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Case Report
Osimertinib Combined with Systemic Chemotherapy for EGFR Mutant, T790M-Negative, Non–Small Cell Lung Cancer Patients Who Develop Leptomeningeal Metastases with Extracranial Progression to Prior EGFR TKI
Hye Ryeon Kim, Hyunji Jo, Hongsik Kim, Joohyun Hong, Sehhoon Park, Hyun Ae Jung, Se-Hoon Lee, Jin-Seok Ahn, Myung-Ju Ahn
Cancer Res Treat. 2023;55(1):344-349.   Published online March 26, 2022
DOI: https://doi.org/10.4143/crt.2021.1603
AbstractAbstract PDFPubReaderePub
Leptomeningeal metastasis (LM) is a rare but fatal clinical condition with a short survival time. The incidence of LM from epidermal growth factor receptor mutant (EGFRm) non–small cell lung cancer (NSCLC) has increased due to the limited efficacy of first- or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in the central nervous system (CNS). Osimertinib is a third-generation, irreversible, CNS penetrant, oral EGFR TKI that demonstrates promising efficacy in CNS metastases regardless of T790M. Herein, we report four cases of T790M-negative EGFRm NSCLC patients treated with osimertinib combined with systemic chemotherapy, who progressed on prior EGFR TKI and developed LM with extracranial lesions. The combination treatment was well tolerated, and the mean overall survival from LM diagnosis was 14.7 months (95% confidence interval, 10.4 to 19.0). These results suggest that osimertinib combined with systemic chemotherapy would be a reasonable treatment option for T790M-negative EGFRm NSCLC patients who develop LM with extracranial progression to prior EGFR TKI. A further prospective study is warranted.

Citations

Citations to this article as recorded by  
  • An overview of the therapeutic strategies for neoplastic meningitis due to breast cancer: when and why?
    Mainak Bardhan, Debankur Dey, Vinay Suresh, Binish Javed, Vyshak Alva Venur, Neha Joe, Ritvika Kalidindi, Ahmad Ozair, Marium Khan, Reshma Mahtani, Simon Lo, Yazmin Odia, Manmeet S. Ahluwalia
    Expert Review of Neurotherapeutics.2024; 24(1): 77.     CrossRef
  • Osimertinib is associated with improved outcomes in pre-treated non-small cell lung cancer leptomeningeal metastases: A systematic review and meta-analysis
    David J.H. Bian, Anna-Maria Lazaratos, Sarah M. Maritan, Andrea Quaiattini, Zhimin Zeng, Zhengfei Zhu, Ugur Sener, Rachna Malani, Yu Jung Kim, Eiki Ichihara, Victor Cohen, April A.N. Rose, Nathaniel Bouganim, Matthew Dankner
    Heliyon.2024; 10(9): e29668.     CrossRef
  • Antineoplastics

    Reactions Weekly.2023; 1943(1): 90.     CrossRef
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  • 2 Web of Science
  • 3 Crossref
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Original Articles
Role of Loss of O6-Methylguanine DNA Methyltransferase (MGMT) Expression in Non-Small Cell Lung Carcinomas (NSCLCs): with Reference to the Relationship with p53 Overexpression
Na-Hye Myong
Cancer Res Treat. 2010;42(2):95-100.   Published online June 30, 2010
DOI: https://doi.org/10.4143/crt.2010.42.2.95
AbstractAbstract PDFPubReaderePub
Purpose

Functional inactivation of the O6-methylguanine-DNA methyltransferase (MGMT) gene has been demonstrated as loss of MGMT protein and suggested that it plays an important role in primary human neoplasia, including lung cancer. It has also been reported to be associated with the G : C→A : T transition mutation in the p53 gene of lung cancer. The aims of this study were to investigate the role of MGMT expression loss and its prognostic significance in non-small cell lung carcinomas (NSCLCs), and its correlation with p53 overexpression as well as influence on patient survival.

Materials and Methods

112 surgically resected NSCLC specimens were reviewed by medical records for their clinicopathologic variables. Their tissue microarray blocks were immunostained with anti-human MGMT and p53 primary antibodies. Correlation between MGMT loss and the clinicopathologic prognostic factors, including p53 overexpression and the single or combined actions of MGMT loss and p53 overexpression on patient survival were statistically analyzed by SPSS15.0.

Results

Reduced or absent MGMT expression was found in 48 of 112 NSCLCs (43%), and significantly associated with nodal metastasis and squamous or undifferentiated cell types. Loss of MGMT expression was correlated with p53 overexpression in adenocarcinomas, but not in overall NSCLCs. Its solitary or combined actions with p53 overexpression did not have influence on patient survival.

Conclusion

Loss of MGMT expression is a relatively common event in NSCLCs and significantly associated with nodal metastasis and p53 overexpression, suggesting that it may play a major role in pulmonary carcinogenesis, and also in disease progression of NSCLCs.

Citations

Citations to this article as recorded by  
  • O 6 -Methylguanine-DNA methyltransferase (MGMT): A drugable target in lung cancer?
    Birgitta I. Hiddinga, Patrick Pauwels, Annelies Janssens, Jan P. van Meerbeeck
    Lung Cancer.2017; 107: 91.     CrossRef
  • Relationship Between the Expression of O6-Methylguanine-DNA Methyltransferase (MGMT) and p53, and the Clinical Response in Metastatic Pancreatic Adenocarcinoma Treated with FOLFIRINOX
    Carole Vitellius, Caroline Eymerit-Morin, Dominique Luet, Lionel Fizanne, Fanny Foubert, Sandrine Bertrais, Marie-Christine Rousselet, François-Xavier Caroli-Bosc
    Clinical Drug Investigation.2017; 37(7): 669.     CrossRef
  • Expression profiling of O6 methylguanine-DNA-methyl transferase in prolactinomas: a correlative study of promoter methylation and pathological features in 136 cases
    Xiao-Bing Jiang, Bin Hu, Dong-Sheng He, Zhi-Gang Mao, Xin Wang, Bing-Bing Song, Yong-Hong Zhu, Hai-Jun Wang
    BMC Cancer.2015;[Epub]     CrossRef
  • Bayesian inference supports a location and neighbour-dependent model of DNA methylation propagation at the MGMT gene promoter in lung tumours
    Nicolas Bonello, James Sampson, John Burn, Ian J. Wilson, Gail McGrown, Geoff P. Margison, Mary Thorncroft, Philip Crossbie, Andrew C. Povey, Mauro Santibanez-Koref, Kevin Walters
    Journal of Theoretical Biology.2013; 336: 87.     CrossRef
  • Immunohistochemical Assessment of O6-Methylguanine-DNA Methyltransferase (MGMT) and Its Relationship with p53 Expression in Endometrial Cancers
    Kyung Eun Lee
    Journal of Cancer Prevention.2013; 18(4): 351.     CrossRef
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  • 5 Crossref
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Phase II Study of Ifosfamide, Epirubicin and Cisplatin(IEP) in Patients with Small Cell Lung Cancer
Hwi Joong Yoon, Hyun Joo Park, Si Young Kim, Kyung Sam Cho, Jung Hee Kim, Sung Eon Hong
J Korean Cancer Assoc. 1998;30(4):728-736.
AbstractAbstract PDF
PURPOSE
Although it is well recognized that SCLC is a chemo and radiosensitive tumor, only fraction of treated patients have a complete remission, fewer still have durable remissions. This study was performed to evaluate the clinical effects of IEP chemotherapy in patients with SCLC.
MATERIALS AND METHODS
Patients with histologically proven SCLC who has measurable disease and previously untreated, were eligible. Treatment consisted of ifosfamide 1000 mg/m2 iv infusion for 1 hour on days 1~5 with mesna uroprotection; epirubicin 60 mg/m2 iv on day 1; and cisplatin 20 mg/m2 iv infusion on days 1~5 with hydration; repeated treatment every 4 weeks RESULTS: Twenty four patients(20 males, 4 females) were eligible for response to IEP chemotherapy. The two patients were excluded because one died before evaluating response to chemotherapy and the other had brain metastasis. The median age was 61(range 34-74). Fifteen patients had a limited disease(LD), nine patients had a extensive disease(ED). The overall response rate was 86.4%(CR 36.4%, PR 50%). In LD, response rate was 86.7%(CR 46.7%) and in ED, response rate was 85.7%(CR 14.3%). The median overall survival time was 43.5 weeks. The median survival time of LD and ED was 46.5 weeks and 43.5 weeks respectively. The median time to progression was 20 weeks in responders. The toxicity was moderate. One toxic death was observed. Grade 1 or 2 non-hematologic toxicities consisted of alopecia, nausea and vomiting in all cases, peripheral neuropathy in 3, hematuria in 2, mucositis in 11, and fever/infection in 6. Hematologic toxic effects included leukopenia(> or =grade.3, 16.5%), anemia(> or =grade 3, 1%), and thrombocytopenia(> or =grade 3, 6.8%).
CONCLUSIONS
These results suggest that IEP chemotherapy may be useful as a treatment strategy in small cell lung cancer, but its efficacy is equivalent. The phase III study should be needed.
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5-Fluorouracil , Ifosfamide and Cisplatin ( FIP ) Combination Chemotherapy for Advanced Non - Small Cell Lung Cancer
Young II Seo, Yougn Suk Park, Jae Myung Lee, Jo Young Choi, Hyun Soo Kim, Byung Dong Cho, Yu Mi Seo, Yun Chang Han, Ho joong Kim, In Gyu Hyun, Ki Suk Shun, Keun Chil Park, Duk Jhe Shun
J Korean Cancer Assoc. 1995;27(2):284-292.
AbstractAbstract PDF
We conducted a phase II trial of combining 5-fluorouracil(5-FU), ifosfamide(IFM), and cisplating(DDP) in previously untreated patients with advanced, unresectable, non-small cell lung cancer(NSCLC). Each cycle consisted of 5-FU 100 mg/m i. v. days 1-5, IFM 1000 mg/m i. v. days 1-3 with mesna, and DDP 100 mg/m i. v. day 1. Cycles were repeated at 3 week intervals. Twenty eight patients were enralled. Age ranged from 36 to 73(median 57 yearsk 24 were male, 4 female. Eleven patients had stage IIIb disease and 17 stage IV. Two patients were not evaluable because of lost to follow up. None had a complete response, 13 patients(50%) had par- tial responses, 8(31%) had stable diseases, and 5(19%) had progressive disesses. The median response duration was 11.2 weeks; the median time to progression was l2 weeks. The overall median survival was 19 weeks(27.5 weeks for responders, 12.8 weeks for non-responders). Majar side effects were alopecia, nausea/vomiting and stomatitis, all of which were we11 tolerated and reversible. By univariate analysis, stage and performance status correlated with time to progression and overall survival time. In conclusion, FIP combination chemotherapy for patients with advanced, unresectable non- small cell lung cancer seems to be an effective and well-tolerated regimen.
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  • 16 Download
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