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Charles L. Bennett MD PhD MPP

Venous Thromboembolism and Mortality Associated With Recombinant Erythropoietin and Darbepoetin Administration for the Treatment of Cancer-Associated Anemia. Charles L. Bennett MD PhD MPP. RADAR Method and Publications. RADAR:

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Charles L. Bennett MD PhD MPP

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  1. Venous Thromboembolism and Mortality Associated With Recombinant Erythropoietin and Darbepoetin Administration for the Treatment of Cancer-Associated Anemia Charles L. Bennett MD PhD MPP

  2. RADAR Method and Publications RADAR: Detect ADR signals, Investigate possible ADR occurrence, Analyze data, Disseminate results RADAR Published Meta-analyses RADAR Published Smaller Analyses

  3. 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)

  4. 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)

  5. Erythropoietin in Solid Tumors Gene • 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. Protein Signal transduction Function / Activity

  6. 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)

  7. HRs: Single Disease Studies vs. Multiple Disease Studies Studies included that assessed single disease populations HR: 1.14 (1.01, 1.26)

  8. HRs: Early terminated studies vs. not Studies included that terminated early n=5 safety related, n=4 non-safety related HR: 1.32 (1.14, 1.52)

  9. Meta-regression Assessing Study Outcomes

  10. 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.

  11. Comparison of Primary Outcomes of Cancer Trials Included in Various Meta-analyses

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