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Home , Cisplatin, Docetaxel, Mitoxantrone, Taxane, Vinorelbine

ANTICANCER RESEARCH 29: 769-776 (2009)

Combination with , and in Metastatic Androgen-resistant : 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. grade 3/4 and toxicity of docetaxel, vinorelbine and oral estramustine in was recorded in 33% of patients and 6% experienced febrile androgen-resistant (ARPC). Patients and neutropenia. and 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 . 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 (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 plus or hydrocortisone was the treatment of reference for ARPC conferring symptomatic bone 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 [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]- or continued until disease progression, unacceptable toxicity, patient’s 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 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 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 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 a documented required at the first step. If 10 PSA responses were observed, then history of previous cancer. The Ethics Committee approved the study a maximum of 54 patients in total would be enrolled in the study. protocol and patient informed consent was in accordance with the Twenty-four or more responses in total would be needed for the international standards of good clinical practice. All patients provided treatment to be accepted. PFS was determined as the time from informed consent according to institutional guidelines. the date of start of treatment until the date of evidence of progression or the date of death from any cause, if progression did Treatment. Patients received docetaxel at 30 mg/m2 as a 30 min not occur until death. OS was defined as the time from the date of infusion on days 1 and 8, vinorelbine at 20 mg/m2 over 10-15 min start of treatment until the date of death from any cause. Surviving infusion on days 1 and 8 and estramustine of 280 mg p.o. daily on patients were censored at the date of last follow-up. Kaplan-Meier days 1 to 7 every 3 weeks. Zoledronic acid (4 mg) was administered curves were used to calculate median PFS and OS. Fisher’s exact to patients with bone metastases on day 1 of each cycle as a 15 min or chi-square tests were used to compare response rates. Although infusion. In each cycle, vinorelbine was administered first, followed the sample size was small, Cox proportional hazards model was by docetaxel infusion. Premedication with 8 mg of used to evaluate the prognostic significance of clinical and given 1 h before docetaxel was required. All patients who had not laboratory parameters, as a secondary endpoint. All comparisons undergone orchiectomy continued treatment with a leutenizing were two-tailed and a level of 5% was used to denote statistical hormone-releasing hormone (LHRH) agonist. Treatment was significance.

770 Pectasides et al: Combination Chemotherapy in Metastatic Androgen-resistant Prostate Cancer

Table I. Patient characteristics. Table II. Toxicity.

Characteristic n (% ) Toxicity Grade n, (% )

No. of patients 52 3 4 Age (years), median, range 66 (47-80) <60 9 (17) Neutropenia 14 (27) 3 (6) 60-75 37 (71) Anemia 4 (8) 1 (2) >75 6 (12) Thrombocytopenia 4 (8) 2 (4) ECOG PS and 6 (12) 0 0 18 (35) Alopecia 10 (19) 0 1 22 (42) Peripheral neuropathy 3 (6) 0 2 12 (23) Stomatitis 3 (6) 0 PSA (ng/ml), median, range 93 (1.2-2850) Myalgia/Arthralgia 1 (2) 0 <5 3 (6) Allergic reaction 1(2) 0 5-100 30 (58) Cardiotoxicity 1 (2) 0 >100 19 (36) Fatigue 2 (4) 0 Prior treatment Edema 1 (2) 0 Orchiectomy or LHRH 52 (100) Thromboembolism 2 (4) 0 Bicalutamide 52 (100) Flutamide 8 (15) 11 (21) Prostate bed irradiation 5 (10) Strontium 2 (4) only extraosseous metastases, while 17 (33% ) patients had Time to AIPC (months), median, range 21.5 (2-89) both extraosseous and bone metastases. <12 16 (31) A total of 310 cycles of docetaxel, vinorelbine and 12-24 12 (23) estramustine were administered to the patients. The weekly >24 24 (46) Site of metastases schedule of docetaxel, vinorelbine and estramustine resulted 2 Bone 44 (85) in a median delivered dose intensity of 19 mg/m /wk, 12.5 0 8 (15) mg/m2/wk and 610 mg/m2/wk, respectively, or 95% , 94% and 1-5 13 (25) 93% of the planned dose intensity. A dose reduction of 20% 6-10 18 (35) was adopted in 41 (14% ) cycles due to grade 3 neutropenia. >10 9 (17) Superscan 4 (8) Treatment was delayed in 52 (18% ) cycles for the following Extraosseous reasons: patient’s request (26 cycles), hematological toxicity Lymph node 13 (25) (10 cycles), non-hematological toxicity (5 cycles) and 5 (10) investigator decision (11 cycles). Lung 4 (8) Extent of metastatic disease Extraosseous only 8 (15) Toxicity. The toxicities that occurred during therapy are Skeletal only 27 (52) summarized in Table II. Toxicity was generally mild. Extraosseous+skeletal 17 (33) Neutropenia grade 3 (27% ) and 4 (6% ) was the most frequent severe adverse effect. However, only 3 patients ECOG: Eastern Cooperative Oncology Group, PS: performance status, developed grade 3 febrile neutropenia, which was AIPC: androgen-independent prostate cancer, PSA: prostate specific antigen, LHRH: -releasing hormone. successfully treated with broad-spectrum antibiotics and G-CSF support. In total 32 (62% ) patients required G-CSF support. Anemia grade 3 and 4 was experienced by 8% and Results 2% of patients, respectively and thrombocytopenia grade 3 and 4 by 8% and 4% , respectively. No patient experienced From February 2001 to May 2005, 52 consecutive patients thrombocytopenic hemorrhage. Three patients (6% ) were registered on the trial. They were treated with the developed grade 3 sensory neuropathy. These 3 patients combination of docetaxel, vinorelbine and estramustine and received >6 cycles of chemotherapy and two of them were followed up until September 2007. Patients with osseous suffered from diabetes mellitus. One (2% ) patient metastases received zoledronic acid. Patient characteristics are experienced grade 3 hypersensitivity reaction and 3 (6% ) shown in Table I. All patients were evaluable for response patients developed grade 3 mucositis/stomatitis. One (2% ) (biochemical, objective) and toxicity. The median number of patient suffered a transient heart attack. Grade 2 alopecia was chemotherapy courses per patient was 6 (range, 2-12). Forty- recorded in 10 (19% ) patients. Edema grade 3 occurred in four (85% ) patients had bone metastases with or without 1 (2% ) patient, while thromboembolism related to other metastatic sites. The remaining 8 (15% ) patients had estramustine in 2 (4% ) patients. No toxic deaths occurred.

771 ANTICANCER RESEARCH 29: 769-776 (2009)

Table III. Response, progression-free survival, overall survival. Table IV. Univariate and multivariate analysis of prognostic factors

Response n (% ) Univariate Multivariate

PSA response (all patients) 29 (56) HR 95% p-Value HR 95% p-Value Extent of disease CI CI Extraosseous only 7/8 (87) Skeletal only 12/27 (44) Extent of disease Extraosseous + skeletal 10/17 (59) Skeletal only 1 - - 1 - - Bone metastases Extraosseous only 1.9 0.6-5.7 0.252 0.9 0.3-3.6 0.986 No 7/8 (87) Skeletal and extraosseous 5.9 2.7-13.1 <0.001 5.2 1.9-13.6 0.001 Yes 22/44 (50) PSA level* (ng/mL) Objective response 5-100 1 - - 1 - - Complete response 1/25 (4) >100 5.8 2.5-13.7 <0.001 4.1 1.5-11.0 0.005 Partial response 11/25 (44) Median PFS 7.6 months *The group with PSA levels <5 ng/mL was excluded from the prognostic Median OS 18.2 months factor analysis because of low number of events (among 3 patients only one died).

Response, PFS and survival. PSA response ≥ 50% from months, 5-100 ng/ml: 20.7 months, >100 ng/ml: 14.7 months), baseline was obtained in 29 (56% ; 95% CI, 42-70% ) both in univariate and multivariate analysis (Table IV). patients (Table III), which exceeds the target of 24 responses for the treatment to be accepted. Moreover, 12 (48% ; 95% Pain response. Pain improvement, characterized by a >50% CI 27-69% ) objective responses were observed among the reduction in analgesic consumption coupled with a >50% 25 patients with measurable disease, including 1 patient with decrease in worst pain score, was recorded in 27 (52% ) out complete response (lung metastases). The median time to of 52, 21 (47% ) out of 45, and 13 (38% ) out of 34 patients, PSA response was 1.9 months (range, 0.4-4.3 months) after after 3, 6 and 12 cycles, respectively. initiation of treatment. Differences according to the sites of disease (extraosseous only vs. skeletal only vs. extraosseous Discussion and skeletal) showed insignificantly better PSA response in patients with no bone metastases (87% vs. 44% vs. 59% , The prognosis of patients with ARPC is poor. The aim of p=0.094). Similarly, patients with soft tissue disease only chemotherapy for ARPC is to prolong patients’ survival, showed better PSA response than those with skeletal improve their quality of life and secondarily to improve the metastases (RR: 87% vs. 50% , p=0.064). Several variables tumor response and prolong the PFS. However, current (age, ECOG PS [0 or 1 vs. 2], PSA baseline, hemoglobin treatment approaches have shown poor response rate, poor level, extent of disease, mode of primary treatment and time long-term survival and lack of definitive salvage from primary diagnosis to hormone-resistant disease) were chemotherapy when first-line treatment has failed. Recently, assessed for possible prognostic value for PSA response. It docetaxel-based chemotherapy has become the new standard was found that none of these parameters was significantly of care for first-line treatment of ARPC. Two recent associated with PSA response. randomized phase III studies showed that docetaxel with After a median follow-up of 37.4 months (95% CI 36-38.8 estramustine or prednisone improved overall survival months), 39 (75% ) out of 52 patients had died. The median compared with mitoxantrone plus prednisone in patients with PFS was 7.6 months (95% CI 6.7-8.4), (range, 0.4 to 20.5 ARPC (23, 24). months) and the median OS was 18.2 months (95% CI, 15.5- Docetaxel acts by promoting the polymerization of 20.8), (range, 4.3 to 31.8 months), as shown in Figure 1. and has been shown to induce bcl-2 phosphorylation and Using Cox proportional hazards model to evaluate the apoptotic cell death. Vinorelbine, a semisynthetic vinca prognostic significance of age, ECOG PS (0 or 1 vs. 2), alkaloid that acts by interfering with microtubule assembly, baseline PSA, hemoglobin level, extent of disease, mode of is also capable of inducing bcl-2 phosphorylation. primary treatment and time from primary diagnosis to Furthermore, vinorelbine is a fairly well-tolerated with hormone-resistant disease, no effect on survival was found. a moderate single-agent activity [15.9% PSA response The only parameters which were found to have an impact on (≥50% reduction of PSA levels), 3 partial responses among survival were the extent of disease (extraosseous and skeletal: 8 patients with measurable disease] in patients with ARPC 13.8 months, extraosseous only: 19.1 months, skeletal only: (9). Preclinical models have demonstrated synergism when 23.1 months) and the levels of PSA (OS: <5 ng/ml: 13.5 both drugs are used together (28).

772 Pectasides et al: Combination Chemotherapy in Metastatic Androgen-resistant Prostate Cancer

Figure 1. Progression-free survival (PFS) and overall survival (OS) curves of the entire population.

The combination of docetaxel-estramustine may enhance Borrega et al. (29) treated 54 ARPC patients with vinorelbine the apoptotic effect or circumvent cellular stress adaptations and estramustine. Sustained PSA decrease >50% was seen in that confer drug resistance. However, the combination of 52% of patients and an overall objective response in 60% of docetaxel-estramustine led to toxicity clearly related to patients. The median survival time was 15 months. estramustine (gastrointestinal intolerance, thrombosis). In Petrylak et al. (19) evaluated the combination of docetaxel addition, an important issue in the management of ARPC is with oral estramustine and dexamethasone in patients with the reduction of chemotherapy-related toxicity. The weekly ARPC. The overall 50% PSA RR was 63% . Among the 18 schedule of docetaxel has been shown to have less patients with bidimentionally evaluable disease, 5 achieved hematological and non-hematological toxicities compared to a PR (28% ). In another study 46 assessable patients with those with a 3-weekly schedule. ARPC were treated with the combination of docetaxel, oral Sweeney et al. (16) conducted a phase II trial combining estramustine and low-dose daily hydrocortisone (18). In the vinorelbine with estramustine. Fifteen out of 21 patients 44 patients in whom pretreatment PSA was elevated, 30 (71% ) had at least a 50% decrease in PSA levels and 1 out (68% ) had a ≥50% decrease and 25 (57% ) had a ≥75% of 8 patients (12.5% ) with measurable disease had a decrease in PSA levels. In the 24 patients with measurable confirmed partial response. The estimated median survival disease the reported response rate was 50% . The median was 15.1 months and the actuarial 1-year OS was 71% . In survival was 20 months and the median time to disease another study, the combination of vinorelbine and progression was 8 months for all patients, and 10 months for estramustine showed a ≥65% decline in pretreatment PSA those with measurable disease. The incidence of level in 9 out of 24 assessable patients (17). Similarly, thromboembolic events during therapy was 9% .

773 ANTICANCER RESEARCH 29: 769-776 (2009)

Several trials using the combination of docetaxel and not a serious problem. Clinically significant vinorelbine have been reported. The results varied in terms of (grade 3) was recorded only in 6% of patients. Severe allergic efficacy and safety and these differences were attributed to reaction and edema grade 3 occurred each in 1 patient, while different schedule and drug doses. Goodin et al. (30) thromboembolism related to estramustine in 2 patients. This conducted a phase II study to evaluate the combination of low rate could be attributed to the fact that all patients received docetaxel (60 mg/m2, day 1) and vinorelbine (15 mg/m2, days prophylaxis with low molecular weight heparin. The high 1 and 8) every 3 weeks in the treatment of 40 patients with tolerability of such a is probably ARPC. A >50% decrease in PSA was observed in 37% and attributed to the combination of 3 at lower doses than 29% of patients with and without prior chemotherapy, those used in doublets and to the use of G-CSF. This is a respectively. Similarly, Koletsky et al. (31) designed a phase II significant advantage since a high proportion of prostate study of vinorelbine (20 mg/m2) and low-dose docetaxel (25 cancer patients are elderly and consequently have co- mg/m2) on days 1 and 8 every 3 weeks in chemotherapy-naive morbidities. Therefore, the regimen offered a satisfactory patients with ARPC. An objective response of 60% was quality of life, considering also the improvement of pain in a observed among patients with measurable disease as well as a significant proportion of patients. 60% PSA response. The vinorelbine/docetaxel doublet was In conclusion, docetaxel at 30 mg/m2 (day 1 and 8), generally well tolerated. Grade 3 or 4 neutropenia developed vinorelbine at 20 mg/m2 (day 1 and 8) and oral estramustine 74% of patients. There were few dose reductions or every 3 weeks is a well-tolerated regimen with high interruptions. In another study, Di Lorenzo et al. (32) biochemical and objective response rates in patients with investigated the combination of docetaxel (25 mg/m2), ARPC. However, it did not differ in terms of response and vinorelbine (10 mg/m2) for 3 consecutive weeks followed by survival compared with other phase II trials testing doublets, a 1-week rest and zoledronic acid as first-line treatment in 40 which could be attributed to the low number of patients patients with ARPC. Among 38 evaluable patients, PSA precluding the detection of small differences. Nevertheless, responses were observed in 50% of patients and PR was its high tolerability and the documented synergy between the observed in 40% of patients with measurable disease. 3 drugs warrants its further study. Real efficacy can be Neutropenia (25% ) was the most important grade 3 demonstrated only in a multicenter, randomized phase III trial hematological toxicity observed. Median PFS was 7 months comparing the combination of docetaxel, vinorelbine and oral and median OS was 17 months. estramustine with docetaxel and estramustine or prednisone. To the best knowledge of the Authors, this is the first trial in which the combination of docetaxel, vinorelbine (on weekly References basis) and oral estramustine was used in the treatment of chemotherapy-naive ARPC. In this study, it has been 1 Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T and Thun demonstrated that this combination is active in patients with MJ: Cancer statistics, 2008. CA Cancer J Clin 58: 71-96, 2008. ARPC. Although limited by small sample size, this study 2 Tannock IF, Osoba D, Stockler MR, Ernst DS, Neville AJ, demonstrated an objective RR for the combination of Moore MJ, Armitage GR, Wilson JJ, Venner PM, Coppin CM and Murphy KC: Chemotherapy with mitoxantrone plus docetaxel, vinorelbine and oral estramustine of 48% , >50% prednisone or prednisone alone for symptomatic hormone- PSA reduction of 56% , median PFS of 7.6 months and median resistant prostate cancer: a Canadian randomized trial with OS of 18.2 months. The site of recurrence was reported to be palliative end points. J Clin Oncol 14: 1756-1764, 1996. associated with response to chemotherapy. Patients with 3 Hellerstedt BA and Pienta KJ: The current state of hormonal extraosseous only, skeletal only, or both extraosseous and therapy for prostate cancer. CA Cancer J Clin 52: 154-179, 2002. skeletal metastases showed distinct PSA responses, although 4 Osoba D, Tannock IF, Ernst DS and Neville AJ: Health-related their difference was not significant (87% vs. 44% vs. 59% , quality of life in men with metastatic prostate cancer treated with prednisone alone or mitoxantrone and prednisone. J Clin Oncol respectively, p=0.094). Furthermore, patients with soft tissue 17: 1654-1663, 1999. disease only showed insignificantly better PSA response than 5 Beer TM, Pierce WC, Lowe BA and Henner WD: Phase II study those with skeletal metastases (RR: 87% vs. 50% , p=0.064). of weekly docetaxel in symptomatic androgen-independent On the other hand, the only parameters which were found to prostate cancer. Ann Oncol 12: 1273-1279, 2001. have an impact on survival were the extent of disease and the 6 Berry W, Dakhil S, Gregurich MA and Asmar L: Phase II trial of baseline levels of PSA. Similar results have been reported in single-agent weekly docetaxel in hormone-refractory, phase II trials using the combination of docetaxel, vinorelbine symptomatic, metastatic carcinoma of the prostate. Semin Oncol (3-weekly or weekly)±zoledronic acid or the combination of 28(4 Suppl 15): 8-15, 2001. 7 Fields-Jones S, Koletsky A, Wilding G, O’Rourke M, O’Rourke estramustine±docetaxel or vinorelbine. T, Eckardt J, Yates B, McGuirt C and Burris HA 3rd: The present study suggested that this regimen is a well- Improvements in clinical benefit with vinorelbine in the tolerated out-patient therapy, with the most significant toxicity treatment of hormone-refractory prostate cancer: a phase II trial. being grade 3 or 4 neutropenia (33% ). Thrombocytopenia was Ann Oncol 10: 1307-1310, 1999.

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Godley PA, Hussain A, Small EJ and Vogelzang NJ: Phase II 31 Koletsky AJ, Guerra ML and Kronish L: Phase II study of study of docetaxel, estramustine, and low-dose hydrocortisone vinorelbine and low-dose docetaxel in chemotherapy-naive in men with hormone-refractory prostate cancer: a final report patients with hormone-refractory prostate cancer. Cancer J 9: of CALGB 9780. Cancer and Leukemia Group B. J Clin Oncol 286-292, 2003. 19: 2509-2516, 2001. 32 Di Lorenzo G, Autorino R, Perdonà S, De Laurentiis M, 19 Petrylak DP, Macarthur RB, O’Connor J, Shelton G, Judge T, D’Armiento M, Cancello G, Mirone V, Imbimbo C, Longo N, Balog J, Pfaff C, Bagiella E, Heitjan D, Fine R, Zuech N, Altieri V, Tortora G, Figg WD and De Placido S: Docetaxel, Sawczuk I, Benson M and Olsson CA: Phase I trial of docetaxel vinorelbine, and zoledronic acid as first-line treatment in patients with estramustine in androgen-independent prostate cancer. with hormone refractory prostate cancer: a phase II study. Eur J Clin Oncol 17: 958-967, 1999. Urol 52: 1020-1027, 2007. 20 Gravis G, Bladou F, Salem N, Macquart-Moulin G, Serment G, Camerlo J, Genre D, Bardou VJ, Maraninchi D and Viens P: Weekly administration of docetaxel for symptomatic metastatic hormone- refractory prostate carcinoma. Cancer 98: 1627-1634, 2003. 21 Brubaker KD, Brown LG, Vessella RL and Corey E: Administration of zoledronic acid enhances the effects of Received September 27, 2008 docetaxel on growth of prostate cancer in the bone environment. Revised December 10, 2008 BMC Cancer 6: 15, 2006. Accepted December 15, 2008

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