非小细胞肺癌脑转移预测模型研究
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摘要
目的
肺癌是当今世界上肿瘤相关死亡率最高的恶性肿瘤,非小细胞肺癌占其中的绝大多数。脑转移在非小细胞肺癌患者中较为常见且是肿瘤复发转移最重要的原因之一。但是,直到现在为止,并没有一种可以简明、准确的预测非小细胞肺癌脑转移的方法。在这篇论文中,我们探索了中国人群中表皮生长因子受体(EGFR)和KRAS基因突变与非小细胞肺癌脑转移风险的关系,并且利用某些临床风险因子和这些基因突变去建立一个非小细胞肺癌脑转移预测模型。
方法
我们的研究是一项回顾性研究,一共收集了191例主要治疗过程在北京协和医院完成的中国非小细胞肺癌患者。我们收集和分析的信息包括EGFR和KRAS基因突变,临床资料包括首诊时的性别,年龄,组织学,原发灶位置,吸烟史,肿瘤分期和淋巴结转移情况等。单因素coX回归模型和多因素coX回归模型先后用于研究EGFR和KRAS基因突变及临床风险因子对非小细胞肺癌脑转移风险的影响。利用这些基因突变和临床参数,及在多因素分析中获取的系数,我们将建立脑转移的风险预测模型。
结果
一共有26位患者在随访过程中发生了脑转移,占研究人群的13.6%。统计结果显示EGFR基因突变(P=0.030),小于等于60岁的年龄(P=0.043)和淋巴结转移(P=0.020)能显著增加非小细胞肺癌患者罹患脑转移的风险。我们利用上述结果,即EGFR基因突变,年龄和淋巴结转移情况,建立了非小细胞肺癌脑转移预测模型和风险积分,并且区分出脑转移的高、中、低危风险组。脑转移高、中、低危风险组3年脑转移发生率估计为30.1%,20.5%和1.5%,具有预测意义(P<0.001)。
结论
EGFR基因突变,小于等于60岁的年龄和淋巴结转移与非小细胞肺癌脑转移风险增加相关。我们利用这个发现建立的非小细胞肺癌脑转移预测模型有显著的预测意义。未来的医疗实践中,对有EGFR突变等高危因素的非小细胞肺癌脑转移高危患者应予密切随诊。关于非小细胞肺癌脑转移预防性治疗(包括预防性全脑放射治疗或靶向治疗)的临床研究应予倡导。
Purpose:Lung cancer is the leading cause of tumor-related death worldwide and most of them are non-small cell lung cancer (NSCLC). Brain metastases are common in patients with non-small cell lung cancer and they are one of the most important causes of tumor relapse. However, nowthere is not any concise and accurate predictive method to judge which NSCLC patient may develop brain metastasis.In this study weinvestigatedthe association between EGFR and KRAS mutation and the risk of developing brain metastasis in a cohort of Chinese NSCLC patientsand made a risk prediction model fordevelopingbrain metastasis in NSCLCwiththe use of both genetic mutations and clinical covariates.
Methods:Altogether191Chinese patients with NSCLCwho have accepted majority of their treatment at Peking Union Medical College Hospital were enrolled in this retrospectivestudy. EGFR and KRAS mutation status and Clinical information including gender, age, cell type, primary location of tumor, smoking history, tumor stage, lymph node metastasis at the time of diagnosis of NSCLCwere obtained and analyzed. Univariate and multivariate Cox regression model was used successivelyto investigatehow EGFR and KRAS mutations and clinical risk factors affected the risk ofbrain metastasis in NSCLC patients. A risk prediction model using genetic mutations and clinical risk factors with the parameter obtained in multivariate Cox regression analysis was established.
Results:A total of26(13.6%) patients were diagnosed with brain metastases during the follow-up period. EGFR mutation (P=0.030), younger age (≤60years)(P=0.043) and lymph node metastasis (P=0.020) were found tosignif icantly increase the risk of developing brain metastasis among NSCLC patients. The prediction modelor risk prediction score for brain metastasis was made and high, intermediate, and low risk group were ranked. The3-year estimating of having brain metastasis for high, intermediate and low risk group was30.1%,20.5%and1.5%, respectively, stratifiedby EGFR mutation, age and lymph node metastasis(P<0.001).
Conclusion:EGFR mutation, younger age≤60years and lymph node metastasis are significantlyassociated with the increasingrisk of developing brain metastasis in NSCLC patients. And the prediction model based on this discover is useful. In the future, NSCLC patients with positive EGFR mutation at high risk for brain metastasis should be considered for close surveillance. And trials of prophylactic therapy using targeted agents or prophylactic cranial irradiation (PCI) therapy should be developed.
肺癌是当今世界上肿瘤相关死亡率最高的恶性肿瘤,非小细胞肺癌占其中的绝大多数。脑转移在非小细胞肺癌患者中较为常见且是肿瘤复发转移最重要的原因之一。但是,直到现在为止,并没有一种可以简明、准确的预测非小细胞肺癌脑转移的方法。在这篇论文中,我们探索了中国人群中表皮生长因子受体(EGFR)和KRAS基因突变与非小细胞肺癌脑转移风险的关系,并且利用某些临床风险因子和这些基因突变去建立一个非小细胞肺癌脑转移预测模型。
方法
我们的研究是一项回顾性研究,一共收集了191例主要治疗过程在北京协和医院完成的中国非小细胞肺癌患者。我们收集和分析的信息包括EGFR和KRAS基因突变,临床资料包括首诊时的性别,年龄,组织学,原发灶位置,吸烟史,肿瘤分期和淋巴结转移情况等。单因素coX回归模型和多因素coX回归模型先后用于研究EGFR和KRAS基因突变及临床风险因子对非小细胞肺癌脑转移风险的影响。利用这些基因突变和临床参数,及在多因素分析中获取的系数,我们将建立脑转移的风险预测模型。
结果
一共有26位患者在随访过程中发生了脑转移,占研究人群的13.6%。统计结果显示EGFR基因突变(P=0.030),小于等于60岁的年龄(P=0.043)和淋巴结转移(P=0.020)能显著增加非小细胞肺癌患者罹患脑转移的风险。我们利用上述结果,即EGFR基因突变,年龄和淋巴结转移情况,建立了非小细胞肺癌脑转移预测模型和风险积分,并且区分出脑转移的高、中、低危风险组。脑转移高、中、低危风险组3年脑转移发生率估计为30.1%,20.5%和1.5%,具有预测意义(P<0.001)。
结论
EGFR基因突变,小于等于60岁的年龄和淋巴结转移与非小细胞肺癌脑转移风险增加相关。我们利用这个发现建立的非小细胞肺癌脑转移预测模型有显著的预测意义。未来的医疗实践中,对有EGFR突变等高危因素的非小细胞肺癌脑转移高危患者应予密切随诊。关于非小细胞肺癌脑转移预防性治疗(包括预防性全脑放射治疗或靶向治疗)的临床研究应予倡导。
Purpose:Lung cancer is the leading cause of tumor-related death worldwide and most of them are non-small cell lung cancer (NSCLC). Brain metastases are common in patients with non-small cell lung cancer and they are one of the most important causes of tumor relapse. However, nowthere is not any concise and accurate predictive method to judge which NSCLC patient may develop brain metastasis.In this study weinvestigatedthe association between EGFR and KRAS mutation and the risk of developing brain metastasis in a cohort of Chinese NSCLC patientsand made a risk prediction model fordevelopingbrain metastasis in NSCLCwiththe use of both genetic mutations and clinical covariates.
Methods:Altogether191Chinese patients with NSCLCwho have accepted majority of their treatment at Peking Union Medical College Hospital were enrolled in this retrospectivestudy. EGFR and KRAS mutation status and Clinical information including gender, age, cell type, primary location of tumor, smoking history, tumor stage, lymph node metastasis at the time of diagnosis of NSCLCwere obtained and analyzed. Univariate and multivariate Cox regression model was used successivelyto investigatehow EGFR and KRAS mutations and clinical risk factors affected the risk ofbrain metastasis in NSCLC patients. A risk prediction model using genetic mutations and clinical risk factors with the parameter obtained in multivariate Cox regression analysis was established.
Results:A total of26(13.6%) patients were diagnosed with brain metastases during the follow-up period. EGFR mutation (P=0.030), younger age (≤60years)(P=0.043) and lymph node metastasis (P=0.020) were found tosignif icantly increase the risk of developing brain metastasis among NSCLC patients. The prediction modelor risk prediction score for brain metastasis was made and high, intermediate, and low risk group were ranked. The3-year estimating of having brain metastasis for high, intermediate and low risk group was30.1%,20.5%and1.5%, respectively, stratifiedby EGFR mutation, age and lymph node metastasis(P<0.001).
Conclusion:EGFR mutation, younger age≤60years and lymph node metastasis are significantlyassociated with the increasingrisk of developing brain metastasis in NSCLC patients. And the prediction model based on this discover is useful. In the future, NSCLC patients with positive EGFR mutation at high risk for brain metastasis should be considered for close surveillance. And trials of prophylactic therapy using targeted agents or prophylactic cranial irradiation (PCI) therapy should be developed.
引文
1. Jemal A, Siegal R, Ward E, et al. Cancer statistics 2008 [J]. CA Cancer J Clin,2008,58(2):71-96.
2. Robnett TJ, Machtay M, Stevenson JP, et al. Factors affecting the risk of brain metastases after definitivechemoradiation for locally advanced non-small-cell lung carcinoma [J]. J Clin Oncol,2001,19(5):1344-9.
3. Alberg AJ, Brock MV, Samet JM. Epidemiology of lung cancer:looking to the future [J]. J Clin Oncol,2005,23(14):3175-85..
4. Felip E, Stahel RA, Pavlidis N. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of non-small-cell lung cancer (NSCLC) [J]. Ann Oncol,2005,16 (Suppl 1):i28-i29.
5. Siegel R, Naishadham D, Jemal A. Cancer Statistics 2012 [J]. CA Cancer J Clin,2012,62(1):10-29.
6. Oh Y, Taylor S, Bekele BN, et al. Number of metastatic sites is a strong predictor of survival in patients with non-small cell lung cancer with or without brain metastases [J]. Cancer,2009,15(13):2930-2938.
7. Schouten LJ, Rutten J, Huveneers HA, et al. Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, lung, and melanoma [J]. Cancer,2002,94(10):2698-705.
8. Cho LC, Dowell JE, Garwood D, et al. Prophylactic cranial irradiation with combined modality therapy for patients with locally advanced non-small cell lung cancer [J]. Semin Oncol,2005,32(3):293-8.
9. Sperduto PW, Kased N, Roberge D, et al. Summary report on the graded prognostic assessment:an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases [J]. J Clin Oncol,2012,30(4):419-25.
10. Park SJ, Kim HT, Lee DH, et al. Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in non-small cell lung cancer patients harboring either exon 19 or 21 mutation [J]. Lung Cancer,2012,77(3):556-60.
11. Heon S, Yeap BY, Lindeman NIet al. The impact of initial gefitinib or erlotinib versus chemotherapy on central nervous system progression in advanced non-small cell lung cancer with EGFR mutations [J]. Clin Cancer Res,2012,18(16):4406-14.
12. Umsawasdi T, Valdivieso M, Chen TT, et al. Role of elective brain irradiation during combined chemoradiotherapy for limited disease non-small cell lung cancer [J]. J Neurooncol,1984,2(3):253-9.
13. Pottgen C, Eberhardt W, Grannass A, et al. Prophylactic cranial irradiation in operable stage IIIA non small-cell lung cancer treated with neoadjuvantchemoradiotherapy:results from a German multi-center randomized trial[J]. J Clin Oncol,2007,25(31):4987-92.
14. Gore EM, Bae K, Wong SJ, et al. Phase III comparison of prophylactic cranial irradiation versus observation in patients with locally advanced non-small-cell lung cancer:primary analysis of radiation therapy oncology group study RTOG 0214 [J]. J Clin Oncol,2011,29(3):272-8.
15. Sun A, Bae K, Gore EM, et al. Phase III trial of prophylactic cranial irradiation compared with observation in patients with locally advanced non-small-cell lung cancer:neurocognitive and quality-of-life analysis [J]. J Clin Oncol,2011,29(3):279-86
16. Hubbs JL, Boyd JA, Hollis D, et al; Factors associated with the development of brain metastases:analysis of 975 patients with early stage nonsmall cell lung cancer [J]. Cancer,2010,116(21):5038-46.
17. Mujoomdar A, Austin JH, Malhotra R, et al. Clinical predictors of metastatic disease to the brain from non-small cell lung carcinoma:primary tumor size, cell type, and lymph node metastases [J]. Radiology,2007,242(3):882-8.
18. Mamon HJ, Yeap BY, Janne PA, et al. High risk of brain metastases in surgically staged IIIA non-small-cell lung cancer patients treated with surgery, chemotherapy, and radiation [J]. J Clin Oncol,2005,23(7):1530-7.
19. Gaspar LE, Chansky K, Albain KS, et al. Time from treatment to subsequent diagnosis of brain metastases in stage III non-small-cell lung cancer:a retrospective review by the Southwest Oncology Group [J]. J Clin Oncol,2005,23 (13):2955-61.
20. Bajard A, Westeel V, Dubiez A, et al. Multivariate analysis of factors predictive of brain metastases in localised non-small cell lung carcinoma [J]. Lung Cancer,2004,45(3):317-23.
21. Ceresoli GL, Reni M, Chiesa G, et al. Brain metastases in locally advanced non-small cell lung carcinoma after multimodality treatment [J]. Cancer,2002,95(3):605-12.
22. Yoo JY, Yang SH, Lee JE, et al. E-cadherin as a predictive marker of brain metastasis in non-small-cell lung cancer, and its regulation by pioglitazone in a preclinical model [J]. J Neurooncol,2012,109(2):219-27.
23. Doebele RC, Lu X, Sumey C, et al. Oncogene Status Predicts Patterns of Metastatic Spread in Treatment-Naive Non-small Cell Lung Cancer [J]. Cancer,2012,118(18):4502-11.
24. Grinberg, Rashi H, Ofek E, Perelman M, et al. The expression of three genes in primary non-small cell lung cancer is associated with metastatic spread to the brain [J]. Clin Cancer Res,2009,15(5):1755-61.
25. Saad AG, Yeap BY, Thunnissen FB, et al. Immunohistochemical markers associated with brain metastases in patients with non-small cell lung carcinoma [J]. Cancer,2008 113(8):2129-38.
26. Milas I, Komaki R, HachiyaT, et al. Epidermal growth factor receptor, cyclooxygenase-2, and BAX expression in the primary non-small cell lung cancer and brain metastases [J]. Clin Cancer Res,2003,9(3):1070-6.
27. D'Amico TA, Aloia TA, Moore MB, et al. Predicting the sites of metastases from lung cancer using molecular biologic markers [J]. Ann Thorac Surg,2001,72 (4):1144-8.
28. Yang CH. EGFR tyrosine kinase inhibitors for the treatment of NSCLC in East Asia:present and future [J]. Lung Cancer,2008,60 (Supplement 2): S23-S30.
29. Noda N, Matsuzoe D, Konno T, et al. K-ras gene mutations in non-small cell lung cancer in Japanese [J]. Oncol Rep,2001,8(4):889-92.
30. Wang YC, Lee HS, Chen SK, et al. Analysis of K-ras gene mutations in lung carcinomas:correlation with gender, histological subtypes, and clinical outcome [J]. J Cancer Res Clin Oncol,1998,124(9):517-22.
31. Rosell R, Li S, Skacel Z, et al. Prognostic impact of mutated K-ras gene in surgically resected non-small cell lung cancer patients [J]. Oncogene,1993,8(9):2407-12.
32. Na Ⅱ, Park JH, Choe du H et al. Association of Epidermal Growth Factor Receptor Mutations with Metastatic Presentations in Non-Small Cell Lung Cancer [J]. ISRN Oncol,2011,2011:756265.
33. Sekine A, Kato T, Hagiwara E, Shinohara T, et al. Metastatic brain tumors from non-small cell lung cancer with EGFR mutations:Distinguishing influence of exon 19 deletion on radiographic features [J]. Lung Cancer,2012,77(1):64-9.
34. Eberhard DA, Johnson BE, Amler LC, et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib [J]. J Clin Oncol,2005,23(25):5900-9
35. Douillard JY, Shepherd FA, Hirsh V, et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer:data from the randomized phase III INTEREST trial [J]. J Clin Oncol,2010,28 (5):744-52.
36. Gow CH, Chien CR, Chang Y, et al. Receptor Mutations on Clinical Response Metastases:Effects of Activating Epidermal Growth Factor Radiotherapy in Lung Adenocarcinoma with Brain [J]. Clin Cancer Res,2008,14(1):162-8.
37. Eichler AF, Kahle KT, Wang DL, et al. EGFR mutation status and survival after diagnosis of brain metastasis in non-small cell lung cancer [J]. Neuro-Oncology,2010,12(11):1193-1199.
38. Pui CH. Central nervous system disease in acute lymphoblastic leukemia: prophylaxis and treatment [J]. Hematol Am SocEduc Program Book,2006,1:142-6.
39. Auperin A, Arriagada R, Pignon JP et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group [J]. N Engl J Med,1999,341 (7):476-84.
40. Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer [J]. N Engl J Med,2007,357 (7):664-72.
2. Robnett TJ, Machtay M, Stevenson JP, et al. Factors affecting the risk of brain metastases after definitivechemoradiation for locally advanced non-small-cell lung carcinoma [J]. J Clin Oncol,2001,19(5):1344-9.
3. Alberg AJ, Brock MV, Samet JM. Epidemiology of lung cancer:looking to the future [J]. J Clin Oncol,2005,23(14):3175-85..
4. Felip E, Stahel RA, Pavlidis N. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of non-small-cell lung cancer (NSCLC) [J]. Ann Oncol,2005,16 (Suppl 1):i28-i29.
5. Siegel R, Naishadham D, Jemal A. Cancer Statistics 2012 [J]. CA Cancer J Clin,2012,62(1):10-29.
6. Oh Y, Taylor S, Bekele BN, et al. Number of metastatic sites is a strong predictor of survival in patients with non-small cell lung cancer with or without brain metastases [J]. Cancer,2009,15(13):2930-2938.
7. Schouten LJ, Rutten J, Huveneers HA, et al. Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, lung, and melanoma [J]. Cancer,2002,94(10):2698-705.
8. Cho LC, Dowell JE, Garwood D, et al. Prophylactic cranial irradiation with combined modality therapy for patients with locally advanced non-small cell lung cancer [J]. Semin Oncol,2005,32(3):293-8.
9. Sperduto PW, Kased N, Roberge D, et al. Summary report on the graded prognostic assessment:an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases [J]. J Clin Oncol,2012,30(4):419-25.
10. Park SJ, Kim HT, Lee DH, et al. Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in non-small cell lung cancer patients harboring either exon 19 or 21 mutation [J]. Lung Cancer,2012,77(3):556-60.
11. Heon S, Yeap BY, Lindeman NIet al. The impact of initial gefitinib or erlotinib versus chemotherapy on central nervous system progression in advanced non-small cell lung cancer with EGFR mutations [J]. Clin Cancer Res,2012,18(16):4406-14.
12. Umsawasdi T, Valdivieso M, Chen TT, et al. Role of elective brain irradiation during combined chemoradiotherapy for limited disease non-small cell lung cancer [J]. J Neurooncol,1984,2(3):253-9.
13. Pottgen C, Eberhardt W, Grannass A, et al. Prophylactic cranial irradiation in operable stage IIIA non small-cell lung cancer treated with neoadjuvantchemoradiotherapy:results from a German multi-center randomized trial[J]. J Clin Oncol,2007,25(31):4987-92.
14. Gore EM, Bae K, Wong SJ, et al. Phase III comparison of prophylactic cranial irradiation versus observation in patients with locally advanced non-small-cell lung cancer:primary analysis of radiation therapy oncology group study RTOG 0214 [J]. J Clin Oncol,2011,29(3):272-8.
15. Sun A, Bae K, Gore EM, et al. Phase III trial of prophylactic cranial irradiation compared with observation in patients with locally advanced non-small-cell lung cancer:neurocognitive and quality-of-life analysis [J]. J Clin Oncol,2011,29(3):279-86
16. Hubbs JL, Boyd JA, Hollis D, et al; Factors associated with the development of brain metastases:analysis of 975 patients with early stage nonsmall cell lung cancer [J]. Cancer,2010,116(21):5038-46.
17. Mujoomdar A, Austin JH, Malhotra R, et al. Clinical predictors of metastatic disease to the brain from non-small cell lung carcinoma:primary tumor size, cell type, and lymph node metastases [J]. Radiology,2007,242(3):882-8.
18. Mamon HJ, Yeap BY, Janne PA, et al. High risk of brain metastases in surgically staged IIIA non-small-cell lung cancer patients treated with surgery, chemotherapy, and radiation [J]. J Clin Oncol,2005,23(7):1530-7.
19. Gaspar LE, Chansky K, Albain KS, et al. Time from treatment to subsequent diagnosis of brain metastases in stage III non-small-cell lung cancer:a retrospective review by the Southwest Oncology Group [J]. J Clin Oncol,2005,23 (13):2955-61.
20. Bajard A, Westeel V, Dubiez A, et al. Multivariate analysis of factors predictive of brain metastases in localised non-small cell lung carcinoma [J]. Lung Cancer,2004,45(3):317-23.
21. Ceresoli GL, Reni M, Chiesa G, et al. Brain metastases in locally advanced non-small cell lung carcinoma after multimodality treatment [J]. Cancer,2002,95(3):605-12.
22. Yoo JY, Yang SH, Lee JE, et al. E-cadherin as a predictive marker of brain metastasis in non-small-cell lung cancer, and its regulation by pioglitazone in a preclinical model [J]. J Neurooncol,2012,109(2):219-27.
23. Doebele RC, Lu X, Sumey C, et al. Oncogene Status Predicts Patterns of Metastatic Spread in Treatment-Naive Non-small Cell Lung Cancer [J]. Cancer,2012,118(18):4502-11.
24. Grinberg, Rashi H, Ofek E, Perelman M, et al. The expression of three genes in primary non-small cell lung cancer is associated with metastatic spread to the brain [J]. Clin Cancer Res,2009,15(5):1755-61.
25. Saad AG, Yeap BY, Thunnissen FB, et al. Immunohistochemical markers associated with brain metastases in patients with non-small cell lung carcinoma [J]. Cancer,2008 113(8):2129-38.
26. Milas I, Komaki R, HachiyaT, et al. Epidermal growth factor receptor, cyclooxygenase-2, and BAX expression in the primary non-small cell lung cancer and brain metastases [J]. Clin Cancer Res,2003,9(3):1070-6.
27. D'Amico TA, Aloia TA, Moore MB, et al. Predicting the sites of metastases from lung cancer using molecular biologic markers [J]. Ann Thorac Surg,2001,72 (4):1144-8.
28. Yang CH. EGFR tyrosine kinase inhibitors for the treatment of NSCLC in East Asia:present and future [J]. Lung Cancer,2008,60 (Supplement 2): S23-S30.
29. Noda N, Matsuzoe D, Konno T, et al. K-ras gene mutations in non-small cell lung cancer in Japanese [J]. Oncol Rep,2001,8(4):889-92.
30. Wang YC, Lee HS, Chen SK, et al. Analysis of K-ras gene mutations in lung carcinomas:correlation with gender, histological subtypes, and clinical outcome [J]. J Cancer Res Clin Oncol,1998,124(9):517-22.
31. Rosell R, Li S, Skacel Z, et al. Prognostic impact of mutated K-ras gene in surgically resected non-small cell lung cancer patients [J]. Oncogene,1993,8(9):2407-12.
32. Na Ⅱ, Park JH, Choe du H et al. Association of Epidermal Growth Factor Receptor Mutations with Metastatic Presentations in Non-Small Cell Lung Cancer [J]. ISRN Oncol,2011,2011:756265.
33. Sekine A, Kato T, Hagiwara E, Shinohara T, et al. Metastatic brain tumors from non-small cell lung cancer with EGFR mutations:Distinguishing influence of exon 19 deletion on radiographic features [J]. Lung Cancer,2012,77(1):64-9.
34. Eberhard DA, Johnson BE, Amler LC, et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib [J]. J Clin Oncol,2005,23(25):5900-9
35. Douillard JY, Shepherd FA, Hirsh V, et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer:data from the randomized phase III INTEREST trial [J]. J Clin Oncol,2010,28 (5):744-52.
36. Gow CH, Chien CR, Chang Y, et al. Receptor Mutations on Clinical Response Metastases:Effects of Activating Epidermal Growth Factor Radiotherapy in Lung Adenocarcinoma with Brain [J]. Clin Cancer Res,2008,14(1):162-8.
37. Eichler AF, Kahle KT, Wang DL, et al. EGFR mutation status and survival after diagnosis of brain metastasis in non-small cell lung cancer [J]. Neuro-Oncology,2010,12(11):1193-1199.
38. Pui CH. Central nervous system disease in acute lymphoblastic leukemia: prophylaxis and treatment [J]. Hematol Am SocEduc Program Book,2006,1:142-6.
39. Auperin A, Arriagada R, Pignon JP et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group [J]. N Engl J Med,1999,341 (7):476-84.
40. Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer [J]. N Engl J Med,2007,357 (7):664-72.
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