Timing of Radiotherapy and Outcome in Patients Receiving Adjuvant Endocrine Therapy

Int. J. Radiation Oncology Biol. Phys., Vol. 80, No. 2, pp. 398–402, 2011Copyright � 2011 Elsevier Inc.

Printed in the USA. All rights reserved0360-3016/$–see front matter

jrobp.2010.02.042
doi:10.1016/j.i
CLINICAL INVESTIGATION Breast

TIMING OF RADIOTHERAPY AND OUTCOME IN PATIENTS RECEIVINGADJUVANT ENDOCRINE THERAPY

PER KARLSSON, M.D.,* BERNARD F. COLE, PH.D.,yzMARCO COLLEONI, M.D.,xMARIO RONCADIN, M.D.,{

BOON H. CHUA, M.D., PH.D.,k ELIZABETH MURRAY, M.D.,# KAREN N. PRICE, B.S.,**

MONICA CASTIGLIONE-GERTSCH, M.D.,yy ARON GOLDHIRSCH, M.D.,zzxx AND GUNTHER GRUBER, M.D.{{

FOR THE INTERNATIONAL BREAST CANCER STUDY GROUP

*Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden; yDepartment of Mathematics and Statistics,University of Vermont College of Engineering and Mathematical Sciences, Burlington, VT; zInternational Breast Cancer Study GroupStatistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA; xDepartment ofMedicine, Research Unit in Medical Senology, European Institute of Oncology, Milan, Italy; {Department of Radiotherapy, Centro diRiferimento Oncologico, Aviano, Italy; kDepartment of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia;#Department of Radiation Oncology, Groote Shuur Hospital and University of Cape Town, Cape Town, South Africa; **InternationalBreast Cancer Study Group Statistical Center, Frontier Science and Technology Research Foundation, Boston, MA; yyInternationalBreast Cancer Study Group Coordinating Center, Bern, Switzerland; zzEuropean Institute of Oncology, Milan, Italy; xxOncologyInstitute of Southern Switzerland, Bellinzona, Switzerland; {{Institut fuer Radiotherapie, Klinik Hirslanden, Zurich, Switzerland

Reprinogy, UniGothenbu(+46) 31-

PrelimiBreast Co

The Intby the Swence andAustralia,

Purpose: To evaluate the association between the interval from breast-conserving surgery (BCS) to radiotherapy(RT) and the clinical outcome among patients treated with adjuvant endocrine therapy.Patients and Methods: Patient information was obtained from three International Breast Cancer Study Grouptrials. The analysis was restricted to 964 patients treated with BCS and adjuvant endocrine therapy. The patientswere divided into two groups according to the median number of days between BCS and RT and into four groupsaccording to the quartile of time between BCS and RT. The endpoints were the interval to local recurrence, disease-free survival, and overall survival. Proportional hazards regression analysis was used to perform comparisonsafter adjustment for baseline factors.Results: The median interval between BCS and RT was 77 days. RT timing was significantly associated with age,menopausal status, and estrogen receptor status. After adjustment for these factors, no significant effect of a RTdelay #20 weeks was found. The adjusted hazard ratio for RT within 77 days vs. after 77 days was 0.94 (95% con-fidence interval [CI], 0.47–1.87) for the interval to local recurrence, 1.05 (95% CI, 0.82–1.34) for disease-free sur-vival, and 1.07 (95% CI, 0.77–1.49) for overall survival. For the interval to local recurrence the adjusted hazardratio for #48, 49–77, and 78–112 days was 0.90 (95% CI, 0.34–2.37), 0.86 (95% CI, 0.33–2.25), and 0.89 (95% CI,0.33–2.41), respectively, relative to $113 days.Conclusion: A RT delay of #20 weeks was significantly associated with baseline factors such as age, menopausalstatus, and estrogen-receptor status. After adjustment for these factors, the timing of RT was not significantlyassociated with the interval to local recurrence, disease-free survival, or overall survival. � 2011 Elsevier Inc.

Breast cancer, Radiotherapy, Radiotherapy timing, Breast-conserving surgery, Endocrine therapy.

INTRODUCTION

Radiotherapy (RT) to the breast after breast-conserving sur-

gery (BCS) reduces the risk of local recurrence and improves

breast cancer-specific survival (1). The optimal interval be-

tween surgery and the start of RT is not known. Theoretically,

t requests to: Per Karlsson, M.D., Department of Oncol-versity of Goteborg, Sahlgrenska University Hospital,rg S 413 45 Sweden. Tel: (+46) 31-342-2246; Fax:820-114; E-mail: [email protected] results were presented in a poster at the St. Gallennference, St. Gallen, Switzerland, March 2009.ernational Breast Cancer Study Group was funded in partiss Group for Clinical Cancer Research, the Frontier Sci-Technology Research Foundation, the Cancer Councilthe Australian New Zealand Breast Cancer Trials Group

398

the risk of recurrence is related to the density of the clonogenic

cells in the surgical bed. Therefore, a delay between surgery

and the start of RT could increase the likelihood of tumor

cell growth and the development of radioresistance (2). Sev-

eral retrospective studies have yielded variable results (3–8).

(National Health Medical Research Council), the National CancerInstitute (Grant CA-75362), the Swedish Cancer Society, the CancerAssociation of South Africa, and the Foundation for Clinical CancerResearch of Eastern Switzerland (OSKK).

Conflict of interest: none.Acknowledgments—We thank the patients, physicians, nurses, anddata managers who participated in the International Breast CancerStudy Group trials.

Received Oct 9, 2009, and in revised form Feb 3, 2010. Acceptedfor publication Feb 11, 2010.

mailto:[email protected]

Table 1. Baseline characteristics

CharacteristicRT within 77 d

(n = 492)RT after 77 d

(n = 472) p*

Age (y) 55.6 � 8.9 58.8 � 7.3 <.0001Menopausal status <.0001

Pre 128 (26) 45 (10)Post 364 (74) 427 (90)

ER status .042Negative 123 (25) 89 (19)Positive 357 (73) 358 (76)Unknown 12 (2) 25 (5)

Tumor grade .941 89 (18) 86 (18)2 237 (48) 221 (47)3 165 (34) 162 (34)Unknown 1 (0) 3 (1)

Positive lymphnodes (n)

.62

0 454 (92) 441 (93)1–3 25 (5) 23 (5)$4 13 (3) 8 (2)

Tumor size (cm) .35#2 371 (75) 366 (78)>2 118 (24) 100 (21)Unknown 3 (1) 6 (1)

Vessel invasion .098No 378 (77) 364 (77)Yes 94 (19) 67 (14)Unknown 20 (4) 41 (9)

Abbreviations: RT = radiotherapy; ER = estrogen receptor.Data presented as number of patients, with percentages in parenthe-

ses, except for age, which is given as mean +/� standard deviation.* Unknown data for given category excluded from calculation of

p values.

Timing of RT for adjuvant breast cancer d P. KARLSSON et al. 399

Generally, on univariate analysis, an increased risk of local

recurrence was observed with a longer delay between surgery

and the start of RT. However, on multivariate analysis, this

effect was not observed. Two systematic reviews showed an

increase in the risk of local recurrence with RT delay of >8

weeks (9, 10). However, these reviews included all subtypes

of breast cancer and a variety of study designs, rendering

interpretation of the results difficult. The risk of local

recurrence in relation to RT delay can vary by breast cancer

subtype and systemic treatment. An International Breast

Cancer Study Group (IBCSG) study has shown that delaying

RT until the completion of chemotherapy did not adversely

affect the treatment outcome (11). No study has examined

the effect of RT delay on local recurrence in breast cancer ex-

clusively in patients receiving endocrine therapy. The aim of

the present study was to investigate the effect of a delay from

BCS to the start of RT in patients treated with endocrine therapy

in three IBCSG trials.

PATIENTS AND METHODS

Patient information was obtained from 1,108 patients who had

undergone BCS and were randomized to selected treatment arms

from IBCSG Trials VII, VIII, and IX. Of the 1,108 patients identi-

fied, 135 did not receive RT and an additional 9 did not have a record

of RT start dates, leaving 964 patients in the analyzed cohort.

Trial VII compared adjuvant tamoxifen alone vs. chemoendocrine

treatment with tamoxifen with concurrent classic cyclophospha-

mide, methotrexate, and 5-fluorouricil (CMF) in postmenopausal pa-

tients with node-positive breast cancer (12). Trial VIII studied

adjuvant ovarian function suppression with luteinizing hormone-

releasing hormone analog for 2 years vs. six courses of CMF vs.

six courses of CMF followed by 18 months of ovarian function sup-

pression in premenopausal patients with node-negative disease (13).

Trial IX compared adjuvant tamoxifen vs. three courses of CMF fol-

lowed by tamoxifen in postmenopausal patients with node-negative

disease (14). The present study was restricted to the following treat-

ment groups receiving adjuvant endocrine therapy: Trial VII, Arm A,

tamoxifen for 5 years (n = 69); Trial VIII, Arm B, luteinizing

hormone-releasing hormone analog for 2 years ((n = 173); Trial

IX, Arm A, tamoxifen for 5 years (n = 374); and Trial IX, Arm B,

CMF�3 followed by tamoxifen for 57 months (n = 370). Trial VII

specified that RT was required for all patients who had undergone

BCS. Although Trials VIII and IX did not mandate RT to the

conserved breast, 88% of the patients who had undergone BCS

were treated with RT. In all three trials, patients who had undergone

BCS and RT and were randomized to receive endocrine therapy

alone were required to begin RT within 3 months of randomization,

and those randomized to receive CMF before tamoxifen in Trial

IX were to begin RT 2 weeks after the end of the last cycle of

chemotherapy.

For the present study, the patients were divided into two groups

according to the median number of days from surgery to the start

of RT. Kaplan-Meier survival curves were plotted for the two

groups, and the log–rank test was used to compare them. The end-

points were the interval to local recurrence, disease-free survival

(DFS), and overall survival (OS), measured from the start of RT.

This approach accounted for how the interval to an event had to

exceed the number of days between surgery and the start of RT.

In addition, the patients were divided into four groups according to

the quartiles of days from surgery until the start of RT. Proportional

hazards regression was used to estimate the hazard ratios (HRs) and

95% confidence intervals (CIs) for the two-group and four-group

analyses following adjustment for baseline factors.. Wald tests

were used to evaluate the heterogeneity among the HRs according

to the four-group analysis. Of the 964 patients in the analytic cohort,

715 had estrogen receptor (ER)-positive disease. All analyses were

repeated for the ER-positive cohort.

RESULTS

The median number of days from surgery to the start of RT

was 77 (mean, 84; standard deviation, 45; range, 14–436). A

total of 409 patients (42%) received RT >90 days after sur-

gery. Table 1 summarizes the baseline characteristics of the

two groups of patients who started RT within or after the me-

dian of 77 days after surgery. Age, premenopausal status, and

hormone receptor status were significantly associated with

RT timing. However, it should be noted that some of these dif-

ferences might have resulted from the CMF-tamoxifen arm of

Trial IX in which patients underwent RT after chemotherapy.

The median follow-up was 10.5 years. The total number of

events was 37 local recurrences, 271 DFS events, and 161

deaths. Adjusting for the differences in baseline characteris-

tics, the HR for starting RT within 77 days relative to after 77

days was 0.94 (95% CI, 0.47–1.87) for local recurrence, 1.05

(95% CI, 0.82–1.34) for DFS, and 1.07 (95% CI, 0.77–1.49)

for OS (Tables 2 and 3). When patients were divided into

Table 2. Adjusted proportional hazards regression resultsdividing at median

RT timing (from surgery) HR 95% CI p

Local recurrence#77 d 0.94 0.47–1.87 .86$78 d 1.00

Disease-free survival#77 d 1.05 0.82–1.34 .73$78 d 1.00

Overall survival#77 d 1.07 0.77–1.49 .67$78 d 1.00

Abbreviations: RT = radiotherapy; HR = hazard ratio; CI = con-fidence interval. Adjustment factors: age, ER status, tumor grade,nodal status, tumor size and vessel invasion status.

Table 4. Adjusted proportional hazards regression resultsaccording to quartiles

RT timing from surgery HR 95% CI p

Local recurrence*#48 d 0.90 0.34–2.37 .8349–77 d 0.86 0.33–2.25 .7678–112 d 0.89 0.33–2.41 .81$113 d 1.00

Disease-free survivaly

#48 d 0.78 0.55–1.10 .1649–77 d 0.95 0.68–1.32 .7578–112 d 0.68 0.47–0.97 .03$113 d 1.00

Overall survivalz

#48 d 0.70 0.45–1.11 .1349–77 d 0.86 0.56–1.31 .4778–112 d 0.50 0.31–0.81 .005$113 d 1.00

Abbreviations as in Table 2.* Overall Wald p = .99.y Overall Wald p = .12.z Overall Wald p = .03. Adjustment factors as in Table 2.

400 I. J. Radiation Oncology d Biology d Physics Volume 80, Number 2, 2011

quartiles according to the surgery-to-RT interval, the

adjusted HRs were not significantly different (Tables 4

and 5). The Kaplan-Meier curves for the interval to local re-

currence, DFS, and OS with the interval to an event from the

start of RT for the two-group analysis and the four-group

analysis are shown in Figs. 1 and 2, respectively. Kaplan-

Meier analysis with the interval to event measured from

Day 77 after surgery gave similar results (data not shown).

The analyses were repeated for the ER-positive cohort (n =

715), with similar results (Tables 3 and 5), with no significant

interactions found between RT timing and ER positivity (data

not shown).

The mean interval from surgery to the start of endocrine

therapy was 33 days in the group that started RT within 77

days and 81 days in the group that started RT after 77

days. Of the 841 patients (89%) who began endocrine therapy

before RT, the mean interval from the start of endocrine ther-

apy to the start of RT was 26 days in the group that started RT

within 77 days and 48 days in the group that started RT after

77 days.

Table 5. Estrogen receptor-positive cohort: adjustedproportional hazards regression results according to quartiles


Local recurrence*#48 d 1.03 0.34–3.14 .9649–77 d 0.67 0.21–2.17 .50

DISCUSSION

After adjustment for differences in the baseline character-

istics, RT timing was not significantly associated with the in-

terval to local recurrence, DFS, or OS in patients receiving

adjuvant endocrine therapy for RT delay of up to about 20

weeks. Postoperative RT after BCS reduces local failure rates

Table 3. Estrogen receptor-positive cohort: adjustedproportional hazards regression results divided at median


Local recurrence#77 d 0.84 0.38–1.89 .68$78 d 1.00

Disease-free survival#77 d 0.95 0.71–1.28 .73$78 d 1.00

Overall survival#77 d 1.16 0.77–1.74 .48$78 d 1.00

Abbreviations as in Table 2. Adjustment factors as in Table 2.

substantially and thus has been well accepted (1). However,

the optimal interval between surgery and the start of RT is

controversial. A recent meta-analysis by Chen et al. (9) indi-

cated an increasing relative risk of 1.11/month of RT delay

for local recurrence in so-called high-quality series, irrespec-

tive of whether chemotherapy was given; however, no signif-

icant effect was found on distant metastasis or OS. That meta-

analysis confirmed a previous systematic review (10), in

which the 5-year local relapse rate was significantly greater

in breast cancer patients starting adjuvant RT >8 weeks after

surgery compared with patients treated within 8 weeks (odds

ratio, 1.62; 95% CI, 1.21–2.16). However, these meta-

analyses included patients with a variety of breast cancer

subtypes and for whom the use of systemic therapy was

78–112 d 0.99 0.31–3.17 .99$113 d 1.00

Disease-free survivaly

#48 d 0.72 0.48–1.09 .1249–77 d 0.82 0.55–1.22 .3278–112 d 0.65 0.42–0.99 .04$113 d 1.00

Overall survivalz

#48 d 0.76 0.44–1.32 .3349–77 d 0.80 0.47–1.38 .4278–112 d 0.42 0.23–0.78 .005$113 d 1.00

Abbreviations as in Table 2.* Overall Wald p = .85.y Overall Wald p = .20.z Overall Wald p = .05. Adjustment factors as in Table 2.

Loca

l rec

urre

nce

free

inte

rval

(%)

0

20

40

60

80

100

Time from Start of Radiotherapy (Years)0 1 2 3 4 5 6 7 8 9 10 11 12

≤ 77 days≥ 78 days

N492472

Events2116

10-YearInterval% ± SE

95 ± 196 ± 1

0.55pDays Surgery to RT

A

DFS

(%)

0

20

40

60

80

100



N492472

Events145126

10-YearDFS% ± SE

72 ± 273 ± 2


B

OS

(%)

0

20

40

60

80

100



N492472

Events8576

10-YearOS% ± SE

83 ± 284 ± 2


C

Fig. 1. Kaplan-Meier curves for (A) interval to local recurrence, (B)disease-free survival (DFS), and (C) overall survival (OS) with in-terval to event from start of radiotherapy (RT) for patients with ra-diotherapy within or after 77 days after surgery. SE = standard error.

Loca

l rec

urre

nce

free

inte

rval

(%)

0

20

40

60

80

100


≤ 48 days49-77 days

N234258

Events1110

10-YearInterval% ± SE

95 ± 295 ± 2

78-112 days≥ 113 days

226246

88

95 ± 296 ± 1


A

DFS

(%)

0

20

40

60

80

100



N234258

Events6778

10-YearDFS% ± SE

72 ± 372 ± 3

78-112 days≥ 113 days

226246

5571

75 ± 372 ± 3


B

OS

(%)

0

20

40

60

80

100



N234258

Events3946

10-YearOS% ± SE

83 ± 383 ± 3

78-112 days≥ 113 days

226246

2947

86 ± 381 ± 3


C

Fig. 2. Kaplan-Meier curves for (A) interval to local recurrence, (B)disease-free survival (DFS), and (C) overall survival (OS) with in-terval to event from start of radiotherapy (RT) in quartiles (#48,49–77, 78–112, and $113 days). SE = standard error.

Timing of RT for adjuvant breast cancer d P. KARLSSON et al. 401

inconsistent. Both of these factors could have affected the lo-

cal recurrence rate. Only a few studies have evaluated the in-

terval of RT after surgery in the absence of chemotherapy.

The more recent meta-analysis (9) identified only four studies

(3, 5, 15, 16), all of which were observational. However, all

had an adequate description of the distribution of relevant

prognostic factors, which were either well balanced

between the comparison groups or appropriately adjusted

for in the analyses. Of the individual studies, the largest by

far (5) examined the effect of RT delay of <6, 6–8, 9–12,

and $13 weeks on 1,962 patients who had undergone

BCS. Of the 1,962 patients, 677 had received tamoxifen,

and no patients had undergone chemotherapy. Of these pa-

tients, 23 had had a RT delay of >20 weeks. At a median

follow-up of 71 months, the local recurrence rate was signif-

icantly associated with the omission of tamoxifen and a high

402 I. J. Radiation Oncology d Biology d Physics Volume 80, Number 2, 2011

histologic tumor grade. The interval between BCS and RT

was not significantly associated with local recurrence in

a model incorporating tamoxifen use and histologic grade,

in contrast to the overall finding of the meta-analysis, but

consistent with our results.

A more recent publication from the British Columbia Can-

cer Agency examined different intervals between surgery and

RT in early-stage breast cancer patients in the absence of che-

motherapy (8). The study yielded results similar to those of

the present study for an RT delay of #20 weeks. However,

a RT delay of >20 weeks resulted in an inferior outcome. Pa-

tients who were not given endocrine therapy were analyzed

separately, and the findings were similar to those for the en-

tire cohort. However, no separate subgroup analysis was

done for patients who were given endocrine therapy (8). In

a recent study from Florence (4), the risk of developing breast

cancer failure for patients without any systemic adjuvant

treatment (n = 1,935) was inversely proportional to the inter-

val between surgery and RT on univariate analysis. However,

timing of RT was not statistically significance on multivariate

analysis. Similar results were obtained in the RT/endocrine

therapy group (n = 1,684) and RT/endocrine therapy/chemo-

therapy group (n = 529). RT timing was statistically signifi-

cant on multivariate analysis only for the RT and

chemotherapy group (n = 672; HR, 1.69; p = .045) (4).

That report also did not provide separate analyses of patients

undergoing RT and endocrine therapy. In a previous publica-

tion by our group, we analyzed the effect of RT delay result-

ing from chemotherapy in IBCSG Trials VI and VII (11). The

present analysis was undertaken, because studies investigat-

ing RT timing in patients with endocrine therapy have been

rare. Similar to others (4), we could not find any effect of

the interval from surgery to RT on local control or other end-

points. However, the present study had too few events to pro-

vide an accurate estimate of the effect of RT delay of >20

weeks. In addition, a limitation of the present study was an

insufficient power to reject an association between an RT de-

lay of shorter intervals and a small increase in the local recur-

rence risk. Nevertheless, and despite its retrospective design,

the present study included patients treated in a randomized

study with defined inclusion/exclusion criteria, uniform adju-

vant therapy, and rigid follow-up control, in contrast to most

previously published observational series.

The question of the effect of sequential or concurrent use

of endocrine treatment and RT on tumor control could not

be addressed in the present study. In IBCSG Trials VII–IX,

most patients started endocrine therapy within 2 days after

randomization, except for those assigned to receive CMF

first, and RT was administered concurrently with endocrine

therapy.

A study of IBCSG Trials VI and VII showed that a delay of

RT from BCS of #6.6 months (28 weeks), during which che-

motherapy was given, did not adversely influence the treat-

ment outcome (11). The results of the present IBCSG study

have indicated that an interval of up to about 20 weeks be-

tween BCS and RT does not increase the risk of local recur-

rence in a cohort of patients receiving standard adjuvant

endocrine treatment.

REFERENCES

1. Clarke M, Collins R, Darby S, et al. Effects of radiotherapy andof differences in the extent of surgery for early breast cancer onlocal recurrence and 15-year survival: An overview of the rand-omised trials. Lancet 2005;366:2087–2106.

2. Fletcher GH. Implications of the density of clonogenic infesta-tion in radiotherapy. Int J Radiat Oncol Biol Phys 1986;12:1675–1680.

3. Clarke DH, Le MG, Sarrazin D, et al. Analysis of local-regionalrelapses in patients with early breast cancers treated by excisionand radiotherapy: Experience of the Institut Gustave-Roussy.Int J Radiat Oncol Biol Phys 1985;11:137–145.

4. Livi L, Borghesi S, Saieva C, et al. Radiotherapy timing in4,820 patients with breast cancer: University of Florence expe-rience. Int J Radiat Oncol Biol Phys 2009;73:365–369.

5. Froud PJ, Mates D, Jackson JS, et al. Effect of time interval be-tween breast-conserving surgery and radiation therapy on ipsi-lateral breast recurrence. Int J Radiat Oncol Biol Phys 2000;46:363–372.

6. Benk V, Joseph L, Fortin P, et al. Effect of delay in initiatingradiotherapy for patients with early stage breast cancer. Clin On-col (R Coll Radiol) 2004;16:6–11.

7. Hebert-Croteau N, Freeman CR, Latreille J, et al. Delay in ad-juvant radiation treatment and outcomes of breast cancer—A re-view. Breast Cancer Res Treat 2002;74:77–94.

8. Olivotto IA, Lesperance ML, Truong PT, et al. Intervals longerthan 20 weeks from breast-conserving surgery to radiation ther-apy are associated with inferior outcome for women with early-stage breast cancer who are not receiving chemotherapy. J ClinOncol 2009;27:16–23.

9. Chen Z, King W, Pearcey R, et al. The relationship betweenwaiting time for radiotherapy and clinical outcomes: A system-atic review of the literature. Radiother Oncol 2008;87:3–16.

10. Huang J, Barbera L, Brouwers M, et al. Does delay in startingtreatment affect the outcomes of radiotherapy? A systematic re-view. J Clin Oncol 2003;21:555–563.

11. Wallgren A, Bernier J, Gelber RD, et al. Timing of radiotherapyand chemotherapy following breast-conserving surgery for pa-tients with node-positive breast cancer. Int J Radiat OncolBiol Phys 1996;35:649–659.

12. International Breast Cancer Study Group. Effectiveness of adju-vant chemotherapy in combination with tamoxifen for node-positive postmenopausal breast cancer patients. J Clin Oncol1997;15:1385–1394.

13. International Breast Cancer Study Group. Adjuvant chemother-apy followed by goserelin versus either modality alone for pre-menopausal lymph node-negative breast cancer: a randomizedtrial. J Natl Cancer Inst 2003;95:1833–1846.

14. International Breast Cancer Study Group. Endocrine respon-siveness and tailoring adjuvant therapy for postmenopausallymph node-negative breast cancer: A randomized trial. J NatlCancer Inst 2002;94:1054–1065.

15. Whelan TJ, Clark RM, Levine MN, et al. The effect of delay ininitiating radiotherapy postlumpectomy on local breast recur-rence. Int J Radiat Oncol Biol Phys 1996;36:280.

16. Vujovic O, Perera F, Dar AR, et al. Does delay in breast irradi-ation following conservative breast surgery in node-negativebreast cancer patients have an impact on risk of recurrence?Int J Radiat Oncol Biol Phys 1998;40:869–874.

Documents

Timing of Radiotherapy and Outcome in Patients Receiving Adjuvant Endocrine Therapy