Neoadjuvant Anlotinib and Epirubicin for T4 Sinonasal Adenoid Cystic Carcinoma

Neoadjuvant Anlotinib Combined With Epirubicin for T4 Stage Sinonasal Adenoid Cystic Carcinoma: A Prospective, Multicenter, Single-Arm, Phase II Clinical Trial

T4 stage sinonasal adenoid cystic carcinoma (SNACC) is a rare but aggressive cancer in the nasal cavity and sinuses. These tumors often invade the skull base, eye socket, or brain covering (dura), making complete surgical removal difficult and carrying a high risk of recurrence even after surgery and radiation. The goal of this study is to test whether a new combination of drugs given before surgery - anlotinib (a targeted therapy) plus epirubicin (a chemotherapy drug) - can improve outcomes for patients with T4 SNACC.

This is a prospective, multicenter, single-arm, phase II clinical trial. Eligible participants will receive 2 cycles of neoadjuvant treatment (anlotinib orally for 2 weeks on/1 week off, plus epirubicin intravenously on day 1 of each 3-week cycle). After completing neoadjuvant therapy, participants will undergo surgery to remove the tumor, followed by postoperative radiotherapy. The main question the study tries to answer is whether this approach increases the 3-year progression-free survival (PFS) rate compared to the historical rate of about 70% with standard treatment (surgery plus radiotherapy alone). Secondary questions include how many tumors shrink after neoadjuvant treatment, how many operations achieve complete removal with negative margins, major pathological response rates, overall survival, safety, quality of life, and the chance of avoiding disfiguring surgeries (such as removal of the eye or part of the skull). The study will enroll about 76 participants from 5 top medical centers in China. If positive, this study may establish a new standard of care for T4 SNACC.

Sinonasal adenoid cystic carcinoma (SNACC) is a rare cancer. T4 stage tumors often invade the skull base, orbit, or dura, making complete surgical removal difficult. Even with surgery and radiotherapy, the 3-year progression-free survival (PFS) is only about 70%, and extensive resection may cause disfigurement or loss of function.

This is a prospective, multicenter, single-arm, phase II trial. Eligible patients will receive 2 cycles of neoadjuvant therapy (anlotinib 10 mg orally on days 1-14 plus epirubicin 70 mg/m² IV on day 1, 21-day cycle). After neoadjuvant treatment, patients undergo surgery followed by postoperative radiotherapy.

The primary endpoint is 3-year PFS rate, compared with the historical rate of 70%. Secondary endpoints include objective response rate, R0 resection rate, major pathological response, overall survival, safety, quality of life, and organ preservation rate. Exploratory endpoints include biomarkers, ctDNA dynamics, and organoid drug sensitivity.

Target sample size is 76 patients from 5 Chinese centers. The study has been approved by the Institutional Review Board of Eye & ENT Hospital of Fudan University (approval number 2026069-1). Written informed consent will be obtained from all participants.

Inclusion Criteria:

• Age 18 to 75 years, any sex.
• Histopathologically confirmed sinonasal adenoid cystic carcinoma (any subtype).
• Stage T4a or T4b according to AJCC 8th edition. If lymph node metastasis is present, it must be surgically resectable. If distant metastasis is present, metastatic lesions must be stable.
• Multidisciplinary team (MDT) assessment confirms that the tumor is technically resectable but with high risk (invasion of skull base, orbit, dura, etc.).
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• Adequate bone marrow, liver, kidney, and cardiac function: absolute neutrophil count ≥1.5×10⁹/L, platelet count ≥100×10⁹/L, hemoglobin ≥90 g/L; ALT/AST ≤2.5×upper limit of normal (ULN), total bilirubin ≤1.5×ULN; creatinine ≤1.5×ULN or creatinine clearance ≥60 mL/min; left ventricular ejection fraction (LVEF) ≥50%.
• Willing to participate and able to provide written informed consent (including for clinical treatment and translational research).

Exclusion Criteria:

• Prior radiotherapy to the head and neck region.
• Prior anthracycline therapy with cumulative dose ≥300 mg/m².
• Known hypersensitivity to any component of anlotinib or epirubicin.
• Uncontrolled hypertension, severe cardiovascular disease, or active infection.
• Pregnant or breastfeeding women.
• Any medical or psychosocial condition that, in the investigator's judgment, may interfere with study compliance or conduct.