Impact of PSA flare-up in patients with hormone-refractory prostate cancer undergoing chemotherapy.

Objectives: The intention of this study is to describe the impact and underlying potential basis of the prostate-specific antigen (PSA) flare-up phenomenon in patients with hormone-refractory prostate cancer (HRPC) treated with docetaxel-based chemotherapy.

Methods: We retrospectively identified 74 consecutive patients who received docetaxel/estramustine-based chemotherapy at our institution. Patients were evaluated based on modified criteria from the Prostate-Specific Antigen Working Group regarding survival and toxicity. Additionally, two androgen receptor mutations derived from patients with advanced disease were analyzed for promiscuous transactivation activity.

Results: The 74 patients were stratified into four groups: response, partial response, flare-up-initial PSA elevation, and progression. Median survival in the flare-up group (n=8) was 20 months and did not differ from the response group (p=0.564). The flare-up group showed a maximum PSA elevation from baseline between 3.4 and 28.3% (between three and six weeks) followed by PSA decline >or=50% from the baseline level in seven of the eight patients. The androgen receptor mutations AR(877) and AR(715) displayed a 37.5- and 5.2-fold increase in transactivation activity by progesterone and a 12.6- and 5.4-fold increase by estrogen compared to the AR(WT), respectively.

Conclusions: A considerable portion of HRPC patients experience an initial PSA flare-up under systemic chemotherapy. In this study, occurrence of flare-up phenomenon did not impact survival. Chemotherapy should be continued a minimum of six weeks before removing patients from a docetaxel-based regimen. We showed evidence that co-medication with dexamethasone/prednisolone and/or estramustine itself can induce an initial PSA flare-up via androgen receptor mutations.