Investigating the Association Between Corticosteroid Use and Improvement in Doxorubicin Liposome-Induced Cutaneous Toxicity: Exploring the Feasibility and Mechanisms of Corticosteroids in Mitigating Liposomal Doxorubicin-Related Dermatologic Adverse Effects.
Background Liposomal doxorubicin exhibits distinct toxicity profiles compared to free-form doxorubicin in clinical practice. Cutaneous toxicity represents the primary dose-limiting adverse effect of liposomal doxorubicin, with incidence and severity demonstrating a dose-dependent relationship . Current management strategies-including dose reduction or extended treatment intervals-yield limited efficacy, often leading to treatment discontinuation due to intolerable symptoms, thereby compromising clinical utility. Mechanistic Insights Our preliminary research identified neutrophils as key mediators in liposomal skin accumulation: Complement receptor 3 (CR3) recognizes iC3b deposited on liposomes via complement activation. Neutrophils phagocytose liposomes and extravasate into cutaneous tissues, driving drug accumulation. Intervention with complement inhibitors significantly reduced liposomal doxorubicin deposition in murine skin by: Blocking complement activation Decreasing iC3b opsonization Inhibiting neutrophil-mediated uptake. Clinical Evidence A retrospective study at our center demonstrated that corticosteroid pretreatment alleviated liposomal doxorubicin-induced hand-foot syndrome (HFS) in a dose-dependent manner : High-dose corticosteroids limited Grade 1 HFS to \<10% of patients16. Findings support complement inhibition as a viable strategy for mitigating cutaneous toxicity7. Study Objectives This prospective study aims to: Correlate corticosteroid use with HFS severity reduction in liposomal doxorubicin therapy.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
182
dexamethasone 12mg d1, PO/IV;
dexamethasone 12mg QD, d1-5, PO/IV.
Liposomal doxorubicin at a dose of 35 mg/m², given via intravenous (IV) infusion every 2 weeks (q2w) or every 3 weeks (q3w).
Fudan University Shanghai Cancer Center
Shanghai, Shanghai Municipality, China
RECRUITINGNumber of participants with hand-foot syndrome (HFS) as assessed by CTCAE v5.0 in the high-dose dexamethasone group
Compared to both the no-dexamethasone group and the standard-dose dexamethasone group, the high-dose dexamethasone group demonstrated reduced incidence of hand-foot syndrome (HFS)
Time frame: 17 months
ncidence of Treatment-Emergent Adverse Events
Standardized terminology for dermatologic adverse events, typically graded per CTCAE (Common Terminology Criteria for Adverse Events) v5.0 criteria
Time frame: 17 months
Disease-free survival (DFS)
Defined as the time from randomization (or treatment initiation in single-arm trials) to disease recurrence or death from any cause.
Time frame: 17 months
Progression-free survival (PFS)
The duration from treatment initiation to tumor progression (per RECIST 1.1 ) or death.
Time frame: 17 months
Overall survival (OS)
Time from randomization to death from any cause
Time frame: 17 months
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Cyclophosphamide 600 mg/m² administered by intravenous infusion every 2 weeks (q2w) or every 3 weeks (q3w).