Lymphedema is a chronic and progressive disease of the lymphatic system characterized by inflammation, increased adipose deposition, and tissue fibrosis. Despite early hypotheses identifying lymphedema as a disease of mechanical lymphatic disruption alone, the progressive inflammatory nature underlying this condition is now well-established. In this review, we provide an overview of the various inflammatory mechanisms that characterize lymphedema development and progression. These mechanisms contribute to the acute and chronic phases of lymphedema, which manifest clinically as inflammation, fibrosis, and adiposity. Furthermore, we highlight the interplay between current therapeutic modalities and the underlying inflammatory microenvironment, as well as opportunities for future therapeutic development.

Lower-extremity lymphedema (LEL) is a progressive, lifelong complication of cancer that places a substantial burden upon cancer survivors’ quality of life (QOL) and psychosocial well-being. Despite its prevalence, cancer-related LEL is inconsistently diagnosed, treated, and poorly recognized by health care professionals. The purpose of this systematic review was to summarize and appraise the quantitative literature evaluating the impact of cancer-related LEL on patients’ psychosocial well-being and QOL. Three databases (PubMed, PROQuest, and Scopus) were searched for observational research articles published before May 1st, 2020. Twenty-one articles were eligible (cross-sectional (n = 16), prospective cohort designs (n = 3), and retrospective cohort designs (n = 2)). The majority of studies reported a negative relationship between cancer-related LEL and global QOL and/or one or more psychosocial domains including (1) physical and functional; (2) psycho-emotional; (3) social, relational and financial. A greater number of LEL symptoms and higher LEL severity were associated with poorer QOL. Although the evidence to date suggests a negative relationship between cancer-related LEL and patients’ QOL and psychosocial well-being, there is a substantial need for longitudinal analyses to examine the directionality and temporality of this effect in order to inform cancer survivorship care modelling and improve patient outcomes after cancer.

Purpose: Lower-extremity lymphedema (LEL) is a lifelong consequence of cancer therapy and can lead to serious physical and psychosocial complications for many cancer survivors. However, clinical knowledge and treatment of LEL remain minimal. The purpose of this study was to integrate perspectives of lymphedema patients and healthcare providers (HCPs) on LEL to develop a novel model for quality lymphedema care.Methods: A mixed-methods approach was implemented. Standardized questionnaires and semi-structured interviews were used to assess psychosocial well-being and experiences of LEL patients. Interviews were also used to evaluate the clinical experiences of HCPs working within tumour groups associated with cancer-related LEL. Thematic analysis was used to analyse qualitative data.Results: Twenty-two patients and eleven HCPs participated in this study. Patient QOL, generalized anxiety and depressive symptom scores revealed a complex interplay between psychosocial well-being and supportive LEL care after cancer. Three themes emerged from interviews with patients (n = 19) and HCPs (n = 11): level of lymphedema knowledge, effectiveness of rehabilitation oncology services and barriers to care.Implications for Cancer Survivors: We developed a novel model for quality lymphedema care that emphasizes the importance of continued physical and psychosocial support for LEL patients, while illustrating the importance of HCPs in facilitating a smooth transition for patients to LEL care after cancer treatment.

Lower extremity lymphedema (LEL) is a common and potentially debilitating chronic condition associated with cancer treatment. Research has outlined the substantial psychosocial and quality-of-life (QOL) sequelae associated with lymphedema, primarily of the upper extremities and through the use of quantitative methods. The purpose of this systematic review was to summarize, synthesize, and appraise qualitative literature exploring the impact of LEL on patients' QOL and psychosocial well-being after cancer treatment. Nine databases were searched for qualitative research articles published before May 1, 2022. Six eligible articles were included. Four studies used individual semistructured interviews, one used open-ended survey questions, and one used structured interviews. There was a total of 248 participants (average age: 59.8 years) included in the reviewed articles, ranging from 13 to 178 participants. Most participants were women and had a history of gynecologic cancer. All studies described psychosocial challenges experienced by individuals with cancer-related LEL. Four key themes were identified: (1) physical burden and functional limitations, (2) psychologic and emotional impacts, (3) financial implications, and (4) relational and social sequelae. Despite available qualitative data suggesting that cancer-related LEL has negative consequences on patients' QOL, there is still a significant need for increased research to broaden our understanding of the cancer-related LEL experience to better inform policy and practical guideline development.

Despite a high prevalence and extensive morbidity, there are no approved pharmacological interventions for lymphedema. Selective inhibition of leukotriene B₄ has been identified as a potential therapeutic target to address the morbidity and symptomatology associated with lymphedema. We aim to evaluate the impact of a novel, selective, orally administered leukotriene B₄ antagonist on objective and subjective measures of lymphedema severity. This is an open-label, prospective cohort study conducted in a single-site tertiary care medical institution on patients with chronic Stage II lymphedema of the lower extremity. Twelve months of daily oral acebilustat (100 mg), superimposed upon continued maintenance lymphedema self-management. Lymphedematous limb volume, skin thickness, tissue architecture, detectable extracellular fluid excess, and quality-of-life were measured throughout treatment, at 3-month intevals. Limb volume was calculated using a standard conical formula conversion of circumferential tape measurements. Skin thickness was evaluated by skinfold caliper, and skin thickness and tissue architecture were quantitatively assessed by ultrasound. As an exploratory biomarker of the tissue response to the therapeutic agent, we developed and implemented an artificial intelligence pipeline to assess qualitative changes in cutaneous ultrasound images. Bioimpedance measurements were used to evaluate detectable extracellular fluid excess, and three quality-of-life questionnaires assessed subjective well-being among participants. Outcomes were compared between visits using linear mixed-effect models. Oral selective leukotriene B₄ antagonism was associated with significant reductions in lymphedematous limb volume 1012.3 mL [95% C.I.: -1457.9 to -565.9, P < 0.0001. Skin thickness was also significantly reduced, with most prominent reductions occurring at the proximal calf and midthigh (-1.1 mm [95% C.I.: -1.8 to -0.4], P = 0.004 and -1.6 mm [95% C.I.: -2.6 to -0.7], P < 0.001, respectively). Ultrasonographic and bioimpedance analyses revealed changes that would support a favorable impact on affected tissue architecture and extracellular fluid accumulation (R₀ 13.8 [95% C.I.: 1.8 to 25.8], P = 0.03). These findings were accompanied by significant improvements in quality-of-life parameters throughout the course of treatment. Selective leukotriene B₄ antagonism is associated with improvement in overall objective and subjective measures of lymphedema. This study provides the first evidence in support of acebilustat as a novel oral therapeutic for chronic lymphedema.