determine whether ultrasensitive PSA doubling time (uDT) correlates with traditional PSA doubling time (tDT).

Patients and methods

In total, 604 consecutive patients undergoing open RP and pelvic lymphadenectomy between 2004 and 2008 (minimum 5 y of follow-up) were studied. To evaluate the postsurgical uPSA level, scatter plot statistics were used. To correlate uDT and tDT in patients with a biochemical recurrence (PSA ≥0.2 ng/ml), at least 2 uPSA and 2 PSA measurements without salvage treatment were required and a weighted Cohen kappa statistic and receiver operating characteristic curve were used to test agreement across the categories.

Results

There were 229 patients without biochemical recurrence who did not have 3 rising PSA values after nadir within ultrasensitive area. Their highest uPSA value was between 0.003 and 0.1 ng/ml. In 97.4% of patients, the highest uPSA value was less than 0.03 ng/ml, and in 89% of these patients, the values were less than 0.02 ng/ml. The median uDT and tDT were 10.2 and 11.4 months, respectively. The weighted Cohen kappa statistic between these 2 groups was 0.30 (95% CI:−0.09 to 0.50), demonstrating a poor agreement of PSA doubling time across categories. The predictive capability of uDT was tested with tDT <9 months. A receiver operating characteristic curve area under the curve value was 0.737 (95% CI:−0.577 to 0.897) demonstrating a fair agreement between the groups.

Conclusions

uPSA values>0.03 ng/ml seems to be valid and can be used in a clinical setting. There was a poor to fair agreement between tDT and uDT. The accuracy of uDT improves when it approaches the traditional PSA threshold of 0.1 ng/ml. Also according to our results, there is no prognostic benefit of uDT calculation.

Introduction

Men have a lifelong risk of 17% to be diagnosed with prostate cancer (PCa), but only a 3% risk of death from PCa [1], [2]. RP is the standard treatment option for localized PCa, and estimating serum prostate-specific antigen (PSA) value is a sensitive tool for evaluating recurrence after surgery. Biochemical recurrence (BCR) after prostatectomy is defined by 2 consecutive PSA values ≥0.2 ng/ml [3], [4]. Approximately 1 of 5 patients experience BCR after radical operation [5]. Less than a third of these patients ultimately develop a clinical progression [6]. The median time to develop metastasis is 8 years after BCR and to death 5 years after the first metastasis [7]. Early and reliable detection of BCR is important because postoperative radiation therapy (RT) is the most effective when administered in an adjuvant setting, or as a salvage therapy when serum PSA level first attains a detectable level [8].

PSA detection methods are ultrasensitive when they detect levels less than 0.1 ng/ml [9]. Usefulness of BCR detection in this ultrasensitive range is unclear. The lowest limit of detection depends on the corresponding laboratory assay. Some assays are capable of detecting minimal levels approaching 0.001 ng/ml [9].

A definition for ultrasensitive PSA (uPSA) relapse is 3 rising uPSA values after nadir [10]. Recurrence seldom occurs in patients with uPSA levels≤0.04 ng/ml 3 years after surgery [11]. This threshold may correlate with a uPSA recurrence rate [11]. Relapse rarely occurs in patients with a very low uPSA nadir after RP when compared with those who have higher uPSA nadir [12]. uPSA may be an early detector for the risk of BCR after RP, but possible other benefits remain unclear.

To predict the risk for PCa-specific mortality (PCSM), PSA doubling time (PSADT) of 9 months or less is an individual risk factor for mortality [5]. traditional PSA doubling time (tDT) is one of the most important prognostic factors in follow-up after RP [5]. By contrast, the usefulness of ultrasensitive PSA doubling time (uDT) is not well studied and according to current knowledge, uDT is significantly more rapid than tDT [13].

The objective of the current study was to evaluate the PSA threshold in ultrasensitive range predicting BCR and to evaluate the relation of uDT and tDT.

Section snippets

Study participants

In total, 604 consecutive patients undergoing open RP and limited lymphadenectomy at Turku University Hospital during 2004 to 2008 were included. The study period was chosen to allow minimum of 5 years of follow-up. The open retropubic operation was performed as initially described by Walsh et al. [14]. Patients who received neoadjuvant or adjuvant androgen deprivation therapy were excluded, and data of 548 patients were analyzed (Fig. 1). The patients were followed up with every 3 months for

Results

The study population characteristics are described in Table 1, and flowchart of the study is depicted in Fig. 1. After the exclusion of 56 patients who received either neoadjuvant or adjuvant androgen deprivation therapy, 548 patients were further analyzed. Only 1 man died of PCa during median follow-up of 5.6 years. There were on an average 9.2 PSA measurements available per patient. The follow-up time was calculated from either the time of the operation or the initiation of adjuvant RT. There

Discussion

In our tertiary care academic center, the uPSA assay has been routinely used since 2004. However, the clinical value of uPSA level has remained unknown. Some patients have received salvage RT with rising uPSA without traditional BCR (2 consecutive values greater than 0.2 ng/ml). According to a previous study, clinical recurrence occurs in less than one-third of men with BCR, and even fewer die of PCa [6]. In our study, only 13% of the patients developed BCR during the follow-up time. In 18

Conclusions

The early detection of BCR is important to avoid delay in salvage treatments. Yet, there is no evidence about the benefit of uDT calculation to support this kind of decision making. The accuracy of assessing uDT improves when the PSA values approach 0.2 ng/ml. uPSA values less than 0.03 ng/ml should be considered nonsignificant and may be a normal variation without the risk of BCR.

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