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Volume matters: Breast induration is associated with irradiated breast volume in the Danish Breast Cancer Group phase III randomized Partial Breast Irradiation trial

Open AccessPublished:October 17, 2022DOI:https://doi.org/10.1016/j.radonc.2022.09.024

      Highlights

      • Dose–response relationship between breast induration and breast volume irradiated to 40 Gy.
      • Irradiated breast volume was significantly smaller with PBI compared to WBI.
      • No difference was found between the whole breast volumes in the two treatment arms.

      Abstract

      Purpose

      The relation between breast induration grade 2–3 at 3 years after radiation therapy and irradiated breast volume was investigated for patients in the Danish Breast Cancer Group (DBCG) Partial Breast Irradiation (PBI) trial. METHODS Treatment plan data was obtained from the Danish radiotherapy plan database. Dosimetric parameters for breast and organs at risk were determined. Breast induration data was obtained from the DBCG database. The volume of the whole breast (CTVp_breast) treated to various dose levels was determined for treatment plans in both arms. Logistic regression was used to assess the frequency of induration on breast volume irradiated to ≥40 Gy. RESULTS PBI and WBI was given to 433 and 432 patients, respectively. Median and interquartile ranges (IQR) for CTVp_breast were 710 mL (467–963 mL; PBI) and 666 mL (443–1012 mL; WBI) (p = 0.98). Median and IQR for CTVp_breast treated to ≥40 Gy was 24.9% (18.6–32.6%; PBI) and 59.8% (53.6–68.5%; WBI). Grade 2–3 induration was observed in 5% (PBI) and 10% (WBI) of the patients. A dose–response relationship was established between irradiated breast volume and frequency of breast induration. From the model, 5% and 10% risks of breast induration were observed for ≥40 Gy delivered to CTVp_breast volumes of 177 mL (95%CI, 94–260 mL) and 426 mL (95%CI, 286–567 mL), respectively. CONCLUSION The frequency of breast induration increased significantly with increasing irradiated breast volume, strongly favouring small volumes and PBI. Thus, treated breast volume – not the breast size itself - is the risk factor for induration. This is the first report directly linking the 40 Gy irradiated breast volume to breast induration.

      Keywords

      Radiation therapy (RT) of the whole breast used to be the standard care after breast-conserving surgery and was shown to significantly lower the risk of local, regional and distant failure and improve overall survival [
      • Darby S.
      • McGale P.
      • Correa C.
      • Taylor C.
      • Arriagada R.
      • Clarke M.
      • et al.
      Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials.
      ]. However, for patients with a relatively low-risk breast cancer partial breast irradiation (PBI) has gained more interest to reduce adverse events by irradiating smaller volumes [
      • Offersen B.V.
      • Overgaard M.
      • Kroman N.
      • Overgaard J.
      Accelerated partial breast irradiation as part of breast conserving therapy of early breast carcinoma: a systematic review.
      ] without a higher risk of local recurrence.
      In 2009 the Danish Breast Cancer Group (DBCG) initiated two randomized controlled trials with moderately hypofractionated external-beam RT of 40 Gy in 15 fractions (fr) to patients operated with breast-conservation for node-negative breast cancer with an indication for whole breast irradiation (WBI): the DBCG HYPO trial [
      • Offersen B.V.
      • Alsner J.
      • Nielsen H.M.
      • Jakobsen E.H.
      • Nielsen M.H.
      • Krause M.
      • et al.
      Hypofractionated versus standard fractionated radiotherapy in patients with early breast cancer or ductal carcinoma in situ in a randomized phase III trial: The DBCG HYPO Trial.
      ] and the DBCG PBI trial [
      • Offersen B.V.
      • Alsner J.
      • Nielsen H.M.
      • Jacobsen E.H.
      • Nielsen M.H.
      • Stenbygaard L.
      • et al.
      Partial Breast Irradiation Versus Whole Breast Irradiation for Early Breast Cancer Patients in a Randomized Phase III Trial: The DBCG PBI Trial.
      ]. The PBI trial was similar to two of the arms in the IMPORT LOW trial, i.e., WBI versus PBI with 40 Gy in 15 fr [
      • Coles C.E.
      • Griffin C.L.
      • Kirby A.M.
      • Titley J.
      • Agrawal R.K.
      • Alhasso A.
      • et al.
      Partial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW trial): 5-year results from a multicentre, randomized, controlled, phase 3, non-inferiority trial.
      ]. The primary endpoint in the DBCG PBI trial was 3-year grade 2–3 breast induration and the rate of induration at 3 years was 9·7% (95% CI 7·0 to 12·9) for WBI and 5·1% (95% CI 3·2 to 7·6) for PBI [
      • Offersen B.V.
      • Alsner J.
      • Nielsen H.M.
      • Jacobsen E.H.
      • Nielsen M.H.
      • Stenbygaard L.
      • et al.
      Partial Breast Irradiation Versus Whole Breast Irradiation for Early Breast Cancer Patients in a Randomized Phase III Trial: The DBCG PBI Trial.
      ]. Breast size was significantly associated with induration with a 3-year incidence of 13% (WBI) and 6% (PBI) for large size versus 6% (WBI) and 5% (PBI) for small size, whereas only few loco-regional recurrences were detected and unrelated to PBI, showing less late effects for patients treated with PBI without compromising the local control rate [
      • Offersen B.V.
      • Alsner J.
      • Nielsen H.M.
      • Jacobsen E.H.
      • Nielsen M.H.
      • Stenbygaard L.
      • et al.
      Partial Breast Irradiation Versus Whole Breast Irradiation for Early Breast Cancer Patients in a Randomized Phase III Trial: The DBCG PBI Trial.
      ]. Other studies have also reported more breast induration in large-breasted patients, thus indicating an association between breast size and induration [
      • Ratosa I.
      • Jenko A.
      • Oblak I.
      Breast size impact on adjuvant radiotherapy adverse effects and dose parameters in treatment planning.
      ,
      • Donovan E.
      • Bleakley N.
      • Denholm E.
      • Evans P.
      • Gothard L.
      • Hanson J.
      Randomised trial of standard 2D radiotherapy (RT) versus intensity modulated radiotherapy (IMRT) in patients prescribed breast radiotherapy.
      ]. However, depending on the location of the tumour in the breast, PBI of large-breasted patients may result in a small irradiated volume not reflected in breast size. Therefore, it may be more accurate to report the risk of induration in relation to irradiated breast volume. This study investigated the frequency of breast induration grade 2–3 in the DBCG PBI trial at 3 years after RT versus the breast volume irradiated to ≥40 Gy.

      Materials and methods

      Patients ≥60 years operated with breast-conservation for early unilateral, unifocal, estrogen receptor (ER) positive ≥1%, human epidermal growth factor receptor 2 (HER-2) negative, grade 1–2, non-lobular breast cancer <21 mm (International Union Against Cancer stage pT1 pN0 M0) with a surgical margin of minimum 2 mm, requiring RT to the residual breast were eligible for inclusion in the DBCG PBI trial. Stratification factors were use of endocrine therapy (yes/no) and institution. The patients were randomized to WBI versus PBI with 40 Gy/15fr/3weeks. A written informed consent according to Good Clinical Practice guidelines and local and national rules of participating institutions was obtained. The trial was approved by the Ethics Committees of all participating centres (ClinicalTrials.gov identifier: NCT00892814).
      Treatment preparation was according to DBCG RT guidelines and details were reported in Offersen et al. [
      • Offersen B.V.
      • Alsner J.
      • Nielsen H.M.
      • Jacobsen E.H.
      • Nielsen M.H.
      • Stenbygaard L.
      • et al.
      Partial Breast Irradiation Versus Whole Breast Irradiation for Early Breast Cancer Patients in a Randomized Phase III Trial: The DBCG PBI Trial.
      ]. In short, surgical clips localized the tumour bed. For the RT planning, the patient was positioned supine in the institutional standard fixation allowing a daily reproducibility of approximately 5 mm. The institutional guideline for respiratory gating was followed. The clinical target volume for the whole breast (CTVp_breast) was delineated following the guidelines of DBCG and ESTRO [
      • Nielsen M.H.
      • Berg M.
      • Pedersen A.N.
      • Andersen K.
      • Glavicic V.
      • Jakobsen E.H.
      • et al.
      Delineation of target volumes and organs at risk in adjuvant radiotherapy of early breast cancer: national guidelines and contouring atlas by the Danish Breast Cancer Cooperative Group.
      ,
      • Offersen B.V.
      • Boersma L.J.
      • Kirkove C.
      • Hol S.
      • Aznar M.C.
      • Sola A.B.
      • et al.
      ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer.
      ]. The partial breast volume (CTVp_PB) was based on delineation of the tumour bed (guided by clips, seroma and pre-operative imaging). From the tumour bed volume, the CTVp_PB was generated by adding a 15 mm margin (cropped inside the whole breast volume). The planning target volume margin depended on institutional guidelines (in most cases 5 mm), and was cropped 5 mm inside the skin surface. The RT was based on a 3D conformal technique with two tangential fields and forward planned field-in-field segments for a homogeneous dose distribution. The CTV was to be covered with doses in the range 95–105%, however an absolute volume of up to 2 mL of the CTV could receive a dose in the range 105–110% of the prescription dose (V42Gy_breast ≤ 2 mL). In PBI treatment plans it was the aim that less than 50% of the CTVp_breast was irradiated to ≥40 Gy (V40Gy_breast < 50%). Dose constraints for lung, heart and left anterior descending coronary artery (LADCA) were V17Gy_lung ≤ 25%, V35Gy_heart ≤ 5%, V17Gy_heart ≤ 10%, Dmax_LADCA ≤ 17 Gy. Regional node RT was not allowed. During the accrual period, RT plans for the patients were stored in the Danish national RT data bank (DcmCollab) [
      • Westberg J.
      • Krogh S.
      • Brink C.
      • Vogelius I.R.
      A DICOM based radiotherapy plan database for research collaboration and reporting.
      ].
      All patients were invited for morbidity evaluation and breast photos at baseline and at follow up visits yearly 1–5, and at 10 years after RT. The primary endpoint was grade 2–3 breast induration reported as cumulative incidence at 3 years and crude incidence rates at 3 and 5 years after RT. For this study, the reported endpoint crude incidence of grade 2–3 breast induration at 3 years after RT was used. However, sensitivity analyses were performed using cumulative incidence at 3 years and crude incidence rate at 5 years as endpoints [
      • Offersen B.V.
      • Alsner J.
      • Nielsen H.M.
      • Jacobsen E.H.
      • Nielsen M.H.
      • Stenbygaard L.
      • et al.
      Partial Breast Irradiation Versus Whole Breast Irradiation for Early Breast Cancer Patients in a Randomized Phase III Trial: The DBCG PBI Trial.
      ].
      Information about treatment arm and breast induration was obtained from the DBCG database. Volumes of the delineated structures and dose-volume histograms were collected from DcmCollab, allowing determination of the volume of structures irradiated to various dose levels in each treatment plan.
      Patient and treatment characteristics were compared using Chi-squared test (categorical data) and Wilcoxon rank-sum test or Students t-test (continuous data). The model was developed on individual patient data using logistic regression with log-transformed volumes:
      pinduration=11+e-(β0+β1ln(volume))


      β0 and β1 are reported with 95% CI. For visualization, patients were binned in quintiles for each treatment arm and actual incidence rates for each group were plotted with the model. C-statistics was used to compare models based on different volume parameters. Wald test was used to compare coefficients from two models in sensitivity analysis on different endpoints. All analyses were performed using Stata 17.0 (StataCorp LLC, Texas, USA).

      Results

      Between May 2009 and March 2016, 880 patients from five Danish centres were recruited and of those 865 were eligible [
      • Offersen B.V.
      • Alsner J.
      • Nielsen H.M.
      • Jacobsen E.H.
      • Nielsen M.H.
      • Stenbygaard L.
      • et al.
      Partial Breast Irradiation Versus Whole Breast Irradiation for Early Breast Cancer Patients in a Randomized Phase III Trial: The DBCG PBI Trial.
      ]. The clinical study on WBI versus PBI was analysed as ‘intention- to-treat’ with 434 patients assigned to WBI (4 treated with PBI) and 431 patients assigned to PBI (2 treated with WBI) [
      • Offersen B.V.
      • Alsner J.
      • Nielsen H.M.
      • Jacobsen E.H.
      • Nielsen M.H.
      • Stenbygaard L.
      • et al.
      Partial Breast Irradiation Versus Whole Breast Irradiation for Early Breast Cancer Patients in a Randomized Phase III Trial: The DBCG PBI Trial.
      ]. The present analysis was performed ‘by-protocol’ and thus includes 432 patients receiving WBI and 433 receiving PBI and treatment plans were available for analysis from all patients but one (Table 1). The patient, tumor and outcome characteristics were balanced between the PBI and WBI cohorts except for the incidence of grade 2–3 induration (Table 1 and Supplementary Fig. 1). A more than fivefold increase in median volume from tumour bed to CTVp_PB and also from CTVp_PB to CTVp_breast was observed for both treatment arms. As expected, V40Gy_breast was larger for WBI than PBI (Fig. 1). For PBI, a much smaller volume of the breast was treated, thus median 24.9% (IQR: 18.6–32.6%) of the breast volume was covered with ≥40 Gy (Table 2 and Supplementary Fig. 2). Table 2 and Supplementary Fig. 2 also show the percentages of breast volumes treated to 38 Gy (V95%_breast), the absolute breast volume irradiated to ≥42 Gy, the number of treatment plans with V42Gy_breast > 2 mL, and the hot spot dose reported as the dose to the 1% of the CTVp_breast covered with highest doses (D1%). For most patients D1% were less than 42 Gy and no treatment plan had an absolute maximum dose (Dmax) above 44 Gy (110%); the maximum Dmax was 43.3 Gy and 43.9 Gy in the PBI and WBI arms, respectively (Supplementary Fig. 2). Data on lung, heart and LADCA doses are given in Table 2 and Supplementary Fig. 2.
      Table 1Patient characteristics and grade 2–3 breast induration 3 years after radiation therapy. The values are given as median values with interquartile ranges or numbers with percentage of total numbers.
      Partial breast irradiation (PBI)

      n = 433
      Whole breast irradiation (WBI)

      n = 432
      p-value
      Age [years], n = 86566 (63–69)66 (64–69)0.34
      Laterality, n = 865
       Left230 (53%)210 (49%)0.18
       Right203 (47%)222 (51%)
      Breast volume (CTVp_breast) [mL], n = 865710 (467–963)666 (443–1012)0.98
      Partial breast volume (CTVp_PB) [mL], n = 842122 (84–180)121 (86–175)0.76
      Tumour bed volume [mL], n = 80822 (14–39)22 (13–40)0.79
      Breast induration at 3 years follow up [n], n = 743
       Grade 0/1350 (95%)336 (90%)0.005
       Grade 2/318 (5%)39 (10%)
      Figure thumbnail gr1
      Fig. 1Distribution of volume of breast irradiated to D ≥ 40 Gy.
      Table 2Dosimetric results listed as median values with interquartile ranges, mean values with 95% CIs, or numbers with percentage of total numbers.
      Partial breast irradiation (PBI)

      n = 433
      Whole breast irradiation (WBI)

      n = 432
      p-value
      V38Gy_breast [%, median w. IQR], n = 86448.6 (39.5–57.9)96.6 (95.1–98.0)<0.0001
      V40Gy_breast [%, median w. IQR], n = 86424.9 (18.6–32.6)59.8 (53.6–68.5)<0.0001
      V42Gy_breast [mL, median w. IQR], n = 8640.00 (0.00–0.09)0.02 (0.00–1.31)<0.0001
      Number of pts with V42Gy_breast > 2 mL [n], n = 86441 (9%)85 (20%)<0.0001
      D1% [Gy, mean w. 95% CI], n = 86441.4 (41.3–41.4)41.6 (41.6–41.7)<0.0001
      V17Gy_lung [%, median w. IQR], n = 8642.2 (1.2–3.4)14.7 (11.4–18.1)<0.0001
      V17Gy_heart (left-breast) [%, median w. IQR], n = 4370.00 (0.00–0.00)0.10 (0.00–0.54)<0.0001
      Number of pts with V17Gy_heart > 0% [n], n = 43739 (9%)151 (37%)<0.0001
      V35Gy_heart (left-breast) [%, median w. IQR], n = 4370.00 (0.0–0.00)0.00 (0.00–0.00)<0.0001
      Number of pts with V35Gy_heart > 0% [n], n = 4378 (2%)41 (10%)<0.0001
      Dmax_LADCA (left-breast) [Gy, median w. IQR], n = 4342.3 (1.3–4.7)11.0 (8.0–15.3)<0.0001
      Number of pts with Dmax_LADCA > 17 Gy [n], n = 4347 (3.1%)38 (16.8%)<0.0001
      Mean heart dose, MHD [Gy, median w. IQR], n = 4370.4 (0.3–0.6)1.2 (1.0–1.6)<0.0001
      Figure thumbnail gr2
      Fig. 2Frequency of grade 2–3 induration at 3 years after RT versus volume of breast irradiated to D ≥ 40 Gy. Model is based on individual data and presented with 95% CI (grey area). For each treatment arm, patients are binned in quintiles and actual incidence rates in each group are presented for comparison.
      Breast induration scores at 3 years after RT were available for 743 (86%) of the patients [
      • Offersen B.V.
      • Alsner J.
      • Nielsen H.M.
      • Jacobsen E.H.
      • Nielsen M.H.
      • Stenbygaard L.
      • et al.
      Partial Breast Irradiation Versus Whole Breast Irradiation for Early Breast Cancer Patients in a Randomized Phase III Trial: The DBCG PBI Trial.
      ] and were significantly different between treatment arms; 18/368 (5%) patients in the PBI arm had grade 2–3 breast induration versus 39/375 (10%) in the WBI arm, p = 0.005 (Table 1).
      The frequency of induration versus V40Gy_breast is shown in Fig. 2 demonstrating an increasing frequency of induration with increasing irradiated breast volume. The model parameters are: β0 = −7.359 (95% CI, −9.753 to −4.965) and β1 = 0.853 (95% CI, 0.449–1.256). According to the model, it is estimated that the risk of breast induration is 5% and 10% when the 40 Gy treated volume is 177 mL (95% CI, 94–260) and 426 mL (95% CI, 286–567), respectively. The model presented in Fig. 2 is based on crude incidence rates of grade 2–3 breast induration at 3 years after RT. In a sensitivity analysis (Supplementary Fig. 3), the model is compared with models based on crude incidence rates at 5 years after RT and on cumulative incidence at 3 years after RT [
      • Offersen B.V.
      • Alsner J.
      • Nielsen H.M.
      • Jacobsen E.H.
      • Nielsen M.H.
      • Stenbygaard L.
      • et al.
      Partial Breast Irradiation Versus Whole Breast Irradiation for Early Breast Cancer Patients in a Randomized Phase III Trial: The DBCG PBI Trial.
      ]. These models are not statistically different from the model presented in Fig. 2.
      For the same volume of breast irradiated above a given dose, the frequency of grade 2–3 breast induration increased for increasing irradiation dose. However, a close similarity of the relation was found for irradiation doses in the range 2 Gy to 40 Gy reflecting the tangential field technique used in the study (Fig. 3A and 3B).
      Figure thumbnail gr3
      Fig. 3Frequency of grade 2–3 induration at 3 years after RT versus volume of breast irradiated to various dose levels with C-statistics to evaluate goodness-of-fit (A). Correlations between the various dose level models (B).
      The irradiated breast volume is correlated with the total breast volume, and with the strongest correlation for WBI (Supplementary Fig. 4A). When risk of induration is modelled using total breast volume, either with WBI, PBI, or combined, the models are weak (Supplementary Fig. 4A). The models are stronger and comparable when risk of induration is modelled using irradiated volume and stratified in WBI versus PBI even though the ranges of volumes are only partly overlapping (Supplementary Fig. 4B). Thus, the strongest model is obtained with irradiated volume in the combined cohort.
      For comparison with a previous study [
      • Peterson D.
      • Truong P.T.
      • Parpia S.
      • Olivotto I.A.
      • Berrang T.
      • Kim D.-H.
      • et al.
      Predictors of adverse cosmetic outcome in the RAPID trial: En exploratory analysis.
      ], models with irradiated volumes are compared with models based on the V95/whole-breast volume ratio (V38Gy_breast [%]) in patients treated with PBI vs WBI (Supplementary Fig. 5).

      Discussion

      Based on the treatment plans from the eligible patients in the DBCG PBI trial and patient morbidity scores, a dose response model for the relation between breast volume irradiated to ≥40 Gy and frequency of breast induration was presented. To our knowledge, this is the first report directly linking a ≥40 Gy irradiated breast volume to breast induration.
      It was found that the frequency of breast induration increased with the volume of breast tissue irradiated to ≥40 Gy, thereby favouring the use of PBI especially for patients with large breasts. The frequency of induration was also modelled for various other breast doses showing a closer correlation for the models for breast volumes in the range 2 Gy to 40 Gy compared to the model for V41Gy due to the nature of the tangential field technique used in the trial. The field technique was based on two tangential fields with forward planned field-in-field segments to obtain a homogeneous dose in the treated volume. In agreement with earlier studies [
      • Donovan E.
      • Bleakley N.
      • Denholm E.
      • Evans P.
      • Gothard L.
      • Hanson J.
      Randomised trial of standard 2D radiotherapy (RT) versus intensity modulated radiotherapy (IMRT) in patients prescribed breast radiotherapy.
      ,
      • Brink C.
      • Lorenzen E.L.
      • Krogh S.L.
      • Westberg J.
      • Berg M.
      • Jensen I.
      • et al.
      DBCG hypo trial validation of radiotherapy parameters from a national databank versus manual reporting.
      ], it was possible with this rather simple technique to reduce hot spots in the irradiated breast volume to very low levels with median D1% values of 41.4 Gy (103.5%) and 41.6 Gy (104%) in the PBI and WBI arms, respectively, and no treatment plans had a Dmax above 110% of the prescription dose [
      • Nielsen M.H.
      • Berg M.
      • Pedersen A.N.
      • Andersen K.
      • Glavicic V.
      • Jakobsen E.H.
      • et al.
      Delineation of target volumes and organs at risk in adjuvant radiotherapy of early breast cancer: national guidelines and contouring atlas by the Danish Breast Cancer Cooperative Group.
      ,
      • Barnett G.C.
      • Wilkinson J.
      • Moody A.M.
      • Wilson C.B.
      • Sharma R.
      • Klager S.
      • et al.
      A randomised controlled trial of forward-planned radiotherapy (IMRT) for early breast cancer: Baseline characteristics and dosimetry results.
      ]. The strict dose constraint of V42Gy_breast ≤ 2 mL in the study, resulted in a violation of this constraint in only 9% (PBI) and 20% (WBI) of the treatment plans, respectively (Table 2 and Supplementary Fig. 2), and therefore it was not possible to obtain a model with sufficient statistical basis for V42Gy.
      Irrespectively of treated volume, the treatment plans in this trial have a homogeneity comparable with inverse planned whole breast plans (IMRT or VMAT) [
      • Hannan R.
      • Thompson R.F.
      • Chen Y.
      • Bernstein K.
      • Kabarriti R.
      • Skinner W.
      • et al.
      Hypofractionated Whole-Breast Radiation Therapy: Does Breast Size Matter?.
      ,
      • De Rose F.
      • Fogliata A.
      • Franceschini D.
      • Iftode C.
      • D’Agostino G.R.
      • Comito T.
      • et al.
      Hypofractionated whole breast irradiation and simultaneous integrated boost in large-breasted patients: Long-term toxicity and cosmesis.
      ]. The doses to lung and heart were low and a high compliance with the protocol-specified constraints was found. However, also for the organs at risk statistically significant lower doses were observed in the PBI plans, thus favouring PBI over WBI.
      The development of this model has merely been possible because of the prospective collection of all treatment plans from the trial in DcmCollab [
      • Westberg J.
      • Krogh S.
      • Brink C.
      • Vogelius I.R.
      A DICOM based radiotherapy plan database for research collaboration and reporting.
      ]. Without this national data bank, the collection of the necessary dosimetric parameters would have been very time consuming and error-prone [
      • Brink C.
      • Lorenzen E.L.
      • Krogh S.L.
      • Westberg J.
      • Berg M.
      • Jensen I.
      • et al.
      DBCG hypo trial validation of radiotherapy parameters from a national databank versus manual reporting.
      ,
      • Thomsen M.S.
      • Berg M.
      • Zimmermann S.
      • Lutz C.M.
      • Makocki S.
      • Jensen I.
      Dose constraints for whole breast radiation therapy based on the quality assessment of treatment plans in the randomised Danish Breast Cancer Group (DBCG) HYPO trial.
      ].
      The radiation dose-volume effect for the breast has been investigated in a number of studies, and large breast size has been identified as a risk factor for late adverse effects after breast RT even after the advent of 3D conformal RT and IMRT [
      • Ratosa I.
      • Jenko A.
      • Oblak I.
      Breast size impact on adjuvant radiotherapy adverse effects and dose parameters in treatment planning.
      ,
      • Mukesh M.
      • Harris E.
      • Jena R.
      • Evans P.
      • Coles C.
      Relationship between irradiated breast volume and late normal tissue complications: A systematic review.
      ,
      • Colciago R.R.
      • Cavallo A.
      • Magri M.C.
      • Vitullo A.
      • LaRocca E.
      • Giandini C.
      • et al.
      Hypofractionated whole-breast radiotherapy in large breast size patients: is it really a resolved issue?.
      ]. Goldsmith et al. concluded based on patients treated in the FAST trial that large-breasted women were more likely than others to suffer adverse effects after RT even when 3D dosimetry was optimised and thereby minimising dose inhomogeneities [
      • Goldsmith C.
      • Haviland J.
      • Tsang Y.
      • Sydenham M.
      • Yarnold J.
      on behalf of the FAST Trialists’ Group. Large breast size as a risk factor for late adverse effects of breast radiotherapy: Is residual dose inhomogeneity, despite 3D treatment planning and delivery, the main explanation?.
      ]. Based on the data presented here, it may be concluded that it is not the breast size itself but rather the volume of breast tissue irradiated to a given dose, that is the risk factor for radiation-induced morbidity.
      The DBCG PBI trial was similar to two of the arms in the IMPORT LOW trial, and patients were treated with 40 Gy in 15 fr/3 weeks for both PBI and WBI [
      • Coles C.E.
      • Griffin C.L.
      • Kirby A.M.
      • Titley J.
      • Agrawal R.K.
      • Alhasso A.
      • et al.
      Partial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW trial): 5-year results from a multicentre, randomized, controlled, phase 3, non-inferiority trial.
      ]. In the RAPID trial, patients were randomised to accelerated PBI (APBI) with 38.5 Gy in 10 fr/1 week versus WBI with either 42.5 Gy in 16 fr/3 weeks or 50 Gy in 25 fr/5 weeks. In the WBI arm boost was permitted [
      • Whelan T.J.
      • Julian J.A.
      • Berrang T.S.
      • Kim D.-H.
      • Germain I.
      • Nichol A.M.
      • et al.
      External beam accelerated partial breast irradiation versus whole breast irradiation after breast conserving surgery in women with ductal carcinoma in situ and node-negative breast cancer (RAPID): a randomised controlled trial.
      ]. More late effects were found in the group of patients treated with APBI compared to WBI. An exploratory analysis showed that a V95/whole breast volume <0.15 was associated with a lower risk of cosmetic deterioration [
      • Peterson D.
      • Truong P.T.
      • Parpia S.
      • Olivotto I.A.
      • Berrang T.
      • Kim D.-H.
      • et al.
      Predictors of adverse cosmetic outcome in the RAPID trial: En exploratory analysis.
      ]. Due to the use of two tangential fields for PBI in the DBCG PBI trial rather than a technique with 3–5 non-coplanar fields as used in the RAPID trial, no PBI patients in the study presented here had a V95/whole breast volume below 0.15 (Supplementary Fig. 2A), however, the V95/whole breast volume on a continuous scale was correlated with the frequency of breast induration (Supplementary Fig. 5). In the APBI-IMRT-Florence Trial, the patients treated with APBI (30 Gy in 5 fr/2 weeks) had less late toxicity than the patients treated with WBI (50 Gy in 25 fr/5 weeks plus a 10 Gy boost) [
      • Meattini I.
      • Marazzo L.
      • Saieva C.
      • Desideri I.
      • Scotti V.
      • Simontacchi G.
      • et al.
      Accelerated partial-breast irradiation compared with whole breast irradiation for early breast cancer: Long-term results of the randomized phase III APBI-IMRT-Florence trial.
      ]. In the randomised trial reported by Strnad et al, all patients in the APBI arm were treated with brachytherapy whereas a total dose of 50–50.4 Gy in 25–28 fr was used in the WBI arm [
      • Strnad V.
      • Ott O.J.
      • Hildebrandt G.
      • Kauer-Dorner D.
      • Knauerhase H.
      • Major T.
      • et al.
      5-year results of accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy versus whole-breast irradiation with boost after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: a randomised, phase 3, non-inferiority trial.
      ]. They found that late toxicity profiles and cosmetic results were similar in the two treatment arms [
      • Polgar C.
      • Ott O.J.
      • Hildebrandt G.
      • Kauer-Dorner D.
      • Knauerhase H.
      • Major T.
      Late side-effects and cosmetic results of accelerated partial breast irradiation with interstitial brachytherapy versus whole-breast irradiation after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: 5-year results of a randomised, controlled, phase 3 trial.
      ]. In partial breast brachytherapy the irradiated volume is smaller than in external beam irradiation. However, the NSABP B39/RTOG 0413 trial, where patients were randomised to PBI administered as either external beam radiation with 38.5 Gy in 10 fr/1 week or 34 Gy with brachytherapy versus WBI with 50 Gy in 25 fr/5 weeks, did not find the same worse late effect pattern for APBI as found in the RAPID trial although only one fourth of the APBI patients were treated with brachytherapy [
      • Vicini F.A.
      • Cecchini R.S.
      • White J.R.
      • Arthur D.W.
      • Julian T.B.
      • Rabinovitch R.A.
      • et al.
      Long-term primary results of accelerated partial breast irradiation after breast-conserving surgery for early-stage breast cancer: a randomised, phase 3, equivalence trial.
      ]. The delivery of 38.5 Gy in 10 fr corresponds to 53 Gy in 2-Gy fractions whereas 40 Gy in 15 fr corresponds to a dose of 46 Gy 2-Gy fractions [
      • Yarnold J.
      • Bentzen S.M.
      • Coles C.
      • Haviland J.
      Hypofractionated whole-breast radiotherapy for women with early breast cancer: Myths and realities.
      ]. Thus, the fractionation in the APBI studies correspond more closely to 50 Gy in 25 fr than 40 Gy in 15 fr.
      In parallel to the DBCG PBI trial, the DBCG also conducted the DBCG HYPO trial during 2009–2014 [
      • Offersen B.V.
      • Alsner J.
      • Nielsen H.M.
      • Jakobsen E.H.
      • Nielsen M.H.
      • Krause M.
      • et al.
      Hypofractionated versus standard fractionated radiotherapy in patients with early breast cancer or ductal carcinoma in situ in a randomized phase III trial: The DBCG HYPO Trial.
      ]. That trial randomized 1880 node-negative early breast cancer patients treated with WBI to 40 Gy in 15 fr versus 50 Gy in 25 fr (sequential boost optional). Treatment plans from the 1550 Danish patients in the trial are collected into the DcmCollab [
      • Westberg J.
      • Krogh S.
      • Brink C.
      • Vogelius I.R.
      A DICOM based radiotherapy plan database for research collaboration and reporting.
      ], and a validation of our dose response model is planned to also include 50 Gy in 25 fr and sequential boost which allows for a comparison with the result from the boost-no boost trial [
      • Collette S.
      • Collette L.
      • Budiharto T.
      • Horiot J.-C.
      • Poortmans P.M.
      • Struikmans H.
      • et al.
      Predictors of the risk of fibrosis at 10 years after breast conserving therapy for early breast cancer – A study based on the EORTC trial 22881–10882 ‘boost versus no boost’.
      ].
      A limitation of the model is that only patients 60 years or older were eligible for the trial and the model is thus restricted to prediction of the risk of induration for elderly patients. Therefore, any age dependence in the adverse effects of radiotherapy was not considered [
      • Lilla C.
      • Ambrosone C.B.
      • Kropp S.
      • Helmbold I.
      • Schmezer P.
      • von Fournier D.
      Predictive factors for late normal tissue complications following radiotherapy for breast cancer.
      ]. This may also be further investigated with the DBCG HYPO data where patients 41 years or older were eligible for the trial.
      The one-week schedule tested in the FAST-forward trial is biologically more equivalent with 40 Gy in 15 fr [
      • Brunt A.M.
      • Haviland J.S.
      • Wheatley D.A.
      • Sydenham M.A.
      • Alhasso A.
      • Bloomfield D.J.
      • et al.
      Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial.
      ]. Instead of reducing the treatment course further from 40 Gy, and considering the very low recurrence rates using PBI in selected patients, the DBCG has decided to go in another direction for this patient group by offering the patients inclusion in the DBCG Natural study (ClinicalTrials.gov Identifier: NCT03646955), where patients are randomised to either 40 Gy in 15 fr PBI or no RT. The primary endpoint is 5-year local recurrence risk aiming to be max 4% in patients not irradiated.
      In conclusion, no differences in tumour bed, partial and whole breast volumes were observed between the patients in the two arms of the DBCG PBI trial, but the irradiated breast volume was significantly smaller with PBI. The frequency of breast induration increased significantly with increasing irradiated breast volume, showing that it is not the breast size itself but rather the volume of breast tissue irradiated to a given dose, that is the risk factor for radiation-induced morbidity. This is the first report directly linking a 40 Gy irradiated breast volume to breast induration, and the dose response relationship will be further validated in the DBCG HYPO trial.

      Acknowledgement

      We thank the patients who participated in this trial and the staff at participating centres and in the DBCG office.

      Disclaimer

      The authors have no conflicts of interest.

      Appendix A. Supplementary material

      The following are the Supplementary data to this article:

      References

        • Darby S.
        • McGale P.
        • Correa C.
        • Taylor C.
        • Arriagada R.
        • Clarke M.
        • et al.
        Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials.
        Lancet. 2011; 378: 1707-1716
        • Offersen B.V.
        • Overgaard M.
        • Kroman N.
        • Overgaard J.
        Accelerated partial breast irradiation as part of breast conserving therapy of early breast carcinoma: a systematic review.
        Radiother Oncol. 2009; 90: 1-13
        • Offersen B.V.
        • Alsner J.
        • Nielsen H.M.
        • Jakobsen E.H.
        • Nielsen M.H.
        • Krause M.
        • et al.
        Hypofractionated versus standard fractionated radiotherapy in patients with early breast cancer or ductal carcinoma in situ in a randomized phase III trial: The DBCG HYPO Trial.
        J Clin Oncol. 2020; 38: 3615-3625
        • Offersen B.V.
        • Alsner J.
        • Nielsen H.M.
        • Jacobsen E.H.
        • Nielsen M.H.
        • Stenbygaard L.
        • et al.
        Partial Breast Irradiation Versus Whole Breast Irradiation for Early Breast Cancer Patients in a Randomized Phase III Trial: The DBCG PBI Trial.
        J Clin Oncol. 2022; https://doi.org/10.1200/JCO.22.00451
        • Coles C.E.
        • Griffin C.L.
        • Kirby A.M.
        • Titley J.
        • Agrawal R.K.
        • Alhasso A.
        • et al.
        Partial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW trial): 5-year results from a multicentre, randomized, controlled, phase 3, non-inferiority trial.
        Lancet. 2017; 390: 1048-1060
        • Ratosa I.
        • Jenko A.
        • Oblak I.
        Breast size impact on adjuvant radiotherapy adverse effects and dose parameters in treatment planning.
        Radiol Oncol. 2018; 52: 233-244
        • Donovan E.
        • Bleakley N.
        • Denholm E.
        • Evans P.
        • Gothard L.
        • Hanson J.
        Randomised trial of standard 2D radiotherapy (RT) versus intensity modulated radiotherapy (IMRT) in patients prescribed breast radiotherapy.
        Radiother Oncol. 2007; 82: 254-264
        • Nielsen M.H.
        • Berg M.
        • Pedersen A.N.
        • Andersen K.
        • Glavicic V.
        • Jakobsen E.H.
        • et al.
        Delineation of target volumes and organs at risk in adjuvant radiotherapy of early breast cancer: national guidelines and contouring atlas by the Danish Breast Cancer Cooperative Group.
        Acta Oncol. 2013; 52: 703-710
        • Offersen B.V.
        • Boersma L.J.
        • Kirkove C.
        • Hol S.
        • Aznar M.C.
        • Sola A.B.
        • et al.
        ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer.
        Radiother Oncol. 2015; 114: 3-10
        • Westberg J.
        • Krogh S.
        • Brink C.
        • Vogelius I.R.
        A DICOM based radiotherapy plan database for research collaboration and reporting.
        J Phys Conf Ser. 2014; 489: 012100
        • Peterson D.
        • Truong P.T.
        • Parpia S.
        • Olivotto I.A.
        • Berrang T.
        • Kim D.-H.
        • et al.
        Predictors of adverse cosmetic outcome in the RAPID trial: En exploratory analysis.
        Int J Rad Oncol Biol Phys. 2015; 91: 968-976
        • Barnett G.C.
        • Wilkinson J.
        • Moody A.M.
        • Wilson C.B.
        • Sharma R.
        • Klager S.
        • et al.
        A randomised controlled trial of forward-planned radiotherapy (IMRT) for early breast cancer: Baseline characteristics and dosimetry results.
        Radiother Oncol. 2009; 92: 34-41
        • Hannan R.
        • Thompson R.F.
        • Chen Y.
        • Bernstein K.
        • Kabarriti R.
        • Skinner W.
        • et al.
        Hypofractionated Whole-Breast Radiation Therapy: Does Breast Size Matter?.
        Int J Rad Oncol Biol Phys. 2012; 84: 894-901
        • De Rose F.
        • Fogliata A.
        • Franceschini D.
        • Iftode C.
        • D’Agostino G.R.
        • Comito T.
        • et al.
        Hypofractionated whole breast irradiation and simultaneous integrated boost in large-breasted patients: Long-term toxicity and cosmesis.
        Clin Breast Cancer. 2020; 20: 527-533
        • Brink C.
        • Lorenzen E.L.
        • Krogh S.L.
        • Westberg J.
        • Berg M.
        • Jensen I.
        • et al.
        DBCG hypo trial validation of radiotherapy parameters from a national databank versus manual reporting.
        Acta Oncol. 2018; 57: 107-112
        • Thomsen M.S.
        • Berg M.
        • Zimmermann S.
        • Lutz C.M.
        • Makocki S.
        • Jensen I.
        Dose constraints for whole breast radiation therapy based on the quality assessment of treatment plans in the randomised Danish Breast Cancer Group (DBCG) HYPO trial.
        Clin Trans Radiat Oncol. 2021; 28: 118-123
        • Mukesh M.
        • Harris E.
        • Jena R.
        • Evans P.
        • Coles C.
        Relationship between irradiated breast volume and late normal tissue complications: A systematic review.
        Radiother Oncol. 2012; 104: 1-10
        • Colciago R.R.
        • Cavallo A.
        • Magri M.C.
        • Vitullo A.
        • LaRocca E.
        • Giandini C.
        • et al.
        Hypofractionated whole-breast radiotherapy in large breast size patients: is it really a resolved issue?.
        Med Oncol. 2021; 38: 107
        • Goldsmith C.
        • Haviland J.
        • Tsang Y.
        • Sydenham M.
        • Yarnold J.
        on behalf of the FAST Trialists’ Group. Large breast size as a risk factor for late adverse effects of breast radiotherapy: Is residual dose inhomogeneity, despite 3D treatment planning and delivery, the main explanation?.
        Radiother Oncol. 2011; 100: 236-240
        • Whelan T.J.
        • Julian J.A.
        • Berrang T.S.
        • Kim D.-H.
        • Germain I.
        • Nichol A.M.
        • et al.
        External beam accelerated partial breast irradiation versus whole breast irradiation after breast conserving surgery in women with ductal carcinoma in situ and node-negative breast cancer (RAPID): a randomised controlled trial.
        Lancet. 2019; 394: 2165-2172
        • Meattini I.
        • Marazzo L.
        • Saieva C.
        • Desideri I.
        • Scotti V.
        • Simontacchi G.
        • et al.
        Accelerated partial-breast irradiation compared with whole breast irradiation for early breast cancer: Long-term results of the randomized phase III APBI-IMRT-Florence trial.
        J Clin Oncol. 2020; 38: 4175-4183
        • Strnad V.
        • Ott O.J.
        • Hildebrandt G.
        • Kauer-Dorner D.
        • Knauerhase H.
        • Major T.
        • et al.
        5-year results of accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy versus whole-breast irradiation with boost after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: a randomised, phase 3, non-inferiority trial.
        Lancet. 2016; 387: 229-238
        • Polgar C.
        • Ott O.J.
        • Hildebrandt G.
        • Kauer-Dorner D.
        • Knauerhase H.
        • Major T.
        Late side-effects and cosmetic results of accelerated partial breast irradiation with interstitial brachytherapy versus whole-breast irradiation after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: 5-year results of a randomised, controlled, phase 3 trial.
        Lancet Oncol. 2017; 18: 259-268
        • Vicini F.A.
        • Cecchini R.S.
        • White J.R.
        • Arthur D.W.
        • Julian T.B.
        • Rabinovitch R.A.
        • et al.
        Long-term primary results of accelerated partial breast irradiation after breast-conserving surgery for early-stage breast cancer: a randomised, phase 3, equivalence trial.
        Lancet. 2019; 394: 2155-2164
        • Yarnold J.
        • Bentzen S.M.
        • Coles C.
        • Haviland J.
        Hypofractionated whole-breast radiotherapy for women with early breast cancer: Myths and realities.
        Int J Rad Oncol Biol Phys. 2011; 79: 1-9
        • Collette S.
        • Collette L.
        • Budiharto T.
        • Horiot J.-C.
        • Poortmans P.M.
        • Struikmans H.
        • et al.
        Predictors of the risk of fibrosis at 10 years after breast conserving therapy for early breast cancer – A study based on the EORTC trial 22881–10882 ‘boost versus no boost’.
        Eur J Cancer. 2008; 44: 2587-2599
        • Lilla C.
        • Ambrosone C.B.
        • Kropp S.
        • Helmbold I.
        • Schmezer P.
        • von Fournier D.
        Predictive factors for late normal tissue complications following radiotherapy for breast cancer.
        Breast Cancer Res Treat. 2007; 106: 143-150
        • Brunt A.M.
        • Haviland J.S.
        • Wheatley D.A.
        • Sydenham M.A.
        • Alhasso A.
        • Bloomfield D.J.
        • et al.
        Hypofractionated breast radiotherapy for 1 week versus 3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomised, phase 3 trial.
        Lancet. 2020; 395: 1613-1626

      Linked Article

      • Not only volumes matter for breast radiation therapy
        Radiotherapy and Oncology
        • Preview
          In contrast to most other indications in radiation oncology, many adhere to field-based techniques based on bony landmarks for breast cancer radiation therapy (RT), representing approximately 25% of the department’s workload [1]. Similarly, the boost volume often is considered erroneously as the “surgical bed” including visible surgical changes, without full understanding of the “tumour bed” concept, often leading to excessively large boost volumes. Therefore, the analysis by Thomsen et al., of the relation between breast induration grade 2–3 at 3 years after RT and the irradiated breast volume, using the data from the Danish Breast Cancer Group (DBCG) phase III prospective trial comparing whole breast irradiation (WBI) with partial breast irradiation (PBI) [2] [cite as additional reference: Thomsen et al, Radiother Oncol 2022] is extremely relevant.
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