Adenoid Cystic Carcinoma, Sinonasal Carcinoma
Conditions
Keywords
Sinonasal Adenoid Cystic Carcinoma, Radiotherapy, Adjuvant, Watchful Waiting, Observational Study, Prospective Studies, Non-Inferiority Trials, Disease-Free Survival
Brief summary
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.
Detailed description
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.
Interventions
RADIATIONPostoperative Radiotherapy
Intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) delivered to the postoperative tumor bed. High-risk clinical target volume (CTV1) receives 60-66 Gy in 30-33 fractions (1.8-2.0 Gy per fraction). Low-risk clinical target volume (CTV2) receives 54-60 Gy in 30-33 fractions. Treatment starts within 4-6 weeks after surgery. Daily image guidance is used. Organs at risk are constrained according to QUANTEC/RTOG guidelines
OTHERObservation
No postoperative radiotherapy or any other form of adjuvant radiation. Patients undergo regular follow-up according to the study protocol, including physical examination, laboratory tests, and imaging (contrast-enhanced MRI of the head and neck every 6 months for the first 3 years and annually thereafter; chest CT annually). Active surveillance is performed to detect any recurrence or metastasis
Sponsors
Eye & ENT Hospital of Fudan University
Study design
Observational model
CASE_CONTROL
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Age ≥18 years and ≤75 years. * Histologically confirmed adenoid cystic carcinoma of cribriform or tubular type (solid type excluded) by central pathology review. * Completed radical surgical resection with postoperative pathology confirming R0 resection (negative microscopic margins). * Tumor stage T1, T2, or T3 according to AJCC 8th edition, with N0 and M0 status. * Tumor originating from the nasal cavity or paranasal sinuses (excluding primary salivary gland tumors metastatic to this region). * ECOG performance status 0 or 1. * Adequate bone marrow, liver, and kidney function within 14 days before enrollment: * Absolute neutrophil count ≥1.5 × 10⁹/L, platelet count ≥100 × 10⁹/L, hemoglobin ≥90 g/L. * Total bilirubin ≤1.5 × upper limit of normal (ULN); AST and ALT ≤2.5 × ULN. * Serum creatinine ≤1.5 × ULN or calculated creatinine clearance ≥60 mL/min (Cockcroft-Gault formula). * Willing and able to provide written informed consent.
Exclusion criteria
* Tumor stage T4, or presence of regional lymph node metastasis (N+), or distant metastasis (M1). * Postoperative pathology showing positive margins (R1 or R2). * Prior head and neck radiotherapy. * Concurrent active malignancy other than adequately treated basal cell carcinoma of the skin or carcinoma in situ of the cervix. * Uncontrolled serious concomitant disease (e.g., unstable angina, recent myocardial infarction, uncontrolled hypertension). * Pregnant or breastfeeding women, or women of childbearing age not using effective contraception. * Psychological, social, or geographic factors that may interfere with study compliance.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 3-year Disease-Free Survival (DFS) | From enrollment up to 3 years post-treatment | DFS is defined as the time from enrollment to the first occurrence of any of the following events: local recurrence, regional recurrence (cervical lymph nodes), distant metastasis, or death from any cause. Patients alive and free from recurrence are censored at the last disease-free assessment. All suspected recurrences are centrally reviewed by a blinded independent central review (BICR) committee using RECIST 1.1 criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | 1, 3, and 5 years after treatment | OS is defined as the time from enrollment to death from any cause. Patients alive at the end of follow-up are censored at the last known alive date. |
| Disease-Free Survival | 1, and 5 years after treatment | DFS is defined as the time from enrollment to first occurrence of local recurrence, regional recurrence, distant metastasis, or death from any cause. Patients alive and free from recurrence are censored at the last disease-free assessment. Same definition as primary outcome but assessed at 1-year and 5-year time points. |
| Local Control Rate (LCR) | From enrollment up to 5 years | LCR is defined as the proportion of patients without local recurrence (at the primary tumor site) after treatment. Local recurrence is confirmed by imaging (contrast-enhanced MRI) and/or biopsy, centrally reviewed by blinded independent central review (BICR) using RECIST 1.1 criteria. |
| EORTC QLQ-C30 | Baseline, and at 6, 12, 24, and 36 months after treatment | QoL is assessed using the Chinese versions of the EORTC QLQ-C30 (core questionnaire). Scores are calculated according to EORTC scoring manuals. Higher scores represent better functioning or worse symptoms depending on the domain. |
| QLQ-H&N35 | Baseline, and at 6, 12, 24, and 36 months after treatment | QoL is assessed using the Chinese versions of the QLQ-H\&N35 (head and neck module). Scores are calculated according to EORTC scoring manuals. Higher scores represent better functioning or worse symptoms depending on the domain. |
| Treatment-Related Toxicity | From start of treatment up to 5 years | Toxicity is graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Acute toxicity (occurring ≤90 days from start of radiotherapy or from surgery in the observation group) and late toxicity (occurring \>90 days) are recorded separately. Specific toxicities include radiation-induced osteoradionecrosis, xerostomia, trismus, pituitary dysfunction, and second primary malignancies. |
Countries
China
Contacts
CONTACTQuan Liu, MD
CONTACTWanpeng Li, MD
Outcome results
None listed