Open access Protocol Which physical therapy intervention is most effective in reducing secondary lymphoedema associated with breast cancer? Protocol for a systematic review and network meta-­analysis Raúl Alberto Aguilera-­Eguía ‍ ‍,1,2 Pamela Seron,3,4 Ruvistay Gutiérrez-­Arias,5,6 Carlos Zaror ‍ ‍4,7,8 To cite: Aguilera-­Eguía RA, ABSTRACT Seron P, Gutiérrez-­Arias R, Introduction Lymphoedema associated with breast STRENGTHS AND LIMITATIONS OF THIS STUDY et al. Which physical therapy cancer is caused by an interruption of the lymphatic ⇒ This study intends to evaluate the efficacy of all intervention is most effective available physical therapy interventions in reducing system, together with factors such as total mastectomy, in reducing secondary breast cancer-­related lymphoedema through a net- axillary dissection, positive lymph nodes, radiotherapy, use lymphoedema associated with of taxanes and obesity. Physiotherapy treatment consists work meta-­analysis. breast cancer? Protocol for a of complex decongestive therapy, manual lymphatic ⇒ This study will be carried out according to the systematic review and network meta-­analysis. BMJ Open drainage and exercises, among other interventions. recommendations of the Cochrane Handbook for 2022;12:e065045. doi:10.1136/ Currently, there are several systematic review and Systematic Reviews of Interventions. bmjopen-2022-065045 randomised controlled trials that evaluate the efficacy ⇒ The quality of the evidence will be evaluated using of these interventions. However, at present, there are the GRADE approach. ► Prepublication history and no studies that compare the effectiveness of all these ⇒ A potential limitation of this study may be the het- additional supplemental material for this paper are available physical therapy interventions. The purpose of this study erogeneity between published studies due to the online. To view these files, is to determine which physical therapy treatment is most characteristics of the interventions. please visit the journal online effective in reducing breast cancer-­related lymphoedema, (http://dx.doi.org/10.1136/​ improving quality of life and reducing pain. bmjopen-2022-065045). Methods and analysis MEDLINE, PEDro, CINAHL, EMBASE, LILACS and Cochrane Central Register capable of spreading.1 2 The WHO considers Received 25 May 2022 it one of the main public health problems in of Controlled Trials will be searched for reports of Accepted 31 August 2022 randomised controlled trials published from database the world and the most recurring in women inception to June 2022. We will only include studies that in developed and developing countries.2 are written in English, Spanish and Portuguese. We will Medical treatments for breast cancer include also search grey literature, preprint servers and clinical (1) local treatments (partial mastectomy/ trial registries. The primary outcomes are reduction of conservative treatment, total mastectomy, secondary lymphoedema associated with breast cancer, axillary dissection and radiation therapy on improvements in quality of life and pain reduction. The the breast and adjacent ganglion chains) risk of bias of individual studies will be evaluated using and (2) systemic treatments (chemotherapy, the Cochrane Risk of Bias 2.0 Tool. A network meta-­ analysis will be performed using a random-­effects model. hormone therapy and monoclonal anti- First, pairs will be directly meta-­analysed and indirect bodies).3 These treatments are not free of comparisons will be made between the different physical adverse consequences, which include anxiety, therapy treatments. The GRADE system will be used alterations in bone health, cardiotoxicity, to assess the overall quality of the body of evidence peripheral neuropathy induced by chemo- © Author(s) (or their associated with the main results. therapy, alterations in cognitive function, employer(s)) 2022. Re-­use Ethics and dissemination This protocol does not require depressive symptoms, falling, fatigue, nausea, permitted under CC BY-­NC. No approval from an ethics committee. The results will be commercial re-­use. See rights pain, diminished physical function, alter- disseminated via peer-­reviewed publications. ations in sexual function, trouble sleeping, and permissions. Published by PROSPERO registration number CDR42022323541. BMJ. intolerance of treatment and secondary For numbered affiliations see lymphoedema associated with breast cancer, end of article. INTRODUCTION which affect the quality of life of those under- Correspondence to Breast cancer is a disease caused by abnormal going treatments.4 Professor Carlos Zaror; and disorganised development of the epithe- Secondary lymphoedema associated with ​carlos.​zaror@​ufrontera.​cl lial cells in the breast ducts or lobes and is breast cancer (BCRL) is considered one Aguilera-­Eguía RA, et al. BMJ Open 2022;12:e065045. doi:10.1136/bmjopen-2022-065045 1 Open access of the most underestimated and debilitating complica- of Interventions. Any amendments to the protocol will be tions of the disease’s treatment.5 The incidence varies in made through PROSPERO. the general population, ranging between 3% and 65%, depending on the type of intervention received by the Eligibility criteria patient and the length of monitoring.5–7 BCRL is caused Type of studies by an interruption of the lymphatic system together with Only RCTs will be included. We will only include studies other factors,5 such as total mastectomy, axillary dissec- that are written in English, Spanish and Portuguese. tion, positive lymph nodes, radiation therapy, use of taxanes and obesity.5 7–10 Clinically, patients refer a heavy Type of participants or rigid sensation in their limbs, limitations in movement, We will include clinical trials on women with BCRL 15 aches and pains in more severe cases, and present hard- years old and over. ening and thickening of the skin or fibrosis.11 Physical therapy treatment (PTT)12 focused on BCRL Type of interventions includes a wide range of interventions, such as complete We will include studies where the intervention incorpo- decongestive therapy, manual lymphatic drainage, low-­ rates any of the following physical therapy interventions level laser therapy, shock waves, pneumatic pumps, or any other reported in the included studies: ► Complete decongestive therapy. Kinesio-­taping, and endurance training/aerobic exer- ► Manual lymphatic drainage. cise, multimodal training, water training, yoga and ► Low-­level laser therapy. Pilates. Currently, there are several systematic reviews that ► Pneumatic pumps. evaluate the efficacy of these different PTTs in reducing ► Kinesio-­taping. BCRL.13–47 ► High-­intensity resistance exercise. Additionally, in 2020, the Academy of Oncologic Phys- ► Moderate-­intensity resistance exercise. ical Therapy of the American Physical Therapy Asso- ► Low-­intensity resistance exercise. ciation published a clinical practice guideline to aid in ► Supervised resistance exercise. making informed decisions based on evidence from ► Unsupervised resistance exercise. each one of the analysed physical therapy interventions ► Supervised endurance training. through different randomised clinical studies (RCTs).12 ► Unsupervised endurance training. However, despite the large quantity of published evidence, ► Resistance exercise plus endurance training. there are currently no studies that compare the efficacy of ► Endurance training plus water endurance training. these PTTs with each other, which makes it difficult to ► Resistance exercise plus endurance training plus determine which treatment is most effective in reducing BCRL, improving quality of life and reducing pain. stretching. ► Yoga. In this context, network meta-­analyses (NMA) emerge ► Pilates. as a useful alternative as they include data from RCTs ► Shock waves. that do not necessarily present the same type of groups ► Any combination of the above physical therapy of comparison as a study network (indirect comparison). Based on this, an NMA allows direct and indirect compari- interventions. sons between all physical therapy interventions, analysing Type of comparisons their efficacy in reducing BCRL. It can also determine The different physical therapy interventions will be which intervention is the most effective and which has compared with each other and with their combinations, the greatest possibility of success compared with other as well as with usual care, education or a group without interventions which have not been previously compared physical therapy interventions. in RCTs.48–50 The purpose of this systematic review and network Type of outcomes of interest meta-­ analysis is to determine the comparative efficacy The outcomes will be on patients’ condition. of the different physical therapy interventions in terms of reducing BCRL, improving quality of life, as well as Primary outcomes reducing pain and incidence of adverse events. ► Reduction of secondary lymphoedema associated with breast cancer, measured by any of the following validated methods: volumetry of water movement, METHODS AND ANALYSIS measurement of the limb’s circumference, bioim- This protocol was registered in PROSPERO pedance spectroscopy, dual X-­ray absorptiometry and (CDR42022323541) and was reported according to the perometry. guidelines of the Preferred Reporting Items for System- ► Improvements in quality of life, evaluated by any vali- atic Review and Meta-­ Analysis Protocols (PRISMA-­P)51 dated scale of generic or specific self-­evaluation (eg, (online supplementary appendix 1). The systematic European Organisation for Research and Treatment review will be carried out according to the recommenda- of Cancer Quality of Life Questionnaire (EORTC tions of the Cochrane Handbook for Systematic Reviews QLQ-­C30) and EORTC QLQ-­BR23 questionnaires. 2 Aguilera-­Eguía RA, et al. BMJ Open 2022;12:e065045. doi:10.1136/bmjopen-2022-065045 Open access ► Pain reduction, evaluated by any validated scale of RoB 2.0 evaluates the following domains: bias derived generic or specific self-­evaluation (eg, numeric rating from the randomisation process, bias due to deviations scales (NRS) and visual analogue scale (VAS)). from planned interventions, bias due to lack of results All follow-­ups reported by the primary studies will be data, bias in the measurement of the result and bias in considered. the selection of the reported results. A series of signal- ling questions will be included for each domain aiming Secondary outcomes to provide a structured approach to obtain relevant infor- ► Adverse events from the physical therapy interven- mation on bias risk assessment. For each domain, the tion, such as increase in lymphoedema and pain. possible risk of bias judgements will be low risk of bias, ► Range of motion, evaluated with goniometry or some concerns and high risk of bias.54 We will also present another validated method. a summary of the ‘risk of bias’ graphically. ► Muscular strength, evaluated with dynamometry or another validated method. Missing data If possible, the authors of the original studies will be Search strategies contacted to obtain information on missing data and The systematic database search will cover publications up further details on any results of interest that could have to June 2022, with initial dates depending on database been measured but were not formally reported in the inception: from 1966 in MEDLINE, 1974 in EMBASE, study. We will not use any other statistical method to 1982 in LILACS, 2008 in Cochrane Central Register of impute missing data. Controlled Trials, 1999 in PEDro and 1984 in CINAHL. The details of the search strategy to be used in MEDLINE, Statistical analysis PEDro, CINAHL, EMBASE, LILACS and Cochrane Relative risk will be used for dichotomous results. As Central Register of Controlled Trials are described in for continuous results, when the results of interest are online supplemental file 2. The search strategy used in measured with the same scales, the mean difference will MEDLINE was adapted so that it may be implemented in be used with the corresponding 95% CI. The standardised the remaining databases. Additionally, we will perform a mean difference will be calculated when the results of search of the European grey literature database (http:// interest are measured with different scales.53 www.opengrey.eu), examine the reference lists of all rele- We will perform a meta-­analysis during the previously vant articles, including studies and previous systematic established period of monitoring. First, we will meta-­ reviews, and examine registers of RCTs (such as www.​ analyse in pairwise (direct) and will use a random-­effects registroensayosclinicos.org, https://clinicaltrials.gov and model for each comparison. A network diagram will then https://www.who.int/clinical-trials-registry-platform), be generated and evaluated to determine the plausibility public access policies (https://publicaccess.nih.gov) and of an NMA. An NMA will be done using a frequentist anal- preprint servers (https://www.medrxiv.org, https://www.​ ysis,48 55 as this focus uses only the information obtained biorxiv.org). in the analysis, which is the statistical meaning’s base, to evaluate a hypothesis from this study’s data.56 Data management Analyses will be done using Stata V.15 software.57 We All search results will be exported to Rayyan Intelligent will use the Stata commands designed for NMA.55 58 59 If Systematic Review (https://www.rayyan.ai).52 Once dupli- the association is not adequate, the information will be cates have been eliminated, two researchers will inde- described. pendently screen by title and abstract and will review Heterogeneity analysis potential full text to be included. In case of discrepancy, We will use two methods to evaluate heterogeneity: the a third researcher will make the final decision (CZ). A first will be an informal, visual inspection; the second will registry will be kept of the reasons for excluding studies. use the inconsistency test (I2). However, the decision on Two researchers will independently extract data from heterogeneity will depend on the value presented by I2, the included studies to a standardised Excel spreadsheet. with greater than 50% indicating considerable hetero- The spreadsheet will include the following sections: study geneity.53 In the pairwise meta-­analysis, we will estimate identification, study design/setting, study population and the heterogeneity for each comparison. In the NMA, a participant demographics, baseline characteristics, details common estimate for heterogeneity variance will be of the intervention and control conditions, outcome data assumed in all physical therapy comparisons. of interest, and follow-­up times. Transitivity analysis Risk of bias of individual studies As a concept, transitivity is based on the homogeneity Two authors of this review will independently evaluate between the studies included in the analysis.48 There- the risk of bias of the included studies according to the fore, it allows evaluation of the singular characteristics of Revised Cochrane Risk of Bias Tool (RoB 2.0).53 In case each study to conclude if the estimators generated by the of discrepancy, a third author will make the final decision statistical analysis are valid or not.49 Transitivity refers to (CZ). the assumption that should be adopted when an indirect Aguilera-­Eguía RA, et al. BMJ Open 2022;12:e065045. doi:10.1136/bmjopen-2022-065045 3 Open access comparison is established via a common comparator (B is Concluding report better than A and A is better than C, so it is assumed that This systematic review will be reported according to the B is better than C).48 54 60 61 For example, patients included extension of the PRISMA guidance for systematic reviews in studies that compare A versus a placebo should be that include network meta-­analysis.68 similar in terms of population, intervention, comparison, We will use the Grading of Recommendations Assess- results of interest and research design to those included ment, Development and Evaluation (GRADE) working in B versus placebo.49 Within this context, we expect that group focus to rate the efficacy estimations’ certainty the supposed transitivity will be maintained once it is based on the NMA for all of the comparisons (direct and assumed that the common treatment used to compare indirect) and all of the results of interest.69 The certainty the different physical therapy interventions is similar in of evidence will be evaluated following the four steps the different RCTs. The supposed transitivity will be eval- proposed to evaluate the efficacy estimations’ quality of uated by comparing the characteristics of the population, the NMA’s treatment70: intervention, comparison, results of interest and research ► Present the treatment’s direct and indirect estimates design of the different physical therapy interventions. for each comparison from the evidence network. The effect’s direct estimate can be determined by a direct Inconsistency analysis comparison (trial A vs trial B), and the indirect esti- We will use the design-­by-­treatment model to evaluate mate by two or more direct comparisons that share a inconsistency as it is the only model that can explain the common comparator (eg, we infer the effects of A vs B different sources of inconsistency that may appear (loop from trial A vs trial C and from trial B vs trial C). inconsistency, multiarm trial, design inconsistency, design-­by-­ ► Rate the quality of each direct and indirect effect treatment interaction). estimate. We will use the node-­splitting method to verify consis- ► Present the NMA estimate for each comparison in the tency between direct and indirect evidence.48 62 63 evidence network. Node-­splitting corresponds to a more general but compu- ► Rate the quality of each NMA effect estimate. tationally intensive analysis, where the evidence is directly We will prepare a table that shows the ‘summary of the or indirectly divided from a particular comparison, or network meta-­analysis findings’ according to the GRADE ‘node’, and can be applied to networks where trial data working group recommendations.71 In order to eval- are available.56 uate the certainty of evidence, we will use the following domains72: risk of bias, inconsistency, indirect evidence, Relative treatment classification inaccuracy and reporting bias. Finally, the certainty of Once the compared efficacy for all the interventions has evidence will be classified as high, moderate, low or very been evaluated, the results will be classified with a focus low.73 on the following64: ► Determining the order of the classification of the physical therapy interventions, using the surface Patient and public involvement under the cumulative ranking curve. Patients and or public were not be involved in this study, ► Probability of being the best intervention. either in planning or the design of the study. Patients were not invited to comment on the study design and were not Additional analysis consulted to develop patient-­relevant outcomes or inter- We expect to perform the following subgroup analysis pret the results. Patients were not invited to contribute to based on the different monitoring periods and quality-­ the writing or editing of this document for readability or of-­life tools. We also plan to perform a sensitivity analysis accuracy. to evaluate the impact of the trials’ quality. Therefore, we consider a sensitivity analysis for each outcome by excluding studies that are at high risk of bias. ETHICS AND DISSEMINATION Reporting bias evaluation This protocol does not require approval from an ethics Reporting bias will only be evaluated if at least 10 trials committee as it is a secondary study that compiles data are included in the meta-­analysis, as less than this number from primary studies. The results will be disseminated via means that the test’s statistical power is too low to distin- peer-­reviewed publications. guish the random from real asymmetry.53 We will use Author affiliations Begg’s test to analyse the funnel plot.65 66 This method is 1 Departamento de Salud Pública, Facultad de Medicina, Universidad Católica de la based on the degree of association between the estimated Santísima Concepción, Concepcion, Chile effect size and its variations.66 Therefore, a strong correla- 2 Department of Paediatrics, Obstetrics and Gynaecology and Preventive Medicine, tion represents reporting bias.67 Universitat Autònoma de Barcelona, Barcelona, Spain 3 Departamento de Ciencias de la Rehabilitación, Facultad de Medicina, Universidad If there is asymmetry, we will examine other causes de La Frontera, Temuco, Chile besides reporting bias, such as selective outcome 4 CIGES, Faculty of Medicine, Universidad de La Frontera, Temuco, Chile reporting, poor methodological quality in smaller studies 5 Servicio de Medicina Física y Rehabilitación, Unidad de Kinesiología, Instituto and heterogeneity. Nacional del Tórax, Santiago, Chile 4 Aguilera-­Eguía RA, et al. BMJ Open 2022;12:e065045. doi:10.1136/bmjopen-2022-065045 Open access 6 Exercise and Rehabilitation Sciences Institute, School of Physical Therapy, Faculty 9 Kilbreath SL, Refshauge KM, Beith JM, et al. Risk factors for of Rehabilitation Sciences, Universidad Andres Bello, Santiago, 7591538, Chile lymphoedema in women with breast cancer: a large prospective 7 Department of Pediatric Dentistry and Orthodontics, Faculty of Dentistry, cohort. Breast 2016;28:29–36. doi:10.1016/j.breast.2016.04.011 10 Shaw C, Mortimer P, Judd PA. A randomized controlled trial of weight Universidad de La Frontera, Temuco, Chile reduction as a treatment for breast cancer-­related lymphedema. 8 Center for Research in Epidemiology, Economics and Oral Public Health (CIEESPO), Cancer 2007;110:1868–74. Faculty of Dentistry, Universidad de La Frontera, Temuco, Chile 11 Dayan JH, Ly CL, Kataru RP, et al. Lymphedema: pathogenesis and novel therapies. Annu Rev Med 2018;69:263–76. Twitter Ruvistay Gutiérrez-­Arias @ruvistay 12 Davies C, Levenhagen K, Ryans K, et al. Interventions for breast Cancer–Related lymphedema: clinical practice guideline from Contributors RAA-­E, CZ, RG-­A and PS contributed to the conception and design the Academy of oncologic physical therapy of APTA. Phys Ther of the study. RAA-­E developed the search strategies. RAA-­E, CZ and PS designed 2020;100:1163–79. the data analysis. All authors drafted the article and made the final approval of the 13 Shao Y, Qi K, Zhou Q-­H, et al. Intermittent pneumatic compression version to be published. pump for breast cancer-­related lymphedema: a systematic review and meta-­analysis of randomized controlled trials. Oncol Res Treat Funding This project was funded by Dirección de Investigación, Universidad 2014;37:170–4. Católica de la Santísima Concepción (project code: DIREG 15/2021). 14 Rogan S, Taeymans J, Luginbuehl H, et al. Therapy modalities to reduce lymphoedema in female breast cancer patients: a systematic Competing interests None declared. review and meta-­analysis. Breast Cancer Res Treat 2016;159:1–14. Patient and public involvement Patients and/or the public were not involved in 15 Smoot B, Chiavola-­Larson L, Lee J, et al. Effect of low-­level laser the design, or conduct, or reporting, or dissemination plans of this research. therapy on pain and swelling in women with breast cancer-­related lymphedema: a systematic review and meta-­analysis. J Cancer Patient consent for publication Not required. Surviv 2015;9:287–304. doi:10.1007/s11764-014-0411-1 16 Liang M, Chen Q, Peng K, et al. Manual lymphatic drainage for Provenance and peer review Not commissioned; externally peer reviewed. lymphedema in patients after breast cancer surgery: a systematic Supplemental material This content has been supplied by the author(s). It has review and meta-­analysis of randomized controlled trials. Medicine not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been 2020;99:e23192. 17 Huang T-­W, Tseng S-­H, Lin C-­C, et al. Effects of manual lymphatic peer-­reviewed. Any opinions or recommendations discussed are solely those drainage on breast cancer-­related lymphedema: a systematic review of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and and meta-­analysis of randomized controlled trials. World J Surg responsibility arising from any reliance placed on the content. Where the content Oncol 2013;11:1–8. includes any translated material, BMJ does not warrant the accuracy and reliability 18 Shao Y, Zhong D-­S. Manual lymphatic drainage for breast cancer-­ of the translations (including but not limited to local regulations, clinical guidelines, related lymphoedema. Eur J Cancer Care 2017;26:e12517. terminology, drug names and drug dosages), and is not responsible for any error 19 Thompson B, Gaitatzis K, Janse de Jonge X, et al. Manual lymphatic and/or omissions arising from translation and adaptation or otherwise. drainage treatment for lymphedema: a systematic review of the literature. J Cancer Surviv 2021;15:244–58. Open access This is an open access article distributed in accordance with the 20 Lin JJ. Cancer treatment. Caring Patients Across Cancer Care Contin Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which Essentials Prim Care 2019;5:93–123. permits others to distribute, remix, adapt, build upon this work non-­commercially, 21 Thomaz JP, Dias TDSM, de Rezende LF. Effect of taping as treatment and license their derivative works on different terms, provided the original work is to reduce breast cancer lymphedema: literature review. J Vasc Bras properly cited, appropriate credit is given, any changes made indicated, and the use 2018;17:136–40. is non-­commercial. See: http://creativecommons.org/licenses/by-nc/4.0/. 22 Kasawara KT, Mapa JMR, Ferreira V, et al. Effects of Kinesio taping on breast cancer-­related lymphedema: a meta-­analysis in clinical Author note RAA-­E is a PhD candidate in Methodology of Biomedical Research trials. Physiother Theory Pract 2018;34:337–45. and Public Health Program, Universitat Autònoma de Barcelona (UAB), Barcelona, 23 Monteiro SE, Resende LV, Felicíssimo MF, et al. Treatment of upper Spain. limb lymphedema with low-­level laser: a systematic review. Fisioter. mov. 2014;27:663–74. ORCID iDs 24 Baxter GD, Liu L, Petrich S, et al. Low level laser therapy Raúl Alberto Aguilera-­Eguía http://orcid.org/0000-0002-4123-4255 (Photobiomodulation therapy) for breast cancer-­related lymphedema: a systematic review. BMC Cancer 2017;17:833. Carlos Zaror http://orcid.org/0000-0001-6942-6956 25 E Lima MTBRM, E Lima JGM, de Andrade MFC, et al. Low-­Level laser therapy in secondary lymphedema after breast cancer: systematic review. Lasers Med Sci 2014;29:1289–95. 26 Cendron SW, Paiva LL, Darski C, et al. 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