Coverage Policy Manual
Policy #: 2018020
Category: Surgery
Initiated: July 2018
Last Review: July 2023
  Surgical Treatments for Lymphedema Secondary to Breast Cancer Treatment
Description:
Surgery and radiotherapy for breast cancer can lead to lymphedema and are some of the most common causes of secondary lymphedema. There is no cure for lymphedema. However, physiologic microsurgical techniques such as lymphaticovenular anastomosis or vascularized lymph node transfer have been developed that may improve lymphatic circulation, thereby decreasing symptoms and risk of infection. This policy focuses on physiologic microsurgical interventions.
 
LYMPHEDEMA
Lymphedema is an accumulation of fluid due to disruption of lymphatic drainage. Lymphedema can be caused by congenital or inherited abnormalities in the lymphatic system (primary lymphedema) but is most often caused by acquired damage to the lymphatic system (secondary lymphedema).
 
Diagnosis and Staging
A diagnosis of secondary lymphedema is based on history (e.g., cancer treatment, trauma) and physical examination (localized, progressive edema and asymmetric limb measurements) when other causes of edema can be excluded. Imaging, such as magnetic resonance imaging (MRI), computed tomography (CT), ultrasound, or lymphoscintigraphy, may be used to differentiate lymphedema from others causes of edema in diagnostically challenging cases.
 
Below is a list of International Society of Lymphology guidance for staging lymphedema based on "softness" or "firmness" of the limb and the changes with an elevation of the limb (International Society of Lymphology Executive Committee, 2016):
 
  • Stage 0 (subclinical) - Swelling is not evident and most patients are asymptomatic despite impaired lymphatic transport
  • Stage I (mild) - Accumulation of fluid that subsides (usually within 24 hours) with limb elevation; soft edema that may pit, without evidence of dermal fibrosis
  • Stage II (moderate) - Does not resolve with limb elevation alone; limb may no longer pit on examination
  • Stage III (severe) - Lymphostatic elephantiasis; pitting can be absent; skin has trophic changes
 
Breast Cancer−Related Lymphedema
Breast cancer treatment is one of the most common causes of secondary lymphedema. Both the surgical removal of lymph nodes and radiotherapy are associated with development lymphedema in patients with breast cancer.
 
In a systematic review of 72 studies (N=29,612 women), DiSipio et al reported that approximately 1 in 5 women who survive breast cancer will develop arm lymphedema (DiSipio, 2013). Reviewers reported that risk factors for development of lymphedema that had a strong level of evidence were extensive surgery (i.e., axillary-lymph-node dissection, greater number of lymph nodes dissected, mastectomy) and being overweight or obese. The incidence of breast cancer-related lymphedema was found by DiSipio et al as well as other authors to be up to 30% at 3 years after treatment (Disipio, 2013; Ribeiro, 2017, Zou, 2018).
 
Studies have also suggested that Black breast cancer survivors are nearly 2.2 times more likely to develop breast cancer-related lymphedema compared to White breast cancer survivors (Dean, 2016). These observations may be linked to racial disparities with regards to access to treatment and the types of treatments received. Black women are more likely than White women to undergo axillary lymph node dissection, which is associated with greater morbidity than the less invasive sentinel lymph node biopsy. While this may be explained in part by Black individuals having a higher likelihood of being diagnosed with more aggressive tumors, there is evidence that even when adjusting for stage and grade of tumors, Black women are more likely to undergo axillary lymph node dissection, putting Black women at greater risk of breast cancer-related lymphedema. Additionally, Black breast cancer survivors, on average, have higher body mass indexes than White breast cancer survivors, which could contribute to development of lymphedema in this setting as well.
 
Management and Treatment
Early and ongoing treatment of lymphedema is necessary. Conservative therapy may consist of several features depending on the severity of the lymphedema. Patients are educated on the importance of self-care including hygiene practices to prevent infection, maintaining ideal body weight through diet and exercise, and limb elevation. Compression therapy consists of repeatedly applying padding and bandages or compression garments. Manual lymphatic drainage (MLD) is a light pressure massage performed by trained physical therapists or by patients designed to move fluid from obstructed areas into functioning lymph vessels and lymph nodes. Complete decongestive therapy is a multiphase treatment program involving all of previously mentioned conservative treatment components at different intensities. Pneumatic compression pumps may also be considered as an adjunct to conservative therapy or as an alternative to self-MLD in patients who have difficulty performing self-MLD. In patients with more advanced lymphedema after fat deposition and tissue fibrosis has occurred, palliative surgery using reductive techniques such as liposuction may be performed.
 
REGULATORY STATUS
Physiologic microsurgery for lymphedema is a surgical procedure and, as such, is not subject to regulation by the U.S. Food and Drug Administration.
 
Coding
There is no specific CPT code for this procedure. Providers may bill the following unlisted code:
38999 (Unlisted procedure, hemic or lymphatic system.)
Policy/
Coverage:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Lymphatic physiologic microsurgery to treat lymphedema (including, but not limited to, lymphatico-lymphatic bypass, lymphovenous bypass, lymphaticovenous anastomosis, autologous lymph node transplantation, and vascularized lymph node transfer) in individuals who have been treated for breast cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, lymphatic physiologic microsurgery to treat lymphedema (including, but not limited to, lymphatico-lymphatic bypass, lymphovenous bypass, lymphaticovenous anastomosis, autologous lymph node transplantation, and vascularized lymph node transfer) in individuals who have been treated for breast cancer is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Lymphatic physiologic microsurgery performed during nodal dissection or breast reconstruction to prevent lymphedema (including, but not limited to, the Lymphatic Microsurgical Preventing Healing Approach) in individuals who are being treated for breast cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, lymphatic physiologic microsurgery performed during nodal dissection or breast reconstruction to prevent lymphedema (including, but not limited to, the Lymphatic Microsurgical Preventing Healing Approach) in individuals who are being treated for breast cancer is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Rationale:
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function—including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.
 
To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.
 
TREATMENT OF SECONDARY LYMPHEDEMA IN BREAST CANCER PATIENTS
 
Clinical Context and Therapy Purpose
The purpose of physiologic microsurgery treatments for lymphedema in patients who have been treated for breast cancer is to provide a treatment option that is an improvement on existing therapies such as conservative therapy with compression garments or bandages, manual lymph drainage or pneumatic pumps, and decongestive therapy. Both surgical treatment and radiotherapy for breast cancer can lead to lymphedema and is one of the most common causes of secondary peripheral lymphedema.
The question addressed in this evidence review is: Does lymphatic physiologic microsurgery for the treatment of breast cancer–related lymphedema improve the net health outcome?
 
The following PICOTS were used to select literature to inform this review.
 
Patients
The relevant population of interest is individuals who have been treated for breast cancer, who have developed secondary lymphedema, and who have insufficient symptom reduction with conservative therapy, who have recurrent cellulitis or lymphangitis, or who are dissatisfied with conservative therapy. Lymphedema in its late chronic phase is irreversible. The surgical techniques of interest in this review are those performed in individuals who have not reached the irreversible stage, ie, those who have functioning lymphatic channels (stage I, II or early stage III).
 
Interventions
This review focuses on physiologic microsurgical interventions; it does not consider reductive (also known as excisional or ablative) surgical interventions (eg, liposuction). Physiologic microsurgical interventions include several techniques and can be broadly grouped into procedures that (1) reconstruct or bypass the obstructed lymphatic vessels to improve lymphatic drainage and (2) transfer lymph tissue into an obstructed area to reestablish lymphatic flow.
 
Comparators
Physiological microsurgery may be used as an adjunct to conservative therapy. Conservative therapy is multimodal. It involves meticulous skin hygiene and care, exercise, compression therapy, and physical therapy (manual lymphatic drainage). Complete decongestive therapy and pneumatic compression pumps are also used as adjuncts to conservative therapy.
 
Outcomes
Objective outcomes of interest include reduction in limb circumference and/or volume and reduction in the rates of infections (eg, cellulitis, lymphangitis). Volume is measured using different methods; eg, tape measurements with geometry formulas, perometry, and water displacement. Bioimpedance spectroscopy may be used to detect changes in tissue fluid accumulation; this technology is reviewed in 2.01.82 (bioimpedance devices for detection and management of lymphedema).
 
Patient-reported outcomes (PROs) of interest include symptoms, quality of life, and functional measures. A systematic review of PRO instruments and outcomes used to assess quality of life in breast cancer patients with lymphedema, Pusic et al found that most studies included generic PRO instruments or oncology PRO instruments (Pusic, 2013). Lymphedema-specific instruments are occasionally used; specifically the Upper Limb Lymphedema 27 was found to have strong psychometric properties.
 
There does not appear to be a consensus on minimally clinically important change for either objective outcomes such as changes in arm volume or subjective measures such as changes to patient symptoms or quality of life.
 
Timing
The existing literature supporting conservative therapies for lymphedema has varying lengths of follow-up, ranging from a few weeks to 1 year. In systematic reviews of microsurgical treatments for lymphedema discussed in the following sections, studies suggest less than a year of follow-up is insufficient to observe outcomes. Therefore, at least 1 year of follow-up is considered necessary to demonstrate efficacy.
 
Setting
Microsurgery for lymphedema is performed by surgeons with advanced training in highly specialized microsurgery and lymphology and also requires specialized imaging tools.
 
Study Selection Criteria
Methodologically credible studies were selected using the following principles:
a. To assess efficacy outcomes, comparative controlled prospective trials were sought, with preference for RCTs;
b. In the absence of such trials, comparative observational studies were sought, with preference for prospective studies.
c. To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
d. Studies with duplicative or overlapping populations were excluded.
 
Because multiple systematic reviews of studies were available for both classes of microsurgery, focus is on systematic reviews published in 2015 or later.
 
Surgeries That Reconstruct or Bypass Using Donor Lymph Vessels
Leung et al reported on a systematic review of surgical management breast cancer−related lymphemdema (Leung, 2015). The search included studies reporting on the efficacy of surgical techniques used for the prevention or treatment of breast cancer−related lymphedema published between 2000 and 2014. Only 1 study on lymphatico-lymphatic bypass (LLB) was identified and published since 2000. The study included 7 patients followed for 2.6 years. One patient had “complete recovery” as measured by circumference of the affected limb and the remaining 6 patients had a “reasonable outcome”. Postsurgery complications were cellulitis, donor-site lymphorrhea, and transient edema of donor leg.
 
Surgeries That Reconstruct or Bypass Using the Venous System
Systematic Reviews
Two systematic reviews specifically evaluating microsurgical procedures using the venous system (lymphaticovenular anastomosis [LVA], lymphovenous bypass) have been reported (Cornelissen, 2018; Scaglioni, 2017). Two broader systematic reviews of treatments for lymphedema including several microsurgical procedures have also been reported (Leung, 2015; Carl, 2017). Cornelissen et al and Leung et al were limited to studies of breast cancer−related lymphedema but the remaining reviews were not. Thirty-four publications on LVA were included across the 4 systematic reviews.
 
Cornelissen et al reported on a systematic review assessing the effect of LVA in breast cancer−related lymphedema (Cornelissen, 2018). Fifteen observational studies were identified (11 prospective, 4 retrospective) with follow-up times ranging from 2 months to 8 years. Although LVA surgery was performed in the included studies, the technical procedure differed among studies: 6 studies used only end-to-end anastomoses; 4 studies used both end-to-end and end-to-side anastomoses; 1 study used the ‘‘Octopus technique’’; and 4 studies did not report the LVA technique used. Only 2 studies included a control group (bandaging, decongestive therapy).
 
Scaglioni et al reported on a systematic review of LVA for the treatment of lymphedema Scaglioni, 2017). Reviewers noted significant variations in surgical techniques, numbers of anastomoses, and supplementary interventions (ie, compressive therapy, additional debulking surgery). Nine studies included secondary lymphedema alone, while 8 studies included patients with both primary and secondary lymphedemas. The number of patients with breast cancer−related lymphedema was not described. As mentioned, the Carl and Leung reviews included multiple surgical techniques. Leung was limited to breast cancer−related lymphedema while Carl was not.
 
In 3 of the reviews, given the variability in the procedures, metrics for measuring the outcomes, and the time periods of reporting, meta-analyses were not possible and only a narrative synthesis provided. In the Carl review, meta-analyses were performed for the outcome measure of percent excess circumference reduction, although only a small subset of studies reported this outcome and could be combined. Risk of bias was assessed in the Cornelissen systematic review and summarized as follows:
 
    •  9 of 15 studies did not describe whether consecutive patients were included, so selection bias is possible;
    • 9 of 15 studies did not describe the surgery team;
    • 5 of 15 studies did not have sufficient follow-up to evaluate the long-term effects of LVA (ie, <1 year).
 
 
Randomized Controlled Trials
No RCTs were identified.
 
Nonrandomized or Observational Studies
Additional single-arm studies have been published since the systematic reviews (Salgarello, 2018). However, these studies suffer from the same limitations as the studies included in the systematic reviews and do not capture longer periods of follow-up and/or larger populations than the existing studies. Therefore they are not discussed further.
 
Subsection Summary: Surgeries That Reconstruct or Bypass Using the Venous System
No controlled trials were identified evaluating the physiologic microsurgeries using techniques such as lymphovenous bypass or LVA that reconstruct or bypass the obstructed lymphatic vessels using the venous system in patients with breast cancer−related lymphedema. Systematic reviews have indicated that most of the available evidence for these procedures comes from uncontrolled studies including fewer than 40 participants each, most of which lack adequate descriptions of how patients were selected for inclusion. Surgical technique, severity of lymphedema, outcomes metrics, and follow-up times varied across studies making it difficult to draw conclusions. Surgical complications have been inconsistently reported but appear to be rare. RCTs of physiologic microsurgeries that bypass the obstructed lymphatic vessels using the venous system plus conservative therapy vs conservative therapy alone are needed.
 
Surgeries That Transfer Lymph Tissue
 
Systematic Reviews
Systematic reviews evaluating microsurgical procedures that transfer lymph tissue (autologous lymph node transfer [ALNT], vascularized lymph node transfer [VLNT]) have been reported. Ozturk et al reported on a systematic review of VLNT for treatment of lymphedema (Ozturk, 2016). They included treatment for both primary and secondary lymphedema and as such comprised a heterogeneous population. However, 191 of 305 of the surgeries were for breast cancer−related lymphedema. Eighteen studies were identified (3 prospective, 15 retrospective). For breast cancer−related lymphedema, VLNT with a skin island or VLNT with an autologous flap was used. There was inconsistent reporting of staging of lymphedema. Reviewers did not state whether any of the studies included a control group. Two systematic reviews of various surgical methods previously described also included a review of lymph node transfer (Leung, 2015; Carl, 2017).
 
In addition to the systematic reviews of efficacy, Demiri et al reported on a systematic review of donor-site complications following ALNT for breast cancer−related lymphedema (Demiri, 2018).
 
In Ozturk and Carl, results for the subgroup of breast cancer−related lymphedema were not presented. Due to differences in outcomes metrics and timing of measurements, meta-analyses were not possible and narrative summaries were provided by Ozturk, Demiri, and Leung. Carl performed meta-analyses for the excess volume outcome but only a few studies could be pooled in the combined estimate. Risk of bias was assessed in Ozturk using a checklist from the American Society of Plastic Surgeons guidelines for therapeutic studies. A summary of the assessment follows:
    • 12 of 18 studies did not report whether patients were selected consecutively and one did not include consecutive patients;
    • 13 of 18 studies had insufficient information on the surgical team;
    • 3 of 18 studies had insufficient follow-up to observe outcomes (ie, <1 year).
 
 
Randomized Controlled Trials
Dionyssiou et al reported on an RCT that evaluated VLNT plus physical therapy vs physical therapy alone for lymphedema in 36 women with stage II breast cancer−related lymphedema (Dionyssiou, 2016). At 18 months, the reduction in excess volume of the affected limb as a percentage of the intact limb was 57% in the VLNT group and 18% in the physical therapy group (treatment effect not reported, p<0.001). The mean number of lymphedema-related infections per patient per year was lower in the VLNT group (0.28 vs 1.16; treatment effect not reported, p=0.001). The trial had several limitations. Notably, there was no description of allocation concealment and the trial was not blinded, possibly introducing both selection and ascertainment bias. The reporting did not describe the power calculations or justify a clinically important difference for the reported outcomes. The trial was not registered, so selective reporting cannot be ruled out.
 
Nonrandomized or Observational Studies
Additional single-arm studies have been published since the systematic reviews (Nguyen, 2017; Ciuidad, 2017; Gennaro, 2017). However, these studies suffer from the same limitations as the studies included in the systematic reviews and do not capture longer periods of follow-up and/or larger populations than the existing studies. Therefore they are not discussed further.
 
Subsection Summary: Surgeries That Transfer Lymph Tissue
One RCT with 36 participants was identified evaluating VLNT that uses lymph tissue transfer in patients with breast cancer−related lymphedema. The trial reported reductions in excess volume of the affected limb and rates of lymphedema-related infections for VLNT plus physical therapy compared with physical therapy alone. Systematic reviews have indicated that most of the remaining available evidence for these procedures comes from uncontrolled studies including fewer than 50 participants each, most of which lacked adequate descriptions of how patients were selected for inclusion. Surgical techniques, severity of lymphedema, outcomes metrics, and follow-up times varied across studies. Although surgical complications were inconsistently reported, a systematic review of complications estimated that donor-site lymphedema occurs in approximately 2% of surgeries and seroma occurs in approximately 4%. Additional RCTs of physiologic microsurgeries that use lymph tissue transfer with conservative therapy vs conservative therapy alone are needed.
 
PREVENTION OF SECONDARY LYMPHEDEMA IN BREAST CANCER PATIENTS
 
Clinical Context and Therapy Purpose
The purpose of lymphatic physiologic microsurgery simultaneous to lymphadenectomy for breast cancer (ie, the Lymphatic Microsurgical Preventing Healing Approach [LYMPHA]) is to prevent lymphedema in individuals who are being treated for breast cancer. While recommendations on preventive measures for lymphedema exist, such as avoiding needle sticks, limb constriction, and air travel, most recommendations are based on clinical opinion. A systematic review of preventive measures for lymphedema by Cemal et al found strong scientific evidence only for the recommendations to maintain a normal body weight or avoid weight gain and to participate in a supervised exercise regimen (Cernal, 2011).
 
LYMPHA is a preventive LVA procedure performed during nodal dissection or reconstructive surgery that involves anastomosing arm lymphatics to a collateral branch of an axillary vein.
 
The question addressed in this evidence review is: Does lymphatic physiological microsurgery for the prevention of breast cancer−related lymphedema improve the net health outcome?
 
The following PICOTS were used to select literature to inform this review.
 
Patients
The relevant population of interest is individuals who are undergoing a lymphadenectomy or breast reconstruction procedure for breast cancer.
 
Interventions
This review focuses on physiologic microsurgical intervention called LYMPHA.
 
Comparators
LYMPHA could be used as an adjunct to standard care. Standard care may involve education regarding lymphedema and recommendations for hygiene, avoidance of blocking flow of fluids in the body, maintaining a normal body weight and exercise, as well as surveillance for lymphedema during follow-up with referral as needed.
 
Outcomes
Outcomes of interest include diagnosis of lymphedema, lymphedema symptoms, quality of life, and operative and postoperative complications. As discussed, the diagnosis of lymphedema is based on history and physical examination (localized, progressive edema, asymmetric limb measurements). There is no universal agreement on measurement criteria for asymmetric limbs. It may be quantified by a 2 or more centimeters difference in limb girth, a 200 mL difference in limb volume, or a 10% limb volume change from baseline (Armer, 2005). Patient report of heaviness or swelling, either "now" or "in the past year" may also be used to suggest lymphedema. The estimated incidence of lymphedema varies by the measurement criteria used (Armer, 2005).
 
Timing
Although lymphedema can occur decades after treatment for breast cancer, approximately 80% of patients that eventually develop lymphedema experience onset within 3 years of treatment. The remaining patients develop edema at a rate of about 1% per year (Petrek, 2001).
 
For the purposes of this review, studies with at least 3 years of follow-up to observe cases of lymphedema are of primary interest.
 
Setting
Microsurgery for lymphedema is performed by highly specialized surgeons with training in microsurgery and lymphology and also requires specialized imaging tools.
 
Study Selection Criteria
Methodologically credible studies were selected as described in the previous section.
 
Systematic Reviews
Jorgensen et al reported on a systematic review of prophylactic LVA and shunts for preventing cancer−related lymphedema, not limited to breast cancer (Jorgensen, 2017). Twelve articles were included in the qualitative analysis (5 specific to breast cancer) and four of those studies (2 specific to breast cancer) were included in a meta-analysis.
 
Jorgensen et al performed a meta-analysis of the incidence of lymphedema that included 4 studies (2 specific to breast cancer) with a control group consisting of patients without prophylactic LVA. The relative risk for incident lymphedema was 0.33 (95% CI, 0.19 to 0.56) favoring prophylactic LVA vs control; however, because the incidence of lymphedema varies over time and the follow-up times varied across studies, it is not clear whether it would be appropriate to pool the risk including all time points.
 
Jorgensen also performed a risk of bias assessment of the included studies. They noted the following:
    • None of the studies had allocation concealment or blinding;
    • Only 1 study was randomized;
    • None of the studies were registered;
    • Only 4 studies had a control group. Selection of the control groups was unclear or a potential source of bias in all 4 controlled studies.
 
Randomized Controlled Trials
Boccardo et al reported on results of an RCT including 46 women referred for axillary dissection for breast cancer treatment between 2008 and 2009 who were randomized to LYMPHA or no preventive surgery (Boccardo, 2011). All LVA procedures were performed by the same surgeon, reported to be skilled in lymphatic microsurgery. The LVA surgeon was not the same surgeon who performed lymph node dissection. The same axillary dissection treatment was performed in the 2 treatment groups. Lymphedema was diagnosed as a difference in excess volume of at least 100 mL compared with preoperative volume measurements. Lymphedema was diagnosed in 1 (4%) woman in the LYMPHA group and 7 women (30 %) in the control group by 18 months of follow-up. The change in volume with respect to baseline was reportedly higher in the control group than in the LYMPHA group at 1, 3, 6, 12, and 18 months (all p<0.01). The trial had several limitations. Notably, the follow-up duration was only 18 months. Methods of randomization and allocation concealment were not described and there was no justification of the sample size. The patients and investigators were not blinded (ie, no sham procedure was performed) and there was no discussion of whether outcome assessors were blinded. There is no indication that the trial was registered.
 
 
Nonrandomized or Observational Studies
Additional single-arm studies have been published since the systematic reviews (Hahamoff, 2018). However, these studies suffer from the same limitations as the studies included in the systematic reviews and do not capture longer periods of follow up and/or larger populations than the existing studies. Therefore they are not discussed further.
 
Section Summary: Prevention of Secondary Lymphedema in Breast Cancer Patients
One RCT with was identified evaluating LYMPHA to prevent lymphedema in 49 patients referred for axillary dissection for breast cancer. The trial reported that lymphedema developed in 4% of women in the LYMPHA group and 30% in the control group by 18 months of follow-up. Longer follow-up is needed to observe incident lymphedema occurring after 18 months and assessed the durability of the procedure. The trial had limitations that could have introduced bias: methods of randomization and allocation concealment were not described, and there was no sham procedure or blinding. Systematic reviews have indicated that most of the remaining available evidence for LYMPHA comes from uncontrolled studies, although 2 controlled observational studies in women with breast cancer have been performed. Selection of the control group was identified as a potential source of bias in both controlled studies. Outcomes metrics and follow-up times varied across studies. Additional RCTs of LYMPHA are needed and 1 such trial is underway.
 
SUMMARY OF EVIDENCE
For individuals who have breast cancer−related secondary lymphedema who receive physiologic microsurgery to treat lymphedema along with continued conservative therapy, the evidence includes a randomized controlled trial, observational studies, and systematic reviews. Relevant outcomes are symptoms, morbid events, functional outcomes, health status measures, quality of life, resource utilization, and treatment-related morbidity. Several physiologic microsurgeries have been developed; examples include lymphaticovenular anastomosis (LVA) and vascularized lymph node transfer (VLNT). No RCTs of LVA or similar surgeries involving the venous system were identified. One RCT of VLNT with 36 participants has been conducted. Systematic reviews have indicated that the preponderance of the available evidence comes from single-arm clinical series from individual institutions. Surgical technique, outcomes metrics, and follow-up time have varied across these studies. These types of studies might be used for preliminary estimates of the amount of volume reduction expected from surgery, the durability of the reduction in volume, and the rates of adverse events. However, these studies are not adequate for determining the comparative efficacy of physiologic microsurgery vs conservative treatment or decongestive therapy, or the comparative efficacy of different microsurgery techniques. Randomized controlled trials are needed. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
For individuals who are undergoing lymphadenectomy for breast cancer who receive physiologic microsurgery to prevent lymphedema, the evidence includes a randomized controlled trial, observational studies, and systematic reviews. Relevant outcomes are symptoms, change in disease status, morbid events, quality of life, and treatment-related morbidity. Lymphatic Microsurgical Preventing Healing Approach (LYMPHA) is a preventive LVA performed during nodal dissection. One RCT including 46 patients has been conducted. The trial reported that lymphedema developed in 4% of women in the LYMPHA group and 30% in the control group by 18 months of follow-up. Longer follow-up is needed to observe incident lymphedema occurring after 18 months and assess the durability of the procedure. The trial methods of randomization and allocation concealment were not described and there was no sham procedure or blinding, potentially introducing bias. The remaining evidence consists of 2 controlled observational studies with inadequate description of control selection and uncontrolled studies. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
PRACTICE GUIDELINES AND POSITION STATEMENTS
 
National Lymphedema Network
The National Lymphedema Network published a position paper on the diagnosis and treatment of lymphedema (NLN, 2011) The paper stated the following on microsurgical procedures:
“Microsurgical and supramicrosurgical (much smaller vessels) techniques have been developed to move lymph vessels to congested areas to try to improve lymphatic drainage. Surgeries involve connecting lymph vessels and veins, lymph nodes and veins, or lymph vessels to lymph vessels. Reductions in limb volume have been reported and a number of preliminary studies have been done, but there are no long-term studies of the effectiveness of these techniques.”
 
International Society of Lymphology
International Society of Lymphology published a consensus document on the diagnosis and treatment of peripheral lymphedema in (ISL, 2016). The document stated the following on lymphaticovenous (or lymphovenous) anastomoses (LVA):
“LVA are currently in use at multiple centers around the world. These procedures have undergone confirmation of long-term patency (in some cases more than 20 years) and some demonstration of improved lymphatic transport (by objective physiologic measurements of long-term efficacy).”
 
U.S. PREVENTIVE SERVICES TASK FORCE RECOMMENDATIONS
No U.S. Preventive Services Task Force recommendations for lymphedema have been identified.
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2019. No new literature was identified that would prompt a change in the coverage statement.
 
2020 Update
A literature search was conducted through June 2020.  There was no new information identified that would prompt a change in the coverage statement.  
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
In a systematic review of 72 studies (N=29,612 women), DiSipio et al reported that approximately 1 in 5 women who survive breast cancer will develop arm lymphedema (DiSipio, 2013). Reviewers reported that risk factors for development of lymphedema that had a strong level of evidence were extensive surgery (ie, axillary-lymph-node dissection, greater number of lymph nodes dissected, mastectomy) and being overweight or obese. The incidence of breast cancer-related lymphedema was found by DiSipio et al as well as other authors to be up to 30% at 3 years after treatment (DiSipio, 2013; Ribeiro, 20147; Zou, 2018).
 
An additional systematic review of PROs by Coriddi et al identified the most commonly used validated scale across 32 studies was the lymph quality of life measure for limb lymphedema (LYMQOL); however, non-validated instruments were used in half of all studies (Coriddi, 2020).
 
An additional systematic review specifically evaluating microsurgical procedures using the venous system (lymphaticovenular anastomosis [LVA], lymphovenous bypass) was identified (Coriddi, 2020). Forty publications on LVA and lymphovenous bypass were included across the 5 systematic reviews.
 
Coriddi et al reported on a systematic review of PROs following surgical treatment of lymphedema, including lymphovenous bypass and vascularized lymph node transfer (VLNT) (Coriddi, 2020). Overall, 32 studies were identified (details regarding study design were not reported) with follow-up ranging from approximately 4 months to 43 months. The number of patients with breast cancer-related lymphedema was not described. The study reported findings for both validated and non-validated instruments assessing quality of life; however, only 18 studies (n=717 patients) reported individual patient data to permit quantitative assessment of the proportion of patients experiencing quality of life improvements.
 
Three systematic reviews of various surgical methods also included a review of lymph node transfer (Leung, 2015; Carl, 2017; Coriddi, 2020). One of these, Corridi et al, reported results stratified by procedure (Corridi, 2020). Forte et al reported results from a systematic review specifically of treatment with vascularized omental lymph node transfer (Forte, 2019).
 
In Forte (2019) and Coriddi (2020), the results in the subgroup of breast cancer-related lymphedema were also not presented.
 
An additional single-arm study using lymph tissue transfer has been published since the systematic reviews (Drobot, 2020). However, this study suffers from the same limitations as the studies included in the systematic reviews and does not capture longer periods of follow-up and/or larger populations than the existing studies. Therefore, it is not discussed further.
 
The American Society of Breast Surgeons published recommendations from an expert panel on preventive and therapeutic options for breast cancer-related lymphedema in 2017 (McLaughlin, 2017). The document stated that "the Panel agrees that LVA and VLNT may be effective for early secondary breast cancer-related lymphedema."
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Chang et al was one of several broader systematic reviews of treatments for lymphedema that included microsurgical procedures (Chang, 2021).
 
Chang et al reported on a systematic review and meta-analysis of LVA, liposuction, and vascularized lymph node transfer (VLNT) for treatment of lymphedema (Chang, 2021). The results of liposuction will not be reviewed. Overall, 66 total studies were included, with 16 studies included on LVA. Follow-up ranged from approximately 6 to 68 months. The number of patients with breast cancer-related lymphedema was not described. In addition, studies evaluating use of these procedures for both upper and lower extremity lymphedema were included. The study reported findings for limb circumference and incidence of cellulitis:
 
    • LVA plus compression reduced circumference by a mean of 3.8 cm (2.93 to 4.67 cm)
    • Reduction in number of cellulitis infections before vs. after surgery (mean difference, 2.57; 95% CI, 1.75 to 3.38)
 
Chang et al also included a review of lymph node transfer (Chang, 2021). Results were stratified by procedure. Results for patients treated with VLNT include:
 
    • Reduction in circumference or volume VLNT (plus compression and complex decongestive therapy) reduced circumference by a mean of 1.64 cm (0.87 to 2.42 cm)
    • Infection frequency Reduction in number of cellulitis infections before vs. after surgery (mean difference, 2.34; 95% CI, 1.82 to 2.85)
 
The American Association of Plastic Surgeons sponsored a conference to create consensus statements and recommendations for surgical treatment and prevention of upper and lower extremity lymphedema (Chang, 2021). The recommendations were based on the results of a systematic review and meta-analysis. The relevant recommendations include:
 
"There is evidence to support that lymphovenous anastomosis can be effective in reducing severity of lymphedema (grade 1C). There is evidence to support that vascular lymph node transplantation can be effective in reducing severity of lymphedema (grade 1B). Currently, there is no consensus on which procedure (lymphovenous bypass versus vascular lymph node transplantation) is more effective (grade 2C). A few studies show that prophylactic lymphovenous bypass in patients undergoing extremity lymphadenectomy may reduce the incidence of lymphedema (grade 1B). More studies with longer follow-up are required to confirm this benefit."
 
The National Comprehensive Cancer Network (NCCN) published recommendations on management of lymphedema as part of its guideline on survivorship; however, it does not discuss physiologic microsurgical techniques (NCCN, 2021). The guideline states that high-level evidence in support of treatments for lymphedema are lacking. In addition, the NCCN guideline on breast cancer does not give recommendations on use of physiological microsurgical techniques for preventing or treating lymphedema (NCCN, 2021).
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Li et al reported results from a systematic review specifically evaluating intra-abdominal VLNT (Li, 2021). The review consisted of 21 studies (non-randomized controlled trial, prospective and retrospective cohorts) that took place through February of 2021 and lasted up to 52 months. Participants included 594 individuals with lymphedema treated with intra-abdominal VLN flaps. Results included: reduction in circumference or volume range 0.38% to 70.8%. Post operative complications included: Donor-site complication rate, 1.4% (0 to 4.1) and Recipient-site complication rate, 3.2% (1.4 to 5.5).
 
Ciudad et al reported on systematic reviews of prophylactic LVA and shunts for preventing cancer-related lymphedema, not limited to breast cancer (Ciudad, 2022). Ciudad et al included 24 studies (15 specific to breast cancer). The study (RCT and observational) took place through 2020 with a duration of 6 to 156 months. There were 1547 participants who underwent prophylactic LVA after oncological treatment. Results include TE (95% CI); p-value [Upper extremity: 5.15% (2.9 to 7.5); <.01 and Lower extremity: 6.66% (<1 to 13.4); <.01] and Risk difference (95% CI); p-value [Upper extremity: -18.7% (-29.5 to -7.9); <.001 and Lower extremity: 30.3% (-46.5 to -14); <.001].
CPT/HCPCS:
38999Unlisted procedure, hemic or lymphatic system
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