厄洛替尼致间质性肺疾病的特点、机制及防治简

厄洛替尼为表皮生长因子受体酪氨酸激酶抑制剂（EGFR—TKI）,临床用于治疗非小细胞肺癌。问质性肺疾病（ILD）是厄洛替尼严重而少见的不良反应,发生率为0．1％～4．8％,病死率为0．8％～2．4％。厄洛替尼引起ILD的中位时间为用药22d,临床表现为干咳、低热、呼吸困难等,影像学检查可见双肺弥漫性磨玻璃样阴影,实验室检查显示低氧血症。男性、高龄、有基础肺部病变及吸烟等为危险因素。厄洛替尼致ILD的主要机制为免疫介导和药物的直接毒性。避免对高危患者用药、使用低剂量、避免与其他化疗药物和／或放射治疗同步应用、加强呼吸功能监测是预防厄洛替尼致ILD的有效措施。一旦发生ILD应立即停用厄洛替尼,换用其他EGFR—TKI。厄洛替尼致ILD的治疗以抑制炎症反应及防止肺纤维化为主要目的,主要措施包括吸氧、应用糖皮质激素,预防感染和对症治疗。     

吉非替尼致间质性肺疾病及其防治

吉非替尼是一种口服选择性表皮生长因子受体酪氨酸激酶抑制剂,用于治疗非小细胞肺癌。吉非替尼可引起间质性肺疾病(ILD),引起ILD的平均时间为24～42d,发生率为0.44%～2.0%,病死率为0.12%～0.5%。ILD主要临床表现为呼吸困难、胸闷、干咳和发绀等,胸部影像学检查可见双肺弥漫性浸润性阴影及蜂窝状间质阴影。高龄、男性、吸烟史、ILD史和长时间用药等为吉非替尼致ILD的危险因素。用药期间应进行胸部影像学检查,一旦发现ILD应及时停药,并给予静脉注射大剂量糖皮质激素、吸氧、抗感染等对症支持治疗,一般预后良好。     

临床药师基于循证方法对1例晚期肺癌脑转移患者的药学监护

目的:通过临床药师基于循证方法对1例肺癌伴脑转移患者实施药学监护,探讨临床药师如何应用文献证据为临床提供治疗建议,更好地发挥临床药师的作用。方法:临床药师在1例肺癌伴脑转移患者的药学监护过程中,在充分评估患者情况后,通过检索Pub Med、CNKI数据库,选择高证据等级的文献作为评价患者用药方案的依据。首先评估了患者使用吉非替尼靶向治疗方案的预期收益;其次依据癌症支持治疗多国协会(MASCC)指南就吉非替尼可能出现的不良反应提出了预防措施;再次通过各类药学检索工具发现和预防了利培酮和昂丹司琼合用可能发生的不良反应。结果:医师在靶向药物选择、不良反应预防以及用药方案调整等方面均采纳了临床药师的建议,避免了抗精神病药与止吐药合用出现的严重不良反应;积极采取预防措施,使吉非替尼引发皮疹的严重程度大幅减少,从而保证了患者治疗过程顺利;患者脑转移症状最终得以控制,顺利出院。结论:以循证药学为基础的药学监护,使药师和医师在药物治疗方面更容易达成共识,同时也保证了药学监护工作的科学性和可靠性。     

临床药师要用药学知识参与临床合理用药

一例肺癌术后复发病人拟口服盐酸厄洛替尼片进行化疗,该药由CYP3A4酶代谢,当与CYP3A4酶的抑制剂或诱导剂联合应用时,应适当调整盐酸厄洛替尼的剂量。该病人同时合并使用了其他6种药物,临床医师就此问题咨询临床药师,临床药师查询资料后给予解答,并由此引发了作者对临床药学工作的思考:临床药师在临床工作中是有用武之地的,但是必须要注重自身专业能力的提高。同时作者发现,国内临床用药的参考资料,如药品说明书和专著的内容有待更新和完善。     

Tyrosine kinase inhibitors for the treatment of acute myeloid leukemia: delineation of anti-leukemic mechanisms of action

Initially, tyrosine kinase inhibitors (TKIs) were developed as targeted therapies that would solely interfere with aberrant tyrosine kinase activation in malignant cells. Nevertheless, preclinical and clinical studies demonstrated that TKI also exhibit “off-target” effects, that is effects not mediated by the assumed mechanisms of action. We and others showed that the epidermal growth factor receptor (EGFR) inhibitors erlotinib and gefitinib exert potent antineoplastic effects on EGFR-negative myeloblasts from patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Here, we undertook a side-by-side comparison of the anti-leukemic efficacy of four different TKI in MDS and AML. Besides the EGFR inhibitor erlotinib, which served as a point of reference, we employed the dual EGFR/HER2 TKI lapatinib, as well as the multikinase inhibitors dasatinib and sorafenib. All four drugs had anti-leukemic effects on cell line models of MDS/AML in vitro as well as on malignant blasts from MDS/AML patients ex vivo. We explored the biological phenomena underlying this anti-leukemic efficacy. Since it is established that a therapeutic benefit in MDS/AML can be conveyed by induction of cell cycle arrest, apoptosis and/or differentiation, we deciphered the individual contribution of these three phenomena to the anti-leukemic action of each of the four TKI. The concomitant assessment of the panel of TKI enables us thus to define (and quantify) their differential capacity to impact on the three biological phenomena, and provide further evidence that these mechanisms are not solely explained by on-target effects.     

细胞角蛋白19片断在间质性肺病诊断中的临床意义

血清细胞角蛋白19片断 （cytokeratin 19 fragment,CYFRA21-1）、神经元特异性烯醇化酶（neuron specific enolization enzyme ,NSE）是用于常规诊断肺癌的检测指标。不仅可以初步诊断肺癌,还可用于其分型。但是在临床中发现,CYFRA21-1在间质性肺病（interstitial lung disease,ILD）患者中出现了较好的特异性,另外,肺癌和间质性肺病在发病机制和鉴别诊断中又存在着密不可分的关系,这将为间质性肺病的诊断提供新的视角。本研究纳入了133例间质性肺病患者为ILD组,133例肺癌患者为肺癌组,159例肺炎患者为肺炎组,分别检测3组患者CYFRA21-1和NSE的水平,检测结果发现：在ILD组中,CYFRA21-1的水平远远高于肺炎组,低于肺癌组,且均有显著性差异。NSE仅在肺癌组超出正常水平,在ILD组和肺炎组均在正常参考值范围内且没有统计学差异。本研究表明,CYFRA21-1在间质性肺病的诊断中有着重要的临床价值,并且CYFRA21-1在间质性肺病诊断中的特异性要高于NSE。     

Angiotensin II type 1 receptor blockade attenuates gefitinib-induced cardiac hypertrophy via adjusting angiotensin II-mediated oxidative stress and JNK/P38 MAPK pathway in a rat model

Gefitinib is a tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR), used for the treatment of advanced or metastatic non-small cell lung cancer. Recently, studies proved that Gefitinib-induced cardiotoxicity through induction of oxidative stress leads to cardiac hypertrophy. The current study was conducted to understand the mechanisms underlying gefitinib-induced cardiac hypertrophy through studying the roles of angiotensin II (AngII), oxidative stress, and mitogen-activated protein kinase (MAPK) pathway. Male Wistar albino rats were treated with valsartan, gefitinib, or both for four weeks. Blood samples were collected for AngII and cardiac markers measurement, and hearts were harvested for histological study and biochemical analysis. Gefitinib caused histological changes in the cardiac tissues and increased levels of cardiac hypertrophy markers, AngII and its receptors. Blocking of AngII type 1 receptor (AT1R) via valsartan protected hearts and normalized cardiac markers, AngII levels, and the expression of its receptors during gefitinib treatment. valsartan attenuated gefitinib-induced NADPH oxidase and oxidative stress leading to down-regulation of JNK/p38-MAPK pathway. Collectively, AT1R blockade adjusted AngII-induced NADPH oxidase and JNK/p38-MAPK leading to attenuation of gefitinib-induced cardiac hypertrophy. This study found a pivotal role of AngII/AT1R signaling in gefitinib-induced cardiac hypertrophy, which may provide novel approaches in the management of EGFRIs-induced cardiotoxicity.     

Successful treatment of erlotinib-induced acute hepatitis and acute interstitial pneumonitis with high-dose corticosteroid: a case report and literature review

Erlotinib, a kind of epidermal growth factor receptor tyrosine kinase inhibitor, is a target therapy and approved for the treatment of metastatic non-small cell lung cancer (NSCLC) and advanced pancreatic cancer. Among these EGFR-TKI agents, including gefitinib and erlotinib, the common dose-limiting toxicities are diarrhea, mucositis and skin rash (Acneform eruptions). In addition to the above adverse effects, infrequent but potentially fatal and lethal entity complications include acute interstitial lung disease (ILD) and acute hepatitis. The incidence of EGFR-TKI agents (gefitinib and erlotinib) induced acute hepatitis is rare and hepatotoxicity of EGFR-TKI agent was rarely discussed. The treatment of EGFR-TKI agents induced acute hepatitis remains uncertain and cessation medication is current policy. Here we reported a case of erlotinib induced interstitial pneumonitis and acute hepatitis with clinical appearance of hypoxemia and general weakness, treated with high dose pulse therapy and showed good recovery.     

Safety of gefitinib in non-small cell lung cancer treatment

ABSTRACT

Introduction: The development of EGFR TKI and the subsequent identification of activating EGFR mutations have dramatically changed how NSCLC is treated. With its recent approval by the US Food and Drug Administration, gefitinib adds to the list of recommended first-line treatments for lung cancer harboring EGFR mutations, which hitherto includes erlotinib and afatinib.

Areas covered: This review summarizes the pharmacological property, clinical efficacy, and safety of gefitinib in major clinical trials and post-marketing studies.

Expert opinion: Gefitinib is a well-tolerated treatment for advanced NSCLC. The most common adverse events are skin reaction and diarrhea, both of which are generally mild, noncumulative, and manageable. Other side effects such as interstitial lung disease and liver toxicity are less common but can be serious. Which EGFR TKI is the preferred first-line treatment is a matter of debate. Gefitinib and erlotinib have comparable efficacy, whereas afatinib may exert superior clinical activity over gefitinib. In terms of the most common toxicities of skin reaction and diarrhea, gefitinib may be the most tolerable of the three. Hence, despite being the earliest EGFR TKI developed, gefitinib continues to be one of the first-line treatments for advanced EGFR-mutated NSCLC, especially when skin and gastrointestinal toxicity is a concern.     

类风湿关节炎与原发性干燥综合征重叠患者继发间质性肺疾病的临床特点分析

目的 探讨类风湿关节炎（RA）与原发性干燥综合征（pSS）重叠患者继发间质性肺疾病（ILD）的临床特点、影像评分及预后的影响。方法 回顾性收集 43 例 RA 和 pSS 重叠（RA-pSS）患者的临床资料及肺高分辨率 CT（HRCT）资料,其中RA-pSS继发ILD组15例,RA-pSS未继发ILD组28例。2组患者年龄、性别、病程比较差异无统计学意义。观察RA-pSS患者的临床资料、肺功能、影像学改变,并对肺HRCT进行评分,分析RA-pSS继发ILD的临床、影像学特点及预后。结果 与RA-pSS未继发ILD组相比,RA-pSS继发ILD患者的C反应蛋白水平明显升高（P＜0.05）;RA-pSS 继发 ILD 组肺 HRCT 最常见的表现是小叶间隔增厚,最常见的 ILD 类型为非特异性间质性肺炎（NSIP）;与非普通型间质性肺炎（非-UIP）组相比,UIP组临床-影像-生理评分（CRP score）明显升高（P＜0.05）;与RA-pSS未继发ILD组相比,RA-pSS继发ILD组的生存率明显降低（P＜0.01）。结论 RA-pSS继发ILD患者炎性指标C反应蛋白水平更高,影像学表现复杂,预后差,应该得到临床的重视。     

原发性干燥综合征合并间质性肺病38例临床分析

目的分析呼吸内科收治的原发性干燥综合症（SS）相关间质性肺病（ILD）的临床特点。方法对2003年1月-2011年7月之间北京大学人民医院呼吸内科收治的SS相关ILD患者资料统计分析。结果共统计患者38例,27例（71.1%）因ILD首诊。32例行肺功能检查,25例（78.1%）弥散功能降低;14例（43.7%）为限制性通气障碍。所有患者胸部高分辨CT（HRCT）均显示ILD,其中7例肺功能正常。23例长期口服糖皮质激素,12例复查胸部HRCT,共9例ILD吸收好转,其中6例支气管肺泡灌洗液（BALF）淋巴细胞增高者经糖皮质激素治疗肺部病变均好转,3例胸部HRCT无明显蜂窝形成但无BALF结果者经糖皮质激素治疗有2例吸收好转。结论 SS常以ILD为首诊原因。胸部HRCT对ILD诊断价值优于肺功能。BALF淋巴细胞升高和/或胸部HRCT无明显蜂窝形成者经糖皮质激素治疗肺部病变可吸收好转。     

FOXO3 mutation predicting gefitinib-induced hepatotoxicity in NSCLC patients through regulation of autophagyOA

Hepatotoxicity is a common side effect for patients treated with gefitinib,but the related pathogenesis is unclear and lacks effective predictor and management strategies.A multi-omics approach integrating pharmacometabolomics,pharmacokinetics and pharmacogenomics was employed in nonsmall cell lung cancer patients to identify the effective predictor for gefitinib-induced hepato toxicity and explore optional therapy substitution.Here,we found that patients with rs4946935 AA,located in Forkhead Bo...     

吉非替尼肝毒性的分子机制及药物防治研究进展

吉非替尼作为第一个上市的表皮生长因子受体酪氨酸激酶抑制剂,在非小细胞肺癌等恶性肿瘤的靶向治疗中具有重要作用,但该药会引发肝毒性等严重的不良反应,须停药进行保肝治疗,极大地影响肿瘤的治疗过程。但吉非替尼所致肝毒性的机制仍不清楚,临床治疗措施也十分有限。本文综述吉非替尼诱导肝毒性的分子机制以及临床常用治疗药物,为临床防治及合理用药提供科学依据。     

EGFR TKI combination with immunotherapy in non-small cell lung cancer

Introduction: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) has significantly improved clinical outcomes compared with chemotherapy in non-small cell lung cancer (NSCLC) patients with sensitizing EGFR gene mutation.

Areas covered: Almost all patients treated with EGFR TKIs eventually develop acquired resistance. It has been reported that activation of the oncogenic EGFR pathway enhances susceptibility of the lung tumors to PD-1 blockade in mouse model, suggesting combination of PD1 blockade with EGFR TKIs may be a promising therapeutic strategy. Nivolumab combined with erlotinib was associated with 19% of grade 3 toxicities. The combination of osimertinib plus durvalumab in pretreated or chemo naïve NSCLC patients showed encouraging clinical activity, however, this combination was associated with high incidence of interstitial lung disease (38%), leading to termination of further enrollment. The combination of gefitinib plus durvalumab demonstrated encouraging activity but higher incidence of grade 3/4 liver enzyme elevation (40–70%). The treatment related Grade 3–4 adverse events were observed in 39% of patients when treated with atezolizumab plus erlotinib.

Expert opinion: Given the relatively high incidence of treatment-related toxicities associated with combination of EGFR TKI and immunotherapy, further development of this approach remains controversial. Until now, the combination of EGFR TKI and immunotherapy should be investigational.     

Severe lung and skin toxicity during treatment with gemcitabine and erlotinib for metastatic pancreatic cancer

Gemcitabine in combination with the oral epidermal growth factor receptor tyrosine kinase inhibitor erlotinib is a new treatment option for patients with advanced pancreatic cancer. The nonhematological side effects of this regimen mainly include diarrhea and skin rash. For each of these drugs, gemcitabine and erlotinib, lung toxicities have been described previously. In this report, we present the first case of a nonlung cancer patient experiencing not only acne-like skin toxicity, but subsequently also severe interstitial lung disease during therapy with gemcitabine and erlotinib. Both therapeutic agents were suspected as a possible cause of this adverse event. An interaction between gemcitabine and erlotinib might have also contributed to the pathogenesis of this pulmonary toxicity. Treatment with high-dose steroids was, however, very effective in our patient and a complete recovery appeared within a few days. Thus, pulmonary side effects should be regarded carefully in pancreatic cancer patients receiving palliative therapy with gemcitabine and erlotinib.     

Clarification of clinical features of interstitial lung disease induced by irinotecan based on postmarketing surveillance data and spontaneous reports

Irinotecan-induced interstitial lung disease (ILD) requires accurate diagnosis, followed by prompt and appropriate treatment. This study was conducted to compile information and imaging data to define the characteristics of irinotecan-induced ILD. Searches were performed on information collected for a drug reexamination application and on data from spontaneous safety reports submitted to Daiichi Sankyo Company, Limited. These database searches revealed 153 cases of serious ILD that occurred in association with irinotecan therapy, and which were reported as adverse drug reactions. Computed tomographic findings obtained after the onset of ILD were categorized based on four typical patterns. A total of 66 patients (including 15 for whom a relationship between death and serious ILD could not be excluded; incidence of serious ILD: 0.74%; death rate of ILD: 0.17%) were detected during the postmarketing surveillance along with 87 patients (22 deaths) that were identified from spontaneous reports. Within 16 weeks of starting treatment, 80.7% of the patients developed ILD. A total of 61.3% of the cases treated using steroids responded to the steroid therapy. These results indicate that there is no specific clinical or imaging feature associated with ILD related to irinotecan and that the prognosis of ILD related to irinotecan was poor in patients with preexisting ILD. The relative risk calculated for the association between preexisting ILD and death was 2.25 (P=0.29). During irinotecan treatments, patients need to be carefully observed for symptoms, especially at 16 weeks after starting treatment. In addition, when patients are receiving this type of therapy, they also need to undergo chest imaging studies.     

Erlotinib resistance is altered after gemcitabine chemotherapy for recurrent non-small-cell lung cancer

We report the case of a male Mongolian lifelong non-smoker with recurrent non-small-cell lung cancer (NSCLC) who developed resistance to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib after initially responding to this agent but then subsequently had another response to a second course of erlotinib treatment after intervening gemcitabine chemotherapy. Sixteen months after the patient received chemoradiotherapy with gemcitabine/cisplatin plus radiotherapy, his recurrent mediastinal metastases were found to have progressed. Treatment with erlotinib was followed by an initial, partial response but evidence of progression was again observed 6 months later. The patient was then treated with gemcitabine chemotherapy, which resulted in a reduction in tumour volume. One month later, progression of mediastinal metastases was again observed and the patient received a second course of erlotinib. Another partial response occurred and the patient's disease remained stable at the 9-month follow-up visit (and with no reported symptom progression at an 11-month telephone follow-up). Genetic examination of tumour tissue collected at the time of the original diagnosis and during the second course of erlotinib therapy revealed activating exon 19 mutation in the EGFR gene. This case suggests that resistance to erlotinib may change following chemotherapy and that repeat erlotinib therapy may be worth considering after chemotherapy in NSCLC patients who initially respond positively to erlotinib treatment but subsequently experience recurrence of disease.     

Erlotinib and vinorelbine in advanced malignant solid tumors: a phase I study

Summary Background Erlotinib is an oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI). Vinorelbine, a vinca alkaloid, interferes with microtubule assembly inhibiting mitosis during metaphase. Both drugs are commonly used as single agents in the treatment of advanced non small cell lung cancer (NSCLC). Given their efficacy in NSCLC and their non-overlapping toxicity profile, we conducted a phase I study of erlotinib and vinorelbine to establish the feasibility and safety of the combination and to determine the maximum tolerated dose (MTD). Patients and methods Patients with advanced solid tumors were treated with vinorelbine intravenously on day 1 and 8 and erlotinib orally daily on a 21 day schedule. The dose levels of vinorelbine/erlotinib were 25 mg/m²/100 mg, 25/150 and 30/150. Results Sixteen patients were enrolled. Five patients were chemo-na?ve; 11 had one prior therapy. The majority of patients had NSCLC (n = 7). Dose limiting toxicities included febrile neutropenia (4 patients) and grade 5 infection (1 patient). Non-hematologic grade 3/4 toxicities included diarrhea, hypokalemia, infection, dyspnea and mucositis. Of 12 patients assessable for radiologic response, there were no objective responses; eight had stable disease. Conclusions (1) The MTD was vinorelbine 25 mg/m² day 1 and 8 with erlotinib 100 mg/day every 21 days. (2) The combination was associated with high rate of febrile neutropenia (25%). (3) Due to subsequent data demonstrating a lack of efficacy of erlotinib in combination with platinum doublets in advanced NSCLC, this combination has not been explored further. Supported in part by University of California Davis Cancer Center Support Grant, Genentech and Glaxo-Smith Kline.     

Tyrosine kinase inhibitors as modulators of ATP binding cassette multidrug transporters: substrates, chemosensitizers or inducers of acquired multidrug resistance?

INTRODUCTION: Anticancer tyrosine kinase inhibitors (TKIs) are small molecule hydrophobic compounds designed to arrest aberrant signaling pathways in malignant cells. Multidrug resistance (MDR) ATP binding cassette (ABC) transporters have recently been recognized as important determinants of the general ADME-Tox (absorption, distribution, metabolism, excretion, toxicity) properties of small molecule TKIs, as well as key factors of resistance against targeted anticancer therapeutics. AREAS COVERED: The article summarizes MDR-related ABC transporter interactions with imatinib, nilotinib, dasatinib, gefitinib, erlotinib, lapatinib, sunitinib and sorafenib, including in vitro and in vivo observations. An array of methods developed to study such interactions is presented. Transporter-TKI interactions relevant to the ADME-Tox properties of TKI drugs, primary or acquired cancer TKI resistance, and drug-drug interactions are also reviewed. EXPERT OPINION: Based on the concept presented in this review, TKI anticancer drugs are considered as compounds recognized by the cellular mechanisms handling xenobiotics. Accordingly, novel anticancer therapies should equally focus on the effectiveness of target inhibition and exploration of potential interactions of the designed molecules by membrane transporters. Thus, targeted hydrophobic small molecule compounds should also be screened to evade xenobiotic-sensing cellular mechanisms.     

厄洛替尼通过下调CD44表达抑制非小细胞肺癌转移的机制研究

目的 探讨表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)下调黏附分子CD44表达抑制非小细胞肺癌转移的机制.方法 采用MTT法检测厄洛替尼对HCC827细胞株的增殖抑制效应及计算药物作用48 h的IC50;采用Transwell和划痕实验检测3组[control、EGF(50 ng/ml)刺激组、厄洛替尼(0.323 μmol/L)处理组]细胞侵袭迁移能力的变化;采用流式细胞术及Western blot方法分别从细胞及蛋白水平检测3组[control、EGF(50 ng/ml)刺激组、厄洛替尼(0.323 μmol/L)处理组]细胞CD44表达水平变化.结果 MTT结果显示,随着药物浓度升高,厄洛替尼对细胞的增殖抑制率也逐渐增大,差异有统计学意义(P＜ 0.05);IC50为0.323 μmol/L.Transwell及划痕实验结果显示,厄洛替尼阻断EGFR信号通路后可降低细胞的侵袭迁移能力(P＜0.05).流式细胞术及Western blot检测三组细胞CD44表达水平变化结果显示:当使用EGF刺激细胞后,CD44表达明显上调,而使用厄洛替尼阻断EGFR信号通路后CD44表达则被明显下调(P＜0.05).结果提示,厄洛替尼抑制肿瘤转移可能与改变CD44表达有关.结论 使用厄洛替尼阻断EGFR信号通路后,可间接下调与肿瘤转移密切相关的黏附分子CD44的表达,进而发挥抑制肿瘤转移的作用.