Upper Extremity Lymphedema after Treatment for Breast Cancer: A Review of the Literature
Lymphedema (LE) is swelling that occurs when protein-rich lymph fluid (ie, plasma proteins, extravascular blood cells, excess water, and parenchymal products) accumulates in the interstitial tissue as a result of damage or trauma.1 It is not a particularly new topic of consideration for practitioners and researchers concerned with skin and wound care. In 1587, the noted Ming Dynasty physician, Gong Tingxian, described phlegm-damp accumulation and a treatment for the condition in his seminal book, Wanbing Huichun.2 Several centuries later (but more than a century ago), three physicians – Max Nonne (Germany) in 1891, William Milroy (US) in 1892, and Henri Meige (France) in 1898 – began to describe congenital LE.3-5 More recently, King and DiFalco6 discussed the rise of LE in an aging population. They highlight the array of skin problems that can be associated with LE (eg, increased fibrosis, hardening of the skin, lobulations, blistering, weeping, skin breakdown) and note that such conditions commonly lead to cellulitis, which further damages the lymphatic system. They state, “…. most lymphedema in this country is the result of surgical treatment for a malignant disease. Because malignancy is increasingly curable, the latent potential for developing lymphedema is a growing medical problem.”6 In the US, there are more than 10 million cancer survivors; of them, more than 2.3 million are breast cancer survivors, the largest group of all cancer survivors (22%).7 Demographic projections suggest that the number of survivors of all types of cancer will continue to grow in the coming years. More than 75% can expect to survive at least 5 years or longer after treatment.7
The transition from cancer treatment to survivorship often is not smooth. A 2006 Institute of Medicine’s (IoM) report8 recommended that cancer patients receive a “survivorship care plan” that contains critical information about treatment late effects, health management behaviors, disease management, and recurrence monitoring. The IoM report also cited critical shortfalls in the transition to survivorship, particularly in providing education about late effects of treatment.
Among the late effects of cancer treatment, secondary upper extremity LE is one of the most poorly understood, relatively underestimated, and least researched complications. Damage occurs from trauma with axillary node dissection9-15; thus, lymphedema can occur after any cancer treatment that affects lymph node drainage. According to various types of studies (prospective descriptive, comparative retrospective, retrospective cohort, descriptive, predictive),9-15 upper extremity LE most often occurs after breast cancer; lower extremity LE most often occurs with uterine cancer, prostate cancer, lymphoma, or melanoma.16
Historically, LE has been viewed as an inconsequential complication of breast cancer12 but the growing population of breast cancer survivors has thrust LE into a new light. Given the 2.3 million breast cancer survivors and an LE incidence of about 25%, approximately 575,000 women may be affected by LE that left untreated or undertreated can result in numbness, impaired arm function, pain, and susceptibility to inflammation and infection.9,12,14,15,17-21 When ineffectively managed, LE is a progressive and increasingly debilitating condition that has no cure.12,13
Lymphedema outcomes and impact on quality of life (QoL) generally have been negative.9,19 Initial shock over LE, followed by anxiety, depression, uncertainty, fear, and sorrow have been reported by survivors in QoL descriptive studies.9,12,17,19,22-32 Negative attitudes and reactions from family, friends, and strangers coupled with social stigmatization have led to social isolation.23,25-32 Breast cancer survivors with LE view the complication as a constant reminder of their cancer; thus, hindering psychological recovery.30
Although LE is incurable, several potentially beneficial LE treatments are available. The purpose of this article is to: 1) describe precipitating events that cause upper extremity LE, 2) describe contributing factors that may increase the likelihood of upper extremity LE onset and exacerbate severity of the condition, and 3) explore the extent to which precipitating events can be avoided and contributing factors modified.
The following literature review is based on a search of articles published in English from 1997 through 2006 that appear in the PubMed database; search terms used were breast cancer and lymphedema. The review is offered with three caveats. First, the majority of the studies reported are retrospective, descriptive analyses with related limitations. Second, nearly all of the data about upper extremity LE relate to breast cancer and are addressed as such. Third, the review will concentrate on secondary lymphedema, which is common in cancer survivors, rather than primary lymphedema, a rare developmental abnormality of the lymphatic system.13,33
Lymphedema is precipitated by trauma. Diagnostic workup and breast cancer treatment requires some degree of axillary trauma or manipulation, whether this occurs via axillary lymph node dissection (ALND), axillary sampling, or sentinel lymph node biopsy (SLNB). Thus, by virtue of diagnosis, workup, and treatment, all breast cancer survivors are at risk of developing upper extremity LE. Axillary trauma initiates the LE process by disrupting lymphatic channels. Although LE may not be expressed until several months to years later (or not at all), the initiating event is non-modifiable.34
Reported incidence rates of upper extremity LE vary widely from 15% to 49%9,12-15,17, 24,34-43 This wide variation is attributed to older, retrospective studies where ALND (eg, up to 25 nodes removed) was combined with axillary radiation therapy as standard treatment for control of local disease. In 2003, Engel et al9 reported the results of one of the first long-term prospective studies of axillary surgery and LE. Using the Munich Cancer Registry, the authors obtained clinical and QoL data from 990 breast cancer patients over a 5-year period. They found that 38% of patients reported arm swelling and limited movement up to 5 years later. Quality of life was significantly reduced (P <.001) for patients with arm problems. Logistic regression showed that the extent of axillary surgery (P <.003) was a significant contributor to LE.
In recent years, SLNB has gained wide clinical acceptance because of reduced arm morbidity and has become the preferred treatment over ALND in patients with early stage disease and clinically negative axillary lymph nodes.10,18,21,44-52 Schijven et al49 retrospectively examined differences in LE outcomes between 213 patients with ALND and 180 patients with SLNB. They found a five-fold lower risk of LE in patients with SLNB, 7.7-fold lower risk of tingling, and 3.2-fold lower risk of pain compared with patients receiving ALND.
Mansel et al45 recently reported on the findings of a multicenter, randomized trial comparing QoL outcomes between patients receiving SLNB (n = 515) or standard axillary surgery (n = 516). They found the relative risks of LE and sensory loss for the SLNB group compared with the axillary treatment group at 12 months were .37 (95% confidence interval [CI] = .23 to .60; absolute rate was 5% versus 13%) and .37 (95% confidence interval [CI] = .27 to .50; absolute rate was 5% versus 31%). They concluded that overall patient recorded QoL and arm function scores were statistically better in the SLNB group (P <.003).
Other investigators have reported similar reduction in both physical and psychological morbidity with SLNB.18,21,46-52 Wilke et al52 conducted a prospective, multicenter trial with the American College of Surgeons Oncology Group Z0010 to examine the prognostic significance of SLNB and to examine surgical complications of SLNB in 5,327 patients. Both univariate and multivariate analyses were used to identify predictors of SLNB complications. The results showed low complications with SLNB that included axillary wound infection (1%) and axillary hematoma (1.4%). At 6 months, 8.6% of the patients studied reported axillary numbness, 3.8% reported decreased upper extremity movement, and 6.9% had upper extremity LE (based on a change of baseline arm circumference of >2 cm). They concluded that SLNB was effective in reducing the incidence of LE.
Purushotham et al47 randomized 298 patients to either ALND or SLNB. They examined physical and psychological outcomes 1 year postoperatively and found a significant reduction in LE, seroma formation, and sensory morbidity.
In summary, precipitating events for upper extremity LE involve some degree of axillary trauma. Standard treatment with ALND and axillary radiation in the past has led to a larger percentage of women experiencing LE morbidity and poor QoL outcomes. The recent move toward SLNB has decreased both the incidence and morbidity associated with upper extremity LE. Patients having SLNB have shown a lower incidence of LE without compromising local control of the disease.18,21,45-52 Although SLNB reduces LE risk and severity, it does not eliminate risk entirely.18,21,45-52
Contributing factors are conditions and/or events that do not necessarily signal the onset of lymphedema but may increase the likelihood of its development and contribute to the severity of the condition.
Axillary radiation. Because axillary radiation results in tissue fibrosis that can constrict lymphatic channels, it is thought to increase the risk and severity of LE.34,37,38 Most of the literature evaluating axillary radiation and LE are retrospective cohort studies. The reported incidence of LE with axillary radiation ranges from 1.8% to 27%, with the higher percent of LE related to routine use of axillary radiation after ALND.
Hinrichs et al40 found an LE incidence of 27% in patients receiving postmastectomy radiation therapy (PMRT). The investigators conducted a chart review of 105 patients who received PMRT and found several radiation factors that contribute to LE. Total radiation dose (P = .0323), posterior axillary boost (P = .047), overlapping radiation technique (P = .037), and radiation therapy given before 1999 (P = .028) were significantly associated with LE. Schijven et al49 found similar results in their retrospective analysis of 393 patients with either ALND or SLNB, where axillary radiation increased the risk of LE by 2.4-fold.
Coen et al36 investigated differences in LE based on type of radiation. Among 727 patients with breast cancer, 32% received both breast and nodal radiation and 68% received breast radiation alone after breast conserving surgery. The investigators conducted a retrospective analysis of LE as defined by a >2-cm difference in forearm circumference compared with the untreated side. With a median follow up of 72 months, the median time between surgery and LE symptoms was 39 months. The investigators found persistent LE in 21 patients. The 10-year actuarial risk for LE was 8.9% for nodal radiation compared with 1.8% risk for LE with breast radiation alone (P = .001). Goffman et al38 analyzed data from 240 women with localized breast cancer at their cancer center. Using t-test and multivariate analyses, they found an upper extremity LE incidence of 7.6%. The investigators concluded that newer standard radiation techniques using tangential fields designed to avoid nodal radiation to the axilla decreased radiation-related LE.
Weight gain, infection, and arm injury. Additional contributing factors that can exacerbate the severity of LE include weight gain, repeated infection, arm injury, and lack of knowledge about LE management. Individually, these contributing factors do not precipitate LE. Petrek et al12 evaluated LE in a cohort of 923 breast cancer survivors 20 years after diagnosis and found three significant contributing factors to upper extremity LE: weight gain after treatment, infection, and injury. Even when patients were overweight or obese at cancer diagnosis, weight gain after treatment was a significant predictor of LE (P = .02). The investigators also found a statistically significant association between arm infection requiring antibiotic therapy or arm injury and the development of LE. The results are similar to other retrospective studies of postmastectomy infection that led to fibrosis and the subsequent development of LE.10,12,16-18,33,44 Severity of LE also increased when patients had repeated or multiple arm infections. Petrek et al12 also found that the maximum time interval between injury or infection and LE onset was within 3 years of diagnosis.
Lack of information. While LE knowledge is improving, historically, survivors and cancer care providers have not been well informed about upper extremity LE symptoms or management. In a descriptive, correlational survey of 72 women with breast cancer, Coward26 reported that while respondents were aware of LE risk, knowledge and use of prevention strategies were poor. In a small pilot study that involved 40 breast cancer survivors with LE and 10 physicians, Paskett et al30 found that women knew little about LE before it developed. Physicians reported that they did not routinely counsel women or provide written instructions about LE prevention or management. Findings from the authors’ pilot studies also indicated that early stage breast cancer survivors are not aware of their LE risks nor did they report that physicians routinely informed them about LE risk.53,54
Quality of life. Quality-of-life outcomes generally have been poor, with survivors reporting reduction of arm strength and movement, limited mobility, and emotional distress.9,12,19,22,24-29,31,32,55 Survivors report being surprised, shocked, and angry when LE develops and have poor self-image and life disruption as a result of LE.22 In addition, an age differential may exist with regard to responses to LE. Armer et al22,56 found that younger women report more symptoms and sensitivity to LE discomfort compared with older women. In their study of 400 women with ALND, 20% of whom developed LE, Ververs et al15 reported that women under the age of 45 years had a six times higher risk of numbness of the arm (OR 6.49; 95% CI 2.58 to 16.38) that interfered with household chores and quality of life.
In summary, the onset of LE varies; it can occur immediately after axillary trauma or after a latent period of several months to years.8,13,16,22,41 A seemingly minor cut, bruise, or laceration causing localized infection or injury that occurs several weeks, months, or years after axillary trauma can precipitate LE.16 Weight gain, repeated infection, advancing age, lack of LE knowledge, and poor LE behavioral practices may increase the likelihood of LE after a precipitating event and also may increase the severity of LE.
Avoidance and Modifiability
Some of the events that trigger the onset of LE are, in theory, avoidable. Practically, however, many such events may be unavoidable realities of treatment and post-treatment survivorship. Similarly, the factors that contribute to the onset of LE and/or its severity may be modifiable or non-modifiable.
Avoiding precipitating events. As previously stated, upper extremity LE is precipitated by axillary trauma after surgery. In theory, such trauma could be avoided if treatment was withheld. However, in the absence of other alternatives, withholding treatment is not a viable alternative.
Trauma associated with breast cancer treatment provides a necessary and possibly sufficient trigger for the onset of LE. In some patients, such trauma may not result in the development of LE for many months or years; in others, the onset of LE may be triggered by the added trauma associated with events of daily living (eg, cuts, pin pricks, physical blows, infection). Although such events are theoretically avoidable, the risk of incurring one or more of these insults is substantial. Education may help reduce the risk of these additional traumatic events but eliminating them entirely is unlikely.
Modifying contributing factors. Axillary radiation, weight gain, repeated infection, arm injury, lack of knowledge, and LE behavior activities predispose survivors to additional risk of LE. Unlike considerations for avoiding precipitating events, with appropriate and effective educational, behavioral, and medical alternatives, some of these factors are modifiable. The condition of the skin and appropriate skin care are extremely important factors in reducing suffering, unnecessary skin breakdown, and the development of additional complications.
Staging and diagnosis. As is the case with pressure ulcers, lymphedema severity is often characterized in terms of stages. However, historical inconsistencies in staging and toxicity grading criteria have created confusion about LE severity. Recently, the National Cancer Institute (NCI) updated its Common Toxicity Criteria for Adverse Events (CTCAE-Version 3).57 The CTCAE-v3 includes additional LE descriptors and has expanded criteria from three grades to five (viz. stages). Several added features include descriptive criteria for volumetric increases, dermal changes, and subcutaneous fibrosis.58 The International Society of Lymphology (ISL) identified progressive LE staging criteria1; ISL staging includes a latent or subclinical condition that may exist for months to years prior to overt LE and change in limb volume.8 Organizational criteria are compared in Table 1.
Severity grading and assessment. Methods to assess LE severity and extent vary considerably. The LE management issue is compounded by the fact that some clinically used methods are inexpensive and inexact and some research methods are costly and burdensome.59-67
Circumferential limb measurement (CLM). This procedure involves comparing the affected and unaffected limbs by circumferential tape measurements at gradients along both limbs.66 Circumferential limb measurement is taken in both arms at several corresponding points with differences noted in size. A 1- to 2-cm difference between the two CLMs has been a common clinical gauge or sign of LE. However, no general agreement exists among various institutions. The procedure lacks sufficient interrater reliability and lack of empirical evidence adds to measurement problems. Furthermore, the practice of CLM is inexact because limb size may differ even within the same person. For example, a right-handed person who may have left-sided LE may have larger right arm limb measurement. Also, a 1-cm difference in a small-framed patient may have different LE implications than the same difference in a large-framed patient.16
Limb volume. Water displacement methods are considered more accurate than circumferential limb measurement but are not without disadvantages.60,62,65 To establish limb volume, each limb is submerged in a cylinder of water and the difference in the rise in water level is measured. Measuring limb volume is a clinically messy procedure that requires some training. The limb must be submerged to the same point and the individual must remain still during measurement. A 200-mm difference in volume may be clinically significant, although again, no standard agreement exists.
Perometry and imaging procedures. Perometry uses infrared lasers to estimate the volume of the limb affected by LE.67 This technique has been shown to be more accurate than either CLM or limb volume but is used infrequently in clinical practice because of cost. Imaging tests and procedures such as lymphoscintigraphy, magnetic resonance imaging, computed tomography, and Doppler ultrasound are complementary rather than definitive procedures used in LE diagnosis.16
Treatment. The variety of clinical treatments available for LE have varying degrees of effectiveness.20,68-78 The most common LE treatment is known as complete or complex decongestive therapy (CDT) and has been used successfully in practice for many years in Europe.60,74,75,77,78 Complex decongestive therapy includes compression, exercise, skin care, and manual lymph drainage (MLD), a specialized set of massage techniques that involves light pressure on the affected limb to move fluid from the end of the limb towards the abdomen.44 This technique has been used clinically in Europe; special training is required because specific strokes, pressure, and sequencing of massage are necessary. Manual lymph drainage is believed to help reduce the concentration of proteins in the interstitial tissues and re-accumulation of lymph.16
Compression helps reduce swelling, increases tissue pressure, and improves venous and lymphatic return.44,68,69,71,75,77,78 Two types of compression are available: bandages/wrapping and garments. Bandages/wrapping are applied by a specially trained lymphedema therapist. When compression bandages are applied correctly, they can help reduce swelling and pain. A prescription is required and garments must be fitted by a trained health professional. Garments are available in different sizes and provide from 20 to 30 mm Hg to more than 50 mm Hg of compression. Compression pumps can remove excess lymph fluid and reduce swelling but do not remove protein from the tissues.16,74
The third and fourth components of CDT are exercise and skin care. Therapeutic exercise helps increase lymph flow and reabsorbs proteins. Trained therapists can provide a prescriptive method of cardiovascular exercise, stretching, aerobic activity, and strength training. Data show that exercise as an individual therapy is not a contraindication after breast cancer therapy nor does it increase the risk of developing LE. Ahmed et al79 reported the results of a large (n = 45) randomized controlled trial conducted to determine whether exercise and weight training were effective in managing LE. They found that a 6-month intervention did not increase risk or add to symptoms of LE. Their study also demonstrated that breast cancer survivors do not need to avoid upper body resistance exercise. The results of a study by Johannson et al80 support that patients with LE can engage in low-intensity exercises without worsening their edema.
Meticulous skin care helps minimize infection risk and hydrate the skin, although no specific evidence-based protocols specify minimum skin care requirements to reduce or manage LE-related skin complications.
While CDT has been used clinically for some years, prospective studies evaluating the effectiveness of the different CDT components are more recent. Mondry et al75 prospectively analyzed the results of CDT in a cohort of 20 patients enrolled in CDT immediately after LE diagnosis. Lymphedema was assessed weekly during weeks 2 through 4 of CDT treatment. The investigators found a median circumferential girth reduction (associated with decreased pain) of 1.5 cm and a median volume reduction of 138 mL. In a related study that added intermittent pneumatic compression (IPC) to CDT, Szuba et al77 randomized 27 patients into either CDT alone or CDT + IPC groups using serial measurement of volume by water displacement, tissue tonometry to measure skin elasticity, and goniometry to measure joint mobility. They found that the addition of IPC to standard CDT resulted in an additional mean volume reduction (45.3% versus 26%; P <.05) and concluded that IPC was well tolerated and an important adjunct to CDT.
Vignes et al81 recently reported on a large prospective cohort of 537 patients with secondary upper extremity LE recruited from a single lymphology unit in France. Before CDT, the mean LE volume was 1,054 ± 633 mL; after CDT volume was 647 ± 351 mL. Subjects were followed for 12 months during the maintenance phase of therapy. Using multivariate analyses, the investigators found that the mean LE volume increased 84 mL (95% CI 56 to 113); LE volumes in 52% of patients increased more than 10%. The investigators found that non-compliance to compression with low-stretch bandages and elastic sleeves were risk factors for increased LE after 1 year of maintenance treatment.
Other LE treatments such as laser therapy and debulking procedures have yielded mixed results.1,16,20,70,73,76 Pharmacologic agents with diuretics, benzopyrones, coumarin, and dietary or herbal supplements such as selenium have not demonstrated effectiveness in managing or treating upper extremity LE.1,73 However, anti-infective agents and pain analgesics can help ease the discomfort associated with LE. Surgical procedures – eg, debulking or resecting excess skin and subcutaneous tissue of advanced fibrosclerotic lymphedema (elephantiasis), microsurgical procedures to create new lymph channels, and reconstructive methods – have not shown specific benefit but are considered adjuncts to CDT.1,16
The incidence of lymphedema historically has been underestimated and understudied. The number of cancer survivors who are at risk for LE is growing by virtue of an aging population and long-term cancer survivorship. In the past, while axillary lymph node dissection resulted in greater numbers and increased severity of LE, recent trends toward SLNB and limited axillary radiation have led to a decline in LE. While perceptions are changing, practitioners and survivors can be better educated about LE. Some advances have been made in both LE staging and toxicity grading criteria. Grading methods of LE carry several research advantages and clinical disadvantages. Lymphedema treatments using CDT have been clinically effective. Recent prospective studies evaluating CDT also have been promising; pharmacologic and surgical interventions have not demonstrated efficacy. Strategies to manage and modify LE are based on clinical observations and additional research is necessary to identify the most efficacious approaches. Further empirical evidence with regard to diagnosis, staging, grading, and treatment to support best practice and a multifaceted framework for describing LE, establishing the level and profile of risk, and tracking changes in LE status are needed. Thus, LE requires a multidisciplinary approach to determine effective evidence-based management.
Considerations, Implications, and Recommendations
Based on the literature review, the authors put forth the following considerations, implications, and recommendations. Comments are grouped according to research and clinical practice and address what the authors believe to be the most pressing issues.
Research recommendations. First, understanding of the incidence and magnitude of LE must improve. To date, the few LE studies available are largely retrospective analyses from single institutions. Further research using population-based studies examining upper extremity LE in cancer survivors is warranted.
Second, no reliable and valid LE assessment tool is available for establishing differential risk of developing LE or risk of LE progressing to a more severe state. In the absence of a meaningful way to determine the extent and profile of LE risk, patients and clinicians must use nonspecific education, treatment, and management strategies. In the future, standardized risk assessment may provide a more comprehensive evaluation of initiating events and contributing factors and will help improve knowledge and understanding of the severity of LE.
Third, collaborative research among researchers in skin/wounds and cancer and clinical partnerships with certified LE specialists and physical therapists could provide a fruitful avenue of study to decrease the burden of LE. For example, Ostomy Wound Management readership has extensive clinical experiences and research evaluating lower extremity LE.80,81 Great potential also exists for examining pathophysiological similarities and differences between upper and lower extremity LE. Another line of collaborative research may include comparing sensory morbidity and co-occurring symptom clusters between upper and lower extremity LE.21,82,83
Fourth, empirical evidence supporting the most effective LE treatment is needed. As described, among the current treatments available, CDT has shown relative success and studies that provide financial and emotional support to cancer survivors with LE influence their adherence to CDT maintenance and could improve LE outcomes. In addition, some evidence shows that a program of exercise and LE weight training among breast cancer survivors may be effective.79,80
Educational programs targeting survivors and practitioners with regard to behavioral interventions to manage and improve LE are needed. For example, tailored pre-treatment counseling and educational strategies can be developed that focus on evidence-based practice to avoid LE and limit its severity and progression.84,85 Practical information about how LE develops and ways to incorporate management of LE into daily living are needed, as are psychoeducational support interventions to help manage or reduce QoL socialization problems.16
Clinical practice. Lymphedema is a significant and complex clinical problem requiring novel multidisciplinary approaches to prevention, early detection, and management. While evidence-based interventions are being studied, practical clinical considerations are warranted. Such considerations, at a minimum, include proper arm care and avoiding further arm and axillary injury. The American Cancer Society (ACS) recently published a cancer patient guide to enhance understanding of LE.16 Its recommendations include the following precautions for patients to lower the risk of triggering LE: maintain physical activity, avoid muscle strain and repetitive motion, and avoid or minimize repeated infection, cuts, bites, pinpricks, and burns. In addition, the ACS suggests that a general physical examination include arm measurements, symptom evaluation, and measurement of protein levels.16 The National Lymphedema Network85 provides excellent daily tips and precautions including LE precautions during air travel. The Lymphology Association of North America86 provides listings of certified LE therapists and treatment centers and offers excellent, practical clinical information.
Lymphedema has not been at the forefront of research or practice for oncology or wound and skin care. As King and DiFalco6 suggested, lymphedema has been an unappreciated medical condition. The long-standing need to elevate practitioner and patient awareness and education recently has become more urgent. While LE is not currently a curable condition, ways to reduce the suffering associated with LE and improve the condition of the skin are available. If skin breaks down, appropriate wound care may be critically important to prevent worsening of LE and/or the possible onset of other debilitating or life-threatening conditions. Not only are multidimensional tools for describing LE, risk, and status changes needed, but also a multidisciplinary approach to LE research and care. Of the many disciplines ultimately represented, two groups are essential: those concerned with cancer and those concerned with skin and wound care.