7083 Background: A treatment (UP) with tegafur-uracil (UFT) and cisplatin in combination with concurrent thoracic radiotherapy (c-TRT) could have favorable efficacy with less toxicity for locally advanced non-small cell lung cancer (LA-NSCLC). We conducted this randomized phase II study to compare this regimen to a treatment (VC) with vinorelbine and cisplatin, which is a commonly used regimen with c-TRT for LA- NSCLC in Japan. Methods: Patients (pts) with LA-NSCLC were randomized to receive UP (UFT400 mg/m2 on days 1-14 and 29-42 and cisplatin 80 mg/m2 on days 8 and 36) or VC (vinorelbine 20 mg/2 on days 1, 8, 29, and 36 and cisplatin 80 mg/m2 on days 1 and 29), stratified by age, gender, histology, and stage. In both arms, c-TRT began on day 1 (total 60Gy in 30 fractions). The primary endpoint was overall response rate (ORR), and secondary endpoints were progression-free survival (PFS), overall survival, and toxicity profile. Assuming that ORR of 80% in eligible pts would indicate potential usefulness while ORR of 60% would be the lower limit of interest, the estimated accrual was 33 pts in each arm. Results: From February 2006 to May 2009, 70 pts were enrolled from 5 institutions. Finally 66 pts were evaluable for efficacy and safety. Patient characteristics were: Male/Female 54/12; median age 62 (range 40-75); Performance status 0/1 31/35; IIIA/IIIB 24/42. ORRs were 80% (95%CI: 67-93) and 71% (95%CI: 55-87) for the UP arm and the VC arm, respectively. With a median follow-up of 11.8 months, median PFS in the UP arm was 7.9 months and in the VC arm was 5.9 months. grade 3/4 neutropenia occurred in 20% and 58% of pts in the arms UP and VC, respectively. There was no remakable difference in other toxicities between both arms. Two pts in the VC arm died of radiation pneumonitis. Conclusions: Combined with c-TRT, UP achieved more preferable efficacy and safety compared with VC, suggesting a promising candidate as a standard regimen with c-TRT for LA-NSALC. Further evaluation of UP with c-TRT is warranted in a phase III setting in comparison with cisplatin-based second generation chemotherapy with c-TRT. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Chugai Pharma, Daiichi Sankyo, Lilly, Novartis, sanofi-aventis
A 71-year-old male patient with adenocarcinoma of the lung and contralateral lung metastasis under administration of pembrolizumab had symptoms of cerebellar ataxia. We suspected that the symptoms were immune-related adverse events (irAE), but the patient was subsequently diagnosed as cerebellitis due to Epstein-Barr virus (EBV) infection. After steroid pulse therapy, the symptoms of cerebellar ataxia improved immediately. Immune checkpoint inhibitors (ICI) can induce neurological adverse events and cause acute cerebellar ataxia. Initially, irAEs were suspected in this case. His clinical data suggested that reactivation of the virus had occurred because the ICI affected his immune system. This is the first report of a case of acute cerebellar ataxia due to EBV under administration of an ICI.
Non-small-cell lung cancer with sensitive mutations of the epidermal growth factor receptor (EGFR) is highly responsive to EGFR tyrosine kinase inhibitors such as gefitinib, but little is known about how its efficacy and safety profile compares with that of standard chemotherapy.We randomly assigned 230 patients with metastatic, non-small-cell lung cancer and EGFR mutations who had not previously received chemotherapy to receive gefitinib or carboplatin-paclitaxel. The primary end point was progression-free survival; secondary end points included overall survival, response rate, and toxic effects.In the planned interim analysis of data for the first 200 patients, progression-free survival was significantly longer in the gefitinib group than in the standard-chemotherapy group (hazard ratio for death or disease progression with gefitinib, 0.36; P<0.001), resulting in early termination of the study. The gefitinib group had a significantly longer median progression-free survival (10.8 months, vs. 5.4 months in the chemotherapy group; hazard ratio, 0.30; 95% confidence interval, 0.22 to 0.41; P<0.001), as well as a higher response rate (73.7% vs. 30.7%, P<0.001). The median overall survival was 30.5 months in the gefitinib group and 23.6 months in the chemotherapy group (P=0.31). The most common adverse events in the gefitinib group were rash (71.1%) and elevated aminotransferase levels (55.3%), and in the chemotherapy group, neutropenia (77.0%), anemia (64.6%), appetite loss (56.6%), and sensory neuropathy (54.9%). One patient receiving gefitinib died from interstitial lung disease.First-line gefitinib for patients with advanced non-small-cell lung cancer who were selected on the basis of EGFR mutations improved progression-free survival, with acceptable toxicity, as compared with standard chemotherapy. (UMIN-CTR number, C000000376.)
DNA mismatch repair (MMR) deficiency leads to changes in the length of nucleotide repeat sequences of tumor DNA. In that situation, DNA replicational errors occur and accumulate during DNA replication. As a result, this mechanism frequently affects the coding regions of oncogenes and tumor suppressor genes and causes carcinogenesis. Recently, DNA MMR deficiency has been recognized as a predictive biomarker for immunotherapy. The aim of this study is to examine the frequency of DNA MMR deficiency and clinicopathological characteristics in surgically resected lung carcinoma (LC) and their correlation.A total of 1153 LCs were examined. Tissue microarrays were constructed. The status of MMR deficiency was evaluated by immunohistochemical analysis of MMR protein expression (hMLH1, hMSH2, hMSH6, and hPMS2). Microsatellite instability analysis, BRAF mutation, and MLH1 methylation analysis were performed for cases that showed MMR deficiency.Only 2 of the 1153 cases (0.17%) showed a loss of hMLH1/hPMS2 protein expression. They also had high levels of microsatellite instability (MSI-H), had neither MLH1 promoter methylation nor BRAF mutation, and were male smokers. Histopathologically, one was a squamous cell carcinoma, and the other was combined small cell carcinoma with squamous cell carcinoma. Regarding PD-L1 protein expression, one had high expression, and the other had none.The frequency of MMR deficiency was very low in LC. However, our two cases were non-adenocarcinoma and differed from previous studies. Because of its very low frequency, MMR deficiency is not a practical biomarker to predict the effect of immune checkpoint inhibitors in LC.
Background: Squamous cell carcinoma (SCC) is the major histological type in lung cancer (LC). The tumor microenvironment (TME) drives tumor progression and metastasis. In the TME, cancer-associated fibroblasts (CAFs) play key roles in carcinogenesis. However, the roles of CAFs in lung SCC remain unknown. In this study, we evaluated whether the CAF phenotype was determined by various CAF-related proteins and whether CAF-related protein expression contributed to clinical outcomes in patients with lung SCC. Methods: We examined the associations of CAF- and epithelial-mesenchymal transition (EMT)-related markers expressed in CAFs, including α-smooth muscle actin (α-SMA), CD10, podoplanin, fibroblast-specific protein 1 (FSP1), platelet-derived growth factor receptor (PDGFR) α, PDGFRβ, adipocyte enhancer-binding protein 1 (AEBP1), fibroblast activation protein (FAP), tenascin-C, Zinc finger E-box binding homeobox 1 (ZEB1), and twist homolog 1 gene (TWIST1), in 108 lung SCC tissues using immunohistochemistry. In addition, cluster analysis was used to identify objective expression patterns of immunohistochemical markers. Finally, the CD3/CD8 ratio was evaluated in order to identify the associations of CAF-related proteins with the CD3/CD8 ratio using immunohistochemistry. Results: SCC samples were classified into two subgroups (CAF-phenotype), which were significantly correlated with disease-free and overall survival using univariate and multivariate analyses. Moreover, high AEBP1 expression was identified as an independent prognostic marker in this cohort by univariate and multivariate analyses. The CD3/CD8 ratio was not correlated with the CAF-phenotype. Conclusions: The presence of a specific subgroup defined by multiple markers could be used for prediction of prognosis in patients with lung SCC. In addition, AEBP1 overexpression played key roles in prediction of a poor prognosis in patients with lung SCC.
