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Zuo Y, Yang P, Yang R, Hou J, Feng R, Liang P, Liu J. Determination of osimertinib concentration in rat plasma and lung/brain tissues. Am J Transl Res 2024; 16:8008-8022. [PMID: 39822485 PMCID: PMC11733393 DOI: 10.62347/syzd2489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Accepted: 12/06/2024] [Indexed: 01/19/2025]
Abstract
OBJECTIVES The aim of this study was to establish an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the detection of osimertinib in rat plasma, lung and brain tissues. METHODS Forty-eight rats were randomly divided into an experimental group (receiving osimertinib at doses of 5, 8, and 10 mg/kg) and a control group. After continuous intragastric administration for 15 days, samples of blood, lung, and brain tissue were collected. Chromatographic separation was achieved using a BEH C18 column with gradient elution, employing a mobile phase of water (containing 0.1% (v/v) formic acid) and acetonitrile. The concentration of osimertinib in the samples was determined using an AB SCIEX 5500 triple quadrupole mass spectrometer operated in positive electrospray ionization (ESI+) and multiple reaction monitoring (MRM) mode. RESULTS A UPLC-MS/MS analytical method for determining osimertinib concentrations was successfully established and validated. A linear relationship was observed for osimertinib concentrations in plasma within the range of 1-300 ng/mL, and in lung and brain tissues within the range of 0.5-50 ng/mL. The selectivity, accuracy, precision, matrix effect, extraction recovery, and stability all meet the requirements of methodological validation criteria. CONCLUSIONS A rapid and sensitive UPLC-MS/MS method was developed and validated for quantifying osimertinib concentrations in rat plasma, lung, and brain tissues, providing a valuable tool for pharmacokinetic and tissue distribution studies.
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Affiliation(s)
- Yalan Zuo
- Department of Pharmacy, The Fourth Hospital of Hebei Medical UniversityShijiazhuang 050000, Hebei, China
| | - Peidan Yang
- College of Pharmacy, Hebei Medical UniversityShijiazhuang 050000, Hebei, China
| | - Ruixia Yang
- Department of Pharmacy, The Fourth Hospital of Hebei Medical UniversityShijiazhuang 050000, Hebei, China
| | - Juan Hou
- Department of Pharmacy, The Fourth Hospital of Hebei Medical UniversityShijiazhuang 050000, Hebei, China
| | - Rui Feng
- Department of Pharmacy, The Fourth Hospital of Hebei Medical UniversityShijiazhuang 050000, Hebei, China
| | - Ping Liang
- Department of Pharmacy, The Fourth Hospital of Hebei Medical UniversityShijiazhuang 050000, Hebei, China
| | - Jiang Liu
- Department of Pharmacy, The Fourth Hospital of Hebei Medical UniversityShijiazhuang 050000, Hebei, China
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Liu Y, Tan Y, Hu L, Li J, Yang J, Diao L, Yang J. Population pharmacokinetics and exposure-response analyses of SAF-189s in Chinese patients with ALK+/ROS1+ non-small cell lung cancer. Front Pharmacol 2024; 15:1418549. [PMID: 39081957 PMCID: PMC11286589 DOI: 10.3389/fphar.2024.1418549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 06/18/2024] [Indexed: 08/02/2024] Open
Abstract
Objective SAF-189s is a potent ALK/ROS1 inhibitor that is currently in clinical development for treating advanced ALK+/ROS1+ non-small cell lung cancer (NSCLC). Comprehensive population pharmacokinetics (PopPK) and exposure-response models were developed to evaluate the efficacy and safety of SAF-189s by integrating data from two clinical studies. Methods The PopPK model was developed using plasma concentration data collected from patients with ALK+/ROS1+ advanced NSCLC (n = 299) and healthy subjects (n = 24). The covariates (demographics, laboratory values, subject types, and concomitant medications) were evaluated to determine their potential influence on the between-patient variability in the pharmacokinetics of SAF-189s. Individual exposure values were then used to investigate the relationships with the efficacy endpoints (overall response rate (ORR), progression-free survival (PFS), and duration of response (DOR)) and key safety endpoints (adverse events of interest). Results The final PopPK model of SAF-189s was described by a one-compartment model with delayed first-order absorption and time-dependent elimination by allowing the clearance to decrease stepwise over time. Age was included as a covariate for apparent clearance (CL/F), while prior anti-cancer therapy in ALK+ patients (ALKPOT) was included for apparent volume of distribution (V/F). There were no apparent exposure-response relationships for any of the efficacy endpoints at doses of 80-210 mg. The relationship between exposure and safety suggested that a higher steady-state exposure was associated with more frequent incidences of hyperglycemia and proteinuria; the 210-mg dose group was also less tolerated than the other low-dose groups. Conclusion PopPK and exposure-response models were developed for SAF-189s, and their results demonstrate that SAF-189s exposures are at the plateau of exposure-response for efficacy. The 210-mg dose group had a significantly higher safety risk, while the 160-mg dose group was well-tolerated. Thus, 160 mg of SAF-189s once daily was selected as the recommended phase III dose for the ALK+/ROS1+ or ROS1+ NSCLC patients.
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Affiliation(s)
- Yinhui Liu
- Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
- Shanghai Fosun Pharmaceutical Development Co., Ltd., Shanghai, China
| | - Yan Tan
- Department of Pharmacometrics, Mosim Co., Ltd, Shanghai, China
| | - Lin Hu
- Shanghai Fosun Pharmaceutical Development Co., Ltd., Shanghai, China
| | - Jinlong Li
- Shanghai Fosun Pharmaceutical Development Co., Ltd., Shanghai, China
| | - Jiansong Yang
- Shanghai Fosun Pharmaceutical Development Co., Ltd., Shanghai, China
| | - Lei Diao
- Department of Pharmacometrics, Mosim Co., Ltd, Shanghai, China
| | - Jin Yang
- Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China
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Peng SONG, Yong CUI. [Progress and Discussion of Perioperative Targeted Therapy in Patients
with EGFR-mutated Resectable Non-small Cell Lung Cancer]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2024; 27:383-390. [PMID: 38880926 PMCID: PMC11183319 DOI: 10.3779/j.issn.1009-3419.2024.106.11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Indexed: 06/18/2024]
Abstract
Lung cancer is still the leading cause of cancer death worldwide. Non-small cell lung cancer (NSCLC) is the main pathological type of lung cancer, accounting for about 80%. Approximately 30% of all patients with NSCLC have resectable early and middle stage disease at the time of diagnosis. Recently, the epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have made a major breakthrough in the adjuvant targeted therapy of EGFR-mutated resectable NSCLC, and are recommended by the guidelines for clinical use. In this review, we summarize the clinical research progress of perioperative adjuvant targeted therapy for EGFR-mutated resectable NSCLC, and discuss the key issues in the clinical researches.
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Uldbjerg EM, Ringgaard L, Andersen KK, Frederiksen LE, Jovanovic A, Meldgaard P. Diagnostic Workup, Treatment Patterns, and Clinical Outcomes in Early-Stage IB-IIIA Non-Small-Cell Lung Cancer Patients in Denmark. Cancers (Basel) 2023; 15:5130. [PMID: 37958305 PMCID: PMC10647574 DOI: 10.3390/cancers15215130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 10/10/2023] [Accepted: 10/19/2023] [Indexed: 11/15/2023] Open
Abstract
Despite recent improvements in early-stage non-small-cell lung cancer (NSCLC), disease relapse remains challenging. Moreover, real-world evidence on long-term follow-up of disease-free survival (DFS) and recurrence patterns in a large, unselected cohort of early-stage NSCLC patients is lacking. This cohort study aimed to assess clinical characteristics, diagnostic workup, treatment, survival, and risk of disease relapse among early-stage NSCLC patients. Adult patients with stage IB, II, or IIIA NSCLC diagnosed and/or treated at Aarhus University Hospital in Denmark from January 2010 to December 2020 were included and followed-up until May 2021. Comprehensive clinical data were collected from electronic medical records of eligible patients and linked to Danish register data. The study population comprised 1341 early-stage NSCLC patients: 22%, 40%, and 38% were diagnosed with stage IB, II, and IIIA disease, respectively. In total, 42% of patients were tested for epidermal growth factor receptor (EGFR), of whom 10% were EGFR-mutation-positive (EGFRm+). Half of all patients received surgery, and nine percent of patients received stereotactic body radiation therapy (SBRT). Disease-free survival 5 years post-diagnosis was 49%, 42%, and 22% for stage IB, II, and stage IIIA patients, respectively. DFS improved over time both for patients treated with surgery and SBRT. However, disease relapse remained a challenge, with approximately 40% of stage IIIA having relapsed 3 years post-diagnosis. This study contributes important knowledge that puts clinical trials on new perioperative treatment modalities for early-stage NSCLC patients into perspective. Our findings cover an essential evidence gap on real-world DFS and recurrence dynamics, confirming that despite an improvement in DFS over time and across different treatment modalities, disease relapse remains a monumental challenge. Therefore, better treatment strategies are needed.
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Affiliation(s)
| | | | | | | | - Aleksandar Jovanovic
- Department of Experimental Oncology, Aarhus University Hospital, 8200 Aarhus, Denmark
| | - Peter Meldgaard
- Department of Oncology, Aarhus University Hospital, 8200 Aarhus, Denmark
- Institute for Clinical Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 35, 8200 Aarhus, Denmark
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Yang Y, Min J, Yang N, Yu Q, Cheng Y, Zhao Y, Li M, Chen H, Ren S, Zhou J, Zhuang W, Qin X, Cao L, Yu Y, Zhang J, He J, Feng J, Yu H, Zhang L, Fang W. Envonalkib versus crizotinib for treatment-naive ALK-positive non-small cell lung cancer: a randomized, multicenter, open-label, phase III trial. Signal Transduct Target Ther 2023; 8:301. [PMID: 37574511 PMCID: PMC10423717 DOI: 10.1038/s41392-023-01538-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 04/28/2023] [Accepted: 06/09/2023] [Indexed: 08/15/2023] Open
Abstract
Anaplastic lymphoma kinase (ALK) rearrangements are present in about 5-6% of non-small cell lung cancer (NSCLC) cases and associated with increased risks of central nervous system (CNS) involvement. Envonalkib, a novel ALK inhibitor, demonstrated promising anti-tumor activity and safety in advanced ALK-positive NSCLC in the first-in-human phase I study. This phase III trial (ClinicalTrials.gov NCT04009317) investigated the efficacy and safety of first-line envonalkib in advanced ALK-positive NSCLC cases. Totally 264 participants were randomized 1:1 to receive envonalkib (n = 131) or crizotinib (n = 133). Median independent review committee (IRC)-assessed progression-free survival (PFS) times were 24.87 (95% confidence interval [CI]: 15.64-30.36) and 11.60 (95% CI: 8.28-13.73) months in the envonalkib and crizotinib groups, respectively (hazard ratio [HR] = 0.47, 95% CI: 0.34-0.64, p < 0.0001). IRC-assessed confirmed objective response rate (ORR) was higher (81.68% vs. 70.68%, p = 0.056) and duration of response was longer (median, 25.79 [95% CI, 16.53-29.47] vs. 11.14 [95% CI, 9.23-16.59] months, p = 0.0003) in the envonalkib group compared with the crizotinib group. In participants with baseline brain target lesions, IRC-assessed CNS-ORR was improved with envonalkib compared with crizotinib (78.95% vs. 23.81%). Overall survival (OS) data were immature, and median OS was not reached in either group (HR = 0.84, 95% CI: 0.48-1.47, p = 0.5741). The 12-month OS rates were 90.6% (95% CI, 84.0%-94.5%) and 89.4% (95% CI, 82.8%-93.6%) in the envonalkib and crizotinib groups, respectively. Grade ≥3 treatment-related adverse events were observed in 55.73% and 42.86% of participants in the envonalkib and crizotinib groups, respectively. Envonalkib significantly improved PFS and delayed brain metastasis progression in advanced ALK-positive NSCLC.
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Affiliation(s)
- Yunpeng Yang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China
| | - Jie Min
- Department of Oncology, The Second Affiliated Hospital of Air Force Medical University, Xi'an, 710038, China
| | - Nong Yang
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, China
| | - Qitao Yu
- Department of Medical Oncology of Respiratory, Affiliated Tumor Hospital of Guangxi Medical University, Guangxi, Nanning, 530021, China
| | - Ying Cheng
- Department of Thoracic Medical Oncology, Jilin Provincial Cancer Hospital, Changchun, 130012, China
| | - Yanqiu Zhao
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450003, China
| | - Manxiang Li
- Department of Respiratory, First Affiliated Hospital of Xian Jiaotong University, Xi'an, 710061, China
| | - Hong Chen
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400050, China
| | - Shou'an Ren
- Department of Respiratory, The First Hospital of Shanxi Medical University, Taiyuan, 030001, China
| | - Jianying Zhou
- Department of Respiratory Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China
| | - Wu Zhuang
- Department of Medical Oncology, Fujian Cancer Hospital, Fuzhou, 350014, China
| | - Xintian Qin
- The First Department of Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510699, China
| | - Lejie Cao
- Department of Respiratory and Critical Care Medicine, Anhui Provincial Hospital, Hefei, 230000, China
| | - Yan Yu
- Department of Respiratory Medicine, Affiliated Cancer Hospital of Harbin Medical University, Harbin, 150000, China
| | - Jian Zhang
- Department of Respiratory Medicine, The First Affiliated Hospital of Air Force Medical University, Xi'an, 710032, China
| | - Jianxing He
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Guangzhou Medical College, Guangzhou Research Institute of Respiratory Disease and China State Key Laboratory of Respiratory Disease, Guangzhou, 510120, China
| | - Jifeng Feng
- Department of Medical Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, 210009, China
| | - Hao Yu
- Department of Biostatistics, Nanjing Medical University, Nanjing, 211166, China
| | - Li Zhang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.
| | - Wenfeng Fang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.
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Li P, Tian X, Wang G, Jiang E, Li Y, Hao G. Acute osimertinib exposure induces electrocardiac changes by synchronously inhibiting the currents of cardiac ion channels. Front Pharmacol 2023; 14:1177003. [PMID: 37324483 PMCID: PMC10267729 DOI: 10.3389/fphar.2023.1177003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 05/16/2023] [Indexed: 06/17/2023] Open
Abstract
Introduction: As the third generation of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), osimertinib has demonstrated more significant cardiotoxicity than previous generations of EGFR-TKIs. Investigating the mechanism of osimertinib cardiotoxicity can provide a reference for a comprehensive understanding of osimertinib-induced cardiotoxicity and the safety of the usage of this drug in clinical practice. Methods: Multichannel electrical mapping with synchronous ECG recording was used to investigate the effects of varying osimertinib concentrations on electrophysiological indicators in isolated Langendorff-perfused hearts of guinea pigs. Additionally, a whole-cell patch clamp was used to detect the impact of osimertinib on the currents of hERG channels transfected into HEK293 cells and the Nav1.5 channel transfected into Chinese hamster ovary cells and acute isolated ventricular myocytes from SD rats. Results: Acute exposure to varying osimertinib concentrations produced prolongation in the PR interval, QT interval, and QRS complex in isolated hearts of guinea pigs. Meanwhile, this exposure could concentration-dependently increase the conduction time in the left atrium, left ventricle, and atrioventricular without affecting the left ventricle conduction velocity. Osimertinib inhibited the hERG channel in a concentration-dependent manner, with an IC50 of 2.21 ± 1.29 μM. Osimertinib also inhibited the Nav1.5 channel in a concentration-dependent manner, with IC50 values in the absence of inactivation, 20% inactivation, and 50% inactivation of 15.58 ± 0.83 μM, 3.24 ± 0.09 μM, and 2.03 ± 0.57 μM, respectively. Osimertinib slightly inhibited the currents of L-type Ca2+ channels in a concentration-dependent manner in acutely isolated rat ventricular myocytes. Discussion: Osimertinib could prolong the QT interval; PR interval; QRS complex; left atrium, left ventricle, and atrioventricular conduction time in isolated guinea pig hearts. Furthermore, osimertinib could block the hERG, Nav1.5, and L-type Ca2+ channels in concentration-dependent manners. Therefore, these findings might be the leading cause of the cardiotoxicity effects, such as QT prolongation and decreased left ventricular ejection fraction.
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Affiliation(s)
- Peiwen Li
- Department of Cardiology, Huaihe Hospital of Henan University, Kaifeng, China
| | - Xiaohui Tian
- Department of Pharmacy, Huaihe Hospital of Henan University, Kaifeng, China
| | - Gongxin Wang
- Department of Research, Scope Research Institute of Electrophysiology, Kaifeng, China
| | - Enshe Jiang
- Institute of Nursing and Health, Henan University, Kaifeng, China
| | - Yanming Li
- Department of Cardiology, Huaihe Hospital of Henan University, Kaifeng, China
| | - Guoliang Hao
- Department of Research, Scope Research Institute of Electrophysiology, Kaifeng, China
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Kris MG, Mitsudomi T, Peters S. Adjuvant therapies in stages I-III epidermal growth factor receptor-mutated lung cancer: current and future perspectives. Transl Lung Cancer Res 2023; 12:824-836. [PMID: 37197636 PMCID: PMC10183392 DOI: 10.21037/tlcr-22-723] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Accepted: 03/08/2023] [Indexed: 05/19/2023]
Abstract
Surgical resection followed by adjuvant cisplatin-based chemotherapy is the recommended treatment for patients with completely resected stage IB-IIIA non-small cell lung cancer (NSCLC). Even with the best management, recurrence is common and increases with disease stage (stage I: 26-45%; stage II: 42-62%; stage III: 70-77%). For patients with metastatic lung cancer and tumours that harbour epidermal growth factor receptor (EGFR) mutations, EGFR-tyrosine kinase inhibitors (TKIs) have improved survival. Their effectiveness in advanced stages of NSCLC raises the possibility that these agents may improve outcomes for patients with resectable EGFR-mutated lung cancer. In the ADAURA study, adjuvant osimertinib provided a significant improvement in disease-free survival (DFS) and reduced central nervous system (CNS) disease recurrence in patients with resected stage IB-IIIA EGFR-mutated NSCLC, with or without prior adjuvant chemotherapy. To reap the maximum benefits of EGFR-TKIs for patients with lung cancer, the early and rapid identification of EGFR mutations [and other oncogenic drivers, such as programmed cell death-ligand 1 (PD-L1), with matched targeted therapies] in diagnostic pathologic specimens has become essential. To ensure patients receive the most appropriate treatment, routine, comprehensive histological, immunohistochemical, and molecular analyses (with multiplex next generation sequencing) should be undertaken at the time of diagnosis. The potential for personalised treatments to cure more patients with early-stage lung cancer can only be realised if all therapies are considered when the care plan is formulated, by the multi-specialty experts managing patients. In this review, we discuss the progress and prospects for adjuvant treatments as part of a comprehensive plan of care for patients with resected stages I-III EGFR-mutated lung cancer, and explore how the field could go beyond DFS and overall survival to make cure a more frequent outcome of treatment in patients with resected EGFR-mutated lung cancer.
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Affiliation(s)
- Mark G. Kris
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Solange Peters
- Centre Hospitalier Universitaire Vaudois, Lausanne University Hospital, Lausanne, Switzerland
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Huang YH, Yang HC, Chiang CL, Wu HM, Luo YH, Hu YS, Lin CJ, Chung WY, Shiau CY, Guo WY, Lee CC. Gamma Knife Radiosurgery Irradiation of Surgical Cavity of Brain Metastases: Factor Analysis and Gene Mutations. LIFE (BASEL, SWITZERLAND) 2023; 13:life13010236. [PMID: 36676186 PMCID: PMC9864800 DOI: 10.3390/life13010236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 01/07/2023] [Accepted: 01/10/2023] [Indexed: 01/19/2023]
Abstract
(1) Background: Surgical resection for the removal of brain metastases often fails to prevent tumor recurrence within the surgical cavity; hence, researchers are divided as to the benefits of radiation treatment following surgical resection. This retrospective study assessed the effects of post-operative stereotactic radiosurgery (SRS) on local tumor control and overall survival. (2) Methods: This study examined the demographics, original tumor characteristics, and surgical outcomes of 97 patients who underwent Gamma Knife Radiosurgery (GKRS) treatment (103 brain metastases). Kaplan-Meier plots and Cox regression were used to correlate clinical features to tumor control and overall survival. (3) Results: The overall tumor control rate was 75.0% and overall 12-month survival was 89.6%. Tumor control rates in the radiation group versus the non-radiation group were as follows: 12 months (83.1% vs. 57.7%) and 24 months (66.1% vs. 50.5%). During the 2-year follow-up period after SRS, the intracranial response rate was higher in the post-craniotomy radiation group than in the non-radiation group (p = 0.027). Cox regression multivariate analysis determined that post-craniotomy irradiation of the surgical cavity is predictive of tumor control (p = 0.035). However, EGFR mutation was not predictive of overall survival or tumor control. (4) Conclusions: Irradiating the surgical cavity after surgery can enhance local tumor control; however, it does not have a significant effect on overall survival.
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Affiliation(s)
- Yi-Han Huang
- Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei 112, Taiwan
| | - Huai-Che Yang
- Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei 112, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
| | - Chi-Lu Chiang
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan
- Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
| | - Hsiu-Mei Wu
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- Department of Radiology, Taipei Veterans General Hospital, Taipei 112, Taiwan
| | - Yung-Hung Luo
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan
| | - Yong-Sin Hu
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- Department of Radiology, Taipei Veterans General Hospital, Taipei 112, Taiwan
| | - Chung-Jung Lin
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- Department of Radiology, Taipei Veterans General Hospital, Taipei 112, Taiwan
| | - Wen-Yuh Chung
- Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei 112, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
| | - Cheng-Ying Shiau
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- Cancer Center, Taipei Veterans General Hospital, Taipei 112, Taiwan
| | - Wan-Yuo Guo
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- Department of Radiology, Taipei Veterans General Hospital, Taipei 112, Taiwan
| | - Cheng-Chia Lee
- Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei 112, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- Brain Research Center, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- Correspondence: ; Tel.: +886-2-28712121
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Chiou GY, Chiang CL, Yang HC, Shen CI, Wu HM, Chen YW, Chen CJ, Luo YH, Hu YS, Lin CJ, Chung WY, Shiau CY, Guo WY, Pan DHC, Lee CC. Combined stereotactic radiosurgery and tyrosine kinase inhibitor therapy versus tyrosine kinase inhibitor therapy alone for the treatment of non-small cell lung cancer patients with brain metastases. J Neurosurg 2022; 137:563-570. [PMID: 34920439 DOI: 10.3171/2021.9.jns211373] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 09/23/2021] [Indexed: 11/06/2022]
Abstract
OBJECTIVE Whether combined radiation and tyrosine kinase inhibitor (TKI) therapy in non-small cell lung cancer (NSCLC) patients with brain metastases (BMs) and epidermal growth factor receptor (EGFR) mutations confers additional benefits over TKI therapy alone remains a matter of debate. The goal of this study was to compare outcomes between combined TKI therapy with stereotactic radiosurgery (SRS) versus TKI therapy alone in NSCLC patients with BMs and EGFR mutations. METHODS Consecutive cases of NSCLC patients with EGFR mutations and BMs treated with TKIs were selected for inclusion in this study. Patients were categorized into two groups based on SRS: TKI therapy alone (group I) and combined SRS and TKI therapy (group II). Patients who had SRS or TKI as salvage therapy and those with prior radiation treatment for BMs were excluded. Tumor control (< 10% increase in tumor volume) and overall survival (OS) rates were compared using Kaplan-Meier analyses. Independent predictors of tumor control and OS were identified using multivariable Cox regression analyses. RESULTS The study cohort comprised 280 patients (n = 90 in group I and n = 190 in group II). Cumulative tumor control rates were higher in group II than in group I (79.8% vs 31.2% at 36 months, p < 0.0001). Cumulative OS rates were comparable between groups I and II (43.8% vs 59.4% at 36 months, p = 0.3203). Independent predictors of tumor control were older age (p < 0.01, HR 1.03), fewer BMs (p < 0.01, HR 1.09), lack of extracranial metastasis (p < 0.02, HR 0.70), and combined SRS and TKI therapy (p < 0.01, HR 0.25). Independent predictors of OS were fewer BMs (p < 0.01, HR 1.04) and a higher Karnofsky Performance Status score (p < 0.01, HR 0.97). CONCLUSIONS Although the OS rate did not differ between TKI therapy with and without SRS, the addition of SRS to TKI therapy resulted in improvement of intracranial tumor control. The lack of effect on survival rate with the addition of SRS may be attributable to extracranial disease progression. The addition of SRS to TKI therapy is recommended for intracranial disease control in NSCLC patients with BMs and EGFR mutations. Potential benefits may include prevention of neurological deficits and seizures. Future prospective studies may help clarify the clinical outcome benefits of SRS in these patients.
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Affiliation(s)
- Guan-Ying Chiou
- 1Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei
| | - Chi-Lu Chiang
- 3School of Medicine, National Yang Ming Chiao Tung University, Taipei
- 5Department of Chest Medicine, Taipei Veterans General Hospital, Taipei
- 8Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; and
| | - Huai-Che Yang
- 1Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei
- 3School of Medicine, National Yang Ming Chiao Tung University, Taipei
| | - Chia-I Shen
- 3School of Medicine, National Yang Ming Chiao Tung University, Taipei
- 5Department of Chest Medicine, Taipei Veterans General Hospital, Taipei
- 8Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; and
| | - Hsiu-Mei Wu
- 2Department of Radiology, Taipei Veterans General Hospital, Taipei
- 3School of Medicine, National Yang Ming Chiao Tung University, Taipei
| | - Yu-Wei Chen
- 1Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei
- 2Department of Radiology, Taipei Veterans General Hospital, Taipei
| | - Ching-Jen Chen
- 9Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia
| | - Yung-Hung Luo
- 3School of Medicine, National Yang Ming Chiao Tung University, Taipei
- 5Department of Chest Medicine, Taipei Veterans General Hospital, Taipei
- 8Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; and
| | - Yong-Sin Hu
- 2Department of Radiology, Taipei Veterans General Hospital, Taipei
- 3School of Medicine, National Yang Ming Chiao Tung University, Taipei
| | - Chung-Jung Lin
- 2Department of Radiology, Taipei Veterans General Hospital, Taipei
- 3School of Medicine, National Yang Ming Chiao Tung University, Taipei
| | - Wen-Yuh Chung
- 1Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei
- 3School of Medicine, National Yang Ming Chiao Tung University, Taipei
| | - Cheng-Ying Shiau
- 3School of Medicine, National Yang Ming Chiao Tung University, Taipei
- 4Cancer Center, Taipei Veterans General Hospital, Taipei
| | - Wan-Yuo Guo
- 2Department of Radiology, Taipei Veterans General Hospital, Taipei
- 3School of Medicine, National Yang Ming Chiao Tung University, Taipei
| | - David Hung-Chi Pan
- 1Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei
- 7Department of Neurosurgery, Shuang Ho Hospital, Taipei Medical University, Taipei
| | - Cheng-Chia Lee
- 1Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei
- 3School of Medicine, National Yang Ming Chiao Tung University, Taipei
- 6Brain Research Center, National Yang Ming Chiao Tung University, Taipei
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10
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Zhu Y, Li L, Zhang P, Zuo Y, Lei Y, Bai J, Cao L, Guo Z. Severe stomatitis caused by osimertinib combined with gefitinib: A case report. Clin Case Rep 2022; 10:e05396. [PMID: 35223006 PMCID: PMC8843833 DOI: 10.1002/ccr3.5396] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 12/31/2021] [Accepted: 01/14/2022] [Indexed: 11/10/2022] Open
Abstract
The 2017 NCCN Guidelines for NSCLC recommend epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) as the first-line treatment for patients with gene-sensitive mutations of pulmonary adenocarcinoma. The TKI combination can effectively inhibit the gene mutations caused by the drug resistance and enhance the antitumor effect. However, more clinical investigations are required of the efficacy and the adverse drug reactions (ADRs) of this combination. A 62-year-old female patient diagnosed as lung adenocarcinoma with brain metastasis, meningeal metastasis, multiple bone metastasis, and liver metastasis was treated with the combination of gefitinib and osimertinib. Evident improvement was observed after 10 days of combined treatment with these tyrosine kinase inhibitors (TKIs), including in the CT features and symptoms. The level of tumor marker CEA decreased significantly after 40 days. However, severe stomatitis occurred after 49 days. By analyzing the relationship between stomatitis and TKI combined treatment based on the temporal correlation, instructions and literature reports, mechanisms, and reaction, we discovered that the combination of the two TKI drugs can increase the incidence and severity of severe stomatitis. Following targeted treatment and drug withdrawal, the patient fully recovered. TKI combination may increase the incidence and severity of stomatitis, suggesting that closely care and timely withdrawal are necessary measures.
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Affiliation(s)
- Ya‐ning Zhu
- Department of PharmacyShaanxi Provincial People's HospitalXi’anChina
| | - Li Li
- Department of PharmacyShaanxi Provincial People's HospitalXi’anChina
| | - Peng Zhang
- Department of PharmacyShaanxi Provincial People's HospitalXi’anChina
| | - Yan Zuo
- Department of PharmacyShaanxi Provincial People's HospitalXi’anChina
| | - Yu Lei
- Department of OncologyShaanxi People’s HospitalXi’anChina
| | - Jun Bai
- Department of OncologyShaanxi People’s HospitalXi’anChina
| | - Lu Cao
- Department of PharmacyShaanxi Provincial People's HospitalXi’anChina
| | - Zhen‐Jun Guo
- Department of PharmacyShaanxi Provincial People's HospitalXi’anChina
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11
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McKay MJ. Brain metastases: increasingly precision medicine-a narrative review. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1629. [PMID: 34926673 PMCID: PMC8640905 DOI: 10.21037/atm-21-3665] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 10/12/2021] [Indexed: 12/13/2022]
Abstract
Objective To broadly review the modern management of brain metastases. Background Brain metastases are the commonest neurological manifestation of cancer and a major cause of morbidity in cancer patients. Brain metastases are increasing in frequency, as a result of longer life expectancy of cancer patients, more sensitive methods for brain metastasis detection and an ageing population. The proportional incidence of brain metastases according to cancer of origin, from greatest to least, is lung cancer, melanoma, renal, breast and colorectal cancers. Patients with lung cancer and melanoma are most likely to have brain metastases at diagnosis. Brain metastases cause a variety of symptoms, depending on their size and location, whether they cause mass effect and oedema, compression of the brain parenchyma, or focal neurological deficits. The major differential diagnoses of brain metastases include primary tumours and vascular/inflammatory lesions. Prognosis is dependent on the site, number and volume of lesions, the patients’ performance status, age and the activity and extent of extracranial disease. Methods English literature articles in PubMed from 1950 to June 2021 were reviewed. Article bibliographies provided further references. Conclusions Treatment of brain metastasis patients has moved from considering them as a homogenous population of patients, to individualised treatment. In those brain metastases patients of satisfactory performance status with a solitary lesion, especially one in a non-eloquent/accessible area causing significant mass effect and/or raised intracranial pressure or for whom the diagnosis is in doubt (histology needed), surgical resection is usually the treatment of choice. For multiple brain metastases, radiotherapy with or without systemic therapies are usually employed. For relatively fit patients with limited numbers of brain metastases (e.g., 4 or less), stereotactic radiosurgery is standard of care. Current clinical trials are testing the efficacy of stereotactic treatment alone for >4 brain metastases (although it is increasingly used for such patients in many centres) as well as integration of local therapies with targeted and immunological therapies in appropriately selected cases. In certain circumstances, cranial irradiation can be omitted.
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Affiliation(s)
- Michael Jerome McKay
- Northern Cancer Service, North West Cancer Centre, Burnie, Tasmania, Australia.,The University of Tasmania, Rural Clinical School, Northwest Regional Hospital, Burnie, Tasmania, Australia
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12
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Chen PY, Wang CC, Hsu CN, Chen CY. Association of EGFR Tyrosine Kinase Inhibitor Treatment With Progression-Free Survival Among Taiwanese Patients With Advanced Lung Adenocarcinoma and EGFR Mutation. Front Pharmacol 2021; 12:720687. [PMID: 34434112 PMCID: PMC8382571 DOI: 10.3389/fphar.2021.720687] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 07/28/2021] [Indexed: 12/25/2022] Open
Abstract
Background: There is limited data on the relative survival rate of first-line therapy of gefitinib, erlotinib (first-generation epidermal growth factor receptor-tyrosine kinase inhibitor [EGFR-TKI]), and afatinib (second-generation EGFR-TKI) in patients with EGFR-mutated advanced lung adenocarcinoma in real-world data, especially in the Asian population. This study aimed to compare the relative survival rate of gefitinib, erlotinib, and afatinib in patients with EGFR-mutated advanced lung adenocarcinoma by real-world data in Taiwan. Methods: This retrospective cohort population-based study included untreated adult patients diagnosed with advanced lung adenocarcinoma who were identified in the Taiwan National Health Insurance Research Database between 2014 and 2017. The date of EGFR-mutated advanced lung adenocarcinoma diagnosis was referred as index date. This outcome evaluated overall survival (OS) and time to treatment failure (TTF) between gefitinib, erlotinib, and afatinib. Switching EGFR-TKIs or chemotherapy and new development of brain metastases were proxies of TTF. Estimated relative treatment effects on OS and TTF among EGFR-TKIs were adjusted by inverse probability of treatment weighting (IPTW) in Cox proportional hazards model. Propensity score (PS) matched pair analyses were performed as sensitivity analyses. Results: The study cohort included 3,695 patients initiated with gefitinib, 3,310 with erlotinib, and 3,041 with afatinib. The mean age among the three treatment groups was 70.4 (±11.6), 66.8 (±11.6), and 64.3 (±11.4) years, and the female percentage was 70.4, 58.6, and 57.7%, respectively. Afatinib showed longer median OS than gefitinib (23.9 vs. 21.3 months; adjusted hazard ratio (aHR), 0.87; p < 0.001) and erlotinib (23.9 vs. 21.8 months; aHR, 0.87; p = 0.001). Consistent results were observed with TTF outcomes. For patients with brain metastases at diagnosis, afatinib showed similar OS with erlotinib (p = 0.917) but superior to gefitinib (p = 0.028). PS matching had similar results with IPTW adjustment in the study population. Conclusion: Afatinib as first-line therapy had better survival outcomes for EGFR-mutated advanced lung adenocarcinoma than gefitinib and erlotinib in the Taiwan population. Both erlotinib and afatinib demonstrated superior treatment effect in patients with initial brain metastases than gefitinib.
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Affiliation(s)
- Po-Yen Chen
- Master Program in Clinical Pharmacy, School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Pharmacy, E-Da Hospital, Kaohsiung, Taiwan
| | - Chin-Chou Wang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, and Department of Occupational Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, Kaohsiung, Taiwan
| | - Chien-Ning Hsu
- Master Program in Clinical Pharmacy, School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Chung-Yu Chen
- Master Program in Clinical Pharmacy, School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Pharmacy, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Center for Big Data Research, Kaohsiung Medical University, Kaohsiung, Taiwan
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13
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Martos-Benítez FD, Soler-Morejón CDD, Lara-Ponce KX, Orama-Requejo V, Burgos-Aragüez D, Larrondo-Muguercia H, Lespoir RW. Critically ill patients with cancer: A clinical perspective. World J Clin Oncol 2020; 11:809-835. [PMID: 33200075 PMCID: PMC7643188 DOI: 10.5306/wjco.v11.i10.809] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Revised: 08/09/2020] [Accepted: 09/14/2020] [Indexed: 02/06/2023] Open
Abstract
Cancer patients account for 15% of all admissions to intensive care unit (ICU) and 5% will experience a critical illness resulting in ICU admission. Mortality rates have decreased during the last decades because of new anticancer therapies and advanced organ support methods. Since early critical care and organ support is associated with improved survival, timely identification of the onset of clinical signs indicating critical illness is crucial to avoid delaying. This article focused on relevant and current information on epidemiology, diagnosis, and treatment of the main clinical disorders experienced by critically ill cancer patients.
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Affiliation(s)
| | | | | | | | | | | | - Rahim W Lespoir
- Intensive Care Unit 8B, Hermanos Ameijeiras Hospital, Havana 10300, Cuba
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14
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Leclair N, Calafiore R, Wu Q, Wolansky L, Bulsara KR. Application of targeted genome sequencing to brain metastasis from non-small cell lung carcinoma: Case report. Neurochirurgie 2020; 66:477-483. [PMID: 33091460 DOI: 10.1016/j.neuchi.2020.09.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 09/11/2020] [Accepted: 09/21/2020] [Indexed: 12/13/2022]
Abstract
Non-small cell lung cancer (NSCLC) is frequently associated with central nervous system metastases resulting in poor outcomes. As newer targeted therapies become available determining which patients can benefit from these therapies has remained challenging, and current molecular testing options rely on a panel of only a handful of known oncogenic drivers. Here, we demonstrate a targeted approach at uncovering clinically relevant variants in cancer-associated genes using genomic sequencing. Our patient underwent targeted sequencing of 212 cancer-associated genes, revealing mutations in six; two of which were in EGFR, an important target for therapy in NSCLC. A multidisciplinary approach involving surgical resection, radiation, and targeted therapy based on the genomic profile and tumor pathology ultimately lead to positive therapeutic response and stable disease. Our report provides a proof of principle for incorporating higher throughput genomic sequencing techniques directly into patient care. We also report an atypical response of an EGFR mutation positive metastatic tumor to immune checkpoint therapy, despite recent reports suggesting that these patients do not benefit from immune checkpoint inhibitors. A brief review of current literature is discussed here to explore links between EGFR mutations and PD-L1 expression, as well as response to targeted therapies.
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Affiliation(s)
- N Leclair
- School of Medicine, University of Connecticut, 263, Farmington Avenue, 06030 Farmington, CT, USA
| | - R Calafiore
- School of Medicine, University of Connecticut, 263, Farmington Avenue, 06030 Farmington, CT, USA
| | - Q Wu
- Department of Pathology and Laboratory Medicine, UConn Health, 263, Farmington Avenue, 06030 Farmington, CT, USA
| | - L Wolansky
- Department of Radiology, UConn Health, 263, Farmington Avenue, 06030 Farmington, CT, USA
| | - K R Bulsara
- Division of Neurosurgery, Department of Surgery, UConn Health, 263, Farmington Avenue, 06030 Farmington, CT, USA.
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15
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Complete Remission of Multiple Brain Metastases in a Patient with EGFR-Mutated Non-Small-Cell Lung Cancer Treated with First-Line Osimertinib without Radiotherapy. Case Rep Oncol Med 2020; 2020:9076168. [PMID: 32257480 PMCID: PMC7109584 DOI: 10.1155/2020/9076168] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Accepted: 03/07/2020] [Indexed: 11/18/2022] Open
Abstract
Osimertinib has demonstrated efficacy against stable or asymptomatic central nervous system (CNS) metastases of epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) in phase 2 and 3 clinical trials that allowed prior CNS radiotherapy. However, the efficacy of osimertinib only or the optimal treatment combination or sequence of radiotherapy has not been investigated. A 74-year-old woman diagnosed with T4N1M1c Stage IVB lung adenocarcinoma with EGFR mutation presented with a left upper lobe mass and multiple bilateral lung metastases. A total of more than 20 asymptomatic multiple brain metastases with a maximum diameter of 12 mm were diagnosed simultaneously. Osimertinib was administered as first-line treatment. Whole brain radiotherapy was deferred because she had no neurological symptoms. After 5 weeks, the multiple brain metastases disappeared completely, together with the response in the lung lesions. This case demonstrated that first-line treatment with osimertinib could even achieve complete remission of multiple brain metastases comprising as many as twenty lesions of EGFR-mutated NSCLC without radiation therapy. Radiation therapy for brain metastases can be deferred or even withheld. A new treatment strategy for EGFR mutated NSCLC with CNS metastases should be investigated using osimertinib, especially regarding optimal combination or sequence of radiotherapy.
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16
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Isla D, Massuti B, Lázaro M, de Alda LR, Gordo R, Ortega-Joaquín N, Oyagüez I. Cost analysis of the management of brain metastases in patients with advanced ALK+ NSCLC: alectinib versus crizotinib. Lung Cancer Manag 2020; 9:LMT28. [PMID: 32256712 PMCID: PMC7110588 DOI: 10.2217/lmt-2019-0011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Aim To estimate management cost of NSCLC ALK+ patients with and without brain metastasis (BM), and to compare annual costs in patients treated with alectinib or crizotinib. Methods Management cost/year (€ 2018) in patients with and without BM was estimated with disaggregated resource consumption provided by local oncologists, including medical visits, hospitalizations, diagnostic/laboratory tests, imaging techniques and surgical procedures. The comparison of costs/year with alectinib and crizotinib, considered the cumulative 12-month incidence of BM in ALEX trial (9.4 and 41.4%, respectively). Results Management cost was €6173.42/patient-year without BM and €21,637.50/patient-year with BM. With alectinib, average cost/patient was lower than crizotinib (€4948.51/patient-year). Conclusion Prevention of BM with alectinib may result in reductions of cost/year in the management of advanced ALK+ NSCLC.
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Affiliation(s)
- Dolores Isla
- Medical Oncology Department, Lozano Blesa University Clinical Hospital, Zaragoza, Spain
| | - Bartomeu Massuti
- Medical Oncology Department, University General Hospital of Alicante, Alicante, Spain
| | - Martín Lázaro
- Medical Oncology Department, University Hospital Complex of Vigo, Vigo, Pontevedra, Spain
| | | | - Rocio Gordo
- Medical Department, Roche Pharma, Madrid, Spain
| | - Nuria Ortega-Joaquín
- Pharmacoeconomics & Outcomes Research Iberia (PORIB), Pozuelo de Alarcón, Madrid, Spain
| | - Itziar Oyagüez
- Pharmacoeconomics & Outcomes Research Iberia (PORIB), Pozuelo de Alarcón, Madrid, Spain
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17
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Yang SH, Kim HY, Lee SI, Jin SJ. The Effect of Epidermal Growth Factor Receptor Mutation on Intracranial Progression-Free Survival of Non-Small Cell Lung Cancer Patients with Brain Metastasis Underwent Gamma Knife Radiosurgery. Brain Tumor Res Treat 2020; 8:103-108. [PMID: 33118342 PMCID: PMC7595855 DOI: 10.14791/btrt.2020.8.e15] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 05/22/2020] [Accepted: 07/14/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The aim of this study was to survey prognostic factors, particularly those focusing on epidermal growth factor receptor (EGFR) mutations, of patients with non-small cell lung cancer (NSCLC) after Gamma Knife Radiosurgery (GKRS) for metastatic brain tumors. METHODS We retrospectively reviewed the medical records of 98 patients with NSCLC who underwent GKRS for brain metastases from August 2010 to July 2017. The primary endpoint was progression-free survival (PFS) of the intracranial disease. We analyzed variables such as age, sex, Karnofsky Performance Status, recursive partitioning analysis (RPA) class, smoking status, primary cancer pathology, EGFR mutations, and time to brain metastases as prognostic factors. RESULTS The median overall survival (OS) of the patients was 16 months [95% confidence interval (CI), 13-21 months]. Median systemic PFS and intracranial PFS were 9 months (95% CI, 8-11 months) and 11 months (95% CI, 7-14 months), respectively. Kaplan-Meier survival analysis revealed that the patients with EGFR mutations had longer intracranial PFS than those without EGFR mutation (median intracranial PFS: 19 vs. 10 months with p=0.01) while they had no benefits in OS and systemic PFS. Furthermore, the patients harboring adenocarcinoma had longer OS (p<0.01) and intracranial PFS (p<0.01) and the patients with lower RPA class had longer OS (p=0.02) and intracranial PFS (p=0.03). CONCLUSION EGFR mutations, primary cancer pathology, and RPA class may be proposed as prognostic factors for intracranial PFS in NSCLC patients after GKRS for brain metastasis in this study.
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Affiliation(s)
- Seung Hyeon Yang
- Department of Neurosurgery, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Hae Yu Kim
- Department of Neurosurgery, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea.,Department of Neurosurgery, Gamma Knife Center, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea.
| | - Sun Il Lee
- Department of Neurosurgery, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea.,Department of Neurosurgery, Gamma Knife Center, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Seong Jin Jin
- Department of Neurosurgery, Gamma Knife Center, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea
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18
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Nakashima T, Nonoshita T, Hirata H, Inoue K, Nagashima A, Yoshitake T, Asai K, Shioyama Y. Adverse Events of Concurrent Radiotherapy and ALK Inhibitors for Brain Metastases of ALK-Rearranged Lung Adenocarcinoma. In Vivo 2020; 34:247-253. [PMID: 31882485 PMCID: PMC6984098 DOI: 10.21873/invivo.11767] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 10/04/2019] [Accepted: 10/11/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND We investigated acute adverse events in patients with brain metastases (BMs) of anaplastic lymphoma kinase-rearranged (ALKr) non-small cell lung cancer (NSCLC) treated with both cranial radiotherapy and tyrosine kinase inhibitors (TKIs) of ALK. PATIENTS AND METHODS Acute AEs were retrospectively investigated in patients with BMs of ALKr-NSCLC who received both whole-brain radiotherapy (WBRT) and ALK-TKI. For comparison, they were also assessed in patients with epidermal growth factor receptor (EGFR)-mutated NSCLC and wild-type with neither ALK rearrangement nor EGFR mutation treated with WBRT. RESULTS Two ALKr cases were consequently eligible. Grade 3 otitis media unexpectedly occurred in both cases, while there was one case out of 11 and one case out of 18 of grade 2 otitis media among the EGFR-mutated cases and wild-type cases (p=0.013), respectively. CONCLUSION Concurrent treatment with WBRT and ALK-TKI may be associated with acute severe ear toxicity in patients with BMs of ALKr-NSCLC.
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Affiliation(s)
- Takaaki Nakashima
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Department of Radiology, Kitakyushu Municipal Medical Center, Kitakyushu, Japan
| | - Takeshi Nonoshita
- Department of Radiology, Kitakyushu Municipal Medical Center, Kitakyushu, Japan
| | - Hidenari Hirata
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kouji Inoue
- Department of Respiratory Medicine, Kitakyushu Municipal Medical Center, Kitakyushu, Japan
| | - Akira Nagashima
- Department of Thoracic Surgery, Kitakyushu Municipal Medical Center, Kitakyushu, Japan
| | - Tadamasa Yoshitake
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kaori Asai
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshiyuki Shioyama
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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19
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Blakely CM, Riess JW. Interpretation of ceritinib clinical trial results and future combination therapy strategies for ALK-rearranged NSCLC. Expert Rev Anticancer Ther 2019; 19:1061-1075. [PMID: 31809604 DOI: 10.1080/14737140.2019.1699792] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Introduction: Lung cancer is the leading cause of cancer-related deaths, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all lung cancer cases. The continued advancement of DNA sequencing technology and the discovery of multiple specific driver mutations underlying many cases of NSCLC are moving clinical intervention toward a more targeted approach. Here we focus on anaplastic lymphoma kinase (ALK), a member of the receptor tyrosine kinase family, as an oncogenic driver in NSCLC. The ALK gene is rearranged in 3-7% of NSCLCs, and targeted inhibition of ALK is a viable therapy option.Areas covered: We discuss the available treatment options for ALK-positive NSCLC with an emphasis on the second-generation ALK inhibitor ceritinib. We also discuss practical treatment strategies and possible strategies to overcome or delay resistance to ALK inhibitors.Expert opinion: With a robust treatment armamentarium for patients with ALK-positive NSCLC, emphasis has shifted to optimizing individualized treatment strategies to further enhance outcomes for these patients.
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Affiliation(s)
- Collin M Blakely
- Department of Medicine, UCSF Helen Diller Comprehensive Cancer Center, San Francisco, CA, USA
| | - Jonathan W Riess
- Department of Medicine, UC Davis Comprehensive Cancer Center, Sacramento, CA, USA
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20
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Liu YT, Zhang K, Li CC, Hu XS, Jiang J, Hao XZ, Wang Y, Li JL, Xing PY, Yang S, Zhang X, Wang GQ, Cai SL, Shi YK. Depth of Response was Associated with Progression-Free Survival in Patients with Advanced Non-small Cell Lung Cancer treated with EGFR-TKI. J Cancer 2019; 10:5108-5113. [PMID: 31602263 PMCID: PMC6775600 DOI: 10.7150/jca.33450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 07/28/2019] [Indexed: 11/05/2022] Open
Abstract
Background: Response Evaluation Criteria in Solid Tumors (RECIST) has been widely utilized to evaluate new therapeutic strategies in cancer. However, RECIST fails to assess the heterogeneity of response in highly active therapies. Depth of response (DepOR), defined as the maximum percentage change in tumor size compared with baseline, may provide a new strategy to evaluate disease response. In the present study, we studied the association between DepOR and progression-free survival (PFS) in patients with advanced non-small cell lung cancer (NSCLC) treated with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Methods: Advanced NSCLC patients harboring EGFR driver mutation (L858R or exon 19 deletion) treated with EGFR-TKI from August 2014 to July 2017 from two sites were retrospetively collected for analysis. Patients were divided into four groups by DepOR (Q1 = 1-25%, Q2 = 26-50%, Q3 = 51-75%, Q4 = 76-100%). Kaplan-Meier curves were plotted for PFS against DepOR and the hazard ratio (HR) was determined through univariable and multivariable cox regression models. Results: In total, 265 patients were included for analysis. The number of patients in Group Q1-Q4 were 91 (34.3%), 73 (27.5%), 65 (24.5%) and 36 (13.6%), respectively. A greater DepOR was significantly associated with a longer PFS (Log-rank P<0.0001). The HRs (95% CI) for PFS comparing patients with different DepOR status were 0.58 (0.42-0.80) for Q2, 0.49 (0.35-0.69) for Q3, and 0.33 (0.22-0.50) for Q4, all compared with patients in Q1. DepOR as a continuous variable was also associated with prolonged PFS (HR, 0.20; 95% CI, 0.13-0.33; P<0.001). Additionally, in the multivariable cox regression model, abnormal LDH, brain metastasis and male were found to be associated with worse PFS outcomes (P<0.05). Conclusion: A greater DepOR is significantly associated with PFS benefit in advanced NSCLC treated with EGFR-TKI, suggesting that it may be a useful clinical outcome to evaluate the response of targeted therapy.
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Affiliation(s)
- Yu-Tao Liu
- Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/ National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P.R. China
| | - Kai Zhang
- Cancer Center of Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, P.R. China
| | - Cheng-Cheng Li
- The Medical Department, 3D Medicines Inc, Shanghai, P.R. China
| | - Xing-Sheng Hu
- Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/ National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P.R. China
| | - Jun Jiang
- Department of radiology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/ National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P.R. China
| | - Xue-Zhi Hao
- Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/ National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P.R. China
| | - Yan Wang
- Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/ National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P.R. China
| | - Jun-Ling Li
- Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/ National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P.R. China
| | - Pu-Yuan Xing
- Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/ National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P.R. China
| | - Sheng Yang
- Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/ National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P.R. China
| | - Xin Zhang
- Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/ National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P.R. China
| | - Guo-Qiang Wang
- The Medical Department, 3D Medicines Inc, Shanghai, P.R. China
| | - Shang-Li Cai
- The Medical Department, 3D Medicines Inc, Shanghai, P.R. China
| | - Yuan-Kai Shi
- Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/ National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P.R. China
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21
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Andratschke N, Kraft J, Nieder C, Tay R, Califano R, Soffietti R, Guckenberger M. Optimal management of brain metastases in oncogenic-driven non-small cell lung cancer (NSCLC). Lung Cancer 2019; 129:63-71. [DOI: 10.1016/j.lungcan.2018.12.009] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 11/29/2018] [Accepted: 12/08/2018] [Indexed: 02/07/2023]
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22
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Achrol AS, Rennert RC, Anders C, Soffietti R, Ahluwalia MS, Nayak L, Peters S, Arvold ND, Harsh GR, Steeg PS, Chang SD. Brain metastases. Nat Rev Dis Primers 2019; 5:5. [PMID: 30655533 DOI: 10.1038/s41572-018-0055-y] [Citation(s) in RCA: 664] [Impact Index Per Article: 110.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
An estimated 20% of all patients with cancer will develop brain metastases, with the majority of brain metastases occurring in those with lung, breast and colorectal cancers, melanoma or renal cell carcinoma. Brain metastases are thought to occur via seeding of circulating tumour cells into the brain microvasculature; within this unique microenvironment, tumour growth is promoted and the penetration of systemic medical therapies is limited. Development of brain metastases remains a substantial contributor to overall cancer mortality in patients with advanced-stage cancer because prognosis remains poor despite multimodal treatments and advances in systemic therapies, which include a combination of surgery, radiotherapy, chemotherapy, immunotherapy and targeted therapies. Thus, interest abounds in understanding the mechanisms that drive brain metastases so that they can be targeted with preventive therapeutic strategies and in understanding the molecular characteristics of brain metastases relative to the primary tumour so that they can inform targeted therapy selection. Increased molecular understanding of the disease will also drive continued development of novel immunotherapies and targeted therapies that have higher bioavailability beyond the blood-tumour barrier and drive advances in radiotherapies and minimally invasive surgical techniques. As these discoveries and innovations move from the realm of basic science to preclinical and clinical applications, future outcomes for patients with brain metastases are almost certain to improve.
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Affiliation(s)
- Achal Singh Achrol
- Department of Neurosurgery and Neurosciences, John Wayne Cancer Institute and Pacific Neuroscience Institute, Santa Monica, CA, USA.
| | - Robert C Rennert
- Department of Neurosurgery, University of California-San Diego, San Diego, CA, USA.
| | - Carey Anders
- Division of Hematology/Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
| | | | - Manmeet S Ahluwalia
- Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, OH, USA
| | - Lakshmi Nayak
- Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Solange Peters
- Medical Oncology, Lausanne University Hospital, Lausanne, Switzerland
| | - Nils D Arvold
- Department of Radiation Oncology, St. Luke's Cancer Center, Duluth, MN, USA
| | - Griffith R Harsh
- Department of Neurosurgery, University of California-Davis, School of Medicine, Sacramento, CA, USA
| | - Patricia S Steeg
- Women's Malignancies Branch, Center for Cancer Research, National Cancer Center, Bethesda, MD, USA
| | - Steven D Chang
- Department of Neurosurgery, University of California-Davis, School of Medicine, Sacramento, CA, USA.
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23
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Kotecha R, Gondi V, Ahluwalia MS, Brastianos PK, Mehta MP. Recent advances in managing brain metastasis. F1000Res 2018; 7:F1000 Faculty Rev-1772. [PMID: 30473769 PMCID: PMC6234720 DOI: 10.12688/f1000research.15903.1] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/02/2018] [Indexed: 12/13/2022] Open
Abstract
Brain metastases are the most common malignancy encountered in the central nervous system (CNS), with up to 30-40% of cancer patients developing brain metastases at some point during the course of their disease. The management of brain metastasis is rapidly evolving and the roles of local therapies such as whole-brain radiation therapy, stereotactic radiosurgery, and resection along with systemic therapies are in flux. An emphasis on the neurocognitive side effects associated with treatment has gained prominence. Novel molecular studies have demonstrated important evolutionary patterns underpinning the development of brain metastasis and leptomeningeal disease, which may be key to unlocking new therapeutic strategies. This article provides a framework for incorporating the results of recent randomized radiotherapy clinical trials into practice, expounds upon the emphasis on cognition being an important driver in therapeutic selection, describes the importance of CNS-penetrating systemic therapies, and provides an overview of the novel molecular insights that will likely set the stage for future developments in this field.
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Affiliation(s)
- Rupesh Kotecha
- Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA
- Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA
| | - Vinai Gondi
- Northwestern Medicine Cancer Center Warrenville, Warrenville, IL, USA
- Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Manmeet S Ahluwalia
- Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
- Department of Hematology/Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Priscilla K Brastianos
- Divisions of Hematology/Oncology and Neuro-Oncology, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Minesh P Mehta
- Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA
- Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA
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24
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Kim DH, Choi YJ, Sung KJ, Yoo SA, Sung YH, Kim JK, Choi CM, Yun M, Lee EY, Jin YS, Cook S, Rho JK, Lee JC. Efficacy of nano-particulated, water-soluble erlotinib against intracranial metastases of EGFR-mutant lung cancer. Mol Oncol 2018; 12:2182-2190. [PMID: 30350450 PMCID: PMC6275278 DOI: 10.1002/1878-0261.12394] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2018] [Revised: 08/20/2018] [Accepted: 10/04/2018] [Indexed: 11/15/2022] Open
Abstract
Central nervous system (CNS) metastasis is one of the serious complications of epidermal growth factor receptor (EGFR)‐mutant lung cancer, which arises due to poor penetration of the brain–blood barrier by EGFR‐tyrosine kinase inhibitors (EGFR‐TKIs). Although osimertinib, a third‐generation EGFR‐TKI, has efficacy against CNS metastases, further treatment modalities are still needed as some of these lesions do not respond to osimertinib, or undergo progression after an initial response to this drug if radiotherapy has already been conducted. Here, we investigated the efficacy of water‐soluble erlotinib (NUFS‐sErt) against these metastases. This agent was synthesized using a nano‐particulation platform technology utilizing fat and supercritical fluid (NUFS™) to resolve the low solubility problem that typically prevents the creation of injectable forms of EGFR‐TKIs. The average NUFS‐sErt particle size was 236.4 nm, and it showed time‐dependent dissolution in culture media. The effects of NUFS‐sErt were similar to those of conventional erlotinib in terms of inhibiting the proliferation of EGFR‐mutant lung cancer cells and suppressing EGFR signaling. In an intraperitoneal xenograft model of HCC827 cells, intraperitoneal administration of NUFS‐sErt produced a dose‐dependent inhibition of tumor growth and enhanced survival rate. Notably, the injection of NUFS‐sErt into the brain ventricle caused significant tumor growth inhibition in an intracranial xenograft model. Hence, our current findings indicate that NUFS‐sErt is a novel, water‐soluble form of erlotinib that can be administered using intraventricular or intrathecal injections. The target cases would be patients with a progressive CNS metastasis and no other therapeutic options. This drug could also be given intravenously to patients with swallowing difficulties or an inability to ingest due to a medical condition.
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Affiliation(s)
- Dong Ha Kim
- Department of Pulmonology and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea.,Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea
| | - Yun Jung Choi
- Department of Pulmonology and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea.,Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea
| | - Ki Jung Sung
- Department of Pulmonology and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea.,Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea
| | - Seon-A Yoo
- Department of Pulmonology and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea.,Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea
| | - Young Hoon Sung
- Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea.,Department of Convergence Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea
| | - Jeong Kon Kim
- Department of Radiology, Research Institute of Radiology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea
| | - Chang-Min Choi
- Department of Pulmonology and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea.,Department of Oncology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea
| | - Miyong Yun
- Department of Bioindustry and Bioresource Engineering, College of Life Sciences, Sejong University, Seoul, South Korea
| | | | | | - Seungho Cook
- Biomedical Sciences, College of Medicine, University of Ulsan, Seoul, South Korea
| | - Jin Kyung Rho
- Department of Convergence Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea
| | - Jae Cheol Lee
- Department of Oncology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea
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25
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Yang Y, Jiang C, Yang Y, Guo L, Huang J, Liu X, Wu C, Zou J. Silencing of LncRNA-HOTAIR decreases drug resistance of Non-Small Cell Lung Cancer cells by inactivating autophagy via suppressing the phosphorylation of ULK1. Biochem Biophys Res Commun 2018; 497:1003-1010. [DOI: 10.1016/j.bbrc.2018.02.141] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 02/15/2018] [Indexed: 02/01/2023]
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26
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De Pas T, Pala L, Catania C, Conforti F. Molecular and clinical features of second-generation anaplastic lymphoma kinase inhibitors: ceritinib. Future Oncol 2017; 13:2629-2644. [DOI: 10.2217/fon-2017-0262] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The discovery of ALK rearrangement in non-small-cell lung cancer (NSCLC) triggered rapid clinical development of a family of specific drugs targeting this alteration, called ALK inhibitors. Despite high rate of responses, the vast majority of patients treated with first-generation ALK inhibitor crizotinib will ultimately develop disease progression. The second-generation ALK inhibitor, ceritinib, is an oral, small-molecule that inhibits the ALK kinase activity with a potency 20-fold greater than crizotinib, being able to tackle some of the principal mechanisms of resistance to crizotinib. Evidences from five large prospective clinical trials have so far showed impressive activity of ceritinib in ALK inhibitor pretreated and naive NSCLC patients. This review will focus on the preclinical and clinical data available regarding ceritinib pharmacology, clinical efficacy and safety profile.
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Affiliation(s)
- Tommaso De Pas
- Medical Oncology of Melanoma & Sarcoma Unit, European Institute of Oncology, Via Ripamonti, 435, 20141 Milan, Italy
| | - Laura Pala
- Medical Oncology of Melanoma & Sarcoma Unit, European Institute of Oncology, Via Ripamonti, 435, 20141 Milan, Italy
| | - Chiara Catania
- Medical Oncology Unit of Respiratory Tract, European Institute of Oncology, Via Ripamonti, 435, 20141 Milan, Italy
| | - Fabio Conforti
- Medical Oncology of Melanoma & Sarcoma Unit, European Institute of Oncology, Via Ripamonti, 435, 20141 Milan, Italy
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27
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Jiang C, Yang Y, Yang Y, Guo L, Huang J, Liu X, Wu C, Zou J. Long Noncoding RNA (lncRNA) HOTAIR Affects Tumorigenesis and Metastasis of Non-Small Cell Lung Cancer by Upregulating miR-613. Oncol Res 2017; 26:725-734. [PMID: 29187267 PMCID: PMC7844735 DOI: 10.3727/096504017x15119467381615] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) is one of the most deadly cancers with poor prognosis. Recent findings suggested that the lncRNA HOTAIR played an important role in tumorigenesis and metastasis. In the present study, HOTAIR was highly expressed in NSCLC tumor tissues and cell lines (H1299, H23, H292, and A549). Downregulation of HOTAIR suppressed cell proliferation and invasion, while it promoted apoptosis of NSCLC cells. The targeting relationship between HOTAIR and miR-613 was first revealed by bioinformatics prediction. miR-613 was found to be lowly expressed in NSCLC tumor tissues and cell lines. Knockdown of HOTAIR increased the expression of miR-613 significantly, and cotransfection with miR-613 inhibitor reversed this increase, indicating that the expression of miR-613 was negatively regulated by HOTAIR. The targeting relationship between HOTAIR and miR-613 was further confirmed through the luciferase report assay. Moreover, the cotransfection of HOTAIR shRNA and miR-613 inhibitor counteracted the tumor inhibition effects of HOTAIR shRNA through promoting cell proliferation and invasion while suppressing apoptosis in NSCLC cells, suggesting that the HOTAIR/miR-613 axis was involved in tumorigenesis and metastasis of NSCLC. In vivo experiments revealed that knockdown of HOTAIR decreased tumor growth and invasion and increased apoptosis and miR-613 expression. In conclusion, our study indicated that downregulation of HOTAIR suppressed tumorigenesis and metastasis of NSCLC via upregulating the expression of miR-613. The HOTAIR/miR-613 axis might provide a new potential therapeutic strategy for NSCLC treatment.
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Affiliation(s)
- Caiyu Jiang
- Department of Respiratory and Critical Care Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Sichuan, P.R. China
| | - Yan Yang
- Department of Respiratory and Critical Care Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Sichuan, P.R. China
| | - Yang Yang
- Department of Respiratory and Critical Care Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Sichuan, P.R. China
| | - Lu Guo
- Department of Respiratory and Critical Care Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Sichuan, P.R. China
| | - Jiang Huang
- Department of Respiratory and Critical Care Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Sichuan, P.R. China
| | - Xingren Liu
- Department of Respiratory and Critical Care Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Sichuan, P.R. China
| | - Chi Wu
- Department of Respiratory and Critical Care Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Sichuan, P.R. China
| | - Jun Zou
- Department of Respiratory and Critical Care Medicine, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Sichuan, P.R. China
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28
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Zhao Z, Li J, Jiang Y, Xu W, Li X, Jing W. CLDN1 Increases Drug Resistance of Non-Small Cell Lung Cancer by Activating Autophagy via Up-Regulation of ULK1 Phosphorylation. Med Sci Monit 2017; 23:2906-2916. [PMID: 28614291 PMCID: PMC5479443 DOI: 10.12659/msm.904177] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Accepted: 05/08/2017] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND The aim of this study was to investigate the expression of CLDN1 in non-small cell lung cancer (NSCLC) and its mechanism of action in cisplatin resistance. MATERIAL AND METHODS A total of 55 patients with NSCLC admitted to our hospital between October 2013 and October 2015 were included. NSCLC tissues and tumor-adjacent tissues (≥5 cm from tumor edge) were collected. Among the 55 patients, 37 had adenocarcinoma and 18 had squamous cell carcinoma. Quantitative real-time polymerase chain reaction was used to determine mRNA expression, and protein expression was examined using Western blotting. CCK-8 assay was used to determine cell proliferation and Transwell assay was used to detect migration and invasion of the cells. Confocal microscopy was used to observe autophagosomes. RESULTS Increased CLDN1 expression promoted the development and metastasis of NSCLC. CLDN1 expression in A549/CDDP cells was up-regulated at both transcriptional and translational levels. Reduced CLDN1 expression decreased the drug resistance, proliferation, migration, and invasion abilities of A549/CDDP cells. Decreased CLDN1 expression promoted the apoptosis of A549/CDDP cells. CLDN1 enhanced CDDP drug resistance of A549 cells by activating autophagy. CLDN1 promoted the autophagy of A549 cells by up-regulating the phosphorylation level of ULK1. CONCLUSIONS The present study demonstrates that expression of CLDN1 in NSCLC is up-regulated and it is correlated with clinicopathological features. CLDN1 activates autophagy through up-regulation of ULK1 phosphorylation and promotes drug resistance of NSCLC cells to CDDP.
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Affiliation(s)
- Zhenhuan Zhao
- Department of Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, P.R. China
| | - Jing Li
- Department of Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, P.R. China
| | - Yan Jiang
- Intensive Care Unit, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, P.R. China
| | - Wen Xu
- Department of Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, P.R. China
| | - Xin Li
- Department of Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, P.R. China
| | - Weili Jing
- Intensive Care Unit, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, P.R. China
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29
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Paradigm shift of therapeutic management of brain metastases in EGFR-mutant non-small cell lung cancer in the era of targeted therapy. Med Oncol 2017; 34:121. [PMID: 28555261 DOI: 10.1007/s12032-017-0978-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Accepted: 05/09/2017] [Indexed: 12/25/2022]
Abstract
Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations commonly present brain metastases (BM) at the time of NSCLC diagnosis or during the clinical course. Conventionally, the prognosis of BM has been extremely poor, but the advent of EGFR-tyrosine kinase inhibitors (TKIs) has drastically improved the prognosis in these patients. Despite the presence of the blood-brain barrier, EGFR-TKIs have dramatic therapeutic effects on both BM and extracranial disease. In addition, recent systemic chemotherapies reportedly play a role in controlling BM. These treatment modalities can potentially replace whole brain radiotherapy (WBRT) to prevent or delay neurocognitive decline. Therefore, how to utilize these treatments is one issue. The other issue is what kind of treatment is best for recurrence after TKI therapy. Recent reports have shown a positive effect of a combination therapy of EGFR-TKI and radiotherapy on BM. Although neurocognitive decline is underscored when WBRT is considered, a survival benefit from WBRT has been proven especially in the potential long survivors with good prognostic index, especially disease-specific graded prognostic index (DS-GPA). In this review, treatment strategy including chemotherapeutic agents and radiotherapy is discussed in terms of risk-benefit balance in conjunction with DS-GPA.
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