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Accurate prediction of postoperative recurrence is important for optimizing the treatment strategies for non-small cell lung cancer (NSCLC). Previous studies identified the PD-L1 expression in NSCLC as a risk factor for postoperative recurrence. This study aimed to examine the contribution of PD-L1 expression to predicting postoperative recurrence using machine learning. The clinical data of 647 patients with NSCLC who underwent surgical resection were collected and stratified into training (80%), validation (10%), and testing (10%) datasets. Machine learning models were trained on the training data using clinical parameters including PD-L1 expression. The top-performing model was assessed on the test data using the SHAP analysis and partial dependence plots to quantify the contribution of the PD-L1 expression. Multivariate Cox proportional hazards model was used to validate the association between PD-L1 expression and postoperative recurrence. The random forest model demonstrated the highest predictive performance with the SHAP analysis, highlighting PD-L1 expression as an important feature, and the multivariate Cox analysis indicated a significant increase in the risk of postoperative recurrence with each increment in PD-L1 expression. These findings suggest that variations in PD-L1 expression may provide valuable information for clinical decision-making regarding lung cancer treatment strategies.
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Antígeno B7-H1 , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Recurrencia Local de Neoplasia , Humanos , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Neoplasias Pulmonares/cirugía , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Factores de Riesgo , Aprendizaje Automático , Biomarcadores de Tumor/metabolismo , Modelos de Riesgos Proporcionales , Periodo Posoperatorio , PronósticoRESUMEN
Introduction: Immune checkpoint inhibitors have recently been approved for the treatment of early-stage NSCLC in the perioperative setting on the basis of phase 3 trials. However, the characteristics of such patients who are susceptible to recurrence after adjuvant chemotherapy or who are likely to benefit from postoperative immunotherapy have remained unclear. Methods: This biomarker study (WJOG12219LTR) was designed to evaluate cancer stem cell markers (CD44 and CD133), programmed death-ligand 1 (PD-L1) expression on tumor cells, CD8 expression on tumor-infiltrating lymphocytes, and tumor mutation burden in completely resected stage II to IIIA NSCLC with the use of archived DNA and tissue samples from the prospective WJOG4107 trial. Tumors were classified as inflamed or noninflamed on the basis of the PD-L1 tumor proportion score and CD8+ tumor-infiltrating lymphocyte density. The association between each potential biomarker and relapse-free survival (RFS) during adjuvant chemotherapy was assessed by Kaplan-Meier analysis. Results: A total of 117 patients were included in this study. The median RFS was not reached (95% confidence intervals [CI]: 22.4 mo-not reached; n = 39) and 23.7 months (95% CI: 14.5-43.6; n = 41) in patients with inflamed or noninflamed adenocarcinoma, respectively (log-rank p = 0.02, hazard ratio of 0.52 [95% CI: 0.29-0.93]). Analysis of the combination of tumor inflammation category and TP53 mutation status revealed that inflamed tumors without TP53 mutations were associated with the longest RFS. Conclusions: PD-L1 expression on tumor cells, CD8+ T cell infiltration, and TP53 mutation status may help identify patients with early-stage NSCLC susceptible to recurrence after adjuvant chemotherapy.
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Background: ALK-tyrosine kinase inhibitors (ALK-TKIs) are effective for treating non-small-cell lung cancer with ALK gene rearrangement; however, resistance is inevitable. Brigatinib is a unique ALK-TKI that is effective against many resistance mutations. However, data on factors associated with its efficacy and resistance mechanisms are limited. Objectives: This study will evaluate the efficacy and safety of brigatinib in the real world and explore factors related to its efficacy, safety, and resistance mechanisms. Design: Prospective observational study. Ethics: This study is approved by the Ethics Committee of Wakayama Medical University. Written informed consent will be obtained from all patients before study-related procedures. Methods and analysis: This study comprises three cohorts. Cohorts A, B, and 0 will enroll patients receiving alectinib as the first ALK-TKI, receiving alectinib as the first ALK-TKI and subsequently cytotoxic agents and/or lorlatinib after alectinib, and without a history of ALK-TKI, respectively. Overall, 100, 30, and 50 patients will be enrolled in Cohorts A, B, and 0, respectively. Circulating tumor DNA before starting brigatinib and at disease progression will be analyzed in all cohorts using a hypersensitive next-generation sequencing (NGS) PGDx Elio plasma resolve panel. Serum protein levels will be analyzed using the Milliplex xMAP assay system with a Luminex 200 (Luminex, Austin, USA). The enrollment period is 31 months and the patients will be observed for 2 years after enrollment. Archived tissues will be collected for NGS analysis, gene expression analysis, and immunohistochemistry staining 1 year after completion of registration. Quality of life and safety evaluation using electronic patient-reported outcomes will be investigated. Discussion: This study will elucidate predictors of ALK-TKI efficacy and resistance mechanisms and evaluate the efficacy and safety of brigatinib in a real-world setting. The results will provide crucial information for establishing treatment strategies, discovering novel biomarkers, and developing new therapeutic agents. Trial registration: UMIN000042439.
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PURPOSE: E7389-LF is a liposomal formulation of eribulin that contributes to tumor vascular remodeling. The phase II part of this phase Ib/II study assessed the efficacy/safety of E7389-LF in combination with nivolumab in several disease cohorts; herein, we report results from the small cell lung cancer (SCLC) cohort. EXPERIMENTAL DESIGN: Patients with unresectable/measurable SCLC and disease progression with first-line platinum-based chemotherapy with/without an immune checkpoint inhibitor (ICI) were enrolled to receive E7389-LF 2.1 mg/m2 plus nivolumab 360 mg intravenously every 3 weeks. The primary objective of this part was to assess the objective response rate (ORR). Secondary objectives included assessments of safety and progression-free survival (PFS); exploratory assessments included overall survival (OS) and biomarkers. RESULTS: Thirty-four patients were enrolled. By the data cut-off date (May 31, 2022), 29 (85.3%) had discontinued. Efficacy/biomarker analyses included 33 patients (1 had their diagnosis changed postenrollment); the ORR of E7389-LF plus nivolumab was 24.2% [95% confidence interval (CI): 11.1-42.3], the median PFS was 3.98 months (95% CI: 2.63-4.40), and, at a median follow-up of 10.6 months, the median OS was not reached (95% CI: not estimable). Notably, 27 of 33 patients (81.8%) had received an ICI as their prior first-line therapy. Treatment-related, treatment-emergent adverse events occurred in 97.1% (any grade) and 82.4% (grade ≥3) of enrolled patients; the most common event was neutropenia. Changes in vascular and immune-related plasma markers were observed. CONCLUSIONS: E7389-LF 2.1 mg/m2 in combination with nivolumab 360 mg every 3 weeks showed notable antitumor activity as second-line therapy for SCLC; no new safety signals were observed compared with either agent as monotherapy. SIGNIFICANCE: This phase II part of a phase Ib/II study assessed liposomal eribulin (E7389-LF) plus nivolumab in 34 patients with pretreated SCLC; 8 of 33 evaluable patients (including 6/27 pretreated with ICIs) had objective responses. The combination was tolerable; increases in vasculature-related biomarkers tended to correlate with responses.
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Furanos , Cetonas , Neoplasias Pulmonares , Policétidos Poliéteres , Carcinoma Pulmonar de Células Pequeñas , Alcaloides de la Vinca , Humanos , Nivolumab/efectos adversos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Alcaloides de la Vinca/uso terapéutico , BiomarcadoresRESUMEN
The phase III IMPACT study (UMIN000044738) compared adjuvant gefitinib with cisplatin plus vinorelbine (cis/vin) in completely resected epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Although the primary endpoint of disease-free survival (DFS) was not met, we searched for molecular predictors of adjuvant gefitinib efficacy. Of 234 patients enrolled in the IMPACT study, 202 patients were analyzed for 409 cancer-related gene mutations and tumor mutation burden using resected lung cancer specimens. Frequent somatic mutations included tumor protein p53 (TP53; 58.4%), CUB and Sushi multiple domains 3 (CSMD3; 11.8%), and NOTCH1 (9.9%). Multivariate analysis showed that NOTCH1 co-mutation was a significant poor prognostic factor for overall survival (OS) in the gefitinib group and cAMP response element binding protein (CREBBP) co-mutation for DFS and OS in the cis/vin group. In patients with NOTCH1 co-mutations, gefitinib group had a shorter OS than cis/vin group (Hazard ratio 5.49, 95% CI 1.07-28.00), with a significant interaction (P for interaction = 0.039). In patients with CREBBP co-mutations, the gefitinib group had a longer DFS than the cis/vin group, with a significant interaction (P for interaction = 0.058). In completely resected EGFR-mutated NSCLC, NOTCH1 and CREBBP mutations might predict poor outcome in patients treated with gefitinib and cis/vin, respectively.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Gefitinib , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirugía , Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Investigación Biomédica Traslacional , Receptores ErbB/genética , Cisplatino , Vinorelbina/uso terapéutico , Mutación/genética , Inhibidores de Proteínas Quinasas/efectos adversos , Receptor Notch1/genética , Proteína de Unión a CREB/genéticaRESUMEN
Importance: Non-small cell lung cancer (NSCLC) with uncommon EGFR mutations is a rare subgroup, composing 14% of all EGFR mutations. Objective: To determine the usefulness of osimertinib in previously untreated patients with metastatic NSCLC harboring uncommon EGFR mutations, excluding exon 20 insertion mutations. Design, Setting, and Participants: This multicenter, open-label, single-group, phase 2 nonrandomized clinical trial enrolled patients from April 10, 2020, to May 31, 2022, with a follow-up of 6 months from the date the last patient was enrolled. The study enrolled 42 patients with uncommon EGFR mutations, of whom 40 were eligible. Intervention: Osimertinib, 80 mg once daily, was administered orally to patients. Main Outcomes and Measures: The primary end point was the overall response rate (ORR). The secondary end points were disease control rate (DCR), progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS), duration of response (DoR), and safety of osimertinib. Patients were included in the study on an intention-to-treat basis. Results: Of the 40 eligible patients, 22 were men (55.0%) and the median age was 72 years (range, 39.0-88.0 years). The most common mutations were G719X (20 [50.0%]), S768I (10 [25.0%]), and L861Q (8 [20.0%]). The ORR was 55.0% (90% CI, 40.9%-68.5%) and the DCR was 90.0% (95% CI, 76.3%-97.2%). The median PFS was 9.4 months (95% CI, 3.7-15.2 months) after a median follow-up of 12.7 months (range, 2.7-30.7 months). The median TTF was 9.5 months (95% CI, 5.6-30.3 months), median OS was not reached (NR; 95% CI, 19.3 months to NR), and median DoR was 22.7 months (95% CI, 9.5 months to NR). The ORR for patients with solitary or compound uncommon EGFR mutations was 45.5% (90% CI, 26.9%-65.3%) and 66.7% (90% CI, 43.7%-83.7%), respectively. Median PFS for patients with solitary or compound uncommon EGFR mutations was 5.4 months (95% CI, 3.6-22.7 months) and 9.8 months (95% CI, 5.1 months to NR), respectively. Median OS for patients with solitary or compound uncommon EGFR mutations was 23.0 months (95% CI, 12.3 months to NR) and NR, respectively. Median DoR for patients with solitary or compound uncommon EGFR mutations was 22.7 months (95% CI, 3.6-22.7 months) or NR (95% CI, 5.7 months to NR), respectively. Grade 3 or 4 adverse events were reported by 11 patients (27.5%), and 5 patients (12.5%) developed interstitial lung disease. All adverse events were manageable, and there were no treatment-related deaths. Conclusions and Relevance: Osimertinib showed clinical activity with manageable toxic effects among previously untreated patients with metastatic NSCLC harboring uncommon EGFR mutations other than exon 20 insertion mutations. The results support the use of osimertinib as a treatment option for this patient population. Trial Registration: Japan Registry of Clinical Trials Identifier: jRCTs071200002.
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Acrilamidas , Compuestos de Anilina , Carcinoma de Pulmón de Células no Pequeñas , Indoles , Neoplasias Pulmonares , Pirimidinas , Masculino , Humanos , Anciano , Femenino , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Receptores ErbB/genética , MutaciónRESUMEN
Introduction: Perioperative treatment in NSCLC has gained marked attention with the introduction of immune checkpoint inhibitors. Such a paradigm shift has given us additional opportunities to evaluate potential biomarkers in patients with these curable disease stages. Methods: This study (WJOG12319LTR) was designed as a biomarker study to evaluate whether soluble immune markers were prognostic or predictive on relapse-free survival in patients with stage II to IIIA NSCLC who underwent complete resection and adjuvant chemotherapy with cisplatin plus S-1, which is an oral fluoropyrimidine formulation that consists of tegafur, gimeracil, and oteracil, or S-1 alone in the previous WJOG4107 study. Archived plasma samples were assayed for soluble (s) forms of programmed cell death protein 1 (sPD-1), programmed death-ligand 1(sPD-L1), and CTLA-4 (sCTLA-4) with the highly sensitive HISCL system. Using time-dependent receiver operating characteristic curve analysis, the area under the curves were derived and optimal cutoff values were determined. Using the cutoff values, whether the marker was prognostic or predictive was assessed by survival analysis. Results: A total of 150 patients were included in the study. The time-dependent receiver operating characteristics analysis revealed that the area under the curves for sPD-1, sPD-L1, and sCTLA-4 were 0.54, 0.51, and 0.58, respectively. The survival analysis did not reject that hazard ratios were 1 in terms of the soluble immune marker and the treatment-marker interaction for all three markers. Conclusions: There was no proof that circulating concentrations of sPD-1, sPD-L1, and sCTLA-4 were prognostic or predictive factors of the outcome for adjuvant chemotherapy after complete resection in patients with NSCLC.
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BACKGROUND: While PD-L1 expression and neutrophil-to-lymphocyte ratio (NLR) are prognostic biomarkers for lung cancer, few studies have considered their interaction. We hypothesized that the product of PD-L1 expression (tumor proportion score) and the NLR (PD-L1 × NLR) might be a postoperative prognostic marker reflecting the immune microenvironment of lung cancer. METHODS: We analyzed the association between PD-L1 × NLR and postoperative recurrence-free survival in 647 patients with NSCLC using multivariable Cox proportional hazards models. RESULTS: In the analysis of PD-L1 × NLR as a categorical variable, the group with PD-L1 × NLR ≥ 25.8 had a significantly higher hazard ratio (HR) than the group with < 25.8 (adjusted HR 1.78, 95% confidence interval [CI] 1.23-2.60). The adjusted HR for PD-L1 × NLR, considered a continuous variable, was 1.004 (95% CI, 1.002-1.006). The risk of postoperative recurrence increased by 1.004-fold for each unit increase in PD-L1 × NLR, and a more than 2-fold increase in risk was observed for values ≥ 170. CONCLUSIONS: PD-L1 × NLR may be used in real-world clinical practice as a novel factor for predicting the risk of postoperative recurrence after lung cancer surgery.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neutrófilos/patología , Pronóstico , Antígeno B7-H1 , Estudios Retrospectivos , Linfocitos/patología , Microambiente TumoralRESUMEN
Background: Next-generation sequencing (NGS) analysis is becoming indispensable for the treatment of advanced lung cancer. NGS analysis requires a large number of cancer cell-containing tissues; however, it is often difficult for small biopsies to obtain the required quantities. In microdissection, only the tumour parts of a tissue specimen are obtained, which thereby increases the tumour content and tumour cell count of the tissue specimen. In this study, we investigated the extent to which the detection rate of genetic mutations changes by increasing the tumour content using microdissection. Patients and methods: This is a retrospective study. In the genetic panel test using the Oncomine Dx Target Test (ODxTT), participants were divided into two groups: before (group A; April 2021-March 2022) and after (group B; April 2022-December 2022) the introduction of microdissection. The submission criteria for ODxTT were tumour content and tumour cell count >30 % and >2000 in group A, and >40 % and >5000 in group B, respectively. We compared the rate of genetic mutations detected using ODxTT between the two groups. Results: This study included 214 consecutive ODxTT cases between April 2021 and December 2022. In group A (n = 112), 65 cases were adenocarcinoma, 84 involved lung tissue, and 64 underwent bronchoscopic sampling, whereas in group B (n = 102), 55 cases were adenocarcinoma, 91 cases involved lung tissue, and 79 cases underwent bronchoscopic sampling. Furthermore, genetic mutations were detected in 39 of 112 cases (35 %) in group A and 59 of 102 cases (58 %) in group B, which was statistically higher in group B (P = 0.0006). Genetic mutations were detected in 45 of 55 adenocarcinoma cases in group B. The genetic mutations detected in epidermal growth factor rescepor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), and mesenchymal epithelial transition (MET) were higher in group B. Conclusion: Increasing the number of tumour cells and tumour content can enhance the detection rate of genetic mutations using ODxTT.
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BACKGROUND: Osteoblastic bone reaction (OBR) refers to an increase in bone density at the site of bone metastasis or the appearance of new sclerotic bone lesions after anticancer treatment. OBR can be misunderstood as disease progression. In this study, we aimed to investigate the prevalence and details of OBR and its association with clinical outcomes in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) treated with osimertinib. METHODS: This was a single-center, retrospective cohort study. We reviewed patients who were diagnosed with EGFR-mutant NSCLC with bone metastasis and received osimertinib as a first-line treatment between February 2018 and October 2022. The OBR was evaluated by comparing baseline computed tomography (CT) scans with the first CT scan after treatment initiation. RESULTS: A total of 45 patients were included in this study. Thirty-seven patients (82%) developed OBR. OBR developed in 94% (n = 16) of patients with sclerotic bone lesions (n = 17) at baseline. Similarly, OBR developed in lytic and mixed bone lesions in 76% and 82% of patients with lytic and mixed lesions, respectively. Progression-free survival (PFS) did not differ significantly between patients with (OBR group) and without OBR (non-OBR group) (median PFS, 24 months vs. 17 months; hazard ratio (HR), 0.62; 95% CI, 0.24-1.6; p = 0.31). In univariate analysis, the OBR group showed a trend toward longer skeletal-related events-free survival (SRE-FS) than the non-OBR group (median SRE-FS, 26 months vs. 12 months; HR, 0.53; 95% CI, 0.21-1.33; p = 0.16). Multivariate analysis showed OBR was a significant independent predictor of SRE-FS (HR, 0.35; 95% CI, 0.13-0.92; p = 0.034). CONCLUSIONS: OBR developed in most patients with NSCLC and bone metastasis who received osimertinib treatment. The increased incidence of OBR in patients with EGFR-mutant NSCLC with bone metastasis treated with osimertinib should not be confused with disease progression, and treatment decisions should be made carefully.
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Enfermedades Óseas , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Estudios Retrospectivos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Progresión de la Enfermedad , Receptores ErbB/genética , MutaciónRESUMEN
BACKGROUND: This study evaluated the efficacy and safety of the combination chemotherapy of docetaxel plus S-1 in patients with previously treated non-small cell lung cancer (NSCLC) compared to docetaxel alone. METHODS: Patients with previously treated NSCLC were randomly assigned to docetaxel alone (arm A) or a combination of docetaxel and S-1 (arm B) for a maximum of four cycles. The primary endpoint was overall survival (OS). RESULTS: The study was terminated early because of poor accrual. The number of patients evaluated were 74 and 77 in arm A and arm B, respectively. The median OS was 9.8 months (95% confidence interval [CI]: 6.8-15.2) and 12.3 months (95% CI: 9.2-14.5) in arms A and B, respectively. In arms A and B, the median progression-free survival was 3.5 months (95% CI: 2.7-4.0) and 4.1 months (95% CI: 3.2-4.7), respectively. No statistically significant difference was observed in OS (hazard ratio [HR]: 0.984, 95% CI: 0.682-1.419, p = 0.4569) or progression-free survival (HR: 0.823, 95% CI: 0.528-1.282, p = 0.0953). The major toxicity was myelosuppression. The incidence of grade 3 or more neutropenia was higher in arm A than in arm B (44.6% vs. 35.1%). However, the incidence of grade 3 or more febrile neutropenia and infection with neutropenia (12.2% vs. 22.1%) was more frequently observed in arm B. CONCLUSIONS: The prematurely terminated study did not show the benefit of two cytotoxic agents over single-agent therapy for previously treated NSCLC patients.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Neutropenia , Humanos , Docetaxel/uso terapéutico , Taxoides/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Resultado del TratamientoRESUMEN
The patients harboring EGFR-mutated non-small-cell lung cancer, treated with EGFR tyrosine kinase inhibitor will lead to longer survival than those having non-small-cell lung cancer (NSCLC) patient who do not harbor EGFR mutations. This ongoing clinical trial is to investigate the secondary chemoprevention effect of osimertinib from CNS with platinum doublets chemotherapy in patients who had progressive disease outside of CNS lesions. The aim of this randomized, phase II trial is to evaluate platinum and pemetrexed chemotherapy followed by pemetrexed maintenance with or without continuation of osimertinib for secondary CNS prevention in patients with brain metastatic NSCLC with EGFR mutation, with other than CNS lesions, but no progressive disease in the CNS lesion after osimertinib. The primary end point is to assess progression-free survival by investigator assessment. The key secondary end points are overall survival, response rate, time to CNS controlling, time to whole-brain irradiation and safety. Clinical trial registration: Japan Registry of Clinical Trials (jRCT), Japan (jRCTs071200029).
The authors are conducting a clinical trial aimed at improving treatment for individuals diagnosed with non-small-cell lung cancer, a specific type of lung cancer. In some cases, this cancer can spread to the brain. This study focuses on patients whose cancer is stable in the brain but progressing in other parts of the body. The study is comparing two different treatment approaches. One involves a combination of two drugs, platinum and pemetrexed, while the other combines these drugs with a third one called osimertinib. The main objective is to determine if continuing osimertinib treatment benefits these patients. The authors are evaluating the time it takes for the cancer to start growing again, known as progression-free survival, to identify the most effective treatment. Progression-free survival represents the duration that patients live without their disease worsening. This study, the EPONA study, will provide valuable insights into optimizing the treatment of this type of cancer.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias del Sistema Nervioso Central , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Pemetrexed , Platino (Metal) , Receptores ErbB/genética , Compuestos de Anilina/efectos adversos , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/genética , Mutación , Inhibidores de Proteínas Quinasas/efectos adversosRESUMEN
BACKGROUND/AIM: Disparities in the results of next-generation sequencing-based multiplex gene panel tests and those of single-gene tests when detecting epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) have been reported. However, the possible underlying causes have not been investigated. The aim of this study was to explore the possibilities and causes of false results obtained using cobas® EGFR Mutation Test v2 (cobas® EGFR) and Oncomine Dx Target Test (ODxTT). PATIENTS AND METHODS: The data of patients with NSCLC who underwent gene assessment using both cobas® EGFR and ODxTT between April 2021 and May 2022 were retrospectively reviewed. Disparate results of EGFR mutation analyses were then reviewed. RESULTS: One hundred and sixteen patients were included in the analysis. The results of six samples were inconsistent. In four samples, exon 20 insertion mutations were detected using cobas® EGFR, but not identified using ODxTT. A fragment analysis was performed on three of the four samples, and all showed negative results for exon 20 insertion. Furthermore, one false negative result was obtained in the ODxTT for both exon 19 deletion and L858R mutations. For exon 19 deletion mutation, a single nucleotide variant from adenine to thymine was identified close to the mutation site. CONCLUSION: False positives for exon 20 insertion may occur when using cobas® EGFR, and false negatives for exon 19 deletion and L858R mutations may occur when using ODxTT.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/diagnóstico , Estudios Retrospectivos , Mutación , Receptores ErbB/genéticaRESUMEN
The global phase III KEYNOTE-407 (NCT02775435) trial showed that pembrolizumab plus chemotherapy prolonged overall and progression-free survival (OS/PFS) versus placebo plus chemotherapy in patients with metastatic squamous non-small-cell lung cancer (NSCLC). We present outcomes of patients from Japan enrolled in KEYNOTE-407. Patients were randomized 1:1 to receive pembrolizumab 200 mg or placebo with paclitaxel 200 mg/m2 every 3 weeks (Q3W) or nab-paclitaxel 100 mg/m2 (weekly) plus carboplatin area under the concentration-time curve of 6 mg/mL/min Q3W for four cycles, followed by pembrolizumab or placebo Q3W for a total of 35 cycles. Primary end-points were OS and PFS per RECIST version 1.1 by blinded independent central review. Fifty patients were randomized at Japanese sites (pembrolizumab plus chemotherapy, n = 22; placebo plus chemotherapy, n = 28). Median follow-up time at data cut-off (May 9, 2019) was 15.1 (range, 0.5-24.0) months. Median OS (95% confidence interval [CI]) was 17.3 (12.5-not reached) versus 11.0 (8.6-19.5) months in the pembrolizumab plus chemotherapy versus placebo plus chemotherapy group (hazard ratio [HR] 0.56; 95% CI, 0.27-1.15). Median PFS (95% CI) was 8.3 (6.1-13.0) versus 7.2 (3.9-8.8) months (HR 0.65; 95% CI, 0.35-1.23). Grade 3-5 adverse events (AEs) occurred in 86% and 75% of patients, respectively. There were three fatal AEs, two of which were treatment-related (one from each treatment group, pneumonitis and pulmonary hemorrhage). Efficacy and safety outcomes were consistent with the global study and support the use of pembrolizumab plus chemotherapy in Japanese patients with metastatic squamous NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Pueblos del Este de Asia , Paclitaxel , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/etiología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
OBJECTIVES: Cisplatin plus irinotecan has been considered as the standard therapy in younger (<70 years old) patients for extensive-disease small-cell lung cancer (ED-SCLC) in Japan. However, there is a lack of high-quality evidence for the use of irinotecan in elderly patients with ED-SCLC. This study aimed to demonstrate that carboplatin plus irinotecan (CI) improves overall survival (OS) in elderly patients with ED-SCLC. MATERIALS AND METHODS: This was a randomized Phase II/III trial which enrolled elderly patients with ED-SCLC. Patients were randomized to the CI or carboplatin plus etoposide (CE) arm in a 1:1 ratio. The CE group intravenously received carboplatin (AUC 5 mg/ml/min on day 1) and etoposide (80 mg/m2 on days 1-3) every 3 weeks for four cycles. The CI group received carboplatin (AUC 4 mg/ml/min on day 1) and irinotecan (50 mg/m2 on days 1 and 8) intravenously every 3 weeks for 4 cycles. RESULTS: In total, 258 patients were enrolled and randomized (CE arm, 129 patients; CI arm, 129 patients). The median overall survival, progression-free survival, and objective response rate of the CE vs. CI arms were 12.0 (95% CI, 9.3-13.7) vs. 13.2 (95% CI, 11.1-14.6) months (HR, 0.85 (95% CI, 0.65-1.11)) (one-sided P = 0.11), 4.4 (95% CI, 4.0-4.7) vs. 4.9 (95% CI, 4.5-5.2) months (HR, 0.85 (95% CI, 0.66-1.09)), and 59.5% vs. 63.2%, respectively. A higher incidence of myelosuppression was observed in the CE group, whereas a higher incidence of gastrointestinal toxicity was observed in the CI group. Three treatment-related deaths occurred (one due to lung infection in the CE arm, and one due to lung infection and sepsis each in the CI arm). CONCLUSIONS: The CI treatment showed favorable efficacy; however, the difference was not statistically significant. These results suggest that CE should remain as the standard chemotherapy regimen for elderly patients with ED-SCLC.
Asunto(s)
Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Anciano , Carboplatino , Etopósido/uso terapéutico , Irinotecán/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Cisplatino/uso terapéuticoRESUMEN
Vocal code paralysis (VCP) is a rare complication of stereotactic body radiation therapy (SBRT). In most previously reported cases of VCP after SBRT, VCP was left-sided because of anatomic vulnerability. Here, we report a case of right-sided VCP following SBRT for non-small-cell lung cancer. The patient was an 81-year-old man who underwent SBRT for synchronous lung cancer of the right upper and inferior lobes. He subsequently developed radiation pneumonitis and received corticosteroids. Lung contraction persisted, and the mediastinum shifted to the right because of lung volume reduction. After corticosteroids discontinuation, the patient developed hoarseness and voice weakness. An endoscopic test showed right-sided VCP. Imaging examinations did not reveal new lesions, including lung cancer recurrence. Therefore, we diagnosed the patient with SBRT-associated VCP and speculated that the injury to the right vagal nerve and recurrent laryngeal nerve resulted from mechanical traction due to intense lung contraction, which might have induced VCP. We should be alert to VCP following SBRT, even if the target lesions are right-sided.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Radiocirugia , Parálisis de los Pliegues Vocales , Masculino , Humanos , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Neoplasias Pulmonares/cirugía , Parálisis de los Pliegues Vocales/etiología , Radiocirugia/efectos adversos , Recurrencia Local de Neoplasia/complicacionesRESUMEN
Dabrafenib plus trametinib is the standard treatment for BRAF V600E-mutated non-small cell lung cancer. No treatment-related cerebral infarction (CI) has been reported in previous clinical trials. Here, we described a 61-year-old Japanese man with BRAF V600E-mutated lung adenocarcinoma treated with dabrafenib plus trametinib as a third-line treatment. On the 10th day of dabrafenib plus trametinib treatment, the patient developed fever and was urgently hospitalized on the 18th day owing to impaired consciousness. The patient had disseminated intravascular coagulation because of infection, was treated with thrombomodulin and ceftriaxone, and subsequently improved. On the 44th day, dabrafenib plus trametinib was resumed with a one-step dose reduction. Three hours after the first oral administration, the patient developed chills, fever, and hypotension. He received intravenous fluids. On the 64th day, 20 mg prednisolone was administered from the previous day, and dabrafenib plus trametinib was resumed with a further one-step reduction in dose. Five hours after the first oral administration, the patient developed fever, hypotension, paralysis of the right upper and lower limbs, and dysarthria appeared. Head magnetic resonance imaging revealed multiple cerebral infarcts. Hemoconcentration because of intravascular dehydration may have caused CI. In conclusion, CI should be taken into consideration during treatment with dabrafenib plus trametinib.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Pulmón de Células no Pequeñas , Infarto Cerebral , Neoplasias Pulmonares , Humanos , Masculino , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Infarto Cerebral/inducido químicamenteRESUMEN
OBJECTIVES: Ramucirumab (RAM) and docetaxel (DOC) are commonly used after first-line therapy for advanced non-small cell lung cancer (NSCLC). Therefore, we aimed to elucidate sequencing strategies of RAM and DOC following prior treatments, including immune checkpoint inhibitor (ICI), cytotoxic agent (CTx) alone, bevacizumab (BEV), and tyrosine kinase inhibitor (TKI). METHODS: We recruited patients with NSCLC who received RAM and DOC and compared the groups with and without prior ICI, CTx alone, BEV, and TKI, respectively. By tumor response to such treatments, the patients were further classified into "complete response (CR) + partial response (PR)," "stable disease," and "progressive disease" groups, respectively. We compared RAM and DOC efficacy among these groups. RESULTS: In total, 237 patients were registered. In the group with prior ICI, the objective response rate and disease control rate were significantly higher than those without prior ICI (p = 0.012 and 0.028, respectively), and the median progression-free survival (PFS) was also significantly longer (p = 0.027). There were no significant differences in PFS between the groups with and without CTx alone, BEV, and TKI. Multivariate analysis revealed that prior ICI was an independent factor associated with better PFS. Furthermore, the prior ICI group with CR + PR significantly prolonged PFS compared to the group without prior ICI (p = 0.013). CONCLUSION: RAM and DOC may be preferably administered after ICI, rather than after CTx alone, BEV, or TKI, and, furthermore, enhanced if the prior ICI has a favorable tumor response.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Docetaxel/uso terapéutico , Neoplasias Pulmonares/patología , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , RamucirumabRESUMEN
BACKGROUND/AIM: Regimens with bevacizumab (Bev) have high response rates. We previously showed the efficacy of Bev plus carboplatin (CBDCA)/nab-paclitaxel (nab-PTX) in the treatment of non-squamous (non-SQ) non-small lung cell cancer (NSCLC) with malignant pleural effusion in a phase II trial. However, few studies have reported the efficacy and safety of this regimen. Therefore, we conducted a retrospective analysis of the efficacy and safety of Bev plus CBDCA/nab-PTX for patients with NSCLC. PATIENTS AND METHODS: We included patients with non-SQ NSCLC that underwent any number of treatment lines. Patients received a maximum of six cycles of Bev plus CBDCA/nab-PTX every three to four weeks followed by Bev plus nab-PTX every three to four weeks without disease progression or severe toxicities. The administration dose was left to the discretion of the attending physician. RESULTS: We enrolled 48 patients treated with Bev plus CBDCA/nab-PTX between June 2015 and August 2021. The best response rate was 56.3% and the disease control rate was 79.2%. Twenty-three patients received maintenance therapy. Median progression-free and overall survival times were 6.8 and 10.4 months, respectively. Common adverse events included hematological toxicities, including ≥grade 3 neutropenia and neurosensory toxicity. One patient experienced severe bleeding events (grade 3 gastrointestinal bleeding) and another experienced grade 5 toxicity (infection). CONCLUSION: The combination of Bev plus CBDCA/nab-PTX showed good efficacy with acceptable toxicities in non-SQ NSCLC patients, despite the inclusion of patients with late treatment lines and poor performance status.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Neutropenia , Humanos , Bevacizumab/efectos adversos , Carboplatino/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Estudios RetrospectivosRESUMEN
Chest computed tomography (CT) is effective for assessing the severity of coronavirus disease 2019 (COVID-19). However, the clinical factors reflecting the disease progression of COVID-19 pneumonia on chest CT and predicting a subsequent exacerbation remain controversial. We conducted a retrospective cohort study of 450 COVID-19 patients. We used an automated image processing tool to quantify the COVID-19 pneumonia lesion extent on chest CT at admission. The factors associated with the lesion extent were estimated by a multiple regression analysis. After adjusting for background factors by propensity score matching, we conducted a multivariate Cox proportional hazards analysis to identify factors associated with severe disease after admission. The multiple regression analysis identified, body-mass index (BMI), lactate dehydrogenase (LDH), C-reactive protein (CRP), and albumin as continuous variables associated with the lesion extent on chest CT. The standardized partial regression coefficients for them were 1.76, 2.42, 1.54, and 0.71. The multivariate Cox proportional hazards analysis identified LDH (hazard ratio, 1.003; 95% confidence interval, 1.001-1.005) as a factor independently associated with the development of severe COVID-19 pneumonia. Increased serum LDH at admission may be useful in real-world clinical practice for the simple screening of COVID-19 patients at high risk of developing subsequent severe disease.