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Risk of heart failure increases with cardiac exposure radiotherapy in breast cancer patients

circ.ahajournals.org
Literature - Saiki H, Petersen IA, Scott CG, et al. - Circulation, 2017, [Epub ahead of print]

Background

Standard treatment for breast cancer patients currently comprises breast conserving surgery plus radiotherapy. However, cardiac radiation during this therapy, even low levels, increases the risk of coronary events [1]. Although cardiomyocytes are resistant to radiation, it induces coronary microvascular endothelial damage and inflammation leading to microvascular rarefaction and myocardial inflammation, oxidative stress and fibroses [2-5]. A growing number of radiotherapy techniques can reduce cardiac exposure, but these are inconsistently utilized [6].

To investigate whether cardiac radiation exposure during contemporary breast cancer radiotherapy may increase the risk of heart failure (HF), in particularly HF with preserved ejection fraction (HFpEF), a population-based case-control study of breast cancer patients treated with CT-guided radiotherapy has been performed.

Main results

  • 59 of 945 breast cancer patients who underwent radiotherapy between 1998 and 2013, developed new onset validated HF after radiotherapy and matched criteria and control. The study included 111 non-HF controls.
  • Most patients (64%) presented with HFpEF. 31% had HF with reduced ejection fraction (HFrEF) and 5% did not have ejection fraction measured coincident with HF diagnosis.
  • EF was ≥40% in 89% of all HF cases with EF measurement.
  • Mean interval from radiotherapy to HF was 5.8 years.
  • The relative risk of HF was higher in patients with more advanced cancer stage and in those with prior history of ischemic heart disease (IHD) or atrial fibrillation (AF) (OR stage 1 and 2 or 3 (vs. 0) 2.14 (95% CI 0.79-5.77) and 4.63 (95% CI 1.45-14.78) respectively, P=0.03, and 5.06 (95% CI 1.34-19.13), P=0.02, and 3.41 (95% CI 1.36-8.55), P=0.009, for prior IHD and AF, respectively).
  • Overall mean cardiac radiation dose (MCRD) was higher in cases (3.3 +/- 2.7 Gy) than controls (2.1 +/- 2.0 Gy, P=0.004) and was higher in women with left (4.1, range 0.6-13.1 Gy) versus right (1.5, range 0.2-5.6 Gy, P<0.001) sided tumors.
  • The crude frequency of HF increased with higher MCRD, as well did the odds of incident HF and HFpEF (adjusted [age, IHD, AF, stage] ORs 7.40, 95% CI 2.77-19.81, P<0.001 and 22.70, 95% CI 4.48-115.10, P<0.001, respectively). The odds increase of incident HFrEF with higher MCRD was not significant.
  • Sensitivity analyses matching by cancer stage rather by tumor side showed similar results, although the magnitude of odds per log MCRD was lower but still substantial.

Conclusion

The odds of incident HF after radiotherapy increased with higher MCRD with predominantly HFpEF or HF with ‘mid-range’ (40-49%) EF and HF began within a few years after radiotherapy. Furthermore, these odds increased with MCRD, even after adjustment for other known risk factors and cancer stage. The current data also underscore the need to reduce MCRD, particularly in older women with HF risk factors, and the importance of techniques to reduce cardiac dose.

References

1. Darby SC, Ewertz M, McGale P, Bennet AM, Blom-Goldman U, Bronnum D, Correa C, Cutter D, Gagliardi G, Gigante B, Jensen MB, Nisbet A, Peto R, Rahimi K, Taylor C and Hall P. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013;368:987-998

2. Stewart FA, Seemann I, Hoving S and Russell NS. Understanding radiation-induced cardiovascular damage and strategies for intervention. Clin Oncol (R Coll Radiol). 2013;25:617-624

3. Stewart FA. Mechanisms and dose-response relationships for radiation-induced cardiovascular disease. Ann ICRP. 2012;41:72-79

4. Schultz-Hector S and Trott KR. Radiation-induced cardiovascular diseases: is the epidemiologic evidence compatible with the radiobiologic data? Int J Radiat Oncol Biol Phys. 2007;67:10-18

5. Darby SC, Cutter DJ, Boerma M, Constine LS, Fajardo LF, Kodama K, Mabuchi K, Marks LB, Mettler FA, Pierce LJ, Trott KR, Yeh ET and Shore RE. Radiation-related heart disease: current knowledge and future prospects. Int J Radiat Oncol Biol Phys. 2010;76:656-665

6. Taylor CW, Wang Z, Macaulay E, Jagsi R, Duane F and Darby SC. Exposure of the Heart in Breast Cancer Radiation Therapy: A Systematic Review of Heart Doses Published During 2003 to 2013. Int J Radiat Oncol Biol Phys. 2015;93:845-853

Find this article online at Circulation

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