ESAs for Cancer-Related 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 meta-analysis. 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Published and unpublished RCTs Epoetin or darbepoetin vs. controlAdults age>18Cancer-related anemia>30 subjects in each groupEnglish, 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 criteriaBaseline hemoglobinChemotherapy (or not)Target hemoglobin

Results

52 trials met criteria4 trials in perioperative patients30 trials in solid tumours10 trials in hematologic cancer11 trials included bothMean duration 12 (2-28) weeks

Cardiovascular events

MI, stroke, CHF, revascularization 14 trials

RR 1.12 (0.83-1.5) Hypertension

17 trialsRR 1.41 (0.94-2.12)

Tumour response

2 trialsNo 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 trialsIncreased risk in ESA groups

• RR1.16 (1.08-1.25)

Thrombotic events13 trialsIncreased 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

ESAs extensively exploded Multiple databases

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 Unpublished literature searched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 reviewersAll flagged articles retrieved

Full text assessed by 2 reviewers for inclusionDisagreements 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 epoTransfusion 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 anemiaBut are not contraindicated…

Questions?