Key Points
• Early detection of breast cancer-related lymphedema (BCRL) can prevent progression to its chronic stage eliminating morbidity and the need for more intensive costly treatments, and helps to reach the most successful outcomes in reducing the burden of disease.
• Herein we reported that periodic monitoring with the use of bioimpedance spectroscopy (BIS) allowed us to identify more patients with subclinical and/or clinical BCRL, compared to evaluation with circumferential volume measurements during the 6-month period.
• We suggest the implementation of BIS assessments into routine breast cancer follow-up programs in order to prevent and manage the potentially devastating effects of chronic BCRL, in patients with breast cancer surgery.
Introduction
Breast cancer is the most common cancer amongst women worldwide, with approximately two million cases each year. The incidence of breast cancer has been increased in recent decades, both in developed and developing countries (1). A report from Turkey reported that the incidence of breast cancer increased more than twice from 24/100,000 in 1993 to 50/100,000 in 2017 (2). In the same study the 5-year survival rate was found to be 86%. With improved surgical procedures and enhanced effectiveness of breast cancer treatment, the number of breast cancer survivors has increased dramatically and a significant number of women are dealing with the potential complications of treatment, including breast cancer-related lymphedema (BCRL) (1, 2, 3).
BCRL is a chronic, progressive condition characterized by accumulation of protein-rich fluid in the interstitial spaces due to disruption of the local lymphatic system after treatment with breast cancer surgery and/or radiation (3, 4). As lymphedema is under-recognized and under-documented, it is likely that the currently accepted rates of incidence and prevalence underestimate its magnitude (5, 6). Estimates of the risk of lymphedema after breast cancer treatment vary widely from 15%–94%, depending on differences in the extent and modality of therapies, discrepancies in diagnostic methods and duration of follow-up (4, 6, 7). Approximately 90% of the expected BCRL cases occur during the first 24 months after treatment (4, 8). Early or subclinical lymphedema can be objectively detected and serially assessed with appropriate surveillance methods but currently there is no consensus on the optimal screening regimen (8, 9, 10, 11). Although a widely accepted methodological approach to the early diagnosis and/or surveillance of BCRL is lacking, bio-impedance spectroscopy (BIS) is perhaps the most commonly used approach for widespread clinical surveillance (8, 9, 10, 11, 12, 13, 14). Screening all patients for the development of BCRL has proven difficult, secondary to logistical and cost-related issues. Therefore, it may be useful to identify which patients are at highest risk of developing BCRL so that they can be targeted and enrolled in prospective surveillance programs. This would facilitate simple preemptive intervention, thereby reducing the development of irreversible, chronic BCRL (15, 16, 17, 18).
Several studies and current guidelines have reported early detection and treatment of BCRL can prevent progression to its chronic stage, eliminating morbidity and the need for more intensive costly treatments (10, 17, 18, 19). Although there are numerous studies supporting the value of prospective surveillance with BIS compared to other methods, prospective studies with Turkish breast cancer patients are lacking (5, 20). Additional data about the frequency of lymphedema in this specific population may be useful to further validate the use of appropriate methods in BCRL screening programs.
The purpose of this study was to report the results of a 6-month surveillance program in order to determine the comparative frequency of subclinical and clinical BCRL, identified by BIS and circumferential volume measurements in a group of breast cancer patients.
Materials and Methods
Study Sample
Female patients who underwent breast cancer surgery in two different oncology centers (Hacettepe University Oncology Hospital and Abdurrahman Oncology Hospital), were enrolled to the study between October 2018 to December 2019. This prospective and descriptive study was approved by the local ethics committee and written informed consent was obtained from all participants. The study met the requirements of the Declaration of Helsinki and was approved by the Institutional Ethics Committee of the Hacettepe University (G0: 17/645).
Eligibility
The inclusion criteria were as follows: 1) aged between 18–65 years; and 2) having unilateral breast cancer surgery (breast conservation or mastectomy) with axillary lymph node dissection (ALND). Patients were excluded if they met the following criteria: 1) patients with history of contralateral breast cancer surgery; 2) previously documented diagnosis of BCRL; 3) having metal implants and/or pacemakers; 4) Patients having locoregional or distant metastases; 5) patients having musculoskeletal or venous disorders on the affected arm which may simulate or mask symptoms of lymphedema; 6) patients having renal and/or heart failure; 7) pregnancy; 8) immobile patients; and 9) patients with cognitive or neurological disorders. Chemotherapy and radiation therapy were allowed during the study.
Demographic and Clinical Data
Demographic and clinical properties including age, gender, Body Mass Index (BMI), marital status, and occupation were recorded. BMI was classified as normal (18.5–24.9 kg/m2), overweight (25–29.9 kg/m2) and obese (>30 kg/m2) (21). Surgical characteristics, including type of breast surgery, either breast conserving therapy (BCT) or mastectomy, axillary surgery type including sentinel lymph node biopsy (SLNB) or ALND and stage of cancer [tumor, node, metastasis (TNM) staging 0–4] (22), and number of removed lymph nodes was collected from medical records. In addition therapeutic information was also collected including adjuvant chemotherapy, radiation therapy (axillary, breast/chest wall) and hormonal therapy.
Volume Measurements
Limb volume was measured using circumferential and BIS measurements (23, 24, 25, 26). The baseline circumferential and BIS measurements were taken 3–6 weeks after the final breast cancer surgery in order to avoid misclassifying transient, post-operative swelling as BCRL. Then all patients underwent postoperative follow-up measurements at regular intervals of three months, during a 6-month period.
Circumferential Volume Measurements
For circumferential measurements, subjects sat straight on a chair with their arms relaxed by their sides and elbows straight. Both arms were measured at each test date. Circumferential measurements were performed using a standard 1-inch retractable tape, starting at the level of ulnar styloid, at 4 cm intervals along the arms and converted to an approximate arm volume to enable estimation of volume. Calculation of the limb segment volumes (millilitres-cm3) was undertaken using a simplified truncated cone formula. Excess limb volume comparing affected and unaffected limbs and difference in excess volume (excess limb volume was expressed as a percentage of the unaffected limb volume, indicating how much larger the affected limb was compared to the unaffected limb) were calculated (23, 24, 25). The presence of subclinical and clinic lymphedema was assessed by inter-limb volume difference (>5% and >10% respectively) based on the serial circumferential measurements in both affected and non-affected extremities (25). Every patient was assessed by the same researcher.
BIS Measurements
BIS measurement was performed using an L-Dex U 400 device (Impedimed, Australia) and analyzed as previously described (26, 27, 28). Measurements were taken with patients in the supine position on a non-metallic surface, with their arms relaxed with palms facing down on a cushion. Electrodes were placed on each hand at the dorsal surface of the wrist between the process of the radial and the ulnar bones and on the dorsal surface of the hand, 1 cm proximal from the peak of the knuckle of the middle finger. A foot electrode was placed midway between the lateral and medial malleol processes on the ankle in the front of the foot (28). Two trained researchers performed all measurements.
The L-Dex ratio is the recommended metric when using BIS (13, 28, 29). The ratio of impedance at RO in the affected versus intact limb, adjusted for gender, upper limb and right left dominance, is expressed as the L-Dex ratio. An L-Dex ratio of -10 to +10 was considered normal. But L-Dex value of >6.5 was recently reported to indicate subclinical lymphedema and values >7 were considered to indicate clinical lymphedema (19).
Diagnosis of Lymphedema
Diagnosis of subclinical or clinical lymphedema is dependent on history, physical examination (3, 29, 30) and objective arm volume changes, which were assessed by arm circumferential measurements (23) and BIS given as an L-Dex value (19, 26).
Functional Status
Functional disability of the affected extremity was evaluated by the Turkish version of quick Disability of Arm, Shoulder and Hand questionnaire (Q-DASH). Q-DASH is a self-reported questionnaire evaluating symptoms and functional tasks associated with limitations of the arm, shoulder and hand. The validated Turkish version of Q-DASH contains 11 items and results in a score ranging from 0–100 with higher scores indicating more functional disability (31).
Quality of Life Assessment
Quality of Life (QoL) was assessed by the Turkish version of the Lymphedema Quality of Life Questionnaire-Arm (LYMQOL-Arm) (32). The LYMQOL-Arm was developed by Keeley et al. (33) to assess the impact of lymphedema of the arms on the QoL of the patients. It consists of four domains with 28 items. These domains are function, appearance, symptoms, and mood. The answers were evaluated on a four-point Likert scale (1 = not at all 2 = a little, 3 = quite a bit, 4 = a lot). Each item received a score between 1 and 4, with higher scores indicating a worse QoL. There is also an overall QoL rating. The ‘overall QoL’ item was scored 0–10. QoL and functional status assessments were performed by the same researcher.
At the first presentation of subclinical lymphedema, patients were provided with preventive methods. Preventive strategies included meticulous skin care, exercises and self-decongestive massage. In addition, they were prescribed over-the-counter compression garments. Patients with clinical lymphedema were referred to the lymphedema unit for complex decongestive therapy (CDT).
Statistical Analysis
Descriptive statistics were used to examine the frequency distributions and calculate the scores of scales and subscales, and defined using either mean ± standard deviation (SD), median and range or percentage values. Continuous variables were tested for normal distribution using the Shapiro-Wilk test. Student’s t-test or Mann-Whitney U test were used as appropriate to compare differences in quantitative variables at different time points. The relationship between volume changes and QoL scores, functional status, as well as with clinical variables, was assessed using Pearson’s correlation for parametric data and with Spearman’s rho (correlation) for nonparametric data. All tests of statistical significance were two sided and considered statistically significant at p<0.05. Analyses were conducted using SPSS, version 21.0 (IBM Inc., Armonk, NY, USA).
Results
Between October 2018 and December 2019, a total of 134 females were screened among the patients who had breast cancer surgery. Of these 27 patients were excluded because of study eligibility criteria and seven patients did not agree to take part in the study. Therefore, the final study cohort size was 100 patients. Due to the unexpected coronavirus disease-2019 (COVID-19) pandemic, the sixth month follow-up measurements of 18 patients could not be performed and thus the data of 82 patients were reported.
The demographic and clinical characteristics of the patients are shown in Table 1. The mean age of the cohort was 49.6±10.42 years old (range: 27–65), and mean of BMI was 27.11 kg/m². A majority of participants were married, overweight/obese, and mostly housewives.
Concerning breast cancer treatment, the most common type of surgery was mastectomy followed by BCT. The majority of the patients had infiltrative ductal carcinoma. The median number of lymph nodes excised was 10 (min: 2–max: 28). The mean (median) time to measurement from surgery was 38 (29) days for all patients. Most of patients received chemotherapy and/or radiation therapy.
The difference in volumes and excess volumes, and L-Dex ratio, which were evaluated at baseline, three and six month follow-up are shown in Table 2. There were significant volume changes determined by circumferential measurements at all time points. Using circumferential measurements, 12 (14.6%) and 10 (12.2%) patients were diagnosed as subclinical lymphedema at the third and sixth month follow-ups, respectively. In regard to clinical lymphedema, 6 (7.3%) and 9 (10.9%) patients were identified at the third and sixth month follow-up respectively. The mean baseline L-Dex score was 2.15±7.69 (range: -14 to 17). Overall, 51 patients (62%) had an abnormal L-Dex score at some point during surveillance. Statistically significant changes during monitoring were observed in L-Dex ratios (p<0.05). Using L-Dex measurement, 19 (23.1%) and 7 (8.53%) subclinical lymphadema was diagnosed in the third and sixth-month follow-up respectively. In contrast, lymphedema based on an L-DEX ratio >10 was found in 11 (13.4%) and 14 (17.1%) patients at the third and sixth month follow-ups respectively. There was a moderate to high correlation between BIS and excess volume by circumferential measurements at both the third and sixth months (r = 0.342*, p = 0.011, r = 0.464**, p<0.001, respectively).
Functional status indicated by Q-DASH scores and the QoL scores are shown in Table 3. The mean values of Q-DASH scores tended to increase during follow-up but did not reach significance at any time point. No significant change in the mean scores of LYMQoL-subgroups was observed at the third and sixth month follow up. There was no correlation between volume measures by either by L-DEX or circumferential measurement and functional and QoL scores at the sixth month follow-up.
There was a positive correlation between the mean L-DEX ratio and excised lymph node number (r = 0.424, p = 0.001) and BMI (r = 0.324, p = 0.017).
The differences in clinical variables, excess volume and L-DEX ratio changes between patients with and without lymphedema are shown in Table 4. In regard to surgical factors, only the mean number of excised lymph nodes was significantly different in patients with and without lymphedema, indicating the impact of axillary node dissection on development of subclinical lymphedema. L-DEX ratio change and excess volume change during the six-month were different between the groups according to the presence of lymphedema, but did not reach significance.
The patients with a diagnosis of subclinical lymphedema were prescribed pressure garments and educated about self-management techniques, while the patients who were diagnosed with clinical lymphedema required CDT.
Discussion and Conclusion
The findings of this study demonstrated that prospective surveillance using BIS can detect subclinical and/or clinical BCRL more sensitively than circumferential volume measurements at the sixth month follow up. BIS identified 36.5% and 25.6% of patients with subclinical/clinical lymphedema at the third and sixth month of follow up, respectively, while 21.9% and 23.1% of patients had subclinical/clinical lymphedema by circumferential measurements at third and sixth months, respectively. However, there was a moderate to high correlation between BIS and circumferential measurements at 3 and 6-month follow-up. Furthermore, this study showed that the number of dissected lymph nodes was significantly associated with the development of lymphedema.
The number of breast cancer survivors is increasing globally and the likelihood of BCRL development as a consequence of breast cancer treatments is of worldwide significance (34). BCRL is a chronic, potentially devastating condition that may require long-term management and is associated with a risk of functional disability and psychosocial impact which may compromise the overall QoL. The optimal management of BCRL is based on early detection and timely intervention in order to prevent chronic and possibly irreversible complications and to reach most successful outcomes in reducing the burden of disease (3, 4, 10). During the earlier subclinical phase, the edema can easily be treated by education, self-massage and compression garments. However, when fibrosis is established more costly treatments, like manual lymphatic drainage multilayer bandaging, and pumps are needed and the lymphedema may not be reversible at advanced stages (10, 17). Current data support a surveillance approach and close monitoring of patients for the early diagnosis and treatment of BCRL in patients with breast cancer (4, 18, 35).
There is no gold standard for measuring sub-clinical lymphedema and it is difficult to know which measure is best for early detection. Current objective measures of BCRL include circumferential tape measurements, water displacement, BIS and perometry, which incorporate differences between limbs or from baseline (3, 7, 30). BIS is considered a reliable and sensitive measurement method which can predict the onset of lymphedema up to 10 months prior to clinically evident lymphedema and has been recommended to define subclinical lymphedema in previous studies (17, 18, 19, 26, 27, 28, 34). Early studies documented a conservative normal range between L-Dex scores >10 but more recently L-Dex score of >7 was considered as an indicator of subclinical lymphedema. (6, 8, 17, 19). Growing data support changing the cut-off point from >10 to >7 and thus improving the sensitivity for detecting subclinical BCRL (11, 18, 34), but few studies have used this cut-off point (19). Our study indicated a difference between comparative frequencies of subclinical/clinical lymphedema by BIS and circumferential volume measurements, supporting the use of this relatively new cut-off point.
Several studies have compared the estimated prevalence of lymphedema using different tools and diagnostic criteria. Previous studies highlighted L-DEX measurements as being more sensitive than circumferential measurements and other, subjective tools (11, 12, 19). One study with 176 women reported the prevalence with circumferential measurements as 0.6% but 11.9% with BIS (36). Kaufman et al. (11) reported 9.8% of patients with subclinical BCRL by BIS, whereas Keeley (18) reported lymphedema rate as 45.6% at 24 months. On the other hand, Soran et al. (34) reported the incidence of subclinical lymphedema to be as 33.8% with monitoring by BIS and only 4.4% were progressed to clinical lymphedema. Ridner et al. (19) compared BIS and circumference tape measurements to detect the magnitude of reduction in the rate of chronic BCRL with structured surveillance and found 17% of patients with clinical lymphedema. From Istanbul, Erdogan Iyigun et al. (20) found 21% of BCRL cases detected by BIS in their cross-sectional study, while Ozaslan and Kuru (5) reported the frequency of lymphedema to be 28% in 245 breast cancer patients. According to our data, overall subclinical and clinical lymphedema rates were 36.5% and 25.6% respectively by BIS measurements, which was higher than in previous studies, probably due to the use of the recently described lower cut-off points. In contrast to early studies from Turkey, we monitored the patients during the sixth months after treatment as a surveillance program and included assessment of functional status and QoL within the follow-up measurements.
Lymphedema impairs QoL, decreases physical functioning and affects psychosocial well-being (3, 24). Few studies have examined the relationship between clinical, functional and QoL variables and objective lymphedema measurements (36, 37). Lee et al. (36) explored the potential impact of the severity of lymphedema, determined by L-Dex, on function and overall QoL in their patient group who had moderate to severe lymphedema. Higher L-Dex was related to poorer function but was not related to overall QOL of their limb lymphedema participants (36). In our study we could not find a relationship between volume changes, by either method assessed, and QoL or functional scores, which may be due to the subclinical and/or newly diagnosed and short-term lymphedema.
Prophylactic intervention could help to prevent and reduce BCRL but it may not be feasible to offer this approach to all patients who undergo breast cancer surgery. Implementing early interventions to only those who need it seems to be more logical and cost-effective. The risk factors for BCRL have previously been identified by several studies and highlighted in recent guidelines (3, 7, 15, 18, 24). Axillary radiation therapy, and BMI were found to increase the incidence of lymphedema (5, 24). The recent study by Erdogan Iyigun et al. (20) evaluated preoperative risk factors and found patient BMI, number of nodes involved and capsular invasion to be associated with preoperative BCRL. According to our results, the number of dissected lymph nodes was the most important factor for the development of subclinical lymphedema. The association of L-DEX scores with risk factors for BCRL was also consistent with previous data (18, 20, 27). Understanding the related factors can be an important strategy to improve postoperative status for high-risk patients, in order to avoid the need to screen all patients, which would be more costly and less efficient. Neither the baseline to six month change in L-Dex nor in excess volume was statistically different between the patients with and without lymphedema, a finding which could be due to the small group size with heterogeneous distribution of the significant variables.
Our study was limited by small sample size and relatively short follow-up, which may limit the power to detect differences and excludes any ability to comment concerning long-term outcomes. Due to the pandemic conditions, we could not complete the follow-up to the end of one year, but the study is ongoing. We plan to follow the patients for at least two years for better long-term data. Another limitation of our study was the lack of preoperative L-Dex data, which may limit definitive conclusions. However, the prospective design and implementation of L-DEX in the first month at initial consultation, as well as regular follow-up during a substantial period, add value to our data. Besides, our findings may add information about the national prevalence of subclinical BCRL in terms of surveillance method, as the first prospective study with a six month follow-up in this country.
In conclusion, regular periodic monitoring using BIS technology allowed the identification of more patients with subclinical and/or clinical BCRL compared to evaluation with circumferential volume measurements during the six month follow up period. This is further evidence to support prospective monitoring for lymphedema in patients with breast cancer. We suggest the implementation of BIS assessment into routine breast cancer follow-up programs in order to prevent and manage the potentially devastating effects of chronic BCRL, in patients after breast cancer surgery.
Acknowledgements: We thank Hacettepe University Scientific Research Project Coordination Unit for the funding of the Bioimpedance device (BAP-Project #16391).
Informed Consent: This prospective and descriptive study was approved by the local ethics committee and written informed consent was obtained from all participants.
Peer-review: Externally peer-reviewed.
Authorship Contributions
Surgical and Medical Practices: L.D., A.B., S.A., C.Ö.; Concept: P.B., E.G.K., C.Ö.; Design: P.B., S.A.; Data Collection and/or Processing: A.Y., A.A.D., E.G.K., S.A., R.A., K.Ü.; Analysis and/or Interpretation: A.Y., R.A.; Literature Search: A.Y., R.A.; Writing: P.B., A.A.D.
Conflict of Interest: No conflict of interest was declared by the authors.
Financial Disclosure: This research received a grant from Hacettepe University Scientific Research Project Coordination Unit (2017/16391).