Medical Policy: 02.01.57
Original Effective Date: January 2017
Reviewed: January 2020
Revised: January 2019
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This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.
Lymphedema is a chronic accumulation of fluid and fibrous tissue that results from the disruption of lymphatic drainage. Primary lymphedema is a disorder of the lymphatic system that occurs on its own, it is inherited and uncommon (congenital lymphedema due to lymphatic aplasia or hypoplasia; Milroy’s disease, an autosomal dominant familial form of congenital lymphedema; lymphedema praecox; lymphedema tarda). Secondary lymphedema is a disorder of lymphatic flow that is caused by some other disease or condition and it is most commonly caused by surgery (lymph node dissection, such as for breast cancer), radiation therapy (especially axillary or inguinal), trauma, and lymphatic obstruction by tumor. Secondary lymphedema may also result from compression of the lymphatic and venous channels resulting from leakage of fluid into interstitial tissues in patients with chronic venous insufficient.
Lymphedema is usually staged observing a patient’s physical condition. The International Society of Lymphology uses the following 3-stage scale for classification of lymphedematous limb:
An increasing number of lymphologists recognize an earlier stage of lymphedema, termed Stage 0, which refers to latent or subclinical condition where swelling is not evidence despite impaired lymphatic transport. Stage 0 exists for months or years before the onset of overt lymphedema.
The detection of subclinical lymphedema i.e. the early detection of lymphedema before clinical symptoms become apparent, is another area of study. Detection of subclinical lymphedema referred to as stage 0 lymphedema is problematic. This approach generally involves comparison of preoperative (i.e. baseline) with postoperative measurements The use of bioimpedance has been proposed as a diagnostic test for this condition. In usual care, lymphedema is recognized clinically or via limb measurements. However, management via bioelectrical impedance spectroscopy has been proposed as a way to implement early treatment of subclinical lymphedema to potentially reduce its severity.
Bioimpedance spectroscopy (BIS) is based on the theory that the level of opposition to the flow of electric current (impedance) through the body is inversely proportional to the volume of fluid in the tissue. In lymphedema with the accumulation of excess interstitial fluid tissue impedance decreases.
The purpose of using bioimpedance spectroscopy (BIS) in patients who have known or suspected lymphedema is to inform a diagnosis of subclinical lymphedema to initiate treatment sooner than with other diagnostic methods.
The relevant population of interest is individuals with known or suspected lymphedema.
The relevant interventions of interest is bioimpedance spectroscopy (BIS).
The relevant comparators of interest are volume displacement and circumferential measurement.
The general outcomes of interest are test accuracy and validity, symptoms, and quality of life (QOL).
The time frame for outcomes varies from months to years after onset of lymphedema symptoms.
During a physical examination conducted by a physician in an inpatient or outpatient setting.
A test must detect the precesnce or absence of a condition, the risk of developing a condition in the future, or treatement response (benefit or adverse).
A technology assessment on the diagnosis and treatment of secondary lymphedema, performed under contract from Agency for Healthcare Research and Quality (AHRQ) by McMaster University Evidence-based Practice Center, was released in May 2010. Most of the diagnostic accuracy and treatment studies were conducted in persons with history of breast cancer. The AHRQ assessment identified 8 studies that reported the sensitivity and specificity of tests to diagnose secondary lymphedema and two of the 8 studies on diagnostic performance of devices to detect secondary lymphedema evaluated bioimpedance devices. Overall, the investigators concluded that based on the evidence, limb and volume circumference are the de facto gold standard tests from which to assess the presence of secondary lymphedema. Although validity assessment suggests good interchangeability between different measures of limb volume or circumference, the heterogeneity of the evidence was to substantial to enable the drawing of conclusions about the type of measure that would be the most appropriate for diagnosing secondary lymphedema.
In 2015, a prospective validation study by Barrio et. al. was performed comparing bioimpedance
(L-Dex) and volume displacement measurements in a cohort of breast cancer patients at risk for lymphedema. Between 2010 and 2014 a total of 223 breast cancer patients were enrolled. Thirty seven patients were excluded, leaving a sample size of 186. Prior to surgery participants received baseline volumetric measurements with bioimpedance device (L-Dex) and volume displacement (VD, the reference standard). Patients then had regular follow-up volumetric measurements every 3 to 6 months for 3 years. At 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 L-Dex 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%. There was no correlation between change in VD and change in L-Dex at 3 months (r = 0.31) or 6 months (r = 0.21). The authors concluded that VD and bioimpedance demonstrated poor correlation with inconsistent overlap of measurements considered abnormal. Of patient with abnormal L-Dex few progressed to lymphedema, most patients with lymphedema did not have prior L-Dex abnormality. Further studies are needed to understand the clinical significance of bioimpedance.
Another 2015 prospective study Blaney et. al. examined the feasibility of a breast cancer related lymphedema (BCRL) screening program, investigating the efficacy of bioimpedance analysis (BIA) compared to circumferential measurements (CM) in detecting BCRL. This was a 12 month prospective feasibility study and participants were recruited from two diagnostic breast clinics. Pre-surgical assessments were conducted, and participants were followed up at quarterly intervals. BIA and CM measurements were conducted at all time points. An L-Dex score of > 10 or a 10-U increase from baseline or a ≥ 5% increase in proximal, distal or total percentage volume difference (PVD) from baseline was indicative of BCRL. Information was collected on subjective symptoms, potential risk factors, demographics and medical data. Feasibility was based on uptake and retention. One hundred twenty six participants were recruited with an attrition rate of 16.2%. Participants mean age was 59 years with the majority having stage I (63.9%), infiltrating ductal carcinoma (87.4%). 31.6% were identified has having BCRL, 90.3% detected by CM and 35.5% by BIA (p = ≤ 0.0001). The authors concluded no significant correlation between BIA and CM. Work needs to continue to establish the most effective screening tool and the natural behavior of BCRL within the first year post surgery.
In 2019, Ridner et. al. conducted a randomized controlled trial (RCT) comparing lymphedema progression rates using volume measurements calculated from the circumference using a tape measure (TM) or bioimpedance spectroscopy (BIS) in breast cancer. Patients were enrolled and randomized to either TM or BIS surveillance. Patients requiring early intervention were prescribed a compression sleeve and gauntlet for 4 weeks and then re-evaluated. The primary endpoint of the trial was the rate of progression to clinical lymphedema requiring complex decongestive physiotherapy (CDP), with progression defined as a TM volume change in the at-risk arm ≥ 10% above the presurgical baseline. This prespecified interim analysis was performed when at least 500 trial participants had ≥ 12 months of follow-up. A total of 508 patients were included in this analysis, with 109 (21.9%) patients triggering pre-threshold interventions. Compared with TM, BIS had a lower rate of trigger (15.8% vs. 28.5%, p < 0.001) and longer times to trigger (9.5 vs. 2.8 months, p = 0.002). Twelve triggering patients progressed to CDP (10 in the TM group [14.7%] and 2 in the BIS group [4.9%]), representing a 67% relative reduction and a 9.8% absolute reduction (p = 0.130). The authors concluded, these interim results demonstrated that post-treatment surveillance with BIS reduced the absolute rates of progression of breast cancer related lymphedema (BCRL) requiring CDP by approximately 10%, a clinically meaningful improvement. These results support the concept of post-treatment surveillance with BIS to detect subclinical BCRL and initiate early intervention.
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy or avoid unnecessary testing.
The ideal study design is a randomized controlled trial (RCT) comparing health outcomes in patients who are managed with and without the use of bioimpedance devices.
A controlled observational study (2014 by Soran et. al.) comparing clinical lymphedema rates in patients managed with and without bioimpedance analysis. This study involved prospective detection of subclinical lymphedema in 186 patients diagnosed with breast cancer undergoing axillary lymph node dissection (ALND) who were managed with L-Dex or tape measurement of limb circumference (circumferential arm measurements). Baseline measurements were obtained at 3-6 month intervals for 5 years. Subclinical lymphedema was defined as L-Dex value outside the normal range or that increased at least 10 units from baseline. Patients diagnosed with subclinical lymphedema received short term physical therapy, compression garments, and education about exercise, elevation, infection precautions, BMI and hand usage. A total of 180 women were included in the analysis. Seventy-two women had both preoperative bioimpedance and tape measurements (preoperative group). Forty-four women had preoperative bioimpedance and tape measurements but only had tape measurements postoperatively (control group). The remaining sixty-four women and postoperative bioimpedance and tape mesurements, but no preoperative measurements (no preoperative group). The authors compared demographic and clinical characteristics of the preoperative and control groups and of the preoperative and postoperative groups; they did not identify any statistically significant differences.
In the preoperative group, 28 of 72 women (36%) were diagnosed with subclinical lymphedema and referred for treatment; 2 women progressed to clinical lymphedema. In the control group, 16 women (36%) developed clinical lymphedema during follow up. A limitation of the study is that there was no alternative method for detecting subclinical lymphedema in the control group so they could receive treatment early. Moreover, the women were not randomized to a treatment group and complete information (pre and post-operative measures of lymphedema) was available for only a subset of the total population.
This study had several limitations, including non-randomized design, lack of blinding, lack of complete information on a substantial number of patients in the study, and lack of a systematic method for diagnosing lymphedema in the control group. The authors reported a significantly lower rate of clinical lymphedema in patients who were managed with bioimpedance analysis (BIA) and who received treatment for subclinical lymphedema. Additional studies to confirm these findings are needed, especially RCTs and trials that include an alternative method for early or subclinical lymphedema detection.
In 2016, Laidley et. al. evaluated the role of bioimpedance spectroscopy (BIS) in the early detection of breast cancer related lymphedema (BCRL), as well as assessment of response to BCRL treatment. A retrospective review of 1,133 patients treated between November 2008 and July 2013 at two surgical practices was performed. Eligible patients (n = 326) underwent preoperative and postoperative L-Dex measurements. Patients were identified as having subclinical lymphedema if they were asymptomatic and the L-Dex score increased >10 U above baseline and were monitored following treatment. Patients were stratified by lymph node dissection technique [sentinel lymph node biopsy (SLNB) versus axillary lymph node dissection (ALND)] and receipt of BCRL treatment. The average age of the cohort was 56.2 years old, and mean follow-up was 21.7 months. Of the 326 patients, 210 underwent SLNB and 116 underwent ALND. BCRL was identified by L-Dex in 40 patients (12.3%). The cumulative incidence rate of subclinical lymphedema was 4.3% for SLNB (n = 9) and 26.7% for ALND (n = 31). Of those diagnosed with BCRL, 50% resolved following treatment, 27.5% underwent treatment without resolution, and 22.5% had resolution without treatment. The prevalence of persistent, clinical BCRL was 0.5% for SLNB and 8.6% for ALND. There are limitations to the current analysis. This was a retrospective review and therefore, subject to the limitations of such an analysis. While the initial cohort was large, due to the small number of events, further data are required to validate these findings. Additionally, they were unable to evaluate other factors associated with an increased risk of lymphedema (i.e., radiation therapy, BMI) due to limits on the data available. Finally, because intervention was based on clinician discretion, no cut point for beginning intervention could be determined at this time. However, this study represents one of the few studies available that demonstrate the ability to use L-Dex as part of routine clinical breast care to identify subclinical BCRL and allow early intervention to prevent long-term chronic BCRL. The authors concluded, this study demonstrates both the feasibility and clinical utility of implementing L-Dex measurements in routine breast cancer care. L-Dex identified patients with possible subclinical BCRL and allowed for assessment of response to therapy.
In 2018, Kilgore et. al. conducted a prospective surveillance monitoring using bioimpedance spectroscopy (BIS) and patient directed self-interventions. Breast cancer patients with unilateral disease high-risk for breast cancer related lymphedema (BCRL) from a single institution were evaluated from November 2014 to December 2017. High risk was defined as axillary lymph node dissection (ALND) with radiation and/or taxane chemotherapy. Patients received preoperative baseline BIS measurements followed by postoperative measurements with at least two follow-ups. Patients with BIS results that were 2 standard deviations above baseline (10 + points) started home conservative interventions for 4-6 weeks. Postintervention measurements were taken to assess improvement. A total of 146 patients high-risk for BCRL were included. Forty-nine patients (34%) developed early BCRL and started self-directed treatment. Forty patients (82%) had elevated BIS measurements return to normal baseline range. Nine (6%) patients had persistent BCRL requiring referral for advanced therapy. Patients with persistent BCRL had significant nodal burden on surgical pathology; eight (89%) had N2/N3 disease. Six (76%) with BCRL refractory to conservative measures died of their breast cancer. The authors concluded, our results demonstrated that early conservative intervention for breast cancer patients high risk for BCRL who were prospectively monitored by utilizing BIS significantly lowers rates of BCRL. These findings support early prospective screening and intervention for BCRL. Early detection with patient-directed interventions improves patient outcomes and decreases the risk of persistent BCRL.
The evidence for bioimpedance devices in individuals who have known or suspected lymphedema includes a technology assessment by AHRQ (Agency for Healthcare Research and Quality), several prospective studies, retrospective studies and one randomizsed controlled trial (RCT). There were no randomized controlled trials (RCTs) evaluating the clinical utility of bioimpedance devices in the management of patients with lymphedema or at high risk of developing lymphedema. While some of the studies show promise in patients managed with bioimpedance devices, the lack of randomized controlled trials (RCTs) provides limited data demonstrating the impact of this test (bioimpedance) on clinical outcomes (clinical utility). Based on the current scientific evidence and because the impact on net health outcome is unknown, use of this testing in the diagnosis or management or patients with known or suspected lymphedema, or to detect subclinical lymphedema is considered investigational. The evidence is insufficient to determine the effects of this technology on net health outcomes.
Lymphedema is a potential side effect after the treatment of axillary lymph node surgery resulting from damage to the lymphatic system. Early detection/diagnosis of lymphedema is key for optimal management. Consider pretreatment measurement of both arms as a baseline for patients with risk factors for lymphedema. See NCCN Guidelines for Survivorship: Lymphedema (SLYMPH-1).
Definition: Lymphedema occurs when lymph fluid accumulates in the interstitial tissue, causing swelling of the limb or other areas such as the neck, trunk, or genitals. It is a common side effect of cancer treatment, occurring on the same side of the body as the cancer treatment, as a result of dysfunction of the lymphatic system.
Stage 0 (latent/subclinical): Lymphatic dysfunction without swelling; subtle symptoms, such as feeling of heaviness or fatigue in the limb, may be present.
Stage 1 (spontaneously reversible): Accumulation of fluid and protein causing swelling; pitting edema may be evident; increased girth, heaviness, and/or stiffness of affected area. For the limbs, swelling is relieved with elevation.
Stage 2 (irreversible): Spongy tissue consistency, with pitting edema that becomes less evident as swelling increases; tissue fibrosis causing hardness and increase in size. For the limbs, swelling is not relieved with elevation.
Stage 3 (lymphostatic elephantiasis): Severe dry, scaly, thickened skin; increased swelling and girth of affected area; can be debilitating.
Ideally, pretreatment limb measurement of both sides should be performed as a baseline prior to initiation of any therapy for those with treatment-related or individual risk factors. If not, the contralateral limb can be used for comparison in the post-treatment setting.
In 2007, the ImpediMed L-Dex U400 was cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process as an aid in the clinical assessment of unilateral lymphedema in the arms in women. It is not intended to diagnose or predict lymphedema. It is a tool to assist in the clinical assessment of lymphedema by a medical provider. L-Dex values that lie outside the normal range may indicate early signs of lymphedema and values that have changed +10 L-Dex units from baseline may also indicate early lymphedema. The L-Dex U400 was discontinued November 1, 2018. ImpediMed will provide product service and support for five years from the date of manufacture of the device.
In 2015, MoistureMeterD was cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process to aid informing a clinical judgement of unilateral lymphedema in women. It is not intended to diagnose or predict lymphedema. It is a tool to assist in the clinical assessment of lymphedema by a medical provider.
In 2018, ImpediMed received FDA 510(k) clearance for SOZO medical device that provides a detailed, individualized measurement of extracellular fluid, intracellular fluid, and total body water, to measure a patient’s fluid status.
Devices using bioimpedance (bioelectrical impedance spectroscopy) are considered investigational for use in the diagnosis, surveillance or treatment of patients with lymphedema including use in subclinical secondary lymphedma because their effectiveness for thesse indications has not been published.
The evidence is insufficient to determine the effects of the technology on net health outcomes.
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