Neuroendocrine tumors (NETs) are rare neoplasms with a wide spectrum of clinical behavior, from the long survival of well-differentiated NETs to the dismal prognosis of high-grade neuroendocrine carcinomas (NECs), being G3 NETs a recently recognized intermediate entity. While the role of chemotherapy is well established in NECs, data on NETs mostly derives from small studies, experts’ opinions, and extrapolating results from small-cell lung cancer studies. This narrative review aims to summarize available evidence about the use of chemotherapy in the setting of G1-2 NETs and G3 NETs. We performed literature research in PubMed Library for all articles published up to September 2022 about the efficacy of chemotherapy in NETs. Treatment regimens with STZ-5FU, CAPTEM, and anti-metabolite-based treatment are the most active and tolerated in gastroenteropancreatic NETs (GEP-NETs) G1-G2, while platinum-based regimens (FOLFOX/XELOX) and TEM/CAPTEM showed the best activity in thoracic NETs. Solid evidence about chemotherapy efficacy in G3 NETs is still lacking. Literature data support the use of chemotherapy in low-intermediate grade NETs after the failure of other therapies or if tumor shrinkage is needed. Studies assessing G3 NETs independently from NECs are needed to better understand the role of chemotherapy in this setting.

PURPOSE: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) revolutionized the therapeutic landscape of non–small-cell lung cancer (NSCLC). However, despite significant survival improvement, the emergence of resistance mechanisms represents a common event. In this meta-analysis, we compared the efficacy and safety of third-generation EGFR-TKIs, the current standard of care, to first-generation EGFR-TKIs with antiangiogenic drugs for the first-line treatment of NSCLC harboring EGFR mutations. MATERIALS AND METHODS: Randomized controlled clinical trials (RCTs) reporting survival data published before September 1, 2022, were searched through the MEDLINE databases (PubMed), the Cochrane Database of Systematic Reviews, and Central Register of Controlled Trials (Wiley). Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and grade 3 or higher treatment-related adverse events (≥3 TRAEs) data were analyzed. RESULTS: Twelve RCTs were included in our meta-analysis, with a total of 3,565 patients. We observed that third-generation EGFR-TKIs and first-generation EGFR-TKIs combined with antiangiogenic drugs provided a similar OS benefit over first-generation EGFR-TKIs in any of the subgroups. However, we indirectly observed a greater PFS benefit of third-generation EGFR-TKIs over first-generation EGFR-TKIs in females, never-smokers, in patients harboring exon 19 deletions, and in those with brain metastasis, as compared with using first-generation EGFR-TKIs plus antiangiogenic drugs. The ORR did not differ between the combination strategy and third-generation EGFR-TKIs. Finally, the risk of developing grade ≥3 TRAEs was higher using the combination of first-generation EGFR-TKIs and antiangiogenic drugs over first-generation EGFR-TKIs than third-generation EGFR-TKIs over first-generation EGFR-TKIs. CONCLUSION: This meta-analysis suggests that the combination strategy may provide an alternative to third-generation EGFR-TKIs, but more data are needed to determine the predictive clinicopathologic characteristics that can influence the treatment choice. Until then, third-generation EGFR-TKIs still represent the first choice in advanced NSCLC harboring EGFR mutations.

PD-1/PD-L1 inhibitors plus platinum-etoposide are standard first-line therapy for extensive-stage small-cell lung cancer (ES-SCLC), but the consistency of benefit across trials and potential PD-1 versus PD-L1 class differences remain debated. We conducted an updated systematic review and meta-analysis of phase III trials in untreated ES-SCLC. MEDLINE, Scopus, and Cochrane CENTRAL were searched through 11 February 2026 for phase III randomized trials comparing platinum-etoposide plus a PD-1/PD-L1 inhibitor versus platinum-etoposide alone. OS and PFS hazard ratios (HRs) were pooled using random-effects (REML). A pre-specified meta-regression tested PD-1 versus PD-L1 class effect (ratio of HRs). Safety endpoints were synthesized using risk ratios (RRs). RoB 2 and GRADE were applied. Six trials (n = 2,897) were included. Chemo-immunotherapy improved OS (HR 0.74, 95% CI 0.67-0.81; I² = 0%) and PFS (HR 0.68, 95% CI 0.58-0.78; I² = 65.6%). No statistically detectable difference between PD-1 and PD-L1 inhibitor classes was identified for OS (ratio of HRs 1.01, 95% CI 0.85-1.21; p = 0.89) or PFS (0.83, 0.64-1.09; p = 0.18). Grade ≥ 3 treatment-related adverse events were not increased (RR 1.01, 0.96-1.06), while immune-mediated adverse events were more frequent (RR 2.39, 1.61-3.54) with substantial heterogeneity. Certainty was high for OS, low for PFS, and moderate-to-very low for safety. Adding a PD-1/PD-L1 inhibitor to platinum-etoposide in first-line ES-SCLC provides a consistent overall survival benefit, with no statistically detectable differences between PD-1 and PD-L1 inhibitor classes. This finding should be interpreted as absence of detectable class-level divergence rather than pharmacologic equivalence.

Neuroendocrine neoplasms (NENs) of the lung are a biologically and clinically diverse group of tumors that includes well-differentiated typical and atypical carcinoids (LNETs), as well as poorly differentiated large-cell neuroendocrine carcinoma and small-cell lung cancer. Despite their relative rarity, the incidence of LNETs is increasing, primarily due to advancements in diagnostic techniques and heightened clinical awareness. While the current World Health Organization (WHO) classification offers a morphological basis for diagnosis and prognosis, particularly for extrapulmonary neuroendocrine neoplasms (ep-NENs), it has limitations in predicting the clinical behavior of pulmonary carcinoids. Recent evidence highlights the inadequacy of traditional criteria in fully capturing the biological complexity and clinical heterogeneity of these tumors. This review explores the evolving landscape of LNETs, focusing on well-differentiated forms and analyzing current classification systems, clinicopathological features, and the emerging role of novel prognostic and predictive biomarkers. Advances in histopathology and molecular profiling have begun to elucidate distinct molecular subsets within carcinoids, offering potential avenues for improved risk stratification and therapeutic decision-making. Although there are limited treatment options for advanced disease, new insights into tumor biology could facilitate the development of personalized therapeutic strategies and pave the way for future innovations in LNET management.