PM R 7 (2015) 296-310

www.pmrjournal.org

Analytical Review: Systematic Search

Exploring the Usefulness of Botanicals as an Adjunctive Treatment for Lymphedema: A Systematic Search and Review Ellen G. Poage, MSN, MPH, NP-C, CLT-LANA, Julia R. Rodrick, OTR, CLT-LANA/WCC, Ausanee Wanchai, PhD, RN, representing American Lymphedema Framework Project Staff, Bob R. Stewart, EdD, Janice N. Cormier, MD, MPH, FACS, Jane M. Armer, PhD, RN, FAAN

Abstract Objectives: To provide a critical analysis of the current published research regarding the use, risks, and benefits of botanicals in the treatment of lymphedema and to provide health professionals with current knowledge of safe, appropriate use of botanicals for treatment of lymphedema. Type: This systematic search and review addresses the use of botanicals in the treatment of lymphedema in order to develop a best evidence synthesis of the research. Literature Survey: Articles were identified from 11 major medical indices published from 2004-2012 using search terms for lymphedema and management. Eighty-five articles met the inclusion criteria of evidence-based lymphedema therapies for the category “complementary and alternative methods for lymphedema therapy.” Methodology: Two clinical lymphedema experts reviewed the studies according to level of evidence guidelines established by the Oncology Nursing Society, Putting Evidence into Practice, and subdivided the methods into subcategories that included Botanical, Pharmaceutical, Physical Agent Modalities, and Modalities of Contemporary Value. The pharmaceutical articles were excluded (5) because they fell outside the inclusion criteria. Twenty-two articles were used in a separate review of physical agent modalities and modalities of contemporary value for lymphedema. Botanicals generated substantial research (11) and warranted its own independent review. Synthesis: The levels of evidence are weak, because research conclusions were limited by size, dose, and study design. A limited number of randomized controlled trials have been performed, and reliability is not always evident, particularly in the context of large systematic reviews where evidence was bundled. Conclusions: Evidence supporting the use of botanicals for the treatment of lymphedema is insufficient. Some evidence suggests benefits for the treatment of chronic venous insufficiency. Development of specific and sensitive measurement methods may change how botanicals are studied and establish a body of evidence for their use.

Introduction Lymphedema is a progressive, chronic disease caused by an impairment of the transport capacity of the lymphatic system, a mechanical failure that results in the accumulation and congestion of protein-rich interstitial fluid within the affected body region [1]. Rockson and Rivera [2] estimate the population prevalence of lymphedema to be 1.3 to 1.4 per 1000. Lymphedema leads to significant secondary health issues and loss of physical function, impeding daily living skills and

resulting in a dramatic reduction in the quality of life [1,3,4]. The standard of care for lymphedema is complete decongestive therapy (CDT) [5-8], which consists of manual lymph drainage (MLD) to mobilize movement of stagnant lymphatic fluid from the limb back to venous circulation, along with use of short-stretch bandages and various other compression garments to reduce refill after MLD [1]. The goals of therapy are to reduce swelling, restore tissue homeostasis, prevent infection, and improve function and quality of life. Successful achievement of these goals is dependent upon specially

1934-1482/$ - see front matter ª 2015 by the American Academy of Physical Medicine and Rehabilitation http://dx.doi.org/10.1016/j.pmrj.2014.09.019

E.G. Poage et al. / PM R 7 (2015) 296-310

trained and experienced therapists and active patient participation [6]. The burdens of both the disease and the therapy are worse when the disease has progressed. Lymphedema and its standard care, CDT, present a lifetime of stressful and physical emotional challenges [9]. CDT is time consuming and costly and often produces inconsistent limb volume reduction [10]. Patients resent and are frustrated by the daily burden of selfcare, which includes therapy, appointments, exercise, bandaging, washing and rolling of bandages, and wearing compression garments [9]. Ever since CDT became the standard of care for lymphedema [5,7,8], patients have sought alternatives [11]. Complementary and alternative medicine (CAM) practices are not considered medicine because insufficient evidence exists to support their use as safe or effective [12]. Nevertheless, in 2007, it was reported that 4 out of 10 adults had used a form of CAM in the past 12 months [12]. People who use CAM are seeking ways to improve their health or to deal with symptoms of chronic disease, such as lymphedema [10,12]. In the United States about half of the population and about 70% of older adults (71 years or older) use dietary supplements [13]. In one study of the use of CAM therapies for patients with cancer, 55% took an herbal or vitamin supplement [14]. Of particular interest, Barton et al [15], authors of a literature review on alternative approaches for lymphedema management, reported the enthusiastic response of participants with breast cancererelated lymphedema to a clinical trial for coumarin, a botanical, as an alternative to CDT. The use of supplements for the treatment of lymphedema would certainly ease the burden of standard therapy. Is There a Place for Botanicals in the Treatment of Lymphedema? The use of plants and their derivatives as healing treatments can be traced to as early as 1500 BC [16]. A recent study [17] reported that of the 252 drugs considered by the World Health Organization as essential, 11% are derived from flowering plants. Botanicals, therefore, are worthy of exploration for management of many chronic conditions, including lymphedema. Lymphedema is caused by an alteration in the transport capacity of the lymphatic system. It is primarily a structural problem that develops into an inflammatory problem. The etiology of lymphedema is considered within the context of 2 broad categories, primary and secondary. Primary lymphedema is the result of dysplasia of the lymph system that is often congenital or can develop later in life with or without various triggering events such as insect bites or trauma. Secondary lymphedema occurs as the result of disruption of the lymph system, most commonly after lymph node dissection or radiation therapy as a means of treating cancer or another inciting event such as

297

trauma, infection, or orthopedic procedures. Likewise, secondary lymphedema may develop as a result of chronic venous insufficiency (CVI) in which impairment of venous valves allows backflow into the interstitial tissues. Initially a healthy lymph system increases transport of this additional fluid, but eventually chronic lymphedema develops. CVI leads to the creation of edema, with valvular incompetence resulting in venous hypertension, endothelial vascular compromise, and inflammation [18,19]. Impaired cutaneous microcirculation triggers inflammatory cytokines, fibroblast growth factors, and proteolytic enzymes, resulting in lipodermatosclerosis and the development of ulcers [18,20]. Capillaries become dilated and their walls become thin and leak, adding fluid and proteins to the interstitial space. Because of their osmotic attraction for water molecules, proteins create an increased lymphatic load. Interstitial congestion burdens the lymph system, altering its transport capacity and triggering secondary lymphedema. A compromised lymph system cannot perform its basic function, which is returning proteins to the circulatory system, and a vicious cycle develops. A 2-fold system of management is needed: (1) a device or agent to increase venous return to decrease capillary permeability and macromolecule leakage, and (2) an agent that is capable of either increasing protein phagocytosis or protein lyses to decrease the lymphatic burden [18-20]. Compression, a standard of care for persons with CVI, benefits both the microcirculation and valvular incompetence [6,20]. Botanicals may benefit the microcirculation by inhibiting inflammatory activity, decreasing blood capillary permeability, and increasing venous tone [18,20]. Because lymph drainage is intimately involved with venous drainage, botanicals may promote both venous and lymph return [19,20]. In some types of lymphedema, no vascular compromise occurs; however, with disease progression (ie, in advanced stages of lymphedema) and in the presence of underlying clinical factors, such as diabetes, smoking, venous collateral development, and medications, a role may exist for botanical treatments [19]. There are 3 categories of venous-modifying botanicals: benzopyrones, saponins, and other plant extracts. Herbal preparations are derived from plant extracts, produced from synthetics and extracts, or produced completely from synthetics [21]. Benzopyrones There are 2 classes of benzopyrones, the alpha and the gamma benzopyrones. Coumarin is the best known of the alpha benzopyrones. Theoretically, it acts either by binding to plasma proteins, which activate macrophage phagocytosis of the coumarin-bound protein carrier, or by stimulating macrophage proteolysis; the

298

Botanicals as Adjunctive Treatment for Lymphedema

proteins are broken into smaller bits and removed through the venous system [19]. This effect on colloid proteins is what makes coumarin hypothetically beneficial for the treatment of lymphedema. Coumarin also has a vasoconstrictive effect [19]. Two groups of gamma benzopyrones are known as flavonoids and the flavones. The flavones act to decrease the number of macromolecules that leak from the venous circulation, so they are considered capillary stabilizers [20]. Flavonoids are plant pigments and, unlike alkaloids, are edible in large quantities. Farinola and Piller [19] suggest that flavonoids may enhance lymph motoricity. Because of their popularity, several gamma benzopyrones will be discussed. Micronized purified flavonoid fraction is derived from plants and citrus rind. The micronized product assists absorption. It affects venous tone, inhibits inflammatory reactions, and reduces leukocyte activation [20]. Daflon, from France, is a combination-micronized product of Diosmin, 150 mg or 500 mg with hesperidin, 50 mg, and is well researched. Both Diosmin and hesperidin improve venous tone, reduce swelling, and have an anti-inflammatory effect that helps restore capillary permeability [22,23]. Rutoside agents are from Sophora japonica. They reduce edema formation by acting on the endothelial cells of veins to reduce microvascular permeability [20]. BN165 or Ginkor Fort is a combination of flavonoids (Ginkgo biloba, troxerutin, and heptaminol) that appears to stimulate macrophage activity and stimulate the lymph system [23].

properties and may also help heal the capillaries to prevent macromolecule seepage [25,26].

Saponins

A systematic review of the literature for articles related to CAM and lymphedema was performed in 3 phases (Figure 1). A research librarian assisted with initial searches using terms the International Lymphoedema Framework utilized in 2006 for the formation of the Best Practice for the Management of Lymphoedema [5], along with additional terms, for all literature related to lymphedema (2004-2009). The databases searched included PubMed, CINAHL, the Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, PapersFirst, ProceedingsFirst, WorldCat, PEDro, National Guidelines Clearing House, ACP Journal Club, and DARE, as well as articles from the archives of the authors through 2011. A total of 5927 references were sent to American Lymphedema Framework Project (ALFP) research associates, who reviewed abstracts and titles to apply broad inclusion and exclusion criteria of lymphedema/nonlymphedema, subsequently excluding 4624 articles. The ALFP authors (B.R.S., J.N.C., and J.M.A.) screened the remaining 1303 articles and further excluded 644 articles that did not meet inclusion criteria. Full articles were requested for the remaining 659 titles for comprehensive review. Studies were grouped by topic, including “complementary and alternative

Saponins are plant compounds that protect plants from insect and fungal predators. One well-known saponin is licorice. In general, they produce an antiinflammatory effect. Horse chestnut seed extract (HCSE) and butcher’s broom are commonly used for venous disease. HCSE is extracted from the seeds of the Aesculus hippocastanum L [24]. Horse chestnut contains the saponin aescin (escin) and the toxic glycoside aesculin (esculin). Aesculin is a hydroxycoumarin (as is warfarin) and has an antithrombin effect; it may cause bleeding or bruising. HCSE has had its toxic constituent aesculin removed, making it more tolerable [24]. Aescin has vasoconstrictive effects and decreases capillary permeability induced by histamine or serotonin [23]. Its mode of action is to inhibit proteolytic enzymes that activate leukocyte activity. It also increases venous tone through its diuretic effect [18,21,23]. Butcher’s broom or Ruscus aculeatus contains the active ingredients ruscinogen and neoruscogenin, both of which are saponins. Through its activation of a-adrenergic receptors, it produces a vasoconstrictive effect. It has diuretic, anti-inflammatory, and venotonic

Other Plant Extracts Oligomeric proanthocyanidins are found in various barks, seeds, and berries. French Maritime pine bark extract, best known as Pycnogenol, is a standardized extract from the bark. It controls the capillary permeability of the altered capillary walls, prevents edema, has anti-inflammatory and antioxidant activity, and affects platelet aggregation. These actions contribute overall to improving venous tone, microangiopathy, and symptoms of CVI [22]. Centella asiatica (gotu kola) is an herb often added to butcher’s broom, HCSE, or both, for added benefit. It seems to enhance reabsorption of interstitial fluid, supporting the subcutaneous tissues and promoting wound healing [23]. Given the increased use of botanicals in the United States, especially among elderly persons, we performed a systematic search and review of the peer-reviewed literature to extract the weight of the evidence and provide best practice recommendations for botanical use and lymphedema. Our review is divided into 3 sections: (1) a description of the methods of research selection; (2) a summary of the research by class of botanical from 2004 to 2011 and weight of the evidence; and (3) recommendations for future research. Methods

E.G. Poage et al. / PM R 7 (2015) 296-310

299

Figure 1. Literature review process. CAM ¼ complementary and alternative medicine.

methods.” Data extraction tables were created for each article reviewed with subdivisions for study design, objectives, sample size, interventions, constructs and measures, and strength and weaknesses. Some 574 articles were excluded because of duplication, inability to obtain English abstract translation, inadequate sample size, insufficient level of evidence because of the study design, and failure to meet inclusion criteria as CAM. In the first phase of screening, 85 articles met the inclusion criteria for CAM. For the second phase, the 85 CAM articles and tables were reviewed by the first and second authors, both experienced lymphedema therapists. The articles were categorized accordingly: botanical, pharmaceutical, physical agent modalities, and modalities of contemporary value. In the third phase, the level of evidence for each study was assessed using the research grading system from the Putting Evidence into Practice level of evidence guidelines (Table 1) [27,28], a system judged to be both reliable and accessible [29]. Each author rated all of the articles, and the final rating was agreed upon using a consensus process based on this system. After this rating was performed, 47 articles were excluded because they fell outside the systematic search and review (SSR) inclusion criteria by definition of these 4 categories, because of the design, or because of the lack of an available English translation for the full manuscript, leaving 38 articles. Of these articles, 22 were categorized as physical agent modalities or modalities of contemporary value and were summarized separately [30]. Upon further extraction, the category of pharmaceuticals (5 articles) was excluded because the prescribing of medications does not meet the

criteria of CAM. This exclusion left 11 articles for the topic of botanicals in lymphedema treatment SSR (Table 2). The purpose of this SSR is to provide a critical analysis of the current published research regarding the use, risks, and benefits of botanicals in the treatment of lymphedema and to provide health professionals with current knowledge of safe, appropriate use of botanicals for lymphedema treatment. Results This review ranked the potential benefit of botanicals as they are being applied for the treatment of lymphedema. In all cases, allergy to any of these substances is an absolute contraindication, and none of these products is recommended for pregnant or lactating women in the United States. The 11 studies (conducted between 2004-2011) that were selected for this review were categorized by botanical classifications, as described earlier. All studies were ranked as benefits balanced with harms or effectiveness not established. The studies are categorized by botanical, and results are presented by the level of evidence with the categories of the botanicals as subheadings. Benefits Balanced With Harms Alpha Benzopyrones Coumarin is reported to increase macrophage activity, thus encouraging the cleansing of extracellular protein that, in turn, would reduce fibrosis formation, which is one of the complications of lymphedema.

300

Botanicals as Adjunctive Treatment for Lymphedema

Table 1 Putting Evidence into Practice weight-of-evidence classification Weight of Evidence Category

Description

Examples

Recommended for practice

Effectiveness is demonstrated by strong evidence from rigorously designed studies, meta-analysis, or systematic reviews; expected benefit exceeds harms

Likely to be effective

Effectiveness has been demonstrated by supportive evidence from a single rigorously conducted RCT, consistent supportive evidence from well-designed RCTs using small samples, or guidelines developed from evidence and supported by expert opinion Clinicians and patients should weigh the beneficial and harmful effects according to individual circumstances and priorities Data currently are insufficient or are of inadequate quality

At least 2 multisite, well-conducted RCTs with at least 100 subjects Panel of expert recommendation derived from explicit literature search strategy; includes thorough analysis; quality rating and synthesis of evidence One well-conducted RCT with fewer than 100 patients or at one or more study sites Guidelines developed by consensus or expert opinion without synthesis or quality rating

Benefits balanced with harms Effectiveness not established Effectiveness unlikely Not recommended for practice

Lack of effectiveness is less well established than those listed under “Not Recommended for Practice” Ineffectiveness or harm clearly is demonstrated or cost or burden exceeds potential benefit

RCTs, meta-analysis, or systematic reviews with documented significant adverse effects in certain significant populations Well-conducted case control study or poorly controlled RCT Conflicting evidence or statistically insignificant results Single RCT with at least 100 subjects that showed no benefit No benefit and unacceptable toxicities found in observational or experimental studies No benefit or excess costs or burden from at least 2 multisite, well-conducted RCTs with at least 100 subjects Discouraged by expert recommendation derived from explicit literature search strategy; includes thorough analysis, quality rating, and synthesis of evidence

RCT ¼ randomized controlled trial. Adapted with permission from Mitchell SA, Friese CR. ONS PEP (Putting Evidence into Practice) weight of evidence classification schema: Decision rules for summative evaluation of a body of evidence. Available at http://www2.ons.org/Research/media/ons/docs/research/outcomes/weightof-evidence-table.pdf. Accessed October 17, 2014.

Although coumarin is infrequently used and is banned in Australia and France, reviews of this wellresearched botanical continue to appear in the literature. Farinola and Piller [19] reviewed the literature to assess coumarin benefits versus risks in the treatment of lymphedema. In one randomized controlled trial (RCT), 24 women with upper extremity lymphedema related to treatment for breast cancer took coumarin, 8 mg daily for 6 months, and did not undergo CDT. Limbs were measured at 4 and 6 months, and a statistically significant reduction in limb diameter was found (P < .05) [19]. Two small literature reviews and one larger review evaluated the same 2 coumarin RCTs to weigh the clinical and quality-of-life benefits of coumarin compared with placebo [15,21,31]. Both RCTs treated upper extremity lymphedema, included a small number of subjects (n ¼ 18 and n ¼ 67), were nonblinded, and were 12-month crossover trials [32,33]. Authors of the first coumarin RCT reported a statistically significant limb volume reduction (P < .001) and symptom improvement compared with placebo, whereas authors of the second RCT actually reported increased limb volume for both the study group and the control group [15,21,31]. The major differences were that CDT continued during the Casley-Smith trial and not during the Loprinzi trial [31].

In another RCT [19], patients with lower extremity lymphedema (N ¼ 76) participated in a multipleintervention study. One group took a mixture of coumarin and flavonoids daily with adjuvant manual lymph drainage performed 1-1.5 hours weekly. The outcomes for this group were compared with groups treated with MLD alone, flavonoid alone, or no treatment. The combined therapy group demonstrated the greatest improvement in limb volume (7.8% in the ankle and 10.3% in the foot with combined therapy). This finding supports the use of botanicals as an adjunctive treatment, because the stand-alone group did not demonstrate the same benefit. Reviews of coumarin RCTs report that although patients with lymphedema could derive health-related and clinical benefits from coumarin, data are insufficient across the trials because of small sample size and variability of design for generalizability. Moreover, 75 cases of idiosyncratic hepatotoxicity occurred, and in 6% of patients treated with coumarin, plasma aminotransferase levels developed that were more than double the upper limit of normal [15,19,21,31]. Coumarin-related hepatotoxicity occurs in humans because of a polymorphism of the liver enzyme responsible for metabolism of coumarin, CYP2A6, a cytochrome P450 pathway [6]. Farinola and Piller [19] argue that a screening test is needed for genetic polymorphisms of CYP2A6 rather than eliminating the use of

E.G. Poage et al. / PM R 7 (2015) 296-310

301

Table 2 Summary of botanicals research reviews and studies Author

Botanical

Design and Sample

Methods

Results

Strengths

Benefits balanced with harms (balance of risks and benefits) RCTs LE defined as >10% of Current evidence Badger et al Various Review of RCT unaffected limb from does not support [21] (2004) benzopyrones comparing effectiveness of any cause; could effectiveness of benzopyrones have had CDT, but benzopyrones with Editors’ comments: placebo in reducing not 6 mo prior to Australia has start of study limb volume in banned the use of LE defined: clinically adults with LE; coumarin because detectable from a compare various of hepatotoxicity peripheral cause of benzopyrones; great than 3-mo assess the duration incidence of Volume reduction and adverse effects; other physical assess impact on QOL, subcutaneous benefits to include tissue, and pain; 15 reduction in the trials met inclusion number of attacks of cellulitis, adverse criteria events Volume (water displacement, electronic volumeter) calculated from surface measurement Physical benefits (VAS, tonometry, QOL) Psychological benefits (Hospital Anxiety Depression scale, Psychological Adjustment to Illness Scale, a diseasespecific QOL) Benzopyrones 3 trials (n ¼ 127) tested oxerutin; 1 trial (n ¼ 57) tested butcher’s broom with hesperidin (Cyclo 3 Fort); 1 trial (n ¼ 104) tested MPFF from diosin; 3 trials (n ¼ 249) tested coumarin combined with troxerutin; 7 trials (N ¼ 603) tested coumarin No long-term F/U for long-term effects of drugs Reduction in volume Focused on the Farinola and Coumarin RCTs using coumarin Defined LE limb Piller [19] for LE; 6 RCTs Limb volume changes benefit of LE Reduction in (2005) reviewed Symptom changes: and this decreased heaviness, symptoms particular Reduction with and pain, immobility botanical without CDT Adverse events: advantage over idiosyncratic the others and The use of hepatotoxicity gives a pharmacogenomics Varying doses of discussion of could lower risk coumarin; trials over of coumarinCYP2A6 different lengths of polymorphism, associated time the liver hepatotoxicity

Weaknesses Insufficient data about research methods (sample allocation, No. of patients in or withdrawn from the studies) Too many combinations used, which confuses findings Coumarin is a benzopyrone Most of the studies are older with no recent science

Idiosyncratic hepatotoxicity

(continued on next page)

302

Botanicals as Adjunctive Treatment for Lymphedema

Table 2 (continued ) Author

Botanical

Barton et al [15] (2006)

Various botanicals coumarin

Kligman et al [31] (2004)

Benzopyrones Coumarin Rutosides Daflon

Design and Sample

Methods

Results

Strengths

Weaknesses

Comparison with other Further research is enzyme botanicals with and required to responsible for without therapy evaluate this metabolizing 3 and 6 mo botanical coumarin Does not specify Double-blind, After 6 mo of Arm circumferences Review of CAM formulation, dose, placebo group coumarin therapy, to calculate arm research in clinical or prior or ongoing 80 participants no significant volume setting signed up on the therapy difference in arm Self-report 27 studies using day it opened Hepatotoxicity observed: questionnaires about edema, arm CAM for symptom 6% with elevated liver and in 1 mo all volume, or the swelling, pressure, management in 150 participants function tests tightness, heaviness, ratios of volume of patients with entered, which affected to normal and loss of mobility cancer (total shows interest arm n ¼ 3852) in alternative 1 RCT double-blind therapies crossover trial focused on breast cancere related LE using coumarin n ¼ 130 (New England Journal of Medicine 1999) A systematic review Definition of LE varied Compression therapy A formal external In 1 trial (Loprinzi) using coumarin, review process of evidence for Reduction in limb volume and manual hepatotoxicity physical therapy, Outcomes expressed as lymphatic drainage was performed developed in 9 of to validate the medical therapies may improve LE, either absolute relevance of the 140 participants using benzopyrones difference in size but further studies treated for 6 mo opinions were reviewed are needed between affected Small studies were Reviewers were 10 RCTs treatments Compression and contralateral underpowered, with for LE related to arm or as the relative garments should be oncologists, sample size ranging breast cancer worn from morning nurses, and change in the from 25-104 physioTwo studies included to night daily and amount of edema None of these studies therapists lower extremity removed at The reduction in used blinded outcome LE but did not symptoms associated bedtime assessments combine these In 2 of 3, significant with LE: impaired This systematic review results with breast reductions in arm function and does not support the cancer patients volume and decreased mobility use of coumarin Studies categorized In the prophylactic improvements in because of adverse by intervention symptoms with study, the No. of effects and lack of being evaluated: active drug patients who benefit for LE and 4 trials evaluated compared with developed LE flavonoids botanicals or placebo QOL and adverse medical therapies effects of treatment No current evidence Data were not to support the use Different interventions pooled, because of medical in 4 placebono 2 trials therapies for LE controlled RCTs; compared the benzopyrones were More and bettersame or similar evaluated in 3 trials; designed and larger treatments 2 used coumarin and trials are needed Significant variation 1 used rutosides; a Consistency in in assessment defining LE fourth used Daflon; overall, 2 of 3 methods benzopyrones trials had reductions in arm volume and improvement in symptoms; 1 study reported hepatotoxicity; no sign difference in arm volume or discomfort score between Daflon and placebo No F/U (continued on next page)

E.G. Poage et al. / PM R 7 (2015) 296-310

303

Table 2 (continued ) Author

Botanical

Design and Sample

Methods

Effectiveness not established Dx of breast cancere Cluzan BN165 (gamma A comparative, related LE of 3 mo et al [34] benzopyrone) 3-arm, doubleduration (2004) blind, placeboA VAS to measure controlled study symptoms of with a gamma discomfort benzopyrone or (heaviness, flavanoid tightness, stiff 48 patients with movements); 3 breast cancere measurements related upper extremity LE and An indirect, functional dynamic having had partial lymphoscintigraphy improvement after initial decongestive scan to measure lymphatic clearance therapy 15 patients were in SF36 to measure quality of life a BN165 2 active capsules group (2A) Serial perometer measurements for 16 patients were in a limb volume (initial, BN165 3 active capsules group (3A) interim and day 56 final) 17 patients were in a placebo group (P) Each patient took 2 similar-appearing capsules (but different dose regimens) of BN165 in the morning and 1 in the evening for 2 mo No F/U

Results

Strengths

Weaknesses

When lymphoDouble-blind, Small sample size scintigraphic randomized, No long-term F/U parameters on day placebo group, It is not clear whether 56 were compared no dropouts, some patients with those at well tolerated, continued with baseline, no without adverse conventional significant decongestive therapy effects differences were found Lymphatic migration speed was increased for group 2A but also for the P group (P < .05) No significant differences were found for volumetry in all groups Reduction in heaviness was found only in group 2A (P ¼ .017) Tightness was significantly reduced in group 2A (P ¼ .012) and in the P group (P ¼ 0.017) Stiffness was significantly reduced in all groups (P < .05) A trend for better results was consistently obtained for group 2A than for the other 2 groups Group 2A displayed less lymphostasis in the swollen limb and a significant improvement in the lymphatic drainage of the contralateral limb, with more functional nodes The half-life and lymphatic migration speed were improved in group 2A No significant change was found in the QOL Conclusion: BN165 is well tolerated and relieves limb heaviness in breast cancererelated LE; further controlled clinical trials are needed (continued on next page)

304

Botanicals as Adjunctive Treatment for Lymphedema

Table 2 (continued ) Author

Botanical

Design and Sample

Pittler et al [35] (2012)

HCSE

Wheat et al [25] (2009)

HCSE

Wollina et al [20] (2006)

HCSE Flavonoids Red vine leaves Centella asiatica Procyanidins Calcium dobesilate Pentoxifylline

Rigorous review Patients improved Diagnosis of CVI standards overall with HCSE Trials were excluded Leg pain was assessed Evidence suggests for poor CVI that HCSE is in 7 placebodiagnostic criteria efficacious and controlled trials: 6 CVI-related symptoms safe for shortreported reduction (leg pain, pruritus, term use in pain while edema) another reported More rigorous, Leg volume, leg large RCTs are a statistically circumference at required to significant ankle and calf assess the improvement Adverse events efficacy of this Leg volume was recorded treatment Trials lasted 2 to 16 wk assessed in 7 option placebo-controlled No F/U trials: 6 trials (n ¼ 502) showed a reduction in favor of HCSE Compared with compression: 1 study indicated the HCSE may be as effective Adverse events: 14dno adverse events; 4dno treatment-related adverse events; 6dGI complaints, dizziness, nausea, headache, and pruritus Risk/benefit ratio of HCSE for shortterm treatment: good Reliable measure Increase in the A prospective, repeat Bilateral baseline percentage of measure design upper limb activity that 15 normal volunteers Lymphoscintigraphy migrated away used to measure from the injection lymphatic drainage site after herbal rate treatment (P ¼ After 3 mo of therapy, .017) F/U lymphoscintigraphy Conclusion: the Horsechestnut Quantitative Complex has the evaluations potential to compared between the 30 matched pairs accelerate lymphatic drainage (right and left arms in normal at baseline and F/U) Horsechestnut Complex population 1 tablet twice daily after a meal for 3 mo No clear definition of The results showed Only RCTs used A literature review reduction of LE discussed, and of treatment of Focused on cases of CVI differed capillary filtration microcirculation studies with a rate and in progression of dysfunction due change in blood improvements in disease to CVI flow and levels of transMicrocirculatory RCTs for different capillary cutaneous PO2 and effects: edema, leg botanicals permeability volume, capillary RCTs: effect of PCO2 filtration rate, botanicals on It suggests that often blood viscosity, local these botanicals CVI-related LE blood flow, etc can be used short RCT HCSE vs monopreparations (placebo, compression garments, or different botanicals) No combination product trials were included 17 trials 10 placebocontrolled; 2 compared against stockings and placebo 4 were controlled against reference medications with HR O-(betahydroxyethyl)rutosides (HR) 1 against pycnogenol Others excluded because of combination products, poor definition CVI, and study design

Methods

Results

Strengths

Weaknesses Manufacturers were contacted to include published and unpublished studies: 1 was included in the 17 trials No long-term risk/benefit Studies had small sample size Methodological rigor varied Risk of positive studies being published while negative studies are unpublished

Small sample size Sample not patients Lack of a control Lack of long-term evaluation Researchers recommend an RTC in patients with unilateral using both a placebo group and the nonaffected limb as control,; which will provide insight into both the mechanism of action and clinical benefits

Lack of details of search methods and studies in review

(continued on next page)

E.G. Poage et al. / PM R 7 (2015) 296-310

305

Table 2 (continued ) Author

Botanical

Cesarone et al [22] (2006)

Pycnogenol Daflon

Abascal et al [37] (2007)

Butcher’s broom HCSE Gotu kola Grape leaf Pycnogenol

Design and Sample

Methods

Results

Botanicals: HCSE; flavonoids, red vine leaves extracts, C asiatica, procyanidins, calcium dobesilate, and pentoxifylline No F/U Severe CVI lower extremities Microcirculatory measurements: constant temperature, before 10 AM and after 30 min of resting in the supine position LDF Resting flux RAS: Capillary filtration by strain gauge plethysmography: measurements taken after 4 and 8 wk VAS was also used Randomized to 3 treatments over 8 wk: 150 mg Pycnogenol: n ¼ 24 300 mg Pycnogenol: n ¼ 20 1000 mg Daflon (Diosmin and hesperidin): n ¼ 42 No compression stockings were used during the study The study was conducted during the summer No dropouts No F/U

term in place of stockings, particularly during summer months Some botanicals improved wound healing

Severe CVI Inclusion criteria Venous reflux in the popliteal vein by color duplex Increase in venous pressure: Ambulatory venous pressure Arteriovenous pressure: >55 mm Hg in included limbs Varicose veins and superficial venous incompetence were associated with deep incompetence Exclusion criteria: diabetics; recent DVTs or patients with suspected or confirmed history of thrombosis in the previous 24 mo Sample: N ¼ 86 Randomized to 3 treatments over 8 wk: 150 mg Pycnogenol: n ¼ 24; 300 mg Pycnogenol: n ¼ 20; 1000 mg Daflon (Diosmin and hesperidin): n ¼ 42 No compression stockings were used during the study The study was conducted during the summer No dropouts 7 RCTs using No review of methods botanicals Compression plus CVI adjuvant botanicals Butcher’s broom Horse chestnut Gotu kola Grape leaf Pycnogenol No described F/U

Strengths

Weaknesses

All microcirculatory Treatments were Not blinded parameters showed well tolerated Randomization not Pycnogenol explained and no adverse advantage (P < .05) effects were and CVI reported improvement in Excellent use of both Pycnogenol microcirdoses culation studies PO2 increase (P < .5) not volume changes PCO2 decreased (P < .5) Higher dose Pycnogenol more effective for edema reduction

Butcher’s broom: reduction in subjective symptoms, reduction in limb circumference, reduction in edema, reduction in itching, paresthesia

Many primarily small studies Many RCT for butcher’s broom Horse chestnut: not enough information to tell

Varying doses in studies with all botanicals; butcher’s broom, horse chestnut: not enough information

(continued on next page)

306

Botanicals as Adjunctive Treatment for Lymphedema

Table 2 (continued ) Author

Botanical

Dennert and Selenium Horneber [38] (2006)

Design and Sample

Methods

Results

Incidence and severity A literature review of chemotherapy/ of effects of radiotherapy-related supplementary toxicities LE selenium on Levels of physical and adverse effects psychological on conventional distress treatments in QOL patients with Incidence and type of cancer adverse effects This update review Selenium supplements included 2 completed studies No F/U and 1 ongoing study Patients with breast cancer, gynecological cancer, and head and neck cancer (n ¼ 20-82)

Strengths

Weaknesses

Horse chestnut: observational study (N ¼ 5000); reduction in all symptoms: pain, tiredness, tension, swelling, and itching, and improved compliance over compression 18 studies used HCSE for 6-12 wk and uniformly show a reduction in ankle circumference and improvement in symptoms Results are better when CVI is not advanced All studies had poor Methodological Currently available quality of methodology quality was evidence is assessed using Small sample size insufficient to a critical support the role of appraisal selenium for checklist alleviating the adverse effects of Rare for a study to include patients oncology with head and treatments neck cancer “More research is needed to find out which doses of selenium supplements can be reasonably used by cancer patients and whether selenium supplements can affect the side effects of cancer therapy”

RCT ¼ randomized controlled trial; QOL ¼ quality of life; LE ¼ lymphedema; CDT ¼ complete decongestive therapy; VAS ¼ visual analog scale; MPFF ¼ micronized purified flavonoid fraction; F/U ¼ follow-up; CAM ¼ complementary and alternative medicine; Dx ¼ diagnosis; SF36 ¼ Short Form 36; HCSE ¼ horse chestnut seed extract; HR ¼ HR O-(beta-hydroxyethyl)-rutosides; CVI ¼ chronic venous insufficiency; GI ¼ gastrointestinal; DVT ¼ deep vein thrombosis; PO2 ¼ partial pressure of oxygen; PCO2 ¼ partial pressure of carbon dioxide; LDF ¼ laser Doppler flowmetry; RAS ¼ rate of ankle swelling.

this potentially beneficial botanical. Pharmocogenomics and improved monitoring could lower the risk of coumarin-associated hepatotoxicity. Additional research is required to evaluate coumarin’s effectiveness in treating lymphedema using the pharmacogenomics framework. Effectiveness Not Established Gamma Benzopyrones Current evidence does not support the use of gamma benzopyrones in treating lymphedema or reducing limb

volume, discomfort, or pain because of the poor quality of these trials. Badger et al [21] conducted a large literature review of RCTs to assess the effectiveness of benzopyrones for reducing and controlling lymphedema. In addition to reviewing coumarin, an alpha benzopyrone, as discussed previously, the authors reviewed 8 studies comparing the effectiveness of the following gamma benzopyrones: oxerutin, Daflon, and Cyclo 3 Fort. Overall, data were insufficient to reach conclusions about the effectiveness of these botanicals. Based on findings from several trials of BN165 (Ginkor Fort, a gamma benzopyrone) for treating venous

E.G. Poage et al. / PM R 7 (2015) 296-310

insufficiency, Cluzan et al [34] developed a small 3-arm, double-blind, placebo-controlled pilot RCT to test the efficacy of BN165 in breast cancererelated upper extremity lymphedema. Forty-eight patients with breast cancererelated lymphedema were randomly assigned to 3 groups: 15 received BN165 in the amount of 2 active capsules daily, 16 received BN165 in the amount of 3 active capsules daily, and 17 patients were in the placebo group. The study lasted 2 months, with measurements taken before inclusion (baseline evaluation), on day 28 (interim visit), and at day 56 (final day). A lymphoscintigraphy scan and questionnaire were administered initially and on the final day of the study. Measurements included a visual analog scale to assess symptoms; an indirect, functional dynamic lymphoscintigraphy scan; a quality-of-life questionnaire; and a serial perometer measurement of limb size. No subjects dropped out of the study, and the product was well tolerated. The study showed improved altered sensation, particularly improved limb heaviness, and less lymphostasis in the 2-capsule group. In general, there was a trend for better results overall with the 2-capsule group than with the 3-capsule or placebo groups. No significant changes occurred in quality of life or volumetric measurements [34]. The study design has merit, and although the trial has a small sample, it is one of the few studies to rigorously study a botanical for a lymphatic system problem. Saponin HCSE, a saponin, has been shown to inhibit the activity of proteolytic enzymes, elastase and hyaluronidase, in vitro [35]. It is thought that this enzyme activity initiates the cascade of events that cause capillary leakage and inflammation in persons with CVI [25,35,36]. A Cochrane review that included evidence from 17 RCTs showed that HCSE reduces edema and leg pain related to CVI when used with compression or as a monotherapy [35]. When compared with compression stockings, one study indicated that HCSE might be effective as an alternative to compression therapy. HCSE is efficacious and safe for short-term use (2-6 weeks) [35,36]. Pittler and Ernst [35] reported that all trials had a small sample size and unreliable methodologies. Absolute contraindications include allergy, and special precautions should be taken for persons with blood disorders; in addition, it is recommended that HCSE be discontinued prior to dental and surgical procedures. It is worth noting that of the 6183 patients who participated in the 17 RCTs, only 46 patients reported adverse events, which primarily included gastrointestinal complaints, dizziness, nausea, headache, and pruritus [35]. HCSE in Combination Therapies The therapeutic benefits of botanicals for lymphedema are difficult to quantify. Most studies measured

307

symptom improvement and change in limb size. In one unique trial with healthy volunteers, participants were studied with a baseline upper limb lymphoscintigraphy. For 3 months, they took an HCSE, butcher’s broom, and Ginkgo biloba combination (Horsechestnut Complex) preparation twice a day after meals and then had a follow-up lymphoscintigraphy scan [25]. Wheat et al [25] report a significant increase in the percentage of lymphatic drainage activity that migrated away from the lymphoscintigraphy injection site when baseline and follow-up series were compared. The recommendation was made to follow up with an RCT of poste breast cancer patients. Further investigations with a blinded, placebo-controlled trial are recommendeddbecause MediHerb Pty Ltd provided Horsechestnut Complex and no blinding took place, the potential for bias exists. In a systematic review of RCTs evaluating therapeutic options for the treatment of microcirculation dysfunction with CVI [20], the authors report that there is a growing body of evidence that the effects of botanicals and compression on microcirculation is quantifiable. Techniques such as laser Doppler flowmetry and transcutaneous measurements of oxygen and carbon dioxide are much less invasive and less costly than lymphoscintigraphy. Wollina et al [20] report a reduction of capillary filtration rate and improvements in levels of transcutaneous partial pressures of oxygen and carbon dioxide with some botanicals (HCSE, micronized purified flavonoids fraction, oxerutin agents, red vine leaf extracts, total triterpenic fraction of C asiatica, procyanidins, Pycnogenol, calcium dobesilate, and pentoxifylline) when used alone, in combination with other botanicals, or when compared with compression stockings. Methodological limitations in study design and sample size were acknowledged. More robustly designed RCTs of targeted herbal regimens with long-term follow-up for persons with lymphedema, not just CVI, is recommended. Pine Bark Extract Versus a Gamma Benzopyrone As quantitative assessment technology improves, more studies can objectively evaluate the therapeutic benefits of various interventions. An excellent example is a recent RCT by Cesarone et al [22] designed to investigate the clinical efficacy of 2 botanical preparations, Pycnogenol (oligomeric proanthocyanidins or pine bark extract) and Daflon (a gamma benzopyrone combination of Diosmin and hesperidin), in 86 patients with CVI. In addition to evaluating changes in signs and symptoms of CVI, researchers obtained rigorous microcirculatory measurements that included keeping the evaluating room temperature constant, measuring the patients before 10 AM, and allowing them to rest supine for a period of 30 minutes prior to measuring. Microcirculatory measurements included laser Doppler flowmetry and resting reflux.

308

Botanicals as Adjunctive Treatment for Lymphedema

Measurements were taken at baseline, 4 weeks, and at the end of the study, which lasted 8 weeks. Patients were randomized into 2 groups to receive either Pycnogenol or Daflon and then into 2 subgroups, based on duration of disease. Patients with a longer disease duration received a larger dose of Pycnogenold300 mg versus 150 mg. Patients in the Daflon group were also stratified by disease duration but received the same dose of Daflond1000 mg. Overall, no subjects dropped out of the study, and no adverse effects were reported. Both the lower and higher dose Pycnogenol groups had a significant improvement in signs/symptoms and microcirculatory parameters compared with the Daflon groups at 4 and 8 weeks [22]. Pycnogenol was associated with decreased ankle swelling by 35%, whereas Daflon was associated with a 19% reduction. Pycnogenol reduced symptoms by 65% versus 32% for those who took Daflon. Microcirculatory oxygen was increased and carbon dioxide decreased in participants who took Pycnogenol, suggesting overall improved tissue circulation. In contrast, Daflon did not appear to improve tissue perfusion. Overall, the higher dose of Pycnogenol was more effective for edema [22]. In another RCT [37], similar findings were reported when only 150 mg of Pycnogenol versus placebo was given. One study limitation was lack of blinding, and for another study, a limitation was the use of 2 different doses of Pycnogenol and not Daflon. A follow-up study to assess possible carry-over long-term benefit would be informative. At a cost of $1 to $3 for one Pycnogenol 100-mg capsule, a pair of compression stockings may be more economical, but treatment with the capsule may be more desirable. The authors did not report the source of the botanicals. Finally, a study to assess the transferability of these measurement techniques for lymphedema is needed. Selenium Although botanical studies are often evaluated on their merit for improving lymph drainage and tissue congestion, some studies have evaluated the benefits of substances to prevent inflammation and infections. Cellulitis is a deleterious consequence of a poorly functioning lymph system; therefore, preventing inflammation and controlling infections are essential. Two Cochrane literature reviews evaluated the effects of selenium, an essential trace element with antioxidant protection in patients with lymphedema [21,38]. In a survey of patients with cancer, 12% were taking selenium to alter their treatment symptoms. Good science is needed to help patients determine best practices [38]. Both reviews examined the same RCT to assess the effectiveness of selenium in reducing recurrence of infection in patients with lymphedema. The RCT had study design flaws and bias, thereby

limiting the interpretation of trial results. Because of very little evidence, taking selenium either as an antiinflammatory or for swelling reduction is not supported [21,38]. A small RCT was conducted to assess the effects of selenium on the development of lymphedema in patients with head and neck tumors [38]. Twenty participants who had undergone oral tumor surgery with bilateral lymph node dissection were included. The trial group received 3000 mg sodium selenite intravenously on the day of surgery and 1000 mg sodium selenite daily (intravenously or per os) as tolerable on days 1 to 21 after surgery. However, the similarity of the groups is not clear, nor are the eligibility criteria specified. Furthermore, it is described as a double-blinded study, but the informed consent form reported that the participants were allocated to the selenium group. The researcher used facial landmarks for measuring, and only 1 of 3 sets of measurements favored selenium. Small sample size and unclear validity and reliability of the measurement technique used resulted in outcomes that are not interpretable or generalizable. Although there were no reported adverse effects of selenium in these studies, selenosis is known to occur with excessive levels of selenium. Therefore, no recommendation for or against selenium use in patients with cancer can be made [38]. Conclusion CDT is effective for the management of lymphedema. However, this method is burdensome and costly, and lack of adherence to treatment protocols is known to be a problem. The purpose of this review was to explore the possible use of botanicals as an effective adjunctive treatment for lymphedema. Their use, thus far, has not been proven effective, in part because of shortcomings in the manner in which potential benefits have been measured. A trend in the emerging evidence indicates that botanicals may contribute to lymphedema management for cases that are vascular in nature. Rigorously designed studies using objective measurement techniques need to be explored and developed to determine therapeutic benefits. Once such studies are performed, the resultant body of evidence may provide the basis upon which to accurately assess whether the use of botanicals in the treatment of lymphedema is beneficial. In addition, Barton et al [15] recommended using herbal preparations from Germany, where more oversight is given to botanical preparations, and these investigators cautioned against using products that have not been evaluated by the Food and Drug Administration. Although there is a paucity of high-quality, peerreviewed published research, the evidence regarding

E.G. Poage et al. / PM R 7 (2015) 296-310

botanicals examined in this review strengthens the body of knowledge and provides a road map for future research to develop high-quality evidence for health professionals and patients. These findings will support health care practitioners as they address the concerns of their patients who are seeking alternatives to standard therapy. References 1. Fo ¨ldi M, Fo ¨ldi E, Kubik S. Textbook of Lymphology: For Physicians and Lymphedema Therapists. San Francisco, CA: Urban and Fisher; 2006. 2. Rockson SG, Rivera KK. Estimating the population burden of lymphedema. Ann N Y Acad Sci 2008;1131:147-154. 3. Ridner SH. The psycho-social impact of lymphedema. Lymphat Res Biol 2009;7:109-112. 4. Fu MR. Breast cancer survivors’ intentions of managing lymphedema. Cancer Nurs 2005;28:446-457. 5. International Lymphoedema Framework. Best Practice for the Management of Lymphoedema. International Consensus. London: MEP Ltd; 2006; 3-52. 6. International Society of Lymphology. The diagnosis and treatment of peripheral lymphedema: 2009 consensus document of the International Society of Lymphology. Lymphology 2009;42: 51-60. 7. Poage EG, Armer JM, Singer M, Shellabarger MJ, Poundall MD. ONS PEP resource: Lymphedema. In: Eaton LH, Tipton JM, eds. Putting Evidence into Practice: Improving Oncology Patient Outcomes. Pittsburgh, PA: Oncology Nursing Society; 2009; 183-192. 8. Lasinski BB, Thrift KM, Squire D, et al. A systematic review of the evidence for complete decongestive therapy in the treatment of lymphedema from 2004 to 2011. Phys Med Rehabil 2012; 4:580-601. 9. Ridner SH, Bonner CM, Deng J, Sinclair VG. Voices from the shadows: Living with lymphedema. Cancer Nurs 2012;35:E18-E26. 10. Radina E, Armer J, Daunt D, Dusold J, Culbertson S. Self-reported management of breast cancer-related lymphoedema. J Lymphoedema 2007;2:12-21. 11. Clodius L. Psycholymphology: Why not all patients with chronic lymphedema want therapy. Lymphology 2006;39:104-107. 12. Barnes PM, Bloom B, Nahin RL. Complementary and alternative medicine use among adults and children: United States, 2007. Natl Health Stat Report 2008;(12):1-23. 13. Bailey RL, Gahche JJ, Lentino CV, et al. Dietary supplement use in the United States, 2003-2006. J Nutr 2011;141:261-266. 14. Fouladbakhsh JM, Stommel M, Given BA, Given CW. Predictors of use of complementary and alternative therapies among patients with cancer. Oncol Nurs Forum 2005;32:1115-1122. 15. Barton DL, Loprinzi C, Jatoi A, et al. Can complementary and alternative medicine clinical cancer research be successfully accomplished? The Mayo CliniceNorth Central Cancer Treatment Group experience. J Soc Integr Oncol 2006;4:143-152. 16. Hallmann-Mikołajczak A. Ebers Papyrus. The Book of Medical Knowledge of the 16th Century BC Egyptians. Archiwum historii i filozofii medycyny/Polskii Towarzystwo Historii Medycyny i Farmacji 2004;67:5. 17. Raskin I, Ribnicky DM, Komarnytsky S, et al. Plants and human health in the twenty-first century. Trends Biotechnol 2002;20:522531. 18. Rathbun SW, Kirkpatrick AC. Treatment of chronic venous insufficiency. Curr Treat Options Cardiovasc Med 2007;9:115-126.

309

19. Farinola N, Piller N. Pharmacogenomics: Its role in re-establishing coumarin as treatment for lymphedema. Lymphat Res Biol 2005;3: 81-86. 20. Wollina U, Abdel-Naser MB, Mani R. A review of the microcirculation in skin in patients with chronic venous insufficiency: The problem and the evidence available for therapeutic options. Int J Low Extrem Wounds 2006;5:169-180. 21. Badger C, Preston N, Seers K, Mortimer P. Benzo-pyrones for reducing and controlling lymphedema of the limbs. Cochrane Database Syst Rev 2004;(2):CD003140. 22. Cesarone MR, Belcaro G, Rohdewald P, et al. Comparison of Pycnogenol and Daflon in treating chronic venous insufficiency: A prospective, controlled study. Clin Appl Thromb Hemost 2006;12: 205-212. 23. Therapeutic Research Faculty. Horse chestnut. Available at: http://naturaldatabase.therapeuticresearch.com/nd/Search.aspx? cs¼&s¼ND&pt¼100&id¼1055&fs¼ND&searchid¼47118452. Accessed October 17, 2014. 24. Asgari RH, Azadbakht M, Sharifpour A, Mazloom D. Preparation and evaluation of horse chestnut seed extract gel and its effect on varicose disease symptoms. J Med Plants 2007;6:25-33. 25. Wheat J, Currie G, Kiat H, Bone K. Improving lymphatic drainage with herbal preparations: A potentially novel approach to management of lymphedema. Aust J Med Herb 2009;21:66-70. 26. Therapeutic Research Faculty. Butcher’s broom. Available at: http://naturaldatabase.therapeuticresearch.com/nd/Search. aspx?pt¼100&id¼320. Accessed October 17, 2014. 27. Mitchell SA, Friese CR. ONS PEP (Putting Evidence into Practice) weight of evidence classification schema: Decision rules for summative evaluation of a body of evidence. Available at: http:// www2.ons.org/Research/media/ons/docs/research/outcomes/ weight-of-evidence-table.pdf. Accessed October 17, 2014. 28. Poage EG, Singer M, Armer JM, Poundall MD, Shellabarger MJ. Demystifying lymphedema: Development of the lymphedema putting evidence into practice card. Clin J Oncol Nurs 2008;12: 951-964. 29. Eaton LH, Tipton JM, Irwin M. Putting Evidence into Practice: Improving Oncology Patient Outcomes. Pittsburgh, PA: Oncology Nursing Society; 2009. 30. Rodrick JR, Poage E, Wanchai A, Stewart BR, Cormier JN, Armer JM. Complementary, alternative, and other non-complete decongestive therapy (CDT) treatment methods in the management of lymphedema: A systematic search and review. PM R 2013; 6:250-274. 31. Kligman L, Wong RK, Johnston M, Laetsch NS. The treatment of lymphedema related to breast cancer: A systematic review and evidence summary. Support Care Cancer 2004;12:421-431. 32. Casley-Smith JR, Morgan RG, Piller NB. Treatment of lymphedema of the arms and legs with 5,6-benzo-alpha-pyrone. N Engl J Med 1993;329:1158-1163. 33. Loprinzi CL, Kugler JW, Sloan JA, et al. Lack of effect of coumarin in women with lymphedema after treatment for breast cancer. N Engl J Med 1999;340:346-350. 34. Cluzan RV, Pecking AP, Mathiex-Fortunet H, Leger Picherit E. Efficacy of BN165 (Ginkor Fort) in breast cancer related upper limb lymphedema: A preliminary study. Lymphology 2004;37:47-52. 35. Pittler MH, Ernst E. Horse chestnut seed extract for chronic venous insufficiency. Cochrane Database Syst Rev 2012;11:CD003230. 36. Hutson P, Love R, Cleary J, et al. Horse chestnut seed extract for the treatment of arm lymphedema. J Clin Oncol 2004;22:80-95. 37. Abascal K, Yarnell E. Botanicals for chronic venous insufficiency. Alternat Complement Ther 2007;13:304-311. 38. Dennert G, Horneber M. Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients. Cochrane Database Syst Rev 2006;3:CD005037.

310

Botanicals as Adjunctive Treatment for Lymphedema

Disclosure E.G.P. Associates in General and Vascular Surgery, a division of 21st Century Oncology, Fort Myers, FL Disclosure: nothing to disclose J.R.R. Springfield Clinic, Springfield, IL; previously St John’s Hospital Rehab South, Springfield, IL Disclosure: nothing to disclose A.W. University of Missouri Sinclair School of Nursing, Columbia, MO; Boromarajonani College of Nursing, Buddhachinaraj, Thailand Disclosure: nothing to disclose B.R.S. University of Missouri Sinclair School of Nursing, Columbia, MO Disclosure: nothing to disclose

This systematic search and review of contemporary peer-reviewed lymphedema literature (2004 to 2012) addresses the possible benefits of botanicals as an adjunctive treatment of lymphedema. It was commissioned by the American Lymphedema Framework Project (ALFP) in partnership with the International Lymphoedema Framework for the purpose of evaluating the efficacy of botanicals in the management of lymphedema. A summary of these findings will be integrated into revisions to the second edition of the Best Practices document (Lymphedema Framework: Best Practice for the Management of Lymphoedema. International Consensus. London: MEP Ltd, 2006). The objectives of the ALFP are to provide evidence of the best practice of lymphedema care, assist in establishing guidelines for the management of lymphedema, and increase awareness of this condition in the United States and worldwide. American Lymphedema Framework Project (ALFP) staff and reference librarian time were supported by industry donations to the ALFP. Submitted for publication February 3, 2014; accepted September 20, 2014.

J.N.C. University of Texas MD Anderson Cancer Center, Houston, TX Disclosure: nothing to disclose J.M.A. University of Missouri Sinclair School of Nursing, Columbia, MO; Ellis Fischel Cancer Center, Columbia, MO. Address correspondence to: J.M.A., Mizzou North, Suite 415, 115 Business Loop 70 West, Columbia, MO 65211; e-mail: [email protected] Disclosure: nothing to disclose