The Role of Prophylactic Cranial Irradiation in Patients With Extensive Stage Small Cell Lung Cancer: A Systematic Review and Meta-Analysis

Introduction

The role of prophylactic cranial irradiation (PCI) is controversial in patients with extensive stage small cell lung cancer. The aim of this study was to determine the impact of PCI in these patients.

Pemetrexed in the Treatment of Leptomeningeal Metastasis in Patients With EGFR-mutant Lung Cancer

IntroductionLeptomeningeal metastasis (LM), still an area of unmet need, has frequently been observed in patients with EGFR-mutant non–small-cell lung cancer (NSCLC). Because the antitumor efficacy of systemic cytotoxic agents against LM is unclear, we explored the role of pemetrexed in the treatment of patients with LM from EGFR-mutant NSCLC.Patients and MethodsWe retrospectively reviewed the medical records of patients with LM from EGFR-mutant NSCLC treated between 2006 and 2016. Post-LM survival was evaluated as well as clinical factors.ResultsIn our patient cohort with EGFR-mutant NSCLC (n = 631), 17.4% (n = 110) developed LM. Their median post-LM survival was 5.7 months (95% confidence interval, [CI], 0.0-12.0 months). Post-LM survival was significantly longer with pemetrexed use after LM (median, 13.7 months; 95% CI, 4.1-23.2 months) than without pemetrexed use after LM (median, 4.0 months; 95% CI, 2.2-5.7 months; P = .008). In the multivariate analyses, no pemetrexed use after LM (vs. use) and no EGFR tyrosine kinase inhibitor use after LM (vs. use) were independently associated with a poor post-LM survival with a hazard ratio of 3.1 (95% CI, 1.5-6.3; P = .002) and 3.0 (95% CI, 1.6-5.8; P = .001), respectively.ConclusionPemetrexed use after LM was independently associated with a longer post-LM survival in patients with EGFR-mutant NSCLC with LM. Prospective studies are warranted to validate this finding.     

Preclinical Modeling of Osimertinib for NSCLC With EGFR Exon 20 Insertion Mutations

IntroductionNSCLC with EGFR exon 20 insertion mutations is the third most common type of EGFR-mutant NSCLC and is resistant to EGFR tyrosine kinase inhibitors (TKIs). This study was conducted to evaluate the efficacies of first- to third-generation EGFR TKIs against NSCLC cells harboring EGFR exon 20 insertion mutations.MethodsWe developed seven EGFR exon 20 insertion-mutant Ba/F3 models and one patient-derived NSCLC (SNU-3173) of subtypes A763insFQEA, V769insASV, D770insSVD, D770insNPG, P772insPR, H773insH, H773insNPH, and H773insAH. Cell viability assays, immunoblotting, and N-ethyl-N-nitrosourea mutagenesis screenings were performed. EGFR exon 20 insertion–mutant structures and couplings with osimertinib, a third-generation EGFR TKI, were modeled and compared.ResultsEGFR exon 20 insertion–mutant NSCLC cells, excluding EGFR A763insFQEA, were resistant to first-generation EGFR TKIs (concentration that inhibits 50% [IC₅₀], 1.1 ± 0.067 to 5.4 ± 0.115 μM). Mutants were sensitive to second-generation EGFR TKIs (IC₅₀, 0.02 ± 0.0002 to 161.8 ± 18.7nM), except EGFR H773insH (IC₅₀, 46.3 ± 8.0 to 352.5 ± 22.7nM). The IC₅₀ ratios for mutant to wild-type cells were higher than those for third-generation EGFR TKIs. Third-generation EGFR TKI osimertinib was highly potent against EGFR exon 20 insertion–mutant cells (IC₅₀, 14.7-62.7 nM), including EGFR H773insH, and spared wild-type EGFR cells. N-ethyl-N-nitrosourea mutagenesis screening of EGFR exon 20 insertion–mutant Ba/F3 cells showed various second sites for EGFR mutations, mostly at exons 20 and 21, including E762K, P794S, and G796D. In addition, osimertinib-resistant cells were established by stepwise exposure to osimertinib and harbored EGFR E762K mutation.ConclusionsOsimertinib is active against EGFR exon 20 insertion–mutant NSCLC and flexibly binds within drug-binding pockets in preclinical models.     

Effects of Adjuvant Chemotherapy on Locally Advanced Upper Tract Urothelial Carcinoma: A Systematic Review and Meta-analysis

IntroductionWe aimed to perform a systematic review and meta-analysis to evaluate the current role of adjuvant chemotherapy (ACH) after radical nephroureterectomy (RNU) in patients with locally advanced upper tract urothelial carcinoma (UTUC).Materials and MethodsThe PubMed/MEDLINE, EMBASE, and Cochrane Library databases were searched for relevant studies in English from January 1980 to April 2019. The inclusion criteria was determined based on the population, intervention, comparator, outcome, and study design. The endpoints were disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS). Hazard ratios (HRs) and 95% confidence intervals (CIs) of each endpoint were extracted from the included studies.ResultsA total of 11 studies were included in the final analysis to investigate the role of ACH in locally advanced UTUC. Overall, 798 patients received ACH after RNU, and 1496 patients underwent RNU alone. The pooled HRs for DFS, CSS, and OS among the studies were 0.59 (95% CI, 0.43-0.81; P = .001), 0.73 (95% CI, 0.55-0.95; P = .02), and 0.84 (95% CI, 0.59-1.19; P = .32), respectively. The quality of evidence of each outcome determined by the Grading of Recommendations, Assessments, Developments, and Evaluation approach was low for 2 outcomes and very low for the other outcome.ConclusionsACH following RNU may improve DFS and CSS in patients with locally advanced UTUC. When comparing previously reported meta-analysis of all UTUC patients, the beneficial effects of ACH on CSS might be more pronounced in patients with locally advanced UTUC.     

Novel Predictive Models of Early Death Less Than 1 Year in Patients With Metastatic Renal Cell Carcinoma After Treatment With First-line Tyrosine Kinase Inhibitors

BackgroundWe aimed to develop a modified International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model that can predict early death less than 1 year in patients with metastatic renal cell carcinoma (mRCC) after receiving first-line tyrosine kinase inhibitors (TKIs).Patients and MethodsWe retrospectively reviewed records of patients with mRCC treated with first-line TKIs at our institution between 2007 and 2012. The primary endpoint was the rate of early death within 1 year after first-line TKI administration. We determined statistically significant factors predicting early death by performing multiple logistic regression. The modified IMDC model 1 was developed using new variables in addition to the risk criteria of the IMDC model, and model 2 was developed using new variables irrespective of the risk classification of IMDC model.ResultsEarly mortality within 1 year of first-line TKI treatment was 19.7% (n = 98) in 462 patients. Although the C-index of the IMDC model for early death was 0.655, the C-index of model 1, which includes 5 variables (previous nephrectomy, body mass index, multiple metastases, previous metastasectomy, and serum albumin level) in addition to the Heng criteria, was 0.823. The C-index of model 2, which includes 7 variables (hemoglobin, neutrophil level, and the 5 variables of model 1) was 0.822. Of note, there was no significant difference in net reclassification index between the 2 models.ConclusionThis is the first study suggesting novel prediction models for early death less than 1 year in patients with mRCC treated with first-line TKI.