Versmessen et al.

BMC Cancer 2012, 12:495

http://www.biomedcentral.com/1471-2407/12/495

RESEARCH ARTICLE Open Access

Health-related quality of life in survivors of stage

I-II breast cancer: randomized trial of
post-operative conventional radiotherapy and
hypofractionated tomotherapy
Harijati Versmessen1*, Vincent Vinh-Hung1,2, Hilde Van Parijs1, Geertje Miedema1, Mia Voordeckers1,
Nele Adriaenssens3,4, Guy Storme1 and Mark De Ridder1

Abstract
Background: Health-related quality of life (HRQOL) assessment is a key component of clinical oncology trials.
However, few breast cancer trials comparing adjuvant conventional radiotherapy (CR) and hypofractionated
tomotherapy (TT) have investigated HRQOL. We compared HRQOL in stage I-II breast cancer patients who were
randomized to receive either CR or TT. Tomotherapy uses an integrated computed tomography scanner to improve
treatment accuracy, aiming to reduce the adverse effects of radiotherapy.
Methods: A total of 121 stage I–II breast cancer patients who had undergone breast conserving surgery (BCS) or
mastectomy (MA) were randomly assigned to receive either CR or TT. CR patients received 25 × 2 Gy over 5 weeks,
and BCS patients also received a sequential boost of 8 × 2 Gy over 2 weeks. TT patients received 15 × 2.8 Gy over 3
weeks, and BCS patients also received a simultaneous integrated boost of 15 × 0.6 Gy over 3 weeks. Patients
completed the EORTC QLQ-C30 and BR23 questionnaires. The mean score (± standard error) was calculated at
baseline, the end of radiotherapy, and at 3 months and 1, 2, and 3 years post-radiotherapy. Data were analyzed by
the 'intention-to-treat' principle.
Results: On the last day of radiotherapy, patients in both treatment arms had decreased global health status and
functioning scores; increased fatigue (clinically meaningful in both treatment arms), nausea and vomiting, and
constipation; decreased arm symptoms; clinically meaningful increased breast symptoms in CR patients and
systemic side effects in TT patients; and slightly decreased body image and future perspective.
At 3 months post-radiotherapy, TT patients had a clinically significant increase in role- and social-functioning scores
and a clinically significant decrease in fatigue. The post-radiotherapy physical-, cognitive- and emotional-functioning
scores improved faster in TT patients than CR patients. TT patients also had a better long-term recovery from
fatigue than CR patients. ANOVA with the Bonferroni correction did not show any significant differences between
groups in HRQOL scores.
Conclusions: TT patients had a better improvement in global health status and role- and cognitive-functioning,
and a faster recovery from fatigue, than CR patients. These results suggest that a shorter fractionation schedule may
reduce the adverse effects of treatment.
Keywords: Health-related quality of life, Breast cancer, Hypofractionated radiotherapy, Adjuvant treatment,
Randomized trial

* Correspondence: Harijati.Versmessen@uzbrussel.be
1
Department of Radiation Oncology, UZ Brussel, Vrije Universiteit Brussel,
Laarbeeklaan 101, 1090 Jette, Brussels, Belgium
Full list of author information is available at the end of the article

© 2012 Versmessen et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the
Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.
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Background over time in standardized questionnaires, while concur-

Breast cancer is the most commonly occurring cancer rently exhibiting deteriorating clinical health [28,29].
in women [1]. Worldwide, breast cancer accounted for Tomotherapy is a new radiotherapy system that uses
23% of new cancer cases and 14% of total cancer deaths an integrated computed tomography scanner to improve
in 2008 [2]. Radiotherapy is standard treatment in all the accuracy of radiotherapy treatment. The radiation is
patients who undergo breast conserving surgery (BCS), delivered helicoidally, allowing highly conformal shaping
and also plays a major role in the treatment of patients of dose distribution while minimizing radiation exposure
who undergo mastectomy (MA) [3]. Adjuvant radiother- to healthy tissues. However, the magnitude of the clinical
apy has been shown to improve local control and advantage of using this system in breast cancer treat-
overall survival, with a 70% reduction in the risk of ment is currently unknown. We therefore designed a
recurrence [4,5] and a 9–12% reduction in the risk of randomized phase III trial to compare CR with hypofrac-
death [6-9]. These improved survival rates are based on tionated tomotherapy (TT), using the TomotherapyW
trials of conventional protocols in which 1.8–2.5 Gy/ system (NCT00459628). The primary endpoint of the
fraction was delivered over 5–7 weeks [6,8,10-12]. There trial was pulmonary or cardiac toxicity, and the second-
has been concern that delivery of > 2 Gy/fraction might ary endpoint was locoregional recurrence. Completion
increase late toxicity and impair cosmesis in BCS of HRQOL questionnaires (EORTC QLQ C-30 & BR-23)
patients [13]. It is known that the late effects are was included in the trial design. The purpose of this
strongly dependent on dose per fraction, with higher paper is to compare the HRQOL questionnaire results
doses per fraction resulting in a greater susceptibility of between the two treatment arms.
healthy tissues to the adverse effects of radiotherapy.
The Early Breast Cancer Trialists' Collaborative Group Methods
reported that radiotherapy using conventional fraction- Breast cancer patients who underwent surgery at the
ation reduced the annual mortality rate of breast cancer University Hospital of Brussels from June 2007 to July
patients by 13%, but increased the annual mortality rate 2011 were screened according to the eligibility criteria in
due to other causes by 21%, and that this increase was the protocol of the TomoBreast study (ClinicalTrials.gov
due primarily to cardiovascular effects [14]. A hypofrac- registration NCT00459628):
tionated schedule has the potential to result in even
more severe adverse effects. 1. Women aged 18 years or older.
Many researchers are investigating hypofractionated 2. Histologically proven invasive unilateral breast
radiotherapy for breast cancer, aiming to determine the carcinoma, stage I or II (T1-3N0 or T1-2N1 M0,
optimal schedule for cosmesis, late toxicity, and locor- American Joint Committee on Cancer (AJCC)/TNM
egional control. Most of the randomized trials that 6th edition).
compare conventional radiotherapy (CR) with hypo- 3. BCS or MA with clear margins and pathological
fractionated radiotherapy have reported on effectiveness nodal status assessed by axillary lymph node
(locoregional control) and safety (acute and late toxicity) dissection or sentinel node biopsy.
[15-24]. However, only a few studies have investigated 4. At least one pre-operative medical imaging scan
cosmesis [15,19,20], and only one study to date has available (computed tomography, magnetic
investigated quality of life (QOL) [19]. resonance imaging, or positron emission
Health-related QOL (HRQOL) assessment is now tomography).
regarded as a key component of clinical oncology trials 5. Informed consent obtained.
[25]. Radiotherapy for breast cancer tends to be stressful
and may increase fatigue, skin irritation, and breast pain Patients who did not meet the inclusion criteria, or
during the first year [26]. Attendance at daily radiotherapy with the following criteria, were excluded:
treatments for up to 6 weeks may also have an impact on
the patient's QOL. It is hoped that use of the hypofractio- 1. Prior breast or thoracic radiotherapy.
nated schedule can reduce this burden by shortening the 2. Pregnancy or lactation.
overall treatment time. 3. Fertile without effective contraception.
Sprangers [27] considered that HRQOL can be mea- 4. Psychiatric or addictive disorder.
sured reliably and validly, and that measurement of
HRQOL helps clinicians to gain insight into patients’ A total of 123 eligible patients gave written informed
perspectives of their disease and treatment. However, consent and were included in the study. These patients
patients may change their perspectives during the course were randomized to the CR (control) or TT (experimen-
of their disease experience, referred to as a ‘response tal) arms using Efron's biased coin design [30]. Patients
shift.’ This may result in patients reporting a stable QOL were stratified by nodal status (N0 vs. N1), type of
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surgery (MA vs. BCS), and chemotherapy sequence (none should start within 6 weeks after breast surgery, or in
vs. sequential vs. concomitant chemotherapy). Two patients cases of sequential chemotherapy, within 6 weeks after
who were randomized to the control arm were later the completion of chemotherapy (Table 1). In reality, CR
excluded from the study. One of these patients had bilateral started an average of 39 days after surgery and TT started
breast cancer, which was not in accordance with the an average of 50 days after surgery in patients who did
eligibility criteria, and the other patient could not par- not receive chemotherapy. CR started an average of
ticipate because she was enrolled in a different study. 43 days after surgery and TT started an average of 49 days
The participant flow chart is presented in Figure 1. In after surgery in patients with concurrent chemotherapy.
November 2011, the 121 eligible patients had all been One patient who received neo-adjuvant chemotherapy
followed up for at least 3 months after the completion received radiotherapy 36 days after surgery. Patients with
of radiotherapy. sequential chemotherapy started CR an average of 23
CR patients received a dose of 50 Gy delivered in 25 days, or TT an average of 25 days, after the completion of
fractions over 5 weeks to the chest wall using tangential chemotherapy.
photon fields, and in patients with pN1 status, to the The European Organisation for Research and Treatment
supraclavicular, infraclavicular, and axillary nodes using of Cancer (EORTC) general cancer quality of life score
an anterior field matched to the tangential fields. BCS (QLQ-C30) questionnaire and its breast cancer module
patients received a sequential boost of 16 Gy delivered (QLQ-BR23) were used to measure HRQOL in this study.
in 8 fractions over 2 weeks to the initial tumor bed using These questionnaires were specifically designed for can-
a direct electron field (cumulative dose 66 Gy over 6.5 cer patients, have undergone extensive testing, and have
or 7 weeks depending on maintenance procedures). TT been confirmed as reliable and valid when measuring
patients received a dose of 42 Gy delivered in 15 frac- QOL outcomes [31,32]. The EORTC QLQ-C30 ques-
tions over 3 weeks to the chest wall of MA patients or tionnaire consists of 30 questions which assess function-
to the whole breast of BCS patients, and to the supracla- ing (physical, role, cognitive, emotional, social) and
vicular, infraclavicular, and axillary nodes in patients symptoms (fatigue, nausea and vomiting, pain, dyspnea,
with pN1 status, using the image-guided TomotherapyW insomnia, appetite loss, constipation, diarrhea, financial
system. BCS patients received a simultaneous integrated difficulty), and a global health status score that assesses
boost of 9 Gy delivered in 15 fractions over the 3 weeks overall QOL. The EORTC QLQ-BR23 questionnaire
(cumulative dose 51 Gy over 3 weeks). consists of 23 questions assessing functioning (body
Concurrent or sequential adjuvant systemic treatments image, sexual functioning, sexual enjoyment, future per-
were allowed. According to the protocol, radiotherapy spective) and symptoms (systemic side effects, upset by

Histology proven stage I or II (T1-3N0 or T1-2N1 M0) breast cancer patients

123 eligibility confirmed & informed consent obtained

123 randomized

64 control arm (CR) 59 experimental arm (TT)

pre-RT: Baseline HRQOL questionnaires (EORTC QLQ-C30 & -BR23)

62* control arm (CR) 59 experimental arm (TT)

MA 50Gy/5weeks; MA 42Gy/3weeks;
BCS 66 Gy/7weeks BCS 51Gy/3weeks
2 excluded

post-RT: HRQOL questionnaires (EORTC QLQ-C30 & -BR23)

& morbidity scoring (RTOG & SOMA-LENT) at:
end radiotherapy,
1-3 months post RT
1, 2, 3 years post RT

* Two patients in the control arm were excluded: one patient due to bilateral breast Ca and the
other patient due to involvement in another study.
Figure 1 Participant flow.
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Table 1 Mean nr of days to start RT after last breast 1 year, two TT patients withdrew at 2 years, and one TT
surgery or last chemotherapy patient withdrew at 3 years.
CR TT The mean (± standard error) of each score was cal-
no adj CT nr of pts 37 29 culated at each time point: baseline, last day of radio-
after last breast surgery 39 50 therapy, 3 months, and 1, 2, and 3 years after the
neo-adj CT nr of pts - 1 completion of radiotherapy. Consistent with previous
after last breast surgery - 36
studies, only differences of greater than ten points on
the transformed questionnaire scale were considered
concurrent CT nr of pts 19 23
clinically meaningful [36-38].
after last breast surgery 43 49
Data were analyzed by the intention-to-treat (ITT)
sequential CT nr of pts 6 6
principle. For each patient, the baseline HRQOL score
after last breast surgery 164 154 was subtracted from the score at each subsequent time
after last CT 23 25 point. The average change at each time point was
compared between treatment arms using the two-sample
hair loss, breast symptoms, arm symptoms). Both ques- t-test (Additional file 1: adjusted QLQ mean scores.xls). A
tionnaires use a four-point response scale (not at all, a positive change indicated improvement of functioning or
little, quite a bit, and very much) to assess each func- worsening of symptoms, and a negative change indicated
tional or symptom item, and a seven-point response worsening of functioning or improvement of symptoms.
scale is used to assess global health status (from very Proportions were compared using Fisher's exact test and
poor to excellent). Raw scores were linearly transformed mean scores were compared using the t-test (two-sided),
into a score of 0–100 for processing according to the with the level of significance set at p < 0.05. Mean scores
EORTC manual [33]. Higher scores in the functioning were also compared using the Bonferroni correction and
and global health status scales represented better func- repeated measures ANOVA. Statistical analyses were
tioning and QOL, whereas higher scores in the symptom conducted using JMP version 8.0.1 (SAS Institute Inc.,
scales indicated greater problems. Cary, NC, USA).
Patients completed the HRQOL questionnaires (EORTC
QLQ-C30 and BR-23) during hospital visits at baseline Patient characteristics
(prior to radiotherapy), on the last day of radiotherapy, at Efron's biased coin design was used to randomize
1–3 months after the completion of radiotherapy, and then patients to treatment arms [30]. Patients in each treatment
yearly for 3 years. Clinical evaluations were performed at arm (CR and TT) were stratified by nodal status, type of
the same time points, and any recurrence of cancer was surgery, and chemotherapy sequence. The baseline patient
documented. The Radiation Therapy Oncology Group and tumor characteristics, adjuvant radio-chemotherapy
(RTOG)/EORTC morbidity scoring schema [34] was used schedules, and hormonal treatments are presented in
to assess acute morbidity, and the RTOG/EORTC and the Table 2.
Subjective Objective Management Analytic/Late Effects on
Normal Tissues (SOMA/LENT) toxicity scales [35] were Baseline quality of life scores
used to assess late morbidity. The mean baseline scores of the EORTC QLQ-C30 and
Patients usually completed the HRQOL questionnaires BR-23 questionnaires in each treatment arm are shown
during their hospitals visits, but if they did not have in Table 3. There were no significant differences in any
time, they were asked to return them by mail. This of the scores between treatment arms at baseline. Only
achieved a 100% return rate at all time points except on eight CR patients and 13 TT patients had hair loss at
the last day of radiotherapy (96% compliance), when five baseline. Of these, two CR patients and five TT patients
patients (two CR patients and three TT patients) who had received adjuvant chemotherapy before the
declined to complete the questionnaires for various rea- start of radiotherapy described the hair loss as "very
sons (inconvenient, too busy, too tired, etc.). Six patients much" at baseline, and the other patients with hair loss
(two CR patients and four TT patients) withdrew from due to other reasons described it as "quite a bit" at base-
the study for various reasons (the patient did not want line. Some patients did not answer the questions about
to undergo all the tests, the hospital was too far from sexual functioning and enjoyment for personal reasons
the home, the family was not available to accompany the (such as religion or being widowed).
patient for hospital visits). These patients therefore did
not complete the HRQOL questionnaires after their Results
withdrawal from the study: one TT patient withdrew at The QLQ-C30 and QLQ-BR23 mean scores at each time
the end of radiotherapy, one CR patient withdrew at 3 point in each treatment arm are presented in Figures 2, 3, 4
months after radiotherapy, one CT patient withdrew at and 5 and Tables 4 and 5.
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Table 2 Baseline characteristics Table 2 Baseline characteristics (Continued)

N (%) CR (n=62) TT (n=59) CMF 2 (8) 2 (7)
Age Anthracycline with taxotere 1 (4) 3 (10)
Mean age at randomization (SD) 58 (11) 55 (11) TCH 2 (8) 1 (3)
>/=65 years old 21 (34) 13 (22) Hormonal therapy (HT)
> 65 years old 41 (66) 46 (78) No HT 9 (14) 11 (19)
Surgery Tamoxifen 26 (42) 16 (28)
Mastectomy 19 (31) 26 (31) Femara 24 (39) 22 (38)
Segmentectomy 43 (69) 33 (69) Zoladex 0 2 (3)
Axillary nodes 10 (16) 16 (27) Tamoxifen + zoladex 3 (5) 6 (10)
Sentinel nodes 43 (69) 30 (51) Femara + zoladex 0 1 (2)
Sentinel & axillary nodes 9 (15) 13 (22) Herceptin (Trastuzumab) 3 (5) 10 (17)
Tumor grade & nodal status
T1 38 (61) 39 (66)
All functional scores and the global health status score
T2 24 (39) 20 (34) in both treatment arms were temporarily decreased on
N0 46 (74) 38 (64) the last day of radiotherapy (Figures 2a–f, Table 4), and
N1, LNR 0.01-0.20 11 (69) 18 (86) subsequently improved over time, except for cognitive
N1, LNR 0.21-0.65 5 (31) 3 (14)
N1, LNR >0.65 0 0 Table 3 Baseline mean scores (SD) by treatment arm
Side EORTC-QLQ C30 CR TT
Right 30 (48) 24 (41) (n=62) (n=59)
Left 32 (52) 35 (59) physical functioning 84,1 (18,7) 83,2 (16,0)
Mean size of largest tumor (mm) (SD) role functioning 70,2 (27,4) 66,4 (29,3)
T1 (<=20 mm) 12,5 (4,8) 13,4 (4,9) cognitive functioning 86,0 (20,5) 82,8 (22,3)
T2 (21–50 mm) 25,4 (6,9) 27,5 (5,9) emotional functioning 78,8 (18,1) 74,4 (20,0)
Quadrant social functioning 80,6 (22,6) 82,2 (19,8)
Central 6 (10) 9 (15) fatigue 29,7 (20,7) 35,0 (24,9)
Supero-interne 12 (19) 10 (17) nausea & vomiting 7,5 (19,0) 5,1 (15,2)
Infero-interne 9 (15) 1 (2) pain 24,7 (24,7) 24,5 (24,4)
Supero-externe 21 (33) 32 (54) global health status 69,0 (21,7) 67,2 (17,5)
Infero-externe 6 (10) 4 (7) dyspnea 11,3 (22,5) 15,3 (26,5)
Overlapping 5 (8) 2 (3) insomnia 26,9 (28,2) 35,0 (29,3)
>/= 2 locations 3 (5) 1 (2) loss of appetite 12,9 (27,2) 10,2 (18,8)
Histology grade obstipation 12,4 (25,8) 11,3 (18,2)
1 17 (27) 16 (27) diarrhea 6,5 (16,9) 4,0 (12,5)
2 25 (40) 29 (49) financial difficulty 9,7 (24,4) 13,0 (24,8)
3 16 (26) 12 (20) EORTC-QLQ BR23 CR TT
Unknown 4 (7) 2 (4) (n=62) (n=59)
Estrogen positive 54 (87) 48 (81) systemic treatment side effects 13,9 (14,2) 15,4 (16,0)
Progesterone positive 45 (73) 46 (78) body image 73,7 (28,6) 73,0 (30,9)
Her2 FISH positive 3 (5) 10 (17) future perspective 52,7 (29,9) 54,2 (29,0)
Adjuvant radio-chemotherapy (RT-CT) schedule arm symptoms 23,8 (22,6) 24,9 (21,6)
No CT 37 (60) 29 (49) breast symptoms 21,9 (18,6) 19,9 (16,6)
RT concurrent with CT 19 (30) 23 (39) CR (n=8) TT (n=13)
RT after CT (sequential)* 6 (10) 7 (12)* upset by hair loss 33,3 (35,6) 35,9 (39,6)
(one patient neo-adj CT)
CR (n=56) TT (n=54)
Chemotherapy type
sexual functioning 22,3 (23,2 25,0 (23,3)
Anthracycline without taxane 4 (16) 5 (17)
CR (n=28) TT (n=33)
Anthracycline with taxane 16 (64) 19 (63)
sexual enjoyment 56,0 (28,8) 55,6 (28,5)
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(a) Physical functioning (b) Role functioning

mean change from baseline +/- SE

Mean change from baseline +/- SE

110 110
100 100
90 90
80 80
70 70
60 60
50 50
40 40
T0 T1 T2 T3 T4 T5 T0 T1 T2 T3 T4 T5
n=121 n=121 n=121 n=101 n=66 n=34 n=121 n=121 n=121 n=101 n=66 n=34

(c) Cognitive functioning (d) Emotional functioning

Mean change from baseline +/- SE

mean change from baseline +/- SE

110 110
100 100
90 90
80 80
70 70
60 60
50 50
40 40
T0 T1 T2 T3 T4 T5 T0 T1 T2 T3 T4 T5
n=121 n=121 n=121 n=101 n=66 n=34 n=121 n=121 n=121 n=101 n=66 n=34

(e) Social functioning (f) Global Health Status

mean change from baseline +/- SE
mean change from baseline +/- SE

110 110

100 100

90 90

80 80
70 70
60 60
50 50
40 40
T0 T1 T2 T3 T4 T5 T0 T1 T2 T3 T4 T5
n=121 n=121 n=121 n=101 n=66 n=34 n=121 n=121 n=121 n=101 n=66 n=34
Figure 2 EORTC QLQ-C30.
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(a) Fatigue symptoms (b) Nausea & vomiting (c) Pain symptoms
mean change from baseline +/- SE

mean change from baseline +/- SE

mean change from baseline +/- SE
60 60 60
50 50 50
40 40 40
30 30 30
20 20 20
10 10 10
0 0 0
-10 -10 -10
T0 T1 T2 T3 T4 T5 T0 T1 T2 T3 T4 T5 T0 T1 T2 T3 T4 T5
n=121 n=121 n=121 n=101 n=66 n=34 n=121 n=121 n=121 n=101 n=66 n=34 n=121 n=121 n=121 n=101 n=66 n=34

(d) Dyspnea (e) Insomnia (f) Loss of appetite

mean change from baseline +/- SE

mean change from baseline +/- SE

mean change from baseline +/- SE

60 60 60

50 50 50

40 40 40
30 30 30
20 20 20
10 10 10
0 0 0
-10 -10 -10
T0 T1 T2 T3 T4 T5 T0 T1 T2 T3 T4 T5 T0 T1 T2 T3 T4 T5
n=121 n=121 n=121 n=101 n=66 n=34 n=121 n=121 n=121 n=101 n=66 n=34 n=121 n=121 n=121 n=101 n=66 n=34

(g) Obstipation (h) Diarrhea (i) Financial difficulty

mean change from baseline +/- SE

mean change from baseline +/- SE

mean change from baseline +/- SE

60 60 60
50 50 50
40 40 40
30 30 30
20 20 20
10 10 10
0 0 0
-10 -10 -10
T0 T1 T2 T3 T4 T5 T0 T1 T2 T3 T4 T5 T0 T1 T2 T3 T4 T5
n=121 n=121 n=121 n=101 n=66 n=34 n=121 n=121 n=121 n=101 n=66 n=34 n=121 n=121 n=121 n=101 n=66 n=34
Figure 3 EORTC QLQ-C30.

functioning in CR patients. On the last day of radiotherapy, months post-radiotherapy, there were clinically meaningful
the global health score was significantly worse in TT increases in the role- and social-functioning scores in TT
patients than CR patients (p = 0.0287) and the social func- patients (10.8 points for each score, Table 4). During the
tioning score was worse in TT patients than CR patients, period from 3 months to 2 years post-radiotherapy, there
but this difference was not significant (p = 0.0635). How- were faster improvements in the physical-, cognitive-, and
ever, analysis using repeated measurements of ANOVA emotional-functioning scores in TT patients than CR
with the Bonferroni correction did not show any significant patients, but these differences were not significant
differences in these scores between treatment arms. At 3 (Figures 2a, 2c, 2d). Figures 2a–f show that TT patients
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(a) Arm symptoms (b) Breast symptoms

mean change from baseline +/- SE

mean change from baseline +/- SE

60 60
50 50
40 40
30 30
20 20
10 10
0 0
-10 -10
T0 T1 T2 T3 T4 T5 T0 T1 T2 T3 T4 T5
n=121 n=121 n=121 n=101 n=66 n=34 n=121 n=121 n=121 n=101 n=66 n=34

(c) Systemic treatment side effects (d) Upset by hair loss

mean change from baseline +/- SE

mean change from baseline +/- SE

60 60
50 50
40 40
30 30
20 20
10 10
0 0
-10 -10
T0 T1 T2 T3 T4 T5 T0 T1 T2 T3 T4 T5
n=121 n=121 n=121 n=101 n=66 n=34 n=21 n=48 n=36 n=18 n=14 n=9
Figure 4 EORTC QLQ-BR23.

experienced greater long-term improvements than CR at 1 year post-radiotherapy, but this increase was not
patients in global health status and in all functioning scores significant.
except for social functioning, but these differences were Both treatment arms had the same breast symptom
not significant. and systemic side effect patterns during the follow-up
Figures 3a–i show that both treatment arms had the period (Figures 4b and 4c). On the last day of radiother-
same patterns of symptoms. Fatigue, nausea and vomit- apy, there were clinically meaningful increases in breast
ing, and constipation were increased on the last day of symptom scores in CR patients (12.4 points) and in sys-
radiotherapy and subsequently decreased over time; pain temic side effect scores in TT patients (11.2 points), and
had already decreased on the last day of radiotherapy these scores subsequently decreased over time. At 3 years
and subsequently decreased further over time; and after the completion of radiotherapy, the breast symptom
dyspnea, insomnia, diarrhea, and financial difficulty scores were increased in TT patients and continued to
fluctuated during the follow-up period. There were decrease in CR patients, but this difference between
clinically meaningful increases in fatigue scores in both treatment arms was not clinically meaningful (9.9 points,
treatment arms on the last day of radiotherapy (10.6 Table 5). The systemic side effects scores were still higher
points in CR patients and 13.1 points in TT patients, than baseline in both treatment arms at 3 years after
Table 5). The fatigue scores in both treatment arms radiotherapy. The degree of hair loss is incorporated into
subsequently decreased, with a clinically meaningful the systemic side effects score. Not all patients reported
reduction in TT patients at 3 months (12.2 points, Table 5). hair loss. Figure 4d shows a fluctuating hair loss score in
Figure 3a shows that the fatigue score eventually recovered both treatment arms.
better in TT patients than CR patients. Figures 5a and 5b show that there were no clinically
Figure 4a shows that the arm symptoms scores had meaningful changes in body image or future perspective
already decreased in both treatment arms on the last scores in either treatment arm. Both scores were slightly
day of radiotherapy. This score continued to decrease decreased on the last day of radiotherapy in both treatment
in CR patients, whereas it was higher in TT patients arms, and subsequently improved over time.
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(a) Body image (b) Future perspective

mean change from baseline +/- SE

mean change from baseline +/- SE

100 100

80 80

60 60

40 40

20 20

0 0
T0 T1 T2 T3 T4 T5 T0 T1 T2 T3 T4 T5
n=121 n=121 n=121 n=101 n=66 n=34 n=121 n=121 n=121 n=101 n=66 n=34

(c) Sexual functioning (d) Sexual enjoyment

mean change from baseline +/- SE

mean change from baseline +/- SE

100
100
80
80

60 60

40 40

20 20

0 0
T0 T1 T2 T3 T4 T5 T0 T1 T2 T3 T4 T5
n=104 n=103 n=106 n=87 n=56 n=28 n=61 n=46 n=61 n=53 n=34 n=17
Figure 5 EORTC QLQ-BR23.

Patients were given the option to decline answering the [19]. In this study, we analyzed all five functioning scores
entire section on sexual functioning, or any part of it. and nine symptom sclores in the QLQ C-30 questionnaire
Therefore, only patients who answered this section were and all four functioning scores and four symptom scores
included in the analysis. The question regarding sexual in the QLQ BR23 questionnaire. The UK Standardisation
enjoyment was only asked if the patient indicated that of Breast Radiotherapy (START) trials A and B [17-19]
they had been sexually active, and only a relatively small presented only three of the QLQ BR23 scores in their
proportion of patients answered this question (Table 5). analysis: breast symptoms, arm symptoms, and body image.
Figure 5c shows relatively stable sexual functioning As expected in breast cancer patients receiving radio-
scores in both treatment arms, which is in accordance therapy, patients in both treatment arms experienced a
with the relatively stable body image and future perspec- decrease in global health status score and all functioning
tive scores over time. As only a small number of patients scores on the last day of radiotherapy (Figures 2a–f,
answered the sexual enjoyment question, it is difficult to Table 4). This is consistent with the findings of the
draw any conclusions about trends in this score randomized study by Whelan et al. [39]. However,
(Figure 5d). Even though the sexual functioning scores another small study conducted by Lee et al. [38] reported
were stable in both TT and CR patients, the sexual enjoy- that radiotherapy did not affect the global health score
ment score increased in CR patients and slowly decreased compared with no radiotherapy in a randomized trial. In
in TT patients. our study, the reasons for the decrease in global health
score were most likely increased fatigue, breast symp-
Discussion toms, systemic side effects, nausea and vomiting, and loss
This is the first study to compare HRQOL between two of appetite, especially when patients received concomi-
adjuvant radiotherapy approaches for breast cancer, CR tant chemotherapy. This decrease in scores on the last
and TT. In November 2011, the median post-radiotherapy day of radiotherapy was approximately the same in both
follow-up time was 26 months (range 4–50 months). treatment arms, except that TT patients had significantly
Table 6 lists the recent studies comparing CR with TT. worse global health status scores and non-significantly
Most of these studies reported toxicity and control rates, worse social functioning scores than CR patients. This
and a few reported on cosmesis [15,19,20] and HRQOL difference might be due to more fatigue, nausea and
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Versmessen et al. BMC Cancer 2012, 12:495
Table 4 EORTC QLQ-C30 mean scores (SE) at each time point
CR &TT at T0 CR at T1 TT at T1 CR at T2 TT at T2 CR at T3 TT at T3 CR at T4 TT at T4 CR at T5 TT at T5
n=121 n=62 n=59 n=62 n=59 n=50 n=51 n=30 n=36 n=16 n=18
physical functioning 83,64 80,08 (1,64) 79,39 (2,03) 80,69 (1,70) 82,03 (2,18) 85,44 (1,96) 83,64 (1,97) 84,08 (3,50) 88,69 (1,88) 84,89 (3,29) 89,89 (3,19)
role functioning 68,32 66,93 (3,51) 64,99 (4,22) 75,70 (3,45) 75,79 a (4,26) 81,86 (4,62) 84,65 (4,45) 85,54 (5,73) 94,08 (5,38) 88,11 (9,41) 97,49 (8,67)
cognitive functioning 84,44 76,10 (2,82) 77,77 (3,02) 80,88 (2,50) 81,27 (2,94) 79,92 (3,60) 83,77 (3,40) 81,10 (4,26) 85,95 (3,51) 80,27 (3,23) 86,52 (5,67)
emotional functioning 76,65 75,96 (2,50) 75,44 (2,60) 75,56 (2,60) 78,52 (2,74) 76,65 (3,46) 77,32 (2,80) 76,65 (4,36) 80,69 (4,14) 77,69 (6,17) 81,34 (4,50)
social functioning 81,40 78,63 (2,10) 71,71 (3,08) 83,86 (2,64) 82,55 a (2,89) 89,39 (3,25) 84,74 (3,69) 92,52 (6,16) 90,50 (4,48) 92,86 (7,41) 89,74 (6,97)
global health status 68,11 67,00 (2,22) 59,02 (2,90) 68,52 (2,24) 65,81 (3,09) 72,28 (2,48) 72,61 (3,14) 72,28 (3,22) 76,19 (3,78) 74,36 (4,06) 78,53 (5,30)
fatigue 32,32 42,88 a (3,11) 45,45 a (3,83) 36,51 (2,45) 33,28 a (3,93) 30,93 (3,15) 27,21 (3,58) 24,55 (4,86) 18,86 (3,71) 21,91 (6,53) 14,96 (5,55)
nausea & vomiting 6,34 8,84 (3,16) 13,31 (3,20) 4,70 (2,77) 7,20 (2,88) 1,47 (3,29) 4,67 (2,62) 3,56 (3,30) −0,23 (3,55) 2,17 (5,99) −2,00 (6,63)
pain 24,52 21,74 (3,68) 24,21 (3,45) 20,42 (3,39) 21,93 (3,93) 16,53 (4,35) 19,18 (3,55) 17,85 (5,34) 15,43 (4,11) 15,14 (7,29) 12,02 (7,38)
dyspnea 13,22 17,11 (3,28) 17,47 (2,45) 24,15 (2,89) 22,42 (4,08) 18,08 (3,71) 15,22 (3,62) 14,33 (4,65) 14,23 (3,97) 19,47 (4,53) 15,31 (5,67)
insomnia 30,85 29,74 (3,96) 30,25 (4,10) 33,59 (4,43) 31,43 (4,67) 28,77 (4,59) 26,19 (4,26) 29,74 (6,08) 19,74 (4,74) 32,94 (6,43) 26,69 (9,56)
loss of appetite 11,57 11,01 (4,00) 20,66 (4,36) 8,84 (3,84) 11,57 (3,18) 0,46 (4,48) 6,90 (2,86) 11,57 a (6,19) 1,47 (4,23) 11,57 (8,05) −5,10 (5,27)
obstipation 11,85 14,07 (3,44) 19,12 (4,03) 12,94 (3,89) 18,74 (3,55) 14,62 (4,95) 9,85 (3,86) 5,18 (3,71) 9,83 (4,34) 7,68 (7,98) −2,74 a (5,24)
diarrhea 5,23 8,01 (2,89) 8,26 (1,99) 9,06 (3,41) 9,83 (2,52) 6,62 (2,97) 5,90 (1,78) 9,68 (3,48) 1,19 (1,92) 5,23 (0,00) 7,32 (4,78)
financial difficulty 11,29 15,18 (2,25) 12,51 (2,59) 14,57 (2,88) 11,87 (2,24) 15,46 (2,74) 8,63 (2,99) 14,63 (6,26) 5,23 (4,22) 15,46 (4,17) 17,54 a (7,59)
a
Indicates more or equal to ten-point difference from previous time point.
T0: baseline, T1: last day RT, T2: 3 months post-RT, T3: 1 year post-RT, T4: 2 years post-RT, T5: 3 years post-RT.

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Table 5 EORTC QLQ-BR23 mean scores (SE) at each time point
CR & TT at T0 CR at T1 TT at T1 CR at T2 TT at T2 CR at T3 TT at T3 CR at T4 TT at T4 CR at T5 TT at T5
n=121 n=62 n=59 n=62 n=59 n=50 n=51 n=30 n=36 n=16 n=18
arm symptoms 24,33 21,00 (2,50) 18,07 (2,32) 21,24 (2,82) 18,01 (2,08) 22,02 (3,73) 26,33 (4,27) 19,89 (5,10) 19,96 (4,40) 11,14 (5,76) 18,78 (6,49)
breast symptoms 20,94 33,30 a (2,78) 29,57 (2,74) 23,67 (2,58) 24,10 (2,35) 17,99 (3,17) 15,94 (2,52) 14,55 (4,24) 12,60 (3,30) 6,87 (5,63) 16,77 (4,99)
body image 73,35 69,60 (2,14) 70,62 (2,49) 73,21 (2,48) 77,80 (2,55) 74,74 (3,67) 77,51 (2,87) 73,62 (5,76) 78,40 (4,93) 74,91 (7,02) 79,08 (7,36)
future perspective 53,44 57,33 (3,64) 51,02 (3,44) 58,36 (3,38) 58,62 (3,26) 61,78 (4,03) 65,44 (3,53) 64,55 (5,84) 64,55 (6,27) 59,69 (7,59) 68,03 (10,08)
a
systemic treatment side effects 14,64 22,50 (1,87) 25,81 (2,83) 22,52 (2,06) 21,21 (2,88) 18,01 (2,20) 17,88 (2,57) 19,40 (3,19) 13,20 (2,95) 17,62 (4,80) 15,24 (4,28)
n=21 n=22 n=26 n=16 n=20 n=8 n=10 n=8 n=6 n=3 n=3
upset by hair loss 34,92 48,25 a (8,16) 27,51 (9,26) 23,81 a (11,11) 40,48 a (5,56) 46,02 a (11,10) 28,25 a (16,33) 1,62 a (0,00) 23,81 (29,40) 34,92 a (0,00) 34,92 a (0,00)
n=104 n=53 n=50 n=53 n=53 n=42 n=45 n=26 n=30 n=13 n=15
sexual functioning 23,85 21,02 (2,68) 23,52 (3,45) 24,48 (3,04) 22,60 (3,36) 24,65 (3,50) 24,59 (2,90) 21,85 (4,44) 27,19 (3,61) 25,14 (6,92) 21,63 (5,36)
n=61 n=23 n=23 n=29 n=32 n=24 n=29 n=15 n=19 n=8 n=9
sexual enjoyment 55,74 53,98 (5,39) 47,40 (3,31) 48,16 (5,77) 50,61 (5,45) 61,29 a (4,86) 49,94 (4,98) 64,07 (5,98) 48,59 (5,16) 62,40 a (6,67) 46,21 (9,52)
a
Indicates more or equal to ten-point difference from previous time point.
T0: baseline, T1: last day RT, T2: 3 months post-RT, T3: 1 year post-RT, T4: 2 years post-RT, T5: 3 years post-RT.

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Versmessen et al. BMC Cancer 2012, 12:495
Table 6 Hypofractionated radiotherapy studies
Trial Period n Hypofraction schedule SIB Mastectomy Regional nodes IMRT/ IGRT Chemotherapy Cosmesis HRQOL
UK Start A [17,19] 1998-2002 2236 3 Gy x 13 F/ 5 weeks No Yes Yes NS Yes Yes Yes
3.2 Gy x 13 F/ 5 weeks
UK Start B [18,19] 1999-2001 2215 2.67 Gy x 15 F/ 3 weeks No Yes Yes NS Yes Yes Yes
Ontario [15] 1993-1996 1234 2.66 Gy x 16 F/ 3 weeks No No No NS Yes Yes No
Egypt NCI [20] 2002-2003 30 2.66 Gy x 16 F/ 3 weeks No No No NS No Yes No
UK FAST [21] 2004-2007 915 5.7 Gy x 5 F/ 5 weeks ? No No Yes No No No
6 Gy x 5 F/ 5 weeks
Hopital Necker (*) [22] 1982-1984 230 5.75 Gy x 4 F/ 17 days No Yes ? NS Yes No No
Royal Marsden Hospital [23] 1986-1998 1410 3 Gy x 13 F/ 5 weeks 3.3 No No Yes NS No No No
Gy x 13 F/ 5 weeks
Lahore [24] 1998-2004 300 5.4 Gy x 5 F/ 1 week 3.5 No Yes Yes NS Yes No No
Gy x 10 F/ 2 weeks
2.66 Gy x 15 F/ 3 weeks
UZ Brussel 2007-2011 121 2.8 Gy [SIB 3.4 Gy]x15 Yes Yes Yes Yes Yes No Yes
F/ 3 weeks
NS: not stated.

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vomiting, loss of appetite, and systemic side effects in TT more frequent in TT patients (49%) than CR patients
patients than CR patients the end of radiotherapy (31%), but the arm symptom scores were comparable
(Figures 2 and 3, Table 4). This might be partially between treatment arms (CR: 23.8 (± 22.6) vs. TT:
explained by the higher proportion of TT patients who 24.9 (± 21.6). The arm symptom scores had already
received concomitant chemotherapy (39%) compared decreased in both treatment arms on the last day of
with CR patients (30%). radiotherapy, and subsequently continued to decrease in
Fortunately, the decreases in global health status and CR patients, whereas the score was higher at 1 year post-
functioning scores were only temporary, and these scores radiotherapy in TT patients. None of these differences were
subsequently improved during the follow-up period, significant. Our findings are in accordance with those of
except that CR patients continued to have worse cognitive the START trial [19], which found that arm symptom
functioning at 3 years post-radiotherapy (Figures 2a–f). scores were highest at baseline and then decreased signifi-
At 3 months post-radiotherapy, there were clinically cantly, and that there were no significant differences in
meaningful increases in role- and social-functioning scores between the treatment arms.
scores in the TT group (Table 4). During the period from Both treatment arms had quite a large increase in
3 months to 2 years post-radiotherapy, there were faster breast symptom scores on the last day of radiotherapy,
improvements in the physical-, cognitive-, and emotional- which was clinically meaningful in CR patients, and
functioning scores in TT patients than CR patients these scores subsequently decreased over time. These
(Figures 2a, 2c, 2d). No specific reason was identified for findings are consistent with the common acute side
these (non-significant) differences, except that CR patients effects of radiotherapy, and are normally transient
were slightly older than TT patients (mean age 58 years [38,39,45-47]. There was a greater increase in the breast
vs. 55 years). The proportion of patients aged > 65 years symptom score on last day of radiotherapy in CR
was 34% in the CR group and 22% in the TT group. patients than TT patients, but this difference was not
At 3 years post-radiotherapy, there were greater significantly different. This could partially be explained
improvements in the global health status score and all by the daily positioning at mm-level by the tomotherapy
functioning scores (except social functioning) in TT system [48]. Taher et al. [20] also found no significant
patients than CR patients, but these differences were not differences in acute skin reactions or cosmetic appear-
significant. Physical-, role-, and cognitive-functioning ance between the two treatment arms. The START trial
scores were between 5.0 and 9.4 points higher in TT [19] found that the BR23 breast symptom score declined
patients than CR patients (Table 4). significantly from baseline to 5 years for all radiotherapy
After a temporarily increasing on the last day of radio- regimens, but there was no significant difference
therapy, the fatigue scores in both treatment arms between treatment arms. A randomized trial by Whelan
decreased during the follow-up period. This is consistent et al. [15] which compared CR and TT schedules used the
with the findings of other studies [38-42] in which EORTC Cosmetic Rating System to measure late radiation
fatigue was the most commonly reported symptom after toxicity. They concluded that the more convenient
radiotherapy. The increase in the fatigue score on the hypofractionated schedule appeared to be an acceptable
last day of radiotherapy was clinically meaningful in both alternative to CR. They found no differences between the
treatment arms. This score had already decreased at 3 treatment arms at 3 and 5 years after randomization, and a
months post-radiotherapy in both treatment arms, and comparable cosmetic outcome at 10 years after treatment
the decrease in TT patients was clinically meaningful [16]. Ongoing follow-up in our study group will determine
(Table 5). There were no significant differences in fatigue long-term breast symptom scores in both treatment arms,
scores between treatment arms at any time points. As which will be reported in the future.
mentioned above, fatigue was one of the factors causing The systemic side effects scores were increased on the
decreased global health status and functioning scores. It last day of radiotherapy in both treatment arms, and the
has been reported that exercise is effective in helping to increase was clinically meaningful in TT patients. This
overcome fatigue during radiotherapy. Patients who increase was most likely due to concomitant chemotherapy.
exercise during radiotherapy have better physical func- There was a subsequent slow decrease in this score in both
tioning and less fatigue, anxiety, and insomnia than treatment arms. However, this score in was still higher than
patients who do not exercise [43,44]. baseline at 3 years post-radiotherapy in both treatment
The HRQOL questionnaires were completed by CR arms. This could be explained by the administration of
patients an average of 42 days after surgery and by TT hormonal therapy to most patients for 5 years (86% of CR
patients an average of 47 days after surgery. Patients patients and 81% of TT patients) and the administration of
were not yet fully recovered from their breast surgery at herceptin to some patients for 1 year (5% of CR patients
that time, which could explain the higher pain and arm and 17% of TT patients) after the completion of
symptom scores at baseline. Axillary node dissection was radiotherapy.
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Both treatment arms shared almost the same pattern different between treatment arms (p = 0.0287). However,
of body image and future perspective scores, and there when the Bonferroni correction for multiple testing was
were no significant differences between groups at any of applied, this difference was no longer significant. This
the time points. Even though patients had undergone could be explained by the small sample size, as a larger
MA or segmentectomy, and some patients had also sample size may be needed to demonstrate significant
undergone chemotherapy, these scores decreased only differences.
slightly at the end of radiotherapy in both treatment Fourth, information regarding sociodemographic factors
arms, and subsequently improved and then remained (marital status, income, occupation, etc.), which has been
stable over time. This was consistent with the relatively found to be related to QOL in cancer patients, was not
stable sexual functioning scores in both treatment arms gathered. Such sociodemographic factors should be consid-
during the follow-up period. Our findings are consistent ered in future trials, especially when evaluation of HRQOL
with those of the START trial [19], which found that is the main objective.
body image scores were similar between treatment arms
over time. They also found a significant improvement in Conclusion
body image score in all treatment arms over time, Our study is the first to compare HRQOL between CR
compared with the baseline score. and TT using the TomotherapyW treatment system. We
found that TT patients had a faster improvement in
Limitations QOL, role- and cognitive-functioning, and fatigue after
The HRQOL questionnaire provides patient-reported radiotherapy than CR patients. The inconvenience of
symptom and functional status, and enhances clinical prolonged daily treatments substantially contributes to
decision making by considering the benefits and toxicity the decreased QOL in breast cancer patients treated
of treatment [49]. The EORTC QLQ-C30 and BR23 with radiotherapy. Our results confirm that radiotherapy
questionnaires were included in this randomized trial of using a shorter fractionation schedule may reduce the
CR and TT to provide further information. The primary burden of treatment and have important QOL benefits
endpoint of the trial was pulmonary or cardiac toxicity, and for breast cancer patients.
the secondary endpoint was locoregional recurrence. This This research was funded by the Foundation against
trial has some limitations. First, the sample size is smaller Cancer, a public interest foundation (SCIE2006-30,
at 2 and 3 years post-radiotherapy than at earlier time ref.nr ANI47).
points, as the median follow-up time is 26 months (range
4–50 months). This limits the ability to draw conclusions Additional file
regarding HRQOL at these time points. However, the avail-
able questionnaire results are presented in the tables and Additional file 1: adjusted_mean_scores.xls.
figures to illustrate trends, especially as one of the main
concerns regarding radiotherapy is long-term toxicity. The Competing interests
final results of the trial can be reported after all patients The authors declare that they have no competing interests.
have completed 3 years of follow-up after radiotherapy.
Authors' contributions
Second, some data are missing due to various reasons: VVH and GS made substantial contributions to the conception and design of
withdrawal of patients from the study, refusal by several the study. VVH, HV, HVP, GM, MV, and NA made substantial contributions to
patients to complete the questionnaire on the last day of the acquisition of data. HV and VVH made substantial contributions to the
analysis and interpretation of data, and were involved in drafting the
radiotherapy, and reluctance by patients to answer sex- manuscript. VVH, HV, GS, and MDR critically revised the manuscript for
related questions. In an ideal situation, there would be important intellectual content. All authors read and approved the final
100% compliance in questionnaire completion at all time manuscript.
points, and the repeated measurements of ANOVA could Author details
be used for analysis. Since ANOVA only takes patients 1
Department of Radiation Oncology, UZ Brussel, Vrije Universiteit Brussel,
with complete datasets into account, there would have to Laarbeeklaan 101, 1090 Jette, Brussels, Belgium. 2Radiation oncology, Geneva
University Hospital, Geneva, Switzerland. 3Department of Physical Therapy,
be no missing values or withdrawals from the study before UZ Brussel, Breast Clinic, Brussels, Belgium. 4Department of Physical Therapy,
3 years of follow-up had been completed. In this study Vrije Universiteit Brussel, Brussels, Belgium.
with incomplete data and a limited number of patients at
Received: 4 January 2012 Accepted: 18 October 2012
2 and 3 years of follow-up, the simpler Student’s t-test was Published: 25 October 2012
used to compare HRQOL scores between the treatment
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doi:10.1186/1471-2407-12-495
Cite this article as: Versmessen et al.: Health-related quality of life in
survivors of stage I-II breast cancer: randomized trial of post-operative
conventional radiotherapy and hypofractionated tomotherapy. BMC
Cancer 2012 12:495.

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