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ARTICLES
Long-Term Results of a Randomized Trial Comparing
Breast-Conserving Therapy With Mastectomy: European
Organization for Research and Treatment of Cancer
10801 Trial
Joop A. van Dongen, Adri C. Voogd, Ian S. Fentiman, Catherine Legrand, Richard
J. Sylvester, David Tong, Emmanuel van der Schueren, Peter A. Helle, Kobus van
Zijl, Harry Bartelink
Breast-conserving therapy (BCT) is widely accepted as an
effective treatment option for patients with early-stage carcinomas of the breast (i.e., tumors 艋2 cm). The largest increase in
the use of BCT was in the 1980s, initiated by the publication of
three randomized studies showing similar survival rates for the
patients who received radical mastectomy and those who received BCT (1–5). The three trials differed substantially with
respect to their size and the disease characteristics of the patients. One trial, at Institut Gustave-Roussy, Paris, France, was
relatively small, containing fewer than 100 patients in each arm,
all having a tumor 2 cm or smaller (1). The Milan trial (2,3)
(containing approximately 350 patients in each arm) also included only patients with tumors 2 cm or smaller. The trial of the
Journal of the National Cancer Institute, Vol. 92, No. 14, July 19, 2000
National Surgical Adjuvant Breast and Bowel Project (NSABP
B-06) (4,5) (consisting of approximately 600 patients in each
arm) included patients with tumors up to 4 cm. In all three trials,
a microscopically complete excision was required for the patients in the BCT arm.
In 1992, the first results of three subsequent trials—those of
the U.S. National Cancer Institute (consisting of approximately
120 patients in each arm) (6), the European Organization for
Research and Treatment of Cancer (EORTC) (containing approximately 450 patients in each arm) (7), and the Danish Breast
Cancer Cooperative Group (DBCG) (containing approximately
450 patients in each arm) (8)—were published. The results of
these trials provided further evidence of the efficacy of BCT for
patients with tumors larger than 2 cm.
To be able to detect even a moderate difference in survival
and risk of local recurrence between BCT and mastectomy, data
from all six trials were analyzed in a systematic overview, or
meta-analysis, by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) (9). This meta-analysis, which was published in 1995, found no differences in overall survival at 10
years. However, it had several limitations. First, data for individual patients in the large NSABP B-06 trial were not included.
Second, most of the patients in the EORTC and DBCG trials had
been followed for fewer than 10 years. Consequently, the 10year estimates of the EBCTCG overview are based largely on
patients with tumors 2 cm or smaller, and evidence for the efficacy of BCT in patients with larger tumors after long-term
follow-up remained limited. Other limitations of the meta-
Affiliations of authors: J. A. van Dongen (Department of Surgery), H. Bartelink (Department of Radiotherapy), The Netherlands Cancer Institute, Amsterdam; A. C. Voogd, Comprehensive Cancer Center South, Eindhoven, The Netherlands; I. S. Fentiman (Hedley Atkins Breast Unit), D. Tong (Guy’s and St.
Thomas’ Cancer Center), Guy’s Hospital, London, U.K.; C. Legrand, R. J.
Sylvester, European Organization for Research and Treatment of Cancer Data
Center, Brussels, Belgium; E. van der Schueren (deceased March 1998), Department of Radiotherapy, University Hospital Gasthuisberg, Leuven, Belgium;
P. A. Helle, Department of Radiotherapy, Dr. Daniël den Hoed Cancer Center,
Rotterdam, The Netherlands; K. van Zijl, Breast Unit, University of Stellenbosch, Tijgersberg, South Africa.
Correspondence to: Harry Bartelink, M.D., Ph.D., Department of Radiotherapy, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital,
Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands (e-mail:
[email protected]).
See “Notes” following “References.”
© Oxford University Press
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Background: Breast-conserving therapy (BCT) has been
shown to be as effective as mastectomy in the treatment of
tumors 2 cm or smaller. However, evidence of its efficacy,
over the long term, in patients with tumors larger than 2 cm
is limited. From May 1980 to May 1986, the European Organization for Research and Treatment of Cancer carried
out a randomized, multicenter trial comparing BCT with
modified radical mastectomy for patients with tumors up to
5 cm. In this analysis, we investigated whether the treatments resulted in different overall survival, time to distant
metastasis, or time to locoregional recurrence. Methods: Of
868 eligible breast cancer patients randomly assigned to the
BCT arm or to the modified radical mastectomy arm, 80%
had a tumor of 2.1–5 cm. BCT comprised lumpectomy with
an attempted margin of 1 cm of healthy tissue and complete
axillary clearance, followed by radiotherapy to the breast
and a supplementary dose to the tumor bed. The median
follow-up was 13.4 years. All P values are two-sided. Results:
At 10 years, there was no difference between the two groups
in overall survival (66% for the mastectomy patients and
65% for the BCT patients; P = .11) or in their distant metastasis-free rates (66% for the mastectomy patients and
61% for the BCT patients; P = .24). The rate of locoregional
recurrence (occurring before or at the same time as distant
metastasis) at 10 years did show a statistically significant
difference (12% of the mastectomy and 20% of the BCT
patients; P = .01). Conclusions: BCT and mastectomy demonstrate similar survival rates in a trial in which the great
majority of the patients had stage II breast cancer. [J Natl
Cancer Inst 2000;92:1143–50]
analysis related to the difficulty of controlling for the differences
in treatment techniques between the trials and the variations in
defining local recurrence. The same limitations apply to a more
recent overview (10), which came to the same conclusions as the
meta-analysis of the EBCTCG.
A longer term follow-up would help to resolve the question of
the relative efficacy of BCT and mastectomy for breast cancer
patients with large tumors. The EORTC Breast Cancer Cooperative Group trial began in 1980. The purpose of the trial was
to compare BCT with mastectomy, in particular in the treatment
of clinical stage II breast cancer. Consequently, patients with
tumors up to 5 cm (clinical measurement) were randomly assigned to one therapy or the other. The first results were published after a median follow-up of 6 years (7,11). In this article,
we report findings based on a median follow-up of 13.4 years.
PATIENTS
AND
METHODS
The EORTC study (trial 10801) was open to patient accrual from May 1980
to May 1986. A total of 902 patients with a diagnosis of clinical stage I or II
invasive carcinoma of the breast (12) were enrolled in the trial. Major exclusion
criteria were as follows: patient age of 71 years or older, Karnofsky index below
80% (i.e., unable to carry on normal activity or to do active work), tumor fixed
to the muscles or of questionable operability for some other reason, a multicentric tumor, or a large tumor in a small breast. Also excluded were patients with
a history of other malignancies (apart from basal cell carcinoma of the skin and
in situ carcinoma of the cervix uteri) as well as patients who were unable to
conform to strict follow-up and patients who were judged to be emotionally or
psychologically unfit to undergo BCT or (optional) positive axillary apex biopsy.
Patients were stratified by participating center, carcinoma stage (I or II), and
menopausal status. The participating centers were as follows: Guy’s Hospital,
London, U.K. (n ⳱ 420); The Netherlands Cancer Institute, Amsterdam (n ⳱
202); University Hospital Gasthuisberg, Leuven, Belgium (n ⳱ 108); Breast
Unit, University of Stellenbosch, Tijgersberg, South Africa (n ⳱ 80); Dr. Daniël
den Hoed Cancer Center, Rotterdam, The Netherlands (n ⳱ 50); and three other
hospitals in The Netherlands and Belgium (n ⳱ 42). Randomization was performed centrally at the EORTC Data Center in Brussels, Belgium. In the first 2
years of the trial (i.e., 1980 and 1981), a 2 : 1 randomization was performed—
thus explaining why somewhat more patients were randomly assigned to BCT
(466 patients were assigned to the BCT arm, whereas 436 were assigned to the
mastectomy arm). Fifteen patients decided to undergo BCT after having been
randomly assigned to mastectomy, and 15 decided to be treated with mastectomy
after having been randomly assigned to BCT. In the statistical analysis of the
data, however, these patients remained in the original treatment arm to which
they had been assigned, according to the principle of intent to treat. The study
forms of all patients were reviewed by one of the study coordinators to evaluate
their eligibility for the trial. After review, 34 patients (16 in the mastectomy arm
and 18 in the BCT arm) were excluded from the analysis. Twenty-five patients
were considered to be ineligible because their tumors were more advanced or the
histopathologic diagnosis was incorrect, two because of poor physical condition,
one because of an incomplete examination prior to randomization, and six for
unspecified reasons. Thus, 868 patients remained in the study, of whom 420
were assigned to the mastectomy group and 448 to the BCT group (Fig. 1). Of
these 868 patients, 696 (80%) had a tumor of 2.1–5 cm (see Table 1).
The investigations were approved by the local institutional committee for
medical ethics in each of the centers participating in the study. Informed consent
was obtained from all of the patients entered in the EORTC 10801 trial according
to the approved guidelines of the participating centers.
Treatment
Patients assigned to the mastectomy arm underwent a modified radical mastectomy. Patients assigned to the BCT arm underwent a lumpectomy with an
attempted margin of 1 cm of healthy tissue. Margins were not routinely inked to
assess the microscopic completeness of the lumpectomy, and there were no
instructions in the protocol for re-excision. In general, re-excision took place
only when macroscopic (i.e., palpable) disease was left behind, which was the
1144 ARTICLES
case for only a few patients. Microscopic margin involvement was observed in
217 of the 448 patients in the BCT arm. Microscopically incomplete excision
was not a reason for exclusion. Lumpectomy was followed by radiotherapy
directed to the breast (50 Gy over a 5-week period), with an additional booster
dose of 25 Gy directed to the lumpectomy site via an iridium-192 implant. In 22
patients, implants could not be used for technical reasons; such patients were
given an equivalent booster dose with external irradiation. At Guy’s Hospital, the
irradiation protocol after lumpectomy was slightly different: A flexible iridium192 implant (20 Gy midplane) was placed during surgery, and external-beam
radiotherapy was given at a minimum dose of 46 Gy. Furthermore, Guy’s Hospital accepted only patients whose tumors were no more than 4 cm in diameter.
For patients in both treatment arms, irradiation of the parasternal lymph node
region was indicated for patients with a centrally or medially localized tumor and
for patients with a lateral tumor and histologically proven axillary lymph node
metastases. Postoperative irradiation of the chest wall after mastectomy was
indicated after a microscopically incomplete operation and was given to only 12
patients.
According to the protocol of the trial, six cycles of chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil were indicated for all patients
55 years old or younger with histologically proven axillary lymph node metastases. The dosages were as follows: cyclophosphamide, 100 mg/m2, given orally
on days 1–14; methotrexate, 40 mg/m2, given intravenously on days 1 and 8; and
5-fluorouracil, 600 mg/m2, given intravenously on days 1 and 8. There were no
instructions in the protocol concerning the use of hormonal therapy, but any
adjuvant treatment used at one of the participating centers had to be similar for
both arms and consistent throughout the trial. Indications for adjuvant chemotherapy, hormonal therapy, and adjuvant parasternal radiotherapy were consistent during the trial period and similar for both treatment arms. Some minor
institutional differences in treatment techniques were not considered relevant
because the randomization of the patients was stratified by center.
In preparation for the data analysis, a quality-control program was carried out.
This program included site visits and a review of the medical files of the patients
who were reported to have died and of those who were still alive but had distant
metastases or locoregional recurrence. Clinical results from patients’ follow-up
visits to the centers were reported annually to the EORTC Data Center.
Statistical Analysis
End points were survival, time to distant metastasis, and time to locoregional
recurrence. All relapses within the treated area (breast, chest wall, or axilla) were
considered to be locoregional recurrences, including new tumors and those recurrences appearing before, at the same time as, or after the manifestation of
distant disease. Supraclavicular recurrence was considered to be distant metastasis. Duration of survival, time to distant metastasis, and time to locoregional
recurrence were measured from the date of randomization, were censored at the
last follow-up date, and were estimated with the use of the product-limit method
of Kaplan and Meier (13). The log-rank test was used to compare the results of
BCT and mastectomy. Treatment comparisons were adjusted for the major prog-
Journal of the National Cancer Institute, Vol. 92, No. 14, July 19, 2000
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Patients
Fig. 1. Flow diagram for evaluation of breast-conserving therapy (BCT) versus
mastectomy in a randomized clinical trial of patients with TNM (i.e., tumor–
node–metastasis) clinical stage I or II breast cancer (see “Patients and Methods”
section for details of staging). Incidence of recurrence and death in the two
groups is shown in Table 2.
nostic factors (clinical tumor size, pathologic lymph node status, and age) with
the use of a stratified log-rank test and a Cox proportional hazards model (14).
Using pathologic tumor size instead of the clinical size gave similar results.
However, because information on pathologic tumor size was missing for 22% of
the patients, we used clinical tumor size in the analysis. Moreover, clinical (and
mammographic) tumor size is the only information on which to base the decision
between BCT and radical mastectomy. All P values are two-sided.
Locoregional recurrence and distant metastasis are generally considered to be
nonindependent events. Therefore, the data were also analyzed according to the
approach for competing risks and multiple failures discussed by Gooley et al.
(15), to take into account patients who died or who had distant metastases before
experiencing locoregional progression.
RESULTS
The characteristics of the treatment groups with respect to
age, menopausal status, tumor stage, and adjuvant chemotherapy
were similar (Table 1). Table 2 shows the incidence of events
and causes of death in each group.
There was no difference between the two treatment groups in
overall duration of survival (P ⳱ .11), which at 10 years was
66.1% (95% confidence interval [CI] ⳱ 61.4%–70.7%) for
patients assigned to mastectomy and 65.2% (95% CI ⳱ 59.7%–
70.7%) for patients assigned to BCT (Fig. 2). Adjustment
for clinical tumor size (艋2 cm versus >2 cm), pathologic axillary lymph node status (negative versus positive), and age (<50
years old versus 艌50 years old) in a Cox proportional hazards
model did not reveal a difference between the two treatment groups (hazard ratio [HR] ⳱ 1.13; 95% CI ⳱ 0.92–1.39)
(Table 3).
Distant Metastases
There was no difference in time to distant metastasis between
the two groups (P ⳱ .24). Distant metastasis-free survival at 10
years was 66.3% (95% CI ⳱ 61.6%–70.9%) for patients assigned to mastectomy and 60.5% (95% CI ⳱ 55.8%–65.2%) for
patients assigned to BCT (Fig. 3). No statistically significant
differences in the time to distant metastasis were found between
the two treatment arms after adjustment for clinical tumor size,
pathologic axillary lymph node status, and age (HR ⳱ 1.09;
95% CI ⳱ 0.88–1.35) (Table 3).
Locoregional Recurrence
In the BCT arm, 92 patients developed locoregional recurrence; in 16 of these patients, the locoregional recurrence was
diagnosed after they developed distant metastasis. In the mastectomy arm, 56 patients developed locoregional recurrence; 11
of these patients were diagnosed after developing distant metastasis. Locoregional recurrences occurring after distant metastasis
are considered to be clinically less important than those developing earlier or at the same time as distant metastasis, and the
risk of underreporting is higher. In addition, many of the locoregional recurrences occurring after distant metastasis had not
been confirmed by histologic examination. For these reasons, we
did not take into account the locoregional recurrences occurring
after distant metastasis in our analyses.
In the BCT arm, the locoregional recurrence rate was 11.8%
(95% CI ⳱ 8.5%–15.1%) at 5 years and 19.7% (95% CI ⳱
15.4%–24.0%) at 10 years (Fig. 4). For the mastectomy arm,
these estimates were 9.8% (95% CI ⳱ 6.7%–13.0%) and 12.2%
(95% CI ⳱ 8.7%–15.7%), respectively (Fig. 4). A log-rank test
demonstrated that the locoregional recurrence rate was signifiJournal of the National Cancer Institute, Vol. 92, No. 14, July 19, 2000
Time Interval Until Locoregional Recurrence
Eighty percent of the locoregional recurrences in the mastectomy arm were diagnosed within 5 years after primary treatment,
compared with 59.3% in the BCT arm (Table 5). Among patients who experienced a locoregional recurrence, the median
time until the diagnosis of locoregional recurrence was 3.9 years
after BCT and 2.4 years after mastectomy. The overall survival
for the patients with locoregional recurrence as a first or only
event was similar for both study arms: 33 (63.5%) of the 52
patients with locoregional recurrence in the BCT arm died, compared with 17 (61%) of the 28 patients in the mastectomy arm.
Locoregional Recurrence According to Participating
Center
The proportion of patients with locoregional recurrence varied considerably among the centers participating in the study.
The locoregional recurrence rate ranged from 10.5% to 36.0%
after BCT and from 4.6% to 21.3% after mastectomy. In all
participating centers, the risk of locoregional recurrence appeared to be uniformly higher for patients in the BCT arm than
for patients in the mastectomy arm, except in one, where a
higher incidence of locoregional recurrence was observed in the
mastectomy arm.
DISCUSSION
The results from the EORTC 10801 trial of mostly stage II
breast cancer, now with a median follow-up of 13.4 years,
showed no substantial difference in overall survival between
BCT and mastectomy. Together with the long-term data from
the NSABP-B06 trial, with a median follow-up of 12 years (16),
and the NCI trial, with a median follow-up of 10 years (17),
these new results provide evidence that BCT is a feasible option
for patients with tumors larger than 2 cm.
However, there was a statistically significantly higher risk of
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Overall Survival
cantly higher for the patients assigned to BCT than for the patients assigned to mastectomy (P ⳱ .0097). When competing
risk methods were used to take into account the fact that some
patients will die or will experience distant metastasis before
experiencing locoregional recurrence, the locoregional recurrence rate was still statistically significantly higher for BCT than
for mastectomy.
After adjustment for clinical tumor size, pathologic lymph
node status, and patient age in a Cox model, the locoregional
recurrence risk for the patients assigned to BCT was 1.64 times
that for the patients assigned to mastectomy (95% CI ⳱ 1.12–
2.38) (Table 3). A higher risk of locoregional recurrence was
also found for patients with a positive lymph node status compared with those with a negative lymph node status (HR ⳱ 1.71;
95% CI ⳱ 1.19–2.45) (Table 3).
When considering HRs in various subgroups based on age,
clinical tumor size, and pathologic lymph node status, we found
that locoregional recurrence rates appeared to be higher in the
BCT arm than in the mastectomy arm for patients 50 years old
or older, for patients with a tumor larger than 2 cm, and for
patients with a negative lymph node status (Table 4).
In the BCT arm, the 10-year locoregional recurrence rate for
patients with a microscopically complete excision was 17.6%
(95% CI ⳱ 11.2%–22.3%). For patients with microscopic margin involvement, it was 26.5.% (95% CI ⳱ 22.2%–33.0%).
Table 1. Characteristics of eligible patients
Treatment
Mastectomy (n ⳱ 420)
Characteristic
Breast-conserving therapy (n ⳱ 448)
%
No. of patients
%
Age, y
<50
艌50
Unknown
156
264
0
37.1
62.9
176
271
1
39.3
60.5
0.2
Menopausal status
Premenopausal
Postmenopausal
Artificial menopause
Unknown
171
224
25
0
40.7
53.3
6.0
183
246
17
2
40.8
54.9
3.8
0.4
Tumor stage, clinical*
I
II
Unknown
69
351
0
16.4
83.6
66
381
1
14.7
85.0
0.2
Tumor size, cm, clinical†
艋2.0
2.1–5.0
Unknown
87
333
0
20.7
79.3
83
363
2
18.5
81.0
0.4
Tumor size, cm, pathologic‡
艋2.0
2.1–5.0
Unknown
140
180
100
33.3
42.9
23.8
114
242
92
25.4
54.0
20.5
Clinical lymph node status§
N0
N1A
N1B
Unknown
312
33
75
0
74.3
7.9
17.9
316
38
87
7
70.5
8.5
19.4
1.6
Pathologic lymph node status㛳
pN−
pN+
Unknown
251
163
6
59.8
38.8
1.4
251
194
3
56.0
43.3
0.7
Lymph nodes examined, No.
0–9
10–19
20–29
艌30
62
168
123
67
14.8
40.0
29.3
16.0
64
180
133
71
14.3
40.2
29.7
15.8
Positive lymph nodes, No.
0
1
2–3
4–9
艌10
Unknown
251
68
38
39
18
6
59.8
16.2
9.0
9.3
4.3
1.4
251
92
52
29
21
3
56.0
20.5
11.6
6.5
4.7
0.7
Parasternal irradiation
Yes
No
167
253
39.8
60.2
202
246
45.1
54.9
69
44
50
42.3
27.0
30.7
92
52
50
47.4
26.8
25.8
Adjuvant systemic treatment,¶ pN+ patients
Yes
No
Unknown
*Reference (12).
†Size as measured at palpation; mammographic measurement was used for patients with an unknown measurement at palpation.
‡Postsurgical size, as measured by the pathologist.
§Lymph node status as determined by palpation. N0 ⳱ no palpable homolateral axillary lymph nodes; N1A ⳱ movable homolateral axillary lymph nodes, not
considered to contain growth; N1B ⳱ movable homolateral axillary lymph nodes, considered to contain growth.
㛳Lymph node status as determined by histologic examination. pN− ⳱ no positive lymph nodes found; pN+ ⳱ positive lymph nodes found.
¶Chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil or hormonal therapy with tamoxifen.
locoregional recurrence (occurring in the absence of distant metastasis or before or at the same time as distant metastasis) for
patients in the BCT arm than for patients in the mastectomy arm.
To refine the selection of patients for either treatment, therefore,
risk factors for local recurrence should be determined. Patho1146 ARTICLES
logic lymph node status and, to a lesser degree, clinical tumor
size appeared to be risk factors for locoregional recurrence. Locoregional recurrence rates seemed to be higher after BCT than
after mastectomy in certain subgroups based on age, pathologic
lymph node status, and clinical tumor size. However, the small
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No. of patients
Table 2. Incidence of recurrence and death in the two treatment arms*
Mastectomy (n ⳱ 420)
BCT (n ⳱ 448)
Total (n ⳱ 868)
No. of patients
%†
No. of patients
%†
No. of patients
%†
LRR only
14
3.3
27
6.0
41
4.7
Both LRR and DM
LRR first
Both at the same time
DM first
14
17
11
3.3
4.0
2.6
25
24
16
5.6
5.4
3.6
39
41
27
4.5
4.7
3.1
DM only
112
26.7
120
26.8
232
26.7
Death
Death from malignant disease
Death from cardiovascular disease
Death from other or unknown causes
165
136
11
18
39.3
82.4
6.7
10.9
208
170
19
19
46.4
81.7
9.1
9.1
373
306
30
37
43.0
82.0
8.0
9.9
No recurrence and no death
221
52.6
209
46.7
430
49.5
Fig. 2. Kaplan–Meier curves for overall survival in patients with a diagnosis of clinical stage I or II invasive
carcinoma of the breast after breast-conserving therapy
(BCT) and mastectomy. Five-year survival rates: mastectomy arm, 84.6% (95% confidence interval [CI] ⳱
81.1%–88.2%); BCT arm, 82.3% (95% CI ⳱ 78.7%–
85.9%). Ten-year survival rates: mastectomy arm, 66.1%
(95% CI ⳱ 61.4%–70.7%); BCT arm, 65.2% (95% CI
⳱ 59.7%–70.7%). Thirteen-year survival rates: mastectomy arm, 60.0% (95% CI ⳱ 55.0%–65.0%); BCT arm,
54.9% (95% CI ⳱ 50.1%–59.8%). O ⳱ number of observed deaths; N ⳱ number of patients at risk.
Table 3. Cox proportional hazards model for death, distant metastasis (DM), and locoregional recurrence (LRR) before or at the same
time as DM in 857* patients†
Death
DM
LRR
Hazard ratio (95% CI)
P
Hazard ratio (95% CI)
P
Hazard ratio (95% CI)
P
Univariate
Treatment (unadjusted): BCT versus mastectomy
1.18 (0.96–1.45)
.112
1.14 (0.92–1.41)
.238
1.62 (1.12–2.34)
.0097
Multivariate
Treatment (adjusted): BCT versus mastectomy
Clinical tumor size, cm, 2.1–5.0 versus 艋2.0
Pathologic lymph node status, pN+ versus pN−
Age, 艌50 y versus <50 y
1.13 (0.92–1.39)
1.77 (1.29–2.41)
2.13 (1.74–2.63)
1.28 (1.03–1.59)
.246
.0003
.0001
.025
1.09 (0.88–1.35)
1.73 (1.26–2.39)
1.99 (1.60–2.48)
1.06 (0.85–1.32)
.451
.0008
.0001
.639
1.64 (1.12–2.38)
1.59 (0.95–2.66)
1.71 (1.19–2.45)
0.92 (0.63–1.32)
.01
.081
.004
.637
*Eleven patients were excluded from the model because of missing information.
†CI ⳱ confidence interval, BCT ⳱ breast-conserving therapy, pN+ ⳱ positive lymph nodes, and pN− ⳱ negative lymph nodes.
number of patients with locoregional recurrence did not allow a
formal analysis of risk factors for such recurrence.
Although most locoregional recurrences developed in the first
5 years after treatment, they also developed later, especially in
the BCT group. It has been reported that late recurrences after
Journal of the National Cancer Institute, Vol. 92, No. 14, July 19, 2000
BCT have a better prognosis than early recurrences (i.e., those
occurring in the first 2 or 3 years), possibly because an increasing portion of the recurrences will be new primary tumors (18–
20). These new tumors would have a small impact on the results
of BCT that would be detected only in a meta-analysis of several
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*BCT ⳱ breast-conserving therapy, LRR ⳱ locoregional recurrence, and DM ⳱ distant metastasis.
†Percentages sum to more than 100% because some of the women with recurrence ultimately died.
Fig. 3. Kaplan–Meier curves for time to distant metastasis in patients with a diagnosis of clinical stage I or II
invasive carcinoma of the breast after breastconserving therapy (BCT) and mastectomy. Five-year
distant metastasis-free survival rates: mastectomy arm,
73.6% (95% confidence interval [CI] ⳱ 69.3%–
77.9%); BCT arm, 70.2% (95% CI ⳱ 65.9%–74.6%).
Ten-year distant metastasis-free survival rates: mastectomy arm, 66.3% (95% CI ⳱ 61.6%–70.9%); BCT
arm, 60.5% (95% CI ⳱ 55.8%–65.2%). Thirteen-year
distant metastasis-free survival rates: mastectomy arm,
63.9% (95% CI ⳱ 59.1%–68.8%); BCT arm, 57.6%
(95% CI ⳱ 52.8%–62.4%). O ⳱ number of patients
developing distant metastases; N ⳱ number of patients
at risk.
Downloaded from http://jnci.oxfordjournals.org/ at Instituto Nacional de Cancerologia on April 26, 2014
Fig. 4. Kaplan–Meier curves for time to locoregional
recurrence (as only event or before or at the same time
as distant metastases) after breast-conserving therapy
(BCT) and mastectomy. Five-year locoregional recurrence-free survival rates: mastectomy arm, 90.2%
(95% confidence interval [CI] ⳱ 87.0%–93.4%); BCT
arm, 88.2% (95% CI ⳱ 84.9%–91.5%). Ten-year locoregional recurrence-free survival rates: mastectomy
arm, 87.8% (95% CI ⳱ 84.3%–91.3%); BCT arm,
80.3% (95% CI ⳱ 76.0%–84.6%). Thirteen-year locoregional recurrence-free survival rates: mastectomy
arm, 86.9% (95% CI ⳱ 83.2%–90.6%); BCT arm,
78.5% (95% CI ⳱ 74.0%–83.1%). O ⳱ number of
patients developing locoregional recurrence; N ⳱
number of patients at risk.
thousand patients in each treatment arm with a follow-up of at
least 10–20 years.
Several studies (18,21,22) have tried to determine whether
locoregional recurrence is a source of distant spread of disease,
especially after BCT. These studies have suggested that the majority of the early locoregional recurrences after BCT are associated with the same prognostic factors as distant metastases and
are alternative expressions of the same biologic process. However, these findings do not exclude the possibility of local recurrence as a source of distant spread of disease and subsequent
death, as has been illustrated in studies of the role of adjuvant
radiotherapy in lymph node-positive premenopausal women
(23,24). In an analysis of more than 1000 patients treated at The
Netherlands Cancer Institute (22), it was also shown that local
recurrence was an independent prognostic factor for survival. In
the study reported here, the proportion of patients with locoregional recurrence as the first or only recurrence event was small
1148 ARTICLES
Table 4. Hazard ratios (HRs) for locoregional recurrence after
breast-conserving therapy (BCT) compared with mastectomy in subgroups
based on patient age, clinical tumor size, and pathologic lymph node status
HR (95% CI),* BCT versus mastectomy
Age, y
艋50
>50
1.48 (0.84–2.62)
1.73 (1.06–2.80)
Clinical tumor size, cm
艋2.0
2.1–5.0
1.30 (0.51–3.29)
1.68 (1.12–2.51)
Pathologic lymph node status†
pN−
pN+
1.95 (1.13–3.34)
1.39 (0.83–2.34)
*CI ⳱ confidence interval.
†pN+ ⳱ positive lymph nodes and pN− ⳱ negative lymph nodes.
Journal of the National Cancer Institute, Vol. 92, No. 14, July 19, 2000
Table 5. Interval between primary treatment and locoregional recurrence (LRR) according to treatment group and occurrence of distant
metastasis (DM) (excluding LRR after DM)
Mastectomy arm
LRR only
LRR before DM
BCT arm*
LRR and DM
at the same time
Total
LRR only
LRR before DM
LRR and DM
at the same time
Total
Interval, y
No.
%
No.
%
No.
%
No.
%
No.
%
No.
%
No.
%
No.
%
<2
2–5
>5
3
6
5
14
21.4
42.9
35.7
31.1
8
4
2
14
57.1
28.6
14.3
31.1
9
6
2
17
52.9
35.3
11.8
37.8
20
16
9
45
44.4
35.6
20.0
100
1
8
18
27
3.7
29.6
66.7
35.5
11
9
5
25
44.0
36.0
20.0
32.9
10
6
8
24
41.7
25.0
33.3
31.6
22
23
31
76
29.0
30.3
40.8
100
Total
*BCT ⳱ breast-conserving therapy.
Journal of the National Cancer Institute, Vol. 92, No. 14, July 19, 2000
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relative to the number of patients with distant metastasis, and the
higher risk of locoregional recurrence after BCT does not seem
to be of sufficient magnitude to cause a substantial difference in
rates of distant metastasis and overall survival.
The prognosis of patients with locoregional recurrence after
mastectomy and BCT has been described in more detail in another report (25). That report concluded that the prognosis of
patients with locoregional recurrence after BCT is similar to that
of patients with locoregional recurrence after mastectomy.
We found substantial differences in locoregional recurrence
rates between the centers participating in this study, both when
comparing the two treatment arms and when looking at each
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of pathologists and radiation oncologists, in the selection of
patients for the trial, or in the distribution of risk factors within
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could be due just to chance. The difficulty of ensuring uniformity between the participating centers with respect to these factors illustrates the difficulties of interpreting the data from a
multicenter trial and underlines the need for quality assurance of
treatment techniques and patient selection.
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with breast tumors up to 5 cm needs to be considered in the
context of the eligibility criteria and the treatment techniques
used in the trial. Nowadays, more attention would be paid to
microscopic completeness of the tumor excision in combination
with generally established risk factors of locoregional recurrence, such as young age and an extensive intraductal component. In addition, the EORTC 10801 trial is characterized by a
high radiation dose after BCT, especially the high booster dose,
which impaired the cosmetic results because of increased fibrosis of the breast. Nevertheless, evaluation of the quality of life in
the EORTC 10881 trial showed that BCT helped to maintain the
patients’ body image, resulted in a higher satisfaction with treatment, and yielded no substantial difference from mastectomy
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EORTC is now studying whether lowering the radiation dose to
the breast by omitting the booster dose for patients with a microscopically complete excision will result in an equivalent local
control and improve cosmetic results after BCT.
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and mastectomy still demonstrate similar survival rates for patients with tumors up to 5 cm. Even after this long median
follow-up time, the number of locoregional recurrences in both
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NOTES
We are indebted to Dr. G. van Tienhoven (Academic Medical Center, Amsterdam, The Netherlands) for his advice and to Dr. C. Gawlik (Kassenärztliche
Bundesvereinigung, Cologne, Germany) who previously analyzed data of this
study. We thank Dr. G. Groot (St. Lucas Hospital, Amsterdam) and Dr. G. de
Keizer (Maria Hospital, Tilburg, The Netherlands) for recruitment of additional
patients and Ms. F. Mignolet (EORTC Data Center, Brussels, Belgium), Ms. D.
Ridley (Guy’s Hospital, London, U.K.), Ms. G. Vierstra (Dr. Daniël den Hoed
Cancer Center, Rotterdam, The Netherlands), Ms. M. Mahn (The Netherlands
Cancer Institute, Amsterdam), and Ms. P. Vermeiren (University Hospital Gasthuisberg, Leuven, Belgium) for data management.
Manuscript received October 18, 1999; revised May 16, 2000; accepted May
17, 2000.
Journal of the National Cancer Institute, Vol. 92, No. 14, July 19, 2000
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