Radiotherapy-Related Dose and Irradiated Volume Effects on Breast Cancer Risk Among Hodgkin Lymphoma Survivors

Sander Roberti, MSc; Flora E. van Leeuwen, PhD; Cécile M. Ronckers, PhD; Inge M. Krul, MSc; Florent de Vathaire, PhD; Cristina Veres, MSc; Ibrahima Diallo, PhD; Cécile P.M. Janus, MD; Berthe M.P. Aleman, MD; Nicola S. Russell, MD; Michael Hauptmann, PhD


J Natl Cancer Inst. 2022;114(9):1270-1278. 

In This Article

Abstract and Introduction


Background: Breast cancer (BC) risk is increased among Hodgkin lymphoma (HL) survivors treated with chest radiotherapy. Case-control studies showed a linear radiation dose-response relationship for estimated dose to the breast tumor location. However, these relative risks cannot be used for absolute risk prediction of BC anywhere in the breasts. Furthermore, the independent and joint effects of radiation dose and irradiated volumes are unclear. Therefore, we examined the effects of mean breast dose and various dose-volume parameters on BC risk in HL patients.

Methods: We conducted a nested case-control study of BC among 5-year HL survivors (173 case patients, 464 matched control patients). Dose-volume histograms were obtained from reconstructed voxel-based 3-dimensional dose distributions. Summary parameters of dose-volume histograms were studied next to mean and median breast dose, Gini index, and the new dose metric mean absolute difference of dose, using categorical and linear excess odds ratio (EOR) models. Interactions between dose-volume parameters and mean dose were also examined.

Results: Statistically significant linear dose-response relationships were observed for mean breast dose (EOR per Gy = 0.19, 95% confidence interval [CI] = 0.05 to 1.06) and median dose (EOR/Gy = 0.06, 95% CI = 0.02 to 0.19), with no statistically significant curvature. All metrics except Gini and mean absolute difference were positively correlated with each other. These metrics all showed similar patterns of dose-response that were no longer statistically significant when adjusting for mean dose. No statistically significant modification of the effect of mean dose was observed.

Conclusion: Mean breast dose predicts subsequent BC risk in long-term HL survivors.


Strong evidence exists for a causal relationship between chest radiotherapy (RT) and subsequent breast cancer (BC) among female cancer survivors, including Hodgkin lymphoma (HL).[1,2] Cohort studies among long-term cancer survivors show increasing risk of RT-related BC with younger age at RT, RT fields covering larger breast volumes, and higher prescribed radiation doses.[1–6] Several case-control studies[7–11] demonstrated a linear increase of relative risk (RR) for BC with radiation dose to the affected site in the breast.

Cohort studies on BC risk after chest RT are typically too large to capture heterogeneity of radiation dose distributions in the breast, especially the steep gradients typically seen near shielding blocks.[1,4] Case-control studies have used dose to the breast tumor location (and equivalent location in matched control patients). However, the estimated RR of BC cannot be used for prediction of absolute risk anywhere in the breasts (ie, breast cancer risk experienced by the patient). Yet, this risk is required to inform clinical practice, particularly to assess risks and benefits of novel RT techniques for new patients, including proton therapy,[12,13] and to implement surveillance guidelines among cancer survivors treated with chest RT.[14,15]

Despite the need to understand the role of radiation dose-volume parameters in late effects risk, data are sparse. Specifically, estimated mean breast dose derived from doses to multiple locations in the breast has not been studied as a determinant of subsequent BC risk. Moreover, no standard approach exists in the literature for evaluating radiation dose-volume data and BC risk,[16–21] whereas standard treatment planning systems provide 3-dimensional (3D) dose distributions for organs contoured on the planning computed tomography examination.

Therefore, we examined how the distribution of dose across the breasts of female HL survivors, summarized by mean delivered breast dose and dose-volume parameters, determines BC risk. As radiation-associated BC has a long induction period, we used the Dutch multicenter HL cohort (ie, women treated for HL during 1965–2000 who were followed for several decades).[2]