Surgical treatment algorithm for breast cancer lymphedema—a systematic review

Introduction

Background

Breast cancer-related lymphedema (BCRL) is a debilitating condition that affects a substantial number of breast cancer survivors (1). Conservative treatment with compression therapy, manual lymphatic drainage, exercise, and skincare are widely recognized as the golden standard for managing lymphedema symptoms. While this treatment regime can offer a reduction in edema, alleviate pain, and slow down the progression of the disease, it remains primarily focused on relieving symptoms and is heavily dependent on patient compliance and resource availablility (2-4). However, it has its limitations, being most effective in the early stages of lymphedema, where the lymphatic system may still be stimulated to remove excess fluid. As the disease progresses, the lymphedematous tissue undergoes fibrosis and becomes less pliable, making conservative treatment less effective. Many individuals also find their daily activities restricted due to the use of compression garments. Further limitations include restrictions in activities of daily living due to the use of compression sleeves and the ongoing fitting issues, discomfort and economic burden of new or adjusted compression sleeves. Patients also face time-consuming travel between treatment centers, as the accessibility of lymphedema specialists is impacted by local resource availability (2-5).

Surgical interventions for BCRL include liposuction, lymphovenous anastomosis (LVA), and vascularized lymph node transfer (VLNT), have been available for several years (6-8). The field of lymphedema surgery is expanding swiftly, and studies are continuously published, showing promising results (9). However, there are still many questions that remain unanswered. These include the efficacy of the procedure, the optimal pre-operative planning, identifying the proper treatment for the individual, as well as choice of optimal post-operative management. Another challenge lie in the early lymphedema detection and the absence of standardized methods for diagnostic modalities and criteria, contributing to increased complexity, and thus likely resulting in delayed diagnosis and treatment (10,11).

Reviewing surgical treatments for BCRL is crucial to advance our understanding of the condition, improving patient care, and guiding future research and clinical practice by systematically evaluating the effectiveness of surgical interventions for managing BCRL, providing a comprehensive understanding of their outcomes, benefits, and limitation. This will allow for an evidence-based synthesis and provide a broader understanding of patient outcomes. We believe this will aid future treatment guidelines and research prioritization.

Objective

The aim of this article was to conduct a systematic review on LVA, VLNT, and liposuction for treatment of BCRL to explore its efficacy on arm volume reduction, quality of life, lymph flow, and ultimately develop an optimal, evidence-based treatment algorithm based upon the patients’ characteristics, symptoms and needs. We present this article in accordance with the PRISMA reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-23-503/rc) (12).

Methods

Search strategy

We conducted an electronic literature search in the five databases: EMBASE (Ovid), Medline (Ovid), Cochrane Library, Google Scholar, and ClinicalTrials.gov. The search was conducted on June 18, 2023. The search query included various keywords, such as: “Breast Cancer Related Lymphedema”, “Breast Neoplasms”, “Lymphedema”, “Surgical Anastomosis”, “Lymph Nodes”, and “Lipectomy”. See Table 1 for search terms and string examples and Table S1 for the entire search string. No filter function nor time limit was applied to include all available articles, including non-peer-reviewed ones. All systematic reviews on surgical treatments for BCRL identified through our search strategy were also assessed for potentially relevant literature.

Inclusion and exclusion criteria

All original studies presenting outcomes of LVA, VLNT, or liposuction for patients with unilateral upper extremity lymphedema (UEL) secondary to breast cancer were included. Studies investigating a combination of treatments were excluded, except studies with combined breast reconstruction and VLNT. A model encompassing patient population, interventions, comparison, and outcomes of interests, known as the PICO model, was formulated. For full PICO criteria, see Table 2. Only articles written in English were included. Animal studies, conference abstracts, oral- or poster presentations, case reports, and interventional studies with a study population of less than ten patients in the intervention group were all excluded.

Data extraction

Two independent reviewers conducted the title and abstract screening using Covidence software, followed by full-text review of selected articles. Disagreements were resolved through discussion or consultation with a third reviewer. The following study characteristics were collected in an excel spreadsheet: study design, year of publication, region/area of origin for the article, number of patients, intervention and comparison, lymphedema duration, lymphedema classification, type of surgery, surgery duration, number of performed anastomoses, number of transplanted lymph nodes, donor- and recipient site for VLNT, volume aspirated from liposuction, type of volume measure, arm volume measures, quality of life assessment, lymphatic flow evaluation, the significance of outcomes, complications and flap loss, post-operative management, follow-up duration.

Risk of bias and quality assessment

The quality of included studies was assessed using ROBINS-I for non-randomized studies and ROB2 for randomized controlled trials. For cross-sectional studies, we used a modified Newcastle-Ottawa Quality Assessment Scale, and for observational studies, we applied a systematic checklist to evaluate the risk of bias (13-16). The checklist assessed the reporting and risk of implementing bias in a study on its design, research question, selection of population and recruitment, their exposure- and outcome assessment, loss to follow-up, confounding domains, reporting and transparency, ethical considerations, study funding and conflicts of interest, and lastly the study’s overall risk of bias. The scoring system ranged from zero to 32 points. Zero to eight points indicated a critical risk of bias, nine to sixteen points a serious risk of bias, seventeen to 24 a moderate risk of bias, and 25–32 a low risk of bias, while having in mind the nature of observational studies always has some degree of bias due to the natural design of the study.

Since the included papers did not provide adequate data for a combined analysis, an evaluation of the confidence in evidence from a data synthesis using the GRADE approach for randomized and non-randomized trials was not conducted in this review (17).

Statistical analysis

Due to the substantial heterogeneity observed among the included articles and the insufficient number of randomized and non-randomized controlled trials, no meta-analysis was performed. Heterogeneity in this context refers to the significant variation in study designs, patient populations, interventions, and outcome measurements across the included articles. This variation makes it challenging to pool the data and conduct a meaningful meta-analysis, as the results would be potentially misleading. As such, we will provide a qualitative synthesis of the findings, summarizing the key trends, patterns, and insights observed within the individual studies. The variation in outcomes across studies that reported the same measure of efficacy was analyzed using SPSS and quantified using the I² statistic to assess heterogeneity (18).

Results

The initial literature review revealed 16,593 articles after removing duplicates, of which 827 were included for full-text screening. After thoroughly evaluating full texts, 70 articles fulfilled our inclusion criteria and were selected for data extraction and analysis. An additional three articles were identified and included through relevant systematic reviews, resulting in 73 included articles. The 73 articles were subdivided according to subjects, 24 focused on LVA, 29 on VLNT, 12 on liposuction, and two described both LVA and VLNT, in addition to six ongoing clinical trials. See Figure 1 for the entire screening process. Only three articles were randomized controlled trials, none of which were blinded (5,19,20). Overall, 2,373 patients were included in the study. International Society of Lymphology (ISL) was the most frequently used classification system to evaluate lymphedema stage. Other methods used included the Campisi staging of lymphedema, Cheng Lymphedema Grading System, lymphoscintigraphy, indocyanine green lymphography (ICG-L), Arm Dermal Backflow, M. D. Anderson Scale, and the pitting test, see Table 3 (10,21-26). Amongst patients receiving LVA or VLNT, their lymphedema was classified primarily using ISL with 11.2% stage I, 71.3% stage II, and 17.5% stage III. ISL was not applied in liposuction articles, where the pitting-test was the predominant way of evaluating lymphedema.

Figure 1 PRISMA flow chart presenting the screening process. Articles not retrieved refers to the articles that were initially identified and included for full text screening, but were not obtained or accessed for the review.

The effect of LVA

LVA was described in a total of 26 articles, 33.8% of the included articles, presented the outcome of LVA for treatment of BCRL, see Table 4. The studies were published between 2009 and 2023, with a steady annual increase, reaching its peak in 2022, highlighting the continued relevance of the topic, as indicated in Figure 2.

Figure 2 Graphical presentation of the geographical distribution amongst published data, and year of publication for studies on LVA, VLNT, and liposuction. LVA, lymphovenous anastomosis; VLNT, vascularized lymph node transfer.

Among the 26 articles, 16 (61.2%) were prospective studies (20,27-41), one being a randomized controlled trial (20), one single cross-sectional study (42), and nine (31.0%) followed a retrospective design (43-51). Geographically, the Netherlands (seven articles) (20,30,31,36,41,48,50) and Japan (six articles) (34,39,42,43,45,47) were the most represented regions/areas in the literature. Other contributing regions/areas included Italy (three articles) (27,29,51), France (two articles) (35,38), United Kingdom (two articles) (32,33), United States (two articles), Chile (one article) (28), Peru (one article) (44), Korea (one article) (46) and Taiwan (one article) (49), see Figure 2.

LVA surgery was performed in a total of 914 patients. Sample sizes ranged from 10 to 89 individuals. On average, the duration of lymphedema was 4.7±1.9 years, and the median follow-up period extended to 12 months, ranging from 6 to 60 months. The ISL classification system, utilized to evaluate lymphedema severity, was applied in 16 out of 26 articles (61.5%). In this classification, 12.2% of cases were ISL stage I, 73.3% stage II, and 17.7% stage III. A significant number of studies further divided stage II into sub-groups, with 42.1% classified as stage IIa and 25.3% as stage IIb. Other classifications systems employed, included the Campisi staging of lymphedema (n=5) (35,37,40,41,50), lymphoscintigraphy (n=5) (28,29,34,42,46), ICG-L (n=3) (30,32,34), Arm Dermal Backflow Scale (n=1) (20), and Cheng Lymphedema Grading System (n=1) (49).

Surgery was primarily performed using local anesthesia in 16 articles (76.2%). On average, there were 2.67±1.4 anastomoses performed per patient, and the mean surgery duration was 169.7±65.2 minutes. Ten articles reported no complications following LVA. Others reported the development of cellulitis (three articles) and lymphedema progression (one article).

All 26 articles evaluated the efficacy of LVA by monitoring changes in arm volume. Additionally, 11 articles provided insights into the patients’ quality of life (20,30-32,34,36,41,42,46,48,50), and three articles examined alterations in lymphatic flow (29,41,46). Patients were followed for a mean period of 14 months, with the majority having a follow-up period of 12 months. The longest follow-up duration was 60 months, however results are presented as the mean volume reduction from combined 1-, 3-, and 5-year follow-ups (29), While they report sustained volume reduction over the 5-year study period, long-term data remains limited across the included studies.

Arm volume following LVA

Arm volume measurements in the included articles were conducted using three distinct methods: manual arm circumference (n=20) (20,27-31,34-36,38,39,42-47,49-51), perometer (n=4) (32,33,37,40), and water displacement (n=3) (41,48,50). Manual arm circumference measurements involved assessing the arm circumference at several predefined points to assess changes in arm circumferences or calculate total arm volume using the formula of a blunt cone. Some articles used this volume measure to calculate the excess arm volume, comparing the lymphedematous arm with the unaffected one. A perometer is a device that employs optical scanning or laser technology to capture limb contours and provide volume measurements (52). In contrast, the water displacement method is a volumetric technique that involves submerging the arm in a water basin. The volume of displaced water corresponds to the arm’s volume measured in mL (53).

While arm volume is assessed using only three methods, the presentation of their findings exhibited substantial variability, with 20 different approaches. The UEL index, initially introduced by Yamamoto et al., was the most common method for presenting arm volume (54). This index incorporates arm circumferences relative to the patient’s body mass index (BMI):

UELindex=C12+C22+C32+C42+C52BMI[1]

Here, C_1–5 represents the circumferences in five areas of the upper extremity, and BMI is the patient’s BMI. However, despite being the most frequently employed method, only six studies utilized this approach. The remaining articles present volume changes in various formats, including ratios, mL, cm³, or percentages.

Upon conducting the data analysis, the initial assessment of the included studies indicated a notable variation in effect sizes amongst the articles that reported data for the UEL index. The I² statistic was calculated to quantify this heterogeneity, yielding a value of 0.89, indicating substantial heterogeneity among the studies. Consequently, it was determined that a meta-analysis was unsuitable for this review, and instead, a narrative synthesis was conducted. Across the six studies using the UEL index, the unweighted mean revealed a slight rise of 1.9±11.3. In contrast, studies focusing on percentage-based relative volume reduction presented an average decline of 27.6%±30.9% in excessive arm volume. Overall, the range of results across the reviewed studies was broad, spanning from an 87 mL increase to a 93.5% relative reduction in excess arm volume, underscoring both the diversity in outcomes and the varied methods of reporting within this research area.

Patients’ quality of life after LVA

In evaluating patients’ quality of life, the Lymph-ICF questionnaire was the predominant patient-reported outcome measure (PROM) used in five articles (20,30,31,36,46). Other PROMs included Lymphedema Quality of Life (LYMQOL) (n=2) (32,48), LymphQol (n=1) (50), LeQOLiS (n=1) (42), Short Form-36 (SF-36) (n=1) (41), Visual Analog Scale (VAS) (n=1) (34), and a self-developed questionnaire addressing clinical condition and quality of life (n=1) (51). Patient responses to the Lymph-ICF questionnaire generate a total score within each scale, ranging from 0 to 100, with 0 being the highest health-related quality of life and 100 reflecting the lowest. The smallest real difference has been calculated for each scale to assess clinically significant changes, establishing the minimum score change required to be clinically meaningful for the patients (55). Looking at the Lymph-ICF scores, the mean total score across the studies was 44.5±4.2 pre-operatively and 24.8±7.1 at follow-up, indicating a significant improvement of 19.7±6.8 points. physical function score changed from 48.5±0.7 to 23.0±14.1, mental function from 40.5±2.1 to 15.5±7.8 post-operative, mobility activities from 42.5±2.1 to 21.5±14.9 at follow-up, household activities from 48.5±5.0 to 31.0±0.0 post-operative, and life and social activities from 41.0±0.0 to 20.5±0.5, all non-significant. For a comprehensive overview of the PROMs and their outcomes in the included articles, please see Tables S2-S9.

Lymphatic flow following LVA

Only three articles within this review of LVA provided data on changes in lymphatic flow, evaluated with ICG-L or lymphoscintigraphy (29,41,46). The velocity of ICG was calculated from video recordings as the distance traveled divided by the time elapsed (cm/min) (46). In the case of lymphoscintigraphy, the lymphatic transport index (LyTI) was evaluated and compared to a scale where 0 was considered a completely normal condition and 45 a completely pathological condition (29,41). The ICG-L was only assessed prior to LVA, however, the article found a positive correlation between pre-operative ICG velocity and post-operative volume reduction, indicating that a higher velocity before surgery might lead to a better outcome following surgery (46). Boccardo et al. presented a significant improvement in lymph flow following LVA, with a decrease of LyTI from 31.7±9.4 to 11.2±1.9 at 18 months follow-up (29). On the other side, Damstra et al. reported no significant alteration in lymphatic flow with a decrease from 43.0 [28–45] to 42.2 [30–43] (41).

Patency of anastomoses

Four studies additionally assessed the patency of anastomoses during follow-up appointments, with 76.5% of the anastomoses confirmed as patent and at least one patent LVA found in 82.8% of the patients. These evaluations were performed using ICG-L, which involved observing the flow of ICG dye through the vessels beneath the surgical scars (20,30,48,49).

The effect of VLNT

Our review included 31 studies (40.3%) published between 2006 and 2023, examining VLNT for BCRL, see Table 5. The studies were globally diverse, with notable contributions from Taiwan (nine studies) (49,56-63), United States (four studies) (64-67), as detailed in Figure 2. The study designs comprised 14 retrospectives (8,44,49,56,60,61,68-75), 13 prospectives (57-59,62-67,76-79), two randomized controlled trials (5,19), and two of unspecified designs (80).

The study population involved 972 patients, ranging from ten to 100 per study, with a mean lymphedema duration of 3.9±1.6 years prior to surgery. Notably, one study included two male patients (65). For evaluating the degree of lymphedema, the primary classification was the ISL, used in 15 articles (5,19,44,58,61,64,65,68,70,72,77-81). Other grading systems included the Cheng Lymphedema Grading System (three studies) (49,56,60), M. D. Anderson Scale (one study) (67), Taiwan Lymphoscintigraphy Staging (one study) (59), a modified grading system without further specification (one study) (62), and self-developed classification (three studies) (8,69,74). None of the patients were ISL stage 0. The breakdown of stages was as follows: 11.1% stage I, 74.9% stage II, and 14.1% stage III. Among these, only two studies differentiated between the subcategories of stage II, reporting 6.8% of patients stage Iia, and 7.6% stage IIb.

The majority of studies, 29 studies, used the groin as donor site for vascular lymph nodes. Alternative donor sites included submental (six studies) (49,56,57,59,60,62), gastroepiploic (four studies) (44,61,64,73), subclavicular fossa (three studies) (61,64,77), and lateral thoracic vascularized lymph nodes (three studies) (64,71,81). The axilla was the primary recipient site, mentioned in 21 articles (5,8,19,44,64-72,74-81), followed by the wrist (14 studies) (19,44,49,56-63,68,77,78), elbow (five studies) (19,49,58,62,77), forearm (one study) (73), and unspecified (one study) (64). Fourteen studies combined VLNT with breast reconstruction, predominantly using the deep inferior epigastric perforator (DIEP) flap (10 studies) (19,44,49,67,70,75,76,78,80,81), with variations such as the DIEP or transverse rectus abdominis muscle (TRAM) flap (two studies) (66,69), DIEP or latissimus dorsi (LD) flap (one study) (72), and DIEP, TRAM, or superficial inferior epigastric artery (SIEA) flap (one study) (71). The average surgery duration was 210.7 minutes, ranging from 40.4 to 515 minutes, varying based on the inclusion of breast reconstruction and procedure. Each patient received, on average, 3.2 lymph nodes. Four articles described a partial flap loss in three patients and total flap loss in four (19,44,64,75). Patients were followed for a mean period of 36.3 months, ranging from 6 to 79 months.

However, in studies with extended follow-up, the access to long-term data remains limited, mainly due to substantial loss to follow-up and the observational character of the studies (71,72).

Arm volume following VLNT

All studies, except for one, assessed the effectiveness of VLNT on arm volume. The main outcome measurement was manual arm circumferences, used in 28 articles, with additional methods like perometry (three studies) (66,67,72) and water displacement (one study) (70). Even though manual measurements are commonly used, the way of measuring the patient’s arm, and hereafter presenting the data, differ amongst the studies. Most commonly, the arm circumferences were measured ten cm above and below the elbow, some also measured at the level of the axilla, wrist and mid-palm, however, studies are inconsistent. Most common, changes in arm volume were reported as circumference reduction rates (CRRs), calculated as follow (19):

CRR=(1−ΔArmCircumferenceAftersurgeryΔArmCircumferenceBeforesurgery)×100%[2]

Where Δarm circumference_before represents the difference in arm circumferences between the lymphedematous and unaffected arm before surgery, and Δarm circumference_{after surgery} presents the difference in arm circumference between the lymphedematous and unaffected arm after surgery. Even though a substantial number of articles (nine papers) used the CRR (19,44,49,56,61,63,65,68,79), manual circumferences measures were overall performed in eleven different ways, with different circumference points, presenting either individual circumference differences or the sum of circumferences, for further calculations of the CRR. Even though a substantial number of articles reported their volumetric outcome as CRR, due to limited reporting of data in the included studies, no meta-analysis was conducted as available data was limited, making it impossible to conduct. An unweighted mean of their circumferential reduction rate, a mean relative volume reduction of 43.6%, was seen. However, this number should be interpreted with caution due to the potential risk of bias and unweighted mean.

Patients’ quality of life following VLNT

A total of 14 studies examined the impact on quality of life (5,19,56,59,60,62-65,68-70,75,80), primarily evaluated using the LYMQOL questionnaire (seven studies) (56,59,60,62,65,68,80). Due to a considerable degree of heterogeneity in the reported outcomes, with an I² of 0.95, a meta-analysis was not conducted for LYMQOL scores. Other tools included the Upper Limb Lymphedema 27 (ULL-27) in two studies (64,75), two studies using VAS for pain, function, and arm heaviness (5,19), and the Lymphedema Life Impact Scale (LLIS) in one study (64). Custom-developed questionnaires were used in two studies, with one study also incorporating lymphedema knowledge and health-care seeking behavior questionnaires (59,63,69). Even though a meta-analysis was not possible, all articles reported an improvement in patient-reported outcomes, with an overall improvement of 3.7 points for total quality of life; computed as an unweighted mean for LYMQOL (20,30,31,36,46). Generally, patients were experiencing a greater overall quality of life, with improvement in their lymphedema symptoms, arm function, bodily appearance, and mood.

Lymphatic flow after VLNT

A total of seven articles evaluated the lymph flow following surgery, primarily through lymphoscintigraphy, ICG lymphography or L-Dex score (5,8,71,76,77,79,81). Lymphscintigraphy results were evaluated as activity in implanted lymph nodes, or semi-quantified as the transport index (TI). Articles showed an improvement in lymph flow, and a single article demonstrated an absolute improvement in TI of 3.3, with a significant decrease from 29.0±14.4 to 26.0±14.2 (71). For the results qualitatively described, “improved”, “some improvement” or “effectiveness of lymph nodes” were used as their main outcome. A mean 66.6% of the patients were found to have some improvements or visible lymph nodes following surgery, evaluated by lymphschintigraphy findings. Looking at ICG-lymphangiography, articles mainly subjectively described improvements of dermal backflow patterns, without further description (76,81).

The effect of liposuction

Twelve (15.6%) of the included studies investigated the effect of liposuction on treating BCRL, see Table 6. The studies published in the period 1998 and 2023 had a geographical distribution between Sweden (10 studies) (82-91), the Netherlands (one study) (92), and South Korea (one study) (93), see Figure 2. Eleven out of 12 studies were prospective studies (82-92), while one was retrospective (93). The outcomes for efficacy assessment of liposuction were excessive arm volume reduction (12 articles) (82-93), improvement in health-related quality of life (two articles) (83,88), changes of soft-tissue composition (one article) (89), improvement in lymph flow (one article) (84), reduction in erysipelas incidents (two articles) (82,90), and improvement in tissue tonometry (one article) (89).

Sample sizes ranged from 12 to 130 patients, with a total of 487 patients undergoing liposuction. The mean duration of lymphedema was 9.3±2.0 years before surgery. Five studies applied the pitting test for lymphedema assessment. This test involves exerting pressure on the patient’s arm for one minute (87). Subsequently, they assess whether a temporary indentation or pit forms in the skin and, if so, measure its depth in millimeters to quantify the degree of pitting. Only patients presenting with no- or minimal pitting were offered liposuction. Two studies used the M. D. Anderson Scale, ICG-L, and Arm Dermal Backflow Scale for evaluation (86,93).

A combination of dry liposuction, power-assisted liposuction, and tumescent liposuction was applied across all studies; overall, a mean total volume of 1,596±332.3 mL was aspirated during surgery. In recent times, power-assisted liposuction ad modum Brorson has become the most accepted method (94).

The I² statistic was calculated to quantify the heterogeneity of volume measures, yielding a value of 0.99, indicating substantial heterogeneity among the studies. Consequently, a meta-analysis was unsuitable. Across studies, an unweighted mean reduction of excess arm volume of 1,667.5±132.2 mL was accomplished. Arm volume was evaluated using the water displacement method in ten studies (82-86,88-92); a single study also used DEXA scans (86), another study used plethysmography (87), and the last study used arm circumference measures (93). Only one study presented the surgery duration with a median of 122 (range, 70–220) minutes (91).

A total of 10 studies followed their patients for 12 months (83-86,88-93); a single study had a follow-up time of only 6 months (82) and a single study for 5 years (87), all indicating effective reduction of arm volume, including long-term effects. Ten out of 12 articles described their post-operative routine, all involving immediate compression garments following surgery with minor variations. Brorson et al. also presented the consequences of discontinuing the compression garment with increased arm volume as a consequent (85). Only one study described complications, including paraesthesia in the operated arm, pneumonia, dyspnea, and superficial abrasion caused by compression garments and erysipelas (91). None the studies described any major complications.

One article investigated the effect of liposuction on lymphatic flow, and two articles presented the impact on quality of life, with significant improvements (83,88). Brorson et al. presented a study on patients’ quality of life following liposuction with a statistically significant improvement in shoulder range of motion and a decrease in VAS score regarding pain, hand and arm swelling, and difficulties with activity of daily living (ADL) functions during 1-year follow-up. Regarding their results from Nottingham Health Profile, significant improvements were seen in total score, pain, and housework after 1 year. Looking at patients’ answers from the Psychological General Well-Being Index and Hospital Anxiety Depression Scale, no significant improvements were seen; however, patients undergoing only conservative treatments had a significantly higher score regarding anxiety when compared to the liposuction group (83). Hoffner et al. evaluated the effect on the quality of life using the SF-36 questionnaire and presented a significant improvement at a 1-year follow-up regarding physical functioning, bodily pain, social functioning, mental health, and vitality. An improvement was also seen in their physical and mental component scores, which is an aggregation of the other domains. The results were also compared to normative data with the Swedish reference score from the SF-36 questionnaire, and no significant differences were detected after 1 year of follow-up regarding physical functioning, role physical, role emotional, and general health, indicating they were able to normalize the patient’s quality of life (88).

Only a single study evaluated the changes in lymph flow following surgery, quantified as the clearance of injected activity during indirect lymphoscintigraphy. The study concluded no lymph flow change after liposuction and compression garments. At 12 months follow-up, there was a slight increase in activity of the upper arm; otherwise, no differences were found, indicating no further damage to the lymphatic system following liposuction (84).

Upon data evaluation, an initial assessment of the included studies revealed substantial heterogeneity in the effect size among the selected trials with normally distributed data (87,88). The heterogeneity assessment included calculating the I² statistics quantifying the proportion of total variation in effect sized due to heterogeneity rather than chance. In this analysis, the I² statistics yielded a value of 0.99, indicating significant heterogeneity between the two studies. It was determined that a meta-analysis was not appropriate for this review; instead, a narrative synthesis of the included studies was conducted.

Patient characteristics

The articles included in the present study focused on liposuction presented patients with only minimal or no pitting lymphedema, when selecting patients for the procedure. In contrast, studies exploring both LVA and VLNT primarily utilized the ISL classification system when evaluating patient’s lymphedema. The range of patients included in these studies spanned from stage I to III, with variable results. Only two randomized controlled trials on VLNT, reported outcomes specific for patients in stage II or a combination of stages II and III, with significant volume reduction, improvement in symptoms, and reduction in infection rate. A single randomized controlled trial on manual or robotic-assisted LVA present no significant volume reduction following surgery, for patients classified primarily at stage II, with a single patient in stage I (20). However, it should be noted that this was a pilot study. See Table 7, for summarized data from studies on LVA, VLNT and liposuction.

Ongoing clinical trials

There are currently six ongoing trials investigating the effect of LVA and/or VLNT on BCRL (89,95-100). Two are designed as randomized controlled trials (95,98), three as randomized parallel assignments (97,99,100), and a single pilot study (96). Their outcomes include the effect on arm volume, arm circumference, quality of life, and shoulder mobility. The most extended follow-up planned is 10 years in a single study (100), which investigates the effect of LVA and VLNT on quality of life measured with LYMPH-ICF-UL, LYMPH-Q, EQ-5D-5L, and VAS questionnaires. The ongoing trials are geographically located in the Netherlands (95), Denmark (96), the United Kingdom (97), Sweden (98), Norway (99), and Switzerland (100).

Future perspectives

LVA

In the lastest articles from 2023 to 2021, a noticable difference was observed in planning methods for LVA surgery compared to the other articles. More studies utilized ultrasound, including a single study with ultra-high frequency ultrasound, in the planning of LVA surgery. Surgeons are using ISL more frequently for evaluation the lymphedema, and arm volume were evaluated with manual arm circumference. However, various outcomes were epmloyed when presenting results, including the UEL index, interlimb ratio, circumferenctial reduction rate, relative excess volume, among others. As for PROMs, different questionnaires were applied across the studies. Overall, articles shared a similar follow-up duration, except for one with longer follow-up with 60-month, reporting sustained arm volume reduction. However, specific results for this period were not provided, presenting challenges for a thorough assessment (29).

VLNT

The latest articles from 2023 to 2021 do not notably differ from the other articles in terms of measurement methods, planning methods, or patient populations. Two of the studies have the longest follow-up period among included articles, but due to substantial loss to follow-up, limites data is available to assess long-term effects. Most frequently, studies evaluate arm volume using arm circumferences however, measurements are still performed at different levels, and used to evaluate arm volume with different calculations and presentations.

Liposuction

Among the limited included articles, there is consistency in the reported results across all years of published data. The shift in surgical techniques has moved away from the “dry technique” trend, now favoring the tourniquet combined with the tumescence technique to minimize blood loss in (86,87). Regarding follow-up, outcome measures and patient population, no significant changes in trends has been observed in recent years.

Discussion

The surgical management of BCRL is rapidly evolving and showing promising results. However, the existing evidence is a product of studies with large heterogeneity limiting comparability and meta-analysis. Future studies should focus on building on the existing evidence in order to strengthen the evidence on the field of surgical BCRL treatment.

Liposuction

Liposuction has emerged as an effective method for volume reduction in non-pitting lymphedema, with a significant reduction in arm volume and improved quality of life, compared to compression therapy (83). Although the studies exhibit moderate to high risk of bias, the results are remarkable. Furthermore, a long-term study indicates a sustained reduction in volume, confirming the enduring effectiveness of liposuction for treating lymphedema (87). However, it is important to note that liposuction does not address the underlying lymphatic dysfunction. Consequently, continuous compression garment usage is necessary to maintain the reduced arm volume (85). Another key aspect is the observation that dry liposuction does not further exacerbate damage to the lymphatic channels of the lymphedematous arm, emphasizing its safety and efficiency (84).

Regarding the impacts on health-specific quality of life and its long-term result needs further investigation using disease-specific questionnaires to provide deeper insight into its effect, as studies have only been conducted using unspecific questionnaires (83,88).

VLNT

VLNT intend to rebuild the lymphatic pathways, improving lymphatic function. It aims to address the underlying pathophysiology of lymphedema; however, to our knowledge, whether the lymph node transfer lead to lymphangiogenesis and increased drainage has still not been shown or confirmed. Even though most studies are observational with a high risk of bias, the included studies indicated promising results in limb volume reduction and symptom relief, with significant improvement in two well-conducted randomized controlled trials (5,19). Patients experiencing substantial improvements originate from ISL stages II and III, a group covering patients with and without active pitting lymphedema. However, no statistical differences were found in limb reduction between patients at stages I, II, or III, which may indicate an effective procedure for both patients with mild to more developed stages of lymphedema (72). When combined with breast reconstruction, the effect on limb reduction may be significantly greater compared to transplanted lymph nodes alone (19,49). These results were derived as secondary outcomes from a sample of 15 patients in the randomized controlled trial (RCT) study (19). Additionally, an improved patient-reported quality of life and reduced rate of skin infections has been reported, further emphasizing the positive outcomes of the intervention. A cost analysis revealed that VLNT was significantly less expensive compared to lifelong conservative treatment with physiotherapy and compression. Additionally, the overall expenses increase when accounting for the costs associated with sick leave and antibiotics for recurring lymphedema-related infections (5). Therefore, an intervention like VLNT, which may reduce infection rates and potentially decrease sick leave, calls for further systematic studies to justify its use.

While the potential risk of donor site lymphedema from VLNT is a significant concern, the included studies only report two cases of lower extremity swelling as a complication of the procedure (57,66). The complications reported were primarily related to issues with the microvascular flap, such as flap necrosis, infections, and lymphorrhea, rather than lymphedema at the donor site. It is necessary to consider the possibility of reporting bias, as a limited number of studies reported an approach for evaluating donor-site lymphedema. Additionally, since our primary focus did not include complications, the articles were not selected based on their reporting of such issues. Thus, this review may not fully represent the actual rate of complications.

Another issue of great discussion is the preferred donor- and recipient site for lymph nodes, see Figure 3. Vascular submental lymph nodes may lead to a significantly greater volume reduction than inguinal lymph nodes (57). Furthermore, patients undergoing inguinal VLNT are at greater risk for donor-site lymphedema. In the study conducted by Ho et al., lymphedema of the legs manifested in 7.7% of patients undergoing inguinal VLNT harvest in their study subjects, translating to two cases within a group of thirteen patients (57). Considering the available evidence from a study involving 43 patients, submental lymph nodes seem superior compared to the inguinal lymph nodes, unless other circumstances favor the groin, as the donor site, such as breast reconstruction combined with VLNT or if the patient prefers to avoid scarring on their neck (19,57). Examples on advantages and disadvantages regarding donor- and recipient sites as described in the literature are presented in Table 8 (19,57,58,61,101).

Figure 3 Illustration of the different donor sites (marked with red circles) and recipient sites (marked with blue circles) for VLNT. Donor sites include submental, supraclavicular, omentum, lateral thoracic and inguinal lymph nodes. Recipient sites include axil, elbow and wrist. VLNT, vascularized lymph node transfer.

Regarding the choice of recipient site for lymph node transfer, current studies do not show a significant difference in outcomes between proximal and distal locations. Axillary insertion combined with breast reconstruction appears to be a favorable option, in instances where this is not relevant, the patient’s preference for scar placement should be the primary consideration, given the current evidence (19). Another reason that advocates for axillar placement is in cases of substantial axillary scarring with a restricted range of motion of the shoulder, where a skin flap with lymph nodes might be preferred, and may even aid in decreasing the compression of the axillary vein (68).

LVA

LVA is primarily designed to restore lymphatic drainage. However, as seen in various studies, its effectiveness has been inconsistent. Some studies report limb volume reduction and improvements in symptoms and quality of life, while others have not observed significant changes. Given that most of the data originates from studies with a high risk of bias, it is challenging to asses LVA’s impact on arm volume reduction. Notably, there was a prominent improvement in quality of life and arm function in many studies, although not all reported significant volume reduction. Whether this is due to the placebo effect cannot be ruled out, as well-conducted RCT studies are lacking in this field of research. The actual effectiveness of LVA remains unclear, and further research is essential to elucidate its impact. Evidence suggests that LVA might be more effective in the early stages of lymphedema than in the advances stages (37). Most studies focused on patients in stages II and III, while only 12.2% of included patients were stage I, potentially overlooking the full potential of LVA due to selection bias. A potential hurdle involves recruiting patients in the initial stage of lymphedema, given that almost half of those assessed with lymphedema are unaware of their condition (42). This places an increased responsibility on clinicians to actively monitor our cancer patients, aiming to detect the condition early on and provide the opportunity for prompt intervention (59). The overall goal of lymphedema treatment also warrants discussion. While volume reduction is a key objective, symptom relief and improved functionality may be equally important. The only RCT study amongst the included studies did not show significant volume reduction but did report notable improvements in quality of life.

Most studies employed ICG-L before surgery to identify lymphatic vessels leading up to an area of dermal backflow for anastomosis. The technique has been shown to be superior to surgery without pre-operative guidance (27). A novel approach combines ultra-high frequency ultrasound and ICG-L to locate nearby venules. It could potentially optimize and shorten the duration of the procedure. None of the included articles indicated one anastomosis technique superior to another. Opting for end-to-side rather than end-to-end may be driven by variations in vessel caliber and the potential risk of venous backflow. The most frequent type of anastomoses performed was an end-to-end; see Figure 4 for all types of anastomoses. There is insufficient evidence among the included studies to recommend one technique over the other. A single study indicates significantly greater volume improvements the more anastomoses formed; however, challenges lie in selecting the lymph vessels of dermal backflow and not performing anastomosis on already functioning lymph vessels without blockage.

Figure 4 Illustration of different types of anastomoses between lymph vessels and venules, including end-to-end, sleeved, end-to-side, side-to-side, lambda-shaped and pi-shaped anastomoses.

A shared challenge among lymphedema classification systems is their dependence on subjective assessments and the inherently complex nature of lymphedema. The extent of a patient’s lymphedema may vary depending on the region of the arm being evaluated. This variability adds layers of complexity to the accurate diagnosis of lymphedema, a fact echoed in the varied assessment techniques used in the research we examined. Although the pitting test is advantageous for its accessibility and straightforwardness in both execution and evaluation, it is noteworthy that this method was not used in any of the studies concerning LVA or VLNT we reviewed. Nevertheless, the ISL incorporates the pitting test in its lymphedema assessments, see Table 3. We would recommend maintaining consistency in using the same classification method in the future, facilitating data comparison.

Treatment algorithm

Based on the knowledge available, we have developed a treatment algorithm built upon evidence-based studies and approaches for optimal management and treatment of BCRL, see Figure 5.

Figure 5 The proposed treatment algorithm based on the available knowledge. ICG-L, indocyanine green lymphography; LVA, lymphovenous anastomosis; VLNT, vascularized lymph node transfer; DIEP, deep inferior epigastric artery flap.

Future perspectives

A significant challenge in lymphedema research is the diversity in lymphedema evaluation, measuring methods, and data reporting, making it difficult to compare results across studies. For future research, standardizing these aspects is crucial to better understand the interventions’ actual effects. Transparent reporting of pre- and post-intervention data from well-conducted trials, including statistical details, will significantly enhance the research field, especially relevant for studies on LVA and VLNT. In simpler terms, there is an urgent need for thoroughly executed randomized trials with a well-reasoned and calculated study size. These studies should systematically explore the impact of surgery on arm volume and quality of life while providing comprehensive and accurate data reporting.

Other questions that still remain unanswered are the long-term outcome on arm volume following LVA and VLNT, the impact of LVA on earliest stage of lymphedema, the influence of liposuction on health-related quality of life, and a comparative analysis of VLNT and LVA to determine if patients should be recommended VLNT over LVA or combined approach. Lastly, the variations in outcomes based on different donor- and recipient-sites for VLNT remain to be fully explored.

Regarding measuring arm volume changes, reporting the absolute reduction in mL and percentage for arm differences would provide a more concrete metric for clinicians and researchers. A systematic review by Hidding et al. recommends the utilization of water volumetry for assessing arm volume in breast cancer-related lymphedema (102). This method is highly reliable, exhibiting the lowest variance, standard error of the mean (SEM), and the smallest detectable change (SDC) when compared to tape measurements and perometers. Additionally, perometers are costly instruments compared to water displacement and tape measurements, making them less preferable for primary practice. Moreover, we highlight the importance of screening for BCRL following cancer treatment for early detection and interviention (102).

A COSMIN review identified deficiencies in existing questionnaires for lymphedema patients regarding the quality of life assessments. In response, Klassen et al. developed the LYMPH-Q Upper Extremity Module questionnaire to fill this gap and provide a tool with solid content validity for BCRL (103). None of the studies we reviewed utilized this questionnaire, likely because it was only developed in 2021. Nonetheless, we advocate for its future adoption in assessing the quality of life in patients with BCRL.

Conclusions

In conclusion, liposuction is a valuable option in treating BCRL for patients with non-pitting lymphedema, who can accept lifelong compression therapy, where excess volume is the primary concern. VLNT seems to be effective for patients presenting with both pitting- and non-pitting lymphedema and is especially preferred for patients who also are planning to undergo breast reconstruction, however more high evidence studies are needed to confirm the findings. The effect of LVA is more uncertain, but it seems essential to treat the patients in the early stages to achieve a potential impact. Data is based on articles with high risk of bias and is, therefore, of a low level of evidence.

Thus, to summarize, BCRL is a complex disorder with many uncertain elements. Surgical treatments can be effective in suitable patients, but well-conducted clinical studies in the field are still lacking to uncover several unanswered questions.

Acknowledgments

The authors thank the University Library of Southern Denmark for reviewing the search strategy.

Funding: This work was supported by the ACROBATIC—Research Collaboration Across Surgical Oncology for Better Patient Care, Danish Cancer Society (No. R317-A18255) and Danish Comprehensive Cancer Center Report.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Gland Surgery for the series “Hot Topics in Breast Reconstruction World Wide”. The article has undergone external peer review.

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://gs.amegroups.org/article/view/10.21037/gs-23-503/rc

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-23-503/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.org/article/view/10.21037/gs-23-503/coif). The series “Hot Topics in Breast Reconstruction World Wide” was commissioned by the editorial office without any funding or sponsorship. Funding originated from the ACROBATIC—Research Collaboration Across Surgical Oncology for Better Patient Care, Danish Cancer Society (No. R317-A18255) and Danish Comprehensive Cancer Center Report covers 1 year salary for the first author (C.L.) during her PhD. study. T.E.D. served as the unpaid guest editor of the series and is a committee member of ACROBATIC—Research Collaboration Across Surgical Oncology for Better Patient Care, who has financially supported the main author of this article. J.B.T. serves as an unpaid Honorary Editor-in-Chief of Gland Surgery from November 2022 to October 2024 and served as the unpaid guest editor of the series. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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