非小细胞肺癌发生脑转移的风险因素评估与脑转移患者的靶向治疗效果研究
详细信息    本馆镜像全文|  推荐本文 |  |   获取CNKI官网全文
摘要
研究目的:
     非小细胞肺癌(NSCLC)脑转移的发病率高达30%-50%。NSCLC患者发生脑转移的风险因素目前尚不明确,本文通过对北京协和医院2008-2011年间收治的110例NSCLC患者的资料分析,来评价NSCLC患者发生脑转移(BM)的相关风险因素以及靶向治疗对于已经发生脑转移的患者的疗效。
     材料与方法:
     我们从病案库中随机抽取了从2008年至2011年在北京协和医院诊断为NSCLC的患者的病历资料进行回顾性研究。入组标准为:随机选取;至截止时间,病例完善随访;肺癌组织类型为NSCLC;已检测EGFR与K-ras突变或有条件进行检测。最后入组病例110例,其中脑转移患者22例。危险因素变量包括年龄、性别、吸烟史、家族史、原发灶部位、病理类型、EGFR突变和K-ras突变等。按照NSCLC患者发生与没发生BM的数量与危险因素暴露与否相比较来进行2检验,并计算比值比(Odds Ratio, OR),来确定暴露因素是否为NSCLC患者发生BM的危险因素。对于已经发生脑转移的患者统计其EGFR突变、靶向治疗与生存期的关系,来明确靶向治疗的效果。
     结果:
     经过分析,年龄≤55岁的患者更易发生脑转移;性别、吸烟史、家族史、原发灶部位、有无K-ras突变与NSCLC患者发生脑转移无明显联系;肺癌病理类型为腺癌的NSCLC患者更易发生脑转移,而鳞癌患者更不易发生脑转移;有EGFR突变的患者更易发生脑转移。对于脑转移患者,靶向治疗在有EGFR突变的患者中有明显的效果。
     结论:
     对于NSCLC患者,发生脑转移的主要风险因素有年龄、病理类型、EGFR突变等。其中年龄≤55岁、病理类型为腺癌以及EGFR突变阳性为比较重要的风险因素。希望能通过对于有较多风险因素的NSCLC患者进行密切的随访与干预,降低其发生脑转移的几率,提高NSCLC患者的生存率与预后。对于已经诊断脑转移的患者,采取个体化的综合治疗,特别对于有EGFR突变的患者EGFR-TKI靶向治疗,可以获得较好的疗效。
Objectives
     The morbidity of brain metastasis (BM) of non-small cell lung cancer (NSCLC) reaches up to30%-50%. The occurring risk factors of brain metastasis of patients of NSCLC are yet undefined. This study is to evaluate risk factors of brain metastasis of patients of NSCLC through data analysis of110patients treated at Peking Union Medical College Hospital (PUMCH), and to evaluate the effect of EGFR-TKI targeted therapy in patients who have got BM already.
     Materials and methods
     We retrospectively randomly reviewed the medical charts of patients found to have NSCLC in PUMCH between2008to2011. The set of standard for:random selection; To deadline, cases perfect follow-up; Lung cancer types for NSCLC; Already testing EGFR and K-ras mutation or conditions for testing. At last we got110cases, in which22were diagnosed BM. Expected risk factors included age, sex, smoking history, family history, initial position of cancer, pathological type, EGFR mutations and K-ras mutations. According to whether under the action of function of each possible risk factor in patients with NSCLC, we counted the number of BM and no BM, then calculated the χ2and Odds Ratio (OR), to confirm if there was contact between expected risk factor and BM. In patients who have already got BM, we analyse the relation between EGFR mutation, targeted therapy and survival time to definite the effect of targeted therapy.
     Results
     After an analysis, patients with the age<55years old were more likely to have brain metastasis. Gender, smoking history, family history, initial position of cancer and K-ras mutations did not have obvious effects on BM. The patients with pathological type of adenocarcinoma had more risk of brain metastasis while squamous cell carcinoma had less; Patients with EGFR mutations occurred more brain metastasis.In patients who have got BM, targeted therapy have obvious effect in ones who have EGFR mutations.
     Conclusion
     For patients with NSCLC, the main risk factors of brain metastasis happening are age, pathological type, and EGFR mutations. Age≤55years old, pathologic type being adenocarcinoma, and presence of EGFR mutations are important positive risk factors. We hope to have close follow-up and intervention for the NSCLC patients with many risk factors, to decrease the risk of brain metastases occuring, and to improve the overall survival and prognosis of patients with NSCLC. To patients having the diagnosis of brain metastases, taking individual treatment, especially for patients with EGFR mutations, EGFR-TKI targeted therapy can obtain good effect.
引文
[1]. Bonnette P, Puyo P, Gabriel C, et al. Surgical management of non-small cell lung cancer with synchronous brain metastases. Chest 2001 May; 119:1469-1475.
    [2]. Schrump D, Giaccone G, Kelsey K, Marks L. Non Small Cell Lung Cancer. In: DeVita V, Lawrence T, Rosenberg S, Weinberg R, DePinho R, editors. DeVita, Hellman, and Rosenberg's Cancer:principles and practice of oncology.8th ed. Philadelphia: Lippincott Williams and Wilkins,2008:896-939.
    [3]. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011; 61:69-90.
    [4]. Alberg AJ, Brock MV, Samet JM. Epidemiology of lung cancer:looking to the future. J Clin Oncol 2005; 23:3175-3185.
    [5]. Herbst RS, Bajorin DF, Bleiberg H, Blum D, Hao D, Johnson BE, Ozols RF, Demetri GD, Ganz PA, Kris MG, Levin B, Markman M, Raghavan D, Reaman GH, Sawaya R, Schuchter LM, Sweetenham JW, Vahdat LT, Vokes EE, Winn RJ, Mayer RJ. Clinical Cancer Advances 2005:major research advances in cancer treatment, prevention, and screening—a report from the American Society of Clinical Oncology. J Clin Oncol 2006; 24:190-205.
    [6]. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer statistics,2008. CA Cancer J Clin 2008; 58:71-96.
    [7]. Felip E, Stahel RA, Pavlidis N. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of non-small-cell lung cancer (NSCLC). Ann Oncol 2005; 16 Suppl 1:i28-i29.
    [8]. Posner JB. Management of brain metastases. Rev Neurol 1992; 148:477-487.
    [9]. Yun Oh, Sarah Taylor, Benjamin Nebiyou Bekele, et al. Number of metastatic sites is a strong predictor of survival in patients with nonsmall cell lung cancer with or without brain metastases. Cancer 2009; May 13.
    [10]. Schouten LJ, Rutten J, Huveneers HA, et al. Incidence of brain metastases in a cohort of patients with carcinomaof the breast, colon, kidney, lung, and melanoma. Cancer 2002; 94:2698-2705.
    [11]. Cho LC, Dowell JE, Garwood D, et al. Prophylactic cranial irradiation with combined modality therapy for patients with locally advanced non-samll cell lung cancer. Semin Oncol 2005; 32:293-298.
    [12]. Gaspar L, Scott C, Rotman M, et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 1997; 37:745-751.
    [13]. Chaosu Hu, Eric L, Chang, Samuel J, et al. Nonsmall Cell Lung Cancer Presenting with Synchronous Single Brain Metastasis. Cancer 2006; 106:1998-2004.
    [14]. Mekhail T, Sombeck M, Sollaccio R. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of 1-3 cerebral metastases:results of the EORTC 22952-26001 study. Curr Oncol Rep 2011; Aug 13(4):255-8.
    [15]. Tomofumi Yohena, Ichiro Yoshino, et al. Necessity of Preoperative Screening for Brain Metastasis in Non-small Cell Lung Cancer Patients without Lymph Node Metastasis. Ann Thorac Cardiovasc Surg 2004. Vol.10, No.6.
    [16]. Leigh D, Eken J, Beal JR, Ganti AK, Sahmoun AE. Statins use and risk for brain metastasis from lung cancer. Cancer Invest.2011 Jan; 29(1):68-72.
    [17]. Nakamura H, Ando K, Shinmyo T, et al. Female gender is an independent prognostic factor in non-small-cell lung cancer:a meta-analysis. Ann Thorac Cardiovasc Surg.2011 Oct 25; 17(5):469-80.
    [18]. Yano T, Haro A, Shikada Y, Maruyama R, Maehara Y. Non-small cell lung cancer in never smokers as a representative 'non-smoking-associated lung cancer':epidemiology and clinical features. Int J Clin Oncol.2011 Aug;16(4):287-93.
    [19]. Li N, Shao K, Chen Z, Qiu B, Wang Z, Tan F, Wang J, Tan X, Li B, Xiong M, Zhou F, He J. The impact of positive cancer family history on the clinical features and outcome of patients with non-small cell lung cancer. Fam Cancer.2011 Jun;10(2):331-6.
    [20]. Ye X, Wang S, Ou W, Zeng Z, Lin Y, Zhang B. Risk factor of brain metastasis in locally advanced non-small cell lung cancer after surgery. Zhongguo Fei Ai Za Zhi.2007 Apr 20;10(2):111-115.
    [21]. 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. Lung Cancer.2012 Feb 13.
    [22]. Eichler AF, Kahle KT, Wang DL, et al. EGFR mutation status and survival after diagnosis of brain metastasis in nonsmall cell lung cancer. Neuro Oncol.2010 Nov;12(11):1193-9.
    [23]. Shukuya T, Takahashi T, Naito T, et al. Continuous EGFR-TKI administration following radiotherapy for non-small cell lung cancer patients with isolated CNS failure. Lung Cancer.2011 Dec;74(3):457-61.
    [24]. Kaira K, Takahashi T, Murakami H, et al. Long-term survivors of more than 5 years in advanced non-small cell lung cancer. Lung Cancer.2010 Jan;67(1):120-3.
    [25]. Chang JW, Chou CL, Huang SF, et al. Erlotinib response of EGFR-mutant gefitinib-resistant non-small-cell lung cancer. Lung Cancer.2007 Dec;58(3):414-7.
    [26]. Ramon Andrade de Mello, Dania Sofia Marques, Rui Medeiros, Antonio MF Araujo. Epidermal growth factor receptor and K-Ras in non-small cell lung cancer-molecular pathways involved and targeted therapies. World J Clin Oncol 2011 November 10; 2(11): 367-376.
    [27]. Milella M, Nuzzo C, Bria E, Sperduti I, Visca P, Buttitta F, Antoniani B, Merola R, Gelibter A, Cuppone F, D'Alicandro V, Ceribelli A, Rinaldi M, Cianciulli A, Felicioni L, Malatesta S, Marchetti A, Mottolese M, Cognetti F. EGFR molecular profiling in advanced NSCLC:a prospective phase II study in molecularly/clinically selected patients pretreated with chemotherapy. J Thorac Oncol.2012 Apr; 7(4):672-80.
    [28]. Moldvay J, Petak I. EGFR tyrosine kinase inhibitors in lung cancer management: sensitivity and resistance. Magy Onkol.2012 Mar;56(1):38-49. Epub 2012 Jan 15.
    [29]. Chen G, Kronenberger P, Teugels E, Umelo IA, De Greve J. Targeting the epidermal growth factor receptor in non-small cell lung cancer cells:the effect of combining RNA interference with tyrosine kinase inhibitors or cetuximab. BMC Med.2012 Mar 21; 10:28.
    [30]. Oh IJ, Ban HJ, Kim KS, Kim YC. Retreatment of gefitinib in patients with non-small-cell lung cancer who previously controlled to gefitinib:A single-arm, open-label, phase II study. Lung Cancer.2012 Feb 12.
    [31]. Cho LC,et al. Prophylactic cranial irradiation with combined modality therapy for patients with locally advanced non-small cell lung cancer. Semin Oncol.2005 Jun;32(3):293-8.
    [32]. Fidler IJ,et al. The seed and soil hypothesis:vascularisation and brain metastases. Lancet Oncol.2002,3:53-7.
    [33]. Wang M, et al. J Clin Oncol.29:2011;abstr7608.
    [34]. Johnson JR,et al. Approval summary for erlotinib for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. Clin Cancer Res.2005,11:6414-6421.
    [35]. Li J,et al. Binding of gefitinib, an inhibitor of epidermal growth factor receptor-tyrosine kinase, to plasma proteins and blood cells:in vitro and in cancer patients. Invest New Drugs.2006,24:291-297.
    [36]. Hotta K, Kiura K, Ueoka H, Tabata M, Fujiwara K, Kozuki T, Okada T, Hisamoto A, Tanimoto M. Effect of gefitinib ('Iressa', ZD1839) on brain metastases in patients with advanced non-small-cell lung cancer. Lung Cancer.2004 Nov;46(2):255-61.
    [37]. Chiu CH, Tsai CM, Chen YM, Chiang SC, Liou JL, Perng RP. Gefitinib is active in patients with brain metastases from non-small cell lung cancer and response is related to skin toxicity. Lung Cancer.2005 Jan;47(1):129-38.
    [38]. Kim JE, Lee DH, Choi Y, Yoon DH, Kim SW, Suh C, Lee JS. Epidermal growth factor receptor tyrosine kinase inhibitors as a first-line therapy for never-smokers with adenocarcinoma of the lung having asymptomatic synchronous brain metastasis. Lung Cancer.2009 Sep;65(3):351-4.
    [39]. Wu YL,et al.J Clin Oncol,29:2011;abstr 7605.
    [40]. K.Kim,2011 ASCO. Abstract 7606.
    [41]. Takeda M, Okamoto I, Tsurutani J, Oiso N, Kawada A, Nakagawa K. Clinical Impact of Switching to a Second EGFR-TKI After a Severe AE Related to a First EGFR-TKI in EGFR-mutated NSCLC. Jpn J Clin Oncol.2012 Mar 28.
    [1]. Schrump D, Giaccone G, Kelsey K, Marks L. Non Small Cell Lung Cancer. In: DeVita V, Lawrence T, Rosenberg S, Weinberg R, DePinho R, editors. DeVita, Hellman, and Rosenberg's Cancer:principles and practice of oncology.8th ed. Philadelphia: Lippincott Williams and Wilkins,2008:896-939.
    [2]. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011; 61:69-90.
    [3]. Alberg AJ, Brock MV, Samet JM. Epidemiology of lung cancer:looking to the future. J Clin Oncol 2005; 23:3175-3185.
    [4]. Herbst RS, Bajorin DF, Bleiberg H, Blum D, Hao D, Johnson BE, Ozols RF, Demetri GD, Ganz PA, Kris MG, Levin B, Markman M, Raghavan D, Reaman GH, Sawaya R, Schuchter LM, Sweetenham JW, Vahdat LT, Vokes EE, Winn RJ, Mayer RJ. Clinical Cancer Advances 2005:major research advances in cancer treatment, prevention, and screening—a report from the American Society of Clinical Oncology. J Clin Oncol 2006; 24:190-205.
    [5]. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer statistics,2008. CA Cancer J Clin 2008; 58:71-96.
    [6]. Felip E, Stahel RA, Pavlidis N. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of non-small-cell lung cancer (NSCLC). Ann Oncol 2005;16 Suppl 1:i28-i29.
    [7]. Hanagiri T, Sugio K, Mizukami M, Ichiki Y, Sugaya M, Yasuda M, Takenoyama M, Yasumoto K. Significance of Smoking as a Postoperative Prognostic Factor in Patients with Non-small Cell Lung Cancer. JThorac Oncol 2008; 3:1127-1132.
    [8]. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapynaive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008; 26:3543-3551.
    [9]. Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar C, Paul S, Paoletti P, Einhorn L, Bunn PA. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-smallcell lung cancer previously treated with chemotherapy. J Clin Oncol 2004; 22:1589-1597.
    [10]. Asmis TR, Ding K, Seymour L, Shepherd FA, Leighl NB, Winton TL, Whitehead M, Spaans JN, Graham BC, Goss GD. Age and comorbidity as independent prognostic factors in the treatment of non small-cell lung cancer:a review of National Cancer Institute of Canada Clinical Trials Group trials. J Clin Oncol 2008; 26:54-59.
    [11]. Dajczman E, Kasymjanova G, Kreisman H, Swinton N, Pepe C, Small D. Should patient-rated performance status affect treatment decisions in advanced lung cancer? J Thorac Oncol 2008; 3:1133-1136.
    [12]. Sculier JP, Chansky K, Crowley JJ, Van Meerbeeck J, Goldstraw P. The impact of additional prognostic factors on survival and their relationship with the anatomical extent of disease expressed by the 6th Edition of the TNM Classification of Malignant Tumors and the proposals for the 7th Edition. J Thorac Oncol 2008; 3:457-466.
    [13]. Carvalho L, Cardoso E, Nunes H, Baptista V, Gomes A, Couceiro P. [The IASLC lung cancer staging project. Comparing the current 6(th) TNM edition with the proposed 7(th) edition]. Rev Port Pneumol 2009; 15:67-76.
    [14]. Schouten LJ, Rutten J, Huveneers HA, Twijnstra A. Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer 2002; 94(10):2698-705.
    [15]. Galluzzi S, Payne PM. Brain metastases from primary bronchial carcinoma:a statistical study of 741 necropsies. Br J Cancer 1956; 10(3):408-14.
    [16]. Mekhail T, Sombeck M, Sollaccio R. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of 1-3 cerebral metastases:results of the EORTC 22952-26001 study. Curr Oncol Rep 2011; Aug 13(4):255-8.
    [17]. Louie AV, Rodrigues G, Yaremko B, Yu E, Dar AR, Dingle B, Vincent M, Sanatani M, Younus J, Malthaner R, Inculet R. Management and prognosis in synchronous solitary resected brain metastasis from nonsmall- cell lung cancer. Clin Lung Cancer 2009; 10(3):174-9.
    [18]. Takeshi Hanagiri, Masaru Takenaka, Soich Oka, Yoshiki Shigematsu, Yoshika Nagata, Hidehiko Shimokawa, Hidetaka Uramoto, Fumihiro Tanaka. Results of a Surgical Resection for Patients With Stage IV Non-Small-Cell Lung Cancer. Clin Lung Cancer 2011.
    [19]. Kocher M, Soffietti R, Abacioglu U, Villa S, Fauchon F, Baumert BG, Fariselli L, Tzuk-Shina T, Kortmann RD, Carrie C, Ben Hassel M, Kouri M, Valeinis E, van den Berge D, Collette S, Collette L, Mueller RP. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol.2011 Jan 10;29(2):134-41.
    [20]. Oscar Arrieta, Cynthia Villarreal-Garza, Jesus Zamora, Monika Blake-Cerda, Maria D de la Mata, Diego G Zavala, Sae Muniz-Hernandez, Jaime de la Garza. Long-term survival in patients with non-small cell lung cancer and synchronous brain metastasis treated with whole-brain radiotherapy and thoracic chemoradiation. Radiation Oncology 2011; 6:166.
    [21]. Morris PG, Reiner AS, Szenberg OR, Clarke JL, Panageas KS, Perez HR, Kris MG, Chan TA, Deangelis LM, Omuro AM. Leptomeningeal Metastasis from Non-small Cell Lung Cancer:Survival and the Impact of Whole Brain Radiotherapy. J Thorac Oncol 2011 Nov 15.
    [22]. Rahn DA 3rd, Ray DK, Schlesinger DJ, Steiner L, Sheehan JP, O'Quigley JM, Rich T. Gamma knife radiosurgery for brain metastasis of nonsmall cell lung cancer:is there a difference in outcome between morning and afternoon treatment? Cancer.2011 Jan 15;117(2):414-20.
    [23]. Melloni Q Bandiera A, Gregorc V, Carretta A, Ciriaco P, Vigano M, Franzin A, Bolognesi A, Picozzi P, Zannini P. Combined treatment of non-small cell lung cancer with synchronous brain metastases:a single center experience. J Cardiovasc Surg (Torino).2011 Aug;52(4):613-9.
    [24]. Fotakopoulos G, Alexiou GA, Goussia A, Voulgaris S. Long-term survival after resection of a lung cancer metastasis. J Can Res Ther 2011;7:230-1.
    [25]. Pesce GA, Klingbiel D, Ribi K, Zouhair A, von Moos R, Schlaeppi M, Caspar CB, Fischer N, Anchisi S, Peters S, Cathomas R, Bernhard J, Kotrubczik NM, D'Addario G, Pilop C, Weber DC, Bodis S, Pless M, Mayer M, Stupp R. Outcome, quality of life and cognitive function of patients with brain metastases from non-small cell lung cancer treated with whole brain radiotherapy combined with gefitinib or temozolomide. A randomised phase Ⅱ trial of the Swiss Group for Clinical Cancer Research (SAKK 70/03). Eur J Cancer.2011 Nov 15.
    [26]. Lind JS, Lagerwaard FJ, Smit EF, Postmus PE, Slotman BJ, Senan S. Time for reappraisal of extracranial treatment options? Synchronous brain metastases from nonsmall cell lung cancer. Cancer.2011 Feb 1;117(3):597-605.
    [27]. Girard N, Cottin V, Tronc F, et al. Chemotherapy is the cornerstone of the combined surgical treatment of lung cancer with synchronous brain metastases. Lung Cancer 2006 Jul; 53:51-58.
    [28]. Lo CK, Yu CH, Ma CC, Ko KM, Leung SC. Surgical management of primary non-small-cell carcinoma of lung with synchronous solitary brain metastasis:local experience. Hong Kong Med J.2010 Jun; 16(3):186-91.
    [29]. Fu H, Zhang XL, Xiao Y, Liu XJ, Long C, Hu YD. Evaluation of gefitinib plus radiotherapy in non-small-cell lung cancer patients with brain metastases. Zhonghua Yi Xue Za Zhi.2012 Feb 28;92(8):524-7.
    [30]. Ramon Andrade de Mello, Dania Sofia Marques, Rui Medeiros, Antonio MF Araujo. Epidermal growth factor receptor and K-Ras in non-small cell lung cancer-molecular pathways involved and targeted therapies. World J Clin Oncol 2011 November 10; 2(11): 367-376.

© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号

地址:北京市海淀区学院路29号 邮编:100083

电话:办公室:(+86 10)66554848;文献借阅、咨询服务、科技查新:66554700