Metastatic or unresectable pheochromocytomas and paragangliomas (PPGLs) remain rare but clinically challenging neuroendocrine neoplasms with limited curative options. Traditionally managed with surgery, radionuclide therapy, or cytotoxic chemotherapy, systemic treatments have historically achieved disease stabilization, rather than durable remissions. In recent years, however, the therapeutic landscape has evolved substantially. Radiopharmaceuticals such as131I-MIBG and177Lu-DOTATATE continue to play a pivotal role, achieving disease control in many patients. Cytotoxic regimens, particularly temozolomide, remain relevant, with some studies suggesting that SDHB-mutated PPGLs demonstrate a heightened sensitivity associated with MGMT promoter hypermethylation and reduced MGMT expression. Targeted agents are increasingly important: multi-kinase inhibitors such as sunitinib, anlotinib, and cabozantinib have shown meaningful activity. The landmark approval of belzutifan, a HIF-2α inhibitor, in 2025 represents the first oral targeted therapy for advanced/metastatic PPGL, which is particularly relevant for pseudohypoxic Cluster 1 tumors. Immunotherapy has yielded modest responses with checkpoint inhibitor monotherapy, but ongoing studies of dual checkpoint blockade and TKI–ICI combinations hold promise. Novel approaches, including PARP inhibition, metabolic targeting strategies, and cancer vaccines, are under investigation, especially for aggressive SDHB-related disease. Optimal sequencing of these therapies is emerging as a central challenge, with treatment strategies increasingly tailored to molecular genotype, tumor behavior, and functional imaging phenotype. This review summarizes current evidence and highlights ongoing clinical trials, underscoring a paradigm shift toward precision medicine and rational combination strategies. Collectively, these advances bring cautious optimism that metastatic PPGLs may soon become a more manageable chronic disease with improved survival and quality of life.
转移性或不可切除的嗜铬细胞瘤和副神经节瘤（PPGLs）仍属罕见但临床治疗棘手的神经内分泌肿瘤，其根治性治疗手段有限。传统治疗方式包括手术、放射性核素治疗或细胞毒性化疗，系统性治疗历来以实现疾病稳定为目标，而非持久缓解。然而近年来，治疗格局已发生显著演变。放射性药物如¹³¹I-MIBG和¹⁷⁷Lu-DOTATATE持续发挥关键作用，为众多患者实现疾病控制。以替莫唑胺为代表的细胞毒性方案仍具临床价值，部分研究提示SDHB突变型PPGLs因MGMT启动子高甲基化及表达降低而呈现更高治疗敏感性。靶向药物的重要性日益凸显：舒尼替尼、安罗替尼、卡博替尼等多激酶抑制剂已显示出明确疗效。2025年HIF-2α抑制剂贝组替凡的里程碑式获批，标志着首个针对晚期/转移性PPGL的口服靶向疗法问世，尤其适用于假缺氧型Cluster 1肿瘤。免疫治疗中检查点抑制剂单药疗效有限，但双检查点阻断及TKI-ICI联合疗法的研究持续推进，展现出良好前景。包括PARP抑制剂、代谢靶向策略和癌症疫苗在内的新型疗法正在探索中，尤其针对侵袭性SDHB相关疾病。如何优化这些疗法的序贯应用正成为核心挑战，治疗策略日益趋向根据分子基因型、肿瘤生物学行为及功能影像表型进行个体化定制。本文综述现有证据并重点介绍正在进行中的临床试验，强调治疗范式正朝着精准医疗与合理联合策略的方向转变。总体而言，这些进展使人们审慎乐观地预见，转移性PPGLs有望在改善生存质量的同时，转变为更具可控性的慢性疾病。
肿瘤(癌症)患者之家