Validation and development of a refined M1 category for nasopharyngeal carcinoma based on the version-nine of AJCC/UICC TNM staging system in the immunotherapy era: A multicenter cohort study

Objective: To evaluate the applicability of the M1 category of the version-nine of AJCC/UICC TNM staging system (TNM-9) for M1 nasopharyngeal carcinoma (M1-NPC) in immunotherapy era and propose potential refinements. Methods: M1-NPC patients who underwent palliative chemotherapy and immune checkpoint inhibitors (ICIs) between January 2019 and June 2023 across five institutions were included and re-staged according to TNM-9. Overall survival (OS) and Progression-free survival (PFS) were analyzed. A recursive partitioning analysis (RPA) model was employed to derive a new RPA-M1 category. Results: Among the 472 patients included, 219 were M1a and 253 were M1b. With a median follow-up time of 27 months, the M1a subgroup exhibited significantly higher 2-year OS (90.4 % vs. 73.7 %) and PFS (69.2 % vs. 40.6 %) than M1b subgroup (all P<0.001), which was further confirmed by multivariate analysis (MVA). Additionally, number of involved organs was found to be another independent predictor. New RPA-M1 category were then developed: RPA-M1a (<3 metastatic lesions and confined to one single organ), RPA-M1b (<3 metastatic lesions but involving multiple organs or >3 lesions and confined to one single organ), and RPA-M1c (patients with >3 metastatic lesions and involving multiple organs), with 2-year OS rates of 91.5 %, 81.4 %, and 69.8 %, respectively (P < 0.05) and PFS rates of 72.4 %, 54.3 % and 29.1 %, respectively (P < 0.005). Compared to the M1 Category in TNM-9, RPA-M1 category had a lower Akaike Information Criterion (AIC) and a higher concordance index (C-index) for OS and PFS. Conclusion: The M1 category in the TNM-9 is applicable in the immunotherapy era. The RPA-M1 category offers improve depiction of survival outcomes compared to TNM-9, allowing for more refined stratification of patient outcomes and individulized decision-tailoring.