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Keywords:

  • PSA;
  • doubling time;
  • treatment;
  • prostate;
  • benign disease;
  • cancer;
  • prediction;
  • outcome

Introduction

  1. Top of page
  2. Introduction
  3. General considerations
  4. BPH
  5. Physiological, inflammatory and iatrogenic effects
  6. Untreated prostate cancer
  7. Radical prostatectomy
  8. Radiation therapy
  9. Cryosurgical therapy
  10. Hormonal therapy
  11. Conclusions
  12. References
  13. Author

PSA is an invaluable marker in the diagnosis and surveillance of prostate cancer [1]. The ability of PSA to reflect the presence of underlying prostate tissue, particularly carcinoma, and its precise organ-specificity has revolutionized not only prostate cancer screening and detection, but also the surveillance of patients with prostate cancer after therapy, allowing a simple and sensitive method to assess the response of primary treatments such as surgery, radiation, or hormonal therapy [2].

Although static PSA measurements provide a sensitive measure of disease presence or recurrence, isolated PSA values have some limitations. For example, static PSA values alone cannot describe the behaviour or nature of the underlying disease. However, dynamic PSA values (e.g. doubling times or half-lives) may better reflect disease activity, particularly cancer regression or progression. Characterizing changes in PSA levels may provide a better understanding and even prediction of the clinical behaviour of benign and malignant prostate disease, and therein some insight into the natural history of such diseases. This review discusses the current understanding of PSA kinetics in untreated and treated patients with prostate cancer, and in patients with benign prostatic diseases.

General considerations

  1. Top of page
  2. Introduction
  3. General considerations
  4. BPH
  5. Physiological, inflammatory and iatrogenic effects
  6. Untreated prostate cancer
  7. Radical prostatectomy
  8. Radiation therapy
  9. Cryosurgical therapy
  10. Hormonal therapy
  11. Conclusions
  12. References
  13. Author

PSA is a 34-kDa glycoprotein initially characterized and purified by Wang in 1979 [3]. Although it is now known to exist in several isoforms and with variable binding properties, this review primarily focuses on total PSA measurements, which represent the most commonly used values in clinical practice.

PSA is produced by both benign and malignant prostate tissue with only negligible contributions from extraprostatic sources (e.g. periurethral glands) [4]. It is primarily metabolized by the liver, although patients with end-stage liver disease do not have elevated PSA levels or an impaired ability to metabolize this protein [5]. Indeed, no other known disease states are known to affect the serum half-life of PSA. The median (range) serum half-life of total PSA (free and bound forms) is 2.6 (2.0–3.1) days, with the free PSA fraction having a shorter half-life (1.5 h) than the bound fraction (3.0 days) [6].

Because PSA is produced by prostate tissue, attempts have been made to estimate the serum level of PSA per volume of underlying prostate tissue, i.e. to determine the PSA concentration of both benign and malignant tissue. The PSA concentration varies with age from ≈ 0.03 ng/mL in men < 60 years old to 0.05 ng/mL in men > 60 years old [7]. Corresponding measurements in malignant tissue are estimated to be at least 10-fold higher, but more accurate values for malignancy are not well characterized [8]. Because of the significant inconsistency among patients and the variability among grades of cancer, the use of PSA concentration as a diagnostic tool has remained limited.

For the terminology, most authors have chosen to use ‘doubling time’ to best reflect or characterize the increase in PSA level, terminology which is analogous to half-life measurements for decline or elimination kinetics. The doubling time can be simply defined as the time taken for the serum PSA level to double. Given this definition, shorter doubling times indicate a more rapid rise in PSA levels, and longer (i.e. higher) doubling times suggest a more indolent course. Because PSA changes over time tend to follow a log-linear relationship, the following formula may be used to obtain the doubling time [9].

  • image

where t is the time from the initial to the final PSA measurement. An alternative measurement to describe PSA changes is ‘PSA velocity’. This has been defined as the deviation or change in PSA relative to the elapsed time between measurements [10]. However, PSA velocity (i.e. change in PSA vs change in time) assumes a linear rate of PSA rise, and does not account for the logarithmic changes that are more characteristic of both the rise and elimination of serum PSA.

BPH

  1. Top of page
  2. Introduction
  3. General considerations
  4. BPH
  5. Physiological, inflammatory and iatrogenic effects
  6. Untreated prostate cancer
  7. Radical prostatectomy
  8. Radiation therapy
  9. Cryosurgical therapy
  10. Hormonal therapy
  11. Conclusions
  12. References
  13. Author

PSA is primarily produced by the epithelial cells of both benign and malignant prostate tissue. As the prostate enlarges with age, older men have larger prostates; accordingly, older men would have a higher serum PSA level. Several large studies have confirmed this by showing that serum PSA correlates with and increases with age in men with no prostate cancer, and the factor most responsible for this increase is a concomitant increase in prostate size, i.e. an increasing contribution of PSA-producing BPH tissue. In a study of Olmsted county residents with no prostate cancer, Oesterling et al.[7] reported that the median PSA of 40-year-old men was 0.8 ng/mL, compared with 80-year-old men whose median PSA level was 2.4 ng/mL. Furthermore, these authors showed that the expected increase in prostate size is 1.6%/year or 0.4–0.6 mL/year, depending on prostate size. Thus the PSA level would be expected to increase at ≈ 0.02 ng/mL/year. Extrapolating from the study of Oesterling et al., the expected PSA doubling time would be ≈ 25 years in patients with no prostate cancer.

Physiological, inflammatory and iatrogenic effects

  1. Top of page
  2. Introduction
  3. General considerations
  4. BPH
  5. Physiological, inflammatory and iatrogenic effects
  6. Untreated prostate cancer
  7. Radical prostatectomy
  8. Radiation therapy
  9. Cryosurgical therapy
  10. Hormonal therapy
  11. Conclusions
  12. References
  13. Author

Changes in PSA level may also occur as a result of infection, inflammation, instrumentation, or other benign diseases and physiological variations within the prostate. An appreciation of these effects on serum levels is important for the appropriate interpretation of PSA laboratory values by clinicians. The rise and elimination kinetics of PSA changes will also be discussed in these patients.

Infection and inflammation

The processes of infection and acute inflammation are known to increase serum PSA levels in men. Acute bacterial prostatitis may produce a 5–40-fold increase in baseline PSA values [11]. In a study of primates inoculated with pathogens to create acute bacterial prostatitis, Neal et al.[12] noted a 4–20-fold increase in PSA levels by 1 week after inoculation. Patients with chronically active prostatitis (bacterial) may likewise show concomitant elevations in PSA, but typically to a lesser degree [13,14]. The effects of chronically inactive prostatitis or subclinical inflammation on serum PSA levels are more controversial. Whereas some authors report a correlation between serum PSA levels and inflammation on prostate biopsy or TURP specimens, these effects are modest and do not appear to produce substantial elevations [15,16]. Others have found no correlation of subclinical prostatitis and serum PSA level [17,18].

When acute infection and inflammation produces a significant increase in serum PSA, the cause of this elevation appears to be the associated hypervascularity and disruption of prostate–blood barriers, and not the increased production of PSA by prostatic epithelial cells. In such patients, PSA levels can be expected to return to baseline values 6–8 weeks after the resolution of clinical symptoms.

Urinary retention

Urinary retention may also cause a significant increase in PSA levels, by up to a six-fold [19]. The relief of retention by urethral catheterization results in a relatively rapid decline to about half by 48 h after bladder drainage. There is a close association of urinary retention with prostatic micro-infarction, and it may be these associated micro-infarctions that produce the PSA increases during urinary retention [20,21].

Manipulation, instrumentation and surgery

Iatrogenic elevations in serum PSA occur and may result from manipulation, instrumentation or incision of the prostate gland. The effects of a DRE have perhaps been the most widely scrutinized. Many studies have shown that a routine DRE appear to have no significant effect on serum PSA levels [22–25]. Some authors have shown that although mild but statistically significant increases in PSA may occur in patients with high baseline levels, this typically alters the management strategies of such patients, as they require clinical attention to their baseline elevated PSA value. Those in whom the PSA level was normal did not have an abnormally high level after a DRE [26,27]. More aggressive manipulation of the prostate (i.e. prostatic massage) seems to increase PSA levels as early as 1 h afterward, with levels doubling from baseline [1,28]. Like the routine DRE, TRUS (with no biopsy), urethral catheterization and atraumatic cystoscopy do not significantly alter serum PSA levels [25,29,30].

However, procedures which incise or excise the prostate produce rapid and significant increases in serum PSA values [1,25,30–33]. Prostatic needle biopsies may produce a 4–57-fold increase in PSA level. The rise is almost immediate, with a six-fold increase by 5 min after biopsy. The median time to return to baseline is ≈ 2 weeks, with some patients requiring > 4 weeks before levels are normal [30]. Therefore, it is recommended to wait at least 6 weeks after biopsy before re-checking the serum PSA level. TURP produces a similar rapid and significant increase in PSA level as after biopsy, and a similar duration for the return to baseline [1,30].

Ejaculation, physical activity and stress

Some physiological processes may also affect baseline PSA values. Although some authors have shown no significant effect of ejaculation on PSA level [22,24,34], Tchetgen et al.[35] reported a mild increase in PSA of 0.4 ng/mL at 1 h after ejaculation, which decreased to 0.1 ng/mL by 6 h and returned to baseline by 24 h. Hospitalization may also have an effect on baseline PSA values, with hospitalized patients having a lower serum PSA level than the values before hospitalization [1,36]. To evaluate the possible role of inactivity on PSA levels, Leventhal et al.[36] assessed patients admitted to a coronary care unit after possible myocardial infarction. They noted no change in PSA levels by 6 h after exercise in these patients. However, they confirmed the findings of Stamey et al.[1], in that the hospitalized patients had an overall 30% lower PSA value than their subsequent levels one month after discharge [36]. Leventhal et al. suggested that physiological stress during hospitalization might lower baseline PSA levels.

An understanding of the possible effects of these physiological, pathological and iatrogenic processes on serum PSA levels, and the associated kinetics, must be considered when interpreting PSA values. When PSA levels do not follow this expected course and remain high then further evaluation should be considered, including possible biopsy.

Untreated prostate cancer

  1. Top of page
  2. Introduction
  3. General considerations
  4. BPH
  5. Physiological, inflammatory and iatrogenic effects
  6. Untreated prostate cancer
  7. Radical prostatectomy
  8. Radiation therapy
  9. Cryosurgical therapy
  10. Hormonal therapy
  11. Conclusions
  12. References
  13. Author

In 1991, Schmid et al.[37] reported PSA doubling times in men with untreated prostate cancer, stratifying the doubling times based on the stage of disease. This important study helped to define the natural history of PSA changes in the untreated patient, and thereby provided some insight into the behaviour of untreated prostate cancer. Schmid et al. showed that PSA doubling times correlate with the stage of disease, i.e. patients with localized cancers had significantly longer doubling times (2–4 years or longer) than had patients with advanced or metastatic disease (< 9 months; Table 1). Recent studies confirmed the relatively indolent course in patients with localized disease, but emphasized the wide variation of doubling times in untreated patients with clinically localized disease (15–994 months) [38]. There appears to be a ‘rapid-riser’ subset amongst these patients, characterized by shorter doubling times and a more rapid clinical stage progression [39]. The doubling time in these patients did not correlate with the initial clinical stage or grade, thereby making the prospective identification of this ‘rapid riser’ subset difficult.

Table 1.  PSA doubling times in different conditions
ConditionMedian doubling time (years) Comment
No cancer/BPH25Contribution of PSA-producing BPH tissue which increases with age
Cancer
 Untreated
 T1–2a> 4}‘Rapid-riser’ subset with shorter doubling times (difficult to identify)
 T2b-2c2–4}
 T3–4, N+, M+< 1Rapid doubling time, predicts progression to metastatic disease
Treatment failures
 Surgery0.75Predicted by grade, nodes, extracapsular extension
 Radiation0.75Predicted by pretreatment PSA level, stage, grade
 Cryotherapy0.67Treatment successes may have slow PSA rise secondary to residual benign glands
Hormones
 Localized0.63}Neoadjuvant therapy may cause more rapid doubling time in surgical failures
 Metastatic0.2}

The determination of PSA doubling times has important implications for the subsequent clinical course of the disease. Intuitively, a shorter PSA doubling would suggest a more rapidly progressive cancer. This association was confirmed by Carter et al.[10], who showed that a rapid PSA rise was indeed associated with the development of metastatic disease in patients with untreated prostate cancer.

Radical prostatectomy

  1. Top of page
  2. Introduction
  3. General considerations
  4. BPH
  5. Physiological, inflammatory and iatrogenic effects
  6. Untreated prostate cancer
  7. Radical prostatectomy
  8. Radiation therapy
  9. Cryosurgical therapy
  10. Hormonal therapy
  11. Conclusions
  12. References
  13. Author

After a radical prostatectomy, PSA levels are expected to fall to undetectable levels. Even with current commercially available ultrasensitive assays, the contribution from the periurethral glands or other tissues can be considered negligible. The time to elimination of all PSA present before treatment depends on the initial PSA level and the expected half-life of 2.6 days. In most patients the PSA level after prostatectomy should reach undetectable levels by 6 weeks and failure to do so may reflect residual disease. Similarly, any subsequent rise in PSA into the detectable range should be considered to reflect residual or recurrent disease.

The subsequent kinetics of PSA recurrences after surgery has recently been studied and may provide some insight into to the behaviour of recurrent tumour. The median PSA doubling time of patients in whom radical prostatectomy has failed is 9 months, a value comparable with that in patients with untreated metastatic disease [9]. Factors predictive of a shorter doubling time include the Gleason grade of the primary tumour, lymph node involvement and extent of capsular penetration in the surgical specimen. Interestingly, seminal vesicle involvement and positive margins do not correlate with a more rapid postoperative doubling time.

Like their untreated counterparts, patients with a rapid PSA doubling time after surgery appear to have a more ominous clinical course. Patel et al.[40] showed that a shorter doubling time after surgery predicts a more rapid progression to metastatic disease. Such findings again suggest that the doubling time reflects the biological and clinical aggressiveness of the disease.

Whereas the doubling time predicts clinical recurrence and progression, it does not correlate with biochemical recurrence, i.e. the time to a detectable PSA level after surgery [9,40,41]. This lack of correlation may be explained by the finding that the doubling time and biochemical recurrence time are each predicted by different biological variables. Whereas the doubling time is predicted by grade, capsular penetration, lymph node involvement (i.e. factors suggestive of aggressive primary disease), the time to biochemical recurrence is primarily predicted by positive surgical margins (i.e. the presence and extent of disease after surgery) [9]. Thus early biochemical recurrences reflect the extent of residual disease and not the aggressiveness of that recurrent disease. These findings suggest that early biochemical recurrences are not necessarily aggressive, as characterized by a rapid doubling time and early clinical progression.

Radiation therapy

  1. Top of page
  2. Introduction
  3. General considerations
  4. BPH
  5. Physiological, inflammatory and iatrogenic effects
  6. Untreated prostate cancer
  7. Radical prostatectomy
  8. Radiation therapy
  9. Cryosurgical therapy
  10. Hormonal therapy
  11. Conclusions
  12. References
  13. Author

Radiation therapy for clinically localized prostate cancer remains a common and effective treatment. After completing EBRT, PSA levels begin to decline at ≈ 3 weeks, reaching a nadir at a median of 15 months after therapy. The median half-life of serum PSA after radiation is 1.6–2.5 months [42,43]. There appears to be some variability based on the stage and grade of the primary tumour. Some authors have suggested that slower rates of PSA decline (i.e. a longer half-life) are correlated with higher-grade cancers, and that these patients are at an increased risk of treatment failure [44]. However, others have reported no correlation between the half-life and stage, grade or ultimate clinical response (i.e. local or distant failure rates) [42,43]. While the rate of decline is seemingly unimportant, the ultimate nadir value has prognostic significance; values of < 0.5 ng/mL have the highest 5-year biochemical control rates [43].

After radiation, biochemical failure is now defined as a PSA rise on two consecutive occasions to a level of > 1 ng/mL, or as a PSA rise on three consecutive occasions at any level. The subsequent PSA kinetics after biochemical failure have been described by Stamey et al.[45], who showed that patients failing radiation therapy are characterized by rapid PSA doubling times. At a mean follow-up of 5 years after treatment, the median doubling times of those in whom it failed were 14 months (stage T1N0), 15 months (stage T2), and 7 months (stage T3). In addition patients with N+ disease had a median doubling time of 8 months. When compared with their untreated counterparts (discussed above), Stamey et al. suggested that these patients in whom radiotherapy had failed may have fared better if untreated. Since that initial report, several other series have similarly shown that patients in whom radiation therapy fails have a median PSA doubling time of 9–12 months [43,46,47].

The factors predicting a rapid PSA doubling time after failure include the initial PSA level, and the stage and grade of the primary tumour. Furthermore, as seen in those failing after surgery, a rapid doubling time after radiation correlates with a shorter time to clinical failure and a more rapid progression to metastatic disease [43,46,48,49]. According to Zagars et al.[43], the most ominous predictors were a rapid doubling time (< 7 months) and those in whom disease also recurred within the first year. These findings suggest that a rapid time to biochemical recurrence correlates with a shorter PSA doubling time and a more rapid, progressive clinical course. This is in contrast to the lack of correlation of biochemical recurrence and doubling time seen in surgical failures.

There are few specific data on the PSA kinetics after brachytherapy. Ianuzzi et al.[50] reported that in patients receiving 125I-seed implants for localized prostate cancer, the most significant decline occurred within the first year, and a more gradual decline at 12–24 months; after 24 months there was little change. In their series, those patients who reached a nadir after 1 year (i.e. a longer half-life) had a significantly lower risk of treatment failure. There is little other information about PSA kinetics in patients who fail brachytherapy.

Cryosurgical therapy

  1. Top of page
  2. Introduction
  3. General considerations
  4. BPH
  5. Physiological, inflammatory and iatrogenic effects
  6. Untreated prostate cancer
  7. Radical prostatectomy
  8. Radiation therapy
  9. Cryosurgical therapy
  10. Hormonal therapy
  11. Conclusions
  12. References
  13. Author

Cryosurgical ablation of the prostate has been advocated by some as a primary treatment for localized prostate cancer. Because of the relative novelty of this treatment, the follow-up of treated patients remains limited, and long-term success rates are unknown. After an initial PSA elevation immediately after cryotherapy (as PSA is released from the destroyed epithelial cells), PSA values begin to decline, reaching a prognostically significant nadir by 3 months after treatment. PSA values begin to decrease according to the expected serum half-life of 2.6 days. As a result, a true nadir may be reached as early as 6 weeks, and certainly by 3 months, after treatment. Patients with a PSA nadir value of < 0.5 ng/mL as early as 3 months after therapy had a more favourable outcome than those whose nadir was > 0.5 ng/mL. This threshold of 0.5 ng/mL was more significant and predictive at 12 months after therapy [51,52].

Patients who have no detectable disease (as shown by prostate biopsy) tend to be characterized by a low nadir PSA (< 0.5 ng/mL), which is stable or slowly increases with time; the median rate of rise is < 0.1 ng/mL/year after one year. Patients with persistent or recurrent disease have a higher PSA nadir as early as 3 months after treatment, and are characterized by a more rapid subsequent rise in PSA level. The extrapolated PSA doubling time of patients failing cryosurgical ablation is 8 months [52].

Hormonal therapy

  1. Top of page
  2. Introduction
  3. General considerations
  4. BPH
  5. Physiological, inflammatory and iatrogenic effects
  6. Untreated prostate cancer
  7. Radical prostatectomy
  8. Radiation therapy
  9. Cryosurgical therapy
  10. Hormonal therapy
  11. Conclusions
  12. References
  13. Author

Androgen-deprivation therapy has remained the mainstay for treating prostate cancer, as both a primary, adjuvant and neoadjuvant mode of treatment. After androgen deprivation, most patients have a decline in and then stabilization of PSA level for varying intervals. According to Fowler et al.[53], the median half-life of the PSA decline after initiating hormonal therapy was 8.7 days for patients with metastatic disease and 10.5 days for those with localized disease, with most patients reaching a nadir of < 1 ng/mL.

As previously discussed with surgery and radiation, patients in whom hormonal therapy fails have different PSA kinetics. In the study by Fowler et al., those with localized disease had a PSA doubling time of 7.5 months after failure, compared with patients with metastatic disease who had a PSA doubling time of 2.5 months after becoming androgen-independent [53].

Neoadjuvant hormonal therapy may have a deleterious effect on the kinetics of PSA recurrence after radical prostatectomy. Rabbani et al.[54] recently reported that in patients with recurrent disease after radical prostatectomy, those who received neoadjuvant androgen-deprivation therapy had a significantly shorter doubling time (6 months) than those with recurrence after surgery alone (9 months).

Conclusions

  1. Top of page
  2. Introduction
  3. General considerations
  4. BPH
  5. Physiological, inflammatory and iatrogenic effects
  6. Untreated prostate cancer
  7. Radical prostatectomy
  8. Radiation therapy
  9. Cryosurgical therapy
  10. Hormonal therapy
  11. Conclusions
  12. References
  13. Author

PSA levels can now be interpreted not simply as the static value reflecting the presence or absence of underlying cancer, but as a dynamic indicator of underlying disease activity. By better understanding and characterizing the variables which affect PSA kinetics, the natural history of benign prostate diseases and of treated and untreated prostate cancer may be determined. This kinetic approach to PSA interpretation allows a better prediction of the subsequent behaviour of primary and recurrent prostate disease. Such understanding has important current and future implications on the selection and timing of adjuvant therapies, if any, for primary and recurrent disease.

References

  1. Top of page
  2. Introduction
  3. General considerations
  4. BPH
  5. Physiological, inflammatory and iatrogenic effects
  6. Untreated prostate cancer
  7. Radical prostatectomy
  8. Radiation therapy
  9. Cryosurgical therapy
  10. Hormonal therapy
  11. Conclusions
  12. References
  13. Author
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Author

  1. Top of page
  2. Introduction
  3. General considerations
  4. BPH
  5. Physiological, inflammatory and iatrogenic effects
  6. Untreated prostate cancer
  7. Radical prostatectomy
  8. Radiation therapy
  9. Cryosurgical therapy
  10. Hormonal therapy
  11. Conclusions
  12. References
  13. Author

R.S. Pruthi, MD, Assistant Professor of Surgery, Division of Urology, University of North Carolina, 427 Burnett-Womack Bldg., CB#7235, Chapel Hill, NC, 27599–7235, USA.