relative value of physical examination, mammography, and ... · after neoadjuvant chemotherapy by...
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Vol. 3, 1565-1569, September 1997 Clinical Cancer Research 1565
3 The abbreviations used are: LABC, locally advanced breast carcinoma;
NACT, neoadjuvant chemotherapy; ThM, Tumor-Node-Metastasis.
Relative Value of Physical Examination, Mammography, and Breast
Sonography in Evaluating the Size of the Primary Tumor and
Regional Lymph Node Metastases in Women Receiving
Neoadjuvant Chemotherapy for Locally Advanced
Breast Carcinoma1
Juan Herrada, Revathy B. Iyer,
E. Neely Atkinson, Nour Sneige,
Aman U. Buzdar, and Gabriel N. Hortobagyi2
Departments of Breast Medical Oncology [J. H., A. U. B., G. N. H.],
Diagnostic Radiology [R. B. I.], Biomathematics [E. N. A.], and
Pathology [N. S.], The University of Texas M. D. Anderson Cancer
Center, Houston, Texas 77030
ABSTRACT
The purpose of this study was to correlate physicalexamination and sonographic and mammographic measure-ments of breast tumors and regional lymph nodes withpathological findings and to evaluate the effect of neoadju-
vant chemotherapy on clinical Tumor-Node-Metastasisstage by noninvasive methods. This was a retrospective anal-
ysis of 100 patients with locally advanced breast cancerregistered and treated in prospective trials of neoadjuvant
chemotherapy. All patients received four cycles of a doxo-rubicin-containing regimen and had nomnvasive evaluationof the primary tumor and regional lymph nodes before andafter neoadjuvant chemotherapy by physical examination,sonography, and mammography and underwent breast sur-
gery and axillary dissection within 5 weeks after com-pletion
of neoadjuvant chemotherapy. The correlations betweenclinical and pathological measurements were determined by
Spearman rank correlation analysis. A proportional oddsmodel was used to examine predictive values.
Eighty-three patients had both a clinically detectableprimary tumor and lymph node metastases. Sixty-four pa-tients had a decrease in Tumor-Node-Metastasis stage afterchemotherapy. For 54% of patients, there was concordancein clinical response between the primary tumor and lymph
node compartment; for the rest, results were discordant.Physical examination correlated best with pathological find-
Received 1/10/97; revised 5/15/97; accepted 5/19/97.
The costs of publication of this article were defrayed in part by the
payment of page charges. This article must therefore be hereby marked
advertisement in accordance with 18 U.S.C. Section 1734 solely to
indicate this fact.
I This work was supported in part by Grant CA16672 and by the Nylene
Eckles Professorship in Breast Cancer Research.
2 To whom requests for reprints should be addressed, at Department ofBreast Medical Oncology, Box 56, The University of Texas M. D.Anderson Cancer Center, 15 15 Holcombe Boulevard, Houston, TX77030. Phone: (713)792-2817; Fax: (713)794-4385.
ings in the measurement of the primary tumor (P 0.0003),whereas sonography was the most accurate predictor of size
for axillary lymph nodes (P = 0.0005). The combination ofphysical examination and mammography worked best forassessment of the primary tumor (P 0.003), whereas
combining physical examination with sonography gave op-timal evaluation of regional lymph nodes (P 0.0001).
In conclusion, physical examination is the best nonin-vasive predictor of the real size of locally advanced primary
breast cancer, whereas sonography correlates better with
the real dimensions of axillary lymph nodes. The combina-tion of physical examination with either mammography or
sonography significantly improves the accuracy of noninva-sive assessment of tumor dimensions.
INTRODUCTION
The degree of response to preoperative or neoadjuvant chem-
otherapy is an important indicator of prognosis for patients with
LABC3 (1, 2). Accurate staging is of paramount importance to
determine the extent of disease before and after NACT and thus to
ascertain changes in tumor dimensions. Pathological staging of
surgical specimens (total or partial mastectomy) and lymph node
dissection provides the most accurate information about currently
accepted prognostic indicators. Two of these indicators, tumor size
and, more importantly, axillary lymph node status, are used as a
guide to select optimal adjuvant treatments in breast cancer patients
following NACT and local therapy (3). Clinical assessment of the
primary breast tumor and regional lymph nodes has been done by
physical examination, breast sonography, and mammography.
Some reports (4-6) have suggested that physical examination and
mammography are complementary in the assessment of primary
tumor response; whereas other reports have concluded that sono-
graphic measurements correlate best with pathological findings (7,
8). Fewer data are available on the clinical assessment of lymph
node metastases (9); therefore, the preoperative evaluation of their
response to neoadjuvant chemotherapy remains imprecise. This
limits information about the differential impact of NACT on the
primary breast tumor and nodal metastatic disease. We, therefore,
conducted a study of clinical assessment methods in women with
LABC.
The aims of our study were to: (a) correlate physical
examination and sonographic and mammographic measure-
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Table 1 Patient characteristics and clinical disease stage beforeNACT
Total number of patients 100
Median age in years 47(Range) (29-69)
Primary tumor status (T)T0T1T2T3
Regional lymph node status (N)N0
N,
N2
N3
TNM stageIla (n = 3)
lib (n = 14)
lila (n = 39)
IlIb (n = 44)
2
8
20
4030
115236
3
95
22
7
7
2
3
21
19
1566 Evaluating the Size of Primary Tumor and Lymph Nodes
ments of tumors and regional lymph nodes after NACT with
pathological findings (the gold standard); (b) evaluate the effect
of NACT on clinical TNM stage by comparing baseline and
post-chemotherapy measurements for each of the three clinical
assessment modalities; and (c) assess noninvasively whether
neoadjuvant chemotherapy affects primary tumors and lymph
node metastases differently.
PATIENTS AND METHODS
Study Design. This was a retrospective analysis of pa-
tients registered in prospective trials of NACT for LABC con-
ducted by the Department of Breast Medical Oncology at The
University of Texas M. D. Anderson Cancer Center. The study
population consisted of 100 consecutive women with a histo-
logical diagnosis of LABC who met the following criteria: (a)
received three or four cycles of a doxorubicin-containing com-
bination NACT regimen described in detail previously (10, 1 1);
(b) had clinical (noninvasive) evaluation of the primary tumor
and regional lymph nodes before and after NACT by physical
examination, sonography, and mammography; and (c) under-
went breast surgery and axillary dissection within 5 weeks after
completion of NACT, with the results noted in a detailed path-
ological report. All patients were diagnosed and treated between
1985 and 1994. The median patient age was 47 years (range,
29-69 years). All noninvasive tests considered for this analysis
were performed at The University of Texas M. D. Anderson
Cancer Center. Mammography techniques used during the
course of the study included both film screen and xeromammo-
grams. All images were obtained on dedicated mammography
units: Siemens Mammomat (Stockholm, Sweden) for xeromam-
mography and film screen; and General Electric DMR seno-
graph (GE Medical Systems, Waakesha, WI) for film screen. A
dedicated film processor with extended processing was used. All
positioning was performed by registered mammography tech-
nologists. The sonographic examinations were performed on
three different units with high resolution 7-megahertz transduc-
ers. These units included Accuson (Accuson Corp., Mountain-
view, CA), ATL (Advanced Technology Laboratories, Inc.,
Bothell, WA), and Aloka (Corometrics Medical Systems, Inc.,
Wallingford, CT). Before March 1993, mammography was per-
formed with dedicated mammography units and the xeromam-
mography technique. Subsequent mammography was done us-
ing the low-dose film screen technique. All surgical procedures
were also performed at M. D. Anderson, and the surgical spec-
imens were examined and reported on by our breast patholo-
gists. Information on disease stage and other pretreatment pa-
tient characteristics are summarized in Tables 1 and 2. Most
patients had large, bulky primary tumors, and more than one-
third had bulky, matted axillary lymph nodes. Close to 90% of
the patients had clinically positive axillary lymph nodes.
Methods. The two longest perpendicular dimensions of
the primary tumor and clinically positive regional lymph nodes
were recorded in centimeters and multiplied to determine the
surface area in square centimeters. The primary breast tumor
and lymph node metastasis measurements were obtained by
physical examination, sonography, and mammography per-
formed before the first cycle and after the fourth cycle of NACT
(usually less than a week before the surgical resection). Patients
(T.,N0)
(T2N1)(T3N0)
(T3N1)
(T3N2)
(T,N2)(T1N,)(T0N2)(T4N0)(T4N,)(T4N7)
(T4N3)
with LABC were examined jointly by surgical, medical, and
radiation oncologists to determine the extent of disease and plan
the optimal combination of therapies. This group always in-
cluded the treating medical oncologist. The baseline measure-
ments and the preoperative measurements were the result of a
consensus after a joint physical examination. The measurements
from the physical examination were obtained from a review of
each patient’s chart. At the time of the review, if more than one
set of measurements for the same mass was recorded in the
medical record, the largest dimensions were considered for the
analysis. If more than one tumor was present in the same breast,
only the largest tumor mass was considered for this review.
The sonographic and mammographic measurements were
obtained from a retrospective review of sonograms and mam-
mograms by a single radiologist (R. B. I.), thus avoiding varia-
tions in interpretation of films (12, 13). Areas of microcalcifi-
cations on mammograms were considered nonmeasurable
tumor.
Pathological measurements were obtained from the surgi-
cal pathology report. Measurements were obtained prospec-
tively at the time of the initial interpretation by one of two
dedicated breast pathologists. If more than one tumor was pres-
ent in the same breast (or surgical pathology specimen), only the
largest tumor was considered. For measurement of nodal me-
tastases, the size of the largest lymph node involved by tumor
was considered.
The correlations between clinical and pathological assess-
ments were determined by Spearman rank correlation analysis.
A proportional odds model was used to examine predictive
values. The “Logistic” procedure from the S.A.S. program was
used to establish the concordance between the observed cate-
gory and the category predicted by the regression model.
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Clinical Cancer Research 1567
Table 2 Disease stage of 83” patients after NACT (befo re surgery) as assessed clinically and pathologically
No. of patients (%) according to
Physical examination Sonography Mammography Pathology
Primary tumor status (T)
T0 20(24%) 11 (13%) 21 (25%) 8(10%)T, 13(16%) 26(31%) 17(20%) 35 (42%)T, 33 (40%) 41 (49%) 38 (46%) 30 (36%)T3 11(13%) 5(6%) 6(7%) 8(10%)
T41’ 6(7%) 0(0%) 1 (1%) 2(2%)Regional lymph node status (N)
N0 56 (67%) 43 (52%) 43 (52%) 25 (30%)
N, 21 (25%) 39(47%) 39(47%) 56 (68%)
N, 6(7%) 1(1%) 1(1%) 2(2%)
ThM stage
0 12(14%) 6(7%) 12(14%) 5(6%)
I 11 (13%) 14(17%) 9(11%) 13(16%)
ha 37 (45%) 39 (47%) 37 (45%) 32 (39%)lIb 11 (13%) 20(24%) 19(23%) 24 (29%)lIla 5 (6%) 4 (5%) 5 (6%) 7 (8%)
IIIb 7(8%) 0(0%) 1 (1%) 2(2%)
(1 Seventeen of the initial 100 women were excluded because they had no clinically measurable disease or their films were not available forreview.
1’ Only a measurable residual breast mass with associated skin edema was considered T4.
Table 3 Spearman’s rank correlation coefficie nt (r) of clinical (noninvasive) measurements obtained after NACT (before surgery) compared
with pathological measurements
Noninvasive method of measurement
Correlation with pathology
Tumor size Lymph node size
Physical examination
Sonography
Mammography
r = 0.726 P < 0.0001 r 0.318 P 0.003r = 0.600 P < 0.0001 r = 0.514 P = 0.0001
r 0.649 P < 0.0169 r 0.430 P 0.4251
RESULTS
Thirty-six of the 100 patients evaluated had no change in
clinical TNM stage after NACT, whereas 64 had a decrease of
one or more stages. Of these 64 patients, 2% had a three-stage
decrease (downstaging) in clinical TNM stage, I 2% had a
two-stage decrease, and 86% had a one-stage decrease.
The effects of NACT on the primary breast tumor and
regional lymph node compartments could be evaluated in 83
patients who had clinically evident primary breast tumors and
lymph node metastases at the time of diagnosis of LABC.
Forty-one % of these patients had concordant clinical downstag-
ing of both the primary tumor and regional lymph node metas-
tases; 13% had no appreciable decrease in either compartment;
in 25%, the tumor decreased while the nodal metastases did not;
and in another 2 1 %, the opposite occurred. The difference
between tumor decrease alone (25%) and lymph node decrease
alone (21%) was not significant (P = 0.63).
Measurements done after NACT by each of the three
noninvasive methods were correlated separately with the path-
ological measurements. We found that physical examination
showed the best correlation (correlation coefficient, r - 0.726)
with pathology for the primary tumor, and sonography provided
the best correlation for the lymph nodes (r = 0.5 14; Table 3).
To examine the value of each of the three noninvasive
measurements after NACT in predicting pathological findings,
we established four size categories based on the estimated
surface areas of the mass (in cm2): 0, >0 to 1, > I to 5, and >5.
The data were then fit using the proportional odds model. Let y�
be the categorized size of thej”� patient, e.g., if patientj’s tumor
as measured by pathology is between I and 5 cm (2), then y3 =
3, since this tumor falls into the third size category. Let
denote the probability that y� � i. Then the proportional odds
model assumes that � 1/(1 + exp(-r�)), where r� a + f3,I � � � � � I3pXjp’a is an intercept parameter, X�k is the value
of the k” independent variable for patient j, and �k �5 the slope
parameter for the k#{176}’independent variable. In our analysis, two
independent variables were used: the natural logarithm of the
tumor size as measured by mammography and by sonography.
The results (considering log data only) are summarized in Table
4. For the primary tumor, of the three noninvasive methods,
physical examination was the best predictor of the size of the
residual pathological mass (P 0.0003), followed closely by
sonography (P = 0.0005); mammography had the weakest
correlation with pathological findings (P = 0.0132). For lymph
node metastases, sonography was the best predictor of the
surface area of the largest lymph node (P 0.0005). Mammog-
raphy (P = 0.0132) and physical examination were much less
accurate (P = 0.0181). We also examined the predictive value
of two or three noninvasive methods used in combination. The
results of these analyses are summarized in Tables 5 and 6 and
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1568 Evaluating the Size of Primary Tumor and Lymph Nodes
Table 4 Results of univariate analysis by proportional odds model topredict pathology tumor size using noninvasive measurements
pa
Noninvasive method of
measurement Tumor size Lymph node size
Physical examination 0.0003 0.0 132
Sonography 0.0005 0.0005Mammography 0.0132 0.0181
‘, Compared with pathological measurement.
give the effects of adding variables to the regression model. x2 for
the addition of sonography to physical examination in the model
for primary tumor size is obtained by subtracting the value for the
model containing both physical examination and sonography
(169.064) from the value for the model containing only physical
examination (174.366), yielding 5.302. This value is distributed as
x2 with one degree of freedom, from which the corresponding P
can be obtained. We started our analysis from the physical exam-
ination, because routine clinical practice dictates that this noninva-
sive method be performed first, and in virtually all patients, before
any further test (mammogram or sonogram) is considered. For the
primary tumor, a significant improvement in the predictive value
was noted with the combination of sonography and physical ex-
amination (P = 0.021) and with the combination of mammography
and physical examination (P 0.003). The addition of mammog-
raphy to the combination of physical examination and sonography
significantly further improved the predictive value (P 0.032), but
the addition of sonography to the combination of physical exami-
nation and mammography did not (P 0.377; Table 5). For the
nodal metastases, the combination of mammography and physical
examination improved predictive value over physical examination
alone (0.027), and the combination of breast sonography and phys-
ical examination resulted in an even greater improvement in the
predictive value (P = 0.0001). The addition of mammography to
the combination of physical examination and sonography did not
significantly further improve predictive value (P = 0.612), but
adding sonography to the combination of physical examination and
mammography did (P = 0.001 ; Table 6).
DISCUSSION
In this study, almost two-thirds (64%) of patients with
LABC treated with NACT achieved a decrease in TNM stage.
Primary breast tumors and nodal metastases appeared to be
equally affected by neoadjuvant chemotherapy. However, al-
though these results are in accordance with other clinical obser-
vations, they need to be interpreted cautiously. Our patient
population was selected to evaluate the relative accuracy of the
noninvasive methods used since 1985 to assess LABC. For the
purpose of our study, microcalcifications on mammograms were
considered nonmeasurable disease, and nonpalpable masses
were considered as T0, even if skin changes noted prior to
NACT had not resolved completely afterward.
Adjuvant chemotherapy, given after local control of the
primary tumor, has been demonstrated to improve disease-free
and overall survival rates in patients with breast cancer (14, 15)
The paradigm on which the use of adjuvant chemotherapy is
based is the treatment of micrometastases. Our data suggest that
Table 5 Summary of the effects of adding additional variables to theproportional odds model
The �2 values are the likelihood ratio statistics obtained when thevariables to the right of the + sign are added to the equation containing
the variables in parentheses. All x2 values have one degree of freedom.
x2 values are obtained by subtracting the -2 log likelihood value of themodel with the additional variable from the value for the modelscontaining only the variable(s) in parentheses.
Variables in equation X2
(None) + physical examination 39.529 <0.0001(Physical examination) + sonography 5.302 0.02 13
(Physical examination) + mammography 9.095 0.0026(Physical examination + sonography) 4.572 0.0325
+ mammography(Physical examination + mammography) 0.779 0.3774
+ sonography
the axillary metastatic cell clone, although expressing a more
aggressive phenotype, appears to be as sensitive to chemother-
apy as the primary tumor cells are.
For the assessment of the primary breast tumor, physical
examination measurements in our study showed the highest corre-
lation with and the highest predictive value for the pathological
findings. We, therefore, conclude that physical examination by
experienced examiners remains the best single noninvasive method
of assessing the size of the primary tumor in women with LABC.
However, other investigators have published differing conclusions.
In 1987, Fomage et a!. (7) described 31 breast cancer cases with
pathologically defined T1 (n = 23) and T2 (n = 8) tumors. The
maximal diameters of the tumors, obtained by physical examina-
tion (29 cases), mammography (20 cases), and sonography (31
cases), were correlated with the values at pathological examination.
That study showed that sonography had the highest correlation
coefficient. The lesions included in that study were, however,
generally much smaller than those in our study and might have
been more difficult to delimit on physical examination. In fact, the
largest tumor reported in the study by Fomage et a!. (7) was 3 cm
in longest diameter on pathological evaluation. Furthermore,
Fornage et a!. (7) included only unidimensional measurements,
whereas in our study, we used two-dimensional measurements
because surface area defines tumor extent more accurately. Also, it
should be stressed that the physical examination measurements in
our report usually represented the consensus of two or more expert
breast oncologists. In another study, Serrano-Migallbn et a!. (8)
studied 34 patients with breast masses (16 benign and 18 malig-
nant). The maximum diameters estimated by physical examination,
sonography, and mammography were compared in each case to the
pathological measurements. That 1993 study also concluded that
sonography had the best correlation with pathological findings.
However, differences in patient numbers and methodology may
account for the discrepancy with our results.
For the assessment of lymph node metastases, sonographic
measurements showed the highest correlation with and the high-
est predictive value for the pathological findings. Thus, we
conclude that sonography is the best single noninvasive method
of assessing the extent of nodal involvement based on size of
nodes.
After NACT, the combination of physical examination and
mammography had the best predictive value for the true dimen-
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is to maximize the use of breast-conserving therapy in patients with
large T2 or locally advanced breast cancer.
Pathological complete remission continues to be the best
prognostic factor for metastases-free survival. However, neither
imaging method evaluated in this study is sensitive enough to
identify with certainty the absence of residual malignant cells.
Therefore, we consider that careful monitoring of response to
preoperative systemic therapy with physical examination and
sonography is useful to determine the optimal approaches to
preoperative and operative treatment, whereas findings on pa-
thology are the major determinants to select postoperative sys-
temic therapy and prognosis.
Clinical Cancer Research 1569
Table 6 Summary of the effects of adding additional variables to theproportional odds model for lymph node metastases
The x2 values are the likelihood ratio statistics obtained when thevariables to the right of the + sign are added to the equation containing
the variables in parentheses. All x2values have one degree of freedom.
x2values are obtained by subtracting the -2 log likelihood value of themodel with the additional variable from the value for the modelscontaining only the variable(s) in parentheses.
Variables in equation X2
(None) + physical examination 6.229 0.0126(Physical examination) + sonography 14.895 0.0001(Physical examination) + mammography 4.893 0.0270(Physical examination + sonography) 0.256 0.6129
+ mammography(Physical examination + mammography) 10.258 0.0014
+ sonography
sions of the primary breast tumor, whereas the combination of
physical examination and sonography provided the best assess-
ment of the lymph node metastasis.
It is noteworthy that the tumors located in different com-
partments are best defined by different methods. The different
anatomical structures of the breast and the axillary area may
account for this. Lluch et a!. (9) evaluated 60 patients (33 with
pathologically defined axillary involvement) who underwent
neoadjuvant chemotherapy to study the role of physical exam-
ination, sonography, mammography, and computed tomography
in defining tumor and nodal size; results with these techniques
were compared to the pathologically determined tumor size in
the surgical specimens. Liuch et a!. (9) reported that computed
tomography was the best noninvasive method to detect axillary
involvement, whereas for the primary tumor, physical examina-
tion had the best correlation coefficient, as in our study.
The implication of our study is that for purposes of clinical
practice, both physical examination and sonography should be
routinely used in the evaluation of patients with LABC undergoing
treatment with NACT. Although serial mammography provides an
additional benefit in the assessment of the primary tumor size, it is
not useful in the evaluation of lymph node metastases. Therefore,
serial mammography should be used only in selected cases, such as
those for whom neither sonography nor physical examination iden-
tifies a well-defined, and therefore measurable, tumor. By restrict-
ing the use of serial mammography, unnecessary radiation expo-
sure and expense to the patient could be avoided. However, the role
of a preoperative mammogram after NACT to assess the presence
of nonmeasurable disease as manifested by microcalcifications was
not evaluated in this study. For women in whom breast-conserving
therapy is being considered after downstaging by NACT, careful
diagnostic film screen mammography with appropriate focal spot
magnification views is still recommended to define the extent of
microcalcifications as a predictor of ductal carcinoma extent.
The noninvasive determination of response to neoadjuvant
therapy is important to guide the choice of subsequent therapy. For
instance, if no substantial response to NACT is seen, a different,
non-cross-resistant chemotherapy regimen (or radiotherapy) might
be used preoperatively to enhance resectability or increase the
possibility of breast-conserving surgery. Although these were not
the goals of the present study, the results of this analysis are being
tested in a subsequent clinical trial, in which one of the objectives
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1997;3:1565-1569. Clin Cancer Res J Herrada, R B Iyer, E N Atkinson, et al. carcinoma.neoadjuvant chemotherapy for locally advanced breast and regional lymph node metastases in women receivingbreast sonography in evaluating the size of the primary tumor Relative value of physical examination, mammography, and
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