Challenges and future perspectives for the use of temozolomide in the treatment of SCLC.

Small-cell lung cancer (SCLC), accounting for 10-20 % of all lung tumors, represents the most aggressive high-grade neuroendocrine carcinoma. Most patients are diagnosed with extensive-stage SCLC (ES-SCLC), with brian metastases identified in âˆ¼ 80 % of cases during the disease cours, and the prognosis is dismal, with a 5-year survival rate of less than 5 %. Current available treatments in the second-line setting are limited, and topotecan has long been the only FDA-approved drug in relapsed or refractory ES-SCLC, until the recent approval of lurbinectedin, a selective inhibitor of RNA polymerase II. Temozolomide (TMZ) is an oral alkylating agent, which showed single-agent activity in SCLC, particularly among patients with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. Several studies have revealed the synergistic activity of temozolomide with poly-ADP-ribose polymerase (PARP) inhibitors, that prevent repair of TMZ-induced DNA damage. This review focuses on the rationale for the use of TMZ in ES-SCLC and provides an overview of the main trials that have evaluated and are currently investigating its role, both as a single-agent and in combinations, in relapse or refractory disease.

Chemotherapy in Well Differentiated Neuroendocrine Tumors (NET) G1, G2, and G3: A Narrative Review.

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.

First-Generation Epidermal Growth Factor Receptor Inhibitors Plus Antiangiogenic Drugs Versus Third-Generation Epidermal Growth Factor Receptor Inhibitors in Advanced Non-Small-Cell Lung Cancer: A Meta-Analysis.

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.

The Palliative Prognostic (PaP) Score without Clinical Evaluation Predicts Early Mortality among Advanced NSCLC Patients Treated with Immunotherapy.

Background: An acceptable risk-benefit ratio may encourage the prescription of immune checkpoint inhibitors (ICI) near the late stage of life. The lung immune prognostic index (LIPI) was validated in advanced non-small cell lung cancer (NSCLC) patients treated with ICIs. The palliative prognostic (PaP) score without clinical prediction of survival (PaPwCPS) predicts early mortality probability in terminal cancer patients. Methods: We performed a retrospective study including 182 deceased advanced NSCLC patients, treated with single-agent ICI at our Institution. Two prognostic categories of high and low mortality risk were identified through ROC curve analysis for PaPwCPS and LIPI scores. Results: Most were >65 years of age (68.3%) and received second-line ICI (61.2%). A total of 29 (15.9%) and 131 (72.0%) patients died within 30 and 90 days from treatment start, respectively. A total of 81 patients (44.5%) received ICI during the last month of life. Baseline PaPwCPS and LIPI scores were assessable for 78 patients. The AUC of ROC curves was significantly increased for PaPwCPS as compared with LIPI score for both 30-day and 90-day mortality. A high PaPwCPS score was associated in multivariate analysis with increased 30-day (HR 2.69, p = 0.037) and 90-day (HR 4.01, p < 0.001) mortality risk. A high LIPI score was associated with increased 90-day mortality risk (p < 0.001). Conclusion: We found a tendency towards ICI prescription near the late stage of life. The PaPwCPS score was a reliable predictor of 30- and 90-day mortality.