Prevention of Lymphedema

BACKGROUND: Breast cancer-related lymphedema affects more than 400,000 survivors in the United States. In 2009, lymphatic microsurgical preventive healing approach (LYMPHA) was first described as a surgical technique to prevent lymphedema by bypassing divided arm lymphatics into adjacent veins at the time of an axillary lymph node dissection. We describe the first animal model of LYMPHA.

METHODS: In Yorkshire pigs, each distal hind limb lymphatic system was cannulated and injected with a different fluorophore (human serum albumin-conjugated indocyanine green or Evans Blue). Fluorescence-assisted resection and exploration imaging system was used to map the respective lymphangiosomes to the groin. Baseline lymphatic clearance of each hind limb lymphangiosome was obtained by measuring the fluorescence of each dye from centrally obtained blood samples. A lymphadenectomy versus lymphadenectomy with LYMPHA was then performed. The injections were then repeated to obtain clearance rates that were compared against baseline values.

RESULTS: Human serum albumin-conjugated indocyanine green and Evans Blue allowed for precise lymphatic mapping of each respective hind limb using fluorescence-assisted resection and exploration imaging. Lymphatic clearance from the distal hind limb dropped 68% when comparing baseline clearance versus after a groin lymphadenectomy. In comparison, lymphatic clearance dropped only 21% when comparing baseline clearance versus a lymphadenectomy with LYMPHA.

CONCLUSIONS: We describe the first animal model for LYMPHA, which will enable future studies to further evaluate the efficacy and potential limitations of this technique. Of equal importance, we demonstrate the power of optical imaging to provide real-time lymphatic clearance rates for each hind limb.

BACKGROUND: Breast cancer-related lymphedema (BCRL) is one of the most significant survivorship issues in breast cancer management. Presently, there is no cure for BCRL. The single greatest risk factor for developing BCRL is an axillary lymph node dissection (ALND). Lymphatic Microsurgical Preventative Healing Approach (LYMPHA) is a surgical procedure to reduce the risk of lymphedema in patients undergoing an ALND. We present our single institution results after offering LYMPHA in the context of an established lymphedema surveillance program.

MATERIALS AND METHODS: A retrospective review of our lymphedema surveillance program at the University of Florida was performed over a 2-year period (March 2014-March 2016). LYMPHA was offered to patients undergoing ALND beginning in March 2015. Patients who developed lymphedema were compared with those who did not. Demographics and potential risk factors for development of lymphedema such as age, body mass index, clinical stage, radiotherapy, and chemotherapy were reviewed.

RESULTS: Eighty-seven patients participated in the surveillance program over the study period with an average age of 60 y (range 32-83) and body mass index of 30 kg/m2 (range 17-46). The single most significant risk factor for the development for lymphedema was an ALND (P < 0.001). One of 67 patients undergoing a sentinel lymph node biopsy developed lymphedema (1.5%). Four of 10 patients who underwent an ALND alone developed lymphedema (40%). One of 8 patients in the ALND + LYMPHA group developed transient lymphedema (12.5%).

CONCLUSIONS: Offering LYMPHA with ALND decreased our institutional rate of lymphedema from 40% to 12.5%. Long-term follow-up and randomized control trials are necessary to further elucidate the promise of this surgical technique to reduce the incidence of BCRL.

Although surgical and medical treatment options are available for the treatment of chronic lymphedema, there is no cure. Recent advances in microsurgery have provided an opportunity to perform immediate lymphatic reconstruction after lymphadenectomy for disease prevention. In this review, we provide the historical background leading to a paradigm shift in performing this procedure. We will also discuss the current evidence for immediate lymphatic reconstruction, potential oncologic procedures amenable to this approach, and detail ongoing challenges.

BACKGROUND: Breast cancer-related lymphedema affects 700,000 breast cancer survivors in the United States. Although taxane-based chemotherapy regimens are commonly used in the treatment of breast cancer, the impact of taxanes on the lymphatic system remains poorly understood. This study aims to examine the influence of taxane-based chemotherapy on lymphatic function in breast cancer patients.

METHODS: A retrospective review of a prospectively-maintained database was performed. Consecutive patients with node positive breast cancer who underwent preoperative indocyanine green (ICG) lymphangiograms were identified. Information including patient demographics, baseline measurements, cancer characteristics, and treatment information were retrieved. Preoperative ICG lymphangiography videos were analyzed and lymphatic contractility was quantified for each subject. Multiple regions of interest were selected on each lymphatic channel and signal intensity was recorded for 3 minutes to generate contractility curves. Each lymphatic contraction was identified using a novel, systematic, and algorithmic approach.

RESULTS: Twenty-nine consecutive patients with unilateral node-positive breast cancer were included for analysis. Average patient age was 54.5 (13) years and mean BMI was 26.8 kg/m (4). The mean lymphatic contractility of patients who received taxane-based neoadjuvant chemotherapy was 0.7 contractions/minute (c/m) (n = 19) compared to 1.1 c/m in those who received no neoadjuvant therapy (n = 10), (P = 0.11). In subgroup analysis, patients who reported taxane induced neuropathy demonstrated significantly lower lymphatic contractility values than those who were asymptomatic or did not receive any chemotherapy (P = 0.018).

CONCLUSIONS: In this study, we used a novel method for quantifying and evaluating lymphatic contractility rates in routine ICG lymphangiograms. Diminished lymphatic contractility was noted in patients who received taxane-based neoadjuvant chemotherapy compared with those who did not. Taxane-based neoadjuvant chemotherapy may adversely affect the lymphatic system in the breast cancer population. A larger patient cohort with longer follow-up time is needed to validate this finding and evaluate any potential association with breast cancer-related lymphedema development.

BACKGROUND: Axillary surgery and radiotherapy are important aspects of breast cancer treatment associated with development of lymphedema. Studies demonstrate that Lymphatic Microsurgical Preventive Healing Approach (LYMPHA) may greatly reduce the incidence of lymphedema in high-risk groups. The objective of this study is to summarize the evidence relating lymphedema incidence to axillary lymph node dissection (ALND), regional lymph node radiation (RLNR) therapy, and LYMPHA.

METHODS: We performed a literature search to identify studies involving breast cancer patients undergoing ALND with or without RLNR. Our primary outcome was the development of lymphedema. We analyzed the effect of LYMPHA on lymphedema incidence. We chose the DerSimonian and Laird random-effects meta-analytic model owing to the clinical, methodological, and statistical heterogeneity of studies.

RESULTS: Our search strategy yielded 1476 articles. After screening, 19 studies were included. Data were extracted from 3035 patients, 711 of whom had lymphedema. The lymphedema rate was significantly higher when RLNR was administered with ALND compared with ALND alone (P < 0.001). The pooled cumulative incidence of lymphedema was 14.1% in patients undergoing ALND versus 2.1% in those undergoing LYMPHA and ALND (P = 0.029). The pooled cumulative incidence of lymphedema was 33.4% in those undergoing ALND and RLNR versus 10.3% in those undergoing ALND, RLNR, and LYMPHA (P = 0.004).

CONCLUSION: Axillary lymph node dissection and RLNR are important interventions to obtain regional control for many patients but were found to constitute an increased risk of development of lymphedema. Our findings support that LYMPHA, a preventive surgical technique, may reduce the risk of breast cancer-related lymphedema in high-risk patients.

BACKGROUND:  Upper extremity lymphedema occurs in 25 to 40% of patients after axillary lymph node dissection (ALND). Immediate lymphatic reconstruction (ILR) or the lymphatic micro- surgical preventative healing approach has demonstrated a significant decrease in postoperative rates of lymphedema (LE) from 4 to 12%. Our objective was to map the Mascagni -Sappey pathway, the lateral upper arm draining lymphatics, in patients undergoing ILR to better characterize the drainage pattern of this lymphosome to the axilla.

METHODS:  A retrospective review of our institutional lymphatic database was conducted and consecutive breast cancer patients undergoing ILR were identified from November 2017 through June 2018. Patient demographics, clinical characteristics, and intraoperative records were retrieved and analyzed.

RESULTS:  Twenty-nine consecutive breast cancer patients who underwent ILR after ALND were identified. Patients had a mean age of 54.6years and body mass index (BMI) of 26.6 kg/m2. Fluorescein isothiocyanate (FITC) was injected at the medial upper arm and isosulfan blue was injected at the cephalic vein, or lateral upper arm, prior to ALND. After ALND, an average 2.5 divided lymphatics were identified, and a mean 1.2 lymphatics were bypassed. In all patients, divided FITC lymphatics were identified. However, in only three patients (10%), divided blue lymphatics were identified after ALND.

CONCLUSION:  In this study, variable drainage of the lateral upper arm to the axillary bed was noted. This study is the first to provide a description of intraoperative findings, demonstrating variable drainage patterns of upper extremity lymphatics to the axilla. Moreover, we noted that the lateral- and medial-upper arm lymphosomes have mutually exclusive pathways draining to the axilla. Further study of lymphatic anatomy variability may elucidate the pathophysiology of lymphedema development and influence approaches to immediate lymphatic reconstruction.

MINI: We conducted a cost-utility analysis to evaluate the cost and quality of life of patients undergoing axillary lymph node dissection (ALND) and ALND with regional lymph node radiation (RLNR), with and without lymphatic microsurgical preventive healing approach (LYMPHA), in a node-positive breast cancer population. We found that the addition of LYMPHA to both ALND or ALND with RLNR is more cost-effective.

OBJECTIVE: This manuscript is the first to employ rigorous methodological criteria to critically appraise a surgical preventative technique for breast cancer-related lymphedema from a cost-utility standpoint.

SUMMARY OF BACKGROUND DATA: Breast cancer-related lymphedema is a well-documented complication of breast cancer survivors in the US. In this study, we conduct a cost-utility analysis to evaluate the cost-effectiveness of the LYMPHA.

METHODS: Lymphedema rates after each of the following surgical options: (1) ALND, (2) ALND + LYMPHA, (3) ALND + RLNR, (4) ALND + RLNR + LYMPHA were extracted from a recently published meta-analysis. Procedural costs were calculated using Medicare reimbursement rates. Average utility scores were obtained for each health state using a visual analog scale, then converted to quality-adjusted life years (QALYs). A decision tree was generated and incremental cost-utility ratios (ICUR) were calculated. Multiple sensitivity analyses were performed to evaluate our findings.

RESULTS: ALND with LYMPHA was more cost-effective with an ICUR of $1587.73/QALY. In the decision tree rollback analysis, a clinical effectiveness gain of 1.35 QALY justified an increased incremental cost of $2140. Similarly, the addition of LYMPHA to ALND with RLNR was more cost-effective with an ICUR of $699.84/QALY. In the decision tree rollback analysis, a clinical effectiveness gain of 2.98 QALY justified a higher incremental cost of $2085.00.

CONCLUSIONS: Our study supports that the addition of LYMPHA to both ALND or ALND with RLNR is the more cost-effective treatment option.

Recent studies have provided evidence that lymphovenous bypass-microsurgical re-routing of divided lymphatics to an adjacent vein-performed at the time of lymph node dissection decreases the rate of lymphedema development. Immediate lymphatic reconstruction in this setting is technically demanding, and there is a paucity of literature describing the details of the surgical procedure. In this report, we review the literature supporting immediate lymphatic reconstruction and provide technical details to demystify the operation for surgeons who wish to provide this option to their patients.

BACKGROUND: Breast cancer-related lymphedema affects one in five patients. Its risk is increased by axillary lymph node dissection and regional lymph node radiotherapy. The purpose of this study was to evaluate the impact of immediate lymphatic reconstruction or the lymphatic microsurgical preventative healing approach on postoperative lymphedema incidence.

METHODS: The authors performed a retrospective review of all patients referred for immediate lymphatic reconstruction at the authors' institution from September of 2016 through February of 2019. Patients with preoperative measurements and a minimum of 6 months' follow-up data were identified. Medical records were reviewed for demographics, cancer treatment data, intraoperative management, and lymphedema incidence.

RESULTS: A total of 97 women with unilateral node-positive breast cancer underwent axillary nodal surgery and attempt at immediate lymphatic reconstruction over the study period. Thirty-two patients underwent successful immediate lymphatic reconstruction with a mean patient age of 54 years and body mass index of 28 ± 6 kg/m2. The median number of lymph nodes removed was 14 and the median follow-up time was 11.4 months (range, 6.2 to 26.9 months). Eighty-eight percent of patients underwent adjuvant radiotherapy of which 93 percent received regional lymph node radiotherapy. Mean L-Dex change was 2.9 units and mean change in volumetry by circumferential measurements and perometry was -1.7 percent and 1.3 percent, respectively. At the end of the study period, we found an overall 3.1 percent rate of lymphedema.

CONCLUSION: Using multiple measurement modalities and strict follow-up guidelines, the authors' findings support that immediate lymphatic reconstruction at the time of axillary surgery is a promising, safe approach for lymphedema prevention in a high-risk patient population.

CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

BACKGROUND: The real-time quantification of lymphatic flow remains elusive. Efforts to provide a metric of direct lymphatic function are not clinically translatable and lack reproducibility. Early reports demonstrate the promise of immediate lymphatic reconstruction (immediate lymphovenous bypass after lymphadenectomy) to reduce the risk of lymphedema development. However, there remains a heightened need to appraise this technique in a clinically translatable large-animal model. The aim of the authors' experiment was to evaluate the role of molecular imaging in the quantification of real-time lymphatic flow after lymphadenectomy, and lymphadenectomy with lymphovenous bypass using novel fluorophores in a swine model.

METHODS: A lymphadenectomy or lymphadenectomy with subsequent lymphovenous bypass was performed in 10 female swine. After subdermal fluorophore injection, near-infrared molecular imaging of blood samples was used to evaluate change in lymphatic flow after lymphadenectomy versus after lymphadenectomy with lymphovenous bypass. Continuous imaging evaluating fluorescence of the superficial epigastric vein in the torso and adjacent skin was performed throughout all experiments. Findings between modalities were correlated.

RESULTS: The near-infrared dye signal in central and peripheral blood samples was often difficult to separate from background and proved challenging for reliable quantification. Venous and skin near-infrared imaging demonstrated a lymphatic clearance rate decrease of 70 percent after lymphadenectomy versus a decrease by only 30 percent after lymphadenectomy with immediate lymphovenous bypass.

CONCLUSIONS: In this article, the authors describe a noninvasive, swine, large-animal model to quantify lymphatic clearance using skin imaging. The authors' findings were consistent with results yielded from real-time imaging of the vein. The authors believe this model may have important implications for eventual direct translation to the clinical setting.

Immediate lymphatic reconstruction (ILR) is targeted at preventing breast cancer related lymphedema (BCRL) by anastomosing disrupted arm lymphatic channels to axillary vein tributaries. Inadequate vein length and venous back-bleeding are two technical reasons that lead to ILR procedures being aborted intraoperatively. Recently, our team began routinely harvesting a lower extremity vein graft (LEVG) for all ILR procedures to reduce our abort rate. We describe the surgical approach of an LEVG and evaluate the effects on aborted case rates and intraoperative time. A retrospective review of our institutional lymphatic database was conducted. Two hundred and forty-seven breast cancer patients were taken to the operating room for attempted ILR in the past 5 years. Prior to the use of an LEVG (n = 205), our abort rate was 14%. Since routinely performing an LEVG with ILR (n = 42), we have not aborted a single case. Despite an LEVG requiring one additional anastomosis to connect the vein graft to the native axillary vein tributary, this technique has not changed the intraoperative time for ILR procedures. In this technical contribution, we describe our early experience performing immediate lymphatic reconstruction utilizing a lower extremity vein graft. Implementation of this technique appears to have promising effects on aborted case rates without affecting intraoperative time, and greatly facilitates the lymphovenous anastomosis.

Immediate lymphatic reconstruction (ILR) has become increasingly utilized for the prevention of breast cancer-related lymphedema (BCRL). A growing body of evidence has demonstrated the long-term efficacy of ILR in reducing the rate of BCRL. While certain risk factors for BCRL are well-recognized, such as axillary lymph node dissection, regional lymph node radiation, and elevated body mass index, other potential risk factors such as age and taxane-based chemotherapeutics remain under discussion. Our experience with ILR has highlighted an additional potential risk factor for BCRL. Lymphatic anatomy, specifically compensatory lymphatic channels that bypass the axilla, may play a largely underrecognized role in determining which patients will develop BCRL after ILR. Foundational anatomic knowledge has primarily been based on cadaveric studies that predate the twentieth century. Modern approaches to lymphatic anatomical mapping using indocyanine green lymphography have helped to elucidate baseline lymphatic anatomy and compensatory channels, and certain variations within these channels may act as anatomic risk factors. Therefore, the purpose of this review was to highlight ways in which variations in lymphatic anatomy can inform the application and improve the accessibility of this procedure. As ILR continues to advance and evolve, anatomical mapping of the lymphatic system is valuable to both the patient and lymphatic microsurgeon and is a critical area of future study.

BACKGROUND: Up to one in three patients may go on to develop breast cancer-related lymphedema (BCRL) after treatment. Immediate lymphatic reconstruction (ILR) has been shown in early studies to reduce the risk of BCRL, but long-term outcomes are limited because of its recent introduction and institutions' differing eligibility requirements. This study evaluated the incidence of BCRL in a cohort that underwent ILR over the long term.

METHODS: A retrospective review of all patients referred for ILR at the authors' institution from September of 2016 through September of 2020 was performed. Patients with preoperative measurements, a minimum of 6 months of follow-up data, and at least one completed lymphovenous bypass were identified. Medical records were reviewed for demographics, cancer treatment data, intraoperative management, and lymphedema incidence.

RESULTS: A total of 186 patients with unilateral node-positive breast cancer underwent axillary nodal surgery and an attempt at ILR over the study period. Ninety patients underwent successful ILR and met all eligibility criteria, with a mean patient age of 54 ± 12.1 years and median body mass index of 26.6 kg/m 2 [interquartile range (IQR), 24.0 to 30.7 kg/m 2 ]. The median number of lymph nodes removed was 14 (IQR, eight to 19). Median follow-up was 17 months (range, 6 to 49 months). Eighty-seven percent of patients underwent adjuvant radiotherapy, and among them, 97% received regional lymph node irradiation. The overall rate of lymphedema was 9% at the end of the study period.

CONCLUSIONS: With the use of strict follow-up guidelines over the long term, the authors' findings support that ILR at the time of axillary lymph node dissection is an effective procedure that reduces the risk of BCRL in a high-risk patient population.

CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

PURPOSE: Axillary lymph node dissection (ALND) and regional nodal irradiation (RNI) are the primary causes of breast cancer-related lymphedema (BCRL). Immediate lymphatic reconstruction (ILR) is a novel surgical procedure that reduces the incidence of BCRL after ALND. The ILR anastomosis is placed in a location thought to be outside the standard radiation therapy fields to prevent radiation-induced fibrosis of the reconstructed vessels; however, there is excess risk of BCRL from RNI even after ILR. The purpose of this study was to understand the radiation dose distribution in relation to the ILR anastomosis.

METHODS AND MATERIALS: This prospective study included 13 patients treated with ALND/ILR from October 2020 to June 2022. A twirl clip deployed during surgery was used to identify the ILR anastomosis site during radiation treatment planning. All cases were planned using a 3D-conformal technique with opposed tangents and an obliqued supraclavicular (SCV) field.

RESULTS: RNI deliberately targeted axillary Levels 1 to 3 and the SCV nodal region in 4 patients and was limited to Level 3 and SCV nodes in 9 patients. The ILR clip was located in Level 1 in 12 patients and Level 2 in 1 patient. In patients with radiation directed at only Level 3 and SCV, the ILR clip was still within the radiation field in 5 of these patients and received a median dose of 3939 cGy (range, 2025-4961 cGy). The median dose to the ILR clip was 3939 cGy (range, 139-4961 cGy) for the entire cohort. The median dose was 4275 cGy (range, 2025-4961 cGy) when the ILR clip was within any radiation field and 233 cGy (range, 139-280 cGy) when the clip was outside all fields.

CONCLUSION: The ILR anastomosis was often directly irradiated with 3D-conformal techniques and received substantial radiation dose, even when the site was not deliberately targeted. Long-term analysis will help determine whether minimizing radiation dose to the anastomosis will decrease BCRL rates.

PURPOSE: Immediate lymphatic reconstruction (ILR) is a procedure known to reduce the risk of lymphedema in patients undergoing axillary lymph node dissection (ALND). However, patients who receive adjuvant radiotherapy are at increased risk of lymphedema. The aim of this study was to quantify the extent of radiation at the site of surgical prevention.

METHODS: We recently began deploying clips at the site of ILR to identify the site during radiation planning. A retrospective review was performed to identify breast cancer patients who underwent ILR with clip deployment and adjuvant radiation therapy from October 2020 to April 2022. Patients were excluded if they had not completed radiotherapy. The exposure and dose of radiation received by the site was determined and recorded.

RESULTS: In a cohort of 11 patients, the site fell within the radiation field in 7 patients (64%) and received a median dose of 4280 cGy. Among these 7 patients, 3 had sites located within tissue considered at risk of oncologic recurrence and the remaining 4 sites received radiation from a tangential field treating the breast or chest wall. The median dose to the ILR site for the 4 patients whose sites were outside the radiation fields was 233 cGy.

CONCLUSION: Our findings suggest that even when the site of surgical prevention was not within the targeted radiation field during treatment planning, it remains susceptible to radiation. Strategies for limiting radiation at this site are needed.

BACKGROUND: Recent advances in breast cancer have progressed toward less aggressive axillary surgery. However, axillary lymph node dissection (ALND) remains necessary in specific cases and can increase the risk of lymphedema. Performing ALND with immediate lymphatic reconstruction (ILR) can help lower this risk. This report outlines the implementation of an Axillary Surgery Referral Program (ASRP) to broaden access to ILR, providing insights for institutions considering similar initiatives.

METHODS: A retrospective study analyzed patients referred to the ASRP at Beth Israel Deaconess Medical Center (BIDMC) between 6 January 2017 and 10 December 2022. Patients were identified from a prospective registry, with data subsequently extracted from electronic medical records. This analysis specifically centered on patients referred from external institutions to undergo ALND with ILR.

RESULTS: The program received referrals for 131 patients from institutions across five different states. Annual referrals steadily increased over time. The primary indication for referral was residual axillary disease after neoadjuvant chemotherapy (41.2%). Among the referrals, 20 patients (15.3%) no longer required ALND due to axillary pathologic complete response to neoadjuvant therapy. Care coordination played a crucial role in streamlining the patient care process for both efficiency and effectiveness.

CONCLUSION: The ASRP expands access to ILR for patients with breast cancer, the majority referred for surgical management of residual disease after chemotherapy. The program provides a model for health care institutions aiming to establish similar specialized referral services. Continued program evaluation will be instrumental in refining axillary surgery referral practices and ensuring optimal patient care.

Immediate lymphatic reconstruction (ILR) is recognized as a surgical approach used to reduce the risk of developing secondary lymphedema, and evidence demonstrating the efficacy of ILR is favorable. Our Lymphatic Center has become a centralized location offering ILR for the risk-reduction in breast cancer-related lymphedema (BCRL) in New England. Over the course of our experience, we made several modifications and adapted our approach to enhance the operative success of this procedure. These include advancements in our use of indocyanine green (ICG) imaging to identify baseline lymphatic anatomical variation, utilization of fluorescein isothiocyanate for lymphatic vessel visualization, application of the lymphosome concept to guide arm injection sites, verification of anastomotic patency (using ICG), localization of reconstruction to guide radiation therapy, incorporation of intraoperative tools to facilitate better anatomic visualization of the axilla, and addition of a lower extremity vein graft to mitigate venous-related complications. Collecting information from each surgery in a standardized manner, including intraoperative lymphatic channel measurements, and deploying clips for possible future radiation exposure, enables future studies on ILR patient outcomes. In this contribution, we aimed to share our institutional modifications with the surgical community to facilitate further adoption, conversation, and advancement of ILR for the risk-reduction in BCRL.