Randomized controlled trial of forward-planned intensity modulated radiotherapy for early breast cancer: interim results at 2 years.
ABSTRACT This single-center randomized trial was designed to investigate whether intensity-modulated radiotherapy (IMRT) reduces late toxicity in patients with early-stage breast cancer.
The standard tangential plans of 1,145 nonselected patients were analyzed. The patients with inhomogeneous plans were randomized to a simple method of forward-planned IMRT or standard radiotherapy (RT). The primary endpoint was serial photographic assessment of breast shrinkage.
At 2 years, no significant difference was found in the development of any photographically assessed breast shrinkage between the patients randomized to the interventional or control group (odds ratio, 1.51; 95% confidence interval, 0.83-1.58; p = .41). The patients in the control group were more likely to develop telangiectasia than those in the IMRT group (odds ratio, 1.68; 95% confidence interval 1.13-2.40; p = .009). Poor baseline surgical cosmesis resulted in poor overall cosmesis at 2 years after RT. In patients who had good surgical cosmesis, those randomized to IMRT were less likely to deteriorate to a moderate or poor overall cosmesis than those in the control group (odds ratio, 0.63; 95% confidence interval, 0.39-1.03, p = .061).
IMRT can lead to a significant reduction in telangiectasia at comparatively early follow-up of only 2 years after RT completion. An important component of breast induration and shrinkage will actually result from the surgery and not from the RT. Surgical cosmesis is an important determinant of overall cosmesis and could partially mask the longer term benefits of IMRT at this early stage.
- Cancer/Radiothérapie 5(1):92-4. · 1.48 Impact Factor
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ABSTRACT: The aim of this study was to evaluate the effect of breast size on dose heterogeneity. Twenty women underwent a planning CT scan of the thorax. A three-dimensional treatment plan was devised for each patient using a standard technique of isocentric medial and lateral wedged tangential fields. Three-dimensional dose distributions were derived using an equivalent path length (EPL) inhomogeneity correction and cumulative dose-volume histogram (DVH) data calculated for the breast. Analysis of the DVHs for each patient reveals that 0.2-23.8% of the breast received an absorbed dose outside the desired 95-105% of that prescribed at the isocentre. The degree of dose heterogeneity was most strongly correlated with breast volume (r = 0.70, 95% confidence interval (C.I.) 0.37-0.87). There was also a positive correlation for breast dose heterogeneity versus brassière (bra) cup size (Spearman rank correlation rho = 0.62), breast area (r = 0.39, 95% C.I. -0.06-0.71) and chest wall separation (r = 0.31, 95% C.I. -0.15-0.66). We conclude that breast size is an important determinant of dose heterogeneity within the breast.Radiotherapy and Oncology 04/1995; 34(3):210-8. · 4.52 Impact Factor
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ABSTRACT: Serial photographs have been collected prospectively to evaluate the effect of radiotherapy on normal tissues in the breast. The aim of this study was to compare two methods of scoring radiation-induced changes. Five-year photographs of 400 patients randomised to receive either 42.9 or 39 Gy in 13 fractions to the whole breast after tumour excision of early breast cancer were compared with a post-surgery baseline and scored for change in breast appearance on a three-point graded scale. Two alternative methods of scoring using three observers were compared: (a) scores allocated independently, with independent resolution of discrepancies, and (b) scores allocated by consensus. Treatment effects estimated from the consensus and independent scores were very similar (odds ratio 1.89, 95% confidence interval 1.21-2.96 vs 2.28, 95% confidence interval 1.50-3.47, respectively). Agreement between the scores obtained from each method was reasonable, and the repeatability of the consensus method was good. The consensus method of scoring photographic change in breast appearance seems to be no less sensitive to randomised dose as the independent method of assessment, but is much quicker to administer. The consensus method has been used to score over 3000 sets of photographs in the National Cancer Research Institute Standardisation of Breast Radiotherapy trial.Clinical Oncology 06/2008; 20(7):497-501. · 2.86 Impact Factor
RANDOMIZED CONTROLLED TRIAL OF FORWARD-PLANNED
INTENSITY-MODULATED RADIOTHERAPY FOR EARLY BREAST CANCER:
INTERIM RESULTS AT 2 YEARS
GILLIAN C. BARNETT, B.M., B.CH.,* JENNIFER S. WILKINSON, B.SC.,yANNE M. MOODY, M.B., B.CHIR.,y
CHARLES B. WILSON, M.D.,yNICOLATWYMAN, M.SC.,yGORDON C. WISHART, M.D.,z
NEIL G. BURNET, M.D.,* AND CHARLOTTE E. COLES, PH.D.y
*Department of Oncology, University of Cambridge, Cambridge University Hospitals, National Health Service Foundation Trust,
Cambridge, United Kingdom;yOncology Centre, Cambridge University Hospitals, National Health Services Foundation Trust,
Cambridge, United Kingdom;zCambridge Breast Unit, Addenbrooke’s Hospital, Cambridge, United Kingdom
Purpose: This single-center randomized trial was designed to investigate whether intensity-modulated radiother-
apy (IMRT) reduces late toxicity in patients with early-stage breast cancer.
Methods and Materials: The standard tangential plans of 1,145 nonselected patients were analyzed. The patients
with inhomogeneous plans were randomized to a simple method of forward-planned IMRTor standard radiother-
apy (RT). The primary endpoint was serial photographic assessment of breast shrinkage.
Results: At 2 years, no significant difference was found in the development of any photographically assessed breast
shrinkage between the patients randomized to the interventional or control group (odds ratio, 1.51; 95%
confidenceinterval, 0.83–1.58;p=.41).The patients inthecontrolgroupweremorelikelytodeveloptelangiectasia
cosmesis resulted in poor overall cosmesis at 2 years after RT. In patients who had good surgical cosmesis, those
group (odds ratio, 0.63; 95% confidence interval, 0.39–1.03, p = .061).
Conclusions: IMRT can lead to a significant reduction in telangiectasia at comparatively early follow-up of only 2
years after RT completion. An important component of breast induration and shrinkage will actually result from
the surgery and not from the RT. Surgical cosmesis is an important determinant of overall cosmesis and could
partially mask the longer term benefits of IMRT at this early stage.
? 2011 Elsevier Inc.
Breast cancer, Intensity-modulated radiotherapy, IMRT, Clinical trials.
Radiotherapy (RT) has an established role in the manage-
ment of early, invasive breast cancer to increase both locore-
gional control and survival (1). The current challenge has
been to minimize the morbidity caused by this treatment
without losing efficacy. Conventional two-dimensional RT
breast plans can produce substantial dose inhomogeneities,
particularly in women with larger breasts. This can result
in a worse cosmetic outcome and lead to other late normal
tissue side effects such as breast pain (2). These toxicities
have been shown to have a considerable effect on patients’
physical and psychological well-being (3).
Reprint requests to: Charlotte E. Coles, Ph.D., Oncology Centre,
Box 193, Cambridge University Hospitals, National Health Ser-
vices Foundation Trust, Hills Road, Cambridge CB2 0QQ UK.
Tel: (01) 223-59-6182; Fax: (01) 223-21-7094; E-mail: charlotte.
cer Symposium, December 2009.
Supported by the Breast Cancer Campaign award tosupport are-
search radiographer for 6 years.
and the Royal College of Radiologists; she has also received fund-
ing from Addenbrooke’s Charitable Trust. J. Wilkinson, breast re-
search radiographer, was funded by the Breast Cancer Campaign
and was currently funded by the Comprehensive Local Research
Network. C. Coles, N. Burnet, and G. Wishart were supported by
the Cambridge National Institute of Health Research Biomedical
Conflict of interest: none.
Acknowledgments—We would like to thank Professor John Yar-
nold, Dr. Ellen Donovan, and Dr.Jo Haviland for their helpful com-
ments regarding this report; all the women who participated in the
study and the doctors, nurses, radiographers, and physicists who
were involved in their care; and the members of the Independent
Data Monitoring Committee: Dr. Pippa Corrie (Chair), Dr. Paul
Pharoah, Mr. Arnie Purushotham, Dr. Adrian Harnett. We also
thank Dr. Margaret Daly, Dr. Kate Fife, Dr. Luke Hughes-Davies,
Dr. Catherine Jephcott, Dr. Simon Russell, Professor Robert
Thomas, Dr. James Watson, and Dr. Cathryn Woodward for refer-
ring patients to the trial.
Received May 19, 2010, and in revised form Oct 19, 2010.
Accepted for publication Oct 29, 2010.
Int. J. Radiation Oncology Biol. Phys., Vol. -, No. -, pp. 1–9, 2011
Copyright ? 2011 Elsevier Inc.
Printed in the USA. All rights reserved
0360-3016/$ - see front matter
Intensity-modulated RT (IMRT) allows the radiation
fluence to vary across the beam and can be used to improve
the dose homogeneity in an irradiated volume (4). We have
recently shown that the dosimetry was significantly im-
proved with a simple method of forward-planned IMRT
compared with two-dimensional RT in 815 randomized
patients (5). This has been supported by many dosimetry
studies that also demonstrated improvement with IMRT
compared with two-field tangential RT plans. Currently,
only limited randomized control trial evidence is available
that these dosimetry improvements with IMRT translate
into clinical benefit for these patients (6, 7). Only one
randomized trial has shown a beneficial effect of forward-
planned IMRTon late toxicity in patients with larger breasts
The primary aim of the Cambridge Breast IMRT trial was
to investigate, in a larger trial that included patients with all
using a simple method of forward-planned IMRT, would
decrease late normal tissue toxicity in patients with early
METHODS AND MATERIALS
The Cambridge Breast IMRT trial opened in April 2003 and was
closed to recruitment in June 2007. The trial protocol was devel-
oped at the ‘‘Methods in Clinical Cancer Research’’ workshop in
Flims, Switzerland, in June 2001. This was jointly organized by
the Federation of European Cancer Societies, the American Asso-
ciation for Cancer Research, and the American Society of Clinical
Oncology. The protocol development included specific statistical
advice for the present study. The Cambridge Research Ethics Com-
Cancer Research Institute Radiotherapy Studies Group accepted
the trial as a portfolio trial in April 2002, and it was adopted by
the National Cancer Research Network in March 2003. The patient
characteristics and RT technique used in the Cambridge Breast
IMRT trial have been previously described (5) and have only
been summarized in the present report.
Women were eligible if they had operable unilateral histologi-
cally confirmed invasive breast cancer (Stage T1-T3N0-N1M0)
or ductal carcinoma in situ and required RTafter complete macro-
scopicexcisionofthe tumorusingbreast-conserving surgery.Other
eligibility criteria included age >18 years, no history of contralat-
eral breast cancer, no previous malignancy in the previous 5 years
(except for skin basal cell or squamous carcinoma or in situ
provided written informed consent.
A standard event rate of 40% in the control group at 2 years was
assumed. The difference to be detected was estimated to be 10%,
with a hazard ratio of 0.7. Assuming a minimal average follow-
and 125 events were required in each of the randomized arms. This
sample size was increased by 10% to adjust for possible loss of
Patients with significant dose inhomogeneities, defined by
a $2-cm3volume that was >107% of the prescribed dose, were
randomized to either standard breast RT (control arm) or IMRT
(interventional arm). Randomization was performed by the Bir-
mingham Clinical Trials Unit using random permuted blocks of
mixed block sizes and stratified for T stage and adjuvant therapy.
Patients in the control arm were treated with wedged tangential
fields to the breast. The women randomized to the interventional
arm underwent repeat treatment planning with a simple, manual
forward-planned IMRT technique to reduce the volumes receiving
Fig. 1. Example of photographic scoring of breast shrinkage. (Top) Photographs of 3 patients immediately after surgery
toright breast. (Lower)Two years after radiotherapy showing Patient Awithout shrinkage, Patient B withmild shrinkage,
and Patient C with marked breast shrinkage.
2I. J. Radiation Oncology d Biology d PhysicsVolume -, Number -, 2011
Table 1. Patient, tumor, and treatment characteristics of 1,145 trial participants
Breast volume (cm3)
Diabetes mellitus (n)
Smoking status (n)
Postoperative infection requiring
Postoperative hematoma (n)
Pathologic tumor size (mm)
Mean specimen weight* (g)
Histologic grade (n)
Unknown or not available
Histologic type (n)
Axillary surgery (n)
RT breast boost (n)
Axillary RT (n)
Supraclavicular RT (n)
26–82 29–81 32–8426–84
< .00005 .37
< .00005 < .00005
46 ? 38
72 ? 72
64 ? 45
62 ? 63
.038 .41 .14
0 (0) 2 (<1)
3 (<1) .64
330 (100)1142 (>99)
10 (3)16 (4) 17 (4)43 (4).71
Two-year results of breast IMRT trial d G. C. BARNETTet al.3
>107% and <95% of the prescribed dose (5). Patients with satis-
factory dose homogeneity were not randomized but treated with
standard RTand followed up the same as were the randomized pa-
within 3 weeks, with 6-MV photons prescribed to the International
Commission on Radiation Units and Measurements report 50 refer-
ence point. Mixed energies of 6- and 15-MV photons were used,
when required, in patients with larger separations. Nodal RT and
(5). After RT, all patients were treated equally, irrespective of the
treatment arm to which they had been allocated.
The primary endpoint was serial photographic assessment of
breast shrinkage. Frontal photographs of both breasts were taken
after primary surgery and before the start of RT (baseline) and
repeated at 2 years after RT. Two photographs were taken, one
with the hands resting on the hips and one with the arms raised
above the head. Follow-up photographs were terminated in the
case of local tumor relapse, additional breast surgery, poor health,
multidisciplinary team of seven clinicians (four oncologists, 1 ra-
diographer, 1 surgeon, and 1 breast care nurse) were involved in
the photographic assessment, with a panel of three present at any
one time. At the photographic assessment, all clinicians were
unaware of the treatment arm to which the patient had been allo-
cated. This method has beenvalidated and shown to be as sensitive
as, but quicker than, using three independent scorers, with repeat
scoring of discrepancies and final resolution through discussion
deficit were assessed after surgery and before RT. Overall cosmesis
was assessed using the photographs taken at 2 years, taking into ac-
count the effects of breast surgery and RT. The baseline surgical
cosmesis, surgical deficit, and overall cosmesis were all scored
using a 3-point scale.
The secondary endpoints included the photographic assessment
acute skin toxicity, clinical assessment of late normal tissue effects,
and quality-of-life self-assessment questionnaires. Acute skin reac-
tions were assessed and recorded according to the Radiation Ther-
apy Oncology Group grading system (11). The patients were
assessed weekly during treatment, at RT completion, and 16 weeks
after the end of treatment (i.e., at the routine clinic appointments).
The clinical assessment was made at a trial follow-up appoint-
ment at 2 and 5 years after RT completion. The initial 70 patients
were assessed by an oncologist (C.E.C.) who had trained the breast
research radiographer (J.W.) in clinical assessment at the same
time. A single observer (J.W.) then assessed the remainder of the
patients. Both clinicians were unaware of the allocated treatment
arm at the assessment. The treated breast was examined for the
presence of breast edema, telangiectasia, breast shrinkage, pigmen-
tation changes, and palpable induration of the breast. Each of the
secondary clinical endpoints was graded 0–3 (none, a little, quite
a bit, or very much) on the scale used in the UK Standardisation
of Breast Radiotherapy (START) trials (8, 9). Pigmentation
change was scored from 0 to 2 according to the Late Effects of
Normal Tissue–Subjective Objective Management Analytical
score (12, 13). Locoregional recurrence, metastasis development,
and death were recorded at 2 years from RT completion but were
not included as secondary endpoints.
Thequality oflifewasassessed usingtheEuropeanOrganization
for Research and Treatment of Cancer QLQ-C30 with the breast
cancer module, ‘‘Additional Body Image items’’ (START trial),
and the Hospital Anxiety and Depression Scale (14–16). The
patient self-assessment questionnaires were completed at 6, 24,
and 60 months after RT completion. A full quality-of-life analysis
study, the results from the European Organization for Research and
Table 1. Patient, tumor, and treatment characteristics of 1,145 trial participants (Continued)
No320 (97) 389 (96)393 (96) 1102 (96)
Treatment with AI (n)
Gonadorelin ovarian ablation (n)
8 (2)38 (3)
Abbreviations: DCIS = ductal carcinoma in situ; AI = aromatase inhibitor; RT = radiotherapy.
*Available for 986 of 1,145 patients.
4I. J. Radiation Oncology d Biology d Physics Volume -, Number -, 2011
Treatment of Cancer BR23 questionnaire were used to assess the
pain and hypersensitivity in the treated breast at 2 years after RT
(17). The pain and oversensitivity experienced in the last week
were scored on a scale from 1 to 4 (not at all, a little, quite a bit,
and very much).
The baseline data was compared using the Student t test, Pear-
son’s chi-square test for heterogeneity and trend, and Fisher’s exact
test, as appropriate. The reproducibility of the primary endpoint
was checked by rescoring the photographic assessment of breast
shrinkage on a random 10% subset of the study sample. The pairs
of scores obtained at these two points were compared within
patients, and the weighted k statistic was calculated as a measure
of agreement. The photographic assessment of RT shrinkage and
overall cosmesis were dichotomized by grouping the scores 2 and
3. The clinical endpoints were dichotomized, with scores of 0 as
one group and $1 as the second group. The toxicity endpoints
1145 patients recruited to trial
Dosimetry with standard breast plan:
< 2 cm 3 of breast tissue > 107% ≥ 2 cm3 of breast tissue > 107%
330 patients were
received standard RT
T1-3, N0-1, M0 invasive breast cancer/DCIS requiring RT
Breast conservation surgery with complete tumour excision.
1283 p atients a pp roached to p artici p ate in trial
1 patient not
withdrawn from study
Local recurrence (2)
Contralateral new primary (3)
Standard plan unacceptable (1)
Randomised in error (1)
Mammoplasty for cosmesis (1)
Elective reconstruction (1)
Bilateral prophylactic mastectomies (2)
Husband unwell or died (3)
Patient choice: reason not stated (77)
Unable to contact (8)
Fig. 2. Consolidated Standards Of Reporting Trials diagram of trial. RT = radiotherapy; IMRT = intensity-modulated
Two-year results of breast IMRT trial d G. C. BARNETTet al.5