Venous Thromboembolism and Mortality Associated With Recombinant Erythropoietin and Darbepoetin Admi

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Venous Thromboembolism and Mortality Associated
With Recombinant Erythropoietin and Darbepoetin
Administration for the Treatment of
Cancer-Associated Anemia

• Charles L. Bennett MD PhD MPP

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RADAR Method and Publications
RADAR Detect ADR signals, Investigate possible
ADR occurrence, Analyze data, Disseminate results
RADAR Published Meta-analyses
RADAR Published Smaller Analyses
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Mortality Meta-analysis
Meta-analysis of mortality rates for 52 phase III
oncology trials with 14,047 patients for ESAs
versus placebo or control (updated as of February
2008) HR 1.09 (1.01, 1.18)
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VTE Meta-analysis

• Meta-analysis of VTE rates in 38 phase III trials
  with 8,172 patients for ESAs versus placebo or
  control
• HR 1.57 (1.31,1.87)

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Erythropoietin in Solid Tumors

• Epo and EpoR mRNA are detected in a wide variety
  of solid tumors.
• There is continued debate regarding cell surface
  expression of EpoR in solid tumors with regard to
  the quality of available reagents (e.g., C-20
  antibody).
• However, the number of cell-surface EpoR
  necessary to be activated for functional
  signaling in a cell may be very low (20). This
  is likely beneath the detection limits of
  available methods/technology.
• Depending upon tumor type, signal transduction
  has been detected in the PI3K-Akt, JAK-STAT
  and/or NFkB pathways.
• In different cancers, activation of the
  Epo/EpoR-signaling axis results in proliferation,
  anti-apoptosis, invasion and/or chemoresistance.
• There is no preclinical evidence to suggest that
  Hgb levels affect Epo/EpoR signaling in cancer
  cells.

Gene
Protein
Signal transduction
Function / Activity
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Mortality and Primary Outcomes A Focused
Approach
Studies included with primary outcomes of
survival, disease-free survival,
progression-free survival, or loco-regional
control
HR 1.18 (1.04, 1.35)
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HRs Single Disease Studies vs. Multiple Disease
Studies
Studies included that assessed single disease
populations
HR 1.14 (1.01, 1.26)
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HRs Early terminated studies vs. not
Studies included that terminated early n5
safety related, n4 non-safety related
HR 1.32 (1.14, 1.52)
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Meta-regression Assessing Study Outcomes
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Basic Science Findings and ESAs
A Kuykendal, Bennett CL, McKoy J, Boyle S, West
DP, Edwards B, Courtney M, Sartor O, Lai S, Henke
M. Tumor progression and mortality associated
with administration of erythropoiesis
stimulating agents (ESAs) to cancer patients Is
toxicity due to ESAs or elevated hemoglobin (Hgb)
levels? The Research on Adverse Drug Events and
Reports (RADAR) project, Northwestern University
Chicago, Il. ASCO poster presentation June 2008.
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Comparison of Primary Outcomes of Cancer Trials
Included in Various Meta-analyses