Limb measurements

The wide variety of methods for evaluating limb volume and lack of standardization make it difficult for the clinician to assess the at-risk limb. Options include water displacement, tape measurement, infrared scanning, and bioelectrical impedance measures.[1]

The most common method for diagnosing upper-extremity lymphedema is circumferential upper-extremity measurement using specific anatomical landmarks.[2] Arm circumference measurements are used to estimate volume differences between the affected and unaffected arms. Sequential measurements are taken at four points on both arms: the metacarpal-phalangeal joints, the wrist, 10 cm distal to the lateral epicondyles, and 15 cm proximal to the lateral epicondyles. Differences of 2 cm or more at any point compared with the unaffected arm are considered by some experts to be clinically significant. However, measuring specific differences between arms may have limited clinical relevance because of implications, such as a 3-cm difference between the arm of an obese woman and the arm of a thin woman. In addition, there can be inherent anatomical variations in circumference between the dominant and nondominant limb related to differences in muscle mass. In addition, variations after breast cancer treatment may occur with atrophy of the ipsilateral arm or hypertrophy of the contralateral arm.[3] A small study comparing various methods of assessing upper-limb lymphedema did not show superiority of any one method.[1] Sequential measurements over time, including pretreatment measurements, may prove to be more clinically meaningful.

The water displacement method is another way to evaluate arm edema. A volume difference of 200 mL or more between the affected and opposite arms is typically considered to be a cutoff point to define lymphedema.[4]

Magnetic resonance lymphography (MRL)

This technique involves the intracutaneous injection of a paramagnetic contrast agent, followed by imaging of the lymphatic anatomy, dermal flow patterns, and adjacent fatty tissue. One study of 50 women with breast cancer–related lymphedema compared the lymphatic vessel morphology in their affected and unaffected arms.[5] The lymphedema was staged according to the ISL's 2016 staging system.[6] In all patients, the lymph fluid was in the subcutis but not the subfascial compartment of the affected arm. In stage I patients, the lymphatics were tortuous and dilated, but there was no dermal backflow or regeneration of the lymphatics. In stage II patients, there was soft tissue fibrosis and adipose tissue hypertrophy. The lymphatics were tortuous and dilated, with areas of dermal backflow and regeneration. In stage III patients, the lymphatics were unrecognizable, and there was confluent dermal backflow. The soft tissue fibrosis was more advanced. MRL is safe, feasible, and provides high anatomical detail. However, its role in lymphedema diagnosis remains to be determined.

Staging and grading of severity

The staging system of the ISL reflects likely changes over time based on the pathophysiology of lymphedema. The stages include the following:

The severity of lymphedema may be evaluated using the Common Terminology Criteria for Adverse Events (CTCAE), which was developed for grading adverse events in the context of clinical trials.[7] A key advantage of the CTCAE approach is that it includes both objective measures (interlimb discrepancy) and subjective clinical assessments in diagnosing lymphedema. This approach allows the clinician to address troublesome signs and symptoms that may occur without significant interlimb discrepancy. The CTCAE volume 3 criteria are:

The fifth version of the CTCAE is more streamlined and does not include limb volumes:[8]

Compression garments

Compression garments are used to prevent and treat lymphedema by helping to decrease excess formation of interstitial fluid, prevent reflux of lymphatic fluid, and give a barrier to help muscle pumping of fluid up the lymphatic system.[1] Use of flat knit (inelastic) compression garments is better than elastic compression in both the reduction and maintenance phase of stages II and III lymphedema. Inelastic compression garments allow the lymph fluid to be better propelled through the impaired lymphatic system via skeletal muscles. Flat knit garments also have the advantage of applying pressure to firm and soften edema. This pressure is applied at a uniform gradient over a large area. Circular knit garments deliver more pressure in the distal (narrow) part of the garment and are better for venous insufficiency than lymphedema.

Elastic garments are best used for stage I lymphedema and lymphedema that has been converted to stage II after complete decongestive therapy (CDT).

Intermittent external pneumatic compression

This approach should be used in conjunction with compression garments and only if compression is not enough to prevent or treat lymphedema. Concerns regarding the use of intermittent pneumatic compression include the optimum amount of pressure, treatment schedule, and the need for maintenance therapy after the initial reduction in edema.[2][Level of evidence: I] There is a theoretical concern that pressures higher than 60 mm Hg and long-term use may injure lymphatic vessels.

Intermittent external pneumatic compression may improve lymphedema management when used adjunctively with decongestive lymphatic therapy. A small randomized trial of 23 women with new breast cancer–associated lymphedema found an additional significant volume reduction, compared with manual lymphatic drainage alone (45% vs. 26%).[3][Level of evidence: I] Similarly, improvements were also found in the maintenance phase of therapy.

There are several barriers to multidisciplinary decongestive therapy, including cost, inadequate number of trained therapists, and time commitment. In response to these barriers, a group of researchers conducted a trial of a garment under commercial development.[4] The device was fit to patients, who were instructed to use it twice daily for 8 weeks. The investigators randomly assigned subjects to the device group or a wait-list control group. Use of the device was feasible, although most subjects found twice a day too burdensome. The treated subjects reported greater perceived ability to control lymphedema and subjectively had less swelling. There were no serious adverse events related to device usage. The economic costs of advanced compressive devices in lymphedema related to venous insufficiency compared favorably with other compressive techniques in a study of claims data.[5]

Complete decongestive therapy (CDT)

CDT is the standard of care for stage II lymphedema. However, the optimal program has not been established.

CDT has two phases:

One study compared manual lymphatic drainage with exercise to treat lymphedema in 39 people with oral cavity cancer.[6] Exercise and manual lymphatic drainage each improved neck range of motion and controlled lymphedema, but they appeared to have a better effect when done together.

A systematic review of manual lymphatic drainage in patients with breast cancer reported on ten studies.[7] Four of the studies reported that manual lymphatic drainage could reduce the incidence of lymphedema (risk ratio, 0.58; 95% confidence interval [CI], 0.37–0.93). However, seven of the studies did not show a statistical difference in volumetric changes. They did see a statistical difference in pain control, but not in quality of life.

Physical exercise

Physical exercise may be valuable in the treatment of lymphedema for several reasons, including improvement in lymph flow from muscle contractions and overall cardiovascular function.[8] Conversely, early concerns that exercise may cause harm have not been confirmed.[9,10] Results from a small randomized study suggest that resistance exercise may be offered concurrently with CDT.[11]

A systematic review and meta-analysis reported on 12 prevention and 36 treatment studies of exercise to either prevent or treat cancer-related lymphedema.[8] Most studies (11 of 12 and 32 of 36) enrolled patients with breast cancer. In addition, while most studies investigated some form of resistance training, a few used aerobic exercise alone. The relative risk of developing lymphedema after exercise was 0.90 (95% CI, 0.72–1.13), which was not significant. However, there was a suggested benefit in patients who had more than five lymph nodes removed. In this case, the relative risk was 0.49 (95% CI, 0.28–0.85). For patients in the treatment studies, the standardized mean difference (SMD) in measured outcomes was −0.11 (95% CI, −0.22 to 0.01). The difference compared with the control condition was −0.10 (95% CI, −0.24 to 0.04). Significant differences were detected for discrete outcomes such as pain, upper-body function and strength, lower-body strength, fatigue, and quality of life for those in the exercise group (SMD, 0.3–0.8; P < .05).

The American College of Sports Medicine advises that a supervised, progressive resistance exercise program is safe for patients with or at risk for lymphedema after breast cancer. There is not adequate data about the safety of unsupervised exercise. The safety of exercise in other cancers is unknown.[12]

Pharmacological therapy

Lymphatico-venous anastomosis

LVA surgery is typically used in patients with early-grade lymphedema due to difficulties in finding lymphatic vessels. One study reported results for 42 patients with later-grade, lower-extremity lymphedema who underwent preoperative magnetic resonance lymphangiography and ultrasound.[17] The imaging allowed patients to have an average of five successful anastomoses per limb. Clinical outcomes were favorable, raising the possibility of expanded indications for this surgery.

Immediate lymphatic reconstruction at the time of cancer surgery is under active investigation.

Vascularized lymph node transfer

VLNT involves harvesting healthy lymph nodes and their relevant venous and arterial vessels from a donor site and transferring them to the nodal basin of the affected extremity. The proposed mechanisms of action include providing alternative routes of lymphatic drainage and encouraging lymphangiogenesis to provide new lymph vessels to the extremity. At present, there is scant but promising clinical data on the efficacy of VLNT.[18]

A systematic review and summary of patients with breast cancer–related lymphedema who underwent CDT or VLNT [19] examined the evidence that both interventions favorably impact health-related quality of life measures. As anticipated, the data for VLNT was more limited (two studies, 65 patients) than for CDT (14 studies, 569 patients). However, within these limits, the data for VLNT indicated that improvements were commonly seen. The data for CDT were more heterogenous, and the improvement was often less significant. These data give clinicians a reason to consider surgical intervention, although at present the standard practice seems to be CDT.

In a retrospective study of 124 patients with breast cancer–related lymphedema, the degree of improvement in limb circumference and reduction in episodes of cellulitis appeared to be greater in patients who underwent VLNT than in those who underwent LVA.[16] In addition to the usual caution in interpreting retrospective data, the patients who underwent VLNT were ineligible for LVA based on lymphography results. This finding seems to support the use of imaging to guide patient selection. Two small cohort studies of VLNT in patients with breast cancer demonstrated apparent improvements in objective limb measurements and subjective measures of patients’ health-related quality of life.[20,21]

Liposuction

Nonpitting chronic lymphedema may be due to adipose tissue hypertrophy. In this case, liposuction to remove the excess adipose tissue is an option. Compression garments are still needed after the liposuction. In addition, excision of the redundant skin after liposuction may be required.[22]

One retrospective study compared the frequency of documented episodes of erysipelas in 130 patients before and after they underwent liposuction.[23] As anticipated, the mean excess arm volume decreased from 1,607 mL to negative 43 mL, and the ratio of affected to normal arm decreased from 1.5 to 1.0. The recorded occurrence of erysipelas decreased from 0.47 to 0.06 attacks per year. Similar results were reported in another study,[24] in which the authors reviewed the charts of 105 women with breast cancer–related lymphedema refractory to compressive therapies who underwent liposuction between 1993 and 2012. Notably, patients had to have nonpitting edema. All women benefited, and the benefit persisted for at least 5 years by measurement.

Laser therapy

Low-level laser therapy (LLT) is a noninvasive technique in which affected tissues receive phototherapy of various wavelengths within 650 to 1,000 nanometers. The role of LLT in the care of people with lymphedema is not established, although a 2017 systematic review found promising evidence.[25] The proposed mechanisms of action include cellular proliferation of macrophages with reduction in fibrosis, reduced inflammatory mediators, lymphangiogenesis, and improved lymphatic flow.[25] In addition, carbon dioxide laser treatment may also lead to clinical improvements, though the data are currently only from small case series.[26] The carbon dioxide laser stimulates remodeling of abnormal collagen by matrix metalloproteinases and dermal neocollagenesis by fibroblasts and supports generation of new lymphatic vessels.

Compression garments

A randomized study of women who underwent an axillary dissection suggested that compression sleeves worn from the first postoperative day until 3 months after completion of adjuvant therapy reduced the risk of lymphedema.[1] Women (n = 155) who were randomly assigned to the compression intervention had less arm swelling, as determined by bioimpedance spectroscopy (BIS) thresholds and relative arm volume increase (RAVI), than women assigned to usual care. The cumulative incidence of arm swelling at 1 year was 42% by BIS and 14% by RAVI in women who received compression garments, compared with 52% and 25%, respectively, for usual care. The hazard ratio for developing arm swelling in the compression group relative to the control group was 0.61 (95% confidence interval, 0.43–0.85; P = .004) by BIS and 0.56 (95% CI, 0.33–0.96; P = .034) by RAVI. There were no differences in patient-reported outcomes.

Exercise

A randomized trial suggested that exercise might help prevent lymphedema after breast cancer surgery.[2] The investigators randomly assigned 77 eligible women to a control arm or to 12 months of gym membership with a 13-week training session in weightlifting. Eligibility criteria included a diagnosis of breast cancer within 1 to 5 years, at least two lymph nodes removed, a body mass index (BMI) of less than 50, no prior history of lymphedema, and no asymmetry in the arms greater than 10%. The primary outcome was an increase in affected arm volume of greater than 5% at 1 year. A secondary outcome was clinician-defined lymphedema. The percentages of women who met the criteria for the primary outcome in the control and weightlifting cohorts were 17% and 11%, respectively (P = .04). The reduction in the rate in women who had five or more lymph nodes removed was even greater (22% in the control cohort vs. 7% in the weightlifting cohort; P = .003). However, there were no differences in the rates of clinician-defined lymphedema, which were much lower in each arm (4.4% in the control cohort vs. 1.5% in the weightlifting cohort).

A 2021 randomized trial studied patients with breast cancer who underwent either an axillary or sentinel lymph node dissection.[3] The investigators randomly assigned 568 women to one of two groups. All subjects met with a trained lymphedema prevention educator and received information about lymphedema, including preventive self-care practices. The 315 women receiving the active intervention met with a physical therapist who provided an individual exercise program, weights, and an elastic compression sleeve to wear. The primary end point was the lymphedema-free rate at 18 months. Lymphedema was defined by either an increase in volume of the affected extremity of more than 10% or a doctor’s diagnosis. There were no differences between groups in the primary end point. Overall, 69% of participants in the education-only arm and 70% in the intervention arm were free of lymphedema at 18 months. But adherence in the intervention arm was poor (less than 50%) due to time constraints and a perceived lack of benefit. There were no differences in health-related quality of life between the cohorts.[4]

At present, exercise therapy with compression garments may not effectively prevent lymphedema. Exercise with other interventions has been investigated. For example, one study reported the results of a randomized trial of manual lymphatic drainage in addition to exercise therapy in preventing lymphedema.[5] The investigators randomly assigned 160 women to receive or not receive manual lymphatic drainage in addition to exercise and suggestions to minimize lymphedema. Participants underwent serial volume measurements. At 6 months, 24% of women in the intervention group and 19% in the control group had an increase in volume of greater than 200 mL.

Complete decongestive therapy (CDT)

Compression sleeves alone may prevent progression of less severe lymphedema, but women often need more intensive interventions.[6] In one study, 103 women had post–breast cancer lymphedema that caused at least a 10% increase in volume in the affected arm compared with the unaffected arm. Participants were randomly assigned to either CDT comprising elastic compression garments plus 20 daily manual lymphatic drainage sessions with a trained therapist (n = 57) or elastic compression garments alone (n = 46).[7] The primary outcome was the percentage change in excess arm volume from baseline to 6 weeks. The women assigned to CDT experienced greater absolute volume loss than the women treated with compression garments alone (250 mL vs. 143 mL). However, there were no differences in the mean reduction of excess arm volume between the groups due to baseline differences in arm volumes in the two cohorts. In addition, there were no differences in the secondary outcomes and arm function.

Physical exercise

The results of randomized trials of physical exercise compared with usual care do not consistently demonstrate a benefit for patients with breast cancer and lymphedema. One study showed that women who underwent wide excision and axillary dissection and were randomly assigned to a supervised exercise program (3 hours per week for 12 weeks) reported fewer lymphedema-related symptoms than women assigned to a control group.[8] The exercise group demonstrated greater reduction in extracellular fluid, as assessed with bioimpedance spectroscopy, compared with the control group. There was no significant difference in dermal thickness of the breast, as assessed by ultrasound.

Based on promising results of a facility-based exercise intervention, one trial used a 2 x 2 factorial design to test a home-based exercise program, with or without a weight-loss intervention led by a dietitian.[9] The investigators randomly assigned 351 eligible women into one of four groups: control (n = 90), exercise alone (n = 87), weight loss alone (n = 87), and combined exercise and weight loss (n = 87). All patients received compression garments and consultations with certified lymphedema therapists. Eligibility criteria included evidence of lymphedema by clinical exam or history of lymphedema more than 6 months after surgery, a BMI between 25 and 50, and the ability to exercise but no history of consistent exercising. The primary outcome was the percentage difference between affected and nonaffected limbs. Secondary outcomes included clinician evaluation, patient surveys, and rates of lymphedema exacerbation or cellulitis. There were no differences of note between the various groups in the outcomes. This result raises the possibility that home-based therapies are inferior to facility-based treatment. The role of weight loss, if any, remains to be further elucidated.

Lymph node transplantation

A randomized trial of microsurgical lymph node transplantation and compression-physiotherapy versus compression-physiotherapy alone was reported.[10] The 18 patients who underwent surgery had a greater reduction in limb volume (57% vs. 18%), fewer infectious complications from the lymphedema, and improved symptoms and functional status, compared with patients who received only compression-physiotherapy. The authors estimated that the procedure was cost effective when accounting for the reduction in complications from lymphedema.

Systematic review

A systematic review examined publications related to lymphedema treatment in patients who had been treated for head and neck cancers.[14] The authors identified 23 primary studies, including 14 cohort studies, 7 case reports, and 2 randomized controlled trials. The interventions included manual lymphatic drainage, acupuncture, selenium supplementation, and liposuction.

CDT

A small randomized trial in patients with lymphedema after surgery for head and neck cancer assigned 21 patients to one of three groups: control (n = 7), CDT (n = 7), and home-based therapy (n = 7).[15] The patients who received home-based therapy were taught manual lymphatic drainage techniques. The patients who received CDT wore a compression face mask and received manual lymphatic drainage from a trained therapist; the time commitment was significant. Patients in the CDT group experienced greater volume reduction and no fibrotic complications. The small sample size and the time commitment required to receive CDT suggested the effect should be verified in a larger study before wider adoption.

Advanced pneumatic compression device

The shortage of trained lymphedema therapists and the inconvenience of multiple clinic visits have encouraged the development of a device patients can use at home. In a small randomized trial of such a device, patients were assigned to the device (n = 24) or a wait-list control (n = 25).[16] At 8 weeks, subjects in the active treatment arm reported less distressing symptoms, and repeat endoscopic exams revealed less edema, compared with the control subjects. Assessments of function were not changed. The authors noted that patients tended to use the device once daily rather than the prescribed twice daily. Further study is required.

Liposuction

There is a small randomized trial of submental liposuction in patients who complained of swelling after treatment of head and neck cancer. The ten patients who underwent liposuction reported greater improvements in personal appearance, compared with control subjects, at 6 months. No adverse effects from liposuction were reported.[17]