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?
ABSTRACT Large breast size is associated with an increased risk of late adverse effects after breast conservation surgery and radiotherapy, even when 3D dosimetry is used. The purpose of this study is to test the hypothesis that residual dose inhomogeneity is sufficient to explain the association.
Patients previously treated after breast conservation surgery with whole breast radiotherapy using 3D dosimetry and followed up in the UK FAST hypofractionation trial were selected for this analysis. The residual level of dose inhomogeneity across the whole breast treatment volume was used to test for association between residual dosimetry and post-treatment change in breast appearance at 2 years post-radiotherapy.
At 2 years, 201/279 (72%) of women had no change in photographic breast appearance, 61 (22%) had mild change and 17 (6%) had marked change. Breast size and dosimetry were both significantly associated with late effects in univariate analyses, but only breast size remained an independent significant risk factor for change in breast appearance when included in a multiple regression model together with other prognostic factors (p=0.006 for trend).
Large-breasted women are more likely to suffer change in breast size and shape after whole breast radiotherapy delivered using 3D dosimetry, but residual dose inhomogeneity is insufficient to explain the association.
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ABSTRACT: After breast-conserving radiation therapy most patients experience acute skin toxicity to some degree. This may impair patients' quality of life, cause pain and discomfort. In this study, we investigated treatment and patient-related factors, including genetic polymorphisms, that can modify the risk for severe radiation-induced skin toxicity in breast cancer patients.BMC Cancer 09/2014; 14(1):711. · 3.32 Impact Factor
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?
Christy Goldsmitha,⇑, Joanne Havilandb, Yat Tsangc, Mark Sydenhamb, John Yarnoldd,
on behalf of the FAST Trialists’ Group
aDepartment of Radiotherapy, The Royal Marsden NHS Foundation Trust, London, UK;bInstitute of Cancer Research Clinical Trials and Statistics Unit, Section of Clinical Trials, Sutton,
UK;cDepartment of Medical Physics, Mount Vernon Cancer Centre, Northwood, UK;dSection of Academic Radiotherapy, The Royal Marsden NHS Foundation Trust, Sutton, UK
a r t i c l ei n f o
Received 13 June 2010
Received in revised form 15 December 2010
Accepted 31 December 2010
Available online 4 February 2011
a b s t r a c t
Background and Purpose: Large breast size is associated with an increased risk of late adverse effects after
breast conservation surgery and radiotherapy, even when 3D dosimetry is used. The purpose of this study
is to test the hypothesis that residual dose inhomogeneity is sufficient to explain the association.
Methods: Patients previously treated after breast conservation surgery with whole breast radiotherapy
using 3D dosimetry and followed up in the UK FAST hypofractionation trial were selected for this anal-
ysis. The residual level of dose inhomogeneity across the whole breast treatment volume was used to test
for association between residual dosimetry and post-treatment change in breast appearance at 2 years
Results: At 2 years, 201/279 (72%) of women had no change in photographic breast appearance, 61 (22%)
had mild change and 17 (6%) had marked change. Breast size and dosimetry were both significantly asso-
ciated with late effects in univariate analyses, but only breast size remained an independent significant
risk factor for change in breast appearance when included in a multiple regression model together with
other prognostic factors (p = 0.006 for trend).
Conclusion: Large-breasted women are more likely to suffer change in breast size and shape after whole
breast radiotherapy delivered using 3D dosimetry, but residual dose inhomogeneity is insufficient to
explain the association.
? 2011 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 100 (2011) 236–240
There is retrospective evidence that breast size is a risk factor
for late adverse effects following breast conservation surgery and
adjuvant radiotherapy for early breast cancer [1–9]. Body mass in-
dex, correlated to breast size and brassiere size, has also been
linked to the risk of acute skin reactions and to late cosmesis
[10–12]. Not all studies are confirmatory, but the weight of evi-
dence suggests that the association between the size of the breast
and the risk of early and late adverse effects in the breast is real
[13–16]. Analyses are based on assessments of late adverse effects
made in clinic or from photographs, focusing on changes in breast
size and shape, breast oedema and telangiectasia. Marked acute
skin reactions in the inframammary fold of heavy-breasted
patients may explain part of the association via an increased risk
of consequential late effects.
Suboptimal dosimetry is thought to explain at least part of the
association between breast size and risk of late normal tissue dam-
age after radiotherapy delivered using 2D techniques [1,2,4,6,17]. A
cause and effect relationship is supported by the 5-year results of a
randomised trial (N = 306) comparing 2D and 3D radiation dosim-
etry , but not so far by the 2-year results of a larger confirma-
tory study . Assuming dose distribution matters, it is not
known if residual dose inhomogeneity in patients treated using
3D dosimetry explains a significant component of late adverse ef-
fects in large breasted women. Other factors associated with late
adverse effects, including age , scar visibility, large excision
volume, post-operative complications , smoking and adjuvant
chemotherapy [11,21], appear unlikely to provide an adequate
alternative explanation, since they are not all associated with
breast size. Against this background, a retrospective analysis has been
undertaken to test the hypothesis that residual dose inhomogeneity
of whole breast radiotherapy delivered in conformity with ICRU
recommendations (95–107% of reference) [22,23] accounts for a
significant part of the association between breast size and risk of
late adverse effects.
0167-8140/$ - see front matter ? 2011 Elsevier Ireland Ltd. All rights reserved.
⇑Corresponding author. Address: Department of Radiotherapy, Royal Marsden
Hospital, Fulham Road, Chelsea, London SW3 6JJ, UK.
Radiotherapy and Oncology 100 (2011) 236–240
Contents lists available at ScienceDirect
Radiotherapy and Oncology
journal homepage: www.thegreenjournal.com
Patients were selected from those participating in the UK FAST
hypofractionation trial, which randomised 915 patients between
October 2004 and March 2007 to 25- and 5-fraction regimens of
whole breast radiotherapy after primary tumour excision of early
breast cancer . Eligibility criteria included age P50 years, inva-
sive breast carcinoma, <3 cm microscopic diameter, complete
microscopic resection, negative axillary histology and written in-
formed consent. Women were ineligible for trial entry if they re-
quired a tumour bed radiotherapy boost dose or neo-adjuvant/
50 Gyin25fractionsof2.0 Gyover35 days(Controlgroup),30 Gyin
five fractions of 6.0 Gy or 28.5 Gy in five fractions of 5.7 Gy treating
once a week over 29 days (Test groups 1 and 2). Only a subset of the
18 radiotherapy centres participating in the FAST trial had compat-
for joint analysis. Patients from the six centres with compatible
planning systems were eligible for inclusion in the study.
Virtual simulation and 3D dosimetry in the FAST trial
Participating centres using 3D X-ray computer tomography (CT)
imaging were included. Patients were imaged in the supine posi-
tion using a recommended specialised breast board for immobili-
sation. Reproducibility of position was achieved by matching
orthogonal laser beams with anterior and bilateral skin tattoos.
The clinical target volume (CTV) was defined to include soft tissues
of the whole breast down to the deep fascia, but not including
underlying muscle and ribcage, nor overlying skin and excision
scar. The inferior, medial and lateral limits of the breast were local-
ised by inspection and palpation of the breast before CT images
were collected. The superior border was defined in relation to
the suprasternal notch. The planning target volume (PTV) included
these limits to the CTV plus a 1 cm expansion in four radial direc-
tions. The radiotherapy plan for all patients was generated using
two standard tangential fields with non-divergent posterior beam
edges. The recommended maximum lung distance and maximum
heart distance in the treatment volume was <2 and <1 cm, respec-
tively. Cardiac shielding, where appropriate, was introduced using
a multi-leaf collimator or other shielding technique.
The prescription point was half-way between the anterior lung
surface and the skin surface on the perpendicular bisector of the
posterior treatment beam edge. The FAST protocol followed guide-
lines of the International Commission on Radiation Units and Mea-
surements (ICRU) reports 50 (1993) and 62 (1999) recommending
dose variation throughout the treated volume between ?5% and
+7% [22,23]. If a standard wedged pair was insufficient, full dose
compensation was performed using either missing tissue compen-
sators based on outlines or portal images, or intensity modulated
fields generated by forward or inverse planning. In practice, a
forward-planned multi-leaf collimator (MLC) segment method
was the dose compensation technique most commonly employed
by participating centres. The body contours were obtained by CT
and transferred to the planning system. Standard treatment fields
were applied, and dose homogeneity was evaluated. Any hot spots
of dose greater than 107% were minimised. A sagittal view through
the breast was created with isodose lines greater than 107% dis-
played, see Fig. 1. A segment field was added using MLC to shield
hot spots. If these were still present, an additional segment was
used. The relative weightings of the segment fields tended to be
very small (around 5%). Six MV energy X-rays were recommended
in the majority of patients, but for patient separations >22 cm,
higher energies were considered to optimise dosimetry.
Definition and assessment of late adverse radiation effects in the FAST
The primary endpoint of the FAST trial was change in photo-
graphic breast appearance at 2 and 5 years post-radiotherapy com-
pared to post-surgical baseline photographs. Photographs (two
frontal views of the chest, one with hands on hips and one with
arms raised) were prospectively collected under standard condi-
tions. Pairs of photographs (baseline and follow-up) were reviewed
by observers blinded to treatment allocation and scored for change
in breast appearance according to a three-point graded scale (no
change/mild change/marked change) . The START trial con-
firmed year two to be a valid time point for assessment, given a
strong correlation between photographic scores at years two and
Assessment of dose–volume histogram (DVH) data for current study
Dosimetry data provided by FAST centres with compatible plan-
ning systems for central analysis for this current study were in the
DICOMRT or RTOG format. It was not a mandatory trial require-
ment for participating FAST centres to outline whole breast vol-
umes on CT scans, as already described. In order to carry out the
dose–volume histogram (DVH) analysis required for this study,
the entire dose cube of each radiotherapy plan was exported into
a spreadsheet allowing the DVH data to be calculated for each iso-
dose bin. DVH data were grouped into the following isodose bins:
50–90%, 90–95%, 95–97%, 97–100%, 100–103%, 103–105%, 105–
Assessment of breast size for current study
A measure of breast volume in cubic centimetres (cc) was esti-
mated using radiotherapy planning X-ray CT images, but since the
superior, inferior, medial and lateral limits of the CTV were defined
by inspection and palpation, a breast CTV was not calculated. In-
stead, tissue lying within the 50% isodose line was selected as an
appropriate surrogate measure, less dependent than the 95%
isodose line on the planning system and on the different X-ray
Fig. 1. Illustration of the use of multi-leaf collimators (MLCs) to shield hot-spots
C. Goldsmith et al./Radiotherapy and Oncology 100 (2011) 236–240
energies selected for treatment. The 50% isodose line included non-
target tissues, including ribcage, pectoral muscle and skin, that
contribute to late adverse effects scored in the breast, and lung tis-
sue which does not. This measure of breast volume was validated
against photographic breast size scored clinically by consensus be-
tween three observers applying a three-point graded scale (small,
medium, large) to images taken post-surgery and before radiother-
apy under standard conditions, as previously described [26,27].
A parameter representing the proportion of breast volume
receiving >100% of prescribed dose was created from the dose–
volume histogram data. Raw data for absolute breast volume (rep-
resenting breast size) and percentage volume of breast tissue
receiving >100% of prescribed dose were summarised and tested
using non-parametric methods (median, interquartile range,
Kruskal–Wallis test) as the distributions were skewed. As very
few patients had marked change in breast appearance, the mild
and marked categories were combined for the analysis to define
an endpoint of any change in photographic breast appearance.
The 100% reference point did not represent an arbitrary cut-point
for the analysis. Higher cut-points were considered, but these sam-
pled a more limited part of the dose–volume distribution. It was
assumed that late adverse effects would vary more in response
to large partial volumes exposed to doses ranging from 101% to
107% than to very small partial volumes receiving >107%, for exam-
ple. In the patients with any volumes receiving >107%, the median
percentage volume of treated breast receiving dose >107% was ex-
tremely small (0.1%). This figure for partial breast volumes receiv-
ing >107% of prescribed dose is consistent with previous reports in
the literature . The distribution of volume receiving >100%
dose was split into quartiles for the analysis assessing the effect
of dosimetry on risk of late adverse effects. Logistic regression
was used to assess the effect of breast size and dosimetry on the
risk of any change in photographic breast appearance at 2 years.
Each factor was first tested alone in a univariate model, and then
both were included together to test whether the effects were inde-
pendent of each other. Finally other factors associated with risk of
late adverse effects (such as randomised radiotherapy fractionation
regimen, surgical deficit, age, and adjuvant systemic therapy) were
tested along with breast size and dosimetry in a multiple logistic
regression analysis, and the final model retained those factors
which were statistically significant.
The FAST trial randomised 915 patients between October 2004
and March 2007 . Although 16 out of 18 radiotherapy centres
in the FAST trial used a CT planning system, only six centres had
systems that allowed importation of data for joint analysis using
Guiness software. (Royal Cornwall Hospital, Truro; The Royal
Marsden Hospital, Sutton; Ipswich Hospital; Royal Shrewsbury
Hospital; University Hospital of North Staffordshire, Stoke-on-
Trent and Beatson Oncology Centre, Glasgow). A total of 279
patients at these centres had baseline and 2-year photographs
available for the analysis. The patient tumour and treatment char-
acteristics of the study sample were representative of the FAST trial
population as a whole (n = 915), see Table 1. Age, time between
surgery and randomisation, histological type, pathological tumour
size, and tumour grade were comparable between the sample and
the total FAST population. Adjuvant systemic therapy (endocrine
treatment, usually tamoxifen 20 mg OD for 5 years) and axillary
node sampling were used more frequently in the study sample
than the total FAST population.
At 2 years post-randomisation, 201/279 (72%) women had no
change in photographic breast appearance, 61 (22%) had mild
change and 17 (6%) had marked change. The validity of photo-
graphic scores of breast size was confirmed in comparisons with
breast volume data from the radiotherapy planning systems, see
Fig. 2. There was a statistically significant increase in measured
(p < 0.001), with a median of 778 cc in the small group, 1114 cc
in medium and 1357 cc in large categories. Photographic scores
of breast size in 279 (100%) patients were used for the analysis be-
cause data compatibility issues allowed absolute breast volume
(cc) within the 50% isodose envelope to be estimated for only
171 (61%) women.
Breast size was significantly associated with volume receiv-
ing >100% of the prescribed dose; the median (interquartile range)
volumes receiving >100% were 30.3% (22.7–37.3), 39.7% (33.7–
45.3) and 38.1% (28.8–47.0) for small, medium and large breast
categories, respectively (p < 0.001). Rates of any (mild or marked)
change in photographic breast appearance at 2 years were highest
(50%) in large-breasted women, 33% in the medium-breasted cate-
gory and 21% in small-breasted patients. This trend was statisti-
cally significant in univariate analysis (p < 0.001 for trend;
Table 2). Breast size remained a significant predictor when other
significant risk factors (fractionation schedule and surgical deficit)
and the dosimetry parameter were included in the multiple regres-
sion model (p = 0.006 for trend; Table 2). This confirmed breast size
as an independent risk factor for radiation-induced change in
breast appearance 2 years after radiotherapy using 3D dosimetry.
Only 24% of patients received any dose >107% of prescribed dose,
and there was no significant association with occurrence of late ef-
fects (chi-squared p = 0.64).
Patient characteristics of dosimetry study sample (n = 279) compared with overall
distribution in FAST Trial (n = 915).
Distribution in study
sample, n (%)
in FAST trial (%)
Mean (SD) [range]
63.8 (7.6) [50–88]
62.9 (7.2) [50–88]
Time from surgery to randomisation (weeks)
Median (interquartile range)
5.5 (4.4–7.0) [2.4–
5.8 (4.3–7.4) [0.4–
SNBawith or without sampling
Pathological tumour size (cm)
Mean (SD) [range]
1.3 (0.6) [0.05–4.0]
1.4 (0.7) [0.05–11.4]
Adjuvant systemic therapy
aSNB = sentinel node biopsy.
Large breast size as a risk factor for late adverse effects of breast radiotherapy
The risk of any change in photographic breast appearance at
2 years increased with the proportion of breast volume receiving
>100% of the prescribed dose (22% in the lowest and 39% in the
highest quartiles, respectively), which was significant in univariate
analysis (p = 0.009 for trend; Table 2). However, when breast size
and other significant risk factors (fractionation schedule and surgi-
cal deficit) were included in the multiple regression model, the ef-
fect of dosimetry was no longer significant (p = 0.136 for trend;
Table 2). This suggested that dose inhomogeneity, and other signif-
icant factors, left most of the effect of breast size on risk of late ad-
verse effects unaccounted for, as indicated by odds ratios (95% CI)
for medium and large breasts compared with small of 1.58 (0.83–
3.00) and 3.87 (1.53–9.80), respectively, see Table 2.
Our data confirmed a significant association between breast
size and dose inhomogeneity, in accordance with earlier literature
[1,2,4,6,17]. It also confirmed breast size as a significant risk factor
for change in photographic breast appearance, also consistent with
a majority of published reports [2–9]. The effect of dose inhomoge-
neity on late adverse effects of 2D-planned breast radiotherapy has
been tested in two randomised trials. Donovan et al. 
randomised 306 patients requiring adjuvant whole breast radio-
therapy to 2D radiotherapy using standard wedge compensators
or 3D intensity modulated radiotherapy using multiple static
fields. The 2D-planned patients were 1.7 times more likely to have
a change in breast appearance at 5 years, judged by change in pho-
tographic breast appearance (p = 0.008), an effect not reproduced
at 2 years follow-up in a second trial . Against our expecta-
tions, the present analysis failed to confirm residual dose inhomo-
geneity in patients planned and treated using 3D dosimetry as an
independent risk factor for radiation-induced change in breast
We consider it unlikely that a major effect of residual dose inho-
mogeneity on risk of late effects in large-breasted patients treated
in accordance with IUCC guidelines has been missed. The measure
of breast size, although based on a categorical scale applied to clin-
ical photographs, correlated with absolute breast size measured
from 3D X-ray CT images of the breast in a subset (61%) of patients.
Change in photographic appearance as an indicator of radiotherapy
adverse effects has been well validated in randomised clinical trials
conducted by our group, showing it to be sensitive to small (<10%)
differences in randomised total dose [26,27]. In the present study,
24% of patients received >107% of prescribed dose to an average
partial breast volume of only 0.44%, so a correlation between pa-
tients receiving doses >107% and probability of late effects could
not be expected.
Although breast size and dosimetry were each significantly
associated with late effects of breast radiotherapy on univariate
analysis, dosimetry was no longer significant when included in a
multivariate model including breast size. However, breast size re-
mained an independent significant predictor of late effects when
included in a multivariate model along with fractionation sche-
dule, surgical deficit and dosimetry. The inference is that breast
size, not dosimetry, is the dominant risk factor for late effects fol-
lowing 3D planned breast radiotherapy.
Late effects in this study were assessed by scoring photographic
breast appearance, using the contralateral breast to control for
age- and weight-related changes. The effects of radiotherapy most
easily noticed on photographs are changes in size and shape, with
breast shrinkage the commonest effect. In large- or heavy-breasted
of radiotherapy. Whatever the mechanisms explaining why heavy-
breasted women are more likely to experience breast shrinkage
and other late adverse effects, the challenge is to reduce treatment
morbidity without negatively impacting on local control or survival
rates. This report suggests that residual dose inhomogeneity in
Fig. 2. Comparison of photographic assessment of breast size with actual measured
breast volume. Median (interquartile range) breast volumes according to category
of breast size (shown by bold lines and ends of boxes respectively): 778 cc (660–
922) for small, 1114 cc (846–1347) for medium and 1357 cc (1193–1747) for large;
p < 0.001 for Kruskal–Wallis test.
Results of logistic regression analyses testing association between breast size and breast volume receiving >100% of prescribed dose, with risk of adverse change in 2-year
photographic breast appearance in 279 patients.
Mild/marked change in breast
appearance at 2 years/total (%)
Crude OR (95%CI),
p < 0.001
p = 0.012
p = 0.006
p = 0.009
p = 0.072
p = 0.136
% Volume receiving >100% dosec
aOdds ratio adjusted for breast size and % volume receiving >100% dose.
bOdds ratio adjusted for breast size, % volume receiving >100% dose, fractionation schedule and surgical deficit.
cQuartiles used to define categories.
C. Goldsmith et al./Radiotherapy and Oncology 100 (2011) 236–240
tion would be to consider a small dose reduction to compensate for
the enhanced risk of late adverse effects. A 10% reduction in total
by 20%, assuming a c50 of 2 to describe the slope of the dose re-
sponse curve at the 50% level of effect. In the setting of adjuvant
breast radiotherapy, this dose reduction to whole breast would be
associated with a 61% loss of local tumour control, assuming c95
of 0.2 at the 95% level of local tumour control [27,32].
Large- or heavy-breasted women are more likely than others to
suffer change in breast size and shape after radiotherapy, even
when 3D dosimetry has been optimised.
We acknowledge the FAST Trialists’ Group, which in addition to
the co-authors John Yarnold, Joanne Haviland and Mark Sydenham
includes: Rajiv Agrawal, Royal Shrewsbury Hospital, Shrewsbury;
Abdulla Alhasso, Beatson Oncology Centre, Glasgow; Jane Barrett,
Royal Berkshire Hospital, Reading; Peter Barrett-Lee, Velindre
Hospital, Cardiff; Judith Bliss, Institute of Cancer Research Clinical
Trials and Statistics Unit, Section of Clinical Trials, Sutton; David
Bloomfield, Royal Sussex County Hospital, Brighton; Joanna Bowen,
Cheltenham General Hospital, Cheltenham; Murray Brunt, Univer-
Donovan, The Royal Marsden NHS Foundation Trust, Sutton; Andy
Goodman, Royal Devon & Exeter NHS Trust, Exeter; Marianne Ills-
ley, Royal Surrey County Hospital, Guildford; Assem Rostom, The
Royal Marsden NHS Foundation Trust, Sutton; Elizabeth Sherwin,
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