Corticosteroids for Doxorubicin Liposome-Induced Hand-Foot-Skin Reactions

Official title

The Role of Corticosteroids in Hand & Foot & Skin Reactions Reduction to Doxorubicin Liposomes

Overview

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.

Detailed description

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.

Interventions

• Drug Dexamethasone (12mg d1)
  dexamethasone 12mg d1, PO/IV;
• Drug Dexamethasone (2mg QD, d1-5,)
  dexamethasone 12mg QD, d1-5, PO/IV.
• Drug Doxorubicin hydrochloride liposome injection
  Liposomal doxorubicin at a dose of 35 mg/m², given via intravenous (IV) infusion every 2 weeks (q2w) or every 3 weeks (q3w).
• Drug Cyclophosphamide
  Cyclophosphamide 600 mg/m² administered by intravenous infusion every 2 weeks (q2w) or every 3 weeks (q3w).

Primary outcome measures

• Number of participants with hand-foot syndrome (HFS) as assessed by CTCAE v5.0 in the high-dose dexamethasone group [Time frame: 17 months]

Secondary outcome measures (4)

• ncidence of Treatment-Emergent Adverse Events [Time frame: 17 months]
• Disease-free survival (DFS) [Time frame: 17 months]
• Progression-free survival (PFS) [Time frame: 17 months]
• Overall survival (OS) [Time frame: 17 months]

Eligibility criteria

Inclusion criteria

• Patients aged 18-70 years (inclusive), regardless of gender.
• Diagnosis \& Treatment Plan: Histopathologically confirmed early-stage or advanced breast cancer patients eligible for AC regimen (liposomal doxorubicin + cyclophosphamide) chemotherapy per clinical guidelines.
• ECOG Performance Status: Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1.
• Anticipated survival ≥3 months.
• Organ Function Requirements:

Hematologic: Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L ,Platelet count ≥75 × 10⁹/L Hemoglobin ≥90 g/L

Hepatic:

Non-liver metastasis: Total bilirubin (TBIL) ≤1.5 × upper limit of normal (ULN) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN Liver metastasis: TBIL ≤1.5 × ULN ,ALT and AST ≤5 × ULN

Renal:

Serum creatinine (Cr) ≤1.5 × ULN or creatinine clearance (Ccr) ≥50 mL/min

Coagulation:

International normalized ratio (INR) or prothrombin time (PT) ≤1.5 × ULN Activated partial thromboplastin time (APTT) ≤1.5 × ULN

• Contraception:

Female patients: Must use effective contraception (e.g., intrauterine device \[IUD\], oral contraceptives, or condoms) during the study and for 6 months after study completion. A negative serum pregnancy test within 7 days prior to enrollment is required, and patients must be non-lactating.

Male patients: Must agree to use contraception during the study and for 6 months after study completion.

• Informed Consent: Patients must voluntarily participate, provide signed informed consent, and comply with protocol-specified procedures (blood tests, follow-ups, etc.).

Exclusion criteria

• Received chemotherapy, radiotherapy, biologics, targeted therapy, immunotherapy, or other antitumor treatments within 4 weeks before the first study dose (or within 5 half-lives, whichever is shorter). Exceptions: The washout period may be adjusted per investigator judgment (e.g., shortened to 2 weeks for endocrine therapy to avoid prolonged patient waiting).
• Previous treatment with liposomal doxorubicin or similar formulations.
• Allergy History: Known hypersensitivity to liposomal products or doxorubicin.
• Cardiovascular Diseases:

Severe arrhythmias/conduction abnormalities (e.g., clinically significant ventricular arrhythmias, second- or third-degree AV block).

History of myocardial infarction, coronary artery bypass grafting (CABG), or heart failure (NYHA Class ≥II).

LVEF ≤50%or prolonged QTcF (>450 ms in males; >470 ms in females).

• Active Infections: Grade ≥2 （NCI CTCAE v5.0）
• Immunosuppression:

Active autoimmune diseases, immunodeficiency (e.g., HIV-positive), or congenital/acquired immune disorders.

History of organ transplantation or chronic corticosteroid use.

• HBsAg-positive with HBV-DNA ≥500 IU/mL. Exception: If HBV-DNA <500 IU/mL and chronic hepatitis is deemed stable/inactive by the investigator, enrollment is permitted.
• Other Infections: Positive for HCV antibody or syphilis-specific antibody.
• Neurological/Psychiatric Disorders: History of epilepsy, dementia, or other uncontrolled conditions.
• CNS Metastases: Symptomatic brain or leptomeningeal metastases, or uncontrolled CNS lesions. Exception: Asymptomatic brain metastases or lesions stable for ≥28 days without steroids/antitumor therapy are allowed.
• Any other condition that, per investigator assessment, may compromise patient safety or study compliance.
• Pregnant or breastfeeding women.
• Patients deemed ineligible for the study by the investigator.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Fudan University Shanghai Cancer Center — Shanghai

Identifiers

NCT: NCT07362914 · 2412310-10

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗