Redefining the Role of Chemotherapy and Targeted Cytotoxic Delivery in Lung Neuroendocrine Tumors

The clinicopathological and therapeutic landscape of lung neuroendocrine tumors (NETs) is continuously evolving. Although systemic chemotherapy has historically represented a management cornerstone, the available data are predominantly retrospective and outdated. A critical review of the current literature and public clinical trial registries was performed to evaluate the role of chemotherapy and targeted cytotoxic delivery systems in lung NETs. Given the nature of the review, the evidence was synthesized descriptively. In early-stage disease, the clinical utility of perioperative (neoadjuvant and adjuvant) chemotherapy remains uncertain and lacks universal standardization. In the advanced or metastatic setting, traditional platinum/etoposide regimens demonstrate suboptimal efficacy in controlling well-differentiated carcinoids. Conversely, oral alkylating agents (temozolomide) and combination schedules such as CAPTEM (capecitabine/temozolomide) or temozolomide paired with cabozantinib offer promising response and disease control rates. Future strategies are moving away from unselected systemic cytotoxicity toward targeted delivery and chemo-immunotherapy platforms, leveraging peptide-drug conjugates (PDCs like PEN-221), antibody-drug conjugates (ADCs), and bispecific T-cell engagers (BiTEs) directed against emerging surface targets such as DLL3 (e.g., tarlatamab) and TROP2. There is an urgent, unmet clinical need for prospective, multicenter clinical trials and international registries. Dissecting the complex molecular landscape of lung NETs will be essential to identify predictive biomarkers and actionable therapeutic targets, ultimately transitioning clinical management from empirical, extrapolated choices to robust, evidence-based, stage-specific standards of care.