【作者】 金波；

【导师】 刘云鹏；

【作者基本信息】 中国医科大学 ， 内科学， 2006， 博士

【摘要】 目的 肺癌在世界范围内是发生率和死亡率最高的恶性肿瘤之一,每年大约新诊断140万例,死亡大约120万例。小细胞肺癌(SCLC)占肺癌患者的20%左右,临床进展快,生存期短,对化疗及胸部放疗敏感是其显著特点。多数SCLC患者会发生复发,肿瘤复发或进展后治疗效果通常较差,复发后中位生存时间仅为8～12周。超过80%的肺癌患者是非小细胞肺癌(NSCLC),手术治疗是首选治疗方法,但是NSCLC患者中80%左右为进展期患者,无法手术,需要多学科综合治疗,进展期NSCLC化疗反应较差,一般有效率在30%～40%,1年生存率25%～40%,中位生存时间7～12个月。研究者们自70年代发现肺癌患者就诊及治疗过程中免疫功能常处于抑制状态,且免疫状态可能与患者生存时间有关。学者们在标准治疗中加入干扰素(IFN)等生物反应调节剂,寻求可以延长肺癌患者生存期并且不降低生存质量的方法。 IFN是一组由细胞受某些因素刺激后产生的高活性、多功能的诱生蛋白质,是具有多种生物学作用的细胞因子,主要作用有促进多种细胞表面抗原如MHC-Ⅰ类分子表达,有助于向细胞毒T淋巴细胞(CTL)递呈抗原,或通过激活自然杀伤细胞(NK细胞)和巨噬细胞,增强MHC-Ⅱ类抗原的表达,促使肿瘤细胞非凋亡死亡和干扰细胞增殖,调节分化,抑制新生血管形成,细胞周期阻滞,触发细胞凋亡,此外IFN还有抗病毒活性的重要作用。IFN自从被发现已经近50年,被FDA批准应用于商业用途也已经近20年,然而在肿瘤的治疗上仍然较为局限,仅在肾癌、恶性黑色素瘤等实体肿瘤治疗和慢性粒细胞白血病和多毛细胞白血病等血液系统恶性肿瘤中的作用得到肯定,已经通过多个大样本RCT和Meta分析证实,然而在肺癌治疗中的更多还原

【Abstract】 ObjectivesLung cancer is the leading cause of cancer death in both men and women in the world. An estimated 1,400,000 new cases of lung cancer will be diagnosed every year. Only 14% of all lung cancer patients will be alive 5 years or more after diagnosis. Small cell lung cancer (SCLC) accounts for 20% of all lung cancers. SCLC is considered highly sensitive to chemotherapy and radiotherapy;however, most patients eventually develop recurrent disease. SCLC presents with disseminated disease in nearly all patients, which is managed using combination chemotherapy with chest radiotherapy for those with disease in the chest. Treatment using chemotherapy plus chest radiotherapy can be curative for some patients with SCLC. Patients with curative non - - small - cell lung cancer are typically managed with surgical resection. About 40% of patients with limited -stage disease survive for 2 years, whereas fewer than 5% of those with extensive - stage disease survive for 2 years. Non - small cell lung cancer (NSCLC) accounts for 80% of all lung cancers. Surgery is the first selected treatment for NSCLC. But advanced NSCLC patients, accounting 80% of NSCLC, can not be surgically resected.For patients considered having stage IIB and stage III tumors, where more than one treatment modality ( surgery, radiation therapy, or chemotherapy) is u-sually considered, a multidisciplinary evaluation should be performed. Response rate for chemotherapy is 30% ~ 40% , the 1 - year survival rates for those patients are 25% ~40% .median survival time is 7 ~ 12 month. Researcher found that immune function of patients were inhibited during diagnosis and therapy andthat immune status of patients was related to their survival time. The addition of biological response modifiers ( BRMs, for example BCG, IL - 2, TNF - a and IFN) to standard therapy for patients might prolong survival and retain QOL.Interferons is a group of pleiotropic cytokines that exhibit important biologic activities, including antiviral, antitumor, immunomo - dulatory and angiogene-sis. Recent evidence indicates that IFNs regulate cells proliferation via activation of multiple signaling cascades, involving Jak - stats>p38 MAP kinasesxIRS and CrkL protein. It is indicated that IFNs mosly result in a delayed progression from S - phase to G2 - phase of the cell cycle although IFN can affect every phase of cell cycle. IFNs can effect every phase of mitosis, particularly phase Gl arrest. Interferon stimulated gene (ISGs) are activated after IFNs activate Jak - stats pathway via binding with IFNAR1/2 or IFNGR1/2 . Both direct or indirect effects of IFNs result from induction of a subset of genes, called IFN stimulated genes (ISGs). IFNs may induce cells apoptosis via mitochondria/ cyto-chrome and death receptor pathway. IFN is effective treatment in some solid tumour e. g. renal cell cancer and malignant melanoma,but IFN is contradictory to treat lung cancer.Evidence — based medicine ( EBM) is a clinical decision of incorporating individual clinical experience into the best scientific evidence. Evidence should be searched and examined for EBM in clinical practice. Multiplecentre randomized controlled trials ( RCTs) and systematic reviews (SRs) are golden standard to prove efficacy and safety.. The best evidence is defined with reliable data, standard, and’concrete analysized evaluation. The study methods of EBM include RCTs ,SRs and clinical guidelines. Either SRs or guidelines need to be updated after they are published.Meta - analysis is a trend to define the relation of intervention factor and prognosis of disease because single outcome might result from many factors. This present study investigates the role of IFN in lung cancer collecting RCTs of treatment with IFN to lung cancer.Methods1 eligibility stanard:1) Study objectives are diagnosed with lung cancer with cytology or pathology-2) Trials were randomized controlled trials3) IFN was used in the treatment of lung cancer for induction regimens or maintenance of remission afterchemotherapy.2 study criteria;Major criterias are 1 year and 2 year survival rate, secondary criteria is treatment response rate. Relative risk is evaluated to compare survival rate in group of experiement and controllment.3 Search and evaluation 3.1 Search strategy:Studies were identified by a search of the MEDLINE, EMBAS, OVID databases , Cochrane library, The Cochrane Central Register of Controlled Trials, AS-CO meeting and European Society for Mediccal Oncology using the terms inter-feron and lung cancer. Computer - based searches were supplemented by manual searching of education book of international meeting and reference of the selected studies.Published studies were selected and data extracted by two physician reviewers working independently. In addition, each reviewer assigned a quality-score of 0 to 5 using Jadad method of quality assessment. Data extraction forms were checked against one another and differences were resolved before data entry.3. 2 Search results:Twelve studies and 1 abstract are selected for our 3 studies, all published in English.3. 3 statistical methodDatas are analyzed with RevMan4.2 analysis software supplied by Cochrane centre. Consistency checking are examined at first to select fixed effect model or random effect model, RR and confidence interval are calculated, forest plots areobtained, funnel plots are analyzed.Results1 Meta - analysis of induction chemotherapy combined with interferon in small cell lung cancer1. 1 Five eligible RCTs are published before 2001 about comparing maintain therapy with IFN with observation. Total 307 patients entered maintain therapy group and 286 patients entered controlled group.1. 2 Meta - analysis of 2 - year survival showed RR 1. 42 (0. 98, 2. 07) and indicated IFN can not increase 2 - year survival.1.3 Meta - analysis of 1 - year survival showed RR 1.16 ( 0. 86, 1. 57 ) and indicated IFN can not increase 1 - year survival.1.4 Meta - analysis of 2 - year survival about IFN - a maintain therapy showed RR 2.08 ( 1. 16, 3.72 ) and indicated IFN can increase 2 -year survival.1.5 Meta - analysis of 1 - year survival about IFN - a maintain therapy showed RR 2.99 ( 1.13, 7.93 ) and indicated IFN can increase 1 -year survival.2 Meta - analysis of induction chemotherapy combined with interferon in small cell lung cancer2. 1 Three eligible RCTs are published before 2000 about comparing induction chemotherapy combined with interferon with induction chemotherapy. Total 229 patients entered maintain therapy group and 157 patients entered controlled group.2. 2 Meta - analysis of 1 - year survival showed RR 1. 26 (0. 95, 1. 68) and combination with IFN can not increase 1 - year survival.2.3 Meta - analysis of response rate showed RR 1.16 (0. 98, 1. 38) and indicated IFN can not increase response rate .3 Meta - analysis of induction chemotherapy combined with interferon in advanced non - small cell lung cancer3.1 Five eligible RCTs are published before 1996 about comparing indue-tion chemotherapy combined with interferon with induction chemotherapy. Total 194 patients entered maintain therapy group and 166 patients entered controlled group.3. 2 Meta - analysis of 1 - year survival showed RR 0. 76 (0. 46, 1. 26) and combination with IFN can not increase 1 - year survival.3. 3 Meta - analysis of response rate showed RR 1. 40 (0. 83, 2. 34) and indicated IFN can not increase response rate .3.4 Meta - analysis of leucocytopenia showed RR 2. 61 (1. 70,3. 99) and combination with IFN can increase leucocytopenia.3. 5 Meta - analysis of thrombocytopenia showed RR 0. 76 (0. 46, 1. 26) and combination with IFN can increase thrombocytopenia.DiscussionThe low long survival rate might be related to low immunologic function in lung cancer patients. The mmunologic function disorder display functional transform of T lymphocyte, lethal effect attenuation of NK cell, functional impairment of macrophage etc. Scholars treated lung cancer with IFN to improve patients immune state and prolong survival. The antitumour effect of IFN includes two pathways: mediating tumour cell nonapoptosis death indirectly and inhibiting proliferation directly. The first way is promote surface molecular express including)^ macroglobulin, Fc receptor, tumour associated antigen e. g. MHC -I antigen, increase CTLs lethal effect . The second way is that IFN participate signal transduction pathway including JAKs - STATs, p38 - MAP kinase, IRS -PI3K/Akt -mTOR to affect cell proliferation and induce apoptosis. IFN activate ISGs including TRAIL/Apo2L,Fas/FasL,XIAP related factor - 1 ( XIAP - 1) , Caspase - 4, Caspase - 8, PKR, OAS, IRFs, PML gene, RIDs etc. then induce apoptosis via mitochondria/cytochrome C and death domain pathway.Well - designed RCT Is golden standard to evaluate clinical intervention. Meta - analysis is an overview study in essence and is a summary analysis. There might be bias during Meta - analysis because of limitation. The bias of Meta - a-nalysis consists of selection bias,practice bias and study bias. This present studydo not limit range , language ,time and sample size to search and carry out expansion search about meeting abstract , other databases and reference to decrease selection bias.In the first study " Meta - analysis of induction chemotherapy combined with interferon in small cell lung cancer" , a study is removed because most of patients do not complete therapy. Another study is removed because survival data is not obtained. Meta - analysis of 2 - and 1 - year survival showed RR 1.42 (0.98, 2.07) and RR 1. 16 ( 0. 86, 1.57 ) respectively indicated IFN can not increase 2 - and 1 - year survival.Meta - analysis of 2 - year and 1 - year survival about IFN - a maintain therapy showed RR 2. 08 ( 1.16, 3.72 ) and RR 2.99 ( 1. 13, 7. 93 ) respectively indicated IFN can increase 2 - and 1 - year survival survival.In the second study " Meta - analysis of induction chemotherapy combined with interferon in small cell lung cancer" , Meta - analysis of 1 - year survival showed RR 1. 26 (0. 95, 1. 68) and combination with IFN can not increase 1 -year survival. Meta - analysis of response rate showed RR 1.16 (0. 98, 1. 38) and indicated IFN can not increase response rate.In the second study " Meta - analysis of induction chemotherapy combined with interferon in advanced non - small cell lung cancer" , Meta - analysis of 1 -year survival showed RR 0.76 (0.46, 1.26) and combination with IFN can not increase 1 - year survival. Meta — analysis of response rate showed RR 1.40 (0. 83, 2. 34) and indicated IFN can not increase response rate . Meta - analysis of leucocytopenia and thrombocytopenia showed RR 2.61(1.70,3.99) and RR 0. 76 (0.46, 1.26) respectively indicated combination with IFN can increase leucocytopenia and thrombocytopenia.There are 7 high quality studies of 3 points with Jadad evaluation among 12 eligible studies and 1 abstract in this present study,. Bias might exist because of less cases and chemotherapy regimen.Conclusion1. Maintain therapy with IFN to SCLC can not improve 1 - and 2 - yearsurvival.2. Maintain therapy with IFN - a to SCLC can significantly improve 1 -and 2 - year survival.3. Induction therapy with IFN combination with chemo - therapy to SCLC can not improve 1 - year survival.4. Induction therapy with IFN combination with chemo - therapy to SCLC can not improve response rate.5. Induction therapy with IFN combination with chemo - therapy to NSCLC can not improve 1 - year survival.6. Induction therapy with IFN combination with chemo - therapy to NSCLC can not improve response rate.7. Induction therapy with IFN combination with chemo - therapy to NSCLC can significantly increase leucocytopenia and thrombocytopenia.8. There might be bias in this present study because of less cases. Induction therapy regimen and IFN doses are different might effect result. Multicentre RCTs needed confirm these conclusions.更多还原