Beruflich Dokumente
Kultur Dokumente
Systematic review
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
http://dx.doi.org/10.1016/j.radonc.2014.11.014
0167-8140/ 2014 Elsevier Ireland Ltd. All rights reserved.
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
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
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
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
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.
Dodwell
45
(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).
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).
46
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
47
Fig. 5. Mortality.
48
Financial disclosure/Acknowledgements
None to declare.
49
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