Estimating the risks of breast cancer radiotherapy: Evidence from modern radiation doses to the lungs and heart and from previous randomised trials

Purpose Radiotherapy reduces the absolute risk of breast cancer mortality by a few percent in suitable women, but can cause second cancer or heart disease decades later. We estimated the absolute long-term risks of modern breast cancer radiotherapy. Methods First, a systematic literature review was performed of lung and heart doses in breast cancer regimens published during 2010-15. Second, individual patient data meta-analyses of 40,781 women randomised in 75 trials of breast cancer radiotherapy yielded rate ratios (RRs) for second primary cancers and cause-specific mortality, and excess RRs (ERRs) per Gy for incident lung cancer and cardiac mortality. Smoking status was unavailable. Third, the lung or heart ERRs/Gy in the trials and the 2010-15 doses were combined and applied to current smoker and non-smoker lung cancer and cardiac mortality rates in population-based data. Results Average doses from 647 regimens published 2010-15 were 5.7 Gy whole-lung and 4.4 Gy whole-heart. Median year of irradiation was 2010 (IQR 2008-2011). Meta-analyses yielded lung cancer incidence 10+ years after radiotherapy RR=2.10 (95%CI 1.48-2.98, p Estimated absolute risks from modern radiotherapy were: Lung cancer ~4% for long-term continuing smokers, but 0.3% for non-smokers; cardiac mortality ~1% for smokers and 0.3% for non-smokers. Conclusions For long-term smokers, the absolute risks of modern radiotherapy may outweigh the benefits yet for most non-smokers (and ex-smokers) the benefits of radiotherapy far outweigh the risks. Hence smoking can determine the net effect of radiotherapy on mortality; but smoking cessation substantially reduces radiotherapy-risk.