CLINICAL INVESTIGATION Breast Cancer DUCTAL CARCINOMA IN SITU—THE INFLUENCE OF THE RADIOTHERAPY BOOST
ON LOCAL CONTROL
P HILIP W ONG,M.D.,F.R.C.P.(C),*C HRISTINE L AMBERT,M.D.,F.R.C.P.(C),*
R AMANAKUMAR V.A GNIHOTRAM,P H.D.,y M ARC D A VID,M.D.,F.R.C.P.(C),* M ARIE D UCLOS,M.D.,F.R.C.P.(C),*AND C AROLYN R.F REEMAN,M.B.,B.S.,F.R.C.P.(C)* *Division of Radiation Oncology,McGill University Health Centre,Montreal,QC,Canada;and y Division of Cancer Epidemiology,
Department of Oncology,McGill University,Montreal,QC,Canada
Purpo:Local recurrence(LR)of ductal carcinoma in situ(DCIS)is reduced by whole-breast irradiation after
breast-conrving surgery(BCS).However,the benefit of adding a radiotherapy boost to the surgical cavity for
DCIS is unclear.We sought to determine the impact of the boost on LR in patients with DCIS treated at the McGill
University Health Centre.
Methods and Materials:A total of220concutive cas of DCIS treated with BCS and radiotherapy between Jan-
uary2000and December2006were reviewed.Of the patients,36%received a radiotherapy boost to the surgical
cavity.Median follow-up was46months for the boost and no-boost groups.Kaplan–Meier survival analys and
Cox regression analys were performed.
Results:Compared with the no-boost group,patients in the boost group more frequently had positive and<0.1-cm
margins(48%vs.8%)(p<0.0001)and more frequently were in higher-risk categories as defined by the Van Nuys
Prognostic(VNP)index(p=0.006).Despite being at higher risk for LR,none(0/79)of the patients who received
a boost experienced LR,whereas8of141patients who did not receive a boost experienced an in-breast LR
(log-rank p=0.03).Univariate analysis of prognostic factors(age,tumor size,margin status,histological grade,
necrosis,and VNP risk category)revealed only the prence of necrosis to significantly correlate with LR
(log-rank p=0.003).The whole-breast irradiation do and fractionation schedule did not affect LR rate.
Conclusions:Our results suggest that the u of a radiotherapy boost improves local control in DCIS and may
outweigh the poor prognostic effect of necrosis.Ó2012Elvier Inc.
Breast,Ductal carcinoma in situ,Boost,Radiotherapy.
INTRODUCTION
The incidence of ductal carcinoma in situ(DCIS)has mark-edly incread in recent years as a result of the widespread u of screening mammography,and DCIS now accounts for more than20%of all breast cancers(1).A randomized controlled trial comparing mastectomy with breast-conrving therapy has not been performed,but long-term survival appears to be similar(1).Becau of the low mortality rate,most studies on DCIS have focud on local recurrence(LR).Several prospective trials National Surgical Adjuvant Breast and Bowel Project(NSABP)B-17,Euro-pean Organisation for Rearch and Treatment of Cancer (EORTC)10853,U.K.DCIS,and SweDCIS)have demon-strated that adjuvant whole breast irradiation(WBI)after breast-conrving surgery(BCS)significantly improves the local control of DCIS,as for invasive breast cancers(2–5).
Although the benefit of a boost to the tumor bed after WBI in patients with invasive breast cancer is well established through randomized controlled trials(6,7),the u of a boost is less well studied and has never been tested prospectively in DCIS.Prior randomized studies involving DCIS varied in their recommendation for the u of the boost:at the discretion of the treating physician(NSABP B-17),not recommended(EORTC10853and U.K.DCIS), and not addresd(SweDCIS)(2–5,10).
To our knowledge,the role of the boost in DCIS has been retrospectively examined by only four groups.Omlin et al. assd the role of a boost in373patients#45years of age treated in18institutions in Europe(8).With a median follow-up of72months,local control was improved when
a boost was given in addition to WBI(hazard ratio[HR],
0.45,95%confidence interval[95%CI],0.23–0.90).The
Reprint requests to:Christine Lambert,M.D.,F.R.C.P.(C),De-partment of Radiation Oncology,McGill University Health Centre, 1650Cedar Avenue,Room D5-400,Montreal,QC,Canada H3G 1A4.Tel:(514)934-8040;Fax:(514)934-8392;E-mail:
Prented in part as a poster prentation at the American Society of Clinical Oncology(ASCO)Annual Meeting,June4-82010, Chicago,IL.
Conflict of interest:none.
Int.J.Radiation Oncology Biol.Phys.,V ol.82,No.2,pp.e153–e158,2012
CopyrightÓ2012Elvier Inc.
Printed in the USA.All rights rerved
0360-3016/$-e front matter doi:10.1016/j.ijrobp.2011.03.045
addition of a boost was at the discretion of the treating phy-sician,and the boosted group included a greater percentage of patients with unknown margin status and tumor size.In the same year,Yerushalmi et al.published a smaller study of75patients with DCIS and micro-invasive dia treated with radiotherapy of whom20received a boost to the surgi-cal cavity(SC).The median follow-up was81.5months(9). The authors did notfind any additional value for the u of a boost.Julian et al.prented,at the American Society of Clinical Oncology(ASCO)Annual Meeting2008,their ret-rospective data from NSABP B-24in which692of the1569 patients with DCIS received a boost after50Gy given to the whole breast with or without tamoxifen(11).The authors found a similar rate of local control in the boosted and nonboosted groups despite there being significantly more patients with positive rection margins(21%)in the boosted group.Monteau et al.similarly suggested that the boost may compensate for clo or minimally involved mar-gins in DCIS(12),thus sparing patients from re-excision (Table1).Two multi-institutional randomized trials have been initiated,one by the Tra
ns-Tasman Radiation Oncology Group and the cond in France,to examine the role of the boost in patients with DCIS(13).Accrual began in2007 and2008,respectively.While waiting for the results,we reviewed our own experience in DCIS to determine the impact of the boost in DCIS.
The current study is a retrospective review of the McGill University Health Centre(MUHC)experience in the treat-ment of DCIS with BCS followed by radiotherapy.Patients with DCIS typically receive a boost when the rection mar-gins of the tumor are clo or positive,and no further rec-tion is done.As well,in our institution,WBI is often given using a hypofractionated regimen which has been shown to be noninferior to50Gy/25fractions in invasive breast cancer(14)but has not been prospectively tested in DCIS.
METHODS AND MATERIALS
Patient data collection
A arch of the MUHC databa identified220patients who were treated with radiotherapy for DCIS from January2000until December2006.Internal review board approval from the MUHC was obtained for this project.Chart review was done using the charts from the MUHC Department of Radiation Oncology and the MUHC’s centralized patient information system,OACIS(Emergis V r7.3.0)and Plat
ypus(MUHC V1.8.13).Pathology results were obtained from the patients’charts and were not reviewed centrally. Treatment methods
All patients underwent breast conrving surgery followed by adjuvant radiotherapy.Patients all underwent CT simulation with standard breast board positioning.WBI consisted of two tangential fields using6or mixed6/18-MV photons.For the electron boost, patients underwent ultrasound localization of the SC to help delin-eate thefield.The energy of the electron boost was prescribed ac-cording to the depth of the SC as measured on CT-sim and ultrasound.The do for the electron boost ranged from7.5Gy/3 fractions to16Gy/8fractions.Generally,boost dos of15to16 Gy were rerved for patients with positive margins.In1patient, the boost was delivered using brachytherapy.
At the MUHC,a do fractionation schedule of45Gy/20frac-tions was ud for WBI before the publication of the equivalence study by Whelan et al.(14).Thereafter,the Ontario Clinical Oncol-ogy Group(OCOG)regimen of42.5Gy/16fractions was ud for patients with physical and dosimetric characteristics similar to tho included in the OCOG trial.
Statistical analysis
The Chi-square test was ud to determine the contingency be-tween the patient groups and charac
teristics except for tumor size (Wilcoxon rank-sum test).Descriptive statistics and time to event analys were performed using Kaplan–Meier survival analys and tested for statistical differences with the log-rank test.Time to event was defined from thefirst day of WBI until the date of a pathologically proved local recurrence within the treated breast or last follow-up.Univariate analys using Cox proportional haz-ard ratio of prognostic factors and local recurrence were done.Re-sults significance was defined at a p value#0.05.All analys were done using PASW statistics17(SPSS Inc.,Chicago,IL).
RESULTS
Patient characteristics
Among the220patients with DCIS,the groups that did or did not receive a boost were balanced with respect to age,
Table1.Comparison with previous studies on the effect of the boost
Studies Comparison N Median age(y)Positive margins Necrosis Median f/u Recurrence
Omlin et al.(2006)Boost vs.
no boost 150
166
All<457%
4%
32%
41%
72mo10-y LR:14%
10-y LR:28%
Yerushalmi et al.(2006)Boost vs.
no boost 20
55
小猪仔
5881mo15%
12.7%
Julian et al.(Abstract2008)Boost vs.
no boost 692
877
NSABP B-24:5321%
15%
52%
45%
14y13.8%
14.3%
Monteau et al.(2009)Boost vs.
Re-excision for
clo(<2-mm)
margins 147
55
5350%
74%
60%
64%
89mo7-y LR:9.3%
7-y LR:9.6%
大蒜英语
Current study Boost vs.
no boost
79
121
毛血旺食材585%
0.8%
56%
49%
46mo0%
6%
e154I.J.Radiation Oncology d Biology d Physics V olume82,Number2,2012
tumor size,grade,estrogen receptor (ER)status,and pres-ence of necrosis.The treatment regimens ud for WBI were similarly balanced (Table 2).However,the boosted pa-tients were more frequently categorized into groups at higher risk for recurrence as defined by the Van Nuys Prognostic (VNP)risk grouping (p =0.006)and more frequently had positive or clo surgical margins than tho who had no boost (p =0.0001).Median follow-up for both groups of pa-tients was 46months.
-boost DCIS
Eight patients experienced LR,four cas of which were invasive (Table 3).All eight recurrences occurred in patients who did not receive a boost.The correlation between LR and not receiving a boost was significant (p =0.035)(Fig.1a).
Prognostic factors
Prognostic factors such as age,quality of surgical mar-gins,tumor size,grade,ER status and VNP risk categories were not statistically correlated with LR (Table 4).All 8LR occurred in patients who had tumors with necrosis (5with Grade 2and 3with Grade 3histology),which corre-lated significantly with LR (p =0.0028).Among the patients who did not receive a boost,necrosis was significantly cor-related with LR (p <0.005)(Fig.1b).
ventional fractionation
There was no difference in LR between patients treated using 50-Gy,45-Gy,and 42.4-Gy regimens (Table 4),nor be-tween patients treated with 50-Gy regimens and tho who received hypofractionated regimens (45Gy or 42.4Gy).
Table 3.Characteristics of the patients with local recurrence
Ca Age (y)at diagnosis
VNP risk category T size (cm)Margin Necrosis Histological grade
RT do to whole breast
A 51Low 0.35$0.1cm Prent 242.5
B 53Low 10/48hpf $0.1cm Prent 250
C 47Low 1.5$0.1cm Prent 245
D 55Intermediate 1.5$0.1cm Prent 342.5
E 50Intermediate 1$0.1cm Prent 342.5
F 51Intermediate 2.2$0.1cm Prent 250
G 60Intermediate 2.5<0.1cm Prent 250H
50
Intermediate
1灶王爷的故事
<0.1cm
键盘冲突Prent
3
42.5
Table 2.Clinical characteristics of ductal carcinoma in situ (DCIS)patients by boost status
No boost N =141(%)
Boost N =79(%)Significance test and p value
Age (y)at diagnosis #5034(24%)21(27%)Chi(1)=0.1646p =0.685>50
107(76%)
58(73%)
Median size of tumors (cm)1(0.91–1.13)1(0.73–1.12)Z =À0.572*p =0.5675Tumor Grade 123(16%)12(16%)Chi(2)=0.1678
p =0.92Tumor Grade 265(46%)39(49%)Tumor Grade 348(35%)26(32%)Necrosis no 35(51%)35(44%)Chi(1)=0.9262
p =0.34Necrosis yes 72(49%)72(56%)Margin status
Positive or <0.1cm 11(8%)38(48%)Chi(2)=61.4052p =0.0001$0.1cm 125(89%)37(47%)Unknown
5(4%)4(5%)ER status positive 78(55%)48(61%)Chi(2)=0.7612p =0.683ER status negative 25(18%)1
1(14%)Unknown
38(27%)20(25%)VNP risk group High
1(1%)4(5%)Chi(2)=10.25p =0.006Intermediate 66(43%)47(60%)Low
70(53%)24(31%)Whole breast radiation do 42.4–43Gy 39(28%)29(36%)Chi(1)=1.2006
p =0.55
45Gy 60(44%)29(38%)49–51Gy
42(28%)21(26%)No.with local recurrence 8(6%)0(0%)
Median follow-up (mo)
46.2
46.3
Abbreviation:VNP =Van Nuys Prognostic index.*Wilcoxon rank-sum test.
Impact of radiotherapy boost in DCIS d P.W ONG et al .e155
墨梅的古诗DISCUSSION
Several features in DCIS have been associated with higher risk of local recurrence including young age,high grade,
comedo-type necrosis,and clo or involved margins (1).A scoring system,the VNP index,was developed to deter-mine whether patients would potentially benefit from adju-vant radiotherapy.The VNP index was derived from retrospective analysis of DCIS patients treated with breast conrving surgery (15,16),but has never been prospectively validated,and veral studies have yielded contradictory results as to its value (17–21).Importantly,no subgroups treated by partial mastectomy have yet been identified that do not benefit from adjuvant radiotherapy.We found strong correlation between the prence of necrosis and LR bad on Kaplan–Meier analysis (p =0.0028)but no correlation between age,tumor size,tumor grade,VNP index,and u of a hypofractionated radiother-apy regimen.The lack of correlation between LR and other known prognostic factors is likely condary to the lection bias for patients who are at very high risk (i.e.,tho with young age,positive surgical margins,and very large tumors)to undergo mastectomy instead of breast-con
rving treat-ment,and for patients with involved,clo,or questionable surgical margins to receive a boost.It is possible that,with longer follow-up and more events,the relative importance of some of the factors may become clearer,although more likely that such information will be forthcoming only from the ongoing prospective trials.
Local relap was significantly reduced when a boost was
Fig.Kaplan–Meier curve for local recurrence of ductal carcinoma in situ (DCIS)patients.(a)-boost patients,and (b)no-boost patients with necrosis (+)vs.without necrosis (–).
Table 4.Univariate analysis of ductal carcinoma in situ
(DCIS)patients
Stratification
Univariate HR (95%CI)
Event (LR)
Age (y)at diagnosis:#50 1.0
>50
0.54(0.13–2.29)Tumor size:#1.5cm 1.0
1.6–4.0cm 0.68(0.10–5.69)$4.1cm
0.66(0.08–5.63)Histological grade 1 1.0
2 1.89(0.41–8.08)3
1.69(—)
Margin:Positive OR <0.1cm 1.0
$0.1cm
1.22(0.24–6.17)
VNP category:Low
1.0
VNP category:Intermediate/high 0.46(0.09–2.39)Whole breast radiation do 42.4–43Gy 1.0
医疗商业保险45Gy 0.15(0.02–1.36)50–51Gy 0.60(0.13–2.87)
艺术文字<50Gy 1.0
50–51Gy
1.35(0.32–5.69)
e156I.J.Radiation Oncology d Biology d Physics V olume 82,Number 2,2012
none of the boosted patients experienced LR.All8cas of LR occurred in patients who did not receive a boost and had tumors with necrosis.Other studies(2,11,23,24)have similarly found the prence of necrosis to be a sign of aggressiveness and incread risk of recurrence.Our results suggest that the u of a radiotherapy boost may counteract the poor prognostic effect of necrosis as well as other factors such as poor surgical margins.This is in keeping with the results of Omlin et al.and Monteau et al.(8,12).
In contrast to the results of Julian et al.(11),our data sug-gest that a boost provided a significant improvement in local control.This may be explained by the lower percentage of patients with positive margins in our study(2%vs.21%), perhaps becau of greater care on the part of the surgeons in achieving negative margins since the completion of NSABP B-24.As the do of radiotherapy is more appropri-ate for microscopic rather than gross dia at positive mar-gins,our more completely rected population may better show the efficacy of the boost.Improved accuracy of radio-therapy through the u of CT simulation and ultrasound for localization and planning of the bo
ost for all patients may also have contributed to improved patient outcome.Since the completion of B24,multiple studies have demonstrated the u of only clinical examination to delineate the boost volume to be inadequate,resulting in underdosage in as much as50%of cas(25–27).
Of our patients,71%received hypofractionated regimens of radiotherapy.Our study did notfind a correlation between LR and the u of hypofractionated regimens.Thisfinding was in agreement with a recent publication of similar size (n=266)and follow-up(45months)in which no difference in LR was obrved between patients with DCIS treated with conventional and hypofractionated regimens(28).A pro-spective trial is ongoing to compare the efficacy of hypofrac-tionated regimen to the conventional regimen in DCIS (v NCT00470236).
As with most retrospective studies,inherent differences be-tween patient groups were identified,but the only accentu-ated the efficacy of the boost(Tables2and3).One limitation of the current study is its short follow-up,which may reduce the chance offinding true differences in local con-trol between the different subgroups.With longer follow-up, larger number of events may uncover more risk factors associ-ated with incread risk of local recurrence.In addition,the ab-nce of events in the boost group prevented us from further analys using multiple variables.Nevertheless,necrosis was found to be a highly significant risk factor,supporting its clin-ical importance.Bad on the currently a
vailable data on the efficacy of the boost,it is likely beneficial to patients who are young(8),have clo or positive surgical margins(11, 12),or have necrosis.Results from ongoing prospective trials and larger studies are needed to confirm the above and to better define subgroups that may not benefit from a boost.
REFERENCES
1.Virnig BA,Tuttle TM,Shamliyan T,et al.Ductal carcinoma in
situ of the breast:A systematic review of incidence,treatment, and outcomes.J Natl Cancer Inst;102:170–178.
2.Fisher B,Land S,Mamounas E,et al.Prevention of invasive
breast cancer in women with ductal carcinoma in situ:An update of the National Surgical Adjuvant Breast and Bowel Project experience.Semin Oncol2001;28:400–418.
3.Bijker N,Meijnen P,Peter JL,et al.Breast-conrving treat-
ment with or without radiotherapy in ductal carcinoma-in-situ: Ten-year results of European Organisation for Rearch and Treatment of Cancer randomized pha III trial10853—
a study by the EORTC Breast Cancer Cooperative Group
and EORTC Radiotherapy Group.J Clin Oncol2006;24: 3381–3387.
4.Houghton J,George WD,Cuzick J,et al.Radiotherapy and
tamoxifen in women with completely excid ductal carcinoma in situ of the breast in the UK,Australia,and New Zealand: Randomid controlled trial.Lancet2003;362:95–102.
5.Emdin SO,Granstrand B,Ringberg A,et al.SweDCIS:
Radiotherapy after ctor rection for ductal carcinoma in situ of the breast.Results of a randomid trial in a popula-tion offered mammography screening.Acta Oncol2006;45: 536–543.
6.Romestaing P,Lehingue Y,Carrie C,et al.Role of a10-Gy
boost in the conrvative treatment of early breast cancer: Results of a randomized clinical trial in Lyon,France.J Clin Oncol1997;15:963–968.
7.Bartelink H,Horiot JC,Poortmans PM,et al.Impact of a higher
radiation do on local control and survival in breast-conrving therapy of early breast cancer:10-Year results of
8.Omlin A,Amichetti M,Azria D,et al.Boost radiotherapy in
young women with ductal carcinoma in situ:A multicentre, retrospective study of the Rare Cancer Network.Lancet Oncol 2006;7:652–656.
9.Yerushalmi R,Sulkes A,Mishaeli M,et al.Radiation treatment
for ductal carcinoma in situ(DCIS):Is a boost to the tumor bed necessary?Neoplasma2006;53:507–510.
10.Bijker N,Rutgers EJ,Peter JL,et al.Variations in diagnostic
and therapeutic procedures in a multicentre,randomized clini-cal trial(EORTC10853)investigating breast-conrving treat-ment for DCIS.Eur J Surg Oncol2001;27:135–140.
11.Julian TB,Land SR,Wang Y,et al.Is boost therapy necessary
in the treatment of DCIS?J Clin Oncol2008;26:(May20 suppl;abstr537).
12.Monteau A,Sigal-Zafrani B,Kirova YM,et al.Ductal carci-
noma in situ of the breast with clo or focally involved mar-gins following breast-conrving surgery:Treatment with reexcision or radiotherapy with incread dosage.Int J Radiat Oncol Biol Phys2009;75:1021–1028.
13.Azria D,Auvray H,Barillot I,et al.[Ductal carcinoma in situ:
Role of the boost].Cancer Radiother2008;12:571–576. 14.Whelan T,MacKenzie R,Julian J,et al.Randomized trial of
breast irradiation schedules after lumpectomy for women with lymph node-negative breast cancer.J Natl Cancer Inst 2002;94:1143–1150.
15.Silverstein MJ.An argument against routine u of radio-
therapy for ductal carcinoma in situ.Oncology(Williston Park)2003;17:1511–1533.discussion1533–1514,1539, 1542passim.
16.Silverstein MJ.The University of Southern California/Van
Impact of radiotherapy boost in DCIS d P.W ONG et al.e157
