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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. ©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited. 1 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 ©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 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 ©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited. 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 ©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 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). ©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 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 ©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 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 ©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited. 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. ©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited. Figure 2. Breast MRI for Presurgical Planning �������������� �������������������� ����������������� ������������������������������ ���������������������������� ����� �������� ������������������������� ������������������������� ������������������ ��������������������������� ���������������������� ���� �������� ������������������������ ������������������������ ������������������������������ ����������������������������� ����� �������� ������������������� ���������������������� ��������������������������������� ������������������������������������ �������� ������� ������� ��������� ����� ����������� ������������ �������� ��������� ������������ ������� ������� ��������� ����� ����������������������� ������������������ ������� �������� ��������� ���������� ����������� ����������� ������������ �������� ������� ��� ��������� ������� �������� ��������� ������������� ����������������� ������� ������������ ������� �������� ��������� ��������������� �������� �������������������� ����������������� ������������������������������ ���������������������������� ��������� ��������� ������������� �������� �������������������������� ������������������������� ������������������ ��������������������������� ���������������������� �������� ��������� �������������� �������� ������������������������ ������������������������ ������������������������������ ����������������������������� ��������� ��������� ������������� �������� �������������������� ���������������������� ��������������������������������� ������������������������������������ 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. ���� �������� 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 ©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited. ������ ��� �� �������������������������� ��� �������������������� �������������������� ����������������� ������������ ����������� ������������ ������ ����� ��������������������������������� ������ ��� �� ��������������������������������� ������ ��������� � ����������������� ��� ������ ����� ������������������������������������ ���������������� ������������� �������������������� �������������������� ������������ ������������ ����������� ������������ ������ ����� ��������������������� ��� ������ ����� ��������������������� ��������������� � ����������������� ������ ��� �� ��������������������������������������� ��� ������ ����� ��������������������������������������������� � � � ��������������������������������������������� � � � ������������������������������������ 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 ©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited. 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 References Abraham DC, Jones RC, Jones SE et al. (1996). Evaluation of neoadjuvant chemotherapeutic response of locally advanced breast cancer by magnetic resonance imaging. Cancer, 78(1):91-100. Cohen L, Hack TF, de Moor C et al. (2000). The effects of type of surgery and time on psychological adjustment in women after breast cancer treatment. Ann Surg Oncol, 7(6):427-34. Abrams JS, Phillips PH, Friedman MA. (1995). Meeting highlights: A reappraisal of research results for the local treatment of early stage breast cancer. J Natl Cancer Inst, 87(24):1837-1845. deSouza NM, Kormos DW, Krausz T et al. (1995). MR-guided biopsy of the breast after lumpectomy and radiation therapy using two methods of immobilization in the lateral decubitus position. J Magn Reson Imaging, 5(5):525-8. American Cancer Society. (2004). Cancer Facts and Figures 2004. Atlanta, GA: American Cancer Society, 2004. Also available online at: http://www.cancer.org/docroot/ STT/stt_0.asp . Last accessed January 29, 2004. American Joint Committee on Cancer (AJCC). (2002). Breast. In: AJCC Cancer Staging Manual. 6th ed. New York, NY, Springer, pp 171-180. Arora NK, Gustafson DH, Hawkins RP et al. (2001). Impact of surgery and chemotherapy on the quality of life of younger women with breast carcinoma: a prospective study. Cancer, 92(5):1288-98. Balu-Maestro C, Chapellier C, Bleuse A et al. (2002). Imaging in evaluation of response to neoadjuvant breast cancer treatment benefits of MRI. Breast Cancer Res Treat, 72(145-52. Belli P, Romani M, Costantini M et al. (2002). Role of magnetic resonance imaging in the pre and postchemotherapy evaluation in locally advanced breast carcinoma. Rays, 27(4):279-90. Buchholz TA. (2002). Radiation therapy for locally advanced breast cancer. In: MC Perry, ed. American Society of Clinical Oncology 2004 Educational Book, Alexandria, VA, American Society of Clinical Oncology: 58-62. Cayre A, Cachin F, Maublant J et al. (2002). Single static view 99mTc-sestamibi scintimammography predicts response to neoadjuvant chemotherapy and is related to MDR expression. Int J Oncol, 20(5):1049-55. Cheung YC, Chen SC, Su MY et al. (2003). Monitoring the size and response of locally advanced breast cancers to neoadjuvant chemotherapy (weekly paclitaxel and epirubicin) with serial enhanced MRI. Breast Cancer Res Treat, 78(1):51-8. Clark RM, Whelan T, Levine M et al. (1996). Randomized clinical trial of breast irradiation following lumpectomy and axillary dissection for node-negative breast cancer: an update. Ontario Clinical Oncology Group. J Natl Cancer Inst, 88(22):1659-64. Clauson J, Hsieh YC, Acharya S et al. (2002). Results of the Lynn Sage Second-Opinion Program for local therapy in patients with breast carcinoma: changes in management and determinants of where care is delivered. Cancer, 94(4):889-94. Dorval M, Maunsell E, Deschenes L et al. (1998). Type of mastectomy and quality of life for long term breast carcinoma survivors. Cancer, 83(10):2130-8. Drew PJ, Kerin MJ, Mahapatra T et al. (2001). Evaluation of response to neoadjuvant chemoradiotherapy for locally advanced breast cancer with dynamic contrast-enhanced MRI of the breast. Eur J Surg Oncol, 27(7):617-20. Early Breast Cancer Trialists’ Collaborative Group. (1998). Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet, 352(9132):930-42. Early Breast Cancer Trialists’ Collaborative Group. (2000). Favourable and unfavourable effects on longterm survival of radiotherapy for early breast cancer: an overview of the randomized trials. Lancet, 355:1757-70. Eifel P, Axelson JA, Costa J et al. (2001). National Institutes of Health Consensus Development Conference Statement: adjuvant therapy for breast cancer, November 1-3, 2000. J Natl Cancer Inst, 93(13):979-89. Esserman L, Kaplan E, Partridge S et al. (2001). MRI phenotype is associated with response to doxorubicin and cyclophosphamide neoadjuvant chemotherapy in stage III breast cancer. Ann Surg Oncol, 8(6):549-59. Fisher B, Anderson S, Fisher E et al. (1991). Significance of ipsilateral breast tumour recurrence after lumpectomy. Lancet, 338(8763):327-31. Fisher B, Anderson S, Redmond CK et al. (1995). Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med, 333(22):1456-61. Fisher B, Bryant J, Dignam JJ et al. (2002). Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less. J Clin Oncol, 20(20):4141-49. Fisher B, Bryant J, Wolmark N et al. (1998). Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol, 16(8):2672-85. ©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited. 37 Technology Evaluation Center Fisher B, Wickerham DL, Deutsch M et al. (1992). Breast tumor recurrence following lumpectomy with and without breast irradiation: an overview of recent NSABP findings. Semin Surg Oncol, 8(3):153-60. Kiebert G, Haes J, Van de Velde CJ. (1991). The impact of breast-conserving treatment and mastectomy on the quality of life of early-stage breast cancer patients: a review. J Clin Oncol, 9:1059-1070. Fisher ER, Anderson S, Tan-Chiu E et al. (2001). Fifteen-year prognostic discriminants for invasive breast carcinoma: National Surgical Adjuvant Breast and Bowel Project Protocol-06. Cancer, 91(8 Suppl):1679-87. Knopp MV, Weiss E, Sinn HP et al. (1999). Pathophysiologic basis of contrast enhancement in breast tumors. J Magn Reson Imaging, 10(3):260-6. Fortin A, Larochelle M, Laverdiere J et al. (1999). Local failure is responsible for the decrease in survival for patients with breast cancer treated with conservative surgery and postoperative radiotherapy. J Clin Oncol, 17(1):101-9. Gilles R, Guinebretiere JM, Toussaint C et al. (1994). Locally advanced breast cancer: contrast-enhanced subtraction MR imaging of response to preoperative chemotherapy. Radiology, 191(3):633-8. Goldhirsch A, Glick JH, Gelber RD et al. (1998). Meeting highlights: International Consensus Panel on the Treatment of Primary Breast Cancer. J Natl Cancer Inst, 90(21):1601-8. Goldhirsch A, Wood WC, Gelber RD et al. (2003). Meeting highlights: updated international expert consensus on the primary therapy of early breast cancer. J Clin Oncol, 21(17):3357-65. Haffty BG, Reiss M, Beinfield M et al. (1996). Ipsilateral breast tumor recurrence as a predictor of distant disease: implications for systemic therapy at the time of local relapse. J Clin Oncol, 14(1):52-7. Helbich TH. (2001). Localization and biopsy of breast lesions by magnetic resonance imaging guidance. J Magn Reson Imaging, 13(6):903-11. Holland R, Veling SH, Mravunac M et al. (1985). Histologic multifocality of Tis, T1-2 breast carcinomas. Implications for clinical trials of breast-conserving surgery. Cancer, 56(5):979-90. Huber S, Wagner M, Zuna I et al. (2000). Locally advanced breast carcinoma: evaluation of mammography in the prediction of residual disease after induction chemotherapy. Anticancer Res, 20:553-8. Hutcheon AW, Heys SD. (2004). Primary systemic chemotherapy of large and locally advanced breast cancer. In: MC Perry, ed. American Society of Clinical Oncology 2004 Educational Book, Alexandria, VA, American Society of Clinical Oncology: 63-79. Kuhl CK, Klaschik S, Mielcarek P et al. (1999). Do T2-weighted pulse sequences help with the differential diagnosis of enhancing lesions in dynamic breast MRI? Magn Reson Imaging, 9(2):187-96. Kuhl CK, Morakkabati N, Leutner CC et al. (2001). MR imaging--guided large-core (14-gauge) needle biopsy of small lesions visible at breast MR imaging alone. Radiology, 220(1):31-9. Leach MO. (2002). Assessing response to treatment in breast cancer using magnetic resonance. J Exp Clin Cancer Res, 21(3):39-45. Liberman L. (2004). Breast cancer screening with MRI-what are the data for patients at high risk? N Engl J Med, 351(5):497-500. Liljegren G, Holmberg L, Bergh J et al. (1999). 10-year results after sector resection with or without postoperative radiotherapy for stage I breast cancer: a randomized trial. J Clin Oncol, 17(8):2326-33. Makris A, Powles TJ, Ashley SE et al. (1998). A reduction in the requirements for mastectomy in a randomized trial of neoadjuvant chemoendocrine therapy in primary breast cancer. Ann Oncol, 9(11):1179-84. Martincich L, Montemurro F, De Rosa G et al. (2004). Monitoring response to primary chemotherapy in breast cancer using dynamic contrast-enhanced magnetic resonance imaging. Breast Cancer Res Treat, 83(1):67-76. McTiernan A, Gilligan M, Redmond C. (1997). Assessing individual risk for breast cancer: Risky business. J Clin Epidemiol, 50:547-556. Mirsky D, O’Brien S, McCready D et al. (1997). Breast Cancer Disease Site Group. Surgical management of early stage invasive breast cancer (Stage 1 and 2). Cancer Prev Control, 1(1):10-17. Morris EA, Liberman L, Dershaw DD et al. (2002). Preoperative MR imaging-guided needle localization of breast lesions. 178(5):1211-20. Irwig L, Bennetts A. (1997). Quality of life after breast conservation or mastectomy: a systematic review. Aust N Z J Surg, 67(11):750-4. Morris EA, Schwartz LH, Drotman MB et al. (2000). Evaluation of pectoralis major muscle in patients with posterior breast tumors on breast MR images: early experience. Radiology, 214(1):67-72. Kemperman H, Borger J, Hart A et al. (1995). Prognostic factors for survival after breast conserving therapy for stage I and II breast cancer. The role of local recurrence. Eur J Cancer, 31A(5):690-8. Morrow M, Strom EA, Bassett LW et al. (2002). Standard for breast conservation therapy in the management of invasive breast carcinoma. CA Cancer J Clin, 52(5):277-300. Kerslake RW, Carleton PJ, Fox JN et al. (1995). Dynamic gradient-echo and fat-suppressed spin-echo contrastenhanced MRI of the breast. Clin Radiol, 50(7):440-54. Morrow M, White J, Moughan J et al. (2001). Factors predicting the use of breast-conserving therapy in stage I and II breast carcinoma. J Clin Oncol, 19(8):2254-62. 38 ©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 Morrow M. (2002). Rational local therapy for breast cancer. N Engl J Med, 347(16):1270-1. Moyer A. (1997). Psychosocial outcomes of breastconserving surgery versus mastectomy: a meta-analytic review. Health Psychol, 16(3):284-98. Moyses B, Haegle P, Rodier JF et al. (2002). Assessment of response by breast helical computed tomography to neoadjuvant chemotherapy in large inflammatory breast cancer. Clin Br Cancer, 2(4):304-10. Mumtaz H, Hall-Craggs MA, Davidson T et al. (1997). Staging of symptomatic primary breast cancer with MR imaging. AJR Am J Roentgenol, 169:417-24. Mussurakis S, Gibbs P, Horsman A. (1998). Peripheral enhancement and spatial contrast uptake heterogeneity of primary breast tumours: quantitative assessment with dynamic MRI. J Comput Assist Tomogr, 22(1):35-46. Nakamura S, Kenjo H, Nishio T et al. (2001). 3D-MR mammography-guided breast conserving surgery after neoadjuvant chemotherapy: clinical results and future perspectives with reference to FDG-PET. Breast Cancer, 8(4):351-4. National Cancer Data Base (NCDB). (2004). Public access NCDB benchmark reports. American College of Surgeons’ Commission on Cancer. Available online at http://web.facs.org/ncdbbmr/ncdbbenchmarks.cfm. Last accessed May 2004. National Comprehensive Cancer Network (NCCN). (2004). Breast cancer. In: NCCN Practice Guidelines in Oncology, v.1.2004. Available online at http://www.nccn.org/physician_gls/f_guidelines.html. Last accessed May 2004. National Institutes of Health (NIH) Consensus Development Panel. (2001). National Institutes of Health Consensus Development Conference statement: adjuvant therapy for breast cancer, November 1-3, 2000. J Natl Cancer Inst Monogr, 30:5-15. Also available online at http://consensus.nih.gov/cons/114/114_intro.htm. NIH Consensus Conference. (1990). Treatment of early-stage breast cancer. NIH Consensus Statement Online, 8(6):1-19. Available at http://consensus.nih.gov/ cons/081/081_intro.htm. Last accessed May 2004. NIH Consensus Conference. (1991). Treatment of early-stage breast cancer. JAMA, 265(3):391-5. Nissen MJ, Swenson KK, Ritz LJ et al. (2001). Quality of life after breast carcinoma surgery: a comparison of three surgical procedures. Cancer, 91(7):1238-46. Orel SG, Schnall MD. (2001). MR imaging of the breast for the detection, diagnosis, and staging of breast cancer. Radiology, 220(1):13-30. Orel SG, Schnall MD, Newman RW et al. (1994). MR imaging-guided localization and biopsy of breast lesions: initial experience. Radiology, 193(1):97-102. Partridge SC, Gibbs JE, Lu Y et al. (2002). Accuracy of MR imaging for revealing residual breast cancer in patients who have undergone neoadjuvant chemotherapy. AJR Am J Roentgenol, 179(5):1193-9. Paszat LF, Mackillop WJ, Groome PA et al. (1998). Mortality from myocardial infarction after adjuvant radiotherapy for breast cancer in the surveillance, epidemiology, and end-results cancer registries. J Clin Oncol, 16(8):2625-31. Paszat LF, Mackillop WJ, Groome PA et al. (1999). Mortality from myocardial infarction following postlumpectomy radiotherapy for breast cancer: a population-based study in Ontario, Canada. Int J Radiat Oncol Biol Phys, 43(4):755-62. Pegram MD. (2004). Breast cancer: integration of newer agents into the neoadjuvant setting. In: MC Perry, ed. American Society of Clinical Oncology 2004 Educational Book, Alexandria, VA, American Society of Clinical Oncology: 80-84. Physician Data Query (PDQ). (2004a). Screening for breast cancer. Available online at http://www.nci.nih.gov/ cancerinfo/pdq/screening/breast/healthprofessional/. Last modified March 2004. Last accessed April 2004. Physician Data Query (PDQ). (2004b). Breast cancer prevention. Available online at http://www.nci.nih.gov/ cancerinfo/pdq/prevention/breast/healthprofessional/. Last modified March 2004. Last accessed April 2004. Physician Data Query (PDQ). (2004c). Breast cancer treatment. Available online at http://www.nci.nih.gov/ cancerinfo/pdq/treatment/breast/healthprofessional/. Last modified March 2004. Last accessed April 2004. Pockaj BA, Gray RJ. (2004). Surgical management of locally advanced breast cancer. In: MC Perry, ed. American Society of Clinical Oncology 2004 Educational Book, Alexandria, VA, American Society of Clinical Oncology: 85-91. Rieber A, Brambs HJ, Gabelmann A et al. (2002). Breast MRI for monitoring response of primary breast cancer to neo-adjuvant chemotherapy. Eur Radiol, 12(7):1711-9. Nunes LW, Schnall MD, Orel SG et al. (1997). Breast MR imaging: interpretation model. Radiology, 202(3):833-41. Rieber A, Nussle K, Merkle E et al. (1999). MR mammography: influence of menstrual cycle on the dynamic contrast enhancement of fibrocystic disease. Eur Radiol, 9(6):1107-12. Nunes LW, Schnall MD, Orel SG. (2001). Update of breast MR imaging architectural interpretation model. Radiology, 219(2):484-94. Rieber A, Zeitler H, Rosenthal H et al. (1997). MRI of breast cancer: influence of chemotherapy on sensitivity. Br J Radiol, 70:452-8. Orel SG. (1999). Differentiating benign from malignant enhancing lesions identified at MR imaging of the breast: are time-signal intensity curves an accurate predictor? Radiology, 211(1):5-7. ©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited. 39 Technology Evaluation Center Ries LA, Eisner MP, Kosary CL et al. (2002). SEER Cancer Statistics Review, 1973-1999. Bethesda, MD: National Cancer Institute, 2002. Also available online at: http://seer.cancer.gov/csr/1973_1999/. Last accessed March 18, 2004. van der Hage JA, van de Velde CJ, Julien JP et al. (2001). Preoperative chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer trial 10902. J Clin Oncol, 19(22):4224-37. Rodenko GN, Harms SE, Pruneda JM et al. (1996). MR imaging in the management before surgery of lobular carcinoma of the breast: correlation with pathology. AJR Am J Roentgenol, 167:1415-9. van Tienhoven G, Voogd AC, Peterse JL et al. (1999). Prognosis after treatment for loco-regional recurrence after mastectomy or breast conserving therapy in two randomised trials (EORTC 10801 and DBCG-82TM). EORTC Breast Cancer Cooperative Group and the Danish Breast Cancer Cooperative Group. Eur J Cancer, 35(1):32-8. Rosen EL, Blackwell KL, Baker JA et al. (2003). Accuracy of MRI in the detection of residual breast cancer after neoadjuvant chemotherapy. AJR Am J Roentgenol, 181(5):1275-1282. Rouzier R, Extra JM, Carton M et al. (2001). Primary chemotherapy for operable breast cancer: incidence and prognostic significance of ipsilateral breast tumor recurrence after breast-conserving surgery. J Clin Oncol, 19(18):3828-35. Rowland JH, Desmond KA, Meyerowitz BE et al. (2000). Role of breast reconstructive surgery in physical and emotional outcomes among breast cancer survivors. J Natl Cancer Inst, 92(17):1422-9. Rutqvist LE, Johansson H. (1990). Mortality by laterality of the primary tumour among 55,000 breast cancer patients from the Swedish Cancer Registry. Br J Cancer, 61(6):866-8. Sabiston DC Jr. (1997). Sabiston: Textbook of Surgery. 15th ed. New York: Saunders Co, 569-580. Veronesi U, Marubini E, Del Vecchio M et al. (1995b). Local recurrences and distant metastases after conservative breast cancer treatments: partly independent events. J Natl Cancer Inst, 87(1):19-27. Veronesi U, Salvadori B, Luini A et al. (1995a). Breast conservation is a safe method in patients with small cancer of the breast. Long-term results of three randomised trials on 1,973 patients. Eur J Cancer, 31A(10):1574-9. Wapnir IL, Cody RP, Greco RS. (1999). Subtle differences in quality of life after breast cancer surgery. Ann Surg Oncol, 6(4):359-66. Wasser K, Sinn HP, Fink C et al. (2003a). Accuracy of tumor size measurement in breast cancer using MRI is influenced by histological regression induced by neoadjuvant chemotherapy. Eur Radiol, 13(6):1213-23. Saenz R, Phillips M. (1998). Breast cancer. Prim Care, 25(2):309-321. Wasser K, Klein SK, Fink C et al. (2003b). Evaluation of neoadjuvant chemotherapeutic response of breast cancer using dynamic MRI with high temporal resolution. Eur Radiol, 13(1):80-7. Sherif H, Mahfouz AE, Oellinger H et al. (1997). Peripheral washout sign on contrast-enhanced MR images of the breast. Radiology, 205(1):209-13. Wazer DE. (2000). Contemporary issues in the use of radiation therapy for early invasive breast cancer. Surg Oncol Clin North Am, 9(3):585-601. Shimozuma K, Ganz PA, Petersen L et al. (1999). Quality of life in the first year after breast cancer surgery: rehabilitation needs and patterns of recovery. Breast Cancer Res Treat, 56(1):45-57. Weatherall PT, Evans GF, Metzger GJ et al. (2001). MRI vs. histologic measurement of breast cancer following chemotherapy: comparison with x-ray mammography and palpation. J Magn Reson Imaging, 13:868-75. Singletary SE, Allred C, Ashley P et al. (2002). Revision of the American Joint Committee on Cancer staging system for breast cancer. J Clin Oncol, 20(17):3628-36. West S, King V, Carey TS et al. (2002). Systems to Rate the Strength of Scientific Evidence. Evidence Report/ Technology Assessment No. 47 (Prepared by the Research Triangle Institute–University of North Carolina Evidencebased Practice Center under Contract No. 290-97-0011). AHRQ Publication No. 02-E016. Rockville, MD: Agency for Healthcare Research and Quality. Small W Jr . (2001). Current status of radiation in the treatment of breast cancer. Oncology (Huntingt), 15(4):469-76. Staradub VL, Hsieh YC, Clauson J et al. (2002). Factors that influence surgical choices in women with breast carcinoma. Cancer, 95(6):1185-90. Trecate G, Ceglia E, Stabile F et al. (1999). Locally advanced breast cancer treated with primary chemotherapy: comparison between magnetic resonance imaging and pathologic evaluation of residual disease. Tumori, 85:220-8. Tsuboi N, Ogawa Y, Inomata T et al. (1999). Changes in the findings of dynamic MRI by preoperative CAF chemotherapy for patients with breast cancer of stage II and III: pathologic correlation. Oncol Rep, 6(4):727-32. 40 Whelan T, Clark R, Roberts R et al. (1994). Ipsilateral breast tumor recurrence post-lumpectomy is predictive of subsequent mortality: results from a randomized trial. Investigators of the Ontario Clinical Oncology Group. Int J Radiat Oncol Biol Phys, 30(1):11-6. Winchester DP, Cox JD. (1998). Standards for diagnosis and management of invasive breast carcinoma. American College of Radiology. American College of Surgeons. College of American Pathologists. Society of Surgical Oncology. CA Cancer J Clin, 48(2):83-107. ©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 Winer EP, Morrow M, Osborne CK et al. (2001). Malignant tumors of the breast. Chapter 37, Section 2. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles & Practice of Oncology. Philadelphia, Lippincott Williams & Wilkins: 1651-1716. Wolmark N, Wang J, Mamounas E et al. (2001). Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst Monogr, (30):96-102. Woodward WA, Strom EA, Tucker SL et al. (2003). Changes in the 2003 American Joint Committee on Cancer staging for breast cancer dramatically affect stage-specific survival. J Clin Oncol, 21(17): 3244-8. Zhou X-H, Obuchowski NA, McClish DK. (2002). Statistical Methods in Diagnostic Medicine. John Wiley & Sons, New York, 57-99. ©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited. 41 Technology Evaluation Center 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 ©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 ©2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited. 43 Technology Evaluation Center Technology Evaluation Center Blue Cross and Blue Shield Association 225 North Michigan Avenue Chicago, Illinois 60601-7680 888.832.4321 www.bcbs.com ® Registered marks of the Blue Cross and Blue Shield Association, an Association of Independent Blue Cross and Blue Shield Plans ®’ Registered trademark of Kaiser Permanente © 2004 Blue Cross and Blue Shield Association. Reproduction without prior authorization is prohibited.