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 (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, computed tomography, ultrasound, or lymphoscintigraphy, may be used to differentiate lymphedema from others 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

Stage	Description
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 (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 (i.e., axillary-lymph-node dissection, greater number of lymph nodes dissected, mastectomy) and being overweight or obese.

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 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 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 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.

Related Policies

• Pneumatic Compression Pumps for Treatment of Lymphedema and Venous Ulcers (Policy #013 in the DME Section)
• Bioimpedance Devices for Detection and Management of Lymphedema (Policy #061 in the Medicine Section)
• Low-Level Laser Therapy (Policy #074 in the Treatment Section)

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.

Physiologic microsurgery to treat lymphedema

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 policy 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 policy.

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 policy are those performed in individuals who have not reached the irreversible stage, i.e., those who have functioning lymphatic channels (stage I, II or early stage III) (see Table 1).

Interventions

This policy focuses on physiologic microsurgical interventions; it does not consider reductive (also known as excisional or ablative) surgical interventions (e.g., 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

Purpose	Surgery	Description	Key Features
Bypass or reconstruct obstructed lymph vessels to improve drainage	Lymphatic-lymphatic bypass	Connects functioning lymphatic vessels directly to affected lymphatic vessels; healthy vessels come from donor site	Lymphedema can develop in donor extremity Scaring at donor site
	Lymphovenous bypass and lymphaticovenular anastomosis	Lymphatic vessels in a affected limb are connected to the venous system	Outpatient procedure or usually discharged within a day Quick return to daily activities
Transfer lymph tissue to reestablish lymphatic flow	Autologous lymph node transplantation and vascularized lymph node transfer	Healthy lymph nodes are transferred to the affected limb	Inpatient procedure; requires 2-3 days of hospitalization Lymphedema can develop in donor extremity

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 (e.g., cellulitis, lymphangitis). Volume is measured using different methods; e.g., 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 (2013) found that most studies included generic PRO instruments or oncology PRO instruments.^3, 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 a preference for RCTs;
b. In the absence of such trials, comparative observational studies were sought, with a 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.

Surgeries That Reconstruct or Bypass Using Donor Lymph Vessels

Leung et al (2015) reported on a systematic review of the surgical management of breast cancer-related lymphedema.^4, 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 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.^5,6, Two broader systematic reviews of treatments for lymphedema including several microsurgical procedures have also been reported.^4,7, 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. Thirty-four publications on LVA were included across the 4 systematic reviews. Characteristics of the reviews are shown in Table 3.

Cornelissen et al (2018) reported on a systematic review assessing the effect of LVA in breast cancer-related lymphedema.^5, 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.^6, Reviewers noted significant variations in surgical techniques, numbers of anastomoses, and supplementary interventions (i.e., 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

Study	Dates	Studies	Participants	N (Range)	Design	Duration (Range)
Cornelissen et al (2018)5,	1999-2017	15	With breast cancer- related lymphedema	268 (3-39)	•   Observational or single-arm: 11 •   Prospective: 4	20 mo (2 mo to 8 y)
Scaglioni et al (2017)6,	Up to 2016	18	With lymphedema of any cause except filariasis-related	939 (5-154) (no. with breast cancer-related lymphedema NR)	•   Observational or single arm: 8 •   Prospective: 10	24 mo (5-55 mo)
Carl et al (2017)7,	2000-2016	Overall: 69 LVA: 27a	With extremity lymphedema of any cause	NR	•   Observational or single-arm	LVA: 6-120 mo
Leung et al (2015)4,	2000-2014	Overall: 13 LVA: 6	With breast cancer- related lymphedema	146 (6-89)	•   Observational or single-arm	LVA: 17 mo to 8 y

LVA: lymphaticovenular anastomosis; NR: not reported.
^a Only 12 "high-quality" LVA studies were discussed.

Results of the systematic reviews are shown in Table 4. In 3 of the reviews, given the variability in the procedures, metrics for measuring the outcomes, and the time periods of reporting, meta-analyseswere not possible and only a narrative synthesis was provided. In the Carl (2017) 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 (i.e., <1 year).

Randomized Controlled Trials

No RCTs were identified.

Nonrandomized or Observational Studies

Additional single-arm studies have been published since the systematic reviews.^8, 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, 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. 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, vascularized 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.^9, 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. Two systematic reviews of various surgical methods previously described also included a review of lymph node transfer.^4,7,

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.^10,

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

Study	Dates	Studies	Participants	N (Range)	Design	Duration
Demiri et al (2018)10,	NR	11	With breast cancer- related lymphedema treated with VLNT	189 (8-42)	RCT, observational, or single-arm	Mean, 38 mo (range, 6-132 mo)
Carl et al (2017)7,	2000-2016	Overall: 69 VLNT: 17a	With extremity lymphedema of any cause	NR	Observational or single-arm	NR
Ozturk et al (2016)9,	1980 to 2015	18	With primary or secondary upper- or lower-limb lymphedema (63% breast cancer-related)	305 (6-52)	Observational or single-arm: 3 Prospective: 15	2-132 mo
Leung et al (2015)4,	2000-2014	Overall: 13 LNT: 6	With breast cancer- related lymphedema	80 (3-24)	Observational or single-arm	LNT: 6 mo to 8 y

NR: not reported; RCT: randomized controlled trial; VLNT: vascularized lymph node transfer; LNT: lymph node transfer.

^a Only 10 "high-quality" VLNT studies were discussed.

Results of the systematic reviews are shown in Table 6. In Ozturk (2016) and Carl (2017), 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 and narrative summaries were provided by Ozturk (2016), Demiri (2018), and Leung (2015). 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 one 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 (i.e., <1 year).

^a All etiologies included; results not provided for subgroup of patients with breast cancer-related lymphedema.

Dionyssiou et al (2016) 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.^11, Trial characteristics are shown in Table 7.

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

Study	Countries	Sites	Dates	Participants	Interventions
					Surgery	Control
Dionyssiou et al (2016)11,	Greece	1	2011-2014	Women with stage II, unilateral, upper-limb lymphedema related to breast cancer treatment and 1+ infections during last year	18 received VLNT followed by physical  therapya for 6 mo	18 received physical  therapya for 6 mo

RCT: randomized controlled trial.
^a Physical therapy included manual lymphatic drainage for 1 month and pressure garments for 5 months.

RCT results reported in Dionyssiou (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<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 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

Study	Reduction in Circumference of Affected Limb	Reduction in Volume of Affected Limb	Infections	Function or Quality of Life	Postoperative Complications
Dionyssiou et al (2016)11,		Reduction in Excess Volume of Affected Limb as Percent of Intact Limb at 18 Months	Mean Episodes per Patient per Year	VAS for Functional Impairment at 18 Months
N	NR	36	36	36	18
Surgery	NR	57%	0.28	1.22	4a
Control	NR	18%	1.16	4.61	NA
TE (95% CI); p	NR	NR (NR); <0.001	NR (NR); 0.001	NR (NR); 0.001

CI: confidence interval; NA: not applicable; NR: not reported; RCT: randomized controlled trial;TE: treatment effect; VAS: visual analog scale.
^a Two with mild discomfort at donor side lower limb; 2 with prolonged lymphorrhea at donor area.

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

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Follow-Upe
Dionyssiou et al(2016)11,				4. Did not use validated measures of quality of life 5, 6. No discussion of clinically important differences

The evidence gaps stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
RCT: randomized controlled trial.

^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.

^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.

^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.

^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.

^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.

^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.

^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.

^d Follow-Up 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).

^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.

^f Statistical key: 1. Intervention is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Intervention is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

Additional single-arm studies have been published since the systematic reviews.^12,13,14, 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 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 vs conservative therapy alone are needed.

Physiologic microsurgery to prevent lymphedema

Clinical Context and Therapy Purpose

The purpose of lymphatic physiologic microsurgery simultaneous to lymphadenectomy for breast cancer (i.e., 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.^15,

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 policy 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 policy.

Patients

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

Interventions

This policy 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.^16,17, 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.^17,

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.^18,

For the purposes of this policy, 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 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 a preference for RCTs;
b. In the absence of such trials, comparative observational studies were sought, with a 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.

Systematic Reviews

Jorgensen et al (2017) reported on a systematic review of prophylactic LVA and shunts for preventing cancer-related lymphedema, not limited to breast cancer.^19, Systematic review characteristics are shown in Table 11. 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.

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

Study	Dates	Studies	Participants	N (Range)	Design	Duration, mo
Jorgensen et al (2017)19,	1980-2016	12 (5 specific to breast cancer)	Underwent lymphadenectomy for cancer treatment and prophylactic LVA for prevention of extremity lymphedema	364 (8-74)	RCT, observational, single-arm	6-69

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

Results of the systematic review 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% 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.

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

Study	Incidence of Lymphedema	Lymphedema Symptoms	Quality of Life	Complications
Jorgensen et al(2017)19,
Meta-analysis
n	176	NR	NR	NR
RR (95% CI)	0.33 (0.19 to 0.56)
I2 (p)	0% (0.74)
Qualitative synthesis
N range	8-74	NR	NR	Not clear
Range estimates	0%-30% with varying follow-up times			1 study reported lymphorrhea in 1 patient Unclear if other studies reported no events or did not report on complications

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

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.

Boccardo et al (2011) 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 (control).^20, 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.

Table 13. Characteristics of RCTs of LYMPHA to Prevent Lymphedema

Study	Countries	Sites	Dates	Participants	Diagnosis of Lymphedema	Interventions
						Active	Comparator
Boccardo et al (2011)20,	Italy	1	2008-2009	Women referred for complete axillary dissection for breast cancer treatment	Difference in excess volume of ≥100 mL vs preoperative volume	23 LYMPHA	23 no preventive surgery for lymphedema

LYMPHA: lymphatic microsurgical preventing healing approach; RCT: randomized controlled trial.

Results of the Boccardo (2011) RCT 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<0.01). 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 (i.e., 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.

Table 14. Results of RCTs of LYMPHA to Prevent Lymphedema

Study	Incidence of Lymphedema	Change in Volume of Associated Limb, mL	Symptoms of Lymphedema	Quality of Life	Complications
	Cumulative at 18 Months	At 18 Months
Boccardo et al (2011)20,
N	46	46	NR	NR	NR
LYMPHA	4%	10th percentile: » -60 mLa 90th percentile: » +40 mLa
Control	30%	10th percentile: » +50 mLa 90th percentile: » +130 mLa
TE (95% CI); p	NR (NR); 0.05	NR

CI: confidence interval; 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. Relevance Gaps of RCTs of LYMPHA to Prevent Lymphedema

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Follow-Upe
Boccardo et al (2011)20,				1. No patient reported outcomes 3. No reporting of harms 4. Used 100 mL volume displacement to diagnose lymphedema; 200 mL is more commonly used 5, 6. No discussion of clinically important differences	1. Follow-up of ≥3 y would be needed to assess incidence and durability

The evidence gaps 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. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.

^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.

^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.

^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.

^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

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.

^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.

^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.

^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).

^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.

^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.

Additional single-arm studies have been published since the systematic reviews.^21, 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 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 sham procedure or blinding. Systematic reviews have indicated that most of the remaining available evidence for LYMPHA comes from uncontrolled studies, although two 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 (see NCT03428581).

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 an 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. No RCTs of lymphaticovenular anastomosis or similar surgeries involving the venous system were identified. One RCT of vascularized lymph node transfer 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. RCTs 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 an 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 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 Lymphatic Microsurgical Preventing Healing Approach 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.

SUPPLEMENTAL INFORMATION

Practice Guidelines and Position Statements

National Lymphedema Network

The National Lymphedema Network published a position paper on the diagnosis and treatment of lymphedema in 2011.^22, 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 2016.^1, 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.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this policy are listed in Table 17.

Table 17. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT02790021	Improving Quality of Survivorship for Breast Cancer-related Lymphedema by Lymphaticovenous Anastomosis: A Randomized Controlled Trial	60	Sep 2019
NCT03428581	Preventing Lymphedema in Patients Undergoing Axillary Lymph Node Dissection Via Axillary Reverse Mapping and Lympho-venous Bypass	264	Feb 2023

NCT: national clinical trial.]
________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Surgical Treatments for Breast Cancer-Related Lymphedema
Lymphedema, Surgical Treatments for Breast Cancer-Related
Surgery for Breast Cancer-Related Lymphedema
Lymphatic Physiologic Microsurgery for Lymphedema
Microsurgery for Lymphedema
Lymphatico-Lymphatic Bypass
Lymphovenous Bypass
Lymphaticovenous Anastomosis
Autologous Lymph Node Transplantation
Vascularized Lymph Node Transfer
Lymphatic Microsurgical Preventing Healing Approach (LYMPHA)
LYMPHA (Lymphatic Microsurgical Preventing Healing Approach)

References:
1. International Society of Lymphology Executive Committee. The Diagnosis and Treatment of Peripheral Lymphedema: 2016 Consensus Document of the International Society of Lymphology. 2016; https://journals.uair.arizona.edu/index.php/lymph/article/view/20106. Accessed May 23, 2018.

2. DiSipio T, Rye S, Newman B, et al. Incidence of unilateral arm lymphoedema after breast cancer: a systematic review and meta-analysis. Lancet Oncol. May 2013;14(6):500-515. PMID 23540561.

3. Pusic AL, Cemal Y, Albornoz C, et al. Quality of life among breast cancer patients with lymphedema: a systematic review of patient-reported outcome instruments and outcomes. J Cancer Surviv. Mar 2013;7(1):83- 92. PMID 23212603.

4. Leung N, Furniss D, Giele H. Modern surgical management of breast cancer therapy related upper limb and breast lymphoedema. Maturitas. Apr 2015;80(4):384-390. PMID 25747119.

5. Cornelissen AJM, Beugels J, Ewalds L, et al. The effect of lymphaticovenous anastomosis in breast cancer- related lymphedema: a review of the literature. Lymphat Res Biol. Jan 22 2018. PMID 29356596.

6. Scaglioni MF, Fontein DBY, Arvanitakis M, et al. Systematic review of lymphovenous anastomosis (LVA) for the treatment of lymphedema. Microsurgery. Nov 2017;37(8):947-953. PMID 28972280.

7. Carl HM, Walia G, Bello R, et al. Systematic review of the surgical treatment of extremity lymphedema. J Reconstr Microsurg. Jul 2017;33(6):412-425. PMID 28235214.

8. Salgarello M, Mangialardi ML, Pino V, et al. A prospective evaluation of health-related quality of life following lymphaticovenular anastomosis for upper and lower extremities lymphedema. J Reconstr Microsurg. Apr 24 2018. PMID 29689576.

9. Ozturk CN, Ozturk C, Glasgow M, et al. Free vascularized lymph node transfer for treatment of lymphedema: A systematic evidence based review. J Plast Reconstr Aesthet Surg. Sep 2016;69(9):1234-1247. PMID 27425000.

10. Demiri E, Dionyssiou D, Tsimponis A, et al. Donor-site lymphedema following lymph node transfer for breast cancer-related lymphedema: a systematic review of the literature. Lymphat Res Biol. Feb 2018;16(1):2-8. PMID 29087763.

11. Dionyssiou D, Demiri E, Tsimponis A, et al. A randomized control study of treating secondary stage II breast cancer-related lymphoedema with free lymph node transfer. Breast Cancer Res Treat. Feb 2016;156(1):73-79. PMID 26895326.

12. Nguyen AT, Suami H, Hanasono MM, et al. Long-term outcomes of the minimally invasive free vascularized omental lymphatic flap for the treatment of lymphedema. J Surg Oncol. Jan 2017;115(1):84-89. PMID 27439587.

13. Ciudad P, Agko M, Perez Coca JJ, et al. Comparison of long-term clinical outcomes among different vascularized lymph node transfers: 6-year experience of a single center's approach to the treatment of lymphedema. J Surg Oncol. Nov 2017;116(6):671-682. PMID 28695707.

14. Gennaro P, Gabriele G, Salini C, et al. Our supramicrosurgical experience of lymphaticovenular anastomosis in lymphoedema patients to prevent cellulitis. Eur Rev Med Pharmacol Sci. Feb 2017;21(4):674-679. PMID 28272717.

15. Cemal Y, Pusic A, Mehrara BJ. Preventative measures for lymphedema: separating fact from fiction. J Am Coll Surg. Oct 2011;213(4):543-551. PMID 21802319.

16. Armer JM. The problem of post-breast cancer lymphedema: impact and measurement issues. Cancer Invest. Mar 2005;23(1):76-83. PMID 15779870.

17. Armer JM, Stewart BR. A comparison of four diagnostic criteria for lymphedema in a post-breast cancer population. Lymphat Res Biol. Dec 2005;3(4):208-217. PMID 16379589.

18. Petrek JA, Senie RT, Peters M, et al. Lymphedema in a cohort of breast carcinoma survivors 20 years after diagnosis. Cancer. Sep 15 2001;92(6):1368-1377. PMID 11745212.

19. Jorgensen MG, Toyserkani NM, Sorensen JA. The effect of prophylactic lymphovenous anastomosis and shunts for preventing cancer-related lymphedema: a systematic review and meta-analysis. Microsurgery. Mar 28 2017. PMID 28370317.

20. Boccardo FM, Casabona F, Friedman D, et al. Surgical prevention of arm lymphedema after breast cancer treatment. Ann Surg Oncol. Sep 2011;18(9):2500-2505. PMID 21369739.

21. Hahamoff M, Gupta N, Munoz D, et al. A lymphedema surveillance program for breast cancer patients reveals the promise of surgical prevention. J Surg Res. Feb 1 2018. PMID 29397949.

22. National Lymphedema Network Medical Advisory Comittee. The Diagnosis and Treatment of Lymphedema. Position Statement of the National Lymphedema Network 2011; https://www.lymphnet.org/pdfDocs/nlntreatment.pdf. Accessed May 23, 2018.

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

38999