Sie sind auf Seite 1von 8

Radiotherapy and Oncology 114 (2015) 4249

Contents lists available at ScienceDirect

Radiotherapy and Oncology


journal homepage: www.thegreenjournal.com

Systematic review

Accelerated partial irradiation for breast cancer: Systematic review


and meta-analysis of 8653 women in eight randomized trials
Gustavo Nader Marta a,b,, Cristiane Runo Macedo d, Heloisa de Andrade Carvalho a,c,
Samir Abdallah Hanna a, Joo Luis Fernandes da Silva a, Rachel Riera d
a
Department of Radiation Oncology, Hospital SrioLibans, Brazil; b Department of Radiation Oncology, Instituto do Cncer de So Paulo (ICESP), Faculdade de Medicina da
Universidade de So Paulo, Brazil; c Department of Radiation Oncology, Instituto de Radiologia do Hospital das Clnicas da Faculdade de Medicina da Universidade de So Paulo, Brazil;
d
Brazilian Cochrane Center and Discipline of Emergency Medicine and Evidence-Based Medicine, Universidade Federal de So PauloEscola Paulista de Medicina (UNIFESPEPM),
Brazil

a r t i c l e

i n f o

Article history:
Received 9 July 2014
Received in revised form 4 November 2014
Accepted 4 November 2014
Available online 2 December 2014
Keywords:
Breast cancer
Breast-conserving therapy
Whole-breast irradiation
Accelerated partial breast irradiation

a b s t r a c t
Background and purpose: Accelerated partial breast irradiation (APBI) is the strategy that allows adjuvant
treatment delivery in a shorter period of time in smaller volumes. This study was undertaken to assess
the effectiveness and outcomes of APBI in breast cancer compared with whole-breast irradiation
(WBI). Material and methods: Systematic review and meta-analysis of randomized controlled trials of
WBI versus APBI. Two authors independently selected and assessed the studies regarding eligibility
criteria. Results: Eight studies were selected. A total of 8653 patients were randomly assigned for WBI
versus APBI. Six studies reported local recurrence outcomes. Two studies were matched in 5 years and
only one study for different time of follow-up. Meta-analysis of two trials assessing 1407 participants
showed signicant difference in the WBI versus APBI group regarding the 5-year local recurrence rate
(HR = 4.54, 95% CI: 1.7811.61, p = 0.002). Signicant difference in favor of WBI for different follow-up
times was also found. No differences in nodal recurrence, systemic recurrence, overall survival and
mortality rates were observed. Conclusions: APBI is associated with higher local recurrence compared
to WBI without compromising other clinical outcomes.
2014 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 114 (2015) 4249

Since the early 90s breast-conserving therapy (BCT) has been


established as a safe and standard-of-care procedure for patients
with early stage breast cancer. Breast-conserving surgery followed
by whole breast irradiation (WBI) with or without the inclusion of
lymph node chains yields equivalent results regarding local control
and overall survival when compared to radical mastectomy alone
in several phase III randomized trials [16]. Even for patients considered to be at low risk of ipsilateral tumor recurrence, radiation
therapy (RT) has been associated with a signicant reduction in
disease relapse [7]. Moreover, WBI is related to very low toxicity
rates with a minor impact on the long-term quality of life, and
good outcomes [8].
Nevertheless, WBI usually involves 2530 daily fractions comprising 56 weeks of treatment in conventional schedule, and
about 3 weeks in hypofractionated fashion [9]. In the United States
Corresponding author at: Department of Radiation Oncology, Hospital
SrioLibans, Rua Dona Adma Jafet 91, Sao Paulo, SP 01308-050, Brazil.
E-mail addresses: gnmarta@uol.com.br (G.N. Marta), crisrufa@terra.com.br
(C.R. Macedo), heloisa.carvalho@hc.fm.usp.br (H.A. Carvalho), samir.hanna@hsl.
org.br (S.A. Hanna), jluis@hsl.org.br (J.L.F. da Silva), rachelriera@hotmail.com (R. Riera).

http://dx.doi.org/10.1016/j.radonc.2014.11.014
0167-8140/ 2014 Elsevier Ireland Ltd. All rights reserved.

of America, data regarding treatment delivery have demonstrated


that 1040% of patients submitted to breast-conserving surgery
do not perform adjuvant WBI [1012]. Some features that frequently prevent patients from receiving their prescribed radiation
course are age (older patients are less likely to receive radiotherapy), the socioeconomic status, the travel distance to a radiotherapy facility that may involve higher costs with transport and
temporary lodging, the possibility of not having the appropriate
family support during the period of radiotherapy, absence from
work during such treatment, among others [13]. Therefore, due
to the restricted access to RT centers and the time period required
for WBI, a signicant number of women theoretically eligible for
BCT are treated with mastectomy or quadrantectomy alone
[12,14,15].
For early stage breast cancer, the most common sites of disease
relapse are around the tumor bed. Cancer recurrences outside the
initial site seem to happen with equal incidence following BCT
whether or not adjuvant WBI is used. Hence, the highest benets
of irradiation are associated to the dose delivered at the tissue
neighboring the tumor bed [16,17]. In this scenario, accelerated
partial breast irradiation (APBI), that delivers treatment to a

G.N. Marta et al. / Radiotherapy and Oncology 114 (2015) 4249

limited volume of tissue around the tumor cavity only (partial


breast irradiation), and delivering a larger than standard dose per
fraction within each treatment (accelerated irradiation) has
emerged as an alternative approach to WBI. When compared to
WBI, APBI allows adjuvant treatment to be delivered after BCT over
a shorter period of time (1 week or less). Several methods are available to perform APBI such as intraoperative radiotherapy (IORT)
with electrons or gamma rays, external-beam radiotherapy and
brachytherapy [18]. APBI may optimize the radiation treatment
and improve outcomes of patients that otherwise would decline
WBI. Moreover, APBI is normally associated with less cost than
WBRT [19].
Several trials have already demonstrated the efcacy of APBI
regarding local control rates and cosmetic outcomes [2022]. In
addition, some other randomized trials were undertaken comparing WBI with APBI strategies. Therefore, this systematic review
and meta-analysis was performed to assess the effectiveness and
outcomes of APBI compared with WBI in the adjuvant treatment
of patients with breast cancer.
Methods and methods
Study design
This was a systematic review carried out in accordance with The
Cochrane Collaboration Handbook of Interventions Systematic
Reviews [23]. The manuscript was arranged using the PRISMA
Statement as reporting guidance [24].

43

unclear or low risk of bias according to an assessment of the following items: generation of allocation sequences, allocation concealment, blinding of participants and personnel (performance
bias), blinding of outcome assessment (detection bias), incomplete
data addressed, presence of biases in reports and other sources of
bias that might inuence the studys validity.
Statistical analysis
The size effect of the treatment for the time-to-event outcomes
was calculated by the pooled hazard ratio (HR), followed by the
condence interval (CI) of 95%, from the Petos method of xed
effect. The HR calculation was performed after imputation of the
derivative of expected events (O-E) and log-rank variance (V) for
each included study. For determining O-E, the Z-Score for twotailed p-value was calculated based on relative risk of each study.
The methods used for imputation were previously stated.
Risk ratio and 95% condence intervals were calculated for
dichotomous variables using the xed-effect method. Sensitivity
analyses were carried out excluding studies with high and unclear
risk of bias. Heterogeneity was assessed using Chi-square test and
I2 test. When heterogeneity existed, the related reasons (methodological or clinical) were investigated.
Publication bias was checked through a funnel plot graphic.
Review Manager [RevMan 2012] Version 5.2 software was used
for statistical analyses [27].
Results

Criteria for considering studies for this review

Study selection and characteristics of the included studies

Studies assessing any modality of APBI compared with WBI


were selected. Only randomized controlled trials including previously untreated breast cancer patients (those who had not received
prior radiotherapy or prior chemotherapy) were eligible. Quasirandomized and non-randomized studies were excluded. Adjuvant
systemic treatments were allowed.
The main outcome measures were local recurrence, nodal
recurrence, systemic recurrence, overall survival and mortality.
Secondary outcome measures included toxicity (acute and late
effects of radiation therapy-related toxicity) and cosmesis.

The search strategy retrieved 1215 references. After screening


of the titles and abstracts of these references, 1180 studies were
excluded and 35 full-text articles were selected. Of these, ten
papers, corresponding to eight studies fullled the eligibility
criteria [Dodwell, 2005 [28]; Livi, 2010 [29]; Olivotto, 2013 [30];
Polgar, 2013 [31]; Polgar, 2007 [32]; Ribeiro, 1993 [33]; Ribeiro,
1990 [34]; Rodrguez, 2013 [35]; Vaidya, 2010 [36]; Vaidya, 2014
[37]; Veronesi, 2013 [38]] and were the subject of this analysis.
The owchart of the retrieved studies and the characteristics of
the included studies are presented in Table 1 and Supplementary
Material 1, respectively. A total of 8653 patients were randomly
assigned for WBI versus APBI. Most included patients presented
with tumor stage T1 or T2, and nodal stage N0.

Search methods for identifying studies


The electronic search was conducted with no language, publication year or publication status restrictions. We searched the following databases: Cochrane Central Register of Controlled Trials
(CENTRAL) (The Cochrane Library 2014, Issue 2), MEDLINE (1966
to February 2014), EMBASE (1980 to July 2013) and LILACS (1982
to February 2014) (Supplementary Appendix 1). We also screened
the reference lists of articles. For Medline search, research methodology lters previously published were used [25,26].
Selection of studies and assessment of the risk of bias
Relevant articles were selected and assessed by two reviewers,
and their reference lists were searched for additional trials. Randomized trials identied by the search were assessed to determine
whether they met the inclusion criteria. They were assessed by two
independent reviewers (GNM and SAH). Disagreements were
resolved by a third reviewer (RR).
The risk of bias of the included studies was assessed in accordance with the Cochrane Handbook for Systematic Reviews of
Interventions [23] and was carried out by two reviewers (GNM
and RR) independently. When necessary, a third reviewer (HAC)
solved disagreements. The studies were considered to have high,

Methodological quality of studies


The methodological quality of the included studies, assessed
independently by two observers, is presented in Supplementary
Materials 2 and 3. Overall, and in accordance with the Cochrane risk
of bias table [23], all the eight studies were classied as high risk of
bias taking into account the lack of blinding of patients and/or
outcome assessors. However, except for this item (blinding), ve
studies were considered as high quality and low risk of bias
[29,30,33,34,3638] and the other three had unclear risk of bias
[28,31,32,35].
Local recurrence
Analysis was performed according to follow-up outcomes. We
used the intention-to-treat principle in analyzing data from the
trials. We assessed heterogeneity both visually and statistically
using the I2 test of heterogeneity [24].
Six studies reported local recurrence outcome [28,3138], but
one study [29] did not report sufcient data to be included in the
analysis (Fig. 1). Two studies [35,38] were matched in 5 years

Study

Patients
(n)

44

Table 1
Characteristics of included studies.
Years of
inclusion

Inclusion
criteria

174

1986
1990

pT12 pN01

Livi

520

2005
2008

2135

2006
2011

>40 years;
T 6 2.5 cm;
unifocal tumor;
no EIC
P40 years;
DCIS;
IDC 6 3 cm; pN0

Polgar

258

1998
2004

Ribeiro

708

1982
1987

Rodriguez

102

Olivotto

Unifocal tumor;
6pT2; cN0, pN0,
or pN1mi
(single nodal
>0.2 mm and
62 mm);
histologic grade
62
<70 years;
tumor 64 cm;
cN0

Nodal stage (n)

Grade (n)

N0

N1
N2

III

WBI 31%
APBI 41%

T1
T2

T3
T4

174

39

220

206

48

366

1752

2135

258

249

708

N3

ER + (n)

HER

133

41

11

201

29

202*

1425

302

1471

258

229

P60 years; IDC;


unifocal tumor;
6pT2; cN0 (pN0
axillary status);
histologic
grade 6 2
4875 years;
tumor <2.5 cm

102

102

102

100

1305

949

276

69

989

274

1172

44

3451

1764

304

61

1769

319

1943

264

405

7970

102

5303

637

141

4877

965

4915

309

Veronesi

1305

2000
2007

Vaidya

3451

2000
2012

P45 years; IDC;


T1-T2; unifocal
tumor; no EIC

Total

8653

2 + (n)

WBI arm

APBI arm

Surgery

III

HT (n)

APBI

WBI

90

84

90

84

73

68

137

130

582

604

APBI

40 Gy/
15fx + boost
(15 Gy/5fx)
50 Gy/25fx

55 Gy/20fx

50 Gy/25fx
(large breast
size) or
42.5 Gy/16fx
+/ boost
10 Gy
4050 Gy/
2125fx

38.5 Gy/10fx
twice daily

HDR MI
36.4 Gy/7fx or
electrons 42
50 Gy/2125fx

Wide excision,
negative margins.
ALND/SLNB in
some cases

87

89

40 Gy/15fx
(breast and
regional
nodes)
48 Gy/24fx
+/ boost
(10 Gy/5fx)

4042.5 Gy/8fx
(electrons)

Lumpectomy, no
ALND

37.5 Gy/10fx
twice daily

BCS

51

50

50 Gy/
25fx + boost
(10 Gy/5fx)
4056 Gy +/
boost
16 Gy

21 Gy/1fx
(intraoperative
electrons)
20 Gy (surface
of the tumor
bed)/57 Gy at
1 cm depth

Quadrantectomy
and SLNB or
ALND
Wide excision

47

53

485

489

141

116

753

727

427

393

2121

2111

30 Gy/5fx
(IMRT)

Local excision
and a level 2
ALND
Wide excision or
quadrantectomy,
clear margins
(P5 mm)
BCS, negative
margins, negative
SLNB or ALND

Che (n)
WBI

Note: ALND Axillary lymph node dissection; BCS Breast-conserving surgery; Che Adjuvant therapy with chemotherapy; DCIS Ductal carcinoma in situ; EIC Extensive intraductal carcinoma; ER+ Estrogen receptors
positive; HDR MI High-dose-rate multicatheter interstitial; HER-2+ HER-2 positive; HT Adjuvant therapy with hormone; IDC Invasive ductal carcinoma; IMRT Intensity-modulated radiotherapy; LVSI Lymphovascular
space invasion; SLNB Sentinel lymph node biopsy.
*
Hormonal receptors positive.

Accelerated partial breast irradiation: Meta-analysis

Dodwell

Tumor stage (n)


Tis

G.N. Marta et al. / Radiotherapy and Oncology 114 (2015) 4249

45

Fig. 1. Local recurrence.

(Rodriguez, 2013 [35] and Veronesi, 2014 [38]) and only one study
for each time of follow-up: Vaidya (2010) (4 years) [36], Ribeiro
(1993) [33] (7 years), Dodwell (2005) [28] (8 years), and Polgar
(2013) [31] (10 years). One study [37] also demonstrated 5-year
local recurrence outcome; however, it lacked sufcient data to be
analyzed. Meta-analysis of two trials assessing 1407 participants
showed signicant benet in the WBI versus APBI group with
respect to 5-year local recurrence, with signicant heterogeneity
across these trials (HR = 4.54, 95% CI: 1.7811.61, p = 0.002; p of
heterogeneity = 0.08, I2 = 66%). Polgar (2013) [31] and Ribeiro
(1993) [33] also found signicant benet in favor of WBI for different times of follow up (Fig. 1).

heterogeneity = 0.18, I2 = 44%). Dodwell (2005) [28] also found no


signicant benet between groups in 8 years of follow-up (Fig. 2).
Systemic recurrence
Three studies were included in the systemic recurrence analysis
[28,35,38]. Meta-analysis of two trials assessing 1407 participants
for systemic recurrence did not differ signicantly in the women
treated with APBI compared to those treated with WBI in 5 years
(HR = 1.02, 95% CI: 0.641.61; p = 0.95). There was no statistical
heterogeneity in this comparison (test for heterogeneity: I2 = 0%,
p = 1.00). Dodwell (2005) [28] also did not nd signicant benet
favoring APBI or WBI after 8 years of follow-up (Fig. 3).

Nodal recurrence
Three studies analyzed [28,35,38] nodal recurrence outcome.
For the pooled-in nodal recurrence in 5-year analysis [35,38]
assessing 1407 participants, there was no signicant difference in
the HR between APBI versus WBI with evidence of signicant
heterogeneity (HR = 2.87, 95% CI: 0.869.58, p = 0.09; p of

Overall survival
No difference between groups for 5-year overall survival was
observed. The pooled HR was 1.03 (95% IC: 0.921.15; p = 0.59)
in two studies [35,38] with no evidence of signicant heterogeneity (test for heterogeneity: p = 0.98; I2 = 0%) (Fig. 4).

Fig. 2. Nodal recurrence.

46

Accelerated partial breast irradiation: Meta-analysis

Fig. 3. Systemic recurrence.

Fig. 4. Overall survival.

Mortality
Four studies were included in the breast cancer-related mortality analysis [28,35,37,38]. The mortality rate was not signicantly
different among women treated with APBI (96/2507 3.8%) compared to women who received WBI (106/2525, 4.2%) (RR 0.92,
95% CI: 0.711.20; p = 0.56). There was no statistical heterogeneity
in this comparison (test for heterogeneity: I2 = 0%, p = 0.81)
(Fig. 5).
Toxicity, quality of life and cosmesis
Some of the results of each series were reported in separate
publications. Most studies used only clinician evaluation, and Olivotto [30] reported nurses and patients opinions as well. Different
methods were used for toxicity identication and grading. Skin
alterations, breast induration, breast pain, and fat necrosis were
the main assessed toxicities. Late Effect of Normal Tissue Subjective Objective Management Analytic criteria (LENT-SOMA), Radiation Therapy Oncology Group (RTOG) scores and others were the
systems used for toxicity grading. Three out of the four studies that
reported cosmesis used the Harvard criteria for grading. The only
report addressing specically quality of life was from the TARGIT-A trial [39].
Overall, the rate of severe toxicity was very low (<3%) in both
treatment arms and similar within the studies. Skin toxicity was
more evident in the WBI groups. The incidence of seroma was
higher in the APBI group in the TARGIT-A trial [39] (2.1% versus
0.8%) and the ELIOT trial [38] reported a higher incidence of radiological fat necrosis in the APBI group.
Cosmesis appeared to be slightly better in the WBI groups, but
the APBI groups presented good cosmetic results as well. Supplementary Material 4 summarizes the ndings.
The quality of life parameters, in general, were favorable to the
APBI alone arm of the TARGIT-A study [39]. Patients presented less
pain (21.3 points), breast (7.0 points) and arm symptoms (15.1
points), and better role functioning (78.7 points) when compared
to the WBI group (40.9; 19.0; 32.8 and 60.5 points, respectively).
Due to the variety of evaluation methods with different endpoints, no statistical analysis was performed regarding toxicity,
quality of life and cosmesis.

Discussion
The rationale for APBI approach for early stage disease stems
from the observation that breast cancer recurrences normally
occur adjacent to the surgical cavity [16,17]. By aiming radiation
delivery to a more restricted region, APBI techniques make the
delivery of higher doses in the area of the tumor bed feasible while
reducing the dose to the normal breast tissue and adjacent organs
at risk such as skin, lungs, heart, ribs, brachial plexus, esophagus,
all of which may have reduced risk of toxicities [40].
Moreover, a shorter period of time needed to deliver treatment
might improve the convenience and quality of life of the patients,
possibly reducing the physical and psychological stress related to
the radiotherapy [41,42]. For patients with several comorbidities,
or for those who live far from radiation oncology centers, a short
course of irradiation could increase their adherence and also
reduce the likelihood of mastectomy [13,43]. In regions with
restricted RT centers, patients submitted to BCS might wait for a
long period of time before starting radiotherapy. Delaying the
beginning of adjuvant RT from 20 to 26 weeks after BCS is correlated to reduced survival rates [44,45]. In addition, APBI may
reduce the nal costs of treatment depending on the modality used
[46], since the eventual charge of additional WBI and salvage mastectomy treatments are not balanced [47]. While APBI appears to
show some benets over WBI, the major issue is whether these
advantages are signicant enough to balance a potential risk of
relapse in the untreated breast area receiving APBI, which might
adversely affect clinical outcomes.
There are many available techniques to perform APBI that
include IORT with either gamma-rays, photons or electrons;
three-dimensional or intensity-modulated external-beam radiotherapy (photons or protons) or with stereotactic capabilities; or
brachytherapy (interstitial or intracavitary). Many studies looked
at the clinical outcomes and toxicity related to each of these strategies. It remains unclear whether these different treatment modalities result in the same or different clinical outcomes [48].
In addition, several uncertainties about the radiobiological
effectiveness of APBI exist, as they encompass clear differences in
terms of fractionation (single versus hypofractionated), dose prescription (total delivered dose), and geometry (specially important

G.N. Marta et al. / Radiotherapy and Oncology 114 (2015) 4249

47

Fig. 5. Mortality.

with brachytherapy and cavity treatments). Hence, some APBI


techniques could be involved with inhomogeneous dose delivery
with a potential impact on the local control rates. Besides not been
formally compared one against another in clinical trials, the outcomes of these treatments to date seem satisfactory [49,50]. The
majority of the studies included in this meta-analysis used external
beam radiotherapy [2830,3335]; two [37,38] IORT; and one,
brachytherapy [31].
Patient selection is an important element of whether APBI treatments will truly involve the area at risk of residual disease and
therefore will be as effective and safe as WBI. There are at least four
published consensus statement criteria for the delivery of APBI off
protocol (ASTRO American Society for Radiation Oncology, GECESTRO Groupe Europen de Curietherapie-European Society for
Radiotherapy and Oncology, ABS American Brachytherapy Society,
ASBS American Society of Breast Surgeons) [51]. Briey, the main
characteristics for patients selection are: >50 years old (P60 years
for ASTRO; P45 years for ASBS), no BRCA 1/2 mutations, tumor size
63 cm, unicentric and unifocal tumor, no lymphovascular space
invasion, positive estrogen receptor, no lymph node involvement,
negative margins, no extensive intraductal component and no neoadjuvant therapy (ductal in situ carcinoma and associated lobular
carcinoma in situ are allowed). Moreover, there could be other biology-based issues that will certainly drive to better patient selection.
APBI has always had an appeal for its inherent advantages for
surgeons and for medical and radiation oncologists. Those guidelines were rst published at a time when there were no large trials
with level I evidence available, due to the large amount of patients
being treated out of trials. Thus, guidance was provided for clinicians to judge whether their patients could be safely submitted
to such treatments outside the context of clinical research. This
is the main reason for the low percentage of patients considered
appropriate (or low risk) actually included in the clinical studies
cited in this meta-analysis (Table 1: 102 T3/T4 patients, and 778
N1/N2/N3 patients). Furthermore, two studies did not have any
information about estrogen receptor, margins and multicentric/
multifocal status [28,33]. Also, in the majority of the studies, the
lymphovascular space invasion, the extensive intraductal component and the BRCA 1/2 mutation status were not well described.
Thus, the interpretation of each clinical trial needs to be done with
care and considering the patients selection. No modality will
achieve favorable outcomes if performed in a population at higher
risk of recurrence. We consider this the most important bias of the

contemporary studies because it is almost impossible to stratify


patients by suitability according to the published guidelines.
In this meta-analysis, no differences in nodal recurrence, systemic recurrence, overall survival and breast cancer-related mortality rates were observed among WBI and APBI groups. In other
words, our study has demonstrated that there was no impairment
of these outcomes when APBI was used. Six studies have demonstrated local recurrence outcomes, with follow-ups ranging from
4 to 10 years. There were more ipsilateral breast relapse rates in
patients who underwent APBI compared to WBI group. However,
the absolute relapse rates are still low. The local recurrence risk
should be evaluated with caution in terms of biases of the included
trials. There are some studies in which the APBI target-volume is
not well-dened [28,31,33]. Moreover, is important to point out
that some patients actually underwent additional WBI after APBI
(for instance, 21% of APBI patients from TARGIT A trial).
A previously published meta-analysis [52] that compared treatment results in patients treated with APBI or WBI included only
three trials with a pool of 1140 patients (the last search was
updated on June 2008). The authors demonstrated similar results;
they did not nd any statistically signicant difference between
APBI and WBI groups related to supraclavicular recurrences, distant metastases and death. On the other hand, APBI was associated
with an increased risk of local relapse. This study did not assess
toxicity, cosmesis, and the risk of bias of the included studies.
A more recent meta-analysis [53], with the literature search
ending in June 2013, analyzed the outcomes of 919 patients of four
randomized trials. They found no difference in the 5- and 8-year
overall survival, but the 10-year overall survival favored the APBI
strategy in only one study [OR = 0.56 (95% CI = 0.350.91)]. There
were no differences in the 5-year local recurrence-free survival,
cancer-specic survival, disease-free survival, local recurrence,
the rate of contralateral breast cancer, and distant metastasis. As
pointed out by the authors, these results need to be interpreted
with caution, since the quality of the included studies was not
high, with only one using a computer-generated randomization
method. The study selection method in the present meta-analysis,
besides being more restrictive (only randomized controlled trials
including previously untreated breast cancer patients), was able
to retrieve 8 trials (10 publications) with a total of 8653 patients.
A still low, but signicantly worse outcome regarding local control
was observed with APBI compared to WBI with no differences in
the survival endpoints.

48

Accelerated partial breast irradiation: Meta-analysis

Toxicity and cosmesis were assessed by different methods in


the studies, and only one evaluated quality of life parameters.
Thus, an appropriate statistical analysis of these outcomes could
not be performed. Overall, skin toxicity was lower in the APBI
group, as expected, but seroma and fat necrosis were more present
in this group. However, with both, APBI and WBI strategies the rate
of severe toxicity was very low (<3%). With cosmesis, the same
could be observed: the rates of excellent and good results were
predominant, slightly favoring APBI in some, and WBI in others.
It seems that cosmetic outcomes could be related to treatment
complications itself, like fat necrosis [54], independent of the treatment arm. In the meta-analysis from Ye [53], the rate of excellent/
good cosmetic results was signicantly improved with APBI. In
summary, taken together, APBI is related to low toxicity and similar or better cosmesis rates when compared to WBI ( Supplementary Material 4).
Currently, there are at least eight important ongoing randomized phase III trials that are comparing APBI and WBI [5561].
These studies will involve over 16,000 patients. Among them two
large trials [55,56] stand out: the European Brachytherapy Breast
Cancer GEC-ESTRO Working Group and the National Surgical Adjuvant Breast and Bowel Project (NSABP)/Radiation Therapy Oncology Group (RTOG) trials. The European study [56] with an aim of
randomizing 1170 patients from 12 different centers utilizing multicatheter brachytherapy APBI was designed as a noninferiority
trial. The American study [55] (designed as a trial of equivalence)
will include 3000 patients and APBI can be done using brachytherapy techniques (multicatheter or MammoSite balloon) or external
beam irradiation. In both trials, the primary endpoint is to evaluate
whether local control will be equivalent between WBI and APBI.
While the presently open and pending trials differ in terms of
inclusion criteria and in how APBI is performed, the results of these
trials will help to support the nal and robust evidences if APBI
offers equivalent outcomes as WBI. Meanwhile, new issues concerning APBI are being explored, such as whether APBI could be
performed in the preoperative scenario, if breast magnetic resonance imaging can be used to improve patients selection, and if
brachytherapy APBI schedule can be with a lesser number of fractions [6264].
One of the main limitations of this meta-analysis is related to
the included studies and not to the systematic review itself. All
the eight studies were classied as having a high risk of bias taking
into account the lack of blinding of patients and/or outcome assessors. However, it should be considered that in this kind of intervention, masking is not possible. In addition, it is unlikely that
objective outcomes could be inuenced by the lack of blinding.
The other limitation is the different methods to deliver APBI that
can be very physician-dependent either in dening the target volume or regarding technical skills. Nevertheless, the results are very
similar independent of the used technique. We endorse the fact that
patients selection is the most important issue in this context.
In conclusion, APBI was associated with higher local recurrence
compared to WBI. However, the APBI local relapse rates are also
low and it may present less toxicity with better cosmesis. No differences in nodal recurrence, systemic recurrence, overall survival
and mortality rates were observed between WBI and APBI groups.

Conict of interest statement


None to declare.

Financial disclosure/Acknowledgements
None to declare.

Appendix A. Supplementary data


Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.radonc.2014.11.
014.
References
[1] van Dongen JA, Bartelink H, Fentiman IS, Lerut T, Mignolet F, Olthuis G, et al.
Randomized clinical trial to assess the value of breast-conserving therapy in stage
I and II breast cancer, EORTC 10801 trial. J Natl Cancer Inst Monogr 1992:158.
[2] Jacobson JA, Danforth DN, Cowan KH, dAngelo T, Steinberg SM, Pierce L, et al.
Ten-year results of a comparison of conservation with mastectomy in the
treatment of stage I and II breast cancer. N Engl J Med 1995;332:90711.
[3] Blichert-Toft M, Rose C, Andersen JA, Overgaard M, Axelsson CK, Andersen KW,
et al. Danish randomized trial comparing breast conservation therapy with
mastectomy: six years of life-table analysis. Danish Breast Cancer Cooperative
Group. J Natl Cancer Inst Monogr 1992:1925.
[4] Veronesi U, Saccozzi R, Del Vecchio M, Ban A, Clemente C, De Lena M, et al.
Comparing radical mastectomy with quadrantectomy, axillary dissection, and
radiotherapy in patients with small cancers of the breast. N Engl J Med
1981;305:611.
[5] Fisher B, Anderson S, Bryant J, Margolese RG, Deutsch M, Fisher ER, et al.
Twenty-year follow-up of a randomized trial comparing total mastectomy,
lumpectomy, and lumpectomy plus irradiation for the treatment of invasive
breast cancer. N Engl J Med 2002;347:123341.
[6] Veronesi U, Cascinelli N, Mariani L, Greco M, Saccozzi R, Luini A, et al. Twentyyear follow-up of a randomized study comparing breast-conserving surgery
with radical mastectomy for early breast cancer. N Engl J Med
2002;347:122732.
[7] Hughes KS, Schnaper LA, Bellon JR, Cirrincione CT, Berry DA, McCormick B,
et al. Lumpectomy plus tamoxifen with or without irradiation in women age
70 years or older with early breast cancer: long-term follow-up of CALGB 9343.
J Clin Oncol 2013;31:23827.
[8] Early Breast Cancer Trialists Collaborative G, Darby S, McGale P, Correa C,
Taylor C, Arriagada R, et al. Effect of radiotherapy after breast-conserving
surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis
of individual patient data for 10,801 women in 17 randomised trials. Lancet
2011;378:170716.
[9] Haviland JS, Owen JR, Dewar JA, Agrawal RK, Barrett J, Barrett-Lee PJ, et al. The
UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy
hypofractionation for treatment of early breast cancer: 10-year follow-up
results of two randomised controlled trials. Lancet Oncol 2013;14:108694.
[10] Hershman DL, Buono D, McBride RB, Tsai WY, Joseph KA, Grann VR, et al.
Surgeon characteristics and receipt of adjuvant radiotherapy in women with
breast cancer. J Natl Cancer Inst 2008;100:199206.
[11] Pawlik TM, Buchholz TA, Kuerer HM. The biologic rationale for and emerging
role of accelerated partial breast irradiation for breast cancer. J Am Coll Surg
2004;199:47992.
[12] Voti L, Richardson LC, Reis I, Fleming LE, Mackinnon J, Coebergh JW. The effect
of race/ethnicity and insurance in the administration of standard therapy for
local breast cancer in Florida. Breast Cancer Res Treat 2006;95:8995.
[13] Athas WF, Adams-Cameron M, Hunt WC, Amir-Fazli A, Key CR. Travel distance
to radiation therapy and receipt of radiotherapy following breast-conserving
surgery. J Natl Cancer Inst 2000;92:26971.
[14] Nattinger AB, Kneusel RT, Hoffmann RG, Gilligan MA. Relationship of distance
from a radiotherapy facility and initial breast cancer treatment. J Natl Cancer
Inst 2001;93:13446.
[15] Lazovich DA, White E, Thomas DB, Moe RE. Underutilization of breastconserving surgery and radiation therapy among women with stage I or II
breast cancer. JAMA 1991;266:34338.
[16] Boyages J, Recht A, Connolly JL, Schnitt SJ, Gelman R, Kooy H, et al. Early breast
cancer: predictors of breast recurrence for patients treated with conservative
surgery and radiation therapy. Radiother Oncol 1990;19:2941.
[17] Kurtz JM, Amalric R, Brandone H, Ayme Y, Jacquemier J, Pietra JC, et al. Local
recurrence after breast-conserving surgery and radiotherapy. Frequency, time
course, and prognosis. Cancer 1989;63:19127.
[18] Shah C, Vicini F, Wazer DE, Arthur D, Patel RR. The American Brachytherapy
Society consensus statement for accelerated partial breast irradiation.
Brachytherapy 2013;12:26777.
[19] Lanni T, Keisch M, Shah C, Wobb J, Kestin L, Vicini F. A cost comparison analysis
of adjuvant radiation therapy techniques after breast-conserving surgery.
Breast J 2013;19:1627.
[20] Barry M, Ho A, Morrow M. The evolving role of partial breast irradiation in
early-stage breast cancer. Ann Surg Oncol 2013;20:253440.
[21] Khan AJ, Dale RG, Arthur DW, Haffty BG, Todor DA, Vicini FA. Ultrashort
courses of adjuvant breast radiotherapy: wave of the future or a fools errand?
Cancer 2012;118:196270.
[22] Offersen BV, Overgaard M, Kroman N, Overgaard J. Accelerated partial breast
irradiation as part of breast conserving therapy of early breast carcinoma: a
systematic review. Radiother Oncol 2009;90:113.
[23] Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of
Interventions: Version 5.0.2 [updated September 2011]. The Cochrane
Collaboration; 2008.

G.N. Marta et al. / Radiotherapy and Oncology 114 (2015) 4249


[24] Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The
PRISMA statement for reporting systematic reviews and meta-analyses of
studies that evaluate healthcare interventions: explanation and elaboration.
BMJ 2009;339:b2700.
[25] Haynes RB, McKibbon KA, Wilczynski NL, Walter SD, Werre SR, Hedges T.
Optimal search strategies for retrieving scientically strong studies of
treatment from Medline: analytical survey. BMJ 2005;330:1179.
[26] Clinical Queries using Research Methodology Filters. In: PubMed Help
[Internet]. Bethesda (MD): National Center for Biotechnology Information
(US); 2005. PubMed Help. [Updated 2012 Dec 10]. 2012.
[27] Review Manager (RevMan) [Computer program], Version 5.2, (ed.), The Nordic
Cochrane Centre: The Cochrane Collaboration, Copenhagen, 2012.
[28] Dodwell DJ, Dyker K, Brown J, Hawkins K, Cohen D, Stead M, et al. A
randomised study of whole-breast vs tumour-bed irradiation after local
excision and axillary dissection for early breast cancer. Clin Oncol (R Coll
Radiol) 2005;17:61822.
[29] Livi L, Buonamici FB, Simontacchi G, Scotti V, Fambrini M, Compagnucci A,
et al. Accelerated partial breast irradiation with IMRT: new technical approach
and interim analysis of acute toxicity in a phase III randomized clinical trial.
Int J Radiat Oncol Biol Phys 2010;77:50915.
[30] Olivotto IA, Whelan TJ, Parpia S, Kim DH, Berrang T, Truong PT, et al. Interim
cosmetic and toxicity results from RAPID: a randomized trial of accelerated
partial breast irradiation using three-dimensional conformal external beam
radiation therapy. J Clin Oncol 2013;31:403845.
[31] Polgar C, Fodor J, Major T, Sulyok Z, Kasler M. Breast-conserving therapy with
partial or whole breast irradiation: ten-year results of the Budapest
randomized trial. Radiother Oncol 2013;108:197202.
[32] Polgar C, Fodor J, Major T, Nemeth G, Lovey K, Orosz Z, et al. Breast-conserving
treatment with partial or whole breast irradiation for low-risk invasive breast
carcinoma5-year results of a randomized trial. Int J Radiat Oncol Biol Phys
2007;69:694702.
[33] Ribeiro GG, Magee B, Swindell R, Harris M, Banerjee SS. The Christie Hospital
breast conservation trial: an update at 8 years from inception. Clin Oncol (R
Coll Radiol) 1993;5:27883.
[34] Ribeiro GG, Dunn G, Swindell R, Harris M, Banerjee SS. Conservation of the
breast using two different radiotherapy techniques: interim report of a clinical
trial. Clin Oncol (R Coll Radiol) 1990;2:2734.
[35] Rodriguez N, Sanz X, Dengra J, Foro P, Membrive I, Reig A, et al. Five-year
outcomes, cosmesis, and toxicity with 3-dimensional conformal external beam
radiation therapy to deliver accelerated partial breast irradiation. Int J Radiat
Oncol Biol Phys 2013;87:10517.
[36] Vaidya JS, Joseph DJ, Tobias JS, Bulsara M, Wenz F, Saunders C, et al. Targeted
intraoperative radiotherapy versus whole breast radiotherapy for breast
cancer (TARGIT-A trial): an international, prospective, randomised, noninferiority phase 3 trial. Lancet 2010;376:91102.
[37] Vaidya JS, Wenz F, Bulsara M, Tobias JS, Joseph DJ, Keshtgar M, et al. Riskadapted targeted intraoperative radiotherapy versus whole-breast
radiotherapy for breast cancer: 5-year results for local control and overall
survival from the TARGIT-A randomised trial. Lancet 2014;383:60313.
[38] Veronesi U, Orecchia R, Maisonneuve P, Viale G, Rotmensz N, Sangalli C, et al.
Intraoperative radiotherapy versus external radiotherapy for early breast
cancer (ELIOT): a randomised controlled equivalence trial. Lancet Oncol
2013;14:126977.
[39] Welzel G, Boch A, Sperk E, Hofmann F, Kraus-Tiefenbacher U, Gerhardt A, et al.
Radiation-related quality of life parameters after targeted intraoperative
radiotherapy versus whole breast radiotherapy in patients with breast cancer:
results from the randomized phase III trial TARGIT-A. Radiat Oncol 2013;8:9.
[40] Mukesh M, Harris E, Jena R, Evans P, Coles C. Relationship between irradiated
breast volume and late normal tissue complications: a systematic review.
Radiother Oncol 2012;104:110.
[41] Albuquerque K, Tell D, Lobo P, Millbrandt L, Mathews HL, Janusek LW. Impact
of partial versus whole breast radiation therapy on fatigue, perceived stress,
quality of life and natural killer cell activity in women with breast cancer. BMC
Cancer 2012;12:251.
[42] Kawase E, Karasawa K, Shimotsu S, Izawa H, Hirowatari H, Saito AI, et al.
Estimation of anxiety and depression in patients with early stage breast cancer
before and after radiation therapy. Breast Cancer 2012;19:14752.
[43] Farrow DC, Hunt WC, Samet JM. Geographic variation in the treatment of
localized breast cancer. N Engl J Med 1992;326:1097101.
[44] Mikeljevic JS, Haward R, Johnston C, Crellin A, Dodwell D, Jones A, et al. Trends
in postoperative radiotherapy delay and the effect on survival in breast cancer
patients treated with conservation surgery. Br J Cancer 2004;90:13438.

49

[45] Olivotto IA, Lesperance ML, Truong PT, Nichol A, Berrang T, Tyldesley S, et al.
Intervals longer than 20 weeks from breast-conserving surgery to radiation
therapy are associated with inferior outcome for women with early-stage
breast cancer who are not receiving chemotherapy. J Clin Oncol
2009;27:1623.
[46] Suh WW, Pierce LJ, Vicini FA, Hayman JA. A cost comparison analysis of partial
versus whole-breast irradiation after breast-conserving surgery for early-stage
breast cancer. Int J Radiat Oncol Biol Phys 2005;62:7906.
[47] Shah C, Badiyan S, Khwaja S, Shah H, Chitalia A, Nanavati A, et al. Evaluating
radiotherapy options in breast cancer: does intraoperative radiotherapy
represent the most cost-efcacious option? Clin Breast Cancer 2014;14:1416.
[48] Cox JA, Swanson TA. Current modalities of accelerated partial breast
irradiation. Nat Rev Clin Oncol 2013;10:34456.
[49] Wallner P, Arthur D, Bartelink H, Connolly J, Edmundson G, Giuliano A, et al.
Workshop on partial breast irradiation: state of the art and the science,
Bethesda, MD, December 810, 2002. J Natl Cancer Inst 2004;96:17584.
[50] Chand-Fouche ME, Hannoun-Levi JM. State of the art and perspectives of
accelerated partial breast irradiation in 2014. Cancer Radiother 2014.
[51] Shaitelman SF, Khan AJ, Woodward WA, Arthur DW, Cuttino LW, Bloom ES,
et al. Shortened radiation therapy schedules for early-stage breast cancer: a
review of hypofractionated whole-breast irradiation and accelerated partial
breast irradiation. Breast J 2014;20:13146.
[52] Valachis A, Mauri D, Polyzos NP, Mavroudis D, Georgoulias V, Casazza G.
Partial breast irradiation or whole breast radiotherapy for early breast cancer:
a meta-analysis of randomized controlled trials. Breast J 2010;16:24551.
[53] Ye XP, Bao S, Guo LY, Wang XH, Ma YP, Zhang W, et al. Accelerated partial
breast irradiation for breast cancer: a meta-analysis. Transl Oncol
2013;6:61927.
[54] Lovey K, Fodor J, Major T, Szabo E, Orosz Z, Sulyok Z, et al. Fat necrosis after
partial-breast irradiation with brachytherapy or electron irradiation versus
standard whole-breast radiotherapy4-year results of a randomized trial. Int J
Radiat Oncol Biol Phys 2007;69:72431.
[55] Wolmark NCW. NSABP Protocol B-39, RTOG Protocol 0413: a randomized
phase III study of conventional whole breast irradiation (WBI) versus partial
breast irradiation (PBI) for women with stage 0, I, or II breast cancer. Clin Adv
Hematol Oncol 2011. http://rpc.mdanderson.org/rpc/credentialing/les/
B39_Protocol1.pdf.
[56] Strnad VPC. Interstitial brachytherapy alone versus external beam radiation
therapy after breast conserving surgery for low risk invasive carcinoma and
low risk duct carcinoma in-situ (DCIS) of the female breast.
[57] Coles C, Yarnold J, Group ITM. The IMPORT trials are launched (September
2006). Clin Oncol (R Coll Radiol) 2006;18:58790.
[58] Yarnold J. Randomised Trial Testing Intensity Modulated and Partial Organ
Radiotherapy After Breast Conservation Surgery for Early Breast Cancer.
Available at: http://www.clinicaltrials.gov/ct2/show/NCT00814567; 2008
[accessed July 16, 2014].
[59] Frezza G, Bertoni F, IRMA. Breast Cancer with Low Risk of Local Recurrence:
Partial and Accelerated Radiation with Three-Dimensional Conformal
Radiotherapy (3DCRT) vs. Standard Radiotherapy After Conserving Surgery
(Phase III Study). Available at: http://groups.eortc.be/radio/res/irma/
synopsis_trial_irma1.pdf; 2007 [accessed July 16, 2016].
[60] Danish Breast Cancer Cooperative Group. Partial Breast Versus Whole Breast
Irradiation in Elderly Women Operated on for Early Breast Cancer. Available
at: http://www.clinicaltrials.gov/ct2/show/NCT00892814; 2011 [accessed July
13, 2014].
[61] Belkacemi Y, Bourgier C, Kramar A, Auzac G, Dumas I, Lacornerie T, et al.
SHARE: a French multicenter phase III trial comparing accelerated partial
irradiation versus standard or hypofractionated whole breast irradiation in
breast cancer patients at low risk of local recurrence. Clin Adv Hematol Oncol
2013;11:7683.
[62] AJ K. Safety study for short-course accelerated, hypofractionated partial breast
radiotherapy (APBIin women with early) stage breast cancer using the Contura
MLB; 2010.
[63] Schmitz AC, Pengel KE, Loo CE, van den Bosch MA, Wesseling J, Gertenbach M,
et al. Pre-treatment imaging and pathology characteristics of invasive breast
cancers of limited extent: potential relevance for MRI-guided localized
therapy. Radiother Oncol 2012;104:118.
[64] Palta M, Yoo S, Adamson JD, Prosnitz LR, Horton JK. Preoperative single fraction
partial breast radiotherapy for early-stage breast cancer. Int J Radiat Oncol Biol
Phys 2012;82:3742.

Das könnte Ihnen auch gefallen