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Chemotherapie des hormonrefraktären Prostatakarzinoms
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.
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.
Weight loss is a frequently occurring complication in patients with chronic obstructive pulmonary disease (COPD) and is a determining factor of functional capacity, health status and mortality. Weight loss in COPD is a consequence of increased energy requirements that are not balanced by dietary intake. Both metabolic and mechanical inefficiency contribute to an elevated total daily energy expenditure. Alterations in anabolic and catabolic mediators resulting in a dysbalance between protein synthesis and protein breakdown may cause a disproportionate depletion of fat-free mass in some patients. Nutritional support is indicated for depleted patients with COPD because it provides not only supportive care, but direct intervention through improvement in respiratory and peripheral skeletal muscle function and in exercise performance. A combination of oral nutritional supplements and exercise or anabolic stimulus appears to be the best approach to obtaining significant functional improvement. Patients responding to this treatment even demonstrated a decreased mortality. Poor response was related to the effects of systemic inflammation on dietary intake and catabolism. The efficacy of anti-catabolic modulation requires further investigation.
Significance of Docetaxel in the Chemotherapy of Hormone-Refractory Prostate Cancer Docetaxel (Taxotere®) is a taxoid derived from the European yew tree, taxus baccata. In 4 phase-II studies docetaxel has important single agent activity with an overall prostate-specific antigen response rate of 42% in hormone refractory prostate cancer. Other phase-II studies suggest that the addition of estramustine to docetaxel results in a higher response rate but also in an increased toxicity. At present Docetaxel with and without estramustine is being evaluated in phase-III studies that will provide definitive information about its role in hormone refractory prostate cancer.
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
Prostate cancer represents one of the most prevalent malignancies in men. Standard therapy of metastatic prostate cancer consists of androgen deprivation, which is a palliative therapy yielding a clinical response of limited duration. In hormone-refractory prostate cancer (HRPC), response to chemotherapy with regimens available until about ten years ago has been disappointing. Nowadays, due to increasing life expectancy and earlier diagnosis and therapy of prostate cancer, more patients with hormone-refractory disease are still in relatively good overall condition. With the taxanes, much more effective cytostatic substances for chemotherapy of HRPC are available today. Using modern taxane-based chemotherapy, effective palliation of pain can be achieved in 50–70% of patients with HRPC, while retaining an acceptable quality of life. There is also evidence for improved overall survival after taxane-based chemotherapy, although this remains to be proven by ongoing studies. This article presents an overview of current studies investigating the outcome after taxane-based chemotherapy, as well as new therapeutic approaches in combination with docetaxel.
Hormone refractory disease is observed in less than 20% of newly diagnosed cases of advanced prostatic cancer. In the majority of cases, hormone refractory disease appears after a median time of 18 months of endocrine manipulation and is attributed to the selection and/or cloning of pre-existing or de novo appearing hormone-independent or resistant cell lines. There are no generally accepted rules for second-line management. The varying sets of criteria used by different study groups make comparisons of widely different regimens very difficult. Actually, it seems reasonable to consider length of survival as the only objective response criterion. This implies, however, that there should be an unanimous definition about the moment of primary treatment failure. Indeed, the detection of hormonal escape is a gradual event and the relative length of survival time depends on the chosen moment of therapy administration. To date, monitoring of prostate specific antigen (PSA) has become the best and primary tool to document progression of disease. Earlier diagnosis based on a rise in PSA levels in patients that are still asymptomatic with a good performance status, might provide the opportunity to treat patients that could profit from therapy and give a fair chance to the investigated drug to show efficacity and tolerability. In this paper we will discuss the rationale of the current available second-line therapeutic options in relapsed prostatic cancer.
The number of cases of prostate cancer diagnosed increased by 15% in the past year. This trend is likely to continue as prostate-specific antigen testing was approved for screening during the past year. The result is that mroe patients are being diagnosed at an earlier and presumably curable stage, although the long-term impact on survival has not been proven. Two large national randomized comparisons were initiated to assess the value of early detection (Prostate, Lung, Colorectal, and Ovarian cancer screening trial) and of early treatment (Prostate Cancer Intervention Versus Observation Trial). Evolving data from early detection studies suggest that the majority of cancers diagnosed are clinically significant. Further, criteria for "deferred treatment" approaches are likewise beginning to evolve. The more widespread use of nomograms based on digital rectal examination findings, Gleason grade, and baseline prostate-specific antigen has led to more refined treatment selection. Patients deemed incurable by local means are being referred for combined modality approaches. For more advanced disease, several new hormonal approaches are evolving, and for those with relapsing tumors, responses to antiandrogen withdrawal were extended to Casodex, (Zeneca Pharmaceuticals, Macclesfield, UK) and a number of nonhormonal treatments such as combinations of estramustine and etoposide estramustine and vinblastine, and doxorubicin and ketoconazole are showing clinical benefit.
Objectives:
A wide range of responses have been reported to second-line hormonal therapies, including corticosteroids and the withdrawal of antiandrogens in patients with hormone-refractory prostate cancers. This suggested the need to classify patients on the basis of hormonal sensitivity. A schema was developed by assessing the differences in entry criteria in relation to outcomes for clinical protocols with hydrocortisone alone or in combination with other agents for patients who had progressed after primary hormone therapy.
Methods:
Published clinical trials of patients who had progressed after primary hormone treatment, which included glucocorticoids, were retrieved from Medline listings. The trials included patients treated with hydrocortisone alone, hydrocortisone and aminoglutethimide, hydrocortisone plus suramin, dexamethasone, and prednisone alone or in combination with chemotherapy.
Results:
The definitions used for refractory disease ranged from none, to "progression", to "unsuccessful second medical or surgical castration. "None of the trials included a definition for hormone-refractory disease based on objective criteria. Details were lacking on most trials with respect to the response to and specific types of hormonal therapies. Furthermore, few trials controlled for the potential contribution of the "flutamide withdrawal syndrome" on outcome.
Conclusions:
The term "hormone-refractory" prostate cancer has evolved to include patients with a spectrum of diseases. As utilized in clinical trials of second-line hormonal therapies, patients who have received one and as many as six different treatments have been included in the same study. A new classification of patients based on hormonal sensitivity is proposed to recognize that androgen-independent proliferation, progression of disease despite castrate levels of testosterone, does not necessarily mean that a tumor is refractory to hormonal manipulations. Future trials in hormonally relapsed patients must include more details of the hormonal therapies utilized.
A re-examination of the methods of developing new treatments for patients with prostate cancer whose disease has progressed
during hormone therapy is necessitated by the following: 1) the impact of prostate-specific antigen (PSA) testing on patient
selection, 2) the increasing number of studies using noncytotoxic approaches, and 3) the lack of validated methods to report
outcomes. PSA monitoring after primary therapy has increased the number of patients referred for therapy with a rising value
in this marker or an asymptomatic change in a radionuclide bone scan as the only manifestation(s) of relapse. The development
of drugs for this population of patients presents a unique challenge because the classical criterion used to assess efficacy
in the phase II setting, i.e., the presence of objective changes in measurable disease sites, frequently does not apply. Since
no approach has been proven to prolong survival, the highest priority must be placed on developing new therapies. Standardizing
the methods for evaluating treatments is also essential so that promising strategies are pursued and inactive therapies are
not developed further.
Adenocarcinoma of the prostate is the most prevalent neoplastic disease in men and continues to be a major cause of morbidity and mortality. Death from prostate cancer is associated with objective and biochemical progression following hormonal manipulations often described as hormone refractory prostate cancer (HRPCA). Therapy for HRPCA is primarily palliative and therapeutic efficacy has to be balanced against potential treatment-related side effects. Therapeutic efficacy may be assessed by evaluating the percentage of patients obtaining a PSA decline of > 50%, evaluating the response of bidimensionally measurable disease or by improvements in quality of life assessments. The most effective cytotoxic therapies at the present time seem to be combinations of estramustine phosphate with taxanes and etoposide. Regimes employing ketoconazole with estramustine, vinblastine or bisphosphonates seem to be worthy of further evaluation. Mitoxantrone has an impressive palliative effect in patients, particularly when combined with hydrocortisone. Oral chemotherapeutic regimens with a combination of estramustine phosphate, cyclophosphamide and prednisone appear to offer a less toxic alternative. For the future we need prospective randomized clinical phase-III studies, prognosticators identifying patients as being at high or low risk who might benefit from different therapeutic approaches and generally binding eligibility and response guidelines in order to be able to compare trials of different therapeutic approaches.
The combination of docetaxel and estramustine has exhibited synergistic activity both in prostate cancer cell lines and in patients with hormone-refractory prostate cancer (HRPC). Based on these promising preclinical and phase I/II data, we conducted a study of weekly docetaxel and estramustine in patients with metastatic HRPC and a poor performance status. A total of 30 patients received (1) a 3-day course of oral estramustine during weeks 1 and 2 of each 3-week cycle plus (2) docetaxel, 35 mg/m(2) intravenously on day 2 of weeks 1 and 2. The median number of cycles per patient was 5, ranging from 1 to 22. The median patient age was 74 years (range, 61 to 90 years), and the median baseline Karnofsky performance status was 60% (range, 50% to 80%). Twenty-three patients (76%) had a > or =50% decrease in serum prostate-specific antigen (PSA); 17 (56%) of these patients had a > or =75% decrease in PSA. Pain scores and performance status likewise improved in 70% of patients. Three complete responses and four partial responses were observed among 12 patients with measurable disease. Toxicities were primarily nonhematologic in nature, with the most common being grade 1 through 3 nausea, asthenia, diarrhea, and edema. Given the activity and tolerability of weekly docetaxel and estramustine in this study, this regimen appears to be more suitable than previously studied docetaxel/estramustine administration schedules for treating metastatic HRPC in elderly patients with a poor performance status.
Background:
Recent clinical trials have shown antitumor activity with the combination of docetaxel plus estramustine phosphate (EMP) in the treatment of patients with androgen independent prostate carcinoma (AIPC). However, the most commonly employed treatment schedules with EMP have been associated with significant gastrointestinal, cardiovascular, and thromboembolic toxicity. The authors hypothesized that the therapeutic index of the combination of docetaxel plus EMP for patients with prostate carcinoma could be enhanced by reducing the incidence and severity of EMP-associated toxicity, which could be accomplished by shortening the duration of exposure to EMP. To preserve the therapeutic synergism between docetaxel and EMP, they designed a regimen employing higher doses of oral EMP administered on the day of the docetaxel infusion.
Methods:
From June 1, 1998 through September 28, 2000, 42 patients with AIPC were registered to receive docetaxel (70 mg/m2 intravenously over 1 hour) and EMP (280 mg orally every 6 hours x 5 doses) every 21 days, up to a maximum of 6 cycles. Dexamethasone was administered prior to docetaxel and coumadin 2 mg orally every day was taken during the study treatment period. Patient characteristics included a median age of 68 years, a median Eastern Cooperative Oncology Group performance status of 1, a median prostate specific antigen (PSA) level at study entry of 110.5 ng/mL, and a median of 2 prior hormonal manipulations. Ten patients (25%) had received prior chemotherapy, and 14 patients (33%) had received prior palliative radiation therapy.
Results:
Forty patients were evaluable for response and toxicity. Eighteen patients (45%; 95% confidence interval, 29-62%) had a decline > 50% in PSA level that lasted > 4 weeks with a median time to PSA progression and a median duration of PSA response of approximately 4.0 months. Four of 20 patients (20%) had partial soft tissue responses. Ten of 17 symptomatic patients (59%) had improvement in pain. The median survival for all patients was 13.5 months. The most prominent Grade 3 and 4 toxicities were reversible myelosuppression and fatigue. Nausea, emesis, diarrhea, and peripheral edema were minimal. No thromboembolic or hepatic complications were seen.
Conclusions:
Docetaxel plus 1 multidose day of oral EMP was active in patients with AIPC and was associated with an acceptable toxicity profile. Overall, the therapeutic index of this regimen compared favorably with regimens that employed a longer administration of EMP.
Estramustine 600 mg/m2 can be administered safely with 225 mg/m2 of paclitaxel if administered as a 3-hr infusion for the treatment of hormone refractory prostate cancer. Significant anti-tumor activity has been reconfirmed despite the change in schedule of administration of the paclitaxel.
This phase I study was conducted to identify the maximum tolerated dosage of paclitaxel administered as a 3-hr infusion combined with a stable dosage of estramustine capsules daily in men with hormone refractory prostate cancer. A secondary endpoint was to assess anti-tumor efficacy in this targeted patient population.
Twenty-six male patients, all with hormone refractory prostate cancer were enrolled in this trial. Estramustine was administered at a dosage of 600 mg/m2 daily, and paclitaxel was dose-escalated in cohorts from 125 to 250 mg/m2 administered as an infusion over 3 hr every 21 days. Patients were treated until maximum response was achieved, or toxicity or progressive disease precluded further treatment. Toxicity to determine maximum tolerated dose was assessed only during the first 3-week cycle.
The maximum tolerated dose of paclitaxel on this schedule was 225 mg/m2 based on unacceptable dose-limiting fatigue observed at the next higher dosage level. Other grade 3 or 4 events included myelosuppression, left ventricular dysfunction, elevated liver function tests, deep venous thrombosis, vomiting, and development of depression. Using a response criteria of prostate specific antigen decline of > 50% persisting for a minimum of 6 weeks, eight of 26 patients responded (30.8%). Two of seven patients with documented soft-tissue disease experienced > 50% reductions in size of lesions or number of sites. The median response duration was 6 months, and the median survival time was 16 months.
The recommended phase II dose of paclitaxel is 225 mg/m2 when administered over 3 hr in combination with estramustine. This regimen has an acceptable toxicity profile, is a convenient schedule, and results in significant antitumor activity even in a heavily pre-treated population of patients.
Vinorelbine, a semisynthetic vinca alkaloid, and docetaxel, a semisynthetic taxane, are active single agents in hormone-refractory prostate cancer and have demonstrated synergy in tumor cell lines and animal models. This study was designed to assess the efficacy and tolerability of vinorelbine and low-dose docetaxel in chemotherapy-naive, hormone-refractory prostate cancer patients whose disease had progressed after withdrawal from anti-androgens, despite castrate testosterone levels.
Patients with histologically confirmed hormone-refractory prostate cancer despite testosterone levels < or = 50 ng/mL, Karnofsky performance status > 70, and adequate bone marrow reserve were enrolled. They received vinorelbine, 20 mg/m2, followed by docetaxel, 25 mg/m2, on days 1 and 8 of a 21-day cycle. Tumor response was defined by prespecified reductions from baseline prostate-specific antigen levels or bidimensionally measurable disease. Adjustments in the dose of either agent were based on > or = grade 2 toxicity according to standard criteria.
Twenty-one patients with a mean age of 76 years (range, 60-83 years) and a median prostate-specific antigen level of 116 ng/mL (range, 10.4-4,262 ng/mL) were enrolled and received a total of 152 courses (median, 7.5 courses) of vinorelbine and docetaxel. Of the 19 patients who were evaluable for biochemical response, prostate-specific antigen reductions from baseline of > 75%, > or = 50% to < or = 75%, and < 50% were observed in eight, three, and seven patients, respectively (median prostate-specific antigen decrease, 60% +/- 31%). Of five patients with measurable disease, three were evaluable: one patient had a complete response, and two had partial responses at the site of measurable disease. The vinorelbine/docetaxel doublet was generally well tolerated. In the first two cycles of therapy, six patients had grade 3 and eight patients had grade 4 neutropenia as their worst-grade toxicities; all cases were manageable with granulocyte colony stimulating factor support. Acute respiratory distress syndrome was observed in one patient. There were few dose reductions or interruptions.
Vinorelbine, 20 mg/m2, and low-dose docetaxel, 25 mg/m2, given on days 1 and 8 every 21 days, is a well-tolerated regimen with biochemical and objective response rates comparable to standard therapies in patients with hormone-refractory prostate cancer. A multicenter, randomized trial is under way to compare vinorelbine plus low-dose docetaxel with estramustine plus higher-dose docetaxel (60 mg/m2).
Docetaxel has significant single-agent activity in patients with prostate carcinoma, and ketoconazole has activity as a second-line hormonal agent. In vitro, ketoconazole exhibits synergy with several chemotherapeutic agents. A potential drug interaction exists, however, because both docetaxel and ketoconazole are metabolized hepatically by the cytochrome p450 system (CYP3A4). The authors performed a Phase I study and a pharmacokinetic study evaluating the both tolerability of a docetaxel/ketoconazole combination as well as this potential drug interaction.
For all initial patients, docetaxel was administered intravenously at a dose of 55 mg/m(2) over 1 hour every 21 days. Starting on Day 8 after their first docetaxel dose, cohorts of at least 3-5 new patients were enrolled to receive escalating doses of ketoconazole. When the maximally tolerated dose (MTD) of ketoconazole was reached, the subsequent cohort of patients received an escalating dose of docetaxel. Pharmacokinetic studies were performed after docetaxel infusions on Day 1 (prior to ketoconazole) and Day 22 (after starting ketoconazole).
Twenty-six patients were enrolled and completed at least 2 cycles of treatment. The MTD was ketoconazole 400 mg twice daily and docetaxel 55 mg/m(2). Dose-limiting toxicities included neutropenia and fatigue. Ketoconazole did not cause a consistent effect on docetaxel pharmacokinetics, although there was significant intrapatient and interpatient variability in serum levels.
The recommended Phase II dose for this combination is ketoconazole 400 mg twice daily and docetaxel 55 mg/m(2) every 21 days.
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.