Among neuroendocrine neoplasms (NENs), a non-negligible proportion (9–22%) is represented by sufferers of NENs of unknown primary origin (UPO), a poor prognostic group with largely unmet clinical needs. In the absence of standard therapeutic algorithms, current guidelines suggest that the treatment of UPO-NENs should be based on tumor clinical-pathological characteristics, disease burden, and patient conditions. Chemotherapy represents the backbone for the treatment of high-grade poorly differentiated UPO-NENs, usually providing deep but short-lasting responses. Conversely, the spectrum of available systemic therapy options for well-differentiated UPO-NENs may range from somatostatin analogs in indolent low-grade tumors, to peptide receptor radioligand therapy, tyrosine kinase inhibitors (TKIs), or chemotherapy for more aggressive tumors or in case of high disease burden. In recent years, molecular profiling has provided deep insights into the molecular landscape of UPO-NENs, with both diagnostic and therapeutic implications. Although preliminary, interesting activity data have been provided about upfront chemoimmunotherapy, the use of immune checkpoint inhibitors (ICIs), and the combination of ICIs plus TKIs in this setting. Here, we review the literature from the last 30 years to examine the available evidence about the treatment of UPO-NENs, with a particular focus on future perspectives, including the expanding scenario of targeted agents in this setting.
在神经内分泌肿瘤中，原发灶不明神经内分泌肿瘤患者占不可忽视的比例（9%-22%），该群体预后较差且临床需求远未得到满足。由于缺乏标准治疗路径，现行指南建议其治疗方案应基于肿瘤临床病理特征、疾病负荷及患者状况。化疗是高分化程度差的高级别原发灶不明神经内分泌肿瘤的主要治疗手段，通常能产生显著但短暂的治疗反应。相反，针对高分化原发灶不明神经内分泌肿瘤的全身治疗选择范围较广：惰性低级别肿瘤可使用生长抑素类似物，侵袭性较强或高负荷肿瘤则可选择肽受体放射性核素治疗、酪氨酸激酶抑制剂或化疗。近年来，分子谱分析技术为揭示原发灶不明神经内分泌肿瘤的分子特征提供了深刻见解，兼具诊断与治疗指导价值。尽管尚处初步阶段，已有研究显示前期化学免疫疗法、免疫检查点抑制剂单药及其与酪氨酸激酶抑制剂联合方案在此领域展现出令人关注的活性数据。本文通过回顾近三十年文献，系统梳理原发灶不明神经内分泌肿瘤的治疗证据，特别聚焦未来发展方向，包括该领域靶向药物应用前景的持续拓展。
肿瘤(癌症)患者之家