- Email: [email protected]
Weekly Docetaxel and Bortezomib as First-Line Treatment for Patients with Hormone-Refractory Prostate Cancer: A Minnie Pearl Cancer Research Network Phase II Trial
Original Contribution
Weekly Docetaxel and Bortezomib as First-Line Treatment for Patients with Hormone-Refractory Prostate Cancer: A Minnie Pearl Cancer Research Network Phase II Trial John D. Hainsworth1 Anthony A. Meluch1 David R. Spigel1 John Barton, Jr1 Lisa Simons1 Christina Meng1 Bruce Gould2 F. Anthony Greco1 1Sarah
Cannon Research Institute and Tennessee Oncology, PLLC, Nashville 2Wellstar Health System Cancer Research, Marietta, GA
Clinical Genitourinary Cancer, Vol. 5, No. 4, 278-283, 2007 Key words: Adenocarcinoma, Prostatespecific antigen, Tumor progression Submitted: Nov 8, 2006; Revised: Jan 2, 2007; Accepted: Jan 23, 2007 Address for correspondence: John D. Hainsworth, MD Sarah Cannon Research Institute and Tennessee Oncology, PLLC, 250 25th Ave N, Suite 110 Nashville, TN 37203 Fax: 615-986-0029; e-mail: [email protected] Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1558-7673, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
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Abstract Background: Docetaxel is currently the standard first-line treatment in patients with hormone-refractory prostate cancer (HRPC). Bortezomib, the first proteasome inhibitor in clinical use, demonstrated activity against prostate cancer in phase I trials. For this reason, we evaluated the efficacy of docetaxel plus bortezomib in the first-line treatment of patients with HRPC. Patients and Methods: Between February 2004 and May 2005, 63 eligible patients entered this phase II trial. All patients had metastatic adenocarcinoma of the prostate that had progressed on hormonal therapy. All patients received docetaxel 30 mg/m2 and bortezomib 1.6 mg/m2 on days 1, 8, and 15 of a 28-day cycle. Patients were reevaluated after 8 weeks of treatment; responding and stable patients continued treatment until tumor progression. Results: Sixty patients (95%) received ≥ 2 courses of treatment and were evaluable for response. Fifteen patients (25%; 95% confidence interval, 15%-38%) had a > 50% decrease in serum prostate-specific antigen level with treatment; the median response duration was 8 months. The median progression-free and overall survival times for the entire group were 4.1 months and 13.8 months, respectively; 20% of patients were alive at 2 years. The regimen was well tolerated, with uncommon grade 3/4 toxicity. Conclusion: Treatment with this combination of weekly docetaxel and bortezomib showed no suggestion of improved efficacy versus previous results with docetaxel alone. Bortezomib has minimal activity in patients with HRPC and is unlikely to make any impact on treatment efficacy.
Introduction In 2005, prostate cancer accounted for > 30,000 deaths in the United States. Until quite recently, systemic therapy was unable to extend survival when patients became refractory to hormonal therapy. Recently, treatment with docetaxel has improved survival compared with mitoxantrone/prednisone in 2 large randomized trials and is currently considered standard first-line therapy.1,2 However, these improvements are quite modest, and better treatment is needed. Bortezomib is a novel proteasome inhibitor that is now a component of standard treatment in patients with multiple myeloma.3 One important consequence of proteasome inhibition is the downregulation of nuclear factor–κB, with resultant inhibition of its effects on cell survival, angiogenesis, and metastasis.4 Nuclear factor–κB is known to be a mediator in
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many solid tumor types, including hormone-refractory prostate cancer (HRPC). Interleukin-6, a surrogate marker of nuclear factor–κB activation, is a known autocrine and paracrine growth factor for prostate cancer.5,6 Therefore, proteasome inhibition by bortezomib might provide a novel therapeutic approach in patients with metastatic prostate cancer. In addition, preclinical studies with the combination of docetaxel (the standard treatment in advanced prostate cancer) plus bortezomib showed additive activity without increased toxicity.7 Therefore, there is strong rationale to evaluate this combination in patients with HRPC. Previous clinical experience has documented activity of bortezomib as a single agent in HRPC. In a phase I study, 2 of 21 patients (10%) with measurable disease had partial responses (PRs); an additional 11 patients had PR (2 patients) or stable/minor response (9 patients) using prostate-specific antigen (PSA) criteria.8 A weekly bortezomib dosing schedule was used in this trial, and the recommended phase II dose was 1.6 mg/m2 administered 4 of every 5 weeks. Subsequently, the combination bortezomib/docetaxel was explored in a phase I trial.9 A tolerable dosing schedule of docetaxel 40 mg/m2 and bortezomib 1.6 mg/m2, each given on days 1 and 8 of a 21-day cycle, was defined. In this multicenter, community-based phase II study, we further evaluated the combination docetaxel/bortezomib as firstline therapy in patients with HRPC. We report the results of this trial after a median follow-up of 21 months.
Patients and Methods Patient Eligibility Eligible patients were required to have histologically confirmed adenocarcinoma of the prostate with demonstrable metastatic disease. In addition, patients were required to be refractory to antiandrogen hormonal therapy, as evidenced by the following: radiographic progression of measurable metastatic disease or serial increase in serum PSA levels in patients with nonmeasurable bone metastases. Patients with cancer progression based on increasing PSA levels were required to have a minimum increase of 5 ng/mL, with documentation of 2 consecutive PSA increases from the baseline value, measured within a minimum interval of 1 week. Patients must have experienced progression while on optimal androgen ablation therapy, documented by castrate serum testosterone levels. Patients could not have received previous chemotherapy for prostate cancer; previous radiation therapy was allowed as long as it encompassed ≤ 25% of the patient’s bone marrow reserve and had been completed > 4 weeks before study entry. Continued antiandrogen therapy was allowed as long as it was maintained throughout the patient’s involvement in this study. If antiandrogen therapy was discontinued before study entry, a ≥ 4-week period of observation followed by a repeat evaluation to document disease progression, as defined previously, was required for inclusion. Additional eligibility criteria included the following: Eastern Cooperative Oncology Group performance status (PS) of 0, 1, or 2; adequate bone marrow function as defined by neutrophil count of ≥ 1500/μL, hemoglobin level > 8 g/dL, and platelet count ≥ 100,000/μL; serum bilirubin < 1.5 mg/dL; serum creatinine level
≤ 2 mg/dL (or calculated glomerular filtration > 60 cm3 per minute). Patients were excluded if they had peripheral neuropathy grade > 1 at baseline. Additionally, exclusion criteria included the following: age < 18 years; history of invasive malignancy during the 3 years before study entry; history of significant cardiac dysfunction, cerebral vascular accident, or other serious illness. All patients gave written informed consent before entering this trial. This clinical trial was approved by the TriStar Institutional Review Board and by the institutional review boards at each participating network site.
Pretreatment Evaluation Before entering this trial, all patients were evaluated with a history and physical examination, an assessment of PS, complete blood counts, serum chemistry profile, serum PSA level, chest radiograph, electrocardiogram, radionuclide bone scan or positron emission tomography scan, and computerized tomography of the pelvis. Patients who had not had previous bilateral orchiectomy had measurement of serum testosterone levels.
Treatment Regimen All patients received docetaxel 30 mg/m2 by 30-minute intravenous (I.V.) infusion and bortezomib 1.6 mg/m2 by I.V. infusion on days 1, 8, and 15 of each 28-day cycle. All patients received prophylaxis with dexamethasone before each dose of docetaxel. Dexamethasone was administered as follows: 4 mg orally 12 hours before docetaxel, 8-16 mg I.V. or orally 30 minutes before docetaxel, and 4 mg orally 12 hours after docetaxel. In addition, patients received antiemetic prophylaxis with a 5-HT3 receptor antagonist before each dose of treatment. Patients who were receiving hormonal therapy at the time of study entry were continued on the same treatment during this clinical trial. Cytokines were not used routinely in this trial; however, cytokines were used in patients who developed neutropenia and fever or symptomatic anemia according to standard guidelines. The use of cytokines could not substitute for protocol-prescribed dose reductions.
Dose Modifications Dosing of bortezomib and docetaxel was based on blood counts and clinical assessment performed before each scheduled dose. On day 1 of each treatment cycle, patients received full doses of both agents if absolute neutrophil count (ANC) was > 1500/μL and platelets were > 100,000/μL. If either count was below this minimum level, doses of bortezomib and docetaxel were withheld for 1 week or until counts had increased to above these minimum levels. At that time, both drugs were restarted with a reduction of 1 dosing level for each drug. If blood counts did not return to minimum levels after a delay of 2 weeks, the patient was removed from study. A maximum of 2 dose level reductions were allowed, as follows: dose level –1: docetaxel 25 mg/m2, bortezomib 1.3 mg/m2; dose level –2: docetaxel 20 mg/m2, bortezomib 1 mg/m2. For dosing on days 8 and 15 of each cycle, full doses of both agents were administered if ANC was > 1500/μL and platelet counts were > 100,000/μL. If the ANC was between 1000/μL
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Table 1 Minnie Pearl Cancer Research Network Participating Sites
Tennessee Oncology, PLLC
Nashville, TN
Wellstar Health System Cancer Research
Marietta, GA
Florida Hospital Cancer Institute
Orlando, FL
Northeast Georgia Medical Center Miami Mercy Hospital/Oncology Radiation Associates Integrated Community Oncology Network Associates in Oncology and Hematology The Cancer Center at Alexian Brothers
Gainesville, GA Miami, FL Orange Park, FL Chattanooga, TN Elk Grove Village, IL
Thompson Cancer Survival Center
Knoxville, TN
Northeast Arkansas Clinic
Jonesboro, AR
Cancer and Blood Institute of the Desert University Oncology Associates, PLLC Nebraska Methodist Hospital Cancer Center Consultants in Medical Oncology and Hematology Watson Clinic Center for Research, Inc. Central Jersey Oncology Center
Rancho Mirage, CA Chattanooga, TN Omaha, NE Drexel Hill, PA Lakeland, FL East Brunswick, NJ
and 1500/μL or platelet counts were between 75,000/μL and 100,000/μL, the docetaxel dose was reduced by 1 level, without modification in bortezomib. If ANC was < 1000/μL or platelet counts < 75,000/μL, doses of both drugs were omitted and resumed at a –1 dose level for all subsequent doses, after recovery of blood counts to minimum levels. Patients who developed neutropenic fever during treatment had dose levels of both drugs reduced by 1 dose level for all subsequent cycles. Dose reductions of bortezomib were specified for patients developing peripheral neuropathy. All patients developing grade 2 neuropathy had the dose of bortezomib reduced by 1 level. If grade 2 neuropathy was accompanied by neuropathic pain, bortezomib was reduced by 2 dose levels. Bortezomib was withheld for grade 3 peripheral neuropathy and was reinstituted at dose level –2 when neuropathy improved to grade ≤ 1. Greater levels of neuropathy required discontinuation of bortezomib. For other grade 3 nonhematologic toxicity, doses of the offending agent or agents were withheld until resolution of the toxicity to grade ≤ 1. Treatment was then reinstituted with a dose reduction of 1 dose level. If grade 3 nonhematologic toxicity recurred after 2 dose reductions, the patient was removed from study. A grade 3 toxicity that had not improved after a dose delay of > 2 weeks required discontinuation of study treatment.
Assessment of Efficacy and Toxicity Patients were evaluated for response to treatment after completing 2 courses of treatment (8 weeks). Reevaluation included repeat measurement of the serum PSA level and repeat of pertinent scans in patients with measurable disease. Patients who had an objective response or stable disease (SD) continued treatment
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and were reevaluated every 8 weeks. Treatment was continued until tumor progression was documented or until the patient was unable to tolerate further treatment. All patients who received ≥ 1 dose of treatment were included in the toxicity analysis. Toxicity was assessed using the World Health Organization Common Toxicity Criteria, version 2.0.
Response Criteria Serial serum PSA measurements were obtained in all patients treated. Prostate-specific antigen responses were defined using the Prostate-Specific Antigen Working Group recommendations.10 Patients with PSA decrease of ≥ 50% that persisted for ≥ 4 weeks were classified as responders. In addition, we report the subset of patients with PSA decrease of > 90%. To be considered a responder, patients were required to have an absolute PSA decrease of ≥ 5 ng/mL. Patients with PSA levels increasing by ≥ 25% were defined as having disease progression. Patients who did not meet criteria for response or progression were considered to have SD. Patients who had measurable lesions, in addition to increased serum PSA levels, were also evaluated for response according to World Health Organization criteria.11
Statistical Methods This phase II study was designed to obtain preliminary information regarding the feasibility, toxicity, and efficacy of weekly docetaxel plus bortezomib in the first-line treatment of patients with metastatic HRPC. Previous large trials using docetaxel as first-line treatment in this patient population documented response rates (RRs; using PSA criteria) of 40%-50%.1,2 Therefore, we felt that demonstration of an RR > 50% would be sufficient to indicate the need for further development of this combination regimen. Accrual of 60 patients to this clinical trial was considered sufficient to establish an RR with standard error of ± 14%. All patients who received 2 courses of treatment were considered evaluable for response, and all patients entered were included in the survival analyses. Progression-free survival (PFS) was calculated from the first day of treatment until the documentation of tumor progression. Overall survival (OS) was calculated from date of first treatment until the date of death. Actuarial survival curves were calculated using the method of Kaplan and Meier.12
Results Patient Characteristics This clinical trial was conducted in the Minnie Pearl Cancer Research Network, a community-based clinical trials group (Table 1). Between February 2004 and May 2005, 65 patients entered this trial. On subsequent review, 2 patients did not meet eligibility criteria for this trial (both had increasing serum PSA levels without detectable metastases) and are excluded from further analysis. The clinical characteristics of the 63 eligible patients are summarized in Table 2. The median patient age was 70 years (range, 49-89 years), and 93% of patients had good PS (Eastern Cooperative Oncology Group 0/1). Nineteen
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John D. Hainsworth et al
Figure 1 Progression-Free Survival for the Entire Group
Table 2 Patient Characteristics (N = 63) Median Age, Years (Range)
Number of Patients (%) 70 (49-89)
Sites of Metastases Bone only
28 (44)
Bone plus other sites
29 (46)
Soft tissue only
6 (10)
Histologic Grade Gleason score < 8
36 (57)
Gleason score 8-10
19 (30)
Not available
8 (13)
100
Progression-Free Survival (%)
Characteristic
Median Progression-Free Survival: 4.1 Months (95% CI, 3.5-5.5) Progression-Free Survival: 1 Year = 7% (4 Patients at Risk) 2 Years = 6% (1 Patient at Risk)
80 60 40 20
0
6
12
0
28 (44)
1
31 (49)
2
4 (6)
30
Figure 2 Overall Survival for the Entire Group 100
Prostatectomy
12 (19)
Radiation therapy (external)
16 (25)
Overall Survival (%)
Primary Treatment
Radiation therapy (implants + external)
24
18
Months
Eastern Cooperative Oncology Group Performance Status
1 (2)
Prostatectomy + radiation therapy
20 (32)
Hormonal therapy only (no local treatment)
14 (22)
Site of Treatment Sarah Cannon Research Institute
29 (46)
Network sites
34 (54)
Median Survival: 13.8 Months (95% CI, 10.1-16.5) 1 Year = 55% (34 Patients at Risk) 2 Years = 20% (2 Patients at Risk)
80 60 40 20
0
6
12
18
24
30
Months
patients (30%) had high-grade histology (Gleason score 8-10). Thirty-five patients (56%) had measurable disease, whereas 28 patients (44%) had metastases limited to osseous sites. Fortynine patients (78%) had received primary therapy with radical prostatectomy, radiation therapy, or both, whereas 14 patients (22%) had metastases at diagnosis and had no specific primary therapy. All 63 patients had experienced progression after ≥ 1 form of androgen ablation therapy.
Treatment Received Sixty patients (95%) received ≥ 2 courses of treatment with docetaxel and bortezomib and were evaluable for response. Three patients did not complete 2 courses of therapy for the following reasons: treatment-related nausea and diarrhea (n = 1), intercurrent illness (n = 1), and poor compliance (n = 1). The median number of treatment courses received was 4 (range, 1-8 courses). During the first 2 treatment courses, the percentages of planned drugs actually administered were as follows: docetaxel 95%; bortezomib 95%.
Efficacy Fifteen of 60 evaluable patients (25%; 95% confidence intervals, 15%-38%) had decrease in serum PSA levels by > 50%;
2 of these patients had a > 90% decrease. An additional 31 patients had SD at the time of first reevaluation; in 18 of these patients, SD persisted for > 3 months. Eight of the 35 patients with measurable disease (23%) had PRs. The median duration of response in patients with partial or complete PSA responses was 8 months (range, 4-27 months). The estimated PFS and OS times for this group of patients are shown in Figures 1 and 2. The median PFS was 4.1 months, with 7% of patients progression-free at 1 year. The median OS was 13.8 months, with 20% of patients alive at 2 years.
Toxicity Treatment-related toxicity is summarized in Table 3. A total of 273 courses was administered, and treatment was generally well tolerated. Grade 3/4 myelosuppression was uncommon; only 2 patients (3%) had grade 3/4 neutropenia, and there were no hospitalizations for treatment of neutropenic fever. Severe grade 4 thrombocytopenia occurred in 1 patient (2%); no platelet transfusions were required. Anemia during treatment was common, occurring in 42% of patients (5% grade 3/4). Thirty-three patients (52%) were treated with erythropoietin agents, and 11 patients required red blood cell transfusions. Fa-
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Table 3 Treatment-Related Toxicity (N = 63; 273 Courses) Toxicity
Grade 2
Grade 3
Grade 4
4 (6)
2 (3)
0
Hematologic Neutropenia Thrombocytopenia
6 (10)
0
1 (2)
Anemia
23 (37)
2 (3)
1 (2)
Febrile neutropenia
0
0
0
Bleeding episodes
0
0
0
Platelet transfusions
0
0
0
RBC transfusion
11 (17)
–
–
Erythropoietin agents used
33 (52)
–
–
Fatigue
22 (35)
8 (13)
1 (2)
Nausea/vomiting
6 (10)
7 (11)
0
Diarrhea
8 (13)
5 (8)
0
Arthralgia/myalgia
4 (6)
2 (3)
0
Nonhematologic
Peripheral neuropathy
with single-agent bortezomib at Memorial Sloan-Kettering Cancer Center, only 2 patients had SD at 12 weeks, whereas all others experienced progression.18 These results are consistent with the results of our phase II trial, which showed no suggestion of enhancement of docetaxel efficacy by the addition of bortezomib. The RR observed in our phase II trial seems somewhat lower than has previously been reported with docetaxel with or without estramustine, although probably with overlapping 95% confidence limits. Several aspects of this trial might have contributed to the lower observed RR. First, a randomized trial reported subsequent to the initiation of our trial suggested that weekly administration of docetaxel is inferior to an every-3-week schedule.1 Second, the dose of weekly docetaxel used in this trial (30 mg/m2) was slightly lower than has been reported in other trials (35 mg/m2). Finally, the percentage of patients with measurable disease (vs. boneonly metastases) was unusually high in our group of patients. Objective RRs in this measurable group have traditionally been lower than those in the patients measured by PSA response only. In previous trials, single-agent docetaxel has produced RRs of 20%-30% in the subgroup of patients with measurable disease, similar to our results.
4 (6)
1 (2)
0
Edema
10 (16)
0
0
Skin/nail toxicity
10 (16)
0
0
Hyperlacrimation
2 (3)
0
0
Conclusion
Alopecia
3 (5)
–
–
0
–
–
The combination of weekly docetaxel and bortezomib used in this clinical trial showed no suggestion of improved activity compared with previous results with docetaxel alone. The results of this trial and others suggest that bortezomib has limited activity in the treatment of patients with HRPC and is unlikely to play a role in the treatment of patients with this disease.
Treatment-Related Death Values in parentheses are percentages. Abbreviation: RBC = red blood cell
tigue was the most common nonhematologic toxicity, occurring in 50% of patients (15% grade 3/4). Only 1 patient developed severe (grade 3) neuropathy; an additional 4 patients (6%) had grade 2 neuropathy. Toxicities previously described with weekly docetaxel (skin/nail toxicity, hyperlacrimation, edema, and alopecia) occurred in a minority of patients, but were usually grade ≤ 2. Overall, 5 patients (8%) were removed prematurely from treatment because of toxicity (persistent nausea/vomiting/diarrhea, n = 2; peripheral neuropathy, n = 2; severe fatigue/debility, n = 1). There were no treatment-related deaths.
Discussion In this phase II trial, we documented an overall RR of 25%, with an additional 30% of patients stable for ≥ 3 months on treatment. This combination of weekly docetaxel and bortezomib was well tolerated, with uncommon grade 3/4 toxicity. However, results in this phase II trial do not suggest any improvement in therapy compared with previous results with single-agent docetaxel or docetaxel/estramustine. In multiple phase II/III trials, the RR with docetaxel with or without estramustine has ranged from 40% to 50%.1,2,13-17 Although phase I trials suggested activity for bortezomib in patients with HRPC,8 more recent clinical trials have been disappointing. In a group of 22 evaluable patients treated
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Acknowledgement This study was funded in part by grants from Millennium Pharmaceuticals, Inc, sanofi-aventis, and the Minnie Pearl Foundation.
References 1. Petrylak DP, Tangen CM, Hussain MHA, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004; 351:1513-1520. 2. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351:1502-1512. 3. Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or highdose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005; 352:2487-2498. 4. Huang S, Pettaway CA, Vehara H, et al. Blockade of NF-kappa B activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis. Oncogene 2001; 20:4188-4197. 5. Giri D, Ozen M, Ittmann M. Interleukin-6 is an autocrine growth factor in human prostate cancer. Am J Pathol 2001; 159:2159-2165. 6. Okamoto M, Lee C, Oyasu R. Interleukin-6 as a paracrine and autocrine growth factor in human prostatic carcinoma cells in vitro. Cancer Res 1997; 57:141-146. 7. Nawrocki ST, Sweeney-Gotsch B, Takamori R, et al. The proteasome inhibitor bortezomib enhances the activity of docetaxel in orthotopic human pancreatic tumor xenografts. Mol Cancer Ther 2004; 3:59-70. 8. Goy A, Younes A, McLaughlin P, et al. Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin’s lymphoma. J Clin Oncol 2005; 23:667-675.
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John D. Hainsworth et al 9. O’Connor OA, Wright J, Moskowitz C, et al. Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin’s lymphoma and mantle cell lymphoma. J Clin Oncol 2005; 23:676-684. 10. Bubley GJ, Carducci M, Dahut W, et al. Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol 1999; 17:3461-3467. 11. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92:205216. 12. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53:457-481. 13. Savarese DM, Halabi S, Hars V, et al. Phase II study of docetaxel, estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: a final report of CALGB 9780. J Clin Oncol 2001; 19:2509-2516.
14. Sinibaldi VJ, Carducci MA, Moore-Cooper S, et al. Phase II evaluation of docetaxel plus one-day oral estramustine phosphate in the treatment of patients with androgen independent prostate carcinoma. Cancer 2002; 94:1457-1465. 15. Gravis G, Bladou F, Salem N, et al. Weekly administration of docetaxel for symptomatic metastatic hormone-refractory prostate carcinoma: evaluation of clinical benefit, quality of life, and tolerance. Cancer 2003; 98:16271634. 16. Beer TM, Berry W, Wersinger EM, et al. Weekly docetaxel in elderly patients with prostate cancer. Efficacy and toxicity in patients at least 70 years of age compared with patients younger than 70 years. Clin Prostate Cancer 2003; 2:167-172. 17. Goodman S, Medina P, Capanna T, et al. Effect of docetaxel in patients with hormone-dependent prostate-specific antigen progression after local therapy for prostate cancer. J Clin Oncol 2005; 23:3351-3357. 18. Morris MJ, Beekman KW, Kelly WK, et al. Phase II study of bortezomib for castrate metastatic prostate cancer. J Clin Oncol 2005; 23(16 suppl):411s (Abstract #4633).
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Weekly Docetaxel and Bortezomib as First-Line Treatment for Patients with Hormone-Refractory Prostate Cancer: A Minnie Pearl Cancer Research Network Phase II Trial John D. Hainsworth1 Anthony A. Meluch1 David R. Spigel1 John Barton, Jr1 Lisa Simons1 Christina Meng1 Bruce Gould2 F. Anthony Greco1 1Sarah
Cannon Research Institute and Tennessee Oncology, PLLC, Nashville 2Wellstar Health System Cancer Research, Marietta, GA
Clinical Genitourinary Cancer, Vol. 5, No. 4, 278-283, 2007 Key words: Adenocarcinoma, Prostatespecific antigen, Tumor progression Submitted: Nov 8, 2006; Revised: Jan 2, 2007; Accepted: Jan 23, 2007 Address for correspondence: John D. Hainsworth, MD Sarah Cannon Research Institute and Tennessee Oncology, PLLC, 250 25th Ave N, Suite 110 Nashville, TN 37203 Fax: 615-986-0029; e-mail: [email protected] Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1558-7673, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
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Abstract Background: Docetaxel is currently the standard first-line treatment in patients with hormone-refractory prostate cancer (HRPC). Bortezomib, the first proteasome inhibitor in clinical use, demonstrated activity against prostate cancer in phase I trials. For this reason, we evaluated the efficacy of docetaxel plus bortezomib in the first-line treatment of patients with HRPC. Patients and Methods: Between February 2004 and May 2005, 63 eligible patients entered this phase II trial. All patients had metastatic adenocarcinoma of the prostate that had progressed on hormonal therapy. All patients received docetaxel 30 mg/m2 and bortezomib 1.6 mg/m2 on days 1, 8, and 15 of a 28-day cycle. Patients were reevaluated after 8 weeks of treatment; responding and stable patients continued treatment until tumor progression. Results: Sixty patients (95%) received ≥ 2 courses of treatment and were evaluable for response. Fifteen patients (25%; 95% confidence interval, 15%-38%) had a > 50% decrease in serum prostate-specific antigen level with treatment; the median response duration was 8 months. The median progression-free and overall survival times for the entire group were 4.1 months and 13.8 months, respectively; 20% of patients were alive at 2 years. The regimen was well tolerated, with uncommon grade 3/4 toxicity. Conclusion: Treatment with this combination of weekly docetaxel and bortezomib showed no suggestion of improved efficacy versus previous results with docetaxel alone. Bortezomib has minimal activity in patients with HRPC and is unlikely to make any impact on treatment efficacy.
Introduction In 2005, prostate cancer accounted for > 30,000 deaths in the United States. Until quite recently, systemic therapy was unable to extend survival when patients became refractory to hormonal therapy. Recently, treatment with docetaxel has improved survival compared with mitoxantrone/prednisone in 2 large randomized trials and is currently considered standard first-line therapy.1,2 However, these improvements are quite modest, and better treatment is needed. Bortezomib is a novel proteasome inhibitor that is now a component of standard treatment in patients with multiple myeloma.3 One important consequence of proteasome inhibition is the downregulation of nuclear factor–κB, with resultant inhibition of its effects on cell survival, angiogenesis, and metastasis.4 Nuclear factor–κB is known to be a mediator in
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many solid tumor types, including hormone-refractory prostate cancer (HRPC). Interleukin-6, a surrogate marker of nuclear factor–κB activation, is a known autocrine and paracrine growth factor for prostate cancer.5,6 Therefore, proteasome inhibition by bortezomib might provide a novel therapeutic approach in patients with metastatic prostate cancer. In addition, preclinical studies with the combination of docetaxel (the standard treatment in advanced prostate cancer) plus bortezomib showed additive activity without increased toxicity.7 Therefore, there is strong rationale to evaluate this combination in patients with HRPC. Previous clinical experience has documented activity of bortezomib as a single agent in HRPC. In a phase I study, 2 of 21 patients (10%) with measurable disease had partial responses (PRs); an additional 11 patients had PR (2 patients) or stable/minor response (9 patients) using prostate-specific antigen (PSA) criteria.8 A weekly bortezomib dosing schedule was used in this trial, and the recommended phase II dose was 1.6 mg/m2 administered 4 of every 5 weeks. Subsequently, the combination bortezomib/docetaxel was explored in a phase I trial.9 A tolerable dosing schedule of docetaxel 40 mg/m2 and bortezomib 1.6 mg/m2, each given on days 1 and 8 of a 21-day cycle, was defined. In this multicenter, community-based phase II study, we further evaluated the combination docetaxel/bortezomib as firstline therapy in patients with HRPC. We report the results of this trial after a median follow-up of 21 months.
Patients and Methods Patient Eligibility Eligible patients were required to have histologically confirmed adenocarcinoma of the prostate with demonstrable metastatic disease. In addition, patients were required to be refractory to antiandrogen hormonal therapy, as evidenced by the following: radiographic progression of measurable metastatic disease or serial increase in serum PSA levels in patients with nonmeasurable bone metastases. Patients with cancer progression based on increasing PSA levels were required to have a minimum increase of 5 ng/mL, with documentation of 2 consecutive PSA increases from the baseline value, measured within a minimum interval of 1 week. Patients must have experienced progression while on optimal androgen ablation therapy, documented by castrate serum testosterone levels. Patients could not have received previous chemotherapy for prostate cancer; previous radiation therapy was allowed as long as it encompassed ≤ 25% of the patient’s bone marrow reserve and had been completed > 4 weeks before study entry. Continued antiandrogen therapy was allowed as long as it was maintained throughout the patient’s involvement in this study. If antiandrogen therapy was discontinued before study entry, a ≥ 4-week period of observation followed by a repeat evaluation to document disease progression, as defined previously, was required for inclusion. Additional eligibility criteria included the following: Eastern Cooperative Oncology Group performance status (PS) of 0, 1, or 2; adequate bone marrow function as defined by neutrophil count of ≥ 1500/μL, hemoglobin level > 8 g/dL, and platelet count ≥ 100,000/μL; serum bilirubin < 1.5 mg/dL; serum creatinine level
≤ 2 mg/dL (or calculated glomerular filtration > 60 cm3 per minute). Patients were excluded if they had peripheral neuropathy grade > 1 at baseline. Additionally, exclusion criteria included the following: age < 18 years; history of invasive malignancy during the 3 years before study entry; history of significant cardiac dysfunction, cerebral vascular accident, or other serious illness. All patients gave written informed consent before entering this trial. This clinical trial was approved by the TriStar Institutional Review Board and by the institutional review boards at each participating network site.
Pretreatment Evaluation Before entering this trial, all patients were evaluated with a history and physical examination, an assessment of PS, complete blood counts, serum chemistry profile, serum PSA level, chest radiograph, electrocardiogram, radionuclide bone scan or positron emission tomography scan, and computerized tomography of the pelvis. Patients who had not had previous bilateral orchiectomy had measurement of serum testosterone levels.
Treatment Regimen All patients received docetaxel 30 mg/m2 by 30-minute intravenous (I.V.) infusion and bortezomib 1.6 mg/m2 by I.V. infusion on days 1, 8, and 15 of each 28-day cycle. All patients received prophylaxis with dexamethasone before each dose of docetaxel. Dexamethasone was administered as follows: 4 mg orally 12 hours before docetaxel, 8-16 mg I.V. or orally 30 minutes before docetaxel, and 4 mg orally 12 hours after docetaxel. In addition, patients received antiemetic prophylaxis with a 5-HT3 receptor antagonist before each dose of treatment. Patients who were receiving hormonal therapy at the time of study entry were continued on the same treatment during this clinical trial. Cytokines were not used routinely in this trial; however, cytokines were used in patients who developed neutropenia and fever or symptomatic anemia according to standard guidelines. The use of cytokines could not substitute for protocol-prescribed dose reductions.
Dose Modifications Dosing of bortezomib and docetaxel was based on blood counts and clinical assessment performed before each scheduled dose. On day 1 of each treatment cycle, patients received full doses of both agents if absolute neutrophil count (ANC) was > 1500/μL and platelets were > 100,000/μL. If either count was below this minimum level, doses of bortezomib and docetaxel were withheld for 1 week or until counts had increased to above these minimum levels. At that time, both drugs were restarted with a reduction of 1 dosing level for each drug. If blood counts did not return to minimum levels after a delay of 2 weeks, the patient was removed from study. A maximum of 2 dose level reductions were allowed, as follows: dose level –1: docetaxel 25 mg/m2, bortezomib 1.3 mg/m2; dose level –2: docetaxel 20 mg/m2, bortezomib 1 mg/m2. For dosing on days 8 and 15 of each cycle, full doses of both agents were administered if ANC was > 1500/μL and platelet counts were > 100,000/μL. If the ANC was between 1000/μL
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Table 1 Minnie Pearl Cancer Research Network Participating Sites
Tennessee Oncology, PLLC
Nashville, TN
Wellstar Health System Cancer Research
Marietta, GA
Florida Hospital Cancer Institute
Orlando, FL
Northeast Georgia Medical Center Miami Mercy Hospital/Oncology Radiation Associates Integrated Community Oncology Network Associates in Oncology and Hematology The Cancer Center at Alexian Brothers
Gainesville, GA Miami, FL Orange Park, FL Chattanooga, TN Elk Grove Village, IL
Thompson Cancer Survival Center
Knoxville, TN
Northeast Arkansas Clinic
Jonesboro, AR
Cancer and Blood Institute of the Desert University Oncology Associates, PLLC Nebraska Methodist Hospital Cancer Center Consultants in Medical Oncology and Hematology Watson Clinic Center for Research, Inc. Central Jersey Oncology Center
Rancho Mirage, CA Chattanooga, TN Omaha, NE Drexel Hill, PA Lakeland, FL East Brunswick, NJ
and 1500/μL or platelet counts were between 75,000/μL and 100,000/μL, the docetaxel dose was reduced by 1 level, without modification in bortezomib. If ANC was < 1000/μL or platelet counts < 75,000/μL, doses of both drugs were omitted and resumed at a –1 dose level for all subsequent doses, after recovery of blood counts to minimum levels. Patients who developed neutropenic fever during treatment had dose levels of both drugs reduced by 1 dose level for all subsequent cycles. Dose reductions of bortezomib were specified for patients developing peripheral neuropathy. All patients developing grade 2 neuropathy had the dose of bortezomib reduced by 1 level. If grade 2 neuropathy was accompanied by neuropathic pain, bortezomib was reduced by 2 dose levels. Bortezomib was withheld for grade 3 peripheral neuropathy and was reinstituted at dose level –2 when neuropathy improved to grade ≤ 1. Greater levels of neuropathy required discontinuation of bortezomib. For other grade 3 nonhematologic toxicity, doses of the offending agent or agents were withheld until resolution of the toxicity to grade ≤ 1. Treatment was then reinstituted with a dose reduction of 1 dose level. If grade 3 nonhematologic toxicity recurred after 2 dose reductions, the patient was removed from study. A grade 3 toxicity that had not improved after a dose delay of > 2 weeks required discontinuation of study treatment.
Assessment of Efficacy and Toxicity Patients were evaluated for response to treatment after completing 2 courses of treatment (8 weeks). Reevaluation included repeat measurement of the serum PSA level and repeat of pertinent scans in patients with measurable disease. Patients who had an objective response or stable disease (SD) continued treatment
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and were reevaluated every 8 weeks. Treatment was continued until tumor progression was documented or until the patient was unable to tolerate further treatment. All patients who received ≥ 1 dose of treatment were included in the toxicity analysis. Toxicity was assessed using the World Health Organization Common Toxicity Criteria, version 2.0.
Response Criteria Serial serum PSA measurements were obtained in all patients treated. Prostate-specific antigen responses were defined using the Prostate-Specific Antigen Working Group recommendations.10 Patients with PSA decrease of ≥ 50% that persisted for ≥ 4 weeks were classified as responders. In addition, we report the subset of patients with PSA decrease of > 90%. To be considered a responder, patients were required to have an absolute PSA decrease of ≥ 5 ng/mL. Patients with PSA levels increasing by ≥ 25% were defined as having disease progression. Patients who did not meet criteria for response or progression were considered to have SD. Patients who had measurable lesions, in addition to increased serum PSA levels, were also evaluated for response according to World Health Organization criteria.11
Statistical Methods This phase II study was designed to obtain preliminary information regarding the feasibility, toxicity, and efficacy of weekly docetaxel plus bortezomib in the first-line treatment of patients with metastatic HRPC. Previous large trials using docetaxel as first-line treatment in this patient population documented response rates (RRs; using PSA criteria) of 40%-50%.1,2 Therefore, we felt that demonstration of an RR > 50% would be sufficient to indicate the need for further development of this combination regimen. Accrual of 60 patients to this clinical trial was considered sufficient to establish an RR with standard error of ± 14%. All patients who received 2 courses of treatment were considered evaluable for response, and all patients entered were included in the survival analyses. Progression-free survival (PFS) was calculated from the first day of treatment until the documentation of tumor progression. Overall survival (OS) was calculated from date of first treatment until the date of death. Actuarial survival curves were calculated using the method of Kaplan and Meier.12
Results Patient Characteristics This clinical trial was conducted in the Minnie Pearl Cancer Research Network, a community-based clinical trials group (Table 1). Between February 2004 and May 2005, 65 patients entered this trial. On subsequent review, 2 patients did not meet eligibility criteria for this trial (both had increasing serum PSA levels without detectable metastases) and are excluded from further analysis. The clinical characteristics of the 63 eligible patients are summarized in Table 2. The median patient age was 70 years (range, 49-89 years), and 93% of patients had good PS (Eastern Cooperative Oncology Group 0/1). Nineteen
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Figure 1 Progression-Free Survival for the Entire Group
Table 2 Patient Characteristics (N = 63) Median Age, Years (Range)
Number of Patients (%) 70 (49-89)
Sites of Metastases Bone only
28 (44)
Bone plus other sites
29 (46)
Soft tissue only
6 (10)
Histologic Grade Gleason score < 8
36 (57)
Gleason score 8-10
19 (30)
Not available
8 (13)
100
Progression-Free Survival (%)
Characteristic
Median Progression-Free Survival: 4.1 Months (95% CI, 3.5-5.5) Progression-Free Survival: 1 Year = 7% (4 Patients at Risk) 2 Years = 6% (1 Patient at Risk)
80 60 40 20
0
6
12
0
28 (44)
1
31 (49)
2
4 (6)
30
Figure 2 Overall Survival for the Entire Group 100
Prostatectomy
12 (19)
Radiation therapy (external)
16 (25)
Overall Survival (%)
Primary Treatment
Radiation therapy (implants + external)
24
18
Months
Eastern Cooperative Oncology Group Performance Status
1 (2)
Prostatectomy + radiation therapy
20 (32)
Hormonal therapy only (no local treatment)
14 (22)
Site of Treatment Sarah Cannon Research Institute
29 (46)
Network sites
34 (54)
Median Survival: 13.8 Months (95% CI, 10.1-16.5) 1 Year = 55% (34 Patients at Risk) 2 Years = 20% (2 Patients at Risk)
80 60 40 20
0
6
12
18
24
30
Months
patients (30%) had high-grade histology (Gleason score 8-10). Thirty-five patients (56%) had measurable disease, whereas 28 patients (44%) had metastases limited to osseous sites. Fortynine patients (78%) had received primary therapy with radical prostatectomy, radiation therapy, or both, whereas 14 patients (22%) had metastases at diagnosis and had no specific primary therapy. All 63 patients had experienced progression after ≥ 1 form of androgen ablation therapy.
Treatment Received Sixty patients (95%) received ≥ 2 courses of treatment with docetaxel and bortezomib and were evaluable for response. Three patients did not complete 2 courses of therapy for the following reasons: treatment-related nausea and diarrhea (n = 1), intercurrent illness (n = 1), and poor compliance (n = 1). The median number of treatment courses received was 4 (range, 1-8 courses). During the first 2 treatment courses, the percentages of planned drugs actually administered were as follows: docetaxel 95%; bortezomib 95%.
Efficacy Fifteen of 60 evaluable patients (25%; 95% confidence intervals, 15%-38%) had decrease in serum PSA levels by > 50%;
2 of these patients had a > 90% decrease. An additional 31 patients had SD at the time of first reevaluation; in 18 of these patients, SD persisted for > 3 months. Eight of the 35 patients with measurable disease (23%) had PRs. The median duration of response in patients with partial or complete PSA responses was 8 months (range, 4-27 months). The estimated PFS and OS times for this group of patients are shown in Figures 1 and 2. The median PFS was 4.1 months, with 7% of patients progression-free at 1 year. The median OS was 13.8 months, with 20% of patients alive at 2 years.
Toxicity Treatment-related toxicity is summarized in Table 3. A total of 273 courses was administered, and treatment was generally well tolerated. Grade 3/4 myelosuppression was uncommon; only 2 patients (3%) had grade 3/4 neutropenia, and there were no hospitalizations for treatment of neutropenic fever. Severe grade 4 thrombocytopenia occurred in 1 patient (2%); no platelet transfusions were required. Anemia during treatment was common, occurring in 42% of patients (5% grade 3/4). Thirty-three patients (52%) were treated with erythropoietin agents, and 11 patients required red blood cell transfusions. Fa-
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Table 3 Treatment-Related Toxicity (N = 63; 273 Courses) Toxicity
Grade 2
Grade 3
Grade 4
4 (6)
2 (3)
0
Hematologic Neutropenia Thrombocytopenia
6 (10)
0
1 (2)
Anemia
23 (37)
2 (3)
1 (2)
Febrile neutropenia
0
0
0
Bleeding episodes
0
0
0
Platelet transfusions
0
0
0
RBC transfusion
11 (17)
–
–
Erythropoietin agents used
33 (52)
–
–
Fatigue
22 (35)
8 (13)
1 (2)
Nausea/vomiting
6 (10)
7 (11)
0
Diarrhea
8 (13)
5 (8)
0
Arthralgia/myalgia
4 (6)
2 (3)
0
Nonhematologic
Peripheral neuropathy
with single-agent bortezomib at Memorial Sloan-Kettering Cancer Center, only 2 patients had SD at 12 weeks, whereas all others experienced progression.18 These results are consistent with the results of our phase II trial, which showed no suggestion of enhancement of docetaxel efficacy by the addition of bortezomib. The RR observed in our phase II trial seems somewhat lower than has previously been reported with docetaxel with or without estramustine, although probably with overlapping 95% confidence limits. Several aspects of this trial might have contributed to the lower observed RR. First, a randomized trial reported subsequent to the initiation of our trial suggested that weekly administration of docetaxel is inferior to an every-3-week schedule.1 Second, the dose of weekly docetaxel used in this trial (30 mg/m2) was slightly lower than has been reported in other trials (35 mg/m2). Finally, the percentage of patients with measurable disease (vs. boneonly metastases) was unusually high in our group of patients. Objective RRs in this measurable group have traditionally been lower than those in the patients measured by PSA response only. In previous trials, single-agent docetaxel has produced RRs of 20%-30% in the subgroup of patients with measurable disease, similar to our results.
4 (6)
1 (2)
0
Edema
10 (16)
0
0
Skin/nail toxicity
10 (16)
0
0
Hyperlacrimation
2 (3)
0
0
Conclusion
Alopecia
3 (5)
–
–
0
–
–
The combination of weekly docetaxel and bortezomib used in this clinical trial showed no suggestion of improved activity compared with previous results with docetaxel alone. The results of this trial and others suggest that bortezomib has limited activity in the treatment of patients with HRPC and is unlikely to play a role in the treatment of patients with this disease.
Treatment-Related Death Values in parentheses are percentages. Abbreviation: RBC = red blood cell
tigue was the most common nonhematologic toxicity, occurring in 50% of patients (15% grade 3/4). Only 1 patient developed severe (grade 3) neuropathy; an additional 4 patients (6%) had grade 2 neuropathy. Toxicities previously described with weekly docetaxel (skin/nail toxicity, hyperlacrimation, edema, and alopecia) occurred in a minority of patients, but were usually grade ≤ 2. Overall, 5 patients (8%) were removed prematurely from treatment because of toxicity (persistent nausea/vomiting/diarrhea, n = 2; peripheral neuropathy, n = 2; severe fatigue/debility, n = 1). There were no treatment-related deaths.
Discussion In this phase II trial, we documented an overall RR of 25%, with an additional 30% of patients stable for ≥ 3 months on treatment. This combination of weekly docetaxel and bortezomib was well tolerated, with uncommon grade 3/4 toxicity. However, results in this phase II trial do not suggest any improvement in therapy compared with previous results with single-agent docetaxel or docetaxel/estramustine. In multiple phase II/III trials, the RR with docetaxel with or without estramustine has ranged from 40% to 50%.1,2,13-17 Although phase I trials suggested activity for bortezomib in patients with HRPC,8 more recent clinical trials have been disappointing. In a group of 22 evaluable patients treated
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Acknowledgement This study was funded in part by grants from Millennium Pharmaceuticals, Inc, sanofi-aventis, and the Minnie Pearl Foundation.
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