Download Timing of Radiotherapy and Outcome in Patients Receiving

Int. J. Radiation Oncology Biol. Phys., Vol. 80, No. 2, pp. 398–402, 2011
Copyright Ó 2011 Elsevier Inc.
Printed in the USA. All rights reserved
0360-3016/$–see front matter
doi:10.1016/j.ijrobp.2010.02.042
CLINICAL INVESTIGATION
Breast
TIMING OF RADIOTHERAPY AND OUTCOME IN PATIENTS RECEIVING
ADJUVANT ENDOCRINE THERAPY
PER KARLSSON, M.D.,* BERNARD F. COLE, PH.D.,yz MARCO COLLEONI, M.D.,x MARIO 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 GÜNTHER 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 Group
Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA; xDepartment of
Medicine, Research Unit in Medical Senology, European Institute of Oncology, Milan, Italy; {Department of Radiotherapy, Centro di
Riferimento 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; **International
Breast Cancer Study Group Statistical Center, Frontier Science and Technology Research Foundation, Boston, MA; yyInternational
Breast Cancer Study Group Coordinating Center, Bern, Switzerland; zzEuropean Institute of Oncology, Milan, Italy; xxOncology
Institute of Southern Switzerland, Bellinzona, Switzerland; {{Institut fuer Radiotherapie, Klinik Hirslanden, Zürich, Switzerland
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 Group
trials. The analysis was restricted to 964 patients treated with BCS and adjuvant endocrine therapy. The patients
were divided into two groups according to the median number of days between BCS and RT and into four groups
according to the quartile of time between BCS and RT. The endpoints were the interval to local recurrence, diseasefree survival, and overall survival. Proportional hazards regression analysis was used to perform comparisons
after 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 RT
delay #20 weeks was found. The adjusted hazard ratio for RT within 77 days vs. after 77 days was 0.94 (95% confidence interval [CI], 0.47–1.87) for the interval to local recurrence, 1.05 (95% CI, 0.82–1.34) for disease-free survival, and 1.07 (95% CI, 0.77–1.49) for overall survival. For the interval to local recurrence the adjusted hazard
ratio 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, menopausal
status, and estrogen-receptor status. After adjustment for these factors, the timing of RT was not significantly
associated with the interval to local recurrence, disease-free survival, or overall survival. Ó 2011 Elsevier Inc.
Breast cancer, Radiotherapy, Radiotherapy timing, Breast-conserving surgery, Endocrine therapy.
INTRODUCTION
Radiotherapy (RT) to the breast after breast-conserving surgery (BCS) reduces the risk of local recurrence and improves
breast cancer-specific survival (1). The optimal interval between surgery and the start of RT is not known. Theoretically,
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). Several retrospective studies have yielded variable results (3–8).
Reprint requests to: Per Karlsson, M.D., Department of Oncology, University of Göteborg, Sahlgrenska University Hospital,
Gothenburg S 413 45 Sweden. Tel: (+46) 31-342-2246; Fax:
(+46) 31-820-114; E-mail: [email protected]
Preliminary results were presented in a poster at the St. Gallen
Breast Conference, St. Gallen, Switzerland, March 2009.
The International Breast Cancer Study Group was funded in part
by the Swiss Group for Clinical Cancer Research, the Frontier Science and Technology Research Foundation, the Cancer Council
Australia, the Australian New Zealand Breast Cancer Trials Group
(National Health Medical Research Council), the National Cancer
Institute (Grant CA-75362), the Swedish Cancer Society, the Cancer
Association of South Africa, and the Foundation for Clinical Cancer
Research of Eastern Switzerland (OSKK).
Conflict of interest: none.
Acknowledgments—We thank the patients, physicians, nurses, and
data managers who participated in the International Breast Cancer
Study Group trials.
Received Oct 9, 2009, and in revised form Feb 3, 2010. Accepted
for publication Feb 11, 2010.
398
Timing of RT for adjuvant breast cancer d P. KARLSSON et al.
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 exclusively 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 identified, 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 cyclophosphamide, methotrexate, and 5-fluorouricil (CMF) in postmenopausal patients with node-positive breast cancer (12). Trial VIII studied
adjuvant ovarian function suppression with luteinizing hormonereleasing hormone analog for 2 years vs. six courses of CMF vs.
six courses of CMF followed by 18 months of ovarian function suppression in premenopausal patients with node-negative disease (13).
Trial IX compared adjuvant tamoxifen vs. three courses of CMF followed by tamoxifen in postmenopausal patients with node-negative
disease (14). The present study was restricted to the following treatment 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,
CMF3 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 endpoints 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
399
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 surgery. Table 1 summarizes the baseline characteristics of the
two groups of patients who started RT within or after the median 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 differences 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 characteristics, 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 1. Baseline characteristics
Characteristic
Age (y)
Menopausal status
Pre
Post
ER status
Negative
Positive
Unknown
Tumor grade
1
2
3
Unknown
Positive lymph
nodes (n)
0
1–3
$4
Tumor size (cm)
#2
>2
Unknown
Vessel invasion
No
Yes
Unknown
RT within 77 d
(n = 492)
RT after 77 d
(n = 472)
55.6 8.9
58.8 7.3
128 (26)
364 (74)
45 (10)
427 (90)
123 (25)
357 (73)
12 (2)
89 (19)
358 (76)
25 (5)
89 (18)
237 (48)
165 (34)
1 (0)
86 (18)
221 (47)
162 (34)
3 (1)
p*
<.0001
<.0001
.042
.94
.62
454 (92)
25 (5)
13 (3)
441 (93)
23 (5)
8 (2)
371 (75)
118 (24)
3 (1)
366 (78)
100 (21)
6 (1)
378 (77)
94 (19)
20 (4)
364 (77)
67 (14)
41 (9)
.35
.098
Abbreviations: RT = radiotherapy; ER = estrogen receptor.
Data presented as number of patients, with percentages in parentheses, except for age, which is given as mean +/ standard deviation.
* Unknown data for given category excluded from calculation of
p values.
I. J. Radiation Oncology d Biology d Physics
400
Table 2. Adjusted proportional hazards regression results
dividing at median
RT timing (from surgery)
Local recurrence
#77 d
$78 d
Disease-free survival
#77 d
$78 d
Overall survival
#77 d
$78 d
Table 4. Adjusted proportional hazards regression results
according to quartiles
HR
95% CI
p
0.94
1.00
0.47–1.87
.86
1.05
1.00
0.82–1.34
.73
1.07
1.00
0.77–1.49
.67
Abbreviations: RT = radiotherapy; HR = hazard ratio; CI = confidence interval. Adjustment factors: age, ER status, tumor grade,
nodal status, tumor size and vessel invasion status.
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 recurrence, 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. KaplanMeier 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 therapy 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.
After adjustment for differences in the baseline characteristics, RT timing was not significantly associated with the interval 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: adjusted
proportional hazards regression results divided at median
Local recurrence
#77 d
$78 d
Disease-free survival
#77 d
$78 d
Overall survival
#77 d
$78 d
RT timing from surgery
Local recurrence*
#48 d
49–77 d
78–112 d
$113 d
Disease-free survivaly
#48 d
49–77 d
78–112 d
$113 d
Overall survivalz
#48 d
49–77 d
78–112 d
$113 d
HR
95% CI
p
0.90
0.86
0.89
1.00
0.34–2.37
0.33–2.25
0.33–2.41
.83
.76
.81
0.78
0.95
0.68
1.00
0.55–1.10
0.68–1.32
0.47–0.97
.16
.75
.03
0.70
0.86
0.50
1.00
0.45–1.11
0.56–1.31
0.31–0.81
.13
.47
.005
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.
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) indicated an increasing relative risk of 1.11/month of RT delay
for local recurrence in so-called high-quality series, irrespective of whether chemotherapy was given; however, no significant effect was found on distant metastasis or OS. That metaanalysis 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 metaanalyses included patients with a variety of breast cancer
subtypes and for whom the use of systemic therapy was
Table 5. Estrogen receptor-positive cohort: adjusted
proportional hazards regression results according to quartiles
DISCUSSION
RT timing from surgery
Volume 80, Number 2, 2011
HR
95% CI
p
0.84
1.00
0.38–1.89
.68
0.95
1.00
0.71–1.28
.73
1.16
1.00
0.77–1.74
.48
Abbreviations as in Table 2. Adjustment factors as in Table 2.
RT timing from surgery
Local recurrence*
#48 d
49–77 d
78–112 d
$113 d
Disease-free survivaly
#48 d
49–77 d
78–112 d
$113 d
Overall survivalz
#48 d
49–77 d
78–112 d
$113 d
HR
95% CI
p
1.03
0.67
0.99
1.00
0.34–3.14
0.21–2.17
0.31–3.17
.96
.50
.99
0.72
0.82
0.65
1.00
0.48–1.09
0.55–1.22
0.42–0.99
.12
.32
.04
0.76
0.80
0.42
1.00
0.44–1.32
0.47–1.38
0.23–0.78
.33
.42
.005
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.
Timing of RT for adjuvant breast cancer d P. KARLSSON et al.
A
100
Local recurrence free interval (%)
Local recurrence free interval (%)
A
80
60
40
Days Surgery to RT
≤ 77 days
≥ 78 days
20
0
0
1
2
N
492
472
10-Year
Events Interval% ± SE p
21
95 ± 1
0.55
16
96 ± 1
3
4
5
6
7
8
9
10
Time from Start of Radiotherapy (Years)
11
80
60
40
Days Surgery to RT
≤ 48 days
49-77 days
78-112 days
≥ 113 days
20
0
0
1
2
N
234
258
226
246
10-Year
Events Interval% ± SE p
0.91
11
95 ± 2
10
95 ± 2
8
95 ± 2
8
96 ± 1
3
4
5
6
7
8
9
10
Time from Start of Radiotherapy (Years)
11
12
B
100
100
80
80
60
60
DFS (%)
DFS (%)
100
12
B
40
Days Surgery to RT
≤ 77 days
≥ 78 days
20
0
0
1
2
N
492
472
Events
145
126
10-Year
DFS% ± SE
72 ± 2
73 ± 2
3
4
5
6
7
8
9
10
Time from Start of Radiotherapy (Years)
p
0.55
40
Days Surgery to RT
≤ 48 days
49-77 days
78-112 days
≥ 113 days
20
0
11
0
12
C
1
2
N
234
258
226
246
Events
67
78
55
71
10-Year
DFS% ± SE
72 ± 3
72 ± 3
75 ± 3
72 ± 3
3
4
5
6
7
8
9
10
Time from Start of Radiotherapy (Years)
p
0.39
11
12
C
100
100
80
80
60
60
OS (%)
OS (%)
401
40
Days Surgery to RT
≤ 77 days
≥ 78 days
20
0
0
1
2
N
492
472
Events
85
76
10-Year
OS% ± SE
83 ± 2
84 ± 2
3
4
5
6
7
8
9
10
Time from Start of Radiotherapy (Years)
p
0.79
40
Days Surgery to RT
≤ 48 days
49-77 days
78-112 days
≥ 113 days
20
0
11
12
0
1
2
N
234
258
226
246
Events
39
46
29
47
10-Year
OS% ± SE
83 ± 3
83 ± 3
86 ± 3
81 ± 3
3
4
5
6
7
8
9
10
Time from Start of Radiotherapy (Years)
p
0.22
11
12
Fig. 1. Kaplan-Meier curves for (A) interval to local recurrence, (B)
disease-free survival (DFS), and (C) overall survival (OS) with interval to event from start of radiotherapy (RT) for patients with radiotherapy within or after 77 days after surgery. SE = standard error.
Fig. 2. Kaplan-Meier curves for (A) interval to local recurrence, (B)
disease-free survival (DFS), and (C) overall survival (OS) with interval to event from start of radiotherapy (RT) in quartiles (#48,
49–77, 78–112, and $113 days). SE = standard error.
inconsistent. Both of these factors could have affected the local recurrence rate. Only a few studies have evaluated the interval 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 patients, 23 had had a RT delay of >20 weeks. At a median
follow-up of 71 months, the local recurrence rate was significantly associated with the omission of tamoxifen and a high
402
I. J. Radiation Oncology d Biology d Physics
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 Cancer Agency examined different intervals between surgery and
RT in early-stage breast cancer patients in the absence of chemotherapy (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. Patients who were not given endocrine therapy were analyzed
separately, and the findings were similar to those for the entire 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 interval 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/chemotherapy group (n = 529). RT timing was statistically significant 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 publication by our group, we analyzed the effect of RT delay resulting from chemotherapy in IBCSG Trials VI and VII (11). The
Volume 80, Number 2, 2011
present analysis was undertaken, because studies investigating 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 endpoints. However, the present study had too few events to provide 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 delay of shorter intervals and a small increase in the local recurrence risk. Nevertheless, and despite its retrospective design,
the present study included patients treated in a randomized
study with defined inclusion/exclusion criteria, uniform adjuvant 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 chemotherapy was given, did not adversely influence the treatment outcome (11). The results of the present IBCSG study
have indicated that an interval of up to about 20 weeks between BCS and RT does not increase the risk of local recurrence in a cohort of patients receiving standard adjuvant
endocrine treatment.
REFERENCES
1. Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and
of differences in the extent of surgery for early breast cancer on
local recurrence and 15-year survival: An overview of the randomised trials. Lancet 2005;366:2087–2106.
2. Fletcher GH. Implications of the density of clonogenic infestation in radiotherapy. Int J Radiat Oncol Biol Phys 1986;12:
1675–1680.
3. Clarke DH, Le MG, Sarrazin D, et al. Analysis of local-regional
relapses in patients with early breast cancers treated by excision
and 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 in
4,820 patients with breast cancer: University of Florence experience. Int J Radiat Oncol Biol Phys 2009;73:365–369.
5. Froud PJ, Mates D, Jackson JS, et al. Effect of time interval between breast-conserving surgery and radiation therapy on ipsilateral 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 initiating
radiotherapy for patients with early stage breast cancer. Clin Oncol (R Coll Radiol) 2004;16:6–11.
7. Hebert-Croteau N, Freeman CR, Latreille J, et al. Delay in adjuvant radiation treatment and outcomes of breast cancer—A review. Breast Cancer Res Treat 2002;74:77–94.
8. Olivotto IA, Lesperance ML, Truong PT, et al. Intervals longer
than 20 weeks from breast-conserving surgery to radiation therapy are associated with inferior outcome for women with earlystage breast cancer who are not receiving chemotherapy. J Clin
Oncol 2009;27:16–23.
9. Chen Z, King W, Pearcey R, et al. The relationship between
waiting time for radiotherapy and clinical outcomes: A systematic review of the literature. Radiother Oncol 2008;87:3–16.
10. Huang J, Barbera L, Brouwers M, et al. Does delay in starting
treatment affect the outcomes of radiotherapy? A systematic review. J Clin Oncol 2003;21:555–563.
11. Wallgren A, Bernier J, Gelber RD, et al. Timing of radiotherapy
and chemotherapy following breast-conserving surgery for patients with node-positive breast cancer. Int J Radiat Oncol
Biol Phys 1996;35:649–659.
12. International Breast Cancer Study Group. Effectiveness of adjuvant chemotherapy in combination with tamoxifen for nodepositive postmenopausal breast cancer patients. J Clin Oncol
1997;15:1385–1394.
13. International Breast Cancer Study Group. Adjuvant chemotherapy followed by goserelin versus either modality alone for premenopausal lymph node-negative breast cancer: a randomized
trial. J Natl Cancer Inst 2003;95:1833–1846.
14. International Breast Cancer Study Group. Endocrine responsiveness and tailoring adjuvant therapy for postmenopausal
lymph node-negative breast cancer: A randomized trial. J Natl
Cancer Inst 2002;94:1054–1065.
15. Whelan TJ, Clark RM, Levine MN, et al. The effect of delay in
initiating radiotherapy postlumpectomy on local breast recurrence. Int J Radiat Oncol Biol Phys 1996;36:280.
16. Vujovic O, Perera F, Dar AR, et al. Does delay in breast irradiation following conservative breast surgery in node-negative
breast cancer patients have an impact on risk of recurrence?
Int J Radiat Oncol Biol Phys 1998;40:869–874.