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A systematic review of guidelines for lymphedema and the need for contemporary intersocietal guidelines for the management of lymphedema

Open AccessPublished:May 20, 2020DOI:https://doi.org/10.1016/j.jvsv.2020.03.006

      Abstract

      Objective

      Lymphedema (LED) affects an estimated 35 million patients in the United States and a staggering 140,200 million people worldwide, yet LED is the forgotten vascular disease. Whereas the diagnosis and treatment of arterial and venous diseases have been strengthened by the development of clinical practice guidelines (CPGs), few CPGs are available for LED. Moreover, for CPGs to have their greatest impact, they should be both of high quality and developed using the most rigorous evidence-based methods. We performed a systematic review of the available CPGs for LED, which were assessed for breadth of content and methodologic strength.

      Methods

      A literature search was conducted from National Guideline Clearinghouse (www.guidelines.gov), BMJ Clinical Evidence (http://clinicalevidence.bmj.com), and National Institute for Health and Care Excellence (http://www.nice.org.uk) as well as from MEDLINE and Google, which selected 245 documents. After a horizon scan that identified 13 potential CPGs, 4 satisfied the criteria for LED. These were analyzed for inclusion of key elements of diagnosis and treatment.

      Results

      A horizon scan (abstract review) of the 245 documents identified 10 potential CPGs. Of the 10 documents, 6 claimed to be CPGs, but 2 were limited in scope (rehabilitation or compression only), 2 were consensus statements, 1 was a position statement, and 1 was a systematic review. This process yielded four CPGs: Lymphedema Framework Best Practice for the Management of Lymphedema; Japanese Lymphedema Study Group—A Practice Guideline for the Management of Lymphedema; Clinical Resource Efficiency Support Team Guidelines for the Diagnosis, Assessment and Management of Lymphedema; and Guidelines of the American Venous Forum. Only one of four CPGs was based on a contemporary systematic review (2016 end date of references), whereas the remainder had older systematic reviews (end dates of 2005, 2007, and 2007). Several areas of contemporary diagnosis, treatment, and monitoring of LED were absent.

      Conclusions

      This systematic review of available LED CPGs demonstrates a limited number of guidelines. The four CPGs identified lack contemporary references while demonstrating low overall study quality. Therefore, it is imperative for our vascular societies to develop contemporary high-quality evidence-based CPGs for LED, as they have for other vascular diseases.

      Keywords

      Clinical practice guidelines (CPGs) have become an important feature for diagnosis and management of common medical problems. These guidelines follow a detailed review of the literature to provide evidence-based recommendations for the diagnosis and treatment of a specific medical condition.
      • O’Donnell T.F.
      • Balk E.M.
      The need for an Intersociety Consensus Guideline for venous ulcer.
      CPGs present a uniform treatment protocol for patients, and as a consequence, both the effectiveness and the quality of care should be improved. Moreover, a consensus-driven protocol is usually associated with a reduction in the cost of the care. These compelling factors have positioned the development and implementation of CPGs as a high priority of all health care systems.
      The Institute of Medicine in 1990 characterized CPGs as “systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances.”
      Institute of Medicine
      Guidelines for clinical practice: from development to use.
      This definition has been updated: “Clinical guidelines are statements that include recommendations intended to optimize patient care that are informed by a systematic review of evidence and an assessment of the benefits and harms of alternative care options.”
      Institute of Medicine
      Guidelines for clinical practice: from development to use.
      CPGs are usually prepared by specialty societies, as evidenced by the development of guidelines by the Society for Vascular Surgery for multiple arterial conditions and with the American Venous Forum (AVF) for venous guidelines.
      • Gloviczki P.
      • Comerota A.J.
      • Dalsing M.C.
      • Eklof B.G.
      • Gillespie D.L.
      • Gloviczki M.L.
      • et al.
      The care of patients with varicose veins and associated chronic venous diseases: clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum.
      “Guidelines validate and transfer new techniques through evidence-based systematic reviews and meta-analyses.” Such guidelines “sift through massive amounts of data to provide a consensus on the evidence for treatment of a specific condition. In summary, guidelines promote best practices to achieve best outcomes for the most reasonable healthcare dollar and thereby improve the quality of care.”
      • O’Donnell T.F.
      • Passman M.
      Clinical practice guidelines of the Society for Vascular Surgery (SVS) and the American Venous Forum (AVF): management of venous leg ulcers.
      Although the diagnosis and treatment of arterial and venous disease have been strengthened by the development of CPGs, few contemporary clinical care guidelines are available for lymphedema (LED).
      • Adamczyk L.A.
      • Gordon K.
      • Kholová I.
      • Meijer-Jorna L.B.
      • Telinius N.
      • Gallagher P.J.
      • et al.
      Lymph vessels: the forgotten second circulation in health and disease.
      Toward that purpose, we performed a systematic review of the available CPGs for LED and assessed these CPGs for both their specific recommendations and their breadth of content.
      AGREE Collaboration
      The development and validation of an international appraisal instrument for assessing the quality of clinical practice guidelines: the AGREE project.

      Methods

       Identification of LED guidelines

      A systematic review was conducted during the years 2000 to 2017 from the National Guideline Clearinghouse (www.guidelines.gov), BMJ Clinical Evidence (http://clinicalevidence.bmg.com), and National Institute for Health and Care Excellence (NICE; http://www.nice.org.uk) as well as from MEDLINE and Google, which is illustrated in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines diagram (Fig). The documents to be evaluated were read randomly by the reviewers to avoid biasing the scores from familiarity with the previously evaluated CPGs. The search terms lymphedema guidelines, consensus on lymphedema treatment, management of lymphedema, and management of limb swelling were used.
      Figure thumbnail gr1
      FigPreferred Reporting Items for Systematic Reviews and Meta-Analyses diagram demonstrates the results of the search for lymphedema (LED) guidelines (GL's). The National Guideline Clearinghouse (NGC) yielded 49 potential sources; British Medical Journal (BMJ), 7; National Institute for Health and Care Excellence (NICE), 181; and use of LED guidelines as a reference, an additional 8, which resulted in a total of 245 publications. A horizon scan (abstract review) was then performed, which identified 13 potential documents as LED clinical practice guidelines (CPGs). Ultimately, four documents satisfied criteria for selection as CPGs. BRCA, Breast cancer; POS’N, position statement; SR, systematic review.
      Because the terms clinical practice guideline (CPG), consensus statement, and position paper are frequently used as if they had a similar meaning, our selection of a CPG followed a strict definition. A CPG develops recommendations that are based on a more extensive systematic review of the literature and weighs the potential benefits and harms of these options. Finally, these recommendations are usually subject to rigorous peer review.
      • Brouwers M.
      • Kho M.E.
      • Browman G.P.
      • Burgers J.S.
      • Cluzeau F.
      • Feder G.
      • et al.
      Development of the AGREE II, part 2: assessment of validity of items and tools to support application.
      Criteria from the National Guideline Clearinghouse were applied to the ultimate selection of a CPG in this analysis. By contrast, a clinical consensus statement reflects opinions synthesized from an organized group of experts into a written document. The panel of experts on the topic of interest carefully gather and discuss the scientific data available, but not through a formal evidence review. Finally, a position paper is a document that presents an opinion about an issue, usually that of the author or another specified entity, such as a medical society.

       Key elements of diagnosis, assessment, and treatment

       Diagnosis and assessment

      Each of the CPGs selected was analyzed for its description of specific elements, as follows:
      • Diagnosis: clinical examination (both medical history and physical examination for key pathognomonic findings), duplex ultrasound, imaging by computed tomography (CT) or magnetic resonance imaging (MRI), lymphoscintigraphy
      • Outcome measures: skin condition, objective degree of limb volume reduction determined by water displacement, circumferential girth measurements, perometry, bioimpedance, duplex ultrasound tissue measurements
      • Staging by the International Society of Lymphology criteria
        International Society of Lymphology Executive Committee
        The diagnosis and treatment of peripheral lymphedema.
      • Health-related quality of life assessment, both generic and disease specific

       Types of treatment

      Specific treatment modalities were also identified.
      • Lerman M.
      • Gaebler J.A.
      • Hoy S.
      • Izhakoff J.
      • Gullett L.
      • Niecko T.
      • et al.
      Health and economic benefits of advanced pneumatic compression devices in patients with phlebolymphedema.
      Conservative care—complex decongestive therapy (CDT)—consisted of manual lymphatic drainage (MLD), physical therapy, multilayer LED bandaging, compression garments, and skin care or each individually. Intermittent pneumatic compression devices were divided into simple multichamber nonprogrammable pneumatic devices and advanced programmable compression devices. Surgery was classified as reductive or reconstructive (lymphatic bypass).
      • Hadamitzky C.
      • Pabst R.
      • Gordon K.
      • Vogt P.M.
      Surgical procedures in lymphedema management.

      Results

       Identification of LED guidelines

      The Fig (Preferred Reporting Items for Systematic Reviews and Meta-Analyses diagram) demonstrates the results of the search for LED guidelines. The National Guideline Clearinghouse yielded 49 potential sources (website now closed for new entities); British Medical Journal, 7; NICE, 181; and use of LED guidelines as a reference, an additional 8, which resulted in a total of 245 publications. A horizon scan (abstract review) was then performed, which identified 13 potential documents as LED CPGs. A detailed review of these documents demonstrated that six claimed to be “clinical care guidelines,”
      • Hoffmann-Eßer W.
      • Siering U.
      • Neugebauer E.A.
      • Brockhaus A.C.
      • McGauran N.
      • Eikermann M.
      Guideline appraisal with AGREE II: online survey of the potential influence of AGREE II items on overall assessment of guideline quality and recommendation for use.
      but on analysis, two were limited in scope
      • Brouwers M.C.
      • Kerkvliet K.
      • Spithoff K.
      The AGREE Reporting Checklist: a tool to improve reporting of clinical practice guidelines.
      and dealt with rehabilitation
      • Harris S.R.
      • Schmitz K.H.
      • Campbell K.L.
      • McNeely M.L.
      Clinical practice guidelines for breast cancer rehabilitation: syntheses of guideline recommendations and qualitative appraisals.
      or compression only
      • Kligman L.
      • Wong K.L.
      • Johnston M.
      • Leitsch N.
      The treatment of lymphedema related to breast cancer. Evidence summary report #13-1.
      ; one was a position statement
      Position statement of the National Lymphedema Network
      The diagnosis and treatment of lymphedema.
      and one a systematic review
      • Oremus M.
      • Walker K.
      • Dayes I.
      • Raina P.
      Diagnosis and treatment of secondary lymphedema.
      ; and two documents were consensus statements, not guidelines—the first published by the International Union of Phlebology in 2013

      Lee BB, Andrade M, Antignani PL, Boccardo F, Campisi C, Damstra R, et al. Diagnosis and treatment of primary lymphedema. Consensus document of the International Union of Phlebology (IUP)-2013. Int Angiol 32, 2013, 541–574

      and the second authored by the International Society of Lymphology,
      International Society of Lymphology Executive Committee
      The diagnosis and treatment of peripheral lymphedema.
      published in 2016. Neither of these qualified as true CPGs because of the methodology employed and the National Guideline Clearinghouse criteria previously described. In addition, the International Union of Phlebology consensus statement focused solely on primary LED. As a result, six clinical care guidelines were available for analysis. Two of these six guidelines, however, were eliminated because of their limited scope; one focused on assessing functional disability with a chronic care model,
      • Damstra R.J.
      • Halk A.B.
      Dutch Working Group on Lymphedema. The Dutch lymphedema guidelines based on the International Classification of Functioning, Disability, and Health and the chronic care model.
      and the other was oriented to breast cancer rehabilitation alone.
      • Levenhagen K.
      • Davies C.C.
      • Gilchrist L.
      Diagnosis of upper-quadrant lymphedema secondary to cancer: clinical practice guideline from the Oncology Section of APTA.
      A final document was the position statement of the National Lymphedema Network on the diagnosis and treatment of LED.

      The diagnosis and treatment of lymphedema: position statement of the National Lymphedema Network. Available at: Mylymph.com. Accessed April 10, 2018.

      This document provided no methodology on how the recommendations were formulated.
      In the end, four documents were available for review as LED CPGs: Lymphedema Framework Best Practice for the Management of Lymphedema, published in 2006 (LED F)
      Lymphoedema Framework
      Best practice for the management of lymphoedema. International consensus.
      ; Japanese Lymphedema Study Group—A Practice Guideline for the Management of Lymphedema, published in 2007 (J LED)
      The Japan Lymphoedema Study Group
      A practice guideline for the management of lymphedema.
      ; Clinical Resource Efficiency Support Team (CREST) Guidelines for the Diagnosis, Assessment and Management of Lymphedema, published in 2008 by the Northern Ireland Healthcare Services
      Clinical Resource Efficiency Support Team
      Guidelines for the diagnosis, assessment and management of lymphoedema.
      ; and guidelines of the AVF, published in 2017.

       General characteristics

      Table I demonstrates specific characteristics of each of the four CPGs. Three of the four were sponsored by medical societies. Two of the four were published more than a decade ago and cited references no later than 2007. One CPG (J LED), although published in 2011, had no references later than 2007. The AVF CPG published in 2017 did have contemporary references. One CPG was notably short, 11 pages (J LED), vs the other three CPGs, which were longer and amounted to 47 to 116 pages. The recommended process for development of CPGs is usually to pose several “key questions” that the recommendations should address, but only two of the four CPGs followed that process and in a limited way. Specifically, two CPGs failed to follow the PICO (patient/problem, intervention, comparison, and outcome) framework.
      • Schardt C.
      • Adams M.B.
      • Owens T.
      • Keitz S.
      • Fontelo P.
      Utilization of the PICO framework to improve searching PubMed for clinical questions.
      Most important, as cited in the methodology, formal systematic reviews or meta-analyses to establish an evidentiary base were performed in only two of the four CPGs (CREST and J LED).
      Table ICharacteristics
      GuidelineYear publishedPages (total)SponsorReference yearsStrength of recommendation gradeQuality of evidenceKey questionsSpecific systematic review
      Lymphedema Framework (LED F)200654Multisociety1981-2005A-C, UK National Health Service Health Technology AssessmentNoNoNo consensus process
      Clinical Resource Efficiency Support Team (CREST)2008116Government1982-2007None with recommendations

      Evidence tables grading literature
      8 levelsYes; 61Yes
      Japan Lymphedema Study Group (J LED)201111Society1980-2007NoA-EYes; 11Yes
      American Venous Forum guidelines (AVF)201747SocietyContemporaryGrade 1-2Grade A-CNoNo

       Strength of recommendation and quality of evidence

      One CPG (J LED) provided a grade only for the strength of recommendation, whereas another (CREST) graded only the literature or evidence supporting the recommendations.
      • Reed M.W.
      Scottish Intercollegiate Guidelines Network (SIGN) 84—national clinical guideline for the management of breast cancer in women.
      The LED F CPG classified the strength of recommendations into A, clear research evidence; B, limited supporting research evidence; and C, experienced common-sense judgment. There was no additional assessment of the quality of evidence supporting a recommendation. This guidance document was derived from a national consensus from the United Kingdom on standards of practice for people who were at risk of or who have LED and used the National Health Service Health Technology Assessment model for guideline development.
      • Hanney S.
      • Buxton M.
      • Green C.
      • Coulson D.
      • Raftery J.
      An assessment of the impact of the NHS Health Technology Assessment Programme.
      No key clinical questions were posed, and no apparent specific systematic analysis was performed.
      • Harbour R.
      • Miller J.
      A new system for grading recommendations in evidence based guidelines.
      The CREST CPG was developed with tools employed in the Scottish Intercollegiate Guidelines Network
      • Reed M.W.
      Scottish Intercollegiate Guidelines Network (SIGN) 84—national clinical guideline for the management of breast cancer in women.
      and NICE documents.
      • Gafni A.
      • Birch S.
      NICE methodological guidelines and decision making in the National Health Service in England and Wales.
      The 61 key questions to be addressed were developed by consensus. A specific literature search guided by the questions was conducted. Eight levels of evidence were applied to the relevant articles or evidence, but no level of evidence or strength was applied to the actual recommendations.
      The J LED identified 11 areas to which 11 key questions were applied. A literature search used PubMed, and papers were appraised on a scale of 7 (quality of evidence). Recommendations, however, were graded on a five-level scale, A (highest) to E (lowest).
      The Japan Lymphoedema Study Group
      A practice guideline for the management of lymphedema.
      Finally, the AVF CPG employed the standard Grading of Recommendations Assessment, Development, and Evaluation method: recommendation strength of I (strong) or II (weak) and A to C for the quality of evidence. In the five chapters on LED, 21 recommendations were submitted.

       LED assessment

      Assessment embodies several features: diagnosis of the condition, clinical severity, and determination of the response to treatment (Table II). The LED F CPG recommended staging of LED by the International Society of Lymphology stage method.
      International Society of Lymphology Executive Committee
      The diagnosis and treatment of peripheral lymphedema.
      Several techniques were forwarded for objective assessment of swelling in the extremity: limb volume measurement, circumferential measurements, perometry, and bioimpedance. This CPG recommended duplex ultrasound to assess both tissue thickness and tissue fibrosis. The imaging modalities, CT and MRI, were suggested as a method of ruling out neoplasm as the cause of secondary LED by the LED F and CREST CPGs. Lymphoscintigraphy was favored as the principal method for diagnosing patients when the cause of swelling was unclear. The CREST CPG recommended that clinical history and physical examination with characteristic findings should establish the diagnosis in most cases. The CREST CPG suggested limb volume measurements for determining progress and response to treatment, which was similar to the modalities in the LED F. CREST recommended multiple imaging studies (MRI, CT scan, and duplex ultrasound) to assist in the diagnosis. Lymphoscintigraphy plays a key role in establishing the diagnosis when the diagnosis is unclear. No level of recommendation was provided for the assessment section in these two guidelines. The J LED CPG had no specific recommendations for diagnosis or assessment of response to treatment. Finally, the AVF CPG suggested lymphoscintigraphy as the principal method of diagnosing LED in patients in whom the diagnosis is unclear with a 1B recommendation.
      Table IIDiagnosis and assessment
      Guideline and length in pagesClinicalDuplex ultrasoundCT and MRILymphoscintigraphyStaging or classificationOutcome measures
      Lymphedema Framework (LED F)

      7 pages
      Yes

      Extensive
      Yes, tissue thickness and fibrosisRule out neoplasmTest of choiceInternational Society of LymphologyCircumference

      Perometry

      Bioimpedance
      Clinical Resource Efficiency Support Team (CREST)

      17 pages
      Yes

      Extensive
      Yes, tissue thickness and fibrosisRule out neoplasmTest of choice

      Establishes diagnosis
      Primary/secondaryWater displacement

      Circumference

      Perometry

      Bioimpedance
      Japan Lymphedema Study Group (J LED)This CPG did not address this area.
      American Venous Forum guidelines (AVF)

      12 pages with extensive discussion
      Not pointed toward diagnosisNoNoTest of choicePrimary/secondary

      B, CEAP-L
      No
      CEAP-L, Clinical, Etiology, Anatomy, and Pathophysiology-lymphedema; CPG, clinical practice guideline; CT, computed tomography; MRI, magnetic resonance imaging.

       Treatment of LED

      The goals of treatment for LED are reduction in limb volume and both prevention (through better skin care) and aggressive treatment of infections.
      • Son A.
      • O’Donnell Jr., T.F.
      • Izhakoff J.
      • Gaebler J.A.
      • Niecko T.
      • Iafrati M.D.
      Lymphedema-associated comorbidities and treatment gap.
      Finally, surgery should be used in selected patients (Table III).
      Table IIITreatment
      GuidelineCDTMLDMultilayer bandageCompression garmentsSkin careSurgeryExerciseIntermittent pneumatic compressionDrug therapyPsychosocial
      Lymphedema Framework (LED F)

      34 pages
      Intensive therapyCBCB, extensive discussionReduction,reconstruction, liposuction

      0.5 page
      YesSelected patientsNot indicatedYes
      Clinical Resource Efficiency Support Team (CREST)

      9 Pgs.
      YesYesYes, multilayerYesYes“Not indicated”YesNot discussedNot indicated
      Japan Lymphedema Study Group (J LED)

      7 pages
      NoYes; CYes; CYes; CNot discussedD; reduction, reconstruction, liposuction

      0.5 pages
      Yes; DDED
      American Venous Forum guidelines (AVF)

      GRADE method

      12 pages on overall treatment
      1B1B1B1ACellulitis, 1A Skin, 1CExcisional, 2C

      Reconstruction, 2C

      10 detailed pages
      1C2BNo evidence
      CDT, Complex decongestive therapy; GRADE, Grading of Recommendations Assessment, Development, and Evaluation; MLD, manual lymphatic drainage.

       Conservative care: reduction in limb volume

      In the first phase of treatment, the intensive phase, CDT, which combines MLD, multilayer bandaging, skin care, and exercise, is recommended.

      Lee BB, Andrade M, Antignani PL, Boccardo F, Campisi C, Damstra R, et al. Diagnosis and treatment of primary lymphedema. Consensus document of the International Union of Phlebology (IUP)-2013. Int Angiol 32, 2013, 541–574

      The second phase, the maintenance phase, transfers the control of the condition to the patient for at-home management; the patient is encouraged to practice self-MLD and nocturnal compression bandaging. Lifelong specialized compression garments are used, which should be renewed after 6 months.
      • Oremus M.
      • Walker K.
      • Dayes I.
      • Raina P.
      Diagnosis and treatment of secondary lymphedema.
      CDT was recommended by three CPGs, LED F, CREST, and AVF, but not by the J LED. When the individual elements of CDT were examined, the LED F CPG recommended MLD and compression sleeves, both with a C level. However, multilayer inelastic bandaging received a B grade level of recommendation. The LED F CPG employed five grade levels to score recommendations; MLD received a C grade (“insufficient evidence to develop clinical agreement; treatment recommended based on patient request and clinical results”). The authors opined that MLD is useful, but unfortunately there was no scientific evidence to support the benefit of MLD. Multilayer LED compression bandaging also received a C grade, and the J LED CPG recommended that it be used in the initial treatment of patients with severe LED. These three elements were recommended in the other three CPGs but received a C level of recommendation in the J LED CPG but no level in the CREST CPG and IB in the AVF CPG. The CREST document had an extensive table of indications and contraindications by anatomic location.
      In discussing treatment with pneumatic compression devices, the LED F CPG stated, “Although there is considerable international debate over its effectiveness in LED, intermittent pneumatic compression is widely used. It may form part of an intensive therapy or long-term management in selected patients.”
      Lymphoedema Framework
      Best practice for the management of lymphoedema. International consensus.
      Pneumatic compression treatment is not discussed in the CREST CPG, whereas in the J LED CPG, it received a low (D) recommendation on a scale of A to E. Because of the dates of the literature searches in these three guidelines, none of the more recent randomized controlled trials for pneumatic compression are cited. By contrast, the AVF CPG reviewed multiple contemporary studies including advanced pneumatic compression devices (calibrated gradient compressor with multiple cells). This guideline (6.3.4) concluded, “To reduce lymphedema, we suggest compression pumps in some patients (2B).”
      Essential to good LED care is the importance of appropriate skin care for preventing cellulitis, which is one of the major morbid complications of LED and results in costly hospitalizations.
      • Karaca-Mandic P.
      • Hirsch A.T.
      • Rockson S.G.
      • Ridner S.H.
      The cutaneous, net clinical, and health economic benefits of advanced pneumatic compression devices in patients with lymphedema.
      Finally, worsening of LED due to destruction of lymphatic vessels is common after infection. The LED F CPG devoted an extensive four pages to the discussion of skin care; in addition to the general principles of meticulous hygiene, skin emollients, close observation for breaks in the skin, and prompt treatment of infection, there were specific recommendations for dry skin, hyperkeratosis, folliculitis, and fungal infections. The evidence supporting these recommendations was graded B on a scale of A to C by this CPG. Whereas the CREST CPG summarized the essential elements of skin care treatment without a grade of recommendation, the J LED CPG failed to address this important element of care for LED. The AVF CPG recommended skin care as a part of the overall treatment plan for LED (6.3.1, 1B) and provided a 1A recommendation for both treatment (6.3.8) and prophylaxis (6.3.9) of cellulitis.

       Surgery

      Surgical treatment was divided into two general approaches: extirpative, surgical reduction by excision of tissue (debulking) or liposuction; and lymphatic reconstruction.
      • Hadamitzky C.
      • Pabst R.
      • Gordon K.
      • Vogt P.M.
      Surgical procedures in lymphedema management.
      Only two of the CPGs (LED F and AVF) discussed indications for surgery. The CREST CPG concluded, “There is no indication for surgery in the treatment of lymphedema,” and this approach is currently not available in Northern Ireland. The J LED CPG reviewed various studies and commented on the “small and limited nature of these studies, which restricts any conclusive evidence” but never provided a specific recommendation of surgery.
      The Japan Lymphoedema Study Group
      A practice guideline for the management of lymphedema.
      The AVF CPG extensively discussed (10 pages) the various surgical options and recommended that before adoption, all should require a 6-month trial of conservative treatment (1C); patients with late-stage nonpitting edema should undergo excisional or liposuction procedures in the face of the failure of conservative treatment (2C); and finally, early intervention should be performed in specialized centers for highly selected cases of secondary LED (2C).

       Ancillary measures

      Exercise, elevation, psychosocial support, and palliative care were discussed by both the LED F and the CREST CPGs, whereas the J LED CPG advised deep breathing exercises to promote improved flow through the major lymphatic ducts and peripheral lymph vessels. No assessment of the evidentiary strength was provided for these modalities. The AVF CPG suggested “risk factor modifications,” such as decreasing obesity (1C). Pharmacologic therapy with both diuretics and benzopyrones has been advocated in the past, but three of the guidelines recommend against their use.

      Discussion

      This systematic review demonstrates that the current LED guidelines are limited by lack of contemporary evidence and standard descriptions of both the strength of recommendation and the quality of evidence.
      • Harbour R.
      • Miller J.
      A new system for grading recommendations in evidence based guidelines.
      Although it is estimated that LED affects >5 million patients, its impact is further magnified by its chronicity and lack of a cure. The causes of LED were demonstrated in a study of a large administrative health care claims data set of approximately 90,000 patients. Of 27,000 patients observed for at least a year, breast cancer was the chief morbidity or “cause” of secondary LED and averaged one-third of patients with LED.
      • Son A.
      • O’Donnell Jr., T.F.
      • Izhakoff J.
      • Gaebler J.A.
      • Niecko T.
      • Iafrati M.D.
      Lymphedema-associated comorbidities and treatment gap.
      Advanced chronic venous insufficiency or phlebolymphedema, in which 90% of the patients had a venous ulcer, was the next most common cause. Although probably under-reported, phlebolymphedema was the most common lower extremity and noncancer cause of LED and represented 10.4% of the population. Finally, pelvic cancers contributed 3.3% of patients, so that in the majority of patients, LED was a sequela of cancer treatment.
      Another administrative data set study, which was specifically directed at oncologic patients, revealed that LED prevalence among cancer survivors had increased from 0.95% in 2007 to 1.24% in 2013.
      • Karaca-Mandic P.
      • Hirsch A.T.
      • Rockson S.G.
      • Ridner S.H.
      The cutaneous, net clinical, and health economic benefits of advanced pneumatic compression devices in patients with lymphedema.
      Such patients incurred heavy total costs, which in the aggregate accounted for approximately $62,190/patient per year in this cancer population. Inpatient services contributed the majority of these costs. Providing cost-effective high-quality care is essential. Shih et al
      • Shih Y.C.
      • Xu Y.
      • Cormier J.N.
      • Giordano S.
      • Ridner S.H.
      • Buchholz T.A.
      • et al.
      Incidence, treatment costs, and complications of lymphedema after breast cancer among women of working age: a 2-year follow-up study.
      have shown that patients with breast cancer-related lymphedema (BCRL) had much higher costs than those without LED, whereas BCRL patients were also twice as likely to have developed the complications of lymphangitis or cellulitis (odds ratio, 2.02; P = .009). Compounding this economic impact is that LED is a chronic disease without any current cure. Moreover, LED may not be well recognized by both physicians and patients. Stout et al
      • Stout N.L.
      • Weiss R.
      • Feldman J.L.
      • Stewart B.R.
      • Armer J.M.
      • Cormier J.N.
      • et al.
      A systematic review of care delivery models and economic analyses in lymphedema: health policy impact (2004–2011).
      called attention to the problems facing implementation of better care models for patients with LED when they stated that “in lieu of such infrastructure, coverage and reimbursement for a condition, management is relatively absent, thereby serving to create disincentives for providing adequate care.” All of these reasons point to the obvious need for an evidence-driven CPG for the management of LED.

       Identification of LED guidelines

      It is disappointing that despite 245 publications (Fig), only four actual LED CPGs could be identified. Moreover, three of these are markedly out of date, with references, which should form the evidentiary base for CPG recommendations, more than a decade old. This underlines the necessity for developing a new intersocietal CPG based on contemporary references, which should follow the Appraisal of Guidelines for Research and Evaluation II protocol for guideline development and structure. The small number of CPGs selected for LED is a result of recognized criteria that designate a treatment document a CPG.
      Treatment specific for LED has been shown to vary with the cause of this morbidity; lack of treatment may amount to 25% of patients for some specific causes of LED.
      • Son A.
      • O’Donnell Jr., T.F.
      • Izhakoff J.
      • Gaebler J.A.
      • Niecko T.
      • Iafrati M.D.
      Lymphedema-associated comorbidities and treatment gap.
      This “treatment gap” is probably related to both physicians' and patients' lack of recognition of the importance of LED as the cause of extremity swelling. Patients with BCRL are more likely to undergo treatment directed to LED than are patients with phlebolymphedema, the most common cause of non-cancer-related LED. Again, this gap emphasizes the need for better recognition, diagnosis, and treatment of patients with non-cancer-related LED. CPGs should help reduce this treatment gap for patients with LED, but this systematic review of CPGs for LED demonstrated that three of the four CPGs were outdated as the latest references in those CPGs were more than a decade old (2007).

       Elements of care

      Treatment of LED is usually divided into the early intensive phase and the later maintenance phase. During the intensive phase, patients typically undergo CDT, consisting of MLD, multilayer bandaging, and compression garments.
      • Mayrovitz H.N.
      The standard of care for lymphedema: current concepts and physiological considerations.
      Skin care is also recommended to prevent infections, which is the most common cause of morbidity with LED.
      • Karaca-Mandic P.
      • Hirsch A.T.
      • Rockson S.G.
      • Ridner S.H.
      The cutaneous, net clinical, and health economic benefits of advanced pneumatic compression devices in patients with lymphedema.
      The LED F and CREST CPGs devoted extensive discussions to the individual components of CDT with excellent illustrations. By contrast, the material presented in the J LED CPG was much more limited. The evidence level recommending CDT was moderate for these three CPGs, which was related to the paucity of substantive randomized controlled trials addressing these treatment modalities (Table III). Similarly, the more recent AVF CPG had stronger recommendations for CDT (level I), but the quality of the evidence was rated lower (B). Unfortunately, there is little high-level contemporary evidence for MLD, although a 2015 Cochrane database review showed that this modality is certainly safe while suggesting that MLD may provide additional help to compression bandaging for volume reduction in patients with BCRL.
      • Ezzo J.
      • Manheimer E.
      • McNeely M.L.
      • Howell D.M.
      • Weiss R.
      • Johansson K.I.
      • et al.
      Manual lymphatic drainage for lymphedema following breast cancer treatment.
      In contrast to the evidence for MLD, there is a relatively strong evidentiary basis supporting short-stretch bandages. In one study, multilayered short-stretch bandaging was twice as effective in reducing arm volume compared with standard compression garment use.
      • Moffatt C.J.
      • Franks P.J.
      • Hardy D.
      • Lewis M.
      • Parker V.
      • Feldman J.L.
      A preliminary randomized controlled study to determine the application frequency of a new lymphoedema bandaging system.
      A recommendation for pneumatic compression treatment was hampered by the lack of supporting references in three of the older CPGs. The LED F CPG suggested that intermittent pneumatic compression might play an important role in the long-term management of patients in the maintenance phase. None of the CPGs cited the only randomized controlled trial to compare advanced pneumatic compression devices with simple pneumatic devices. In this study, advanced pneumatic compression devices (EO652) were superior to a simple device (EO651) in reducing limb volume in patients with BCRL.
      • Fife C.E.
      • Davey S.
      • Maus E.A.
      • Guilliod R.
      • Mayrovitz H.N.
      A randomized controlled trial comparing two types of pneumatic compression for breast cancer-related lymphedema treatment in the home.
      Cellulitis is one of the more feared complications of LED because of the potential not only for destroying existing lymphatic vessels but also for a fatal outcome. In addition, several studies have shown the major economic impact of this complication.
      • Karaca-Mandic P.
      • Hirsch A.T.
      • Rockson S.G.
      • Ridner S.H.
      The cutaneous, net clinical, and health economic benefits of advanced pneumatic compression devices in patients with lymphedema.
      ,
      • Shih Y.C.
      • Xu Y.
      • Cormier J.N.
      • Giordano S.
      • Ridner S.H.
      • Buchholz T.A.
      • et al.
      Incidence, treatment costs, and complications of lymphedema after breast cancer among women of working age: a 2-year follow-up study.
      Therefore, prevention of this complication is essential. The four CPGs varied in the amount of discussion addressing this topic. The most detailed discussion was found in the LED F CPG, in which general principles were supplemented by advice on specific problems with the skin. The evidentiary strength was graded B in this CPG, whereas the CREST CPG had a short discussion of the elements of skin care but did not provide a graded recommendation. The AVF CPG presented both treatment for cellulitis and methods for preventing this complication, both with the highest level of recommendation and quality of evidence, 1A.
      Surgery in the management of LED falls into two categories: extirpative, reduction, and debulking surgery, whereby edematous tissue is removed by either an open technique or liposuction; and lymphatic reconstruction, whereby lymph vessel to vein anastomoses or lymph node to vein anastomoses are performed.
      • Kung T.A.
      • Champaneria M.C.
      • Maki J.H.
      • Neligan P.C.
      Current concepts in the surgical management of lymphedema.
      The indications for surgical procedures, which are limited to a highly selected group of patients, are well summarized in the LED F and AVF CPGs: severe deformity or marked disability due to swelling, removal of redundant tissue after successful conservative therapy, lack of response to compression therapy, recurrent cellulitis, intractable pain, lymphangiosarcoma (all generally reduction surgery), and proximal lymphatic obstruction with patent distal lymphatics (lymphatic reconstruction). There was an extensive discussion of surgery for LED in the AVF CPG. One of the prime contemporary indications for reductive surgery is large-volume LED of an advanced nature with subcutaneous lipid deposits and fibrosis. In this condition, conservative measures with compression of any type may have limited impact on limb volume. The CREST CPG expressed that there was no indication for surgery, whereas the J LED CPG provided little information on the indications or about surgical approaches.

      Conclusions

      Whereas our vascular societies have developed important guidelines for arterial and venous diseases, this systematic review of CPGs for LED shows a limited number of guidelines, the majority of which unfortunately rely on outdated data and are of low overall study quality. Therefore, it is imperative for our vascular societies to develop contemporary high-quality evidence-based CPGs for LED.

      Author contributions

      Conception and design: TO
      Analysis and interpretation: TO, GA, MI
      Data collection: TO, GA
      Writing the article: TO
      Critical revision of the article: TO, GA, MI
      Final approval of the article: TO, GA, MI
      Statistical analysis: Not applicable
      Obtained funding: Not applicable
      Overall responsibility: TO

      References

        • O’Donnell T.F.
        • Balk E.M.
        The need for an Intersociety Consensus Guideline for venous ulcer.
        J Vasc Surg. 2011; 54: 83S-90S
        • Institute of Medicine
        Guidelines for clinical practice: from development to use.
        National Academies Press, Washington, DC1992
        • Gloviczki P.
        • Comerota A.J.
        • Dalsing M.C.
        • Eklof B.G.
        • Gillespie D.L.
        • Gloviczki M.L.
        • et al.
        The care of patients with varicose veins and associated chronic venous diseases: clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum.
        J Vasc Surg. 2011; 53: 2S-48S
        • O’Donnell T.F.
        • Passman M.
        Clinical practice guidelines of the Society for Vascular Surgery (SVS) and the American Venous Forum (AVF): management of venous leg ulcers.
        J Vasc Surg. 2014; 60: 1S-90S
        • Adamczyk L.A.
        • Gordon K.
        • Kholová I.
        • Meijer-Jorna L.B.
        • Telinius N.
        • Gallagher P.J.
        • et al.
        Lymph vessels: the forgotten second circulation in health and disease.
        Virchows Arch. 2016; 469: 3-17
        • AGREE Collaboration
        The development and validation of an international appraisal instrument for assessing the quality of clinical practice guidelines: the AGREE project.
        Qual Saf Health Care. 2003; 12: 18-23
        • Brouwers M.
        • Kho M.E.
        • Browman G.P.
        • Burgers J.S.
        • Cluzeau F.
        • Feder G.
        • et al.
        Development of the AGREE II, part 2: assessment of validity of items and tools to support application.
        CMAJ. 2010; 182: E472-E478
        • International Society of Lymphology Executive Committee
        The diagnosis and treatment of peripheral lymphedema.
        Lymphology. 1995; 28: 113-117
        • Lerman M.
        • Gaebler J.A.
        • Hoy S.
        • Izhakoff J.
        • Gullett L.
        • Niecko T.
        • et al.
        Health and economic benefits of advanced pneumatic compression devices in patients with phlebolymphedema.
        J Vasc Surg. 2019; 69: 571-580
        • Hadamitzky C.
        • Pabst R.
        • Gordon K.
        • Vogt P.M.
        Surgical procedures in lymphedema management.
        J Vasc Surg Venous Lymphat Disord. 2014; 2: 461-468
        • Hoffmann-Eßer W.
        • Siering U.
        • Neugebauer E.A.
        • Brockhaus A.C.
        • McGauran N.
        • Eikermann M.
        Guideline appraisal with AGREE II: online survey of the potential influence of AGREE II items on overall assessment of guideline quality and recommendation for use.
        BMC Health Serv Res. 2018; 18: 143
        • Brouwers M.C.
        • Kerkvliet K.
        • Spithoff K.
        The AGREE Reporting Checklist: a tool to improve reporting of clinical practice guidelines.
        BMJ. 2016; 352: i1152
        • Harris S.R.
        • Schmitz K.H.
        • Campbell K.L.
        • McNeely M.L.
        Clinical practice guidelines for breast cancer rehabilitation: syntheses of guideline recommendations and qualitative appraisals.
        Cancer. 2012; 118: 2312-2324
        • Kligman L.
        • Wong K.L.
        • Johnston M.
        • Leitsch N.
        The treatment of lymphedema related to breast cancer. Evidence summary report #13-1.
        (Available at:) (Accessed April 23, 2018)
        • Position statement of the National Lymphedema Network
        The diagnosis and treatment of lymphedema.
        (Available at:) (Accessed July 20, 2018)
        • Oremus M.
        • Walker K.
        • Dayes I.
        • Raina P.
        Diagnosis and treatment of secondary lymphedema.
        Agency for Healthcare Research and Quality (US), Rockville, Md2010
      1. Lee BB, Andrade M, Antignani PL, Boccardo F, Campisi C, Damstra R, et al. Diagnosis and treatment of primary lymphedema. Consensus document of the International Union of Phlebology (IUP)-2013. Int Angiol 32, 2013, 541–574

        • Damstra R.J.
        • Halk A.B.
        Dutch Working Group on Lymphedema. The Dutch lymphedema guidelines based on the International Classification of Functioning, Disability, and Health and the chronic care model.
        J Vasc Surg Venous Lymphat Disord. 2017; 5: 756-765
        • Levenhagen K.
        • Davies C.C.
        • Gilchrist L.
        Diagnosis of upper-quadrant lymphedema secondary to cancer: clinical practice guideline from the Oncology Section of APTA.
        Rehabil Oncol. 2017; 35: E1-E18
      2. The diagnosis and treatment of lymphedema: position statement of the National Lymphedema Network. Available at: Mylymph.com. Accessed April 10, 2018.

        • Lymphoedema Framework
        Best practice for the management of lymphoedema. International consensus.
        MEP Ltd, London2006
        • The Japan Lymphoedema Study Group
        A practice guideline for the management of lymphedema.
        J Lymphoedema. 2011; 6: 60-71
        • Clinical Resource Efficiency Support Team
        Guidelines for the diagnosis, assessment and management of lymphoedema.
        (Available at:) (Accessed April 14, 2018)
      3. Gloviczki P. Handbook of venous disorders: guidelines of the American Venous Forum. 4th ed. CRC Press, Boca Raton, Fla2017
        • Schardt C.
        • Adams M.B.
        • Owens T.
        • Keitz S.
        • Fontelo P.
        Utilization of the PICO framework to improve searching PubMed for clinical questions.
        BMC Med Inform Decis Mak. 2007; 7: 1-16
        • Reed M.W.
        Scottish Intercollegiate Guidelines Network (SIGN) 84—national clinical guideline for the management of breast cancer in women.
        Clin Oncol. 2007; 19: 588-590
        • Hanney S.
        • Buxton M.
        • Green C.
        • Coulson D.
        • Raftery J.
        An assessment of the impact of the NHS Health Technology Assessment Programme.
        Health Technol Assess. 2007; 11: 1-180
        • Harbour R.
        • Miller J.
        A new system for grading recommendations in evidence based guidelines.
        BMJ. 2001; 323: 334-336
        • Gafni A.
        • Birch S.
        NICE methodological guidelines and decision making in the National Health Service in England and Wales.
        Pharmacoeconomics. 2003; 21: 149-157
        • Son A.
        • O’Donnell Jr., T.F.
        • Izhakoff J.
        • Gaebler J.A.
        • Niecko T.
        • Iafrati M.D.
        Lymphedema-associated comorbidities and treatment gap.
        J Vasc Surg Venous Lymphat Disord. 2019; 7: 724-730
        • Karaca-Mandic P.
        • Hirsch A.T.
        • Rockson S.G.
        • Ridner S.H.
        The cutaneous, net clinical, and health economic benefits of advanced pneumatic compression devices in patients with lymphedema.
        JAMA Dermatol. 2015; 151: 1187-1193
        • Shih Y.C.
        • Xu Y.
        • Cormier J.N.
        • Giordano S.
        • Ridner S.H.
        • Buchholz T.A.
        • et al.
        Incidence, treatment costs, and complications of lymphedema after breast cancer among women of working age: a 2-year follow-up study.
        J Clin Oncol. 2009; 27: 2007-2014
        • Stout N.L.
        • Weiss R.
        • Feldman J.L.
        • Stewart B.R.
        • Armer J.M.
        • Cormier J.N.
        • et al.
        A systematic review of care delivery models and economic analyses in lymphedema: health policy impact (2004–2011).
        Lymphology. 2013; 46: 27-41
        • Mayrovitz H.N.
        The standard of care for lymphedema: current concepts and physiological considerations.
        Lymphat Res Biol. 2009; 7: 101-108
        • Ezzo J.
        • Manheimer E.
        • McNeely M.L.
        • Howell D.M.
        • Weiss R.
        • Johansson K.I.
        • et al.
        Manual lymphatic drainage for lymphedema following breast cancer treatment.
        Cochrane Database Syst Rev. 2015; 5: CD003475
        • Moffatt C.J.
        • Franks P.J.
        • Hardy D.
        • Lewis M.
        • Parker V.
        • Feldman J.L.
        A preliminary randomized controlled study to determine the application frequency of a new lymphoedema bandaging system.
        Br J Dermatol. 2012; 166: 624-632
        • Fife C.E.
        • Davey S.
        • Maus E.A.
        • Guilliod R.
        • Mayrovitz H.N.
        A randomized controlled trial comparing two types of pneumatic compression for breast cancer-related lymphedema treatment in the home.
        Support Care Cancer. 2012; 20: 3279-3286
        • Kung T.A.
        • Champaneria M.C.
        • Maki J.H.
        • Neligan P.C.
        Current concepts in the surgical management of lymphedema.
        Plast Reconstr Surg. 2017; 139: 1003e-1013e