caht

, Ha a

adialogiaMed

a r t i c l e i n f o

Article history:Received 9 July 2014Received in revised form 4 November 2014

a b s t r a c t

sidered to be at low risk of ipsilateral tumor recurrence, radiation

good outcomes [8].

prising 56 weeks of treatment in conventional schedule, andabout 3 weeks in hypofractionated fashion [9]. In the United States

temporary lodging, the possibility of not having the appropriatepy, absence from]. Therefoe period re

for WBI, a signicant number of women theoretically eligible for

[12,14,15].For early stage breast cancer, the most common sites of disease

relapse are around the tumor bed. Cancer recurrences outside theinitial site seem to happen with equal incidence following BCTwhether or not adjuvant WBI is used. Hence, the highest benetsof irradiation are associated to the dose delivered at the tissueneighboring the tumor bed [16,17]. In this scenario, acceleratedpartial breast irradiation (APBI), that delivers treatment to a

Corresponding author at: Department of Radiation Oncology, HospitalSrioLibans, 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).

Radiotherapy and Oncology 114 (2015) 4249

Contents lists availab

Radiotherapy a

journal homepage: wwwNevertheless, WBI usually involves 2530 daily fractions com- BCT are treated with mastectomy or quadrantectomy alonetherapy (RT) has been associated with a signicant reduction indisease relapse [7]. Moreover, WBI is related to very low toxicityrates with a minor impact on the long-term quality of life, and

family support during the period of radiotherawork during such treatment, among others [13to the restricted access to RT centers and the timhttp://dx.doi.org/10.1016/j.radonc.2014.11.0140167-8140/ 2014 Elsevier Ireland Ltd. All rights reserved.re, duequiredSince the early 90s breast-conserving therapy (BCT) has beenestablished as a safe and standard-of-care procedure for patientswith early stage breast cancer. Breast-conserving surgery followedby whole breast irradiation (WBI) with or without the inclusion oflymph node chains yields equivalent results regarding local controland overall survival when compared to radical mastectomy alonein several phase III randomized trials [16]. Even for patients con-

of America, data regarding treatment delivery have demonstratedthat 1040% of patients submitted to breast-conserving surgerydo not perform adjuvant WBI [1012]. Some features that fre-quently prevent patients from receiving their prescribed radiationcourse are age (older patients are less likely to receive radiother-apy), the socioeconomic status, the travel distance to a radiother-apy facility that may involve higher costs with transport andAccepted 4 November 2014Available online 2 December 2014

Keywords:Breast cancerBreast-conserving therapyWhole-breast irradiationAccelerated partial breast irradiationBackground and purpose: Accelerated partial breast irradiation (APBI) is the strategy that allows adjuvanttreatment delivery in a shorter period of time in smaller volumes. This study was undertaken to assessthe 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 ofWBI versus APBI. Two authors independently selected and assessed the studies regarding eligibilitycriteria. Results: Eight studies were selected. A total of 8653 patients were randomly assigned for WBIversus APBI. Six studies reported local recurrence outcomes. Two studies were matched in 5 years andonly one study for different time of follow-up. Meta-analysis of two trials assessing 1407 participantsshowed 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-uptimes was also found. No differences in nodal recurrence, systemic recurrence, overall survival andmortality rates were observed. Conclusions: APBI is associated with higher local recurrence comparedto WBI without compromising other clinical outcomes.

2014 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 114 (2015) 4249Systematic review

Accelerated partial irradiation for breastand meta-analysis of 8653 women in eig

Gustavo Nader Marta a,b,, Cristiane Runo Macedo dSamir Abdallah Hanna a, Joo Luis Fernandes da SilvaDepartment of Radiation Oncology, Hospital SrioLibans, Brazil; bDepartment of RUniversidade de So Paulo, Brazil; cDepartment of Radiation Oncology, Instituto de RadiodBrazilian Cochrane Center and Discipline of Emergency Medicine and Evidence-BasedBrazilncer: Systematic reviewrandomized trials

eloisa de Andrade Carvalho a,c,, Rachel Riera d

tion Oncology, Instituto do Cncer de So Paulo (ICESP), Faculdade de Medicina dado Hospital das Clnicas da Faculdade de Medicina da Universidade de So Paulo, Brazil;icine, Universidade Federal de So PauloEscola Paulista de Medicina (UNIFESPEPM),

le at ScienceDirect

nd Oncology

. thegreenjournal .com

WBI. Moreover, APBI is normally associated with less cost than

prior radiotherapy or prior chemotherapy) were eligible. Quasi-

dichotomous variables using the xed-effect method. Sensitivity

y anrandomized and non-randomized studies were excluded. Adjuvantsystemic treatments were allowed.

The main outcome measures were local recurrence, nodalrecurrence, systemic recurrence, overall survival and mortality.Secondary outcome measures included toxicity (acute and lateeffects of radiation therapy-related toxicity) and cosmesis.

Search methods for identifying studies

The electronic search was conducted with no language, publica-tion year or publication status restrictions. We searched the fol-lowing databases: Cochrane Central Register of Controlled Trials(CENTRAL) (The Cochrane Library 2014, Issue 2), MEDLINE (1966to February 2014), EMBASE (1980 to July 2013) and LILACS (1982to February 2014) (Supplementary Appendix 1). We also screenedthe reference lists of articles. For Medline search, research method-ology 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. Ran-domized trials identied by the search were assessed to determinewhether they met the inclusion criteria. They were assessed by twoindependent reviewers (GNM and SAH). Disagreements wereresolved by a third reviewer (RR).

The risk of bias of the included studies was assessed in accor-dance with the Cochrane Handbook for Systematic Reviews ofStudy design

This was a systematic review carried out in accordance with TheCochrane Collaboration Handbook of Interventions SystematicReviews [23]. The manuscript was arranged using the PRISMAStatement as reporting guidance [24].

Criteria for considering studies for this review

Studies assessing any modality of APBI compared with WBIwere selected. Only randomized controlled trials including previ-ously untreated breast cancer patients (those who had not receivedWBRT [19].Several trials have already demonstrated the efcacy of APBI

regarding local control rates and cosmetic outcomes [2022]. Inaddition, some other randomized trials were undertaken compar-ing WBI with APBI strategies. Therefore, this systematic reviewand meta-analysis was performed to assess the effectiveness andoutcomes of APBI compared with WBI in the adjuvant treatmentof patients with breast cancer.

Methods and methodslimited volume of tissue around the tumor cavity only (partialbreast irradiation), and delivering a larger than standard dose perfraction within each treatment (accelerated irradiation) hasemerged as an alternative approach to WBI. When compared toWBI, APBI allows adjuvant treatment to be delivered after BCT overa shorter period of time (1 week or less). Several methods are avail-able to perform APBI such as intraoperative radiotherapy (IORT)with electrons or gamma rays, external-beam radiotherapy andbrachytherapy [18]. APBI may optimize the radiation treatmentand improve outcomes of patients that otherwise would decline

G.N. Marta et al. / RadiotherapInterventions [23] and was carried out by two reviewers (GNMand RR) independently. When necessary, a third reviewer (HAC)solved disagreements. The studies were considered to have high,Local recurrence

Analysis was performed according to follow-up outcomes. Weused the intention-to-treat principle in analyzing data from thetrials. We assessed heterogeneity both visually and statisticallyusing the I2 test of heterogeneity [24].analyses were carried out excluding studies with high and unclearrisk of bias. Heterogeneity was assessed using Chi-square test andI2 test. When heterogeneity existed, the related reasons (methodo-logical or clinical) were investigated.

Publication bias was checked through a funnel plot graphic.Review Manager [RevMan 2012] Version 5.2 software was usedfor statistical analyses [27].

Results

Study selection and characteristics of the included studies

The search strategy retrieved 1215 references. After screeningof the titles and abstracts of these references, 1180 studies wereexcluded and 35 full-text articles were selected. Of these, tenpapers, corresponding to eight studies fullled the eligibilitycriteria [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 ofthe included studies are presented in Table 1 and SupplementaryMaterial 1, respectively. A total of 8653 patients were randomlyassigned for WBI versus APBI. Most included patients presentedwith tumor stage T1 or T2, and nodal stage N0.

Methodological quality of studies

The methodological quality of the included studies, assessedindependently by two observers, is presented in SupplementaryMaterials 2 and 3. Overall, and in accordancewith the Cochrane riskof bias table [23], all the eight studies were classied as high risk ofbias taking into account the lack of blinding of patients and/oroutcome assessors. However, except for this item (blinding), vestudies 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].Statistical analysis

The size effect of the treatment for the time-to-event outcomeswas calculated by the pooled hazard ratio (HR), followed by thecondence interval (CI) of 95%, from the Petos method of xedeffect. The HR calculation was performed after imputation of thederivative of expected events (O-E) and log-rank variance (V) foreach included study. For determining O-E, the Z-Score for two-tailed 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 forunclear or low risk of bias according to an assessment of the fol-lowing items: generation of allocation sequences, allocation con-cealment, blinding of participants and personnel (performancebias), blinding of outcome assessment (detection bias), incompletedata addressed, presence of biases in reports and other sources ofbias that might inuence the studys validity.

d Oncology 114 (2015) 4249 43Six studies reported local recurrence outcome [28,3138], butone study [29] did not report sufcient data to be included in theanalysis (Fig. 1). Two studies [35,38] were matched in 5 years

Table 1Characteristics of included studies.

Study Patients(n)

Years ofinclusion

Inclusioncriteria

Tumor stage (n) Nodal stage (n) Grade (n) ER + (n) HER 2 + (n) WBI arm APBI arm Surgery Che (n) HT (n)Tis T1

T2T3T4

N0 N1N2

N3 III III WBI APBI WBI APBI

Dodwell 174 19861990

pT12 pN01 0 174 0 WBI 31%APBI 41%

133 41 40 Gy/15fx + boost(15 Gy/5fx)

55 Gy/20fx Local excisionand a level 2ALND

90 84 90 84

Livi 520 20052008

>40 years;T 6 2.5 cm;unifocal tumor;no EIC

39 220 0 206 48 11 201 29 202* 50 Gy/25fx 30 Gy/5fx(IMRT)

Wide excision orquadrantectomy,clear margins(P5 mm)

8 7 73 68

Olivotto 2135 20062011

P40 years;DCIS;IDC 6 3 cm; pN0

366 1752 0 2135 0 0 1425 302 1471 50 Gy/25fx(large breastsize) or42.5 Gy/16fx+/ boost10 Gy

38.5 Gy/10fxtwice daily

BCS, negativemargins, negativeSLNB or ALND

137 130 582 604

Polgar 258 19982004

Unifocal tumor;6pT2; cN0, pN0,or pN1mi(single nodal>0.2 mm and62 mm);histologic grade62

0 258 0 249 9 0 258 0 229 4050 Gy/2125fx

HDR MI36.4 Gy/7fx orelectrons 4250 Gy/2125fx

Wide excision,negative margins.ALND/SLNB insome cases

2 2 87 89

Ribeiro 708 19821987

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

al re

G.N. Marta et al. / Radiotherapy and Oncology 114 (2015) 4249 45(Rodriguez, 2013 [35] and Veronesi, 2014 [38]) and only one studyfor 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

Fig. 1. Loclocal recurrence outcome; however, it lacked sufcient data to beanalyzed. Meta-analysis of two trials assessing 1407 participantsshowed signicant benet in the WBI versus APBI group withrespect to 5-year local recurrence, with signicant heterogeneityacross these trials (HR = 4.54, 95% CI: 1.7811.61, p = 0.002; p ofheterogeneity = 0.08, I2 = 66%). Polgar (2013) [31] and Ribeiro(1993) [33] also found signicant benet in favor of WBI for differ-ent 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 inthe HR between APBI versus WBI with evidence of signicantheterogeneity (HR = 2.87, 95% CI: 0.869.58, p = 0.09; p of

Fig. 2. Nodal rsignicant benet between groups in 8 years of follow-up (Fig. 2).currence.Systemic recurrence

Three studies were included in the systemic recurrence analysis[28,35,38]. Meta-analysis of two trials assessing 1407 participantsfor systemic recurrence did not differ signicantly in the womentreated 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 statisticalheterogeneity in this comparison (test for heterogeneity: I2 = 0%,p = 1.00). Dodwell (2005) [28] also did not nd signicant benetfavoring APBI or WBI after 8 years of follow-up (Fig. 3).

Overall survival

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

ecurrence.

mic

erall

t irrMortality

Four studies were included in the breast cancer-related mortal-ity analysis [28,35,37,38]. The mortality rate was not signicantlydifferent among women treated with APBI (96/2507 3.8%) com-pared to women who received WBI (106/2525, 4.2%) (RR 0.92,95% CI: 0.711.20; p = 0.56). There was no statistical heterogeneityin this comparison (test for heterogeneity: I2 = 0%, p = 0.81)(Fig. 5).

Toxicity, quality of life and cosmesis

Fig. 3. Syste

Fig. 4. Ov

46 Accelerated partial breasSome of the results of each series were reported in separatepublications. Most studies used only clinician evaluation, and Oliv-otto [30] reported nurses and patients opinions as well. Differentmethods were used for toxicity identication and grading. Skinalterations, breast induration, breast pain, and fat necrosis werethe main assessed toxicities. Late Effect of Normal Tissue Subjec-tive Objective Management Analytic criteria (LENT-SOMA), Radia-tion Therapy Oncology Group (RTOG) scores and others were thesystems used for toxicity grading. Three out of the four studies thatreported cosmesis used the Harvard criteria for grading. The onlyreport addressing specically quality of life was from the TAR-GIT-A trial [39].

Overall, the rate of severe toxicity was very low (

Mor

y anwith brachytherapy and cavity treatments). Hence, some APBItechniques could be involved with inhomogeneous dose deliverywith a potential impact on the local control rates. Besides not beenformally compared one against another in clinical trials, the out-comes of these treatments to date seem satisfactory [49,50]. Themajority of the studies included in this meta-analysis used externalbeam radiotherapy [2830,3335]; two [37,38] IORT; and one,brachytherapy [31].

Patient selection is an important element of whether APBI treat-ments will truly involve the area at risk of residual disease andtherefore will be as effective and safe as WBI. There are at least fourpublished consensus statement criteria for the delivery of APBI offprotocol (ASTRO American Society for Radiation Oncology, GEC-ESTRO Groupe Europen de Curietherapie-European Society forRadiotherapy and Oncology, ABS American Brachytherapy Society,ASBS American Society of Breast Surgeons) [51]. Briey, the maincharacteristics for patients selection are: >50 years old (P60 yearsfor ASTRO;P45 years for ASBS), no BRCA 1/2mutations, tumor size

Fig. 5.

G.N. Marta et al. / Radiotherap63 cm, unicentric and unifocal tumor, no lymphovascular spaceinvasion, positive estrogen receptor, no lymph node involvement,negative margins, no extensive intraductal component and no neo-adjuvant therapy (ductal in situ carcinoma and associated lobularcarcinoma in situ are allowed). Moreover, there could be other biol-ogy-based issues that will certainly drive to better patient selection.

APBI has always had an appeal for its inherent advantages forsurgeons and for medical and radiation oncologists. Those guide-lines were rst published at a time when there were no large trialswith level I evidence available, due to the large amount of patientsbeing treated out of trials. Thus, guidance was provided for clini-cians to judge whether their patients could be safely submittedto such treatments outside the context of clinical research. Thisis the main reason for the low percentage of patients consideredappropriate (or low risk) actually included in the clinical studiescited in this meta-analysis (Table 1: 102 T3/T4 patients, and 778N1/N2/N3 patients). Furthermore, two studies did not have anyinformation about estrogen receptor, margins and multicentric/multifocal status [28,33]. Also, in the majority of the studies, thelymphovascular space invasion, the extensive intraductal compo-nent and the BRCA 1/2 mutation status were not well described.Thus, the interpretation of each clinical trial needs to be done withcare and considering the patients selection. No modality willachieve favorable outcomes if performed in a population at higherrisk of recurrence. We consider this the most important bias of thecontemporary studies because it is almost impossible to stratifypatients by suitability according to the published guidelines.

In this meta-analysis, no differences in nodal recurrence, sys-temic recurrence, overall survival and breast cancer-related mor-tality rates were observed among WBI and APBI groups. In otherwords, our study has demonstrated that there was no impairmentof these outcomes when APBI was used. Six studies have demon-strated local recurrence outcomes, with follow-ups ranging from4 to 10 years. There were more ipsilateral breast relapse rates inpatients who underwent APBI compared to WBI group. However,the absolute relapse rates are still low. The local recurrence riskshould be evaluated with caution in terms of biases of the includedtrials. There are some studies in which the APBI target-volume isnot well-dened [28,31,33]. Moreover, is important to point outthat 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 treat-ment results in patients treated with APBI or WBI included only

tality.

d Oncology 114 (2015) 4249 47three trials with a pool of 1140 patients (the last search wasupdated on June 2008). The authors demonstrated similar results;they did not nd any statistically signicant difference betweenAPBI and WBI groups related to supraclavicular recurrences, dis-tant metastases and death. On the other hand, APBI was associatedwith an increased risk of local relapse. This study did not assesstoxicity, cosmesis, and the risk of bias of the included studies.

A more recent meta-analysis [53], with the literature searchending in June 2013, analyzed the outcomes of 919 patients of fourrandomized trials. They found no difference in the 5- and 8-yearoverall survival, but the 10-year overall survival favored the APBIstrategy in only one study [OR = 0.56 (95% CI = 0.350.91)]. Therewere 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. Aspointed out by the authors, these results need to be interpretedwith caution, since the quality of the included studies was nothigh, with only one using a computer-generated randomizationmethod. The study selection method in the present meta-analysis,besides being more restrictive (only randomized controlled trialsincluding previously untreated breast cancer patients), was ableto retrieve 8 trials (10 publications) with a total of 8653 patients.A still low, but signicantly worse outcome regarding local controlwas observed with APBI compared to WBI with no differences inthe survival endpoints.

Toxicity and cosmesis were assessed by different methods inthe studies, and only one evaluated quality of life parameters.

in this group. However, with both, APBI and WBI strategies the rateof severe toxicity was very low (

[24] Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. ThePRISMA statement for reporting systematic reviews and meta-analyses ofstudies 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 oftreatment 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.

[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 radiationtherapy are associated with inferior outcome for women with early-stagebreast cancer who are not receiving chemotherapy. J Clin Oncol2009;27:1623.

[46] Suh WW, Pierce LJ, Vicini FA, Hayman JA. A cost comparison analysis of partialversus whole-breast irradiation after breast-conserving surgery for early-stagebreast 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. Evaluatingradiotherapy options in breast cancer: does intraoperative radiotherapyrepresent the most cost-efcacious option? Clin Breast Cancer 2014;14:1416.

G.N. Marta et al. / Radiotherapy and Oncology 114 (2015) 4249 49[27] Review Manager (RevMan) [Computer program], Version 5.2, (ed.), The NordicCochrane Centre: The Cochrane Collaboration, Copenhagen, 2012.

[28] Dodwell DJ, Dyker K, Brown J, Hawkins K, Cohen D, Stead M, et al. Arandomised study of whole-breast vs tumour-bed irradiation after localexcision and axillary dissection for early breast cancer. Clin Oncol (R CollRadiol) 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 approachand 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. Interimcosmetic and toxicity results from RAPID: a randomized trial of acceleratedpartial breast irradiation using three-dimensional conformal external beamradiation therapy. J Clin Oncol 2013;31:403845.

[31] Polgar C, Fodor J, Major T, Sulyok Z, Kasler M. Breast-conserving therapy withpartial or whole breast irradiation: ten-year results of the Budapestrandomized trial. Radiother Oncol 2013;108:197202.

[32] Polgar C, Fodor J, Major T, Nemeth G, Lovey K, Orosz Z, et al. Breast-conservingtreatment with partial or whole breast irradiation for low-risk invasive breastcarcinoma5-year results of a randomized trial. Int J Radiat Oncol Biol Phys2007;69:694702.

[33] Ribeiro GG, Magee B, Swindell R, Harris M, Banerjee SS. The Christie Hospitalbreast conservation trial: an update at 8 years from inception. Clin Oncol (RColl Radiol) 1993;5:27883.

[34] Ribeiro GG, Dunn G, Swindell R, Harris M, Banerjee SS. Conservation of thebreast using two different radiotherapy techniques: interim report of a clinicaltrial. Clin Oncol (R Coll Radiol) 1990;2:2734.

[35] Rodriguez N, Sanz X, Dengra J, Foro P, Membrive I, Reig A, et al. Five-yearoutcomes, cosmesis, and toxicity with 3-dimensional conformal external beamradiation therapy to deliver accelerated partial breast irradiation. Int J RadiatOncol Biol Phys 2013;87:10517.

[36] Vaidya JS, Joseph DJ, Tobias JS, Bulsara M, Wenz F, Saunders C, et al. Targetedintraoperative radiotherapy versus whole breast radiotherapy for breastcancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority phase 3 trial. Lancet 2010;376:91102.

[37] Vaidya JS, Wenz F, Bulsara M, Tobias JS, Joseph DJ, Keshtgar M, et al. Risk-adapted targeted intraoperative radiotherapy versus whole-breastradiotherapy for breast cancer: 5-year results for local control and overallsurvival 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 breastcancer (ELIOT): a randomised controlled equivalence trial. Lancet Oncol2013;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 intraoperativeradiotherapy 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 irradiatedbreast 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. Impactof partial versus whole breast radiation therapy on fatigue, perceived stress,quality of life and natural killer cell activity in women with breast cancer. BMCCancer 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 cancerbefore and after radiation therapy. Breast Cancer 2012;19:14752.

[43] Farrow DC, Hunt WC, Samet JM. Geographic variation in the treatment oflocalized breast cancer. N Engl J Med 1992;326:1097101.

[44] Mikeljevic JS, Haward R, Johnston C, Crellin A, Dodwell D, Jones A, et al. Trendsin postoperative radiotherapy delay and the effect on survival in breast cancerpatients treated with conservation surgery. Br J Cancer 2004;90:13438.[48] Cox JA, Swanson TA. Current modalities of accelerated partial breastirradiation. 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 ofaccelerated 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: areview of hypofractionated whole-breast irradiation and accelerated partialbreast 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 partialbreast irradiation for breast cancer: a meta-analysis. Transl Oncol2013;6:61927.

[54] Lovey K, Fodor J, Major T, Szabo E, Orosz Z, Sulyok Z, et al. Fat necrosis afterpartial-breast irradiation with brachytherapy or electron irradiation versusstandard whole-breast radiotherapy4-year results of a randomized trial. Int JRadiat Oncol Biol Phys 2007;69:72431.

[55] Wolmark NCW. NSABP Protocol B-39, RTOG Protocol 0413: a randomizedphase III study of conventional whole breast irradiation (WBI) versus partialbreast irradiation (PBI) for women with stage 0, I, or II breast cancer. Clin AdvHematol Oncol 2011. http://rpc.mdanderson.org/rpc/credentialing/les/B39_Protocol1.pdf.

[56] Strnad VPC. Interstitial brachytherapy alone versus external beam radiationtherapy after breast conserving surgery for low risk invasive carcinoma andlow risk duct carcinoma in-situ (DCIS) of the female breast.

[57] Coles C, Yarnold J, Group ITM. The IMPORT trials are launched (September2006). Clin Oncol (R Coll Radiol) 2006;18:58790.

[58] Yarnold J. Randomised Trial Testing Intensity Modulated and Partial OrganRadiotherapy 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 ConformalRadiotherapy (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 BreastIrradiation in Elderly Women Operated on for Early Breast Cancer. Availableat: http://www.clinicaltrials.gov/ct2/show/NCT00892814; 2011 [accessed July13, 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 partialirradiation versus standard or hypofractionated whole breast irradiation inbreast cancer patients at low risk of local recurrence. Clin Adv Hematol Oncol2013;11:7683.

[62] AJ K. Safety study for short-course accelerated, hypofractionated partial breastradiotherapy (APBIin women with early) stage breast cancer using the ConturaMLB; 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 breastcancers of limited extent: potential relevance for MRI-guided localizedtherapy. Radiother Oncol 2012;104:118.

[64] Palta M, Yoo S, Adamson JD, Prosnitz LR, Horton JK. Preoperative single fractionpartial breast radiotherapy for early-stage breast cancer. Int J Radiat Oncol BiolPhys 2012;82:3742.

Accelerated partial irradiation for breast cancer: Systematic review and meta-analysis of 8653 women in eight randomized trialsMethods and methodsStudy designCriteria for considering studies for this reviewSearch methods for identifying studiesSelection of studies and assessment of the risk of biasStatistical analysis

ResultsStudy selection and characteristics of the included studiesMethodological quality of studiesLocal recurrenceNodal recurrenceSystemic recurrenceOverall survivalMortalityToxicity, quality of life and cosmesis

DiscussionConflict of interest statementFinancial disclosure/AcknowledgementsAppendix A Supplementary dataReferences