ESAs for CancerRelated Anemia TMR Journal Club Shuen Tan October 6, 2009 Tonelli M, Hemmelgarn B, Reiman T, et al. Benefits and harms of erythropoiesis-stimulating agents for anemia related to cancer: a metaanalysis. CMAJ 180(11): E62-71, 2009. Anemia in Cancer Related to cancer Related to chemotherapy Associated with: quality of life survival ESAs: Benefit vs. Harm Benefits Improved QOL Decreased transfusions ? survival Harm Thromboembolism HTN Stimulate tumour growth (Cost) ? survival Methods Systematic review of ESAs for the treatment of cancer-related anemia Published and unpublished RCTs Epoetin or darbepoetin vs. control Adults age>18 Cancer-related anemia >30 subjects in each group English, French, Spanish, or Mandarin “Any” Outcomes Mortality Cardiac events Hospital admission Quality of life Hypertension RBC transfusion Adverse events Subgroups American Society of Clinical Oncology criteria Baseline hemoglobin Chemotherapy (or not) Target hemoglobin Results 52 trials met criteria 4 trials in perioperative patients 30 trials in solid tumours 10 trials in hematologic cancer 11 trials included both Mean duration 12 (2-28) weeks Cardiovascular events MI, stroke, CHF, revascularization 14 trials RR 1.12 (0.83-1.5) Hypertension 17 trials RR 1.41 (0.94-2.12) Tumour response 2 trials No difference for complete response • RR 0.88 (0.69-1.12) No difference for partial response • RR 0.70 (0.44-1.11) Serious Adverse Events 21 trials Increased risk in ESA groups • RR1.16 (1.08-1.25) Thrombotic events 13 trials Increased risk in ESA groups • RR 1.69 (1.27-2.24) Sub-group analyses No differences between any groups and total study population Do the American Society of Clinical Oncology guidelines permit identification of patients most likely to benefit? Validity 1. Did the authors ask a focused clinical question? For the most part, Yes Well-defined patient group Broad but reasonable disease category No specific outcomes stated Included studies that “reported one or more outcomes” 2. Were the criteria used to select articles for inclusion appropriate? Yes Study type well-defined Patients well-defined Therapy well-defined Outcomes not defined Languages reasonably dealt with Only 25/2025 studies could not be assessed because of translation 3. Is it unlikely that important, relevant studies were missed? Yes Very thorough search strategy Multiple databases ESAs extensively exploded CancerLit? Unpublished literature searched Some papers included that were published after search dates 3. Is it unlikely that important, relevant studies were missed? Very small percentage of citations could not be retrieved (32/2025) Abstracts screened by 2 reviewers All flagged articles retrieved Full text assessed by 2 reviewers for inclusion Disagreements resolved with a third reviewer 4. Was the validity of the included studies appraised (study quality)? Yes Chalmers index More detailed version of the Jadad score Randomization, blinding, and handling of withdrawals Rated statistical analysis, presentation of results, and source of funding as well Not entirely clear if the final rating was subjective Does not appear to have been incorporated into the meta-analysis 5. Were assessments of studies reproducible (data abstraction)? Yes? One reviewer abstracted data A second reviewer checked for accuracy 6. Were the results similar from study to study (homogeneity)? Yes Random effects model Quantified heterogeneity with the I2 statistic (=0% for all calculations) Calculates proportion of total variation in the estimates of treatment effects that is due to heterogeneity between studies Issues related to the included studies Overall, systematic review was well done Limitations to applying results to patients Short follow-up time (median 12 weeks) Low-moderate quality scores • Many had unblinded treatment groups Majority were privately funded Relevance Will the results change my practice? Are the outcomes important to my patients? Populations of Interest Solid organ vs. hematologic cancer Anemic (100 vs. 120) vs. very anemic (<100) Long-term (>12 weeks) vs. short-term (<12 weeks) vs. really short-term (2-3 doses) Chemo vs. no chemo Shuen’s Thoughts -- Con Increased reluctance to recommend use in pre-op anemia risk of thrombosis with surgical stress response Thoracic, bowel surgery not typically associated with high blood loss Lower targets, as few doses as possible Anemia associated with survival, but does treatment with ESA make a difference? Shuen’s Thoughts -- Pro Risk-benefit study of ESA vs. no ESA but does not compare to other treatments (e.g. transfusion) Improved quality of life ? Uncertain diagnosis Based on studies of low-moderate quality CancerCare’s Patients Any changes in practice? Is transfusion a “better” treament for anemia than Epo? Non-random oncologist #1 Following ASCO guidelines Non-random oncologist #2 Rarely uses epo Transfusion more common Patients Can a reasonable patient choose? quality of life with survival quality of life with survival ? quality of life with transfusion and ? Survival Cause of increased mortality unclear Thromboembolism? Tumour progression? Something else? Dose or duration-dependent? Conclusion The use of ESAs in cancer patients is associated with increased mortality and serious adverse events, but improved quality of life and decreased transfusions The ASCO guidelines for the use of ESAs do not appear to identify a lower-risk, higher-benefit group Conclusion ESAs should be used cautiously in any patient with a cancer diagnosis, regardless of type of cancer, chemotherapy, or degree of anemia But are not contraindicated… Questions?