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Risk of cardiotoxicity induced by adjuvant anthracycline-based chemotherapy and radiotherapy in young and old Asian women with breast cancer

Risiko der Kardiotoxizität induziert durch adjuvante anthrazyklinbasierte Chemotherapie und Strahlentherapie bei jungen und alten asiatischen Frauen mit Brustkrebs

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Abstract

Purpose

The risk of cardiotoxicity induced by adjuvant anthracycline-based chemotherapy (CT) and radiotherapy (RT) is yet to be investigated in a large-scale randomized controlled trial with an adequate sample size of young and old women with breast cancer.

Patients and methods

To compare the occurrence of major heart events (heart failure and coronary artery disease) in patients with breast cancer, 3489 women who underwent surgical resection of the breast tumor were retrospectively selected from the Taiwan National Health Insurance Research Database. The patients were categorized into the following groups based on their treatment modalities: group 1 (n = 1113), no treatment; group 2 (n = 646), adjuvant RT alone; group 3 (n = 705), adjuvant anthracycline-based CT alone; and group 4 (n = 1025), combined adjuvant RT and anthracycline-based CT.

Results

The mean patient age was 50.35 years. Subsequent coronary artery disease and heart failure were identified in 244 (7.0%) and 206 (5.9%) patients, respectively. All three adjuvant therapies were significant independent prognostic factors of major heart events (adjusted hazard ratio [95% confidence interval]: 1.47 [1.24–1.73]; 1.48 [1.25–1.75], and 1.92 [1.65–2.23] in groups 2, 3, and 4, respectively). In patients aged ≥50 years with breast cancer who underwent surgery, the log-rank p values of groups 2 and 3 after adjustment were 0.537 and 0.001, respectively.

Conclusion

Adjuvant RT can increase cardiotoxicity in patients with breast cancer, particularly when used in combination with anthracycline-based CT. Therefore, it should be offered with optimal heart-sparing techniques, particularly in younger patients with good prognosis and long life expectancy.

Zusammenfassung

Zielsetzung

Das Risiko einer Kardiotoxizität durch adjuvante anthrazyklinbasierte Chemotherapie (CT) und Strahlentherapie (RT) muss noch in einer groß angelegten randomisierten kontrollierten Studie mit einer angemessenen Stichprobe von jungen und alten Frauen mit Brustkrebs untersucht werden.

Patienten und Methoden

Um das Auftreten von schweren Herzerkrankungen (Herzinsuffizienz und koronare Herzkrankheit) bei Patientinnen mit Brustkrebs zu vergleichen, wurden 3489 Frauen, bei denen eine chirurgische Resektion des Brusttumors durchgeführt worden war, retrospektiv aus der Taiwan National Health Insurance Research Database ausgewählt. Die Patienten wurden basierend auf ihren Behandlungsmodalitäten in die folgenden Gruppen eingeteilt: Gruppe 1 (n = 1113), keine Behandlung; Gruppe 2 (n = 646), nur adjuvante RT; Gruppe 3 (n = 705), nur adjuvante anthrazyklinbasierte CT; und Gruppe 4 (n = 1025), kombinierte adjuvante RT und anthrazyklinbasierte CT.

Ergebnisse

Das durchschnittliche Patientenalter betrug 50,35 Jahre. Nachfolgende Koronararterienerkrankung und Herzinsuffizienz wurden bei 244 (7,0 %) bzw. 206 (5,9 %) Patienten festgestellt. Alle 3 adjuvanten Therapien waren signifikante unabhängige prognostische Faktoren für schwere, das Herz betreffende Zwischenfälle (bereinigtes Hazard Ratio [95%-Konfidenzintervall]: 1,47 [1,24–1,73]; 1,48 [1,25–1,75] und 1,92 [1,65–2,23] in den Gruppen 2, 3 bzw. 4). Bei Patienten im Alter von ≥50 Jahren mit Brustkrebs, die sich einer Operation unterziehen mussten, betrugen die logarithmischen p-Werte der Gruppen 2 und 3 nach Anpassung 0,537 bzw. 0,001.

Schlussfolgerung

Adjuvante RT kann die Kardiotoxizität bei Patientinnen mit Brustkrebs erhöhen, insbesondere wenn sie in Kombination mit anthrazyklinbasierter CT angewendet wird. Daher sollte sie mit optimalen herzschonenden Techniken angeboten werden, insbesondere bei jüngeren Patienten mit guter Prognose und langer Lebenserwartung.

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Abbreviations

aHR:

Adjusted hazard ratio

CAD:

Coronary artery disease

CI:

Confidence interval

CT:

Chemotherapy

DM:

Diabetes mellitus

HR:

Hazard ratio

HF:

Heart failure

HTN:

Hypertension

ICD-9-CM:

International Classification of Diseases, Ninth Revision, Clinical Modification

IPTW:

Inverse probability of treatment weighting

NHIRD:

National Health Insurance Research Database

RT:

Radiotherapy

SD:

Standard deviation

TIA:

Transient ischemic attack

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Acknowledgements

We would like to thank Taipei Medical University for funding (108-wf-swf-09).

Author Contributions

Conception and Design: Chih-Hsin Lee, Jun-Fu Zhang and Szu-Yuan Wu; Collection and Assembly of Data: J Chih-Hsin Lee, Jun-Fu Zhang, Kevin Sheng-Po Yuan, Alexander T.H. Wu and Szu-Yuan Wu; Data Analysis and Interpretation: Chih-Hsin Lee, Jun-Fu Zhang and Szu-Yuan Wu; Administrative Support: Szu-Yuan Wu; Manuscript Writing: All authors; Final Approval of Manuscript: All authors

Funding

Taipei Medical University and Wan Fang Hospital (108-wf-swf-09)

Author information

Authors and Affiliations

  1. Division of Pulmonary Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

    Chih-Hsin Lee MD, PhD & Jun-Fu Zhang MS

  2. Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, China

    Szu-Yuan Wu MD, MPH, PhD

  3. Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

    Chih-Hsin Lee MD, PhD & Szu-Yuan Wu MD, MPH, PhD

  4. Department of Otorhinolaryngology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

    Kevin Sheng-Po Yuan MD, MS

  5. Ph.D. Program for Translational Medicine, Taipei Medical University, Taipei, Taiwan

    Alexander T. H. Wu PhD

  6. Department of Radiation Oncology, Wan Fang Medical Center, Taipei Medical University, No. 111, Section 3, Hsing-Long Road, 116, Taipei, Taiwan

    Szu-Yuan Wu MD, MPH, PhD

  7. Epidemiology and Bioinformatics Center, Wan fang Hospital, Taipei Medical University, Taipei, Taiwan

    Chih-Hsin Lee MD, PhD & Szu-Yuan Wu MD, MPH, PhD

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  1. Chih-Hsin Lee MD, PhD
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  3. Kevin Sheng-Po Yuan MD, MS
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  4. Alexander T. H. Wu PhD
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Corresponding author

Correspondence to Szu-Yuan Wu MD, MPH, PhD.

Ethics declarations

Conflict of interest

C.-H. Lee, J.-F. Zhang, K.S.-P. Yuan, A.T.H. Wu and S.-Y. Wu declare that they have no competing interests.

Ethical standards

Our protocols were reviewed and approved by the Institutional Review Board of Taipei Medical University (TMU-JIRB No. 201402018).

Additional information

Chih-Hsin Lee died before publishing this article.

Availability of data and material: The datasets supporting the study conclusions are included within this manuscript and its additional files.

Caption Electronic Supplementary Material

66_2019_1428_MOESM1_ESM.docx

Table S1. Multivariate Cox regression analysis in Asian women with breast cancer who underwent surgery and received different adjuvant treatments (outcome of interest: coronary artery disease).

66_2019_1428_MOESM2_ESM.docx

Table S2. Multivariate Cox regression analysis in Asian women with breast cancer who underwent surgery and received different adjuvant treatments (outcome of interest: heart failure).

66_2019_1428_MOESM3_ESM.docx

Table S3. Multivariate Cox regression analysis in Asian women with breast cancer who underwent surgery and received different adjuvant treatments (interaction analysis for age and adjuvant therapies).

66_2019_1428_MOESM4_ESM.docx

Table S4. Multivariate Cox regression analysis in old (age ≥50 years) Asian women with breast cancer who underwent surgery and received different adjuvant treatments (interaction analysis for radiotherapy and anthracycline-based chemotherapy).

66_2019_1428_MOESM5_ESM.docx

Table S5. Multivariate Cox regression analysis in young (age <50 years) Asian women with breast cancer who underwent surgery and received different adjuvant treatments (interaction analysis for radiotherapy and anthracycline-based chemotherapy).

66_2019_1428_MOESM6_ESM.docx

Table S6. Competing risk analysis by using the cause-specific proportional hazard model in Asian women with breast cancer who underwent surgery and received different adjuvant treatments (endpoint of interest: death).

66_2019_1428_MOESM7_ESM.docx

Table S7. Multivariate Cox regression in 3073 surviving Asian women with breast cancer who underwent surgery and received different adjuvant treatments for risk factors of major cardiac events.

66_2019_1428_MOESM8_ESM.docx

Table S8. Multivariate Cox regression analysis in Asian women with breast cancer who underwent surgery and received different adjuvant treatments (outcome of interest: major cardiac events)

66_2019_1428_MOESM9_ESM.docx

Figure S1. Estimates of cumulative incidence of major cardiac events in Asian women with breast cancer who underwent surgery, as obtained using the inverse probability of treatment weighting-adjusted Kaplan–Meier method and stratified by total dose of radiotherapy.

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Lee, CH., Zhang, JF., Yuan, K.SP. et al. Risk of cardiotoxicity induced by adjuvant anthracycline-based chemotherapy and radiotherapy in young and old Asian women with breast cancer. Strahlenther Onkol 195, 629–639 (2019). https://doi.org/10.1007/s00066-019-01428-7

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