Diagnostic Methods, Risk Factors, Prevention, and Management of Breast Cancer-Related Lymphedema: Past, Present, and Future Directions

Abstract

Purpose of Review

Breast cancer-related lymphedema (BCRL) is a chronic, adverse, and much feared complication of breast cancer treatment, which affects approximately 20% of patients following breast cancer treatment. BCRL has a tremendous impact on breast cancer survivors, including physical impairments and significant psychological consequences. The intent of this review is to discuss recent studies and analyses regarding the risk factors, diagnosis, prevention through early screening and intervention, and management of BCRL.

Recent Findings

Highly-evidenced risk factors for BCRL include axillary lymph node dissection, lack of reconstruction, radiation to the lymph nodes, high BMI at diagnosis, weight fluctuations during and after treatment, subclinical edema within and beyond 3 months after surgery, and cellulitis in the at-risk arm. Avoidance of potential risk factors can serve as a method of prevention. Through establishing a screening program by which breast cancer patients are measured pre-operatively and at follow-ups, are objectively assessed through a weight-adjusted analysis, and are clinically assessed for signs and symptoms, BCRL can be tracked accurately and treated effectively. Management of BCRL is done by a trained professional, with research mounting towards the use of compression bandaging as a first line intervention against BCRL. Finally, exercise is safe for breast cancer patients with and without BCRL and does not incite or exacerbate symptoms of BCRL.

Summary

Recent research has shed light on BCRL risk factors, diagnosis, prevention, and management. We hope that education on these aspects of BCRL will promote an informed, consistent approach and encourage additional research in this field to improve patient outcomes and quality of life in breast cancer survivors.

Introduction

With the steady increase in the number of long-term survivors of early breast cancer due to ongoing medical advancements [1], emphasis on treating the chronic complications of treatment, including breast cancer-related lymphedema (BCRL), has increased [2]. Reported BCRL incidence in the literature ranges from 5 to 50% [3•]. A recent meta-analysis estimates that approximately one in five breast cancer survivors will develop BCRL [4] with a median onset of 14–18 months after surgery [5]. The pathophysiology and related processes contributing to BCRL are largely unknown [6]. Although there is no definitive cure for lymphedema, early intervention can limit progression of edema and significantly improve signs and symptoms [7••].

BCRL is characterized by improper drainage from lymphatic vessels [2, 8] and the subsequent accumulation of protein-rich fluid in the interstitial space [9]. Such fluid accumulation can result in abnormal swelling of the arm, shoulder, hand, breast, and/or trunk on the side treated for breast cancer [2, 4, 10–12]. Symptoms of lymphedema include arm tightness, heaviness, and in later stages, impaired limb function [10]. BCRL also negatively impacts a patient’s body image and quality of life (QOL), contributing to increased rates of anxiety and depression amongst breast cancer survivors [2, 13, 14]. The risk of developing BCRL persists throughout a patient’s lifetime, which may explain why BCRL causes considerable distress amongst patients [7••].

The multi-dimensional impact that BCRL can have on a patient’s well-being has led to research focused on the prevention and treatment of this condition. Screening programs and research targeted at identifying potential preventative methods have continued to evolve. As a result of ongoing research regarding patient outcomes from radiation and lymph node surgery, physicians have shifted away from more invasive, high-risk surgical and treatment approaches [1–17]. There are several studies that have identified risk factors for BCRL, allowing practitioners to identify those at the highest risk for developing BCRL [3•, 4, 5, 18–27, 28•]. Lastly, research in the management and treatment of BCRL has allowed for significant improvements in patient outcomes. This review explores the risk factors, diagnosis, prevention, and management of BCRL, in an effort to ultimately improve the QOL of breast cancer survivors.

Diagnosis

Methods

Several notable advances in the diagnosis of BCRL are due to new measurement techniques, which have supplemented the more traditional methods such as water displacement and circumferential tape measurement (see Table 1) [8, 29, 30]. Water displacement, though accurate and inexpensive, comes at the cost of time-intensive cleaning to meet hygienic standards and the need for a strict protocol to ensure accuracy [30]. Additionally, this technique cannot be used to localize swelling in a specific segment of the arm [31]. Circumferential tape measurement is also an inexpensive, reliable, and highly accessible measurement tool in a variety of healthcare settings [32, 33]. However, since the measurement process takes substantial time for both patient and provider, the perceived low cost of this technique needs to be reconsidered in the context of these important disadvantages [34]. Furthermore, it is common for multiple providers to measure the arm for lymphedema screening purposes [7••]. As such, inter-rater variability can generate error with the tape measurement without significant training and provider experience, reducing the consistency and accuracy of values obtained [35].

Table 1.

BCRL diagnostic method advantages and disadvantages

Diagnosis method	Advantages	Disadvantages
Water displacement	Accurate Inexpensive	Time consuming Required strict protocol
Circumferential tape measurement	Inexpensive Reliable Highly accessible	Time consuming Low inter-rater reliability without significant training
Perometry	Quick Highly reproducible Accurate Segmental volumes Identifies subclinical BCRL	Expensive Large size
Bioimpedance spectroscopy	Quick Portable Potentially identifies subclinical BCRL	Limited to unilateral patients Expensive

The disadvantages associated with the aforementioned methods in measuring BCRL have led to well-validated and more efficient measurement devices. One such device for measurement is the Perometer, which calculates total limb volume utilizing infrared sensors [30, 36]. Measurements are highly reproducible [37] and are completed within 2–3 min for both arms, the device can be wiped clean in seconds between patients, and a well-established measurement protocol is available [7••]. The Perometer is a valid and reliable measure of limb volume, and it is highly sensitive, allowing for subclinical detection of BCRL in patients [5, 33, 36, 38]. Perometry also allows for specific segments of the limb to be measured, which is helpful for detecting isolated edema in a section of the arm or hand. Drawbacks of the Perometer include its cost and large size [39].

Another modern measurement technique is bioimpedance spectroscopy (BIS). This machine passes an electrical current through the limb to establish impedance scores and ratios between arms which reflect the amount of extracellular fluid in the arm [40]. Recommendations for measurement methodology are published and available to the user [41]. There are several advantages to this method, including its portability and ability to complete measurements within 4–5 min [39, 42]. A limitation to this technique is that it measures only patients who have undergone unilateral breast surgery, excluding those who receive bilateral breast surgery. Jain et al. demonstrated that inter- and intra-rater reliability for BIS is high in a study involving ten patients [43]. The literature also suggests that BIS can detect subclinical lymphedema [29,44,45•]. Bundred et al. compared BIS to perometry and found moderate correlation between the methods at both 3 and 6 months [45•], though further studies with a longer follow-up time are needed to evaluate the sensitivity and specificity of the BIS method in detecting subclinical BCRL [46].

It is important to note that diagnosis of BCRL should not be made through volumetric methods or through BIS alone. A clinical examination as well as subjective information, including patient-related outcome measures, signs, and symptoms, should be included in any screening and diagnosis of BCRL [11, 47–51]. There are several comprehensive, well-validated outcome measures available to evaluate breast cancer-related lymphedema [48–50, 52].

Quantification

Though sensitivity has improved with recent developments in measurement and detection, Sun et al. analyzed 1028 patients and reported that without a baseline measurement prior to surgery, diagnoses of subclinical and clinical lymphedema are missed 40–50% of the time. Furthermore, this study found that roughly half of lymphedema cases that are diagnosed without a baseline measurement are most likely over-diagnoses. This is largely because arms are rarely symmetrical at baseline. 2.9 and 28.3% of patients had >10 or >5% asymmetry, respectively, at their baseline measurement (Fig. 1). From these findings, it is clear that pre-operative measurements for at-risk patients must be implemented for accurate BCRL diagnosis [53••, 54]. Furthermore, research presented on BCRL that does not include a pre-operative measurement must be reviewed closely for inaccuracies in the diagnosis of lymphedema.

Fig. 1.

Histogram of arm asymmetry. Baseline asymmetries of >5 and 10% are shaded light and dark pink, respectively

Ancukiewicz et al. demonstrated that absolute volume changes as a quantification method for BCRL is flawed. As seen in Fig. 2, specificity depends highly on the patient’s body size. The arm size of patients diagnosed with breast cancer varies within a broad range: the ratio of largest to smallest arm volume in this patient sample was more than 5:1. With such variation, the visual—and likely the functional—impact of the same absolute increase in arm size (200 mL or 2 cm) is very different in patients with small and large arms. For example, Fig. 2 depicts that an increase of 200 mL in arm volume corresponds to a 15.4 and 3.3% increase in relative arm volume for arms of 1300 and 6000 mL volumes, respectively. Thus, the absolute and relative criteria for diagnosis of BCRL are mutually inconsistent in populations with heterogeneous arm sizes. Absolute volume change correlates with pre-operative arm volume, patient weight, and BMI but relative volume change is independent of patient weight. As such, relative volume change, which incorporates baseline volume, is better suited than absolute volume change as the standard quantification method for BCRL [55].

Fig. 2.

Relative volume change after a 200-mL arm volume increase

For unilateral breast surgery, Ancukiewicz et al. established a method for measuring relative volume change (RVC) by taking into account the pre-operative and post-operative follow-up volumes on the ipsilateral arm (A1 and A2, respectively) and the pre-operative and post-operative follow-up volumes (U1 and U2) on the contralateral arm. RVC is thus modeled as RVC = [(A2*U1)/(U2*A1)–1]. The contralateral arm operates as a control as it assumes any weight gained equally distributes amongst the arms [56].

Since patients undergoing bilateral breast surgery do not have a contralateral arm to use as a control, Miller et al. formulated a revised model for this subset of patients, which incorporates a patient’s weight at each arm measurement. This study demonstrated a 1:1 linear relationship between change in patient weight and contralateral arm volume in unilateral breast surgery patients, thus proposing a weight-adjusted change (WAC) formula to quantify arm volume in patients treated with bilateral breast surgery [57]. Furthermore, the WAC formula was validated by demonstrating that the RVC formula [56] and the WAC formula quantified BCRL similarly in unilateral breast surgery patients, defined as ≥10% arm volume change from baseline. The WAC formula takes into account the pre-operative and postoperative arm volumes on the surgical side (A1 and A2) as well as the pre-operative and post-operative weights of the patient (W1 and W2), as WAC = [(A2*W1)/(W2*A1)–1]. It should be noted that arm volume calculated from tape measurement, perometry, or water displacement may be entered into the RVC or WAC formulas for unilateral or bilateral patients, respectively [51].

There is no universal definition for lymphedema diagnosis, and consequently, there exists no universal diagnostic method for the condition [58]. However, there has been a general consensus in the literature that an arm volume change of ≥10% is indicative of lymphedema. Some studies, however, have used an arm volume change of >3% as an appropriate threshold for intervention with compression [59] and certainly edema <10% is worthy of attention in those at risk. When utilizing BIS for measurement, the impedance value generated is converted to an L-Dex score [60]. Patients with an L-Dex score of greater than 10 units above pre-operative baseline or greater than 3 standard deviations above normative data are considered to have BCRL [60].

It has been suggested to choose one method of measurement which includes a pre-operative measurement whenever possible and to measure at set intervals throughout and beyond treatment as part of a screening program. This would allow for calculation of volume change as compared to baseline in order to successfully screen for, diagnose, and treat lymphedema as early as possible [7••, 53••].

Risk Factors

Numerous risk factors have been reported in the literature for BCRL, including regional lymph node radiation, method of breast and axillary surgery, high BMI at time of diagnosis, weight fluctuations during breast cancer treatment, subclinical edema, and cellulitis [4, 5, 18–27, 28•, 61–63].

Radiation Therapy

Tsai et al. found that any type of radiation therapy (relative risk (RR) = 1.92; 95% CI 1.61–2.28) was an independent risk factor for lymphedema development, as compared to no radiotherapy [18]. Warren et al. sought to determine the risk associated with several radiation therapy (RT) methods on BCRL development. A cohort of 1476 breast cancer patients was subdivided into the five treatment categories: no radiation, partial breast irradiation (PBI), whole breast (WBI)/chest wall irradiation alone, or WBI/chest wall radiation with regional lymph node radiation (RLNR). Patients who received RLNR were further differentiated into patients receiving a posterior axillary boost (PAB) along with the supraclavicular irradiation (SC) versus patients who only received SC. Analysis showed that the 2-year cumulative incidences of BCRL were 3.0% in the no radiation cohort, 3.1% in the breast or chest wall alone cohort, 21.9% in the SC cohort, and 21.1% in the SC and PAB cohort. RLNR was found to be an independent risk factor for BCRL development, though the BCRL risk between SC only and SC with PAB did not differ. Following these results, Warren et al. recommend that this high-risk population of breast cancer patients receiving RLNR should be prospectively screened for BCRL [28•].

In an effort to further assess the effect of RT on BCRL, Leong et al. compared hypofractionated nodal RT (defined as >2Gy/fraction) and conventional fractionated nodal RT (defined as ≤2Gy/fraction). The study cohort consisted of 708 patients whose self-reported arm symptoms were comprised of arm and hand swelling, stiffness, pain, numbness, and immobility. There was no difference in patient-reported arm symptoms or disability when comparing hypofractionated nodal RT to conventional fractionated nodal RT. Arm and shoulder function, however, was impaired in the conventional RT group [61].

Axillary Surgery Type

Axillary lymph node dissection (ALND) has consistently been identified as an independent risk factor for the development of BCRL. Miller et al. examined a cohort of 627 patients who underwent 664 mastectomies for a median follow-up of 23 months. For mastectomy patients, a positive sentinel lymph node biopsy (SLNB) and radiation therapy (RT) resulted in a lower than 10% incidence of lymphedema compared to ALND with or without radiation (30.1 and 19.3%, respectively). Results indicate that avoiding ALND would significantly reduce lymphedema risk in those with a positive SLNB [63]. Tsai et al. published a comprehensive report calculating the relative risk of several treatment-related factors from 98 independent studies. They found that ALND increased the risk of lymphedema compared to no ALND (RR = 3.47; 95% CI 2.34–5.15) as well as compared to SLNB (RR = 3.07; 95% CI 2.20–4.29) [18].

Lack of Breast Reconstruction

The risk of lymphedema after breast reconstruction has been a topic of recent interest; Miller et al. compared immediate reconstruction to immediate autologous reconstruction through multivariate analysis with a prospective cohort of breast cancer patients screened pre-operatively and post-operatively via perometry. The cohort consisted of 616 individual patients with 891 total mastectomies. After 2 years, 26.7% of patients without an implant developed BCRL, 9.9% of patients opting for the immediate autologous developed BCRL, and only 4% of patients who opted for the immediate implant developed BCRL [62]. These results demonstrate that reconstruction, specifically immediate reconstruction, can result in a lower BCRL risk when compared to no breast reconstruction following a mastectomy. Basta et al., however, found that reconstruction does not modify lymphedema risk. It is important to note that there was no diagnostic consensus for BCRL as well as no indication of preoperative measurements in Basta’s study, which limits the study’s findings [64].

High BMI and Weight Fluctuations

Apart from treatment-related risk factors, high BMI at diagnosis (≥30 kg/m²) is a frequently published risk factor for lymphedema development [4, 18–23, 25, 26, 65]. Jammallo et al. reported on a cohort of 787 patients who were prospectively screened for BCRL via perometry. The study showed that BMI ≥30 was an independent risk factor for BCRL. Weight fluctuations (loss or gain) greater than 10 lbs per month post-operatively also resulted in a higher risk of BCRL [19]. Fu et al. screened women via BIS and found similar results. Women who were obese were more likely to develop lymphedema—defined as an L-Dex ratio >7.1—than women who were in the normal/underweight group and the overweight group pre-operatively, 4–8 weeks post-operatively, and 12 months post-operatively [65].

Subclinical Edema

Studies on subclinical edema have elucidated other risk factors of BCRL. Specht et al. assessed whether arm volume changes at various time intervals influenced the risk of developing BCRL. The group prospectively screened 1173 patients via perometry and found that low-level volume changes (RVC of ≥3 and <5, and ≥5 and <10%) within 3 months of surgery were significantly associated with BCRL development. Additionally, volume changes of RVC ≥5 and <10% were significantly associated with BCRL development greater than 3 months post-operatively, while an RVC of ≥3 and <5% greater than 3 months post-operatively was not associated with BCRL development. Results of this study suggest that patients with an RVC from ≥3 to <5% within 3 months of surgery and ≥5 to <10% at any point should be monitored closely and may greatly benefit from early intervention [5].

Cellulitis

Finally, Ferguson et al. found, through multivariate analysis, that cellulitis significantly increased the risk of BCRL [24•]. Indelicato et al. found that those with BCRL were more likely to develop delayed breast cellulitis. In this study, 22% of the patients with cellulitis developed recurrent episodes of cellulitis, which was more prevalent in patients with BCRL. Thus, cellulitis may increase the risk for developing BCRL, and vice versa [3•, 24•, 27], but further exploration is needed to understand the relationship between lymphedema development and cellulitis [24•].

Screening and Prevention

Routine screening allows for subclinical detection and therefore early treatment of lymphedema, which can aid in preventing further progression of edema [44, 45•, 66]. Brunelle et al. described the establishment and feasibility of a screening program at Massachusetts General Hospital (MGH), where all breast cancer patients are monitored for BCRL throughout their treatment and at follow-up visits with their treating oncologist. To date, over 4500 patients have been screened with pre-operative baseline perometry measurements and routine post-operative measurements with an accompanying survey for at least 5 years. Patients are screened for signs and symptoms of BCRL and a clinical exam ensues to confirm a diagnosis. Additionally, those at higher risk of BCRL are more frequently monitored [67]. In order to maximize consistency, the group implemented a well-defined measurement protocol [7].

Stout et al. prospectively measured 196 women via perometry pre-operatively and at 3-month intervals after surgery. Upon the diagnosis of lymphedema, defined in this study as a >3% increase in limb volume, patients received compression garments as treatment. Significant volume reduction was attained from the 4-week intervention and results were maintained at the average follow-up time 4.8 months after the completion of the intervention. This study again supports screening and early intervention but is limited by its small sample size and non-randomized design [54].

Screening and early prevention may have financial benefits. By estimating costs using the 2009 Medicare physician fee schedule, Stout et al. found the cost per year to manage early-stage BCRL through a prospective screening model is $636.19. The cost per year to manage late-stage BCRL through the traditional model is $3124.92 [68]. Though more research is necessary to determine the cost-effectiveness of screening and early intervention, this study provides compelling preliminary evidence.

Precautionary Guidelines

Ferguson et al. sought to determine the relationship between non-treatment-related risk factors and development of BCRL. The group prospectively screened 632 patients via perometry who had undergone unilateral or bilateral breast surgery. Data on the number of blood draws, blood pressure readings, injections, and incidence of infection in the at-risk arm as well as the number of flights taken since the last measurement was collected via patient self-report. Multivariate analysis showed no significant association between lymphedema development and undergoing one or more blood draws, blood pressure readings, infection to the ipsilateral arm, or air travel [24•]. It should be noted that the number of events within the cohort was low, and more research is needed to definitively establish the effect on BCRL risk of these precautionary behaviors.

The National Lymphedema Network provides several precautionary lifestyle recommendations for at-risk patients [69]. These include avoiding the constriction of the at-risk arm (i.e., blood pressure cuffs, tourniquets, and tight clothing), avoiding venous puncture (i.e., blood draws and intravenous sticks), and wearing a compression sleeve during air travel. There exists limited high-level data supporting or refuting their efficacy [3•, 70]. Therefore, Asdourian et al. have advocated for a more rigorous and evidence-based analysis of the lifestyle risk exposures for BCRL, with the goal of minimizing the risk of developing BCRL while maximizing QOL [3•].

Management

Treatment

Driven by the need to ensure best practice for BCRL intervention amongst healthcare professionals, the Lymphology Association of North America (LANA) has devised recommended standards for a certified lymphedema therapist. A practitioner must complete at least 135 hours of complete decongestive therapy (CDT) coursework, which involves the following: an in-depth understanding of the pathophysiology of lymphatic function, manual lymph drainage (MLD), compression bandaging (CB), lymphatic exercise, skin care, and education on the self-management of lymphedema. Practitioners must also be currently licensed as a physical therapist, occupational therapist, or another related medical profession [71].

There is neither high-level evidence for nor consensus on the appropriate threshold to initiate intervention for BCRL. Close screening is recommended for patients with elevated arm volume >3–<5% in the 3 months after surgery, but these patients do not appear to progress to volume >10%, and intervention at 3–≤5% is not warranted [5]. However, further investigation of a ≥5–<10% threshold is indicated, as these patients may tend to progress to volume >10%. Justification for early intervention should be a focus in the literature.

Treatment of BCRL involves two main phases: the first is reductive CDT and the second is maintenance therapy. Reductive CDT involves individualized therapy administered by a certified lymphedema therapist. Patients are seen frequently until the limb volume reaches a stable state, usually within a few weeks. The maintenance phase follows, emphasizing self-care, including some or all of self-lymphatic drainage, compression garments, exercise, and a skin care routine [72].

In its entirety, CDT has been the main treatment for BCRL for many years. It has been found to effectively treat BCRL; however, parameters and protocols of CDT programs vary, making it difficult to establish best practice guidelines for frequency and duration [11, 73]. Studies generally look at CDT in its entirety, but there is less literature and poorer quality of studies on the role of each of its components, including exercise, skin care, compression, and MLD.

There exists increasingly more evidence for utilizing CB as the first-line intervention for BCRL. Stout et al. found that wearing a compression sleeve for a 4-week period successfully treated subclinical lymphedema (LE) [54]. In patients with established BCRL, McNeely et al. conducted a randomized controlled trial to assess whether the addition of MLD to CB reduced BCRL. Fifty women were measured via water displacement and circumferential tape measurement. CB reduced arm volume successfully, with or without the addition of MLD [74]. In a randomized trial, Andersen et al. assessed 42 patients with BCRL who were treated with CDT with or without MLD. The group found that edema volume, measured by circumferential tape measurement, and LE symptoms did not significantly differ between the two groups [75]. Finally, Dayes et al. conducted a randomized trial comparing CB to daily manual lymphatic drainage and CB. The trial measured 103 women via circumferential tape measurement and arm function and QOL was assessed. The group found no significant difference in volume reduction, arm function, and QOL measures between the two groups [76]. These studies assessing CB are all limited by their small sample size; however, because CDT is resource intensive for the patient and the healthcare system, these data provide invaluable insight into management of BCRL. In a recent editorial, Javid et al. follows this research to suggest that early LE should not be treated first with MLD [77], but rather with compression.

Intermittent pneumatic compression (IPC) technology has improved significantly over the past few decades [78]. Several studies have assessed the efficacy of IPC. Uzkeser et al. conducted a randomized controlled trial with 31 LE patients comparing CDT alone to CDT with the addition of IPC. The study found volume reduction in both groups with no significant difference between the groups [79]. Shao et al. conducted a meta-analysis of the published randomized controlled studies assessing IPC efficacy in BCRL management. The group found that recent studies, though lacking in quality, have not demonstrated IPC’s efficacy in LE treatment [80].

Some studies evaluating IPC, however, have demonstrated its usefulness in BCRL management. Szolnoky et al. sought to assess the use of IPC in conjunction with CDT involving MLD. Twenty-seven women were randomly placed in either cohort and LE was measured via circumferential arm measurement and a self-reported symptom questionnaire at the beginning and end of therapy, and 1 and 2 months after the initiation of therapy. Though both groups exhibited volume reduction, there was significantly more reduction in the IPC cohort at all time points [81]. Gurdal et al. found similar results in their study comparing MLD + CB and IPC + self-lymphatic drainage (SLD). All patients, no matter the treatment method, experienced volume reduction with no significant difference between the two cohorts. They further noted that IPC may be preferential to patients with BCRL as the treatment can be done while at home [82]. The use of IPC remains controversial and more high-level evidence is needed to assess its true efficacy. This method should be individualized and may supplement a patient’s treatment by a certified lymphedema therapist.

It is important to note that management as discussed in this review is non-surgical. Techniques such as liposuction, lymph node transfers, and lympho-venous anastomoses [8, 83] are also aimed at BCRL prevention or management. Research is evolving quickly in this area; however, this is beyond the scope of this review.

Exercise

Exercise is an integral part of care for patients at risk for lymphedema development as well as those with a confirmed breast cancer diagnosis. The American College of Sports Medicine has issued exercise guidelines for breast cancer survivors. This panel urges cancer patients to remain active, maintaining daily activity during adjuvant therapies as well as resuming daily activity as soon as possible following surgery. Patients are recommended to complete 150 min/week of moderate level activity (e.g., walking) or 75 min/week of vigorous level activity (e.g., running). These recommendations should be included in the plan of care for every breast cancer survivor [84].

There exists a misconception that breast cancer survivors should limit the use of the at-risk arm to avoid BCRL development. However, this avoidance could lead to adverse effects such as increased risk of injury or subsequent weight gain [85], which itself has been shown to be a risk factor for BCRL [19]. Several exercise trials in patients with breast cancer have demonstrated that a progressive program of regular aerobic and resistance exercise is safe and does not incite BCRL [86–88].

Schmitz et al. performed a randomized controlled trial with 141 patients with stable BCRL, in which arm volume was measured using water displacement. The group sought to assess the effect of progressive weight lifting on LE exacerbation, and severity and number of symptoms, as well as muscle strength. After 1 year, patients with lymphedema in the weight lifting cohort were shown to have no change in limb swelling compared to the control group. The weight lifting cohort showed a decreased incidence of BCRL exacerbation and symptoms, as well as an increase in strength. Schmitz et al.’s work has also demonstrated that there is no upper limit for the amount of weight used, if weight addition is progressive [85].

Cormie et al. sought to measure the acute inflammatory response before and after low-, moderate-, and high-load resistance exercise of the upper body in a randomized, crossover study. Twenty-one patients with a BCRL diagnosis were measured via BIS. Symptoms were assessed and venous blood samples were taken in order to determine levels of inflammatory and exercise-induced muscle markers. The group found that regardless of the resistance load, there was no significant difference in inflammatory response, arm swelling, or symptom scores [89•].

Finally, a recent meta-analysis by Rogan et al. evaluated the current literature on the effects of exercise as well as treatment success. The group evaluated four different randomized controlled trials with four unique protocols for the exercise regimen. All four studies showed a reduction in limb fluid, and the group’s meta-analysis demonstrated a 200-mL fluid reduction from exercise alone. It is essential to emphasize that exercise, under close supervision [8], is safe and beneficial for patients at risk of BCRL development, as well as for those with a confirmed diagnosis of BCRL [85, 90, 91].

Recently, a growing number of studies investigated the efficacy of other modes of exercise on BCRL. Fisher et al. reported that when six women with a confirmed BCRL diagnosis practiced Hatha Yoga three times per week for 8 weeks, arm volume significantly decreased while QOL and self-reported arm function remained stable [92]. Letellier et al. conducted a randomized controlled pilot and reported that when 25 women took part in a 12-week aqua lymphatic therapy (ALT) intervention, there was no change in limb volume, though grip strength improved, in both groups [93], and only the ALT group demonstrated a significant reduction in pain and an overall higher QOL. Studies are evolving quickly, supporting exercise for patients with BCRL. Larger randomized controlled trials are necessary to gain high-level evidence for alternative exercise interventions.

Future Directions

While current research and advances are promising, there is much to be done in BCRL research. Treatment and prevention of lymphedema must be a team approach, involving certified lymphedema therapists as well as treating oncologists and surgeons. In order to efficiently collaborate with one another, there must be universal agreement in defining, measuring, and quantifying lymphedema. Shifting from an impairment-based model towards a screening-based model will allow for increasingly early diagnosis and intervention and will allow the development of high-level evidence in support of screening and early intervention for BCRL. Finally, high-level research to define the role of precautionary behaviors in the risk of BCRL development is imperative.

Conclusion

The tremendous physical and psychosocial impact of BCRL on a breast cancer survivor is clear [2, 7••, 13, 14]. Practitioners must approach this condition with a full understanding of which patients are at risk, effective prevention, routine screening, early diagnosis, and management.

There exists no diagnostic consensus for defining BCRL, largely due to the multitude of measurement techniques available [58]. This will likely continue, given varying resources between healthcare systems and facilities. Of utmost importance, however, is establishing a screening program where newly diagnosed breast cancer patients are measured pre-operatively and post-operatively—at regularly scheduled follow-up visits—and are monitored clinically in order to screen for signs and symptoms of BCRL [7••]. Paired with an accurate analysis technique that controls for weight fluctuations, lymphedema development can be tracked accurately and effectively [53••, 54–57].

Well-substantiated treatment-related risk factors for BCRL include ALND, lack of reconstruction, and RLNR [18, 28, 63]. Non-treatment-related risk factors include high BMI at time of diagnosis (≥30), weight fluctuations of ±10 lbs per month post-operatively, subclinical edema within and beyond 3 months after surgery, and cellulitis in the at-risk arm [4, 5, 18–27, 65]. Identifying individual risk factors and educating patients of their individual risk are essential for BCRL prevention.

As BCRL is a highly feared complication [94] amongst breast cancer survivors, it is essential that well-substantiated precautionary guidelines be specified [3•, 24•]. More rigorous research must be done in this field to ensure that precautionary guidelines given to patients are backed by high-level scientific evidence.

In today’s patient-centered healthcare environment, the patient’s quality of life after cancer treatment must be prioritized. This means addressing a patient’s physical and psychological well-being, which are both affected by BCRL. We believe that prevention, diagnosis, and management of breast cancer-related lymphedema operate most effectively in concert as part of an effective lymphedema screening and treatment program offered from diagnosis throughout survivorship.