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Keywords:

  • prostatic neoplasms;
  • chemotherapy;
  • ketoconazole;
  • steroid 17-alpha-hydroxylase;
  • androgen antagonists

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

BACKGROUND

Preliminary data suggest a potential decreased benefit of docetaxel in patients with metastatic, castration-resistant prostate cancer (mCRPC) who previously received abiraterone acetate, a novel androgen synthesis inhibitor (ASI). Cancer and Leukemia Group B (CALGB) trial 90401 (Alliance), a phase 3 trial in patients with mCRPC who received docetaxel-based chemotherapy, offered the opportunity to evaluate effect of prior ketoconazole, an earlier generation ASI, on clinical outcomes after docetaxel.

METHODS

In CALGB trial 90401, 1050 men with chemotherapy-naive mCRPC were randomized to receive treatment with docetaxel and prednisone that included either bevacizumab or placebo. In total, 1005 men (96%) had data available regarding prior ketoconazole therapy. The observed effects of prior ketoconazole on overall survival (OS), progression-free survival (PFS), prostate-specific antigen (PSA) decline, and the objective response rate (ORR) were assessed using proportional hazards and Poisson regression methods adjusted for validated prognostic factors and treatment arm.

RESULTS

Baseline characteristics between patients who did (N = 277) and did not (N = 728) receive prior ketoconazole therapy were similar. There were no statistically significant differences between patients who did and those who did not receive prior ketoconazole therapy with respect to OS (median OS, 21.1 months vs 22.3 months, respectively; stratified log-rank P = .635), PFS (median PFS, 8.1 months vs 8.6 months, respectively; stratified log-rank P = .342), the proportion achieving a decline ≥50% in PSA (61% vs 66%, respectively; relative risk, 1.09; adjusted P = .129), or ORR (39% vs 43%, respectively; relative risk, 1.11; adjusted P = .366).

CONCLUSIONS

As measured by OS, PFS, PSA, and the ORR, there was no evidence that prior treatment with ketoconazole had an impact on the clinical outcomes of patients with mCRPC who received subsequent docetaxel-based therapy. The current results highlight the need for prospective studies to assess for potential cross-resistance with novel ASIs and to define the optimal sequence of therapy in mCRPC. Cancer 2013;119:3636–3643. © 2013 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Prostate cancer is the second leading cause of cancer-related mortality among men in the United States.[1] Although a significant number of men with advanced disease eventually die of metastatic, castrate-resistant prostate cancer (mCRPC), the past decade has borne witness to multiple agents with various mechanisms of action that have demonstrated an improvement in overall survival (OS) in randomized phase 3, placebo-controlled, clinical trials. Among these agents are taxane-based cytotoxic chemotherapy[2-4]; androgen synthesis inhibitors (ASIs), such as abiraterone acetate[5, 6]; and the androgen receptor (AR) antagonist enzalutamide (MDV3100).[7, 8] Optimizing the sequence (or combinations) of therapy, assessing for evidence of acquired cross-resistance, and discovering mechanisms of treatment resistance have become of increasing clinical importance in the treatment of patients with mCRPC.

A retrospective, single-institution series suggested that patients with mCRPC who receive adrenal ASIs like abiraterone acetate may acquire cross-resistance to subsequent taxane-based chemotherapy.[9] The putative biologic mechanism explaining this cross-resistance stems from the observation that taxanes exert their antineoplastic effect on prostate cancer in part by down-regulating signaling through the AR pathway. Taxanes exert this effect by targeting the AR association with tubulin, inhibiting AR nuclear translocation, and down-regulating AR-mediated gene expression.[10] Thus, it is hypothesized that prior exposure to agents targeting the androgen axis, such as abiraterone acetate, may shift the tumor phenotype toward a more “androgen-insensitive” disease state that is partially resistant to further inhibition of androgen signaling with taxane-based chemotherapy.

Abiraterone acetate has only recently been approved in mCRPC by the US Food and Drug Administration for use in both the predocetaxel and postdocetaxel setting. Ketoconazole is a generic, widely available ASI that has been in clinical use for mCRPC since the 1990s. Ketoconazole blocks androgen synthesis by the inhibition of several enzymes within the androgen synthetic pathway, including side chain cleavase, which converts cholesterol to pregnenolone, and cytochrome P-45017 α (CYP17), which converts pregnenolone to the androgen dehydroepiandrostenedione (DHEA) through 2 enzymatic steps and is the same enzyme targeted by abiraterone.[11-14] Ketoconazole has demonstrated significant clinical activity in mCRPC in several prior prospective clinical trials and is a standard treatment option in this disease setting.[15, 16] The Cancer and Leukemia Group B (CALGB), now a part of the Alliance for Clinical Trials in Oncology, designed CALGB 90401, a randomized phase 3 trial in which 1050 patients with mCRPC received docetaxel-based chemotherapy. This trial offered the opportunity to evaluate the effect of prior treatment with ketoconazole, an earlier generation ASI, on clinical outcomes after docetaxel treatment.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Study Design and Hypothesis

A retrospective analysis was undertaken of data collected from the intergroup study CALGB 90401, a randomized, placebo-controlled, phase 3 trial of docetaxel and prednisone with or without bevacizumab in men with mCRPC.[17] The objective was to assess whether prior androgen synthesis inhibition with ketoconazole impacted clinical outcomes with subsequent docetaxel-based chemotherapy as a means of further investigating the potential for acquired cross-resistance between these therapeutic approaches for men with mCRPC.

Study Population

The eligibility requirements for CALGB 90401 were described previously.[17] In brief, eligible patients had metastatic prostate cancer with disease progression in the setting of a castrate level of serum testosterone (≤50 ng/dL) and after antiandrogen withdrawal, as defined by Prostate-Specific Antigen Working Group 1 consensus criteria.[18] Patients were required to be ≥4 weeks from discontinuation of secondary hormone therapies, including ketoconazole or antiandrogens. Patients were required to discontinue 5-α reductase inhibitors at any time before study entry. Prior bisphosphonate use was allowed provided that the dose was stable for >4 weeks before protocol therapy (denosumab was not commercially available at the time). Key exclusion criteria included prior chemotherapy or antiangiogenic therapy, an Eastern Cooperative Oncology Group performance status >2, uncontrolled hypertension, congestive heart failure (New York Heart Association class II, III, or IV), an arterial thromboembolic event within 12 months of study entry, or grade ≥2 peripheral neuropathy.

CALGB 90401 Study Design and Treatment

Patients enrolled onto CALGB 90401 were randomized with equal probability to receive docetaxel/prednisone plus placebo or docetaxel/prednisone plus bevacizumab.[17] Randomization was stratified by: age (<65 years or ≥65 years), predicted 24-month survival probability using a validated nomogram for castrate-resistant prostate cancer (CRPC)[19] (<0%, 10%-29.9%, or ≥30%), and prior history of arterial thromboembolic events (yes or no). Treatment was continued until patients developed either disease progression or unacceptable toxicity for a maximum of 2 years. Patients were assessed by serum prostate-specific antigen (PSA) measurement with each cycle of therapy and by bone scans and computed tomography scans of the abdomen/pelvis every 3 months. The primary endpoint was OS; and, as previously reported, no difference between treatment arms was detected.[17] In total, 1050 patients were accrued between May 2005 and December 2007 across 310 investigational sites within the United States. CALGB 90401 was approved by the local ethics committees of all participating centers. Each participant signed an institutional review board-approved, protocol-specific informed consent in accordance with federal and institutional guidelines.

Members of the CALGB Audit Committee visit all participating institutions at least once every 3 years to review source documents as part of the CALGB quality-assurance program. The auditors verify compliance with federal regulations and protocol requirements, including those pertaining to eligibility, treatment, adverse events, tumor response, and outcome, in a sample of protocols at each institution. Such on-site review of medical records was performed for a subgroup of 141 patients (13%) of the 1050 patients under this study.

Statistical Methods and Data Analysis

The primary endpoint was OS, which was defined as the time interval from the date of randomization to the date of death from any cause. In addition, the effect of prior ketoconazole use on other endpoints, including progression-free survival (PFS), a PSA decline ≥50% from baseline, and the objective response proportion (defined according to Response Evaluation Criteria in Solid Tumors [RECIST] version 1.0), was evaluated. PFS was calculated from the date of randomization to the date of either progression or death from any cause, whichever occurred first. Progression was defined using PSA Working Group 1 criteria,[18] with the exception that more than 2 new bone lesions were required to define bone progression on a bone scan.

Information about prior ketoconazole use was collected prospectively at the time of study entry, before randomization; however, data on duration of prior ketoconazole use, whether ketoconazole was used in the hormone-sensitive or castration-resistant setting, or prior response to ketoconazole were not collected prospectively on this trial. The Kaplan-Meier product-limit approach[20] was used to estimate the OS and PFS distribution as a function of prior ketoconazole use. A proportional hazards model[21] was used to assess the prognostic significance of prior ketoconazole use in predicting OS and PFS, adjusting for the prospectively defined stratification factors and for the PFS endpoint, the treatment arm (which a previous report indicated had an effect on PFS, but not on OS). The Poisson regression method[22] was used to assess the prognostic significance of prior ketoconazole use in predicting the probability of a decline ≥50% in serum PSA from baseline and the probability of experiencing an objective response, as defined by RECIST 1.0 criteria, adjusting for the stratification factors and treatment arm.[23] Tests of a treatment arm by prior ketoconazole use interaction in predicting outcomes on docetaxel were performed, and no significant interactions between treatment arms were noted in predicting clinical outcomes. Data collection and analysis were undertaken by the Alliance (formerly CALGB) Statistical and Data Center. The date of data cutoff was January 13, 2013.

S-plus statistical software (TIBCO Spotfire S+ version 8.1; TIBCO Spotfire Inc., Somerville, Mass) was used for the data analyses, and all statistical tests were 2-sided. No adjustment was made for multiple comparisons for this retrospective analysis.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Patient Disposition and Baseline Characteristics

In total, 1050 patients were randomized to receive docetaxel plus prednisone with or without bevacizumab. Of these 1050 patients, 1005 (96%) had data available regarding prior ketoconazole use (Fig. 1). The baseline characteristics of these 1005 patients, including known prognostic factors in mCRPC, are summarized in Table 1. Not surprisingly, the 4% of patients for whom data were not available with regard to prior ketoconazole use had demographic and baseline patient characteristics similar to those of the 96% of patients who had data available. Of the 1005 patients who were available for this analysis, 28% had received prior treatment with ketoconazole for CRPC. The 2 groups (those who had and had not received prior ketoconazole) had similar baseline characteristics, including age, Eastern Cooperative Oncology Group performance status, median alkaline phosphatase and hemoglobin levels, and the presence of visceral metastases. There were numeric differences between groups in the median baseline serum PSA and lactate dehydrogenase levels, which were higher in the group that had received prior ketoconazole therapy. However, the 2 groups had a similar 24-month predicted survival probability using a validated prognostic model in CRPC, which included PSA and lactate dehydrogenase levels among its 7 factors.[19] The median baseline serum testosterone levels and study arm assignment between patients who had and had not received prior ketoconazole therapy were similar.

image

Figure 1. Patient disposition is illustrated. In total, 1050 patients were enrolled on Cancer and Leukemia Group B (CALGB) trial 90401.

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Table 1. Baseline Characteristics Among Men With and Without Prior Ketoconazole Use Enrolled on Cancer and Leukemia Group B Trial 90401
 Percentage of Patients 
VariablePrior Ketoconazole, N = 277No Prior Ketoconazole, N = 728Total, N = 1005
  1. Abbreviations: ECOG, Eastern Cooperative Oncology Group; IQR, interquartile range; LDH, lactate dehydrogenase; PSA, prostate-specific antigen.

  2. a

    *Assessed by a validated prognostic nomogram in castration-resistant prostate cancer.[19]

Race   
White888888
Age   
<65 y343333
≥65 y666767
Median age (IQR), y69.0 (62.0–75.0)68.0 (62.0–74.0)69.0 (62.0–75.0)
Prior history of arterial events   
Yes888
No929292
Predicted survival probability at 24 mo, %a   
<10201718
10–29.9343434
≥30454847
ECOG performance status   
0555555
1424041
2454
Measurable disease524950
Sites of metastases   
Bone888586
Liver466
Lung101010
Lymph node454243
Other141414
Median alkaline phosphatase (IQR), U/L122.0 (86.0–227.0)117.0 (82.5–225.5)119.0 (83.0–226.0)
Median hemoglobin (IQR), g/dL12.7 (11.5–13.8)12.7 (11.7–13.8)12.7 (11.7–13.8)
Median LDH (IQR), U/L211.0 (170.0–332.0)201.5 (164.0–282.5)205.0 (166.0–298.0)
Median PSA (IQR), ng/mL121.9 (47.2–316.6)73.3 (25.6–228.7)85.3 (31.0–241.6)
Median testosterone (IQR), ng/dL20.0 (10.0–26.0)20.0 (11.0–27.0)20.0 (11.0–27.0)
Treatment arm   
Docetaxel + bevacizumab524950
Docetaxel only485150

Impact of Prior Ketoconazole Therapy on Clinical Outcomes

In total, 968 deaths were observed, and the median follow-up for the patients who remained alive was 57 months (95% confidence interval [CI], 52.3-59.7 months). The median OS on CALGB 90401 was 21.1 months (95% CI, 19.6-23.8 months) for those who had received prior ketoconazole and 22.3 months (95% CI, 21.1-24.0 months) for those who had not received prior ketoconazole (P = .315). The Kaplan-Meier OS curves are depicted in Figure 2A. Adjusting for the stratification factors, the hazard ratio for death among patients who had received prior ketoconazole was 1.04 compared with patients who had not received prior ketoconazole (95% CI, 0.89-1.20; P = .635).

image

Figure 2. (Top) Kaplan-Meier curves illustrate overall survival (OS) according to prior ketoconazole (keto) exposure on Cancer and Leukemia Group B (CALGB) trial 90401. (Bottom) Kaplan-Meier curves illustrate progression-free survival (PFS) according to prior ketoconazole exposure. CI indicates confidence interval.

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Similar results were obtained for PFS. The median PFS for patients who had received prior ketoconazole was 8.1 months (95% CI, 7.6-9.4 months) versus 8.6 months (95% CI, 8.0-9.1 months) for those who had not received prior ketoconazole (P = .177). Using a proportional hazards model adjusted for treatment arm and the stratification factors, the hazard ratio for PFS among the patients who had received prior ketoconazole was 1.07 compared with the patients who had not received prior ketoconazole (95% CI, 0.92-1.23; P = .342). The Kaplan-Meier PFS curves are provided in Figure 2B.

Additional analyses were carried out examining the impact of prior ketoconazole therapy on the objective response rate (among the patients who had measurable disease at baseline) according to RECIST 1.0 criteria as well as the proportion of patients with a decline ≥50% in PSA from baseline on docetaxel-based chemotherapy. There was no significant effect of prior receipt of ketoconazole on the objective response rate or of PSA declines ≥50% from baseline with docetaxel-based therapy (Table 2).

Table 2. Multivariable Analyses: Impact of Prior Ketoconazole Use on Clinical Endpoints in Cancer and Leukemia Group B Trial 90401
 Prior Ketoconazole Use  
Clinical EndpointYes, n = 277No, n = 728HR [95% CI]P
  1. Abbreviations: CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; PSA, prostate-specific antigen.

  2. a

    The analysis was adjusted for stratification factors (age, prior history of adverse events, and predicted OS probability at 24 months).

  3. b

    The analysis was adjusted for stratification factors (age, prior history of adverse events, and predicted OS probability at 24 months) and treatment arm.

  4. c

    The relative risk was estimated using a modified Poisson regression approach.[22]

OS: Median (95% CI), mo21.1 (19.7–24.2)22.3 (21.2–24.0)1.04 (0.90–1.20)0.635a
PFS: Median (95% CI), mo8.1 (7.6–9.4)8.6 (8.0–9.1)1.07 (0.93–1.24)0.342b
Patients with ≥50% decline in PSA (95% CI), %61 (54–67)66 (63–70)1.09 (0.98–1.21)c0.129b
Objective response (95% CI), % [no. with measurable disease]39 (31–47) [156]43 (38–49) [356]1.11 (0.88–1.41)c0.366b

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

The current analysis suggests that prior exposure to the ASI ketoconazole does not impact clinical outcomes on docetaxel-based therapy in a large cohort of patients with mCRPC, as measured by overall and progression-free survival, objective response rate, and PSA decline ≥50% from baseline. The study results provide no evidence of cross-resistance between androgen synthesis inhibition and taxane-based chemotherapy in patients with mCRPC. Although the use of ketoconazole in current clinical practice has declined significantly with the introduction of agents such as abiraterone and enzalutamide, the current results may have implications for the sequencing of contemporary ASIs before taxane-based chemotherapy in mCRPC, including abiraterone acetate and others in clinical development (ie, orteronel, galeterone). These newer agents share a mechanism of action similar to that of ketoconazole with respect to inhibiting adrenal androgen production, a key source of ligand for the AR in the castrate-resistant state.[24]

Two retrospective series of patients who received abiraterone followed by docetaxel recently have been reported.[9, 25] In one series of 35 patients who received docetaxel after disease progression on abiraterone, 25.7% (95% CI, 12.5%-43.3%) had a PSA decline ≥50%. The median time to PSA progression and OS were 4.6 months (95% CI, 4.2-5.9 months) and 12.5 months (95% CI, 10.6-19.4 months), respectively, outcomes that seemingly are inferior to those achieved in the registrational phase 3 trials of docetaxel in mCRPC.[2, 3] In contrast, in another small, retrospective case series of 14 patients who received docetaxel after disease progression on abiraterone, 43% of patients achieved a decline in serum PSA ≥50% from baseline, and the median time to progression on docetaxel (4.3 months) was qualitatively similar to that achieved on prior abiraterone therapy (4.8 months).[25]

Those retrospective analyses are intriguing. However, caution in their interpretation is warranted, given the small sample sizes, the lack of comparator arms, and the potential for selection bias, because docetaxel therapy was chosen according to the discretion of the individual treating physician in both series. In the current analysis, the large numbers of patients (1005 of the 1050 patients enrolled on CALGB 90401), the similar distribution in baseline prognostic factors among men with and without prior ketoconazole exposure, and the prospectively assessed outcomes on docetaxel-based chemotherapy all provide support to the hypothesis that androgen synthesis inhibition does not have a detrimental impact on subsequent taxane-based chemotherapy.

However, there are several limitations to the current results. First, it is not known whether the potency of prior androgen synthesis inhibition may influence clinical outcomes with subsequent taxane-based chemotherapy. Preclinical studies have demonstrated that ketoconazole is a less potent ASI compared with abiraterone acetate, which selectively targets the CYP17 enzyme.[24] In contrast to abiraterone, ketoconazole has not demonstrated an OS benefit in the CRPC disease setting.[16] It is not known whether more potent androgen synthesis inhibition will result in the emergence of cross-resistance to subsequent taxane-based chemotherapy.

Second, these results may have been confounded by a heterogeneous study population with respect to duration of prior ketoconazole therapy, whether ketoconazole was applied in the hormone-sensitive or castration-resistant setting, and reason for discontinuation of ketoconazole, none of which were captured prospectively on CALGB 90401 and may influence patterns of cross-resistance. It is possible that many patients received other secondary hormone agents before study enrollment, which may have influenced subsequent clinical outcomes with ketoconazole and/or docetaxel-based chemotherapy. Duration of and response to secondary hormone maneuvers like ketoconazole therapy may provide a clinical measure of “androgen sensitivity,” which could potentially influence treatment outcomes with subsequent docetaxel therapy.

Although the current results suggest the lack of a deleterious effect from prior androgen synthesis inhibition on the efficacy of docetaxel-based chemotherapy, this does not rule out the possibility of cross-resistance and ultimately highlights the need for future studies addressing the sequencing of therapy in mCRPC. Prospective clinical trials designed with adequate statistical power will be needed to test for potential cross-resistance between various modalities of therapy and to define the optimal sequence of therapy in mCRPC.

Conclusions

As measured by OS, PFS, objective response rate, and a decline ≥50% in PSA, there is no evidence that prior treatment with the androgen synthesis inhibitor ketoconazole has an impact on clinical outcomes in patients with mCRPC who receive subsequent docetaxel therapy. Future prospectively designed studies are needed to further assess for potential cross-resistance between novel androgen synthesis inhibitors like abiraterone acetate and taxane-based chemotherapy and to define the optimal sequence of therapy as additional agents become available for clinical use in mCRPC.

FUNDING SUPPORT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

The research for CALGB 90401 (Alliance) was supported in part by grants from the National Cancer Institute (NCI) to the Alliance for Clinical Trials in Oncology (Monica M. Bertagnolli, MD, Chair; grant CA31946) and to the Alliance Statistics and Data Center (Daniel J. Sargent, PhD; grant CA33601).

Drs. Aggarwal and Small were supported by NCI grant CA60138 ; Dr. Halabi was supported by NCI grant CA33601; Dr. Kelly was supported by NCI grant CA13650; Dr. George was supported by NCI grant CA7577; Dr. Mahoney was supported by NCI grant CA5808; Dr. Millard was supported by NCI grant CA11789; Dr. Stadler was supported by NCI grant CA41287; Dr. Morris was supported by NCI grant CA77651; Dr. Kantoff was supported by NCI grant CA32291; Dr. Monk was supported by NCI grant CA77658; and Dr. Carducci was supported by NCI grant CA16116.

The following institutions participated in this study: Alliance Statistics and Data Center, Duke University Medical Center, Durham, NC (Daniel J. Sargent, PhD; supported by NCI grant CA33601); Christiana Care Health Services, Inc. Community Clinical Oncology Program (CCOP), Wilmington, Del (Stephen Grubbs, MD; supported by CA45418); Dana-Farber Cancer Institute, Boston, Mass (Harold J. Burstein, MD, PhD; supported by CA32291); Dartmouth Medical School-Norris Cotton Cancer Center, Lebanon, NH (Konstantin Dragnev, MD; supported by CA04326); Duke University Medical Center, Durham, NC (Jeffrey Crawford, MD; supported by CA47577); Greenville CCOP, Greenville, SC (Jeffrey Giguere, MD; supported by CA29165); Heartland Cancer Research CCOP, St. Louis, Mo (Alan P. Lyss, MD; supported by CA114558 to Missouri Baptist Medical Center); Hematology-Oncology Associates of Central New York CCOP, Syracuse, NY (Jeffrey Kirshner, MD; supported by CA45389); Illinois Oncology Research Association, Peoria, Ill (John W. Kugler, MD; supported by CA35113); Kansas City CCOP, Kansas City, Mo (Rakesh Gaur, MD); Massachusetts General Hospital, Boston, Mass (Jeffrey W. Clark, MD; supported by CA32291); Memorial Sloan-Kettering Cancer Center, New York, NY (Clifford A. Hudis, MD; supported by CA77651); Missouri Baptist Medical Center, St. Louis, Mo (Alan P. Lyss, MD; supported by CA114558-02 [a grant only to be used for studies that accrued patients after June 1, 2005; the institution received no grant before 2005, and Missouri was an at-large member]); Monter Cancer Center of North Shore-LIJ Health Systems, Lake Success, NY (Daniel Budman, MD; supported by CA35279); Mount Sinai Medical Center, Miami, Fla (Michael A. Schwartz, MD; supported by CA45564); Mount Sinai School of Medicine, New York, NY (Lewis R. Silverman, MD; supported by CA04457); Nevada Cancer Research Foundation CCOP, Las Vegas, Nev (John A. Ellerton, MD; supported by CA35421); New Hampshire Oncology-Hematology PA, Concord, NH (Douglas J. Weckstein, MD); North Shore University Health System CCOP, Evanston, Ill (David L. Grinblatt, MD); Northern Indiana Cancer Research Consortium CCOP, South Bend, Ind (Rafat Ansari, MD; supported by CA86726); Rhode Island Hospital, Providence, RI (William Sikov, MD; supported by CA08025); Roswell Park Cancer Institute, Buffalo, NY (Ellis Levine, MD; supported by CA59518); Sibley Memorial Hospital, Washington, DC (Frederick Barr, MD); Southeast Cancer Control Consortium Inc. CCOP, Goldsboro, NC (James N. Atkins, MD; supported by CA45808); State University of New York Upstate Medical University, Syracuse, NY (Stephen L. Graziano, MD; supported by CA21060); The Ohio State University Medical Center, Columbus, Ohio (Clara D. Bloomfield, MD; supported by CA77658); University of California at San Diego, San Diego, Calif (Barbara A. Parker, MD; supported by CA11789); University of California at San Francisco, San Francisco, Calif (Charles J. Ryan, MD; supported by CA60138); University of Chicago, Chicago, Ill (Hedy L. Kindler, MD; supported by CA41287); University of Illinois Minority-Based CCOP, Chicago, Ill (David J. Peace, MD; supported by CA74811); University of Iowa, Iowa City, Iowa (Daniel A. Vaena, MD; supported by CA47642); University of Maryland Greenebaum Cancer Center, Baltimore, MD (Martin Edelman, MD; supported by CA31983); University of Minnesota, Minneapolis, Minn (Bruce A. Peterson, MD; supported by CA16450); University of Nebraska Medical Center, Omaha, Neb (Apar Ganti, MD; supported by CA77298); University of North Carolina at Chapel Hill, Chapel Hill, NC (Thomas C. Shea, MD; supported by CA47559); University of Oklahoma, Oklahoma City, Okla (Shubham Pant, MD; supported by CA37447); University of Vermont, Burlington, Vt (Steven M. Grunberg, MD; supported by CA77406); Washington University School of Medicine, St. Louis, Mo (Nancy Bartlett, MD; supported by CA77440); Weill Medical College of Cornell University, New York, NY (John Leonard, MD; supported by CA07968); Western Pennsylvania Cancer Institute, Pittsburgh, Pa, John Lister, MD); and Yale University, New Haven, Conn (Lyndsay N. Harris, MD; supported by CA16359).

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES

Dr. Aggarwal was supported by an institutional grant from the CALGB Cooperative Group. Dr. George has received compensation as a consultant from Sanofi, Genentech, Astellas, Medviaiton, Exelixis, Viamet, Novartis, Teva, Bayer, and Dendreon; he has received institutional support through grants from Novartis, GSK, Exelixis, Genentech, Janssen Pharmaceuticals, Millennium Pharmaceuticals, and Progenex/Molecular Insight; and he has received lecture fees from Dendreon, Sanofi, Pfizer, Novartis, and Amgen. Dr. Millard has received compensation as a consultant to Ambrx Inc. and Centocor Ortho Biotec. Dr. Stadler received a grant from CALGB. Dr. Morris is an uncompensated consultant to Bayer and has received compensation as a consultant to Millennium Pharmaceuticals. Dr. Monk has received lecture fees from Sanofi Aventis. Dr. Carducci received a grant from the Eastern Cooperative Oncology Group.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SUPPORT
  8. CONFLICT OF INTEREST DISCLOSURES
  9. REFERENCES
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