Systemic Management of Adrenal Malignancies: Adrenocortical carcinoma and pheochromocytoma/paraganglioma.

Abstract

Adrenal malignancies include adrenocortical carcinoma (ACC) and pheochromocytoma/paraganglioma (PPGL), rare endocrine tumors that share an adrenal or extra-adrenal location but differ substantially in origin, hormonal activity, molecular alterations, metastatic potential, and systemic treatment. In ACC, management is guided by stage, resectability, Ki-67, hormone secretion, tumor volume, and pace of progression. Mitotane remains the central ACC-specific therapy, used according to recurrence risk after surgery and as monotherapy in selected patients with advanced, low-volume disease. When rapid tumor control is needed, etoposide, doxorubicin, cisplatin, and mitotane remains the standard first-line regimen. Immune checkpoint inhibitors and multikinase inhibitors have shown activity in some patients, but validated predictive biomarkers are lacking, and access across Europe is limited by reimbursement differences. In later lines, chemotherapy may still be appropriate, including platinum rechallenge in selected cases. PPGL care is increasingly driven by genetics, biochemistry, and functional imaging. Germline testing, biochemical phenotype, and imaging findings are essential for risk assessment and treatment choice. Cyclophosphamide, vincristine, and dacarbazine may be considered for aggressive disease, rapid growth, or high tumor burden. Targeted and radiopharmaceutical approaches have expanded options, including high-specific-activity 131I-iobenguane for MIBG-avid tumors, 177Lu-DOTATATE for somatostatin receptor-positive disease, antiangiogenic tyrosine kinase inhibitors, and HIF-2α inhibition with belzutifan in selected molecular contexts. For both ACC and PPGL, controlling steroid or catecholamine excess is crucial, because endocrine complications affect treatment tolerance and outcomes. Future progress requires robust biomarkers, rational treatment sequencing, and trials using disease-specific endpoints beyond radiographic response and integrating patient-centered endocrine, molecular, and overall clinical measures of benefit.