Article

Chemotherapie des hormonrefraktären Prostatakarzinoms

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  • Paracelsus Kliniken Düsseldorf Germany
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Abstract

Die lange Zeit herrschende Skepsis bezüglich einer Chemotherapie des hormonrefraktären Prostatakarzinoms (HRPC) ist einer Welle von Enthusiasmus gewichen. In Phase-II-Studien mit taxanhaltigen Kombinationstherapien konnten zum Teil hohe Ansprechraten erzielt werden. Von einer Resistenz des HRPC gegenüber Chemotherapie kann also nicht mehr länger die Rede sein. Es bleibt abzuwarten, inwieweit die Kombinationen auch einen Überlebensvorteil haben. Dies wird derzeit in Phase-III-Studien überprüft. An eine palliative Chemotherapie sollte bei Patienten mit HRPC vor allem dann gedacht werden, wenn die initiale Hormontherapie nur kurz gewirkt hat und bereits mehrere Hormontherapien durchlaufen wurden [39]. Die Chemotherapie ist jedoch bislang noch keine Standardtherapie des HRPC. Patienten sollten daher möglichst in klinische Studien eingebracht werden.

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Article
Die derzeitige Therapie des HRPCA stellt unabhängig vom zeitlichen Beginn allenfalls eine palliative Option dar. Mit den zur Verfügung stehenden Behandlungsmöglichkeiten ist zurzeit nur eine Verlängerung des progressfreien Zeitraums möglich. Durch zwei unabhängige Phase-III-Studien konnte überzeugend nachgewiesen werden, dass eine Chemotherapie mit Docetaxel die Überlebenszeit von Patienten mit HRPCA verlängern kann. Seit 2004 ist Docetaxel zur Therapie des HRPCA zugelassen und bildet gegenwärtig das Standardtherapieschema.Temporäre initiale PSA-Erhöhungen sind bereits bei der Androgendeprivation im fortgeschrittenen Stadium beobachtet worden. Dieses so genannte „Flare-up-Phänomen“ konnte auch bei Patienten mit HRPCA, die mit liposomalem Doxorubicin behandelt wurden, beobachtet werden. PSA-Anstiege von 37-514% in den ersten vier bis acht Wochen der Therapie wurden erfasst. Über deren prognostische Relevanz ist jedoch bisher noch keine Aussage gemacht worden. Ein PSA-Flare-up-Phänomen wurde auch klinisch bei einem Teil der Patienten mit HRPCA, die mit Docetaxel behandelt werden, beobachtet.Seit 2002 wurden 41 Patienten im hormonrefraktären Stadium mit einem Docetaxel-Therapieschema am Universitätsklinikum Marburg behandelt. Bei fünf (12,2%) Fällen konnte ein Flare-up-Phänomen nach sieben Wochen identifiziert werden. Bei 24 (58,5%) Patienten war ein kontinuierlicher PSA-Abfall zu beobachten, 12 (29,2%) zeigten eine kontinuierliche Progression in Form von nichtreversiblen PSA-Anstiegen. Die durchgeführte Kaplan-Meier-Analyse ergab keine Unterschiede zwischen den Überlebenszeiten der Patienten mit initialem PSA-Flare-up (Gruppe 3, Flare) und den Patienten der Gruppe, die schon zu Anfang mit einem PSA-Abfall reagiert hatten (Gruppe1, Response) (p=0,434). Bei der Patientengruppe, die nicht auf die Therapie reagierte (Gruppe 2, Progression), wurden deutlich kürzere Überlebenszeiten festgestellt.Die vorliegende Arbeit beschreibt eine identische Prognose für Patienten mit einem PSA-Flare-Phänomen verglichen mit Patienten, die direkt auf eine Docetaxel-Chemotherapie ansprechen. Deshalb sollte ein initialer temporärer PSA-Anstieg nicht zu einem vorzeitigen Abbruch der Docetaxel-Therapie führen, falls keine klinischen Zeichen der Progression zu beobachten sind. 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.
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BACKGROUND Preclinical data suggest that the combination of intravenous (i.v.) paclitaxel, carboplatin, oral etoposide, and oral estramustine (TEEC) has significant activity in patients with advanced, hormone-refractory prostate carcinoma. The authors conducted this clinical trial to evaluate the addition of carboplatin to the three-drug combination of paclitaxel, estramustine, and etoposide (TEE).METHODS Twenty patients with carcinoma of the prostate that was progressing despite hormone therapy were enrolled on this Phase II trial. Patients were treated with oral estramustine, 280 mg three times daily, and oral etoposide, 50 mg/m2, once daily on Days 1–7, with i.v. paclitaxel, 135 mg/m2, over 1 hour followed by carboplatin (area under the curve, 5) on Day 2 of each 21-day treatment cycle. Patients were evaluated for response after three cycles, and three additional cycles were given to responding or stable patients.RESULTSNineteen patients were evaluable for response, and 12 patients had measurable disease at baseline. The measurable response rate was 58% (7 of 12 patients; 95% confidence interval [95% CI], 28–85%), and all of those were partial responses. Eleven patients had decreases > 50% from their baseline prostate specific antigen levels during therapy, for a response rate of 58% (95% CI, 34–80%) by this criterion. The median time to disease progression was 5.5 months, with a median survival of 14.2 months. Major toxicities included Grade (according to version 2 of the National Cancer Institute Common Toxicity Criteria) 4 neutropenia in 4 patients, Grade 4 thrombocytopenia in 4 patients, and anemia ≥ Grade 3 in 4 patients. One patient had a deep vein thrombosis.CONCLUSIONS The combination of TEEC was active in patients with hormone-refractory prostate carcinoma. The regimen was tolerable, with primarily hematologic toxicity. The addition of carboplatin to TEE did not appear to add to the efficacy of the three-drug combination of antimicrotubule agents. Cancer 2003;98:269–76. © 2003 American Cancer Society.DOI 10.1002/cncr.11494
Article
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Article
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Article
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Article
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Article
The objective of the current study was to evaluate the efficacy and toxicity of weekly paclitaxel, oral etoposide, and estramustine phosphate in the treatment of patients with advanced, hormone-refractory prostate carcinoma. Patients with hormone-refractory prostate carcinoma who had received no more than one previous chemotherapy regimen were eligible for this trial. Forty-two patients were treated between February 1998 and March 2000. Toxicity was excessive in the first 3 patients treated (Grade 3-4 leukopenia, 3 patients; death due to sepsis, 1 patient); the remaining 39 patients received lower doses of etoposide and estramustine phosphate (paclitaxel 50 mg/m(2) as a 1-hour, intravenous infusion on Days 1, 8, 15; etoposide 50 mg orally twice daily on Days 1-10; and estramustine phosphate 280 mg orally 3 times daily on Days 1-10). Courses were repeated every 28 days. Patients were evaluated for objective and/or serologic response after two courses of treatment; responding patients continued treatment for six courses. Fourteen of 40 evaluable patients (35%) had either an objective response or a serologic response to treatment. The median survival for the entire group was 9.5 months, with 1-year, 2-year, and 3-year survival rates of 38%, 12%, and 10%, respectively. Neutropenia was the most common Grade 3-4 toxicity and occurred in 38% of patients (11% of courses). Thirteen patients (33%) had severe fatigue, and 2 patients had treatment-related deaths due to sepsis. Although the three-drug combination had activity in patients with hormone-refractory prostate carcinoma, the results did not appear any better than the results achieved with less toxic taxane/estramustine phosphate combinations. Further development of this three-drug regimen is not recommended.