Electrical impedance scanning of the breast is considered investigational and is not covered.

Transcription

1 ARBenefits Approval: 09/28/2011 Effective Date: 01/01/2012 Revision Date: Code(s): Medical Policy Title: Electrical Impedance Scanning of the Breast Document: ARB0127 Administered by: Public Statement: Electrical impedance scanning of the breast involves the transmission of continuous electricity into the body using either an electrical patch attached to the arm or a handheld cylinder. The electrical current travels through the breast, where it is then measured at skin level by a probe placed on the breast. This test is used as an adjunct to mammography to improve patient selection for biopsy. It is not clear that use of electrical impedance scanning improves health outcomes. This procedure is not covered. Medical Policy Statement: Electrical impedance scanning of the breast is considered investigational and is not covered. Background: Mammographic abnormalities can be stratified into categories called BI-RADS (Breast Imaging Reporting Data System), which reflect the risk of malignancy given the mammographic appearance. Scores range from 1 to 5 as follows: Score / Characteristics and Probability of Malignancy 1. No abnormality noted; probability of malignancy 0 2. Benign finding (e.g., fibroadenomas, lipoma) Page 1 of 7

2 3. Probably benign finding - Short follow-up suggested (This category includes lesions with high probability of being benign, but the radiologist would prefer to establish its stability, and thus repeat mammography at 6 months is typically recommended. The probability of malignancy is estimated at 2%) 4. Suspicious abnormality - Biopsy should be considered (These lesions do not have the characteristic morphologies of breast cancer but have a definite probability of being malignant. The radiologist has sufficient concern to urge a biopsy. The probability of malignancy ranges from 2% 80% in this category) 5. Highly suggestive of malignancy (The probability of malignancy ranges from 80% 100%) Electrical impedance studies are used as an adjunct to mammography to improve patient selection for biopsy in patients with equivocal indications, i.e., those designated as a BI-RADS category 3 or 4. There are two potential scenarios: 1. To deselect patients for biopsy, where the key diagnostic statistic is the negative predictive value. Presumably, this role of electrical impedance scanning would be focused on patients with a BI-RADS 4 lesion, for which biopsy is typically recommended. It may also apply to some patients with a BI-RADS 3 lesion who have been recommended to have a biopsy. The relevant question is whether patients with BIRADS 3 or 4 mammographic abnormalities recommended for biopsy, who have negative results on electrical impedance testing, can reliably forego breast biopsy. Given the relatively low morbidity and high diagnostic accuracy of the gold standard of breast biopsy coupled with the adverse consequences of missing or delaying diagnosis of breast cancer, the negative predictive value of electrical impedance testing would have to be extremely high to influence treatment decisions. The negative predictive value is determined partially by the sensitivity of the test; the higher the sensitivity, the higher the negative predictive value. The negative predictive value will also vary according to the prevalence of disease. Among a population of patients with mammographic abnormalities highly suggestive of breast cancer, the negative predictive value will be lower compared to a population of patients with mammographic abnormalities not suggestive of breast cancer. As noted above, the labeled indication for the T-Scan focuses on its use in patients with equivocal mammographic findings. 2. To positively select patients for biopsy, where the positive predictive value is the key diagnostic parameter. As noted, management options for patients with BI-RADS 3 lesions include watchful waiting with repeat mammography. However, positive results of electrical impedance may tip the balance such that biopsy is more definitively recommended. The T-Scan 2000 was approved by the FDA through the PMA process, and thus the clinical data to support its safety and effectiveness are available in the FDA summary of Page 2 of 7

3 safety and effectiveness, which is reviewed below. The key pieces of data presented to the FDA were from a multicenter blinded study that intended to test the hypothesis that adjunctive combination of T-Scan with mammography can provide diagnostic accuracy significantly better than mammography alone. The results of this study were reported in terms of sensitivity and specificity instead of positive and negative predictive value. The blinded study presented to the FDA consisted of a total of 2,456 patients of whom 882 underwent biopsy and T-Scan. The mammography and T-Scan were performed in a blinded fashion; i.e., each imaging procedure was performed and interpreted without knowledge of the results from any other imaging modality or patient information. A final test set composed of 504 breasts that had undergone biopsy (179 malignant, 325 benign) was available for re-reading (380 patients were excluded due to unavailability of the original mammogram or incomplete T-Scan image). The test set was re-read and scored blindly using T-Scan images alone, using mammograms alone, and using adjunctive combination of mammogram and T-Scan images. Each of the scores was compared against the results of biopsy. Panels of patients each were organized for blinded rereading of the T-Scans and mammograms. The panels were composed of patients with both malignant and benign biopsy results, as well as screening patients that did not undergo biopsy. The screening patients were added to the panels so that the readers could not assume that all patients had suspicious mammographic findings. The key subgroup was the 273 patients with equivocal mammographic abnormalities. These included BI-RADS 3 and some BI-RADS 4 cases, in which the probability of malignancy was estimated to be between 0 and 50%. Using biopsy results as the gold standard, the sensitivity of the combined mammogram and T-Scan compared to mammogram alone increased from 60% to 82%, while the specificity increased from 41% to 57%. Both of these are statistically significant increases. However, it is unclear from this study if these diagnostic parameters would enable patients with equivocal mammographic abnormalities to forego biopsy. Recalculating the data reveals that the key parameter of the negative predictive value of the combined test is 93%. Therefore, if the decision to forego biopsy was based on a negative result of the combined mammogram and T-Scan, 7% of those with malignant lesions would miss or delay a diagnosis of breast cancer. As noted, this study included some BI-RADS 3 or 4 lesions, but it is not specified whether the biopsies were performed in these subjects as part of the study protocol or based on clinical suspicion and/or imaging results. The analysis of diagnostic performance included only patients who were scheduled for biopsy, which introduces the potential for verification bias. It is uncertain whether these selected cases would be similar to unselected consecutive cases of BI-RADS 3 or 4 lesions that would not be referred for biopsy in clinical practice, The positive predictive value of adjunctive use of the T-Scan was reported to be 30% among subjects who had undergone biopsy and had BI-RADS 3 or 4 lesions and an 18% prevalence of malignancy. However, the limitations and potential bias in this analysis prohibit conclusions regarding the effectiveness of using the T-Scan in positively selecting patients for biopsy. For example, it is unknown how many of the original 2,456 patients had equivocal lesions and decided to forego biopsy. This is the critical group to evaluate the role of the T- Page 3 of 7

4 Scan to positively select those patients for biopsy who would otherwise forego biopsy. While this unselected population and outcome are admittedly more difficult to study, ideally one would like to design a trial in which all patients with equivocal lesions, which would otherwise be referred for follow-up imaging, undergo both T-Scan and biopsy or some other appropriate reference standard such as prolonged clinical follow-up. In this setting, the diagnostic performance and predictive value of T-Scan could be evaluated in the actual intended use. The Intended Use study presented to the FDA consisted of 74 consecutive biopsy cases in which the Tscan was approved for clinical use in its full intended mode; i.e., the T-Scan was targeted at lesions previously identified by mammography or physical examination, and the T-Scan interpretation was done adjunctively. Of these, there were a total of 36 cases for which biopsy results, mammograms, and Tscans were available and where the mammographic results were equivocal. The sensitivity of the mammography alone was 66.7% increasing to 93.3% (28 of 30 cases) when the T-Scan was used adjunctively. The corresponding values of specificity were 50% increasing to 83.3% (5 of 6 cases) when the T-Scan was added. The positive predictive value of adjunctive use of T-Scan was 97% (28 of 29 cases), although the prevalence of malignancy in this subgroup was also very high at 83%. Despite these positive findings, the small number of cases in this study along with the potential bias associated with the fact that analysis was restricted only to half of subjects who received the reference standard makes this evidence insufficient to draw conclusions. A literature search reveals a variety of case series. Some studies focused on the technical capability of electrical impedance scanning. All of those studies that reported on the diagnostic performance of electrical impedance scanning reported an inferior performance compared to that reported in the FDA Summary of Safety and Effectiveness. Fuchsjaeger and colleagues further explored the adjunctive role of electrical impedance scanning (EIS) in 121 patients with 128 BI-RADS-IV lesions identified on mammography. Specifically, the results of impedance imaging were compared with ultrasound as a technique of further classifying benign lesions such that patients could be managed as a BI-RADS-III lesion with a recommended 6-month follow-up instead of biopsy. Therefore, in this setting, the most relative statistic is the negative predictive value, which can be used to deselect patients from biopsy. Based on histopathology from a subsequent biopsy, there were 37 malignant lesions and 91 benign lesions. The negative predictive value of impedance imaging was 97.1% vs. 92.0% for ultrasound. It is unclear whether this diagnostic performance would be adequate to defer biopsy. Stojadinovic and colleagues explored a novel role for impedance scanning as a primary screening technique in younger women (younger than 40 years) at average risk of breast cancer. This indication has not been approved by the FDA. Currently, there are no specific screening recommendations other than breast self-examination in this population, in part due to decreased sensitivity of mammograms in imaging dense breast, common in younger populations. Impedance scanning is based on the Page 4 of 7

5 difference in electrical conductivity in benign versus malignant tissue and is not impacted by breast density. This study included 1,103 women who were undergoing screening with a clinical breast examination and women who were specifically referred for breast biopsy (the reasons for the referral were not stated). A total of 580 of the women were under 40 years old, the targeted age group for primary screening with electrical impedance scanning. Twenty-nine cancers were identified among the entire group of 1,103; 6 of these were in women under 40. Based on this small number of cancers, the sensitivity and specificity of impedance scanning in women under 40 was 50% and 90%, respectively. It should also be noted that of the 580 in the under 40 group, 132 (23%) presented with palpable breast lesions, and only 2 of the 6 identified cancers were nonpalpable, and all cancers were found in women specifically referred for breast biopsy; none were found in the general screening population. As noted by the authors, this is a preliminary study, and further data with longer follow-up are needed. However, the authors hypothesize that impedance scanning could evolve into a routine part of a physical exam performed in a physician office setting. A positive scan would then prompt further imaging with either an MRI or ultrasound. In what appears to be a follow-up study, results were reported for 1,361 consecutively enrolled asymptomatic women ages years (used to measure specificity) and 189 women ages years who had a suspicious breast abnormality and were referred for biopsy (used to measure sensitivity). The researchers assumed that none of the women in the first group had breast cancer and, consequently, that any positive EIS results were false positives; no follow-up data were collected on these women. In the second group of women with breast abnormalities, 59.3% were aged The specificity in the first group was 95% (assuming that all positive results were incorrect); the specificity in the second group among women with benign breast disease was 80.7%. The sensitivity in the second group was 38%, but it ranged from 29% among women aged to 42% among women aged The authors concluded that the relative probability that a woman with a positive EIS result currently has breast cancer is 7.68 and that about one cancer would be detected for every 77 women referred for follow-up. This study has a number of limitations, including the assumption that none of the women in the specificity arm had cancer (the authors argue that this assumption is likely to have little impact on the overall results given the low prevalence of cancer in this population); the age difference between the two groups (and the difference in sensitivity by age, although whether or not this is statistically significant is not reported), and the measurement of sensitivity and specificity in two different populations. The authors themselves conclude that the results are encouraging but that further largescale, long-term follow-up studies are required and underway in the intended use populations. The FDA s Obstetrics and Gynecological Devices Panel had a number of concerns about the study, and the FDA has not approved the device for this use. Further research has also been performed on the characteristics of electromagnetic breast imaging in distinguishing between normal breast tissue and abnormal tissue, and between cancerous and benign abnormal tissue. EIS was one of the three electromagnetic imaging modalities used in women with mammography results rated as Breast Imaging Reporting and Data System (BI-RADS) category 1 (negative; 53 Page 5 of 7

6 women) or categories 4 (suspicious for malignancy) or 5 (highly suspicious for malignancy) (97 women in abnormal group). The focus was on a prospective, quantitative assessment of the contrast in electromagnetic properties between normal and abnormal tissue. EIS results were available for 62 abnormal cases and 36 normal controls; EIS data were not available for 19 cases due to technical difficulties and 33 cases due to analytical difficulties (data calibration). EIS was found to help in discrimination between normal and abnormal tissue but may not aid in distinguishing between cancer and other abnormal pathological findings. Using results from all three modalities examined (EIS, microwave imaging spectroscopy, and near-infrared spectral tomography) did not substantially improve the ability to identify breast cancer. In another follow-up study, Stojadinivoc and co-workers reported on 1,751 patients in the specificity group and 390 patients (with 87 cancers) in the sensitivity group (Stojadinivoc, 2008). The patients were recruited at 22 sites in the United States and 7 in Israel. The specificity calculated for the first group (assuming all positive test results were incorrect) was 94.7% (95% CI: %). One center had a specificity of 84%, while the others ranged from 89% to 97%. Sensitivity calculated for the second group was 26.4% (95% CI: %). The number of cancers at each site was small; the sensitivity per site ranged from 0% to 53%. Combining these results and the assumption that the prevalence of breast cancer in an average-risk group of women years of age, the authors estimated that for every 136 women with a positive T-scan result, one would have cancer. If all T-scan-positive women in this age group underwent mammography, it is estimated that about 1 in 194 women would have cancer (this estimate is lower because of the less than perfect sensitivity of mammography). The authors state that this detection rate is higher than would be found among a randomly selected group of 30- to 39-year-old women or among women younger than 40 years of age with an affected first-degree relative (about one cancer detected in every 333 women). The relative probability of cancer in a T-Scan-positive woman is estimated to be 4.95 (95% CI: ). These calculations apparently do not include the patients in whom T-Scans were attempted but not completed: 14 women in the specificity group and 4 women in the sensitivity group. Sixty-six results in the second group were considered unreliable because of technical difficulties, but the authors argue that these problems might have been corrected if the examiners had not been blinded to the results and, therefore, were unaware of the problems; examiners in the specificity group were not blinded. The sensitivity of this test remains low, even in a group of women with a deliberately higher prevalence of cancer than would be expected in a screening population. References: Fuchsjaeger MH, Flory D, et al.(2005) The negative predictive value of electrical impedance scanning in BI-RADS category IV breast lesions. Invest Radiol 2005; 40: Page 6 of 7

7 Malich A, Boehm T, et al.(2001) Additional value of electrical impedance scanning: experience of 240 histologically-proven breast lesions. Eur J Cancer 2001; 37: Malich A, Boehm T, et al.(2001) Differentiation of mammographically suspicious lesions: evaluation of breast ultrasound, MRI mammography and electrical impedance scanning as adjunctive technologies in breast cancer detection. Clin Radiol 2001; 56: Malich A, Fritsch T, et al.(2000) Electrical impedance scanning for classifying suspicious breast lesions: first results. Eur Radiol 2000; 10: Martin G, Martin R, et al.(2002) Electrical impedance scanning in breast cancer imaging: correlation with mammographic and histologic diagnosis. Eur Radiol 2002; 12: Perlet C, Kessler M, et al.(2000) Electrical impedance measurement of the breast: effect of hormonal changes associated with the menstrual cycle. Eur Radiol 2000; 10: Poplack SP, Tosteson TD, et al.(2007) Electromagnetic breast imaging: results of a pilot study in women with abnormal mammograms. Radiology, 2007; 243: Stojadinovic A, Moskovitz O, et al.(2006) Prospective study of electrical impedance scanning for identifying young women at risk for breast cancer. Breast Cancer Res Treatment 2006; 97: Stojadinovic A, Nissan A, et al.(2005) Electrical impedance scanning for the early detection of breast cancer in young women: preliminary results of a multicenter prospective clinical trial. J Clin Oncol 2005; 23: Stojadinovic A, Nissan A, Shriver CD, et al.(2008) Electrical impedance scanning as a new breast cancer risk stratification tool for young women. J Surg Oncol Feb 1;97(2): Wersebe A, Siegmann K, et al.(2002) Diagnostic potential of targeted electrical impedance scanning in classifying suspicious breast lesions. Invest Radiol 2002; 37: Application to Products This policy applies to ARBenefits. Consult ARBenefits Summary Plan Description (SPD) for additional information. Last modified by: Date: Page 7 of 7