Prostate CancerAnalysis of T1c Prostate Cancers Treated at Very Low Prostate-Specific Antigen Levels
Introduction
Historically, patients with a normal digital rectal examination (DRE) and a serum prostate-specific antigen (PSA) level >4.0 ng/ml were recommended to undergo prostate biopsy given the 20–30% risk of prostate cancer (pCA) [1]. The majority of patients diagnosed on the basis of an elevated PSA level have biologically important cancers, and the rate of indolent cancer (defined as a specimen Gleason score of 2–6, no extraprostatic extension, tumor volume <0.5 cm3) is 10–30% [2], [3]. Compared to cancers detected on the basis of symptoms or abnormal DRE, T1c cancers are more likely to be detected at an early and curable stage [4], [5].
Catalona et al and others have argued that a 4.0 PSA threshold for biopsy is more frequently associated with under- rather than overdiagnosis, as rates of non–organ-confined cancer (25–35%) are two to four times higher than indolent cancer (5–15%) [6], [7], [8], [9]. Compared to cancers detected at PSA >4.0, cancers detected in the 2.6–4.0 PSA range are more likely to be organ-confined without a substantial difference in the rate of indolent cancer [6], [8], [10]. In a longitudinal screening study, a decreased rate of biochemical recurrence (BCR) was observed for patients treated by radical prostatectomy (RP) after lowering the PSA threshold for biopsy from 4.0 to 2.5 [7]. As such, a lowering of the PSA threshold for biopsy to 2.5 has been advocated to increase the detection of clinically significant cancers at a more curable stage, and this had been adopted in the guidelines of some professional societies [11], [12].
The Prostate Cancer Prevention Trial (PCPT) has challenged the validity of any PSA threshold for biopsy, since no value had sufficient sensitivity and specificity for the detection of pCA, and a continuum of risk at all PSA values was observed among patients who were biopsied without accepted indications [13]. Among patients with PSA <1.0 and 1.1–2.0, the cancer-detection rate was 9% and 17%, respectively, and the corresponding proportion of cancers graded as biopsy Gleason 7–10 was 11% and 12%, respectively [14]. These results indicate that there is no safe lower limit for PSA and the risk of pCA. A risk calculator was subsequently developed based on age, race, family history, prior negative prostate biopsy, and the PSA and DRE result within 1 yr prior to biopsy [15]. For example, based on a 20% risk of pCA, a 55-yr-old Caucasian male with a negative DRE and no family history of pCA would be recommended to undergo prostate biopsy at a PSA level of 1.5.
The optimal PSA threshold for biopsy is one that maximizes the detection of biologically significant but curable cancers and subsequently reduces cancer-specific mortality while minimizing overdiagnosis and the number of patients subjected to further diagnostic testing. The pathologic characteristics and treatment outcome of patients diagnosed below currently accepted PSA thresholds for biopsy (≤2.5 ng/ml) are poorly defined. We analyzed the outcome of patients with T1c pCA treated at very low PSA levels (≤2.5) and compared them to patients with PSA 2.6–4.0 to determine whether any therapeutic advantage exists to justify lowering accepted PSA thresholds for biopsy.
Section snippets
Methods
Between 1998 and 2006, 5920 patients with localized pCA were treated at our institution, with 3003 undergoing RP, 1641 undergoing brachytherapy, and 1276 undergoing external-beam radiotherapy (EBRT). Of these patients, 267 (4.5%) had clinical stage T1c and PSA 2.6–4.0 and 84 (1.4%) had T1c and PSA ≤2.5. No patient in either group had received prior therapy or 5α-reductase inhibitors. Patients treated prior to 1998 were excluded because prostate biopsy at PSA levels <4.0 and normal DRE was not
Results
The median PSA for patients with PSA ≤2.5 was 2.0 (IQR: 1.4–2.3), and it was 3.5 (IQR: 3.1–3.7) for PSA 2.6–4.0 (Table 2). No significant differences between groups were observed in the demographic features, family history of pCA, prior negative prostate biopsy, number of positive and negative biopsy cores, or treatments received. No man had biopsy Gleason score 9–10. One patient (1.6%) with PSA ≤2.5 and five patients (2.5%) with PSA 2.6–4.0 had biopsy Gleason 8. The rate of cancer for those
Discussion
Screening for pCA is controversial; definitive evidence that mortality is reduced is lacking, although results from screening trials in Europe (using a PSA threshold of 3.0) and the United States (using a PSA threshold of 4.0) are anticipated soon. Even more controversial is the optimal PSA threshold at which to recommend prostate biopsy. PSA >2.5 is a widely accepted threshold for biopsy based on evidence that biologically significant cancers are detected at a more curable stage compared to a
Conclusions
Given the substantial incidence of pCA (and high-grade cancers) at PSA ≤2.5 but lack of tangible benefits associated with such an early diagnosis, physicians and patients are left to wonder when a prostate biopsy should be performed. For the individual patient, the significance of a PSA level should be interpreted in a broad clinical context, including age, life expectancy, ethnicity, family history, DRE, prostate size, results of prior prostate biopsy, PSA kinetics, and use of 5α-reductase
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