Medical Policy

Policy Num:      07.001.119
Policy Name:   Surgical Treatments for Breast Cancer-Related Lymphedema
Policy ID:          [07.001.119]  [Ac / B / M- / P-]  [7.01.162]

Last Review:     October 10, 2024
Next Review:     October 20, 2025
 

Related Policies:

08.001.029 - Pneumatic Compression Pumps for Treatment of Lymphedema and Venous Ulcers
08.001.009 - Low Level Laser Therapy
02.001.048 - Bioimpedance Devices for Detection and Management of Lymphedema

Surgical Treatments for Breast Cancer-Related Lymphedema

summary

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 review focuses on physiologic microsurgical interventions and will not consider reductive (also known as excisional or ablative) surgical interventions such as liposuction.

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 randomized controlled trials (RCTs), 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 and vascularized lymph node transfer (VLNT). An ongoing RCT of lymphaticovenular anastomosis was identified, but analyses of comparative outcomes between groups are limited at this time. 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 versus conservative treatment or decongestive therapy, or the comparative efficacy of different microsurgery techniques. Randomized controlled trials are needed. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are undergoing lymphadenectomy for breast cancer who receive physiologic microsurgery to prevent lymphedema, the evidence includes a RCT, an ongoing RCT, 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 lymphaticovenular anastomosis performed during nodal dissection. One RCT including 46 women 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. However, because the cumulative incidence of lymphedema after breast cancer treatment approximates 30% at 3 years, longer follow-up is needed to assess the durability of the procedure. The trial methods of randomization and allocation concealment were not described and there was no blinding, potentially introducing bias. The remaining evidence consists of uncontrolled studies and systematic reviews of these studies. An ongoing RCT indicated improved lymphedema at 24 months (n=40) with immediate lymphatic reconstruction compared with controls (9.5% vs. 32%; p=.014), but conclusions based on this RCT are pending final analysis. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

Objective

This evidence review addresses 2 uses of physiologic microsurgery for breast cancer related lymphedema.

1. Does the use of physiologic microsurgery as an adjunct to conservative treatment for individuals who have breast cancer treatment related lymphedema improve the net health outcome as measured by improved symptoms, function, and quality of life?

2. Does the use of physiologic microsurgery for individuals who are undergoing treatment for breast cancer improve the net health outcome as measured by reduction in the incidence of lymphedema?

policy Statements

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.

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.

policy Guidelines

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

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 (eg, 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, computed tomography, ultrasound, or lymphoscintigraphy, may be used to differentiate lymphedema from other causes of edema in diagnostically challenging cases.

Table 1 lists 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.^1,

Table 1. Recommendations for Staging Lymphedema

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 of lymphedema in individuals with breast cancer.

In a systematic review of 72 studies (N=29,612 women), DiSipio et al (2013) reported that approximately 1 in 5 women who survive breast cancer will develop arm lymphedema.^2, 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.^2,3,4,

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.^5, 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. Individuals 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 is a light pressure massage performed by trained physical therapists or by individuals 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 the 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-manual lymphatic drainage in patients who have difficulty performing self-manual lymphatic drainage. In individuals 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.

Rationale

This evidence review was created in July 2018 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through July 24, 2024.

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 1 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. Randomized controlled trials 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.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1

Physiologic Microsurgery to Treat Lymphedema

Clinical Context and Therapy Purpose

The purpose of physiologic microsurgery treatments for lymphedema in individuals 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 are some of the most common causes of secondary peripheral lymphedema.

The following PICO was used to select literature to inform this review.

Populations

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) (Table 1).

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. Table 2 includes a brief description of the surgeries.

Table 2. Physiologic Microsurgical Interventions for Lymphedema

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 a 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 found that most studies included generic PRO instruments or oncology PRO instruments.^6, Lymphedema-specific instruments are occasionally used; specifically, the Upper Limb Lymphedema 27 was found to have strong psychometric properties. An additional systematic review of PROs by Coriddi et al (2020) 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.^7,

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.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Because multiple systematic reviews of studies were available for both classes of microsurgery, the focus is on systematic reviews published in 2015 or later.

Review of Evidence

Surgeries That Reconstruct or Bypass Using Donor Lymph Vessels

Systematic Review

Leung et al (2015) reported on a systematic review of the surgical management of breast cancer-related lymphedema.^8, 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 was identified and published since 2000. The study included 7 patients followed for 2.6 years. One patient had "complete recovery" as measured by the 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 the donor leg.

Surgeries That Reconstruct or Bypass Using the Venous System

Systematic Reviews

Three systematic reviews specifically evaluating microsurgical procedures using the venous system (lymphaticovenular anastomosis [LVA], lymphovenous bypass) have been reported.^9,10,7,Three broader systematic reviews of treatments for lymphedema including several microsurgical procedures have also been reported.^8,11,12, Corneilissen et al (2018) and Leung et al (2015) were limited to studies of breast cancer-related lymphedema but the remaining reviews were not. The overlap between the primary studies included in the systematic reviews is shown in Appendix Table 1. Forty publications on LVA and lymphovenous bypass were included across the 5 systematic reviews. Characteristics of the reviews are shown in Table 3.

Chang et al (2021) reported on a systematic review and meta-analysis of LVA, liposuction, and vascularized lymph node transfer (VLNT) for treatment of lymphedema.^12, 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. Results for patients treated with lymphovenous bypass are presented in Table 4.

Coriddi et al (2020) reported on a systematic review of PROs following surgical treatment of lymphedema, including lymphovenous bypass and VLNT.^7, 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. Results for patients treated with lymphovenous bypass are presented in Table 4.

Cornelissen et al (2018) reported on a systematic review assessing the effect of LVA in breast cancer-related lymphedema.^9, 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 (2017) reported on a systematic review of LVA for the treatment of lymphedema.^10, 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 (2017) and Leung (2015) reviews included multiple surgical techniques. Leung (2015) was limited to breast cancer-related lymphedema while Carl (2017) was not.

Table 3. Characteristics of Systematic Reviews Assessing Lymphedema Surgeries Using the Venous System

Results of the systematic reviews are shown in Table 4. In 4 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 was provided. In the Chang (2021) and Carl (2017) reviews, meta-analyses were performed for the outcome measure of percent excess circumference reduction, although only a limited 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).

Table 4. Results of Systematic Reviews Assessing Lymphedema Surgeries Using the Venous System

Randomized Controlled Trials

Interim results of an ongoing multicenter RCT (NCT02790021) in women with breast cancer-related lymphedema were published by Jonis et al (2024).^13, One hundred women with Stage 1 or 2a lymphedema were randomized to LVA surgery or conservative treatment, and 92 were included in the interim analysis. The primary outcome was quality of life as measured by the Lymphedema Functioning Disability and Health (Lymph-ICF) questionnaire. Total ICF scores improved in both groups at 6 months (-8.57 [95% CI, -15.69 to 1.45] and -2.65 [95% CI, -8.26 to 2.95] in the LVA and conservative groups, respectively). However, the results were not statistically significant. There was no significant volume reduction in either group from baseline. No firm conclusions can be made pending final results of the trial.

Nonrandomized or Observational Studies

Additional single-arm studies have been published since the systematic reviews.^14, 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

Systematic reviews have indicated that most of the available evidence for lymphovenous bypass or LVA 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, the severity of lymphedema, outcomes metrics, and follow-up times varied across studies making it difficult to synthesize the evidence. Surgical complications have been inconsistently reported but appear to be rare. Randomized controlled trials of physiologic microsurgeries that bypass the obstructed lymphatic vessels using the venous system plus conservative therapy versus conservative therapy alone are needed.

Surgeries that Transfer Lymph Tissue

Review of Evidence

Systematic Reviews

Systematic reviews evaluating microsurgical procedures that transfer lymph tissue (autologous lymph node transfer, VLNT) have been reported. The overlap between the primary studies included in the systematic reviews is shown in Appendix Table 2. Characteristics of systematic reviews of surgeries for lymphedema are shown in Table 5. Ozturk et al (2016) reported on a systematic review of VLNT for treatment of lymphedema.^15, 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 the staging of lymphedema. Reviewers did not state whether any of the studies included a control group. Four systematic reviews of various surgical methods previously described also included a review of lymph node transfer.^8,11,7,12, Two of these, Chang et al (2021) and Corridi et al (2020), reported results stratified by procedure; results for patients treated with VLNT are presented in Table 5.^7,12, Forte et al (2019) reported results from a systematic review specifically of treatment with vascularized omental lymph node transfer.^16, Li et al (2021) reported results from a systematic review specifically evaluating intra-abdominal VLNT.^17,

In addition to the systematic reviews of efficacy, Demiri et al (2018) reported on a systematic review of donor-site complications following autologous lymph node transfer for breast cancer-related lymphedema.^18,

Table 5. Characteristics of Systematic Reviews Assessing Lymphedema Surgeries Using Lymph Tissue Transfer

Results of the systematic reviews are shown in Table 6. In Ozturk (2016), Carl (2017), Forte (2019), Coriddi (2020), Chang et al (2021), and Li et al (2021), results in the subgroup of breast cancer-related lymphedema were not presented so the table includes all available participants. Due to differences in outcomes metrics and timing of measurements, meta-analyses were not possible for most outcomes and narrative summaries were provided by Ozturk (2016), Demiri (2018), Leung (2015), and Li et al (2021). Chang (2021) and Carl (2017) 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 (2016) 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 1 did not include consecutive patients;

• 13 of 18 studies had insufficient information on the surgical team;

• 3 of 18 studies had an insufficient follow-up to observe outcomes (ie, <1 year).

Table 6. Results of Systematic Reviews Assessing Lymphedema Surgeries Using Lymph Tissue Transfer

Randomized Controlled Trials

Dionyssiou et al (2016) reported on a RCT that evaluated VLNT plus physical therapy versus physical therapy alone for lymphedema in 36 women with stage II breast cancer-related lymphedema.^19, Trial characteristics are shown in Table 7.

Table 7. Characteristics of RCTs of Lymphedema Surgeries Using Lymph Tissue Transfer

Results reported in Dionyssiou et al (2016) are shown in Table 8. At 18 months, the reduction in the 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<.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=.001). The trial had several limitations described in Tables 9 and 10. 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.

Table 8. Results of RCTs of Lymphedema Surgeries Using Lymph Tissue Transfer

Table 9. Study Relevance Limitations of RCTs of Lymphedema Surgeries Using Lymph Tissue Transfer

Table 10. Study Design and Conduct Limitations of RCTs of Lymphedema Surgeries Using Lymph Tissue Transfer

Nonrandomized or Observational Studies

Additional single-arm studies using lymph tissue transfer have been published since the systematic reviews.^20,21,22,23, 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 the 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, the 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 versus conservative therapy alone are needed.

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 (RCT), 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 and vascularized lymph node transfer (VLNT). No RCTs of lymphaticovenular anastomosis 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 versus conservative treatment or decongestive therapy, or the comparative efficacy of different microsurgery techniques. Randomized controlled trials are needed. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 2

Physiologic Microsurgery to Prevent Lymphedema

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 (2011) 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.^24,

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 following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals who are undergoing a lymphadenectomy or breast reconstruction procedure for breast cancer.

Interventions

This review focuses on a 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 the 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.^25,26, Patient reports 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.^26,

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Because multiple systematic reviews of studies were available for both classes of microsurgery, the focus is on systematic reviews published in 2015 or later.

Review of Evidence

Systematic Reviews

Ciudad et al (2022) and Jorgensen et al (2017) reported on systematic reviews of prophylactic LVA and shunts for preventing cancer-related lymphedema, not limited to breast cancer.^27,28, Systematic review characteristics are shown in Table 11. Jorgensen et al (2017) included 12 articles in the qualitative analysis (5 specific to breast cancer) and 4 of those studies (2 specific to breast cancer) were included in a meta-analysis. Ciudad et al (2022) included 24 studies (15 specific to breast cancer). The overlap between the primary studies included in the systematic reviews is shown in Appendix Table 3.

Table 11. Characteristics of Systematic Reviews of LYMPHA to Prevent Lymphedema

LVA: lymphaticovenular anastomosis; LYMPHA: Lymphatic Microsurgical Preventing Healing Approach; RCT: randomized controlled trial.

Results of the systematic reviews are shown in Table 12. Jorgensen et al (2017) 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% confidence interval [CI], 0.19 to 0.56) favoring prophylactic LVA versus 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. Ciudad et al (2022) reported that the pooled cumulative rate of upper and lower extremity lymphedema after oncological surgical treatment and LVA was 5.15% (95% CI, 2.9 to 7.5) and 6.66% (95% CI, <1 to 13.4), respectively. When compared to no intervention, the LVA reduced the incidence of upper and lower limb lymphedema by -18.7% (95% CI, -29.5 to -7.9) and -30.3% (95% CI, -46.5% to -14%), respectively.

Table 12. Results of Systematic Reviews of LYMPHA to Prevent Lymphedema

CI: confidence interval; LYMPHA: Lymphatic Microsurgical Preventing Healing Approach; NR: not reported; RR: relative risk; TE: treatment effect.

Jorgensen (2017) 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.

Ciudad et al (2022) also performed a risk of bias assessment and noted that "all articles were highly biased, and the protocols of the included studies were not documented on international registries."

Randomized Controlled Trials

Boccardo et al (2011) reported on results of a 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 (control).^29, 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. Trial characteristics are shown in Table 13. Results are shown in Table 14. 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<.01). The trial had several limitations described in Tables 15 and 16. 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.

Coriddi et al (2023) reported on interim results of a RCT (NCT04241341) in 144 women with breast cancer undergoing axillary lymph node dissection.^30, Women were randomized to immediate lymphatic reconstruction with lymphatic anastomosis to a regional vein or control. At the time of interim analysis only 40 individuals had the full 24 month follow-up, and interim results were reported for 99 women who had completed 12 months of follow-up. Trial characteristics and results are summarized in Tables 13 and 14. The major limitations of this report include the preliminary status of the results, the small sample size, and the single-center design.

Table 13. Characteristics of RCTs of LYMPHA to Prevent Lymphedema

ALND: axillary lymph node dissection; ILR: immediate lymphatic reconstruction; LYMPHA: lymphatic microsurgical preventing healing approach; RCT: randomized controlled trial; RVC: relative volume change.

Table 14. Results of RCTs of LYMPHA to Prevent Lymphedema

CI: confidence interval; ILR: immediate lymphatic reconstruction; LYMPHA: Lymphatic Microsurgical Preventing Healing Approach; NR: not reported; RCT: randomized controlled trial; TE: treatment effect.
^a Estimated based visual inspection of figure.

Table 15. Study Relevance Limitations of RCTs of LYMPHA to Prevent Lymphedema

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
LYMPHA: lymphatic microsurgical preventing healing approach; RCT: randomized controlled trial.
^a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

Table 16. Study Design and Conduct Limitations of RCTs of LYMPHA to Prevent Lymphedema

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
CI: confidence interval; LYMPHA: lymphatic microsurgical preventing healing approach; RCT: randomized controlled trial.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias; 5. Other.
^b Blinding key: 1. Participants or study staff not blinded; 2. Outcome assessors not blinded; 3. Outcome assessed by treating physician; 4. Other.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication; 4. Other.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials); 7. Other.
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference; 4. Other.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated; 5. Other.

Nonrandomized or Observational Studies

Additional single-arm studies have been published since the systematic reviews.^31, 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: Physiologic Microsurgery to Prevent Lymphedema

One completed RCT 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 assess 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 blinding. An interim analysis of a RCT in 99 women randomized to immediate lymphatic reconstruction at the time of axillary dissection or no reconstruction at that time found reduced lymphedema at 12 and 24 months of follow-up. Systematic reviews have indicated that most of the remaining available evidence for LYMPHA comes from uncontrolled studies, although 2 observational studies in women with breast cancer with control groups including patients without prophylactic LVA 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 (see NCT03428581).

For individuals who are undergoing lymphadenectomy for breast cancer who receive physiologic microsurgery to prevent lymphedema, the evidence includes a RCT, 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 lymphaticovenular anastomosis 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. However, because the cumulative incidence of lymphedema after breast cancer treatment approximates 30% at 3 years, longer follow-up is needed to assess the durability of the procedure. The trial methods of randomization and allocation concealment were not described and there was no blinding, potentially introducing bias. The remaining evidence consists of uncontrolled studies and systematic reviews of these studies. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Association of Plastic Surgeons

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.^12, 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."

American Society of Breast Surgeons

The American Society of Breast Surgeons published recommendations from an expert panel on preventive and therapeutic options for breast cancer-related lymphedema in 2017.^32, The document stated that "the Panel agrees that LVA [lymphaticovenular anastomosis] and VLNT [vascularized lymph node transfer] may be effective for early secondary breast cancer-related lymphedema."

International Society of Lymphology

The International Society of Lymphology published an updated consensus document on the diagnosis and treatment of peripheral lymphedema in 2020.^1, [Executive Committee of the International Society o.... 20; 53(1): 3-19. PMID 32521126] 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 25 years) and some demonstration of improved lymphatic transport (by objective physiologic measurements of long-term efficacy). Multiple lymphatic-venous anastomoses in a single surgical site, with both the superficial and deep lymphatics, allow the creation of a positive pressure gradient (lymphatic-venous) and evade the phenomenon of gravitational reflux without interrupting the distal peripheral superficial lymphatic pathways. Some centers particularly in areas of endemic filariasis also practice lymph nodal-venous shunts as a derivative method. Multiple centers are using LVA (Lymphatic Microsurgical Preventing Healing Approach [LYMPHA]) as a preventative measure in high risk patients."

National Comprehensive Cancer Network

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.^33, 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.^33,

National Lymphedema Network

The National Lymphedema Network published a position paper on the diagnosis and treatment of lymphedema in 2011.^34, The paper provided the following statements, although notably, the document has been retracted and the Network is currently in the process of drafting a new position statement:

"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."

An update of this position paper is in development as of July 2024.

U.S. Preventive Services Task Force Recommendations

No U.S. Preventive Services Task Force recommendations for lymphedema have been identified.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this review are listed in Table 17.

Table 17. Summary of Key Trials

NCT: national clinical trial.

References

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Policy History