Die prognostische Relevanz eines initialen PSA-Anstiegs unterChemotherapie mit Docetaxel bei hormonrefraktäremProstatakarzinom

The hormone refractory stage of prostate cancer developes 18-36 months after medicinal or surgical treatment. An asymptomatic progress marked by PSA surges is appearing earlier than the disease progression with bone pain and anaemia. Until today, the treatment of HRPC, independent of the beginning, represents just a palliative option. At the moment the available treatment can only prolong the progress free period. Recently, two independent phase-III-studies provided evidence that docetaxel based chemotherapy significantly prolongs survival among men with hormone-refractory prostate cancer. Therefore, in 2004 docetaxel was approved for treatment of HRPC and is now the standard first-line therapy in many urological departments. The determination of the Serum PSA is regarded as a suitable tool for response evaluation during both local and systemic treatment of prostate cancer. In most cases the PSA level correlates with the tumour volume, and a 30% decrease or more of PSA during chemotherapy of HRPC has been associated with prolonged survival. Initial PSA surges are well known in androgen-deprivation therapy of advanced prostate cancer. This so called flare phenomenon has also been observed in HRPC patients treated with liposomal doxorubicin. Initial PSA increases in the range of 37-514% during the first 4-8 weeks could be observed. So far no study evaluated the clinical significance and prognostic relevance of these initial PSA surges in patients receiving doxorubicin. Until today we have also observed this flare phenomenon in a significant fraction of patients receiving docetaxel for treatment of HRPC. In this study the incidence and clinical impact of a flare phenomenon was evaluated, particularly with regard to the question if these reversible PSA increases might predict unfavourable prognosis Zusammenfassung 50 and should lead to an early discontinuation or change of treatment. Since 2002, 41 patients with HRPC were treated with a docetaxel based first-line regime at the university hospital in Marburg. A PSA flare phenomenon after 7 weeks could be identified for 5 patients (12,2%). A continuous PSA decline could be observed for 24 (58,5%) patients, complete therapeutic failure was recognized for 12 (29,2%) patients marked by an irreversible PSA surge. Kaplan-Meier- Survival analysis revealed that the mean survival for patients with a PSA flare phenomenon (group 3) was not different from primary responders (group 1) (p=0,434). In contrast, the mean survival of those patients who completely failed to respond to docetaxel (group 2) was noticeably shorter, so that the mean survival time of those patients (group 2, Progression) is statistically totally different to the mean survival of group 1 (Response) and group 3 (Flare) (p= 0,001 and 0,007). The pathophysiologic basis for the flare phenomenon remains elusive. One explanation might be that HRPC represents a malignant condition with immense intercellular heterogeneity concerning drug sensitivity, cell cycle kinetics and PSA expression. A different explanation could be the release of PSA from lytic tumour cells and thus might reflect a certain sensitivity of the tumour cells to the chemotherapy. The present study clearly indicates that patients showing an initial PSA flare phenomenon and patients with immediate biochemical response have about the same prognosis. Therefore, an initial rise of PSA should not result in early discontinuation of docetaxel based treatment; at least if there are no signs of disease progression.