Cohort studyindependent cross-checkabstract checked★ key study I-CHM-108 standard review
Heart failure after doxorubicin by dose
Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials.
Overview
Swain SM et al.. Cancer 2003 · PMID 12767102 · DOI 10.1002/cncr.11407
About 5% of 630 patients developed heart failure; risk rose steeply at high cumulative doses (26% estimated at 550 mg/m2).
Does the study support the specific claim? Yes · Methodological quality: moderate
Plain-language summary
Study explained simply
- What did the researchers want to find out?
Estimate heart failure risk by dose
- How was the study done?
Re-analysis of three trials
- How many people, animals or samples were studied?
630 patients
- What was actually found?
Risk climbs with dose and age
- How large was the observed effect?
26% at 550 mg/m2 (model estimate)
- What do the results mean in everyday life?
This is why doctors cap the total dose and monitor the heart
- What are the study's limitations?
High doses, old trials
- What does it say about Elawady's specific claim?
Supports the dose-dependence claim
- Do the results apply to Germany and Europe?
High
- What can explicitly not be concluded from this study?
Cannot give risk for modern low-dose regimens
Scientific in-depth review
1. Full reference
- Authors
- Swain SM et al.
- Journal
- Cancer
- Year
- 2003
- Identifier
- PMID 12767102 DOI 10.1002/cncr.11407
- Verification
- verified – PubMed efetch 2026-10-26 (PublicationType and CommentsCorrections checked); Crossref 2026-10-26
- Retracted
- no
- Corrections
- none
- Extent checked
- abstract only
- Conflicts of interest and funding
Not stated in abstract (non-US-government research support listed).
2. Research question
What is the incidence of doxorubicin-related CHF by cumulative dose?
3. Study design and population
- Study design
- Cohort study – Retrospective analysis of doxorubicin-plus-placebo arms of three phase III RCTs
- Population
Patients with breast cancer or small-cell lung cancer receiving doxorubicin
- Country
USA/international trials
- Period
Trials 1980s-1990s
- Sample size
630 patients
- Inclusion and exclusion criteria
Doxorubicin-plus-placebo arms of three phase III trials
4. Methods and endpoints
- Exposure / intervention
Cumulative doxorubicin dose
- Comparator
Lower cumulative doses
- Endpoints
Congestive heart failure
- Statistical methods
Cumulative incidence by dose (model-based)
5. Actual results
- Results
32 of 630 patients (5.1%) had CHF; estimated cumulative 26% would develop CHF at 550 mg/m2; age >65 years associated with higher incidence above 400 mg/m2; >50% of CHF cases had LVEF reduction <30%.
- Absolute risks
26% estimated at 550 mg/m2 cumulative dose
- Authors' conclusion
Doxorubicin-related CHF occurs more often and at lower cumulative doses than previously reported; LVEF is not an accurate predictor.
6. Strengths
- Prospectively collected trial data
- Dose-response
7. Weaknesses
- Retrospective analysis; mostly advanced (metastatic) disease with high cumulative doses
- Old dosing practices
8. Risk of bias
- Orienting tool
- ROBINS-E
- Type of assessment
- simplified assessment (abstract only)
- Full formal assessment
- no
- Overall risk of bias
- some concerns
- Rationale
Secondary analysis; ascertainment in trials reasonably systematic.
9. Assessment of the statistical interpretation
Crude proportion 5.1% recomputed; dose-specific estimates are model-based (stats/C-CHM-01.py).
10. Relevance to the specific claim
Supports the claim that anthracycline heart damage is dose-dependent; the high doses here (up to 550 mg/m2) exceed the cumulative doses in the EBCTCG 2023 adjuvant trials (about 200-300 mg/m2 doxorubicin-equivalent).
11. Independent contrary findings
EBCTCG 2023 (I-CHM-101): no excess cardiovascular death at modern adjuvant doses within about 5 years.
12. Transferability to Germany and Europe
Applicable biology; modern dose limits derive from such data.
13. Overall methodological judgement
Credible dose-response evidence for doxorubicin cardiotoxicity.
| Multidimensional assessment | |
|---|---|
| Authenticity of the source | verified |
| Methodological quality | moderate |
| Risk of bias | some concerns |
| Precision of results | moderate |
| Directness | direct |
| Reproducibility | replicated |
| Consistency with the overall evidence | consistent |
| Regional transferability | high |
| Adequacy of the interpretation (by the archive) | not applicable |
14. Open questions
Long-term risk at modern doses.