Fractionation sensitivity and dose response of late adverse effects in the breast after radiotherapy for early breast cancer: long-term results of a randomised trial

Abstract

Background and purpose: Unlike squamous carcinomas, breast adenocarcinoma may be as sensitive to fraction size as late dose-limiting normal tissues. If so, fewer larger fractions would be as safe and effective as regimens based on 2.0 Gy fractions. The first step is to test the effects of radiotherapy fractions O2.0 Gy on late normal tissue responses in the breast after tumour excision and radiotherapy for early breast cancer.Patients and methods: One thousand four-hundred and ten women with T1-3 N0-1 M0 invasive breast cancer were randomised between 1986-98 into one of three radiotherapy regimens after local tumour excision of early stage breast cancer; 50 Gy in 25 fractions (F) vs two dose levels of a test schedule giving 39 or 42.9 Gy in 13 F over 5 weeks. Fraction sizes were 2.0, 3.0 and 3.3 Gy, respectively. The primary endpoint was late change in breast appearance compared to post-surgical appearance scored from annual photographs blinded to treatment allocation. Secondary endpoints included palpable breast induration (fibrosis) and ipsilateral tumour recurrence.Results: After a minimum 5-year follow up, the risk of scoring any change in breast appearance after 50 Gy/25 F, 39 Gy/13 F and 42.9 Gy/13 F was 39.6, 30.3 and 45.7%, from which an a/b value of 3.6 Gy (95% CI 1.8-5.4) is estimated. The a/b value for palpable breast induration was 3.1 Gy (95% CI 1.8-4.4).Conclusions: An a/b value of around 3 Gy for late normal tissue changes in the breast is derived from the estimated equivalence of 41.6 Gy in 13 fractions and 50 Gy in 25 fractions over 5 weeks, in line with trial predictions. q 2005 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 75 (2005) 9-17.

The photon dose calculation algorithm used in breast radiotherapy has significant impact on the parameters of radiobiological models

“…Least square fitting resulted in new parameters for the AAA, the Acuros‐M, and the Acuros‐W algorithms (Table 4). The relative seriality of the breast, $\mathrm{s}=0.12$, (28) and $\alpha /\beta =3\hspace{0.17em}\text{Gy}$ (26) were kept fixed.…”

“…Again, first the BED method (22) was applied with $\alpha /\beta =3\hspace{0.17em}\text{Gy}$ (26) . Next, the NTCP was calculated using the relative seriality model for inhomogeneous dose distributions (27) using Eq.…”

The impact of dose heterogeneity on late normal tissue complication risk after hypofractionated whole breast radiotherapy

“…This endpoint has been well established and validated in randomised clinical trials, indicating it to be sensitive to small (<10%) differences in randomised total dose [1][2][3]7,11]. The 2-year timepoint is predictive of the relative effects of randomised groups at longer follow up, even though the absolute rate of adverse effects continues to rise for at least a decade and probably for life [7,22,23]. The limiting factor is not, therefore, the 2-year timepoint, but the total number of adverse events available for analysis, and particularly when stratified by treatment schedule.…”

“…Radiotherapy and Oncology 104 (2012) 143-147 The routine use of hypofractionation in breast radiotherapy is supported by outcome data of four large randomised clinical trials in women with early breast cancer [1][2][3][4][5][6][7]. Residual concerns include the impact of dose inhomogeneity on the risk of adverse effects after hypofractionated schedules, so-called 'treble trouble' [8][9][10].…”

Normal tissue complication probability (NTCP) parameters for breast fibrosis: Pooled results from two randomised trials

“…Results from the START-pilot trial [24] were used to independently assess the goodness of fit of the predicted NTCP models. The START-pilot trial randomised 1410 patients into one of three whole breast RT dose fractionations: 50 Gy in 25 fractions or 39 Gy in 13 fractions or 42.9 Gy in 13 fractions.…”