PSA in the era of biologic and targeted therapy

A wealth of data establishes PSA as a marker of tumor aggressiveness, tumor stage, drug response and survival. Controversy and concern persists regarding PSA's role as a marker of disease stabilization and response induced by cytostatic and immunotherapies when compared to cytolytic therapies. An evaluation of the difficulties surrounding PSA interpretation has been addressed [42].

Two vaccine trials, Sipuleucel-T (Provenge) [43, 44, 45] and the TRICOM PROSTVAC [46, 47] demonstrated a significant overall survival benefit without any consistent decline in PSA, raising questions about the value of PSA response for non-hormonal, non-cytotoxic therapies. In addition, wide fluctuations have been observed in PSA values due to a transient effect of some drugs on PSA production seemingly independent of cell proliferation. The independent, non-proliferative effect of drugs on PSA expression should be considered when interpreting PSA response data. These aberrant PSA effects must be considered together with imaging results and clinical evaluation of the patient. Nevertheless, it has been consistent that post therapy a >50% PSA decline in pre-treatment PSA carries a significant overall survival advantage [48, 35].

Kelly [48] reported on 110 assessable patients treated on seven sequential protocols at Memorial Sloan-Kettering Cancer Center for hormone-refractory prostate cancer a statistically significant survival advantage in 110 patients with >50% PSA decline (>25 months survival) versus those without a 50% PSA decline (8.6 months survival). These results suggest that post therapy PSA declines can be used as a surrogate end point to evaluate new agents in hormone-refractory prostate cancer and criteria for response need prospective validation for phase III trials. Smith et al. [49] showed that a PSA decline > 50% for at least 8 weeks resulted in a longer mean survival time of 91 weeks versus 38 weeks for patients showing a smaller PSA reduction. An improved PSA response was associated with prolonged survival in the TAX 327 study (Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer), with a median survival of 33 months when the PSA was normalized (<4 ng/mL) versus 15.8 months for an abnormal PSA [50, 51].

Heidenreich [52], the chair of the European Association of Urology oversaw the EAU 2012 Prostate Cancer Guidelines. He acknowledged that the PSA has been validated to be the most clinically useful tumor marker of treatment failure following local therapy and of tumor response as well as of tumor progression following hormonal treatment.

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