Modern Hypofractionation Schedules for Tangential Whole Breast Irradiation Decrease the Fraction Size-corrected Dose to the Heart

Abstract

Aims

Hypofractionation of postoperative radiotherapy for breast cancer has been evaluated in a number of large randomised clinical trials, but concerns remain over the late cardiac toxicity. In this study, we examined the predictions of the linear quadratic model on the estimated fraction size-corrected dose to the heart for four evidence-based hypofractionation regimens.

Materials and methods

Dose plans for 60 left-sided breast cancer patients were analysed. All patients were planned with tangential fields for whole breast irradiation. Dose distributions were corrected to the equivalent dose in 2 Gy fractions (EQD₂) using the linear quadratic model for five different fractionation schedules (50 Gy/25 fractions and four hypofractionation regimens) and for a range of α/β values (0–5 Gy). The mean EQD₂ to the heart ($D_{\text{mean}}^{{\text{EQD}}_2}$) and the volume receiving 40 Gy ($V_{40\text{Gy}}^{{\text{EQD}}_2}$), both as calculated from the EQD₂ dose distributions, were compared between schedules.

Results

For α/β = 3 Gy, $V_{40\text{Gy}}^{{\text{EQD}}_2}$ favours hypofractionation for 40 Gy/15 fractions, 39 Gy/13 fractions and 42.5 Gy/16 fractions, but not for 41.6 Gy/13 fractions. All of the hypofractionation schedules result in lower $D_{\text{mean}}^{{\text{EQD}}_2}$ compared with normofractionation. These results hold as long as α/β ≳ 1.5 Gy. If the heart is blocked from the treatment beam, the fraction size-corrected dose is lower for the first three hypofractionation schedules, compared with normofractionation, even for α/β = ∼1 Gy.

Conclusion

For standard tangential field whole breast irradiation, most of the examined hypofractionation schedules are estimated to spare the heart when compared with normofractionation. The dose to the heart, adjusted for fraction size using the linear quadratic model, will generally be lower after hypofractionated compared with normofractionated schedules, even for very low values of α/β.

Introduction

Postoperative whole breast irradiation for breast cancer patients both reduces the risk of local recurrence and improves overall survival [1]. Although a normofractionated schedule of 50 Gy in 25 fractions has been the standard treatment in most countries, moderate hypofractionation is now being introduced in many places.

Over 7000 patients have been enrolled in large, randomised clinical trials comparing hypofractionated with normofractionated radiotherapy [2], [3], [4], [5], [6]. The results suggest that α/β of breast cancer is in the range of 3–5 Gy [4], [5], [7]. As a result, several hypofractionation regimens have been identified, with disease control rates and toxicity profiles comparable with those seen with normofractionated whole breast irradiation after breast-conserving surgery [8], [9].

Still, concerns are nonetheless being raised over the safety of hypofractionation in terms of long-term toxicity [10], especially concerning mortality from radiation-induced heart disease, the sceptics arguing that the follow-up is still insufficient to judge the incidence of cardiac toxicity [11]. After a follow-up of 10 years, however, the Ontario Clinical Oncology Group trial [2] saw no difference in death due to cardiac disease between hypo- and normofractionated whole breast irradiation (nine and 12 deaths, respectively). This is consistent with the results of the British START A [5] and START B [6] trials, although the median follow-up was shorter (5.1 and 6.0 years).

Theoretical estimates of the cardiac toxicity after hypofractionation as compared with normofractionation depend on the fractionation sensitivity of the heart, quantified by the α/β ratio of the linear-quadratic model. Generally, a generic ‘late tissue damage’ α/β ratio of 3 Gy has been assumed, corresponding to relatively high fractionation sensitivity. There have, however, been suggestions of an even lower α/β for the heart, possibly as low as 1 Gy, although the data arguably are not very strong [12].

In this study, we compared fraction size-corrected dose distributions to the heart for four hypofractionation schedules with the normofractionated schedule of 50 Gy in 25 fractions, for a range of α/β values. The four schedules were those tested in three large, multi-institutional, randomised trials of hypofractionation: the British START A [5] and START B [6] trials and the Ontario Clinical Oncology Group trial of 42.5 Gy in 16 fractions [2].