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Lymphedema following breast cancer treatment and impact on quality of life: A review
Critical Reviews in Oncology/Hematology 92 (2014) 227–234
Lymphedema following breast cancer treatment and impact on quality of life: A review Nadine R. Taghian a , Cynthia L. Miller a , Lauren S. Jammallo a , Jean O’Toole b , Melissa N. Skolny a,∗ a
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States Department of Physical Therapy, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States
b
Accepted 25 June 2014
Contents 1. 2. 3. 4. 5.
6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Measurement techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Definition of breast cancer-related lymphedema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Impact of breast cancer-related lymphedema on quality of life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Physical impact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Psychological impact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Emotional well-being . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract Lymphedema resulting from breast cancer treatment is a chronic condition which can significantly compromise quality of life. We sought to review various aspects of breast-cancer related lymphedema including measurement techniques, definitions, risk factors, and specifically, impact on physical, psychological, and emotional well-being of women treated for breast cancer. For the purpose of this review, we performed a literature search using PubMed for articles on lymphedema secondary to breast cancer treatment published since 1997. While improvements in breast cancer therapy have contributed to a decrease in the incidence of lymphedema, the overall negative impact the condition has on patients and survivors has remained unchanged. The development of lymphedema results in physical impairments including compromised function, diminished strength, fatigue, and pain in the affected arm. Affected women may have decreased self-confidence resulting from a distorted body image. Negative emotions reported by women with lymphedema include anxiety, frustration, sadness, anger, fear, and increased self-consciousness. Lymphedema secondary to breast cancer treatment remains a significant quality of life issue, with known consequences related to a woman’s physical, psychological, and emotional well-being. © 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Lymphedema; Breast cancer; Quality of life
∗ Corresponding author at: Department of Radiation Oncology, Cox 3 Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, United States. Tel.: +1 617 643 1306; fax: +1 617 726 3603. E-mail address: [email protected] (M.N. Skolny).
http://dx.doi.org/10.1016/j.critrevonc.2014.06.004 1040-8428/© 2014 Elsevier Ireland Ltd. All rights reserved.
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1. Introduction Lymphedema is an accumulation of fluid in the interstitial tissues due to the inability of the lymphatic system to transport lymph fluid out of the affected area [1]. Women who have undergone surgical or radiation treatment for breast cancer are at a lifelong risk of developing lymphedema, which can cause swelling in the arm, hand, shoulder, breast, or chest wall [1]. The condition may result in physical and psychological consequences, which can negatively impact a woman’s quality of life (QOL) and compromise her emotional wellbeing. Lymphedema can physically impair arm function by limiting range of motion, as well as causing feelings of pain, heaviness, and numbness in the upper extremity [2–6]. Psychologically, women may have decreased self-confidence due to a disturbance in body image, and experience negative emotions such as anxiety, frustration, sadness, anger, and increased self-consciousness [4–9]. Coping with the consequences of developing lymphedema is a challenge that more than 15% of all breast cancer patients and survivors may face [10]. Routine use of sentinel lymph node biopsy (SLNB) rather than axillary lymph node dissection (ALND) for node-negative breast cancer patients has resulted in a decreased incidence of lymphedema, with rates of >20% associated with ALND compared to 3.5–11% for SLNB [10–15]. However, lymphedema incidence varies widely across studies, likely due to inconsistencies in measurement techniques and criteria for lymphedema [16]. Despite the lower incidence of lymphedema associated with SLNB axillary staging of breast cancer, lymphedema remains a significant concern for survivors. It has been reported that most cases of lymphedema occur within 2–5 years of surgery [10], however, it is commonly believed that the risk of lymphedema remains for a lifetime [17,18]. A meta-analysis by Disipio et al. indicated that the incidence of lymphedema increases up to 24 months after breast cancer diagnosis or surgery, with 15% of cases emerging at 5 years or later [10]. Arm swelling caused by lymphedema may serve as a constant reminder of a woman’s suffering from breast cancer; although the disease has been eradicated from her body, she may be faced with a chronically swollen arm which significantly compromises her QOL (Fig. 1) [5,8]. Here we review the lack of standardization in lymphedema measurement and definition, risk factors for lymphedema, and, specifically, the impact of lymphedema on the QOL of women treated for breast cancer.
2. Measurement techniques Lymphedema of the upper extremity can be measured in various ways, including circumferential measurements, water displacement volumetry, optoelectronic perometry, and bioimpedance spectroscopy (BIS) [19,20]. The type of measurement technique utilized per institution has not been
Fig. 1. Advanced lymphedema. By perometry, this woman’s right arm is 30% larger than her left and is physically distorted, which makes fitting into clothing with sleeves a challenge. The weight of the arm results in functional impairment and difficulty completing the daily tasks of everyday life.
shown to be influenced by and does not vary depending on the type of breast surgery. A review of published findings demonstrate that institutions typically choose one measurement technique for assessing arm volume changes for all their patients regardless of the type of surgery or treatment for their breast cancer. Circumferential measurements involve the use of tape measurements to record circumference at various points along the arm, which can then be converted to an approximate arm volume using the truncated cone formula [4,16,21–23]. In addition to converting the arm circumference measurements to a volume, these measurements may be used as a stand alone measurement. Water displacement involves submerging the arm in a water tank and calculating the volume of the displaced fluid [4,16,22]. All of the above methods can be used to determine arm volume, but circumferential measurements may be inaccurate, and water displacement can be messy and unsanitary [16]. The optoelectronic perometer is a device which utilizes a sliding frame containing infrared light sensors to measure arm volume with a high degree of accuracy [4,16,22]. The Perometer is large and expensive; however, it has been demonstrated to be highly accurate in quantifying arm volume and is easy to use with high inter- and intra-rater reliability compared to circumferential and water displacement [23–25]. A study by Godoy et al. compared the sensitivity and specificity of perometry and water displacement for diagnosing lymphedema using two definitions of lymphedema, including a volume increase of 200 mL or 10% compared to the contralateral limb. The results indicated that the sensitivity of perometry was higher when compared to water displacement when lymphedema was defined as either a 200 mL or 10% increase in the affected limb (Fig. 2) [26].
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arms, and accounts for factors unrelated to lymphedema that may cause changes in arm size, such as weight gain [22,31,32].
4. Risk factors
Fig. 2. By perometry, this woman’s left arm is 13% larger than her right. Most clinicians classify a 10% volume difference between the arms as clinical lymphedema.
Bioimpedance spectroscopy (BIS) is a different method which measures the impedance of a low-strength electrical current passed through the body to determine the amount of extracellular fluid in the affected arm [20]. Unlike the previous three methods, it calculates an impedance ratio as opposed to arm volume or circumference, and may be particularly effective in detecting early-stage lymphedema [4,16,21,22]. A study by Cornish et al. estimated the sensitivity and specificity of BIS at 1.0 and .98 respectively [20]. This is consistent with the findings of a 2011 study by Smoot et al., which sought to compare the diagnostic accuracy of lymphedema measurement methods including a subjective questionnaire. BIS was found to have the highest accuracy, with an area under the curve (AUC) of .88 when the patient’s dominant arm was affected [27]. Another study by Jain et al. found the validity of BIS and perometry to be concordant [28]. Given the variety of tools available for lymphedema assessment, there is no existing standard method of measurement in the literature or clinical practice.
3. Definition of breast cancer-related lymphedema The definition of lymphedema has yet to be standardized as well. Most criteria involve comparing the size of the at-risk arm with the arm on the opposite side, or assessing change in size of the at-risk arm compared to a pre-surgery measurement. Commonly used definitions for lymphedema of the arm include a >2 cm difference in circumference, >200 ml difference in volume, or a >3–10% difference in circumference or volume [19,29,30]. The definition of lymphedema corresponding to BIS is an impedance ratio >3 standard deviations outside of the normal range [20]. We have previously described an accurate method of quantifying lymphedema which involves use of relative (percent) change in volume of the at-risk arm compared to a pre-surgical measurement, with adjustment for change in size of the opposite arm [31]. This method takes into account pre-surgical asymmetry between
The most frequently-cited risk factor for lymphedema secondary to breast cancer treatment is ALND [10,14,18,33–37]. A recent meta-analysis indicated that women who underwent ALND as part of their surgical treatment for breast cancer had a 4-times higher incidence of lymphedema compared with those who underwent SLNB (19.9% versus 5.6%, respectively) [10]. Results from recent studies may impact approaches for treatment of the axilla in breast cancer patients, with increasing trend toward SLNB rather than ALND even in node-positive patients. The ACOSOG Z0011 study found no significant difference in overall survival (OS), disease-free survival (DFS), or rates of regional recurrence for women with limited nodal involvement who underwent lumpectomy with randomization to SLNB and breast radiation or completion ALND [36,37]. Rates of lymphedema from this trial have yet to be reported. In addition, preliminary results from the AMAROS trial indicated no significant difference in OS or DFS among women with a positive SLNB randomized to completion ALND versus axillary radiation [38]. In this study, lymphedema rates at 1-year were 15% for SLNB with axillary radiation, compared with 25% for ALND without axillary radiation (p < 0.001 vs SLNB + axillary radiation) and 59% for ALND with axillary radiation (p < 0.001 vs SLNB + axillary radiation), with similar findings at 5 years [39]. In a recent study by our group, we reported a 2-year lymphedema incidence of 2% for SLNB without RLNR, 6% for SLNB with RLNR, 10% for ALND without RLNR, and 18% for ALND with RLNR [40]. Another study by our group evaluating only mastectomy patients demonstrated a 2-year lymphedema incidence of 10% for SLNB with radiation therapy (chest wall with or without RLNR) compared with 19% for ALND without radiation and 30% for ALND with radiation therapy (chest wall with or without RLNR). The lowest incidence of lymphedema was 2% for women who underwent SLNB without radiation therapy [41]. Thus evolution in management of the axilla should result in decreased lymphedema rates, as more women are eligible for less invasive axillary treatments. The ALMANAC study was the first large, prospective trial evaluating the impact of SLNB compared with ALND on quality of life and arm function. Participants were surveyed over the course of 18 months at 1,3, 6, 12 and 18-month time points post-operatively. Results from the study demonstrated that the number of women who reported swelling, tenderness, numbness, pain and decrease in arm function was higher at various time points in women who received completion ALND compared with SLNB. It is important to note that this difference was not statistically significant at all of the study
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time points. When evaluating overall QOL using the FACT-B questionnaire at designated time points, the scores for women who underwent SLNB were higher than their pre-operative baseline from 3 months onwards. In comparison, scores for women who underwent ALND had decreased compared to baseline until 12 months after final surgery [42]. These findings suggest that women who undergo SLNB for their axillary staging experience less treatment-related morbidities and an overall higher post-operative QOL compared with those who undergo ALND. Thus increasing use of SLNB for management of the axilla in breast cancer patients should not only decrease lymphedema rates, but could also decrease the likelihood of developing other treatment-related morbidities which impact QOL. Additional lymphedema risk factors that have been suggested include, higher body mass index (BMI) or obesity, nodal radiation, mastectomy, number of lymph nodes removed and number of positive lymph nodes, adjuvant chemotherapy, and decreased physical activity levels [1,3,10,12,13,19,33,35,43–55]. A study by our group evaluating the impact of body mass index (BMI) on development of lymphedema demonstrated that women with a pre-operative BMI of ≥30 had a 3.58 times increased risk of lymphedema compared to a BMI of <25 (p = 0.001) and 2.46 times increased risk compared to a BMI of 25–30 (p = 0.012) [56]. A 2009 meta-analysis by Tsai et al. indicated risk ratios of 2.97 for nodal radiation (versus no nodal radiation), 1.42 for mastectomy (versus lumpectomy), 1.54 for positive lymph nodes (versus no positive lymph nodes), and 1.11 for chemotherapy (versus no chemotherapy) [19]. However, risk ratios corresponding to these factors vary widely across studies, likely due to differences in study design, characteristics of patient cohorts, lymphedema measurement methods, and criteria for lymphedema. A number of other factors are believed to increase the risk of developing lymphedema, including blood draws and blood pressure of the affected arm, exposure to extreme temperatures, and air travel [57]. Clinicians may advise women treated for breast cancer to engage in lymphedema riskreduction practices to protect the arm, including avoidance of extreme temperatures (hot tubs, saunas), use of compression garments (particularly for air travel), aggressive skin care to prevent infection, and avoidance of injections, blood draws, or constriction of the arm (blood pressure or tight clothing) [57]. However, these precautionary measures are based primarily on anecdotal experience and are not evidence-based, warranting further research.
5. Impact of breast cancer-related lymphedema on quality of life 5.1. Physical impact Physical symptoms associated with lymphedema include diminished strength, limited range of motion, fatigue, and
pain, as well as sensations of tingling and heaviness in the affected arm [2–5,7,58–60]. The most common and significant physical limitation caused by lymphedema is decreased function of the affected arm; affected women may suffer from reduced elbow flexion and grip strength as well as limitations in shoulder abduction [2]. As a result of these complications, women may be prevented from returning to the level of activity they experienced prior to breast cancer diagnosis [1,39]. Women with lymphedema may also experience difficulty performing everyday activities such as work, household chores, and getting dressed [1,7,8,61,62]. Furthermore, they may be unable to wear tight-fitting clothes, and those who develop lymphedema in the hand may experience difficulty writing or putting on tight jewelry [3,4,6]. Several studies have found that increased exercise and activity are beneficial for relief of swelling and reduction in pain associated with lymphedema [2,6,39]. Kim et al. performed a randomized-controlled study to investigate the effects of active versus non-active resistance training on arm volume and its relation to quality of life. The authors found that active resistance training resulted in a significant reduction in arm volume. In addition, both active and non-active resistance training resulted in significantly improved physical function, bone pain, and mental health [63]. In contrast, a randomized study by McKenzie et al. found no statistically significant difference in arm volumes of participants who performed strength and cardio exercises compared with those who did not [64]. However, the authors did find that participants who exercised had increased overall QOL due to feeling healthier and possessing greater confidence in their ability to use their affected arm [64]. Schmitz et al. further confirmed this finding in a study of 141 subjects randomized to light-resistance weight training or maintenance of regular exercise habits [65]. No significant difference in arm swelling was found between the groups, and the group randomized to weight training experienced decreased severity of arm and hand symptoms, increased muscular strength, and a lower incidence of lymphedema exacerbations [65]. While exercise is generally considered beneficial with regard to QOL, more research is needed investigating the effects of exercise and its impact on risk of developing or worsening pre-existing lymphedema. 5.2. Psychological impact Physical arm morbidities caused by lymphedema can lead to negative feelings, particularly regarding one’s body image [7,8,62,66,67]. Reports in the literature indicate that women with lymphedema experience concerns about the appearance of their arms, hands, and shoulders because of the swelling [8,62,66]. For some, internal perception and external criticisms have resulted in an overall negative body image [4,5,8]. In evaluations of the perceptions and feelings of breast cancer patients with lymphedema, some women describe feeling as though they have lost control of their bodies and their appearance [8,62]. Women who do not find themselves
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physically attractive may struggle with lowered selfconfidence and this disturbance in self-image can negatively influence their sexual interests and activity [5–8,58,66,67]. Women who develop lymphedema may hide their affected arm out of embarrassment and shame. It can become particularly difficult and uncomfortable to conceal the affected arm under clothing during the warmer months of the year, since heat may exacerbate swelling [8]. This may result in selfimposed social isolation due to a woman’s inability to conceal her affected arm [68]. A study by Ridner et al. evaluated the emotions of 39 women coping with lymphedema. The authors reported that women experienced frustration and insecurity when they were unable to go places where they could not hide their arm, which led to an avoidance of going out altogether [5,8]. Similarly, Vassard et al. showed that women with lymphedema struggle with social avoidance [5]. Thus, a swollen arm related to lymphedema may cause women to feel insecure about their bodies, alter their daily activities, buy concealing clothing, and avoid social situations [1,4,5,8,61]. 5.3. Emotional well-being The development of lymphedema may also significantly impact a woman’s emotional well-being. Women with lymphedema have been shown to experience stress, anxiety, sadness, anger, frustration, and guilt because of the condition [4–9]. Women may also feel as though their identity has been compromised because they are constantly associated with their condition [8]. A lack of understanding about lymphedema by family and friends may lead women to feel that others are unable to understand the severity of the condition [7]. A study by Ridner et al. evaluated 53 women with breast cancer-related lymphedema to evaluate a potential association between frequencies of lymphedema symptoms and emotional distress [7]. The authors found that many negative feelings were linked to relationship changes with loved ones [7]. Likewise, in another study by Ridner et al., study participants with lymphedema reported feeling guilty because of an increased dependence on family and friends related to development of the condition [8]. Since arm swelling can be very symptomatic and limit physical activity, affected women may become less independent and feel as though they are a burden to their loved ones [8,62]. Breast cancer patients and survivors with lymphedema have been shown to utilize various methods of coping with the condition. In a study conducted by Ridner et al., many women quit smoking and limited their alcohol consumption after being diagnosed with lymphedema. In addition, they became more active and motivated to stay healthy, refusing to let lymphedema take control of their lives. However, lymphedema may have the opposite effect on some other women, who have been noted to make poor choices about nutrition and continue to live an unhealthy lifestyle because they are depressed about having developed the condition [7]. Women with lymphedema may live in constant fear that the condition will worsen, causing them to change their
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normal lifestyles [4,6,8]. Even the possibility of developing lymphedema has been shown to cause fear and anxiety among breast cancer survivors [69–71]. Women with lymphedema may avoid going outside in warmer weather out of fear of increasing their arm swelling and experiencing trauma which could lead to infection or cellulitis [8]. Fear of developing lymphedema may impact a woman’s decisions to engage in physical activity and exercise, leading to avoidance of strenuous upper-body activities [72,73]. Limited use of the at-risk arm may compromise QOL, as well as lead to potential consequences of inactivity such as prolonged arm weakness and weight gain [74]. Thus, fear of lymphedema may result in overall decreased QOL for breast cancer survivors with and without the condition.
6. Conclusion Advances in the treatment of breast cancer have significantly improved survival from the disease. Therefore, greater emphasis should be placed on addressing the long-term complications of treatment known to significantly impact QOL, such as breast cancer-related lymphedema. Lymphedema affects many important aspects of a woman’s life, including her physical, psychological, and emotional well-being. We recommend screening for early detection of lymphedema and the generation of Level 1 evidence to evaluate the efficacy of early intervention in preventing progression of the condition. In addition, early education about lymphedema for women diagnosed with breast cancer is important, such that women are aware of the risk factors, symptoms, and QOL implications associated with the condition. Women who develop lymphedema should be educated on appropriate activities such as weight lifting or mild upper extremity exercises which could potentially improve their physical and psychological wellbeing without exacerbating the condition.
Conflicts of interest None of the authors have any conflicts of interest to disclose and all authors have read and approved the manuscript.
Reviewers David Azria, M.D., Ph.D., Head of service, CRLC Val d’Aurelle, Radiation Oncology, Rue croix verte, F-34298 Montpellier, France. Celine Bourgier, M.D., Ph.D., CRLC Val d’Aurelle, Radiation Oncology, 208, Avenue des Apothicaires, F-34298 Montpellier Cedex, France. Yazid Belkacemi, M.D., Ph.D., Henri Mondor, Radiation Oncology, 51 Av Mal De Lattre de Tassigny, Creteil, France.
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Acknowledgements The project described was supported by award numbers R01CA139118 (AGT), P50CA089393 (AGT) from the National Cancer Institute and the Adele McKinnon Research Fund for Breast Cancer-Related Lymphedema. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.
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Biography Melissa Skolny Clinical Research Program Manager, earned her M.S. in Health Administration degree from Roberts and Wesleyan College in 2009. She has spent the past four years working for the Breast Cancer-Related Lymphedema Studies program at Massachusetts General Hospital. Her main clinical interests include early identification of breast cancer survivors at high risk for lymphedema and potential prevention methods for breast cancer-related lymphedema.
Lymphedema following breast cancer treatment and impact on quality of life: A review Nadine R. Taghian a , Cynthia L. Miller a , Lauren S. Jammallo a , Jean O’Toole b , Melissa N. Skolny a,∗ a
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States Department of Physical Therapy, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States
b
Accepted 25 June 2014
Contents 1. 2. 3. 4. 5.
6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Measurement techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Definition of breast cancer-related lymphedema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Impact of breast cancer-related lymphedema on quality of life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Physical impact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Psychological impact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Emotional well-being . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract Lymphedema resulting from breast cancer treatment is a chronic condition which can significantly compromise quality of life. We sought to review various aspects of breast-cancer related lymphedema including measurement techniques, definitions, risk factors, and specifically, impact on physical, psychological, and emotional well-being of women treated for breast cancer. For the purpose of this review, we performed a literature search using PubMed for articles on lymphedema secondary to breast cancer treatment published since 1997. While improvements in breast cancer therapy have contributed to a decrease in the incidence of lymphedema, the overall negative impact the condition has on patients and survivors has remained unchanged. The development of lymphedema results in physical impairments including compromised function, diminished strength, fatigue, and pain in the affected arm. Affected women may have decreased self-confidence resulting from a distorted body image. Negative emotions reported by women with lymphedema include anxiety, frustration, sadness, anger, fear, and increased self-consciousness. Lymphedema secondary to breast cancer treatment remains a significant quality of life issue, with known consequences related to a woman’s physical, psychological, and emotional well-being. © 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Lymphedema; Breast cancer; Quality of life
∗ Corresponding author at: Department of Radiation Oncology, Cox 3 Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, United States. Tel.: +1 617 643 1306; fax: +1 617 726 3603. E-mail address: [email protected] (M.N. Skolny).
http://dx.doi.org/10.1016/j.critrevonc.2014.06.004 1040-8428/© 2014 Elsevier Ireland Ltd. All rights reserved.
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1. Introduction Lymphedema is an accumulation of fluid in the interstitial tissues due to the inability of the lymphatic system to transport lymph fluid out of the affected area [1]. Women who have undergone surgical or radiation treatment for breast cancer are at a lifelong risk of developing lymphedema, which can cause swelling in the arm, hand, shoulder, breast, or chest wall [1]. The condition may result in physical and psychological consequences, which can negatively impact a woman’s quality of life (QOL) and compromise her emotional wellbeing. Lymphedema can physically impair arm function by limiting range of motion, as well as causing feelings of pain, heaviness, and numbness in the upper extremity [2–6]. Psychologically, women may have decreased self-confidence due to a disturbance in body image, and experience negative emotions such as anxiety, frustration, sadness, anger, and increased self-consciousness [4–9]. Coping with the consequences of developing lymphedema is a challenge that more than 15% of all breast cancer patients and survivors may face [10]. Routine use of sentinel lymph node biopsy (SLNB) rather than axillary lymph node dissection (ALND) for node-negative breast cancer patients has resulted in a decreased incidence of lymphedema, with rates of >20% associated with ALND compared to 3.5–11% for SLNB [10–15]. However, lymphedema incidence varies widely across studies, likely due to inconsistencies in measurement techniques and criteria for lymphedema [16]. Despite the lower incidence of lymphedema associated with SLNB axillary staging of breast cancer, lymphedema remains a significant concern for survivors. It has been reported that most cases of lymphedema occur within 2–5 years of surgery [10], however, it is commonly believed that the risk of lymphedema remains for a lifetime [17,18]. A meta-analysis by Disipio et al. indicated that the incidence of lymphedema increases up to 24 months after breast cancer diagnosis or surgery, with 15% of cases emerging at 5 years or later [10]. Arm swelling caused by lymphedema may serve as a constant reminder of a woman’s suffering from breast cancer; although the disease has been eradicated from her body, she may be faced with a chronically swollen arm which significantly compromises her QOL (Fig. 1) [5,8]. Here we review the lack of standardization in lymphedema measurement and definition, risk factors for lymphedema, and, specifically, the impact of lymphedema on the QOL of women treated for breast cancer.
2. Measurement techniques Lymphedema of the upper extremity can be measured in various ways, including circumferential measurements, water displacement volumetry, optoelectronic perometry, and bioimpedance spectroscopy (BIS) [19,20]. The type of measurement technique utilized per institution has not been
Fig. 1. Advanced lymphedema. By perometry, this woman’s right arm is 30% larger than her left and is physically distorted, which makes fitting into clothing with sleeves a challenge. The weight of the arm results in functional impairment and difficulty completing the daily tasks of everyday life.
shown to be influenced by and does not vary depending on the type of breast surgery. A review of published findings demonstrate that institutions typically choose one measurement technique for assessing arm volume changes for all their patients regardless of the type of surgery or treatment for their breast cancer. Circumferential measurements involve the use of tape measurements to record circumference at various points along the arm, which can then be converted to an approximate arm volume using the truncated cone formula [4,16,21–23]. In addition to converting the arm circumference measurements to a volume, these measurements may be used as a stand alone measurement. Water displacement involves submerging the arm in a water tank and calculating the volume of the displaced fluid [4,16,22]. All of the above methods can be used to determine arm volume, but circumferential measurements may be inaccurate, and water displacement can be messy and unsanitary [16]. The optoelectronic perometer is a device which utilizes a sliding frame containing infrared light sensors to measure arm volume with a high degree of accuracy [4,16,22]. The Perometer is large and expensive; however, it has been demonstrated to be highly accurate in quantifying arm volume and is easy to use with high inter- and intra-rater reliability compared to circumferential and water displacement [23–25]. A study by Godoy et al. compared the sensitivity and specificity of perometry and water displacement for diagnosing lymphedema using two definitions of lymphedema, including a volume increase of 200 mL or 10% compared to the contralateral limb. The results indicated that the sensitivity of perometry was higher when compared to water displacement when lymphedema was defined as either a 200 mL or 10% increase in the affected limb (Fig. 2) [26].
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arms, and accounts for factors unrelated to lymphedema that may cause changes in arm size, such as weight gain [22,31,32].
4. Risk factors
Fig. 2. By perometry, this woman’s left arm is 13% larger than her right. Most clinicians classify a 10% volume difference between the arms as clinical lymphedema.
Bioimpedance spectroscopy (BIS) is a different method which measures the impedance of a low-strength electrical current passed through the body to determine the amount of extracellular fluid in the affected arm [20]. Unlike the previous three methods, it calculates an impedance ratio as opposed to arm volume or circumference, and may be particularly effective in detecting early-stage lymphedema [4,16,21,22]. A study by Cornish et al. estimated the sensitivity and specificity of BIS at 1.0 and .98 respectively [20]. This is consistent with the findings of a 2011 study by Smoot et al., which sought to compare the diagnostic accuracy of lymphedema measurement methods including a subjective questionnaire. BIS was found to have the highest accuracy, with an area under the curve (AUC) of .88 when the patient’s dominant arm was affected [27]. Another study by Jain et al. found the validity of BIS and perometry to be concordant [28]. Given the variety of tools available for lymphedema assessment, there is no existing standard method of measurement in the literature or clinical practice.
3. Definition of breast cancer-related lymphedema The definition of lymphedema has yet to be standardized as well. Most criteria involve comparing the size of the at-risk arm with the arm on the opposite side, or assessing change in size of the at-risk arm compared to a pre-surgery measurement. Commonly used definitions for lymphedema of the arm include a >2 cm difference in circumference, >200 ml difference in volume, or a >3–10% difference in circumference or volume [19,29,30]. The definition of lymphedema corresponding to BIS is an impedance ratio >3 standard deviations outside of the normal range [20]. We have previously described an accurate method of quantifying lymphedema which involves use of relative (percent) change in volume of the at-risk arm compared to a pre-surgical measurement, with adjustment for change in size of the opposite arm [31]. This method takes into account pre-surgical asymmetry between
The most frequently-cited risk factor for lymphedema secondary to breast cancer treatment is ALND [10,14,18,33–37]. A recent meta-analysis indicated that women who underwent ALND as part of their surgical treatment for breast cancer had a 4-times higher incidence of lymphedema compared with those who underwent SLNB (19.9% versus 5.6%, respectively) [10]. Results from recent studies may impact approaches for treatment of the axilla in breast cancer patients, with increasing trend toward SLNB rather than ALND even in node-positive patients. The ACOSOG Z0011 study found no significant difference in overall survival (OS), disease-free survival (DFS), or rates of regional recurrence for women with limited nodal involvement who underwent lumpectomy with randomization to SLNB and breast radiation or completion ALND [36,37]. Rates of lymphedema from this trial have yet to be reported. In addition, preliminary results from the AMAROS trial indicated no significant difference in OS or DFS among women with a positive SLNB randomized to completion ALND versus axillary radiation [38]. In this study, lymphedema rates at 1-year were 15% for SLNB with axillary radiation, compared with 25% for ALND without axillary radiation (p < 0.001 vs SLNB + axillary radiation) and 59% for ALND with axillary radiation (p < 0.001 vs SLNB + axillary radiation), with similar findings at 5 years [39]. In a recent study by our group, we reported a 2-year lymphedema incidence of 2% for SLNB without RLNR, 6% for SLNB with RLNR, 10% for ALND without RLNR, and 18% for ALND with RLNR [40]. Another study by our group evaluating only mastectomy patients demonstrated a 2-year lymphedema incidence of 10% for SLNB with radiation therapy (chest wall with or without RLNR) compared with 19% for ALND without radiation and 30% for ALND with radiation therapy (chest wall with or without RLNR). The lowest incidence of lymphedema was 2% for women who underwent SLNB without radiation therapy [41]. Thus evolution in management of the axilla should result in decreased lymphedema rates, as more women are eligible for less invasive axillary treatments. The ALMANAC study was the first large, prospective trial evaluating the impact of SLNB compared with ALND on quality of life and arm function. Participants were surveyed over the course of 18 months at 1,3, 6, 12 and 18-month time points post-operatively. Results from the study demonstrated that the number of women who reported swelling, tenderness, numbness, pain and decrease in arm function was higher at various time points in women who received completion ALND compared with SLNB. It is important to note that this difference was not statistically significant at all of the study
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time points. When evaluating overall QOL using the FACT-B questionnaire at designated time points, the scores for women who underwent SLNB were higher than their pre-operative baseline from 3 months onwards. In comparison, scores for women who underwent ALND had decreased compared to baseline until 12 months after final surgery [42]. These findings suggest that women who undergo SLNB for their axillary staging experience less treatment-related morbidities and an overall higher post-operative QOL compared with those who undergo ALND. Thus increasing use of SLNB for management of the axilla in breast cancer patients should not only decrease lymphedema rates, but could also decrease the likelihood of developing other treatment-related morbidities which impact QOL. Additional lymphedema risk factors that have been suggested include, higher body mass index (BMI) or obesity, nodal radiation, mastectomy, number of lymph nodes removed and number of positive lymph nodes, adjuvant chemotherapy, and decreased physical activity levels [1,3,10,12,13,19,33,35,43–55]. A study by our group evaluating the impact of body mass index (BMI) on development of lymphedema demonstrated that women with a pre-operative BMI of ≥30 had a 3.58 times increased risk of lymphedema compared to a BMI of <25 (p = 0.001) and 2.46 times increased risk compared to a BMI of 25–30 (p = 0.012) [56]. A 2009 meta-analysis by Tsai et al. indicated risk ratios of 2.97 for nodal radiation (versus no nodal radiation), 1.42 for mastectomy (versus lumpectomy), 1.54 for positive lymph nodes (versus no positive lymph nodes), and 1.11 for chemotherapy (versus no chemotherapy) [19]. However, risk ratios corresponding to these factors vary widely across studies, likely due to differences in study design, characteristics of patient cohorts, lymphedema measurement methods, and criteria for lymphedema. A number of other factors are believed to increase the risk of developing lymphedema, including blood draws and blood pressure of the affected arm, exposure to extreme temperatures, and air travel [57]. Clinicians may advise women treated for breast cancer to engage in lymphedema riskreduction practices to protect the arm, including avoidance of extreme temperatures (hot tubs, saunas), use of compression garments (particularly for air travel), aggressive skin care to prevent infection, and avoidance of injections, blood draws, or constriction of the arm (blood pressure or tight clothing) [57]. However, these precautionary measures are based primarily on anecdotal experience and are not evidence-based, warranting further research.
5. Impact of breast cancer-related lymphedema on quality of life 5.1. Physical impact Physical symptoms associated with lymphedema include diminished strength, limited range of motion, fatigue, and
pain, as well as sensations of tingling and heaviness in the affected arm [2–5,7,58–60]. The most common and significant physical limitation caused by lymphedema is decreased function of the affected arm; affected women may suffer from reduced elbow flexion and grip strength as well as limitations in shoulder abduction [2]. As a result of these complications, women may be prevented from returning to the level of activity they experienced prior to breast cancer diagnosis [1,39]. Women with lymphedema may also experience difficulty performing everyday activities such as work, household chores, and getting dressed [1,7,8,61,62]. Furthermore, they may be unable to wear tight-fitting clothes, and those who develop lymphedema in the hand may experience difficulty writing or putting on tight jewelry [3,4,6]. Several studies have found that increased exercise and activity are beneficial for relief of swelling and reduction in pain associated with lymphedema [2,6,39]. Kim et al. performed a randomized-controlled study to investigate the effects of active versus non-active resistance training on arm volume and its relation to quality of life. The authors found that active resistance training resulted in a significant reduction in arm volume. In addition, both active and non-active resistance training resulted in significantly improved physical function, bone pain, and mental health [63]. In contrast, a randomized study by McKenzie et al. found no statistically significant difference in arm volumes of participants who performed strength and cardio exercises compared with those who did not [64]. However, the authors did find that participants who exercised had increased overall QOL due to feeling healthier and possessing greater confidence in their ability to use their affected arm [64]. Schmitz et al. further confirmed this finding in a study of 141 subjects randomized to light-resistance weight training or maintenance of regular exercise habits [65]. No significant difference in arm swelling was found between the groups, and the group randomized to weight training experienced decreased severity of arm and hand symptoms, increased muscular strength, and a lower incidence of lymphedema exacerbations [65]. While exercise is generally considered beneficial with regard to QOL, more research is needed investigating the effects of exercise and its impact on risk of developing or worsening pre-existing lymphedema. 5.2. Psychological impact Physical arm morbidities caused by lymphedema can lead to negative feelings, particularly regarding one’s body image [7,8,62,66,67]. Reports in the literature indicate that women with lymphedema experience concerns about the appearance of their arms, hands, and shoulders because of the swelling [8,62,66]. For some, internal perception and external criticisms have resulted in an overall negative body image [4,5,8]. In evaluations of the perceptions and feelings of breast cancer patients with lymphedema, some women describe feeling as though they have lost control of their bodies and their appearance [8,62]. Women who do not find themselves
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physically attractive may struggle with lowered selfconfidence and this disturbance in self-image can negatively influence their sexual interests and activity [5–8,58,66,67]. Women who develop lymphedema may hide their affected arm out of embarrassment and shame. It can become particularly difficult and uncomfortable to conceal the affected arm under clothing during the warmer months of the year, since heat may exacerbate swelling [8]. This may result in selfimposed social isolation due to a woman’s inability to conceal her affected arm [68]. A study by Ridner et al. evaluated the emotions of 39 women coping with lymphedema. The authors reported that women experienced frustration and insecurity when they were unable to go places where they could not hide their arm, which led to an avoidance of going out altogether [5,8]. Similarly, Vassard et al. showed that women with lymphedema struggle with social avoidance [5]. Thus, a swollen arm related to lymphedema may cause women to feel insecure about their bodies, alter their daily activities, buy concealing clothing, and avoid social situations [1,4,5,8,61]. 5.3. Emotional well-being The development of lymphedema may also significantly impact a woman’s emotional well-being. Women with lymphedema have been shown to experience stress, anxiety, sadness, anger, frustration, and guilt because of the condition [4–9]. Women may also feel as though their identity has been compromised because they are constantly associated with their condition [8]. A lack of understanding about lymphedema by family and friends may lead women to feel that others are unable to understand the severity of the condition [7]. A study by Ridner et al. evaluated 53 women with breast cancer-related lymphedema to evaluate a potential association between frequencies of lymphedema symptoms and emotional distress [7]. The authors found that many negative feelings were linked to relationship changes with loved ones [7]. Likewise, in another study by Ridner et al., study participants with lymphedema reported feeling guilty because of an increased dependence on family and friends related to development of the condition [8]. Since arm swelling can be very symptomatic and limit physical activity, affected women may become less independent and feel as though they are a burden to their loved ones [8,62]. Breast cancer patients and survivors with lymphedema have been shown to utilize various methods of coping with the condition. In a study conducted by Ridner et al., many women quit smoking and limited their alcohol consumption after being diagnosed with lymphedema. In addition, they became more active and motivated to stay healthy, refusing to let lymphedema take control of their lives. However, lymphedema may have the opposite effect on some other women, who have been noted to make poor choices about nutrition and continue to live an unhealthy lifestyle because they are depressed about having developed the condition [7]. Women with lymphedema may live in constant fear that the condition will worsen, causing them to change their
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normal lifestyles [4,6,8]. Even the possibility of developing lymphedema has been shown to cause fear and anxiety among breast cancer survivors [69–71]. Women with lymphedema may avoid going outside in warmer weather out of fear of increasing their arm swelling and experiencing trauma which could lead to infection or cellulitis [8]. Fear of developing lymphedema may impact a woman’s decisions to engage in physical activity and exercise, leading to avoidance of strenuous upper-body activities [72,73]. Limited use of the at-risk arm may compromise QOL, as well as lead to potential consequences of inactivity such as prolonged arm weakness and weight gain [74]. Thus, fear of lymphedema may result in overall decreased QOL for breast cancer survivors with and without the condition.
6. Conclusion Advances in the treatment of breast cancer have significantly improved survival from the disease. Therefore, greater emphasis should be placed on addressing the long-term complications of treatment known to significantly impact QOL, such as breast cancer-related lymphedema. Lymphedema affects many important aspects of a woman’s life, including her physical, psychological, and emotional well-being. We recommend screening for early detection of lymphedema and the generation of Level 1 evidence to evaluate the efficacy of early intervention in preventing progression of the condition. In addition, early education about lymphedema for women diagnosed with breast cancer is important, such that women are aware of the risk factors, symptoms, and QOL implications associated with the condition. Women who develop lymphedema should be educated on appropriate activities such as weight lifting or mild upper extremity exercises which could potentially improve their physical and psychological wellbeing without exacerbating the condition.
Conflicts of interest None of the authors have any conflicts of interest to disclose and all authors have read and approved the manuscript.
Reviewers David Azria, M.D., Ph.D., Head of service, CRLC Val d’Aurelle, Radiation Oncology, Rue croix verte, F-34298 Montpellier, France. Celine Bourgier, M.D., Ph.D., CRLC Val d’Aurelle, Radiation Oncology, 208, Avenue des Apothicaires, F-34298 Montpellier Cedex, France. Yazid Belkacemi, M.D., Ph.D., Henri Mondor, Radiation Oncology, 51 Av Mal De Lattre de Tassigny, Creteil, France.
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Acknowledgements The project described was supported by award numbers R01CA139118 (AGT), P50CA089393 (AGT) from the National Cancer Institute and the Adele McKinnon Research Fund for Breast Cancer-Related Lymphedema. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.
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Biography Melissa Skolny Clinical Research Program Manager, earned her M.S. in Health Administration degree from Roberts and Wesleyan College in 2009. She has spent the past four years working for the Breast Cancer-Related Lymphedema Studies program at Massachusetts General Hospital. Her main clinical interests include early identification of breast cancer survivors at high risk for lymphedema and potential prevention methods for breast cancer-related lymphedema.