Advances in the prevention and treatment of breast cancer-related lymphedema.

PURPOSE: Breast cancer-related lymphedema (BCRL) represents a lifelong risk for breast cancer survivors and once acquired becomes a lifelong burden. This review summarizes current BCRL prevention and treatment strategies. FINDINGS: Risk factors for BCRL have been extensively studied and their identification has affected breast cancer treatment practice, with sentinel lymph node removal now standard of care for patients with early stage breast cancer without sentinel lymph node metastases. Early surveillance and timely management aim to reduce BCRL incidence and progression, and are further facilitated by patient education, which many breast cancer survivors report not having adequately received. Surgical approaches to BCRL prevention include axillary reverse mapping, lymphatic microsurgical preventative healing (LYMPHA) and Simplified LYMPHA (SLYMPHA). Complete decongestive therapy (CDT) remains the standard of care for patients with BCRL. Among CDT components, facilitating manual lymphatic drainage (MLD) using indocyanine green fluorescence lymphography has been proposed. Intermittent pneumatic compression, nonpneumatic active compression devices, and low-level laser therapy appear promising in lymphedema management. Reconstructive microsurgical techniques such as lymphovenous anastomosis and vascular lymph node transfer are growing surgical considerations for patients as well as liposuction-based procedures for addressing fatty fibrosis formation from chronic lymphedema. Long-term self-management adherence remains problematic, and lack of diagnosis and measurement consensus precludes a comparison of outcomes. Currently, no pharmacological approaches have proven successful. CONCLUSION: Progress in prevention and treatment of BCRL continues, requiring advances in early diagnosis, patient education, expert consensus and novel treatments designed for lymphatic rehabilitation following insults.

Physical Therapy in Women with Early Stage Lipedema: Potential Impact of Multimodal Manual Therapy, Compression, Exercise, and Education Interventions.

Background: Lipedema is a distinct adipose disorder from obesity necessitating awareness as well as different management approaches to address pain and optimize quality of life (QoL). The purpose of this proof-of-principle study is to evaluate the therapeutic potential of physical therapy interventions in women with lipedema. Methods and Results: Participants with Stage 1-2 lipedema and early Stage 0-1 lymphedema (n = 5, age = 38.4 ± 13.4 years, body mass index = 27.2 ± 4.3 kg/m2) underwent nine visits of physical therapy in 6 weeks for management of symptoms impacting functional mobility and QoL. Pre- and post-therapy, participants were scanned with 3 Tesla sodium and water magnetic resonance imaging (MRI), underwent biophysical measurements, and completed questionnaires measuring function and QoL (patient-specific functional scale, PSFS, and RAND-36). Pain was measured at each visit using the 0-10 visual analog scale (VAS). Treatment effect was calculated for all study variables. The primary symptomatology measures of pain and function revealed clinically significant post-treatment improvements and large treatment effects (Cohen's d for pain VAS = -2.5 and PSFS = 4.4). The primary sodium MRI measures, leg skin sodium, and subcutaneous adipose tissue (SAT) sodium, reduced following treatment and revealed large treatment effects (Cohen's d for skin sodium = -1.2 and SAT sodium = -0.9). Conclusions: This proof-of-principle study provides support that persons with lipedema can benefit from physical therapy to manage characteristic symptoms of leg pain and improve QoL. Objective MRI measurement of reduced tissue sodium in the skin and SAT regions indicates reduced inflammation in the treated limbs. Further research is warranted to optimize the conservative therapy approach in lipedema, a condition for which curative and disease-modifying treatments are unavailable.

CEST MRI quantification procedures for breast cancer treatment-related lymphedema therapy evaluation.

PURPOSE: To quantify chemical exchange saturation transfer contrast in upper extremities of participants with lymphedema before and after standardized lymphatic mobilization therapy using correction procedures for B0 and B1 heterogeneity, and T1 relaxation. METHODS: Females with (n = 12) and without (n = 17) breast cancer treatment-related lymphedema (BCRL) matched for age and body mass index were scanned at 3.0T MRI. B1 efficiency and T1 were calculated in series with chemical exchange saturation transfer in bilateral axilla (B1 amplitude = 2µT, Δω = ±5.5 ppm, slices = 9, spatial resolution = 1.8 × 1.47 × 5.5 mm3 ). B1 dispersion measurements (B1 = 1-3 µT; increment = 0.5 µT) were performed in controls (n = 6 arms in 3 subjects). BCRL participants were scanned pre- and post-manual lymphatic drainage (MLD) therapy. Chemical exchange saturation transfer amide proton transfer (APT) and nuclear Overhauser effect (NOE) metrics corrected for B1 efficiency were calculated, including proton transfer ratio (PTR'), magnetization transfer ratio asymmetry (MTRasymmetry') , and apparent exchange-dependent relaxation (AREX'). Nonparametric tests were used to evaluate relationships between metrics in BCRL participants pre- versus post-MLD (two-sided P < 0.05 required for significance). RESULTS: B1 dispersion experiments showed nonlinear dependence of Z-values on B1 efficiency in the upper extremities; PTR' showed < 1% mean fractional difference between subject-specific and group-level correction procedures. PTR'APT significantly correlated with T1 (Spearman's rho = 0.57, P < 0.001) and body mass index (Spearman's rho = -0.37, P = 0.029) in controls and with lymphedema stage (Spearman's rho = 0.48, P = 0.017) in BCRL participants. Following MLD therapy, PTR'APT significantly increased in the affected arm of BCRL participants (pre- vs. post-MLD: 0.41 ± 0.05 vs. 0.43 ± 0.03, P = 0.02), consistent with treatment effects from mobilized lymphatic fluid. CONCLUSION: Chemical exchange saturation transfer metrics, following appropriate correction procedures, respond to lymphatic mobilization therapies and may have potential for evaluating treatments in participants with secondary lymphedema.

Bilateral Changes in Deep Tissue Environment After Manual Lymphatic Drainage in Patients with Breast Cancer Treatment-Related Lymphedema.

BACKGROUND: Breast cancer treatment-related lymphedema (BCRL) arises from a mechanical insufficiency following cancer therapies. Early BCRL detection and personalized intervention require an improved understanding of the physiological processes that initiate lymphatic impairment. Here, internal magnetic resonance imaging (MRI) measures of the tissue microenvironment were paired with clinical measures of tissue structure to test fundamental hypotheses regarding structural tissue and muscle changes after the commonly used therapeutic intervention of manual lymphatic drainage (MLD). METHODS AND RESULTS: Measurements to identify lymphatic dysfunction in healthy volunteers (n = 29) and patients with BCRL (n = 16) consisted of (1) limb volume, tissue dielectric constant, and bioelectrical impedance (i.e., non-MRI measures); (2) qualitative 3 Tesla diffusion-weighted, T1-weighted and T2-weighted MRI; and (3) quantitative multi-echo T2 MRI of the axilla. Measurements were repeated in patients immediately following MLD. Normative control and BCRL T2 values were quantified and a signed Wilcoxon Rank-Sum test was applied (significance: two-sided p < 0.05). Non-MRI measures yielded significant capacity for discriminating between arms with versus without clinical signs of BCRL, yet yielded no change in response to MLD. Alternatively, a significant increase in deep tissue T2 on the involved (pre T2 = 0.0371 ± 0.003 seconds; post T2 = 0.0389 ± 0.003; p = 0.029) and contralateral (pre T2 = 0.0365 ± 0.002; post T2 = 0.0395 ± 0.002; p < 0.01) arms was observed. Trends for larger T2 increases on the involved side after MLD in patients with stage 2 BCRL relative to earlier stages 0 and 1 BCRL were observed, consistent with tissue composition changes in later stages of BCRL manifesting as breakdown of fibrotic tissue after MLD in the involved arm. Contrast consistent with relocation of fluid to the contralateral quadrant was observed in all stages. CONCLUSION: Quantitative deep tissue T2 MRI values yielded significant changes following MLD treatment, whereas non-MRI measurements did not vary. These findings highlight that internal imaging measures of tissue composition may be useful for evaluating how current and emerging therapies impact tissue function.

Lymphedema evaluation using noninvasive 3T MR lymphangiography.

PURPOSE: To exploit the long 3.0T relaxation times and low flow velocity of lymphatic fluid to develop a noninvasive 3.0T lymphangiography sequence and evaluate its relevance in patients with lymphedema. MATERIALS AND METHODS: A 3.0T turbo-spin-echo (TSE) pulse train with long echo time (TEeffective = 600 msec; shot-duration = 13.2 msec) and TSE-factor (TSE-factor = 90) was developed and signal evolution simulated. The method was evaluated in healthy adults (n = 11) and patients with unilateral breast cancer treatment-related lymphedema (BCRL; n = 25), with a subgroup (n = 5) of BCRL participants scanned before and after manual lymphatic drainage (MLD) therapy. Maximal lymphatic vessel cross-sectional area, signal-to-noise-ratio (SNR), and results from a five-point categorical scoring system were recorded. Nonparametric tests were applied to evaluate study parameter differences between controls and patients, as well as between affected and contralateral sides in patients (significance criteria: two-sided P < 0.05). RESULTS: Patient volunteers demonstrated larger lymphatic cross-sectional areas in the affected (arm = 12.9 ± 6.3 mm2 ; torso = 17.2 ± 15.6 mm2 ) vs. contralateral (arm = 9.4 ± 3.9 mm2 ; torso = 9.1 ± 4.6 mm2 ) side; this difference was significant both for the arm (P = 0.014) and torso (P = 0.025). Affected (arm: P = 0.010; torso: P = 0.016) but not contralateral (arm: P = 0.42; torso: P = 0.71) vessel areas were significantly elevated compared with control values. Lymphatic cross-sectional areas reduced following MLD on the affected side (pre-MLD: arm = 8.8 ± 1.8 mm2 ; torso = 31.4 ± 26.0 mm2 ; post-MLD: arm = 6.6 ± 1.8 mm2 ; torso = 23.1 ± 24.3 mm2 ). This change was significant in the torso (P = 0.036). The categorical scoring was found to be less specific for detecting lateralizing disease compared to lymphatic-vessel areas. CONCLUSION: A 3.0T lymphangiography sequence is proposed, which allows for upper extremity lymph stasis to be detected in ∼10 minutes without exogenous contrast agents. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2017;46:1349-1360.