Efficacy and Safety of First-line Pembrolizumab Plus Platinum and Pemetrexed in Elderly Patients with Non-squamous Non-small-cell Lung Cancer.

Objective Pembrolizumab plus platinum and pemetrexed (Pemb-Plt-PEM) combination therapy is an effective first-line treatment for advanced non-squamous non-small-cell lung cancer (NSCLC), regardless of programmed death ligand 1 expression. However, the effectiveness and feasibility of first-line Pemb-Plt-PEM therapy in elderly patients (≥75 years old) remain unclear. Therefore, this study investigated the safety and efficacy of first-line Pemb-Plt-PEM in elderly patients with nonsquamous NSCLC. Methods We retrospectively evaluated the data of patients ≥75 years old with non-squamous NSCLC who were treated with first-line Pemb-Plt-PEM from December 2018 to December 2020 at 10 institutes in Japan. Data on patient characteristics, efficacy of pemb-Plt-PEM therapy, and the type and severity of adverse events were reviewed. Results Thirty patients [20 men and 10 women; median age: 76 (range: 75-82) years old] were included in the analysis. The overall response rate, disease control rate, median progression-free survival (PFS), and median overall survival (OS) were 40.0%, 66.7%, and 7.5 and 24.0 months, respectively. The treatment-related deaths were caused by pneumonitis. First-line Pemb-Plt-PEM was associated with the PFS, based on the neutrophil-to-lymphocyte ratio (NLR). The PFS for low and high NLR values was 10.1 and 2.0 months, respectively. Furthermore, the sex and NLR influenced the association between Pemb-Plt-PEM and the OS. The OS for low and high NLR values was 32.8 and 2.6 months, respectively. Conclusion First-line pemb-Plt-PEM therapy is effective and feasible in elderly patients with non-squamous NSCLC.

Mirtazapine plus granisetron and dexamethasone for carboplatin-induced nausea and vomiting in patients with thoracic cancers: A prospective multicenter phase II trial.

BACKGROUND: Mirtazapine blocks 5-hydroxytryptamine type (5-HT)2A, 5-HT2C, 5-HT3 and histamine H1 receptors, similarly to olanzapine. This study aimed to investigate the efficacy and safety of mirtazapine plus granisetron and dexamethasone for carboplatin (CBDCA)-induced nausea and vomiting in patients with thoracic cancers. METHODS: We conducted a prospective, open-label, single-arm, multicenter, phase II trial in four institutions in Japan. Registered patients were moderately to highly emetogenic chemotherapy-naïve, and were scheduled to receive CBDCA at area under the curve (AUC) ≥ 4 mg/mL per minute. Patients received mirtazapine 15 mg/day orally at bedtime for four consecutive days, in combination with granisetron and dexamethasone. Primary endpoint was complete response (CR; no emesis and no use of rescue medication) rate during the delayed period (24-120 h). RESULTS: Between July 2022 and July 2023, 52 patients were enrolled, and 48 patients were evaluated. CR rates in the delayed (24-120 h), overall (0-120 h), and acute periods (0-24 h) were 83.3%, 83.3%, and 100%, respectively. No grade 3 or higher treatment-related adverse events were observed except for one patient who had grade 3 dry mouth as evaluated by Common Terminology Criteria for Adverse Events version 5.0. CONCLUSIONS: Prophylactic antiemetic therapy with mirtazapine plus granisetron and dexamethasone shows promising efficacy and an acceptable safety profile. This three-drug combination appears to be a reasonable treatment approach in patients with thoracic cancers receiving a CBDCA-based regimen at AUC ≥ 4 mg/mL per minute.

Prognostic Potential of the Prognostic Nutritional Index in Non-Small Cell Lung Cancer Patients Receiving Pembrolizumab Combination Therapy with Carboplatin and Paclitaxel/Nab-Paclitaxel.

INTRODUCTION: Pembrolizumab (Pemb) therapy in conjunction with carboplatin and paclitaxel (PTX)/nab-PTX has been efficacious in treating non-small cell lung cancer (NSCLC). However, the response predictors of this combination therapy (Pemb-combination) remain undetermined. We aimed to evaluate whether Glasgow prognostic score (GPS), neutrophil-to-lymphocyte ratio (NLR), body mass index (BMI), platelet-to-lymphocyte ratio (PLR), and prognostic nutritional index (PNI) are potential factors in prognosticating the response to Pemb-combination therapy in advanced NSCLC patients. METHODS: We retrospectively recruited 144 NSCLC patients receiving first-line treatment with Pemb-combination therapy from 13 institutions between December 1, 2018, and December 31, 2020. GPS, NLR, BMI, PLR, and PNI were assessed for their efficacy as prognostic indicators. Cox proportional hazard models and the Kaplan-Meier method were used to compare the progression-free survival (PFS) and overall survival (OS) of the patients. RESULTS: The treatment exhibited a response rate of 63.1% (95% confidence interval [CI]: 55.0-70.6%). Following Pemb-combination administration, the median PFS and OS were 7.3 (95% CI: 5.3-9.4) and 16.5 (95% CI: 13.9-22.1) months, respectively. Contrary to PNI, NLR, GPS, BMI, and PLR did not display substantially different PFS in univariate analysis. However, multivariate analysis did not identify PNI as an independent prognostic factor for PFS. Furthermore, univariate analysis revealed that GPS, BMI, and PLR exhibited similar values for OS but not NLR and PNI. Patients with PNI ≥45 were predicted to have better OS than those with PNI <45 (OS: 23.4 and 13.9 months, respectively, p = 0.0028). Multivariate analysis did not establish NLR as an independent prognostic factor for OS. CONCLUSION: The PNI evidently predicted OS in NSCLC patients treated with Pemb-combination as first-line therapy, thereby validating its efficiency as a prognostic indicator of NSCLC.

Using the neutrophil-to-lymphocyte ratio to predict the outcome of individuals with nonsquamous non-small cell lung cancer receiving pembrolizumab plus platinum and pemetrexed.

BACKGROUND: Factors predicting the response to pembrolizumab plus platinum and pemetrexed combination therapy (Pemb-Plt-PEM) in nonsquamous non-small cell lung cancer (non-sq NSCLC) are unclear. We investigated the Glasgow Prognostic (GP) score, neutrophil-to-lymphocyte ratio (NLR), and body mass index (BMI) as predictors of response to initial treatment with combination therapy in individuals with advanced non-sq NSCLC. METHODS: We retrospectively reviewed 236 patients who received initial treatment with combination therapy for non-sq NSCLC at 13 institutions between December 2018 and December 2020. The usefulness of the GP score, NLR, and BMI as prognostic indicators was assessed. Cox proportional hazard models and the Kaplan-Meier method were used to compare progression-free survival (PFS) and overall survival (OS). RESULTS: The response rate was 51.2% (95% CI: 44.9-57.5%). The median PFS and OS after beginning Pemb-Plt-PEM were 8.8 (95% CI: 7.0-11.9) months and 23.6 (95% CI: 18.7-28.6) months, respectively. The NLR independently predicted the efficacy of Pemb-Plt-PEM-the PFS and OS were more prolonged in individuals with NLR <5 than in those with NLR ≥5 (PFS: 12.8 vs. 5.3 months, p = 0.0002; OS: 29.4 vs. 12.0 months, p < 0.0001). BMI predicted the treatment response-individuals with BMI ≥22.0 kg/m2 had longer OS than did those with BMI < 22.0 kg/m2 (OS: 28.4 vs. 18.4 months, p = 0.0086). CONCLUSIONS: The NLR significantly predicted PFS and OS, whereas BMI predicted OS, in individuals who initially received Pemb-Plt-PEM for non-sq NSCLC. These factors might be prognosis predictors in non-sq NSCLC.

Post-progression survival after atezolizumab plus carboplatin and etoposide as first-line chemotherapy in small cell lung cancer has a significant impact on overall survival.

BACKGROUND: The effect of first-line chemotherapy on overall survival (OS) may be significantly influenced by subsequent therapy for patients with extensive disease small cell lung cancer (ED-SCLC). Therefore, we evaluated the relationship between progression-free survival (PFS), post-progression survival (PPS), and OS of ED-SCLC patients treated with atezolizumab plus carboplatin and etoposide as first-line therapy. METHODS: We analyzed the data of 57 patients with relapsed ED-SCLC treated with atezolizumab plus carboplatin and etoposide (AteCE) as first-line chemotherapy between August 2019 and September 2020. The respective correlations between PFS-OS and PPS-OS following first-line AteCE treatment were examined at the individual patient level. RESULTS: Spearman's rank correlation analysis and linear regression analysis showed that PPS strongly correlated with OS (r = 0.93, p < 0.05, R2  = 0.85) and that PFS moderately correlated with OS (r = 0.55, p < 0.05, R2  = 0.28). Performance status at relapse (0-1/≥2), number of cycles of atezolizumab maintenance therapy (<3/≥3), and platinum rechallenge chemotherapy all significantly positively correlated with PPS (p < 0.05). CONCLUSIONS: Upon comparing OS-PFS and OS-PPS in this patient population, OS and PPS were found to have a stronger correlation. These results suggest that performance status at relapse, atezolizumab maintenance, or chemotherapy rechallenge could affect PPS.

Clinical impact of post-progression survival in patients with locally advanced non-small cell lung cancer after chemoradiotherapy.

BACKGROUND: The efficacy of first-line chemoradiotherapy for overall survival (OS) might be confounded by the subsequent treatments in patients with locally advanced non-small cell lung cancer (NSCLC). In this study, we assessed the associations of progression-free survival (PFS) and post-progression survival (PPS) with OS after chemoradiotherapy for locally advanced NSCLC using patient-level data. PATIENTS AND METHODS: Between January 2011 and December 2018, 45 patients with locally advanced NSCLC who had received first-line chemoradiotherapy and in whom recurrence occurred were analysed. The associations of PFS and PPS with OS were analysed at the individual level. RESULTS: Linear regression and Spearman rank correlation analyses revealed that PPS was strongly correlated with OS (r = 0.72, p < 0.05, R2 = 0.54), whereas PFS was moderately correlated with OS (r = 0.58, p < 0.05, R2 = 0.34). The Glasgow prognostic score and liver metastases at recurrence were significantly associated with PPS (p < 0.001). CONCLUSIONS: The current analysis of individual-level data of patients treated with first-line chemoradiotherapy implied that PPS had a higher impact on OS than PFS in patients with locally advanced NSCLC. Additionally, current perceptions indicate that treatment beyond progression after first-line chemoradiotherapy might strongly affect OS.

Post-Progression Survival Highly Influences Overall Survival in Driver Gene Mutation/Translocation Negative or Unknown Type of Non-Small Cell Lung Cancer.

INTRODUCTION: In stage I-III non-small cell lung cancer (NSCLC), which is considered operable, surgical resection is the most efficacious treatment and is considered to provide a cure. However, after complete surgical resection, approximately 50% of patients with stage I-IIIA NSCLC experience recurrence and death. Once postoperative recurrence of NSCLC occurs, the prognosis is significantly poor, and the course of treatment after recurrence may influence overall survival (OS). Consequently, we investigated the relationship between relapse-free survival (RFS), post-progression survival (PPS), and OS in patients with postoperative recurrence of NSCLC with driver gene mutation/translocation negative or unknown status. METHODS: Between January 2007 and September 2019, 101 patients with driver gene mutation/translocation negative or unknown status of NSCLC who underwent complete resection and in whom recurrence occurred were analyzed. The associations between RFS, PPS, and OS were analyzed at the individual patient level. RESULTS: Linear regression and Spearman rank correlation analyses revealed that PPS was strongly associated with OS (r = 0.83, p < 0.0001, R2 = 0.71), whereas RFS was moderately correlated with OS (r = 0.65, p < 0.0001, R2 = 0.48). In the multivariate analysis, performance status at relapse, administration of immune checkpoint inhibitors, and radiotherapy for oligo-recurrences were significantly associated with PPS (p < 0.001). CONCLUSION: Current analysis of individual-level data of patients who underwent complete resection implied that PPS had a higher impact on OS than RFS in patients with postoperative recurrence of driver gene mutation/translocation negative or unknown status of NSCLC. Additionally, current perceptions indicate that treatment beyond progression after complete surgical resection might strongly affect OS.

Course of postoperative relapse in non-small cell lung cancer is strongly associated with post-progression survival.

BACKGROUND: For early-stage non-small cell lung cancer (NSCLC), surgical resection is considered the most effective treatment strategy and curative treatment. Unfortunately, even after complete resection, almost half of all patients with stage I-IIIA NSCLC relapse and die. Although the possibility of a cure for postoperative recurrence of NSCLC is significantly low, the course of subsequent treatment can possibly affect overall survival (OS). Here, we examined the association of relapse-free survival (RFS) and post-progression survival (PPS) with OS in patients with postoperative recurrence of NSCLC. METHODS: We evaluated 128 patients with NSCLC who underwent complete resection between January 2007 and December 2018. The association between RFS and PPS on OS was examined at the patient level. RESULTS: Spearman's rank correlation and linear regression analyses revealed that PPS was strongly correlated with OS (r = 0.83, p < 0.05, R2  = 0.72), whereas RFS was weakly associated with OS (r = 0.56, p < 0.05, R2  = 0.37). Additionally, the performance status at relapse and administration of tyrosine kinase inhibitors were significantly correlated with PPS. CONCLUSIONS: PPS was significantly more strongly correlated with OS than was RFS in patients with postoperative recurrence of NSCLC. These results suggest that therapy following postoperative recurrence affects OS. Therefore, it is necessary to validate these promising results in a large prospective study.

Management of Lung Cancer-Associated Malignant Pericardial Effusion with Intrapericardial Administration of Carboplatin: A Retrospective Study.

It has been reported that 5.1-7.0% of acute pericarditis are carcinomatous pericarditis. Malignant pericardial effusion (MPE) can progress to cardiac tamponade, which is a life-threatening condition. The effectiveness and feasibility of intrapericardial instillation of carboplatin (CBDCA; 150 mg/body) have never been evaluated in patients with lung cancer, which is the most common cause of MPE. Therefore, we evaluated the effectiveness and feasibility of intrapericardial administration of CBDCA following catheter drainage in patients with lung cancer-associated MPE. In this retrospective study, 21 patients with symptomatic lung cancer-associated MPE, who were administered intrapericardial CBDCA (150 mg/body) at Gunma Prefectural Cancer Center between January 2005 and March 2018, were included. The patients' characteristics, response to treatment, and toxicity incidence were evaluated. Thirty days after the intrapericardial administration of CBDCA, MPE was controlled in 66.7% of the cases. The median survival period from the day of administration until death or last follow-up was 71 days (range: 10-2435 days). Grade 1-2 pain, nausea, fever, and neutropenia were noted after intrapericardial CBDCA administration. No treatment-related deaths were noted in the current study. Intrapericardial administration of CBDCA (150 mg/body) did not cause serious toxicity, and patients exhibited promising responses to lung cancer-associated MPE. Prospective studies using larger sample sizes are needed to explore the efficacy and safety of this treatment for managing lung cancer-associated MPE.

Glutathione redox regulates TGF-beta-induced fibrogenic effects through Smad3 activation.

Transforming growth factor-beta (TGF-beta) plays a pivotal role in the fibrogenic action involved in the induction of connective tissue growth factor (CTGF), extracellular matrix and fibroblast transformation. Smad3 mediates TGF-beta signaling related to the fibrotic response. In human lung fibroblasts or bronchial smooth muscle cells, we demonstrated that an increase in the intracellular glutathione level suppressed TGF-beta1-induced phosphorylation of Smad3, while inhibiting TGF-beta1-induced expressions of CTGF, collagen type1, fibronectin and transformation into myofibroblasts, which are characterized by the expression of alpha-smooth muscle actin. These data indicate that the intracellular glutathione redox status regulates TGF-beta-induced fibrogenic effects through Smad3 activation.

C-Jun-NH2-terminal kinase mediates expression of connective tissue growth factor induced by transforming growth factor-beta1 in human lung fibroblasts.

Many of the fibrogenic effects of transforming growth factor-beta (TGF-beta) might be mediated by connective tissue growth factor (CTGF). The present study investigates the role of mitogen-activated protein (MAP) kinase in the expression of CTGF mRNA in the human lung fibroblast line, HFL-1. TGF-beta1 enhanced CTGF mRNA levels in a time- and concentration-dependent manner, and this enhancement was also dependent upon transcription. Inhibition of p38 MAP kinase or extracellular signal-regulated kinase (ERK) activation did not affect TGF-beta1-induced CTGF expression. On the other hand, specific inhibitors of phosphatidylinositol 3-kinase (PI3K) suppressed TGF-beta1-induced CTGF expression in a concentration-dependent manner. TGF-beta1 activated c-Jun NH2-terminal kinase (JNK) and p38 MAP kinase, but not ERK in HFL-1 cells. PI3K inhibitors dose-dependently suppressed TGF-beta1-induced JNK, but not p38 MAP kinase activation. Finally, JNK1 and JNK2 antisense oligonucleotides attenuated cellular levels of JNK1 and JNK2 protein, respectively, and repressed TGF-beta1-induced CTGF expression. These results suggest that TGF-beta1-induced CTGF mRNA expression is mediated through the JNK-dependent pathway, whereas p38 MAP kinase and ERK pathways minimally contribute.

Ambroxol inhibits platelet-derived growth factor production in human monocytic cells.

Several growth factors, including platelet-derived growth factor (PDGF), have been implicated in the mechanism of lung and airway remodeling. We investigated the effect of ambroxol, trans-4-[(2-amino-3,5-dibromobenzyl) amino] cyclohexanol hydrochloride, on the lipopolysaccharide-induced PDGF production in human monocytic cells, THP-1. Ambroxol inhibited the lipopolysaccharide-induced PDGF-AB production via PDGF-A mRNA expression. Lipopolysaccharide activated p44/42 extracellular signal-regulated kinase (ERK), and ambroxol attenuated the lipopolysaccharide-induced p44/42 ERK activation. Furthermore, mitogen-activated protein kinase kinase (MEK)-1-specific inhibitor, 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD 98059), blocked the lipopolysaccharide-induced p44/42 ERK activation and PDGF production. These findings indicate that ambroxol inhibits the lipopolysaccharide-induced PDGF production due to the suppression of p44/42 ERK activity.