Prostate news article, August 2004
| PSA TESTING
FOR THE EARLY DETECTION OF PROSTATE CANCER
Professor Roger S Kirby St George's Hospital. London |
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The value of serum prostate specific antigen (PSA) testing for the early detection of prostate cancer has been one of the most contentious issues in medicine for more than a decade. A recent publication by Dr Ian Thompson reporting that a substantial number of men harbour adenocarcinoma in spite of having a PSA value <4.0 ng/ml has further fuelled this ongoing controversy. Using the placebo arm of a randomised study of the use of finasteride to prevent the development of prostate cancer as the study group these investigators found that 15.2% of these 2950 men were found to harbour prostate tumours, 14.9% of which had a Gleason score of 7 or higher. The relationship between the PSA value and the risk of adenocarcinoma appears to hold, and those with higher PSA values appear to have a greater risk of higher grade cancers, although there is considerable overlap in the distributions among grades. A small but significant number of patients however had higher grade cancers even though their PSA value was extremely low.
What are the implications of these rather unexpected findings? The current practice of reassuring men whose PSA is below 4.0 ng/ml that they are unlikely to harbour prostate cancer no longer appears justified. The initial reaction to these new data might be to advocate an across the board reduction in the PSA cut-off point which indicates prostate biopsy to 2.5 ng/ml. Although this manoeuvre would undoubtedly increase the detection of prostate cancer, it would also heighten the risk of detection of clinically insignificant tumours. Furthermore, even a cut-off point of 2.5 ng/ml would risk missing detection in a number of patients who turn out to have prostate cancer in spite of having a PSA of < 2.5 ng/ml.
One of the central problems in advising patients with prostate cancer is the lack of firm evidence about the effectiveness of the various treatment options. In this respect two important data have recently been reported. Firstly Holmberg et al have confirmed that radical prostatectomy reduces the risk of development of metastases by around 50% (fig 1). Secondly, Johansson and colleagues from Sweden have reported that patients with prostate cancer who are managed by watchful waiting have a substantial mortality from cancer even as long as 15-20 years after the initial diagnosis. The prostate cancer mortality rate increases from 15 per 1000 person-years during the first 15 years to 44 per 1000 person years beyond 15 years of follow-up. Clearly many these deaths, and the morbidity that preceded them, could most likely have been averted by judicious earlier intervention. These new data make a stronger case for more aggressive interventions in prostate cancer patients with longer life expectancies.
So how are we to advise men concerned that they may be suffering from localised prostate cancer and who wish to avoid developing advanced disease in the future? First and foremost, the uncertainties about prostate cancer diagnosis and treatment need to be clearly explained. Second that PSA, while remaining a useful, but imperfect, predictor of prostate cancer (the higher the PSA, the greater the risk that prostate cancer may be present), cannot completely exclude clinically significant prostate cancer. Currently, transrectal ultrasound-guided biopsy of the prostate is the only reliable way to accomplish this. Third, even if cancer is diagnosed, not every patient requires treatment. Active surveillance should certainly be discussed as an option in patients with lower Gleason scores and smaller volume tumours, before more aggressive treatment options are pursued.
Fortunately, just as the shine appears to be fading on PSA as a tumour marker, at least in terms of its ability to rule out prostate cancer, other alternatives are appearing on the horizon. For example DD3PCA3 is the most prostate cancer-specific gene described to date. A quantitative RT-PCR analysis has been developed. Prostate tumours showed a 66 fold up-regulation of DD3PCA3 when compared with benign prostatic tissue. This up-regulation was found in more than 95% of prostate cancer specimens studied. Therefore this DD3PCA3 - based RT-PCR assay was used for the identification of prostate cancer in urine sediments obtained after prostatic massage. In a group of 108 men with a PSA value of > 3.0 ng/ml 24 were shown to have prostate cancer on biopsy. Of these 24 men, 16 were shown to be positive for DD3PCA3. Furthermore, a negative value of 90% was calculated. This new test appears at this stage to have the potential to improve the accuracy of diagnosis and thus reduce significantly the number of unnecessary prostate biopsies required to diagnosis this most common cancer of men.