Medical management


Two pharmacologic methods have been used to address high PSA. The oldest, administration of antibiotics, is enticing in its simplicity. However, studies have failed to show that empiric treatment can decrease the need for biopsy, and there remains concern that men whose PSA levels decrease might receive false reassurance of benignity. Finally, antibiotics are associated with some cost and risk, including the risk of bacterial resistance, so the practice is strongly discouraged. 50, 51, 52, 53, 54

By contrast, there has been substantial interest in administration of 5-alpha reductase inhibitors (5-ARI), including finasteride and dutasteride, to improve cancer detection as well as to reduce the risk of being diagnosed with low-risk PCa that might be better left unknown. The positive biopsy rate has been shown to be reduced by almost 25% for both finasteride (in the primary prevention setting) and dutasteride (in patients following an initial negative biopsy that showed no HGPIN and no atypia). 



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Initial studies suggested that PSA levels decrease by approximately 40-50% when these medications are given for at least six months in men without PCa, and that failure to reach these levels should increase the index of suspicion for undiagnosed PCa. Although this appears to be the case with finasteride, it did not reflect cancer risk in the Reduction by Dutasteride of Prostate Cancer Events trial. 55 Furthermore, the use of both 5-ARI’s has been shown to reduce the likelihood men will undergo biopsy. 56 Caution is worthwhile in considering a “5-ARI challenge” as part of the diagnostic evaluation based on limited validation.

A rise of 0.3 ng/mL or more in men taking finasteride may be a better indicator of prostate cancer, 57 but any rise in PSA levels should lead to further evaluation in men taking dutasteride, according to the manufacturer’s application to the FDA for an indication for PCa risk reduction (unpublished data). Whether this necessitates immediate repeat biopsy has not been demonstrated, and the author believes this would not be a valid singular criterion for repeat biopsy in the absence of other risk features as discussed herein.

Emerging options

A number of new technologies are in development to assist in the identification of unrecognized PCa following initial biopsy. A full discussion is beyond the scope of this report, but one that deserves mention is PCA3, a novel PCa-specific gene that was shown to be strongly over-expressed in more than 95% of PCa tumors.

It is measured in urine obtained following an “attentive DRE” and is FDA approved for identification of PCa in men with elevated PSA following a negative biopsy. Values occur on a continuum of PCa risk, but using a predefined cutoff level of 35, an abnormal reading indicates a high likelihood of having a positive repeat biopsy. A number of other urine-based markers are under investigation and some combination is likely to play a role in the decision to biopsy in the future.


Summary


The first step in managing a patient after negative biopsy is to determine whether the biopsy was truly negative, i.e., no HGPIN or ASAP. If so, the threshold to repeat biopsy should be low if features such as very low percent-free PSA, multifocal HGPIN, or ASAP are present. PCA3 and a number of nomograms can further define relative risk of PCa, but they do not lead to an easy definition of when a repeat biopsy is indicated.

Importantly, all singular parameters are unable to make the decision to perform a repeat biopsy. Thus, the clinician must consider as much information as necessary to make the decision, acknowledging to the patient that no decision tool developed to date can clarify which patient merits a repeat biopsy, so clinical judgment will inevitably play a role in this decision for the foreseeable future. For many patients with persistent suspicious findings as described in this piece, PCa is not ruled out until a repeat biopsy is obtained. 


When that decision leads to repeat biopsy, we use a 20-core transrectal saturation biopsy in the office setting under periprosatic block, especially if the patient has undergone more than one prior biopsy, although most centers continue to use 12-14 core templates.

Our preference for the former is based on higher cancer detection rates without incurring additional cost or demonstrable risk. MRI and template biopsies are promising but have not been validated to date. Medical management with antibiotics should be limited to the setting of infection, but 5-ARI medications may improve cancer detection: malignancy is suggested if the medications fail to result in a 40%-50% decrease in PSA, or if the PSA rises substantially during 
their administration.


Finally, patients with atypia have an almost automatic indication for a repeat biopsy. Patients with HGPIN merit delayed interval biopsy approximately every three years if healthy enough to justify treating PCa. Otherwise, it is uncommon that patients without these pathological findings would benefit from more than two total biopsies in the absence of major change in PSA or DRE findings.

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