Prostate news article, August 2006
| PROSTATE
SPECIFIC ANTIGEN (PSA) KINETICS AND THE DIAGNOSIS OF CLINICALLY SIGNIFICANT PROSTATE CANCER
Professor Roger S Kirby Visiting Professor to St George's Hospital, London |
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Although prostate cancer is one of the most prevalent malignancies it is also one of the most puzzling diseases to affect men beyond middle age. While some sufferers present with advanced disease, which progresses rapidly after a brief response to hormonal therapy; others are detected at an early stage, often on the basis of prostate specific antigen (PSA) testing, when the disease may in fact pose little threat to the individual within his natural life span. Annually almost 10,000 men die of prostate cancer in the UK, but this toll must be set against the more than 30,000 new cases are diagnosed each year. This 3:1 ratio of diagnosis to death poses central dilemma that faces those of us interested in this disease: namely how to distinguish the dangerous “tiger” cancers from the harmless “pussy cats” that may in fact need no active treatment?
Recently some progress has been made in this important clinical area. However, it has to be remembered that predicting the future is always a risky business; informing men that they have a cancer which is unlikely to progress, when the opposite eventually turns out to be the case, leaves the door wide open to unhappiness and even litigation. In cancer prognostication, the stakes are high.
It is now increasingly accepted that a one-off PSA measurement is of only limited value both diagnostically and in terms of prognosis. When the PSA is only modestly elevated above the generally accepted cut-point of 4.0 ng/ml, the increase is most commonly due to benign prostatic hyperplasia (BPH), which is present in more than 43% of men beyond 60 years of age. This is because BPH is characterised by epithelial hyperplasia, and it is precisely the prostatic epithelium that elaborates and secretes PSA. In the absence of cancer the PSA value turns out to be quite an accurate surrogate for prostate volume (1). BPH only develops slowly, so the PSA value in the men affected remains elevated but relatively stable. By contrast, the more aggressive prostate cancers, which are the ones we really need to treat, exhibit a rapid, almost exponential, rise in so-called PSA velocity (PSAV) and PSA doubling time (PSADT). PSA kinetics (ie change over time) therefore may provide the clue as to which prostate cancers are potentially dangerous.
A role for PSAV in the detection of clinically significant prostate cancer was first investigated by Carter et al. in a small case-controlled study using prospective data from the Baltimore study of ageing (2). Serial PSA measurements were analysed over a 25-year period in 20 men with BPH, 18 with prostate cancer and 16 men with no prostate disease (controls). Significantly, PSAV differed significantly at 5 to 10 years before the diagnosis of prostate cancer. With a PSAV >0.75ng/ml/yr, detection occurred at a median of 2.6 years prior to the diagnosis of prostate cancer in 72% of cases, showing higher accuracy with PSA<4.0ng/ml increasing the specificity from 60% to 90%.
Subsequently the same group applied the concept of PSAV to men with PSA levels of 2.0-4.0 ng/ml. In this small study they noted a significant difference in PSAV between benign (median 0.12ng/ml/yr) and malignant (median 0.24ng/ml/yr) cases. The increased relative risk of having prostate cancer for a PSAV of >0.1 was 6.53 (3). Lynn et al. examined the effect of short-term PSAV prior to prostate biopsy over a mean interval of 2.2 months. Recently, the largest study on PSAV has been undertaken by Berger et al. who performed a retrospective analysis of PSAV in 2815 men (353 cancer cases, 2462 benign cases) over a ten year study period. This team clearly demonstrated that in a screened population PSAV differs in men with cancer compared with those with no cancer (0.409 ng/ml/yr versus 0.03 ng/ml/yr) (4). They suggested that a PSAV value of 0.75ng/ml/yr may be too high in patients with PSA levels between 4.0ng/ml and10.0ng/ml, thereby risking missing significant cancers with lower PSA increases.
PSA kinetics following surgery or radiotherapy
PSAV may also be of use as a prognostic marker in patients after treatment for their prostate cancer. D’Amico et al. studied 1095 men with localised prostate cancer and assessed PSAV in the year before diagnosis and subsequent radical prostatectomy. They commented that a high pre-operative PSAV was associated with lymph node metastases, worse pathological stage and grade (5). Sengupta et al. performed the largest study to date into pre-operative PSA kinetics with over 2200 men analysed. These results concurred with D’Amico et al. They noted that PSAV was a useful predictor of post-operative outcome and eventual death from prostate cancer (6). Pound et al. performed a retrospective study of 1997 men after radical prostatectomy. Multivariate analysis revealed that a PSA doubling time (PSADT) of less than 10 months was independently associated with the development of distant metastases (7). Similar correlations have been noted in the setting of external beam radiotherapy (EBRT). Zagars et al. found a PSADT <8months had a 7-year actuarial metastatic rate of 54%, while patients with a PSADT >8months had only a 7% metastatic rate (8). Furthermore, patients who had a rapid PSADT and a rising PSA within the first year after radiotherapy had a 50% chance of developing metastases by 3 years. Using two multi-institutional databases totalling 8,669 prostate cancer patients, D’Amico et al. reported a significant correlation between post-failure PSADT ≤3months and prostate cancer-specific death within 6 years with a hazard ratio of 19.6 compared with patients with a more protracted PSADT (9). In fact D’Amico reported it to be a surrogate end point for prostate cancer specific mortality. This held true for patients treated with either radiotherapy or radical prostatectomy.
Conclusion
A test for prostate cancer that distinguishes clinically significant tumours from latent cancers and BPH is urgently needed. Rather than using a one-off PSA threshold to detect prostate cancer, a PSAV or PSADT may provide significant advantages. While the evidence is not conclusive, results so far suggest that PSA kinetics may be helpful in prostate cancer prognostication and also allow earlier detection of the very cancers that most require active treatment by either surgery or radiotherapy.
References
1. Roehrborn CG, Boyle P, Gould AL, et al: Serum prostate-specific antigen as a predictor of prostate volume in men with benign prostatic hyperplasia. Urology 1999;53:581--589.
2. Carter H, Pearson J, Metter E. Longitudinal evaluation of prostate-specific antigen in men with and without prostate disease. JAMA 1992: 267(16):2215-2220.
3. Fang J, Metter E, Landis P, Carter H. PSA velocity for assessing prostate cancer risk in men with PSA levels between 2.0 and 4.0ng/ml. Urology 2002: 59(6):889-893.
4. Berger A, et al. Longitudinal PSA changes in men with and without prostate cancer: assessment of prostate cancer risk. Prostate 2005: 64(3):240-245.
5. D'Amico A, Chen M, Roehl K, et al. Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Eng J Med 2004: 351:125.
6. Sengupta S, Myers R, Slezak J, et al. Preoperative prostate specific antigen doubling time and velocity are strong and independent predictors of outcomes following radical prostatectomy. J Urol 2005: 174:2191-2196.
7.Pound C, Partin A, Eisenberger M. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999: 281:1591-1597.
8. Zagars G, Pollock A. Kinetics of serum prostate-specific antigen after external beam radiation for clinically localized prostate cancer. Radiother Oncol 1997: 44:213-221.
9. D'Amico A, Moul J, Carroll P, et al. Prostate specific antigen doubling time as a surrogate end point for prostate cancer specific mortality following radical prostatectomy or radiation therapy. J Urol 2004: 172:S42-S47.