Abstract Objective To identify the main risk factors for metachronous metastatic nasopharyngeal carcinoma (NPC) in different periods after radiotherapy and estimate the weight of various factors in the early or late metachronous metastasis (EMM/LMM) groups. Methods This retrospective registry consists of 4434 patients with newly diagnosed NPC. Cox regression analysis was used to assess the independent significance of various risk factors. The Interactive Risk Attributable Program (IRAP) was used to calculate the attributable risks (ARs) for metastatic patients during different periods. Results Among 514 metastatic patients, 346 (67.32%) patients diagnosed with metastasis within 2 years after treatment were classified into the EMM group, while other 168 patients were classified into the LMM group. The ARs of T-stage, N-stage, pre-Epstein-Barr virus (EBV) DNA, post-EBV DNA, age, sex, pre-neutrophil-to-lymphocyte ratio, pre-platelet-to-lymphocyte ratio, pre-hemoglobin (HB), and post-HB were 20.19, 67.25, 2.81, 14.28, 18.50, - 11.17%, 14.54, 9.60, 3.74% and - 9.79%, respectively, in the EMM group. In the LMM group, the corresponding ARs were 3.68, 49.11, - 18.04%, 2.19, 6.11, 0.36, 4.62, 19.77, 9.57 and 7.76%, respectively. After multivariable adjustment, the total AR for tumor-related factors was 78.19%, and that for patient-related factors was 26.07% in the EMM group. In the LMM group, the total AR of tumor-related factors was 43.85%, while the weights of patient-related factors was 39.97%. In addition, except for these identified tumor- and patient-related factors, other unevaluated factors played a more important role in patients with late metastasis, with the weight increasing by 15.77%, from 17.76% in the EMM group to 33.53% in the LMM group. Conclusion Most metachronous metastatic NPC cases occurred in the first 2 years after treatment. Early metastasis was mainly affected by tumor-related factors, which accounted for a declining percentage in the LMM group.
