Evaluation of Response to Treatment in Breast Cancer-related Lymphedema

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Introduction
Breast cancer is the most common type of cancer among women [1]. Increased survival rates due to screening and early treatment results in functional impairments and disabilities after survival rather than the death, with long-term complications of the disease and the treatment becoming more and more common [2], [3].
Breast cancer related lymphedema (BCRL) is one of the most common problems in the course of the treatment. Having an incidence of 5-42%, BCRL has devastating effects on the quality of life and the healthcare costs in patients with breast cancer [4]. After the treatment for malignancy, lymphatic system may have dysfunctions resulting in excess protein-rich uid in interstitial compartment, which is manifested as lymphedema.
There are many methods for the diagnosis of lymphedema, including circumferential measurements, water displacement method volumetry, perometry, bioimpedence spectroscopy, tonometry, lymphography, lymphoscintigraphy and magnetic resonance imaging [5] .Although there is not a consensus about the preference for the methods, volume related methods (Circumferential measurements, water displacement method volumetry, perometry) are usually preferred over other methods, while bioimpedance spectroscopy becoming more common for the earlier diagnosis for the BCRL [6,7].

CLUE (Breast Cancer-Related Lymphedema of the Upper Extremity) is a tool that was developed by
Spinelli et al to assess the presence and severity of the lymphedema in these patients [8]. Having both objective and subjective measures, CLUE scores are shown to be a valid and reliable scale to assess BCRL.
While there are many therapeutic approches in the management of BCRL, the gold standard method is considered the complete decongestive therapy [9]. The lack of a consensus is also valid for the measures of follow-up in the course of the therapy, with volume related methods preferred more often, like the diagnostic measures [10]. Use of bioimpedence spectroscopy and CLUE scores also require more evidence for justi cation of their use in evaluating the effectiveness of the therapy [8].
The aim of this study was to assess and compare the response to the BCRL treatment with CLUE scores, bioimpedence spectroscopy and the volume-assessments /measurements. A secondary aim of the study was to show whether CLUE has a place in the treatment response, and its correlation with the other measures of lymphedema.

Participants:
Sixty-two patients who were admitted to the lymphedema diagnosis and treatment clinic with BCRL were invited to take place in this study. Inclusion criteria were being older than 18 years and the presence of unilateral lymphedema in the affected upper extremity after mastectomy for breast cancer. Exclusion   criteria were the presence of bilateral lymphedema, primary bone tumours or bone metastasis, circulatory  problems of the upper extremities (peripheral vascular disease, thrombosis etc), elephantiasis, local  infections involving upper extremities or systemic infections, lymphangitis carcinomatosa, congestive heart failure, ongoing radiotherapy, having a history of prosthetics for the upper extremities and the present use of medications which could affect uids or electrodes, such as diuretics. After the application of these criteria, 40 patients were eventually included in this study.
This study was approved by ethics committee of the institution, and all patients were obtained informed consent before their inclusion in the study.

Outcome Measures:
After medical histories of the patients were taken, a detailed physical examination by a physician was performed. Details of the cancer therapy history were recorded, as well as the ndings obtained in the physical examination. Diagnosis of lymphedema was con rmed by a physician specialized in this area.
Joint range of motion and manual muscle tests were also measured for the patients' upper extremities.
Assessment of the upper-extremity volumes: Bilateral upper-extremity volumes were assessed using circumferential measures according to the frustum model, with measurements being taken at 5 cm intervals, starting from 1st to 5th metacarpal joints' level and ascending upwards [11]. Clinically signi cant lymphedema was de ned as the 10% difference between extremity volumes, and patients were followed-up weekly with the measurements, with the nal assessment being after the therapy [10]. CLUE (Breast Cancer-Related Lymphedema of the Upper Extremity) score: Patients were evaluated with CLUE score before and after the therapy. Consisting of four domains de ned as obscuration of anatomical architecture (0-18 points), deviation from normal anatomical architecture (0-18 points), tissue score (0-18 points), edema score (0-18 points), this tool was designed by Spinellli et al in 2019 to assess the presence and the severity of the upper extremity lymphedema in patients with breast cancerrelated lymphededema in three areas: Hands and ngers, wrists and forearms, from elbows to shoulders[8]. This tool was applied to the patients by a quali ed physician in lymphedema, and former scores of the patients were blinded to the evaluator when applying the tool after the therapy.
Functional assessment of the upper extremities: Upper extremity functions were assessed using The Disabilities of the Arm, Shoulder and Hand Score (QuickDASH). QuickDASH includes 19 questions regarding the functional use of the affected upper extremities. Each question has a score of 0 to 5, with higher scores indicating worse functional state. QuickDASH was shown to be valid and reliable to assess the functional use of the upper extremity, by Duger et al [12].
Bioimpedance Spectroscopy: Before and after the therapy, a lymphedema index was measured using a bioimpedence spectroscopy device, L-Dex U400 (Impedimed, Brisbane-Australia). Using electricity below the sensory thresholds of the patients, this device detects the changes in the interstitial uid and produces a lymphedema index score. Indices higher than 10 are considered pathologic, indicating the presence of lymphedema. Patients were instructed about the measurement in detail, and were told to get adequate hydration, and avoid liquids that may have diuretic effects, such as tea or coffee, in order to preserve their normal balance of electrolytes before the measurements. Reliability and validity of the bioimpedance spectroscopy methods was shown by Avila et al [13].
Hand-grip strength: Hand-grip strength was measured using a JAMAR hand dynamometer. Measurements were obtained with patients standing up, with their arms adducted in a neutral position, and elbow positioned in a 90 degree angle. This measurement was performed 3 times consecutively, and the mean of their values were recorded as kgf. Hand-grip strength measurements by JAMAR dynamometers were shown to be valid and reliable in a study performed by Shechtman et al [14].
Complete Decongestive Therapy (CDT): All patients were included in the complete decongestive therapy program. This therapy includes patient education, skin care, exercises, manual lymphatic drainage (self), and compression bandage therapy. After this intensive phase of the therapy, maintenance phase, which includes the preservation of the gains through the use of stockings and maintaining the exercises and manual lymphatic drainage, begins. This study encompasses only the intensive phase of the complete decongestive therapy.
Patients were informed about skin care and protective approach for lymphedema. They were asked to hydrate adequately and control their weight [15]. A booklet containing the information above alongside with exercises and frequently asked questions were also given to all patients, and the things they would have to do were told in each visit.
All patients were prescribed lymphedema speci c exercises involving muscle contractions on the upper extremity joints while taking complete decongestive therapy, 30 minutes each day. They were speci cally informed that exercise does not aggravate the severity of their lymphedema. A daily self-applied manual lymphatic drainage technique which helps the drainage of the lymphatic uid through anatomical pathways was also instructed [16].
Multilayer short stretch bandages were applied to the patients with self manual lymphatic drainage. Intensive phase was given 5 days a week, and short stretch bandages applied for 23 hours a day with 1 hour interval. To increase the local pressure on the areas required, foams were added. Patients were screened with arm circumferential measurements once a week and after gaining a plateau in the volumes, patients were prescribed compression garments. All of the patients completed the therapy without any adverse events observed.

Statistical Analysis
Statistical analyses of the data was conducted using SPSS (Statistical Package for the Social Sciences) version 22 (IBM Corporation). Descriptive statistics were used to evaluate demographic and clinical data.
To assess whether the data were compatible with normal distribution, Shapiro-Wilk test was used. Variables were expressed either as median (minimum-maximum) or mean±(standard deviation) for numeric data, and number(%) for categorical data. Dependent variables compatible with normal distribution was tested using t tests for dependent variables, and for the ones with non normal distribution, Wilcoxon's signed rank test was used. Spearman's correlation test was used to assess the correlation between variables. Statistical signi cance was set as p < 0.05.

Results
A total of 40 patients were included in the analyses. Mean age and the body mass indices of the patients weres 57.8 ± 12.46, and 30.99 ± 4.69, respectively. 95% of the patient were right handed, and the prevalence of the right arm lymphedema was 50%. Demographic and clinical characteristics of the patients are presented in Table 1.  Comparisons of the outcomes before and after CDT showed improvements in volumes (14.43% reduction), bioimpedance spectroscopy values (BIS) (46.25% reduction) and CLUE scores (31.77% reduction in total score), including CLUE total, anatomic, edema, and tissue subscores in the extremities with lymphedema (p < 0.05). Changes in hand-grip strength (3.59% reduction) and QuickDASH scores (1.35% reduction) were not found to be statistically signi cant before and after the therapy (p > 0.05).
Correlation analyses showed that CLUE total score and BIS values were correlated with the reduction in the volumes (p = 0.04 and p < 0.001, respectively). Moreover, CLUE total score was also found to be positively correlated with the BIS values (p < 0.001). Hand grip strength and QuickDASH scores were not found to be correlated with the changes in the volume (p = 0.475 and p = 0.210, respectively) and CLUE total scores (p = 0.21 and p = 0.57, respecively)( Table 2)   Table 2 Changes before and after the treatment

Discussion
Results of this study indicates that a complete decongestive therapy is an e cient management method for the patients with breast cancer-related lymphedema. Moreover, the improvements also accompany changes in CLUE scores and BIS values, shown in both comparisons and correlation analyses. Conversely, hand-grip strengths and QuickDASH scores do not show these changes.
Assessment of lymphedema with standardized measures is a critical issue for both clinical and academical purposes. Therefore, Spinelli et al have proposed a new method to assess BCRL of the upper extremity [8]. Although this scoring system (CLUE) is based on a physical examination, the main difference is CLUE's being structurized and having scores that require to be recorded for each area of the affected extremity, as well as the characteristic ndings of lymphedema. Common clinical practice usually involves the recording of positive ndings for BCRL, which is subjective for each observer in severity. We aimed to compare this novel standardized tool for lymphedema with volumetric changes, BIS, hand grip strength and disability related to upper extremity (QuickDASH). Our another goal was to test CLUE's potential to be used in evaluating the treatment response. The only use of the CLUE in evaluating the treatment response was in a study conducted by Schmitz et al, which evaluated the effects of the exercise or weight loss in patients with BCRL [17]. All of the groups except controls were found to bene t from these interventions in their outcome measures without any differences in their interventions, including CLUE. Still, the study had a longer follow-up interval of 12 months, and use of CLUE in a shortterm, more intensive form of therapy alongside with BIS is an important contribution to the literature. We have found that a 31.77% reduction in CLUE scores was present with the complete decongestive therapy.
Moreover, these changes were found to be correlated with the volume reductions and BIS values.
Volumetric measurements are used in follow-ups of BCRL extensively, both in clinical practice and studies. They were found to be useful for follow-ups in a study evaluating the effects of complete decongestive therapy on quality of life, depression, neuropathic pain and fatigue in patients with BCRL[18]. Our study also showed reductions in volumes (14.43%), which was found to be statistically signi cant.
BIS values of the patients showed improvements after the therapy, which were found to be statistically signi cant. The value of BIS for treatment response is still is not clearly de ned in the literature, making this study the rst one to use BIS for this purpose. Stout et al proposed BIS as a method to assess subclinical lymphedema [7]. Shortly after its introduction to lymphedema assessment methods, BIS has been in use to assess subclinical lymphedema. Ward et al showed that BIS was a more sensitive indicator of lymphedema when compared to volumetric methods [13]. Improvements in BIS scores and positive correlations found between BIS and volumetric changes as well as CLUE scores also indicate that BIS can be helpful for the assessing treatment response and following up BCRL patients.
Although QuickDASH scores were found to be improved after the therapy, these changes were not found to be statistically signi cant. Gencay et al used QuickDASH in a study evaluating the effects of kinesiotaping on BCRL patients, and it was found not to be signi cantly improved either [19]. QuickDASH is a patient reported measure of upper extremity functions and effects of the disabilities on activities of daily life, and it was applied to the patients right after the therapy. Complete decongestive therapy involves bandaging, immobilization, and problems related to these practices, such as pain and joint restrictions. Application of QuickDASH right after the therapy may have resulted in patients' being unable to realize the positive changes the volume reduction that may provide, and focus on the negative aspects of this therapy involving restriction of the affected extremity instead.  [21]. Similarly, our study has shown a 3.5% decrease in the hand-grip strength, which is statistically insigni cant. As a result of the relative immobilization as a part of the intervention, this nding underlines the importance of preserving strength in this group of patients through strengthening exercises. Although the patients were given remedial exercises, resistance exercises were not a part of the interventions in this intensive phase of the complete decongestive therapy. Since there is no data regarding this issue in the current literature, this may prove to be very important for the clinical practice.

Strengths and limitations:
This is the rst study that uses both CLUE score and BIS for the follow-up of the complete decongestive therapy for BCRL. It also has volumetric measurements, hand-grip strength and functional status of the upper extremity outcome measures, which provides multi-dimensional assessment of the therapy. Detection of a correlation between CLUE scores and volumetric changes as well as the changes in BIS values strengthens the value of CLUE for the clinical practice.
The main limitation of the study was the limited number of patients. A higher number of patients could have given a more precise result with the statistical analyses. Moreover, this study was conducted in a single center. Although inter-rater variability of CLUE were shown to be excellent [8], multi-centric studies would give a better idea for the use of the measures in this study for the routine clinical practice.

Conclusion
In conclusion, development of a structured clinical assessment like CLUE provides clinicians a standardized evaluation for BCRL. For the novel studies aiming to assess treatment responses to patients with BCRL, use of CLUE and BIS alongside with routinely used volumetric methods are encouraged. No funding was received.
Con icts of interest/Competing interests: