Lymphedema
Number: 0069
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Scope of Policy
This Clinical Policy Bulletin addresses lymphedema.
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Medical Necessity
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Complex Decongestive Physiotherapy
Aetna considers a course of complex decongestive physiotherapy (CDP), also called complete decongestive therapy, or manual lymphoid drainage, medically necessary when both of the following criteria are met:
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The member has any of the following conditions:
- Evidence of ulceration due to lymphedema; or
- Intractable lymphedema of the extremities, unrelieved by elevation; or
- One or more previous admissions to treat complications of intractable lymphedema (i.e., cellulitis, ulceration); and
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The member has shown a past record of compliance and the member or his/her caregiver is capable of following the instructions associated with CDP.
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Lymphedema Pumps
Aetna considers lymphedema pumps (pneumatic compression devices) medically necessary durable medical equipment (DME) for home use according to the following criteria:
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Pneumatic Compression Device Without Calibrated Gradient Pressure
Aetna considers home use of a non-segmented (unicompartmental) device or segmented (multicompartmental) pneumatic compression device without manual control of the pressure in each chamber medically necessary for members with chronic and severe lymphedema when all of the following requirements are met:
- The member has a diagnosis of lymphedema; and
- The member has persistence of chronic and severe lymphedema as identified by the documented presence of at least one of the following clinical findings:
- Marked hyperkeratosis with hyperplasia and hyperpigmentation
- Papillomatosis cutis lymphostatica
- Deformity of elephantiasis
- Skin breakdown with persisting lymphorrhea, or
- Detailed measurements over time confirming the persistence of the lymphedema with a history evidencing a likely etiology; and
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In addition to this documented persistence, the lymphedema is then documented to be unresponsive to other clinical treatment over the course of a required four-week trial of conservative therapy that must include all of the following:
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Regular and compliant use of an appropriate compression bandage system or compression garment to provide adequate graduated compression:
- Adequate compression is defined as sufficient pressure at the lowest pressure point to cause fluid movement and (sufficient pressure across the gradient (from highest to lowest pressure point) to move fluid from distal to proximal. The compression used must not create a tourniquet effect at any point.
- Regular and compliant use of an appropriate compression bandage system or compression garment to provide adequate graduated compression:
- Regular exercise; and
- Elevation of the limb.
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When available, manual lymphatic drainage is a key component of conservative treatment as is appropriate medication treatment when there is concurrent congestive failure.
At the end of the 4-week trial, if there has been improvement, then a pneumatic compression device is considered not medically necessary. Where improvement has occurred, the trial of conservative therapy must be continued with subsequent reassessment at intervals at least 1 week apart. Only when no significant improvement has occurred in the most recent 4 weeks and the medical necessity criteria above are still met, may the lymphedema be considered unresponsive to conservative therapy, and a pneumatic compression device without calibrated gradient pressure would be considered medically necessary.
At a minimum, re-assessments conducted for a trial must include detailed measurements, obtained in the same manner and with reference to the same anatomic landmarks, prior to and at the conclusion of the various trials and therapy, with bilateral comparisons where appropriate.
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Pneumatic Compression Device With Calibrated Gradient Pressure
Aetna considers home use of a segmented pneumatic compression device with manual control of the pressure in each chamber medically necessary for the treatment of lymphedema extending onto the chest, trunk and/or abdomen when all of the following are met:
- The member has the diagnosis of lymphedema; and
- The member meets medical necessity criteria for a pneumatic compression device as described above; and
- The member has lymphedema extending onto the chest, trunk and/or abdomen that extends past the limits of a standard compression sleeve, and the chest, trunk and/or abdominal lymphedema has failed to improve with a four-week trial demonstrating failed response to treatment with a pneumatic compression device without calibrated gradient pressure is required. The four-week trial of conservative therapy must include all of the following:
- At least 4 weeks of regular, daily, multiple-hour home usage of a pneumatic compression device without calibrated gradient pressure after careful, in-person fitting, training and supervision by a technician who is skilled in and who regularly and successfully uses the appliance provided; and
- Compliant use of an appropriate compression bandage system or compression garment to provide adequate graduated compression:
- Adequate compression is defined as sufficient pressure at the lowest pressure point to cause fluid movement and sufficient pressure across the gradient (from highest to lowest pressure point) to move fluid from distal to proximal. The compression used must not create a tourniquet effect at any point;
- The garment may be prefabricated or custom-fabricated but must provide adequate graduated compression starting with a minimum of 30 mmHg distally; and
- Regular exercise; and
- Elevation where appropriate; and
- Manual lymphatic drainage (where available) and self-manual lymphatic drainage (MLD) for at least 30 minutes per day; and
- Evaluation of diet and implementation of any necessary change; and
- Medications as appropriate (e.g. diuretics and/or other treatment of congestive failure, etc.); and
- Correction (where possible) of anemia and/or hypoprotenemia.
At the end of the 4-week trial, if there has been improvement of the lymphedema extending onto the chest, trunk and/or abdomen, then a pneumatic compression device with calibrated gradient pressure is considered not medically necessary. Where improvement has occurred, the trial of conservative therapy must be continued with subsequent reassessment at intervals at least 1 week apart. When and only when no significant improvement has occurred in the most recent 4 weeks and the medical necessity criteria above are still met, a pneumatic compression device with calibrated gradient pressure is considered medically necessary.
Note: For members without DME benefits, lymphedema pumps are only covered for members with arm lymphedema due to mastectomy for breast cancer who meet the criteria for a lymphedema pump stated above.Footnote1*
- A 2-phase lymph preparation and drainage therapy device (e.g., Flexitouch Device, Tactile Systems Technology, Minneapolis, MN; LymphaPress Optimal, Lympha Press USA, Manalapan, NJ) is considered equally effective to standard segmented pneumatic compression devices with calibrated gradient pressure.
- Aetna considers the ACTitouch Adaptive Compression Therapy System equally effective to standard segmented pneumatic compression devices without calibrated gradient pressure.
- Note: Although the literature suggests that the use of lymphedema pumps is commonly initiated in the hospital, there is no medical necessity for this practice unless the member has other complications of lymphedema (i.e., cellulitis) that would require hospitalization. The use of lymphedema pumps can be initiated in the clinic or in the home setting.
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Static Compression Sleeves
Aetna considers static compression sleeves (e.g., the ReidSleeve, ArmAssist) to be medically necessary supplies for members with intractable lymphedema of the arms. Note: 3 static compression sleeves and/or gloves per affected arm are considered medically necessary in the initial purchase; and no more than 2 replacements per affected arm every 6 months is considered medically necessary. (Sleeves and gloves are separate items; as such, if both should be required for treatment,three gloves and three sleeves per affected arm would be considered medically necessary initially, with two additional of each in subsequent 6 month intervals, if needed.) For members whose plans exclude coverage of supplies, static compression sleeves are only covered for intractable lymphedema of the arms due to mastectomy for breast cancer.Footnote1*
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Excisional Procedures (Debulking, Liposuction)
Aetna considers excisionial procedures (debulking, liposuction including suction-assisted protein lipectomy (SAPL); also known as suction lipectomy) medically necessary for the treatment of chronic refractory lymphedema.
Footnote1*Note: HR 4328 (Public Law 105-277) requires individual and employer group health plans (including indemnity, PPO, POS and HMOs), that provide medical and surgical benefits with respect to a mastectomy, to provide coverage for lymphedema treatment in a manner determined in consultation with the attending physician and the member for a participant or beneficiary who is receiving benefits for a mastectomy and who elects breast reconstruction after the mastectomy. Therapy is subject to annual deductibles and co-insurance provisions for physical therapy. Therapy is not subject to visit limitation provisions for physical therapy.
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Experimental and Investigational
The following procedures are considered experimental and investigational because the effectiveness of these approaches has not been established:
- Acoustic radiation force impulse elastography for measurement of tissue stiffness in limb lymphedema
- Acupuncture for the treatment of breast cancer-related lymphedema
- Advanced pneumatic compression (e.g., the Flexitouch device) for the treatment of head and neck edema
- Aquatic therapy / aqua lymphatic therapy for the treatment of lymphedema
- Bioimpedance devices (e.g., L-Dex U400) for the diagnosis or management of lymphedema
- Bioelectrical impedance analysis for evaluation of limb lymphedema
- Combined adipose-derived stem cell and vascularized lymph node transfer for treatment of secondary lymphedema.
- >Compression bras for post-mastectomy lymphedema
- Compression garments for lymphedema of the genitals, head, and neck
- Extracorporeal shockwave therapy for the treatment of breast cancer-related lymphedema (BCRL)
- Fibro-lipo-lympho-aspiration (FLLA) for the treatment of lymphedema
- Genetic testing for predisposition to lymphedema following breast cancer therapy
- Immediate lymphatic reconstruction for the prevention of BCRL
- Koya Dayspring System for the promotion of wound healing; and treatment of lymphedema, and venous insufficiency
- Low-level light therapy (also known as low-level laser therapy and photo-bio-modulation therapy for the treatment of lymphedema
- Lymph node transfer (also known as vascularized lymph node transfer) for the treatment of lymphedema due to cervical cancer or melanoma, post-mastectomy lymphedema
- Magnetic resonance imaging for evaluation of therapeutic response in BCRL
- >Matrix rhythm therapy for the treatment of lymphedema
- Microsurgical treatments (microsurgical lymphatico-venous anastomosis, lymphatic-capsular-venous anastomosis, lymphovenous bypass) for the treatment of members with chronic obstructive lymphedema
- Minimally invasive tissue excision with possible redundant skin excision (the MITESE procedure) for the treatment of chronic lymphedema
- Platelet-rich plasma for the treatment of lymphedema
- Pneumatic compression devices with calibrated gradient pressure used to treat lymphedema not extending onto the chest, trunk and/or abdomen
- Reverse lymphatic mapping
- Tissue transfers (e.g., omental flap) for the treatment of lymphedema
- Whole body vibration for the treatment of lymphedema.
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Related Policies
- CPB 0097 - External Breast Prosthesis
- CPB 0500 - Intermittent Pneumatic Compression Devices (for pneumatic compression devices for chronic venous insufficiency)
- CPB 0482 - Compression Garments for the Legs
Background
Lymphedema refers to edema (i.e., swelling) due to inadequate lymphatic circulation related to either- defective development of the lymphatics (primary lymphedema); or
- destruction or obliteration of the lymphatic system (secondary lymphedema) due to either trauma, wounds, surgery, radiation therapy, or infection with a tropical filarial parasite.
Primary lymphedema typically involves the lower extremities and typically afflicts females. When it arises at birth it is called lymphedema congenita, before the age of 35 it is called lymphedema praecox, and when arising later in life it is called lymphedema tarda. Secondary lymphedema occurs most commonly after lymph node dissections. For example, 10 to 20 % of women with breast cancer who have undergone axillary dissection will experience lymphedema. Leg edema can result after groin dissection, most typically for melanoma. Lymphedema results in a feeling of heaviness, aching or tightness. In severe cases, mobility can be impaired. Development of angiosarcoma, know as the Stewart-Trewes syndrome, is a very rare complication of long standing severe lymphedema.
Lymphedema, as discussed below, is just one group of conditions that can be a cause of accumulation of fluid in the tissue. Lymphedema arises from disorders of the lymphatic system. It is essential to rule out other causes of edema in order to diagnose lymphedema. Edema from other causes is not classified as lymphedema for purposes of Medicare reimbursement for PCDs (E0650-E0652).
Primary Lymphedema
Primary lymphedema is a disorder of the lymphatic system that occurs on its own. It is inherited and uncommon. Examples (not all-inclusive) are:
- Congenital lymphedema due to lymphatic aplasia or hypoplasia
- Milroy's disease, an autosomal dominant familial form of congenital lymphedema
- Lymphedema praecox
- Lymphedema tarda.
Secondary Lymphedema
Secondary lymphedema is a disorder of lymphatic flow that is caused by some other disease or condition. It is more common than primary lymphedema. It is most commonly caused by surgery (especially lymph node dissection, such as for breast cancer), radiation therapy (especially axillary or inguinal), trauma, lymphatic obstruction by tumor, and, in developing countries, lymphatic filariasis. Secondary lymphedema may also result from compression of the lymphatic and venous channels resulting from leakage of fluid into interstitial tissues in patients with chronic venous insufficiency. (See below)
Lymphedema is usually staged by observing a patient’s physical condition. The International Society of Lymphology uses the following 3-stage scale for classification of a lymphedematous limb:
Stage 1: Early accumulation of fluid relatively high in protein content (e.g., in comparison with "venous" edema) that subsides with limb elevation. Pitting may occur.
Stage II: Limb elevation alone rarely reduces tissue swelling and pitting may or may not occur as tissue fibrosis develops.
Stage III: Lymphostatic elephantiasis. Pitting is absent and trophic skin changes such as acanthosis, fat deposits, and warty overgrowths develop.
An increasing number of lymphologists recognize an earlier stage of lymphedema, termed Stage 0, which refers to a latent or subclinical condition where swelling is not evident despite impaired lymphatic transport. Stage 0 may exist for months or years before the onset of overt lymphedema.
Cormeir and associates (2010) performed a systematic review and meta-analysis of the oncology-related literature excluding breast cancer to derive estimates of lymphedema incidence and to identify potential risk factors among various malignancies. The authors systematically reviewed 3 major medical indices (MEDLINE, Cochrane Library databases, and Scopus) to identify studies (1972 to 2008) that included a prospective assessment of lymphedema after cancer treatment. Studies were categorized according to malignancy, and data included treatment, complications, lymphedema measurement criteria, lymphedema incidence, and follow-up interval. A quality assessment of individual studies was performed using established criteria for systematic reviews. Bayesian meta-analytic techniques were applied to derive summary estimates when sufficient data were available. A total of 47 studies (7,779 cancer survivors) met inclusion criteria: melanoma (n = 15), gynecological malignancies (n = 22), genito-urinary cancers (n = 8), head/neck cancers (n = 1), and sarcomas (n = 1). The overall incidence of lymphedema was 15.5 % and varied by malignancy (p < 0.001): melanoma = 16 % (upper extremity, 5 %; lower extremity, 28 %); gynecological = 20 %; genito-urinary = 10 %; head/neck = 4 %; and sarcoma = 30 %. Increased lymphedema risk was also noted for patients undergoing pelvic dissections (22 %) and radiation therapy (31 %). Objective measurement methods and longer follow-up were both associated with increased lymphedema incidence. The authors concluded that lymphedema is a common condition affecting cancer survivors with various malignancies. The incidence of lymphedema is related to the type and extent of treatment, anatomical location, heterogeneity of assessment methods, and length of follow-up.
Lymphedema is diagnosed based upon the patients history and physical examination. The most widely accepted measure of lymphedema is limb circumference compared with that of the unaffected limb or compared with that of the same limb before the interventions or events that led to lymphedema. Imaging is usually not necessary unless an obstructive cause of the lymphedema is suspected (e.g., tumor).
Bioimpedance is a non-invasive method for estimating body composition based on the electrical conductive properties of various tissues. It is thought that bioimpedance devices can detect developing lymphedema before any clinical signs are visible. Devices using bioimpedance have been proposed as a diagnostic test of subclinical lymphedema (Stage 0) for the early identification of patients at risk of developing lymphedema. Proponents who support the approach to diagnose subclinical disease believe that early treatment of subclinical lymphedema will result in less severe chronic disease. One bioimpedance device is the ImpediMed LDex™ U400 (ImpediMed Limited, San Diego, CA), cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process in 2008. Thus, the manufacturer was not required to provide the evidence of clinical efficacy that is necessary to support a premarket approval (PMA). According to the FDA clearance letter, the device is "to aid in the clinical assessment of unilateral lymphedema of the arm in women." The FDA labeling states that the device is "not intended to diagnose or predict lymphedema of an extremity." ImediMed's L-Dex technology utilizes the characteristics of frequency dependent current flow to quantify changes in extracellular fluid in the patient's limb.
Czerniec and colleagues (2010) reported on measurement of lymphedema to determine the relationship between physical methods of measuring lymphedema and self-reported swelling. Lymphedema in women with (n = 33) and without (n = 18) unilateral arm lymphedema secondary to breast cancer was measured by self-report, bioimpedance spectroscopy, perometer, and the truncated cone method. The physical measurement tools were highly reliable (ICC((2,1)): 0.94 to 1.00) with high concordance (r(c): 0.89 to 0.99). Self-report correlated moderately with physical measurements (r = 0.65 to 0.71) and was moderately reliable (ICC((2,1)): 0.70). The authors concluded that lymphedema assessment methods are concordant and reliable but not interchangeable.
There is a lack of reliable evidence that intervention in the subclinical stage of lymphedema detected by bioimpedance improves outcomes over close monitoring and intervention when lymphedema becomes clinically evident by standard measures (e.g., limb volume measurement). A study by Stout Gergich et al (2008) has been cited to support initiation of lymphedema treatment at a subclinical stage. The study by Stout Gergich, et al. (2008) is not an National Institute of Health clinical practice guideline or clinical practice recommendation, but is a report of a case-control study to investigate the efficacy of a different technology, perometry, in the diagnosis and management of subclinical lymphedema in patients with early-stage breast cancer. Stout Gergich, et al. (2008) states that "The views expressed in this article are those of the author(s) and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the U.S. Government." The article states that "further research is needed" to validate bioimpedance in the context of a surveillance tool.
In the study by Stout Gergich, et al. (2008), lymphedema was identified in 43 of 196 women who participated in a prospective breast cancer morbidity trial. This study used another method of measurement, periometry, to detect lymphedema at an early stage. Limb volume was measured pre-operatively and at 3-month intervals after surgery. If an increase of greater than 3 % in upper limb volume developed compared with the preoperative volume, then a diagnosis of lymphedema was made, and a compression garment intervention was prescribed for 4 weeks. Upon reduction of lymphedema, garment wear was continued only during strenuous activity, with symptoms of heaviness, or with visible swelling. Statistical analysis was a repeated-measures analysis of variance by time and limb (p less than or equal to 0.001) comparing the lymphedema cohort with an age-matched control group. The investigators reported that the time to onset of lymphedema averaged 6.9 months post-operatively. The mean (± standard deviation) affected limb volume increase was 83 ml (± 119 ml; 6.5 % ± 9.9 %) at lymphedema onset (p = 0.005) compared with baseline. After the intervention, a statistically significant mean 48 ml (± 103 ml; 4.1 % ± 8.8 %) volume decrease was realized (p less than 0.0001). The mean duration of the intervention was 4.4 weeks (± 2.9 weeks). Volume reduction was maintained at an average follow-up of 4.8 months (± 4.1 months) after the intervention. The study did not provide evidence, however, that clinical outcomes were improved by initiating lymphedema treatment at the subclinical stage versus initiating lymphedema treatment at the earliest stage where lymphedema becomes clinically apparent using standard measurements (e.g., limb circumference measurements).
An assessment by the Australia and New Zealand Horizon Scanning Network (2008) concluded: "The Impedimed Imp™ SFB7 device appears to be effective for diagnosis of lymphoedema, although the studies were small in nature and lacked high quality design. Larger studies in which the device is directly compared with the standard methods for lymphoedema diagnosis are required. Additionally, varied stages of lymphoedema manifestation should be included."
An ad hoc group organized by the Avon Foundation for Women (2011) organized to discuss advances in the early detection and intervention of lymphedema recommended perometry or bioimpedance in the early detection of lymphedema. A reading of the full text of the recommendation reveals that the primary support for use of perometry or bioimpedance spectroscopy is the study by Stout Gergich, et al. (2008); the limitations of this study are summarized above.
The 2011 National Accreditation Program for Breast Centers (NAPBC) Standards lists lymphedema management and risk reduction practices among breast center supportive services. The NAPBC Standards lists the National Lymphedema Network resource center as a recommended resource on this topic. However, the NAPBC standards include no discussion of bioimpedance, or requirement for bioimpedance as a requirement for accreditation.
The National Lymphedema Network position statement, Screening and Measurement for Early Detection of Breast Cancer Related Lymphedema, updated April 2011, states that circumferential tape measurements are acceptable means of measuring limb volume. The current position statement states "bioelectrical spectroscopy (BIS) or infrared perometry are suggested as alternative or adjunctive methods to circumferential measurement."
A technology assessment of the diagnosis and management of secondary lymphedema prepared for the Agency for Healthcare Research and Quality (Oremus et al, 2010) concluded: "There is consistent evidence to indicate that lymphedema can be reliably measured using circumferential measures or volume displacement ... There is too little evidence to draw conclusions about the reliability of other tests such as tonometry, ultrasound, lymphoscintigraphy, or bioimpedance."
The Northern Ireland CREST Committee guidelines for lymphedema (2008) recommend circumferential limb volume measurement for assessing limb volume. Bioimpedance measurement is described as promising, noting that it should be considered over the next 5 years. The CREST guideline development group identified continued research into the reliability and validity of diagnostic methods such as bioimpedance analysis among priorities for future research in Northern Ireland.
The National Cancer Institute Physician Data Query (PDQ) on lymphedema (NCI, 2011) states that circumferential upper-extremity measurement is the most widely used method to diagnose upper-extremity lymphedema. Bioimpedance is listed among several other options for evaluating limb volume. The PDQ also stated that a study comparing various methods of assessing upper-limb lymphedema did not show any superiority of any one method; for support, the PDQ cited a study by Ridner, et al. (2007) comparing circumferential limb measurements to bioimpedance and perometry.
Several other guidelines that have been cited for support of bioimpedance spectroscopy make no recommendation for use of this technology. A report of an Institute of Medicine workshop (Hewitt, et al., 2006) includes no recommendation for, or reference to, bioimpedance spectroscopy for lymphedema. The workshop report identifies assessments of the value of lymphedema prevention, early diagnosis, and surveillance as areas in need of further research. A 2009 consensus document on diagnosis and treatment of peripheral lymphedema, from the International Society of Lymphology makes no reference to or recommendation for bioimpedance spectroscopy. Canadian guidelines on the care and treatment of lymphedema (Harris, et al., 2001) make no recommendation for bioimpedance spectroscopy. The guidelines recommend circumferential measurements and state that other methods "are being evaluated in research settings."
The federal Women’s Health and Cancer Rights Act of 1998 requires health insurance policies that cover mastectomy to also provide coverage for reconstructive surgery, prostheses, and physical complications of mastectomy, including lymphedema. However, the Act does not require health insurers to cover bioimpedance spectroscopy or other interventions of unproven value.
Results of available studies do not provide consistent evidence that bioimpedance is any more reliable than current methods for detection of lymphedema. In addition, there is a lack of clinical studies demonstrating that incorporation of bioimpedance into lymphedema management improves clinical outcomes. Long-term studies demonstrating the effectiveness of bioimpedance testing over conventional monitoring techniques for lymphedema are needed.
Conservative treatment of lymphedema focuses on a combination of physical therapies: elevation of the arm or leg, manual physical therapy, wearing of various types of compression stockings/bandages, or pneumatic pumps.
The use of elastic stockings is considered a valuable component of lymphedema therapy, and appears to be critical to the long term success of treatment. Compliance with elastic stocking may be problematic since they are frequently hot, uncomfortable, and considered unsightly by some. Lack of compliance may result in requests for further treatment, such as pneumatic pumps or complex decongestive physiotherapy. However, elastic garments are a component of all treatments of lymphedema and compliance has a major impact on the success of any treatment of lymphedema.
PCDs consist of an inflatable garment for the arm or leg and an electrical pneumatic pump that fills the garment with compressed air. The garment is intermittently inflated and deflated with cycle times and pressures that vary between devices.
A non-segmented pneumatic compressor (E0650) is a device which has a single outflow port on the compressor. The fact that the air from the single tube may be transmitted to a sleeve/appliance with multiple compartments or segments (E0671-E0673) does not affect the coding of the compressor.
A segmented pneumatic compressor (E0651, E0652) is a device which has multiple outflow ports on the compressor which lead to distinct segments on the appliance which inflate sequentially. A segmented device without calibrated gradient pressure (E0651) is one in which either (a) the same pressure is present in each segment or (b) there is a predetermined pressure gradient in successive segments but no ability to individually set or adjust pressures in each of several segments. In an E0651 device the pressure is usually set by a single control on the distal segment. A segmented device with calibrated gradient pressure (E0652) is characterized by a manual control on at least three outflow ports which can deliver an individually determined pressure to each segmental unit. The fact that the tubing and/or appliance are capable of achieving a pressure gradient does not classify the compressor as E0652 because this is not a calibrated gradient pressure.
Segmental gradient pressure pneumatic appliances (E0671-E0673) are appliances/sleeves which are used with a non-segmented pneumatic compressor (E0650) but which achieve a pressure gradient through the design of the tubing and/or air chambers.
Pneumatic pumps can consist either of static uni-compartmental pumps where an equal amount of pressure is applied throughout the edematous limb, or a sequential pump which essentially attempts to "wring out" the edema by graded compression from distal to proximal. Due to the short cycles of pressure, higher pressures can be applied compared to the static pumps. Pressures higher than the systolic blood pressure are avoided; pressures up to 80 to 90 mm Hg are typical. At this point sequential pumps (such as the Lymphapress or the Wright linear sequential pump) appear to be more commonly used than static pumps. The Lymphapress device is composed of a series of overlapping cells that apply a sequential pattern of compression moving distally to proximally along the affected limb. Using this strategy, higher levels of pressure can be applied compared to other uni-compartmental devices which apply the same degree of pressure along the entire limb. The Lymphapress device seems to be effective in acutely decreasing lymphedema, and many patients have purchased this device for home use.
Newer, advanced pneumatic compression devices with additional features that the more "traditional" type of pumps do not offer have been developed. A two-stage multichamber programmable pneumatic compression device operates in two separate phases. These devices are proposed to be based on the principles of manual lymph drainage (treat the proximal areas first, which is theorized to prepare the distal areas for drainage). The first phase is a "preparatory" phase, followed by the treatment or drainage phase, which utilizes light variable pressure to drain the fluid/ blood from the distal treatment areas. The second phase may be controlled by multiple programmable options. Examples of this type of pump include, but may not be limited to, the Flexitouch or LymphaPress Optimal.
The Flexitouch Device (Tactile Systems Technology, Minneapolis, MN) is a 2-phase lymph preparation and drainage therapy device. The device consists of an electronic controller unit and garments which are worn on the trunk and upper and lower affected extremities and connected to the controller unit by tubing harnesses. The garment consists of 32 inflatable chambers that sequentially inflate and deflate at 1 to 3 second intervals, according to 1 of the 13 pre-programmed treatment patterns selected. Chamber pressure and treatment times can be adjusted. The manufacturer states that device’s sequential action evacuates lymph from the trunk and extremities and drains it into the venous system. The garments are made from stretch material and are fitted with Velcro enclosures, so custom fitting of garments is not required. There are no published studies comparing the effectiveness of this 2-phase lymph preparation and drainage therapy device to standard segmented pneumatic compression devices.
The ACTitouch Adaptive Compression therapy system is another more recently developed pump device. It combines intermittent pneumatic compression with a sustained gradient pressure. It may be used when stationary or when ambulating (walking).
Drug therapy with benzopyrone can also result in slow reduction of lymphedema. This drug is a proteolytic agent that acts by activating macrophages, which then break down the protein-rich lymphedema fluid, thus decreasing its viscosity and thereby facilitating its flow.
Complex Decongestive Physiotherapy (CDP) Basic Components
A technique developed in Germany, complex decongestive physiotherapy (CDP), has been introduced in the United States. It is most frequently offered in specialized clinics. Patients attend the clinics for 1 to 4 weeks; CDP consists of 4 basic components as follows:
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Meticulous skin and nail care:
The protein rich lymphedema fluid is highly susceptible to infection which can then further damage the lymphatics resulting in a vicious cycle. Thus meticulous skin and nail care is required. Emollients are often used to prevent drying and cracking of the skin and all fungal infections must be treated promptly.
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Manual lymphatic drainage (MLD):
This massage technique seems to be the unique component of this multi-disciplinary approach and is based on the concept that the lymphatic system is subdivided into individual lymphotomes which communicate through collateral channels. The idea behind MLD is to increase the collateral circulation between these lymphotomes, such that the lymphedema fluid can be shunted from an inadequately draining lymphotome into a normal one. Thus, unlike other massage techniques, MLD begins with massage of the contralateral truncal lymphotome and then progresses toward the edematous extremity. Theoretically, in this way the collateral circulation is opened and dilated and the lymphatic drainage is "decongested." There is no specific description of the technique of MLD, or theories as to how this technique can open and dilate collateral channels. Patients enrolled in the CDP clinic may undergo 1 to 2 such MLD sessions (about 45 mins each) each day.
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Bandaging:
After the MLD session, the lymphedematous limb is wrapped with a pure cotton, minimally elastic bandages in order to provide adequate tissue pressure which in turn prevents re-accumulation of lymphedema.
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Remedial Exercises:
During the clinical sessions the patients receive additional counseling in various aspects of self management, such as skin care, nutrition, weight control, etc. Prior to discharge from the clinic, the patient is fitted with an elastic support garment. It is recommended that this garment be worn as much as possible, and even at night. Some clinics may recommend wearing the bandages at night, and the compressive garment during the day. The use of these garments can be gradually reduced as the patient improves; however, typically, the patient will need to continue wearing the compressive garment at least part time. An initial course of CDP may require 30 days, or in the case of lower extremity care, 45 days.
No conservative treatment is entirely curative and all require a committed physical therapy team and a committed and compliant patient.
Surgery, though not curative and rarely performed, has been suggested as a treatment for those with refractory lymphedema who have not improved with conservative management. Lymphedema surgery may be classified as reconstructive or excisional. Excisional surgical procedures for lymphedema include, but may not be limited to, debulking and liposuction. Excisional surgical procedures involve resection of the redundant tissue that may develop in long-standing severe lymphedema and elephantiasis. Reconstructive surgical procedures include, but may not be limited to, microsurgical treatment (eg, microsurgical lymphatico-venous anastomosis, lymphatic-capsular-venous anastomosis, lymphovenous bypass), lymph node transfer (also known as vascularized lymph node transfer) and tissue transfers. Reconstructive (physiologic) surgical procedures attempt to provide or enhance lymphatic drainage with either anastomoses between lymphatic systems (i.e., linking subcutaneous tissues with the deep lymphatics), creating lymphovenous anastomoses or creation of artificial lymph channels. These surgical techniques are controversial and rarely used.
Damstra and colleagues (2009) prospectively determined the effect of lympho-venous anastomosis (LVA) on breast cancer related lymphedema (BCRL) and reviewed the current literature. A total of 10 patients who were previously treated for breast cancer by surgery, radiotherapy, and chemotherapy, and were unresponsive to 12-weeks of non-operative treatment, underwent an LVA procedure. Objective measurements were gathered for circumferential measurement and water volumetry, and quality of life. Various types of lympho-scintigraphy were performed pre-operatively and post-operatively at 3 and 12 months. Treatment was embedded in a multi-disciplinary setting. Post-operative volume measurements initially showed a 4.8 % reduction of lymphedema at 3 months and a 2 % reduction after 1 year. Various scintigraphic parameters showed some improvement. Quality of life questionnaires reported minimal improvement. Reviewing the literature, only retrospective studies were found; these reported varying results for LVA procedures. The selection of patients, classification of lymphedema, indications and types of LVA, and additional therapeutic options were heterogeneous, not comparable, and lacked a validated method of effect-assessment. The authors concluded that their findings showed a minimal reduction in volume of lymphedema following LVA; in the literature, there was no convincing evidence of the success of LVA. They noted that non-operative treatment and elastic stockings are still preferred by most patients with lymphedema, especially in early stages with few irreversible changes.
In a randomized, single-blinded, controlled trial, Devoogdt et al (2011) determined the preventive effect of manual lymph drainage on the development of lymphedema related to breast cancer. A total of 160 consecutive patients with breast cancer and unilateral axillary lymph node dissection were included in this study. The randomization was stratified for body mass index (BMI) and axillary irradiation and treatment allocation was concealed. Randomization was done independently from recruitment and treatment. Baseline characteristics were comparable between the groups. For 6 months, the intervention group (n = 79) performed a treatment program consisting of guidelines about the prevention of lymphedema, exercise therapy, and manual lymph drainage. The control group (n = 81) performed the same program without manual lymph drainage. Main outcome measures included cumulative incidence of arm lymphedema and time to develop arm lymphedema, defined as an increase in arm volume of 200 ml or more in the value before surgery. Four patients in the intervention group and 2 in the control group were lost to follow-up. At 12 months after surgery, the cumulative incidence rate for arm lymphedema was comparable between the intervention group (24 %) and control group (19 %) (odds ratio 1.3, 95 % confidence interval [CI]: 0.6 to 2.9; p = 0.45). The time to develop arm lymphedema was comparable between the 2 group during the first year after surgery (hazard ratio 1.3, 0.6 to 2.5; p = 0.49). The sample size calculation was based on a presumed odds ratio of 0.3, which is not included in the 95 % CI. This odds ratio was calculated as (presumed cumulative incidence of lymphedema in intervention group/presumed cumulative incidence of no lymphedema in intervention group)×(presumed cumulative incidence of no lymphedema in control group/presumed cumulative incidence of lymphedema in control group) or (10/90)×(70/30). The authors concluded that manual lymph drainage in addition to guidelines and exercise therapy after axillary lymph node dissection for breast cancer is unlikely to have a medium to large effect in reducing the incidence of arm lymphedema in the short-term.
Vascularized Lymph Node Transfer
Lin et al (2009) evaluated the outcome of vascularized groin lymph node transfer using the wrist as a recipient site in patients with post-mastectomy upper extremity lymphedema. Between January of 1997 and June of 2005, 13 consecutive patients with a mean age of 50.69 +/- 11.25 years underwent vascularized groin lymph node transfer for post-mastectomy upper extremity lymphedema. A vascularized groin lymph node nourished by the superficial circumflex iliac vessels was harvested and transferred to the dorsal wrist of the lymphedematous limb. The superficial radial artery and the cephalic vein were used as the recipient vessels. Outcome was assessed by upper limb girth, incidence of cellulitis, and lympho-scintigraphy. All flaps survived, and 1 flap required re-exploration, with successful salvage. No donor-site morbidity was encountered. At a mean follow-up of 56.31 +/- 27.12 months, the mean reduction rate (50.55 +/- 19.26 %) of the lymphedematous limb was statistically significant between the pre-operative and post-operative groups (p < 0.01). The incidence of cellulitis was decreased in 11 patients. Post-operative lympho-scintigraphy indicated improved lymph drainage of the affected arm, revealing decreased lymph stasis and rapid lymphatic clearance. A hypothesis was proposed that the vascularized groin lymph node transfer might act as an internal pump and suction pathway for lymphatic clearance of lymphedematous limb. The authors concluded that vascularized groin lymph node transfer using the wrist as a recipient site is a novel and reliable procedure that significantly improves post-mastectomy upper extremity lymphedema. Drawback of this study included small sample size and lack of a control group.
Gharb et al (2011) reported the outcome of vascularized lymph node transfer with hilar perforators compared with the conventional technique. A total of 21 patients affected by early stage II upper limb lymphedema were included in this study. Of them, 11 patients received a free groin flap containing lymph nodes, and 10 patients received vascularized inguinal lymph nodes with hilar perforators. Mean follow-up was 46 and 40 months, respectively. Complications, secondary procedures, circumference of the limb, and subjective symptomatology were registered. The differences were evaluated statistically. The limb circumferences decreased significantly in the new group. The number of secondary procedures was significantly higher in the standard group. There were 2 cases of partial flap loss and donor site lymphorrhea in the standard group. In both the groups, visual analog scale scores improved after the operation. The authors concluded that transfer of vascularized inguinal lymph nodes based on the hilar perforators improves the outcomes in the treatment of early lymphedema of the upper extremity. Drawback of this study included small sample size and lack of a control group.
Cormier and colleagues (2012) performed a systematic review of the literature to examine contemporary peer-reviewed literature (2004 to 2010) evaluating the surgical treatment of lymphedema. A comprehensive search of 11 major medical indices was performed. Selected articles were sorted to identify those related to the surgical treatment of lymphedema. Extracted data included the number of patients, specific surgical procedure performed, length of follow-up, criteria for defining lymphedema, measurement methods, volume or circumference reduction, and reported complications. A total of 20 studies met inclusion criteria; procedures were categorized as excisional procedures (n = 8), lymphatic reconstruction (n = 8), and tissue transfer (n = 4). The reported incidence of volume reduction of lymphedema in these studies varied from 118 % reduction to a 13 % increase over the follow-up intervals ranging from 6 months to 15 years. The largest reported reductions were noted after excisional procedures (91.1 %), lymphatic reconstruction (54.9 %), and tissue transfer procedures (47.6 %). Procedure complications were rarely reported. The authors concluded that a number of surgical approaches have demonstrated beneficial effects for select patients with lymphedema. Most of these reports, however, were based on small numbers of patients, use non-standardized or inconsistent measurement techniques, and lack long-term follow-up. The proposed benefits of any surgical approach should be evaluated in the context of the potential morbidity to the individual patient and the availability of surgical expertise. In addition, although these surgical techniques have shown promising results, nearly all note that the procedures do not obviate the need for continued use of conventional therapies, including compression, for long-term maintenance.
Also, an UpToDate review on "Operative management of primary and secondary lymphedema" (Mehrara, 2012) stated that "similar to flap transfers, lymph node transfers are not commonly performed. Although these procedures may hold some promise, additional studies are required to evaluate their efficacy and to identify patient populations that are most likely to benefit …. Outcome data for lymph node transfer procedures are based upon small series of patients. Effective engraftment of non-vascularized transfer of lymph node grafts has not been clearly demonstrated. Harvesting of lymph nodes for transfer may cause lymphedema in the donor extremity".
An UpToDate review on "Lymphedema: Prevention and treatment" (Mohler and Mondry, 2012) did not mention the use of whole body vibration as a management toll.
Dylke et al (2014) examined if bioimpedance spectroscopy was suitable for detection of hand lymphedema. The hands of 50 participants without a history of lymphedema were measured with perometry and bioimpedance spectroscopy after positioning 2 ways for 3 minutes:- both hands rested at heart height; and
- the dominant hand at heart height and the non-dominant hand at head height.
In addition, 10 women with secondary hand lymphedema were also measured. Impedance and volume measurements were found to be strongly related (dominant hand r = -0.794). Both measurements were reliable (ICC(2,1) = 0.900 to 0.967 and 0.988 to 0.996, respectively). Impedance was more sensitive to small changes in hand volume due to the postural change (position × device interaction: F = 23.9, p < 0.001). Finally, impedance measurements had better discrimination of women with lymphedema than volume measurements. The authors concluded that bioimpedance spectroscopy is a promising tool for the detection of secondary hand lymphedema.
Cheng et al (2013) noted that vascularized groin lymph node flap transfer is an emerging approach to the treatment of post-mastectomy upper limb lymphedema. These investigators described the pertinent flap anatomy, surgical technique including different recipient sites, and outcome of this technique. A total of 10 cadaveric dissections were performed to clarify the vascular supply of the superficial groin lymph nodes; and 10 patients underwent vascularized groin lymph node flap transfer for post-mastectomy upper limb lymphedema using the wrist (n = 8) or elbow (n = 2) as a recipient site; and 10 patients who chose to undergo physical therapy (PT) were used as controls. Intra-operatively, indocyanine green (iCG) was injected subcutaneously on the flap margin to observe the lymph drainage. Outcomes were assessed using improvement of circumferential differentiation, reduction rate, and decreased number of episodes of cellulitis. A mean 6.2 ± 1.3 groin lymph nodes with consistent pedicles were identified in the cadaveric dissections. After ICG injection, the fluorescence was drained from the flap edge into the donor vein, followed by the recipient vein. At a mean follow-up of 39.1 ± 15.7 months, the mean improvement of circumferential differentiation was 7.3 ± 2.7 % and the reduction rate was 40.4 ± 16.1 % in the vascularized groin lymph node group, which were statistically greater than those of the PT group (1.7 ± 4.6 % and 8.3 ± 34.7 %, respectively; p < 0.01 and p = 0.02, respectively). The authors concluded that the superficial groin lymph nodes were confirmed as vascularized with reliable arterial perfusion. They stated that vascularized groin lymph node flap transfer using the wrist or elbow as a recipient site is an effectives approach to treating post-mastectomy upper limb lymphedema. The findings of this small study need to be validated by well-designed studies.
UpToDate reviews on "Management of locally advanced cervical cancer" (De Los Santos and Straughn, 2014), and "Management of recurrent or metastatic cervical cancer" (Wright, 2014) do not mention vascularized lymph node transfer as a management tool.
Furthermore, NCCN’s clinical practice guideline on "Cervical cancer" (Version 2.2015) does not mention vascularized lymph node transfer as a management tool.
Ketterer (2014) noted that surgical options for treating lymphedema have expanded in recent years. For many years the only treatment options were conservative non-surgical therapies and excisional surgeries. Advances in microsurgery have made it possible to reconstruct lymphatic function. Reconstructive surgical options include lymphatico-venular bypass, lymphatico-lymphatic bypass, and vascularized lymph node transfer (VLNT). The authors concluded that currently, there is no consensus on how or when to surgically treat lymphedema, and more studies are needed to evaluate the risks and effectiveness of each of these techniques.
Basta et al (2014) quantified the safety and effectiveness of microsurgery for lymphedema through a systematic meta-analysis. A literature search was conducted to identify all articles involving microsurgical treatment of lymphedema. Studies meeting criteria for inclusion were rated on methodologic quality based on the American Society of Plastic Surgeons levels of evidence. Demographic information, cause of lymphedema, and surgical technique were recorded. Quantitative change in lymphedema as well as peri-operative complications were noted. A total of 27 studies were included, with 24 offering level IV evidence and 3 offering level III evidence. Lympho-venous shunt procedures were performed in 22 studies and lymph node transplantation was performed in 5. Excess circumference was reduced by 48.8 ± 6.0 %, and absolute circumference was reduced by 3.31 ± 0.73 cm. Studies reporting change in volume demonstrated a reduction in excess volume by 56.6 ± 9.1 %; and absolute volume was reduced by 23.6 ± 2.1 %. The incidence of no improvement in lymphedema post-operatively was 11.8 %, and 91.2 % of patients reported subjective improvement. Approximately 64.8 % of patients discontinued compression garments at follow-up. Complications included operative-site infection (4.7 %), lymphorrhea (7.7 %), re-exploration for flap congestion (2.7 %), and additional procedures (22.6 %). The authors concluded that operative interventions for peripheral lymphedema appear to provide consistent quantitative improvements post-operatively, with a relatively wide safety margin. Lymph node transplantation may provide better outcomes compared with lympho-venous shunt, but well-designed head-to-head comparisons are needed to evaluate this further.
Raju and Chang (2015) performed a comprehensive literature review of VLNT with updates and comparisons on current application, techniques, results, studies and possible future implications. The review was conducted over major medical indices (PubMed-MEDLINE, Factiva, Scopus, Sciencedirect, EMBASE). Search terms were focused on vascularized, lymph node transfer (also autologous, lymph node transplant) to cover both human and animal studies. Each study was verified for the nature of the procedure; a free microsurgical flap containing lymph nodes for the purpose of relieving lymphedema. There were human and animal studies that individually reported clear benefits, but because of methodological shortcomings comparative studies with uniform patient selection and monitoring were lacking. The authors concluded that although the results with the use of VLNT for treatment of lymphedema have been largely positive, further exploration into standardized protocols for diagnosis, treatment optimization, and patient outcomes assessment is needed.
In a systematic review, Ozturk and colleagues (2016) evaluated the current evidence on VLNT and examined if there is objective data concerning improved outcomes. These researchers performed a literature search of PubMed, Embase and CENTRAL electronic databases to identify articles written in the English language on VLNT for treatment of lymphedema. Publications were selected according to inclusion criteria. Papers reporting adjunct techniques and those that did not describe outcomes were excluded. Data including patient demographics, surgical technique, complications and outcomes were extracted. A quality score was calculated for each article. A total of 18 studies were included with an overall study population of 305 patients. Mean quality score of articles was 5.3 with levels of evidence range from II to IV. Among 182 patients who underwent limb circumference assessment, 165 (91 %) showed post-operative improvement. Reduction of limb volume was noted in 98 of 114 (86 %) patients; 92patients underwent lymphoscintigraphy/lymphangiography and 55 (60 %) demonstrated moderate or significant improvement of flow. Patient satisfaction was questioned in 105 patients and with exception of 7 patients, all reported a high satisfaction level with significant relief in symptoms and improved quality of life (QOL). Publications also reported a reduction in infectious episodes. The authors concluded that VLNT appeared to provide improvement in lymphedema. However, they stated that more studies with standardized methods for reporting outcomes and uniform patient selection are needed to evaluate this technique thoroughly.
Scaglioni and associates (2018) evaluated outcomes and complications of VLNT. Several early preliminary studies have reported promising outcomes, but they were limited by small numbers, short follow-up, and were inconsistent in addressing the origin and recipient site of the transferred lymph nodes as well as the donor site morbidity. These investigators performed a review of literature using PubMed-Medline, Embase for key words VLNT (also autologous, lymph node transplant); only human studies were included. A total of 24 studies encompassing 271 VLNTs were included. The inguinal nodes were the most commonly used donor site followed by the lateral thoracic lymph nodes. The lateral thoracic lymph nodes were the least effective and had the highest complication rates (27.5 %) compared to other lymph node donor sites (inguinal: 10.3 % and supraclavicular: 5.6 %). Upper extremity lymphedema responded better compared to lower extremity (74.2 versus 53.2 %), but there was no difference in placing the lymph nodes more proximally versus distally on the extremity (proximal: 76.9 % versus distal: 80.4 %). The authors concluded that VLNT for lymphedema treatment is a promising operative technique showing beneficial results in early but also in advanced stage lymphedema.
Cornelissen and co-workers (2017) stated that lymph node transfer has been performed to treat lymphedema for several years. The goal of this procedure is to provide a bridge between the lymphatic system distal and proximal to the lymph node dissection. There is a lack of consensus about the necessity of an additional vascular anastomosis for the transplanted lymph nodes. These investigators performed a systematic literature search in Cochrane Library database CENTRAL, Medline, and Embase of animal studies using lymph node transplantation with and without additional vascularization in March 2016. The strategy used for the search was: (("Models, Animal"[Mesh]) and (("Lymphedema"[Mesh]) or "Lymph Nodes"[Mesh]) or "Lymph Node Excision"[Mesh])) and ((vascularized lymph node transfer) or ((non-vascularized lymph node transfer) or lymph node graft)). The primary outcomes were: survival of transplanted lymph node and lymphatic vessel regeneration. A total of 16 studies were included; vascularization and the use of growth factors were significantly associated with lymph node survival; and lymphatic vessels regeneration was independent from vascularization. The authors concluded that according to the findings of this study, additional vascular anastomosis might improve the transplanted lymph node survival. Moreover, they stated that further studies in both experimental and clinical setting are needed in order to support it.
Carl and colleagues (2017) noted that although conservative management of lymphedema remains the first-line approach, surgery is effective in select patients. These investigators reviewed the literature and developed a treatment algorithm based on the highest quality lymphedema research. They performed a systematic literature review to examine the surgical treatments for lymphedema. Studies were categorized into 5 groups:- excision,
- liposuction,
- LVA,
- VLNT, and
- combined/multiple approaches.
Studies were scored for methodological quality using the methodological index for non-randomized studies (MINORS) scoring system. A total of 69 articles met inclusion criteria and were assigned MINORS scores with a maximum score of 16 or 24 for non-comparative or comparative studies, respectively. The average MINORS scores using non-comparative criteria were 12.1 for excision, 13.2 for liposuction, 12.6 for LVA, 13.1 for VLNT, and 13.5 for combined/multiple approaches. Loss to follow-up was the most common cause of low scores; 39 studies scoring greater than 12/16 or greater than 19/24 were considered high quality. In studies measuring excess volume reduction, the mean reduction was 96.6 % (95 % CI: 86.2 to 107 %) for liposuction, 33.1 % (95 % CI: 14.4 to 51.9 %) for LVA, and 26.4 % (95 % CI: - 7.98 to 60.8 %) for VLNT. Included excision articles did not report excess volume reduction. The authors concluded that although the overall quality of lymphedema literature was fair, the MINORS scoring system was an effective method to isolate high-quality studies. These studies were used to develop an evidence-based algorithm to guide clinical practice. They stated that further studies with a particular focus on patient follow-up will improve the validity of lymphedema surgery research. The mean excess volume reduction with VLNT was 26.4 %, which was less than for the other procedures included in the review (liposuction, LVA). Furthermore, for VLNT, the 95 % CI crossed zero, meaning that the mean excess volume reduction failed to reach statistical significance. The authors also noted that the biggest drawback of this study was the heterogeneity of the included studies in terms of patients’ lymphedema stage and etiology, method of assessing surgical outcomes, and inconsistent reporting of complications and quality of life outcomes. They also stated that to better delineate indications for LVA versus VLNT and validate their proposed algorithm, more head-to-head comparative studies that adopt an accepted staging system, such as the ISL system, are needed. Also, randomized controlled trial (RCTs) with homogeneous patient populations in term of etiology and stage that compare surgical treatments to conservative therapies would help further define the most appropriate interventions for patients according to their clinical stage. Furthermore, additional studies with a particular focus on patient follow-up would help improve the validity of lymphedema surgery research.
Saaristo et al (2012) stated that post-operative lymphedema after breast cancer surgery is a challenging problem. Recently, a novel microvascular lymph node transfer technique provided a fresh hope for patients with lymphedema. These researchers aimed to combine this new method with the standard breast reconstruction. During 2008 to 2010, these investigators performed free lower abdominal flap breast reconstruction in 87 patients. For all patients with lymphedema symptoms (n = 9), the authors used a modified lower abdominal reconstruction flap containing lymph nodes and lymphatic vessels surrounding the superficial circumflex vessel pedicle. Operation time, donor site morbidity, and post-operative recovery between the 2 groups (lymphedema breast reconstruction and breast reconstruction) were compared. The effect on the post-operative lymphatic vessel function was examined. The average operation time was 426 mins in the lymphedema breast reconstruction group and 391 mins in the breast reconstruction group. The post-operative abdominal seroma formation was increased in patients with lymphedema. Post-operative lymphoscintigraphy demonstrated at least some improvement in lymphatic vessel function in 5 of 6 patients with lymphedema. The upper limb perimeter decreased in 7 of 9 patients. Physiotherapy and compression was no longer needed in 3 of 9 patients. Importantly, these researchers found that human lymph nodes express high levels of endogenous lymphatic vessel growth factors. Transfer of the lymph nodes and the resulting endogenous growth factor expression may thereby induce the regrowth of lymphatic network in the axilla. No edema problems were detected in the lymph node donor area. The authors concluded that simultaneous breast and lymphatic reconstruction was an ideal option for patients who suffer from lymphedema after mastectomy and axillary dissection. This was a small (n = 9) study; its findings need to be validated by well-designed studies.Becker et al (2012) stated that lymphedema is a chronic and progressive condition that occurs after cancer treatment. Autologous lymph node transplant, or microsurgical vascularized lymph node transfer (ALNT), is a surgical therapeutic option that brings vascularized vascular endothelial growth factor-C-producing tissue into the operated field to promote lymphangiogenesis and bridge the distal obstructed lymphatic system with the proximal lymphatic system. Operative techniques for upper- and lower-extremity ALNT were described with 3 donor lymph node flaps (inguinal, thoracic, cervical). Surgical technique was described for the combination of ALNT with abdominal flaps and non-abdominal flaps. Imaging showing restoration of lymphatic drainage after ALNT was shown.
Coriddi et al (2017) noted that vascularized lymph node transfer (VLNT) is a surgical treatment for lymphedema. Multiple donor sites have been described and each has significant disadvantages. These researchers proposed the jejunal mesentery as a novel donor site for VLNT. These investigators performed a cadaveric anatomic study analyzing jejunal lymph nodes (LNs) and described outcomes from the first patients who received jejunal mesenteric VLNT for treatment of lymphedema. In 5 cadavers, the average numbers of total LNs and peripheral LNs were identified in the proximal, middle, and distal segments of jejunum. Totals counted were 19.2/13.8/9.6, (SD 7.0/4.4/1.1), respectively; of those, 10.4/6.8/3.4 (SD 3.6/2.3/2.6), respectively, were in the periphery. There were significantly more total and peripheral lymph nodes in the proximal segment compared with the middle and distal segments (p = 0.027 and p = 0.008, respectively). The jejunal VLNT was used in 15 patients for treatment of upper (n = 8) or lower (n = 7) extremity lymphedema. Average follow-up was 9.1 (± 6.4) months (range of 1 to 19 months). Of 14 patients with viable flaps (93.3 %), 12 had subjective improvement (87.5 %); 10 patients had pre-operative measurements, and of those, 7 had objective improvement in lymphedema (70 %). The authors concluded that the jejunal mesenteric VLNT was an excellent option for lymphedema treatment because there was no risk of donor site lymphedema or nerve damage, and the scar was easily concealed; harvest from the periphery of the proximal jejunum was optimal. Improvement from lymphedema can be expected in a majority of patients.
In a recent review on "Lymphedema: Pathogenesis and novel therapies", Dayan et al (2018) stated that lymphedema affects up to 1 in 6 patients who undergo treatment for a solid tumor in the United States. Its prevalence has increased as more effective oncologic therapies have improved patient survival, but there remains no definitive cure. Recent research has elucidated new details in the pathogenesis of the disease and has demonstrated that it is fundamentally an immunologic process that ultimately results in inflammation, fibro-adipose deposition, impaired lymph-angiogenesis, and dysfunctional lymphatic pumping. These findings have allowed for the development of novel medical and surgical therapies that may potentially alter the standard of care for a disease that has largely been treated by compression; lymph node transfer was one of the key words listed in this review.
Qian et al (2018) reviewed the current progress of clinical and experimental research of vascularized lymph node transfer for lymphedema. The domestic and abroad literature about vascularized lymph node transfer in treatment of lymphedema was reviewed and analyzed. Experimental studies in animal model indicated that vascularized lymph node transfer can improve lymph node survival and show a promising effectiveness in reducing lymphedema. "Lymphatic wick" and "lymph pump" were the 2 main hypotheses proposed to explain the potential functional mechanism of vascularized lymph node transfer in treatment of lymphedema. Improvement in lymphedema symptoms have been reported in most of the clinical trials, but the level of evidence to advocate this procedure in the treatment of lymphedema remains low because of the small number of the cases and problems in their methodologies. The authors concluded that based on current evidence, vascularized lymph node transfer appeared to be a promising treatment for lymphedema, but long-term well-designed studies are needed to further explore the effectiveness of this procedure.
Gallagher et al (2018) stated that lymphedema is a chronic, progressive disease with no curative treatment. Breast cancer therapy is the most common cause of secondary lymphedema in the developed world. Treatment includes non-surgical and surgical strategies. Conservative measures are reserved for sub-clinical lymphedema. Surgical options are divided into physiologic (to restore function) and reductive (to remove diseased tissue). Early stage disease is managed with physiologic procedures. Reductive treatment is reserved for moderate-to-severe staged disease owing to high morbidity. Surgical options effectively decrease edema and improve QOL. The authors concluded that further research is needed to establish the best management of lymphedema. Lymph node transfer is one of the key words of this review.
Furthermore, an UpToDate review on "Surgical treatment of primary and secondary lymphedema" (Mehrara, 2018) states that "Prospective studies are needed to identify specific clinical settings where patients would be most likely to benefit from this procedure".
Schaverien et al (2018) noted that vascularized lymph node transfer (VLNT) involves the microvascular transplantation of functional lymph nodes into an extremity to restore physiological lymphatic function. It is most commonly performed by transferring combined deep inferior epigastric artery perforator and superficial inguinal lymph node flaps for post-mastectomy breast reconstruction. For patients who do not require or are unable to undergo free abdominal breast reconstruction or have lymphedema affecting the lower extremity, several other VLNT options are available. These include flaps harvested from within the axillary, inguinal, or cervical lymph node basins, and lymph node flaps from within the abdominal cavity. The authors stated that the choice of technique is dependent on patient acceptable of scar location, risk of donor site lymphedema, and acceptance of the risks of an intra-abdominal procedure. The choice of orthotopic or heterotopic placement of the lymph node transplant is dependent on acceptance of scar locations, where the pitting edema is localized, and outcomes from dual level lymph node transfers are awaited. Reverse lymphatic mapping is essential for lymph nodes harvested from within the axillary or inguinal lymph node basins to avoid the dreaded consequence of donor site lymphedema, and surgeons performing these procedures must have a detailed knowledge of anatomy of these regions to avoid straying into the lymphatic drainage pathways of the extremities. These researchers stated that further outcomes data for more recently described flaps are awaited to aid surgical treatment algorithms for patients with lymphedema.
Pappalardo et al (2018) stated that as lymphatic microsurgery has become more common, VLNT ascended to the forefront in many centers for the surgical management of advanced stages of lymphedema showing substantial clinical improvement. However, no consensus has been reached among experts regarding many details of the procedures, including patient selection criteria, type of treatment, donor, and recipient sites and postoperative evaluation of the outcome.
Liu and Ma (2018) reviewed the clinical progress of microsurgical management for lymphedema. The literature on microsurgical treatment for lymphedema at home and abroad in recent years was reviewed and analyzed. At present, conservative treatment is the main treatment for lymphedema, which has limited effectiveness only for early stages of lymphedema; and it is not curative and demands patient compliance. In contrast, microsurgical approaches can solve the problems in the prevention or management of lymphedema and showed promising results, such as LVA, VLNT, and other lymphatic reconstructions. The authors concluded that microsurgical approaches like LVA and VLNT have been broadly used in recent years, the effectiveness and safety have been proved. However, these investigators stated that the evidence of long-term randomized controlled studies is still needed to establish standard treatment practices.
An assessment by the Ludwig Boltzmann Institute for Health Technology Assessment on "Lympho-venous anastomoses in patients with primary and secondary lymphedema" (Rosian and Stanak, 2018) concluded: that 1 non-RCT and 4 prospective single-arm studies were evaluated. Overall, the level of evidence was "very low" for the outcomes of clinical safety and effectiveness. Based on the available evidence, no conclusions could be made as to whether the assessed procedure of LVA was at least as effective and safer as the comparator VLNT or conservative therapy.
Fan et al (2019) presented their "String of Pearls" technique for upper and lower extremity lymphedema based off the right gastro-epiploic artery. The entire laparoscopically harvested omentum was placed via a longitudinal incision at the lymphedematous area, and anastomosed proximally, with additional distal venous outflow. This approach preserves the native lymphatico-venous architecture, distributes free lymphatic tissue along the axis of the extremity, and allows for scar release. The additional vein serves to restore bi-directional physiologic drainage inherent in the omentum and providing further lymphatico-venous drainage. These researchers presented 2 cases of upper and lower extremity lymphedema as a result of malignancy treated using this method. The first case was a result of breast cancer in a 55-year old woman with orthotopically placed omentum, and the second case a result of malignant nodular fasciitis in the distal lower extremity in a 56-year old woman with distally placed omentum. No complications occurred. At 3 months follow-up, there was a 25 % and 28 % reduction in lower and upper extremity volume, respectively, with no recurrent cellulitis episodes. The safety and feasibility of placement of the entire omentum longitudinally with additional venous anastomosis were apparent; however, long-term studies are needed.
Fernandez Penuela et al (2019) noted that conservative non-surgical treatment has traditionally been applied to lymphedema. Early surgical procedures were invasive and disfiguring and their long-term success was often limited. In contrast, contemporary surgical techniques are much less invasive and have been shown to be effective in reducing excess limb volume, the risk of cellulitis, and the need for compression garments. Microsurgical procedures such as lympho-venous anastomosis (LVA) and VLNT can treat the excess fluid component of lymphedema and are gaining in popularity. In this study, these researchers evaluated the possibility of generating lymphedema in the hind-limb of a rabbit and then described its treatment with microsurgical lymph node transfer without lymph vessel transfer. In experimental rabbit models, animals first underwent surgery in which the popliteal lymph node was removed to create lymphedema in the hind-limb. After 15 days, another operation was performed to excise the contralateral popliteal lymph node and transfer it to the limb with lymphedema. This model showed that lymph node transfer was able to reduce lymphedema in the rabbit's hind-limb; intervened hind-limb: basal volume (51.94 ± 11.23), volume day transfer (73.40 ± 26.47), and final volume (50.13 ± 12). The authors have developed a feasible model to microsurgically induce and treat lymphedema by lymph node transfer that showed promising results.
Furthermore, an UpToDate review on "Surgical treatment of primary and secondary lymphedema" (Mehrara, 2019) states that "Vascularized lymph node transfer – Lymph node transfer is a procedure that includes the transfer of healthy lymph nodes en bloc from one nodal basin to the site of obstruction. The recipient site can be the site of the prior lymph node excision or a nonanatomic site. Some authors have suggested that a "lymphatic pump" is created when lymph nodes are transferred non-anatomically; however, the mechanisms regulating lymphatic repair in this setting remain unknown. The nodes are most commonly transferred using microsurgical techniques with arterial and venous anastomosis at the recipient site; there is usually no lymphatic anastomosis with this approach. A limiting factor of this approach is that lymphedema can develop in the donor extremity. This possibility has led to the use of mesenteric lymph nodes (e.g., omentum, intestinal mesentery lymph nodes) as an alternative since harvesting lymph nodes from these areas does not result in lymphedema. These issues have to be balanced, however, with potential complications from intra-abdominal procedures (e.g., hernia, small bowel obstruction, pancreatic injury). Prospective studies are needed to identify specific clinical settings where patients would be most likely to benefit from this procedure. However, systematic reviews of previously reported outcomes support a beneficial role (i.e., decreased limb volume and improved quality of life) for this procedure in the majority of patients". Furthermore, vascularized lymph node transfer is not mentioned in the "Summary and Recommendations" section of this review.
Forte et al (2019) noted that although physiologic surgeries for lymphedema (i.e., lympho-venous bypass, vascularized lymph node transplantation) are becoming well established, unpredictable outcomes have still been reported in some studies. These researchers examined ways to improve these surgery outcomes. They conduct a comprehensive systematic review of targeted therapy administration in the surgical treatment of lymphedema using the PubMed database. Eligibility criteria excluded papers that reported surgical treatment of lymphedema without the use of targeted therapies and also papers describing targeted therapies in non-surgical treatment of lymphedema. Abstracts, presentations, reviews, and meta-analyses were also excluded. Extracted data included the year of study, country, lymphedema model, surgical technique, targeted therapy agent, therapy delivery, findings, and outcomes. From 823 potential papers found in the literature, 10 studies fulfilled the eligibility criteria. All papers were experimental, and most of them on small animal model (7/10). Different targeted therapies were proposed, but all of them were associated with lymph node transplantation. The most common targeted therapy proposed mechanism was growth factor delivery (8/10). However, 1 paper used adipose-stem cell, and 1 paper proposed the use of sterile inflammation. The pooled publications assessing targeted therapy administration in the surgical treatment of lymphedema demonstrated encouraging data for positive outcomes. The authors concluded that to-date, all studies were experimental and related to lymph node transfer.
Ciudad et al (2020) noted that VLNT is an emerging surgical treatment for lymphedema. However, literature-comparing outcomes of upper limb lymphedema (ULL) and lower limb lymphedema (LLL) is limited. These researchers compared the long-term clinical outcomes on ULL versus LLL in patients treated with VLNT. A retrospective study retrieving data from patients with International Society of Lymphology (ISL) stages II to III who underwent different VLNTs from July 2010 to July 2016 in the authors’ institution was performed. Demographics pre-operatively, and clinical data (limb circumference, infectious episodes, lymphoscintigraphic studies) pre-operatively and post-operatively were recorded. Clinical outcomes by extremity were also analyzed. A total of 83 patients with lymphedema (ULL: n = 30, LLL: n = 53) were included. Mean follow-up time was 32.8 months (range of 24 to 49 months). Mean circumference reduction was higher in patients with ULL compared to with LLL (28.6 ± 8.6 versus 22.3 ± 10.1, p < 0.001), and for patients with secondary lymphedema (24.8 ± 9.6, p < 0.001) than for patients with primary lymphedema (18.9 ± 14, p > 0.05). Infectious episodes per year pre-operative and post-operative showed that LLL patients had higher reduction on infection rate compared with ULL patients (2.4 ± 1.1 versus 1.9 ± 1.2, p < 0.001). The authors concluded that VLNT is a promising surgical therapeutic option for patients with lymphedema. Moreover, the findings of this study suggested that VLNT may have a more beneficial outcome in patients with ULL and with secondary lymphedema.
In a Cochrane review, Markkula and colleagues (2019) compared the efficacy of surgical interventions for the prevention of the development and treatment of lymphedema in the arm after breast cancer treatment. The authors concluded that there is low-certainty evidence that lymphaticovenular anastomosis is effective in preventing the development of lymphedema following breast cancer treatment based on the findings from 2 studies. One study providing very low-certainty evidence found that VLNT was an effective option in the treatment of established stage 2 lymphedema related to breast cancer. Important secondary outcomes in this review were rarely reported in the included studies. These researchers stated that more high-quality RCTs are needed to further elucidate the effectiveness of surgical interventions in the prevention and treatment of lymphedema following breast cancer treatment.
Masia et al (2016) stated that lymphedema is a well-known sequela of breast cancer; but no consensus has been reached regarding the ideal treatment. Surgical approaches, however, are receiving increased attention. Various microsurgical reconstructive techniques have been examined to restore anatomy and function of the lymphatic system in upper limb breast cancer-related lymphedema (BCRL). These investigators combined 2 techniques, lymphatico-venous anastomosis (LVA) and autologous lymph node transplantation (ALNT) after carefully selecting those who may benefit from the surgery. They called this the "combined surgical treatment (CST)" approach. From June 2007 to December 2011, these researchers carried out CST in 106 patients with upper limb BCRL. Clinical evaluation and diagnostic imaging studies were performed pre-operatively in all the patients. CST was offered to patients with stage I/II lymphedema, according to the criteria of the International Society of Lymphology (ISL). Overall, 59 of the 106 patients underwent LVA, 7 underwent ALNT, and 40 underwent both the techniques. All 47 lymph node (LN)-flaps survived, but 11 (22 %) required surgical revision within 3 days. A total of 21 LN-flaps (45 %) showed no radiotracer uptake at 1 year. Around 1 to 7 LVAs for each patient (average 3.4) were performed. Pre-operative versus post-operative excess circumference decreased between 12 % and 86.7% (average 39.72 %). Arm circumference decreased between 0.9 and 6.1 cm (average 2.75 cm). The number of episodes of lymphangitis per year decreased from 1.8 to 0.2. The authors concluded that pre-operative assessment was essential to select patients who could benefit from surgery for lymphedema and to choose the best surgical approach in each case; the satisfactory results in well-selected cases encouraged further research into surgical treatment for BCRL. This was a study that examined the combined use of LVA and ALNT for the treatment of BCRL (only 7 subjects underwent ALNT alone).
The authors stated that despite promising results, surgical treatment for lymphedema is still in its early days. In the future they need to standardize protocols for pre-operative studies and surgical treatment. Comparative prospective studies with uniform patient selection are needed to clarify the real contribution of micro-lymphatic surgery for the treatment of BCRL. Moreover, these researchers need to further their understanding of the anatomy and physiology of the lymphatic system and of the pathophysiology of lymphedema, especially via in-vivo studies. To reach these targets these investigators will need further development of highly specific imaging techniques to gain additional functional information.
De Brucker et al (2016) noted that BCRL affects multiple aspects of patients' daily lives. These researchers examined the impact of vascularized lymph node transfer (VNLT) on the quality of life (QOL) in patients with lymphedema. Between 2007 and 2012, a total of 25 women with BCRL underwent VLNT. In 22 cases, the patients underwent a simultaneous deep inferior epigastric artery perforator (DIEP) flap breast reconstruction based on the superficial circumflex iliac artery. The influence on QOL was evaluated using the Upper Limb Lymphedema-27 questionnaire, which includes physical, psychological, and social dimensions. These investigators also examined risk factors for lymphedema, such as body mass index (BMI), smoking, age, and time between start of lymphedema and VLNT, and their impact on QOL. A total of 21 patients (84 %) had an improvement of QOL after VLNT. The mean physical, psychological, and social scores were significantly improved post-operatively (p < 0.001). Risk factors for the development of lymphedema did not influence QOL among patients with BCRL. Skin infections disappeared in 50 %of the cases; 11 patients (44 %) discontinued compression therapy at a mean post-operative time interval of 29 months (range of 8 to 64 months). In the other patients (56 %), the average frequency of compression therapy decreased from 3 sessions to 1 session per week. The authors concluded that VLNT significantly improved QOL among patients with BCRL. Moreover, these researchers stated that his cross-sectional survey involved patients completing the pre-operative and post-operative Upper Limb Lymphedema-27 questionnaire at the time of their final post-operative visit. This may have introduced recall bias; however, the mean post-operative scores were consistent with other studies. These investigators stated that future prospective studies are recommended. Level of Evidence = IV.
Chang et al (2020) stated that patients with BCRL can be treated with a simultaneous DIEP flap, VLNT, and LVA for aesthetic breast reconstruction and lymphedema in one operation. These researchers carried out a comparison of prospectively followed patients who underwent free flap breast reconstruction with VLNT and LVA to a retrospective cohort of patients who underwent free flap breast reconstruction with VLNT alone. A total of 33 patients underwent DIEP flap reconstruction with VLNT and LVA, and 21 received a free flap with VLNT alone. There were no significant differences in demographics, adjuvant chemotherapy, or radiation therapy. The average number of nodes removed was also equivalent (21.2 versus 21.4 nodes). Two anastomoses per patient, on average, were performed (range of 1 to 4) in the combined cohort, and all patients (100 %) reported a subjective improvement in symptoms, compared with 81.0 % of patients undergoing only VLNT (p = 0.019). Perometer measurements demonstrated a significant reduction between the groups at early time-points [3 months, 40.7 % versus 20.0 % (p = 0.037); 6 months, 57.0 % versus 44.5 % (p = 0.043)]; however, the difference was not statistically significant at 12 months (60.4 %versus 57.8 %; p = 0.43). The authors concluded that this was the 1st prospective study demonstrating the safety and effectiveness of a combined DIEP flap with VLNT and LVA, which may be superior to VLNT alone. Level of Evidence = III.
The authors stated that this study was limited to a small sample size (n = 33). The limited numbers prevented performing multi-variate analysis, but univariate analysis demonstrated improved overall outcomes using the “BRILIANT” approach. These findings suggested this approach may have a profound impact on breast cancer patients who are in need of reconstruction and also suffering from lymphedema.
Hamdi et al (2021) noted that donor site morbidity related to VLNT remains a cause of worry among surgeons. These investigators examined donor site morbidity after VLNT with or without concomitant DIEP flap breast reconstruction. Furthermore, they evaluated their surgical approach to examine if it reduces the morbidity rate. They carried out a retrospective chart review of donor site complications and surgical techniques from 2006 to 2018. Patients' medical histories and demographic data were analyzed for risk factors. Patients were contacted by telephone for a long-term follow-up questionnaire. A literature review was implemented to evaluate the reported donor site complications and surgical strategies in literature. Complications were evaluated with and without concomitant autologous breast reconstruction (DIEP flap). A total of 89 patients were included in this case series; 65 cases (73 %) were combined with DIEP flap breast reconstruction. Seroma rate diminished from 60 % in the first 39 cases to 18 % in the last 5 years (50 cases) (p < 0.001). Lymphedema of the afferent lower limb was described in the literature but did not occur in this series. The authors concluded that seroma formation was the most common donor site morbidity after groin VLNT flap harvest, especially when combined with DIEP flap breast reconstruction. This study entailed the largest reported series of combined VLNT + DIEP flaps and described surgical strategies on how to decrease seroma formation and avoid iatrogenic lymphedema of the lower limb. This trial looked at donor site morbidity after groin VLNT in women undergoing breast reconstruction.
The authors stated that the drawbacks of this study were on the one hand its retrospective character, which entailed a risk of detection bias, but reduced the risk of performance bias. A 2nd drawback was that the surgical method was altered gradually over time and entailed a learning curve; hence, no strict correlation could be calculated between the occurrence of donor site morbidity and surgical method. The fact that there was only clinical evaluation and no technical investigation used to post-operatively detect iatrogenic lymphedema in the lower limb can be seen as a limitation, but every single report in literature on this condition described the lymphedema as clinically apparent.
Ward et al (2021) noted that lymphoedema after cancer treatment is a chronic and disabling complication that presents a significant health care burden during survivorship with limited therapeutic options. VLNT can reconstruct lymphatic flow to reduce limb volumes; however, limited higher-order evidence exists to support its effectiveness. In a systematic review and meta-analysis, these investigators examined the effectiveness of VLNT in reducing upper limb (UL) or lower limb (LL) volume and cellulitis episodes in patients with cancer treatment-related lymphoedema (CTRL). PubMed, Medline (Ovid) and Embase databases were searched between January 1974 and December 2019. Full-length articles where VLNT was the sole therapeutic procedure for CTRL, reporting volumetric limb, frequency of infection episodes and/or lymphoedema-specific QoL data, were included in a random-effects meta-analysis of CRR. Methodological quality was assessed using STROBE/CONSORT, and a novel, lymphoedema-specific scoring tool was used to assess lymphoedema-specific methodological reporting. Sensitivity analyses on the site of VLNT harvest and recipient location were performed. A total of 31 studies (581 patients) were eligible for inclusion. VLNT led to significant limb volume reductions in UL (above elbow pooled CRRs [CRRP] = 42.7 % [95 % CI: 36.5 to 48.8]; below elbow CRRP = 34.1 % [95 % CI: 33.0 to 35.1]) and LL (above knee CRRP = 46.8 % [95 % CI: 43.2 to 50.4]; below knee CRRP = 54.6 % [95 % CI: 39.0 to 70.2]) CTRL. VLNT flaps from extra-abdominal donor sites were associated with greater volume reductions (CRRP = 49.5 % [95 % CI: 46.5 to 52.5]) than those from intra-abdominal donor sites (CRRP = 39.6 % [95 % CI: 37.2 to 42.0]) and synchronous autologous breast reconstruction/VLNT flaps (CRRP = 32.7 % [95 % CI: 11.1 to 54.4]) (p < 0.05). VLNT was also found to reduce the mean number of cellulitis episodes by 2.1 episodes per year (95 % CI: -2.7 to -1.4) and increased lymphedema-specific QoL scores (mean difference in Lymphoedema-Specific Quality of Life (LYMQOL) "overall domain" = +4.26). The authors concluded that VLNT was effective in reducing excess limb volume and cellulitis episodes in both UL and LL lymphedema after cancer treatment. Moreover, these researchers stated that most studies were judged methodologically low quality. The appraisal of VLNT would benefit from standardized outcome reporting and more methodologically rigorous RCTs.
The authors stated that the limitations of this study were the large number of studies of low methodological quality, including 13 studies with less than or equal to 10 patients. Furthermore, follow-up was short, with only 8 studies following up patients for more than 24 months. The variability in pre-operative lymphedema duration, stage and follow-up should be acknowledged when considering generalizability. Furthermore, because of dataset heterogeneity, it was impossible to adjust for confounders such as BMI or individual cancer treatments. Related to this, there was likely to be significant variation in cancer stage at diagnosis and oncological treatments received. Thus, the management of regional lymph nodes in similar cases may be different, impacting CTRL incidence and effectiveness of VLNT. Similarly, some studies were published more than 10 years ago, and more recently, there has been a trend towards de-escalation of nodal surgery in favor of radiotherapy. These researchers were unable to adjust for these trends, which supported their recommendations for more robust methodological evaluations in new surgical interventions for lymphedema. Finally, it is important to interpret the findings in the broader context of lymphedema management and resource utilization. Although the findings of this analysis suggested that VLNT could offer significant reductions in limb volume, further economic analysis is needed to link this to meaningful clinical outcomes and examine impact on resource utilization. For example, further work should interpret what a CRR of 40 % equates to in terms of the de-escalating CGT grade or daily duration and in what proportion of patients would VLNT make CGT obsolete? There are no published data that define the relationship between volume reduction and down-grading CGT or symptoms experienced. Furthermore, considering the design of RCTs, a high degree of patient engagement is essential to ensure quantified outcomes are meaningful clinically and are representative of physiological changes. Finally, it would be pertinent to integrate health economic analyses into trial designs to examine cost-effectiveness against pre-existing interventions.
Chocron et al (2022) stated that VLNT is being used with increasing frequency for the treatment of BCRL; however, there is a lack of consensus in the surgical field as to which recipient site should be utilized. In a systematic review and meta-analysis, these researchers examined the evidence comparing the wrist and axilla as recipient sites for VLNT in BCRL. Demographic data, as well as circumference reduction rate (CRR), excess volume reduction (EVR), post-operative decrease in infections per year, post-operative discontinuation of compression garments, and overall pooled complication rate were extracted from included studies. These were compared through a meta-analysis. A total of 37 studies met the inclusion criteria for a total of 689 patients. VLNTs to the wrist and axilla resulted in a decrease in CRR of 42.1 % and 51.5 %, and a decrease in EVR of 35.6 % and 48.8 %, respectively. However, this meta-analysis showed no significant differences between CRR or EVR and between wrist and axilla as recipient sites. Similarly, these investigators found no differences in post-operative decrease in infections per year, post-operative discontinuation of compression garments, and overall pooled complication rate. The authors concluded that these findings suggested non-inferiority between the wrist and axilla as recipient sites for VLNT in the context of BCRL. Moreover, these researchers stated that in the absence of randomized, prospective data, they hoped these results can be used as an evidence-based reference and facilitate future studies.
Winters et al (2022) noted that VLNT has become an increasingly popular technique for treating lymphedema. However, although many studies have been performed, its effectiveness in increasing patients' quality of life (QoL) and reducing lymphedema in the affected body part has remained controversial. In a systematic review, these investigators examined the evidence for VLNT for treating BCRL. The Medline, Embase, and Cochrane Central databases were searched for studies of patients with BCRL who had received VLNT. The study methods were assessed using the MINORS (methodologic index for nonrandomized studies) tool. The primary outcomes were the change in volume difference between the arms and QoL. The secondary outcomes were skin infection, complications, and discontinuation of compression garment use. A total of 17 studies were included for qualitative synthesis and 8 for meta-analysis. The average reduction rate between the healthy and affected arms in the studies included in the meta-analysis was 40.31 %. A total of 5 studies had evaluated QoL, and all 5 studies had reported that QoL was significantly increased. A total of 8 studies had evaluated skin infections, of which 3 had reported the annual infection rates before and after surgery. In these studies, infection rate had decreased significantly; 3 studies had described usage of compression garments. When the patients were pooled, 27 of 60 were able to discontinue use of the compression garment. The donor and recipient complication rates were 12.1 % and 7.3 %, respectively. The authors concluded that the current evidence indicates that VLNT could improve the volume differences between the arms in patients with unilateral lymphedema by approximately 40 %. Furthermore, although determined from a few studies, it is likely that VLNT has a positive effect on patients' QoL, the number of skin infections, and compression garment usage and coincided with a low complication rate. Moreover, these researchers stated that further trials should confirm these findings to compare VLNT to conservative management.
The authors noted that the biggest drawback on evaluation of arm difference reduction was the lack of thorough description of compression garment usage before and after VLNT in most studies. It was possible that patients were more compliant to compression therapy after surgery. Thus, without a standardized protocol the possible bias caused by compression garment could not be excluded. These investigators also stated that when reviewing the current literature, they identified no trials that compared conservative treatment head on to VLNT. Only the study by Lin et al (2009) used an adequate control group (VLNT + microsurgical breast reconstruction versus only microsurgical breast reconstruction). To further examine the effect of VLNT, prospective trials are needed with a fixed compression therapy protocol to isolate the effect of the transplanted lymph nodes.
Ciudad et al (2022) stated that post-traumatic lymphedema develops more frequently than expected and reports on its management are scarce. These investigators reported the clinical outcomes of a case series of post-traumatic lymphedema patients treated with different VLNTs. A total of 5 patients with secondary post-traumatic lower limb lymphedema treated with VLNT were included in this report. The groin-VLNT (n = 1), supraclavicular-VLNT (n = 2), and gastroepiploic-VLNT (n = 2) were implemented. The average flap area was 69.8 cm2. Patients underwent post-operative complex decompressive therapy for an average of 10.0 months. The average mean CRR was 24.4 % (range of 10.2 % to 37.6 %). Post-surgical reduction in the number of infection episodes per year was observed in all patients. The mean follow-up was 34.2 months. The authors concluded that VLNT is a promising surgical treatment for post-traumatic lymphedema patients. Moreover, these researchers stated that more studies are needed to evaluate and compare surgical outcomes with other causes of secondary lymphedema treated with VLNT to evaluate its efficacy. They also noted that despite the positive outcomes shown by VLNT, lymphedema can still recur, especially in more advanced stages of disease as previously reported.
Furthermore, an UpToDate review on “Surgical treatment of primary and secondary lymphedema” (Mehrara, 2022) states that “Vascularized lymph node transplant -- Lymph node transplant is a procedure that includes the transplantation of healthy lymph nodes en bloc from one nodal basin to the site of obstruction. The recipient site can be the site of the prior lymph node excision or a nonanatomic site. Some authors have suggested that a "lymphatic pump" is created when lymph nodes are transferred nonanatomically; however, the mechanisms regulating lymphatic repair in this setting remain unknown. The nodes are mostly transplanted using microsurgical techniques with arterial and venous anastomosis at the recipient site; there is usually no lymphatic anastomosis with this approach. A limiting factor of this approach is that lymphedema can develop in the donor extremity. This possibility has led to the use of mesenteric lymph nodes (e.g., omentum, intestinal mesentery lymph nodes) as an alternative since harvesting lymph nodes from these areas does not result in lymphedema. These issues have to be balanced, however, with potential complications from intra-abdominal procedures (e.g., hernia, small bowel obstruction, pancreatic injury). Prospective studies are needed to identify specific clinical settings where patients would be most likely to benefit from this procedure”. Vascularized lymph node transplant is not listed in the “Summary and Recommendations” section of this UTD review.
Microsurgical Lymphatico-Venous Anastomosis
Chang et al (2013) prospectively examined the efficacy of lymphovenous bypass in patients with lymphedema secondary to cancer treatment. This trial enrolled 100 consecutive patients with extremity lymphedema secondary to cancer treatment; 65 patients underwent lymphovenous bypass with indocyanine green(ICG) fluorescent lymphangiography. Evaluation included qualitative assessment and quantitative volumetric analysis before and 3, 6, and 12 months after bypass. Lymphovenous bypass was performed in 89 upper extremities (UE) and 11 lower extremities (LE). For UE lymphedemas, the mean pre-operative volume differential was 32 %. Symptom improvement was reported by 96 % of patients and quantitative improvement was noted by 74 %. The overall mean volume differential reduction was 33 % at 3 months, 36 % at 6 months, and 42 % at 12 months after surgery. The mean volume differential reductions at 3, 6, and 12 months after lymphovenous bypass in patients with stage 1 or 2 lymphedema (58, 52, and 61 %, respectively) were significantly larger than those in the patients with stage 3 or 4 lymphedema (12, 16, and 17 %, respectively); 11 bypasses were performed in 7 patients with LE lymphedema, with a mean pre-operative volume differential of 38 p%. Only 4 (57 %) of these patients reported symptom improvement; post-operative volume measurements were available for only 2 of these 4 subjects. The authors concluded that lymphovenous bypass could be effective in reducing lymphedema severity, particularly in patients with early-stage UE lymphedema; ICG lymphangiography accurately identified functional lymphatic vessels and may have a role in objectively assessing lymphedema severity and patient selection. Level of evidence = IV.
Mihara et al (2014) noted that one of the complications of lymphedema is recurrent cellulitis. In a retrospective study, these researchers examined if lymphatico-venous anastomosis (LVA) was effective at reducing cellulitis in patients with lymphedema. This trial included patients with arm/leg lymphedema who underwent LVA. The frequency of cellulitis was compared before and after surgery. The diagnostic criteria for cellulitis were a fever of 38.5° C or higher, and warmth/redness in the affected limb(s). A total of 95 patients were included. The mean number of episodes of cellulitis in the year preceding surgery was 1.46, compared with 0.18 in the year after surgery (p < 0·001). The authors concluded that LVA reduced the rate of cellulitis in these patients with lymphoedema. Moreover, these researchers stated that drawbacks of this study included its retrospective design. They stated that further investigation with a controlled study should be carried out. The effects of this treatment for lymphedema caused by filariasis, which affects a greater number of patients worldwide, will also need to be validated. This study addressed the use of LVA in reducing cellulitis in patients with lymphedema.
Chen et al (2015) stated that super-microsurgical LVA is a promising treatment modality for lymphedema; however, its practice is restricted by the surgeon/equipment-related factors, and its effectiveness limited by technical constraints. In a pilot study, these researchers examined the feasibility of a modified “octopus” LVA technique in addressing the above problems. A total of 9 consecutive lymphedema patients underwent LVA procedure using the “octopus” technique; 6 had the upper extremity (UE) disease, and 3 had the lower extremity (LE) disease. Except for 1 patient having primary LE lymphedema, all had secondary disease related to cancer treatment. Disease severity ranged from Campisi stage Ib to IV. Qualitative and quantitative assessments were carried out pre-operatively, as well as at 1, 3, and 6 months. A total of 130 lymphaticovenular drainage pathways were created in 39 “octopus” LVAs. All patients experienced prompt relief of lymphedema symptoms during the 1st post-operative week and continued to improve during the study period. None had post-operative complications. All had disease regression as demonstrated by statistically significant decrease in limb measurements (p = 0.0003) and severity down-staging. The modified technique was found to be easier than the standard super-microsurgical technique and could be performed using a standard surgical microscope. The authors concluded that the “octopus” technique was a viable, effective technical alternative to the standard LVA technique; it may simplify this technically challenging procedure. These preliminary findings from a pilot study need to be validated by well-designed studies.
Torrisi et al (2015) stated that recent advances in microsurgery such as lymphatico-venous bypass (LVB) have been shown to decrease limb volumes and improve subjective symptoms in patients with lymphedema. However, to-date, it remains unknown if these procedures can reverse the pathological tissue changes associated with lymphedema. These investigators analyzed skin tissue changes in patients before and after LVB. Matched skin biopsy samples were collected from normal and lymphedematous limbs of 6 patients with unilateral breast cancer-related upper extremity (UE) lymphedema before and 6 months after LVB. Biopsy specimens were fixed and analyzed for inflammation, fibrosis, hyperkeratosis, and lymphangiogenesis. Six months following LVB, 83 % of patients had symptomatic improvement in their lymphedema. Histological analysis at this time demonstrated a significant decrease in tissue CD4(+) cell inflammation in lymphedematous limb (but not normal limb) biopsies (p < 0.01). These changes were associated with significantly decreased tissue fibrosis as demonstrated by decreased collagen type I deposition and TGF-β1 expression (all p < 0.01). In addition, these researchers found a significant decrease in epidermal thickness, decreased numbers of proliferating basal keratinocytes, and decreased number of LYVE-1(+) lymphatic vessels in lymphedematous limbs after LVB. The authors concluded that they showed, for the first time, that microsurgical LVB not only improved symptomatology of lymphedema, but also helped to improve pathologic changes in the skin. These researchers stated that these findings suggested that the some of the pathologic changes of lymphedema were reversible and may be related to lymphatic fluid stasis. This was a small study (n = 6) that examined the effects of LVB on UE lymphedema.
These investigators noted that analysis of the histological changes in the 1 patient in this study who did not experience symptomatic improvement provided some interesting insights. For example, although this patient had a statistically significant decrease in CD4+ cell inflammation (p = 0.0313), in contrast to the other patients in this study there were no changes in the number of lymphatic vessels, the number of TGFβ+ cells, or the thickness of the epidermis after LVB. Thus, it was possible that this patient had an incomplete response to LVB or that some of the bypasses thrombosed or became dysfunctional after surgery. They stated that future studies with increased numbers of patients and more formal quality of life (QOL) measurements will be needed to answer these questions. Furthermore, these researchers hypothesized that the differences found in this study after LVB (i.e., decreased inflammation and fibrosis) would occur after any treatment for lymphedema that decreases lymphatic fluid stasis. This concept is supported by previous studies demonstrating decreased inflammation and expression of inflammatory cytokines after decongestive therapy. However, in this study, the patients did not have additional physical therapy or massage and simply continued their pre-operative program. Thus, the authors did not think that this fact contributed to their observations. They stated that future studies designed to analyze histological changes after manual lymphatic drainage therapy or correlation of volumetric changes and inflammatory responses would be interesting and will provide additional insights.
Cancer Care Ontario (2015) noted that there is limited evidence regarding the effectiveness of surgical interventions for the treatment of breast cancer-related lymphedema. A small prospective study among 10 patients who were unresponsive to 12-weeks of non-operative treatment and were treated with lympho-venous anastomosis demonstrated a 4.8 % reduction of lymphedema at 3 months and a 2 % reduction after 1 year. Improvement in reported quality of life was minimal. The LYMPHA technique (lymphatic-venous anastomoses at the time of axillary dissection) was prospectively compared to axillary dissection alone in 46 women with breast cancer. At 6 months, lymphedema occurred in 1 patient in the treatment group (4.34 %) versus 7 patients (30.43 %) in the control group; no statistically significant differences in the arm volume were observed in the treatment group during follow-up, while the arm volume in the control group showed a significant increase after 1, 3, and 6 months from operation. There was significant difference between the 2 groups in the volume changes with respect to baseline after 1, 3, 6, 12, and 18 months after surgery (every timing p value < 0.01). Despite these promising results, prospective RCT data are lacking and there is a large variation in the selection of patients, classification of lymphedema, and indications and types of anastomosis procedures described in retrospective studies. Additional research is needed to better understand the effectiveness of surgery as a treatment modality for breast cancer survivors with lymphedema.
Mihara et al (2016) stated that the impact of lymphatico-venous anastomosis (LVA) on lymphedema has yet to be defined. In a retrospective study, these investigators examined the clinical evidence regarding the effectiveness of LVA in lower limb lymphedema. A total of 84 patients (162 limbs; 73 women and 11 men) with lower limb lymphedema who underwent multi-site LVA in the authors' clinic between August of 2010 and May of 2014 were included. Lymphedema was diagnosed using lymphoscintigraphy and indocyanine green (ICG) lymphography. All LVAs were performed under local anesthesia. The lymphatic vessels that were identified were classified using the normal, ectasis, contraction, and sclerosis type (NECST) classification. Limb circumference, subjective symptoms, and frequency of cellulitis were evaluated. The average patient age was 60 years (range of 24 to 94 years); mean post-operative follow-up period was 18.3 months (range of 6 to 51 months). The post-operative change rate in limb circumference indicated that 67 limbs (47.7 %) were classified as improved, 35 (27.3 %) were classified as stable, and 32 (25 %) were classified as worse. Post-operative interview revealed improvement in subjective symptoms in 67 limbs (61.5 %), no change in 38 (34.9 %), and exacerbation in 4 (3.7 %). The post-operative mean occurrence of cellulitis was decreased to 0.13 times per year compared with 0.89 pre-operatively, which was statistically significant (p = 0.00084). Multiple regression analysis using the post-anastomosis limb circumference and NECST classification confirmed the following results: change rate (%) = -0.40 + (0.30 × N) + (-0.84 × E) + (0.22 × C) + (-0.61 × S). The authors concluded that LVAs was effective for lower limb lymphedema, in point of limb circumference, subjective symptoms, and the frequency of cellulitis. Level of evidence = IV.
Silva and Chang (2016) noted that lymphedema is a debilitating disease that is commonly caused by cancer and its treatments in the developed world. Surgery is an option for refractory disease. Lympho-venous bypass and vascularized lymph node transfer are newer modalities that show great promise. The authors stated that further work is needed to determine proper patient selection and ensure minimum donor site morbidity. Liposuction and direct excision still have a role, especially in advanced cases. Further investigations into prevention of iatrogenic lymphedema are underway.
Loh et al (2017) stated that the successful completion of the 5th World Symposium for Lymphedema Surgery (WSLS) marked another milestone in the development and advancement of the management of lymphedema. These researchers presented their experience in organizing such a scientific lymphedema conference as well as a summary of 7 variable live surgeries used for treating lymphedema. An update of current knowledge and determination of future direction in the treatment of lymphedema was made possible via WSLS.
Nguyen et al (2017) stated that the free vascularized omental lymphatic flap provides an option without the risk for iatrogenic donor site lymphedema that plagues alternative lymph node transfer donor sites. The omental flap has been associated with significant morbidity in the past; however, with modern techniques and advanced in technology, a minimally invasive approach to flap harvest is feasible. These researchers presented the long-term outcomes of the minimally invasive free vascularized omental lymphatic flap for the treatment of lymphedema. All consecutive patients with advanced lymphedema undergoing minimally invasive free vascularized omental lymphatic flap transfer were included. Peri-operative evaluation included qualitative assessments, lymphoscintigraphy, and volumetric measurements. A total of 42 patients underwent a free omental lymphatic flap and had a mean follow-up of 14 (3 to 32) months. Subjective improvements were noted in 83 % of patients. Mean volumetric improvement was 22 %. Complications occurred in 16 % (n = 7) of patients; which included 1 episode of pancreatitis and 1 flap loss. Post-operative imaging revealed viable lymphatic transfers. Cellulitis history was present in 74 % (n = 31) patients with post-operative cellulitis occurring in 5 % (n = 2) patients. The authors concluded that the minimally invasive free vascularized omental lymphatic flap provided a safe donor site, a durable and versatile flap, and an effective therapy against lymphedema and lymphedema-related cellulitis. This study did not address the use of lympho-venous bypass.
Scaglioni et al (2017) noted that lymphedema is a chronic condition caused by the obstruction or impairment of lymphatic fluid transport resulting in irreversible skin fibrosis. Besides conservative therapy, surgical techniques for lymphedema including liposuction, lymphatico-lymphatic bypass, LVA, and vascularized lymph node transfer (VLNT) are options with increasing popularity in the recent past. In a systematic review, these investigators examined the efficacy of LVA for the treatment of lymphedema. Both objective and subjective outcomes of surgical treatment were evaluated. Studies were identified via systematic review in PubMed database up to September 2016. Only original articles that exclusively carried out LVA for lymphedema treatment were included. The primary endpoint was the objective of a subjective post-operative lymphedema reduction. A total of 293 titles were identified, out of which 18 studies including 939 patients were deemed eligible. The studies included in this review described significant variations in surgical techniques, number of anastomoses and supplementary interventions. All studies reported objective reductions in circumference measurements. Subjective symptom relief was found in 50 % to 100 % of the patients as well as a reduction in the number of cellulitis episodes in all investigated cases. The authors concluded that although the studies included in this review showed great heterogeneity, LVA surgery revealed both objective and subjective improvements in most patients.
Chang et al (2018) noted that the field of lymphedema surgery has witnessed tremendous advancements over the years and has been coupled to the rapid growth of super-microsurgical techniques. A lympho-venous bypass or lymphatico-venular anastomosis (LVA) is a new technique that requires identification of patent, residual lymphatic channels and performing an anastomosis to a recipient venule, thereby allowing outflow of lymphatic fluid and improvement in a patient's lymphedema. The authors provided a summary of the maturation of the technique, as well as the technical aspects of the approach and the current outcomes in the treatment of post-mastectomy lymphedema. These researchers stated that overall, this operation has had a profound impact with a dramatic improvement in the overwhelming majority of patients who have been treated. The widespread implementation of this technique, however, is still limited, and the majority of operations and studies come from a select group of specialized, high-volume institutions across the world. However, as the number of professionals trained to perform the LVA grows, the number of patients who will benefit from this operation and achieve some relief from their debilitating condition will hopefully increase as well. The authors concluded that the full potential of the LVA remains to be determined, and future studies are needed to optimize the long-term outcomes and applications of this operation for the treatment of lymphedema.
Jorgensen and colleagues (2018) noted that lymphedema is one of the most dreaded side effects to any cancer treatment involving lymphadenectomy. Progressed lymphedema is adversely complex and currently there is no widely acknowledged curative treatment. Thus, recent focus has shifted to risk reduction and prevention. It has been hypothesized that bypassing lymphatic vessels to veins prophylactically, could minimize the lymphatic dysfunction seen following lymphadenectomy. In a systematic review and meta-analysis, these investigators examined this possible future treatment modality by reviewing studies that treated patients with prophylactic lympho-venous anastomosis (LVA) for the prevention of secondary lymphedema following lymphadenectomy. A systematic search yielded 12 articles included in the qualitative analysis and 4 of these were further eligible to be included in the quantitative analysis. These researchers found that patients treated with prophylactic LVA had a significant reduction in lymphedema incidence (relative risk [RR]: 0.33, 95 % CI: 0.19 to 0.56) when compared to patients receiving no prophylactic treatment (p < 0.0001). The authors concluded that prophylactic LVA in relation to lymphadenectomy showed promising results, however because of the low number of eligible studies and method heterogeneity between studies, there is an urgent need for uniformly high quality studies, before the treatment can be concluded effective.
AlJindan et al (2019) compared the outcomes between side-to-end and end-to-end lymphovenous anastomosis configurations for unilateral extremity lymphedema. Between April 2013 and June 2017, lymphovenous anastomosis was indicated for 58 patients who pre-operatively had patent lymphatic ducts by ICG lymphography, including 20 patients with UE lymphedema and 38 patients with LE lymphedema. Either an end-to-end or a side-to-end lymphovenous anastomosis was used to anastomose the subdermal venule to the lymphatic duct. The circumferential difference and episodes of cellulitis were used as outcome measurements. A total of 23 patients underwent an end-to-end lymphovenous anastomosis and 35 patients underwent side-to-end lymphovenous anastomosis. All patients had an immediate patency evaluated by ICG lymphography and patent blue assessments. All patients returned to their daily routine without the use of any compression garments. At an average follow-up of 16.5 months (range of 13.4 to 19.6 months), the improvement of circumferential difference (3.2 %; range of 1.8 to 4.6 %) in the side-to-end group was statistically greater than that in the end-to-end group (2.2 %; range of 1 to 3.4 %; p = 0.04). The overall episodes of cellulitis were significantly reduced from 1.7 times/year (range of 1.3 to 2.1 times/year) to 0.7 times/year (rang of, 0.3 to 1.1 times/year; p < 0.001), but no difference was observed between the 2 groups. The authors concluded that both side-to-end and end-to-end lymphovenous anastomosis configurations were effective surgical approaches for improving early-grade extremity lymphedema. Side-to-end lymphovenous anastomosis has the advantages of having greater efficacy for lymph drainage, requiring only one anastomosis and eliminating the need to use compression garments. Level of evidence = III.
Chung et al (2019) stated that when performing lymphovenous anastomosis, it is sometimes difficult to find venules in the proximity of an ideal lymphatic vessel that have a similar diameter to that of the lymphatic vessel. In this situation, larger venules can be used. These investigators examined the efficacy of and patient satisfaction with lymphovenous bypass with sleeve-in anastomosis. Between January 2014 and December 2016, these researchers carried out this procedure in 18 patients (8 UE and 10 LE) with secondary lymphedema. Lymphovenous bypass with sleeve-in anastomosis was performed under microscopy after injecting ICG dye. The circumferential diameter was measured before lymphovenous bypass and at 1, 2, and 6 months after the procedure. An outcomes survey that included patients' qualitative satisfaction with lymphovenous bypass was conducted at 6 months post-operatively. Almost all patients showed quantitative improvements after surgery. The circumferential reduction rate in patients with stage II lymphedema of both the UE and LE was significantly greater than in their counterparts with stage III/IV lymphedema. The circumferential reduction rate was lower in LE patients than in UE patients. The authors concluded that lymphovenous bypass surgery with sleeve-in anastomosis in lymphedema patients was beneficial, and appeared to be effective, when adequately-sized venules could not be found in the proximity of an ideal lymphatic vessel. Moreover, these researchers stated that these findings were preliminary, and longer-term results and verification of these findings by other studies are needed to further popularize this treatment for lymphedema.
The authors stated that this study had several drawbacks. In this series, the follow-up period after surgery was short (6 months). Almost all study patients experienced volume reduction at 6 months after surgery. However, whether the volume would decrease more as time goes on or whether lymphedema will relapse was uncertain. The long-term effects of lymphovenous anastomosis are still controversial and future studies are needed. Furthermore, the sample size was too small (n = 18) to show statistically significant differences between groups, and thus may not have adequately represented the efficacy of lymphovenous bypass with the sleeve-in method in this broadening population of patients.
Miller et al (2019) noted that thoracic duct injury can be a devastating injury with disruption of lymphatic flow leading to potentially chylothorax and/or severe lymphedema. Standard treatment modalities include thoracic duct ligation or embolization for chylothorax, but therapeutic options to-date are few for resultant lymphedema. In a case-report, these researchers described LVB of the thoracic duct to the jugular venous system in a 21-year old man with secondary lymphedema after iatrogenic thoracic duct injury. The patient experienced improvement of lymphedema symptoms including decreased weight and limb girth as well as normalization of serum markers indicating improved lymphatic delivery to the venous system. Lymphangiogram at 3 months post-op demonstrated patency of the lymphatico-venous anastomoses. At 6-month follow-up, the patient had returned to his pre-operative level of activity and showed continued improvement of his lymphedema symptoms. The authors concluded that LVB of the thoracic duct may be an effective technique to treat secondary lymphedema from thoracic duct obstruction, although further studies are needed to determine long-term efficacy.
Chang et al (2020) noted that lymphedema is a lifelong, debilitating condition that plagues a large portion of patients who have undergone multi-modality therapy for breast cancer. With the increasing experience in super-microsurgical treatment of lymphedema, reconstructive surgeons have made a tremendous impact in improving the QOL of patients suffering from breast cancer related lymphedema. These investigators provided a historical review of the authors’ evolution in treatment and management of breast cancer-related lymphedema and implementation of their new algorithm. They also carried out a retrospective review of patients who have undergone both the lymphovenous bypass and vascularized lymph node transfer with autologous breast reconstruction. The combined Breast Reconstruction Including Lymphovenous bypass and Inguinal to Axillary Node Transfer (BRILIANT) demonstrated promising outcomes – 38 patients (average age of 52.9 years, average BMI of 32.6 kg/m2) who have undergone the BRILIANT approach had all demonstrated improvements in their lymphedema. With an average follow-up of 19.1 months, no patients suffered a post-operative cellulitis, and 81.6 % of patients also demonstrated a volume reduction. The authors concluded that their new algorithm combining breast reconstruction with lymphedema surgery represents an evolution in their approach to treatment of breast cancer-related lymphedema has demonstrated promising results with long-term outcomes.
Forte et al (2020c) stated that lymphedema is an accumulation of protein-rich fluid in the interstitial spaces resulting from impairment in the lymphatic circulation that could impair QOL and cause considerable morbidity. Lower extremity lymphedema (LEL) has an overall incidence rate of 20 %. Conservative therapies are the 1st step in treatment of LEL; however, they do not provide a cure because they fail to address the underlying physiologic dysfunction of the lymphatic system. Among several surgical alternatives, LVA has gained popularity due to its improved outcomes and less invasive approach. These investigators examined the published literature on LVA for the treatment of LEL and analyzed the surgical outcomes. PubMed database was used to carry out a comprehensive literature review of all articles describing LVA for the treatment of LEL from November 1985 to June 2019. Search terms included "lymphovenous" OR "lymphaticovenous" AND "bypass" OR "anastomosis" OR "shunt" AND "lower extremity lymphedema". A total of 95 articles were identified in the initial query, out of which 58 individual articles were deemed eligible. The studies included in this review described notable variations in surgical techniques, number of anastomoses, and supplementary interventions. All, except 1 study, reported positive outcomes based on limb circumference and volume changes or subjective clinical improvement. The largest reduction rate in limb circumference and volume was 63.8 %. The authors concluded that LVA demonstrated a considerable reduction in limb volume and improvement in subjective findings of lymphedema in the majority of patients. The maintained effectiveness of this treatment modality in long-term follow-up suggested great efficacy of LVA in the treatment of LEL. Moreover, these investigators stated that larger, randomized, multi-center studies are needed to validate the findings of this systematic review.
The authors stated that as with all systematic reviews, this study had several drawbacks. Due to the general lack of large volume studies addressing LVA in the LE, these researchers were restricted to a limited range of reported data; thus, a thorough statistical analysis was not possible. Considerable heterogeneity exists among the reported outcomes in each study; therefore, there is a potential for bias in interpreting data, as it was possible that not all studies captured reliable co-morbidity data or outcomes over a long-period of time. A risk of selective reporting bias could also be encountered when documentation of subjective patient symptoms was involved.
Forte et al (2020b) noted that breast cancer-related lymphedema is a long-term condition that affects almost half of breast cancer survivors. Clinical studies have examined the benefits of lymphaticovenular anastomosis (LVA) for the treatment of UE lymphedema following breast cancer, however, there is still controversy if it improves lymphedema. In a literature review, these researchers examined the studies and outcomes related to LVA for breast cancer-related lymphedema. They carried out a PubMed/Medline search using "lymphovenous bypass", "upper extremity lymphedema", "arm lymphedema after breast cancer treatment", and "lymphaticovenular anastomosis" as key words. Only English articles reporting outcomes after LVA were included. They found 22 articles that met the inclusion criteria. Positive outcomes were found in 21 studies with an objective volume reduction and subjective symptoms relief after LVA. The authors concluded that the findings of this review on LVA for breast cancer-related upper extremity lymphedema demonstrated a significant decrease in UE volumes and improvement in subjective findings of lymphedema in most patients. Importantly, this response was maintained in long-term follow-up. They stated that there is evidence to suggest great efficacy in LVA in the UE following breast cancer extirpation. Moreover, these researchers stated that larger, randomized, multi-center studies are needed to validate the associations found in this review of the literature.
The authors stated that this study had several limitations. First, there was a general lack of large-volume studies addressing LVA in the UE following breast cancer. Moreover, there was an inability to pool data based on different protocols, varying techniques and measurement of the outcomes for statistical analyses. Despite this, these researchers felt that their study reported valuable pooled data, particularly pertaining to overall positive outcomes in LVA in the UE across 21 of the 22 studies identified. Furthermore, this review was limited by the heterogeneity of the patient populations and classification systems used in the included studies, as well as the English language inclusion criteria. As such, there is a potential for bias in interpreting the data reported in each study, the co-morbidity data and reporting outcomes over a long-period of time.
Furthermore, an UpToDate review on “Surgical treatment of primary and secondary lymphedema” (Mehrara, 2021a) states that “Lymphaticovenular anastomosis -- This is a super-microsurgical technique used to anastomose distal subdermal lymphatic vessels and adjacent venules less than 0.8 mm in diameter. Distal subdermal lymphatics are less affected by lymphedema and are more readily available for a bypass procedure than deeper lymphatic channels. The pressure in the subdermal venules is lower than found in the deeper, larger veins. Hence, there is less venous backflow in the subdermal vessels, and, at least in theory, this should result in a permanent improvement of lymphedema”. Moreover, the “Summary and Recommendations” section does not mention LVA.
Omental Flap for the Treatment of Lymphedema
Abbas and Seitz (2011) stated that inguinal nodes dissection is associated with high rates of morbidity, lymphedema in particular is a chronic disabling condition which is a common complication following this operation. Prevention or minimization of this condition is an important aim when considering this procedure. Many technical modifications have been suggested for this purpose. This systematic review aimed at assessing the effectiveness of the available strategies to reduce the risk and severity of leg lymphedema. For this review, MEDLINE and EMBASE were searched to identify studies that reported surgical strategies designed to reduce complications of groin dissection and in particular leg lymphedema. Studies that reported outcome of long saphenous vein sparing, fascia preserving dissection, microvascular surgery, sartorius transposition and omental pedicle flap were located. Data were collected using predefined inclusion and exclusion criteria. A combined odds ratio (OR) was calculated combining studies suitable for meta-analysis using the random effect model. The search result defined few studies that reported results of saphenous vein sparing technique; some of those studies were found suitable for meta-analysis based on the Newcastle-Ottawa scale for non-randomized studies. The meta-analysis showed significant reduction of lymphedema (OR 0.24, 95 % CI: 0.11 to 0.53) and other complications of inguinal node dissection. There were no randomized studies to address this problem; there were also isolated studies that reported benefits of other techniques but none of them was suitable for meta-analysis. The authors concluded that meta-analysis of the reported studies on sparing the long saphenous vein in inguinal nodes dissection suggested a reduced rate of lymphedema and other post-operative complications. Other methods that may be beneficial are fascia preserving dissection, pedicled omental flap and microsurgery; however sartorius transposition has not been shown to reduce the rate of complications. They stated that randomized controlled trials (RCTs) are needed to prove the benefits of various technical modifications.
Nguyen and Suami (2015) noted that advances in microsurgery have displayed promising results for the treatment of lymphedema. The use of vascularized lymph node transfers has increased in popularity but incurs the potential risk for donor-site lymphedema. The omentum has been previously described for the treatment of lymphedema but has been overlooked because of presumed high morbidity, including the need for celiotomy and pedicled complications. The authors presented a novel technique and early results of the laparoscopic free omental lymphatic flap for the management of lymphedema. The minimally invasive harvest avoided both the previously associated morbidity of this flap and the risk of iatrogenic lymphedema to the donor site.
Reverse Lymphatic Mapping
The technique of reverse lymphatic mapping appears to be used for vascularized lymph node transfer.
Ochoa et al (2014) hypothesized that mapping the lymphatic drainage of the arm with blue dye (axillary reverse mapping [ARM]) during axillary lymphadenectomy decreases the likelihood of disruption of lymphatics and subsequent lymphedema. This institutional review board-approved study involved 360 patients undergoing sentinel lymph node biopsy (SLNB) and/or axillary lymph node dissection (ALND) from May 2006 to October 2011. Technetium sulfur colloid (4 ml) was injected sub-areolarly, and 5 ml of blue dye was injected subcutaneously in the volar surface ipsilateral upper extremity (ARM). Data were collected on variations in lymphatic drainage, successful identification and protection of arm lymphatics, cross-over, and occurrence of lymphedema. A group of 360 patients underwent SLNB and/or ALND, 348 of whom underwent a SLNB. Of those, 237 (68.1 %) had a SLNB only, and 111 (31.9 %) went on to an ALND owing to a positive axilla. An additional 12 of 360 (3.3 %) axilla had ALND owing to a clinically positive axilla/pre-operative core needle biopsy. In 96 % of patients with SLNB (334/348), breast SLNs were hot but not blue; cross-over (SLN hot and blue) was seen in 14 of 348 patients (4 %). Blue lymphatics were identified in 80 of 237 SLN incisions (33.7 %) and in 93 of 123 ALND (75.4 %). Average follow-up was 12 months (range of 3 to 48) and resulted in a SLNB lymphedema rate of 1.7 % (4/237) and ALND of 2.4 % (3/123). The authors concluded that ARM identified substantial lymphatic variations draining the upper extremities and facilitated preservation. Metastases in ARM-identified lymph nodes were acceptably low, indicating that ARM is safe. They stated that ARM added to present-day ALND and SLNB may be useful to lesser rates of lymphedema.
Seyednejad et al (2014) stated that ARM is a surgical technique that was first described in 2007 as a method for preserving the lymphatic drainage of the arm during sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND) for breast cancer. These researchers found that the ARM technique had several limitations that include a poor success rate for identification of arm lymph nodes (ARM nodes) and lymphatics. The occurrence of common lymphatic drainage pathways of the arm and the breast in a subset of patients also raised concerns regarding its oncological soundness. Furthermore, the effectiveness of the ARM procedure in reducing lymphedema risk in breast cancer patients that undergo a variety of treatments has yet to be clearly defined.
Dayan et al (2015) introduced the technique of reverse lymphatic mapping for vascularized lymph node transfer. This physiologic technique allows one to identify which lymph nodes drain the trunk as opposed to the extremity, to minimize the risk of iatrogenic lymphedema. These investigators performed a prospective study of patients undergoing vascularized lymph node transfer using the reverse lymphatic mapping technique. Patients received technetium injections in the first and second web-spaces of the foot and intra-dermal indo-cyanine green (ICG) injections in the lower abdomen. Lymphatic vessels were traced to the lymph nodes draining the lower abdomen that were harvested; a gamma probe was used to localize lymph nodes draining the lower extremity, which were avoided. In cases of vascularized axillary lymph node transfer, technetium was injected into the hand and ICG was injected into the back and lateral chest. Ten-second counts were recorded of the lymph node flap and the sentinel node draining the extremity for comparison. A total of 35 patients underwent vascularized lymph node transfer (19 groin and 16 axillary lymph node transfers) guided by reverse lymphatic mapping. Follow-up time was 1 to 30 months. Mean 10-second count using the gamma probe for all lymph node flaps was 88.6 (SD, 123; median of 39); mean 10-second count of extremity sentinel nodes was 2,462 (SD, 2,115; median of 2,000). On average, 10-second signal strength of the lymph node flap was 6.0 % that of the extremity sentinel node. The authors concluded that reverse lymphatic mapping guides vascularized lymph node flap harvest based on physiologic drainage patterns of the trunk and limb that may minimize the risk of iatrogenic lymphedema. The findings of this small study need to be validated by well-designed studies.
Yue and colleagues (2015) noted that ARM procedure can distinguish lymphatics draining the arm from those draining the breast. It has been proposed to preserve lymphatic drainage of the upper limbs and reduce the incidence of upper limb lymphedema during breast cancer surgery. These researchers evaluated the feasibility of ARM in modified radical mastectomy and to evaluate its effect on prevention of lymphedema. From January 2012 to March 2014, a prospective study was performed in 265 breast cancer patients who underwent modified radical mastectomy. Patients were divided into 2 groups:- 127 patients (47.93 %, control group) received a traditional ALND, and
- 138 patients (52.07 %, experimental group) received ARM preservation of the nodes and lymphatics during ALND.
Radioactive tracer and methylene blue were used for ARM of the nodes and lymphatics. All of the identified ARM nodes were diagnosed using fine needle aspiration cytology for assessment of metastatic status. All resected axillary lymph nodes were conducted in a pathology examination to evaluate tumor metastasis. Data were collected on variations in identification of the ARM nodes and lymphatics, the metastasis of ARM nodes, and the occurrence of lymphedema. In the experimental group, the ARM procedure was successfully conducted in 129 cases (93.48 %); ARM nodes metastasis occurred in 11 patients (8.53 %). The median follow-up time was 20 months, at the last evaluation there were 42 patients who developed upper limb lymphedema in the control group (33.07 %), and in the experimental group the incidence of lymphedema was 5.93 % (7/118; p < 0.001). None of the patients had nodal relapses during the follow-up time. The authors concluded that ARM appears to be a feasible technique with which to identify upper arm nodes and lymphatics during the modified radical mastectomy procedure. This was a feasibility study.
An UpToDate review on "Technique of axillary lymph node dissection" (Margenthaler, 2015) states that "Axillary reverse mapping – Axillary reverse mapping (ARM) is an experimental technique, being investigated as a method of preserving the upper extremity lymphatics during ALND in an attempt to reduce the risk of postoperative lymphedema. Blue dye is injected in the upper inner ipsilateral arm and blue lymphatics and nodes are avoided during ALND. In two studies of 23 patients each, metastases were present in the nodes related to ARM sampling in 14 and 60 % of patients, respectively. Thus, further studies are needed to determine the long-term oncologic outcomes of this novel technique, which should not be used outside of a clinical trial".
Also, National Comprehensive Cancer Network’s clinical practice guideline on "Breast cancer" (Version 2.2015) does not mention reverse lymphatic mapping as a management tool.
Furthermore, there is an ongoing phase I/II clinical trial – "VST-1001 (Dilute Fluorescein) for Lymphatic Mapping & Localization of Lymph Nodes in Patients with Breast Cancer" that is still recruiting subjects (Last verified November 2014).
Gebruers and Tjalma (2016) stated that breast cancer is the most common malignancy in women worldwide. Fortunately, the overall survival is good. Therefore it is important to focus on the morbidities related to breast cancer treatment. One of the most dreaded morbidities is lymphedema. In 2007 the axillary reverse mapping (ARM) was introduced to limit the invasiveness in the axilla during breast cancer surgery. It is hypothesized that ARM is able to limit the incidence of breast cancer related lymphedema (BCRL) considerably. This systematic review aimed to answer the following research questions:- which approaches for ARM are described?
- is ARM surgical feasible and oncological safe? and
- does ARM decrease the incidence of lymphedema after sentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND)?
A total of 27 papers were retrieved using 4 electronic databases (PubMed, Web of Science, Medline and Cochrane clinical trials; assessed until May 13, 2015). The level of evidence of these studies was low (mostly level 3). The authors concluded that the ARM procedure is feasible although ARM-node rates have a broad range. Additionally, from a theoretical point there is a clear benefit from ARM in terms of lymphedema prevention. However, from a practical point there is little scientific data to support this due to the lack of studies; and especially because of the different methods and definitions for lymphedema used in the different studies.
Beek and colleagues (2016) noted that ARM is a technique by which the lymphatic drainage of the upper extremity that traverses the axillary region can be differentiated from the lymphatic drainage of the breast during ALND. Adding this procedure to ALND may reduce upper extremity lymphedema by preserving upper extremity drainage. These investigators reviewed the current literature on the ARM procedure and discussed the feasibility, safety and relevance of this technique. A PubMed literature search was performed until August 12, 2015. A total of 31 studies were included in this review. The studies indicated that the ARM procedure adequately identified the upper extremity lymph nodes and lymphatics in the axillary basin using blue dye or fluorescence. Preservation of ARM lymph nodes and corresponding lymphatics was proven to be oncologically safe in clinically node-negative breast cancer patients with metastatic lymph node involvement in the SLN who are advised to undergo a completion ALND. The authors concluded that the ARM procedure is technically feasible with a high visualization rate using blue dye or fluorescence; ALND combined with ARM can be regarded as a promising surgical refinement in order to reduce the incidence of upper extremity lymphedema in selected groups of patients.
Suction-Assisted Protein Lipectomy (SAPL) for the Treatment of Lymphedema
Granzow et al (2014a) noted that surgical treatment of chronic lymphedema has seen significant advances. Suction-assisted protein lipectomy (SAPL) has been shown to safely and effectively reduce the solid component of swelling in chronic lymphedema. However, these patients must continuously use compression garments to control and prevent recurrence. Microsurgery procedures, including lymphatico-venous anastomosis (LVA) and vascularized lymph node transfer (VLNT), have been shown to be effective in the management of the fluid component of lymphedema and allow for decreased garment use. SAPL and VLNT were applied together in a 2-stage approach in 2 patients with chronic lymphedema after treatment for breast cancer. SAPL was used first to remove the chronic, solid component of the soft-tissue excess. Volume excess in these patients' arms was reduced an average of approximately 83 % and 110 % after SAPL surgery. After the arms had sufficiently healed and the volume reductions had stabilized, VLNT was performed to reduce the need for continuous compression and reduce fluid re-accumulation. Following the VLNT procedures, the patients were able to remove their compression garments consistently during the day and still maintain their volume reductions. Neither patient had any post-operative episodes of cellulitis. SAPL and VLNT can be combined to achieve optimal outcomes in patients with chronic lymphedema.
Granzow et al (2014b) stated that effective surgical treatments for lymphedema now can address the fluid and solid phases of the disease process. Microsurgical procedures, including LVA and VLNT, target the fluid component that predominates at earlier stages of the disease. Suction-assisted protein lipectomy addresses the solid component that typically presents later as chronic, non-pitting lymphedema of an extremity. These researchers assessed the outcomes of patients who underwent selective application of these 3 surgical procedures as part of an effective system to treat lymphedema. This was a retrospective chart review of patients with lymphedema who underwent complete decongestive therapy followed by surgical treatment with SAPL, LVA, or VLNT. The primary outcomes measured were post-operative volume reduction (SAPL), daily requirement for compression garments and lymphedema therapy (VLNT and LVA), and the incidence of severe cellulitis. A total of 26 patients were included in the study, of which 10 underwent SAPL and 16 underwent LVA or VLNT. The average reduction of excess volume by SAPL was 3,212 ml in legs and 943 ml in arms, or a volume reduction of 87 % and 111 %, respectively, when compared with the unaffected, opposite sides. Microsurgical procedures (VLNT and LVA) significantly reduced the need for both compression garment use (p = 0.003) and lymphedema therapy (p < 0.0001). The overall rate of cellulitis decreased from 58 % before surgery to 15 % after surgery (p < 0.0001). The authors concluded that when applied appropriately to properly selected patients, surgical procedures used in the treatment of lymphedema are effective and safe. This was a small (n = 10 for SAPL), retrospective study; its findings need to be validated by well-designed studies.
Guidance from the National Institute for Health and Care Excellence (NICE, 2017) states that "Current evidence on the safety and efficacy of liposuction for chronic lymphoedema is adequate to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit."
Low-Level Light / Laser Therapy
In a narrative non-systematic review, Zecha and associates (2016a) stated that there is evidence supporting the effectiveness of low level laser therapy (LLLT), also known as photo-bio-modulation therapy (PBMT), for the management of oral mucositis (OM) in patients undergoing radiotherapy for head and neck cancer (HNC). Recent advances in PBMT technology, together with a better understanding of mechanisms involved, may expand the applications for PBMT in the management of other complications associated with HNC treatment. These researchers described PBMT mechanisms of action, dosimetry, and safety aspects and provided a basis for a companion paper (part 2) which described the potential breadth of potential applications of PBMT in the management of side-effects of chemo-radiation therapy (CRT) in patients being treated for HNC and proposed PBMT parameters. These investigators reviewed PBMT mechanisms of action and dosimetric considerations. Virtually, all conditions modulated by PBMT (e.g., ulceration, inflammation, lymphedema, pain, fibrosis, neurological and muscular injury) are thought to be involved in the pathogenesis of CRT-induced complications in patients treated for HNC. The impact of PBMT on tumor behavior and tumor response to treatment has been insufficiently studied. In-vitro studies assessing the effect of PBMT on tumor cells reported conflicting results, perhaps attributable to inconsistencies of PBMT power and dose. Nonetheless, the biological bases for the broad clinical activities ascribed to PBMT have also been noted to be similar to those activities and pathways associated with negative tumor behaviors and impeded response to treatment. While there are no anecdotal descriptions of poor tumor outcomes in patients treated with PBMT, confirming its neutrality with respect to cancer responsiveness is a critical priority. The authors concluded that based on its therapeutic effects, PBMT may have utility in a broad range of oral, oropharyngeal, facial, and neck complications of HNC treatment. They stated that although evidence suggested that PBMT using LLLT is safe in HNC patients, more research is imperative and vigilance remains warranted to detect any potential adverse effects of PBMT on cancer treatment outcomes and survival.
Zecha and associates (2016b) stated that PBMT may have potential applications in the management of a broad range of side effects of CRT in patients being treated for HNC. For OM management, optimal PBMT parameters identified were as follows: wavelength, typically between 633 and 685 nm or 780 to 830 nm; energy density, laser or light-emitting diode (LED) output between 10 and 150 mW; dose, 2 to 3 J (J/cm(2)), and no more than 6 J/cm(2) on the tissue surface treated; treatment schedule, 2 to 3 times a week up to daily; emission type, pulsed (less than 100 Hz); and route of delivery, intra-orally and/or transcutaneously. To facilitate further studies, these researchers proposed potentially effective PBMT parameters for prophylactic and therapeutic use in supportive care for dermatitis, dysphagia, dry mouth, dysgeusia, trismus, necrosis, lymphedema, and voice/speech alterations. The authors concluded that PBMT may have a role in supportive care for a broad range of complications associated with the treatment of HNC with CRT. The suggested PBMT irradiation and dosimetric parameters, which are potentially effective for these complications, are intended to provide guidance for well-designed future studies. It is imperative that such studies include elucidating the effects of PBMT on oncology treatment outcomes
Robijns and colleagues (2016) noted that breast cancer and its treatments can bring along serious side effects such as fatigue, skin toxicity, lymphedema, pain, and nausea. These can substantially affect the patients' QOL. Thus, supportive care for breast cancer patients is an essential mainstay in the treatment. Low-level light therapy also named PBMT is a non-invasive, therapeutic option used to stimulate wound healing and reduce inflammation, edema, and pain. It is used in different medical settings ranging from dermatology, physiotherapy, and neurology to dentistry. In the last 20 years, LLLT is becoming a new treatment modality in supportive care for breast cancer. In this review, all existing literature concerning the use of LLLT for breast cancer was used to provide evidence in the following domains: OM, radio-dermatitis (RD), lymphedema, chemotherapy-induced peripheral neuropathy (CIPN), and osteonecrosis of the jaw (ONJ). The authors concluded that the findings of this review suggested that LLLT is a promising option for the management of breast cancer treatment-related side effects. However, they stated that it still remains important to define appropriate treatment and irradiation parameters for each condition in order to ensure the effectiveness of LLLT.
In a randomized controlled feasibility study, Baxter and colleagues (2018) determined the feasibility of conducting a full scale RCT examining the effectiveness of LLLT, also known as photo-bio-modulation (PBM) therapy, used in addition to conventional therapy, for managing BCRL. Patients with BCRL were recruited from the Southern District Health Board (New Zealand) via lymphedema therapists' referrals, and randomly allocated into either the laser group, which received BCRL conventional therapy (e.g., wearing compression garments, massage therapy, and/or exercise) plus a 6-week LLLT (PBM) intervention program (wavelength: 980/810 nm (80:20 ratio); output power: 500 mW beam spot size: 5 cm2 ; irradiance: 100 mW/cm2 ; treatment time per area: 1 minute dosage per area treated: 30J (6J/cm2 ); 10 points of treatment from axilla to wrist total LLLT (PBM) treatment time: 10 minutes total dosage delivered: 300 J), or the control group, which received BCRL conventional therapy alone. Feasibility was determined by recruitment and randomization rates, retention of participants and treatment protocol adherence, and was assessed during the recruiting and intervention periods. Data on participant satisfaction and adverse reactions of LLLT (PBM) were collected on completion of this study. Clinical outcomes (i.e., limb circumference, participant's perceived symptoms, psychological impacts, and activity disability) were assessed at baseline, and 6 and 12 weeks post-randomization. Over a 6-month recruitment window, 17 participants with BCRL were recruited in the study, and randomized into the 2 groups (recruitment rate of 81 %, and randomization rate of 100 %). Treatment adherence was high in the laser group (88.9 % of participants completed all treatments). Retention rates were 88.9 % for the laser group and 100 % for the control group at both 6 and 12 weeks post-randomization. All participants who completed LLLT (PBM) treatment indicated that they were satisfied with the treatment. No serious adverse reactions were reported in this study. Clinical outcomes failed to show additional benefits of LLLT (PBM) intervention. The authors concluded that this study demonstrated that it is feasible to conduct a fully powered RCT to definitively test the effectiveness of the additional use of LLLT (PBM) in the management of BCRL. For such a trial, 114 participants will be needed at baseline.
Matrix Rhythm Therapy
Narin and colleagues (2016) noted that primary lymphedema occurs because of genetic predisposition and developmental insufficiency of the lymphatic system. Matrix rhythm therapy (MRT) was developed as an external and dynamic method that supplies rhythmic mobilization of the fluids in tissues. These researchers examined the effects of MRT in primary lymphedema. A 36-year old female with left lower limb lymphedema was evaluated. Leg circumference was measured before and at the end of treatment, and 1 and 3 months later. The circumferences were converted to volumetric values; 20 sessions of MRT (5 days/week) were applied to the affected leg, spine, and abdominal regions. Patient satisfaction was assessed with the Global Rating of Change scale. Volumetric values were 1,573.28 ml before treatment, 1,573.13 ml at the end of treatment, 1,516.70 ml 1 month later, and 1,441.61 ml 3 months later. At the end of treatment, the volumetric reduction was not significant; however, when compared with baseline, measurements at 1 and 3 months decreased by 3.59 % and 8.36 %, respectively; and the Global Rating of Change score was 2. The authors concluded that MRT could not reduce lymphedema when used alone, but long-term treatment may show positive effects.
Platelet-Rich Plasma
Akgul and associates (2016) stated that platelet-rich plasma (PRP) is an autologous concentrated preparation of human platelets contained in a small volume of plasma that is characterized by hemostatic and tissue-repairing effects. Being enriched by various kinds of growth factors, and their tissue-repairing effects have made them the focus of attention for use in tissue regeneration. These researchers noted that PRP has been safely used and documented in many different fields, including orthopedics, sports injuries, dental and periodontal surgery, and cosmetic, plastic, cardiovascular, general, and maxillofacial surgery. The current evidence obtained from in-vitro and animal studies pointed out that PRP may potentially be used to regenerate injured lymphatic vessels to treat or prevent lymphedema. Thus, these investigators reviewed existing literature on the clinical uses of PRP in lymphedema and examined if there is enough evidence to support the use of PRP in clinical practice as a therapeutic option. In contrast to in-vitro and animal models, there is no clinical trial regarding the use of PRP in lymphedema treatment. Only 2 animal studies matched to this research area yielded positive and promising results in terms of the potential role of PRP for lymphedema therapies in the future. The authors concluded that it is clear that this is an important issue that should be studied in greater depth to clarify the effectiveness of PRP in the management of lymphedema.
Diagnosis of Upper-Quadrant Lymphedema Secondary to Cancer
The clinical practice guideline from the oncology section of the American Physical Therapy Association (APTA) (Levenhagen et al, 2017) stated that "There are emerging diagnostic methods that detect tissue quality, visualize edema, or evaluate structural lymphatic transport capacity. These methods include 3D camera, tissue dielectric constant (TDC), dual-energy x-ray absorptiometry (DXA), magnetic resonance imaging (MRI), computed tomography (CT), lymphoscintigraphy, lymphography, and tonometry. Because of lack of evidence, high costs, or the invasive nature for some of these tests, these methods are not recommended to be incorporated into general clinical practice for diagnosing secondary upper-quadrant lymphedema (SUQL) at this time. Lymphatic system imaging, including lymphoscintigraphy and lymphography, can be useful in determining the full extent of lymphatic system impairment, and the results may assist the clinician when traditional interventions are not successful. Another emerging area is the diagnosis and assessment of lymphedema in patients treated for head and neck cancer. A combined approach of head and neck external lymphedema and fibrosis (HN-ELAF), circumferential measurement at the upper neck point, and TDC may be useful for diagnostic purposes. Little research is currently available to guide the diagnosis of hand, trunk, and breast lymphedema. Moreover, they stated that the bulk of the evidence includes patients with upper-extremity lymphedema due to breast cancer treatments. Further research is needed for diagnosing lymphedema both in the trunk and in the head and neck region. Furthermore, they noted that early diagnosis is crucial to maintain QOL and minimize upper-quadrant morbidity for patients at risk for SUQL; thus, there is a need for research to determine appropriate pre-operative measurements and prospective monitoring protocols.
Aquatic Therapy / Aqua Lymphatic Therapy for the Treatment of Lymphedema
Yeung and colleagues (2018) stated that aquatic therapy has several proposed benefits for people with lymphedema. These researchers performed a systematic review of the evidence for aquatic therapy in lymphedema management. Five electronic databases were searched to identify RCTs of people with lymphedema, which compared aquatic therapy with other lymphedema interventions. Qualitative analysis was undertaken where quantitative analysis was not possible. Study quality was assessed using physiotherapy evidence database (PEDro) scores. The strength of evidence was evaluated using the Grades of Recommendations Assessment, Development and Evaluation (GRADE) approach; 4 RCTs of moderate quality (average PEDro score of 6.5/10) were included in the review; 2 studies provided results for inclusion in meta-analysis. There was moderate-level evidence of no significant short-term differences in lymphedema status (as measured by lymphedema relative volume) between patients who completed aqua lymphatic therapy (ALT) compared to land-based standard care (standardized mean difference [SMD]: 0.14; 95 % CI: -0.37 to 0.64, I2 = 0 %, p = 0.59); and low-quality evidence of no significant difference between ALT and standard care for improving upper limb (UL) physical function (SMD -0.27, 95 % CI: -0.78 to 0.23, I2 = 0 %, p = 0.29). No adverse events (AEs) were reported. The authors concluded that current evidence indicated no significant benefit of ALT over standard land-based care for improving lymphedema status or physical function in people with UL lymphedema. Moreover, they stated that further research is needed to strengthen the evidence from 4 studies in people with UL lymphedema, and to establish the effectiveness of this intervention in people with lower limb lymphedema.
In a pilot study, Dionne and colleagues (2018) examined if patients with lower limb lymphedema (LLL) could benefit from water immersion exercise training to improve functional capacity, QOL, and help control/diminish limb volume. A total of 11 subjects were recruited to participate and 4 declined to pursue the study for personal reasons. A convenient sample of 7 female affected by either bilateral or unilateral LLL volunteered for this pilot study. Patients had primary or secondary lymphedema as complications of melanoma or gynecologic cancers. An aquatic training exercise intervention of moderate to vigorous intensity was conducted for a 6-week period (12 sessions; each of 45 mins). This innovative circuit training program consisted of yoga exercises, aqua-jogging, pedaling on a water bike, and muscular training on an aqua-step and a trampoline. The physical characteristics of water could be used to overcome the physical and medical limitations encountered on dry land for patients with LLL to exercise and reach training benefits. Outcome measures were the 6-min walk test (6MWT), hand-grip strength test, QOL for limb lymphedema questionnaire (LYMQOL), bioelectrical impedance spectroscopy, and limb circumference. The distance covered in the 6MWT and the hand-grip strength were significantly improved. A trend toward an increase in the overall QOL score was noticeable, whereas a significantly improved emotions score was observed with the LYMQOL questionnaire. Limb circumferential volume was significantly lower and impedance was increased, denoting a decrease in lymphatic fluid. The authors concluded that innovative aquatic exercise training program allowed moderate and vigorous intensity activities for patients with LLL, increased functional capacity and QOL. Thus, immersion exercise did not appear to exacerbate LLL and a randomized clinical trial with larger numbers is needed to consolidate the findings of this study.
Combined Adipose-Derived Stem Cells and Vascularized Lymph Node Transfers for the Treatment of Secondary Lymphedema
Hayashida and colleagues (2017) noted that secondary lymphedema is often observed in post-malignancy treatment of the breast and the gynecologic organs, but effective therapies have not been established in chronic cases even with advanced physiologic operations. Currently, reconstructive surgery with novel approaches has been attempted. In this experimental study, the hind-limbs of 10-week-old male C57BL/6J mice, after 30-Gy x-irradiation, surgical lymph node dissection, and 5-mm gap creation, were divided into 4 groups, with vascularized lymph node transfer abdominal flap and 1.0 × 10 adipose-derived stem cells. Lymphatic flow assessment, a water-displacement plethysmometer paw volumetry test, tissue quantification of lymphatic vessels, and functional analysis of lymphatic vessels and nodes were performed. Photodynamic eye images, using indocyanine green fluorescence, demonstrated immediate staining in sub-iliac lymph nodes, and linear pattern imaging of the proximal region was observed with the combined treatment of adipose-derived stem cells and vascularized lymph node transfer. Both percentage improvement and percentage deterioration with the combined treatment of adipose-derived stem cells and vascularized lymph node transfer were significantly better than with other treatments (p < 0.05). The numbers of lymphatic vessels with LYVE-1 immunoreactivity significantly increased in mice treated with adipose-derived stem cells (p < 0.05), and B16 melanoma cells were metastasized in groups treated with vascularized lymph node transfers by day 28. The authors concluded that adipose-derived stem cells increased the number of lymphatic vessels and vascularized lymph node transfers induced the lymphatic flow drainage to the circulatory system. They stated that combined adipose-derived stem cell and vascularized lymph node transfer treatment in secondary lymphedema may effectively decrease edema volume and restore lymphatic function by lymphangiogenesis and the lymphatic-to-venous circulation route. These preliminary findings need to be validated by well-designed studies.
Acoustic Radiation Force Impulse Elastography for Measurement of Tissue Stiffness in Limb Lymphedema
Chan and colleagues (2018) examined the feasibility of cutaneous and subcutaneous limb tissue elasticity measurement in patients with limb lymphedema by using acoustic radiation force impulse (ARFI) elastography. From July 2015 to June 2017, ARFI elastography was performed in 64 participants with lymphedema (7 men and 57 women; age range of 23 to 85 years) by using a US system. Tissue stiffness quantification with shear-wave velocity (SWV) was obtained in the cutaneous and subcutaneous limb tissues. Lymphoscintigraphy was the reference standard. SWV was significantly higher in limbs with lymphatic obstruction than in unaffected limbs (cutaneous tissue: 2.75 m/sec versus 1.74 m/sec, respectively; subcutaneous tissue: 1.90 m/sec versus 1.35 m/sec, respectively; p < 0.001). SWV was significantly different among limbs without lymphatic drainage obstruction, with partial obstruction, and with total obstruction (cutaneous tissue: 1.74 m/sec versus 2.75 m/sec versus 2.77 m/sec; subcutaneous tissue: 1.35 m/sec versus 1.90 m/sec versus 1.90 m/sec, respectively; p < 0.001). By using a cut-off value of 2.10 m/sec and 1.43 m/sec for cutaneous and subcutaneous tissue, respectively, sensitivity was 83.1 % (59 of 71) and 80.3 % (57 of 71), and specificity was 86.0 % (49 of 57) and 70.2 % (40 of 57) for manifestation of lymphatic obstruction. The corresponding areas under the receiver operating characteristic curve were 0.91 and 0.83, respectively. The authors concluded that ARFI elastography showed that cutaneous and subcutaneous tissues were stiffer in lymphedematous limbs than in unaffected limbs; they stated that ARFI elastography is a feasible imaging modality for non-invasive tissue stiffness quantification in limb lymphedema. These preliminary findings need to be further investigated.
Bioelectrical Impedance Analysis for Evaluation of Limb Lymphedema
In a systematic review, Asklof and associates (2018) summarized the current knowledge of non-invasive bioelectrical impedance analysis (BIA) used with gynecological surgical patients in regard to post-operative development of lymphedema and determination of peri-operative fluid balance, and as a prognostic factor in cancer mortality and a predictor of post-operative complications. The databases PubMed, Medline, Scopus Web of Science, the Cochrane Library, and reference lists of selected articles were searched for relevant articles published during the period January 2008 to April 2018. Only studies published in English were retrieved. A total of 37 articles were evaluated. Where gynecological studies were lacking, studies with a study population from neighboring clinical fields were used instead. Studies on the clinical use of BIA with gynecological surgical patients were divided into 3 categories: the post-operative development of lower limb lymphedema (n = 7), peri-operative hydration measuring (n = 3), and the BIA parameter phase angle as a prognostic factor in cancer survival and as predictive for post-operative complications (n = 6). Of these 16 studies only 3 used a pure gynecological study population; 3 different methods of BIA were used in these articles: single frequency-BIA, multi-frequency-BIA and bio-impedance spectroscopy; BIA was found to detect lymphedema with a sensitivity of 73 % and a specificity of 84 %. Studies indicated that BIA was able to detect lower limb lymphedema at an early stage even before it became clinically detectable. During post-operative hydration measurements, an increase in extracellular fluid volume and extracellular fluid volume in relation to total body fluid volume, as well as a decrease in phase angle, were associated with higher frequencies of post-operative complications. Moreover, low values for the phase angle have been associated with increased mortality in cancer patients. However, the number of studies in this field was limited. From this review, BIA appeared to be a useful tool for use in the clinical setting of the gynecological surgical patient. The theoretical approach of using bioelectrical impedance values to measure the fluid distribution in the body compartments offers wide opportunities in the clinical setting. However, so far, all studies have set up cut-off limits within the study population, and reference values for a general population need to be defined. There are also rather few studies on a gynecological study population. Hence, there is a need for further studies within gynecological surgery focusing on early detection of lower limb lymphedema, peri-operative fluid balance, and post-operative complications in order to establish the value of BIA in clinical praxis.
Genetic Testing for Predisposition to Lymphedema Following Breast Cancer Therapy
Newman and associates (2012) stated that known risk factors for secondary lymphedema only partially explain who develops lymphedema following cancer, suggesting that inherited genetic susceptibility may influence risk. Moreover, identification of molecular signatures could facilitate lymphedema risk prediction prior to surgery or lead to effective drug therapies for prevention or treatment. Recent advances in the molecular biology underlying development of the lymphatic system and related congenital disorders implicated a number of potential candidate genes to explore in relation to secondary lymphedema. These investigators undertook a nested case-control study, with participants who had developed lymphedema after surgical intervention within the first 18 months of their breast cancer diagnosis serving as cases (n = 22) and those without lymphedema serving as controls (n = 98), identified from a prospective, population-based, cohort study in Queensland, Australia. TagSNPs that covered all known genetic variation in the genes SOX18, VEGFC, VEGFD, VEGFR2, VEGFR3, RORC, FOXC2, LYVE1, ADM, and PROX1 were selected for genotyping. Multiple SNPs within 3 receptor genes, VEGFR2, VEGFR3, and RORC, were associated with lymphedema defined by statistical significance (p < 0.05) or extreme risk estimates (OR less than 0.5 or greater than 2.0). The authors concluded that these provocative, albeit preliminary, findings regarding possible genetic predisposition to secondary lymphedema following breast cancer treatment warrant further attention for potential replication using larger data-sets.
Visser and colleagues (2019) noted that secondary lymphedema is a complication following breast cancer therapy and constitutes the main form of lymphedema in the Western countries. These researchers provided an overview of the genetic predisposition and secondary lymphedema. They carried out a systematic search between February and June 2017 in Medline and Embase. Search terms included Genes, Genetic Predisposition to Disease, Lymphedema, Breast Cancer Lymphedema, Secondary Lymphedema, Breast Cancer-Related Lymphedema, and Humans. Only original articles regarding the possible relationship between genetic variation and the development of secondary lymphedema in humans were included in this review. A total of 459 records were collected. After removal of duplicates, non-topic-related publications, and records not presenting original data, 6 full-text studies were included. Associations between genetic factors and the development of secondary lymphedema were found for variations in HGF, MET, GJC2, IL1A, IL4, IL6, IL10, IL13, VEGF-C, NFKB2, LCP-2, NRP-2, SYK, VCAM1, FOXC2, VEGFR2, VEGFR3, and RORC. The authors concluded that in patients with secondary lymphedema following breast cancer therapy, genetic variations were found in 18 genes. These researchers stated that these compelling, although preliminary, findings may suggest a possible role for genetic predisposition in the development of lymphedema following breast cancer therapy.
Acupuncture for Breast Cancer-Related Lymphedema
Chien and associates (2019) stated that breast cancer-related lymphedema (BCRL) is hard to control. Management may include lymphatic drainage, skin care, bandaging, or even surgery. Since acupuncture has been proven to affect the neurophysiology and neuroendocrine systems, it has the potential to control BCRL. In a systematic review and meta-analysis, these researchers examined the effect of acupuncture in BCRL in RCTs. They carried out a literature search, following the PRISMA statement and without language restrictions. A total of 5 databases were searched from inception through September 2018. Only studies that met the eligibility criteria of evaluating the effect of acupuncture on lymphedema in breast cancer were included. The methodological quality of these trials was assessed using the Cochrane criteria, and meta-analysis software (RevMan 5.3) was used for analysis. These investigators examined 178 breast cancer patients from 6 trials. All included RCTs had medium-to-high quality, based on the modified Jadad scale. The systematic review showed that acupuncture was safe and had a trend to improve symptoms, however, trials did not consistently measure outcomes. The meta-analysis showed that acupuncture produced no significant improvement in the extent of lymphedema as compared with the control intervention (-1.90; 95 % CI: -5.39 to 1.59, p = 0.29). None of the studies reported serious AEs. The authors concluded that acupuncture was safe and exhibited a trend to improve the lymphedema related to breast cancer, however, it did not significantly change arm circumference in BCRL. These researchers stated that future studies should include both subjective and objective measurements and large-scale studies are needed.
Yu and co-workers (2020) performed a systematic review and meta-analysis of published RCTs to evaluate the effectiveness of acupuncture in the prevention of BCRL. Searching strategies were performed with the following keywords: "Breast cancer", "Acupuncture", "neoplasm" and "lymphoedema" with derivations and different combinations of these keywords. The following databases were searched: PubMed, Cochrane Library, EMBASE, Web of Science, CNKI, WanFang, and CBM. Studies published in English and Chinese were considered for inclusion in this study. Study selection, risk of bias assessment and data extraction were independently conducted. Statistical analyses were conducted with RevMan software (version 5.3). A total of 8 studies were identified by the search strategy, and 519 patients were included in this study. The effective rate was higher (OR: 4.23; 95 % CI: 2.11 to 8.49; Z = 4.07, p < 0.0001) in the experimental group than that in the control group. There were no significant improvements in the front flexion (MD: 0.19; 95 % CI: -3.68 to 4.06; Z = 0.09, p = 0.92) or the back extension (MD: 0.42; 95 % CI: -2.22 to 3.06; Z = 0.31, p = 0.75) movements of the shoulder between the experimental and control groups. The authors concluded that acupuncture may be an effective method for improving the condition of BCRL. However, due to the high risk of bias and the low quality of the available studies, further high-quality RCTs are needed to confirm the efficacy of acupuncture for patients with BCRL.
Hou and colleagues (2019) carried out a comprehensive analysis of clinical studies on acupuncture treatment for BCRL to examine the safety and the efficacy of acupuncture treatment and provide evidence for the clinical decision-making. Public databases, mainly including China Academic Journals Full-text Database, Database of Chinese Sci-Tech Journal, Wanfang, PubMed, Embase and the Cochrane Library, from the establishment of databases to December 2018 were searched for RCTs of acupuncture for BCRL. Clinical RCT on the treatment of BCRL with acupuncture combined with drugs or functional exercise were enrolled for the analysis. Bias risk and quality were assessed by 2 investigators according to the Cochrane Handbook 5.1.0 standard, and the Revman 5.3 software was used for meta-analysis. A total of 13 studies were included in this analysis, comprising 747 patients (377 in the treatment group and 370 in the control group). The results of meta-analysis showed that acupuncture intervention could improve the total effective rate for the treatment of BCRL (OR = 4.62; 95 % CI: 2.61 to 8.17). Recent studies suggested that acupuncture therapy could alleviate the UL swelling and improve the subjective pain and discomfort in patients with BCRL, regardless of the control intervention used. However, the number of high-quality RCT was low. Moreover, most of the studies adopted inconsistent efficacy indicators. The authors concluded that additional blinded, large-sample, randomized, well-controlled studies with objective and uniform efficacy indicators are needed to confirm the findings.
Manual Lymphatic Drainage
Thompson and colleagues (2021) stated that MLD massage is widely accepted as a conservative treatment for lymphedema. In a systematic review, these investigators examined the methodologies used in recent research and evaluated the effectiveness of MLD for those at-risk of or living with lymphedema. They searches the electronic data-bases Embase, PubMed, CINAHL Complete and Cochrane Central Register of Controlled Trials using relevant terms. Studies comparing MLD with another intervention or control in patients at-risk of or with lymphedema were included. Studies were critically appraised with the PEDro scale. A total of 17 studies with a total of 867 female and 2 male subjects were included. Only studies examining breast cancer-related lymphedema were identified. Some studies reported positive effects of MLD on volume reduction, QOL and symptom-related outcomes compared with other treatments, while other studies reported no additional benefit of MLD as a component of complex decongestive therapy (CDT). In patients at-risk, MLD was reported to reduce incidence of lymphedema in some studies, while others reported no such benefits. The authors concluded that the reviewed studies reported conflicting findings and were often limited by methodological issues. This review highlighted the need for further experimental studies on the effectiveness of MLD in lymphedema. Moreover, these researchers stated that there is some evidence that MLD in early stages following breast cancer surgery may help prevent progression to clinical lymphedema. MLD may also provide additional benefits in volume reduction for mild lymphedema. However, in moderate-to-severe lymphedema, MLD may not provide additional benefit when combined with CDT.
Extracorporeal Shockwave Therapy for the Treatment of Lymphedema in Breast Cancer-Related Lymphedema
Lee and colleagues (2020) examined the effects of extracorporeal shockwave therapy (ESWT) on improving lymphedema, QOL, and fibrous tissue in patients with stage-2 lymphedema; breast cancer-related lymphedema (BCRL) patients referred to the rehabilitation center were recruited. These researchers enrolled stage-2 lymphedema patients who had firmness of the skin at their forearm, a circumference difference of more than 2 cm between each arm, or a volume difference between upper extremities greater than 200 ml, confirmed by lymphoscintigraphy. Subjects were randomly divided into the ESWT group and the control group; ESWT was administered for 3 weeks (2 sessions per week); both groups received complex decongestive physical therapy. All subjects were evaluated at baseline and at 3 weeks after treatment. The measurements performed included visual analog scale (VAS) score, volume, circumference, QuickDASH (Quick Disabilities of the Arm, Shoulder and Hand) score, bioelectrical impedance, and skin thickness. Subjects in both groups (n = 15 in each group) completed the 3-week therapy experiment. No significant differences were observed in demographic characteristics between groups. After the 3-week treatment period, improvement was noted in the circumference difference below the elbow, volume, ratio of extracellular water to total body water, and skin thickness in the ESWT group. A significant difference was found in all the above-mentioned areas except in circumference below the elbow in the ESWT group. The authors concluded that ESWT reduced edema and skin fibrosis without significant complications; thus, ESWT can be used together with complex decongestive physical therapy for treating lymphedema.
The authors stated that this study had several drawbacks such as the small sample size (n = 15 for the ESWT group); thus further research including more patient groups is needed. In addition, there could have been a selection bias, as only patients with stage-2 lymphedema were included in the sample; therefore, it was difficult to derive meaningful results in VAS and QuickDASH scores. Furthermore, although the short-term effects of ESWT could be examined in this study, further assessments to identify the long-term effects are needed. Finally, according to previous studies, a skin-fold caliper was used to measure fibrosis, a complication of lymphedema. However, this method has the limitation that the amount of fibrosis could not be precisely determined. Several previous studies have used a variety of methods to measure fibrosis, but there is no current gold standard, warranting further research.
Use of Magnetic Resonance Imaging for Evaluation of Therapeutic Response in Breast Cancer-Related Lymphedema
Donahue and associates (2020) stated that BCRL evaluation is often carried out using portable measures of limb volume and bioimpedance asymmetry. In this review, quantitative MRI is used to examine deep and superficial tissue impairment, in both surgical and contralateral quadrants, to test the hypothesis that BCRL impairment is frequently bilateral and extends beyond regions commonly evaluated with portable external devices. 3-T MRI was used to examine BCRL topographical impairment. Female BCRL (n = 33; age of 54.1 ± 11.2 years; stage = 1.5 ± 0.8) and healthy (n = 33; age of 49.4 ± 11.0 years) subjects underwent quantitative upper limb MRI relaxometry (T2), bioimpedance asymmetry, arm volume asymmetry, and physical evaluation. Parametric tests were used to examine study measurements between BCRL and healthy subjects; between surgical and contralateral limbs; and in relation to clinical indicators of disease severity; 2-sided p-value < 0.05 was required for significance. Bioimpedance asymmetry was significantly correlated with MRI-measured water relaxation (T2) in superficial tissue. Deep muscle (T2 = 37.6 ± 3.5 ms) and superficial tissue (T2 = 49.8 ± 13.2 ms) relaxation times were symmetric in healthy subjects. In the surgical limbs of BCRL subjects, deep muscle (T2 = 40.5 ± 4.9 ms) and superficial tissue (T2 = 56.0 ± 14.8 ms) relaxation times were elevated compared to healthy subjects, consistent with an edematous micro-environment. This elevation was also observed in contralateral limbs of BCRL subjects (deep muscle T2 = 40.3 ± 5.7 ms; superficial T2 = 56.6 ± 13.8 ms). The authors concluded that regional MRI measurements substantiated a growing literature speculating that superficial and deep tissue, in surgical and contralateral quadrants, is affected in BCRL. The implications of these findings in the context of titrating treatment regimens and understanding malignancy recurrence were discussed.
Forte and colleagues (2020a) noted that BCRL is a common co-morbidity in BC survivors. Although MRI is widely used to examine therapeutic response of patients with various medical conditions, it is not routinely used to evaluate lymphedema patients. In a systematic review, these investigators examined the literature to identify studies on the use of MRI to evaluate therapy for BCRL. They hypothesized that MRI could provide information otherwise not possible through other examinations. On October 21, 2019, these investigators carried out a systematic review on the PubMed/Medline and Scopus data-bases, without time-frame or language limitations, to identify studies on the use of MRI to evaluate therapy for BCRL. They excluded studies that examined other applications of MRI, such as lymphedema diagnosis and surgical planning. Of 63 potential articles identified with the search, 3 case series fulfilled the eligibility criteria. A total of 53 patients with BCRL were included and quantitatively evaluated with MRI before and after manual lymphatic drainage. Authors used MRI or MR lymphagiography to examine factors such as lymphatic vessel cross-sectional area (CSA), tissue water relaxation time (T2), and chemical exchange saturation transfer. The only study that compared MRI measurement with standard examinations reported that MRI added information to the therapy evaluation. The authors concluded that MRI appeared to be a promising tool for quantitative measurement of therapeutic response in patients with BCRL; however, the identified studies focused on only MLD and were limited by the small numbers of patients. These researchers stated that more studies with greater numbers of subjects that compare proposed MRI measures with those of standard examinations are needed to shed light on the topic.
The authors stated that this systematic review had several drawbacks, such as potential bias in the collection and analysis of information presented in each study. Moreover, they searched only the PubMed/ Medline and Scopus data-bases. These investigators also acknowledged that the studies included in this review measured the characteristics of healthy volunteers, which was not described in this study because the analysis was focused on their patients who underwent therapy. However, this systematic review provided information on the use of MRI to evaluate therapy for BCRL, which is an important topic because of both lymphedema prevalence and debate regarding the efficacy of lymphedema therapies. These researchers encouraged further studies that investigate the cost-effectiveness of examinations in this setting.
Koya Dayspring System
The Koya Dayspring System is a wearable compression system that uses sequential gradient compression for the treatment and management of patients with lymphedema and provides patients with mobility during treatment. The Koya Dayspring system is also indicated for the treatment of venous insufficiency and promotion of wound healing. The Koya Dayspring system consists of a segmental gradient compression device that provides comparable compression to existing pneumatic pumps via segments that contract and relax flexible frames in a segmental appliance without the use of air. When a patient uses the compressor in conjunction with the appliance, the device creates the desired, calibrated, gradient pressures in the appliance and moves excess fluid in a rhythmic, distal to proximal manner. The function of the Dayspring System (non-pneumatic) allows patients to be mobile during treatment.
Rockson et al (2021) stated that a diagnosis of lymphedema comes with a lifetime requirement for careful self-care and treatment to control skin deterioration and the consequences of excessive fluid and protein build-up leading to abnormal limb volume and an increased risk of infection. The burden of care and psychosocial aspects of physical disfiguration and loss of function are associated with compromised QOL. The current standard therapeutic intervention is CDT with manual lymph drainage and frequent wearing of compression garments. With insurance limitations on therapy visits and the time and travel required, additional home therapeutic options are needed. Pneumatic compression pumps that mimic the manual massage pressure and pattern are sometimes prescribed, but these are bulky, difficult to apply, and require immobility during treatment. In an open-label, pilot study (n = 40 subjects), these researchers examined the QOL and limb volume maintenance efficacy of a novel wearable compression device (the Dayspring System) that is low-profile, easy-to-use, and allows for mobility during treatment. After 28 days of use, participant had a statistically significant 18 % (p < 0.001) improvement in overall QOL as measured by the Lymphedema Quality-of-Life Questionnaire compared with baseline. Individual QOL domains, and limb volume improved with therapy. Adherence was 98 % over the course of the study. The authors concluded that the findings of this study suggested the Dayspring wearable compression device was safe and effective, and improved QOL as well as limb volume. These researchers stated that this novel, low-profile device was easy to use and allowed for mobility during treatment, addressing a potential barrier to adherence with pneumatic compression devices. The findings of this pilot study need to be validated by well-designed studies.
An UpToDate review on “Clinical staging and conservative management of peripheral lymphedema” (Mehrara, 2021b) does not mention wearable compression device as a management option.
Furthermore, UpToDate reviews on “Basic principles of wound healing” (Armstrong and Meyr, 2021a), and “Risk factors for impaired wound healing and wound complications” (Armstrong and Meyr, 2021b) do not mention wearable compression device as a management option.
Rockson et al (2022a) stated that a diagnosis of lymphedema comes with a lifetime requirement for careful self-care and treatment to control skin deterioration and the consequences of excessive fluid and protein buildup leading to abnormal limb volume and an increased risk of infection. The burden of care and psychosocial aspects of physical disfiguration and loss of function are associated with compromised QOL. The current standard therapeutic intervention is CDT with manual lymph drainage and frequent wearing of compression garments. With insurance limitations on therapy visits and the time and travel required, additional home treatment options are needed. Pneumatic compression pumps that mimic the manual massage pressure and pattern are sometimes prescribed, but these are bulky, difficult to apply, and require immobility during treatment. In a controlled, open-label, pilot study (n = 40), these researchers examined the QOL and limb volume maintenance effectiveness of a novel wearable compression system (Dayspring) that is low-profile, easy-to-use, and allows for mobility during treatment. After 28 days of use, subjects had a statistically significant 18 % (p < 0.001) improvement in overall QOL as measured by the Lymphedema QOL Questionnaire (LYMQOL) compared with baseline. Individual QOL domains, and limb volume improved with therapy. Adherence was 98 % over the course of the study. Results of the clinical evaluation suggested the Dayspring wearable compression device is safe and effective and improves QOL and limb volume. The authors concluded that this novel, low-profile device is easy to use and allows for mobility during treatment, addressing a potential barrier to adherence with pneumatic compression devices.
Rockson et al (2022b) noted that lower extremity lymphedema (LEL) can result in detriments to QOL and impose a significant economic burden on patients and payers. A common component of treatment is pneumatic compression, which requires patients to remain immobile. In an open-label, non-randomized, pilot study, these investigators examined a novel non-pneumatic compression device (NPCD) that allows patients to remain active during compression treatment to examine if it would reduce swelling and improves QOL. This 12-week trial included adult patients with primary or secondary unilateral LEL, and measured changes in limb edema and QOL using the (LYMQOL. A total of 24 subjects were enrolled; the majority were female (n = 17) with secondary lymphedema (n = 21); 18 participants completed the study. Statistically significant improvements were observed in overall QOL, aggregated LYMQOL total score, and 3 of the 4 LYMQOL subscales (Function, Appearance, Mood). The 4rth (Symptoms) trended toward significant improvement (p = 0.06). The average reduction in affected limb edema was 39.4 %. The authors concluded that the novel NPCD produced statistically significant improvements in QOL, functioning, and edema volume of patients with LEL. Moreover, these researchers stated that future studies are needed to directly compare the safety and effectiveness of the novel NPCD to a traditional pneumatic compression device for the treatment of LEL.
The authors stated that a drawback of this trial was the lack of a control group, either with use of a comparator pneumatic compression device or comparison with no device use. Control observations would facilitate direct statistical comparison that would strengthen the statistical implications of the observed changes with NPCD use. Furthermore, the responsiveness of the LYMQOL to treatment intervention has not been validated; thus, these investigators could not determine the clinical significance of the observed domain scores. However, a study of a traditional pneumatic compression device observed no significant change in LYMQOL scores after 12 or 24 weeks, while a significant improvement of 1.1-points was observed after 52 weeks. It is notable that this historical long-term improvement in QOL, as reported, is only modestly higher than the 0.83-point improvement observed in the current study after only 12 weeks of device use. Finally, these researchers did not collect data on adherence; lack of adherence would potentially influence the observed effectiveness of the device.
Rockson et al (2022c) stated that advanced pneumatic compression devices (APCDs) have been shown to be an effective intervention for lymphedema when used as part of a self-care maintenance treatment regimen. However, adherence to self-care is poor, and APCDs require patients to be immobile during treatment. In a randomized, cross-over, head-to-head study, these investigators examined the safety and effectiveness of a novel NPCD for the treatment of lymphedema versus an APCD; this trial was carried out at 5 U.S. sites in 2021. Subjects were randomized to either the NPCD or a commercially available APCD. They used the randomly assigned initial device for 28 days with a 4-week wash-out period before switching to a comparable 28-day utilization of the 2nd device. Data from 50 adult women with unilateral breast cancer-related lymphedema (BCRL) were analyzed. When compared with the APCD, the NPCD was associated with greater mean reduction in limb edema volume (64.6 % versus 27.7 %, p < 0.001), significantly greater mean improvements in QOL scores, greater adherence (95.6 % versus 49.8 %, p < 0.001), and greater satisfaction with the device (90 % versus 14 %, p < 0.001). Patients indicated that the NPCD facilitated exercise and was convenient for travel. No AEs were reported. The authors concluded that these findings suggested that the NPCD is non-inferior to the APCD in reducing the edema volume in patients with lymphedema and produced superior outcomes for volume reduction and symptom relief. The patients were more adherent to therapy and more satisfied with the device than they were when using the APCD. Moreover, these researchers stated that future studies are needed to examine the effects of early intervention and will aid in determining long-term adherence to the use of the device to prevent the progression of lymphedema.
Immediate Lymphatic Reconstruction for the Prevention of Breast Cancer-Related Lymphedema
Johnson et al (2020) stated that upper extremity (UE) lymphedema occurs in 25 % to 40 % of patients after axillary lymph node dissection (ALND). Immediate lymphatic reconstruction (ILR) or the lymphatic micro- surgical preventative healing approach has demonstrated a significant decrease in post-operative rates of lymphedema (LE) from 4 % to 12 % (??? 1.2 %). These researchers mapped the Mascagni-Sappey pathway, the lateral upper arm draining lymphatics, in patients undergoing ILR to better characterize the drainage pattern of this lymphosome to the axilla. They carried out a retrospective review of their institutional lymphatic database and consecutive breast cancer patients undergoing ILR were identified from November 2017 through June 2018. Patient demographics, clinical characteristics, and intra-operative records were retrieved and analyzed. A total of 29 consecutive breast cancer patients who underwent ILR after ALND were identified. Patients had a mean age of 54.6 years and body mass index (BMI) of 26.6 kg/m2. Fluorescein isothiocyanate (FITC) was injected at the medial upper arm and isosulfan blue was injected at the cephalic vein, or lateral upper arm, prior to ALND. After ALND, an average 2.5 divided lymphatics were identified, and a mean 1.2 lymphatics were bypassed. In all patients, divided FITC lymphatics were identified. However, in only 3 patients (10 %), divided blue lymphatics were identified after ALND. The authors concluded that in this study, variable drainage of the lateral upper arm to the axillary bed was noted. This study was the 1st to provide a description of intra-operative findings, demonstrating variable drainage patterns of UE lymphatics to the axilla. Moreover, these investigators noted that the lateral- and medial-upper arm lymphosomes have mutually exclusive pathways draining to the axilla. These researchers stated that further study of lymphatic anatomy variability may elucidate the pathophysiology of lymphedema development and influence approaches to ILR.
The authors stated that there are limitations to this study. While this study clearly demonstrated the intra-operative findings as they related to lateral pathway drainage to the axilla, these researchers were unable to qualify if this pathway is simultaneously draining to the supraclavicular/infraclavicular nodes in patients. However, no patient in this study underwent a level III lymph node dissection, precluding any evaluation of drainage to these nodal basins. There were no differences in baseline demographics and pre-operative treatment between groups, further supporting that these findings reflected existing anatomic variations. Moreover, these researchers recognized the need for further study in a larger patient population with prolonged follow-up to evaluate its true influence on LE development.
Johnson et al (2021a) examined the impact of ILR or the lymphatic microsurgical preventative healing approach on post-operative lymphedema incidence. These researchers carried out a retrospective review of all patients referred for ILR at the authors' institution from September 2016 to February 2019. Patients with pre-operative measurements and a minimum of 6 months' follow-up data were identified. Medical records were reviewed for demographics, cancer treatment data, intra-operative management, and lymphedema incidence. A total of 97 women with unilateral node-positive breast cancer underwent axillary nodal surgery and attempt at ILR over the study period; 32 patients underwent successful ILR with a mean patient age of 54 years and body mass index (BMI) of 28 ± 6 kg/m2. The median number of lymph nodes removed was 14 and the median follow-up time was 11.4 months (range of 6.2 to 26.9 months); 88 % of patients underwent adjuvant radiotherapy of which 93 % received regional lymph node radiotherapy (RLNR). Mean L-Dex change was 2.9 units and mean change in volumetry by circumferential measurements and perometry was -1.7 % and 1.3 %, respectively. At the end of the study period, these investigators found an overall 3.1 % rate of lymphedema. The authors concluded that using multiple measurement modalities and strict follow-up guidelines, these findings supported that ILR at the time of axillary surgery is a promising, safe approach for lymphedema prevention in a high-risk patient population. Level of Evidence = IV.
Johnson et al (2021b) carried out a cost-utility analysis to examine the cost and quality of life (QOL) of patients undergoing ALND and ALND with RLNR, with and without lymphatic microsurgical preventive healing approach (LYMPHA), in a node-positive breast cancer population. These investigators found that the addition of LYMPHA to both ALND; or ALND with RLNR is more cost-effective. This trial was the 1st to employ rigorous methodological criteria to critically appraise a surgical preventative technique for breast cancer-related lymphedema (BCRL) from a cost-utility standpoint. BCRL is a well-documented complication of breast cancer survivors in the U.S. In this study, these researchers conducted a cost-utility analysis to evaluate the cost-effectiveness of the LYMPHA. Lymphedema rates after each of the following surgical options: (i) ALND, (ii) ALND + LYMPHA, (iii) ALND + RLNR, and (iv) ALND + RLNR + LYMPHA were extracted from a recently published meta-analysis. Procedural costs were calculated using Medicare reimbursement rates. Average utility scores were obtained for each health state using a visual analog scale (VAS), then converted to quality-adjusted life years (QALYs). A decision tree was generated; and incremental cost-utility ratios (ICUR) were calculated. Multiple sensitivity analyses were performed to evaluate these findings. ALND with LYMPHA was more cost-effective with an ICUR of $1587.73/QALY. In the decision tree roll-back analysis, a clinical effectiveness gain of 1.35 QALY justified an increased incremental cost of $2,140. Similarly, the addition of LYMPHA to ALND with RLNR was more cost-effective with an ICUR of $699.84/QALY. In the decision tree roll-back analysis, a clinical effectiveness gain of 2.98 QALY justified a higher incremental cost of $2,085.00. The authors concluded that the findings of this study supported that the addition of LYMPHA to both ALND; or ALND with RLNR was the more cost-effective therapeutic option.
Cook et al (2021) noted that lymphedema is progressive arm swelling from lymphatic dysfunction which can occur in 30 % patients undergoing axillary dissection/radiation for breast cancer. ILR is performed in an attempt decrease the risk of lymphedema in patients undergoing ALND. In a retrospective, single-center study, these researchers examined the effectiveness of ILR in preventing lymphedema rates in ALND patients. They carried out an institutional review board (IRB)-approved review of all patients who underwent ILR from 2017 to 2019. Patient demographics, co-morbidities, operative and pathologic findings, number of LVAs, limb measurements, complications, and follow-up were recorded and analyzed. Student's sample t-test, Fisher's exact test, and ANOVA were used to analyze data; significance was set at p < 0.05. A total of 33 patients were included in this analysis; 3 patients (9.1 %) developed persistent lymphedema, and 2 patients (6.1 %) developed transient arm edema that resolved with compression and massage therapy. A significant effect was found for BMI and the number of lymph nodes taken on the development of lymphedema (p < 0.01). The authors concluded that the rate of lymphedema in this series was 9.1 %, which was an improvement from historical rates of lymphedema. These researchers stated that these findings supported ILR as a technique that potentially decreases the incidence of lymphedema after axillary lymphadenectomy. Obesity and number of lymph nodes removed were significant predictive variables for the development of lymphedema following LVA.
Cook and colleagues (2022) stated that lymphedema affects up to 250 million people worldwide. In patients with breast cancers, lymphedema occurs in 30 % who undergo axillary lymph node dissection (ALND). Immediate lymphatic reconstruction (ILR), also known as lymphatic microsurgical preventing healing approach (LyMPHA), is a method to lower the risk of lymphedema by performing prophylactic lympho-venous anastomoses at the time of ALND. These researchers examined the risk reduction of ILR in preventing lymphedema. They noted that lymphedema has significant effects on the QOL and morbidity of patients. Several techniques have been described to manage lymphedema after development, but prophylactic treatment of lymphedema with ILR may decrease risk of development to 6.6 %. Moreover, these researchers stated that long-term studies are needed to demonstrate the effectiveness of ILR as a prophylactic approach for the management of lymphedema in patients undergoing lymph node dissection.
Furthermore, an UpToDate review on “Breast cancer-associated lymphedema” (Mehrara, 2022) states that “Lymphatic reconstruction -- Lymphovenous bypass (referred to as lymphatic microsurgical preventing healing approach [LYMPHA] or immediate lymphatic reconstruction [ILR]) can also be performed at the time of lymph node dissection to help prevent lymphedema. In the largest series of 74 patients with an average follow-up of four years, only 4 % of patients treated with LYMPHA developed lymphedema compared with historical rates of 15 to 65 %. Several centers have ongoing studies attempting to confirm the validity of these findings”.
Minimally Invasive Tissue Excision with Possible Redundant Skin Excision (the MITESE Procedure)
UpToDate reviews on “Clinical staging and conservative management of peripheral lymphedema” (Mehrara, 2021b) and “Surgical treatment of primary and secondary lymphedema” (Mehrara, 2021a) and do not mention minimally invasive tissue excision with possible redundant skin excision (the MITESE procedure) as a management / therapeutic option.
Bioimpedance
Forte et al (2021) stated that that bioimpedance spectroscopy (BIS) has been suggested as a useful tool for early diagnosis of breast cancer-related lymphedema (BCRL). These researchers described the outcomes of published studies that examined bioimpedance analysis as a method for prospective surveillance and early diagnosis of BCRL. They queried the PubMed, Ovid Medline, and Embase databases to identify studies that examined the use of BIS as a diagnostic tool. These investigators used the keywords "bioimpedance" AND ("lymphedema" OR "lymphoedema") in the search. Only English-language studies that reported quantitative outcomes for patients with BCRL were included. Of 152, 235 and 116 identified articles in PubMed, Ovid Medline and Embase databases, only 22 were included. Use of bioimpedance analysis for prospective surveillance has been shown to prevent chronic BCRL. All the cross-sectional and retrospective studies that evaluated bioimpedance for diagnosis of BCRL reported significantly different L-Dex scores between lymphedema patients and healthy participants. Furthermore, bioimpedance scores were positively correlated with volume of lymphedema. The authors concluded that bioimpedance analysis is a potential tool with demonstrated benefits for prevention of chronic BCRL and may be an economic and great alternative for early diagnosis of BCRL. However, the accuracy of BIS for BCRL assessment has not been determined, and consequently further studies are needed.
Sutherland et al (2021) examined if BIS measurements can accurately evaluate changes in BCRL in patients undergoing lympho-venous bypass (LVB). Patients undergoing LVB for BCRL refractory to conservative treatment from January 2015 to December 2018 were identified from an IRB-approved prospectively maintained database at a single institution. All breast cancer patients were evaluated with baseline BIS measurements before any oncologic surgery and serial BIS during follow-up office visits including before and after LVB. Clinicopathologic information, LVB operative details, and pre- and post-LVB operative BIS measurements were collected. Analysis focused on clinically significant BIS change, defined as 2 standard deviations (SD), and comparing LVB anastomosis to BIS changes. During the study timeframe, a total of 9 patients underwent LVB for treatment of BCRL. The majority (78 %) received radiation, taxane chemotherapy, and underwent axillary dissection. An average of 5.6 LVB anastomoses were carried out per patient. The average change in BIS following LVB was a 3-SD reduction, indicating a clinically significant change. This improvement was stable over time, with persistent 2-SD reduction at 22 months post-operatively. The number of LVB anastomoses performed did not significantly correlate with the degree of BIS change. The authors concluded that this was the 1st study to employ BIS measurements to evaluate response to LVB surgical intervention for BCRL. These researchers stated that BIS measurements demonstrated clinically significant improvement following LVB, providing objective evidence in support of this surgical treatment for BCRL. They noted that BIS changes should be reported as key objective data in future studies assessing BCRL interventions, including response to LVB.
Chang et al (2021) developed an innovative wireless device for bioimpedance analysis for post-dual-site free vascularized lymph node transfer (VLNT) evaluation. A total of 7 patients received dual-site free VLNT for unilateral upper or lower limb lymphedema. A total of 10 healthy college students were enrolled in the healthy control group. The device was applied to the affected and unaffected limbs to assess segmental alterations in bioimpedance. The affected proximal limb showed a significant increase in bioimpedance at post-operative 6th month (3.3 [2.8, 3.6], p = 0.001) with 10-kHz currents for better penetration, although the difference was not significant (3.3 [3.3, 3.8]) at 1-kHz. The bioimpedance of the affected distal limb significantly increased after dual-site free VLNT surgery, whether passing with the 1-kHz (1.6 [0.7, 3.4], p = 0.030, post-operative 1st month; 2.8 [1.0, 4.2], p = 0.027, post-operative 3rd month; and 1.3 [1.3, 3.4], p = 0.009, post-operative 6th month) or 10-kHz current ((1.4 [0.5, 2.7], p = 0.049, post-operative 1st month; 3.2 [0.9, 6.3], p = 0.003, post-operative 3rd month; and 3.6 [2.5, 4.1], p < 0.001, post-operative 6th month). Bioimpedance alterations on the affected distal limb were significantly correlated with follow-up time (rho = 0.456, p = 0.029 detected at 10-kHz). The authors concluded that the dual-site free VLNT treatment is a promising method to improve refractory limb lymphedema by enhancing the lymphatic drainage. Their innovative wireless bioimpedance monitoring device demonstrated clinically significant and continuous improvement in lymphedema after dual-site-free VLNT treatment. The increase in bioimpedance after dual-site free VLNT treatment correlated with a decrease in circumference. The novel wireless bioimpedance device was proven to segmentally assess the lymphedema condition quantitatively by truly reflecting the fluid volume distribution in the limbs. It could also be an optimal evaluation for outcome surveillance during rehabilitation programs. Moreover, these researchers stated that the application of this innovative bioimpedance device for long-term monitoring of lymphedema treatment outcomes still needs to be validated.
The authors stated that this study had several drawbacks. First, the number of dual-site VLNT surgery was still short; thus, these investigators only examined the difference through the proximal limb (thigh/arm) and distal limb (calf/forearm) in this study. Perhaps they could consider subdividing it into 4groups (thigh, arm, calf, and forearm) in the future. Furthermore, the very small sample size (n = 7) may have affected the reliability of the study. Second, the bioimpedance device detected only segmental bioimpedance to represent the water volume distribution. The device could not analyze the nutritional status of the patient and the soft tissue composition, including adipose and muscle tissues. Third, the detection depth of the device would depend on the adjustment of the frequency; thus, the tomography imaging method could be developed with multi-segment measurement in future studies. These researchers may examine multi-segment measurements to display the actual water distribution pattern of the entire extremity in the future. Fourth, a correlation between the bioimpedance method and image assessment, such as lymphoscintigraphy, ICG lymphangiography, and magnetic resonance lymphangiography, is still lacking. Fifth, these researchers recommended using the device for post-operative surveillance and rehabilitation tracking. Patients with severe fibrosis may not be suitable due to the lack of deeper penetration. Sixth, there is no precision value (ml) for volume corresponding to the bioimpedance at present. Seventh, the performance metrics of the bioimpedance device in terms of accuracy and precision of measurement against known impedances should be further examined.
Gillespie et al (2021) noted that BCRL affects more than 1 in 5 women treated for breast cancer, and women remain at lifelong risk. Screening for BCRL is recommended by several national and international organizations for women at risk of BCRL, and multiple methods of objective screening measurement exist. These researchers compared the use of perometry and BIS for early identification of BCRL in a cohort of 138 prospectively screened patients. At each screening visit, a patient's relative volume change (RVC) from perometer measurements and change in L-Dex from baseline (ΔL-Dex) using BIS was calculated. There was a negligible correlation between RVC and ΔL-Dex (r = 0.195). Multiple thresholds of BCRL were examined: RVC greater than or equal to 5 % and greater than or equal to 10 % as well as and ΔL-Dex greater than or equal to 6.5 and greater than or equal to 10. While some patients developed an elevated RVC and ΔL-Dex, many demonstrated elevations in only 1 threshold category. Moreover, the majority of patients with RVC greater than or equal to 5 %, ΔL-Dex greater than or equal to 6.5, or ΔL-Dex greater than or equal to 10 regressed to non-elevated measurements without intervention. The authors concluded that these findings suggested a role for combining multiple screening methods for early identification of BCRL. In addition, BCRL diagnosis must incorporate patient symptoms and clinical evaluation with objective measurements obtained from techniques such as perometry and BIS.
Shah et al (2021) stated that chronic BCRL is a potentially serious complication following treatment. Monitoring for progression to BCRL may allow for earlier detection and intervention, reducing the rate of progression to chronic BCRL. In a meta-analysis, these researchers examined the impact of monitoring techniques on the incidence of chronic BCRL among patients monitored by BIS and circumference as compared to background rates. Eligible peer-reviewed studies from PubMed, CINHAL, or Google Scholar that were published in English from 2013 onward and conducted in North America, Europe, or Oceania. Incidence rates abstracted from studies were classified by BCRL monitoring method: background (no standardized BIS or circumference assessments), BIS or circumference. A random-effects model was used to calculate a pooled annualized estimate of BCRL incidence while accounting for clinical and methodological heterogeneity. Subgroup analyses examined differences in duration of follow-up as well as breast and axillary surgery. A total of 50 studies were included, representing over 67,000 women. The annualized incidence of BCRL was 4.9 % (95 % CI: 4.3 to 5.5) for background studies (n = 35), 1.5 % (95 % CI: 0.6 to 2.4) for BIS-monitored studies (n = 7), and 7.7 % (95 % CI: 5.6 to 9.8) for circumference-monitored studies (n = 11). The cumulative BCRL incidence rate in BIS-monitored patients was 3.1 % as compared to 12.9 % with background monitoring (69 % reduction) and 17.0 % with circumference-monitored patients (81 % reduction). The authors concluded that evidence suggested that monitoring with BIS allowing for early intervention significantly reduced the relative risk (RR) of chronic BCRL with a 69 % and 81 % reduction compared to background and circumference, respectively. Circumference monitoring did not appear to provide a benefit with respect to chronic BCRL incidence. These investigators stated that based on these results, BIS should be considered for BCRL screening in order to detect subclinical BCRL and reduce rates of chronic BCRL, especially in high-risk patients.
The authors stated that his meta-analysis had several important drawbacks. First, there were relatively few studies (n = 7) that used BIS to monitor progression to chronic BCRL. Second, only 28 % of BIS patients had axillary lymph node dissection (ALND), versus 73 % of circumference patients, suggesting the latter group was at disproportionately greater risk of BCRL. Third, data on patient body mass index (BMI) in many studies were either not available or were not presented continuously. Fourth, most studies did not provide data specifically on taxane-based chemotherapy or RNI (radiation fields including axilla vs axilla + supraclavicular versus supraclavicular alone), which are also risk factors for BCRL. It would have been advantageous to include subgroup analyses on BMI, taxane-base chemotherapy, and RNI, as they are known to increase patient’s risk for BCRL. Definitions of BCRL varied across studies. However, there were no standard clinical cut-points for many of these measures other than BIS. For the BIS studies, in particular, there was greater consistency, with BCRL defined as an increase of 10 units or more in L-Dex scores. Finally, the background group was heterogeneous, although consistent with the previous meta-analysis. A sensitivity analysis was carried out on the background studies to evaluate the BCRL rates for studies with no active monitoring in comparison to other commonly performed monitoring methods (e.g., water displacement) that were included in the background. With no monitoring (n = 11), the annualized incidence rate for BCRL was 3.7 %. Background studies with other methods of monitoring (n = 24) had an annualized incidence rate of 7.6 %. This difference indicated the possibility of detection bias when evaluating the low incidence rate of the patients in the no monitoring group. Without active monitoring, it was highly possible for patients to develop BCRL and go undiagnosed, which could bias the results.
Advanced Pneumatic Compression (e.g., the Flexitouch Device) for the Treatment of Head and Neck Edema
In a functional, usability single-arm study, Mayrovitz et al (2018) examined ease of use, fit, comfort, and potential clinical benefits of advanced pneumatic compression treatment of cancer-related head and neck lymphedema (HNL). Patient-reported comfort and other treatment aspects were examined; and multiple face and neck measurements were obtained on 44 patients with head and neck lymphedema before and after 1 treatment session to evaluate usability and treatment-related lymphedema changes. A majority of the patients (82 %) reported the treatment was comfortable; most patients (61 %) reported feeling better after treatment, and 93 % reported that they would be likely to use this therapy at home. One treatment produced overall small but highly statistically significant reductions in composite metrics (mean ± SD) of the face (82.5 ± 4.3 cm versus 80.9 ± 4.1 cm; p < 0.001) and neck (120.4 ± 12.2 cm versus 119.2 ± 12.1 cm; p < 0.001) with no adverse events (AEs). The authors concluded that results found the treatment to be safe, easy to use, and well-tolerated while demonstrating edema reduction after a single initial treatment. Moreover, these researchers stated that within the limitations of this single‐arm, single‐treatment study design, the findings of this study indicated the potential utility of this technology. Furthermore, these findings provided a basis and foundation for subsequent evaluations of a more extensive nature with studies that have longer device usage and patient follow‐up and a suitable control group.
Gutierrez et al (2019) described the findings of 10 head and neck cancer (HNC) survivors diagnosed with HNL who were imaged using near-infrared fluorescence lymphatic imaging (NIRFLI) before and immediately after an initial advance pneumatic compression device (APCD) treatment and again after 2 weeks of daily at-home use. Images assessed the impact of pneumatic compression therapy on lymphatic drainage. Facial composite measurement scores assessed reduction/increase in external swelling, and survey results were obtained. After a single pneumatic compression treatment, NIRFLI showed enhanced lymphatic uptake and drainage in all subjects. After 2 weeks of daily treatment, areas of dermal back-flow disappeared or were reduced in 6 of 8 subjects presenting with back-flow. The authors concluded that in general, reductions in facial composite measurement scores tracked with reductions in back-flow and subject-reported improvements; however, these researchers stated that further investigations examining lymphatic response to longer durations of treatment and its durability could definitively determine whether APCD can ameliorate all back-flow and potentially mitigate or prevent HNL.
In an observational study, Gutierrez et al (2020) HNC survivors experience HNL, which requires treatment to prevent morbidity. These investigators examined the self-reported outcomes and satisfaction of patients with HNC receiving treatment for HNL with an APCD. HNC survivors (n = 205) prescribed with an at-home Flexitouch head and neck APCD completed pretreatment and posttreatment self-reported assessments addressing effectiveness, function, and symptoms. Subjects’ average age was 60 years with 74 % male. Pre- and post-responses for 25 or more days of use were assessed via the non-parametric Wilcoxon Signed Rank test. Analysis revealed statistically significant improvement in all symptoms and all function items (p < 0.00001). Compliance with prescribed therapy (at least 30 mins per daily) was high with 71 % of subjects reporting daily use and 87 % reporting overall satisfaction. The authors concluded that studied parameters, such as ability to carry out activities of daily living (ADL) and functional improvements in swallowing and breathing, demonstrated statistically significant positive changes from pre‐ to post‐device use. These investigators stated that the findings of this study suggested the potential utility of at‐home use of this device in contributing to improved quality of life (QOL) in this patient population and provided a rationale for a subsequent randomized controlled trial (RCT) to objectively evaluate improvement in symptoms with the use of a head and neck APCD.
The authors stated that this study had several drawbacks. First, the lack of a control group did not allow for conclusions on effectiveness; however, the study met its primary objective of examining patient‐reported outcomes and satisfaction with the Flexitouch system for home use. The survey results will be used to inform the design of a future randomized trial. Second, as an observational study, additional drawbacks included wide variation in the time interval (25 to 288 days) between the pre-treatment and post-treatment assessments. Third, data were collected via a Tactile Medical customer survey and not a validated patient‐reported outcomes (PRO) questionnaire. Although this questionnaire provided valuable insight into patient satisfaction and device usability, use of a validated survey would strengthen future prospective studies.
Ridner et al (2021) noted that lymphedema associated with HNC therapy causes adverse clinical outcomes. Standard treatment includes professionally administered complete decongestive therapy (CDT). Cost and availability of trained therapists are known barriers to therapy; and APCD may address these issues. In a randomized, wait-list controlled trial, these researchers examined an APCD in post-treatment HNC patients with lymphedema. Eligible patients had completed treatment for HNC, were disease-free, and had lymphedema at enrollment. Subjects were randomized to wait-list lymphedema self-management (standard of care [SOC]) or lymphedema self-management plus the use of the APCD bid. Safety (CTCAE V4.0) and feasibility were primary endpoints; secondary endpoints included effectiveness measure by objective examination and patient reported outcomes (symptoms, QOL, function), adherence barriers, and satisfaction. Assessments were conducted at baseline and weeks 4 and 8. A total of 49 patients were enrolled (wait-list n = 25; intervention n = 24). In total, 43 patients completed the study. No device-related serious AEs were reported. Most patients used the APCD once-daily, instead of the prescribed twice-daily, citing time related factors as barriers to use. APCD use was associated with significant improvement in perceived ability to control lymphedema (p = 0.003) and visible external swelling (front view p < 0.001, right view p = 0.004, left p = 0.005), as well as less reported pain. The findings of this study supported the safety and feasibility of the APCD for the treatment of secondary lymphedema in HNC patients. Moreover, these researchers stated that symptom outcomes provided evidence for promising preliminary effectiveness of the device; they stated that further research in a larger RCT is needed.
Fibro-Lipo-Lympho-Aspiration (FLLA) for the Treatment of Lymphedema
Campisi et al (2017) stated that in lymphedema, excess adipose tissue occurs with progression of the disease because of chronic lymph stasis, impeding lymphatic flow. Recently, lipo-suction has been employed as a less-invasive procedure to remove this excess tissue. Given the existing poor lymph drainage in patients with lymphatic diseases, extra caution should be taken to avoid damaging lymphatic vessels during lipo-suction. These researchers developed a new technique (Fibro-Lipo-Lymph-Aspiration with a Lymph Vessel Sparing Procedure [FLLA-LVSP]) to improve chronic swelling in patients with advanced lymphedema. The FLLA-LSVP highlighted the superficial lymphatic pathways in the treated limb. This visibility allowed surgeons to avoid these pathways, while removing the maximum amount of excess tissue. A total of 146 patients with primary or secondary lymphedema that had already been treated by lymphatic microsurgery, in Genoa, Italy, were included in this retrospective study. All patients had residual fibrotic/adipose tissue, resistant to conservative treatments. Indocyanine green (ICG) fluorescent dye and Blue Patent Violet dye were injected laterally/medially to the main superficial veins at the wrist/ankle of the limb to be treated. Using a photodynamic camera, the superficial lymphatic network was made visible and sketched onto the skin in indelible ink. After the micro-lymphography, the excess adipose tissue was carefully aspirated. Pre-operative and post-operative excess limb volumes were calculated using circumferential measurements and the formula of a frustum. For the upper limb, 0.80 L, on average, and 2.42 L for the lower limb were removed with the FLLA-LVSP. For the upper limb, there was an average pre-surgery excess volume of 20.19 %, which was reduced to 2.68 % following FLLA-LVSP (Z score = -6.90, p < 0.001). Similarly, for the lower limb, there was an average pre-surgery excess limb volume of 21.24 % and a reduction to 2.64 % post-operatively (Z score = -3.57, p < 0.01). Immediate post-operative micro-lymphography and Blue Patent Violet test confirmed no lymphatic complications. No episodes of post-operative infection occurred. The authors concluded that FLLA-LVSP was efficient. An entire leg could be completed within 90 mins. Recovery time was short, and cosmetic results were immediate. More importantly, the removal of excess tissue was completed without further damage to lymphatic vessels. When used after microsurgery, FLLA-LVSP offered the possibility of removing almost all obstacles to lymphatic flow.
The authors stated that this study had several drawbacks, notably (its retrospective design, and) the relatively small sample size that gave an incomplete comparison of primary versus secondary lymphedema, especially in the upper limb group (however, this also reflected the nature of the patient sample, as secondary lymphedema due to breast cancer treatment is more frequent than primary upper limb lymphedema). Although the clinical presentation of primary and secondary lymphedemas is virtually indistinguishable, primary lymphedemas are more often due to lymphatic malformations, such as hypoplasia or anaplasia, rather than obstruction/disruption. However, there is reason to believe that the ultimate progressive damage to the lymphatic pathways is the same in both cases (evident by similar patterns on ICG lymphography, for example) and so are the underlying genetic mutations involved in the disease. In this study, these researchers also observed that there was no difference between the primary and secondary lymphedemas in their sample in terms of excess limb volume; thus, the results obtained should be applicable to all forms of lymphedema, although further clinical research with larger sample sizes is needed. With regard to the surgical technique, the FLLA-LVSP uses a combined approach to visualize the lymphatic pathways so that these could be spared by the liposuction cannula. Obviously, the main lymphatic pathways in the affected limb lie in close proximity to main veins, such as the great saphenous vein (GSV) in the lower limb. These pathways are where the initial adipose and fibrotic tissue deposits occur and most likely have the greatest density of excess tissue. The FLLA-LVSP will not remove all of the excess tissue from these areas, to avoid lymphatic injury. Theoretically, it is not possible to remove 100 % of the excess tissue in a treated limb, and these investigators found that there remained, on average, 2 % excess tissue. The authors did not, however, believe that this detracted from the success of the FLLA-LVSP, because they were able to achieve pleasing aesthetic results, even if not a 100 % reduction, with the prevention of lymphatic injuries, ultimately allowing patients to reduce or eliminate the use of compressive garments.
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