Estimating the Risks of Breast Cancer Radiotherapy: Evidence From Modern Radiation Doses to the Lungs and Heart and From Previous Randomized Trials

Abstract

Purpose Radiotherapy reduces the absolute risk of breast cancer mortality by a few percentage points in suitable women but can cause a 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 to 2015. Second, individual patient data meta-analyses of 40,781 women randomly assigned to breast cancer radiotherapy versus no radiotherapy in 75 trials 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 per Gy in the trials and the 2010 to 2015 doses were combined and applied to current smoker and nonsmoker lung cancer and cardiac mortality rates in population-based data. Results Average doses from 647 regimens published during 2010 to 2015 were 5.7 Gy for whole lung and 4.4 Gy for whole heart. The median year of irradiation was 2010 (interquartile range [IQR], 2008 to 2011). Meta-analyses yielded lung cancer incidence ≥ 10 years after radiotherapy RR of 2.10 (95% CI, 1.48 to 2.98; P < .001) on the basis of 134 cancers, indicating 0.11 (95% CI, 0.05 to 0.20) ERR per Gy whole-lung dose. For cardiac mortality, RR was 1.30 (95% CI, 1.15 to 1.46; P < .001) on the basis of 1,253 cardiac deaths. Detailed analyses indicated 0.04 (95% CI, 0.02 to 0.06) ERR per Gy whole-heart dose. Estimated absolute risks from modern radiotherapy were as follows: lung cancer, approximately 4% for long-term continuing smokers and 0.3% for nonsmokers; and cardiac mortality, approximately 1% for smokers and 0.3% for nonsmokers. Conclusion For long-term smokers, the absolute risks of modern radiotherapy may outweigh the benefits, yet for most nonsmokers (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.

The connection between the breast and heart in a woman: Breast cancer and cardiovascular disease

“…More recent studies have had conflicting results, with many single institution studies and large data registries showing no increased cardiovascular risk, whereas others support an increased risk for cardiovascular disease associated with radiation . Nonetheless, a recent meta‐analysis spanning the years 2010 to 2015 demonstrated a mean radiation dose to the heart of 4.4 Gy and a hazard ratio for cardiovascular deaths of 1.30 ( P < 0.001) for those who received radiation compared with those who did not, with a proportional increase in cardiac mortality of 0.04 per Gy …”

What Is the Best Management of cN0pN1(sn) Breast Cancer Patients

“…This includes using modern radiation facilities to obtain a homogeneous dose distribution in the target volumes that are clearly defined and delineated according to the ESTRO target volume consensus, respiratory control during RT, and informing the patient about the risks from continuing smoking if she is a smoker [44,45,46]. The risk of late radiation-induced morbidity after modern RT is no doubt less than described in previous reports from patients treated decades ago.…”

Proton Therapy for Breast Cancer: Progress & Pitfalls

“…Therefore, there is strong evidence to support efforts to limit even low dose cardiac exposure. Of note, the absolute risks of cardiac toxicity from RT appear higher in smokers [17] and patients with other cardiac risk factors including receipt of potentially cardiotoxic chemotherapy agents commonly used for the treatment of breast cancer. There are many parameters we do not yet understand about cardiac risk from RT, including importance of dose to cardiac substructures, mechanism of injury and which dose parameters are most meaningful [18].…”

“…There are many parameters we do not yet understand about cardiac risk from RT, including importance of dose to cardiac substructures, mechanism of injury and which dose parameters are most meaningful [18]. However, based on current models and typical dose metrics achieved with PBT, as shown in Table 1, significant reductions in late cardiac toxicity would be expected for many patients compared with advanced photon planning [17,19,20]. is an important area of investigation.…”