This randomized controlled trial compares 6 versus 3 cycles of neoadjuvant chemotherapy in patients with potentially resectable locally advanced thymic epithelial tumors (TETs, WHO type AB/B/C, AJCC TNM stage IIIA-IVA). Patients are randomized 1:1 to receive either 6 or 3 cycles of chemotherapy (cisplatin + doxorubicin + cyclophosphamide for type B; nab-paclitaxel + carboplatin for type C thymoma/thymic carcinoma) every 3 weeks, followed by surgical resection when feasible. The primary endpoint is event-free survival (EFS). The study aims to determine whether extended neoadjuvant chemotherapy improves surgical outcomes and long-term survival in this rare malignancy.

Thymic epithelial tumors (TETs) are rare mediastinal malignancies. Locally advanced, potentially resectable TETs present a significant clinical challenge, with limited prospective data on optimal neoadjuvant chemotherapy duration. Retrospective data from Shanghai General Hospital suggest that 6 cycles of neoadjuvant chemotherapy may yield higher objective response rates (75% vs 33.3%) and R0 resection rates (68.75% vs 33.33%) compared to 3 cycles.

This is a single-center, prospective, open-label, randomized controlled trial. Eligible patients are adults (18-65 years) with histologically confirmed WHO type AB, B1, B2, B3 thymoma or thymic carcinoma (type C), AJCC TNM stage IIIA-IVA, deemed potentially resectable by multidisciplinary team (MDT) evaluation, ECOG PS 0-1, with adequate organ function, no prior anti-tumor therapy.

Randomization: 1:1, stratified by histological subtype (type B vs type C), using central randomization with block size 4.

Treatment:

• Type B thymoma arm: cisplatin 50 mg/m² + doxorubicin 50 mg/m² + cyclophosphamide 500 mg/m², Q3W
• Type C thymic carcinoma arm: nab-paclitaxel 200 mg/m² + carboplatin AUC 5, Q3W
• Control group: 3 cycles; Experimental group: 6 cycles

Imaging assessment (RECIST 1.1) every 2 cycles. CR/PR: proceed to surgery; SD: continue chemotherapy; PD: radical radiotherapy.

Post-operative radiotherapy as indicated (R0: 45-50 Gy; R1: 54 Gy; R2: 60-70 Gy).

Primary endpoint: Event-Free Survival (EFS), defined as time from randomization to first occurrence of tumor recurrence, progression, or death.

Sample size: 116 patients (58 per arm), based on ORR comparison (25% vs 50%, α=0.05, power=0.80, 5% dropout/year).

Follow-up: 3 years post-enrollment (total study duration 6 years).

Inclusion Criteria:

• Histologically or cytologically confirmed thymic epithelial tumor (thymoma or thymic carcinoma)
• Locally advanced, potentially resectable disease (Masaoka-Koga stage III or IVA), as evaluated by a multidisciplinary team (MDT) including thoracic surgery and thoracic oncology
• Age 18 to 65 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Adequate bone marrow function: absolute neutrophil count (ANC) ≥1.5×10⁹/L, platelet count ≥100×10⁹/L, hemoglobin ≥90 g/L
• Adequate liver function: total bilirubin ≤1.5× upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN
• Adequate renal function: creatinine clearance ≥50 mL/min (Cockcroft-Gault formula)
• No prior systemic anticancer therapy for thymic epithelial tumor
• At least one measurable lesion per RECIST v1.1
• Willing to accept randomization and able to comply with study procedures
• Written informed consent obtained prior to any study-related procedures

Exclusion Criteria:

• Prior chemotherapy, targeted therapy, or immunotherapy for thymic epithelial tumor
• Prior thoracic radiation therapy
• Active autoimmune disease requiring systemic treatment within the past 2 years
• Known hypersensitivity or contraindication to study drugs (cisplatin, epirubicin, etoposide, ifosfamide, or any component of these formulations)
• Severe cardiac dysfunction: New York Heart Association (NYHA) class III or IV heart failure, or left ventricular ejection fraction (LVEF) <50%
• Active hepatitis B (HBsAg positive with HBV DNA ≥2000 IU/mL), active hepatitis C, or known HIV infection
• Pregnancy or lactation; women of childbearing potential unwilling to use adequate contraception
• Other malignancy within 5 years prior to enrollment, except for adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix
• Uncontrolled active infection requiring systemic therapy
• Any condition that, in the investigator's judgment, would preclude safe participation in the study

Individual participant data will not be shared at this time due to patient privacy concerns and regulatory requirements. Aggregate data will be published in peer-reviewed journals.