This systematic scoping review aimed to evaluate the efficacy of systemically absorbed pharmacotherapy agents and herbal supplements in preventing or treating BCRL among adult patients ≥ 18 years old at the time of diagnosis with stage I-III BC who either developed BCRL or were at risk for BCRL following BC treatment. Eligible comparators included placebo, standard of care (e.g., compression therapy, CDT), alternative pharmacologic agents, or no treatment. In studies without an explicit comparator arm, pre-post changes were evaluated descriptively in alignment with scoping review methodology. Primary outcomes, as elaborated below, included incidence of BCRL for prevention studies or change in BCRL severity in response to treatment. This study was conducted according to the JBI Manual for Evidence Synthesis (17) and adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (18). The review protocol is registered with PROSPERO, registration ID CRD420251055134 (19).

PubMED, Embase (Elsevier), Web of Science Core Collection (Clarivate), the Cumulative Index to Nursing and Allied Health Literature (CINAHL, EBSCO) were searched for studies that investigated the effects of anti-inflammatories, anti-thrombotic agents, anti-coagulants, and blood product components on BCRL severity (Supplementary Table S2). Surgical, device-based, and rehabilitative interventions were outside the prespecified scope of this review. A medical librarian (KD) and two reviewers (SPM, DQ) designed the search strategy, which queried Medical Subject Heading (MeSH) and entry terms for non-steroidal anti-inflammatory agents (NSAIDs) (aspirin, ketoprofen, ibuprofen), anti-coagulants (apixaban, rivaraxaban, edoxaban, fondaparinux, heparin, dalteparin, enoxaparin, argatroban, bivalirudin, dabigatran, desirudin, warfarin), cyclosporine, hydroxychloroquine, tacrolimus, sirolimus, leukotriene antagonists, platelet-rich plasma, immunosuppressive agents, herbs/medicinal plants, and dietary supplements. The search was carried out on May 24^th, 2025. In addition to results generated from the final search strategy, a post hoc hand search was performed to identify relevant studies not captured by indexing or database coverage. This approach was intended to identify emerging therapies and novel pharmacological agents that may have been recently published or not indexed. The complete list of generic and brand-name agents is provided in Supplementary Table S1.

Peer-reviewed studies published in English between 1993 and 2025 that reported the primary outcomes of interest, incidence or change in severity of BCRL, were included. Eligibility criteria for study inclusion were if the studies (1) focused on adult patients diagnosed with stage I-III BC; (2) used systemically absorbed pharmacologic agents to prevent or treat BCRL; (3) used either quantitative or qualitative measures to understand change in severity; (4) used quantitative measures of limb volume, arm circumference, bioimpedance score (BIS), and clinical staging. Studies that considered topical agents or preclinical investigations were excluded. Data pertaining to quality-of-life (QoL), though not considered a primary outcome of interest, was collected and is available in the Supplementary Material. Qualitative assessments included patient-reported outcomes addressing arm heaviness, hardness, perceived disability, tightness/tension, and pain. Systematic reviews, protocols for ongoing clinical trials, preclinical and non-human studies, editorials, conference abstracts, and studies not exclusive to patients with BCRL were excluded. Although surgical, device-based, topical, and rehabilitative programming interventions were excluded a priori, studies were included if these interventions were delivered concomitantly with a pharmacologic or herbal agent and the latter was the exposure of interest.

Three reviewers (LJS, CL, CA) independently screened and reviewed articles and abstracted data related to primary and secondary outcomes. Articles were screened using Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia) (20). Two reviewers (CL and SPM) created a data abstraction form. Duplicate records, titles, and abstracts were removed. An additional reviewer (DQ) resolved disagreements or discrepancies.

Given the substantial heterogeneity across included studies, a meta-analysis was not feasible. Instead, we conducted a structured narrative synthesis following JBI and PRISMA-ScR guidance (17, 18). Study quality and risk of bias were assessed using the National Heart, Lung, and Blood Institute Quality Assessment Tools (21), selected by study type. While no formal weighting was applied, the risk of bias assessments informed interpretation of findings.

The search resulted in 217 unique records (Figure 1). Of these, 180 were excluded due to irrelevant content in the title and abstract. Thirty-seven articles were included in the full-text review. A total of 24 studies, the majority of which were randomized controlled trials (n = 13) were included (Tables 1A, B). Twenty-one studies focused on pharmacotherapy for BCRL treatment (1B), whereas 3 evaluated agents in a preventative context (1A). To characterize treatment response, studies used several different methods to quantify changes in BCRL severity. Studies described four primary approaches to quantify improvements in BCRL severity: 1) serial circumferential measurements to estimate limb volume indirectly (25, 28–30, 32, 34, 38–40), 2) displaced water volume techniques to measure changes in limb volume (22, 26, 27, 33, 35, 36, 41), and 3) bioelectrical impedance analysis to estimate limb fluid distribution and body composition (23, 31, 42) 4) perometry utilizing infrared light to create a three-dimensional image of the affected limb (24, 37). Definitions and staging of BCRL were not standardized across the 24 studies. Several studies adhered to International Society of Lymphology (ISL) guidelines (23, 25, 31, 33, 34, 37, 40) while others applied internal diagnostic criteria or relied on absolute limb circumference differences without established validation (22, 24, 26–30, 32, 35, 36, 38, 39, 41, 42). Duration of therapies tested ranged from two weeks to 12 months. Co-interventions, which were inconsistently reported, included calorie restriction and CDT or components of CDT- compression garments, manual lymphatic drainage, or other exercise-based interventions. Only three studies conducted follow-up assessments after treatment cessation (25, 31, 37). The heterogeneity of the studies in pharmacologic and herbal agents as well as outcome measures limited this review to conduct further meta-analysis. Risk of bias assessment highlighted other challenges to data synthesis and interpretation including clearly defined study population, research objectives, and interventions (Figures 2A–C). Overall, randomized controlled trials were generally of moderate quality (2A); prospective cohorts were largely at low risk of bias (2B); and retrospective cohorts demonstrated variable but overall low-to-moderate quality (2C).

Two studies examined anti-diabetic medications (22, 23). GLP-1 receptor agonists (GLP-1 RAs) may reduce BCRL risk by improving insulin sensitivity, decreasing pro-inflammatory signaling, and preserving lymphatic vessel integrity. Brown et al. (23) reported that patients (n = 36) receiving GLP-1 RAs after axillary lymph node dissection had significantly lower odds of developing BCRL at a median 75-month follow-up (OR 0.16, 95% CI 0.05–0.40; p < 0.0001), with minor adverse events reported (nausea, diarrhea, vomiting, and constipation). The usage international classification of disease codes was used to assess those who developed lymphedema. Conversely, risk for developing BCRL in patients taking thiazolidinediones, which can cause fluid retention, were evaluated in a retrospective cohort of 162 post-surgical survivors (22). After adjustment for confounders, thiazolidinediones were not associated with increased BCRL risk, assessed via circumferential measurement.

Four studies evaluated herbal agents (26, 27, 31, 41). In their randomized controlled trial (RCT), Han et al. (31) found that five sessions of intravenous sodium selenite infusion over two weeks compared to regular saline infusion, assessed by BIS, was associated with clinical improvement from stage III to stage II BCRL (10/12 (83%) selenium vs 1/11 (9%) placebo, p = 0.002) at one month post-intervention. Two publications assessed the herbal formulation of Paeoniae rubra (moutan cortex) and Astragulus, which has been shown to promote lymphatic flow and reduce interstitial fluid accumulation (26, 27). Both studies utilized water displacement for limb volume and tape measurement for limb circumference. One of these studies represented an expanded prospective cohort building on the other, and neither reported statistically significant improvement in arm volume, measured via water displacement, after 6 months of supplementation (p > 0.05–2020 study; p = 0.068 in 2024). Belcaro et al. (41) conducted a non-randomized registry study comparing arm volume in 32 patients who received Robuvit, a natural French oak wood extract proposed to reduce inflammation, as an adjunct to CDT with 33 patients who received CDT alone. After two months, mean volume reduction was greater in the Robuvit^® plus CDT group (-654 ± 21 mL) (p < 0.05) than in the CDT-only group (-433 ± 23 mL).

Two retrospective cohort studies considered anti-inflammatory and steroidal agents (22, 24). In their retrospective cohort of 162 post-surgical BC survivors, Borg et al. (22) did not observe a significant association between NSAIDs (prescribed to 6 patients) or corticosteroids (prescribed to 8 patients) and BCRL development. Similarly, no significant associations were noted in the retrospective case-control study performed by Meijer et al. (24) between NSAIDs (p = 0.971), corticosteroids (p = 0.999) or aspirin (p = 0.449) and BCRL development. Limb volume was measured via perometry and utilized relative volume change formula.

Two previously mentioned studies also included anti-hypertensives (22, 24), which have been postulated to lead to fluid retention and peripheral edema given increased capillary hydrostatic pressure.

In the Borg et al. (22) study, calcium channel blockers, minoxidil, methyldopa, hydralazine, clonidine, and beta blockers, were prescribed to 49 patients, of whom 35 subsequently developed BCRL. On multivariable analysis, none of these agents were significantly associated with increased risk for BCRL. Meijer et al. (24) also investigated the effect of calcium channel blockers (amlodipine, nifedipine, felodipine, diltiazem) and similarly observed no significant association between these agents and BCRL.

Eight studies explored flavonoid-derived venoactive compounds, including diosmin and coumarin (25, 28–30, 32–34, 42). Results were inconsistent. In their crossover RCT, Loprinzi et al. (32) found no significant difference in arm volume between placebo and 6 months of oral coumarin. They utilized tape measurements and calculated volume using the formula for the volume of a cylinder. No difference in arm volume, measured via the opto-electricon device (Volumeter^®), was noted in the Burgos et al. (33) multi-center RCT comparing two doses of Lysedem (coumarin and troxerutin). Pecking et al. (29) conducted an RCT of Daflon (diosmin and hesperidin) versus placebo with no observed difference in limb volume via perometry. Cluzan et al. (30) evaluated two different doses of BN165 (coumarin, proanthocyanidins and flavones) to placebo in an RCT; after two months, there was no statistically significant difference in arm swelling, as assessed by perometer.

In contrast, several studies did find benefit. Smith et al. (34) conducted a 12-month crossover RCT of coumarin versus placebo in patients with stage II BCRL and noted that limb volume decreased from 46% to 26% above the unaffected limb (p < 0.001). Limb volume was measured by water-displacement. In their RCT, Cacchio et al. (25) compared Linfadren (diosmin, coumarin, arbutin) combined with CDT with CDT alone in 48 patients. After six weeks of treatment, measured by tape measure using the truncated cone method, mean edema volume decreased by 521 mL (from 581.8 to 460.1 mL) in patients receiving Linfadren plus CDT, compared to a 265 mL reduction (from 330.1 to 199.8 mL) with CDT alone (p <.0001). Three months post-treatment, mean limb volume in both groups remained stable, and no adverse events were reported. Cluzan et al. (28) found that after 3 months of treatment with Cyclo-3-Fort (ruscus aculeatus, hesperidin methyl chalcone, and ascorbic acid), there was a 12.9% decrease in upper limb volume compared to a 2.6% increase in the placebo group (p = 0.009). Limb volume was determined using the truncated cone method. Pereira de Godoy et al. (42) prospectively evaluated Daflon in patients with mild BCRL for one month. BIS analysis showed improvement in limb fluid content (p < 0.04).

Three studies investigated agents that could increase circulating VEGF in the prevention (1) (40) or treatment (2) (38, 39) of BCRL. Rannikko et al. (40) evaluated Lymfactin^®, a VEGF-C gene therapy designed to promote lymphangiogenesis and restore lymphatic flow, in patients undergoing vascularized lymph node transfer. After 12 months, excess arm volume decreased by a median of 30.0% (136 ± 189 mL) in the treatment group compared with 23% (164 ± 133 mL) in the placebo group (p > 0.05). Arm volume was measured by tape measure using the truncated cone method. A phase I trial by Leppäpuska et al. (39) treated patients with two doses of Lymfactin^® and found that the higher-dose group demonstrated an average 46% reduction in excess arm volume at 12 months. This study also measured arm volume by tape measure using the truncated cone method. A retrospective cohort from Brown et al. (38) assessed the impact of 6 weeks of oral doxycycline, which inhibits VEGF-C signaling, but no changes in disease stage were observed, and differences in limb volume, via truncated cone method and BIS, at 17-week follow-up were not statistically significant.

One study explored immune modulation through cytokine blockade. Mehrara et al. (37) administered QBX258, a monoclonal IL-4/IL-13 neutralizing antibody, to nine patients with stage I–II BCRL for four months with 16–20 weeks of follow-up. Volume differences assessed using Perometry showed clinical improvements, although detailed quantitative outcomes were limited.

Two studies investigated synbiotic supplements, which combine prebiotics and probiotics and are hypothesized to improve intestinal homeostasis and attenuate systemic inflammation by downregulating pro-inflammatory cytokines (35, 36). Navaei et al. (35) performed a trial of patients with stage I–II BCRL randomized to receiving Lactocare plus a low-calorie diet or a low-calorie diet alone for 10 weeks. Excess limb volume, measured using water displacement, showed no significant difference between the groups, and no additional co-interventions were included. A subsequent trial by Vafa et al. (36) evaluated a similar synbiotic formulation. This trial enrolled 121 patients with stage I–II BCRL randomized to a synbiotic plus calorie restriction, placebo plus calorie restriction, or placebo alone. CDT was permitted as a co-intervention. After 10 weeks, edema volume, measured via water displacement, decreased significantly in the calorie-restricted synbiotic group compared to placebo (p = 0.002); however, the difference between the calorie-restricted synbiotic and calorie-restricted placebo groups was not significant. The observed reduction in edema volume was attributed primarily to calorie restriction rather than synbiotic supplementation.