sc0 ls0 ws4">(ipsilateral breast-PTV): V15 50%; heart: V3 10%; ipsilateral lung: V10 20%; controlateral lung: V5 10% and
controlateral breast: maximum dose 1 Gy. We required PTV coverage of 90%. Patient set-up was verif ied ever y day
before treatment using portal images. No tumour bed boost was delivered. Clinical assessments of early normal tissue
reaction were carried out every day during radiotherapy and 10 days after the end of the treatment. After radiotherapy,
we visited all patients every 3 months during the first 2 years and ever y six month thereaf ter. Fron tal and lateral p ictur es
of the breast were taken on the first day of treatment (baseline), at the end of treatment, 10 days after the end of treat-
ment and at the first follow-up. Any change in breast appearance compared with the baseline picture was scored on a
four-point RTOG for acute and late radiation morbidity scoring scale. Results: No local or distant recurrences were ob-
served and then confirmed by mammograms performed every year and breast ultrasound performed every six months.
For acute and late toxicity, only 2 patients developed acute effects at the end of the treatment. Conclusion: The clinical
outcomes observed in ten patients demon strate a good feasibility of the schedu le adopted both in terms of tumour con-
trol and acute and late toxicity, with good co smetics results. Long term follow-up and a large number of patien ts will be
needed for full evaluation.
Keywords: Breast Cancer; Partial Breast I rradiation; Hy pofractioned
1. Introduction
In the past decades, a major change has occurred in the
local management of breast cancer, from a mutilating
therapeutic approach to a conservative approach with
osmetic and functional aims. The use of conservative
surgery combined with whole-breast irradiation has been
established as a valid alternative to mastectomy. The
Copyright © 2012 SciRes. JCT
Hypofractioned Radiation Therapy in the Treatm ent of Partial Breast: 30 Gy in Five Consecutive Fractions
1152
conservative approach consists in the removal of the tu-
mor, followed by 5 - 7 weeks of daily whole breast irra-
diation (total dose of 50 Gy delivered to the entire breast
and 10 - 16 Gy boost delivered to the tu mor bed). A dis-
advantage of this approach is the increase of the non-
breast-cancer-related morbidity due to irradiation of non-
target tissue [1,2] and the prolonged duration of treat-
ment.
Observation from earlier studies demonstrated that
distant recurrences, in quadrants other than that origin-
nally involved by the tumour, occur infrequently (range,
0.6% - 6%) [3-13].
A strategy that aims at improving the therapeutic ratio
and at reducing treatment duration, in women with rela-
tively low risk of local tumour relapse, involves limited
high-radiation doses to the index quadrant and reduces
doses to breast tissue remote from the tumour bed
[14,15]. Radiobiological analysis of clinical data has
shown that breast adenocarcinomas have an
/
ratio of
4 Gy, like late reacting normal tissues. Consequently,
hypo-fractionation in breast cancer may have a reason-
able radiobiological support. Recent prospective studies
have thus explored the techniques of only treating the
tumor bed of the breast, i.e. partial breast irradiation
(PBI), for patients with early-stage breast cancer using
different technical approaches [16-24]. These studies
have investigated the use of low-dose-rate and high-dose-
rate brachytherapy and the use of External-Beam Radio-
therapy (EBRT) for partial breast irradiation.
The purpose of this study is to evaluate feasibility,
tumor control and acute and late toxicity of a specific
hypo-fractionated 3D-CRT in the treatment of partial
breast in postmenopausal patients with early breast can-
cer, using five consecutive 6 Gy fractions.
2. Material and Methods
2.1. Patients
Sarting on January 2008 ten patients, out of all those who
underwent breast conservative surgery for invasive breast
carcinoma, received postoperative radiotherapy delivered
to the index quadrant only after having provided full
written informed consent. The in clusion criteria are listed
in Table 1. All of the patients enro lled in the study were
in postmenopausal status, age ranged from 70 to 84 years
(median 76 years). Eight patients had Stage I invasive
ductal carcinoma and two patients had Stage I invasive
lobular carcinoma. Tumour size ranged between 10 mm
and 20 mm, with a median of 14 mm. Seven patients had
positive estrogenic receptors and received Tamoxifen, no
patients received chemotherapy. All patients underwent
lumpectomy with negative surgical margins. The sur-
geons were requested to place clips at the borders of the
surgical bed, using a minimum of six clips. The presence
of surgical clips represented a selection criteria to avoid
geographic misses. Of the ten patients, five were treated
for left breast disease, and five for right breast disease.
The main patients’ characteristics are listed in Table 2.
Clinical assessments of early normal tissue reaction were
carried out every day during radiotherapy and after 10
days from the end of the treatment. After radiotherapy,
all of the patients underwen t a clinical examination every
3 months during the first two years and every six months
subsequently. Median follow-up from the end of irradia-
tion was 21.1 months (range, 10 - 48 m ont h s ).
Bilateral mammogram, and bilateral breast ultrasound
were obtained once a year during follow-up. An echo-
cardiogram was obtained in patients with left breast can-
cer. Frontal and lateral pictures (depending on the tumour
Table 1. Inclusion criteria.
Age > 70 aa
Patological stage pT1 pN0
Surgical margin negative (>2 mm)
Clips placed in tumor bed
Full informed consent from patient
No lymphovascular invasion
Unifocal
Intraductal component < 25%
ER and PgR positive
ER = Esrogen Receptor; PgR = Progesteron Receptor
Table 2. Baseline patient characteristics (n = 10).
Characteristics Patients
Breast side
Right 5
Left 5
Tumor estrogen receptor status
Positive 10
Negative 0
Tumor progesterone receptor status
Positive 10
Negative 0
Tumor Her-2 status
Score 0 3
Score 1 2
Score 2 2
Score 3 1
Unknown 2
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Hypofractioned Radiation Therapy in the Treatm ent of Partial Breast: 30 Gy in Five Consecutive Fractions 1153
site) of the breast were taken on the first day of treatment
(baseline), at the end of the treatment, after 10 days from
the end of the treatment and at the first follow-up visit
(Figure 1). Any changes in breast appearance were com-
pared with the baseline picture and was scored on a four-
point RTOG for acute and late radiation morbidity scor-
ing scale.
2.2. Patient Positioning and Image Acquisition
Patients underwent Computed Tomography (CT) imag-
ing in supine position with a commercial breast board
immobilization device in order to keep th eir arms raised.
CT scanning was performed with a 0.5 cm scan spacing.
The scans extended to completely cover the involved
breast, lungs, and a 5 cm margin in the cranial and caudal
directions.
2.3. Treatment Planning
The prescribed do se to the 95% isodose was 3000 cG y in
5 fractions (600 cGy/fr) in 5 consecutive days. All pa-
tients were treated in the supine position. The treatment
was developed using Precise Plan Treatment Planning
System® (Elekta, Crowley, United Kingdom) and four
no-coplanar 6 MV photon fields were used (Elekta Pre-
cise® Linear Accelerator, Crawley, United Kingdom).
The planning volumes were defined as follows: the
gross targ et volume (GTV) was contou r ed on th e su rgical
clips placed during surgery, the clinical target volume
(CTV) was draobtained with a uniform 1 cm three di-
mensional margin around the surgical clips (GTV) and
Figure 1. Photo captured 12 month after the end of radio-
therapy.
the planning target volume (PTV) was defined as the
CTV plus a uniform 1 cm three dimensional margin. The
PTV was limited to 3 mm from the skin surface and 3
mm from the lung-chest wall interface. As organ at risk
(OAR) we considered the ipsilateral and contralateral
breast, the ipsilateral and controateral lung and the heart.
The heart was contoured from the first CT slice below
the pulmonary artery to the apex inferiorly. Both lungs
were contoured in their entirety (Figure 2).
The constraints used are listed in Table 3. Less than
20% of the ipsilateral lung had to receive 30% of the
prescribed dose (V10 20%); less than 10% of the con-
tralateral lung had to receive 15% of the prescribed dose
(V5 10%); less than 10% o f the con toured h eart volu me
had to receive 10% of the prescribed dose (V3 10%);
maximum dose to the controlateral breast was <1 Gy. We
also attempted to maintain the 50% volume of the ipsi-
lateral breast (IB) minus planning target volume (PTV)
(IB-PTV), to receive less than 50% (15 Gy) of the pre-
scribed dose. Patient set-up was verified every day
Figure 2. Target and organ at risk (OAR) conturing. Pink is
the Gross Tumor Volume (GTV); Light green is the Clinical
Target Volume (CTV); Red is the Planning Target Volume
(PTV); Blue is the ipsilateral breast; Cyan is the contro-
lateral breast; Orange is the heart; Violet is the ipsilateral
lung; Green is the controlater al lung.
Table 3. Constraints for OAR.
OAR Constraints
Ipsilateral Lung V10 < 20%
Controlateral Lung V5 < 10%
Heart V3 < 10%
Ipsilateral Breast-PTV V15 < 50%
Controlateral Breast <1 Gy
OAR = organs at risk; PTV = planning target volume
Copyright © 2012 SciRes. JCT
Hypofractioned Radiation Therapy in the Treatm ent of Partial Breast: 30 Gy in Five Consecutive Fractions
Copyright © 2012 SciRes. JCT
1154
before treatment, using orthogonal portal images (Gantry
0˚ and 90˚, coach 0˚) and 2 portal images of the treatment
beams.
3. Results
The target coverage was acceptable for all patients. The
dose-volume constraints of OARs were always respected.
Only in 1 patient the uninvolved breast dose-volume
constraint was not respected given that the 82% of unin-
volved breast volume received more than 15 Gy (Table
4). This was probably due to the anatomic positio n of the
tumour (supero-internal quadrant) and to the small vol-
ume of the breast (435 cc).
We observed grade 1 acute skin toxicity (Radiation
Therapy Oncology Group scale) developing during the
first week after the end of treatment in 2 patients (20%).
No patients had late skin toxicity. No difference was ob-
served between patient who received or not Tamoxifen.
No patients experienced a reduction in left ventricular
ejection fraction or in forced expiratory volume. To date
no local recurrence was observed.
4. Discussion
In the far past years the treatment for breast cancer was
mastectomy while actually the gold standard for patients
with early-stage breast cancer is conservative with a
cosmetic and functional surgical approach followed by
radiotherapy to increase local control and overall survival
[25]. The standard radiation therapy treatment has a du-
ration of 5 - 7 weeks and the delivered dose is 50 Gy in
25 daily fractions delivered to the entire breast plus 10
Gy boost to the tumour bed. This approach has the dis-
advantage of prolonged duration, which can be a serious
inconvenience for patients that have to travel every day
for a prolonged period to the radiation therapy centre,
especially for the elderly ones. Several clinical trials have
demonstrated that shorter radiation schedules, justified
by radiobiological models, delivering larger doses per
fraction in shorter periods of time [26-30] offer equiva-
lent local control and same acute and late toxicity com-
pared to the standard radiation therapy courses. Whelan
et al. [27] examined whether a 22-day radiation therapy
fractionation schedule was as effective, on the local con-
trol, as the traditional 35-day schedule in 1934 women
with invasive breast cancer who underwent BCS with
pathologically clear resection margins and negative axil-
lary lymph nodes. Patients were randomly assigned to
receive 42.5 Gy in 16 fraction over 22 days or 50 Gy in
25 fraction over 35 days to the whole breast. With a me-
dian follow-up of 12 years no differences in local recu-
rences, disease free or overall survival rates and cosmetic
results were recorded. They concluded that the more
convenient 22-d ay fractionation schedule app ear to be an
acceptable alternative to the 35-day schedule. The
START A (Standardization of Breast Radiotherapy) from
the UK trial has shown that 41.6 Gy in 13 fractions or 39
Gy in 13 fractions are similar to the standard treatment
(50 Gy in 25 fractions) in terms of local-regional tumour
control and late normal tissue effects [28]; this results are
consistent with those of the START B trial, which has
shown that a radiation schedule of 40 Gy in 15 fractions
offers equivalent results to the standard schedule of 50
Gy in 25 fractions [29]. Livi et al. [30] evaluated the in-
cidence of loco-regional recurrence and the cosmetic
results in a group of 539 patients with breast cancer
treated with a hypo-fractionated schedule after conserva-
tive surgery. The dose delivered was 44 Gy (2.75 daily
fraction) and the tumour bed boost was 10 Gy (Electron
beam). They obtained a low local relapse and good tol-
erance (76.4% patients showing grade 0 - 1 late toxicity,
20.9% patients grade 2 and 2.5% patients grade 3; no
patients with grade 4 toxicity was observed). All this
fraction regimen do not represent the limits of hypofrac-
tionation for whole breast radiotherapy. The UK FAST
trial [31] randomized 915 women 50 years old or older
with node-negative tumours, following breast conserva-
tive surgery, to receive whole breast radiotherapy deliv-
ered using 3D dosimetry to a total dose of 50 Gy in 25
fractions (control) versus 28.5 Gy or 30 Gy in 5 once-
weekly fractions of 5.7 Gy or 6.0 Gy with no tumour bed
boost. The first analysis showed good results in terms of
late normal tissue responses and tumour control. A
schedule of 30 Gy in 5 fractions over 15 days to the
Table 4. DVH analysis: OAR doses.
OAR Patient
1 Patient
2 Patient
3 Patient
4 Patient
5 Patient
6 Patient
7 Patient
8 Patient
9 Patient
10
Hearth: dose to 10% volume 0.5 Gy 1 Gy 0.5 Gy1 Gy 2 Gy 0.5 Gy1 Gy 0.1 Gy 1 Gy 1 Gy
Ipsilateral Lung: dose to 20% volume 1 Gy 4 Gy 2 Gy 1.5 Gy4 Gy 1 Gy 2 Gy 1 Gy 1 Gy 2 Gy
Controlateral Lung: dose to 10% volume 0.1 Gy 0.4 Gy0.1 Gy0.1 Gy1 Gy 0.1 Gy0.1 Gy 0.1 Gy 0.1 Gy0.1 Gy
Controlateral Breast: dose to whole organ 0.2 Gy 0.6 Gy0.5 Gy0.1 Gy0.9 Gy0.1 Gy0.1 Gy 0.1 Gy 0.1 Gy0.3 Gy
Ipsilateral Breast-PTV: dose to 50% volume 4.5 Gy 4 Gy 27 Gy10 Gy7 Gy 12 Gy14 Gy 5 Gy 6 Gy 10 Gy
DVH = dose-volume histogram; OAR = organ at risk.
Hypofractioned Radiation Therapy in the Treatm ent of Partial Breast: 30 Gy in Five Consecutive Fractions 1155
whole breast, using 3D dosimetry, reported very mild
acute reactions and acceptable 2-year outcome in terms
of change in breast appearance compared to a matched
sample of patients treated to 50 Gy in 25 fractions [32].
Observations that th e vast majority of ipsilateral breast
recurrences occur in close proximity to the lumpectomy
cavity have led to question the opportunity of elective
partial breast irradiation (PBI), treating only the tumor
bed. Baglan KL et al. [21] presented a 3D-CRT tech-
nique for partial breast irradiation in supin e position. The
prescribed dose was 34 Gy in 5 patients and 38.5 Gy in 4
patients, delivered in 10 fractions twice daily over 5
consecutive days. They reported an excellent patient tol-
erance with minimal acute toxicity. No skin changes
were noted during treatment, and at the in itial 4 - 8-week
follow-up examination, only mild localized hyperpig-
mentation and/or erythema were observed. Formenti S. et
al. [22] reported the clinical and dose-volume histogram
results in 47 patients accrued to a 3D-CRT accelerated
partial breast irradiation (APBI) protocol in the prone
position. The prescribed do se was 30 Gy at 6 Gy/fraction
delivered in 5 fractions within 10 days. The lun g and the
heart were spared by treating in the prone position. Acute
toxicity was mild (Grade 1 - 2 erythema). With a median
follow-up of 18 month only grade 1 late toxicity occurred,
and no patient developed local recurrence. Livi L. et al.
[23] compared, in a randomized phase III clinical trial,
conventional (tangential field) fractionated whole breast
treatment (Arm A, 128 patients) with accelerated partial
breast irradiation plus intensity-modulated radiotherapy
(Arm B, 131 patients). For patients in Arm B (PBI) the
prescribed dose was 30 Gy in 5 fractions, 6 Gy/fraction.
The rate of Grade 1 and Grade 2 acute skin toxicity was
respectively 22% and 19% in Arm A (Radiation Therapy
Oncology Group scale). The tolerance in Arm B was
excellent with only 5% Grade 1 and 0.8% Grade 2 acute
skin toxicity. With a median 9.6 years of follow-up An-
tonucci et al. [24] compared a group of patients treated
with APBI vs a similar group of patients treated with
whole breast irradiation to determine the potential dif-
ferences in local recurrence rates according to the vol-
ume breast tissue irradiated. The cumulative incidence of
ipsilateral breast tumour recurrences at 10 years was 5%.
On matched-pair analysis, the rate of ipsilateral breast
tumour recurrences was not significantly statistically
different between the patient groups. These data suggest
the potential efficacy of APBI in selected low-risk pa-
tients. Different studies [33-38] demonstrate that breast
cancer has the same radiobiological behaviour of late
reacting normal tissue (
/
ratio of 4 Gy), late effects
(fibrosis and telangiectasia) have
/
ratio of 2 Gy and 4
Gy respectively, and acute reaction (erythema and des-
quamation) 8 Gy and 11 Gy respectiv ely. To co mpare th e
fractionation schedule of 30 Gy delivered in 5 consecu-
tive days with the conventional fractionation of 50 Gy
delivered in 32 days, the Biologically Effective Dose
(BEDs) has to be calculated assuming cell repopulation
during treatment. The BEDs formula taking into account
cell repopulation is the fo llow:



BED1ln 2.
pot k
nddTT T
 

 


were n is the number of fraction, d is the dose per frac-
tion,
/
is a tissue-specific and effect-specific parameter
associated with the linear-quadratic model, T is the ov er-
all time of radiotherapy (days, with first day counted as
day 0), Tk is the Kick-off time of repopulation in the tis-
sue of interest (21 days) [26,39,40],
is the radiosensi-
tivity coefficient of non recoverable damage (0.35) [34,
41] and Tpot is the potential doubling time of cancer re-
population cells (3 days) [4 2,43]. This correction for cell
proliferation causes the tumour standard treatment BED
values to decrease by 3 Gy (from 75 Gy to 72 Gy). The
BED values of PBI schedule were calculated with the
standard equation:

BED 1.nd d


considering that the treatment is accomplished within a
period that is shorter than th e lag period. Table 5 lists the
BEDs for tumour control, the early responses (erythema
and desquamation), and the late responses (telangiectasia
and fibrosis). The BEDs for normal tissue acute effects
were generally lower for the 30 Gy hypo-fractionated
schedule than for the standard 50 Gy treatment, indicat-
ing that the risk of radiation-induced complications
should be lower in the PBI schedule.
According with the literature experience [22,23,31,32]
and to our very preliminary results we want to increase
our experience of a 30 Gy (6 Gy/fraction) fractionation
schedule delivered in 5 consecutive days, with three-
dimensional conformal radiotherapy (3D-CRT), without
considering an intermediate time period in order to have
a complete cellular recovery between fractions (>24 h).
The proposal of such a simpler and less expensive tech-
nique, compared to Intensity Modulated Radiotherapy
Table 5. Biologically effective doses (BED).
α/β (Gy) Standard
(50 Gy) Hypofractionated
(30 Gy)
Erythema 8 63 53
Desquamation11 59 46
Teleangectasia4 75 75
Fibrosis 2 100 120
Tumor 4 75 75
Tumor* 4 72 75
*Taking into account cell proliferation during course of treatment.
Copyright © 2012 SciRes. JCT
Hypofractioned Radiation Therapy in the Treatm ent of Partial Breast: 30 Gy in Five Consecutive Fractions
1156
(IMRT), with an excellent coverage of the target volume
and excellent results in term of dose-volume histogram
for OARs for all patients (Table 4), seems feseable but
deserves more experience and long term results before
beeing delivered to a larg er population of patients.
5. Conclusion
The clinical results observed in ten patients demonstrated
a good feasibility of the schedule adopted both in terms
of tumour control rate and acute and late toxicity, with
good cosmetics results. Encouraged by the protocol study
of the University of Florence [23] (where the age inclu-
sion criteria is >40 y), we propose to go on with this
study delivering this sch edu le to patients younger than 70
years in order to achieve a larger number experience.
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