ESAs for Cancer-Related Anemia

1. ESAs for Cancer-Related Anemia TMR Journal Club Shuen Tan October 6, 2009

2. Tonelli M, Hemmelgarn B, Reiman T, et al. Benefits and harms of erythropoiesis-stimulating agents for anemia related to cancer: a meta-analysis. CMAJ 180(11): E62-71, 2009.

3. Anemia in Cancer • Related to cancer • Related to chemotherapy • Associated with: •  quality of life •  survival

4. Benefits Improved QOL Decreased transfusions ? survival Harm Thromboembolism HTN Stimulate tumour growth (Cost) ? survival ESAs: Benefit vs. Harm

5. Methods • Systematic review of ESAs for the treatment of cancer-related anemia • Published and unpublished RCTs • Epoetin or darbepoetin vs. control • Adults age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

6. “Any” Outcomes • Mortality • Cardiac events • Hospital admission • Quality of life • Hypertension • RBC transfusion • Adverse events

7. Subgroups • American Society of Clinical Oncology criteria • Baseline hemoglobin • Chemotherapy (or not) • Target hemoglobin

8. 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

9. 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)

10. 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)

11. All-Cause Mortality

12. Quality of Life

13. Blood Transfusion

14. 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)

15. 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?

16. Validity

17. 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”

18. 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

19. 3. Is it unlikely that important, relevant studies were missed? • Yes • Very thorough search strategy • ESAs extensively exploded • Multiple databases • CancerLit? • Unpublished literature searched • Some papers included that were published after search dates

20. 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

21. 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

22. 5. Were assessments of studies reproducible (data abstraction)? • Yes? • One reviewer abstracted data • A second reviewer checked for accuracy

23. 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

24. 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

25. Relevance Will the results change my practice? Are the outcomes important to my patients?

26. 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

27. 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?

28. 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

29. 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

30. 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?

31. 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

32. 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…

33. Questions?