Introduction

As breast cancer survival rates improve, quality of life and survivorship issues have become increasingly important. Breast cancer-related lymphedema (BCRL), a chronic and feared sequela of breast cancer (BC) treatment, has garnered research focus. It is imperative that healthcare professionals caring for patients throughout and beyond BC treatment are knowledgeable about BCRL, in order to educate, diagnose, and refer patients appropriately. This review summarizes BCRL risk factors, screening, treatment, and the role of radiation therapy (RT) in BCRL development.

Definition

Lymphedema is defined as the accumulation of protein-dense fluid in the interstitial space of the limb, breast, and/or trunk on the side of BC treatment as a result of disruption of the lymphatic vasculature and subsequent drainage impairment [1]. Such pathological buildup can generate not only physical symptoms of swelling, heaviness, tightness, pain, tingling, and impaired movement but can also cause psychological consequences such as stress, anxiety, and depression [2, 3].

Incidence

BCRL incidence is not well established, mainly due to the lack of a universally accepted definition and well-defined diagnostic criteria. Its calculated incidence reportedly ranges from 5 to 50% [4•, 5, 6]. A recent comprehensive meta-analysis determined the incidence as 21.4%, making it one of the most common and impactful chronic conditions following BC treatment [4•]. This is even more relevant given that the risk of BCRL is a lifelong threat for patients treated for BC.

Diagnostic Criteria

Unfortunately, there is no consensus on specific diagnostic criteria for BCRL. Lymphedema diagnosis should be established clinically by a certified lymphedema therapist (CLT) or healthcare provider familiar with BCRL and should include objective measurements of the affected region, subjective symptoms using a validated outcome measure, and clinical examination. There are several measurement tools available to help screen for BCRL; however, the BCRL criteria vary within tools and across institutions. Inconsistencies in quantification methods may hamper consistent and accurate calculations of BCRL incidence and prevalence, considering that the methods are not interchangeable [7,8,9].

Measurement Tools

Volumetric measurement methods include water displacement, circumferential tape measure, and perometry, and another measurement tool includes bioimpedance spectroscopy (BIS). The perometer and BIS tools are pictured in Fig. 1.

Fig. 1
figure 1

Tools to quantify breast cancer-related lymphedema (BCRL). a Perometer. b SOZO® Digital Health Platform, ImpediMed Limited

Full size image

Water displacement was used historically and involves submerging the limb in a container of water, with the immersed limb’s volume equal to that of the water displaced. While reliable, valid, and accurate [7], the process is cumbersome and time-consuming as the water container requires strict hygienic emptying and sterilizing between patients. This limits the clinical utility of this practice, which has fallen out of use.

Circumferential measurements are taken with a tape measure every 4 or 10 cm along the length of the upper limb or from anatomical landmarks [10] and should be converted into arm volumes using the truncated cone formula, via commercially available software programs [11]. The tape measure is easy, inexpensive, and convenient for office use. It is reliable for quantifying arm volume change [7]; however, the measuring process is user and experience dependent, can take considerable time, and may lead to inter-rater variability in the setting of long-term BCRL screening and follow-ups [12].

The perometer is comprised of a frame containing infrared light receivers that is moved along the patient’s arm while abducted to 90 degrees (Fig. 1a). The arm’s circumference is calculated every 4.7 mm and its volume is automatically computed using the truncated cone method. Three measurements of each arm are taken, and the median limb volume is calculated. Perometry is a reliable, valid, diagnostically accurate, and efficient tool to quantify arm volumes with reproducible results [7, 13•, 14, 15]. Moreover, its high sensitivity allows for detecting subclinical edema, a known BCRL risk factor [16••, 17]. Nevertheless, the perometer is expensive and requires devoted clinical space, limiting its accessibility.

BIS calculates impedance ratios by passing an electrical current through the body and measuring resistance to flow. The resulting L-Dex score, which compares the affected extremity to the unaffected extremity, reflects the amount of extracellular fluid in the affected extremity. An L-Dex score change of ≥ 10 from preoperative baseline is typically considered diagnostic of lymphedema [7, 18], but a value of > 7.1 has been cited in the literature to discriminate between patients with and without BCRL [19•, 20]. A presurgical baseline is required, as some patients have abnormal readings preoperatively [19•, 21•]. BIS generates quick results with high reliability in detecting established BCRL [7, 19•, 20] and a newer machine (Fig. 1b) can also be used in patients who underwent bilateral breast surgeries [22]. Limitations include its costliness, size, and inability to detect later-stage, fat-dominant lymphedema [19•, 20, 23]. Moreover, its ability to identify early-stage subclinical edema is not well supported [23, 24, 25••]. Bundred et al.’s recent multi-center cohort study followed patients with preoperative baselines for a median of 36 months and compared the accuracy of BIS and volumetric measurement tools to diagnose BCRL, defined as relative arm volume increase (RAVI) of > 10% [25••]. The cohort’s 2-year lymphedema incidence using L-Dex ≥ 10 criterion was 45.2%, which is significantly higher than both the 22.4% rate detected with RAVI > 10% and 24.5% of patients that required compression sleeves. While there was a moderate correlation between BIS and RAVI at 6 months, long-term data revealed BIS overdiagnosed BCRL with a 12% false-positive rate, and RAVI correlated better with symptoms and quality of life. Conclusions drawn ascertain that BIS should not be used in isolation for BCRL screening and diagnosis [25••, 26].

Relative vs. Absolute Change

Volumetric change may be described as absolute (i.e., percent volume difference between the affected and unaffected arms) or relative (i.e., percent volume difference from preoperative baseline). Lymphedema’s definition varies widely. Several absolute thresholds have been used in the literature, including an increase of 2 cm in tape measure circumference or 200 ml in limb volume. However, they constitute flawed, unreliable BCRL definitions [16••, 17, 19•, 21•, 27, 28••, 29], as they do not account for the natural asymmetry between a patient’s arms at preoperative baseline, leading to misdiagnosis up to 50% of the time. This was demonstrated in Sun et al.’s prospective screening study. They found a natural asymmetry between a patient’s arms of ≥ 5% in 28.3% of the subjects and a difference of ≥ 10% in 2.9% of patients [28••]. To mimic cases without a baseline, the investigators substituted early postoperative measurements as pseudo-baselines in their analysis. With pseudo-baselines, BCRL was underdiagnosed and overdiagnosed in 50.0% and 54.8% of cases, respectively. Preoperative baselines are also essential in BIS measurements [19•, 21•]. Regardless of the tool used, a preoperative baseline is crucial for accurate BCRL screening and diagnosis.

The Lymphedema Research Program at Massachusetts General Hospital (MGH) developed the relative volume change (RVC) and the weight-adjusted volume change (WAC) formulae for patients undergoing unilateral and bilateral BC surgery, respectively [30, 31]. The RVC equation gauges volume changes of the affected arm in relation to the unaffected arm (A2 and U2, respectively) compared to their baselines (A1 and U1, respectively), whereby RVC = [(A2*U1)/(U2*A1) − 1] [30]. The WAC formula considers the two limbs independently in the setting of postoperative weight (W2) fluctuations in comparison to the weight at baseline (W1), whereby WAC = [(A2*W1)/(W2*A1) − 1] [31]. A common and accurate definition of lymphedema diagnosis is a relative increase of ≥ 10% in arm volume from baseline [9, 19•, 23, 28••, 29,30,31, 32•].

Symptoms

Quantification of arm swelling constitutes only part of lymphedema diagnosis, as it should incorporate BCRL-related symptoms reported by the patient. The role of symptoms is not clearly delineated, as studies have not shown a direct relation between symptoms’ severity and the magnitude of lymphedema [33, 34]. However, patient-reported symptoms of heaviness, current swelling, and numbness could be indicators of BCRL [33]. The presence of symptoms before lymphedema onset was associated with a higher risk of subsequent BCRL [34, 35]. Lymphedema-specific, validated questionnaires [33, 36,37,38] are available to help guide screening, diagnosis, and treatment.

Clinical Exam

To date, there has not been a reliable, valid, quantifiable method to evaluate BCRL clinically. The Cancer-Related Lymphedema of the Upper Extremity (CLUE) tool is a standardized BCRL clinical examination across three anatomical regions (digits/hand, wrist/forearm, elbow/upper arm) and four subscores (obscuration of anatomical architecture, deviation from normal anatomic contour, tissue texture, edema) [39]. It was recently developed and validated for use in research and clinical care.

BCRL Screening

Although a screening-based model is strongly supported in the literature and recommended [9, 10, 23, 28••, 40•, 41••, 42••, 43,44,45,46,47] over an impairment-based model, this is not universally applied. Prospective BCRL screening is longitudinal and incorporates objective measurements, including preoperative baseline measured via a valid, reliable, and feasible tool; a validated, patient-reported outcome measure; and multidisciplinary coordination to identify at-risk patients, ensure comprehensive patient education, and refer as needed to a CLT [41••].

The MGH Lymphedema Research Program initiated such a screening program in 2005, consisting of a multidisciplinary team of medical, surgical and radiation oncologists, CLTs, and nurses [41••]. Patients treated for BC are screened prospectively for BCRL throughout treatment and follow-ups using perometry measurements, patient-reported outcome measures, and clinical examination as indicated. Patients demonstrating elevated measurements or symptoms are routinely referred for CLT evaluation [41••].

Timing of BCRL after BC Treatment

In a recent prospective study, McDuff et al. studied the time course of lymphedema in a cohort of 2171 patients treated for BC. BCRL was found to most likely occur within 12–30 months after BC surgery [42••]. However, this timeframe differed depending on axillary surgery and nodal irradiation. Patients who underwent axillary lymph node dissection (ALND) without regional lymph node radiation (RLNR) had the earliest and highest risk of developing lymphedema, which peaked in the first 6–12 months. Patients who received ALND+RLNR had later onset BCRL, with the hazard ratio (HR) highest at 18–24 months. BCRL development occurred later in those receiving sentinel lymph node biopsy (SLNB) and RLNR, peaking between 36 and 48 months. Moreover, this cohort’s estimated cumulative incidence was 7.1% at 2 years and 13.7% at 5 years. Given this data and the fact that BCRL risk never decreases to zero, BCRL screening should last beyond 2 years, for at least 3–4 years.

Risk Factors

In the literature, there are several well-established risk factors as well as other potentially emerging risk factors, which are all reviewed below.

Axillary Surgery

Axillary surgery has been established as a risk factor for BCRL [4, 6, 8, 48, 49••, 50,51,52,53, 54•, 55•]. Although both ALND and SLNB put patients at risk for lymphedema by interfering with the lymphatic system through lymph node (LN) removal, ALND carries a notably higher risk. A meta-analysis has revealed that BCRL incidence in patients undergoing ALND was 19.9% (95% CI: 13.5–28.2), almost quadruple the rate in patients who had SLNB (5.6%) [4•]. This may be explained by considerably more tissue disruption and more LNs removed in ALND [48, 49••, 50, 51]. Kilbreath et al. noted that the incidence rate of BCRL among patients who have had more than five LNs removed was almost six times that of patients with less than five LNs removed (18.2% vs. 3.3%, respectively) [49••]. Another study found that a cutoff of > 10 LNs removed in ALND significantly raised BCRL incidence from 6 to 27% compared to ALND of ≤ 10 nodes [50]. However, both studies quantified BCRL without baseline preoperative measurements [49••, 50]. It is hypothesized that increased BCRL risk with a higher number of LNs removed reflects the type/extent of axillary surgery.

Body Mass Index at Breast Cancer Diagnosis and Weight Fluctuations

Obesity at BC diagnosis, defined as body mass index (BMI) ≥ 30 kg/m2, increases BCRL risk [25••, 32•, 51, 55•, 56,57,58, 59••]. Ridner and colleagues prospectively screened patients for lymphedema and demonstrated that high BMI at BC diagnosis multiplies the patient’s risk of ensuing lymphedema by up to 3.6 times as compared to a baseline BMI ≤ 30 (odds ratio (OR) 3.59, 95% CI: 1.42–9.04) [56]. Similarly, Jammallo et al. found that a BMI ≥ 30 was an independent predictor of BCRL and that a weight gain or loss of ten pounds or more per month after surgery was correlated with greater lymphedema risk (HR 1.97, P < 0.0001) [58]. A 2019 clinical trial randomized patients to a home-based resistance exercise program, a weight loss program, a combination of the two, or to the control group. Weight loss did not affect BCRL outcome [60••, 61]. Ongoing research should be directed towards understanding the effects of weight fluctuations and developing integrative clinical interventions to achieve and/or maintain ideal body weight.

Cellulitis and Seroma

Ipsilateral cellulitis and seroma are each independent BCRL risk factors [32•, 49••, 62••, 63•, 64]. A recent review by Asdourian et al. found that current and previous ipsilateral skin infections occurring in the affected arm were significantly associated with increased arm volume [62••]. A 2017 large retrospective study demonstrated that postoperative seroma was an independent risk factor, almost doubling BCRL risk (HR 1.92; 95% CI: 1.30–2.85) [64].

Subclinical Lymphedema

Subclinical edema, which is increased arm volume from the baseline that does not qualify as clinical lymphedema (i.e., visible on clinical exam, symptoms reported), is a risk factor for BCRL [32•, 49••, 51]. Regular arm measurements are necessary to detect subclinical edema, reinforcing the need for routine BCRL screening. By prospectively screening 1173 patients using perometry, Specht et al. found that increases in arm volume within the first 3 months post-surgery, by 3 to < 5% and 5 to < 10%, respectively, were significantly correlated with amplified BCRL risk (HR 2.52, P = 0.007; HR 3.24 P < 0.0001, respectively) [32•]. Arm volume increases of 5 to < 10% occurring after 3 postoperative months was associated with a significant risk of progression to RVC ≥ 10% (HR 2.97, P < 0.0001) [32•].

Regional Lymph Node Radiation

RT is a cornerstone of BC multidisciplinary treatment, and RLNR is considered an iatrogenic risk factor for BCRL [6, 49••, 51,52,53, 65, 66••, 67•, 68•, 69, 70•]. A prospective cohort study on patients with preoperative baseline showed that receiving RLNR significantly increases lymphedema risk (HR 1.70, P = 0.025), compared to only breast/chest wall radiation [51]. The cohort of patients who received no radiation or breast/chest wall radiation alone had 3.0% and 3.1% 2-year cumulative BCRL incidence, respectively. This is in contrast to a significantly higher 21.9% and 21.1% in patients treated with radiotherapy to supraclavicular (SCV) nodes with and without posterior axillary boost, respectively. However, these BCRL rates with RLNR are not stratified by type of axillary surgery. Shaitelman et al. found that RLNR addition to breast/chest wall radiation was associated with a higher BCRL incidence (OR 2.85; 95% CI 1.24–6.55). The combination ALND+RLNR was associated with an 18.2% incidence, a significantly higher rate than the 9.4% seen with ALND without RLNR. However, among patients treated with SLNB, the association of lymphedema with RLNR was not significant (95% CI 0.54–4.66) [65]. Naoum et al. prospectively evaluated 1815 patients in a BCRL screening program to evaluate the impact of axillary surgery and RLNR on local tumor control and BCRL (defined as RVC ≥ 10% increase arising ≥ 3 months postoperatively). The 5-year cumulative BCRL incidence rates were 30.1%, 24.9%, 10.7%, and 8.0% for ALND+RLNR, ALND alone, SLNB+RLNR, and SLNB alone, respectively. There was no significant local tumor control difference between SLNB+RLNR and ALND alone groups. Multivariable analysis adjusted for BMI and breast surgery type revealed there was no significant difference between SLNB alone and SLNB+RLNR groups regarding BCRL rates. Additionally, there was no significant BCRL rates difference between ALND alone and ALND+RLNR groups. However, a significant BCRL difference between SLNB+RLNR and ALND alone groups was detected. The authors concluded that while RLNR increases BCRL risk, the main contributing factor to BCRL risk is the type of axillary surgery received [67•].

In a large prospective cohort study, Chandra et al. showed that the SCV field lateral border, SCV dosage (5000 vs. 5040 cGy), beam energy (6-MV vs. 10-MV), tangent type (normal vs. wide), and fraction size (180 vs 200 cGy) do not correlate with BCRL [68•]. Conversely, Gross et al. noted that the extent of the SCV field’s lateral border significantly affected BCRL risk [69]. Furthermore, irradiating the anterior-lateral thoracic vessel juncture, with a radiation dose < 38.6 Gy, reportedly significantly decreased BCRL incidence (HR 0.13; P < .001) [53]. However, they defined BCRL as an absolute arm circumference change of 2 or 2.5 cm, failing to incorporate preoperative measurements. Further research is required to delineate the role of these findings with more accurate BCRL definitions.

Emerging BCRL Risk Factors

Chemotherapy

The association between chemotherapy and BCRL risk is not well defined. In some studies, chemotherapy has been reported to be significantly associated with lymphedema [4•, 49••, 50, 53, 59••, 70•, 71,72,73], whereas no such statistical significance was found in other studies [42••, 54•, 55•, 74]. A 2019 study of 486 patients treated for BC identified that a longer duration of neoadjuvant chemotherapy (NAC), namely ≥ 144 days, is associated with higher lymphedema incidence than in patients treated with NAC < 144 days [59••]. The type of chemotherapy regimen (i.e., anthracycline based, taxane based, or both) was not associated with lymphedema. BCRL was defined as a volume increase of ≥ 10% compared with baseline and/or the contralateral limb, limiting BCRL accuracy for those without baseline. The authors postulated that the higher BCRL rate observed could be related to the total chemotherapy dose or to delays due to toxicity.

Swaroop and colleagues prospectively screened 1121 patients treated for BC for lymphedema, defined as RVC ≥ 10% from preoperative baseline, and found that taxane-based chemotherapy was not associated with increased BCRL risk when compared to no chemotherapy and non-taxane chemotherapy (P = 0.62; P = 0.40, respectively) [54•]. However, taxane-based chemotherapy has been cited to correlate with an increased risk of fluid retention and lymphedema [49••, 53, 70•, 71, 72]. Kilbreath et al. showed that arm swelling at 6 and 12 months were both significantly associated with taxane-based chemotherapy, each representing independent risk factors for BCRL, established using BIS [49••]. This paper carried significant limitations in that baseline was not incorporated and circumference difference was used to measure swelling.

Interestingly, a 2019 study showed a tendency towards significance between trastuzumab intake and breast lymphedema (P = 0.09) [74]. In a retrospective analysis, Invernizzi et al. found that receipt vs. non-receipt of trastuzumab was significantly associated with almost triple the risk for BCRL (HR 2.7, 95% CI 1.31–5.55) [73]. BCRL was defined by circumferential difference without preoperative measurements, and the number of patients receiving trastuzumab was small (30 of n = 368, 8.15%), calling for more robust evidence.

Breast Reconstruction

The link between breast reconstruction after mastectomy and BCRL risk is emerging [55•, 75,76,77,78]. Miller et al. prospectively screened BC patients with preoperative measurements for BCRL. Their multivariate analysis revealed that immediate implant or expander-based reconstruction, but not immediate autologous reconstruction, was associated with reduced lymphedema risk compared to mastectomy alone (HR 0.432; P < 0.0001, HR 0.706; P = 0.2151, respectively) [55•]. A 2018 meta-analysis concluded that breast reconstruction was correlated with significantly lower odds of BCRL (P < 0.001), when compared to mastectomy and breast-conserving surgery. No statistically significant difference was found between an implant-based and autologous reconstruction [78]. This association may be due to tissue adhesion and fibrosis occurring without reconstruction, obstructing lymphatic flow [77]. Autologous reconstruction has been hypothesized to reduce postoperative fibrosis and subsequent obstruction [77], and implant reconstruction could possibly induce tissue ischemia stimulating angiogenesis and lymphatic regeneration [76]. These underlying mechanism theories remain nondefinitive. Furthermore, there was significant heterogeneity in the included studies’ study design and BCRL definitions [78].

Medical Procedures on the Ipsilateral Arm and Lifestyle Factors

Receiving medical procedures on the ipsilateral arm to BC as well as lifestyle factors that have been studied have not been associated with a statistically significant increase in arm volume [49••, 53, 62••, 63•, 79].

A 2019 retrospective study showed that port-sidedness, whether it was ipsilateral or contralateral to BC location and surgery, was not associated with BCRL [79]. Other medical procedures including blood draws, injections, blood pressure readings, and lifestyle factors such as air travel were not significantly associated with increased arm volume [53, 62••, 63•]. The lack of evidence for the roles of these factors in BCRL risk should be discussed with patients. Abiding to strict precautionary measures may add a significant burden on patients who have endured BC treatment [62••]. Personalization of BCRL management and risk stratification should guide BCRL risk assessment and patient education.

Genetic Susceptibility

The abovementioned risk factors can only partially account for a BC patient’s BCRL risk, as some women with these risk factors do not develop secondary lymphedema whereas others do. Genetic predisposition has also been proposed to affect BCRL risk. Genetic variations, such as single-nucleic polymorphisms (SNPs), in genes involved in inflammatory pathways, can modify a patient’s physiologic reactions to trauma and therefore their vulnerability for subsequent lymphedema. A recent systemic review identified 18 possible genes variations linked to BCRL in women who had received BC treatment, with some of the genes shown to be involved in primary lymphedema pathogenesis [80]. One of the included studies concluded that certain genotypic SNPs were associated, not with limb volume increase, but rather with clusters of eight or more symptoms, highlighting the importance of symptoms inclusion in lymphedema definition [81]. While promising, these findings are nevertheless preliminary, based on studies with significant limitations such as small samples and heterogenous lymphedema definitions [80].

BCRL Management

Complete Decongestive Therapy

The standard of care for BCRL treatment is complete decongestive therapy (CDT) under the direction of a CLT. CDT is two staged and may include the following: exercise, manual lymphatic drainage (MLD), compression bandaging, and patient education [82,83,84,85,86, 87••, 88••]. The first phase is reductive CDT, wherein frequent appointments with a CLT aim to reduce limb swelling until stabilization. The second phase consists of maintenance including self-MLD, maintenance compression, skin care, and exercise. Not all components are necessarily used in every patient as the regime should be individualized.

Exercise is necessary for patients treated for BC who are at risk for or have developed BCRL. It has been established that exercise neither causes nor worsens BCRL [86, 87••, 88••, 89••, 90,91,92] and recommendations have encouraged patients to engage in exercise safely and progressively under supervision [90,91,92]. A randomized controlled trial in women with BCRL and women at risk for BCRL showed no differences in lymphedema risk and arm volumes between the controls and those assigned to a progressive weight lifting program [83, 84]. Less severe symptoms (P = 0.03) and fewer lymphedema exacerbations at 1 year were noted in the intervention group (14% vs. 29%, P = 0.04) [83]. Exercise guidelines specific to patients treated for BC are available [88••, 89••, 90,91,92] and should be followed closely to avoid injury.

Lymphatic Surgery

There are two types of surgical procedures that constitute second-line therapy for BCRL [93, 94]. Debulking surgeries entail removing edematous or fibrotic excess volume by liposuction in patients with non-pitting or fat-dominant edema [93,94,95]. Overall arm volume reduction has been reported with this approach [95, 96]; however, it requires consistent use of compression garments for maintenance [93, 96]. Physiologic procedures target the underlying pathology of BCRL by restoring lymphatic fluid flow [93, 97]. They involve harvesting LNs and connecting their vasculature to the axilla’s lymphatics (i.e., vascularized LN transplant) or constructing anastomoses between the vascular and lymphatic systems (i.e., lymphovenous anastomosis). They work best in patients with pitting edema and have led to reductions in BCRL volume [93, 97, 98]. Both surgical interventions offer effective results, and the literature continues to evolve in this area.

Lymphatic Surgery and BCRL Prevention

Recently, preventive surgical approaches have been developed to locate susceptible parts of the arm’s lymphatic system and avoid damaging them during axillary surgery.

Axillary reverse mapping (ARM) is a surgical technique wherein a tracer is injected to identify LNs draining the arm to avoid their removal. ARM has been associated with lower BCRL rates [99, 100]. A 2017 systematic review found that lymphedema incidence was lower after SLNB and ARM than after SLNB alone. The authors highlighted the varied methods and timing of lymphedema diagnosis and the need for well-designed trials to better establish the efficacy of ARM and, given the possible overlap between axillary and upper extremity LN, the necessity of assessing oncologic safety [101].

Another surgical preventive method garnering attention is the lymphatic microsurgical preventative healing approach (LYMPHA), wherein an anastomosis is created between the lymphatic and venous systems during axillary surgery. This technique has shown favorable results and an association with lower lymphedema rates [102].

Drug Therapy

There are current ongoing studies investigating the potential role of drug therapy on chronic lymphedema. Pilot data examining tissue changes has shown that patients with lymphedema receiving the anti-inflammatory drug ketoprofen demonstrated reduced skin thickness, improved histopathology, and decreased plasma granulocyte CSF (G-CSF) expression [103]. This group is currently recruiting to an observational prospective cohort study of patients with lymphedema treated with ketoprofen. This study, incorporating limb volume changes, looks to further understand treatment response to ketoprofen [104]. Drug therapy represents for the moment a developing but hopeful endeavor in BCRL treatment.

Conclusion

Lymphedema is a devastating condition with significant consequences for patients who have already endured BC treatment. Due to high BC incidence and the rising survival after treatment, BCRL represents a field of expanding research. Well-known risk factors include ALND, RLNR, high BMI at diagnosis, subclinical edema, and ipsilateral skin infection. Ongoing research is making progress in studying BCRL onset, screening, risk factors, risk prediction, and treatment. Patients treated for BC should be routinely screened and evaluated for BCRL and stratified according to their different risk factors. Screening for BCRL is evidence based and strongly recommended, but unfortunately not universally adopted. Essential components of a BCRL screening program include preoperative baseline arm volume measures, consistent arm volume measurements, and regular evaluation of patient symptoms and clinical presentation for as long as possible, but at least 3 to 4 years after BC surgery. BCRL treatment is multifaceted and may include conservative and surgical options that target the affected arm’s volume, the patient’s symptoms, and function. Surgical interventions hold promise to prevent or reduce BCRL. A multidisciplinary team approach is absolutely essential for a successful BCRL screening and treatment program.

Future Direction

Future research should aim to identify thresholds for intervention for BIS and arm volume measurements (perometry and circumferential tape measure converted to volume). Research efforts should definitively quantify the role of systemic therapy, breast reconstruction surgery, RT’s parameters and medical procedures, and precautionary lifestyle behaviors on BCRL risk.

The lack of standardization of BCRL quantification and the absence of an established consensus continue to be fundamental obstacles to comparing and generalizing studies’ results and supplementing evidence-based practices and knowledge. Collaboration to establish a comprehensive definition of BCRL incorporating patient-reported symptoms and preoperative baseline is imperative for the advancement of BCRL screening, management, and research.