The impact of monitoring techniques on progression to chronic breast cancer-related lymphedema: a meta-analysis comparing bioimpedance spectroscopy versus circumferential measurements

Background Chronic breast cancer-related lymphedema (BCRL) is a potentially serious complication following treatment. Monitoring for progression to BCRL may allow for earlier detection and intervention, reducing the rate of progression to chronic BCRL. Therefore, the purpose of this meta-analysis is to evaluate the impact of monitoring techniques on the incidence of chronic BCRL among patients monitored by bioimpedance spectroscopy (BIS) and circumference as compared to background rates. Methods Eligible peer-reviewed studies from PubMed, CINHAL, or Google Scholar that were published in English from 2013 onward and conducted in North America, Europe, or Oceania. Incidence rates abstracted from studies were classified by BCRL monitoring method: background (no standardized BIS or circumference assessments), BIS or circumference. A random-effects model was used to calculate a pooled annualized estimate of BCRL incidence while accounting for clinical and methodological heterogeneity. Subgroup analyses examined differences in duration of follow-up as well as breast and axillary surgery. Results 50 studies were included, representing over 67,000 women. The annualized incidence of BCRL was 4.9% (95% CI: 4.3–5.5) for background studies (n = 35), 1.5% (95% CI: 0.6–2.4) for BIS-monitored studies (n = 7), and 7.7% (95% CI: 5.6–9.8) for circumference-monitored studies (n = 11). The cumulative BCRL incidence rate in BIS-monitored patients was 3.1% as compared to 12.9% with background monitoring (69% reduction) and 17.0% with circumference-monitored patients (81% reduction). Conclusions Evidence suggests that monitoring with BIS allowing for early intervention significantly reduces the relative risk of chronic BCRL with a 69% and 81% reduction compared to background and circumference, respectively. Circumference monitoring did not appear to provide a benefit with respect to chronic BCRL incidence. Based on these results, BIS should be considered for BCRL screening in order to detect subclinical BCRL and reduce rates of chronic BCRL, particularly in high-risk patients. Electronic supplementary material The online version of this article (10.1007/s10549-020-05988-6) contains supplementary material, which is available to authorized users.


Introduction
Lymphedema is a common and potentially serious complication of breast cancer (BC) treatment and has been associated with the extent of breast and axillary surgery, regional nodal irradiation (RNI), and taxane-based chemotherapy. [1][2][3] A recent meta-analysis reported that breast cancerrelated lymphedema (BCRL) affects approximately 19% of breast cancer patients with follow-up ≥ 12 and < 24 months after treatment. Significant heterogeneity in BCRL incidence rates exists due to different monitoring methods, follow-up periods, patient BCRL risk profiles, and study designs. [1, 1 3 4] Patients with chronic BCRL have reduced quality of life which can be attributed to functional impairment or disability, discomfort, and infection, as well as higher medical costs. [1,2,[5][6][7] Psychologically, chronic BCRL may also cause anxiety, depression, and social difficulty. [1,2,4] It is therefore important to identify BCRL early, in the subclinical phase of the process, allowing for earlier intervention, thereby reducing the development of the severe and irreversible symptoms of chronic BCRL. [5] In particular, patients who undergo mastectomy, axillary lymph node dissection (ALND), RNI, or taxane-based chemotherapy have an increased risk of developing BCRL and with being highrisk would benefit from prospective BCRL assessment. [8] There are several different methods commonly used to detect for and monitor BCRL including tape measurement and water displacement [5][6][7]9]. Both of these methods are considered standard for lymphedema monitoring. [7] However, these methods can be highly variable and prone to bias from human measurement, resulting in inter-and intraobserver variability, while being less able to detect subclinical BCRL. [7,10] Bioelectrical impedance (bioimpedance) or bioimpedance spectroscopy (BIS) has emerged as a promising diagnostic tool, able to objectively quantify BCRL by measuring resistance to electrical current flow through a patient's body, giving a more accurate and consistent representation of body composition, and aiding in the assessment of subclinical BCRL earlier than standard methods. [5,6,8,9] Due to the capability of BIS to aid in the assessment of subclinical lymphedema and trigger early intervention, it can potentially reduce the rate of progression to chronic BCRL (clinically assessed BCRL occurring > 3 months postoperatively), resulting in substantial cost savings and improved quality of life, especially in high-risk patients. [3,9,11] However, because BIS has not been considered the standard BCRL monitoring method, it is not usually covered by health insurance companies despite studies demonstrating reduced chronic BCRL using BIS as well as cost-effectiveness with the technique. [5,12].
A previous meta-analysis from DiSipio et al. evaluated the incidence of BCRL and risk factors finding that approximately one in five women will develop BCRL post-treatment with increased risk for those undergoing ALND and mastectomy [4]. We therefore conducted a meta-analysis in order to determine the relative reduction in progression to chronic BCRL among BC patients, comparing (a) BIS monitoring as a trigger for early intervention, using the L-Dex U400 device; (b) limb circumference monitoring with tape measure; and (c) the background rate of progression. The primary outcome of interest was annual progression to chronic BCRL in patients experiencing either (a) the background rate of progression, with either no monitoring or monitoring without standardized BCRL circumference or BIS assessments; (b) monitoring with BIS and early intervention; or (c) monitoring with tape measures of limb circumference with or without intervention.

Eligibility criteria
With the intent to provide an update to the previous metaanalysis conducted by DiSipio et al. in 2013, we conducted a systematic literature review to identify studies investigating chronic BCRL occurrence or progression in adult women with breast cancer. [4] In order to be eligible, each peerreviewed study must have been published in English in 2013 or later (up to 2019 when search was performed) and conducted in North America, Europe, or Oceania. Studies were included as background studies if they reported the BCRL rate over any postsurgical time frame in any group of female breast cancer patients, regardless of study design, as the previous meta-analysis did not exclude studies based on monitoring method. Prospective surveillance and retrospective chart review studies were included as circumference or BIS studies if they specifically described using the L-Dex U400 BIS device or the tape measure method, included a presurgical baseline measurement, and reported the BCRL rate over any postoperative time frame. Randomized controlled trials were included in the tape measure or BIS groups if they included a BIS group, a circumference-monitoring group, or both, with a presurgical baseline measurement, in direct comparison to each other or to a control group with no monitoring. All data abstraction, analyses, and interpretation were conducted without the involvement of the sponsor.

Information sources and search strategy
The systematic literature search was conducted following PRISMA guidelines and focused on the electronic databases PUBMED and CINAHL.
[13] In addition, a Google Scholar search was conducted in which the first three pages of results were reviewed to identify potential additional references. Reviewers also screened references cited in recent publications in which the L-Dex U400 device was used to identify additional studies potentially eligible for inclusion.
The literature search made use of the following terms to identify relevant publications without limiting by date: "breast cancer" AND (lymphedema OR lymphoedema OR "lymphatic edema") AND (incidence OR prevalence OR rate); "breast cancer" AND (lymphedema OR lymphoedema OR "lymphatic edema") AND (monitoring OR surveillance); or "breast cancer" AND (lymphedema OR lymphoedema OR "lymphatic edema") AND ("bioelectrical impedance" OR "bioimpedance" OR "bioimpedance 1 3 spectroscopy" OR "BIS" OR "L-Dex" OR "bioimpedance analysis" OR "BIA").

Reference screening
Two independent reviewers initially screened all study abstracts considered eligible. Exclusions during this stage were based on deviations of methodologies and populations from the predefined criteria, as well as sources other than peer-reviewed journals, and any duplicate references. The reviewers then compared their inclusion decisions for all abstracts. Any discrepancies were resolved through discussion; if a conclusion could not be reached, the decision for inclusion or exclusion was made by a senior author. A reference manager tool, Mendeley, allowed for compilation, screening, and tagging for inclusion/exclusion of the publications was identified from the systematic literature search. At this point, articles published prior to 2013 were excluded so the results would be a true extension of the DiSipio metaanalysis. [4] Next, the two reviewers conducted an independent screening of 10% of the full-length texts for each study and ensured there was 80% agreement in their decisions. [14] The each reviewer then reviewed half of the remaining full-text articles. This screening excluded any articles that a full-text reading found to lack BCRL incidence or progression rates, usable counts to determine rates, clearly defined follow-up periods, or identification of the specific device used if a BIS device was part of the methodology, or that included only self-reported lymphedema.

Data abstraction
Following completion of the full-text review, two reviewers abstracted all elements of interest from the full-length texts. Primary abstraction of articles was performed by ND, with support by AS. All data abstracted were thoroughly checked by the other reviewer to ensure accuracy in abstraction. Any discrepancies throughout the abstraction process were resolved through discussion; if a conclusion could not be reached, decisions were made by a senior author. In addition to basic study information (year of publication, location, design, start and end dates for data collection, study duration, patient inclusion and exclusion criteria, percent of participants lost to follow-up, definition of progression to lymphedema, and lymphedema measurement methods), key data elements for each arm related to patient demographics, treatment, and development of lymphedema were abstracted. These included age, race, and body mass index (BMI) of participants; percent of patients experiencing mastectomy, breast conservation techniques, ALND, sentinel lymph node biopsy (SLNB), taxane chemotherapy, or RNI; the final number of patients in the study arm diagnosed with progression to chronic BCRL (in the case of studies with early intervention (which could be variable interventions including compression sleeve or other therapies), this meant the number diagnosed following intervention, not the number triggering early intervention); and the mean time to progression. To be included in the BIS monitoring group, the studies classified patients with chronic BCRL as having an L-Dex score of ten or greater; to be included in the circumference monitoring group, the studies used the accepted standard of two cm difference or more. If the studies used non-standard methods, such as volume calculations, they were included within the background group and categorized as monitoring. Studies could contribute data to more than one group if they included multiple arms and separate arms met inclusion criteria for different groups. Monitoring via bioimpedance assessment (BIA) is based on a smaller range of frequencies (or even a single frequency) than BIS and was assigned to the background group.

Statistical analysis and synthesis
Stata (version 13; StataCorp LLC, College Station, Texas) was used to conduct all analyses. Synthesis of studies reporting rates of chronic BCRL in the absence of monitoring via tape measurement of limb circumference or BIS provided estimates for the background rate of chronic BCRL. Rate of progression to chronic BCRL was then synthesized for studies involving surveillance and early intervention based on BIS or tape measurement. A random-effects model was used in the analysis to account for both clinical and methodological heterogeneity. Known risk factors for BCRL were assessed via subgroup analyses. Sufficient data were available on the proportion of patients undergoing ALND, SLNB, and Mastectomy. Thresholds were selected empirically from the data. Other known risk factors not included due to a lack of data were BMI, taxane chemotherapy, and RNI.

Results
A total of 2,259 individual references were identified from the literature searches (Fig. 1). Of these, 1922 (85·1%) were excluded during the initial review of abstracts and titles for not meeting eligibility criteria. Of the remaining 337 studies which then underwent full-text review, 143 studies were excluded due to being published prior to 2013. Of the remaining 194, an additional 144 articles (74·2%) were excluded, leaving 50 articles included in the analysis. Of the 50 studies remaining for inclusion in the meta-analysis, 27 were prospective surveillance designs, 14 were retrospective chart reviews, and nine were RCTs. 35 studies provided estimates of the background rate of progression to BCRL; 11 studies provided estimates for monitoring with tape measurement; and 7 studies provided estimates for monitoring with BIS. Three studies contributed data to more than one arm. [15][16][17] One study reported an incidence of 0, which was set to 0·5. This continuity correction is supported in the literature for analyses including only one study with a zero count. [18,19] Mean or median length of follow-up across studies ranged from one to ten years. Tables 1 and 2  and Supplemental Table S1 summarize characteristics of the studies included; of note differences in the rates of ALND did exist. [8,[15][16][17].
Forty-five studies provided data on the percentage of patients receiving ALND. Overall rates of clinical BCRL were higher in studies with a majority (> 50%) of patients undergoing ALND (Table 4). This difference was observed for all three study arms, although it was most pronounced for BIS-monitored patients (Fig. 3a-c). BIS-monitored patients had a 56% reduced rate of progression compared to circumference-monitored patients in studies with > 50% ALND, and an 84% reduced rate of progression compared to circumference-monitored patients in studies with ≤ 50% ALND. BIS-monitored patients had a 68% reduced rate of progression compared to background studies in patients with ≤ 50% ALND. Forty-three studies provided data on the percentage of patients receiving mastectomy. Rates of clinical BCRL were lower in BIS and circumference-monitored studies with a high rate (> 40%) of patients receiving mastectomy compared to those with ≤ 40% of patients, but not for the background group. BIS-monitored patients had a 79% reduced rate of progression compared to circumferencemonitored patients in studies with > 40% mastectomy, and a 7% reduced rate of progression compared to circumferencemonitored patients in studies with a ≤ 40% mastectomy (not statistically significant) ( Table 4). BIS-monitored patients had a 75% reduced rate of progression compared to background rates for patients with > 40% mastectomy.
With respect to the potential for follow-up bias, the rates of clinical BCRL differed significantly for studies with average or median follow-up of ≤ 2 years versus those with > 2 years of follow-up ( Table 3). The pooled rate of BCRL in studies with follow-up of ≤ 2 years was more than double that of longer studies for background and BIS studies ( Fig. 2a, b) but the difference was not as pronounced in tape measurement studies (Fig. 2c).

Discussion
The results of this meta-analysis demonstrate that patients followed with BIS surveillance were significantly less likely to develop chronic BCRL annually (and overall) as compared to the background rate and tape measurement. This difference was not only statistically significant but clinically as well; the annualized BCRL incidence rate was 69% (3.4% absolute difference) lower than the observed background rate and 81% (6.2% absolute difference) lower than that observed with tape measurement. Importantly, patients monitored with BIS had a lower annualized incidence even in high-risk populations (> 40% mastectomy and > 50% ALND). Similarly, a clinically significant difference in the cumulative BCRL incidence rate was noted with a 9.8% absolute reduction compared to observed background rate and a 13.9% absolute reduction as compared with tape measurement. While there were differences in rates of ALND  (Table 4), the benefits of BIS were confirmed (Annualized Incidence 6.8% vs. 15.4% with circumference, comparative ratio 0.44). It is important to recognize that screening techniques such as BIS do not directly reduce rates of BCRL; rather, these findings support that BIS is able to identify changes in fluid content earlier within the patient's limb prior to the development of BCRL, and therefore, the benefit of BIS monitoring is to trigger early intervention in breast cancer patients at risk for chronic BCRL. This earlier diagnosis and intervention along with informing patients likely contribute to the reduction in BCRL allowing for the reversal of the increased fluid volume preventing chronic BCRL which is of substantial clinical importance. [12].
Our results are consistent with previous studies. This study builds on and supports the meta-analysis conducted by DiSipio et al. [4] The cumulative incidence observed in background rate studies, 12.9% (95% CI 11·3-14·4), is smaller but in a similar range to the cumulative incidence observed by DiSipio et al. (16·6%, 95% CI 13·6-20·2) and is likely consistent with changes in clinical practice over time; a higher rate of annual and cumulative BCRL was seen with circumference as compared to background and this may reflect that, consistent with DiSipio et al., all studies that used non-standard methods (ex. perometry, volume calculation) were included in the background group. Subgroup analyses were also consistent with prior research in identifying ALND as a risk factor for BCRL. Mastectomy as a risk factor was not confirmed in the background rate pooled estimates, although annualized incidence was higher in studies with more than 40% of patients undergoing mastectomy; this may reflect the increasing use of mastectomy with SLNB (and not ALND) as compared to previous studies. However, for both BIS and tape measurement monitoring studies, the annualized rate of BCRL was lower when the rate of mastectomy was higher (Table 4).
BIS monitoring enables early detection of changes in fluid in affected limbs, particularly in high-risk patient subgroups; additionally, despite potential concerns regarding challenges with implementation, studies have demonstrated the ability implementing this into a standard practice with clinical guidelines available as well [66,67]. Early detection can be used to trigger interventions, typically consisting of some combination of compression garments, massage, and physical therapy, to prevent development of chronic BCRL. Such prevention measures improve patient quality of life and reduce the public health burden of chronic BCRL [1,6,7,9]. Compared to no monitoring, BIS-monitored studies had an overall reduced chronic BCRL relative rate of 59%. Compared to tape measurement of circumference, BIS-monitored studies had a reduced relative rate of over 80%. These results provide further evidence in favor of BIS in preventing progression to BCRL in comparison to currently accepted methods of monitoring, possibly due to higher sensitivity of BIS to subclinical volume changes [5,8,10]. There is now ample evidence that active monitoring of BCRL significantly reduces the risk of progression to BCRL. While  this study compared the effectiveness of monitoring with BIS versus tape measurement for the development of BCRL, future studies should compare BIS to other accepted surveillance methods individually in a prospective study design evaluating high-risk patients. Additionally, recent data and the PREVENT trial have reduced the change initiating a trigger for intervention from 10 to 6.5, potentially further increasing the sensitivity of BIS to detect subclinical BCRL [17,68].
A key strength of this study is the robust statistical analyses performed. Multiple risk factors of interest were examined for increased risk of BCRL. However, several important limitations must be noted. First, there were relatively few studies (n = 7) that used BIS to monitor progression to chronic BCRL. Second, only 28% of BIS patients had ALND, versus 73% of circumference patients, suggesting the latter group was at disproportionately greater risk of BCRL. Third, data on patient BMI in many studies were either not available or were not presented continuously. Fourth, most studies did not provide data specifically on taxane-based chemotherapy or RNI (radiation fields including axilla vs axilla + supraclavicular vs. supraclavicular alone), which are also risk factors for BCRL. It would have been advantageous to include subgroup analyses on BMI, taxane-base chemotherapy, and RNI, as they are known to increase patient's risk for BCRL. Definitions of BCRL varied across studies. However, there are no standard clinical cut-points for many of these measures other than BIS [17]. For the BIS studies, in particular, there was greater consistency, with BCRL defined as an increase of 10 units or more in L-Dex scores. Finally, the background group was heterogeneous, though consistent with the previous meta-analysis [4]. A sensitivity analysis was conducted on the background studies to evaluate the BCRL rates for studies with no active monitoring in comparison to other commonly performed monitoring methods (e.g., water displacement) that were included in the background. With no monitoring (n = 11), the annualized incidence rate for BCRL was 3·7%. Background studies with other methods of monitoring (n = 24) had an annualized incidence rate of 7·6%. This difference indicates the possibility of detection bias when evaluating the low incidence rate of the patients in the no monitoring group. Without active monitoring, it is highly possible for year cut point. Each study is represented by its estimated annualized incidence. The red dotted line is the overall pooled estimated annualized incidence. The light green circles represent the weight for each study to calculate the overall annualized incidence rate and are from the random-effects analysis. The diamond shapes are the variances for each cut point as well as the overall study variance Fig. 3 a Background studies combined for SLNB and ALND. b BIS studies combined for SLNB and ALND. c Circumference studies with SLNB and ALND. Each study is represented by its estimated annualized incidence. The red dotted line is the overall pooled estimated annualized incidence. The light green circles represent the weight for each study to calculate the overall annualized incidence rate and are from the random-effects analysis. The diamond shapes are the variances for each cut point as well as the overall study variance patients to develop BCRL and go undiagnosed, which can bias the results.