摘要Background:Second primary malignancies(SPMs)account for over 30%of total deaths in head and neck cancer(HNC)patients.The increasing use of radiotherapy raises concerns about the elevated risk of radiation-associated SPMs.This study aimed to investigate the age-stratified association between radiotherapy and SPM risk in survivors of non-metastatic primary HNC.Methods:Using data from the Surveillance,Epidemiology,and End Results program(2004-2015),incidence rate ratios(IRRs)and standardized incidence ratios(SIRs)were evaluated for solid and hematologic SPMs associated with radiotherapy within different age groups.Follow-up for hematologic and solid SPMs began 2 and 5 years,respectively,after the diagnosis of first primary HNC.The IRRs for SPMs were compared between radiotherapy-exposed and unexposed groups using multivariable modified Poisson regression.The SIRs were computed as the ratio of observed cancers in the cohort to expected cases derived from sex-,age-,and calendar year-matched general population incidence rates.Results:The study included 75,209 2-year survivors,with 73.2%being male and a median age of 60 years.Of these,58,063 had survived 5 years or more.Radiotherapy was associated with an increased risk of solid SPMs[IRR=1.16,95%confidence interval(CI)1.08-1.24;P<0.001].The associations varied significantly among young(aged 15-39 years),middle-aged(aged 40-64 years),and elderly(aged 65-89 years)patients.Specifically,radiotherapy was associated with an increased risk of solid SPMs in middle-aged patients(IRR=1.21,95%CI 1.11-1.32;P<0.001),and a decreased risk of hematologic SPMs in elderly patients(IRR=0.77,95%CI 0.60-0.99;P=0.045).Compared with the general population,young patients had an elevated risk of radiotherapy-associated second primary non-Hodgkin lymphoma(SIR=4.01,95%CI 1.47-8.74).Middle-aged patients showed the highest SIR for SPMs in the bones/joints(SIR=7.72,95%CI 4.32-12.73),while elderly patients had the highest SIR for second primary esophageal malignancies(SIR=3.87,95%CI 2.91-5.05).Males were more likely to develop solid SPMs compared to females.Conclusions:This study reveals an age-stratified association between radiotherapy and the risk of SPMs in HNC patients.These findings highlight the importance of considering patient age when making treatment decisions for HNC and suggest that long-term surveillance is necessary for high-risk groups.