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Factors affecting outcome in locally advanced breast cancer
Surgical Oncology 1992; 1: 347-355
Factors affecting outcome in locally advanced breast cancer E. R. SANCHEZ-FORGACH*,
E. P. MAMOUNAS*, J. WARNEKE*, D. DRISCOLLt, L. E. BLUMENSONS AND T. N. TSANGARIS*
Departments of *Surgical Oncology, tScientific Computing, and $Biomathematics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263, USA
Patients
presenting
group for which factors
have
patients
a direct
diagnosed
considered oestrogen clinical
impact
with
receptor
IIIA,
staging.
and type
Nearly
Although
aggressively
groups
pathological
of patients
staging,
was
from multimodality Keywords:
with
therapy.
breast cancer,
IIIB
and
improved
demonstrated
an outcome
Oncology
locally advanced,
which
encompasses
patients
with
prognosis. diameter with
a
diverse
outcome,
metastasis nodes).
invasion, may
be
subtype
Since
Correspondence: Breast
Buffalo,
Park
National
of poor
are 5 cm or greater size, may
ulceration,
oedema Axillary
present
in
multimodality
by
of the therapy.
by clinical
enough
or
to be spared
factors.
it is assumed taken
that microscopic
place at the time
sis. The consensus
of opinion
modality
In spite that,
treatment.
This
will succumb
report
menopausal
is an status,
(peau
hormone
node
affect
or
fixed
(DFS) in patients
carcinoma
a recurrence
in one-third
be identified
prognostic
of patients
present
clinical
LABC is poor, and they
good
lymph
(moveable
breast
series,
isolated
receptor
overall
dissemination of initial
favours
multi-
a high percentage
to the disease. assessment
clinical
of factors
and pathological
status and treatment
survival
diagno-
using
- age, staging,
-which
(OS) and disease-free
may
survival
with LABC.
(IBC) is a
loco-regional
with a high incidence
Service, Cancer
N.
Tsangaris,
Department Institute,
Elm
of
MD,
Surgical
and
treat-
MATERIALS
Grant CA16056
AND
METHODS
of systemic The
Associate Oncology,
Carlton
awarded
charts
Roswell
Streets,
USA.
in part by Research Cancer
generally
of their
Theodore
NY 14263,
Supported
group
was a
between
of LABC.
in most
ment is associated
Roswell
and
nodules.
Inflammatory
distinct
heterogeneous
In LABC, tumours and, regardless
skin
(LABC) is a category
lesions
d’orange), and satellite
Chief,
cancer
only
1992; 1: 347-355.
has already breast
for diseaseanalysis,
developed
recurrence
could
When stage,
ER status
of correlation
and systemic
failure,
advanced
predictors
with
of 104
carcinoma.
in a multivariate
presenting
outcome
records
pathological
significant
site of first
a diverse
To assess which
breast
stage,
of the patients
the
INTRODUCTION Locally
constitute
medical
T,N,M,
were
loco-regional
Surgical
the
clinical
a high degree
for patients
with
(LABC)
for both DFS and OS, while
was
two-thirds
no group
reviewed
(OS). However,
predictor
recurrence
we
of therapy
survival
by 5 years. The prognosis be treated
stage
cancer
have been instituted.
analysis),
for OS. There
Loco-regional
patients
stage
was a significant
and pathological
breast
modalities
(univariate
status
predictor
advanced
on outcome,
(DFS) and overall
stage
significant 5 years.
locally
of treatment
individually
free survival
should
with
a variety
347
patients
reviewed
composed
of patients
(previously
IIB) breast
Institute.
104 Cancer
1990 were T,N,M,
by the
of
Park
cancer
treated
Institute
retrospectively. with
stage
considered (AJCC,
for
between
LABC
and
The group
was
IIIA, stage
IIIB and
IIIA, now classified
TNM
at
1982
Classification,
as 1988
E. R. Sanchez-Forgach
348 ed.),
who
were
pathological analytical
classified
clinically
examination
purposes,
of
the patients
divided
into three
groups:
T,N,M,
and stage
IIIA disease;
IIIA);
group
disease; sidered with
II - patients
and
group
inoperable
I - patients
with
IIIB
(surgery
(RT)), systemic
(CT and/or
therapy
was
IIIB
were
con-
treated
and
IBC
was categorized radiation
hormone
therapy
therapy
(HT))
(CT). For analytical
classified
plus systemic
stage
(CT)
and/or
chemotherapy
all stage
patients
who
chemotherapy
as loco-regional,
therapy,
and neoadju-
vant therapy. From 1982 to 1985, oestrogen receptors were quantified
and progesterone
by a dextran-coated
char-
coal assay, with positive values equal to or greater than
10 fentomoles
per milligram
cytosol
More recently, the enzyme
immunoassay
has
EWPR-EIA
been
Abbott
used
(Abbott
Laboratories,
Abbott
values equal to or greater
protein.
technique Monoclonal,
Park, II), with
positive
than 15 fentomoles
per
milligram.
Statistical
analysis
Events for DFS included recurrence
Table
1. Distribution of patient and tumour characteristics
For sub-
operable
administered
after
further
(formerly
with
as loco-regional
loco-regional
group
Ill -stage
patients. The therapy
purposes,
and/or specimen.
were
at diagnosis
neoadjuvant
and neoadjuvant
the
et al.
time from surgery to first
Characteristics
No. patients (available information)
(%)
Total group
104 103 33
100
Age <50 >50 Menopausal status Premenopausal status Postmenopausal ER status
100
31.2 68.8 100 29.2 70.8 100 58.6
70 96 28 68 94 55
(+) (-) PR status
39
41.4
69
(+) (-) Clinical nodal status N, N, N* Clinical stage Group I Group II Group Ill Pathologic stage Group I Group II Group Ill Treatment Loco-regional Loco-regional + systemic Neoadjuvant
100
38
55
31
45
103
100
33
32
48
46.7
22
21.3
98
100
57
58.2
31
31.6
10
10.2
81
100
35
43.2 44.4
36
12.4
10 104
100
30
28.8
64
61.5
10
9.6
or to death from any cause. Events for
OS included
time from
surgery to death from any
cause. Estimated
survival
by the Kaplan-Meier cance
with
respect
distributions
were
method
Tests of signifi-
[I].
to survival
calculated
distributions
were
status, clinical nodes, clinical and pathological and type of therapy are presented nine per cent (69%)
stage
in Table 1. Sixty-
of the patients
were
over 50
based on the log rank test [2]. A Cox Proportional
years of age and 71% were
Hazards model was used to determine
nine per cent (59%) of the tumours were oestrogen
whether
age,
postmenopausal.
menopausal
status, clinical nodal status, clinical and
receptor positive and 55% were progesterone
pathological
stage,
tor positive. Thirty-two
ER and PR status, and type of
per cent (32%)
therapy were related to OS and DFS [2]. The degree
negative
of
the axilla. There
was a high degree
between
and
agreement
between
staging was calculated
clinical
and
pathological
by the Kappa statistic [3].
K=0.485, patients RESULTS
62%
The study evaluated
104 patients.
The median
of the population was 58 years (range 24-97 The distribution
age
years).
of patients according to age, meno-
pausal status, oestrogen
and progesterone
receptor
nodes and 21% clinical
P
received
pathological Twenty-nine
loco-regional
loco-regional
of correlation
staging
treatment
received neoadjuvant
therapy (Fig. 2).
Surgery was the primary treatment eight patients. Modified
only, and
and systemic deemed
following
(Fig. 1,
per cent (29%) of
were
performed
recep-
had clinically
had lymph nodes fixed in
Ten per cent (10%)
and was
Fifty-
therapy.
inoperable
and
in 93 patients
preoperative
radical mastectomy
CT in was the
Outcome factors - locally advanced breast cancer common first-line surgical therapy (88.2%)
most
the
most
(87.5%).
common
Only 9.7%
second-line
surgical
of the patients
and
349
therapy were significant
predictors
(Table 5). The 5-year OS for patients in group I was
therapy
had breast-con-
59%
vs. 42%
for patients
in group
serving surgery with or without axillary node dissec-
patients in group Ill (P
tion (Table 2).
patients
had
negative
patients (P=O.O06,
The median follow-up 2-108
time was 35 months (range
months). Breast cancer recurred in 62% of the
patients 0.6-76
at a median months).
were loco-regional. recurrence
time
of 14 months
Over 50%
(range
Figure 3 presents the site of first
ity with which the patient OS for the whole
was treated.
a 62%
a multivariate
5-year
II and 0%
OS vs. 40%
for
Fig. 6). However,
analysis was performed,
stage remained
a significant
in
(Fig. 5). ER-positive ER-
when
only clinical
predictor for both DFS
and OS, while ER status was a significant
of the first recurrences
and its relation to the therapeutic
for DFS and OS
predictor
only for OS (Table 6).
modal-
The 5-year
group was 40%. The 5-year
DFS
DISCUSSION
was 29% (Fig. 4). Results for DFS and OS for each prognostic
factor are presented
respectively.
A
factors revealed
in Tables 3 and 4,
univariate
analysis
that when
considered
clinical and pathological
2A
28
I
prognostic
3A
of LABC has evolved rapidly over the
Until 1943, radical
ized by Halsted,
individually,
year,
mastectomy,
was the standard
Haagensen
& Stout
as popular-
therapy.
published
a review
which they identified
a group of features
with
such as extensive
poor outcome,
In that in
associated oedema
of
the skin overlying the breast, satellite nodules, inter-
stage
30
I
I
The treatment years.
stage, ER status and type of
Pathological 1
of
Not staged
1
Total
I
I Table 2. Type of surgery performed Number
Surgery First line therapy Modified
Not staged
-
-
-
-
93
radical mastectomy
of patients
(%) 100
82
88.2
Total mastectomy
2
2.2
Lumpectomy
5
5.4
4
4.3
and axillary
node dissection Total
5
23
n Perfect Figure 1. Correlation
29
’
39
8
Lumpectomy
104
alone
Second line therapy correlation.
between
k=O.485.
P
Modified
clinical and pathological
8
radical mastectomy
Total mastectomy
staging.
Surgery 93 p+5
I Secondary
Figure 2. First-line therapy in patients in LABC.
modalities
treatment
100
7
87.5
1
12.5
E. R. Sanchez-Forgach et al.
350
80
5
0
IO Number
15 20 of patients
25
30
Figure 3. Location of first recurrence and relation to adjuvant therapy in 64 patients who developed recurrence.
20
All
patients
-o-
0 0
I 12
6
I I 18 24
I 30
Disease-free
I 36
I 42
I 48
I 54
I
I
I
60
66
72
survival
100
costal or paracostal
nodules,
supraclavicular
nodal
patients
termed
were
oedema
metastasis
of the arm,
and
‘categorically
IBC. These
80
inoperable’;
there were no 5-year survivors and the local recurrence rate was over 50% [41. The poor survival of these patients and the high rate
of loco-regional
cians to attempt
recurrence
treatment
prompted
with
modalities
than surgery. Baclesse et al. showed radiation
therapy
was an effective
~0-0-0-0
physiother
that high-dose local treatment,
011’ 0
6
12
18 24 Months
although he did not observe any effect on OS or DF5
151.
30
‘1
36
42
following
48
1
’
54
60
11
66
72
diognosis
Figure 4. Overall survival and disease-free survival of all
During
the
conducted
197Os, many whether
or radiation therapy
control.
reduced
and
to determine
mastectomy local
1960s
Combinations
local recurrence
cantly
improve
control
does
survival not
trials were
modified
radical
(RT) yielded better
of
surgery
and
RT
rates, but did not signifi[6-81.
improve
The fact that
survival
local
indicates
most patients with LABC have occult metastasis the time
of presentation.
multimodality
For this reason,
regimens
were
and systemic therapy
aimed at decreasing
the high incidence
in OS (56%
vs. 46%,
P=O.O5)
mode
at
regional
therapy
patients.
Neoadjuvant
an
has been
of systemic
a significant in stage
unique in that surgery primary
A combina-
tion of loco-regional
Buzdar et al. reported
in
The group of patients
that
several
instituted
attempt to increase OS and DFS [9-II].
failure.
patients.
increase Ill breast
neoadjuvant phosphamide,
5-fluorouracil, followed
adriamycin
achieved
at the time of diag-
survival shows that clinical stage is
a significant
predictor
in a univariate
with IBC). Our analysis of
of outcome
or multivariate
staging rendered
interchangeable considered
analysis
when considered
setting.
model,
results with clini-
separately but
Pathological
could
in the multinot
be
run
because of the high degree of corre-
in most patients by surgery,
lation between
the two. ER status was a significant
response
[13]. Other reports confirm
that DFS is better in complete than in non-responders
inoperable
to patients
simultaneously
a much better survival than partial respon-
ders or non-responders
CT was restricted
loc-
in some
cyclo-
RT and CT, patients with initial complete
and
with
added
factors affecting
variate
In studies
been
as the
and
patients
when
[12].
(RT) have
Systemic
nosis (including
cal stage when
to controls
in this series is
has been maintained
treatment.
who were considered
cancer patients treated with adjuvant chemotherapy compared
of
presented
[ 141.
or partial responders
predictor dually,
of OS and DFS when
but lost significance
variate
analysis.
variate
analysis
considered
PR was excluded because
indivi-
for DFS in the multifrom the multi-
PR assays were
only from a small subset of patients.
available
Outcome
Table 3. Survival and tumour
according
factors - /ocaJiy advanced breast
cancer
351
to patient Characteristic
characteristics
Total group Age Q50 >50 Menopausal
Log rank
Median
Estimated
(months)
(W
5 year
(P)
57.4
49
-
44.9 *
42
49.3 *
48
0.18
51
status
Premenopausal
status
Postmenopausal
0.35
53
ER status (+) (-) PR status
*
62
49.3
40
*
‘-I-’
A I,-, U.IU
6i
49.3
37
N,
53.9
45
N,
61.5
55
27.6
39
1-I Clinical
0.006
nodal status
N* Clinical stage Group
I
69.3
59
Group Group
II Ill
45.9
42 0
Pathologic
18.8
0.06
< 0.0001
stage
Group
I
61.8
58
Group
II
57.4
47
Group
Ill
18.8
0
< 0.0001
Treatment Loco-regional Loco-regional
+ systemic
Neoadjuvant
The type of therapy was a significant predictor for OS and DFS. When stems
from
adjuvant
therapy
compared treated
the fact with
analysed that
patients
had a very the
other
with loco-regional
systemic
therapy,
were
study
does
not
poor outcome groups,
and
when
patients different
the retrospective permit
neo-
with or without
not significantly
regarding the effect of treatment tion of treatment
significance
receiving
therapy,
from each other. However, of the
closely,
any
nature
extrapolation
because the selec-
was based primarily on the sever-
The
remaining
factors
evaluated
- age,
meno-
pausal status, clinical nodal status - were not significant predictors universal
of outcome.
standard
adjuvant
therapy
analysis
and
Because
followed
regimens
comparison
for
to these with
there was no administering patients,
other
valid
controlled
67 48
18.8
0
studies was not possible. firmly 49%
established
< 0.0001
None the less, it can be
that the estimated
and DFS of 29%
5-year
are comparable
OS of
with results
from other series in which multimodality
approaches
have been used [15-171. The
design
emphasize evaluate degree
of multimodality
preoperative with
pathological
of correlation
treatments
which
prompted
us to
CT has
clinical
whether
adequately
signifies
staging
correlates
staging.
The
that
clinician’s
the
high
staging of patients with LABC is fairly accurate that
ity of the disease at presentation.
* 53.9
most
neoadjuvant
patients
enrolled
in
protocols
CT as part of the treatment
and using
will not be
under or over treated. The applied
issue
of whether
adjuvant
in this subset of breast
still debated.
Primary
tumours
RT should
cancer greater
patients
be is
than 5 cm,
positive axillary nodes, a positive surgical margin, or
E. R. Sanchez-Forgach et al.
352
Table 4. Disease-free survival
Characteristic
Total group Age <50 >50 Menopausal status Premenopausal status Postmenopausal ER status (+) (-) PR status (+) I-) Clinical nodal status N, N, N, Clinical stage Group I Group II Group Ill Pathologic stage Group I Group II Group Ill Treatment Loco-regional Loco-regional + systemic Neoadjuvant
Median (months)
Estimated 5 year
Log rank
(%)
(P)
24
29
-
17.7 27.4
13 34
0.06
23.6 24.4
12 34
0.20
27.4 13.1
34 21
0.02
31.9 21.3
36 31
0.26
22.7 24.4 7.2
26 35 16
0.03
27.4 21.3 3.0
35 19 0
< 0.0001
23.1 24.0 3.0
28 27 0
< 0.0001
44.3 22.8 3.0
51 23 0
< 0.0001
Disease-free survival
Overall survival
Factor
No. patients
No. failures
Menopausal status
103 96
Clinical nodal status - .._ -. ..---. -.-.--
103
46 43 47 47 39 40 26 47
Age
Clinical stage
98
Pathologic stage
81
ER status
94
PR status
69 104
Therapy
pathological lymphatic
evidence invasion
of
dermal,
are factors
high risk for local recurrence variate
analysis conducted
P value
0.18
67
0.06
63
0.2
0.09
66
0.12
0.0001
67
0.0003
0.001
55
0.01
0.007
61
0.02
0.10
41
0.28
0.0001
68
0.0004
perineural
[18-211.
recurrence
or a
In a multiet al., these
factors were found to correlate significantly risk of an isolated
with
with the
[22]. The addition
of
Table 5. Univariate analysis of factors
affecting survival
P value
0.35
associated
by Fowble
No. failures
according to patient and tumour characteristics
RT to mastectomy loco-regional [18-211
to
has been
recurrences 5-10%
[23,
shown
from 241.
In our
regional
recurrences
patients.
Only one of the patients
was
treated
with
developed
adjuvant
to decrease
an average in
series, 33%
with
RT, while
of 30% locoof
the
recurrence 11 patients
353
Outcome factors - locally advanced breast cancer Overall
survival
Overall
'm-mim
40
\
A-A
20 I
0
6
I 12
I 18
I 24
I 30
A-A-A I 36
Disease-free
--2_ 'm-m
\
2o
\
111
I 42
I 60
54
48
I 66
-
-O-
0’
’ 6
0
’ 12
0
I2
I8
24
'm -m-m,
$0
Months
Figure 5. Outcome
- 0-0 - .
-.-.“.-.
m-m-m-m
I P<0.0001 I I 42 48 54
I
6
.
36
following
’ 18
I 60
20
I
’ 24
’ 30
72
I 6
0
nl
I2
%
free
’ 42
’ 48
’ 54
’ 60
’ 66
’ 72
66
72
survival
I8
‘O-0 k
‘*-o-o-o
n-m-m
24
30
Months
Figure 6. Outcome
P=0.02
'0,.
n\
diagnosis
of patients according to clinical stage.
’ 36
't
o\
I
66
'm
39 Putients
n \
o,
negative
Disease100 ‘0 \
'm
lrn
55 Patients
ER positive
- -m- ER
I 72
survival
‘*
m-m
P=0.006
P~0.0001
\
(Jr
survival
36
42
following
according
'm-m-m-m-m
54
48
60
diagnosis
to oestrogen
receptor
status.
were
treated
with
shown to increase in a narrow compared and/or
CT. Postoperative DFS, improve
quality of life and,
subset of patients,
increase
Oslo series, a statistically of distant
postoperative
metastasis
decrease
&
Stout
was obtained
warmth
to mastec-
clinically by the presence usually in addi-
tion to peau d’orange. A distinct pathological The treatment in
IBC
treated
patients
tomy+CT
[29].
A
with
in DFS or OS
P value
0.14
0.07
0.31
0.23
Clinical nodal status 0.95
0.53
Menopausal
status
Clinical stage*
0.006
ER status?
0.02
0.05 0.14
Therapy
0.76
0.99
results were obtained when pathological
tPR status excluded
to increase sample size.
Sloan-Kettering
In our series, seven of 10 patients in group Ill had a diagnosis of IBC. After neoadjuvant
Cancer Center study found that all patients treated
(radiotherapy
surgery and radiotherapy,
[29]. These
by surgery, had residual
findings
were
contradicted
by
those from MD Anderson
where
plete responses following
CT had 89% loco-regional
control [30].
stage
was entered.
with induction CT, followed disease
survival
neoadjuvant
+ CT + RT, or in mastec-
Memororial
(n = 84,
No. failures = 36) No. failures = 56)
*Similar
of IBC patients is highly controver-
CT + RT + CT, mastectomy
Disease-free
in =84,
feature
is the presence of dermal lymphatic invasion [28]. sial. Koh could not find any difference
Overall survival
with
inflammatory
and induration,
analysis of factors affecting survival
P value
Age considered
breast cancer (IBC) as a contraindication tomy [4]. IBC is diagnosed
Factor
in the
RT [26, 271.
Haagensen
of erythema,
CT
I and
in the Stockholm significant
Table 6. Multivariate
OS, when
to patients who only receive adjuvant
HT [25]. Moreover,
incidence
RT has been
patients with com-
chemotherapy
in one), two of those patients received
further
chemotherapy,
therapy
and one received be
two received surgery and one
had
further
chemo-
no further treatment.
conclusions
could
pathological
and therapeutic
reached
regarding
variables
No
clinical,
because
of
E. R. Sanchez-Forgach
354
the small subset of patients. It is possible that some additional
patients presented
cal characteristics deemed were
operable
offered
at the time
surgery
patients were
of presentation
those
in the IBC group in this
a restrospective
review
3. Fleiss
diffuse
tumour
tumour
were
found
to
be
of a
pare
our results
sistency
with
different What
with
which
protocols
is evident
improvement percentage their
encountered other patients and
series
is that
of patients
response
[32].
problems
succumb for
to become
IIIB
DFS and a 75%
OS
treatment,
with LABC patients
therapy,
testing the value of neoadjuvant followed
and radiation protocol
enrollment,
radiotherapy
and
In conclusion,
In
we
patients
not
recommend
for
patients
status and therapy,
were
identified
receptor
from univariate
analysis, most of these factors lost their significance when
ity
examined
in combination.
In our study, we
were unable to isolate a group of LABC patients with a prognosis
good enough
to preclude
using multi-
modality therapy in their treatment.
breast
radio-
breast.
Surg
radiation
cancer.
Cancer
Anticancer
AI I f-B”,
breast
and a review
local1984;
2:
modal-
cancer:
One
of the literature.
D, Elias EG, Wiernik
breast K-n, ,\a”
C\AI V..,
cancer. Cm&h “lllllll
cancer.
Am J C/in Oncoll989; GN, Ames
of stage
117:
f-2 Tnn_\rcasr V. a”11 yuu,
in breast
12: 123-8.
breast
AU,
et a/. Manage-
cancer
with
primary
therapy.
Cancer
6. RC. Multimodality
J, Langiands
metastatic
advanced 1982;
trial
and radiation
breast cancer.
chemotherapy
Surg
IUnrtnh.an\,i I”, L”Y”yy’
FC, Buzdar
surgery
14. Hobar PC, Jones advanced
Arch
chemotherapy
Ill primary
1988; 62: 2507-I
PH. Mastectomy
for locally
TI IL,
of FAC adjuvant
Boyages
Oncol
B, et a/. Combined
advanced
results
13. Hortobagyi
i5.
advanced
C/in
to chemotherapy
metastatic
882-6. El,,&..,. 12. Y”L”cll
J
Res 1987; 7: 733-6.
J, Morris
as an adjuvant or
DC, et a/. Aggressive for
and
breast
treatment
of locally
Arch Surg 1988; 123: 951-5. AO. Tine efficacy
radiotherapy
cancer.
in
of combined
advanced
non-
lnt J Radiat Oncol Biol Phys
1988; 14: 71-8. 16. Hortobagyi
GN, Kau SW, Buzdar
chemotherapy
AU,
for stage
Ill primary
Salmon
S, ed. Adjuvant
Therapy
Orlando,
FL: Grune and Stratton M, Lesnich in
m
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of Cancer,
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GJ. Chemotherapy stage
et al. Induction
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1982; 117: 879-81.
EL, Meier
incomplete
breast
PP, Tormey
FE, Turner
experience
18. Valaguss
457-86.
followed
B, et al. Primary
carcinoma.
institution’s
mastectomy
1. Kaplan
of the
therapy
of locally
17. Perloff
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Factors affecting outcome in locally advanced breast cancer E. R. SANCHEZ-FORGACH*,
E. P. MAMOUNAS*, J. WARNEKE*, D. DRISCOLLt, L. E. BLUMENSONS AND T. N. TSANGARIS*
Departments of *Surgical Oncology, tScientific Computing, and $Biomathematics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, New York 14263, USA
Patients
presenting
group for which factors
have
patients
a direct
diagnosed
considered oestrogen clinical
impact
with
receptor
IIIA,
staging.
and type
Nearly
Although
aggressively
groups
pathological
of patients
staging,
was
from multimodality Keywords:
with
therapy.
breast cancer,
IIIB
and
improved
demonstrated
an outcome
Oncology
locally advanced,
which
encompasses
patients
with
prognosis. diameter with
a
diverse
outcome,
metastasis nodes).
invasion, may
be
subtype
Since
Correspondence: Breast
Buffalo,
Park
National
of poor
are 5 cm or greater size, may
ulceration,
oedema Axillary
present
in
multimodality
by
of the therapy.
by clinical
enough
or
to be spared
factors.
it is assumed taken
that microscopic
place at the time
sis. The consensus
of opinion
modality
In spite that,
treatment.
This
will succumb
report
menopausal
is an status,
(peau
hormone
node
affect
or
fixed
(DFS) in patients
carcinoma
a recurrence
in one-third
be identified
prognostic
of patients
present
clinical
LABC is poor, and they
good
lymph
(moveable
breast
series,
isolated
receptor
overall
dissemination of initial
favours
multi-
a high percentage
to the disease. assessment
clinical
of factors
and pathological
status and treatment
survival
diagno-
using
- age, staging,
-which
(OS) and disease-free
may
survival
with LABC.
(IBC) is a
loco-regional
with a high incidence
Service, Cancer
N.
Tsangaris,
Department Institute,
Elm
of
MD,
Surgical
and
treat-
MATERIALS
Grant CA16056
AND
METHODS
of systemic The
Associate Oncology,
Carlton
awarded
charts
Roswell
Streets,
USA.
in part by Research Cancer
generally
of their
Theodore
NY 14263,
Supported
group
was a
between
of LABC.
in most
ment is associated
Roswell
and
nodules.
Inflammatory
distinct
heterogeneous
In LABC, tumours and, regardless
skin
(LABC) is a category
lesions
d’orange), and satellite
Chief,
cancer
only
1992; 1: 347-355.
has already breast
for diseaseanalysis,
developed
recurrence
could
When stage,
ER status
of correlation
and systemic
failure,
advanced
predictors
with
of 104
carcinoma.
in a multivariate
presenting
outcome
records
pathological
significant
site of first
a diverse
To assess which
breast
stage,
of the patients
the
INTRODUCTION Locally
constitute
medical
T,N,M,
were
loco-regional
Surgical
the
clinical
a high degree
for patients
with
(LABC)
for both DFS and OS, while
was
two-thirds
no group
reviewed
(OS). However,
predictor
recurrence
we
of therapy
survival
by 5 years. The prognosis be treated
stage
cancer
have been instituted.
analysis),
for OS. There
Loco-regional
patients
stage
was a significant
and pathological
breast
modalities
(univariate
status
predictor
advanced
on outcome,
(DFS) and overall
stage
significant 5 years.
locally
of treatment
individually
free survival
should
with
a variety
347
patients
reviewed
composed
of patients
(previously
IIB) breast
Institute.
104 Cancer
1990 were T,N,M,
by the
of
Park
cancer
treated
Institute
retrospectively. with
stage
considered (AJCC,
for
between
LABC
and
The group
was
IIIA, stage
IIIB and
IIIA, now classified
TNM
at
1982
Classification,
as 1988
E. R. Sanchez-Forgach
348 ed.),
who
were
pathological analytical
classified
clinically
examination
purposes,
of
the patients
divided
into three
groups:
T,N,M,
and stage
IIIA disease;
IIIA);
group
disease; sidered with
II - patients
and
group
inoperable
I - patients
with
IIIB
(surgery
(RT)), systemic
(CT and/or
therapy
was
IIIB
were
con-
treated
and
IBC
was categorized radiation
hormone
therapy
therapy
(HT))
(CT). For analytical
classified
plus systemic
stage
(CT)
and/or
chemotherapy
all stage
patients
who
chemotherapy
as loco-regional,
therapy,
and neoadju-
vant therapy. From 1982 to 1985, oestrogen receptors were quantified
and progesterone
by a dextran-coated
char-
coal assay, with positive values equal to or greater than
10 fentomoles
per milligram
cytosol
More recently, the enzyme
immunoassay
has
EWPR-EIA
been
Abbott
used
(Abbott
Laboratories,
Abbott
values equal to or greater
protein.
technique Monoclonal,
Park, II), with
positive
than 15 fentomoles
per
milligram.
Statistical
analysis
Events for DFS included recurrence
Table
1. Distribution of patient and tumour characteristics
For sub-
operable
administered
after
further
(formerly
with
as loco-regional
loco-regional
group
Ill -stage
patients. The therapy
purposes,
and/or specimen.
were
at diagnosis
neoadjuvant
and neoadjuvant
the
et al.
time from surgery to first
Characteristics
No. patients (available information)
(%)
Total group
104 103 33
100
Age <50 >50 Menopausal status Premenopausal status Postmenopausal ER status
100
31.2 68.8 100 29.2 70.8 100 58.6
70 96 28 68 94 55
(+) (-) PR status
39
41.4
69
(+) (-) Clinical nodal status N, N, N* Clinical stage Group I Group II Group Ill Pathologic stage Group I Group II Group Ill Treatment Loco-regional Loco-regional + systemic Neoadjuvant
100
38
55
31
45
103
100
33
32
48
46.7
22
21.3
98
100
57
58.2
31
31.6
10
10.2
81
100
35
43.2 44.4
36
12.4
10 104
100
30
28.8
64
61.5
10
9.6
or to death from any cause. Events for
OS included
time from
surgery to death from any
cause. Estimated
survival
by the Kaplan-Meier cance
with
respect
distributions
were
method
Tests of signifi-
[I].
to survival
calculated
distributions
were
status, clinical nodes, clinical and pathological and type of therapy are presented nine per cent (69%)
stage
in Table 1. Sixty-
of the patients
were
over 50
based on the log rank test [2]. A Cox Proportional
years of age and 71% were
Hazards model was used to determine
nine per cent (59%) of the tumours were oestrogen
whether
age,
postmenopausal.
menopausal
status, clinical nodal status, clinical and
receptor positive and 55% were progesterone
pathological
stage,
tor positive. Thirty-two
ER and PR status, and type of
per cent (32%)
therapy were related to OS and DFS [2]. The degree
negative
of
the axilla. There
was a high degree
between
and
agreement
between
staging was calculated
clinical
and
pathological
by the Kappa statistic [3].
K=0.485, patients RESULTS
62%
The study evaluated
104 patients.
The median
of the population was 58 years (range 24-97 The distribution
age
years).
of patients according to age, meno-
pausal status, oestrogen
and progesterone
receptor
nodes and 21% clinical
P
received
pathological Twenty-nine
loco-regional
loco-regional
of correlation
staging
treatment
received neoadjuvant
therapy (Fig. 2).
Surgery was the primary treatment eight patients. Modified
only, and
and systemic deemed
following
(Fig. 1,
per cent (29%) of
were
performed
recep-
had clinically
had lymph nodes fixed in
Ten per cent (10%)
and was
Fifty-
therapy.
inoperable
and
in 93 patients
preoperative
radical mastectomy
CT in was the
Outcome factors - locally advanced breast cancer common first-line surgical therapy (88.2%)
most
the
most
(87.5%).
common
Only 9.7%
second-line
surgical
of the patients
and
349
therapy were significant
predictors
(Table 5). The 5-year OS for patients in group I was
therapy
had breast-con-
59%
vs. 42%
for patients
in group
serving surgery with or without axillary node dissec-
patients in group Ill (P
tion (Table 2).
patients
had
negative
patients (P=O.O06,
The median follow-up 2-108
time was 35 months (range
months). Breast cancer recurred in 62% of the
patients 0.6-76
at a median months).
were loco-regional. recurrence
time
of 14 months
Over 50%
(range
Figure 3 presents the site of first
ity with which the patient OS for the whole
was treated.
a 62%
a multivariate
5-year
II and 0%
OS vs. 40%
for
Fig. 6). However,
analysis was performed,
stage remained
a significant
in
(Fig. 5). ER-positive ER-
when
only clinical
predictor for both DFS
and OS, while ER status was a significant
of the first recurrences
and its relation to the therapeutic
for DFS and OS
predictor
only for OS (Table 6).
modal-
The 5-year
group was 40%. The 5-year
DFS
DISCUSSION
was 29% (Fig. 4). Results for DFS and OS for each prognostic
factor are presented
respectively.
A
factors revealed
in Tables 3 and 4,
univariate
analysis
that when
considered
clinical and pathological
2A
28
I
prognostic
3A
of LABC has evolved rapidly over the
Until 1943, radical
ized by Halsted,
individually,
year,
mastectomy,
was the standard
Haagensen
& Stout
as popular-
therapy.
published
a review
which they identified
a group of features
with
such as extensive
poor outcome,
In that in
associated oedema
of
the skin overlying the breast, satellite nodules, inter-
stage
30
I
I
The treatment years.
stage, ER status and type of
Pathological 1
of
Not staged
1
Total
I
I Table 2. Type of surgery performed Number
Surgery First line therapy Modified
Not staged
-
-
-
-
93
radical mastectomy
of patients
(%) 100
82
88.2
Total mastectomy
2
2.2
Lumpectomy
5
5.4
4
4.3
and axillary
node dissection Total
5
23
n Perfect Figure 1. Correlation
29
’
39
8
Lumpectomy
104
alone
Second line therapy correlation.
between
k=O.485.
P
Modified
clinical and pathological
8
radical mastectomy
Total mastectomy
staging.
Surgery 93 p+5
I Secondary
Figure 2. First-line therapy in patients in LABC.
modalities
treatment
100
7
87.5
1
12.5
E. R. Sanchez-Forgach et al.
350
80
5
0
IO Number
15 20 of patients
25
30
Figure 3. Location of first recurrence and relation to adjuvant therapy in 64 patients who developed recurrence.
20
All
patients
-o-
0 0
I 12
6
I I 18 24
I 30
Disease-free
I 36
I 42
I 48
I 54
I
I
I
60
66
72
survival
100
costal or paracostal
nodules,
supraclavicular
nodal
patients
termed
were
oedema
metastasis
of the arm,
and
‘categorically
IBC. These
80
inoperable’;
there were no 5-year survivors and the local recurrence rate was over 50% [41. The poor survival of these patients and the high rate
of loco-regional
cians to attempt
recurrence
treatment
prompted
with
modalities
than surgery. Baclesse et al. showed radiation
therapy
was an effective
~0-0-0-0
physiother
that high-dose local treatment,
011’ 0
6
12
18 24 Months
although he did not observe any effect on OS or DF5
151.
30
‘1
36
42
following
48
1
’
54
60
11
66
72
diognosis
Figure 4. Overall survival and disease-free survival of all
During
the
conducted
197Os, many whether
or radiation therapy
control.
reduced
and
to determine
mastectomy local
1960s
Combinations
local recurrence
cantly
improve
control
does
survival not
trials were
modified
radical
(RT) yielded better
of
surgery
and
RT
rates, but did not signifi[6-81.
improve
The fact that
survival
local
indicates
most patients with LABC have occult metastasis the time
of presentation.
multimodality
For this reason,
regimens
were
and systemic therapy
aimed at decreasing
the high incidence
in OS (56%
vs. 46%,
P=O.O5)
mode
at
regional
therapy
patients.
Neoadjuvant
an
has been
of systemic
a significant in stage
unique in that surgery primary
A combina-
tion of loco-regional
Buzdar et al. reported
in
The group of patients
that
several
instituted
attempt to increase OS and DFS [9-II].
failure.
patients.
increase Ill breast
neoadjuvant phosphamide,
5-fluorouracil, followed
adriamycin
achieved
at the time of diag-
survival shows that clinical stage is
a significant
predictor
in a univariate
with IBC). Our analysis of
of outcome
or multivariate
staging rendered
interchangeable considered
analysis
when considered
setting.
model,
results with clini-
separately but
Pathological
could
in the multinot
be
run
because of the high degree of corre-
in most patients by surgery,
lation between
the two. ER status was a significant
response
[13]. Other reports confirm
that DFS is better in complete than in non-responders
inoperable
to patients
simultaneously
a much better survival than partial respon-
ders or non-responders
CT was restricted
loc-
in some
cyclo-
RT and CT, patients with initial complete
and
with
added
factors affecting
variate
In studies
been
as the
and
patients
when
[12].
(RT) have
Systemic
nosis (including
cal stage when
to controls
in this series is
has been maintained
treatment.
who were considered
cancer patients treated with adjuvant chemotherapy compared
of
presented
[ 141.
or partial responders
predictor dually,
of OS and DFS when
but lost significance
variate
analysis.
variate
analysis
considered
PR was excluded because
indivi-
for DFS in the multifrom the multi-
PR assays were
only from a small subset of patients.
available
Outcome
Table 3. Survival and tumour
according
factors - /ocaJiy advanced breast
cancer
351
to patient Characteristic
characteristics
Total group Age Q50 >50 Menopausal
Log rank
Median
Estimated
(months)
(W
5 year
(P)
57.4
49
-
44.9 *
42
49.3 *
48
0.18
51
status
Premenopausal
status
Postmenopausal
0.35
53
ER status (+) (-) PR status
*
62
49.3
40
*
‘-I-’
A I,-, U.IU
6i
49.3
37
N,
53.9
45
N,
61.5
55
27.6
39
1-I Clinical
0.006
nodal status
N* Clinical stage Group
I
69.3
59
Group Group
II Ill
45.9
42 0
Pathologic
18.8
0.06
< 0.0001
stage
Group
I
61.8
58
Group
II
57.4
47
Group
Ill
18.8
0
< 0.0001
Treatment Loco-regional Loco-regional
+ systemic
Neoadjuvant
The type of therapy was a significant predictor for OS and DFS. When stems
from
adjuvant
therapy
compared treated
the fact with
analysed that
patients
had a very the
other
with loco-regional
systemic
therapy,
were
study
does
not
poor outcome groups,
and
when
patients different
the retrospective permit
neo-
with or without
not significantly
regarding the effect of treatment tion of treatment
significance
receiving
therapy,
from each other. However, of the
closely,
any
nature
extrapolation
because the selec-
was based primarily on the sever-
The
remaining
factors
evaluated
- age,
meno-
pausal status, clinical nodal status - were not significant predictors universal
of outcome.
standard
adjuvant
therapy
analysis
and
Because
followed
regimens
comparison
for
to these with
there was no administering patients,
other
valid
controlled
67 48
18.8
0
studies was not possible. firmly 49%
established
< 0.0001
None the less, it can be
that the estimated
and DFS of 29%
5-year
are comparable
OS of
with results
from other series in which multimodality
approaches
have been used [15-171. The
design
emphasize evaluate degree
of multimodality
preoperative with
pathological
of correlation
treatments
which
prompted
us to
CT has
clinical
whether
adequately
signifies
staging
correlates
staging.
The
that
clinician’s
the
high
staging of patients with LABC is fairly accurate that
ity of the disease at presentation.
* 53.9
most
neoadjuvant
patients
enrolled
in
protocols
CT as part of the treatment
and using
will not be
under or over treated. The applied
issue
of whether
adjuvant
in this subset of breast
still debated.
Primary
tumours
RT should
cancer greater
patients
be is
than 5 cm,
positive axillary nodes, a positive surgical margin, or
E. R. Sanchez-Forgach et al.
352
Table 4. Disease-free survival
Characteristic
Total group Age <50 >50 Menopausal status Premenopausal status Postmenopausal ER status (+) (-) PR status (+) I-) Clinical nodal status N, N, N, Clinical stage Group I Group II Group Ill Pathologic stage Group I Group II Group Ill Treatment Loco-regional Loco-regional + systemic Neoadjuvant
Median (months)
Estimated 5 year
Log rank
(%)
(P)
24
29
-
17.7 27.4
13 34
0.06
23.6 24.4
12 34
0.20
27.4 13.1
34 21
0.02
31.9 21.3
36 31
0.26
22.7 24.4 7.2
26 35 16
0.03
27.4 21.3 3.0
35 19 0
< 0.0001
23.1 24.0 3.0
28 27 0
< 0.0001
44.3 22.8 3.0
51 23 0
< 0.0001
Disease-free survival
Overall survival
Factor
No. patients
No. failures
Menopausal status
103 96
Clinical nodal status - .._ -. ..---. -.-.--
103
46 43 47 47 39 40 26 47
Age
Clinical stage
98
Pathologic stage
81
ER status
94
PR status
69 104
Therapy
pathological lymphatic
evidence invasion
of
dermal,
are factors
high risk for local recurrence variate
analysis conducted
P value
0.18
67
0.06
63
0.2
0.09
66
0.12
0.0001
67
0.0003
0.001
55
0.01
0.007
61
0.02
0.10
41
0.28
0.0001
68
0.0004
perineural
[18-211.
recurrence
or a
In a multiet al., these
factors were found to correlate significantly risk of an isolated
with
with the
[22]. The addition
of
Table 5. Univariate analysis of factors
affecting survival
P value
0.35
associated
by Fowble
No. failures
according to patient and tumour characteristics
RT to mastectomy loco-regional [18-211
to
has been
recurrences 5-10%
[23,
shown
from 241.
In our
regional
recurrences
patients.
Only one of the patients
was
treated
with
developed
adjuvant
to decrease
an average in
series, 33%
with
RT, while
of 30% locoof
the
recurrence 11 patients
353
Outcome factors - locally advanced breast cancer Overall
survival
Overall
'm-mim
40
\
A-A
20 I
0
6
I 12
I 18
I 24
I 30
A-A-A I 36
Disease-free
--2_ 'm-m
\
2o
\
111
I 42
I 60
54
48
I 66
-
-O-
0’
’ 6
0
’ 12
0
I2
I8
24
'm -m-m,
$0
Months
Figure 5. Outcome
- 0-0 - .
-.-.“.-.
m-m-m-m
I P<0.0001 I I 42 48 54
I
6
.
36
following
’ 18
I 60
20
I
’ 24
’ 30
72
I 6
0
nl
I2
%
free
’ 42
’ 48
’ 54
’ 60
’ 66
’ 72
66
72
survival
I8
‘O-0 k
‘*-o-o-o
n-m-m
24
30
Months
Figure 6. Outcome
P=0.02
'0,.
n\
diagnosis
of patients according to clinical stage.
’ 36
't
o\
I
66
'm
39 Putients
n \
o,
negative
Disease100 ‘0 \
'm
lrn
55 Patients
ER positive
- -m- ER
I 72
survival
‘*
m-m
P=0.006
P~0.0001
\
(Jr
survival
36
42
following
according
'm-m-m-m-m
54
48
60
diagnosis
to oestrogen
receptor
status.
were
treated
with
shown to increase in a narrow compared and/or
CT. Postoperative DFS, improve
quality of life and,
subset of patients,
increase
Oslo series, a statistically of distant
postoperative
metastasis
decrease
&
Stout
was obtained
warmth
to mastec-
clinically by the presence usually in addi-
tion to peau d’orange. A distinct pathological The treatment in
IBC
treated
patients
tomy+CT
[29].
A
with
in DFS or OS
P value
0.14
0.07
0.31
0.23
Clinical nodal status 0.95
0.53
Menopausal
status
Clinical stage*
0.006
ER status?
0.02
0.05 0.14
Therapy
0.76
0.99
results were obtained when pathological
tPR status excluded
to increase sample size.
Sloan-Kettering
In our series, seven of 10 patients in group Ill had a diagnosis of IBC. After neoadjuvant
Cancer Center study found that all patients treated
(radiotherapy
surgery and radiotherapy,
[29]. These
by surgery, had residual
findings
were
contradicted
by
those from MD Anderson
where
plete responses following
CT had 89% loco-regional
control [30].
stage
was entered.
with induction CT, followed disease
survival
neoadjuvant
+ CT + RT, or in mastec-
Memororial
(n = 84,
No. failures = 36) No. failures = 56)
*Similar
of IBC patients is highly controver-
CT + RT + CT, mastectomy
Disease-free
in =84,
feature
is the presence of dermal lymphatic invasion [28]. sial. Koh could not find any difference
Overall survival
with
inflammatory
and induration,
analysis of factors affecting survival
P value
Age considered
breast cancer (IBC) as a contraindication tomy [4]. IBC is diagnosed
Factor
in the
RT [26, 271.
Haagensen
of erythema,
CT
I and
in the Stockholm significant
Table 6. Multivariate
OS, when
to patients who only receive adjuvant
HT [25]. Moreover,
incidence
RT has been
patients with com-
chemotherapy
in one), two of those patients received
further
chemotherapy,
therapy
and one received be
two received surgery and one
had
further
chemo-
no further treatment.
conclusions
could
pathological
and therapeutic
reached
regarding
variables
No
clinical,
because
of
E. R. Sanchez-Forgach
354
the small subset of patients. It is possible that some additional
patients presented
cal characteristics deemed were
operable
offered
at the time
surgery
patients were
of presentation
those
in the IBC group in this
a restrospective
review
3. Fleiss
diffuse
tumour
tumour
were
found
to
be
of a
pare
our results
sistency
with
different What
with
which
protocols
is evident
improvement percentage their
encountered other patients and
series
is that
of patients
response
[32].
problems
succumb for
to become
IIIB
DFS and a 75%
OS
treatment,
with LABC patients
therapy,
testing the value of neoadjuvant followed
and radiation protocol
enrollment,
radiotherapy
and
In conclusion,
In
we
patients
not
recommend
for
patients
status and therapy,
were
identified
receptor
from univariate
analysis, most of these factors lost their significance when
ity
examined
in combination.
In our study, we
were unable to isolate a group of LABC patients with a prognosis
good enough
to preclude
using multi-
modality therapy in their treatment.
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radio-
breast.
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