Patterns of response and survival in metastatic paragangliomas and pheochromocytomas: Experience from two Spanish neuroendocrine tumor centers.

Metastatic pheochromocytomas and paragangliomas (mPPGLs) are uncommon, heterogeneous neuroendocrine tumors lacking standardized systemic treatment pathways. Evidence on treatment response predictors and outcome-based stratification remains limited. We conducted a retrospective study of 49 patients with mPPGLs treated between 2010 and 2024 at two Spanish referral centers. We evaluated clinical characteristics, systemic treatment patterns, radiologic responses (per RECIST), and survival outcomes. Patients were stratified into five clinical evolution patterns based on treatment response and disease trajectory. The most common indications for initiating systemic therapy were radiologic progression (59.5%) and high tumor burden (31%). First-line treatments included somatostatin analogues (SSAs, 40.5%), radionuclide therapies (33.3%: 177Lu 9.5% and 131I-MIBG 23.8%), and chemotherapy (23.8%). Partial response rates were higher with chemotherapy, 131I-MIBG, and 177Lu compared with SSAs. Tumor burden at treatment initiation appeared to be more closely associated with radiologic response than radiologic progression. Progression-free survival (PFS) appeared to differ according to first-line treatment type, with longer PFS observed in patients receiving radionuclide therapies. The median overall survival from systemic treatment initiation was 48 months. Five clinical evolution patterns were identified, highlighting disease heterogeneity. Radiologic progression remains the main trigger for systemic treatment in mPPGLs; however, initial tumor burden appears to be a stronger predictor of treatment response. Our proposed five-pattern clinical classification may contribute to prognostication and therapeutic individualization. Prospective studies are a key unmet need to determine the optimal timing and sequencing of systemic therapies in mPPGL.