Outcomes of different treatment patterns for adenoid cystic carcinoma of the anterior craniofacial area: A multi-institutional study on 578 patients

Background: Adenoid cystic carcinoma of the anterior craniofacial region (ACF-ACC) is challenging to treat due to extensive subclinical spread and proximity to critical structures. Although surgery followed by radiotherapy (RT) is the current standard, real-world outcomes with modern photon and particle therapy remain insufficiently characterized. Methods: We retrospectively analyzed 578 patients with ACF-ACC treated at eight international centers (1984-2023). Clinicopathologic features, treatment patterns, and outcomes were assessed. Anatomical extension was classified using hierarchical clustering. Comparative analyses of gross total resection (GTR) and non-surgical treatment (NST) were adjusted using propensity score matching and multivariable Cox and Fine-Gray models. Primary endpoints were local recurrence-free survival (LRFS) and cumulative incidence of local recurrence (LRCI). Results: Most tumors arose in the sinonasal tract (75.8%) and were low/intermediate grade (68.6%). Long-term outcomes showed high local and distant recurrence (20-year LRCI: 74.1%; cumulative incidence of distant metastasis: 55.6%). GTR followed by adjuvant RT, especially with proton therapy (PT), achieved the best local control. R2 resections provided no advantage over NST. Within the NST cohort (n = 110), PT yielded higher complete response rates than photon RT, while responders demonstrated local control comparable to surgically treated patients. Ten-year >= G3 toxicity incidence was 36%. Conclusions: For ACF-ACC, GTR plus modern RT provides the strongest local control, and R2 surgery should be avoided. PT is an effective definitive option for selected patients, supporting future response-guided treatment strategies.