• docetaxel;
  • bevacizumab;
  • castrate-resistant prostate cancer;
  • progression-free survival


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  2. Abstract


The use of docetaxel prolongs survival for patients with castrate-resistant prostate cancer (CRPC). Inhibition of vascular endothelial growth factor (VEGF) with bevacizumab may further enhance the antitumor effect of docetaxel and estramustine in patients with CRPC.


This cooperative group trial enrolled men with CRPC. Patients received oral estramustine 280 mg 3 times daily on Days 1 through 5 of every cycle plus 70 mg/m2 docetaxel and 15 mg/kg bevacizumab on Day 2 every 3 weeks. Prostate-specific antigen (PSA) values were monitored every cycle, and imaging studies were obtained every 3 cycles. The primary endpoint was progression-free survival (PFS), and the secondary objectives were safety, PSA decline, measurable disease response, and overall survival.


Seventy-nine patients were enrolled; and 77 patients received a median of 8 cycles and were evaluable. A 50% PSA decline was observed in 58 patients (75%). Twenty-three of 39 patients with measurable disease had a partial response (59%). The median PFS was 8 months, and the overall median survival was 24 months. Neutropenia without fever (69%), fatigue (25%), and thrombosis/emboli (9%) were the most common severe toxicities. Twenty-four of 77 patients were removed from protocol treatment because of disease progression, 35 of 77 patients were removed because of a physician or patient decision, and 15 patients were removed secondary to toxicity.


The combination of docetaxel, estramustine, and bevacizumab was tolerable but complicated by toxicity. Although the endpoint of PFS did not meet the desired level, encouraging antitumor activity and overall survival were observed. Further phase 3 evaluation of the role of bevacizumab in CRPC is ongoing. Cancer 2011. © 2010 American Cancer Society.

Metastatic prostate cancer often is treated by castration, which provides temporary palliation of symptoms and control of tumor growth.1 In the past, treatment for patients with castrate-resistant prostate cancer (CRPC) was focused on palliative therapy; however, the introduction of docetaxel-based therapies has led to improved survival. The use of docetaxel has exhibited a survival advantage over mitoxantrone and has become standard treatment for patients with CRPC.2, 3 However, the overall survival advantage of 2.9 months is modest, and further therapies that improve the survival of patients who receive docetaxel-based therapies are needed.4

Before the completion of the phase 3 trials of docetaxel versus mitoxantrone, the Cancer and Leukemia Group B (CALGB) developed a series of sequential studies to evaluate the addition of novel agents to the docetaxel backbone. The addition of carboplatin was tolerated but increased the myelosuppression of the regimen without any clear signal of increased activity.5 Exisulind, which investigators believed would induce apoptosis in malignant cells, also was combined with docetaxel and estramustine,6 but significant morbidity was associated with that combination without a substantial improvement in efficacy.

Vascular endothelial growth factor (VEGF) is a glycoprotein that is important in promoting tumor angiogenesis7, 8 and plays a critical role in the progression of human prostate cancer. The fms-like tyrosine kinase/kinase insert domain receptor (Flk-1/KDR) receptors are expressed in human prostate cancers and are correlated with higher grade lesions and outcome.9 Expression of VEGF is observed in prostate tumors and in plasma and urine from patients with metastatic disease, and increasing VEGF expression is correlated with disease progression.10, 11 Studies have demonstrated that plasma and urine VEGF levels in patients with CRPC are independent predictors of survival.12, 13 Therefore, we believed that bevacizumab, a humanized murine monoclonal antibody that neutralizes VEGF activity, would be a reasonable therapeutic approach for the treatment of advanced prostate cancer. In a single-center study with bevacizumab administered at a dose of 10 mg/kg every 2 weeks to 15 patients with CRPC, bevacizumab was well tolerated. However, as expected with this class of agents, minimal evidence of activity was observed with monotherapy.14 Evolving data in other cancers suggested that the overall benefit of VEGF blockade is more apparent when bevacizumab is combined with a cytotoxic agent. On the basis of the compelling in vivo data, the established importance of circulating VEGF levels in CRPC, and the safety of bevacizumab, we conducted a multi-institutional trial of combined docetaxel, estramustine, and bevacizumab.


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  2. Abstract

Patient Selection

This study was approved by the Executive Committee of the CALGB and by the institutional review board at each participating site. All patients provided written, informed consent. All patients were required to have evidence of metastatic prostate cancer despite castrate levels of testosterone (≤50 ng/mL). Patients also were required to have evidence of progressive metastatic disease with documented, measurable disease progression on cross-sectional imaging, new lesions on a bone scan, or 2 sequential rises in PSA with a baseline PSA >5 ng/mL. Antiandrogens and megestrol acetate had to be discontinued for at least 4 weeks before registration, and patients were required to have evidence of progression noted after those agents were discontinued. All patients were required to continue receiving a luteinizing hormone-releasing hormone (LHRH) agonist if they had not undergone orchiectomy. Patients were not allowed to have received prior cytotoxic therapy or other antiangiogenesis agents, including thalidomide. Patients may have undergone major surgery or received radiation therapy only if it was at least 4 weeks before study entry and may have received radionuclide therapy only if it was at least 8 weeks before study entry. All patients had to have an Eastern Cooperative Oncology Group (ECOG) performance status ≤2; no significant peripheral neuropathy; and no prior myocardial infarction, deep venous thrombosis, pulmonary embolus, or other major thromboembolic event within 1 year of entry. Patients who required full-dose anticoagulation also were excluded. Patients were required to have a granulocyte count >1500/μL, a platelet count >100,000/μL, a creatinine level <1.5 times the upper limit of normal (ULN), a bilirubin level less than the ULN, an aspartate aminotransferase level <1.5 times the ULN, and a dipstick urinalysis ≤1+ protein. Patients who had received stable bisphosphonate therapy for at least 4 weeks before entry were allowed to continue, but initiation of bisphosphonate therapy was not allowed.

Treatment and Evaluation

Therapy was based on 21-day cycles. Patients received estramustine phosphate (Emcyt; Pharmacia Oncology, Peapack, NJ) 280 mg 3 times daily on Days 1 through 5, decadron 8 mg twice daily on Days 1 through 3, docetaxel (Taxotere; Sanofi-Aventis, Bridgewater, NJ) 70 mg/m2 on Day 2 intravenously over 1 hour, and bevacizumab (supplied by Genentech Inc., South San Francisco, Calif; distributed by the National Cancer Institute, Bethesda, Md) 15 mg/kg administered intravenously after docetaxel on Day 2. The first infusion of bevacizumab was administered over 90 minutes, the second infusion was administered over 60 minutes, and the third and subsequent doses were administered over 30 minutes if the drug was well tolerated. The bevacizumab dose was 5 mg/kg weekly, consistent with most other malignancies, and it was given every 3 weeks in coordination with chemotherapy administration. Warfarin 2 mg daily was encouraged but not mandated as prophylaxis for thrombosis from estramustine unless a contraindication existed. Hematologic growth factors were allowed according to American Society of Clinical guidelines, but prophylactic use was not allowed.

Patients were evaluated every cycle for PSA levels and every third cycle with bone scans and computed tomography scans of the abdomen and pelvis. Patients were encouraged to have their blood pressure monitored weekly, and weekly blood counts were required. Liver function tests, including bilirubin, transaminase levels, and alkaline phosphatase levels, along with urinalyses were required before the administration of chemotherapy at each cycle.

The therapy was withheld for an absolute neutrophil count <1500/μL, for a platelet count <100,000/μL (with a dose reduction to 75% of the starting docetaxel dose upon recovery), or for any episode of febrile neutropenia. For aspartate aminotransferase elevations >1.5 times the ULN, the dose of docetaxel was reduced to 60 mg/m2; and, for bilirubin levels >1.5 times the ULN or aspartate aminotransferase levels >5 times the ULN, the docetaxel dose was withheld. When the docetaxel dose was withheld, the estramustine and bevacizumab doses also were withheld. For grade 2 neurotoxicity, the estramustine was reduced by 50%, and it was withheld for grade 3 toxicity. For grade 3 neurotoxicity, the docetaxel dose was reduced to 75%. For persistent grade 3 neurotoxicity, the docetaxel was withheld. If chemotherapy was withheld for >3 weeks, then the patient was removed from protocol treatment. For thromboembolic events, once anticoagulated, patients were allowed to continue on protocol with discontinuation of bevacizumab and estramustine. For proteinuria >2+ on a dipstick urinalysis, a 24-hour urine protein measurement was required; and, if the protein level was >2000 mg daily, then bevacizumab was withheld.

Disease progression and response were based on PSA Working Group Consensus Criteria,15 and the Response Evaluation Criteria in Solid Tumors (RECIST) were used to evaluate patients who had measurable disease. Bone scan progression was defined as any new lesions.

Statistical Design and Data Analysis

The primary endpoint of this study was time to progression. PFS was defined as the interval between treatment initiation and the date of progression or death, whichever occurred first. Sample size computation was based on the primary endpoint. The null hypothesis was that the median time to progression would ≤11 months, and the alternative hypothesis was that the median time to progression would be ≥16 months (a 45% increase). The target sample size was 79 patients assuming an ineligibility rate of 10%. The normal approximation to the exact exponential test was used for sample size computation, and the following assumptions were made: 1) a type I error rate of .05, 2) power = 89% (type II error rate = 11%), 3) an accrual rate of 4 patients per month over a 18-month accrual period, 4) a 24-month follow-up period, and 5) the time to progression would follow an exponential distribution. Under the alternative hypothesis, 55 progression events were expected at the end of the trial.

Toxicity was an important secondary endpoint, with a hypothesized null hypothesis that the acceptable toxicity probability was ≤.80 versus the alternative hypothesis that the acceptable toxicity probability was ≥.90. Unacceptable toxicity was defined as death, grade 4 febrile neutropenia, or any serious grade 3 or grade 4 toxicity, excluding nausea, vomiting, alopecia, or hypersensitivity. For the purpose of this study, “serious” toxicity was defined as cardiac toxicity, thrombosis/embolism, or central nervous system hemorrhage/bleeding. Toxicity was monitored using a 3-stage design after 15 patients, 35 patients, and 72 patients were enrolled and received 1 full cycle of therapy. This design had a type I error rate of .10 and a power of 89% based on binomial simulations. The decision rules for the continuation of accrual required that at least 11 of 15 patients, at least 27 of 35 patients, and at least 62 of 72 did not experience unacceptable toxicity.

Other endpoints that we considered were PSA PFS, overall survival, the duration of objective response, and the duration of PSA decline. PFS was defined as the interval between treatment initiation and the date of any disease progression (bone, PSA PFS, soft tissue), or clinical deterioration, or death, whichever occurred first. PSA PFS was defined as the time to first biochemical progression using the PSA consensus criteria or death, whichever occurred first. Overall survival was defined as the interval between treatment initiation and the date of death. The duration of response was calculated from the date of the first complete or partial response to the date that the patient had disease progression. The duration of PSA response was defined as the interval between the date of the first 50% PSA decline to the date when the patient met the criteria for disease progression. The 95% confidence interval (CI) for the objective response rate was computed based on the binomial distribution. Overall survival, objective PFS, PSA PFS, and PFS distributions were estimated using the Kaplan-Meier product-limit method.16

Members of the Audit Committee visit all participating institutions at least once every 3 years to review source documents as part of the quality-assurance program of the CALGB. The auditors verify compliance with federal regulations and protocol requirements in a sample of protocols at each institution. On-site review of medical records was done on a subgroup of 39 patients of the 79 patients (49%) in the current study. Patient registration and data collection were managed by the CALGB Statistical Center. Data quality assurance included a careful review of data by CALGB Statistical Center staff and by the study chairperson. CALGB statisticians performed all statistical analyses.


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  2. Abstract

Patient Characteristics

Seventy-nine patients were enrolled between October 2001 and November 2002, and 77 of those patients were eligible and assessable for treatment outcome (1 patient did not meet eligibility criteria, and 1 patient was registered but never received therapy). The median patient age was 69, and the median PSA level at enrollment was 123 ng/mL (range, 0.1-2231 ng/mL) (Table 1). The median time since diagnosis was 4 years (overall range, of 0-17 years). Eighty-six percent of the patients had bone disease, and 19% had visceral involvement. Overall, 51% of patients had measurable disease according to RECIST.

Table 1. Demographics
VariablePercentage of Patients [Range]
  1. PSA indicates prostate-specific antigen.

Age, y69 [48-88]
 Other or unknown7%
Time since diagnosis, y4 [0-17]
Performance status
Laboratory values 
 Hemoglobin, g/dL12.7 [8.1-14.8]
  Interquartile range11.7-13.5
 PSA, ng/mL123 [0.1-2231]
  Interquartile range50-289
 Alkaline phosphatase, U/L182 [41-5250]
  Interquartile range98-361
Extent of disease
 Measurable disease-total51%
  Lymph nodes41%
  Visceral disease19%
  Soft tissues disease18%
 Bone disease86%

Study Treatment

The median number of cycles of therapy administered was 8 (range, 1-30 cycles of therapy). Of 77 evaluable patients, 24 patients (31%) came off therapy because of disease progression, 15 patients (19%) stopped because of protocol-defined toxicity, and 35 patients (45%) because of a physician or patient decision but were not required by the protocol to stop. Three patients (4%) died during therapy. Patients who stopped therapy based on a physician or patient decision (n = 35) did not have protocol-defined disease progression but opted for a “treatment break.” After such a break, patients were not allowed to resume protocol therapy but could restart docetaxel-based therapies with the agreement of their physicians. Data detailing subsequent treatments were not collected prospectively.

Dose reductions in 1 or more of the 3 drugs in 1 or more cycles occurred in 37 of 77 patients (48%). The common reasons for dose reductions included hematologic toxicity (12%), gastrointestinal toxicity (6%), central nervous system toxicity (5%), and other (27%), such as fatigue and depression. Some patients had more than 1 simultaneous requirement for dose reduction.

Clinical Outcomes

Fifty-eight of 77 patients (75%; 95%CI, 64%-84%) had a >50% post-therapy decline in PSA that was confirmed at least 1 month later. A waterfall plot of the PSA decline at 12 weeks after the start of therapy is provided in Figure 1.

thumbnail image

Figure 1. This waterfall plot illustrates prostate-specific antigen responses at 12 weeks after the initiation of therapy.

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The median time to PSA response was 1.4 months, the median time to PSA progression was 9.2 months (95%CI, 7.5-10.9 months), and the median duration of PSA decline was 8.5 months (95%CI, 6.1-9.8 months). Twenty-three of 39 men with measurable disease (59%; 95%CI, 42%-74%) had a partial response according to RECIST criteria, and the median response duration in measurable disease was 21.5 months (95%CI, 14.6-26.7 months).

The median time to any progression for patients was 8 months (95%CI, 5.9-9.5 months). Patients with measurable disease had a median time to measurable disease progression of 16.5 months (95%CI, 10.9-23.2 months). Seventy-five patients died. Sixty-eight of those patients (90.7%) died of prostate cancer, and the median follow-up for surviving patients at the time of the current report was 69 months. The median overall survival was 24 months (95%CI, 20.3-26.5 months) (Fig. 2).

thumbnail image

Figure 2. This Kaplan-Meier plot illustrates overall survival for patients from the date of enrollment.

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Adverse Events

Table 2 presents the adverse events that probably, possibly, and definitely were related to treatment. Three patients died on study. One patient died of an infection without neutropenia, 1 patient who died had a mesenteric vein thrombosis, and the other patient who died had a bowel perforation that was complicated by severe metabolic acidosis. Grade 3 or 4 leukopenia and neutropenia occurred in 53% and 62% of patients, respectively; however, febrile neutropenia occurred in only 3 patients (4%). Overall, severe (grade 3-5) febrile neutropenia and infections with and without neutropenia were observed in 17 patients (22%).

Table 2. Adverse Events
 No. of Patients (%)
Toxicity, N=77Grade 1Grade 2Grade 3Grade 4Grade 5
  1. WBC indicates white blood cells; GI, gastrointestinal; AST, aspartate aminotransferase; CNS, central nervous system.

Leukocytes, total WBC5 (6)18 (23)27 (35)23 (30)0 (0)
Neutrophils4 (5)2 (3)14 (18)39 (51)0 (0)
Platelets27 (35)5 (6)2 (3)1 (1)0 (0)
Febrile neutropenia0 (0)0 (0)2 (3)1 (1)0 (0)
Documented infections0 (0)0 (0)8 (10)0 (0)0 (0)
Infection without neutropenia2 (3)13 (17)3 (4)0 (0)1 (1)
Cardiac arrhythmia3 (4)0 (0)5 (6)1 (1)0 (0)
Edema20 (26)10 (13)3 (4)0 (0)0 (0)
Hypertension8 (10)1 (1)3 (4)1 (1)0 (0)
Hypotension0 (0)2 (3)2 (3)0 (0)0 (0)
P-T wave prolongation7 (9)6 (8)6 (8)0 (0)0 (0)
Fatigue15 (19)36 (47)15 (19)4 (5)0 (0)
Anorexia16 (21)20 (26)2 (3)0 (0)0 (0)
Colitis0 (0)1 (1)0 (0)1 (1)0 (0)
Constipation15 (19)13 (17)3 (4)0 (0)0 (0)
Diarrhea21 (27)15 (19)5 (6)0 (0)0 (0)
Dehydration2 (3)4 (5)2 (3)0 (0)0 (0)
Ileus/obstruction0 (0)0 (0)4 (5)0 (0)0
Stomatitis/mucositis11 (14)16 (21)3 (4)0 (0)0 (0)
Nausea32 (42)13 (17)4 (5)0 (0)0 (0)
EpistaxisA32 (42)0 (0)1 (1)0 (0)0 (0)
Hemorrhage6 (8)0 (0)1 (1)0 (0)0 (0)
Melana/GI bleed0 (0)0 (0)2 (3)0 (0)0 (0)
Transaminase, AST5 (6)3 (4)3 (4)0 (0)0 (0)
Acidosis0 (0)0 (0)0 (0)0 (0)1 (1)
Hypoalbuminemia20 (26)10 (13)3 (4)0 (0)0 (0)
Hyperglycemia11 (14)15 (19)3 (4)1 (1)0 (0)
Hypokalemia6 (8)0 (0)2 (3)1 (1)0 (0)
Hyponatremia13 (17)0 (0)5 (6)0 (0)0 (0)
CNS ischemia0 (0)0 (0)1 (1)1 (1)0 (0)
CNS hemorrhage/bleed0 (0)0 (0)1 (1)0 (0)0 (0)
Mood alteration8 (10)3 (4)3 (4)0 (0)0 (0)
Neuropathy20 (26)14 (18)4 (5)0 (0)0 (0)
Syncope0 (0)0 (0)4 (5)0 (0)0 (0)
Bone pain1 (1)8 (10)4 (5)0 (0)0 (0)
Neuropathic pain1 (1)1 (1)0 (0)1 (1)0 (0)
Pain7 (9)16 (21)11 (14)0 (0)0 (0)
Cough11 (14)1 (1)3 (4)0 (0)0 (0)
Dyspnea0 (0)13 (17)3 (4)3 (4)0 (0)
Proteinuria11 (14)5 (6)1 (1)0 (0)0 (0)
Thrombosis/embolism0 (0)0 (0)4 (5)2 (3)1 (1)

Fatigue was common, and 25% of patients had severe grade 3 or 4 fatigue, which required a dose reduction in 4 patients, delayed therapy in 2 patients, and resulted in discontinuing therapy in at least 6 patients. The median onset of the severe fatigue occurred at 7 cycles. Seven patients (9%) had thromboembolic complications, 4 patients (5%) developed deep venous thrombosis, and 3 patients (4%) had pulmonary emboli, which resulted in the death of 1 patient. One patient had a grade 4 cerebral hemorrhage in the left parietal lobe associated with mild aphasia and partially recovered. Two patients had grade 3 or 4 cerebral vascular accidents, and 1 was associated with grade 3 hyponatremia with resolution of mental status changes after treatment.

Low-grade epistaxis occurred in 42% of patients, 1 patient had grade 3 epistaxis, and 2 patients had self-limited grade 3 gastrointestinal bleeds. Mild hypertension (grade 1 and 2) was observed in 11% of patients, and more severe (grade 3 or 4) hypertension was observed in 5% of patients without serious complications. Low-grade proteinuria was observed in 20% of patients, but grade 3 or 4 proteinuria was observed in only 1 patient after 22 cycles of therapy and improved after that patient discontinued bevacizumab.


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  2. Abstract

The addition of bevacizumab to standard chemotherapy has significantly improved the survival of patients with colon cancer, and data suggests that bevacizumab may play a similar role in patients with CRPC. To further extend the regimen of docetaxel and estramustine that was tested by the CALGB,17 bevacizumab was added to evaluate the safety and clinical activity of this combination. Although studies now suggest that the addition of estramustine may add little clinical benefit to docetaxel, the current study was designed and implemented before the release of those data.2, 3

The combination of estramustine, docetaxel, and bevacizumab had encouraging antitumor activity: Seventy-five percent of patients in the current study had PSA declines ≥50% after therapy, and 59% of patients with measurable disease achieved a complete or partial response. These are very favorable results compared with the results observed in many docetaxel-based trials (Table 3). Nevertheless, PFS, which was our primary endpoint, was 8.1 months and did not meet the specified study endpoint of 11 months. However, the 11-month PFS was an ambitious goal, and evolving information now calls into question whether PFS is an adequate endpoint in a nonrandomized study.18 In addition, it should be noted that most of our patients who came off therapy stopped not for progression but because of the need for a break from treatment, which would shorten an endpoint like PFS. Similarly, overall survival in a nonrandomized study is difficult to interpret. However, the median survival of 24 months (95%CI, 20.3-26.5 months) that was observed in our patients surpassed the survival that was observed from sequential clinical trials in a similar population by the CALGB in which carboplatin or exisulind was added to the docetaxel and estramustine backbone.5, 6

Table 3. Comparison of Adverse Events for Docetaxel-Based Regimens
 Percentage of Patients
VariableDoc/Pred: TAX-327 (Tannock 20042)Doc/EMP/Pred: SWOG 9906 (Petrylak 20043)Doc/EMP/Pred/Bev: CALGB 90006 (Current Study)
  1. Doc indicates docetaxel; Pred, prednisone; TAX-327, a multicenter study of docetaxel with prednisone versus mitoxantrone plus prednisone in hormone-resistant prostate cancer; EMP, estramustine phosphate; SWOG, Southwest Oncology Group; Bev, bevacizumab; CALGB, Cancer and Leukemia Group B; PSA, prostate-specific antigen; CR, complete response; PR, partial response.

Adverse events, grade 3, 4, or 5
 Febrile neutropenia354
 Death, treatment related0.32.43.8
Clinical outcomes
 50% PSA decline3212.575
 CR/PR, measurable disease121759
 Progression-free survival, mo∼
 Overall survival, mo19.217.524.0

Bevacizumab can be added to the docetaxel and estramustine backbone safely but is associated with some increase in toxicity. Neutropenia was observed in 69% of our patients, which was 2 to 3 times greater than what was reported from the pivotal phase 3 studies with docetaxel in patients CRPC.2, 3 Some of this frequency was because we obtained blood counts on a weekly basis, which was not done on the other docetaxel trials. However, this high level of neutropenia did not translate into an increased incidence of febrile neutropenia.

Bevacizumab-induced grade 3 or 4 hypertension was observed in 5% of patients but was controlled. There were 3 treatment-related deaths among patients who received the bevacizumab combination. Those deaths were attributed to an infection without neutropenia, a mesenteric vein thrombosis, and a bowel perforation. Although the addition of bevacizumab appears to have contributed to the deaths of these patients, the mortality from arterial thromboembolic events or other causes in the current study does not appear to be higher than that reported in other studies of other tumors in elderly populations that received bevacizumab combinations.19 In addition, it is clear that the use of estramustine may have contributed to some of these vascular-related events. The incidence of thrombosis in the current trial was not different from that in other trials that used estramustine.20 Overall, the safety data from our study indicate that the addition of bevacizumab to docetaxel may modestly increase the morbidity of the therapy in this elderly population, and appropriate patient selection is required to maintain safety when using bevacizumab.

In summary, the current phase 2 trial has demonstrated that the addition of VEGF blockade with bevacizumab to a docetaxel-based regimen for the treatment of patients with metastatic CRPC is feasible, well tolerated, and may provide clinical benefit. The encouraging results observed with this regimen have formed the basis for an intergroup, phase 3, double-blind, placebo-controlled trial in CRPC that is comparing docetaxel and prednisone with or without bevacizumab with a primary endpoint of overall survival. That study is fully accrued, and the data are maturing.


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  2. Abstract

Partial funding for this study was provided by Sanofi-Aventis, US. Joel Picus has received research support from Genentech and Sanofi-Aventis. W. Kevin Kelly received clinical trial research support from Genentech. Nicholas J. Vogelzang is a consultant for Genentech and Sandofi Aventis. Walter M. Stadler received consulting and research support from Genentech/Roche. The research for Cancer and Leukemia Group B (CALGB) 90006 was supported in part by grants from the National Cancer Institute (CA31946) to the CALGB (Richard L. Schilsky, MD, Chairman) and to the CALGB Statistical Center (Stephen George, PhD). This study also was supported by the following grants from the National Cancer Institute, National Institutes of Health: CA31946, CA33601, CA45418, CA32291, CA35279, CA77658, CA45389, CA60318, CA41287, CA16450, CA77298, CA47559, CA77406, and CA77440.


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  2. Abstract
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