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Combination Chemotherapy with Docetaxel, Vinorelbine and Estramustine Phosphate in Metastatic Androgen-Resistant Prostate Cancer: a Single Institution Experience

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Combination Chemotherapy with Docetaxel, Vinorelbine and Estramustine Phosphate in Metastatic Androgen-Resistant Prostate Cancer: a Single Institution Experience ANTICANCER RESEARCH 29: 769-776 (2009) Combination Chemotherapy with Docetaxel, Vinorelbine and Estramustine Phosphate in Metastatic Androgen-resistant Prostate Cancer: A Single Institution Experience DIMITRIOS PECTASIDES, EIRINI PECTASIDES, GEORGE PAPAXOINIS, ANNA KOUMARIANOU, AMANDA PSYRRI, NIKOLAOS XIROS, NIKOLAOS TOUNTAS, KONSTANTINOS KAMPOSIORAS, GEORGE PAPATSIBAS, THEOFANIS FLOROS, PANAGIOTIS GOUVERIS, SOFIA KARAGEORGOPOULOU and THEOFANIS ECONOMOPOULOS Second Department of Internal Medicine, Propaedeutic, Oncology Section, University of Athens, Attikon University Hospital, Haidari, Athens, Greece Abstract. The aim of this study was to evaluate the activity generally mild except for myelotoxicity. Neutropenia grade 3/4 and toxicity of docetaxel, vinorelbine and oral estramustine in was recorded in 33% of patients and 6% experienced febrile androgen-resistant prostate cancer (ARPC). Patients and neutropenia. Anemia and thrombocytopenia grade 3 or 4 were Methods: Fifty-two eligible patients were treated with docetaxel not a problem. Three patients (6% ) developed grade 3 sensory at 30 mg/m2 (day 1 and 8), vinorelbine at 20 mg/m2 (day 1 and neuropathy and 2 patients (4% ) developed grade 3 fatigue. 8), and oral estramustine of 280 mg p.o. (daily on days 1 to 7) Edema grade 3 occurred in 1 (2% ) patient and every 3 weeks for 12 cycles. Patients with osseous metastases thromboembolism grade 3 occurred in 2 (4% ) patients. received zoledronic acid of 4 mg every 3 weeks. Low molecular Conclusion: The combination of docetaxel, vinorelbine and oral weight heparin was administered on a prophylaxis basis to all estramustine is a well-tolerated regimen with high biochemical patients. Results: A prostate-specific antigen (PSA) response and objective response rates in patients with ARPC. ≥50% from baseline was obtained in 29 (56% ; 95% confidence interval [CI], 42-70% ) patients. Objective Prostate cancer is the most common cancer in men, accounting responses among the 25 patients with measurable disease were for an estimated 186,320 new cases and 28,660 deaths in 2007 observed in 48% (95% CI, 27-69% ), including 1 patient with in the United States (1). Early-stage prostate cancer can be complete response (CR) and 11 patients with partial response cured with surgery or radiotherapy; however, this is not the (PR). Patients with extraosseous only, skeletal only, and case for metastatic disease. Approximately, 10-20% of men extraosseous and skeletal metastases showed different PSA have metastatic disease at presentation. Treatment of metastatic responses (87% vs. 44% vs. 59% , respectively, p=0.094). disease is palliative. About 80% of patients with metastatic Furthermore, patients with soft tissue disease only showed prostate cancer have a rapid response to surgical or medical insignificantly better PSA response than those with skeletal castration with a symptomatic improvement and a reduction in metastases (response rate: 87% vs. 50% , p=0.064). The serum prostate-specific antigen (PSA). Nevertheless, in almost median progression-free survival was 7.6 months (95% CI, all patients, the disease eventually becomes androgen- 6.7-8.4 months) and the median overall survival was 18.2 independent at a median of 18 to 24 months (2). months (95% CI, 15.5-20.8 months). The only parameters Until recently, chemotherapy was considered ineffective in which were found to have an impact on survival were the extent metastatic androgen-resistant prostate cancer (ARPC). of disease and the baseline levels of PSA. Toxicity was Mitoxantrone plus prednisone or hydrocortisone was the treatment of reference for ARPC conferring symptomatic bone pain relief but no survival advantage (3, 4). Recently, docetaxel has replaced mitoxantrone as the standard of care Correspondence to: D. Pectasides, Second Department of Internal for patients with ARPC. Phase II studies of docetaxel have Medicine, Propaedeutic, Oncology Section, Attikon University shown PSA responses (defined as a decline in serum PSA Hospital, Rimini 1, Haidari, Athens, Greece. Tel: +30 2105831691/ levels of at least 50% ) in up to 50% of patients (5, 6). +30 2106008610, Fax: +30 2105831666/+30 2106008610, e-mail: Similarly, vinorelbine, an agent that blocks the microtubule [email protected] apparatus, has demonstrated PSA responses ranging between Key Words: Chemotherapy, docetaxel, vinorelbine, estramustine, 8% and 17% (7-9). With the emergence of preclinical data zoledronic acid, androgen-resistant prostate cancer. demonstrating synergy for combined anti-microtubular 0250-7005/2009 $2.00+.40 769 ANTICANCER RESEARCH 29: 769-776 (2009) therapy (estramustine phosphate [EMP]-taxane or vinca continued until disease progression, unacceptable toxicity, patient’s alkaloid plus taxane) (10-15), several phase II studies have refusal, or until a maximum of 12 cycles of chemotherapy. been conducted demonstrating that this is a promising Evaluation. The pre-treatment evaluation included medical history, approach (16-19). Furthermore, the use of docetaxel in a physical examination, computed tomography (CT) of the chest, weekly schedule appears to minimize myelosupression and abdomen and pelvis, bone scanning, MUGA (multiple gated has been associated with mild to moderate non-hematological acquisition), a complete blood count (CBC) and measurement of toxicity (20). serum PSA and serum testosterone. At every cycle, pretreatment During the preparations of this trial, additional data have evaluation was repeated, excluding MUGA scanning, measurement emerged. Preclinical studies showed that zoledronic acid, in of serum testosterone and baseline imaging studies. Imaging studies were repeated every 3 cycles. Hematological toxicity was evaluated addition to having bone resorption inhibiting properties, also by CBC performed on each visit at the clinic. Pain intensity and exhibits antitumoral effects (21). It also appears that analgesic consumption were evaluated at every cycle. combined treatment with docetaxel and zoledronic acid causes additive and/or synergistic cytostatic effects (22). Two Response evaluation. The Prostate-Specific Antigen Working Group recent randomized phase III studies showed that docetaxel criteria were used to evaluate the PSA response (25). A partial with estramustine or prednisone improved overall survival response was defined as a reduction by >50% over baseline on 2 consecutive measurements taken at least 4 weeks apart. An increase compared with mitoxantrone plus prednisone (23, 24). in PSA level <25% from baseline was considered stable disease. Based on these data, a trial was conducted to determine the Progressive disease was defined as a 25% increase in the serum efficacy and tolerability of a combination of docetaxel, PSA level on 2 consecutive measurements taken at least 4 weeks vinorelbine, estramustine phosphate and prednisone in ARPC. apart. An objective tumor response by radiographic evaluation in patients with measurable disease was assessed according to the Patients and Methods World Health Organization criteria (26). Pain response was measured via a self-administered numeric rating scale. The pain assessment was based on a scale of 0 to 10, Eligible patients were those with histologically proven adeno- where 0 represents no pain and 10 represents severe pain. Analgesic carcinoma of the prostate and documented disease progression use was self-recorded daily and analgesic scores were recorded by (documented locoregional or distant metastases and/or PSA increase) investigators on the basis of analgesics administered (0: none, 1: after androgen ablation therapy and antiandrogen withdrawal. The minor analgesics, 2: mild narcotic, 3: moderate narcotic 4: strong main eligibility criteria were as follows: Eastern Cooperative narcotic) using a modification of a Radiation Therapy Oncology Oncology Group (ECOG) performance status (PS) 0 to 2, life Group score (27). expectancy ≥3 months, previous hormonal therapy, progressive disease after hormonal therapy [PSA >50% measured on two Statistical analysis. Statistical analysis was performed using SPSS consecutive estimations, progression on bone scan (evidence of new 14.0 statistical software package (SPSS Inc., Chicago, IL, USA). lesions) or computed tomography scan], no prior chemotherapy, The primary end point of this phase II study was response rate granulocyte count of at least 1,500/μL, platelet count of at least [objective response rate (ORR), PSA response ≥50% rate (PSA 100,000/μL, serum creatinine level <1.5 mg/dl, serum bilirubin <1.5 RR)]. Secondary end-points included pain assessment, median mg/dl, and transaminase values of no more than twice the upper progression-free survival (PFS) and median overall survival (OS). normal limit. Any radiation therapy had to have been completed Sample size calculation was based on the PSA RR, since some within at least 4 weeks or radiopharmaceutical treatment within 3 patients did not have clinically or radiologically measurable months prior to the initiation of therapy. Normal cardiac function was disease. According to the Simon’s two-stage minimax design, with required. Prior treatment with corticosteroids was allowed. Patients a significance level of 0.05 and a power of 0.80, and making the were excluded from the study if they had brain metastases, suffered hypothesis that PSA RR would be at least 50% and the minimum from uncontrolled chronic disease or severe infection, >grade 2 acceptable PSA RR 33% , a sample of 26 patients would be peripheral neuropathy not related to cancer, or had
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