Complex physical therapy employing self-adjusting garment (ReadyWrap®) in breast cancer-related lymphedema cases in Brazilian women: a protocol for a randomized controlled trial

One of the main late breast cancer treatment-associated complications is lymphedema, a chronic progressive condition that can develop months or years after treatment. This condition generally affects 1 in 5 women, and its risk increases in patients undergoing radiotherapy, affected limb chemotherapy infusion, obese women, patients presenting seroma development after surgery, a greater number of removed lymph nodes, or presenting an advanced disease stage at diagnosis [1‐4]. According to a study carried out with a cohort of Brazilian women, the cumulative incidence of lymphedema ranges from 13.5% in 2 years to 41.1% in 10 years [2].

Breast cancer-associated lymphedema results from lymphatic system impairment due to lymphatic fluid drainage obstruction and/or interruption, which leads to the accumulation of protein-rich fluids in interstitial spaces, resulting in local edema in the affected area. This phenomenon can affect the upper limb ipsilateral to the surgery, as well as the chest wall and scapular region [3, 5]. When untreated, edema causes progressive structural skin distortion, such as thickening and loss of elasticity, as well as sensory alterations, and pain, also increasing the risk of infections [5]. Because of this, women with this condition present a variety of physical and psychosocial problems, leading to daily activity limitations and negatively affecting their functionality and quality of life [1, 3, 6, 7].

In this context, lymphedema treatment should be initiated at the first signs, aiming towards a better clinical condition resolution and lower quality of life impacts. The gold standard treatment for lymphedema recommended by the International Society of Lymphology [8] is complex decongestive therapy (CDT), consisting in a combination of manual lymphatic drainage, compression therapy, therapeutic exercises, and skin care [4, 9].

Compression therapy is one of the main therapeutic physiotherapy resources to reduce lymphedema-affected limb volume and improve fibrosclerotic changes. This method consists of two distinct phases, the first aiming to maximize limb volume, traditionally performed with compressive bandages, and the second aiming to maintain limb volume, replacing the bandage by a compressive mesh [5, 9].

Studies have established the use of self-adjusting garments to replace or complement the use of bandages and/or compressive meshes [10, 11]. These garments are defined as a prefabricated system consisting of inelastic material containing self-adjusting compressible components according to the size and shape of the patient’s upper limb, comprising one of their main advantages, as these garments can be adapted by the patients themselves, allowing for adjustments with decreasing limb volumes [11]. Thus, costs associated to individual consultations can be minimized while still maintaining lymphedema control effectiveness. These garments can also be potentially useful for patients who live far from treatment centers or who present functional or social difficulties in commuting.

Few studies, however, have evaluated the effectiveness of compression therapy employing self-adjusting garments compared to compressive bandages in the volume reduction phase (phase 1) and meshes in the volume maintenance phase (phase 2) of upper limbs presenting lymphedema secondary to breast cancer.

The primary aim of this study is to evaluate the effectiveness of a self-adjusting compression garment (ReadyWrap®) in reducing and maintaining upper limb volume in women presenting breast cancer-related lymphedema compared to standard compression therapy. Secondary objectives consist in comparing upper limb volume and tissue changes, muscle strength, functionality, and symptoms, as well as health-related quality of life, while also assessing the incidence of adverse events, treatment adherence, and material and professional costs according to the intervention group.

The trial design is as follows: single-blind, superiority, randomized controlled clinical trial, with a 1:1 allocation ratio for each group. Phase 1 participants cannot be part of phase 2 study and vice versa.

This is a clinical trial developed in a public cancer treatment reference hospital in the city of Rio de Janeiro, Brazil, which will compare the standard lymphedema treatment with a self-adjusting compression garment according to treatment phase (upper limb volume reduction or maintenance).

Women aged 18 years and older diagnosed with upper limb lymphedema following surgical breast cancer treatment over 6 months previously and evaluated by the hospital’s physiotherapy service will be eligible for the study. The inclusion criteria were defined according to breast cancer-associated lymphedema treatment stages (Table 1):

The following will be excluded from both treatment phases: women presenting the following: lymphedema prior to surgery; lymphedema or bilateral lymphadenectomy; phlogistic signs in the swollen limb; submitted to compressive bandaging in the last 3 months; previous history of allergic reaction to the material employed used in compression therapy; locally, regionally, or remotely active disease; undergoing chemotherapy or radiotherapy; presenting functional upper limb changes prior to the breast cancer diagnosis; presenting heart disease and uncompensated systemic arterial hypertension; psychiatric, mental, and neurological disorders or any cognitive impairment that make answering questionnaires impossible.

Eligible candidates will be invited by sector physiotherapists to participate in the study. If they agree, they will be forwarded to a space reserved for signing the free and informed consent form (FICF), an interview, and initial evaluation with the study researchers.

Item not applicable in this research, as biological samples are not used to evaluate the study outcomes.

The control group participants will receive the standard institutional therapy, consisting of the gold standard in lymphedema secondary to breast cancer treatment. Thus, the standard intervention group comprising phase 1 will receive the compressive bandaging treatment, while the standard intervention group of phase 2 will receive the compressive mesh treatment.

The evaluations, interventions, and data collection steps will be carried out by three professional physiotherapists with at least 2 years of experience in compression therapy, all trained and qualified for this purpose. All participants will be guided on the research procedures and will receive a booklet with guidance on performing daily home upper limb exercises, skin care, and daily living activities according to the applied institutional routine [12], which does not include manual lymphatic drainage. Compression therapy will be indicated according to the treatment phase (1 or 2) and intervention group (experimental or control). Participants will be randomly allocated to the following treatment groups (Fig. 1).

Treatment suspension before the proposed period will be implemented when side effects occur, such as allergic reactions or poor adaptation to the employed material, as well as limb volume increases greater than 10% of the initial volume, affected upper limb infection and decompensated systemic blood pressure. In the case of any other unforeseen changes, the patient will be evaluated by the health team and any necessary procedures will be adopted.

With the aim of improving treatment adherence, the volunteers will receive a therapeutic diary for use in the first 30 days, in which they must notify exercise performance, garment use, and any arm symptoms during treatment daily. In addition, a face-to-face consultation for the phase 1 groups (A and B) and a teleconsultation for the phase 2 groups (C and D) will be performed within 7 days of study inclusion.

It is important to note that any other lymphedema treatment intervention employed by the study participants will not be restricted. Patients should carry out their normal routines and the only interference of this study will be the type of provided compression therapy. Thus, all patients will be instructed to only use the provided compression therapy.

If an increase of over 10% of the initial volume of the upper limb presenting lymphedema is observed during the 30-day reassessment after participant inclusion, compromising patient functionality and/or quality of life, the participant will be directed to the standard treatment offered by the institution’s physiotherapy service. At the end of the study, regardless of the allocation group and results, participants will be directed to lymphedema treatment according to the institutional routine.

Figure 1 depicts the patient recruitment, intervention, and evaluation schedule during this study.

Considering the benefits of complex physical therapy when there is a percentage reduction in excess limb volume of 22% to 73% [21], and, for the use of compressive therapy, an estimated response of 33.5% reduction in excess limb volume [22], we stipulated a 35% variation in treatment response between the groups, with an estimated treatment response of 45% in the control group (standard care) and 80% in the intervention group. The sample size was calculated considering a confidence level of 95% with a study power of 80% and a 1:1:1:1 ratio between the intervention groups. Thus, a total population of 120 patients (30 in each group) will be required. To cover possible losses to follow-up and treatment interruption, a total of 20% will be added to the number of participants Therefore, the total sample to be included in this study will be of 144 women (36 in each group).

Volunteer recruitment will take place at the health institution itself, through post-operative breast cancer follow-up consultations conducted in the physiotherapy sector. The researchers will indicate patients scheduled for consultation who meet the eligibility criteria to participate in the research to the physiotherapy team. If accepted, the patient will be forwarded to the research sector to sign the free and informed consent form and be allocated in a treatment group.

The choice between the intervention groups is made from the sequential opening of sealed opaque envelopes, and inside each envelope, there was a card numbered from 01 to 36 for group A or B in phase 1 and for group C or D in phase 2. For each participant who agreed to participate in the study, one of the envelopes was open, depending on the intended lymphedema treatment phase, being randomized between an experimental or control group.

Sequentially numbered, opaque, sealed envelopes containing the code that determines participant allocation in the experimental or standard group will be made available according to the treatment phase (phase 1 or phase 2), allocated at a 1:1 ratio in each group. Due to the study characteristics, the allocation will not be blinded and will be revealed to both the participant and the researcher after randomization.

After recruiting by sector physiotherapists, the participants will sign the free and informed consent form alongside the study researchers, and volunteer randomization in each study arm will be carried out. The study group will be revealed to both the patient and the researcher at the same time.

This comprises a simple blind study in which only the statistical researcher responsible for analyzing the collected data will be blinded.

Due to the study characteristics, both the study participants and the research physiotherapist will be aware of the allocation groups. Consequently, no non-blinding procedure is planned.

The data collection will take place through interviews, physical examinations, and medical record analyses. All data will be collected by experienced physiotherapists. The interviews will consist of semi-structured questionnaires produced by the researchers, in addition to questionnaires validated for the Brazilian population. Regarding the physical examination, the volume of the upper limb with lymphedema will be evaluated using perimetry, tissue characteristics using thermography, and muscle strength will be evaluated using dynamometry. These assessment resources will be used for all participants included in the study and performed before and after the initial 30 days of treatment and during follow-up (6 and 12 months). Data regarding oncological treatment and lymphedema treatment history will be obtained from physical and electronic medical records.

Study participants will receive the necessary information to understand the evaluation flow and the importance of completing the follow-up, comprising a teleconsultation within 7 days after study inclusion (at the beginning of the treatment) and face-to-face returns for reassessment in 30 days, 6 months, and 1 year. Any study participant can withdraw and leave the study at any time without necessarily explaining the reasons for withdrawal. Thus, whenever problems contacting the participant by phone (call or text message) arise, the institution will ask the institution to send a telegram to the participant’s registered address, instructing them to contact the physiotherapy sector to schedule their appointment.

Data will be collected by two physiotherapists who will fill in the information on paper sheets. These will be stored in a safe place for a period of up to 5 years in case there is a need for revision or request by the ethics and research committee. The responsibility for filling in the data in the electronic spreadsheet will be for the same initial collectors who will manually fill. A third member of the study group will review all the data in the electronic database, checking with the paper forms, before exporting to Statistical Package for the Social Science (SPSS).

All patients received a random identification number to guaranteeing anonymity. The information collected on paper forms will be stored in a safe place at the Institution’s Clinical Research Division for a period of up to 5 years, in case there is a need for review or request by the ethics and research committee. The data stored in an electronic spreadsheet will be under the responsibility of the main author.

Not applicable, as no biological material will be collected during this study.

A descriptive analysis of the sociodemographic and clinical characteristics of the study population will be carried out through the distribution of absolute and relative frequencies for categorical variables and central tendency and dispersion measures for continuous variables. The thermographic analysis will be obtained by the average difference in temperatures of one limb in relation to the other and a cut-off point will be established. Data normality will be calculated using the Kolmogorov–Smirnov test. Group comparisons will be done by using Student’s t test or Wilcoxon test for continuous variables and chi-square test for categorical variables. The effect size of the mean outcomes will be calculated using Glass’s delta (considering 0.2 as small, 0.5 as medium, and 0.8 as large effects) [23]. Associations between the variables of interest and the outcome will be performed using univariate linear regression. Variables presenting p ≤ 0.20 will be included in the multiple linear regression model employing the stepwise forward method, and those with p < 0.05 or with clinical relevance will be maintained in the adjusted model. A significance level of 5% will be accepted, at a confidence interval of 95%. Statistical tests will be performed using the SPSS version 23.0 software.

An initial analysis is planned with the data obtained in the 30-day evaluation after study inclusion of each volunteer for both groups, with the statistical analysis carried out by the blind researcher according to the statistical planning.

There is no plan for subgroup analyses.

Outcome assessments will be performed by intention to treat and protocol adherence will be verified.

The collected and stored data analyzed in this study may be made available by the main investigator in case of formal request with plausible justification for its use.

This is a study developed in a single location and with few researchers involved. Therefore, no judging committee is included. However, team support is available, as follows: the principal investigator assumes the supervision of the judging committee and technical responsibility for the physiotherapeutic conducts applied to the study participants and is also responsible in case of adverse effects; the study project coordinator carries out test registrations, coordinates technical visits, guarantees the reports, and assists in data organization and protection; physiotherapist 1 performs reassessments and organizes and protects data quality; physiotherapist 2 identifies potential recruits, signals the sector’s physiotherapy team, receives patients, informs the protocol, advises on the informed consent form, performs evaluations, and ensures participant follow-up according to the applied protocol.

A data monitoring committee was not formed for this study. This decision was made based on the absence of serious adverse effects by the applied treatments, both in the experimental treatment and the control, which is the institution’s standard. In any case, control and notifications by the research physiotherapists involved in the study of possible adverse effects and undesirable symptoms reported by the volunteers will be performed. If unwanted effects resulting from the treatment are observed, the participant will withdraw from the study and the institutional routine will be conducted, depending on the situation, and all necessary medical support will be provided.

The occurrence and intensity of the following symptoms will be verified during the first and second treatment phases through reports and notes made in the therapeutic diary: contact dermatitis, skin infection, uncompensated arterial hypertension, and worsening of upper limb volume by 10% of the initial volume, among other unforeseen effects. In addition, all participants will also be provided with a telephone contact that will serve as a communication channel between participants and therapists for reporting adverse events, unpleasant symptoms, questions about lymphedema treatment, and guidance, when relevant. Treatment suspension before the proposed period will take place when side effects are observed, such as allergic reaction or poor adaptation to the applied material, increase in upper limb volume by 10% of the initial volume, affected upper limb infection, and decompensated blood pressure. If any other unforeseen change occurs, the case will be evaluated by the health team and the necessary procedures will be adopted.

No audits were planned or contracted for this study.

Any and all substantial changes that will affect the conduct of this research project will be communicated to the research ethics committee of the previously registered and approved institution for analysis and any judgment. In case the changes affect the participants in any way, they will also be informed about such changes.

The results of this study will be disseminated through indexed publications in peer-reviewed scientific journals and will also be presented to health professionals at national and international scientific events and disseminated on social media for the general population.

This is the first study to comparatively evaluate the use of a self-adjusting compression garment versus traditional therapeutic compression resources applied to lymphedema treatments in two treatment phases, namely volume reduction and maintenance in the Brazilian population. Furthermore, this study is a pioneer in the use of clinical thermography to assess lymphedema tissue characteristics in affected upper limbs. Finally, the planned follow-up will allow for the observation of both short- and long-term outcomes.

Due to the characteristics of this type of study, this clinical trial is single blinded, as there is no possibility of blinding the participants or therapists.