LYMPHATIC RESEARCH AND BIOLOGY Volume 13, Number 1, 2015 ª Mary Ann Liebert, Inc. DOI: 10.1089/lrb.2014.0014
Bioelectrical Impedance for Detecting and Monitoring Lymphedema in Patients with Breast Cancer. Preliminary Results of the Florence Nightingale Breast Study Group
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Zeynep Erdogan Iyigun, MD,1 Derya Selamoglu, MD,2 Gul Alco, MD,3 Kezban Nur Pilancı, MD,4 Cetin Ordu, MD,5 Filiz Agacayak, MD,6 Filiz Elbu¨ken, MD,6 Atilla Bozdogan,2 Serkan Ilgun, MD,2 Fusun Guler Uysal, MD,2 and Vahit Ozmen, MD 2
Abstract
The aim of this study was to evaluate the efficacy of bioimpedance spectroscopy for the follow-up of patients with lymphedema in Turkey and its benefits in the diagnosis of stage 0, 1, and 2 lymphedema in patients who are under treatment for breast cancer. Thirty-seven female patients with breast cancer who underwent surgical procedures in our Breast Health Centre were followed up for lymphedema using bioimpedance, and clinical measurements were taken for a minimum period of 1 year at 3-month intervals. Patients who had been monitored regularly between November, 2011, and September, 2013, were enrolled to the study. In total, 8 patients developed lymphedema with an overall rate of 21.6%. Among the 8 patients who developed lymphedema, 4 had Stage 2, 1 had Stage 1, and 3 had Stage 0 lymphedema. Stage 0 lymphedema could not be detected with clinical measurements. During the patients’ 1-year follow-up period using measurements of bioimpedance, a statistically significant relationship was observed between the occurrence of lymphedema and the disease characteristics. including the number of the extracted and remaining lymph nodes and the region of radiotherapy ( p = 0.042, p = 0.024, p = 0.040). Bioimpedance analysis seems to be a practical and reliable method for the early diagnosis of lymphedema. It is believed that regular monitoring of patients in the high-risk group using bioimpedance analyses increases the ability to treat lymphedema.
irreversible fluid collection called elephantiasis.2,3 Diagnosis of lymphedema and the initiation of treatment at an early stage leads to fewer limb measurements, prevention of joint dysfunction, reduction of extremity infections, greater treatment compliance, and consequently to an increased quality of life.4 The diagnosis of lymphedema is based on limb circumference measurements, volumetric measurements, and the patient’s own evaluation. However, these techniques can only indirectly assess the extracellular fluid volume, are dependent on the individual, are time consuming and difficult to apply, and cannot diagnose lymphedema at Stage 0. Other methods that are helpful for an early diagnosis of lymphedema include computed tomography and magnetic resonance; however, they are not routinely used because they involve radiation and are costly methods.5 Over the past 20 years, bioimpedance spectroscopy has started to be employed in the early diagnosis and monitoring
Introduction
B
reast cancer is the most frequently observed types of cancer among women in Turkey and around the world. It is also one of the causes of most common cancerrelated mortailities.1–3 Although mortality rates have been decreased in recent years by efficient screening programs, the development of surgical techniques, and new chemotherapy and radiotherapy alternatives, morbidity rates are increasing. Lymphedema observed subsequent to breast cancer therapy is among the important complications of breast cancer treatment.1 Lymphedema is evaluated in four stages: In Stage 0, lymphatic flow is disturbed but there is no apparent edema in the extremities; in Stage 1, the circumference of the extremities has increased but the edema recedes with elevation; in Stage 2, the edema does not recede with elevation and may present as pitting or nonpitting; and Stage 3 involves the
Departments of 1Physical Therapy and Rehabilitation and 4Medical Oncology, Istanbul Bilim University, Istanbul, Turkey. Departments of 2Breast Surgery, 3Radiation Oncology, 5Radiology, and 6Physical Therapy and Rehabilitation, Florence Nightingale Hospital, Istanbul, Turkey.
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BIOELECTRICAL IMPEDANCE FOR DETECTING LYMPHEDEMA
of treatment of lymphedema. This method was shown to be more sensitive than circumferential measurements and able to detect very small differences in the extracellular volumes between the arms.16 Bioimpedance spectroscopy assesses lymph fluid change by measuring the impedance to a lowfrequency electrical current traveling through the body. This low-frequency electrical current is not able to pass through cell membranes, which makes it possible to measure extracellular fluid directly.6–8 Impedance ratio thresholds for the dominant and nondominant limb are set at three standard deviations above the population mean. This ratio is known as the L-dex ratio and ranges from - 10 to + 10.16,36 Although there are many studies on early diagnosis of lymphedema using bioimpedance, there are few studies about its place in staging of lymphedema. The aim of this study was to evaluate the efficacy of the bioimpedance spectroscopy for the follow-up of patients with lymphedema in our country and its benefits in the diagnosis of stages 0, 1, and 2 lymphedema in patients who are under treatment for breast cancer. Patients and Methods
This study was approved by the Istanbul Bilim University Science Ethical Committee. The data of this study was collected by the retrospective analysis of regular patient records. One hundred twenty-nine female patients with breast cancer who underwent surgical procedures in our Breast Health Centre and had preoperative bioimpedance measurement between November, 2011, and September, 2013, were included the study. Patients who did not have regular 3-month-interval measurements were excluded from the analysis (n = 92). The inclusion criterion was surgery due to early-stage breast cancer. The exclusion criteria were a history of bilateral breast cancer, previous axillary surgery to the same or opposite side, or a history of lymphedema, secondary conditions such as pregnancy or cardiac or renal dysfunction that may affect the fluid distribution within the body, and any pacemakers or metal implants that may have hindered the function of the bioimpedance device. The examination for lymphedema was conducted during regular 3-monthly consultions with a breast surgeon. Data were recorded including the identity, age, dominant limb, daily use of the arms, body mass index, time and method of the surgery, histopathology results, and adjuvant treatments of the patients included in the study. Lymphedema was examined by an experienced specialist of Physical Therapy and Rehabilitation from our Breast Health Centre. During the examination, any pitting edema and subcutaneous fibrosis, Stemmer’s sign, range of motion of the upper limb joints, and sensory and motor functions were evaluated. Also, circumference measurements were performed at nine points, including the proximal aspect of the fourth finger, the level of the metacarpal joint, the wrist; 5, 10 and 15 cm above the styloid process, and 5, 10 and 15 cm above the medial epicondyle of both arms, and the differences were recorded. The stage of the lymphedema was determined during the physical examination.9 The bioimpedance measurement was performed using a multi-frequency bioimpedance analysis device developed for extracellular fluid measurement (L-Dex U400, ImpediMed,
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Australia). During the procedure, an alternative current with a frequency between 3 KHz and 1000 KHz was applied through the electrodes placed at the wrists and the resistance of the extracellular fluid against this current was measured. Before the measurement, the patent’s age, dominant limb, and the side of surgery was entered into the device. For the measurement, the patient was brought to the supine position, and after both wrists and right ankle of the patient were cleaned with a skin antiseptic, special electrodes were attached. The colored wires of the device were connected to the electrodes in line with the instruction manual and measurements were conducted first on the right arm, followed by the left arm. The difference of the extracellular fluid between both arms was recorded as the unit of lymphedema. L-Dex ratios greater than 10 were accepted as lymphedema.36 The measurements were conducted preoperatively and at the third, sixth, ninth, and twelfth postoperative months. Patients in whom Stage 1 and 2 lymphedema was observed received complex decongestive therapy, which is indicated to be efficient in the literature. Phase 1 of this treatment was administered at the hospital; phase 2 was administered at home. Phase 1 included the patient education, manual lymphatic drainage treatment, multi-layered bandaging and exercises; and phase 2 involved self drainages, compression garments, exercise, and training.32 Statistical analysis
The statistical analyses were conducted using the SPSS 17.0 software package. The difference between the groups was investigated using the Chi-square test. Statistical significance was based on a value of p < 0.05. Results
The median age of the 37 patients enrolled in the study was 48 years (range: 30–72 years). Among the patients, 8 (21.6%) had undergone mastectomies, and breast-preserving surgery was performed in 29 patients (78.4%) (Table 1). The sentinel lymph node was negative in 9 patients (24.3%), and 28 patients (75.6%) with positive lymph nodes underwent axillary dissections. During the axillary dissection, 10–16 lymph nodes were removed in 9 patients, 16–20 were removed in 11 patients, and more than 20 lymph nodes were removed in 7 patients. Twenty-eight patients received chemotherapy, radiotherapy, and hormonotherapy, 5 patients received chemotherapy and radiotherapy, 3 patients received radiotherapy and hormonotherapy, and 1 patient received only hormonotherapy. At the end of the 12-month follow up, lymphedema developed in 8 (21.6%) among the followed-up patients. All the patients who developed lymphedema had undergone axillary dissections, chemotherapy, and radiotherapy. During the 1-year follow-up period of the patients using bioimpedance measurement, a statistically significant relationship was observed between the occurrence of lymphedema and the disease characteristics including the number of the extracted and remaining lymph nodes and the region of radiotherapy ( p = 0.042, p = 0.024, p = 0.040, respectively). In our study, no statistically significant relationship was found between age, surgical procedure, tumor localization, systemic treatment, body mass index, and lymphedema ( p > 0.05).
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IYIGUN ET AL.
Table 1. Study Data
Table 2. L-dex Scores Pre-op LS
3rd month LS
6th month LS
9th month LS
12th month LS
- 6.8 - 0.8 2.8 - 4.2 1.5 6.1 3 11.5
2.3 6.7 - 12.6 3.4 - 5.6 9 - 1.6 1
10.1 19.9 7.6 10.8 4.7 12 - 0.6 9.2
7.8 9.5 - 5.6 - 3.2 3.2 13.2 27.6 38
0.3 4.6 - 7.5 1 20.1 47
48 years (30–72)
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Median age Surgery Breast preserving surgery Mastectomy Side Right Left Axillary intervention SLNB ALND pN Stage pN0 pN1 pN2 pN3 Tumor type IDC ILC Mixed Chemotherapy Yes No Radiotherapy Yes No Radiotherapy region Breast Breast + supraclavicular Hormonotherapy Yes No BMI < 25 ‡ 25
n
%
29 8
78.4 21.6
18 19
48.6 51.4
9 28
24.3 75.7
9 18 5 5
24.3 48.6 13.5 13.5
29 6 2
78.4 16.2 5.4
34 3
91.9 8.1
36 1
97.3 2.7
10 26
27.8 72.2
31 6
83.8 16.2
Discussion
24 13
64.9 35.1
Studies focusing on the incidence of lymphedema after breast cancer treatment revealed that the frequency of
Patient Patient Patient Patient Patient Patient Patient Patient Patient
1 2 3 4 5 6 7 8
LS, Lymphedema score.
Among the 8 patients who developed lymphedema, four patients had Stage 2, 1 had Stage 1, and 3 had Stage 0 lymphedema, respectively. Patients 1, 2, and 4 were diagnosed at the sixth month. These patients had no symptoms, and stage 0 lymphedema was diagnosed by using bioempedance analysis during the regular control. The patients were treated with home-based therapy and regular use of compression garments. Patient 3 was diagnosed as having stage 1 lymphedema at the third month, The patient attended the followup appointment presenting with swelling of the arm. The patient’s abduction and flexion movements of the arm were restricted, there was a mean 2.5 cm circumferential difference betweem the arms, and there were no signs of fibrosis. The patient was treated with complex decongestive therapy and shoulder exercises at the clinic. Patient 6 had a stage 1 lymphedema at the sixth month that was diagnosed using bioimpedance analysis; however, the patient refused the complex decongestive therapy and was followed up with home-based therapy. During the follow up her symptoms did not regress, but progressed to stage 2 lymphedema by the end of the 12 months. Patients 5, 7, and 8 reported having acute swelling of the arm after excessive use of the arm. The excessive-use histories for Patients 5, 7, and 8 were housework for 5 hours, playing the guitar for 2 hours, and excessive sport
activity (1 hour treadmill-walking and weight-bearing exercises), respectively. Although the symptoms in the Stage 2 lymphedema patients subsided with the complex decongestive therapy, their stages did not change. However, in the patients with Stage 1 lymphedema, the symptoms and the bioimpedance measurement results improved after the complex decongestive therapy, and the condition of the 3 patients with Stage 0 lymphedema returned to normal through the home treatment program and the regular use of compression garments. L-dex scores are shown in Table 2. An increase was observed in the preoperative measurements of patients in lymphedema group during the follow up measurements at the 3rd and 12th postoperative months (Fig. 1).
FIG. 1. Preoperative measurements and the measurements at the third and twelfth postoperative months.
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BIOELECTRICAL IMPEDANCE FOR DETECTING LYMPHEDEMA
lymphedema varies between 13%–65%.10–12 This difference in the ratios depends on the different diagnostic and treatment methods and the difference between the timing of the lymphedema measurements. In a study conducted on 218 patients in Turkey, the incidence of lymphedema in the 12th month was 24.8% based on circumferential measurements.13 In our study, 21.6% of the patients developed lymphedema. Compared with the related literature, the ratios observed in the present study are slightly lower. This may be associated with the different diagnostic methods and patient numbers in the studies. This is the first study that assesses the use of bioimpedance analysis for detecting lymphedema in Turkey. At the 1 year follow-up of 37 patients, 8 cases of lymphedema were detected. Among the patients with lymphedema, 5 were early stage and these returned to normal after treatment. The diagnosis of lymphedema depends on the difference of the fluid volume between both limbs and the measurements of the same limb at different time points. The conventional diagnostic methods are circumferential measurements, volume changes, and individual evaluations.33,34 Among these methods, circumferential measurements are the most frequentlyused methods in clinics due to their practicality; however, the intra- and inter-observer variability is rather high because there is no standardization for its application.14 Also, these methods are inadequate to diagnose lymphedema during the subclinical stage. However, an early diagnosis is of utmost importance to treat lymphedema.15 The superiority of bioimpedance analysis is its ability to diagnose lymphedema at an early stage. In our study, 3 patients were diagnosed as having lymphedema with no arm swelling at stage 0, and two patients were diagnosed as having stage 1. Patient 6, who did not accept the complex decongestive therapy, progressed to stage 2 during the follow-up period. In a study by Stout Gergich et al.,15 a volumeter was used for the diagnosis of early-stage lymphedema, the diagnosis was based on a 3% change between two measurements and significant changes were observed through the use of compression garments in the follow-up volume measurements.15 In the study by Fu et al., the progress of lymphedema was significantly slowed down in patients who were informed about lymphedema symptoms and the preventive measures.17 In our study, patients with Stage 0 lymphedema were recommended to take preventive measures and to wear compression garments, which led to a regression in the lymphedema during their follow up. The difference between those studies and ours is the use of bioimpedance analysis and the diagnosis of lymphedema before clinical symptoms. In patients with Stage 2 lymphedema, the complex decongestive therapy led to a reduction in their arm circumferences, although no regression could be achieved in the stage of lymphedema. Stage 0 and 1 lymphedema, classified as early-stage lymphedema, is reversible because fibrosis has yet to occur in the tissues. However, if no measures are taken, the condition leads to subcutaneous fibrosis, which hinders the healing of lymphedema. Therefore, lymphedema can be more efficiently treated during the early stages.18,19 In our study, an L-dex score greater then 10 units was considered as lymphedema. The circumferential measurements and clinical evaluation also played a role for diagnosis and staging. We used preoperative measurements for monitoring the change of L-dex score and detected that the change
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from baseline 3 months after surgery was higher in patients with lymphedema (Fig. 1). In a study by Cornish et al.,16 the diagnosis of lymphedema could be made 10 months before its clinical manifestation using bioimpedance spectroscopy. Our results are consistent with this result. In the literature, the rate of lymphedema development following sentinel lymph node biopsies is 5%–7%.22,23 However, in the study by Ozcinar et al., this ratio was 1.9%.13 In our study, no lymphedema was detected in the SLNB group, this may be related with the short duration of follow up and the limited number of patients. Axillary dissections (AD) are accepted as definitive and independent risk factors for the development of lymphedema.2,10,18 Nevertheless, the literature that indicates a correlation between the number of the lymph nodes removed during the axillary dissection and the risk of lymphedema has yet to be validated.22,24 In the study by Goldberg et al., lymphedema was observed in 31 out of 600 patients and no difference in terms of lymphedema development was observed between the 1–9 lymph node dissection group, and the 1–17 lymph node dissection group.23 On the other hand, Meeske et al. studied 494 patients who had undergone breast surgery, and noted dissection of more than 10 lymph nodes increased the lymphedema ratio.25 In our study, we observed that dissection of more than 15 lymph nodes increased the ratio of lymphedema. Radiotherapy of the supraclavicular lymph nodes significantly increases the risk of lymphedema compared with radiotherapy to the breast.13,26 In the study by Warren et al., the risk of lymphedema was 3% in the patients who received no radiotherapy, and was 3.1% after radiotherapy directed to the breast and chest wall, and 21.9% in radiotherapy of the supraclavicular area.27 In line with these findings, all the patients who developed lymphedema in our study had received radiotherapy to the supraclavicular lymph nodes. Kim et al.28 observed that the number of dissected lymph nodes, chemotherapy, and radiotherapy to the supraclavicular lymph nodes were independent risk factors for lymphedema development. The presence of one risk factor was associated with a 3% increase in the incidence of lymphedema, two risk factors led to a 19% increase, and three risk factors caused a 38% increase in the incidence of lymphedema.28 In our study, with the exception of one patient, all the patients who developed lymphedema had received chemotherapy and supraclavicular radiotherapy, and had 15 or more lymph nodes extracted. Information suggesting that a body mass index of 30 or above increases the risk of lymphedema was not in line with our results.7,29,30,35 We are of the opinion that this incompliance is associated with the limited number of patients in the lymphedema group and that the majority of our patients had a BMI value below 30. When taking into consideration the cost of treatment for advanced-stage lymphedema and morbidity-related complications including infections, the diagnosis and treatment of early-stage lymphedema through bioimpedance analysis performed during follow up is very beneficial.31 Despite the advantages of bioimpedance analysis for the patient, compliance was insufficient for our hospital. Overall, of the 129 patients who began the follow-up process, only 37 completed the study. The reason of this insufficient compliance rate was patients’ lack of knowledge about lymphedema and
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IYIGUN ET AL.
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importance of early diagnosis. Patients do not consider lymphedema and its morbidities a priority in their first-year cancer treatment and thus neglect their routine follow-up for lymphedema. In conclusion, lymphedema is a condition that reduces the quality of life of patients due to its complications and it is only fully treatable if it is diagnosed at an early stage. Bioimpedance analysis seems to be a practical and reliable method for the early diagnosis of lymphedema. It is believed that regular monitoring of patients who are in the high-risk group using bioimpedance analyses increases the chance of treatment in lymphedema. The limited number of the patients and the short follow-up period are the main limitations of this study.
12.
13. 14. 15.
Acknowledgments
16.
The authors would like to thank Mr. David Chapman for his meticulous editing of the manuscript.
17.
Author Disclosure Statement
No competing financial interests exist.
18.
References
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26. Hayes SB, Freedman GM, Li T, Anderson PR, Ross E. Does axillary boost increase lymphedema compared with supraclavicular radiation alone after breast conservation? Int J Radiat Oncol Biol Phys 2008;72:1449–1455. 27. Warren LE, Miller CL, Horick N, Skolny MN, Jammollo LS, Sadek BT, Shenouda MN, O’Toole JA, Macdonald SM, Specht MC, Taghian AG. The impact of radiation therapy on the risk of lymphedema after treatment for breast cancer: A prospective cohort study. 2014;88:565–571. 28. Kim M, Kim SW, Lee SU, Lee NK, Jung SY, Kim TH, Lee ES, Kang HS, Shin KH. A model to estimate the risk of breast cancer-related lymphedema: Combinations of treatmentrelated factors of the number of dissected axillary nodes, adjuvant chemotherapy, and radiation therapy. Int J Radiat Oncol Biol Phys 2013;86:498–503. 29. Jammallo LS, Miller CL, Singer M, Horick NK, Skolny MN, Specht MC, O’Toole J, Taghian AG. Impact of body mass index and weight fluctuation on lymphedema risk in patients treated for breast cancer. Breast Cancer Res Treat 2013;142:59–67. 30. Soran A, Wu WC, Dirican A, Johnson R, Andacoglu O, Wilson J. Estimating the probability of lymphedema after breast cancer surgery. Am J Clin Oncol 2011;34:506–510. 31. Bilir SP, DeKoven MP, Munakata J. Economic benefits of BIS-aided assessment of post-BC lymphedema in the United States. Am J Manag Care 2012;18:234–241. 32. Foldi E, Foldi M, Clodius L. The lymhedema choas: A lancet. Ann Plast Surg 1989;22:505–515.
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33. Shah C, Arthur D, Riutta J, Whitworth P, Vicini FA. Breast-cancer related lymphedema: A review of procedurespecific incidence rates, clinical assessment aids, treatment paradigms, and risk reduction. Breast J 2012;18: 357–361. 34. Armer JM, Steward BR. A comparison of four diagnostic criteria for lymphedema in a post breast cancer population. Lymphat Res Biol 2005;3:208–217. 35. Norman SA, Locacio Ar, Kallan Mj. Risk factors for lymhedema after breast cancer treatment. Cancer Epidemiol Biomark 2010;19:2734–2746. 36. Ward LC, Dylke E, Czernic S, Isenring E, Kilbreath SL. Confirmation of the reference impedance ratios used for assessment of breast cancer-related lymphedema by bioelectrical impedance. Lymphat Res Biol 2011:9:47–51.
Address correspondence to: _ Zeynep Erdogan Iyigun, MD Department of Physical Theraphy and Rehabilitation Istanbul Bilim University Buyukdere str., No. 120 Esentepe, Sisli Istanbul, 34394 Turkey E-mail: [email protected]
Bioelectrical Impedance for Detecting and Monitoring Lymphedema in Patients with Breast Cancer. Preliminary Results of the Florence Nightingale Breast Study Group
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Zeynep Erdogan Iyigun, MD,1 Derya Selamoglu, MD,2 Gul Alco, MD,3 Kezban Nur Pilancı, MD,4 Cetin Ordu, MD,5 Filiz Agacayak, MD,6 Filiz Elbu¨ken, MD,6 Atilla Bozdogan,2 Serkan Ilgun, MD,2 Fusun Guler Uysal, MD,2 and Vahit Ozmen, MD 2
Abstract
The aim of this study was to evaluate the efficacy of bioimpedance spectroscopy for the follow-up of patients with lymphedema in Turkey and its benefits in the diagnosis of stage 0, 1, and 2 lymphedema in patients who are under treatment for breast cancer. Thirty-seven female patients with breast cancer who underwent surgical procedures in our Breast Health Centre were followed up for lymphedema using bioimpedance, and clinical measurements were taken for a minimum period of 1 year at 3-month intervals. Patients who had been monitored regularly between November, 2011, and September, 2013, were enrolled to the study. In total, 8 patients developed lymphedema with an overall rate of 21.6%. Among the 8 patients who developed lymphedema, 4 had Stage 2, 1 had Stage 1, and 3 had Stage 0 lymphedema. Stage 0 lymphedema could not be detected with clinical measurements. During the patients’ 1-year follow-up period using measurements of bioimpedance, a statistically significant relationship was observed between the occurrence of lymphedema and the disease characteristics. including the number of the extracted and remaining lymph nodes and the region of radiotherapy ( p = 0.042, p = 0.024, p = 0.040). Bioimpedance analysis seems to be a practical and reliable method for the early diagnosis of lymphedema. It is believed that regular monitoring of patients in the high-risk group using bioimpedance analyses increases the ability to treat lymphedema.
irreversible fluid collection called elephantiasis.2,3 Diagnosis of lymphedema and the initiation of treatment at an early stage leads to fewer limb measurements, prevention of joint dysfunction, reduction of extremity infections, greater treatment compliance, and consequently to an increased quality of life.4 The diagnosis of lymphedema is based on limb circumference measurements, volumetric measurements, and the patient’s own evaluation. However, these techniques can only indirectly assess the extracellular fluid volume, are dependent on the individual, are time consuming and difficult to apply, and cannot diagnose lymphedema at Stage 0. Other methods that are helpful for an early diagnosis of lymphedema include computed tomography and magnetic resonance; however, they are not routinely used because they involve radiation and are costly methods.5 Over the past 20 years, bioimpedance spectroscopy has started to be employed in the early diagnosis and monitoring
Introduction
B
reast cancer is the most frequently observed types of cancer among women in Turkey and around the world. It is also one of the causes of most common cancerrelated mortailities.1–3 Although mortality rates have been decreased in recent years by efficient screening programs, the development of surgical techniques, and new chemotherapy and radiotherapy alternatives, morbidity rates are increasing. Lymphedema observed subsequent to breast cancer therapy is among the important complications of breast cancer treatment.1 Lymphedema is evaluated in four stages: In Stage 0, lymphatic flow is disturbed but there is no apparent edema in the extremities; in Stage 1, the circumference of the extremities has increased but the edema recedes with elevation; in Stage 2, the edema does not recede with elevation and may present as pitting or nonpitting; and Stage 3 involves the
Departments of 1Physical Therapy and Rehabilitation and 4Medical Oncology, Istanbul Bilim University, Istanbul, Turkey. Departments of 2Breast Surgery, 3Radiation Oncology, 5Radiology, and 6Physical Therapy and Rehabilitation, Florence Nightingale Hospital, Istanbul, Turkey.
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BIOELECTRICAL IMPEDANCE FOR DETECTING LYMPHEDEMA
of treatment of lymphedema. This method was shown to be more sensitive than circumferential measurements and able to detect very small differences in the extracellular volumes between the arms.16 Bioimpedance spectroscopy assesses lymph fluid change by measuring the impedance to a lowfrequency electrical current traveling through the body. This low-frequency electrical current is not able to pass through cell membranes, which makes it possible to measure extracellular fluid directly.6–8 Impedance ratio thresholds for the dominant and nondominant limb are set at three standard deviations above the population mean. This ratio is known as the L-dex ratio and ranges from - 10 to + 10.16,36 Although there are many studies on early diagnosis of lymphedema using bioimpedance, there are few studies about its place in staging of lymphedema. The aim of this study was to evaluate the efficacy of the bioimpedance spectroscopy for the follow-up of patients with lymphedema in our country and its benefits in the diagnosis of stages 0, 1, and 2 lymphedema in patients who are under treatment for breast cancer. Patients and Methods
This study was approved by the Istanbul Bilim University Science Ethical Committee. The data of this study was collected by the retrospective analysis of regular patient records. One hundred twenty-nine female patients with breast cancer who underwent surgical procedures in our Breast Health Centre and had preoperative bioimpedance measurement between November, 2011, and September, 2013, were included the study. Patients who did not have regular 3-month-interval measurements were excluded from the analysis (n = 92). The inclusion criterion was surgery due to early-stage breast cancer. The exclusion criteria were a history of bilateral breast cancer, previous axillary surgery to the same or opposite side, or a history of lymphedema, secondary conditions such as pregnancy or cardiac or renal dysfunction that may affect the fluid distribution within the body, and any pacemakers or metal implants that may have hindered the function of the bioimpedance device. The examination for lymphedema was conducted during regular 3-monthly consultions with a breast surgeon. Data were recorded including the identity, age, dominant limb, daily use of the arms, body mass index, time and method of the surgery, histopathology results, and adjuvant treatments of the patients included in the study. Lymphedema was examined by an experienced specialist of Physical Therapy and Rehabilitation from our Breast Health Centre. During the examination, any pitting edema and subcutaneous fibrosis, Stemmer’s sign, range of motion of the upper limb joints, and sensory and motor functions were evaluated. Also, circumference measurements were performed at nine points, including the proximal aspect of the fourth finger, the level of the metacarpal joint, the wrist; 5, 10 and 15 cm above the styloid process, and 5, 10 and 15 cm above the medial epicondyle of both arms, and the differences were recorded. The stage of the lymphedema was determined during the physical examination.9 The bioimpedance measurement was performed using a multi-frequency bioimpedance analysis device developed for extracellular fluid measurement (L-Dex U400, ImpediMed,
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Australia). During the procedure, an alternative current with a frequency between 3 KHz and 1000 KHz was applied through the electrodes placed at the wrists and the resistance of the extracellular fluid against this current was measured. Before the measurement, the patent’s age, dominant limb, and the side of surgery was entered into the device. For the measurement, the patient was brought to the supine position, and after both wrists and right ankle of the patient were cleaned with a skin antiseptic, special electrodes were attached. The colored wires of the device were connected to the electrodes in line with the instruction manual and measurements were conducted first on the right arm, followed by the left arm. The difference of the extracellular fluid between both arms was recorded as the unit of lymphedema. L-Dex ratios greater than 10 were accepted as lymphedema.36 The measurements were conducted preoperatively and at the third, sixth, ninth, and twelfth postoperative months. Patients in whom Stage 1 and 2 lymphedema was observed received complex decongestive therapy, which is indicated to be efficient in the literature. Phase 1 of this treatment was administered at the hospital; phase 2 was administered at home. Phase 1 included the patient education, manual lymphatic drainage treatment, multi-layered bandaging and exercises; and phase 2 involved self drainages, compression garments, exercise, and training.32 Statistical analysis
The statistical analyses were conducted using the SPSS 17.0 software package. The difference between the groups was investigated using the Chi-square test. Statistical significance was based on a value of p < 0.05. Results
The median age of the 37 patients enrolled in the study was 48 years (range: 30–72 years). Among the patients, 8 (21.6%) had undergone mastectomies, and breast-preserving surgery was performed in 29 patients (78.4%) (Table 1). The sentinel lymph node was negative in 9 patients (24.3%), and 28 patients (75.6%) with positive lymph nodes underwent axillary dissections. During the axillary dissection, 10–16 lymph nodes were removed in 9 patients, 16–20 were removed in 11 patients, and more than 20 lymph nodes were removed in 7 patients. Twenty-eight patients received chemotherapy, radiotherapy, and hormonotherapy, 5 patients received chemotherapy and radiotherapy, 3 patients received radiotherapy and hormonotherapy, and 1 patient received only hormonotherapy. At the end of the 12-month follow up, lymphedema developed in 8 (21.6%) among the followed-up patients. All the patients who developed lymphedema had undergone axillary dissections, chemotherapy, and radiotherapy. During the 1-year follow-up period of the patients using bioimpedance measurement, a statistically significant relationship was observed between the occurrence of lymphedema and the disease characteristics including the number of the extracted and remaining lymph nodes and the region of radiotherapy ( p = 0.042, p = 0.024, p = 0.040, respectively). In our study, no statistically significant relationship was found between age, surgical procedure, tumor localization, systemic treatment, body mass index, and lymphedema ( p > 0.05).
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IYIGUN ET AL.
Table 1. Study Data
Table 2. L-dex Scores Pre-op LS
3rd month LS
6th month LS
9th month LS
12th month LS
- 6.8 - 0.8 2.8 - 4.2 1.5 6.1 3 11.5
2.3 6.7 - 12.6 3.4 - 5.6 9 - 1.6 1
10.1 19.9 7.6 10.8 4.7 12 - 0.6 9.2
7.8 9.5 - 5.6 - 3.2 3.2 13.2 27.6 38
0.3 4.6 - 7.5 1 20.1 47
48 years (30–72)
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Median age Surgery Breast preserving surgery Mastectomy Side Right Left Axillary intervention SLNB ALND pN Stage pN0 pN1 pN2 pN3 Tumor type IDC ILC Mixed Chemotherapy Yes No Radiotherapy Yes No Radiotherapy region Breast Breast + supraclavicular Hormonotherapy Yes No BMI < 25 ‡ 25
n
%
29 8
78.4 21.6
18 19
48.6 51.4
9 28
24.3 75.7
9 18 5 5
24.3 48.6 13.5 13.5
29 6 2
78.4 16.2 5.4
34 3
91.9 8.1
36 1
97.3 2.7
10 26
27.8 72.2
31 6
83.8 16.2
Discussion
24 13
64.9 35.1
Studies focusing on the incidence of lymphedema after breast cancer treatment revealed that the frequency of
Patient Patient Patient Patient Patient Patient Patient Patient Patient
1 2 3 4 5 6 7 8
LS, Lymphedema score.
Among the 8 patients who developed lymphedema, four patients had Stage 2, 1 had Stage 1, and 3 had Stage 0 lymphedema, respectively. Patients 1, 2, and 4 were diagnosed at the sixth month. These patients had no symptoms, and stage 0 lymphedema was diagnosed by using bioempedance analysis during the regular control. The patients were treated with home-based therapy and regular use of compression garments. Patient 3 was diagnosed as having stage 1 lymphedema at the third month, The patient attended the followup appointment presenting with swelling of the arm. The patient’s abduction and flexion movements of the arm were restricted, there was a mean 2.5 cm circumferential difference betweem the arms, and there were no signs of fibrosis. The patient was treated with complex decongestive therapy and shoulder exercises at the clinic. Patient 6 had a stage 1 lymphedema at the sixth month that was diagnosed using bioimpedance analysis; however, the patient refused the complex decongestive therapy and was followed up with home-based therapy. During the follow up her symptoms did not regress, but progressed to stage 2 lymphedema by the end of the 12 months. Patients 5, 7, and 8 reported having acute swelling of the arm after excessive use of the arm. The excessive-use histories for Patients 5, 7, and 8 were housework for 5 hours, playing the guitar for 2 hours, and excessive sport
activity (1 hour treadmill-walking and weight-bearing exercises), respectively. Although the symptoms in the Stage 2 lymphedema patients subsided with the complex decongestive therapy, their stages did not change. However, in the patients with Stage 1 lymphedema, the symptoms and the bioimpedance measurement results improved after the complex decongestive therapy, and the condition of the 3 patients with Stage 0 lymphedema returned to normal through the home treatment program and the regular use of compression garments. L-dex scores are shown in Table 2. An increase was observed in the preoperative measurements of patients in lymphedema group during the follow up measurements at the 3rd and 12th postoperative months (Fig. 1).
FIG. 1. Preoperative measurements and the measurements at the third and twelfth postoperative months.
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BIOELECTRICAL IMPEDANCE FOR DETECTING LYMPHEDEMA
lymphedema varies between 13%–65%.10–12 This difference in the ratios depends on the different diagnostic and treatment methods and the difference between the timing of the lymphedema measurements. In a study conducted on 218 patients in Turkey, the incidence of lymphedema in the 12th month was 24.8% based on circumferential measurements.13 In our study, 21.6% of the patients developed lymphedema. Compared with the related literature, the ratios observed in the present study are slightly lower. This may be associated with the different diagnostic methods and patient numbers in the studies. This is the first study that assesses the use of bioimpedance analysis for detecting lymphedema in Turkey. At the 1 year follow-up of 37 patients, 8 cases of lymphedema were detected. Among the patients with lymphedema, 5 were early stage and these returned to normal after treatment. The diagnosis of lymphedema depends on the difference of the fluid volume between both limbs and the measurements of the same limb at different time points. The conventional diagnostic methods are circumferential measurements, volume changes, and individual evaluations.33,34 Among these methods, circumferential measurements are the most frequentlyused methods in clinics due to their practicality; however, the intra- and inter-observer variability is rather high because there is no standardization for its application.14 Also, these methods are inadequate to diagnose lymphedema during the subclinical stage. However, an early diagnosis is of utmost importance to treat lymphedema.15 The superiority of bioimpedance analysis is its ability to diagnose lymphedema at an early stage. In our study, 3 patients were diagnosed as having lymphedema with no arm swelling at stage 0, and two patients were diagnosed as having stage 1. Patient 6, who did not accept the complex decongestive therapy, progressed to stage 2 during the follow-up period. In a study by Stout Gergich et al.,15 a volumeter was used for the diagnosis of early-stage lymphedema, the diagnosis was based on a 3% change between two measurements and significant changes were observed through the use of compression garments in the follow-up volume measurements.15 In the study by Fu et al., the progress of lymphedema was significantly slowed down in patients who were informed about lymphedema symptoms and the preventive measures.17 In our study, patients with Stage 0 lymphedema were recommended to take preventive measures and to wear compression garments, which led to a regression in the lymphedema during their follow up. The difference between those studies and ours is the use of bioimpedance analysis and the diagnosis of lymphedema before clinical symptoms. In patients with Stage 2 lymphedema, the complex decongestive therapy led to a reduction in their arm circumferences, although no regression could be achieved in the stage of lymphedema. Stage 0 and 1 lymphedema, classified as early-stage lymphedema, is reversible because fibrosis has yet to occur in the tissues. However, if no measures are taken, the condition leads to subcutaneous fibrosis, which hinders the healing of lymphedema. Therefore, lymphedema can be more efficiently treated during the early stages.18,19 In our study, an L-dex score greater then 10 units was considered as lymphedema. The circumferential measurements and clinical evaluation also played a role for diagnosis and staging. We used preoperative measurements for monitoring the change of L-dex score and detected that the change
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from baseline 3 months after surgery was higher in patients with lymphedema (Fig. 1). In a study by Cornish et al.,16 the diagnosis of lymphedema could be made 10 months before its clinical manifestation using bioimpedance spectroscopy. Our results are consistent with this result. In the literature, the rate of lymphedema development following sentinel lymph node biopsies is 5%–7%.22,23 However, in the study by Ozcinar et al., this ratio was 1.9%.13 In our study, no lymphedema was detected in the SLNB group, this may be related with the short duration of follow up and the limited number of patients. Axillary dissections (AD) are accepted as definitive and independent risk factors for the development of lymphedema.2,10,18 Nevertheless, the literature that indicates a correlation between the number of the lymph nodes removed during the axillary dissection and the risk of lymphedema has yet to be validated.22,24 In the study by Goldberg et al., lymphedema was observed in 31 out of 600 patients and no difference in terms of lymphedema development was observed between the 1–9 lymph node dissection group, and the 1–17 lymph node dissection group.23 On the other hand, Meeske et al. studied 494 patients who had undergone breast surgery, and noted dissection of more than 10 lymph nodes increased the lymphedema ratio.25 In our study, we observed that dissection of more than 15 lymph nodes increased the ratio of lymphedema. Radiotherapy of the supraclavicular lymph nodes significantly increases the risk of lymphedema compared with radiotherapy to the breast.13,26 In the study by Warren et al., the risk of lymphedema was 3% in the patients who received no radiotherapy, and was 3.1% after radiotherapy directed to the breast and chest wall, and 21.9% in radiotherapy of the supraclavicular area.27 In line with these findings, all the patients who developed lymphedema in our study had received radiotherapy to the supraclavicular lymph nodes. Kim et al.28 observed that the number of dissected lymph nodes, chemotherapy, and radiotherapy to the supraclavicular lymph nodes were independent risk factors for lymphedema development. The presence of one risk factor was associated with a 3% increase in the incidence of lymphedema, two risk factors led to a 19% increase, and three risk factors caused a 38% increase in the incidence of lymphedema.28 In our study, with the exception of one patient, all the patients who developed lymphedema had received chemotherapy and supraclavicular radiotherapy, and had 15 or more lymph nodes extracted. Information suggesting that a body mass index of 30 or above increases the risk of lymphedema was not in line with our results.7,29,30,35 We are of the opinion that this incompliance is associated with the limited number of patients in the lymphedema group and that the majority of our patients had a BMI value below 30. When taking into consideration the cost of treatment for advanced-stage lymphedema and morbidity-related complications including infections, the diagnosis and treatment of early-stage lymphedema through bioimpedance analysis performed during follow up is very beneficial.31 Despite the advantages of bioimpedance analysis for the patient, compliance was insufficient for our hospital. Overall, of the 129 patients who began the follow-up process, only 37 completed the study. The reason of this insufficient compliance rate was patients’ lack of knowledge about lymphedema and
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IYIGUN ET AL.
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importance of early diagnosis. Patients do not consider lymphedema and its morbidities a priority in their first-year cancer treatment and thus neglect their routine follow-up for lymphedema. In conclusion, lymphedema is a condition that reduces the quality of life of patients due to its complications and it is only fully treatable if it is diagnosed at an early stage. Bioimpedance analysis seems to be a practical and reliable method for the early diagnosis of lymphedema. It is believed that regular monitoring of patients who are in the high-risk group using bioimpedance analyses increases the chance of treatment in lymphedema. The limited number of the patients and the short follow-up period are the main limitations of this study.
12.
13. 14. 15.
Acknowledgments
16.
The authors would like to thank Mr. David Chapman for his meticulous editing of the manuscript.
17.
Author Disclosure Statement
No competing financial interests exist.
18.
References
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Address correspondence to: _ Zeynep Erdogan Iyigun, MD Department of Physical Theraphy and Rehabilitation Istanbul Bilim University Buyukdere str., No. 120 Esentepe, Sisli Istanbul, 34394 Turkey E-mail: [email protected]
