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Technology Evaluation Center
Breast MRI for Management of
Patients with Locally Advanced
Breast Cancer Who Are Being
Referred for Neoadjuvant
Chemotherapy
Assessment
Program
Volume 19, No. 7
September 2004
Executive Summary
The objective of this Assessment is to evaluate the clinical effectiveness of magnetic resonance
imaging (MRI) of the breast for management of patients with locally advanced breast cancer who are
being referred for neoadjuvant chemotherapy in order to shrink the tumor to a size eligible for breast
conservation therapy (BCT). Assessment of the extent of residual tumor after neoadjuvant therapy
by conventional techniques (physical exam and mammography) is relatively inaccurate. Breast MRI
has been proposed to evaluate the extent of tumor after completion of neoadjuvant chemotherapy to
determine which patients have become eligible for BCT. The MRI scan before chemotherapy is used
for comparison to demonstrate tumor location so that the tumor can be optimally evaluated after
chemotherapy even when the tumor size and degree of contrast enhancement are greatly reduced
in a very responsive tumor.
Breast MRI has also been proposed as a means to evaluate the response of tumor early in the course
of neoadjuvant chemotherapy in order to guide choice of chemotherapy regimen. Reduction in tumor
size occurs late in the course of chemotherapy; however, tumor vascularity decreases relatively early
in responsive tumors. Contrast enhancement on MRI is related to tumor vascularity. Thus, reduction
in the degree of enhancement on breast MRI is a measure of early response to chemotherapy. Reliable
early determination of lack of response to chemotherapy (e.g., after first or second cycle) might spare
the patient additional exposure to ineffective treatment and permit changes to a different, possibly
more effective, chemotherapy regimen.
Based on the available evidence, the Blue Cross and Blue Shield Association Medical Advisory Panel
made the following judgments about whether the use of MRI for management of patients with locally
advanced breast cancer who are being referred for neoadjuvant chemotherapy meets the Blue Cross
and Blue Shield Association Technology Evaluation Center (TEC) criteria.
1. The technology must have final approval from the appropriate governmental regulatory bodies.
®
®
BlueCross
BlueShield
Association
The technology meets the first TEC criterion. MR imaging of the breast can be performed using
commercially available MR scanners and intravenous MR contrast agents. Specialized breast coils
such as the OBC-300 Breast Array Coil ® (MRI Devices Corp., Waukesha, WI) and MR-compatible
equipment for performing biopsy have been developed and cleared for marketing via the U.S. Food
and Drug Administration (FDA) 510(k) process as substantially equivalent to predicate devices for
use “in conjunction with a magnetic resonance scanner to produce diagnostic images of the breast
and axillary tissues that can be interpreted by a trained physician” (Model OBC-300 Breast Array Coil
510(k) notification letter dated December 3, 1999).
An Association
of Independent
Blue Cross and
Blue Shield Plans
NOTICE OF PURPOSE: TEC Assessments are scientific opinions, provided solely for informational purposes. TEC Assessments
should not be construed to suggest that the Blue Cross Blue Shield Association, Kaiser Permanente Medical Care Program or the
TEC Program recommends, advocates, requires, encourages, or discourages any particular treatment, procedure, or service; any
particular course of treatment, procedure, or service; or the payment or non-payment of the technology or technologies evaluated.
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Technology Evaluation Center
2. The scientific evidence must permit conclusions concerning the effect of the technology
on health outcomes.
A search of the literature was conducted to identify studies using contrast-enhanced breast MRI.
Eligible studies were published in English as full-length, peer-reviewed journal articles, using
human subjects, and reporting diagnostic performance characteristics for MRI and alternative
tests when appropriate or effect of MRI on health outcomes.
The best evidence would be direct evidence from randomized, controlled trials that assess the
effects of breast MRI on breast cancer-related morbidity or mortality. Such trials have not been
published. The best available evidence is from studies that report the diagnostic performance
characteristics of breast MRI to define the extent of tumor and/or tumor response after neoadjuvant chemotherapy and compare results of MRI with conventional tests using histopathology
as an independent reference standard. While these diagnostic intermediate outcomes are related
to the use of BCT and the outcomes of breast conservation and avoidance of re-excision surgery,
the relationship with long-term health outcomes is not as clear. It may be that patients who are
downstaged by chemotherapy before BCT have higher recurrence rates compared to those who
were initially eligible for BCT. Nevertheless, the short-term benefits of breast conservation and
avoidance of re-excision surgery are considered important health outcomes and can be used to
model the effects of using MRI for presurgical planning in patients with locally advanced breast
cancer who are referred for neoadjuvant chemotherapy.
Breast MRI Performed Before and After Completion of Neoadjuvant Chemotherapy for
Presurgical Planning. The available body of evidence is somewhat limited by small sample sizes,
lack of consistent outcomes measures and reporting, and lack of consistent statistical comparisons; however, several prospective well-designed studies are included. These studies consistently
show that MRI appears to provide a more accurate preoperative assessment of residual tumor
following neoadjuvant chemotherapy compared with conventional clinical staging alternatives.
Despite limitations, the available evidence is considered sufficient to permit conclusions.
Eighteen studies (total n=558) evaluate the use of MRI after neoadjuvant chemotherapy to
demonstrate the presence, size, and extent of residual tumor and compare results against histopathology, the independent reference standard. Six of these studies (total n=179) compare MRI
with conventional clinical staging alternatives. Four additional studies (total n=179) describe the
preoperative use of MRI to identify tumor involvement of the pectoralis muscle/chest wall, skin,
and nipple, although neoadjuvant chemotherapy was not applied, and 3 of these compared MRI
with conventional alternatives.
Compared with histopathology, the reference standard, MRI demonstrates the presence of residual
tumor with estimated sensitivity ranging from 90–100% and specificity from 50–100%. MRI estimated the size and extent of tumor correctly in comparison with pathologic evaluation in 57%,
63%, 66%, 83%, and 97% of cases among 5 studies reporting these results. Correlation coefficients
for size of residual tumor on MRI were generally good to excellent, ranging from 0.72 to 0.98.
Chest wall invasion was correctly determined by MRI with 100% sensitivity and 100% specificity
in 23 cases included in 3 studies. In another study, extension of tumor to the skin was suggested
by MRI in 4 of 4 true-positive cases, although MRI also reported 2 false-positive cases.
Among the 9 studies comparing MRI with conventional alternatives, MRI appeared to be more
sensitive than conventional alternatives in identifying the presence of residual tumor and defining the size and extent of residual tumor. A small prospective, double-blinded study (n=17) found
MRI to be 100% sensitive and specific for defining residual tumor after chemotherapy. Conversely,
mammography achieved 90% sensitivity and 57% specificity (mammography results were all
considered equivocal), and clinical exam was only 50% sensitive and 86% specific. Similarly,
another larger prospective study (n=52) reported correlation of residual tumor size on MRI of 0.89
and clinical exam of 0.60. MRI identified all residual tumor cases, whereas clinical exam had 5
false-negative results. Clinical exam and mammography were not able to distinguish chest wall
involvement as reliably as MRI. Nipple involvement (Paget’s disease) was correctly identified by
2
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Breast MRI for Patients with Locally Advanced Breast Cancer Referred for Neoadjuvant Chemotherapy
MRI in 4 of 4 cases, whereas mammography or clinical exam identified nipple involvement in
only 1 or 2 of these cases, respectively.
Breast MRI Performed Before and During Neoadjuvant Chemotherapy for Chemotherapy
Planning. The available body of evidence using MRI for planning chemotherapy is limited to a
few studies with a lack of consistent outcome measures and reporting, as well as small sample
sizes and a lack of consistent statistical comparisons. The most important parameter would be
a high negative predictive value for identifying tumors that are nonresponsive to neoadjuvant
chemotherapy. However, results are not consistent, and there is insufficient evidence to determine
whether breast MRI can reliably predict response to neoadjuvant chemotherapy.
Six studies (total n=206) performed breast MRI during the course of neoadjuvant chemotherapy.
The type of chemotherapy regimen used, timing of the MRI scans, and methods for measuring
tumor response on MRI were variable. Four of these 6 studies were prospective in design, but
only 2 included more than 50 subjects. Four provided clear descriptions of the study populations,
and 3 appeared to avoid spectrum bias. All studies used histopathologic reference standard for
determining final response to chemotherapy, and all studies interpreted MRI blinded to reference
standard results. All 6 studies avoided verification bias.
The most important use of MRI would be to reliably identify patients whose tumors were not
responding to neoadjuvant chemotherapy. Two studies provide estimates of NPV, which were
38% and 83%. The 4 other studies do not clearly separate partial-responders from nonresponders,
making it impossible to correctly determine negative predictive value. At least a few patients
in these studies failed to show a response on MRI after 2 cycles of neoadjuvant chemotherapy
but went on to have at least a partial response. Thus, early appearance on MRI is not a reliable
predictor of final tumor response.
Reduction of enhancement on MRI may indicate responsive tumor; however, it seems unlikely
that this information would change patient management.
3. The technology must improve the net health outcome; and
4. The technology must be as beneficial as any established alternatives.
Breast MRI Performed Before and After Completion of Neoadjuvant Chemotherapy for
Presurgical Planning. The available studies consistently show that breast MRI appears to be better
than conventional presurgical clinical staging methods at determining extent and size of residual
tumor. However, it should be noted that breast MRI would not be used as a replacement for histopathologic assessment. Since MRI appears to provide a more accurate determination of tumor
size and extent compared with clinical staging, it is likely that MRI would be more accurate in
determining eligibility for BCT. Thus, discordant results on MRI would most likely be correct MRI
findings and incorrect clinical findings. Using MRI staging results instead of clinical staging for
presurgical planning would lead to an improvement in net health outcome by increasing the use of
BCT when appropriate and avoiding the need for re-excision surgery when BCT is not appropriate.
Breast MRI Performed Before and During Neoadjuvant Chemotherapy for Chemotherapy
Planning. There is insufficient evidence to permit conclusions on the effect on health outcomes
of using breast MRI to provide an early prediction of the response to neoadjuvant chemotherapy.
5. The improvement must be attainable outside the investigational settings.
Breast MRI Performed Before and After Completion of Neoadjuvant Chemotherapy for
Presurgical Planning. The improvements in health outcomes achieved in the investigational
settings would likely be attainable outside the investigational settings when breast MRI is conducted by operators of similar experience in patients with locally advanced breast cancer who
are being referred for neoadjuvant chemotherapy.
©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.
3
Technology Evaluation Center
Breast MRI Performed Before and During Neoadjuvant Chemotherapy for Chemotherapy
Planning. Whether the use of breast MRI to provide an early prediction of the response
to neoadjuvant chemotherapy improves health outcomes has not been demonstrated in the
investigational setting.
Therefore, based on the above, the use of breast MRI before chemotherapy and after completion
of neoadjuvant chemotherapy to define the size and extent of tumor to guide the decision to use
breast-conservation therapy meets TEC criteria. The use of breast MRI before and during neoadjuvant chemotherapy to provide an early prediction of the response to neoadjuvant chemotherapy
does not meet the TEC criteria.
Contents
Assessment Objective
5
Review of Evidence
14
Background
5
Summary of Application of the
Technology Evaluation Criteria
33
References
37
Appendix
42
Methods
11
Formulation of the Assessment
12
Published in cooperation with Kaiser Foundation Health Plan and
Southern California Permanente Medical Group.
TEC Staff Contributors
Lead Author—Carole Redding Flamm, M.D., M.P.H.; Co-Author—Jerome Seidenfeld, Ph.D.; TEC Executive Director—Naomi
Aronson, Ph.D.; Managing Scientific Editor—Kathleen M. Ziegler, Pharm.D.; Research/Editorial Staff—Claudia J. Bonnell, B.S.N.,
M.L.S.; Maxine A. Gere, M.S.
Acknowledgments—Staff would like to thank Ted Speroff, Ph.D., and David Samson for their contributions to the research and
development of this Assessment.
Blue Cross and Blue Shield Association Medical Advisory Panel
Allan M. Korn, M.D., F.A.C.P.—Chairman, Senior Vice President, Clinical Affairs/Medical Director, Blue Cross and Blue
Shield Association; David M. Eddy, M.D., Ph.D.—Scientific Advisor, Senior Advisor for Health Policy and Management, Kaiser
Permanente, Southern California. ■ Panel Members Peter C. Albertsen, M.D., Professor, Chief of Urology, and Residency Program
Director, University of Connecticut Health Center; Edgar Black, M.D., Vice President, Chief Medical Officer, BlueCross BlueShield
of the Rochester Area; Helen Darling, M.A., President, Washington Business Group on Health; Josef E. Fischer, M.D., F.A.C.S.,
Mallinckrodt Professor of Surgery, Harvard Medical School and Chair, Department of Surgery, Beth Israel Deaconess Medical
Center—American College of Surgeons Appointee; Alan M. Garber, M.D., Ph.D., Professor of Medicine, Economics, and Health Research and
Policy, Stanford University; Steven N. Goodman, M.D., M.H.S., Ph.D., Associate Professor, Johns Hopkins School of Medicine, Department of
Oncology, Division of Biostatistics (joint appointments in Epidemiology, Biostatistics, and Pediatrics)—American Academy of Pediatrics
Appointee; Michael A.W. Hattwick, M.D., Woodburn Internal Medicine Associates, Ltd. American College of Physicians Appointee;
I. Craig Henderson, M.D., Adjunct Professor of Medicine, University of California, San Francisco; Mark A. Hlatky, M.D., Professor of
Health Research and Policy and of Medicine (Cardiovascular Medicine), Stanford University School of Medicine; Bernard Lo, M.D.,
Professor of Medicine and Director, Program in Medical Ethics, University of California, San Francisco; Barbara J. McNeil, M.D., Ph.D.,
Ridley Watts Professor and Head of Health Care Policy, Harvard Medical School, Professor of Radiology, Brigham and Women’s Hospital;
Brent O’Connell, M.D., M.H.S.A., Vice President and Medical Director, Pennsylvania Blue Shield/Highmark, Inc.; Stephen G. Pauker,
M.D., M.A.C.P., F.A.C.C., Sara Murray Jordan Professor of Medicine, Tufts University School of Medicine; and Vice-Chairman for Clinical
Affairs and Associate Physician-in-Chief, Department of Medicine, New England Medical Center; William R. Phillips, M.D., M.P.H., Clinical
Professor of Family Medicine, University of Washington—American Academy of Family Physicians’ Appointee; Earl P. Steinberg, M.D.,
M.P.P., President, Resolution Health, Inc.; Paul J. Wallace, M.D., Executive Director, Care Management Institute, Kaiser Permanente;
A. Eugene Washington, M.D., M.Sc., Executive Vice Chancellor, University of California, San Francisco; Jed Weissberg, M.D.,
Associate Executive Director for Quality and Performance Improvement, The Permanente Federation.
CONFIDENTIAL: This document contains proprietary information that is intended solely for Blue Cross and Blue Shield Plans
and other subscribers to the TEC Program. The contents of this document are not to be provided in any manner to any other
parties without the express written consent of the Blue Cross and Blue Shield Association.
4
©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.
Breast MRI for Patients with Locally Advanced Breast Cancer Referred for Neoadjuvant Chemotherapy
Assessment Objective
The objective of this Assessment is to evaluate
the clinical effectiveness of magnetic resonance
imaging (MRI) of the breast for management
of patients with locally advanced breast cancer
who are being referred for neoadjuvant chemotherapy in order to shrink the tumor to a size
eligible for breast conservation therapy (BCT).
Assessment of the extent of residual tumor
after neoadjuvant therapy by conventional
techniques (physical exam and mammography)
is relatively inaccurate. Breast MRI has been
proposed to evaluate the extent of tumor after
completion of neoadjuvant chemotherapy to
determine which patients have become eligible
for BCT. The MRI scan before chemotherapy
is used for comparison to demonstrate tumor
location so that the tumor can be optimally
evaluated after chemotherapy even when the
tumor size and degree of contrast enhancement
are greatly reduced in a very responsive tumor.
Breast MRI has also been proposed as a means
to evaluate the response of tumor early in the
course of neoadjuvant chemotherapy in order
to guide choice of chemotherapy regimen.
Reduction in tumor size occurs late in the
course of chemotherapy; however, tumor vascularity decreases relatively early in responsive tumors. Contrast enhancement on MRI is
related to tumor vascularity. Thus, reduction
in the degree of enhancement on breast MRI is
a measure of early response to chemotherapy.
Reliable early determination of lack of response
to chemotherapy (e.g., after first or second
cycle) might spare the patient additional
exposure to ineffective treatment and permit
changes to a different, possibly more effective,
chemotherapy regimen.
Background
Breast Cancer
Breast cancer is the most common non-cutaneous malignancy and the second most frequent
cause of cancer death among women in the
U.S. (PDQ 2004a). Estimated cumulatively
from birth, a woman’s risk for invasive breast
cancer is 1 in 8 (12.5%) if she lives to age 90
(PDQ 2004b). However, the cumulative risk
for eventually receiving the diagnosis changes
as women age without breast cancer. For
example, it is 1 in 7 (13.5%) at 30 years and 1
in 10 (10%) at 60 years of age (Ries et al. 2002).
The American Cancer Society estimates there
will be 215,990 new cases and 40,110 deaths of
invasive breast cancer in the U.S. during 2004
(American Cancer Society 2004). Factors that
increase breast cancer risk include younger
age at menarche, older age at first full-term
pregnancy, older age at menopause, nulliparity,
presence or history of benign breast disease,
positive family history of a first-degree relative with breast cancer, certain mutations in
the BRCA1 or BRCA2 genes, use of hormone
replacement therapy, ionizing radiation to the
breast (particularly early in life), substantial
alcohol consumption, and obesity or a higher
body mass index (McTiernan et al. 1997; Winer
et al. 2001; PDQ 2004a).
While neoplastic tissue may originate anywhere
within the mammary gland, a convenient
scheme divides breast cancers by their origin
from lobular or ductal cells (Winer et al. 2001).
Ductal and lobular carcinomas are subdivided
further into noninvasive (in situ) and invasive
(or infiltrating) cancers. Ductal carcinoma in
situ (DCIS), also termed intraductal carcinoma,
became a common diagnosis over the past
several decades since it is detectable as clustered microcalcifications on mammograms.
In contrast, lobular carcinoma in situ (LCIS)
remains an infrequent diagnosis with an
unknown incidence in the general population.
It is usually an incidental microscopic finding
in breast tissue removed for another reason.
Invasive ductal or lobular carcinomas penetrate
the gland’s basement membrane (Saenz and
Phillips 1998).
Diagnosis and Staging
Most breast cancer patients present initially
either with a breast mass detected by clinical
or self-examination, or with an abnormality
on screening mammography (PDQ 2004a).
Subsequently, fine-needle aspiration, stereotactic core needle biopsy, or open surgical biopsy
provides tissue for a definitive diagnosis.
Following diagnosis, staging assesses the extent
of disease based on tumor size, regional lymph
node involvement, and presence or absence
of distant metastasis (Winer et al. 2001; PDQ
2004c). Staging provides prognostic information
and aids in selecting treatment. The number
of involved nodes is the single best predictor of
long-term prognosis. The most common sites of
regional involvement are the axillary, internal
mammary, and supraclavicular nodes. The
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5
Technology Evaluation Center
most frequent distant metastatic sites are the
lung, liver, pleura, bone, and brain.
Clinical staging evaluation includes bilateral
mammography (to evaluate for synchronous
cancer), a complete physical exam, chest
radiograph, and liver function tests (Saenz and
Phillips 1998; Winer et al. 2001). An abdominal
CT scan or ultrasound is done in patients with
abnormal liver enzymes or symptoms. Bone
scans are reserved for patients with bone
symptoms or locally advanced breast cancer
(stage III and above), while a head CT scan is
done for those with neurological symptoms.
Based on the presurgical evaluation, the
patient’s cancer is assigned a clinical stage
using the American Joint Committee on Cancer
(AJCC) TNM system (American Joint Committee
on Cancer 2002; Figure 1). This classification
describes tumor size (T), number of involved
nodes (N), and evidence of distant metastasis
(M) (Figure 1). Initial treatment options are
selected using the presurgical tumor stage.
Patients with early stage invasive breast cancers
(defined as stage I or II) usually undergo some
form of local surgical excision, seeking to
remove the tumor completely. A postsurgical
classification (pTNM) is then re-assigned using
the TNM schema modified for lymph nodes
evaluated by histopathology (PDQ 2004c).
The AJCC staging system’s 6th edition classifies
certain nodal categories as stage III that were
previously considered stage II (Singletary et al.
2002). Investigators note that because of this
“stage migration,” subgroup survival for these
stages in series classified with the new system
may appear superior to that of series classified
using older versions (Woodward et al. 2003).
Locally Advanced Breast Cancer
Studies have inconsistently defined locally
advanced breast cancer (Winer et al. 2001).
All investigators included patients with stage
IIIB disease (see Figure 1; American Joint
Committee on Cancer 2002), usually considered
inoperable. These tumors either extend into
the chest wall or skin, or are inflammatory
cancers. Some investigators also included stage
IIIA disease, considered operable unless clinically staged as N2 based on apparent disease
in ipsilateral fixed axillary nodes or internal
mammary nodes (Winer et al. 2001; National
Comprehensive Cancer Network 2004). In
some studies (that used earlier versions of
AJCC staging), locally advanced disease also
6
included patients with positive supraclavicular
lymph nodes, previously considered stage IV
disease but now regarded as stage IIIC (N3c;
see Figure 1). All studies consistently excluded
patients with distant metastasis (M1) from the
definition of locally advanced breast cancer.
Currently, locally advanced disease is uncommon among newly diagnosed breast cancer
patients in the U.S. and other economically
developed countries (Winer et al. 2001). Data
available from the National Cancer Data Base
(NCDB 2004) show that, in 2001, only 5.9%
of 155,596 newly diagnosed patients reported
by 1,248 U.S. hospitals had stage III disease at
diagnosis. NCDB data also show that 6.4% of
164,964 patients diagnosed in 1999, and 7.0%
of 156,985 patients diagnosed in 1997, had
stage III at diagnosis. The incidence of locally
advanced and metastatic breast cancer at diagnosis has been declining over several decades,
with corresponding increases in the incidence
of DCIS and early stage disease. Clinicians
attribute these changes to increased use and
improved quality of mammographic screening.
Historically, surgery and radiation therapy by
themselves did little to improve survival of
patients with locally advanced breast cancer
(Winer et al. 2001; Pockaj and Gray 2004;
Buchholz 2004). In contrast, studies show that
systemic chemotherapy improves treatment
outcomes for these patients, particularly when
used preoperatively (also termed neoadjuvant
or primary systemic chemotherapy) (reviewed
in Winer et al. 2001; Hutcheon and Heys 2004;
Pegram 2004). Neoadjuvant chemotherapy
potentially can convert inoperable locally
advanced breast cancer to operability, by reducing the disease extent. It also may decrease
tumor size to permit breast-conserving surgery
in some patients who would otherwise require
modified radical mastectomy.
Neoadjuvant Chemotherapy
Six trials have randomized breast cancer
patients to preoperative (neoadjuvant) or
postoperative (adjuvant) chemotherapy
(reviewed in Winer et al. 2001; Hutcheon and
Heys 2004). The trials were heterogeneous with
respect to patient eligibility criteria; specific
neoadjuvant chemotherapy regimens (most
often anthracycline-based); inclusion and
timing of radiation therapy; and in proportion
of randomized patients treated as assigned.
Their results showed little difference between
patients with operable breast cancer given
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Breast MRI for Patients with Locally Advanced Breast Cancer Referred for Neoadjuvant Chemotherapy
Figure 1. TNM Clinical Staging per American Joint Committee on Cancer, 6th edition
Stage
Stage
Stage
Stage
Stage
Stage
Stage
Stage
0
I
II A
II B
III A
III B
III C
IV
Tis, N0, M0
T1*, N0, M0
T0, N1, M0 or T1*, N1, M0 or T2, N0, M0
T2, N1, M0 or T3, N0, M0
T0, N2, M0 or T1*, N2, M0 or T2, N2, M0 or T3, N1 or N2, M0
T4, any N, M0
Any T, N3, M0
Any T, any N, M1
*T1 includes T1mic
Tumor
TX
Tis
T0
T1
T2
T3
T4
Primary tumor cannot be assessed
Carcinoma in situ (ductal, lobular, or Paget’s disease of the nipple)
No evidence of primary tumor
Tumor ≤2 cm in greatest dimension
T1mic microinvasion, ≤0.1 cm in greatest dimension
T1a
>0.1 cm but ≤0.5 cm in greatest dimension
T1b
>0.5 cm but ≤1.0 cm in greatest dimension
T1c
>1.0 cm but ≤2.0 cm in greatest dimension
Tumor >2 cm but ≤5 cm in greatest dimension
Tumor >5 cm in greatest dimension
Tumor any size with direct extension into chest wall or skin
T4a
extension to chest wall, not including pectoralis muscle
T4b
edema or ulceration of the skin or satellite skin nodules in the same breast only
T4c
T4a and T4b
T4d
inflammatory carcinoma
Regional Lymph Nodes
NX
Regional nodes cannot be assessed (e.g., previously removed)
N0
No regional lymph node metastasis
N1
Metastasis to movable ipsilateral axillary lymph node(s)
N2
Metastasis to ipsilateral axillary node(s), fixed to one or more structures, or in clinically apparent*
ipsilateral internal mammary nodes without clinically evident metastasis to other lymph nodes
N2a
metastasis to ipsilateral axillary nodes, fixed to one another (matted) or to other structures
N2b
metastasis only in clinically apparent* ipsilateral mammary nodes without clinically evident
axillary lymph node metastasis
N3
Metastasis to
N3a
ipsilateral infraclavicular lymph node(s), with or without axillary lymph node involvement
N3b
clinically apparent* ipsilateral internal mammary lymph node(s) in the presence of clinically
evident axillary lymph node metastasis
N3c
ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary
lymph node metastases
*Clinically apparent is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination or grossly visible
Metastases
MX
Presence or absence of distant metastasis cannot be assessed
M0
No distant metastasis
M1
Distant metastasis present
©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.
7
Technology Evaluation Center
neoadjuvant or adjuvant therapy in overall or
disease-free survival (Buchholz 2004; Hutcheon
and Heys 2004). However, they showed uniformly that neoadjuvant therapy increased
the proportion of patients deemed eligible for
breast-conserving surgery.
The largest of the 6 trials, NSABP B-18, randomized 1,523 patients with T1–3, N0–1, M0
breast cancer to 4 cycles of doxorubicin plus
cyclophosphamide at the same doses before or
after surgery (Fisher et al. 1998, 2002; Wolmark
et al. 2001). Patients were stratified by age
and by clinically estimated tumor size (≤2 cm,
2.1–5 cm, or >5 cm), and surgeons specified the
planned type of surgery before randomizing
patients. In the initial report, data were available on 1,495 eligible patients (98.2%). Of 752
patients in the postoperative chemotherapy
arm, 450 (59.8%) underwent BCT (lumpectomy
plus radiation therapy). In the neoadjuvant
arm, 504 (67.8%) of 743 patients received BCT.
While the other 5 trials also reported higher
rates of BCT in the neoadjuvant therapy arms
(reviewed in Winer et al. 2001; Hutcheon and
Heys 2004), the magnitude of this difference
varied and likely reflected differences in patient
characteristics at baseline (e.g., proportion with
T1-2 tumors), among other factors.
For patients in the neoadjuvant arm of NSABP
B-18, ipsilateral breast tumor recurrence (IBTR)
appeared more frequently among those initially
planned for mastectomy but then downstaged
and shifted to BCT than among those originally
eligible for BCT (Wolmark et al. 2001), although
this was not attributed to a true increase in risk
for IBTR. Surgeons selected lumpectomy for
487 (65.5%) of 743 patients randomized to neoadjuvant therapy, of whom 435 (89.3%) were
treated as planned. Of 256 women intended
for mastectomy, 69 (27%) were downstaged
and given lumpectomy after clinical responses
to neoadjuvant therapy. By 9 years’ median
follow-up, IBTR occurred in 43 (9.9%) of the
women initially selected for lumpectomy and
in 11 (15.9%) of those downstaged to lumpectomy after neoadjuvant therapy. However,
this difference was not statistically significant
after adjusting for contributions to IBTR risk in
younger patients not given tamoxifen (used only
for those 50 years of age or older in this study)
and in those with larger tumors. Furthermore,
2 other randomized trials reported no significant differences in IBTR rates between those
converted to BCT after neoadjuvant therapy
and those eligible for BCT before neoadjuvant
8
therapy (Makris et al. 1998; van der Hage
et al. 2001).
Importantly, NSABP B-18 also reported that
those with a pathologic complete response
(pCR) had the longest survival duration
(Wolmark et al. 2001). Patients with a clinical
complete response (cCR) to neoadjuvant
chemotherapy confirmed postsurgery as pCR
had significantly longer survival (85% overall
and 75% disease-free at 9 years) than did those
with a cCR but residual invasive disease by
postsurgical pathology (73% overall and 58%
disease-free at 9 years). These differences
remained statistically significant even after
adjusting for differences in baseline characteristics (adjusted p=0.006 for overall and
p=0.0004 for disease-free survival).
Additional data from NSABP B-18 established
that clinical response to neoadjuvant therapy
is relatively inaccurate to predict pathologic
response determined after surgery. Of 208
patients judged to have a cCR, 38% achieved
a pCR, 30% had a partial pathologic response
(pPR), and 32% had no pathologic response
(pNR) (Fisher et al. 2002). Of 260 with a partial
clinical response, 13% achieved a pCR, 17%
achieved a pPR, and 70% were pNR. Finally, of
115 clinically classified as nonresponders, 8%
achieved a pCR and 10% achieved a pPR.
Taken together, these findings suggest at least
2 potential directions for improving the outcomes and evaluation of neoadjuvant therapy
for locally advanced breast cancer. First, more
accurate methods to predict tumor size and
pathologic responses might improve selection
of patients for conversion from mastectomy to
BCT, thus lowering the risk of IBTR, and potentially improving outcomes. Second, if response
to neoadjuvant therapy could be evaluated
accurately after 1 or 2 cycles, changes in drug
regimen might convert some partial or nonresponders to pCR and thus improve survival.
Effects of Surgical Treatments for Breast Cancer
on Quality of Life
Although outcomes of BCT and modified
radical mastectomy (MRM) are similar with
respect to recurrence and mortality, some
patients choose MRM as the psychologically
preferred treatment. Many studies have evaluated the impact of different surgical procedures
on quality of life (QOL) after primary therapy
for early breast cancer (reviewed by Kiebert et
al. 1991; Irwig and Bennetts 1997; Moyer 1997).
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Breast MRI for Patients with Locally Advanced Breast Cancer Referred for Neoadjuvant Chemotherapy
Factors that limited conclusions from most
early studies included methodological flaws,
their retrospective design, inadequately involving patients in selecting treatments, and variability in the definitions and instruments used
to measure QOL (Kiebert et al. 1991).
A meta-analysis of findings reported by 40
studies calculated mean weighted effect sizes
for 6 psychosocial outcomes (Moyer 1997). The
analysis suggested modest advantages for BCT
in psychological, marital-sexual, and social
adjustment; body self-image; and cancer-related
anxiety. However, some outcomes were also
affected by methods used to assign treatment
and by time after surgery at which QOL was
measured. A systematic review reported that
quality of study design and conduct was generally poor in 6 QOL studies on patients randomized to BCT or MRM (Irwig and Bennetts 1997).
Five of 6 studies measured body self-image, and
each reported it was more favorable in women
randomized to BCT than in those randomized
to MRM. However, no other dimension of QOL
measured in these studies differed significantly
between surgical alternatives, including perceptions of psychological health, sexual or physical
health, anxiety, or global QOL.
Most recent studies also concluded that surgical
choice for early breast cancer had little lasting
impact on QOL dimensions other than body
self-image or feelings of attractiveness, which
were less favorable after mastectomy (Dorval
et al. 1998; Wapnir et al. 1999; Shimozuma et
al. 1999; Rowland et al. 2000; Arora et al. 2001;
Nissen et al. 2001). However, Dorval et al.
(1998) reported that age at diagnosis altered
the effect of surgical choice on psychological distress: women younger than 50 years
reported less distress with BCT than mastectomy, while those older than 50 years reported
more distress with BCT. Another study reported
that psychological distress and QOL scores
were roughly equivalent up to 40 months
after BCT or mastectomy (Cohen et al. 2000).
From 40 through 60 months, those given BCT
reported significantly more distress and marginally worse QOL scores.
Magnetic Resonance Imaging of the Breast
Over the past decade, MRI of the breast has
been studied in a variety of clinical settings,
including both benign and malignant conditions
of the breast. MRI has shown clinical utility in
evaluating silicone breast implants for rupture,
yet controversy remains regarding the role
MRI should play in the evaluation of patients
with known or suspected breast cancer.
Breast MRI is performed using commercially
available MRI machines; however, technical
approaches to MRI of the breast vary (Orel
and Schnall 2001; Liberman 2004). Breast
tissues generally have similar signal intensities as tumor tissue on routine MRI sequences.
However, malignant breast lesions typically
demonstrate significant enhancement following
the IV administration of contrast agents
containing gadolinium-chelates. Tumor
enhancement relates to increased angiogenesis
in tumor tissues and increased vascular permeability (Knopp et al. 1999). While the vast
majority of malignant breast lesions exhibit
contrast enhancement, some malignancies
may not (e.g., lobular carcinoma, ductal carcinoma in situ [DCIS]), and some benign breast
conditions may demonstrate marked contrast
enhancement (e.g., fibroadenoma, inflammatory conditions). Normal breast tissues may
demonstrate diffuse enhancement that relates
to hormonal influences. Thus, performing
MRI during the first 2 weeks of the menstrual
cycle has been recommended to reduce this
phenomenon (Rieber et al. 1999).
MRI scanning is performed both before contrast
administration (pre-contrast) and after contrast administration (post-contrast); however,
there are several different technical methods
employed by investigators. Post-contrast images
maximizing spatial resolution (better detail in
images) may be obtained using high-resolution MRI sequences or maximizing temporal
resolution using dynamic imaging. High-resolution MRI generally requires several minutes to
acquire the data and, thus, only 1 or 2 sets of
post-contrast images may be obtained during
the 5-minute period of enhancement after
contrast injection. Dynamic imaging sequences
sacrifice some spatial resolution and are each
acquired within seconds so that imaging may
be rapidly repeated during the enhancement
period. High-resolution imaging demonstrates
the presence of enhancing lesions, but does not
provide dynamic information on the variation
of enhancement levels over time.
The observation that contrast enhancement
of a breast lesion is a nonspecific feature has
led investigators to explore whether patterns
of lesion enhancement on dynamic imaging
after contrast bolus might provide a greater
degree of specificity in diagnosing malignancy.
©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.
9
Technology Evaluation Center
Typically, malignant lesions reach peak
enhancement early and then wash out more
quickly. Benign lesions that show enhancement
(such as fibroadenoma) generally demonstrate
a less rapid initial increase in enhancement
and continue to enhance over time; however,
there is variability and overlap in these patterns, and time-enhancement patterns alone
do not provide an accurate diagnosis in all
cases (Kuhl et al. 1999; Orel 1999).
MR systems (approximately 0.5 Tesla) have
been studied as well. Low-field strengths have
inherent limitations in sensitivity for detecting
gadolinium enhancement and lower signal-tonoise ratios compared to high-field imaging
and may require longer data acquisition times.
Possible advantages of low-field systems are
lower cost and the potential for “open-access”
designs, permitting access to the patient for
MRI-guided biopsy.
In preoperative evaluation and staging of a
known breast tumor, whole breast imaging
would be necessary. In designing the MRI
sequence, it might be preferable to maximize
sensitivity (i.e., lesion detection) at the expense
of specificity. Studies using dynamic contrastenhanced MRI to examine primary breast
cancers after the administration of chemotherapy have observed a reduction in the degree
of contrast enhancement, particularly in tumors
that are responsive to chemotherapy (Leach
2002). The pharmacokinetic profile of dynamic
contrast enhancement may change with a flattening of the typically early enhancement peak
of malignant tissues, and the overall level of
contrast enhancement may be reduced, reflecting decreased blood supply as tumor cells die.
MRI of the breast is typically performed with
the patient in a prone position with the breasts
hanging through a cutout in the table. The use
of a dedicated breast coil is recommended.
Some studies have explored using breast compression. When MRI-guided biopsy of a lesion
is planned, the patient may be positioned on
her side to permit easier access to the breast
for biopsy. Biopsy of breast lesions identified
on MRI has been accomplished using MRIcompatible needles and localization equipment
(Morris et al. 2002; Kuhl et al. 2001; Helbich
2001; Orel et al. 1994; deSouza et al. 1995).
Some investigators have incorporated additional criteria into the determination of MRI
results in an attempt to increase the specificity
without compromising sensitivity (Liberman
2004; Nunes et al. 2001, 1997). Descriptive features of lesion morphology such as those used
in X-ray mammography may be helpful in this
regard. For example, lesions with irregular
or spiculated margins are characteristically
malignant while lesions with smooth, regular
margins are usually benign (Nunes et al. 1997).
Others have studied the distribution pattern of
contrast enhancement within a lesion, noting
whether there is uniform or heterogeneous
enhancement. One study of 79 enhancing
lesions in 49 women noted that rapid washout
of contrast enhancement from the periphery
of the lesion was 100% specific in identifying
malignancy, although this feature was only
seen in about half of the malignant lesions
studied (Sherif et al. 1997). Another study
of 94 lesions in 91 women also found 100%
specificity of a peripheral enhancement
pattern, but only 34% of malignancies could
be detected by using this feature alone
(Mussurakis et al. 1998).
The magnetic field strength of the MRI machine
employed varies in the literature. Most studies
use a general-purpose high-field MRI system
(1.0–1.5 Tesla) for imaging, although low-field
10
Other Technologies to Evaluate Response
to Neoadjuvant Chemotherapy
Huber et al. (2000) examined the ability of
mammography to determine the extent of
tumor following neoadjuvant chemotherapy in
48 cancers in 44 patients with stage-III breast
carcinoma. The authors divided cases into 2
subgroups: (1) lesion more than 50% defined,
or (2) lesion less than 50% defined on mammography. In group 1 (n=34) the correlation
coefficient for size on mammography compared
with histopathology was 0.77 (p=n.r.), whereas
for group 2 (n=14), the correlation coefficient
was only –0.19 (p=n.r.).
Contrast-enhanced helical CT of the breast
has been explored as another alternative for
preoperative evaluation of extent of tumor
after neoadjuvant chemotherapy (Moyses et
al. 2002). This test uses the same concept of
contrast enhancement as a marker of tumor
vascularity and may be an option for patients
who are not able to undergo MRI imaging. In a
study of 43 patients with inflammatory breast
cancer, correlation coefficients of tumor size
with histopathology were 0.69, 0.49, and 0.29
for helical CT, clinical/macroscopic evaluation,
and mammography, respectively. Estimation of
tumor size was highest among the subgroup of
rounded opacities, with helical CT achieving a
0.97 correlation coefficient.
Preliminary results using either 31-P or 1-H
MR spectroscopy have been reviewed by
Leach et al. (2002). These results suggest that
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Breast MRI for Patients with Locally Advanced Breast Cancer Referred for Neoadjuvant Chemotherapy
metabolic changes are observable early in
the course of chemotherapy and further study
would be of interest to determine the diagnostic
performance of these findings for evaluating
response to chemotherapy.
A study by Cayre et al. (2002) suggested
that 99m-Tc-sestamibi scintimammography
tracer uptake may be inversely proportional
to expression of multidrug resistance protein.
In this prospective study of 45 subjects with
primary breast carcinoma, scintimammography
was 100% specific and 36–38% sensitive for
detecting chemotherapy resistance. Absence
of 99m-Tc-sestamibi uptake was noted on scintimammography in 31% of subjects and this
may be a useful means to identify those subjects with multiple drug resistance and lack of
pathological response to chemotherapy.
FDA Status. MR imaging of the breast can
be performed using commercially available
MR scanners and intravenous MR contrast
agents. Specialized breast coils such as the
OBC-300 Breast Array Coil ® (MRI Devices
Corp., Waukesha, WI) and MR-compatible
equipment for performing biopsy have been
developed and cleared for marketing via the
U.S. Food and Drug Administration (FDA)
510(k) process as substantially equivalent to
predicate devices for use “in conjunction with
a magnetic resonance scanner to produce diagnostic images of the breast and axillary tissues
that can be interpreted by a trained physician”
(Model OBC-300 Breast Array Coil 510(k)
notification letter dated December 3, 1999).
Methods
Search Methods
Studies of breast MRI used for evaluation
of breast cancer were identified through a
computerized online search of the MEDLINE
database (via PubMed) through July 2004. The
Medical Subject Headings ® (MeSH ®) used were
“magnetic resonance imaging” and “breast
neoplasms,” and the search was restricted to
clinical trial and review publication types.
The search was also restricted to Englishlanguage publications and studies using human
subjects. To identify additional studies and
more recent publications, the MEDLINE search
was supplemented by searches of Current
Contents, by manual searches of the most
recent issues of the pertinent journals, and
by reading the reference lists in the most
recently published papers.
Study Selection Criteria
Studies were required to meet all the following
criteria in order to be included in the review of
evidence. Single case reports were excluded.
■ Included patients with locally advanced
breast cancer who would be potential
candidates for neoadjuvant chemotherapy
■ Used contrast-enhanced MRI of the breast
■ Applied an appropriate reference standard
■ Reported sensitivity and/or specificity of
MRI or sufficient data to generate a 2×2
contingency table
■ Included only human subjects
■ Published in English as a full-length,
peer-reviewed, journal article
Medical Advisory Panel
Current Assessment. This Assessment was
reviewed by the Blue Cross and Blue Shield
Association Medical Advisory Panel (MAP) on
June 2, 2004. In order to maintain the timeliness
of the scientific information in this Assessment,
literature searches were performed subsequent
to the Panel’s review (see “Search Methods”).
If the search updates identified any additional
studies that met the criteria for detailed review,
the results of these studies were included in the
table(s) and text where appropriate. There were
no studies that would change the conclusions
of this Assessment.
Previous Assessments. No prior TEC
Assessment has been conducted for this
patient indication1.
Assessing Study Quality
Each of the studies included in the evidence
tables was classified according to a prespecified
set of study quality characteristics.
The following indications for MRI of the breast in breast cancer were addressed in a prior Technology Evaluation Center (TEC)
Assessment (Volume 19, Number 1) reviewed February 12, 2004: (a) detection of breast cancer in patients who have breast
characteristics limiting the sensitivity of mammography; (b) detection of suspected occult breast primary tumor in patients with
axillary nodal adenocarcinoma and negative mammography and clinical breast exam; (c) diagnosis of low-suspicion findings
on conventional testing referred for short-interval follow-up instead of immediate biopsy; and (d) diagnosis of suspicious breast
lesions in order to avoid biopsy. The use of MRI for screening in patients at high genetic risk of breast cancer has been addressed
in a previous TEC Assessment (2003; Volume 18, Number 15). The use of breast MRI to evaluate the extent of tumor in patients
with clinically localized breast cancer is addressed in a separate Assessment, which was also evaluated June 2, 2004.
1
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11
Technology Evaluation Center
■
■
■
■
■
■
Study design was categorized as prospective
(“P”), retrospective (“R”), or uncertain (“?”).
Whether the study population was clearly
described was rated as “Y” for yes; “N”
for no; or “?” when there was insufficient
information to determine.
Spectrum bias was considered present if
the selected subjects did not include the full
array of patient characteristics in the target
population (Zhou et al. 2002). Frequently,
poorly described retrospective studies where
reasons for performing MRI were not welldefined or retrospective studies that included
only highly selected patients were deemed
more susceptible to spectrum bias compared
with prospective, consecutive series that
were likely to include a representative spectrum of patients.
Interpretation of MRI studies blinded to
the results of other tests or the reference
standard was rated.
Interpretation of the reference standard
blinded to the results of the MRI findings
was rated using the same categories.
Avoidance of verification bias was considered to be true when consecutively enrolled
patients were subjected to MRI and the reference standard was obtained independent of
the results of the MRI study, and all enrolled
patients were included in the final analysis.
Studies were coded with a question mark when
insufficient information was provided to make
a yes (“Y”) or no (“N”) determination. These
study quality characteristics used here are
among those described in a review of systems
for rating the quality of studies of diagnostic
tests (West et al. 2002) published by the Agency
for Healthcare Research and Quality (AHRQ).
Confidence intervals were calculated by the
modified Wald method using the calculator
available at (http://graphpad.com/quickcalcs/
ConfInterval1.cfm).
Formulation of the Assessment
Patient Indication
Patients are those with locally advanced breast
cancer who are being referred for neoadjuvant
chemotherapy.
12
Technologies to be Compared
Breast MRI is proposed for use in two situations:
1) before and after completion of neoadjuvant
chemotherapy to determine extent of tumor
to plan surgery; and 2) before and during the
course of neoadjuvant chemotherapy to determine tumor response to guide chemotherapy
decisions. The reference standard for determining extent of tumor and response to neoadjuvant chemotherapy is the histopathological
assessment, which determines the presence of
viable tumor cells and tumor size. Preoperative
biopsy samples can be obtained during the
course of chemotherapy to identify viable tumor
versus necrotic or fibrotic tissues; however,
this method is subject to sampling errors and
cannot determine overall tumor size.
Conventional presurgical methods for evaluating extent of tumor and response to chemotherapy are physical exam, mammography,
and sometimes ultrasonography. Gross tissue
examination during surgery may also be used
to determine extent of tumor. Breast MRI may
be used as a replacement for conventional
methods for guiding management decisions,
and the performance of MRI may be compared
to these alternatives. The diagnostic performance of breast MRI will be compared with
histopathological assessment as the reference
standard, but MRI will not be considered a
replacement for histopathological assessment.
Health Outcomes
Breast MRI for Presurgical Planning
Performed Before and After Completion of
Neoadjuvant Chemotherapy. Health outcomes
of interest include morbidity or mortality from
breast cancer, preservation of the breast, and
avoidance of additional surgery. Intermediate
outcomes include the diagnostic performance
of breast MRI to predict tumor size and extent
compared to histopathology and alternatives.
An algorithm illustrating the effects on health
outcomes of using breast MRI staging as
compared to clinical staging is provided in
Figure 2. When MRI staging provides the same
results as clinical staging would have, there
is no incremental effect on health outcomes.
The following scenarios outline the potential
health outcome effects that can occur when
MRI staging yields discordant results from what
would have been obtained with clinical staging.
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Figure 2. Breast MRI for Presurgical Planning
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Breast MRI for Patients with Locally Advanced Breast Cancer Referred for Neoadjuvant Chemotherapy
©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.
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13
Technology Evaluation Center
When MRI suggests the patient is eligible for
BCT, whereas clinical staging had suggested
the patient was not eligible:
■ MRI may be beneficial when it correctly
defines the extent of tumor (true negative)2
and permits breast conservation.
■ MRI may be harmful when it underestimates
the extent of tumor (false negative) so that
initial BCT results in positive margins. This
may lead to additional re-excision surgery
or conversion to mastectomy with the added
morbidity of additional surgical procedures
compared with performing mastectomy
upfront, based on clinical staging.
health outcomes and a high negative predictive
value (NPV) would be most important.
When MRI suggests the patient is not eligible
for BCT, whereas clinical staging had suggested
the patient was eligible:
■ MRI may be beneficial when it correctly
identifies advanced disease (true positive)
and leads to appropriate mastectomy, avoiding the added morbidity associated with an
initial attempt at BCT leading to positive
margins and need for additional surgery.
■ MRI may be harmful when it overestimates
the extent of disease in a patient who was
truly eligible for BCT (false positive) resulting in loss of breast tissue.
Assessment Questions
1. Does the evidence demonstrate that,
compared with conventional alternatives,
breast MRI before and after completion
of neoadjuvant chemotherapy improves
estimation of residual tumor size and extent?
If so, does the use of MRI improve the net
health outcome?
2. Does the evidence demonstrate that, compared with conventional alternatives, breast
MRI before and during neoadjuvant chemotherapy provides an early and reliable
prediction of tumor that is nonresponsive to
neoadjuvant chemotherapy? If so, does the
use of MRI improve the net health outcome?
Breast MRI Performed Before and During
Neoadjuvant Chemotherapy. Health outcomes
of interest include morbidity or mortality
from breast cancer, avoidance of morbidity
from ineffective chemotherapy, and increased
potential for breast conservation surgery when
a change is made to more effective chemotherapy. Intermediate outcomes include the
diagnostic performance of early breast MRI to
predict final response to chemotherapy.
An algorithm illustrating the effects on health
outcomes of using breast MRI to evaluate
response to chemotherapy as compared to
clinical evaluation is provided in Figure 3.
When tumor showing no response to chemotherapy (i.e., negative result) is seen on
an MRI2, neoadjuvant chemotherapy would
either be discontinued or changed to another
regimen. MRI showing a response (complete or
partial response=positive result) would presumably not change therapy. Thus, only negative
MRI results would change management and
■
■
MRI would be beneficial when it accurately
demonstrates a lack of tumor response
(true negative) and spares the patient the
added morbidity of ineffective chemotherapy.
Chemotherapy may also be changed to a
more effective therapy which may, in turn,
permit breast conservation.
MRI may be harmful when it falsely suggests
a lack of tumor response (false negative)
and leads to premature discontinuation of
effective chemotherapy.
Review of Evidence
Overview
The best evidence would be direct evidence
from randomized, controlled trials that assess
the effects of breast MRI on breast cancerrelated morbidity or mortality. Such trials
have not been published. The best available
evidence is from studies that report the diagnostic performance characteristics of breast
MRI to define the extent of tumor and/or tumor
response after neoadjuvant chemotherapy and
compare results of MRI with conventional tests
using histopathology as an independent reference standard. While these diagnostic intermediate outcomes are related to the use of BCT
and the upfront benefit of breast conservation,
it may be that patients who are downstaged by
neoadjuvant chemotherapy before BCT have
adverse long-term outcomes such as higher
For categorizing tumor response to chemotherapy on MRI, tumor showing no response to chemotherapy is considered a
“negative result”; while responsive tumor (decreased enhancement) is considered a “positive result.” For categorizing tumor size
and extent to guide preoperative decision making, an MRI with tumor eligible for BCT is considered to be a “negative” study;
while tumor that is too extensive for BCT is considered a “positive result.”
2
14
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15
CRc
PRc
NRc
cinical complete response
clinical partial response
clinical nonresponse
CRm
PRm
NRm
MRI complete response
MRI partial response
MRI nonresponse
CRp
PRp
NRp
pathological complete response
pathological partial response
pathological nonresponse
Breast MRI for Patients with Locally Advanced Breast Cancer Referred for Neoadjuvant Chemotherapy
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Figure 3. Breast MRI for Chemotherapy Planning
Technology Evaluation Center
recurrence rates compared to those who were
initially eligible for BCT.
Eighteen studies (total n=558) evaluate the
use of MRI after neoadjuvant chemotherapy
in an appropriate population to demonstrate
the presence, size, and extent of residual
tumor, but only 17 studies compare results
against histopathology. Six of these studies
(Table 1A; total n=206) performed MRI before
chemotherapy, during the course of neoadjuvant chemotherapy, and after completion of
neoadjuvant chemotherapy, whereas 12 studies
(Table 1B; total n=352) only performed MRI
before and after completion of neoadjuvant
chemotherapy. Six of these studies (total n=179)
compare MRI with conventional alternatives.
There are several studies reported from the
same institutions/authors and the degree of
overlap in the included patient populations is
difficult to assess (Rieber et al. 2002; Rieber et
al. 1997b; Wasser et al. 2003a, 2003b). Results
from all studies were included, since different articles reported complementary findings.
Nine used prospective study design. Three
studies included more than 50 subjects. All
but 3 studies provided clear descriptions of the
study population, but in 10 studies, spectrum
bias was either a potential problem or impossible to assess. All but 2 studies specified that
MRI was evaluated without knowledge of reference standard results, and 12 studies stated
that reference standard determinations were
made without knowledge of the MRI results.
Extended clinical or imaging follow-up was
also used as a reference standard for some
patients in Drew et al. (2001). The potential
for verification bias was difficult to assess in
4 studies, although 14 studies were thought to
be less prone to this bias.
Four additional studies (Table 2) address the
diagnostic performance of MRI for evaluating extent of disease in patients with locally
advanced disease; however, these studies do
not employ neoadjuvant chemotherapy. Two
studies are prospective and 2 include more
than 50 subjects. Three studies compared
MRI with conventional alternatives (Morris et
al. 2000; Mumtaz et al. 1997; Rodenko et al.
1996), and 2 of these interpreted MRI without
knowledge of other findings. Three of 4 studies
clearly interpreted MRI and the reference
standard without knowledge of the results of
the other and also avoided obvious verification
bias. All 4 studies used surgical findings and/or
histopathology as reference standards.
16
Does the evidence demonstrate that, compared with conventional alternatives, breast
MRI before and after completion of neoadjuvant chemotherapy improves estimation
of residual tumor size and extent? If so,
does the use of MRI improve the net health
outcome?
Seventeen studies, summarized in Table 3
(total n=543), evaluate the use of MRI after
neoadjuvant chemotherapy to demonstrate the
presence, size, and extent of residual tumor
and compare results against histopathology.
The study by Nakamura et al. (2001) is not
included here because the results comparing MRI against pathology were not clearly
reported. Tumor sizes were generally compared using maximum tumor diameter or
volume measurements and sizes were compared directly or using correlation coefficient
statistics. Six studies (total n=179) compare
MRI with conventional alternatives. Four
additional studies, detailed in Table 2 (total
n=179), describe the preoperative use of MRI
to identify tumor involvement of the pectoralis
muscle/chest wall, skin, and nipple, although
neoadjuvant chemotherapy was not applied.
Three of these 4 studies compared MRI with
conventional alternatives.
Compared with histopathology, the independent reference standard, MRI demonstrates
the presence of residual tumor with estimated
sensitivity ranging from 90–100% and specificity from 50–100%. MRI estimated the size and
extent of tumor correctly in comparison with
pathologic evaluation in 57%, 63%, 66%, 83%
and 97% of cases among 5 studies reporting
these results (Rosen et al. 2003; Balu-Maestro
et al. 2002; Rieber et al. 2002; Gilles et al. 1994;
Abraham et al. 1996). Correlation coefficients
for size of residual tumor on MRI compared
with histopathology were generally good to
excellent, ranging from 0.72 to 0.98 (Partridge
et al. 2002; Rosen et al. 2003; Martincich et al.
2004; Cheung et al. 2003; Esserman et al. 2001;
Wasser et al. 2003a). Chest wall invasion was
correctly determined by MRI with 100% sensitivity and 100% specificity in 23 cases included
in 3 studies (Morris et al. 2000; Kerslake et al.
1995; Rodenko et al. 1996). Extension of tumor
to the skin was suggested by MRI in 4 of 4 truepositive cases, although MRI also reported 2
false-positive cases (Rodenko et al. 1996).
Among the 9 studies that compared MRI with
other conventional alternatives for clinical
©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.
n
Description
Interpretation
Population Clearly
Described
Spectrum
Bias Avoided
MRI Blinded to Clinical
and Other Tests
MRI Blinded to RS
RS Blinded to MRI
Verification
Bias Avoided
Rieber et al.
58
Pts with large
DCE-MRI
P
Y
Y
?
Y
?
Y
mammary cancer
Subtraction
? gross or
undergoing
Breast coil
micro
Ulm, Germany
chemotherapy
1.5 T
? dates
prior to surgery
Author
MRI
Year
2002
Population
Technique and
Reference
Standard
Results of Evaluation
Comments
Histopath
Change in size:
Breast MRI was accurate in
predicting response based
Histology
MRI
CR
PR
NR
4
8
28
4
2
10
CR
2
on size in 66% (38/58) but
underestimated tumor size
in 50% of lesions that were
MRI done
PR
3-5 cycles:
before and after
NR
anthracyclines and
chemotherapy.
taxanes (E or P) or
MRI done
(NPV=10/12=83%)
anthracyclines and
during chemo
Enhancement changes (n=24)
cyclophosphamide
in 24 patients.
MRI done before 6th week was not
significantly reduced in
size after chemo
58
Enhancement results
were unclear
reliable in predicting response,
whereas MRI done after 6th week
was reliable.
Martincich
Stage II/III
DCE-MRI
Histopath
Correlation of residual tumor size
Does not compare with
operable (T>3cm)
Fat suppression
? gross or
of 0.72 (p<0.001) between MRI and
US or mammography
or inoperable
Subtraction
micro
histopathology
Torino, Italy
locally advanced
Dedicated
3/00 –8/02
breast cancer
surface coil
Combination of reduced tumor
>65%
1.5 T
volume* and reduced early contrast
**Reduction in
enhancement** on MRI was
enhancement
– 100% sensitive and 92% specific
>58% for homogeneous
et al. 2004
30
doxorubicin x4
paclitaxel x4
MRI done at
P
Y
Y
?
Y
Y
Y
*Reduction in size
baseline, after 2
in predicting grade 5 pathologic
lesions or >38% for ring-
cycles and after
CR (28/30 correct)
enhancing lesions
completion of
Reduced tumor volume on MRI was
chemo
– 91% sensitive and 84% specific
in predicting grade 4 or 5 (major
response)
17
Abbreviations Key: See Appendix
Breast MRI for Patients with Locally Advanced Breast Cancer Referred for Neoadjuvant Chemotherapy
MRI Technique
Design
©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.
Table 1A. MRI Performed Before, During, and After Neoadjuvant Chemotherapy in Patients with Locally Advanced Breast Cancer
Table 1A. MRI Performed Before, During, and After Neoadjuvant Chemotherapy in Patients with Locally Advanced Breast Cancer (cont’d)
Description
Interpretation
Design
Population Clearly
Described
Spectrum
Bias Avoided
MRI Blinded to Clinical
and Other Tests
MRI Blinded to RS
RS Blinded to MRI
Verification
Bias Avoided
Cheung et al.
33
Locally advanced
DCE-MRI
P
Y
Y
?
Y
Y
Y
breast cancer pts
Fat suppression
having chemotherapy
Breast coil
size and microscopy tumor size;
prior to surgery
1.5 T
whereas gross palpable tumor
*Reduction in size >30%
measurements had 0.64 (p<0.001)
considered responders
©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.
MRI
Year
2003
Taiwan
Population
Technique and
Reference
Standard
Results of Evaluation
Comments
Histopath
Correlation of 0.98 (p<0.001)
Does not compare with
micro
between MRI residual tumor
US or mammography
12/99 –11/01
Tumor size at
MRI done at
correlation but differences between
baseline 2.7 to 10 cm.
baseline and after
measurement methods were not
None of the subjects with
After chemotherapy
1st and 3rd cycles
statistically significant
early size reduction <45%
0–10 cm.
of chemotherapy
on MRI went on to have
Response based on size reduction*:
paclitaxel x3
e pirubicin x3
Early
Final
Final
MRI
MRI
Pathology
CR
Combined 4 (12%)
PR
12 (36%)
NR 21 (64%)
final complete response.
3 (9%)
19 (58%) ? 22 (67%)
10 (30%) ? 8 (24%)
(NPV=8/21=38%)
Residual DCIS seen on histology
in 1 case rated CR on MRI.
Rieber et al.
13
Breast cancers
DCE-MRI
1997
pts
ranging from
Subtraction
Histology
95.0 cubic cm
tumor size in group
3 to 10 cm in size
Breast coil
MRI
69.1 cubic cm
of responders
Ulm, Germany
(avg. 6.5 cm)
1.5 T
MRI and histology agreed in
?dates
Responders (n=8) and
P
?
N
N
Y
?Y
Y
Histopath
Tumor volume for responders post rx
measurements for nonresponders.
non-responders (n=5)
65 MRI done
based on percent
before, during,
Responders showed decreased
change from pre
and after
enhancement even after 1st cycle
to post MRI
chemotherapy in
whereas nonresponders showed no
volume estimates
13 patients.
decrease in enhancement.
Decrease in contrast medium uptake
epirubicin x4
led to 4 FN (i.e., failure to show
cyclophosphamide x4
residual tumor) and underestimation
of tumor extent in 2 other patients
MRI underestimated
Technology Evaluation Center
n
18
MRI Technique
Author
Technique and
Description
Interpretation
Population Clearly
Described
Spectrum
Bias Avoided
MRI Blinded to Clinical
and Other Tests
MRI Blinded to RS
RS Blinded to MRI
Verification
Bias Avoided
R
Y
N
?
Y
Y
Y
Author
MRI
Year
MRI
Technique
n
Wasser et al.
21
2003
Breast tumor
DCE-MRI
≥3 cm who
Breast coil
completed
1.5 T
Reference
Standard
Results of Evaluation
Comments
Histopath
No false-positive cases (i.e., no
cases where MRI showed suspicious
area despite complete histological
Heidelberg,
neoadjuvant
Germany
chemo and had
MRI done
10/95-12/99
MRI less than
before and after
Among 16 pts who got MRI during
2 weeks before
chemotherapy
chemotherapy, tumor regression
surgery
as well as
(size reduction >25%) occurred in
during chemo
10 pts. Reduction in enhancement
in 16 pts
was visible after 1st cycle of chemo
paclitaxel x4
response)
epirubicin x4
whereas reduction in size was not
seen until after 3rd cycle. There was
a trend toward reduced enhancement
in nonresponders as well.
Balu-
51
51 pts with
DCE-MRI
Percent tumor size correctly
Responder
Maestro et
pts
53 ductal and
Subtraction
estimated
results unclear:
al. 2002
60
7 invasive lobular
Dedicated coil
63% MRI
MRI suggested early
lesions
carcinomas
?T
52% clinical exam
complete response
Nice, France
undergoing
? dates
chemotherapy
MRI done
prior to surgery
before chemo
and after 3
Various chemo
cycles and
regimens
after 6 cycles
4–6 cycles:
preoperatively
31 EN, 6 Den,
6 DT, 8 EnFE
R
N
?
?
Y
Y
Y
Histopath
38% mammography
(lack of enhancement)
43% US
in 15 cases with PPV
of only 33%
Change in size:
Histology
MRI
CR
PR/NR
CR
5
10
PR
0
45
NR
19
(NPV=100%)
10
60
Breast MRI for Patients with Locally Advanced Breast Cancer Referred for Neoadjuvant Chemotherapy
Population
Design
©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.
Table 1A. MRI Performed Before, During, and After Neoadjuvant Chemotherapy in Patients with Locally Advanced Breast Cancer (cont’d)
n
Description
Interpretation
Design
Population Clearly
Described
Spectrum
Bias Avoided
MRI Blinded to Clinical
and Other Tests
MRI Blinded to RS
RS Blinded to MRI
Verification
Bias Avoided
©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.
MRI Technique
Partridge et al.
52
Pts with invasive
DCE-MRI
P
N
?
?Y
?
?
?
2002
pts
cancer who
Fat suppression
got neoadjuvant
breast coil
chemo
1.5 T
Author
MRI
Year
UCSF
Population
Technique and
? dates
doxorubicin x4
MRI done
cyclophosphamide x4
before and after
and 12 cycles
chemo
paclitaxel in 9 pts
Reference
Standard
Results of Evaluation
Histopath
Correlation with pathology (95% CI)
No comparison
Clinical
0.60
(0.39, 0.75) p<0.001
with mammo.
MRI
0.89
(0.82, 0.93) p<0.001
MRI detected all cases
of residual tumor.
MRI excluding 5 measurement
Clinical examination
problem cases 0.94 (0.89, 0.97)
had 5 false negatives.
MRI assessment had negligible bias
MRI enhancement
toward over-assessment of lesion
changes not correlated
size, mean error = 0.09 cm
with pathologic response.
Mean residual tumor
size was 3.7 cm
Clinical examination underestimates
on pathology
lesion size, mean error = -0.51 cm
Abbreviations Key: See Appendix
Comments
Technology Evaluation Center
20
Table 1B. MRI Performed Before and After Neoadjuvant Chemotherapy in Patients with Locally Advanced Breast Cancer
Technique and
Interpretation
Population Clearly
Described
Spectrum
Bias Avoided
MRI Blinded to Clinical
and Other Tests
MRI Blinded to RS
RS Blinded to MRI
Verification
Bias Avoided
RODEO MRI
P
Y
Y
Y
Y
Y
Y
Author
MRI
Year
MRI Technique
n
Description
Abraham et al.
39
Stage II – IV
1996
pts
40 br
Baylor Univ
’90 –’94
Reference
Standard
Results of Evaluation
Comments
Histologic
Category
Pathology
MRI
Mammography
Pre/post
measure of
No res. disease
4
5
underestimated
doxorubicin-based
contrast
tumor size
Single quadrant
12
12
tumor response in
chemo x
Fat suppression
Small volume
15
14
12/25 cases (48%).
4–5 cycles.
Breast coil
N=31
Chemo
1.5 T
mastectomy
discontinued if
2+ quadrants
Extensive
9
9
MRI revealed more
Total
40
40
residual disease than
no response after
MRI done
3 cycles.
before and
In the 31 mastectomy specimens,
clinical assessments.
after chemo.
MRI agreed with pathology in 30 of
Agreement of response
31 (97%) cases. The 1 FN MRI had
rating between MRI
Mammo done
small residual foci of carcinoma in
and surgical oncologist
before and
breast and lymphatic spaces on path.
(kappa=0.08) and MRI
after chemo in
and medical oncologist
MRI
25 patients.
Mammo
(kappa=0.15) were not
CR
PR
NR
CR
1
0
0
PR
0
8
0
NR
0
8
4
Indet
4
0
0
significant.
25
Breast MRI for Patients with Locally Advanced Breast Cancer Referred for Neoadjuvant Chemotherapy
Population
Design
©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.
Table 1B. MRI Performed Before and After Neoadjuvant Chemotherapy in Patients with Locally Advanced Breast Cancer (cont’d)
21
Table 1B. MRI Performed Before and After Neoadjuvant Chemotherapy in Patients with Locally Advanced Breast Cancer (cont’d)
Interpretation
Design
Population Clearly
Described
Spectrum
Bias Avoided
MRI Blindeded to Clinical
and Other Tests
MRI Blinded to RS
RS Blinded to MRI
Verification
Bias Avoided
RODEO MRI
P
Y
Y
Y
Y
Y
Y
©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.
MRI
Year
Reference
MRI Technique
n
Description
Standard
Abraham et al.
39
(see previous page)
1996
pts
Pre/post
measure of
cont’d
40
contrast
tumor size
br
Fat suppression
Results of Evaluation
Breast coil
n=31
’90 –’94
1.5 T
mastectomy
(see previous page)
MRI
Histologic
Baylor Univ
Comments
Surgical
Oncol
CR
PR
NR
CR
3
7
1
PR
2
17
3
NR
1
5
1
MRI done
40
before and after
chemo.
MRI
Medical
Mammo done
Oncol
CR
PR
NR
chemo in 25
CR
3
9
0
patients.
PR
3
16
2
NR
0
4
3
before and after
40
Esserman
33
Stage III
DCE-MRI
Histologic
Residual tumor size measured by
et al. 2001
pts
before and after
Fat suppression
measure of
pathology and MRI longest distance
neoadjuvant
breast coil
tumor size
after chemotherapy had r-square of
chemotherapy
1.5 T
0.92 (p<0.0001)
doxorubicin x4
MRI done
MRI appearance before chemo
cyclophosphamide x4
before and
was categorized into 5 different
after chemo
patterns. These patterns appeared
UCSF
P
Y
Y
?
Y
Y
Y
? dates
to predict likelihood of response to
chemotherapy.
Smaller residual tumor size
(p<0.0001) and larger % change in
tumor diameter (p=0.015) on MRI
were both associated with lack of
tumor recurrence.
Technology Evaluation Center
Technique and
22
Population
Author
Technique and
Description
Interpretation
Population Clearly
Described
Spectrum
Bias Avoided
MRI Blinded to Clinical
and Other Tests
MRI Blinded to RS
RS Blinded to MRI
Verification
Bias Avoided
P
Y
?
?
Y
Y
Y
Author
MRI
Year
Reference
MRI Technique
n
Standard
Results of Evaluation
Comments
Gilles et al.
18
18 who got MRI
DCE-MRI
1994
pts
out of 25 with
Subtraction
Pathology
Evaluation of pts with
*MRI FN had 2-mm
readings
residual disease
locally advanced
Custom coil
classified
Villejuif,
breast cancer
1.5 T
into focal
France
Excluded
and diffuse
11/92–7/93
inflammatory
MRI done
cancer
before and
Classification of extent
after chemo
of residual disease
invasive tumor residual
Clinical Mammo MRI
Path
Pos
13
9
17
18
Neg
3
5
1*
0
cluster
**Two MRI
underestimates:
One was in situ tumor,
other was additional
Treated with
Pathology
MRI focal
MRI diffuse
3-4 cycles of:
Focal
13
2
FU/doxorubicin/
Diffuse
2**
0
cyclophosphamide
Agreement was 15 out of 18 (83%)
isolated tumor cells
(n=19) or
doxorubicin/
vincristine/cyclophosphamide/
5-FU; prednisone
(n=6)
Drew et al.
17
Stage III-IV
DCE-MRI
2001
pts
following
Fat
(n=12)
neoadjuvant
suppression
Follow-up
chemotherapy
Breast coil
1.5 T
UK
’94–?
Various chemo
P
Y
Y
Y
Y
Y
Y
Histologic
Detection of residual tumor:
10 pts with residual
Se
Sp
NPV
PPV
disease and 7 pts with
Clinical
0.50
0.86
0.55
0.83
no evidence of residual
(n=5)
Mammo
0.90
0.57
0.80
0.75
disease
2.8 to 2.5
DCE-MRI
1.00
1.00
—
—
years
regimens of 8
MRI done
Mammo results counted as TP
cycles:
before and
were actually considered “equivocal”
mitoxantrone/
after chemo
by readers.
methotrexate/
23
mitomycin or
CMF or FEC
Breast MRI for Patients with Locally Advanced Breast Cancer Referred for Neoadjuvant Chemotherapy
Population
Design
©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.
Table 1B. MRI Performed Before and After Neoadjuvant Chemotherapy in Patients with Locally Advanced Breast Cancer (cont’d)
n
Description
Interpretation
Design
Population Clearly
Described
Spectrum
Bias Avoided
MRI Blinded to Clinical
and Other Tests
MRI Blinded to RS
RS Blinded to MRI
Verification
Bias Avoided
©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.
MRI Technique
Belli et al.
45
Stage IIA-IIIB
DCE-MRI
R
Y
?
Y
Y
Y
Y
Author
MRI
Year
Population
Technique and
2002
Reference
Standard
Results of Evaluation
Histopath
68% of lesions had MRI and histology
Dedicated coil
Rome, Italy
CMF-A-CMF or
Subtraction
ET for 3 or 6 cycles
1.5 T
Comments
size within 1mm or less
’98–‘01
Mean (mm)
SD
MRI
25.9
18.6
Histology
24.9
17.2
C=cyclo-
MRI done
phosphamide
before
M=methotrexate
and after
For residual tumor, MRI had
F=fluorouracil
chemotherapy.
90% sensitivity; 100% specificity
A=Adriamycin
Mammo and
E=epirubicin
US done before
MRI suggested complete response
T=? Taxol
only.
in 8 patients, but histology showed
residual microfoci of carcinoma in
4 of these cases.
Tsuboi et al.
1999
Kochi, Japan
31
Stage II and III
DCE-MRI
Pathological MRI Enhancement
When MRI showed
with preoperative
Fat suppression
Grade
Flattened
No change
absence of linear
neoadjuvant
Breast coil
0 (NR)
0
0
enhancement around
chemotherapy
1.5 T
1a (PR)
8
2
tumor, margins were
1b (PR)
6
8
negative in 9/10 cases,
’95 –‘98
?P
Y
Y
?
Y
?
?
Histopath
1–5 cycles of:
MRI done
2 (PR)
2
5
whereas, 12/13 cases
cyclophosphamide
before
3 (CR)
0
0
with remarkable linear
pirarubicin
and after
5-FU
chemotherapy
enhancement had positive
Thus enhancement was reduced in
margins. 8 cases not
duration of chemo
16 of 31 cases with PR. No cases of
included in this analysis
based on tumor
CR identified.
size and clinical
response
(?indeterminate MRI
pattern)
Technology Evaluation Center
24
Table 1B. MRI Performed Before and After Neoadjuvant Chemotherapy in Patients with Locally Advanced Breast Cancer (cont’d)
n
Description
Interpretation
Population Clearly
Described
Spectrum
Bias Avoided
MRI Blinded to Clinical
and Other Tests
MRI Blinded to RS
RS Blinded to MRI
Verification
Bias Avoided
Trecate et al.
30
30 who got
DCE-MRI
?
Y
?
?
Y
Y
Y
1999
pts
satisfactory MRI
Subtraction
out of 44 with
Dedicated coil
Milan, Italy
locally advanced
1.5 T
11/95–4/98
breast cancer
Author
MRI
Year
Population
Technique and
Reference
Standard
Results of Evaluation
Comments
Histopath
Presence of enhancement post
Numbers disagree in
chemo predicting residual tumor:
MRI
paper. Article states Sp
Se
Sp
NPV
PPV
as 0.75 but text reads
0.96
0.50
0.66
0.93
2 FP and 2 TN, which is
consistent with reported
TNM: T4 b,c,d
MRI done
N0-2, M0
before and after
predictive values.
chemo
Adriamycin x4
paclitaxel x4
then 5-FU x3
vinorelbine x3
cyclophosphamide x3
Wasser et al.
2003a
Heidelberg,
31
Stage II and
DCE-MRI
Correlation between MRI size and
MRI has good
III undergoing
Breast coil
histological size
correspondence when
neoadjuvant
1.5 T
All tumors
chemotherapy
Y
N
?
Y
Y
Y
Histopath
0.74 (p<0.0001)
there is no response but
(n=31)
incorrect size estimates
MRI done
w/o histol regression 0.83 (p<0.0007)
when there is tumor
Tumor size on MRI
before and after
(n=12)
response. No tendency
0–12 cm.
chemotherapy
histol regression
Germany
10/95–12/00
R
0.48 (p<0.051)
(n=17)
epirubicin and
Results not easily tabulated.
paclitaxel or
MRI correctly predicted 2 cases
cyclophosphamide
with CR.
for MRI to over- or
underestimate size.
Breast MRI for Patients with Locally Advanced Breast Cancer Referred for Neoadjuvant Chemotherapy
MRI Technique
Design
©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.
Table 1B. MRI Performed Before and After Neoadjuvant Chemotherapy in Patients with Locally Advanced Breast Cancer (cont’d)
25
n
Description
Interpretation
Design
Population Clearly
Described
Spectrum
Bias Avoided
MRI Blinded to Clinical
and Other Tests
MRI Blinded to RS
RS Blinded to MRI
Verification
Bias Avoided
©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.
MRI Technique
Weatherall
20
Postchemotherapy
DCE-MRI
R
Y
?
?
N
?
?
et al. 2001
lesions pts
Author
MRI
Year
Population
Technique and
Reference
Standard
Results of Evaluation
Histologic
Estimation of tumor size:
Subtraction
measure of
Breast coil
tumor size
UT
Adriamycin x3-6
Southwestern
Cytoxan x3-6
4/97–10/99
Some also got
MRI done
5-FU, paclitaxel,
before and
or XRT
after chemo
Stage II (T>3.5cm)
Pre/post
(n=8) or Stage IIIa
contrast
5-mm serial
(n=7)
Fat suppression
sections
Nakamura
et al. 2001
15
Tokyo, Japan
?dates
Adriamycin x4
1.5 T
R
p
MRI
0.92–0.93 <0.0001
Palp
0.68–0.72 <0.005
Mammo 0.56–0.63 <0.05
US
?
Y
?
?
Y
?
?
Histopath
Comments
(n=20)
(n=20)
(n=17)
0.23–0.53 <0.05–0.25 (n=8)
MRI showed PR in 14/15 cases.
Study does not compare
surgical plan without MRI
BCT performed in 13 of 15 cases.
information and does not
Breast coil
1 BCT converted to mastectomy
clearly report correlation
1.5 T
due to positive margins.
of MRI with pathology.
docetaxel x4
1 BCT required boost XRT due to
MRI done
microscopically positive margins.
before
Thus, 11 of 15 got BCT.
and after
chemotherapy
Technology Evaluation Center
26
Table 1B. MRI Performed Before and After Neoadjuvant Chemotherapy in Patients with Locally Advanced Breast Cancer (cont’d)
Table 1B. MRI Performed Before and After Neoadjuvant Chemotherapy in Patients with Locally Advanced Breast Cancer (cont’d)
Description
Interpretation
Population Clearly
Described
Spectrum
Bias Avoided
MRI Blinded to Clinical
and Other Tests
MRI Blinded to RS
RS Blinded to MRI
Verification
Bias Avoided
Rosen et al.
21
R
Y
Y
Y
Y
Y
Y
MRI
Year
Population
Technique and
Reference
Standard
Results of Evaluation
Comments
Stage II-IIIB
Pre/post
Histologic
MRI prediction of final tumor size:
On MRI, correlation
2003
or T2-T4d
contrast with
measure of
Within ≤1 cm
12 (57%)
with histology was 0.85
Fat-
tumor size
Underestimated by >1 cm
2 (10%)
for focal and 0.69 for
Duke Univ
(n=17)
suppression
Overestimated by >1 cm
7 (33%)
nonfocal lesions.
5/00–12/02
paclitaxel x4
Breast coil
doxorubicin x4
1.5 T
For focal lesions, size
Mean
hyperthermia
correlation was better for
size
Breast
MRI done
(cm)
MRI (0.85) than physical
SD
r
exam (0.67).
before
Before chemo
(n=4)
and after
Physical exam
5.5
3.3
*Note: tables and text
docetaxel x4
chemotherapy
MRI
6.2
2.5
disagree in article
Physical exam*
2.2
2.6
0.65
4 of 21 patients got BCT.
MRI
3.7
2.1
0.75
1 of these had (+) margins
Pathology
3.0
2.4
doxorubicin x4
After chemo
Overall:
requiring re-excision
but did not require
Differences between MRI and
mastectomy.
physical exam not statistically
significant.
Enhancement results not
analyzed in detail.
One “false-positive” case in which MRI
showed 4.3 cm region of patchy, mild
enhancement after chemotherapy,
but pathology noted no invasive
cancer but did note multicentric in situ
carcinoma present diffusely.
One “false-negative” case in which
MRI did not show enhancement of
a 0.5-cm invasive ductal carcinoma
27
after chemotherapy.
Breast MRI for Patients with Locally Advanced Breast Cancer Referred for Neoadjuvant Chemotherapy
n
Design
©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.
MRI Technique
Author
Description
Interpretation
Population Clearly
Described
Spectrum
Bias Avoided
MRI Blinded to Clinical
and Other Tests
MRI Blinded to RS
RS Blinded to MRI
Morris et al.
19
Breast masses
Pre/post
P
Y
Y
?
?Y
?N
located in
contrast with
posterior third
fat suppression
Sensitivity 100% (5/5)
Memorial
of breast.
or subtraction
Specificity 100% (14/14)
Sloan-
13 had deep
1.5 T
Kettering
palpable masses
’94–‘98
considered fixed
Distance of
muscles with obliteration of the fat plane and muscle
to the chest wall
mass from
enhancement. All 5 proven to have PM involvement at
on exam.
pectoralis
surgery (true positive)
12 suggested
muscle (PM),
involvement on
obliteration
Fourteen (74%) showed no muscle enhancement. Six
mammo and 10
of fat plane
of these masses abutted the muscle and obliterated the
of these were
between
intervening fat plane. All were free of PM involvement at
inseparable from
mass and PM,
surgery (true negative).
pectoralis muscle.
enhancement
7 had normal
of PM
MRI
Year
2000
Population
Technique and
Verification
Bias Avoided
n
Design
©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.
MRI Technique
Author
Reference Standard
Results
?
Surgical findings
Detection of tumor involvement of pectoralis muscle
and histopathology
based on PM enhancement
Five (26%) had masses that abutted the pectoralis
Clinical exam:
mammo that
Sensitivity 100% (5/5)
missed the tumor.
Specificity 0% (0/14)
17 malignant
Mammography results not reported in detail.
2 benign
Surgical treatment:
11 patients had lumpectomy
6 patients had modified radical mastectomy
1 patient had radical mastectomy
1 patient had partial chest wall resection
Technology Evaluation Center
28
Table 2. Breast MRI for Preoperative Evaluation of Extent of Tumor to Pectoralis Muscle/Chest Wall, Skin, or Nipple
Description
Interpretation
Population Clearly
Described
Spectrum
Bias Avoided
MRI Blinded to Clinical
and Other Tests
MRI Blinded to RS
RS Blinded to MRI
Mumtaz et al.
90
P
Y
Y
Y
Y
Y
MRI
Year
Population
Technique and
Reference Standard
Results
Y
Histopathol
4 cases of Paget’s disease of the nipple seen on
Symptomatic
Pre/post
1997
breast cancer who
contrast
4/4 MRI
London, UK
got preop MRI
Breast coil
1/4 Mammo
1.0 T
2/4 Clinical exam
? dates
Kerslake et al.
Patients with
DCE-MRI
1995
50
breast cancer who
Fat suppression
Hull, UK
got preop MRI
Breast coil
?dates
R
Y
N
N
Y
Y
Y
Histopathol
R
N
?
Y
Y
Y
Y
Pathologic analysis
Invasion of chest wall accurately predicted in 3 cases
1.5 T
Rodenko et al.
20
Patients with
Contrast-
1996
pts
infiltrating lobular
enhanced
of mastectomy
Invasion of chest wall
1
0
carcinoma who
High-resolution
specimen in
Extension to chest wall
7
0
1
had breast MRI
RODEO MRI
18 patients
Extension to skin
6
0
4
(not dynamic)
(5-mm sections)
fat suppression
or lumpectomy
? coil
specimen in
1.5 T
2 patients.
Baylor
?dates
MRI
Mammography
Pathology
1
Breast MRI for Patients with Locally Advanced Breast Cancer Referred for Neoadjuvant Chemotherapy
n
Author
Verification
Bias Avoided
MRI Technique
Design
©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.
Table 2. Breast MRI for Preoperative Evaluation of Extent of Tumor to Pectoralis Muscle/Chest Wall, Skin, or Nipple (cont’d)
29
Table 3. Summary: MRI for Evaluation of Presence of Residual Tumor, Size, and Extent
©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.
Study
n
Design
Abraham
1996
39
Drew 2001
Pathology
MRI
Mammography
Clinical
P
Agreed with pathology 97% (30/31)
Underestimated degree
of response.
Disagreed with MRI in
48% (12/25).
Disagreed with
MRI in 45–48%
No significant
agreement with
MRI - kappa only
0.08–0.15
17
P
100% sensitivity
100% specificity
90% sensitivity
57% specificity
but TP mammo were
read as equivocal
50% sensitivity
86% specificity
Rosen 2003
21
R
Partridge
2002
52
BaluMaestro
2002
Mean 3.7, SD 2.1 cm
Correlation 0.75 (95% CI: 0.57–0.94)
MRI prediction of final tumor size:
Within ≤1 cm
12 (57%)
Underestimated by >1 cm
2 (10%)
Overestimated by >1 cm
7 (33%)
Mean 2.2, SD=2.6 cm
Correlation 0.65
(95% CI: 0.32–0.9)
P
Correlation 0.89 (p<0.001)
Detected all cases of residual tumor
Correlation 0.60
(p<0.001)
Had 5 FN cases
51
R
63% correct size
38% correct size
52% correct size
Gilles 1994
18
P
Showed residual in 94% and showed correct
extent in 83%.
Showed residual 64%
Showed residual 81%
Weatherall
20
R
0.92–0.93
p<0.0001
(n=20)
0.56–0.63 p<0.05
0.68–0.72 p<0.005
(n=20)
2001
Rieber 2002
58
P
Mean 3.0, SD=2.4
cm
Size reduction agreed with pathology 66%.
Underestimated size in 50% of responders
(n=17)
Ultrasound
43% correct size
0.23–0.53 p<0.05–0.25
(n=8)
Technology Evaluation Center
30
Results
Table 3. Summary: MRI for Evaluation of Presence of Residual Tumor, Size, and Extent (cont’d)
Study
n
Design
Pathology
Martincich
2004
30
P
Cheung 2003
33
P
Microscopy
Gross
Correlation 0.98 (p<0.001)
Correlation 0.64 (p<0.001)
Size reduction had 75% PPV (3/4) for
prediction of CR
Rieber 1997
13
P
Avg. vol = 95.0 cc
Avg. vol = 69.1 cc
Wasser
21
R
No false-positive cases (i.e., no cases where
MRI showed residual tumor with pathol CR)
Esserman
2001
33
P
Correlation 0.92 (p<0.0001)
Belli 2002
45
R
Tsuboi 1999
31
?P
When MRI showed absence of linear
enhancement around tumor, margins were
negative in 9/10 cases, whereas, 12/13 cases
with remarkable linear enhancement had
positive margins. 8 cases not included in this
analysis (?indeterminate MRI pattern)
Trecate 1999
30
?
96% sensitivity, 50% specificity
NPV 66%, PPV 93%
Wasser
31
R
Correlation:
All tumors 0.74 (p<0.0001)
No regression 0.83 (p<0.0007)
Regression 0.48 (p<0.051)
Correlation 0.72 (p<0.001)
Size reduction of 65% was 91% sensitive
and 84% specific in predicting major
pathologic response
2003b
2003a
MRI
Mean 24.9 mm
SD 17.2 mm
Mean 25.9 mm
SD 18.6 mm
90% sensitivity
100% specificity
Mammography
Clinical
Ultrasound
Breast MRI for Patients with Locally Advanced Breast Cancer Referred for Neoadjuvant Chemotherapy
©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.
Results
31
Technology Evaluation Center
staging, MRI appeared to be more sensitive
in identifying the presence of residual tumor
and defining the size and extent of residual
tumor. A small prospective, double-blinded
study (Drew et al. 2001; n=17) found MRI to be
100% sensitive and 100% specific for defining
residual tumor after chemotherapy. Conversely,
mammography achieved 90% sensitivity and
57% specificity (positive mammography results
were all considered equivocal), and clinical
exam was only 50% sensitive and 86% specific.
Similarly, another larger prospective study
(Partridge et al. 2002; n=52) reported correlation of residual tumor size on MRI of 0.89 and
clinical exam of 0.60. MRI identified all residual
tumor cases; whereas clinical exam had 5
false-negative results. Clinical exam and mammography were not able to distinguish chest
wall involvement as reliably as MRI (Morris et
al. 2000; Rodenko et al. 1996). Nipple involvement (Paget’s disease) was correctly identified
by MRI in 4 of 4 cases; whereas mammography
or clinical exam identified nipple involvement
in only one or 2 of these cases, respectively
(Mumtaz et al. 1997).
No studies were identified that reported the
direct effects of breast MRI on health outcomes in patients with locally advanced breast
cancer referred for neoadjuvant chemotherapy.
However, using the algorithm provided in
Figure 2, the effects of using MRI instead of
clinical findings for staging and presurgical
planning may be estimated. Since MRI appears
to provide a more accurate determination of
tumor size and extent compared with clinical
staging, it is likely that MRI would be more
accurate in determining eligibility for BCT.
Thus, discordant results on MRI would most
likely be correct MRI findings and incorrect
clinical findings. Using MRI staging results
instead of clinical staging for presurgical planning would lead to an improvement in net
health outcome by increasing the use of BCT
when appropriate and avoiding the need for reexcision surgery when BCT is not appropriate.
Summary
The available body of evidence is somewhat
limited but includes several prospective welldesigned studies and is considered sufficient
to permit conclusions. The available evidence
demonstrates that the diagnostic performance
of breast MRI, an intermediate outcome,
appears to be better than conventional methods
of presurgical evaluation at determining extent
32
and size of residual tumor. Using breast MRI
staging instead of conventional methods of
clinical staging to guide surgical decisionmaking is likely to improve the net health
outcome by increasing breast conservation and
avoiding unnecessary additional surgeries.
Does the evidence demonstrate that, compared with conventional alternatives, breast
MRI before and during neoadjuvant chemotherapy provides an early and reliable
prediction of tumor that is nonresponsive to
neoadjuvant chemotherapy? If so, does the
use of MRI improve the net health outcome?
Six studies (Table 1A; total n=206) performed
breast MRI during the course of neoadjuvant
chemotherapy. The type of chemotherapy
regimen used and timing of the MRI scans were
variable. Studies evaluated response to chemotherapy using either change in tumor size or
change in the degree of contrast enhancement
on MRI. Changes in tumor size were measured
in various ways including absolute or relative
changes in volume or diameter. The degree
of contrast enhancement was analyzed using
various qualitative or quantitative assessment
parameters, and results were not consistently
and clearly reported in all studies.
Four of these 6 studies were prospective in
design, but only 2 included more than 50 subjects. Four provided clear descriptions of the
study populations, and 3 appeared to avoid
spectrum bias. All studies used histopathologic reference standard for determining final
response to chemotherapy, and all studies
interpreted MRI blinded to reference standard
results. All 6 studies avoided verification bias.
The most important use of MRI would be to
reliably identify patients whose tumors were
not responding to neoadjuvant chemotherapy.
Two studies provide estimates of NPV (Cheung
et al. 2003; Rieber et al. 2002) which were
38% and 83%. The 4 other studies do not
clearly separate partial-responders from nonresponders, making it impossible to correctly
determine negative predictive value. At least a
few patients in these studies failed to show a
response on MRI after 2 cycles of neoadjuvant
chemotherapy but went on to have at least a
partial response. Thus, early appearance of
nonresponse on MRI is not a reliable predictor
of final tumor response.
©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.
Breast MRI for Patients with Locally Advanced Breast Cancer Referred for Neoadjuvant Chemotherapy
Lack of enhancement and size reduction on
early MRI may help to identify tumors likely to
demonstrate a complete response; however, it
is not clear how this information would influence patient management. Martincich et al.
(2004; n=30) conducted a prospective study
in which MRI, performed after 2 cycles in a
4-cycle chemotherapy regimen, was 100%
sensitive and 92% specific in predicting a
final complete pathologic response when both
reduction in contrast enhancement and reduction in tumor size (>65%) were considered.
Balu-Maestro et al. (2002) retrospectively
studied 60 lesions in 51 patients who had MRI
performed after 3 cycles in a 4- to 6-cycle
regimen. MRI was 100% sensitive and 82%
specific in predicting a final complete response.
However, the positive predictive value was
only 33%; 5 of 15 nonenhancing lesions were
true complete responders. Cheung et al. (2003;
n=33) prospectively performed MRI after the
first cycle in a 3-cycle chemotherapy regimen
and analyzed the results using tumor size
reduction. None of the patients with an early
size reduction of less than 45% went on to have
a final complete response.
Figure 3, the effects of using MRI instead of
clinical findings to identify nonresponsive
tumors may be estimated if the diagnostic
performance characteristics of MRI were
established in the literature. While preliminary
evidence using breast MRI in this manner
suggests that reductions in contrast enhancement may occur in chemotherapy-responsive
tumors, MRI has not yet been proven to be
a sufficiently reliable means of identifying
nonresponders and may be misleading. Thus,
the potential harms associated with denying
patients the benefit of effective chemotherapy
by prematurely discontinuing therapy based
on false-negative MRI results may outweigh
the benefit to those with true-negative MRI
results who are spared the toxicity of ineffective
chemotherapy. Furthermore, it has not been
demonstrated that offering a different chemotherapy regimen to a patient whose disease
has been nonresponsive will improve the rate
of response. While preliminary studies suggest
that early breast MRI may be very sensitive for
identifying those who may subsequently experience a complete response, it is not clear that
this information would change management.
The issue of when to perform early MRI assessment is also of interest. Two prospective studies
conducted at a single institution (Rieber et al.
2002, 1997) reported that responders showed
reductions in contrast enhancement on MRI
that reliably predicted response when MRI
was performed after 6 weeks, but not before
6 weeks. However, decreases in contrast
enhancement led to underestimation of tumor
extent in 6 of 13 cases in Rieber et al. (1997).
This study used relatively thick MRI sections
(4 mm), which may account for its relatively
high false-negative rate compared with other
studies. Wasser et al. (2003b) conducted a
retrospective study that also found decreases
in contrast enhancement on MRI after the first
cycle of chemotherapy in patients who became
responders; although there was also a trend
for reduced enhancement in nonresponders
as well. Reductions in tumor size were not
observed in this study until after the third
cycle of chemotherapy.
Summary
The available body of evidence using MRI
for planning chemotherapy is limited to a few
studies with a lack of consistent outcomes
measures and reporting as well as small
sample sizes and a lack of consistent statistical
comparisons. The most important parameter
would be a high negative predictive value for
identifying tumors that are nonresponsive to
neoadjuvant chemotherapy. However, results
are not consistent, and there is insufficient
evidence to determine whether breast MRI
can reliably predict response to neoadjuvant
chemotherapy.
No studies were identified that reported the
direct effects of breast MRI on health outcomes in patients with locally advanced breast
cancer referred for neoadjuvant chemotherapy.
However, using the algorithm provided in
Summary of Application of the
Technology Evaluation Criteria
Based on the available evidence, the Blue
Cross and Blue Shield Association Medical
Advisory Panel made the following judgments
about whether the use of breast MRI for
management of patients with locally advanced
breast cancer who are being referred for
neoadjuvant chemotherapy meets the Blue
Cross and Blue Shield Association Technology
Evaluation Center (TEC) criteria.
©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.
33
Technology Evaluation Center
1. The technology must have final
approval from the appropriate
governmental regulatory bodies.
The technology meets the first TEC criterion.
MR imaging of the breast can be performed
using commercially available MR scanners and
intravenous MR contrast agents. Specialized
breast coils such as the OBC-300 Breast Array
Coil® (MRI Devices Corp., Waukesha, WI)
and MR-compatible equipment for performing biopsy have been developed and cleared
for marketing via the U.S. Food and Drug
Administration (FDA) 510(k) process as substantially equivalent to predicate devices for
use “in conjunction with a magnetic resonance
scanner to produce diagnostic images of
the breast and axillary tissues that can be
interpreted by a trained physician” (Model
OBC-300 Breast Array Coil 510(k) notification
letter dated December 3, 1999).
2. The scientific evidence must permit
conclusions concerning the effect of
the technology on health outcomes.
A search of the literature was conducted to
identify studies using contrast-enhanced breast
MRI. Eligible studies were published in English
as full-length, peer-reviewed journal articles,
using human subjects, and reporting diagnostic
performance characteristics for MRI and
alternative tests when appropriate or effect
of MRI on health outcomes.
The best evidence would be direct evidence
from randomized, controlled trials that assess
the effects of breast MRI on breast cancerrelated morbidity or mortality. Such trials
have not been published. The best available
evidence is from studies that report the diagnostic performance characteristics of breast
MRI to define the extent of tumor and/or tumor
response after neoadjuvant chemotherapy
and compare results of MRI with conventional
tests using histopathology as an independent
reference standard. While these diagnostic
intermediate outcomes are related to the use
of BCT and the outcomes of breast conservation and avoidance of re-excision surgery, the
relationship with long-term health outcomes
is not as clear. It may be that patients who are
downstaged by chemotherapy before BCT have
higher recurrence rates compared to those who
were initially eligible for BCT. Nevertheless, the
short-term benefits of breast conservation and
avoidance of re-excision surgery are considered
34
important health outcomes and can be used
to model the effects of using MRI for presurgical planning in patients with locally advanced
breast cancer who are referred for neoadjuvant
chemotherapy.
Breast MRI Performed Before and After
Completion of Neoadjuvant Chemotherapy
for Presurgical Planning. The available body
of evidence is somewhat limited by small
sample sizes, lack of consistent outcomes
measures and reporting, and lack of consistent
statistical comparisons; however, several prospective well-designed studies are included.
These studies consistently show that MRI
appears to provide a more accurate preoperative assessment of residual tumor following
neoadjuvant chemotherapy compared with
conventional clinical staging alternatives.
Despite limitations, the available evidence is
considered sufficient to permit conclusions.
Eighteen studies (total n=558) evaluate the
use of MRI after neoadjuvant chemotherapy
to demonstrate the presence, size, and extent
of residual tumor and compare results against
histopathology, the independent reference
standard. Six of these studies (total n=179)
compare MRI with conventional clinical staging
alternatives. Four additional studies (total
n=179) describe the preoperative use of MRI
to identify tumor involvement of the pectoralis
muscle/chest wall, skin, and nipple, although
neoadjuvant chemotherapy was not applied,
and 3 of these compared MRI with conventional
alternatives.
Compared with histopathology, the reference
standard, MRI demonstrates the presence
of residual tumor with estimated sensitivity
ranging from 90–100% and specificity from
50–100%. MRI estimated the size and extent of
tumor correctly in comparison with pathologic
evaluation in 57%, 63%, 66%, 83%, and 97% of
cases among 5 studies reporting these results.
Correlation coefficients for size of residual
tumor on MRI were generally good to excellent,
ranging from 0.72 to 0.98. Chest wall invasion
was correctly determined by MRI with 100%
sensitivity and 100% specificity in 23 cases
included in 3 studies. In another study, extension of tumor to the skin was suggested by
MRI in 4 of 4 true-positive cases, although
MRI also reported 2 false-positive cases.
Among the 9 studies comparing MRI with
conventional alternatives, MRI appeared to be
©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.
Breast MRI for Patients with Locally Advanced Breast Cancer Referred for Neoadjuvant Chemotherapy
more sensitive than conventional alternatives in
identifying the presence of residual tumor and
defining the size and extent of residual tumor. A
small prospective, double-blinded study (n=17)
found MRI to be 100% sensitive and specific for
defining residual tumor after chemotherapy.
Conversely, mammography achieved 90%
sensitivity and 57% specificity (mammography
results were all considered equivocal), and
clinical exam was only 50% sensitive and 86%
specific. Similarly, another larger prospective
study (n=52) reported correlation of residual
tumor size on MRI of 0.89 and clinical exam of
0.60. MRI identified all residual tumor cases,
whereas clinical exam had 5 false-negative
results. Clinical exam and mammography were
not able to distinguish chest wall involvement
as reliably as MRI. Nipple involvement (Paget’s
disease) was correctly identified by MRI in
4 of 4 cases, whereas, mammography or clinical
exam identified nipple involvement in only
1 or 2 of these cases, respectively.
Breast MRI Performed Before and
During Neoadjuvant Chemotherapy for
Chemotherapy Planning. The available body
of evidence using MRI for planning chemotherapy is limited to a few studies with a lack
of consistent outcome measures and reporting
as well as small sample sizes and a lack of
consistent statistical comparisons. The most
important parameter would be a high negative
predictive value for identifying tumors that are
nonresponsive to neoadjuvant chemotherapy.
However, results are not consistent, and there
is insufficient evidence to determine whether
breast MRI can reliably predict response to
neoadjuvant chemotherapy.
Six studies (total n=206) performed breast
MRI during the course of neoadjuvant chemotherapy. The type of chemotherapy regimen
used, timing of the MRI scans, and methods
for measuring tumor response on MRI were
variable. Four of these 6 studies were prospective in design, but only 2 included more than
50 subjects. Four provided clear descriptions
of the study populations, and 3 appeared to
avoid spectrum bias. All studies used histopathologic reference standard for determining
final response to chemotherapy, and all studies
interpreted MRI blinded to reference standard
results. All 6 studies avoided verification bias.
The most important use of MRI would be to
reliably identify patients whose tumors were
not responding to neoadjuvant chemotherapy.
Two studies provide estimates of NPV, which
were 38% and 83%. The 4 other studies do
not clearly separate partial-responders from
nonresponders, making it impossible to correctly determine negative predictive value.
At least a few patients in these studies failed
to show a response on MRI after 2 cycles of
neoadjuvant chemotherapy but went on to
have at least a partial response. Thus, early
appearance on MRI is not a reliable predictor
of final tumor response.
Reduction of enhancement on MRI may
indicate responsive tumor; however, it
seems unlikely that this information would
change patient management.
3. The technology must improve
the net health outcome; and
4. The technology must be as beneficial
as any established alternatives.
Breast MRI Performed Before and After
Completion of Neoadjuvant Chemotherapy
for Presurgical Planning. The available
studies consistently show that breast MRI
appears to be better than conventional presurgical clinical staging methods at determining
extent and size of residual tumor. However,
it should be noted that breast MRI would not
be used as a replacement for histopathologic
assessment. Since MRI appears to provide a
more accurate determination of tumor size
and extent compared with clinical staging,
it is likely that MRI would be more accurate
in determining eligibility for BCT. Thus, discordant results on MRI would most likely be
correct MRI findings and incorrect clinical
findings. Using MRI staging results instead of
clinical staging for presurgical planning would
lead to an improvement in net health outcome
by increasing the use of BCT when appropriate
and avoiding the need for re-excision surgery
when BCT is not appropriate.
Breast MRI Performed Before and
During Neoadjuvant Chemotherapy for
Chemotherapy Planning. There is insufficient
evidence to permit conclusions on the effect
on health outcomes of using breast MRI to
provide an early prediction of the response to
neoadjuvant chemotherapy.
©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.
35
Technology Evaluation Center
5. The improvement must be attainable
outside the investigational settings.
Breast MRI Performed Before and After
Completion of Neoadjuvant Chemotherapy
for Presurgical Planning. The improvements
in health outcomes achieved in the investigational settings would likely be attainable
outside the investigational settings when
breast MRI is conducted by operators of similar
experience in patients with locally advanced
breast cancer who are being referred for neoadjuvant chemotherapy.
Breast MRI Performed Before and
During Neoadjuvant Chemotherapy for
Chemotherapy Planning. Whether the use
of breast MRI to provide an early prediction
of the response to neoadjuvant chemotherapy
improves health outcomes has not been
demonstrated in the investigational setting.
Therefore, based on the above, the use of
breast MRI before chemotherapy and after
completion of neoadjuvant chemotherapy to
define the size and extent of tumor to guide
the decision to use breast-conservation therapy
meets the TEC criteria. The use of breast MRI
before and during neoadjuvant chemotherapy
to provide an early prediction of the response
to neoadjuvant chemotherapy does not meet
the TEC criteria.
NOTICE OF PURPOSE: TEC Assessments are scientific opinions, provided solely for informational purposes. TEC Assessments
should not be construed to suggest that the Blue Cross Blue Shield Association, Kaiser Permanente Medical Care Program or the
TEC Program recommends, advocates, requires, encourages, or discourages any particular treatment, procedure, or service; any
particular course of treatment, procedure, or service; or the payment or non-payment of the technology or technologies evaluated.
CONFIDENTIAL: This document contains proprietary information that is intended solely for Blue Cross and Blue Shield Plans
and other subscribers to the TEC Program. The contents of this document are not to be provided in any manner to any other
parties without the express written consent of the Blue Cross and Blue Shield Association.
36
©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.
Breast MRI for Patients with Locally Advanced Breast Cancer Referred for Neoadjuvant Chemotherapy
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Appendix
Key to Abbreviations in Tables
(-)
(+)
?
A
abn
avg
BCT
C
CI
cm
conv
d
D
DCE
E
En
EPI
f/u
F
FN
FNA(B)
FP
histopath
ILC
LR
M
m
mammo
measure
min
42
negative
positive
uncertain
Adriamycin
abnormal
average
breast-conservation treatment
cyclophosphamide
confidence interval
centimeter
conventional
days
doxorubicin
dynamic contrast-enhanced
epirubicin
Endoxan
echo-planar imaging
follow-up
5-fluorouracil
false negative
fine-needle aspiration (biopsy)
false positive
histopathology
invasive lobular cancer
likelihood ratio
methotrexate
months
mammography
measurement
minute
mm
MRI
N
N
n; N
NPV
P
P
PE
postop
PPV
Prev
pt(s)
R
RS
rx
Sens
SI
Spec
T
T
TN
TP
US
vs.
w/
XRT
y
Y
millimeter
magnetic resonance imaging
Navelbine
no
number
negative predictive value
paclitaxel
prospective
physical exam
postoperative
positive predictive value
prevalence
patient(s)
retrospective
reference standard
treatment
sensitivity
signal intensity
specificity
Taxol
Tesla
true negative
true positive
ultrasound
versus
with
radiation therapy
years
yes
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Breast MRI for Patients with Locally Advanced Breast Cancer Referred for Neoadjuvant Chemotherapy
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