| Summary: | <h4>Purpose</h4> <p>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.</p> <h4>Methods</h4> <p>First, a systematic literature review was performed of lung and heart doses in breast cancer regimens published during 2010-15.</p> <br/> <p>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.</p> <br/> <p>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.</p> <h4>Results</h4> <p>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).</p> <br/> <p>Meta-analyses yielded lung cancer incidence 10+ years after radiotherapy RR=2.10 (95%CI 1.48-2.98, p<0.0001) based on 134 cancers, indicating 0.11 (0.05-0.20) ERR/Gy whole-lung dose. For cardiac mortality RR=1.30 (1.15-1.46, p<0.0001) based on 1253 cardiac deaths. Detailed analyses indicated 0.04 (0.02-0.06) ERR/Gy whole-heart dose.</p> <br/> <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.</p> <h4>Conclusions</h4> <p>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.</p>
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