The Impact of Combined Exercise on Lymphedema, Body Composition, Muscle Strength, and Quality of Life in Breast Cancer Survivors

- Background - Arm lymphedema is a common, debilitating complication following breast cancer treatment, affecting 20-40% of breast cancer survivors. Breast cancer-related lymphedema (BCRL) is characterized by chronic limb swelling resulting from a significant complication caused by axillary lymph node removal and radiotherapy-induced fibrosis. Symptoms include limb swelling, weakness, decreased mobility, pain, and heaviness, significantly impacting quality of life, daily activities, emotional distress, and social isolation.

Exercise has emerged as a promising non-invasive intervention for BCRL management, supported by leading organizations such as the International Society of Lymphology and the American Society of Breast Surgeons. While traditionally viewed as a risk factor for exacerbating the condition, recent research has highlighted its therapeutic benefits. Strength exercise improves lymphatic function and reduces symptom severity through muscle pump and lymphatic vessel contraction. Aerobic exercise also supports lymph flow through blood circulation and respiration, which creates pressure changes in the thoracic-abdominal cavities and compresses and decompresses lymphatic vessels. Despite the isolated benefits of both types of exercise, the combined exercise (aerobic + strength) may yield additional benefits. However, the effects of combined exercise remain unexplored in BCRL patients. Strength exercise is associated with improved lymphatic function and increased muscle strength, e.g., handgrip strength - a vital health parameter. Aerobic exercise has been linked to enhancements in body composition, cardiometabolic health, inflammatory profile, increased quality of life, and reduced symptoms of anxiety and depression. Therefore, it is justified to explore the potential benefits of combined exercise for patients with BCRL. Although assessing lymphedema remains challenging in clinical practice, the lymphedema index (L-Dex), based on bioelectrical impedance spectroscopy (BIS), provides an objective method for detecting BCRL. The device measures extracellular fluid resistance using the L-Dex ratio, which compares dominant and non-dominant arm values. Although a precise method, it has never been tested in a combined exercise intervention.

From a more mechanistic standpoint, it is known that body water compartments, including total body water (TBW), extracellular water (ECW), and Intracellular water (ICW) plays a crucial role in fluid balance and cellular function. In BCRL, disruptions in this balance - particularly an elevated ECW:ICW (E:I) ratio-may reflect swelling and symptom severity. Research with a clinical population (e.g., elderly or patients with heart failure) suggests that a higher appendicular E:I ratio correlates with lower handgrip and mobility, independent of skeletal muscle mass. These findings suggest that interventions to improve the E:I ratio could enhance overall strength and health. Exercise has been previously demonstrated to improve the E:I ratio in older women and was associated with increased muscle strength. Although our research team has investigated these water compartments in athletes, no study has evaluated them via dilution techniques in BCRL patients. Given the importance of fluid dynamics in lymphedema management, examining these parameters-particularly in response to combined exercise-is crucial to advancing current clinical practice. Another vital point is that acute responses to fluid dynamics have received less attention in research, which may provide insights into the effects of exercise on BCRL and corroborate long-term alterations. Although commonly used, circumferences provide little detailed information about fluids. In contrast, ultrasound combined with plasma volume (PV) analysis has been proposed as a novel method to detect fluid shifts in trained men. Combining ultrasound to assess muscle thickness with PV measurement allows conclusions about acute muscle and vascular fluid, offering insights into the body's response to exercise. This could be valuable for understanding acute fluid mechanisms in BCRL.

In summary, despite progress in BCRL management, gaps remain in understanding the effects of combined exercise on lymphedema and body water compartments. Additionally, research on the acute impact of exercise on fluid mechanisms is needed, as these responses have been less explored in this population. The LymFit project primarily aims to assess the effects of 12 weeks of combined exercise on L-Dex in BCRL patients. Secondary objectives include evaluating exercise's effects on i) E:I ratio (dilution techniques); ii) Body composition (dual-energy X-ray absorptiometry), handgrip strength (dynamometry), cardiorespiratory fitness, quality of life, arm disability, anxiety, depression (questionnaires), and inflammatory profile (blood analysis). The project also examines acute exercise (pre- to post-session) responses on iii) Lymphedema (L-Dex) and iv) Fluid shifts (ultrasound muscle thickness + PV measurement).

• Design - This study will be a randomized controlled trial (RCT) involving a usual care group (UG) and an experimental group (EG) during 12 weeks of intervention. No exercise advice will be provided in the UC, whereas the EG will receive the CDT and three one-hour weekly exercise sessions.
• Hypothesis - A 12-week combined exercise program will: a) reduce the L-Dex in BCRL patients; b) enhance the E:I ratio, indicating improved fluid balance; and c) improve body composition, handgrip strength, cardiorespiratory fitness, quality of life, and inflammatory profile.