SPARE-1st: Surgery Alone vs Surgery Plus Postoperative Radiotherapy for Sinonasal Adenoid Cystic Carcinoma

Overview

Background: Sinonasal adenoid cystic carcinoma (ACC) is a rare type of cancer that starts in the nasal cavity or sinuses. Although surgery can remove the tumor, doctors often recommend radiation therapy after surgery to reduce the chance of the cancer coming back. However, radiation can cause long-term side effects such as bone damage, dry mouth, or difficulty opening the mouth. For patients whose tumor has been completely removed (called R0 resection) and who have early-stage disease (T1-T3) without spread to lymph nodes or other organs, it is not clear whether routine radiation therapy is always needed. Study Objective: This study aims to find out whether simply watching and waiting (surgery alone) is not worse than adding radiation therapy (surgery plus radiation) in terms of keeping patients free from cancer for at least 3 years. If surgery alone is shown to be as good as surgery plus radiation, some patients may be able to avoid the side effects of radiation. Study Design: This is a prospective, multicenter, real-world study. It is not a randomized trial - patients and their doctors will decide together whether to have radiation after surgery. We will follow about 200 patients from many hospitals across China. About half will receive surgery alone, and the other half will receive surgery followed by radiation therapy. All patients will be followed for at least 3 years. Hypothesis: We hypothesize that surgery alone is not inferior to surgery plus radiation therapy for 3-year disease-free survival, with a non-inferiority margin of a hazard ratio of 1.35. In other words, even if surgery alone has a slightly higher risk of cancer returning, the difference is small enough that avoiding radiation side effects may still be worthwhile. Main Outcome: The main outcome is the percentage of patients who are alive and free from cancer recurrence (local, regional, or distant) or death from any cause at 3 years after treatment. Potential Impact: If our hypothesis is confirmed, this study could change current practice. Many patients with completely resected, early-stage sinonasal ACC might safely avoid postoperative radiation and its long-term side effects, improving their quality of life without compromising cancer control.

Study Design Overview This is a prospective, multicenter, observational real-world study conducted at approximately 16 hospitals across China. Patients with completely resected (R0), T1-T3, N0M0 sinonasal adenoid cystic carcinoma (ACC) are enrolled after surgery. The study does not randomize patients; instead, treatment assignment (postoperative radiotherapy vs. observation alone) is determined by shared decision-making between the patient and the attending physician, reflecting routine clinical practice. Treatment Groups Radiotherapy group: Patients receive intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) at a dose of 60-66 Gy to the high-risk clinical target volume (CTV1) and 54-60 Gy to the low-risk CTV2, starting within 4-6 weeks after surgery. Observation group: Patients undergo regular follow-up without postoperative radiotherapy. All patients receive the same standardized follow-up schedule and supportive care. Sample Size and Power A total of 200 patients (approximately 100 per group) are planned. Based on historical data from the lead center (3-year disease-free survival \[DFS\] of 70% in the radiotherapy group vs. 62% in the observation group, corresponding to a hazard ratio \[HR\] of 1.35), with a two-sided alpha of 0.05 and power of 80%, this sample size is expected to yield approximately 80-90 DFS events over the 3-year follow-up period. Statistical Methods Primary analysis: The non-inferiority of observation versus radiotherapy for 3-year DFS will be assessed using a Cox proportional hazards model with inverse probability of treatment weighting (IPTW) based on propensity scores. The non-inferiority margin is set at HR = 1.35 (upper bound of the 95% confidence interval must be \<1.35). Propensity score model: Includes age, sex, T stage (T1/T2 vs. T3), tumor site, histologic subtype (cribriform/tubular proportion), perineural invasion, margin distance, Ki-67 index, ECOG performance status, and comorbidities. Sensitivity analyses: Multivariable Cox regression, propensity score matching (1:1, caliper 0.2), instrumental variable analysis (using center preference as the instrument), and E-value analysis will be performed. Secondary endpoints: Overall survival (1, 3, 5 years), 1-year and 5-year DFS, local control rate, distant metastasis rate, quality of life (EORTC QLQ-C30 and QLQ-H\&N35), and treatment-related toxicity (CTCAE v5.0) will be compared between groups using appropriate methods (Kaplan-Meier, log-rank test, or competing risk models). Data Collection and Follow-up Baseline data: Demographics, clinical and pathologic characteristics, surgical details. Follow-up visits: Every 4 months for the first 2 years, every 6 months for years 3-5, and annually thereafter. Each visit includes physical examination, laboratory tests, and toxicity assessment. Imaging: Contrast-enhanced MRI every 6 months for the first 3 years and annually for years 4-5 (or whenever clinically indicated). Chest CT annually. All suspected recurrences are centrally reviewed by a blinded independent central review (BICR) committee using RECIST 1.1 criteria. Quality Control and Data Monitoring An independent Data Monitoring Committee (DMC) comprising clinical experts, biostatisticians, and ethicists will review safety data (serious adverse events) every 6 months and overall data quality annually. Central pathology review confirms the diagnosis and histologic subtype for all enrolled patients. Electronic data capture (EDC) with source data verification (SDV) will be used. Ethics and Dissemination The study protocol has been approved by the Ethics Committee of the Eye \& ENT Hospital of Fudan University (approval number: 2026042-1). All participating centers will obtain local ethics approval. Written informed consent will be obtained from all patients. Results will be submitted for publication in peer-reviewed journals regardless of the outcome.