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Journal of Clinical Oncology, Vol 26, No 21 (July 20), 2008: pp. 3536-3542 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.4899 Lymphedema After Breast Cancer: Incidence, Risk Factors, and Effect on Upper Body Function
From the Institute of Health and Biomedical Innovation, School of Public Health; and School of Physical and Chemical Sciences, Queensland University of Technology, Kelvin Grove, Queensland, Australia Corresponding author: Sandra Hayes, MD, Institute of Health and Biomedical Innovation, School of Public Health, Faculty of Health, Queensland University of Technology, Victoria Park Rd, Kelvin Grove, QLD 4059, Australia; e-mail: sc.hayes{at}qut.edu.au
Purpose Secondary lymphedema is associated with adverse physical and psychosocial consequences among women with breast cancer (BC). This article describes the prevalence and incidence of lymphedema between 6 and 18 months after BC treatment; personal, treatment, and behavioral correlates of lymphedema status; and the presence of other upper-body symptoms (UBS) and function (UBF). Patients and Methods A population-based sample of Australian women (n = 287) with recently diagnosed, invasive BC were evaluated on five occasions using bioimpedance spectroscopy. Lymphedema was diagnosed when the ratio of impedance values, comparing treated and untreated sides, was three standard deviations more than normative data. UBF was assessed using the validated Disability of the Arm, Shoulder, and Hand questionnaire. Results From 6 to 18 months after surgery, 33% (n = 62) of the sample were classified as having lymphedema; of these, 40% had long-term lymphedema. Although older age, more extensive surgery or axillary node dissection, and experiencing one or more treatment-related complication(s) or symptom(s) at baseline were associated with increased odds, lower socioeconomic status, having a partner, greater child care responsibilities, being treated on the dominant side, participation in regular activity, and having good UBF were associated with decreased odds of lymphedema. Not surprisingly, lymphedema leads to reduced UBF; however, BC survivors report high prevalences of other UBS (34% to 62%), irrespective of their lymphedema status. Conclusion Lymphedema is a public health issue deserving greater attention. More systematic surveillance for earlier detection and the potential benefits of physical activity to prevent lymphedema and mitigate symptoms warrant further clinical integration and research.
Secondary lymphedema is arguably the most problematic and dreaded complication of breast cancer treatment.3 Although the incidence is generally accepted at approximately 30%, reported rates vary greatly, ranging between 2% and 83%.3-5 Lymphedema may present immediately or years after treatment,6 although the majority of cases occur during the first 18 months.5-7 Little is known about lymphedema prevention, and it is regarded as an incurable, progressive, disfiguring, and disabling disorder that is difficult to treat. Our understanding is further complicated by inconsistent relationships reported for a range of potential personal, disease, and treatment-related risk factors.9 Differences in lymphedema measurement techniques, definitions of what constitutes lymphedema, and timing of lymphedema assessments contribute to inconsistencies in the scientific literature and confusion surrounding clinical practice. Most findings on incidence and risk factors have been derived from studies that use indirect measures of lymphedema, in particular, circumferences and water displacement. Although not yet globally considered the gold standard, multifrequency bioelectrical impedance, now referred to as bioimpedance spectroscopy (BIS), can directly, accurately, and reliably measure lymphedema.10 The purpose of this investigation was to determine prevalence and incidence of lymphedema, as defined by use of BIS, from 6 to 18 months after treatment for breast cancer among a population-based sample of women residing in Southeast Queensland, Australia. Secondary objectives were to assess the relationships between a range of personal, treatment, and behavioral characteristics and odds of lymphedema, determine the prevalence of other treatment-related upper-body symptoms in those with and without lymphedema, and determine the effect of lymphedema on upper-body function.
Patients After ethical approval, 511 women diagnosed with unilateral breast cancer within the previous 6 months (diagnosed in 2002),  75 years of age, and residing within a 100-km radius of Brisbane, Queensland, were randomly selected from the Queensland Cancer Registry to participate in the study. Younger women (< 50 years) were over-sampled to ensure adequate numbers were available for specific age group analyses. Doctor consent was required before contacting eligible participants and was obtained for 82% of the sample (n = 417). Of these, informed consent was obtained for 287 women (69%). This study forms part of a larger investigation, known as the Pulling Through Study, which was designed to track and assess the physical and psychosocial recovery of women after breast cancer treatment. Participation involved a clinical assessment and/or completion of a self-administered questionnaire. Some of the women (26%) agreed to participate in the study on a questionnaire-only basis.
Testing Protocol
BIS
Risk Factor, Treatment-Related Symptoms, and Upper-Body Function The DASH13 collects information about the level of difficulty experienced when performing specific tasks, the extent to which any upper-body problem interferes with normal activities, and severity of specific upper-body symptoms. Final scores range from 0 to 100, where 0 reflects no disability (good function) and 100 reflects extensive disability (poor function). To our knowledge, this is the first use of the DASH questionnaire to assess arm function among women with breast cancer. During the final testing session, the median score in our sample was 7 (95% CI, 5.2 to 10.8) and was used to categorize the sample into those with better or poorer arm function than most, noting that the latter group did not necessarily have poor function.
Statistical Methods Presence of mild to extreme treatment-related upper-body symptoms at baseline, reported by those never having lymphedema, those with lymphedema during 9 to 18 months after surgery, and the entire sample, were calculated and compared. A model to assess potential risk factors for poorer upper-body function incorporated those baseline characteristics included in the final lymphedema model, in addition to having lymphedema at any stage during the 6 to 18 months after surgery (cumulative burden). Statistical procedures were performed using the packages SPSS version 13 for Windows (SPSS Inc, Chicago, IL) and SUDAAN (Research Triangle Park, NC), and all analysis used weighting procedures to address the over-sampling of younger women (weights of 1.0 for those < 50 years and 1.3 for those 50 to 74 years of age).
In comparison with the population of patients with breast cancer in Queensland, our sample had smaller tumors and fewer positive nodes. Age and number of lymph nodes examined were similar between the groups. Demographic and disease characteristics were similar for the women in this study and those in the target sample (Table 1), as well as between those (n = 158) with complete (lymphedema status available at all five testing phases) and those (n = 53) with incomplete data sets (data not shown).
Lymphedema Prevalence, Cumulative Burden, and Incidence Point prevalence across the study period ranged between 7.5% and 14.7% (Table 2). By 18 months after surgery, more than 30% of the women showed evidence of lymphedema at one or more testing phases. Of these 62 women, 58% had transitory symptoms (ie, for no longer than 3 months) that presented at any time between 6 and 18 months after surgery. Approximately 39% (n = 24) had measurable evidence of the condition for more than 3 months, and of these, the majority (63%) presented with symptoms at the first evaluation (6 months after treatment). Additionally, 63% of the women with long-term lymphedema experienced intermittent periods without symptoms. Incidence of lymphedema between 9 and 18 months after surgery was 23.4% (Table 2).
Risk Factors Table 3 presents mutual adjustment for all potential risk factors, with adjusted findings, when compared with bivariate associations, being generally stronger. Older age, more extensive surgery (ie, mastectomy), and having a sedentary lifestyle significantly increased odds (three- to six-fold) of lymphedema. Removal of 20 or more lymph nodes, experiencing one or more treatment-related complication or symptom, and being single each increased odds 2.6- to 5.0-fold, but CIs were wide and included 1.0. Conversely, having a lower yearly income significantly decreased odds of lymphedema over the following 12 months five-fold. Being treated on the dominant side, having greater childcare responsibilities, receiving chemotherapy, and having better than average upper-body function were each associated with a halving or greater reduction in lymphedema odds, but results were not statistically significant.
Presence of Other Treatment-Related Upper-Body Symptoms The study sample reported high prevalences of symptoms at baseline, with the lowest being for poor range of arm movement (34%) and the highest being for numbness (62%; Fig 1). Women who developed lymphedema between 9 and 18 months reported higher prevalences of upper-body symptoms at baseline when compared with women without subsequent lymphedema; the greatest differences between the groups (> 10%) were for pain (P < .05), stiffness, weakness, and numbness.
Effect of Having Lymphedema on Upper-Body Function After adjustment for all characteristics presented in Table 3 (except for baseline upper-body function), having lymphedema between 6 and 18 months after surgery was associated with having poorer upper-body function by 18 months after surgery (OR = 1.9; 95% CI, 0.8 to 4.6; P = .15). This association weakened when baseline upper-body function was also considered but remained clinically important (OR = 1.5; 95% CI, 0.5 to 4.7; P = .53).
This longitudinal study, using a direct measure of lymphedema, highlights that at any point in time during the first 18 months of recovery from breast cancer, at least one in 10 women is experiencing the condition. Furthermore, by 18 months after surgery, at least 30% of breast cancer survivors have, or have had, lymphedema. Approximately 60% of these women had transitory symptoms, whereby the lymphedema dissipated with or without treatment. However, 40% of patients experienced long-term lymphedema lasting for more than 3 months, with or without intermittent periods of relief. Women with lymphedema were twice as likely to have poorer upper-body function when compared with women who had not developed arm swelling. Breast cancer continues to be the most common cancer among Australian women, with 11,000 women being diagnosed yearly.16 Therefore, based on our findings from a representative, population-based sample, in Australia alone, each year more than 3,000 women will experience lymphedema after breast cancer. In the United States, these figures are substantially higher; there are more than 2 million American breast cancer survivors, and as a conservative estimate, more than 200,000 of these women are living with secondary lymphedema.6 Clearly, lymphedema is a public health issue of concern. Our data demonstrate that approximately two thirds of those classified with long-term lymphedema developed measurable symptoms by 6 months after surgery. Early diagnosis and treatment of lymphedema is believed to lead to better outcomes.17 Consequently, the integration of a lymphedema assessment during a routine follow-up visit could lead to significant declines in the emotional, physical, and financial costs of lymphedema to breast cancer survivors as well as to society. However, appropriate timing of this assessment is crucial. If assessed too early, as within 3 months of surgery, normal postoperative swelling could be misconstrued as evidence of lymphedema.9 For the majority of breast cancer cases, treatment is usually complete within 3 to 6 months after diagnosis. Taking timing of treatment cessation into account, as well as results from this work showing that two thirds of those with lymphedema developed the condition by 6 months, it seems logical to assess lymphedema status toward the end of treatment, but definitely by 6 months after surgery. We observed that new cases (n = 8) became apparent as late as 18 months after treatment. Regrettably, our surveillance ceased at that time. Other prospective studies with longer follow-up identified new cases arising 3 years after surgery,5 whereas a retrospective study found new cases as late as 10 years after diagnosis.18 There is accumulating evidence to suggest that the majority of cases occur by 12 months after diagnosis (70% of our cases and 80% of others5). However, longer-term follow-up using a direct measure of lymphedema status warrants further investigation. It is generally accepted that more extensive treatment, in particular surgery5,19-21 and lymph node removal,7,21-23 as well as having adjuvant treatment such as radiation,18,19,21,22,24 increases risk of lymphedema. Our work also demonstrates that more extensive breast surgery increases odds of lymphedema six-fold (irrespective of extent of axillary dissection) and having more than 20 lymph nodes removed during axillary dissection (irrespective of extent of surgery) increases odds four-fold. The reasons behind the independent association between lymphedema and mastectomy cannot be determined from these data but warrant clinical consideration. In our data, having one to 10 lymph nodes removed or 10 to 19 lymph nodes removed showed no statistical or clinical association with lymphedema development (ORs were 0.9 and 1.4, respectively, with CIs overlapping 1.0). In contrast to previous work, we found no association with radiation treatment. The differences in these results may be due to more refined radiation techniques being implemented in more recent years or to the use of BIS to diagnose lymphedema rather than circumferences or self-reported arm swelling. Alternatively, it is plausible that those undertaking radiation are exposed to more advice about shoulder recovery in Australia, and that this advice is associated with lymphedema prevention. This also may explain why having chemotherapy was associated with a protective effect. The relationship between lymphedema incidence and personal characteristics has been given relatively little attention in previous research. Age is the most studied, with the majority of work reporting no statistical association.5,7,18,19,24 However, trends in the data suggest increased risk with advancing age in at least three studies.5,18,24 Our work demonstrated that being 50 years or older was associated with three-fold increased odds of developing lymphedema (P < .05). We also found that the odds of developing lymphedema were more than doubled in the absence of having a significant other (that is, being married or being in a de facto relationship), indicating that partner support may play an important role in physical as well as psychosocial recovery after breast cancer. In contrast, we found no association between being overweight or obese and odds of lymphedema, whereas others have reported positive associations.5,7,22,24-26 The differences in these findings may be explained by variations in lymphedema assessment methods. Previous work used indirect (circumferences, water displacement, and so on) or self-reported methods for identifying cases, which are more prone to measurement error. In particular, fluctuations in weight that are unrelated to lymphedema are more likely to be captured by these techniques. In contrast, BIS, the method used in this study, directly measures extracellular fluid changes. This is an important consideration, because it is well known that weight gain is common after treatment for breast cancer.27 Further novel findings relating to personal characteristics identified that having younger children and lower socioeconomic status (as defined by income) were associated with five- to 10-fold reduced odds of lymphedema. These reductions in odds might be related to use of the treated side. Women with young children may find it harder to protect/avoid use of their treated side, and our data indicate that lower incomes were associated with having more manual occupations (blue-collar workers or homemakers). Other independent characteristics found to reduce lymphedema odds that further support this use decreases risk theory include being treated on the dominant side, having better than average upper-body function, and participating in sufficient levels of physical activity at baseline. Other researchers have found either no association7,19 or increased risk28 with being treated on the dominant side and lymphedema but have reported similar inverse relationships between activity levels and lymphedema risk.26,29 Importantly, there is no evidence to suggest that use of the treated side increases risk. Despite observing associations between treatment-related complications and symptoms at baseline and subsequent development of lymphedema, it is currently not possible to use these as indicators of lymphedema risk in a clinical setting because their prevalence is high even among women who did not develop lymphedema (ranging between 35% for tingling and 62% for numbness). The assessment of symptom intensity did not further aid using symptoms to identify at-risk women. These findings are derived from longitudinal data, using a population-based, representative sample of women with breast cancer. Estimates of incidence, prevalence, and cumulative burden are likely conservative, given that participants tended to have less extensive disease than the target population. The prospective design and inclusion of only incident cases in logistic regression analyses allowed us to determine characteristics that increase odds of developing lymphedema rather than only identifying factors associated concurrently with presence of the condition. Furthermore, lymphedema was assessed using a direct, objective measure of extracellular fluid, and personal, treatment, and behavioral characteristics were extensively measured. The limited statistical power, as a consequence of the number of lymphedema cases that arose between 9 and 18 months after surgery, represents the primary limitation of the work. Small numbers among exposed and nonexposed lymphedema cases likely produced more extreme OR estimates (ie, overestimates) for positive and inverse associations. Nevertheless, despite relatively wide CIs, statistical significance was attained for a number of characteristics. Additionally, we retained in multivariable analyses those characteristics that met a priori criteria for possible clinical importance for comparison with other studies. In summary, these data present current estimates of lymphedema prevalence and cumulative burden. In doing so, it is evident that lymphedema after treatment for breast cancer is a disease that is common in our society, warranting greater public awareness. Those at risk, as well as health professionals working with those at risk, should be provided with the education and assistance required for prevention and early detection of lymphedema. A number of the identified risk factors, in particular sufficient physical activity and use of the affected arm, are amenable to interventions and should be investigated for their preventive and therapeutic effects among women after treatment for breast cancer.
The author(s) indicated no potential conflicts of interest.
Conception and design: Sandra C. Hayes, Bruce Cornish, Diana Battistutta, Beth Newman Collection and assembly of data: Sandra C. Hayes, Beth Newman Data analysis and interpretation: Sandra C. Hayes, Monika Janda, Bruce Cornish, Diana Battistutta, Beth Newman Manuscript writing: Sandra C. Hayes, Monika Janda, Bruce Cornish, Diana Battistutta, Beth Newman Final approval of manuscript: Sandra C. Hayes, Monika Janda, Bruce Cornish, Diana Battistutta, Beth Newman
We thank Sheree Harrison for study implementation, Elizabeth Winkler for statistical analysis, and the women and clinicians who made this research possible.
Supported by the National Breast Cancer Foundation (NBCF; funding for the Pulling Through Study) and Johnson and Johnson (contributions to NBCF to fund the fellowship of S.C.H.). Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
1.5) important were incorporated into four separate models (categorized as patient characteristics, treatment, treatment-related complications, and behaviors) to examine the independent associations with odds among inter-related characteristics. Those that retained theoretical, statistical, or clinical importance were incorporated into one model to further consider independent relationships. Results are expressed as ORs and 95% CIs, with a two-tailed P < .05 taken as evidence of statistical significance and OR 
