This study was approved by the Institutional Review Board (IRB) of a larger metropolitan health system and was registered as clinical trial #10-00923. Physicians and nurse practitioners referred potential participants from March 2011, to June 2016. To be enrolled in the trial, potential participants who were willing to participate in the trial had to (1) meet the inclusion and exclusion criteria (Table 1) and (2) obtain written approval from their referring physician, who agreed to allow the patient to participate in the trial.
A double-blind, randomized, placebo-controlled design was used for this pilot study to explore the effectiveness of LLLT on lymphedema as a complementary intervention to CDT when compared with CDT treatment alone. The primary outcomes were lymphedema symptoms, limb volume, and QOL. We hypothesized that patients in the active laser group would have significantly fewer symptoms, better limb volume, and improved QOL in comparison with those in the inactive laser group.
Oncologists affiliated with the medical center were informed about the trial. Women who came to the clinic for a lymphedema evaluation were offered a study flyer for participation into the trial. Fifty-four women who met the inclusion criteria were identified. Twenty-two women agreed to participate in the study. Informed consent was obtained from all participants, and subjects were randomized into either an active laser group or an inactive laser group. One subject consented to the study and was randomized, then changed her mind before data collection was performed, so a total of twenty-one women participated in the study (Fig. 1).
Randomization and blindness
After participants signed the informed consent, they were randomized and assigned into either an active laser intervention group (laser group) or an inactive laser placebo-control group (placebo group) using a non-stratified permuted-block design. Varying block sizes were used to minimize the possibility of predicting the allocation sequence. The study’s statistician, who was not involved in treatment intervention or data collection, performed the randomization. Participants were blinded to the laser allocation. Lymphedema therapists and research assessors who collected outcomes data were also blinded to the randomization of group allocation, as well as to the allocation of the active and inactive laser devices. All clinicians who administrated the laser therapy were blinded to the allocation of the lasers. This was made possible because both the active and inactive laser device presented the same red light during the treatment.
Since CDT has been the standard treatment for breast cancer-related lymphedema (BCRL) , all study participants received CDT in this trial. The detailed description of CDT can be found in Table 2. The use of LLL (the LTU-904 laser by RianCorp) was added to CDT. The study utilized a total of 4 lasers, 2 active and 2 inactive laser devices, which were pre-calibrated to provide either active or placebo laser treatment. This information was blinded to participants, lymphedema therapists, and researchers who evaluated outcome measures. Lymphedema therapists were trained in the application of the LLL, and complementary LLLT was administered twice a week at the beginning of each lymphedema treatment session before CDT.
LLLT was performed using a standardized fabric treatment grid made from cut fabric sheets. The grid was pre-fashioned with 40 punctured holes as marked treatment sites, and the holes were divided into four color-coded groups: red, blue, green, and black. The holes alternated colors to allow for spacing of ≥ 2 cm between consecutive same-colored holes. Participants were given their own fabric treatment grid to be used for the duration of the study. The fabric grid was draped over the underarm and medial to lateral chest wall of the affected upper quadrant using pre-determined anatomical landmarks to ensure consistency with each treatment. The laser treatment was applied with the participant positioned in supine with the affected arm abducted to 90° (Fig. 2). The laser was applied over the standardized grid using a corresponding set of color-coded holes alternating each session on a 4-week cycle (Fig. 3). LLLT was applied on the high setting for 1 min at each of 10 sites in the axilla and a portion of the chest wall on the affected side, for a total of 8–16 sessions depending on the time frame needed to achieve clinical goals. The dose per application site was 1.5 J per centimeter squared (J/cm2), for a total dose of 15 J/cm2 delivered at each treatment session.
Members of the research team who were blind to the randomization of the LLL device collected data. Lymphedema therapists were trained in the application of LLLT. Both groups received individualized CDT as determined by their treating therapist. Treatment sessions using LLLT as an adjunct to CDT ranged between 8 and 16 sessions, with the final number of visits for each subject determined by the time needed to achieve maximal circumferential reduction as assessed by girth measurements, and palpation of soft tissue texture/density improvement. Demographic and medical information was obtained at the first visit after evaluation. Data collection of selected outcome measures was performed at the first visit after evaluation, after 8 treatment sessions, after the final treatment session, and at long-term follow-up at 3, 6, and 12 months (Table 3). We followed the research procedures used in our prior studies [38, 39], including use of the perometer as recommended by the manufacturers [38,39,40]. Protection of human subjects was ensured by following the guidelines set forth by the IRB. Each participant signed the written consent to the study.
Clinical and outcome measures
Demographic and medical information
A structured interview tool was used to gather demographic and medical information [38,39,40]. Demographic and medical data collected included age, ethnicity, occupation, education, diagnosis, treatment, nodal status, numbers of lymph nodes removed, co-morbidities, and family and medical history (such as breast cancer history, breast cancer gene status, and family history of lymphedema). Medical information was verified by reviewing participants’ medical records as needed.
Height and BMI
Height was measured without shoes on to the nearest 0.1 cm with a portable stadiometer. An electrical bioimpedance device (InBody 520, Biospace Co., Ltd.) was employed to measure the weight, and the device automatically calculated BMI using the formula: weight (kg)/height (m2) .
Lymphedema symptoms and symptom distress
The lymphedema and breast cancer symptom experience index (BCLE-SEI) is a valid, reliable, 5-point Likert-type self-report instrument to assess symptoms related to lymphedema or fluid accumulation [40,41,42]. This instrument consists of two parts, one evaluating the occurrence of lymphedema symptoms and another evaluating QOL in terms of symptom distress. The lymphedema symptom assessment (part 1) assesses impaired limb mobility in the shoulder, arm, elbow, wrist, and fingers. It also assesses arm swelling, breast swelling, chest wall swelling, heaviness, firmness, tightness, stiffness, numbness, tenderness, pain/aching/soreness, redness, blistering, burning, stabbing, tingling (pain and needles), hotness, seroma, and limb fatigue/weakness. Symptom distress (part 2) evaluates the adverse impact and suffering evoked by one’s experience of lymphedema symptoms [40,41,42]. Symptom distress includes dimensions of daily living, social function, sleep disturbance, sexuality, emotional/ psychological distress, and days absent from work.
Infrared perometer measurement of limb volume
Perometry was performed on each arm as it was held horizontally. The Perometer 350S maps a 3-dimensional graph of the affected and non-affected extremities using numerous rectilinear light beams and interfaces with a computer for data analysis and storage. A 3-dimensional limb image was generated and LV was calculated. This optoelectronic method has a standard deviation of 8.9 ml (arm), less than 0.5% of LV with repeated measuring. Procedures for perometry were based on protocol used in other research .
Demographic and treatment variables
Adherence to the Research Program we defined participants’ adherence to the research program as patients having completed each follow-up visit without loss to follow-up. SPSS version 22 (IBM, Armonk, NY, USA) was used for statistical analysis. Descriptive statistics were calculated for baseline demographic (age, weight, BMI, percentage of body fat, marital status, employment, retirement status, disability) and clinical characteristics (primary cancer stage, secondary cancer stage, mastectomy, lumpectomy, chemotherapy, radiation, auxiliary lymph node treatment, lymph nodes removed, family history of lymphedema) overall and within each treatment arm. All point estimates were generated with 95% confidence intervals. Mean and standard deviations were used to summarize continuous variables; frequencies and percentages were used to summarize categorical variables.
Lymphedema symptoms, limb volume, and QOL
Because even a 5% limb volume increase enables detectable differences in QOL, lymphedema was defined as a perometer measurement of ≥ 5% limb volume increase in the ipsilateral arm in comparison with the changes in the contralateral arm . As the 24 lymphedema symptoms denote clusters of symptoms, i.e., groups of more than two symptoms that occur together, to indicate different biological mechanism , we categorized the 24 symptoms into three identifying symptom clusters of impaired limb mobility (limb mobility in the shoulder, arm, elbow, wrist, and fingers, tightness and stiffness), fluid accumulation symptoms (arm swelling, breast swelling, chest wall swelling, seroma, heaviness, and firmness), and pain/discomfort symptoms (pain/aching/soreness, numbness, tenderness, redness, blistering, burning, stabbing, tingling, hotness, limb fatigue/weakness).
Distributions of the outcome variables, including (a) limb volume by perometer ≥ 5%, (b) count of lymphedema symptoms (0 vs 1–24 symptoms), (c) symptom clusters (reporting 2 or more symptoms related to impaired limb mobility, fluid accumulation, and pain/discomfort), and (d) symptom distress, were summarized at each time point (visit 1 to visit 6) and associations with laser treatment groups (active versus inactive) were estimated. Chi-square analyses were performed to estimate for the associations between categorical demographic and clinical predictors and laser treatment groups. Fisher’s exact tests were conducted when data did not meet the assumptions of Pearson’s chi-square (cells with expected counts < 5). Independent group t tests were used to compare groups on continuous variables.