Management of Pulmonary Large-Cell Neuroendocrine Carcinoma (LCNEC): An Updated Review

Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is an uncommon and aggressive malignancy, accounting for approximately 3% of all primary lung malignancies. Due to its rarity, the treatment paradigm for LCNEC is primarily derived from retrospective data from non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). This review synthesizes current evidence and discusses emerging treatment strategies. For medically fit patients with resectable disease, surgical resection, in particular lobectomy, should be offered, while stereotactic body radiation therapy can be reserved for medically inoperable patients. Adjuvant chemotherapy is suggested for most resected tumors, with SCLC regimens (eg, etoposide-cisplatin) associated with better outcomes; however, very early-stage tumors (stage IA) warrant individualized decision-making. There is currently no evidence supporting the use of adjuvant immunotherapy in LCNEC. The role of adjuvant radiotherapy, neoadjuvant therapy and prophylactic cranial irradiation in LCNEC remains undefined. For unresectable, locally advanced disease, concurrent chemoradiation with etoposide-cisplatin followed by consolidation durvalumab is recommended, although the optimal dose-fractionation and the duration of consolidation immunotherapy remain to be investigated. In metastatic disease, etoposide-platinum chemotherapy remains the first-line treatment, while targeted therapy can be considered if tumors harbor actionable genomic alterations. The potential benefit of immunotherapy is currently under investigation. While several second-line treatment options have been reported with modest efficacy, local ablative treatment has shown promise in oligometastatic LCNEC. Among the most promising emerging treatment strategies are DLL3-targeting therapies, buoyed by the recent success of tarlatamab in SCLC. The evolving role of molecular profiling in prognostication and treatment decision-making is also examined.