Metastatic Status Modifies the Survival Association of Neoadjuvant Radiotherapy in Malignant Peripheral Nerve Sheath Tumors: A Nationwide Analysis

PURPOSE: Malignant peripheral nerve sheath tumors (MPNSTs) are rare, aggressive sarcomas with poor overall survival (OS). Radiotherapy timing is extrapolated from other soft-tissue sarcomas, and no prior MPNST-specific analysis has formally tested whether neoadjuvant radiotherapy (NRT) effects are modified by metastatic status. We evaluated NRT's association with R0 resection and OS by metastatic status. METHODS: Retrospective cohort of MPNST patients in the National Cancer Database (2005-2023). Multivariable logistic regression evaluated NRT and R0 resection. Cox proportional hazards models tested an NRT-by-metastatic status interaction, with hospital-level frailty terms addressing inter-facility correlation. Propensity score matching (1:1) reduced confounding. Sensitivity analyses addressed guarantee-time bias and confounding. Causal mediation evaluated R0 as a mediator of the NRT-survival relationship. RESULTS: Of 2241 patients, 24.2% received NRT. NRT increased the odds of R0 resection (OR 2.17, 95% CI 1.60-2.98; p < 0.001) but was not associated with improved survival overall. The NRT-survival association was modified by metastatic status (interaction p < 0.001): metastatic patients receiving NRT had better survival (matched HR 0.41, 95% CI 0.23-0.72; p = 0.004), whereas no survival benefit was seen in localized disease (worse in some analyses). This signal was consistent across guarantee-time sensitivity analyses but was not mediated by margins. CONCLUSION: NRT improves the odds of R0 resection in MPNST, but improved margins do not yield a uniform survival benefit. The NRT-survival association is modified by metastatic status; the metastatic signal, though robust to guarantee-time bias, was not mediated by margins and rests on a small subgroup. These findings are hypothesis-generating and warrant a prospective study.