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The Breast 18 (2009) 143–149

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The Breast

journal homepage: www.elsevier .com/brst

Review

Post-operative radiotherapy for ductal carcinoma in situ of the breast – Asystematic review of the randomised trials

Annabel Goodwin a, Sharon Parker b, Davina Ghersi b, Nicholas Wilcken c,*

a Familial Cancer Service, Westmead Hospital, Westmead 2145, Australiab Systematic Reviews and Healthcare Assessment, NHMRC Clinical Trials Centre, The University of Sydney, Camperdown 2050, Australiac Medical Oncology, Westmead and Nepean Hospitals, The University of Sydney, Westmead 2145, Australia

a r t i c l e i n f o

Article history:Received 11 March 2009Received in revised form15 April 2009Accepted 16 April 2009

Keywords:Ductal carcinoma in situRadiotherapyMeta-analysis

* Corresponding author.E-mail address: nicholas_wilcken@wmi.usyd.edu.a

0960-9776/$ – see front matter � 2009 Elsevier Ltd.doi:10.1016/j.breast.2009.04.003

a b s t r a c t

Aim: To summarise the results of randomised trials testing the addition of radiotherapy (RT) to breastconserving surgery for ductal carcinoma in situ (DCIS); to determine whether there are subsets ofwomen with DCIS who do not benefit from RT; and to determine what the balance may be betweenreduction in risk of recurrence and long-term toxicity.

Methods: We performed a systematic review to resolve these questions, using standard Cochranemethodology to identify, select and appraise relevant randomised trials.

Results: Four randomised controlled trials involving 3925 women were identified. All were high qualitywith minimal risk of bias. Analysis confirmed a statistically significant benefit from the addition ofradiotherapy on all ipsilateral breast events (HR¼ 0.49; 95% CI 0.41–0.58, p< 0.00001). All subgroupsanalysed (margin status, age and grade) benefited from the addition of radiotherapy. Nine womenrequire treatment with radiotherapy to prevent one ipsilateral breast recurrence (NNT¼ 9). Deaths dueto vascular disease, pulmonary toxicity and second cancers were low and not significantly higher forwomen who received radiotherapy.

Concluding statement: Radiotherapy was beneficial in all clinically relevant subgroups. Longer follow-upis required to detect any long-term toxicity from use of radiotherapy. To date, no increase in toxicity hasbeen identified.

� 2009 Elsevier Ltd. All rights reserved.

Introduction

Ductal carcinoma in situ (DCIS) of the breast is a pre-malignantcondition with an uncertain natural history. Modern screeningprograms have made DCIS a more common diagnosis than in thepast. However, determining which DCIS lesions, if left untreated,might progress to invasive (and therefore potentially lethal) canceris currently not possible.

While mastectomy effectively cures the condition, there hasbeen an obvious desire to pursue less radical treatment options.Breast conserving surgery (BCS) allows retention of the breast butwith an increased risk of local recurrence, and half such recurrenceswill be invasive cancers. The local recurrence rate is influenced bya number of factors, such as size, grade and margin status, buta reasonable average figure is 16% at 5 years.1 Randomised trials

u (N. Wilcken).

All rights reserved.

suggest that this figure might be reduced to approximately 8% withthe addition of radiotherapy.

Short-term complications of radiotherapy include thetemporary discomfort of a skin reaction (such as a rash orredness), radiation pneumonitis and a significant amount of timespent attending hospital for treatment over a period of four tosix weeks. Knowledge of long-term complications is based onolder trials of radiotherapy following surgery for invasive breastcancer. These include a modest increase in vascular death,2

pulmonary toxicity including lung cancer and pulmonaryfibrosis, second malignancies and contralateral breast cancer.However, newer radiotherapy techniques in use today such asconformal fields result in a lower radiotherapy dose to thesurrounding normal tissues and may result in lower long-termcomplications.

We therefore conducted a systematic review of the literature toexamine both the benefits and the harms of post-operative radio-therapy for DCIS, and to prospectively determine whether there aresubgroups of women with DCIS who do not get an overall benefitand can safely omit radiotherapy.

A. Goodwin et al. / The Breast 18 (2009) 143–149144

Methods

We used standard Cochrane methodology to identify, select andappraise relevant randomised trials (http://www.mrw.interscience.wiley.com/cochrane/clabout/articles/BREASTCA/frame.html).

In brief, the Cochrane Breast Cancer Group Specialised Registerwas searched on 17/01/2008. Studies with the keywords ‘radio-therapy’, ‘dcis’ or ‘ductal carcinoma’ or text words ‘dcis’, ‘ductalcarcinoma in situ’ or ‘intraductal carcinoma in situ’ were extractedfor consideration. This search was complemented by searches ofthe Cochrane Central Register of Controlled Trials (The CochraneLibrary Issue 1, 2008), Medline (February 2008) and Embase(February 2008), reference lists of articles and handsearching ofrelevant conference abstracts.

Eligibility was independently determined by two investigators(AG, NW), according to predetermined criteria. Studies fulfillingeligibility criteria were independently evaluated for quality usingthe methods described in the Cochrane Handbook.3 Inclusioncriteria were: randomised controlled clinical trials including onlypatients with pure DCIS (no invasive cancer) comparing breastconserving surgery (lumpectomy, quadrantectomy, segmentalmastectomy) þ/� radiotherapy. Trials where patients receivedtamoxifen were acceptable provided this was given in both studyarms.

Data extracted included patient demographics, time to eventdata for recurrence and information about toxicity. Two authors(AG, SP) extracted the hazard ratio (HR) and associated variancesfor all ipsilateral breast events indirectly using the methodsdescribed by Parmar (1998).4 For three trials we used data extrac-ted from published Kaplan–Meier curves (NSABP, 20015; SweDCIS,20086; UKCCCR, 20037). For the EORTC trial (EORTC, 20068) weused available summary statistics to determine the HR and itsvariance. A fixed effects model was used for the primary analysis.There were three planned subgroup analyses: i) surgical marginsclear or not; ii) over 50 years compared to under 50 years and iii)documented presence of marked comedo necrosis or not.

Results

Six trials fulfilled the inclusion criteria (Fig. 1). Two trials iden-tified have closed to accrual, but follow-up is continuing and nodata are available from these trials (NCT00077168; RTOG 98). Fourtrials were included in our review (EORTC, 20068; NSABP, 20015;SweDCIS, 20086; UKCCCR, 20037).

Description of the trials

The EORTC trial (EORTC, 20068) – a randomised controlled trialinvestigating the role of radiotherapy after local excision of DCIS.Participants in this multicentre trial were 1010 women recruited inEurope between March 1986 and July 1996. The trial has publisheddata with a median follow-up of 10.5 years.

The NSABP trial (NSABP, 20015) – a randomised controlled trialinvestigating the role of radiotherapy after lumpectomy for DCIS.Participants in this multicentre trial were 818 women recruited inthe United States of America and Canada between October 1985and December 1990. The trial has follow-up data for a mean of 10.7years.

The SweDCIS trial (SweDCIS, 20086) – a randomised controlledtrial investigating the role of radiotherapy after sector resection forDCIS. Participants in this multicentre trial were 1067 womenrecruited in Sweden between September 1987 and December 1999.The trial has follow-up data for a mean of 8.4 years.

The UKCCCR trial (UKCCCR, 20037) – a multicentre randomisedcontrolled trial investigating the effectiveness of adjuvant

radiotherapy and tamoxifen for DCIS in a 2-by-2 factorial design.Patients were either randomised to both treatments or randomisedto either one with an elective decision to give or withhold the othertreatment. Recruitment from breast screening programmescommenced in May 1990 in the United Kingdom and September1991 in Australia/New Zealand and concluded in August 1998. Intotal, 1030 women were randomised to radiotherapy/no radio-therapy in this trial of 1701 women. The trial has published datafrom a median follow-up of 4.4 years.

The risk of bias was low as the quality of all four included studieswas high.

Benefit of radiotherapy

We calculated the hazard ratio and its associated variance foreach of the four trials for all ipsilateral breast events and pooled thisresult. The pooled HR for all ipsilateral breast events (Fig. 2) washighly statistically significant in favour of radiotherapy (HR 0.49;95% CI 0.41–0.58, p< 0.00001).

Individual trial results were all consistent with the pooled HRfor all ipsilateral breast events. The EORTC trial8 found the 10-yearlocal relapse-free rate was 85% with adjuvant radiotherapycompared to 74% (HR 0.53, log rank p< 0.001). The UKCCCR trial7

found the absolute risk of all ipsilateral events was reduced by 8.9%(from 13.7% in the control arm to 4.8% in the RT arm). The SweDCIStrial6 found the absolute risk reduction was 16% at 10 years, cor-responding to a relative risk of 0.40 (95% CI 0.30–0.54). The NSABPtrial5 found the cumulative incidence of ipsilateral recurrence at 12years was 31.7% in the control group compared to 15.7% in the RTgroup (RR 0.43; 95% CI 0.32–0.58, p< 0.000005).

Separate data for in situ versus invasive recurrence werereported differently between trials, preventing pooling of all fourtrials for these outcomes. However, each individual trial confirmeda reduction in both in situ and invasive cancer associated with theuse of RT, consistent with the main result (data not shown).

All trials reported excellent survival in both the RT and controlgroups. In the NSABP trial5 overall survival was 86% (control)compared to 87% (RT) at 12 years follow-up. In the EORTC trial,8 10-year survival was 95% in both groups and 10-year metastasis freesurvival was 96% in both groups. The SweDCIS trial6 did not reportsurvival, but the number of women with either breast cancer deathor other death was similar in each group (8.4% in the RT groupcompared to 9.6% in the control corresponding to a survival of 92%and 90% respectively). The UKCCCR trial7 did not report survivalaccording to randomisation to radiotherapy or not, but included alltrial participants (not all randomised to RT), and survival was 97.9%in the control group and 96.2% in the RT group.

Subgroup analysis of benefit

The EORTC trial8 and SweDCIS trial6 both conducted subgroupanalysis of the benefit from radiotherapy. The EORTC trial foundwith multivariate analysis young age (40 years or less), interme-diately or poorly differentiated DCIS, cribriform or solid growthpattern or doubtful margins were risk factors for recurrence but allsubgroups benefited from addition of radiotherapy. The SweDCIStrial found minimal benefit for RT in women under age 50 (who hada 6% risk reduction) but marked benefit for RT in women over age60 years (with an 18% risk reduction), which was not confoundedby focality, lesion size, completeness of excision or detection mode.

A separate report from the NSABP trial9 found a benefit for RT inall groups according to the pathological feature studied but thepresence or absence of comedo necrosis was an independentpredictor of recurrence risk. When moderate/marked comedonecrosis was present, the RR was 0.30 compared to an RR of 0.52

Database search: (N=total number of hits)

Medline N=124 Embase 2002-2008 N=307 Cochrane Central N=150

CBCG Specialised Register

N=35

Handsearching

Conference abstracts N=0 Reference Lists N=0

Journal N=1

Excluded trials: N=7

Not RCT (n=1)

Registered trial report unable tolocate further details (n=2)

Ineligible, trial includes onlyinvasive breast cancer (n=4)

Total N= 7

Potentially appropriate RCT to be included in themeta-analysis (n=38)

20 reports of eligible trials

Included trials N=4

References to RCT identified: Total N=617

References to RCTs identified and screened for retrieval N=45

Randomised controlled trial ongoing(n=2)

Reports of eligible trials n=36

Duplicate reports n=16

Fig. 1. QUORUM flow diagram.

A. Goodwin et al. / The Breast 18 (2009) 143–149 145

Fig. 2. Pooled result for all 4 trials testing the addition of RT to breast conserving surgery; all ipsilateral events.

A. Goodwin et al. / The Breast 18 (2009) 143–149146

with its absence. No subgroup information was provided from theUKCCCR trial.7

We prospectively planned to analyse the benefit of radiotherapyin the following subgroups: whether DCIS was completely excised(margins clear) or not, age greater than 50 versus less than 50 andcomedo necrosis present versus absent.

Information regarding completeness of excision was availablefor 2272 women; 73.5% of participants in the EORTC trial,8 70.8% ofparticipants in the NSABP trial10 and 89.2% of participants in theSweDCIS trial.6 Data were extracted and pooled for these partici-pants (Fig. 3). RT was equally effective in both groups. In the groupwith complete excision the RR was 0.48 (95% CI 0.39–0.59,p< 0.00001), and for those with incomplete excision, the calcu-lated RR was 0.55 (95% CI 0.38–0.78, p¼ 0.0010).

The trials defined young age differently. The EORTC trial8

reported data for women under or over age 40 years. For womenover age 40 years the HR was 0.59 (95% CI 0.43–0.81) p¼ 0.001, andin the small group of 41 women under age 40, the HR calculatedfrom reported summary statistics was 0.33 (95% CI 0.13–0.88)p¼ 0.03. The NSABP trial10 and SweDCIS trial6 reported data onwomen over or under age 50 years. Data were pooled from thesetwo trials (Fig. 4). For women over age 50 years the RR was 0.35(95% CI 0.27–0.46) p< 0.00001, and for women under age 50 yearsthe RR was 0.67 (95% CI 0.48–0.93) p¼ 0.02.

Ipsilateral breast event rates according to histological subtypewere available for two trials, the NSABP trial,10 available for 83.1% oftrial participants and the EORTC trial,8 available for 76.4% of trial

Fig. 3. Pooled result for 3 trials testing the addition of RT t

participants. Data were pooled (Fig. 5) and a benefit from RT wasfound both in the presence and absence of comedo necrosis. In thepresence of comedo necrosis, the overall RR was 0.44 (95% CI0.33–0.59) p< 0.00001. In the absence of comedo necrosis, the RRwas 0.60 (95% CI 0.45–0.81), p< 0.0009. The SweDCIS trial6

reported on a cohort of 271 women (25.4% trial participants) andreported of those, if comedo necrosis was present the HR was 0.40(95% CI 0.23–0.67) and if comedo necrosis was absent the HR was0.07 (95% CI 0.01–0.42) with p¼ 0.068 for the test for interaction).

Number required to treat

We pooled results from the four trials (NSABP, 20015; UKCCCR,20037; SweDCIS, 20086; and EORTC, 20068) to calculate the inci-dence of all ipsilateral breast recurrence. Ipsilateral recurrence was11.6% for women who received radiotherapy compared to 23.9% forwomen treated with surgery alone. Nine women require treatmentwith radiotherapy to prevent one ipsilateral breast recurrence.

Potential harm from radiotherapy

We attempted to assess data on toxicity in all four trials. For theUKCCCR trial7 toxicity data were not provided for the interventionand control groups but only for the whole group of 1694 patients.Attempts to contact trial investigators were not successful. Infor-mation about cause of death was not reported for non-breastcancer death for the SweDCIS trial.6 Contact was made with a trial

o breast conserving surgery: clear margins versus not.

Fig. 4. Pooled result for 2 trials testing the addition of RT to breast conserving surgery: age greater than 50 years versus age less than 50 years.

A. Goodwin et al. / The Breast 18 (2009) 143–149 147

investigator and this information is not yet available. Overall, therewas a low number of deaths in each of the four trials. It is recog-nised that longer follow-up will increase the incidence of any long-term toxicity. Median follow-up ranged from 4.4 years to 10.5 yearsfor these trials.

Three trials had information about the cause of non-breastcancer deaths. There were seven deaths due to vascular causes inthe NSABP trial10 (six in the control arm and one in the RT arm), thefirst report of the EORTC trial11 reported two vascular deaths (onein each arm) and subsequently8 reported seven vascular deaths(arm not specified). The UKCCCR trial7 reported six vascular deaths.There were no reports of pulmonary toxicity in any of the trials.Reports of second cancers did not always specify the type of

Fig. 5. Pooled result for 2 trials testing the addition of RT to breas

malignancy. In the NSABP trial,5,10 one woman died of either lungcancer or metastatic breast cancer (could not be determined).Eighteen second cancers occurred in the control group includingtwo lung cancers and three endometrial cancers. Twenty secondcancers occurred in the radiotherapy group including one lungcancer, one oesophageal cancer, one bone cancer, one soft tissuecancer, one cancer in the lymph nodes and two endometrialcancers. In the EORTC trial,8 there was one mediastinal lymphoma(RT arm) in the first EORTC trial report11 and in the subsequentreport there were thirteen malignancies other than breast cancer(type and arm of study not specified). The UKCCCR trial7 reportednine deaths due to another malignancy (type and arm of study notspecified). There were no reports of osteoradionecrosis in any trial.

t conserving surgery: comedo necrosis present versus absent.

A. Goodwin et al. / The Breast 18 (2009) 143–149148

There was insufficient follow-up data reported to adequately assessfor long-term toxicity from the addition of radiotherapy.

Given data from invasive breast cancer trials suggesting anincrease in contralateral invasive breast cancer associated with RT,information was collated for this outcome in the DCIS trials.Contralateral breast events were similar in both radiotherapy andcontrol groups for all trials. In the NSABP trial5 rates were 4.5% inthe control and 7.3% in the RT group (RR 1.46; 95% CI 0.81–2.61,p¼ 0.26). In the EORTC trial8 rates were 5.6% in the control and 7.7%in the RT group (95% CI 0.87–2.30, p¼ 0.16). The UKCCCR trial7

found similar contralateral breast event rates (2%) in each group(HR¼ 0.82, p¼ 0.65). The SweDCIS trial6 reported 5.9% contralat-eral breast cancer in the control arm and 6.5% in the RT arm.

There was no information about any short-term toxicity asso-ciated with RT in any of the four trials. There were no quality of lifedata reported in any of the trials.

Discussion

We did not identify any previous meta-analyses on this topic.This systematic review and meta-analysis has confirmed the indi-vidual trial results of a benefit of adding radiotherapy to breastconserving surgery for DCIS. Results pooled from four trials iden-tified by a comprehensive search strategy demonstrate a highlystatistically and clinically significant reduction in ipsilateral breastevents (HR 0.49; 95% CI 0.41–0.58, p< 0.00001). All four trials werelarge multicentre trials, with excellent randomisation procedures,use of allocation concealment and intention to treat analysis. Therewas no heterogeneity present between trials.

The characteristics of women included in these four trials reflectthe population of women commonly diagnosed with DCIS today. Inthese studies, the majority of women had clinically impalpableDCIS diagnosed by screening mammography. The reported medianages of women were just over 50 years. This further strengthens theapplicability of the results of this meta-analysis to most womenseen in clinics for treatment of DCIS.

The validity of our results is high due to the quality of theincluded studies and our comprehensive search strategy. Twosmaller trials were identified whose results are not yet available butwhen available, these results are unlikely to influence the overallresult. It is also possible that unpublished eligible trials weremissed by our search strategy. We welcome contact by any trialinvestigators if this is the case. We feel it is unlikely there are anyother trials with sufficient patient numbers to influence our results.A small number of trial participants were excluded from analysis insome of the included trials but all participants were accounted for.This is therefore unlikely to influence any of the trial results.

The benefit from the addition of radiotherapy to breastconserving surgery was homogeneous between each individualtrial and was confirmed on extraction and pooling of data. Thefollowing subgroups were planned for analysis prior to our review:complete surgical excision of DCIS compared to incomplete exci-sion, older age compared to younger age, and presence of marked/moderate comedo necrosis compared to its absence. Pooling ofresults for all of these subgroups showed benefit from the use ofradiotherapy. The 95% confidence intervals of the HR wereoverlapping.

To assess the balance between benefit from radiotherapy andpossible toxicity from treatment, the cause of death was assessedfrom all studies. Overall, long-term harm was not well reported inthese trials. With available information however, there was noevidence of excess deaths attributable to the addition of radio-therapy, either due to vascular disease, pulmonary toxicity orsecond malignancies. Rate of death due to any cause was low inboth arms of all trials and was similar between trials. However, it is

important to recognise that these trials were powered for localcontrol rather than survival, and a difference in survival due tolong-term toxicity from use of radiotherapy may not be detectable.

However, if long-term toxicity due to radiotherapy does occur,a longer follow-up period may be required to show such an effect.In relation to the potential risk of contralateral breast cancer,a recent study12 with a long median follow-up time of 13.8 yearshas found an increase in contralateral breast cancer risk with use oftangential RT fields following breast conserving surgery for womentreated under age 45. Counterbalancing this, radiotherapy tech-niques continue to improve, with the likely result that any long-term harm associated with the use of radiotherapy may be reducedeven further for patients in the future.

Short-term toxicity from radiotherapy was not reported andthere were no quality of life data in any of the trials. Assessment ofany potential short-term harm from use of radiotherapy wastherefore not possible. However the powerful efficacy of RT acrossall relevant subgroups confirmed in this review and the lack ofsignificant long-term toxicity argue that harm from any short-termtoxicity is outweighed by these substantial benefits.

Conflicts of interest statement

None declared.

Acknowledgements

The authors would like to thank Nicole Holcroft for her assis-tance with the development of search strategies. We would alsolike to thank Patrick Fitzgerald, Associate Professor Dianne O’Con-nell and Professor Val Gebski for advice in developing the analysissection of this protocol and Angela Webster for her advice about thereview.

Contributions of authors

NW and AG reviewed articles for inclusion in the meta-analysisand assessed the quality of the trials. AG and SP extracted data. AGand NW wrote the review and all authors contributed to the finalreview. DG designed the review and wrote the initial protocol. AGrevised the protocol in 2008. All other authors commented on theprotocol. NW is the guarantor.

This is a version of a Cochrane Review, which is available inThe Cochrane Library. A more detailed review is published in theCochrane Database of Systematic Reviews Goodwin A, Parker S,Ghersi D, Wilcken N. Post-operative radiotherapy for ductalcarcinoma in situ of the breast. Cochrane Database of SystematicReviews 2009, Issue 1. Art. No.: CD000563. DOI: 10.1002/14651858.CD000563.pub3. Cochrane systematic reviews areregularly updated to include new research, and in response tofeedback from readers.

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