Original Article Breast Evidence Mapping of the Treatments for Breast Cancer–related Lymphedema Ali M. Al-Sakkaf, MD, FEBS, Abstract FACS* Background: Women treated for breast cancer are facing a lifetime risk of develop- Jaume Masia, MD, PhD* ing lymphedema, which occurs in up to 40% of this population. There is a lack of Ariadna Auladell-Rispau, MSc† evidence and limited knowledge regarding the treatment of breast cancer–related Aliaa I. Shamardal, MD‡ lymphedema (BCRL). The aim of this study was to identify, describe, and organize Luis Vasconcello-Castillo, PT§¶ the currently available evidence in the treatment of BCRL. Ivan Sola, BSc†║ Methods: We conducted an evidence mapping review study according to the Xavier Bonfill, MD, PhD†║ methodology proposed by Global Evidence Mapping. We performed a system- atic search in Medline, Embase, Central (Cochrane), and Epistemonikos, from 2000–2020. We included studies about all treatment types for BCRL, including surgical and nonsurgical treatment. Results were summarized in narrative and tabular forms. Results: A total of 240 studies were included in this mapping review, distributed as follows: 147 experimental studies [102 randomized clinical trials (RCTs) and 45 quasi-experimental clinical trials], 48 observational studies (34 prospective and 14 retrospective studies), and 45 systematic reviews (17 of them with metanalysis). Most of the RCTs were on nonsurgical interventions. Only two RCTs addressed surgical intervention. Conclusions: In the last 20 years, there were an average of 12 publications per year on the treatment of BCRL. Recently this lack of attention has been par- tially corrected, as the majority were published in the past 5 years. However, most of them were on nonsurgical interventions. Well-designed RCTs on surgery are needed to measure the effectiveness of the applied interventions. (Plast Reconstr Surg Glob Open 2022;10:e4045; doi: 10.1097/GOX.0000000000004045; Published online 18 January 2022.) INTRODUCTION Given that the 5-year survival rate for breast cancer is now More than 1.38 million women worldwide were esti- 90%, experiencing breast cancer is ultimately about qual- mated to be diagnosed with breast cancer in 2008, account- ity of life.1 Women treated for breast cancer face a lifetime ing for 23% of all diagnosed cancers among women.1 risk of developing lymphedema, which occurs in up to 40% of this population and negatively affects breast can- cer survivors’ quality of life.2–5 From *Department of Plastic Surgery, Hospital de la Santa Creu i Patients with lymphedema have a significantly Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain; decreased quality of life, with frequent infections, reduced †Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, range of motion, and a cosmetic deformity that is difficult Spain; ‡Health Education England-East Midlands, London, UK; to conceal.6 Treatment for breast cancer–related lymph- §Department of Physical Therapy, Faculty of Medicine, University edema (BCRL) has mostly been symptomatic in nature of Chile, Santiago, Chile; ¶International Physiotherapy Research and designed mainly to prevent swelling progression.7 Network (PhysioEvidence); and ║Iberoamerican Cochrane Centre, BCRL treatment might involve (1) surgical treatments, Biomedical Research Institute Sant Pau (IIB Sant Pau), CIBERESP, which currently include the different microsurgery tech- Universitat Autònoma de Barcelona, Barcelona, Spain. niques and liposuction, or (2) nonsurgical treatments, Received for publication November 10, 2021; accepted November which might include pharmacotherapy, diet, exercise, and 16, 2021. physiotherapy options. Copyright © 2022 The Authors. Published by Wolters Kluwer Health, In the past decades, major advancements in the lym- Inc. on behalf of The American Society of Plastic Surgeons. This phatic imaging and surgical instruments and techniques have is an open-access article distributed under the terms of the Creative rekindled broader interest among surgeons in the pursuit of Commons Attribution-Non Commercial-No Derivatives License 4.0 a more effective treatment for lymphedema.8 Nonsurgical (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in Disclosure: The authors have no financial interests to any way or used commercially without permission from the journal. declare in relation to the content of this article. DOI: 10.1097/GOX.0000000000004045 www.PRSGlobalOpen.com 1 PRS Global Open • 2022 treatments are taking part in both prevention and treatment of BCRL, and they include a great variety of options, mainly Takeaways physiotherapy like complex physical therapy, intermittent Question: There is a lack of evidence and limited knowl- pneumatic compression, or compressive garments.9 edge regarding the treatment of breast cancer–related The limited knowledge regarding the treatment of lymphedema. BCRL, together with the insufficient standardization of Findings: A total of 240 studies were included in this the different therapeutic options, warrants highlight- mapping review, most of them nonsurgical interventions. ing the available evidence using an innovative approach Among these studies, there were 102 randomized clinical provided by evidence mapping, combined with a detailed trials, with only two RCTs addressing surgical interventions description of the available randomized clinical trials (RCTs) published in the literature. Meaning: More surgical randomized clinical trials are Evidence mapping allows a visual understanding of the needed in the future to measure the real effectiveness of evidence base of any treatment, apart from supporting the the applied interventions. process of decision-making by facilitating information in a user-friendly format.10 Furthermore, it is the best study design when there is an abundance and a diversity of research and an excellent way to identify gaps in a topic area.10 Library, and Epistemonikos. A search algorithm was Thus, the main objective of this study was to identify, designed, including a combination of controlled vocabu- describe, and organize the currently available evidence in lary, Medical Subject Headings (MeSH) descriptors, free the treatment of BCRL, with an additional focus on RCTs, text terms and thesaurus terms when available, with no especially in relation to surgical interventions. In addition, language restriction. We did not search for grey literature. the study aimed to identify the existing gaps of knowledge and to provide recommendations for future research. Study Selection and Data Extraction The studies retrieved by titles and abstract were uploaded to Mendeley and then managed with the software PATIENTS AND METHODS Rayyan QCRI. After removing duplicates, three reviewers (AMA, AIS, and LVC) independently screened all titles Study Design and abstracts, with each article being screened by at least An evidence mapping study was conducted accord- two reviewers. Afterward, a full-text screening was done by ing to the methodology proposed by Global Evidence the same reviewers who confirmed eligibility based on the Mapping.11 This evidence mapping adhered to the inclusion and exclusion criteria. Disagreements between PRISMA-Extension for Scoping Reviews.12 All methods two reviewers were resolved mainly by the third reviewer were specified a priori in a protocol (available on request). or by consensus. For each individual study, data extraction was conducted separately by the two reviewers (AMA and Eligibility Criteria AIS). Results were then compared, and in case of disagree- We have used the PICOS framework (population, inter- ment, the third reviewer (LVC) acted as a referee to reach vention, comparison, outcome and study design) to formu- consensus. late the eligibility criteria.13 We considered eligible patients (older than 18 years old) with BCRL. We included all treat- Data Synthesis and Analysis ment types for BCRL, including surgical and nonsurgical The obtained results are presented in a narrative and treatment. We considered studies with all kinds of com- visual format using tables, graphs, and a bubble plot. A flow parison and studies without comparison groups. Due to the chart for the whole process of study selection was elabo- nature of the study, all types of outcomes were eligible. We rated based on the PRISMA-P diagram.14 The analysis of the included the following study designs from the year 2000 to selected studies was divided in two parts: a general mapping 2020: RCTs, quasi-experimental clinical trials, observational description of all studies included in this mapping review, studies (retrospective, prospective), and systematic reviews and a detailed description of the included RCTs. (SRs) with or without metanalysis. We selected the most updated publication when we identified studies published on the same topic and by the same team. We excluded ani- RESULTS mal studies, in vitro studies, single case reports, case series, letters to the editor, narrative reviews, studies including dif- Studies Selection ferent types of edema or mixed edema, studies including The flow chart of the studies selection is shown in less than 10 patients or reviews with fewer than three studies Figure 1. The search yielded a total of 4993 studies. After and studies addressing other than treatment of BCRL or removing 1751 duplicates, we proceeded with 3242 studies addressing both prevention and treatment together. to screen by title and abstract. In total, 2889 studies were excluded for not being related to the review’s main topic. Search Strategy Then, a full-text review was done for 353 studies. After The search strategy was conducted in MEDLINE (via the resolution of discrepancies by consensus between PubMed), Embase (via Ovid), Cochrane Central Register researchers, we excluded 106 studies. Similarly, seven of Controlled Trials (CENTRAL) via The Cochrane studies where the full-text was missing were also excluded 2 Al-Sakkaf et al. • Mapping of BCRL Treatments Fig. 1. PRISMA flow diagram and selection process of studies on BCRL. from the descriptive analysis. Finally, a total of 240 studies Countries were included in this mapping review. The published studies were distributed among differ- The main reason for excluding studies was that the ent countries worldwide. The United States of America articles were published as conference abstracts (41); other had the highest number of publications (32) followed by reasons included foreign languages (other than English Turkey (19), Australia (17), China (16), South Korea (14), and Spanish) (19), wrong population (18), wrong design Brazil (12), the United Kingdom (12), and Iran (10). The (7), wrong objective (6), published protocol (3), case rest of the countries had fewer than 10 published studies report (1), editorial reply (1), literature review (1), popu- (Fig. 2). lation less than 10 patients (7), reviews including less than three studies (2), and the aforementioned missing full- Study Design text (7). We identified 147 experimental studies (102 RCTs and 45 quasi-experimental clinical trials), 48 observational Characteristics of All Included Studies studies (34 prospective studies and 14 retrospective stud- Publication Year and Language ies), and 45 SRs (28 SRs without metanalysis and 17 with We observed a marked increase in the number of pub- metanalysis) (Table 2). lications in the past 5 years; 139 (58%) of the published studies in the treatment of BCRL were from 2016 to 2020 Intervention Type (Table 1). As defined in the eligibility criteria, we included The identified studies included different types of inter- only studies published in English and Spanish. Overall, vention (42 surgical treatment and 198 nonsurgical treat- only two studies were published in Spanish, and the rest ment). Most of the surgical interventions were combined (238 studies) were all in English. with a nonsurgical treatment, such as garment, exercise, or 3 PRS Global Open • 2022 Table 1. Distribution of the Total Studies and RCTs on BCRL (12), the USA (11), Turkey (8), South Korea (8), the UK by Publication Year (7), China (5), and Poland (5). The remaining countries published fewer than five clinical trials. Years Total Studies, N (%) RCTs, N (%) 2000–2004 15 (6.25) 9 (9) Population Characteristics and RCTs Design 2005–2009 33 (13.75) 13 (13) 2010–2014 53 (22) 28 (27) These RCTs included patients with BCRL affecting the 2015–2020 139 (58) 52 (51) ipsilateral arm, but three studies described breast or chest Total 240 (100) 102 (100) lymphedema secondary to breast conservative treatment or mastectomy. Three trials studied BCRL only in over- others. The distribution of the intervention type accord- weight or obese patients. All were parallel with two arm ing to the study design is described in Figure 3. groups, but there were five crossover design trials, and five RCTs comparing three arm groups. Characteristics of the RCTs We encountered some RCTs that included the same population and methodology protocol and were performed Publication Year and Language by the same team but measuring different outcomes and/ Out of the total RCTs, 52 (51%) were published in the or describing subgroup analysis. These studies have been past 5 years, and they all were published in the English included as separate studies and analyzed independently. language (Table 1). Countries Intervention Type During the last 20 years, RCTs have been published in Overall, most of the RCTs were on nonsurgical treat- many different countries, the main ones being Australia ment, and there was a large diversity in nonsurgical Fig. 2. Geographic distribution of the published studies on BCRL. A, Total number of studies B, Randomized clinical trials. 4 Al-Sakkaf et al. • Mapping of BCRL Treatments Table 2. Frequency of the Study Design among Total of movements, and quality of life. Other measured out- Studies in the Treatment of BCRL comes were patient adherence, satisfaction, safety and adverse events, skin changes, infection and inflamma- Study Design No. Studies (%) tory markers, cost of treatments, or intervention duration Interventional 147 (61.25) (Fig. 4). RCTs 102 (42.5) Quasi experimental 45 (18.75) Observational 48 (20) Effect of Intervention Prospective 34 (14.16) Most of the RCT results favored toward intervention Retrospective 14 (5.84) Systemic reviews 45 (18.75) (59). Some other studies favored toward the comparison SR without meta-analysis 28 (11.67) group (7), and the rest of the trials had no difference of SR with meta-analysis 17 (7.08) Total 240 (100) effect by applying the intervention (37). The therapeutic results according to the intervention type among the RCTs are described in Figure 5. treatment options, mostly regarding physiotherapy treat- ments, such as different kinds of sleeves/bandages, kinesio DISCUSSION tape, manual lymphatic drainage, pneumatic compression As we perceived that the available evidence of the treat- pump, decongestive compression therapy, exercise proto- ment for BCRL is not proportional to the importance of cols (active, resistant, aqua exercise), yoga, weight loss, this health condition, which is considered as significant acupuncture or different pharmacotherapy, laser therapy, problem for women who had been treated for breast can- satellite ganglionic block, etc. cer, we decided to conduct a mapping review to identify Among the nonsurgical treatment trials, we also found and to make a broad picture of the current situation of two studies addressing autologous stem cell transplanta- this important topic. tion (ASC), which is considered a minimally invasive There is a variety of methodological standards to medical intervention; both studies were done in a surgery develop a mapping review, but we decided to follow the setting (Table 3). Global Evidence Mapping initiative because it is very ratio- There were only two RCTs on surgical treatment: the nal and systematic.11 This methodology includes three first trial about lymphovenous anastomosis (LVA), and core tasks: setting the topic area’s boundaries and the con- the second trial about vascularized lymph node transfer text in question, searching and selecting relevant studies, (VLNT). The characteristics of the included RCTs on sur- and reporting on search results and study characteristics.11 gical intervention are described in Table 4. In the last 20 years, we identified 240 publications about the treatment for BCRL, which means an average Measured Outcomes of 12 publications per year. Recently, this lack of atten- There was a wide variety of outcomes measured in tion has been partially corrected when the majority of these trials and most of the trials focused on more than these articles (58%) were published in the past 5 years. one outcome. The main outcome measured was the arm We assume that this is due to the availability of new treat- volume and circumference, followed by lymphedema ment options and techniques in the recent years, as well symptoms like heaviness or pain, arm function and range as an increase in the interest of clinical research among Fig. 3. Distribution of the intervention type according to the study design among the total studies (total: n = 240) on BCRL. 5 PRS Global Open • 2022 Table 3. Frequency of the Specific Treatment on BCRL In our findings, of the total 240 articles that we have according to the Intervention Type among the RCTs identified, about 81% were primary studies, which include a considerably large number of interventional studies Intervention No. (61%) and observational studies (20%). However, about Type Specific Treatment RCTs 19% of the total publications were SRs, which might Surgical Lymphovenous anastomosis 1 indicate a considerable gap in secondary studies. Even treatment (robot-assisted) (N = 2) Vascularized lymph node transfer 1 though well-conducted SRs are considered higher quality Nonsurgical Exercise (active, resistant, aqua exercise) 18 evidence than other studies in decision-making for clini- treatment Compression sleeve/bandage 14 cal practice and health policy,22 it was not the goal of this (N = 100) Kinesio tape 10 Manual lymphatic drainage 10 study to analyze these SRs. Pneumatic compression pump 10 Due to the fact that RCTs are highly controlled and Pharmacotherapy 8 Laser therapy/electrical therapy 8 managed studies, and their level of evidence is higher Yoga 4 than other types of primary studies,23 on this mapping Acupuncture 3 review, we have decided to focus more on these RCTs and Decongestive compression therapy 3 Satellite ganglionic block 3 to provide more description of their data. Diet and weight loss 3 Of the total 102 RCTs that we have identified, there Autologous stem cells transplantation 2 were 100 RCTs on nonsurgical treatment and only two Hyperbaric oxygen therapy 1 Extra corporal shock wave therapy 1 studies addressing surgical treatment,15,16 which indicates Others 2 the insufficient number of RCTs in the field of lymph- Total 102 edema surgery. This could be mainly due to the usual and general difficulties to design RCTs to assess the sur- health professionals about the effectiveness and safety gical procedures compared with pharmaceutical agents.24 of these treatments. Due to the extreme importance of Therefore, despite the progressive use of the different sur- BCRL and its physical and psychosocial consequences, gical interventions in clinical practice, there is currently more research is needed in this field to strengthen the not enough high-quality research to assess their effective- evidence base and ensure patients receive clinically effec- ness.25 This highlights the current need for well-designed tive treatment.17 RCTs to compare the effectiveness of the broad range of We have observed in this review that surgical interven- these surgical modalities, as well as in relation to nonsurgi- tions in these articles were mainly distributed between cal therapy. microsurgical techniques (LVA, vascularized lymph node Sometimes the scarcity of RCTs has been justified due transfer) and liposuction. These surgical procedures to the difficulty of blinding, but this requirement is not focused on re-establishing the function of the lymphatic absolutely necessary in designing RCTs and could be over- system and reducing the volume, respectively, which might come with alternative designs to maximize the validity and reflect the common surgical practice nowadays.18 On the to reduce the chance of assessment bias.26 However, we other hand, there was great diversity of nonsurgical inter- assumed that well-designed non-randomized prospective ventions, and usually there was a mix of different options studies were conducted on surgical intervention. that have been used to treat a considerably large number We observed that many RCTs described combined of patients with BCRL.19 treatment options for patients with BCRL. Likewise, we Our results show that the country with the most have identified that studies addressing the surgical inter- research on this topic was the USA, followed by three ventions were also accompanied by garments and/or main countries: Turkey, Australia, and China. Moreover, physiotherapy. This signifies the importance of a multidis- there was significant variability among the countries in ciplinary team in lymphedema treatment provided by a the treatment options that have been assessed in these group of healthcare professionals.27 studies, which supports the diversity of the treatment Among the total number of RCTs, three studies assessed worldwide.20, 21 exclusively the treatment effectiveness in overweight and Table 4. Characteristics of the Included Randomized Clinical Trials on Surgical Intervention for BCRL No. Comparison Outcome Reported Study Country Title Patients Intervention Group Measured Results van Mulken Netherlands First-in-human robotic supermicro- 20 Robot-assisted Manual super- Upper limb No difference et al15 surgery using a dedicated micro- supermicrosur- microsurgical volume, quality surgical robot for treating breast gical lym- lymphatico- of life, duration cancer-related lymphedema: a phatico-venous venous of surgery, and randomized pilot trial anastomosis anastomosis quality of LVA LVA anastomosis Dionyssiou Greece A randomized control study of 36 Vascularized Physiotherapy Upper limb Favors toward et al16 treating secondary stage II lymph node and volume, interven- breast-cancer–related lymph- transfer, phys- compression infection, and tion oedema with free lymph node iotherapy, and alone lymphedema transfer compression symptoms 6 Al-Sakkaf et al. • Mapping of BCRL Treatments Fig. 4. Distribution of the measured outcomes in the randomized control trials on BCRL. Fig. 5. Evidence mapping of the therapeutic results according to the type of intervention among the randomized clinical trials on BCRL. 7 PRS Global Open • 2022 obese patients.28–30 Given the fact that obese individu- Recently this lack of attention has been partially corrected, als have three times the risk of developing lymphedema as the majority of the studies were published in the past 5 compared with the non-obese population,31 we assumed years. However, most of these studies were on nonsurgical that this population was well represented in the totality of interventions. RCTs. Moreover, there were three RCTs that assessed the Most of the RCTs focused on nonsurgical treatment, treatment effectiveness for lymphedema of the breast and and only two RCTs addressed the effectiveness of surgi- chest, which could combine the arm lymphedema.32–34 cal treatment. Therefore, well-designed RCTs on surgical Unfortunately, these lymphedema sites are usually missed interventions are needed to measure their real effective- during the clinical assessment and treatment of BCRL. ness before wider use in regular clinical practice. There was a wide heterogeneity among the published Ali M. Al-Sakkaf, MD, FEBS, FACS studies in terms of population characteristics, interven- Hospital de la Santa Creu i Sant Pau tion types, measured outcomes, and study design. This Universitat Autònoma de Barcelona should be addressed clearly for future research to provide Calle de Zaragoza 79, 3-2 evidence about the treatment effectiveness and could be Barcelona 08006 complemented by SRs if the primary studies are valid and Spain available in number. E-mail: sakaf_250@yahoo.com Even though there was a great variability of the measured outcomes in these RCTs and the majority focused on more REFERENCES than one outcome, almost 90% of them measured the limb 1. Fu MR. 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