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A Prospective Validation Study of Bioimpedance with Volume Displacement in Early-Stage Breast Cancer Patients at Risk for Lymphedema
A Prospective Validation Study of Bioimpedance with Volume Displacement in Early-Stage Breast Cancer Patients at Risk for Lymphedema Barrio AV, Eaton A, Frazier TG (Memorial Sloan Kettering Cancer Ctr, NY; The Bryn Mawr Hosp, Bryn Mawr, PA)
Conclusions.dVD and bioimpedance demonstrated poor correlation with inconsistent overlap of measurements considered abnormal. Of patients with an abnormal L-Dex, few progressed to lymphedema; most patients with lymphedema did not have a prior L-Dex abnormality. Further studies are needed to understand the clinical significance of bioimpedance.
Ann Surg Oncol 22;S370-S375, 2015
Background.dAlthough volume displacement (VD) is considered the gold standard for diagnosing breast cancer-related lymphedema, it is inconvenient. We compared bioimpedance (L-Dex) and VD measurements in a prospective cohort of breast cancer patients at risk for lymphedema. Methods.dBetween 2010 and 2014, a total of 223 breast cancer patients were enrolled. Following exclusions (n ¼ 37), 186 received baseline VD and L-Dex; follow-up measurements were performed at 3e6 months intervals for 3 years. At each visit, patients fitted into one of three categories: normal (normal VD and L-Dex); abnormal L-Dex (L-Dex >10 or increase in 10 from baseline and normal VD); or lymphedema (relative arm volume difference of >10 % by VD ± abnormal LDex). Change in L-Dex was plotted against change in VD; correlation was assessed using the Pearson correlation. Results.dAt a median follow-up of 18.2 months, 152 patients were normal, 25 had an abnormal L-Dex, and 9 developed lymphedema without a prior LDex abnormality. Of the 25 abnormal L-Dex patients, 4 progressed to lymphedema, for a total of 13 patients with lymphedema. Evaluating all time points, 186 patients had 829 follow-up measurements. Sensitivity and specificity of L-Dex compared with VD were 75 and 93 %, respectively. There was no correlation between change in VD and change in L-Dex at 3 months (r ¼ 0.31) or 6 months (r ¼ 0.21).
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In this article by Barrio and colleagues, the authors detailed a longterm follow-up study that is much needed in the quest to elucidate the validity of bioimpedance for early detection of breast cancer-related lymphedema. The researchers used an ideal study design, beginning with a baseline and following the patients for 3 years at regular intervals. In this study, bioimpedance was analyzed against water displacement; although cumbersome, water displacement is the current gold standard for lymphedema measurement. The vast majority of previously published studies with the same goal compared bioimpedance to circumference measurements, which are known to be variable and prone to operator error and could lead to skewed results in terms of true lymphedema diagnosis. The authors stated that bioimpedance has been studied primarily as a diagnostic tool and that it has only been hypothesized that it can also be used for early detection of breast cancer-related lymphedema. They stated the need for longitudinal studies to test this hypothesis, and this is exactly what they provided. The study consisted of 186 patients, all of whom had axillary surgery, with a total of 829 measurements, a fairly substantial sample size. All volumetric measurements were calculated as a relative volume difference from a pre-surgery baseline. In addition, the bioimpedance measurements were performed according to the guidelines of the
Breast Diseases: A Year BookÒ Quarterly Vol 27 No 3 2016
manufacturers, including placing the patients supine before the measurement and removing all socks and jewelry. Results from the bioimpedance measurements were analyzed using the LDex scores derived from the impedance ratios. An abnormal L-Dex score was defined as either a score of greater than 10 or a 10-unit increase from baseline. These 2 definitions are the ways the manufacturers explain that the scores can be interpreted, with a positive result from either indicating lymphedema. Given that this study was examining bioimpedance as a predictive model, if an abnormal L-Dex and abnormal volume were obtained with no prior abnormal L-Dex, the abnormal results were considered a false negative. This interpretation is based on the claims that bioimpedance should be able to detect the increase in fluid earlier than it would be diagnosed by volume displacement. The authors quoted a well-known study by Cornish and colleagues1 that reported that bioimpedance can detect fluid increase as early as 10 months before volumetric methods can. Barrio and colleagues contested this claim by stating that 8 of the 20 patients who developed lymphedema in the Cornish et al study were diagnosed almost immediately after their abnormal bioimpedance reading, which does not allow for sufficient “lag time” to consider the abnormal reading to be early detection. In the results for L-Dex as a predictor for lymphedema, 25 patients presented with abnormal L-Dex scores. Of these, only four were later diagnosed with lymphedema. In total, 13 patients in the study were diagnosed with lymphedema, the other 9 of whom never exhibited abnormal LDex. These results yield a sensitivity for L-Dex as a lymphedema predictor of 31% and a specificity of 88%. These values severely contradict previous literature. The previously mentioned study reported 100% sensitivity and
98% specificity, and in a study by Soran and colleagues,2 the authors stated that they detected lymphedema early in 76% of patients using bioimpedance. However, none of these studies provided long-term follow-up, as the present study has. Although LDex did miss 9 of the 13 lymphedema patients, the negative predictive value was still 93% since there were many true negatives in the cohort. On the other hand, the positive predictive value for L-Dex was 18% since bioimpedance was able to detect only 4 true positives. Despite the clear results, some may argue that a sample size of 13 patients with lymphedema is not large enough to exclude bioimpedance as a predictor for lymphedema. However, the rate of 21 of 25 false positives should probably be alarming to physicians, as these numbers would result in vast overtreatment of patients. These false positives also were not likely due to human error given that 11 of the 21 patients had at least 2 abnormal L-Dex scores. As a general screening tool and not one applied selectively for predictive purposes, L-Dex in this study showed 75% sensitivity. In a similar long-term follow-up study from 2015, Bundred and colleagues3 showed that bioimpedance had 73% sensitivity, and they also identified 91 false positives. For the patients who completed all 3 years of follow-up for the study, the likelihood of developing future edema is quite small given that most edemas develop by 2 years posttreatment. The patients who had abnormal L-Dex scores can certainly be ranked as false positives. However, the median follow-up after abnormal L-Dex scores was only 10 months. For the patients who did not complete all
3 years of follow-up on this study, we would highly encourage the authors to publish the rest of those data when they become available. Those data would allow them to conclude with certainty that the remaining patients did not develop edema either. With the rest of these data in hand, the statement “L-Dex performed poorly as a predictor of lymphedema” would be even stronger. One downfall to this study was the lack of patients in the sentinel lymph node biopsy group who developed lymphedema. With only 1 lymphedema case in this group, it is virtually impossible to reach a conclusion about the ability of bioimpedance to identify the lower-risk population. The L-Dex score for this patient was normal, which may warrant further research into the sensitivity of bioimpedance in patients with minimal axillary surgery. In addition to the predictive abilities of bioimpedance, this study also noted its diagnostic sensitivity and the use of bioimpedance with diagnosed lymphedema patients. As noted in the results, at the time of diagnosis, the LDex scores in 12 of the 13 lymphedema patients were abnormal, confirming results seen in many previous studies involving bioimpedance detecting preestablished lymphedema. However, as the lymphedema patients were followed up past their diagnosis, the authors found very little correlation between volume displacement measurements and bioimpedance. As explained in the Discussion, a well-known disadvantage of bioimpedance is its inability to measure lymphedema in later stages, when the fluid undergoes fibrosis and adipogenesis. The current study confirmed this fact.
Overall, this article positively contributes to the pool of literature regarding the use of bioimpedance to detect breast cancererelated lymphedema. The study provided the necessary study design and the much-needed long-term follow-up to reach more informed conclusions about this device. Aside from the disadvantage of few patients being diagnosed with lymphedema, the results are very clear and confirm past speculations that bioimpedance is a useful diagnostic tool but may not be adequate as a predictor of lymphedema. If the authors are able to publish the remaining follow-up data for those patients with abnormal L-Dex, their conclusions would be even more informative. C. Seward, BS M. Skolny, NP A. Taghian, MD, PhD
References 1. Cornish BH, Chapman M, Hirst C, et al. Early diagnosis of lymphedema using multiple frequency bioimpedance. Lymphology. 2001;34: 2-11. 2. Soran A, Menekse E, Girgis M, DeGore L, Johnson R. Breast cancerrelated lymphedema after axillary lymph node dissection: does early post-operative model work? Support Cancer Care. 2016;24:1413-1419. 3. Bundred NJ, Stockton C, Keeley V, et al. Investigators of BEA/PLACE Studies. Comparison of multifrequency bioimpedance with perometry for the early detection and intervention of lymphoedema after axillary node clearance for breast cancer. Breast Cancer Res Treat. 2015;151:121-129.
Breast Diseases: A Year BookÒ Quarterly Vol 27 No 3 2016
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Conclusions.dVD and bioimpedance demonstrated poor correlation with inconsistent overlap of measurements considered abnormal. Of patients with an abnormal L-Dex, few progressed to lymphedema; most patients with lymphedema did not have a prior L-Dex abnormality. Further studies are needed to understand the clinical significance of bioimpedance.
Ann Surg Oncol 22;S370-S375, 2015
Background.dAlthough volume displacement (VD) is considered the gold standard for diagnosing breast cancer-related lymphedema, it is inconvenient. We compared bioimpedance (L-Dex) and VD measurements in a prospective cohort of breast cancer patients at risk for lymphedema. Methods.dBetween 2010 and 2014, a total of 223 breast cancer patients were enrolled. Following exclusions (n ¼ 37), 186 received baseline VD and L-Dex; follow-up measurements were performed at 3e6 months intervals for 3 years. At each visit, patients fitted into one of three categories: normal (normal VD and L-Dex); abnormal L-Dex (L-Dex >10 or increase in 10 from baseline and normal VD); or lymphedema (relative arm volume difference of >10 % by VD ± abnormal LDex). Change in L-Dex was plotted against change in VD; correlation was assessed using the Pearson correlation. Results.dAt a median follow-up of 18.2 months, 152 patients were normal, 25 had an abnormal L-Dex, and 9 developed lymphedema without a prior LDex abnormality. Of the 25 abnormal L-Dex patients, 4 progressed to lymphedema, for a total of 13 patients with lymphedema. Evaluating all time points, 186 patients had 829 follow-up measurements. Sensitivity and specificity of L-Dex compared with VD were 75 and 93 %, respectively. There was no correlation between change in VD and change in L-Dex at 3 months (r ¼ 0.31) or 6 months (r ¼ 0.21).
230
In this article by Barrio and colleagues, the authors detailed a longterm follow-up study that is much needed in the quest to elucidate the validity of bioimpedance for early detection of breast cancer-related lymphedema. The researchers used an ideal study design, beginning with a baseline and following the patients for 3 years at regular intervals. In this study, bioimpedance was analyzed against water displacement; although cumbersome, water displacement is the current gold standard for lymphedema measurement. The vast majority of previously published studies with the same goal compared bioimpedance to circumference measurements, which are known to be variable and prone to operator error and could lead to skewed results in terms of true lymphedema diagnosis. The authors stated that bioimpedance has been studied primarily as a diagnostic tool and that it has only been hypothesized that it can also be used for early detection of breast cancer-related lymphedema. They stated the need for longitudinal studies to test this hypothesis, and this is exactly what they provided. The study consisted of 186 patients, all of whom had axillary surgery, with a total of 829 measurements, a fairly substantial sample size. All volumetric measurements were calculated as a relative volume difference from a pre-surgery baseline. In addition, the bioimpedance measurements were performed according to the guidelines of the
Breast Diseases: A Year BookÒ Quarterly Vol 27 No 3 2016
manufacturers, including placing the patients supine before the measurement and removing all socks and jewelry. Results from the bioimpedance measurements were analyzed using the LDex scores derived from the impedance ratios. An abnormal L-Dex score was defined as either a score of greater than 10 or a 10-unit increase from baseline. These 2 definitions are the ways the manufacturers explain that the scores can be interpreted, with a positive result from either indicating lymphedema. Given that this study was examining bioimpedance as a predictive model, if an abnormal L-Dex and abnormal volume were obtained with no prior abnormal L-Dex, the abnormal results were considered a false negative. This interpretation is based on the claims that bioimpedance should be able to detect the increase in fluid earlier than it would be diagnosed by volume displacement. The authors quoted a well-known study by Cornish and colleagues1 that reported that bioimpedance can detect fluid increase as early as 10 months before volumetric methods can. Barrio and colleagues contested this claim by stating that 8 of the 20 patients who developed lymphedema in the Cornish et al study were diagnosed almost immediately after their abnormal bioimpedance reading, which does not allow for sufficient “lag time” to consider the abnormal reading to be early detection. In the results for L-Dex as a predictor for lymphedema, 25 patients presented with abnormal L-Dex scores. Of these, only four were later diagnosed with lymphedema. In total, 13 patients in the study were diagnosed with lymphedema, the other 9 of whom never exhibited abnormal LDex. These results yield a sensitivity for L-Dex as a lymphedema predictor of 31% and a specificity of 88%. These values severely contradict previous literature. The previously mentioned study reported 100% sensitivity and
98% specificity, and in a study by Soran and colleagues,2 the authors stated that they detected lymphedema early in 76% of patients using bioimpedance. However, none of these studies provided long-term follow-up, as the present study has. Although LDex did miss 9 of the 13 lymphedema patients, the negative predictive value was still 93% since there were many true negatives in the cohort. On the other hand, the positive predictive value for L-Dex was 18% since bioimpedance was able to detect only 4 true positives. Despite the clear results, some may argue that a sample size of 13 patients with lymphedema is not large enough to exclude bioimpedance as a predictor for lymphedema. However, the rate of 21 of 25 false positives should probably be alarming to physicians, as these numbers would result in vast overtreatment of patients. These false positives also were not likely due to human error given that 11 of the 21 patients had at least 2 abnormal L-Dex scores. As a general screening tool and not one applied selectively for predictive purposes, L-Dex in this study showed 75% sensitivity. In a similar long-term follow-up study from 2015, Bundred and colleagues3 showed that bioimpedance had 73% sensitivity, and they also identified 91 false positives. For the patients who completed all 3 years of follow-up for the study, the likelihood of developing future edema is quite small given that most edemas develop by 2 years posttreatment. The patients who had abnormal L-Dex scores can certainly be ranked as false positives. However, the median follow-up after abnormal L-Dex scores was only 10 months. For the patients who did not complete all
3 years of follow-up on this study, we would highly encourage the authors to publish the rest of those data when they become available. Those data would allow them to conclude with certainty that the remaining patients did not develop edema either. With the rest of these data in hand, the statement “L-Dex performed poorly as a predictor of lymphedema” would be even stronger. One downfall to this study was the lack of patients in the sentinel lymph node biopsy group who developed lymphedema. With only 1 lymphedema case in this group, it is virtually impossible to reach a conclusion about the ability of bioimpedance to identify the lower-risk population. The L-Dex score for this patient was normal, which may warrant further research into the sensitivity of bioimpedance in patients with minimal axillary surgery. In addition to the predictive abilities of bioimpedance, this study also noted its diagnostic sensitivity and the use of bioimpedance with diagnosed lymphedema patients. As noted in the results, at the time of diagnosis, the LDex scores in 12 of the 13 lymphedema patients were abnormal, confirming results seen in many previous studies involving bioimpedance detecting preestablished lymphedema. However, as the lymphedema patients were followed up past their diagnosis, the authors found very little correlation between volume displacement measurements and bioimpedance. As explained in the Discussion, a well-known disadvantage of bioimpedance is its inability to measure lymphedema in later stages, when the fluid undergoes fibrosis and adipogenesis. The current study confirmed this fact.
Overall, this article positively contributes to the pool of literature regarding the use of bioimpedance to detect breast cancererelated lymphedema. The study provided the necessary study design and the much-needed long-term follow-up to reach more informed conclusions about this device. Aside from the disadvantage of few patients being diagnosed with lymphedema, the results are very clear and confirm past speculations that bioimpedance is a useful diagnostic tool but may not be adequate as a predictor of lymphedema. If the authors are able to publish the remaining follow-up data for those patients with abnormal L-Dex, their conclusions would be even more informative. C. Seward, BS M. Skolny, NP A. Taghian, MD, PhD
References 1. Cornish BH, Chapman M, Hirst C, et al. Early diagnosis of lymphedema using multiple frequency bioimpedance. Lymphology. 2001;34: 2-11. 2. Soran A, Menekse E, Girgis M, DeGore L, Johnson R. Breast cancerrelated lymphedema after axillary lymph node dissection: does early post-operative model work? Support Cancer Care. 2016;24:1413-1419. 3. Bundred NJ, Stockton C, Keeley V, et al. Investigators of BEA/PLACE Studies. Comparison of multifrequency bioimpedance with perometry for the early detection and intervention of lymphoedema after axillary node clearance for breast cancer. Breast Cancer Res Treat. 2015;151:121-129.
Breast Diseases: A Year BookÒ Quarterly Vol 27 No 3 2016
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