Upper-body morbidity after breast cancer†‡§¶
Incidence and evidence for evaluation, prevention, and management within a prospective surveillance model of care
The articles in this supplement were commissioned based on presentations and deliberations at a Roundtable Meeting on a Prospective Model of Care for Breast Cancer Rehabilitation, held February 24-25, 2011, at the American Cancer Society National Home Office, in Atlanta, Georgia.
The opinions or views expressed in this supplement are those of the authors, and do not necessarily reflect the opinions or recommendations of the editors or the American Cancer Society. The views expressed in this article are those of the authors and do not reflect the official positions or views of the Department of Defense, the US Navy, or the US Government.
A Prospective Surveillance Model for Rehabilitation for Women With Breast Cancer, Supplement to Cancer
Re-use of this article is permitted in accordance with the Terms and Conditions set out at http://wileyonlinelibrary.com/onlineopen#OnlineOpen_Terms
The purpose of this paper is to review the incidence of upper-body morbidity (arm and breast symptoms, impairments, and lymphedema), methods for diagnosis, and prevention and treatment strategies. It was also the purpose to highlight the evidence base for integration of prospective surveillance for upper-body morbidity within standard clinical care of women with breast cancer. Between 10% and 64% of women report upper-body symptoms between 6 months and 3 years after breast cancer, and approximately 20% develop lymphedema. Symptoms remain common into longer-term survivorship, and although lymphedema may be transient for some, those who present with mild lymphedema are at increased risk of developing moderate to severe lymphedema. The etiology of morbidity seems to be multifactorial, with the most consistent risk factors being those associated with extent of treatment. However, known risk factors cannot reliably distinguish between those who will and will not develop upper-body morbidity. Upper-body morbidity may be treatable with physical therapy. There is also evidence in support of integrating regular surveillance for upper-body morbidity into the routine care provided to women with breast cancer, with early diagnosis potentially contributing to more effective management and prevention of progression of these conditions. Cancer 2012;118(8 suppl). © 2012 American Cancer Society.
Overview of the Epidemiology of Upper-Body Morbidity
Upper-body morbidity after breast cancer is typically characterized by the presence of sensory or motor symptoms and impairments such as pain, weakness, tightness, poor range of motion, nerve palsies, altered movement patterns or muscle recruitment, numbness, or swelling in the shoulder, arm, and/or breast of the affected side. Upper-body morbidity is typically associated with alterations in the use and function of the upper body and adverse physical, psychosocial, and social ramifications that profoundly influence all aspects of daily life and hence quality of life (QOL).1-7 Arguably, lymphedema (swelling) is regarded as the most feared and problematic.5 The purpose of this paper is to review upper-body morbidity incidence and risk factors, methods for diagnosis, and prevention and treatment strategies. The evidence base for integration of prospective surveillance of upper-body morbidity within standard clinical care of women with breast cancer will also be highlighted.
Incidence of Upper-Body Morbidity After Breast Cancer
Upper-body symptoms and impairments
Despite advances in breast cancer treatment methods that have led to less invasive surgical techniques, such as sentinel node biopsy,8, 9 and more refined radiation techniques, such as intensity modulation,10, 11 upper-body symptoms and impairments that impact function and QOL remain common. Incidence of individual symptoms, such as pain and weakness, as well as nerve palsies, skin fragility, soft tissue fibrosis, and inflammation have been the focus of prior research studies.12-21
In the past 10 years, the presence of upper-body symptoms after breast cancer has been evaluated in >20 studies,2, 9, 22-41 including 7 cohort studies involving population-based samples (Table 1).22-24, 27, 33, 34, 42 A wide range in prevalence was reported across these studies, with higher rates generally observed in cohort studies compared with clinical trials. Symptoms (which may have included any 1 or more of the following: weakness, stiffness, numbness, tingling, pain, poor range of motion, swelling) were assessed in these studies via self-report methods using validated or nonvalidated questions. The majority of studies assessed only a subset of the known symptoms reported by women with breast cancer (eg, weakness, stiffness, and tingling were rarely assessed), and it is plausible that the entire spectrum of possible upper-body symptoms that women may experience is yet to be fully understood. The inclusion of mild symptoms as being indicative of morbidity was variable. At least 10%, but as many as 60%, of women report at least 1 upper-body symptom at any point from 6 months to 3 years after breast cancer surgery (Table 1). Pain (eg, breast, axilla, myofascial pain) has possibly received the most attention of all symptoms, with its prevalence ranging from 12% to 51%.13, 14
Table 1. Prevalence of Upper-Body Symptoms Reported by Prospective, Population-Based Cohort Studies
|1. Albert 200622||389 (Germany)||Swelling, poor ROM, pain||27%||19%||20%||21%||19%|
|2. Arndt 200623||314 (Germany)||Swelling, poor ROM, pain|| ||24%-30%|| || || |
|3. Engel 200324||990 (Germany)||Swelling, poor ROM|| ||47%|| ||44%||40%|
|4. McCredie 200133||809 (Australia)||Stiffness, swelling, numbness, pain|| ||16%-61%|| ||21%-66%||22%-54%|
|5. Paskett 200734||622 (USA)||Swelling||20%||36%||44%||48%||54%|
|6. Hayes 201027||285 (Australia)||Tingling, weakness, pain, poor ROM, numbness, stiffness, swelling||10%-29%||10%-22%||10%-19%|| || |
|7. Janz 200742||1372 (USA)||Breast, arm/shoulder pain||46%-53%|| || || || |
One challenge in drawing conclusions about the frequency of upper-body symptoms is that studies vary with regard to length of follow-up. There are 2 population-based studies that have assessed upper-body symptoms beyond 3 years. Results suggest similar prevalence at 4 to 5 years postsurgery (up to 56% of women report at least 1 symptom)24, 33 to that observed during 6 months to 3 years postsurgery. Also, the presence of multiple symptoms is more common than having 1 symptom alone. In a population-based, prospective cohort study of Australian women, the majority of those reporting moderate to extreme symptoms reported multiple symptoms between 6 and 18 months postsurgery (56%-68% across time points).27 In this issue of Cancer, it is noted that at 6 years postdiagnosis, >50% of breast cancer survivors from that same Australian cohort report 1 or more upper-body symptom (see Schmitz et al in this supplement).43 Taken together, these results indicate that upper-body morbidity is common after breast cancer and remains common well beyond the treatment period.
Lymphedema is caused by a disruption of the lymphatic system that in the initial stages leads to the accumulation of fluid in the interstitial tissue space (that is, increases in extracellular fluid) and eventually clinically manifests as swelling of the arm, breast, shoulder, neck, or torso.44 Later stages of lymphedema are characterized by deposition of fibrotic and adipose tissue.45
It is well established that the chosen diagnostic method used to assess lymphedema influences the results found in observational studies.46-48 Bioimpedance spectroscopy assesses changes in extracellular fluid and has been shown to identify limb changes before clinical presentation of the condition and until the condition becomes nonpitting (fibrotic).49 Methods that assess limb size (such as water displacement, perometry, or circumferences), with or without conversion of the measure of size to limb volume, can detect nonpitting and pitting lymphedema of sufficient magnitude, but may be insensitive to early changes in extracellular fluid. Self-report methods (such as the Norman questionnaire,50 the Lymphedema Breast Cancer Questionnaire,51 the Lymphoedema Quality of Life Inventory,52 items from validated QOL-specific questionnaires [such as FACTB+453 and the European Organization for Research and Treatment of Cancer QLQ-C3054] or nonvalidated questions) take into account perceived sensory and size changes, as well as presence and intensity of related symptoms. However, as demonstrated earlier, the presence of symptoms is common in women after breast cancer, and this is irrespective of lymphedema status.27 A study that used multiple measures to assess lymphedema status in women 6 months after breast surgery found that 40% of those with objective lymphedema (defined by bioimpedance spectroscopy) did not self-report swelling, and 40% of those without objective lymphedema did.48 A USA-based study similarly found that breast cancer survivors met 4 different lymphedema criteria at various rates of occurrence (43%-94%), with 11% meeting all 4 criteria and 84% meeting at least 1 criterion.55 All clinical measures, when undertaken by trained personnel, and the validated self-report measures have proven repeatability. However, each method's accuracy in diagnosing cases (as well as avoiding misclassification of noncases) depends on which other diagnostic method it is being compared with.56 As yet, there is no agreement on which method, or combination of methods, reflects the most accurate diagnostic tool.
Given the variation in available diagnostic methods, which ultimately assess different attributes of lymphedema, it is not surprising that the extent of the public health burden posed by secondary lymphedema has long been clouded by wide variations in reported incidence. Reported rates in women after treatment for breast cancer have varied from 6% to 80%.57 Also contributing to the wide variation in incidence is timing of measurement (2 months to 20 years after breast cancer) and the type of cohort evaluated (studies may have included only those who underwent axillary dissection and/or radiation therapy).
In the past 5 years, 11 prospectively designed studies (graded as level II prognostic studies according to the National Health and Medical Research Council, Australia)58 have reported incidence estimates of secondary lymphedema after breast cancer (Table 2). These studies used objective diagnostic criteria and included samples generally representative of the larger breast cancer population. Median reported incidence in these 11 studies was 20% (range, 0%-94%). It therefore seems plausible to suggest that from 6 months postsurgery, approximately 1 in 5 patients treated for breast cancer will experience secondary lymphedema. The median rate appears to increase with longer follow-up, escalating from 11% up to 12 months to 36% beyond 12 months. Findings also suggest that 45% to 60% of patients with long-term secondary lymphedema present with the condition by 6 months postsurgery,46, 59 whereas 70% to 80% present by 12 months postsurgery.59, 60 Consequently, it seems clear that despite advances in breast cancer treatment over the past decade, lymphedema continues to be a common concern, with new cases presenting well beyond the active treatment period.
Table 2. Reported Incidence of Secondary Lymphedema (Objectively Measured) in Prospectively Designed Breast Cancer Cohort Studies Published Between 2007 and 2011
|Australia|| || || || || |
| Hayes 200856||211||BIS, >3 SD than normative data, circ, >5 cm differencea||11%||8%-11%||12%-15%|
|Belgium|| || || || || |
| Devoogdt 2011150||49||circ, >10% differencea|| || ||18%|
|Canada|| || || || || |
| Helyer 2010151||137||per, >200 mL differencea|| || ||12%|
| Thomas-MacLean 200838||347||circ, 3 definitions of differencea|| ||9%-16%|| |
|England|| || || || || |
| Bennett Britton 2007152||50||circ, >10% differencea|| ||11%||28%|
|Korea|| || || || || |
| Yang 201041||191||circ, >1 cm differencea||9%||12.0%|| |
|Norway|| || || || || |
| Nesvold 2008153||263||circ ≥2 cm changeb or ≥10% differencea|| || ||RM=20%, BCT=8%|
|Sweden|| || || || || |
| Celebioglu 2007154||60||per, >10% differencea|| || ||SLNB=0%, ALND=20%|
|USA|| || || || || |
| Armer & Stewart 201055||213||circ, ≥2 cm change,b per ≥200 mL or ≥10% changeb||11%-44%||22%-66%||29%-94%c|
| McLaughlin 2008155||936||circ, >2 cm changeb|| || ||SLNB=5%, ALND=16%|
| Wernicke 2011156||223||circ, 1 cm differencea|| || ||SLNB=5%, ALND=35%|
Lymphedema is regarded as a persistent or chronic condition. However, results from 2 prospective studies, 1 using an objective measure60 of lymphedema status and the other a validated self-report measure,61 suggest this may not be the case for all women. The studies demonstrated that up to 60% of women with evidence of lymphedema had acute lymphedema (lasting no more than 5 months), dissipating with or without treatment (although commencement of, or adherence to, treatment was not formally assessed). Between 30% and 40% had chronic and/or progressive lymphedema, and between 15% and 22% had fluctuating lymphedema, which may have included intermittent periods without symptoms. Therefore, lymphedema seems transitory for some, with or without treatment, and long-term for others, with or without intermittent periods of relief. This variable nature of lymphedema may further contribute to the wide range of incidence reported throughout the literature. Importantly, however, those who present with mild lymphedema are at increased risk (up to 3× increased risk) of developing moderate to severe lymphedema.61, 62
Identifying Known Risk Factors for the Development or Exacerbation of Upper-Body Morbidity
The extent of upper-body morbidity after treatment for breast cancer has been a major driving force in the quest for identifying less invasive treatment strategies that could reduce morbidity without adversely influencing survival.26 An established and growing literature base clearly demonstrates that upper-body morbidity is higher among those who undertake more invasive treatment options, such as axillary dissection versus sentinel node biopsy, mastectomy versus breast-conserving surgery, and/or radiation to the breast/chest wall and regional nodes versus radiation to the breast/chest wall only.31, 63-67
Injury to the intercostal brachial or thoracodorsal nerve may occur with axillary lymph node dissection and is a major cause of axillary paresthesia, muscular dysfunction (eg, dysfunction of the serratus anterior or latissimus dorsi), and pain.14, 68 Nerve injuries may resolve over several months without therapeutic intervention; however, muscle recruitment pattern, flow-on effect to surrounding musculature, and use of the arm may be permanently altered without intervention.69
Research on radiation-induced upper-body morbidity has uncovered a wide range of issues, including skin fragility,16, 17 fibrosis, and inflammatory changes to the soft tissue in the irradiated area,17, 70 as well as brachial plexopathies and other neuropathic impairments that may lead to sensory and motor changes.71-73 Radiation-induced soft tissue fibrosis is generally mild, and chronic radiation fibrosis is rare. Nonetheless, chronic fibrosis is significant and problematic, and unfortunately its development and effective management is not well understood. Clinically, it is noted that fibrosis contributes to diminished joint mobility and may foster short and potentially long-term shoulder, scapulae, and postural changes. Historically, because of poor shielding techniques and inadvertent exposure of the plexus to the radiation beam, radiation therapy has also contributed to severe brachial plexopathies and neuropathic impairments.71 However, modern techniques protect the brachial plexus and prevent inadvertent nerve damage. Brachial plexopathy is now considered rare, even in women for whom the supraclavicular and axillary regions are treated. Nonetheless, when it occurs, sensory and motor changes in the upper body occur, with severe cases experiencing paralysis. Results from 2 studies with >2 decades of follow-up72, 73 have shown that the rate of radiation-induced soft tissue damage and neuropathies was estimated to be 1% per year, netting a cumulative incidence of near 20% by 20 years post-therapy.72, 73 Although this incidence estimate may no longer be representative of women treated with radiation therapy for breast cancer today, it underscores the need for long-term follow-up.
The contribution of diagnostic factors (including tumor size, positive lymph node status, stage of cancer), physiological characteristics (such as lymphatic transport, vein wall movement, and venous anatomy and flow), and patient and behavioral characteristics (including body mass index, age, treatment on the dominant side, physical activity levels, and socioeconomic status) with respect to development of lymphedema have also been evaluated.57 To date, results derived from prospective cohort studies suggest that stage of disease, node status, and adjuvant therapy other than radiation therapy does not impact lymphedema risk.57 However, as adjuvant therapies continue to evolve, their relation with lymphedema risk will require continued exploration.
More work is also required to better understand the physiological changes associated with increased risk of lymphedema. Higher body mass index has long been considered a risk factor for lymphedema.59, 74-79 However, when findings from more recent studies are considered, the relation is less clear, with several prospective cohort studies demonstrating no relation between higher body mass index and lymphedema risk.9, 60, 80 Nonetheless, higher body mass index has never been associated with reduced risk, and the importance of maintaining healthy body weight in relation to other breast cancer outcomes is clear (see Demark-Wahnefried et al in this supplement).81 The relation between age and risk of lymphedema is mixed, with some studies showing no relation,9, 59, 80 whereas others show increased risk with increasing age.60, 82, 83 Race, upper-body function,60 and physical activity levels60, 84, 85 may also be associated with lymphedema risk; specifically, being African American,86 having lower than average upper-body function, and being sedentary have been associated with increased lymphedema risk.60 Finally, those with lymphedema are more likely to report multiple upper-body symptoms, and the presence of symptoms has been significantly associated with subsequent lymphedema development.27
Although several risk factors for the development of lymphedema have been identified, at present it is not possible to accurately predict who will and will not develop this condition.87 In a prospective, population-based study of 287 newly diagnosed breast cancer patients, 12 key treatment-related, personal, and behavioral characteristics were identified as important factors with respect to lymphedema risk. However, together they explained no greater than 35% of the variation between those who did and did not develop lymphedema.27
Methods to Detect Upper-Body Morbidity
Self-report and objective methods available for detecting and monitoring lymphedema were reviewed in an earlier section (Incidence of Upper-Body Morbidity After Breast Cancer). When deciding which assessment method(s) are optimal, several factors must be considered, such as the sensitivity and specificity of the measure, whether the measure has been shown to detect subclinical lymphedema (before patients report symptoms), and whether the measure is affordable, transportable, practical for clinic use, noninvasive, and time efficient.88 Given that different methods assess different elements of lymphedema, the use of multiple assessment methods is ideal, particularly for tracking change over time.
Shoulder function can also be evaluated using any 1 or more of self-report or clinical methods. Validated questionnaires such as the BREAST-Q89 and the Disability of the Arm, Shoulder and Hand questionnaire90 provide comprehensive self-report assessment of upper-body morbidity, as well as the presence and severity of specific symptoms. Standardized procedures exist for the assessment of active and passive shoulder range of motion in all planes using goniometry,91 whereas strength and function can be assessed using isometric and isokinetic dynamometry and/or maximal or submaximal performance of set tasks/exercises using the repetition maximum method.92 However, upper-body assessment may also involve palpation of areas, particularly in the assessment of myofascial pain93 and tightness.31 Visual inspection of posture of the whole body, as well as the upper body in routine position, performance of spontaneous activities, and during planned tasks provides additional information regarding upper-body function.94 Finally, it is noted that a clinical assessment involves understanding existing function in addition to revealing specific impairments.94
Evidence-Based Prevention and Treatment Strategies
Prevention strategies for minimizing upper-body morbidity have focused on the use of less invasive treatment methods when clinical presentation of the disease allows and the use of shoulder exercises after breast cancer surgery to optimize function. The evidence base for prevention and treatment of upper-body morbidity is presented below.
Upper-body symptoms and impairments
Studies that have assessed the effectiveness of postoperative physical therapy contend that physical therapy is beneficial for upper-body function and does not cause any adverse effects.95-99 These studies have been limited in sample size. In general, there is scant evidence base for the efficacy of rehabilitative (eg, physical therapy) or exercise interventions to prevent or treat upper-body symptoms or shoulder dysfunction in breast cancer survivors beyond studies specific to lymphedema. In the absence of a strong evidence base, the commonly used clinical approach to treating several upper-body symptoms and impairments is outlined below.
Standard physical therapy approaches to dealing with pain include gentle range of motion exercises, stretching, acupressure, and myofascial stretching, as well as dry needle techniques.93 Patient education to identify positions or activities that alleviate the symptoms is important for self-care management, and a gradual, progressive mobility program is encouraged. Clinically, pain management often requires an ongoing, multidisciplinary approach to monitor changes with treatment and assess response to medication. New onset pain or increasing pain may have additional etiologies, including tumor infiltration of the brachial plexus or tumor recurrence.100
Early assessment and intervention postsurgery, by way of education and shoulder exercises, are important to correct subtle treatment-related changes in scapulae position and stability that left untreated may lead to upper-body symptoms and impairments, and also to correct muscle recruitment imbalance.95, 101 Ongoing assessment and education is necessary to determine whether tissue changes that may occur during and beyond the adjuvant treatment period, such as shortening of the pectoralis major, perpetuate existing, or lead to the development of, upper-body morbidity.102 Range of motion exercises play a particularly important role during and after radiation treatment to enhance tissue extensibility and promote normal movement patterns101 and should be encouraged indefinitely to avoid tissue contracture and concomitant alterations to the joint mechanics of the shoulder. Furthermore, manual techniques such as myofascial release have also been considered useful in improving tissue extensibility and enhancing mobility.103
In the prevention of lymphedema, 2 randomized, controlled trials, 1 evaluating the effectiveness of a “physiotherapy management care plan” (including education and progressive exercises)104 and the other evaluating a physical therapy program that included manual lymph drainage, massage of scar tissue, and progressive exercises,105 have demonstrated clinically relevant benefits. Both studies showed a higher proportion of women with lymphedema in the comparison group, compared with the physical therapy intervention group. The trial that included manual lymph drainage as part of the intervention demonstrated that the risk ratio for developing lymphedema in the intervention group was 0.25 (95% confidence interval, 1.10-0.79) compared with the control group. Results from another randomized, controlled trial suggest that delayed (7 days postoperative) versus early (within 48 hours postoperative) commencement of shoulder exercises was more favorable with respect to lymphedema development.106
Notably, however, the commonly available risk-reducing lymphedema guidelines are loosely based on what will minimize the production of lymph, which is directly proportional to blood flow, and what will minimize blockage to lymph transport.107 For example, heat, infections, and exercise may increase blood flow and therefore lymph production in the arm, whereas tight clothing may obstruct lymph flow.107 Unfortunately, the evidence to support or refute these guidelines is scarce. There is a clear need for well-designed, population-based, prospective studies to investigate the potential causal relation between participating in risky behaviors and subsequent lymphedema development. Until this occurs, it seems reasonable for prevention strategies to be discussed with women, especially in the context of encouraging healthy behaviors, such as participation in regular exercise and maintaining healthy body weight. In fact, results from a prospective, population-based cohort study as well as a randomized, controlled trial suggest that participating in regular exercise after breast cancer may prevent the development of lymphedema.60, 108
The goals of secondary lymphedema management include reduction of swelling, prevention of progression, alleviation of associated symptoms, prevention of infection, and improvement in function and QOL. Treatment options can be broadly categorized as conservative, surgical, pharmacologic, or alternative. The evidence behind lymphedema treatment options has previously been reviewed.57, 109, 110 Findings from these reviews, as well as results from treatment studies published in the past 3 years, are summarized below to provide an overview of the evidence for various lymphedema treatment options.
Treatment effects (limb volume reductions) for conservative treatment options are in the range of 8% to 66%, with several studies reporting continued reductions over 6 to 12 months follow-up. Volume reductions achieved by manual lymph drainage or pneumatic pumps tended to be higher when therapy was combined with other conservative treatment options, such as compression and massage. However, compression alone or in combination with other treatment led to volume reductions of 4% to 60% measured at 4 weeks to 6 months follow-up. When reported, response rates varied between 28% and 66%, and characteristics of those lost to follow-up were typically not reported. Lack of reference to clinically meaningful changes, questionable representativeness of the sample, potential bias caused by significant numbers lost to follow-up (likely more so for those not experiencing treatment effects), and lack of control group and/or adjustment for potential confounders severely influence the strength of these findings. Nonetheless, there is a growing body of low-level evidence in support of these therapies, which ultimately form the primary method currently used to treat lymphedema.111
Low-level laser therapy (light source treatment that generates light of a single wavelength, but does not emit heat, sound, or vibration) has been used as a form of lymphedema treatment since 1995 in some countries, but only received US Food and Drug Administration approval in 2007.112 Research in the area is limited and should be regarded as encouraging but preliminary. A randomized trial of low-level laser therapy (LTU-904 handheld laser; RianCorp, Richmond, Australia) in women with postmastectomy lymphedema reported a trend toward reductions in arm volumes over time after 2 cycles of treatment, but that despite these reductions, volumes at the 3-month follow-up were not statistically different from baseline values.113 Other studies have reported 16% to 79% volume reductions (using various handheld laser devices), but compare changes to another treatment group114 or lack a control group.112, 115, 116
There have been several investigations evaluating the role of exercise on lymphedema status, with various methodological qualities. Randomized, controlled trials have evaluated the role of combined exercise and relaxation therapy,117 aqua therapy,118 combined aerobic- and resistance-based exercise,119 and weight training.120, 121 Sample size within these studies ranged between 31 and 141, intervention duration ranged from 8 weeks to 12 months, and lymphedema status as well as other physical and psychosocial outcomes were typically assessed. All studies demonstrated that exercise did not exacerbate existing lymphedema and had positive effects on other outcomes influencing function and QOL. The largest of the trials, evaluating a 12-month weight-training intervention (n = 141), also demonstrated significant improvements in lymphedema-associated symptom severity, as well as reduced lymphedema exacerbations, compared with the control group.121 The results of these trials support the use of progressive exercise, with supervision at least in the earlier part of the intervention, in optimizing upper-body outcomes. Current lymphedema prevention guidelines have been labeled risk averse and may therefore encourage women to avoid use of their arms and bodies. Results from exercise intervention studies involving women with lymphedema highlight the need for encouragement rather than avoidance of participation in physical activity after breast cancer.122
The association between body weight and lymphedema risk has led to 2 studies investigating the potential for weight-reduction strategies to reduce lymphedema.123, 124 Although results suggest that weight-reducing strategies may be useful in the management of lymphedema, further studies utilizing larger sample sizes and lymphedema assessment methods that are not sensitive to weight changes are warranted (eg, bioelectrical impedance spectroscopy).
The use of medications to manage secondary lymphedema is of continued interest, with emphasis to date being placed on benzopyrones and selenium compounds. Systematic reviews of the literature evaluating the use of these compounds in lymphedema management report that there is no evidence in support of their use.125, 126 More recently, a randomized, controlled study of 12 months treatment with pentoxifylline (which is used to improve blood flow through peripheral blood vessels) and vitamin E for the prevention of radiation-induced side effects in breast cancer patients (n = 83) showed increases in arm volume in the control group but no change in the intervention group.127
Surgery for lymphedema includes debulking procedures to remove excess skin and subcutaneous tissue (eg, liposuction) or the creation of new pathways for draining lymph (eg, microsurgery, lymphatic-venous anastomosis). Surgery is typically only recommended when conservative treatment options have failed to be effective, and lymphedema is chronic and pitting. Although limited by study design (comparative studies without concurrent controls or case series) and small sample size, excellent results from studies evaluating liposuction128-130 and lymphatic vessel-isolated vein anastomosis131, 132 have been reported, with complete resolution of excess limb volume, in addition to improvements in function and QOL, being reported in several liposuction studies.128-130 The potential for scarring and other complications, as well as the need for continued use of compression garments after surgery, restricts the use of this treatment to a specific subset of women with relatively severe lymphedema who experience no response to conservative treatment.
There is significant room for improvement in studies evaluating treatment for lymphedema. Weak designs continue to influence the strength of the findings reported, and there is high potential for over-reporting of treatment effects. Despite the need for more research into effective lymphedema treatment strategies, several treatment guidelines have been developed using the available evidence (Australia: National Breast and Ovarian Cancer Centre133; Canada: Health Canadal134; Europe: European Society for Breast Cancer Specialists135; Sweden: Swedish Cancer Society136; United Kingdom: National Institute for Health and Clinical Excellence, Clinical Resources Efficiency Support Team137; USA: National Lymphedema Network,138 Agency for Healthcare Research and Quality,139 and Oncology Nursing Society140).
Overview of the Potential Role That Prospective Surveillance Would Play in Early Identification and Treatment, and Whether There Is a Need to Establish Baseline Measures
Prospective surveillance may play an important role in the early detection and management of upper-body morbidity. Within the broader breast cancer setting, impairments detected within the hospital setting are more likely to receive intervention, and this is particularly the case for low socioeconomic and minority status groups.141, 142 This may be as a consequence of increased scrutiny in the inpatient setting, the presence of critical pathways, and/or the absence of specific access barriers.
More specific to upper-body morbidity, however, results from a prospective, cohort study provide preliminary findings that support the integration of formal regular surveillance.143 In this study, lymphedema was identified in 43 of 196 women prospectively followed. When an increase in limb volume of >3% compared with preoperative volume (as assessed via perometry) was observed, compression garments were prescribed for 4 weeks. Limb volumes were significantly reduced after the compression garment period. Notably this was a cohort study and not a randomized, controlled treatment trial, limiting the strength of these findings. Nonetheless, even if the 3% limb volume change represented postsurgical swelling, which may spontaneously resolve, other research has reported higher risk for lymphedema at 6 to 9 months after surgery after postsurgical swelling.144 Furthermore, others have also demonstrated that those with mild lymphedema are at greater risk of developing chronic and more severe lymphedema.61 Importantly, this prospective surveillance cohort study demonstrated that regular assessment of upper-body morbidity (including preoperative measures) in a busy breast cancer clinic is possible, and that women were accepting of wearing compression garments for a 4-week period (although compliance with garment wear was not tracked). This garment intervention is in contrast to many lymphedema treatment options that are considered costly with respect to time, finances, and lifestyle.57 These findings are supported by another prospective breast cancer cohort study, which spanned a 10-year period (n = 292).145 Results from this study also demonstrated that the integration of regular surveillance is feasible and beneficial. Furthermore, early diagnosis and treatment translated to more manageable lymphedema; 80% of those diagnosed with lymphedema throughout the follow-up period did not exceed 20% limb ratio volumes.
The personal costs associated with lymphedema are well known and documented, but data have only recently become available to demonstrate the potential overall financial costs. Women with lymphedema after breast cancer have between $14,887 and $23,167 more medical costs when compared with women without lymphedema.146 Women with lymphedema also have more productive days lost than those without (73 vs 56 days). So although there is a clear desire to minimize overdiagnosis of lymphedema, this must be balanced by what may be gained with early diagnosis and intervention.
The evidence presented throughout this paper provides support for the integration of regular surveillance of upper-body morbidity within standard breast cancer care, as is recommended by the prospective model published in this supplement (see Stout et al in this supplement).147 Preoperative assessment of upper-body morbidity is ideal, particularly for bilateral breast cancer cases; however, preoperative assessment is not true baseline, with the contribution of the cancer to upper-body morbidity currently unknown. Furthermore, regular postoperative surveillance can still be successful in the absence of preoperative measures. For unilateral breast cancer, presence and severity of upper-body symptoms, impairments, and lymphedema can be compared with the contralateral limb, and for some lymphedema measures, such as bioimpedance spectroscopy, comparisons can be made with the lower limb in the absence of an unaffected upper limb.148 Long-term follow-up after breast cancer has merit because of the observations that physical impairments may persist for years after treatment (see Schmitz et al in this supplement)43 and that some types of upper-body morbidities (eg, radiation damage) may persist for decades after treatment.71, 72
Comprehensive assessment of upper-body morbidity using clinical and self-report methods is ideal, although it may be impractical to administer in a busy clinic setting. A possible solution may be to ensure comprehensive assessment occurs in the first instance (preoperative and/or first postoperative assessment), with subsequent reliance on 1 or select method(s) for follow-up measurements, with adverse changes in self-report symptoms or the clinical measure dictating a subsequent more comprehensive assessment. Regularity of the measurement may be variable within treating centers and scheduled among normal postoperative adjuvant treatment or postadjuvant treatment visits. Monthly to once every 3 months seems a reasonable surveillance interval, through to 12 months postsurgery, with less regular surveillance occurring beyond that period. Given that lymphedema may be transient, fluctuating, or chronic, consideration may be given to increasing regularity of surveillance when clinical evidence of the condition presents or patients self-report change in symptoms, and initiation of treatment only after a predefined threshold (volume or time) is met. Also, diagnosis of lymphedema within the first 3 months after surgery or radiation is cautioned, as there is the risk of misclassifying normal post-treatment swelling. Surveillance should be supplemented with patient education on early signs and symptoms of upper-body morbidity, in particular progression of severity of concerns.149
Upper-body morbidity is common after breast cancer, and although more extensive treatment has been consistently linked with higher incidence of morbidity, morbidity remains common despite the introduction of less invasive treatment options. Upper-body symptoms, impairments, and lymphedema typically present within the first 12 months after breast surgery (although cases can present years later), and as such, integration of regular surveillance into standard breast cancer care is considered appropriate and has been shown to be feasible. Participation in regular and progressive physical activity after a breast cancer diagnosis may optimize function and QOL, as well as minimize upper-body morbidity. Upper-body morbidity seems amenable to physical therapies, with early diagnosis likely facilitating more effective treatment, as well as prevention of progression.
We thank all participants of the think tank, whose comments enriched discussions and clarified rehabilitation issues faced by women with breast cancer; and Tracey Di Sipio and Sheree Rye for undertaking the review of the literature and extraction of data necessary for completing this article.
Support for this meeting and supplement was provided by the American Cancer Society, through the Longaberger Company®, a direct selling company offering home products including handcrafted baskets made in Ohio, and the Longaberger Horizon of Hope® Campaign, which provided a grant to the American Cancer Society for breast cancer research and education. S.C.H.'s fellowship position is supported by the National Breast Cancer Foundation, Australia.
CONFLICT OF INTEREST DISCLOSURES
The authors made no disclosures.