摘要
小细胞肺癌是肺癌的一种未分化癌，约占肺癌的20%，恶性程度较高、生物学行为恶劣、预后较差。癌细胞起源于较大支气管的肺Kulchitsky细胞，属于神经内分泌肿瘤，具有特殊的生物学行为，生存期短，进展快，常伴有内分泌异常或类癌综合征。较其他类型肺癌诊断前驱症状期短，确诊如不治疗，中位生存期不足3个月，2年生存率小于1%。小细胞肺癌分期特殊，分为局限期和广泛期，大多数小细胞肺癌患者确诊时已属广泛期，局限期所占比例仅为1/3。由于患者较早出现淋巴道转移和血行转移，因此在肺癌的各种类型中，小细胞肺癌预后最差。
小细胞肺癌对放疗及化疗敏感度均较高，治疗上应以全身化疗为主，联合放疗和手术为主要治疗手段，因此综合治疗是治疗小细胞肺癌成功的关键。但是针对局限期小细胞肺癌患者，采取何种综合治疗模式目前尚不明确。如何根据临床情况选择合理化综合治疗方案，在提高治疗疗效的同时准确地评估预后，已成为目前研究的热点。因此本研究旨在探讨小细胞肺癌综合治疗的疗效，分析不同治疗模式对预后的影响，从而为临床选择标准治疗方案提供依据。
小细胞肺癌属于神经内分泌肿瘤，其特殊的生物学行为可能与其表达的某种肿瘤标记物有关。胃泌素释放肽（gastrin-releasing peptide, GRP）及其受体（GRP receptor, GRPR）是近年来研究较多肿瘤标记物，在小细胞肺癌中高表达。GRP通过与相应受体结合促进癌细胞增殖、血管生成、浸润转移等多个步骤，刺激肿瘤的生长及侵袭、转移。本研究旨在探讨小细胞肺癌组织中表达的GRP及GRPR与肿瘤侵袭、转移的相关性，判断其作为小细胞肺癌肿瘤标记物的灵敏度及特异度，并为肿瘤的靶向治疗研究提供依据。
第一部分：局限期小细胞肺癌综合治疗预后分析
目的：探讨局限期小细胞肺癌接受综合治疗后的疗效及预后影响因素分析。
方法：回顾性分析2006年1月至2008年6月于河北医科大学第四医院综合治疗的158例局限期小细胞肺癌患者的临床资料，所有病例均经病理证实，男性120例（75.9%）、女性38例（24.1%），中位年龄55岁（范围24~78岁），治疗前肿瘤中位体积95.0cm3（范围3.2~3600.0cm3）。接受化疗者146例（92.4%），化疗方案以EP、EC为主，平均化疗5个周期（范围1~17个）；接受胸部放疗者120例（75.9%），中位剂量54Gy（范围30.0~70.0Gy）；接受手术者49例（31.0%），其中楔形切除2例、段切除3例、叶切除25例、全肺切除19例。综合治疗模式包括：放疗±化疗109例（69.0%）、手术±化疗38例（24.1%）、手术+放疗±化疗11例（6.9%）。采用Kaplan-Meier法计算生存率，采用Log-rank法进行单因素分析，多因素分析采用COX比例风险模型筛选影响预后因素，P＜0.05判定为具有统计学意义。
结果：全组患者治疗后总有效率（CR+PR）86.7%，中位生存期24个月，1、2、3年生存率为76.3%、48.9%、39.1%。放疗±化疗组、手术±化疗组、手术+放疗±化疗组1、2、3年生存率分别为73.0%、41.4%、30.3%，79.0%、60.5%、54.4%和90.9%、81.8%、71.6%，差异有统计学意义（P=0.015），但是按临床分期分层后发现三组患者远期生存间未见明显差异。单因素分析显示临床分期、近期疗效、化疗、放疗、放疗剂量、手术对预后产生明显影响（P＜0.05）；多因素分析显示近期疗效、化疗、放疗剂量是影响患者预后的独立因素。
结论：手术、放疗、化疗综合治疗模式治疗局限期小细胞肺癌的预后未见明显差异，而近期疗效、化疗参与、放疗剂量是影响预后的独立因素，综合治疗方案的优选还有待进一步研究。
第二部分：局部放疗联合化学治疗局限期小细胞肺癌的疗效分析
目的：探讨局部放疗联合全身化疗治疗局限期小细胞肺癌的疗效及相关因素分析。
方法：回顾性分析2006年1月至2008年6月在河北医科大学第四医院放疗科接受治疗的107例局限期小细胞肺癌患者临床资料，所有病例均经病理学证实，男性82例（76.6%）、女性25例（23.4%），中位年龄54岁（范围24~73岁），治疗前肿瘤中位直径6.0cm（范围2.0~12.2cm），中位体积135.0cm3（范围3.2~489.0cm3）。所有患者均接受胸部放疗，累及照射组82例（76.6%），包括肺部肿瘤及（或）转移的纵隔和锁上淋巴结，中位剂量56.0Gy（范围36.0~66.0Gy）；累及区+预防照射组25例（23.4%），累及区包括肺部肿瘤及（或）转移的纵隔和锁上淋巴结，中位剂量56.0Gy（范围50.0~70.0Gy），再勾画同侧肺门、纵隔±锁上淋巴引流区进行预防性照射，中位剂量40.0Gy（范围30.0~52.0Gy）。接受化疗者99例（92.5%），化疗方案以EP、EC为主，化疗中位周期数为5个周期（范围1~10个）。放化综合治疗的联合模式分为序贯组25例、巩固组25例、同期组49例，根据放疗参与时间的早晚分为先放疗组28例、早放疗组49例、晚放疗组22例。采用Kaplan-Meier法计算局部控制率、生存率、远处转移率，采用Log-rank法进行单因素分析及COX比例风险模型进行多因素分析，筛选局部控制、预后、远处转移的影响因素。
结果：(1)全组患者治疗后总有效率（CR+PR）87.9%，1、2、3年局部控制率分别为83.1%、70.0%、64.0%，单因素分析发现近期疗效、化疗对肿瘤局部控制产生明显影响，多因素分析发现，肿瘤体积、T分期、近期疗效、放疗剂量、GTVD_(mean)、PTVCI是影响肿瘤局部控制的独立因素。(2)全组患者1、2、3年生存率分别为73.8%、38.8%、27.6%，中位生存期19个月，单因素分析发现肿瘤体积、化疗、PTVD_(95)对预后产生明显影响，多因素分析发现，治疗前合并胸腔积液、肿瘤体积、T分期、化疗、放疗范围、放疗剂量、GTVHI、PTVD_(mean)、PTVD_(95)是影响患者预后的独立因素。(3)全组患者1、2、3年远处转移率分别为44.2%、67.4%、70.3%，单因素分析发现肿瘤体积、T分期、近期疗效、局部控制、化疗、放疗范围对发生远处转移均有明显影响，多因素分析发现，年龄、肿瘤体积、T分期、放疗范围、PTVCI是影响远处转移的独立因素。
结论：胸部放疗与全身化疗的不同联合方式对患者的局控率、远处转移率、生存率均未见明显影响。肿瘤体积、T分期对局限期小细胞肺癌的局部控制、远处转移、预后均有明显影响。第三部分：小细胞肺癌相关肿瘤标记物的研究
目的：探讨小细胞肺癌肿瘤标记物与局部控制、预后及远处转移的关系及预测远处转移的价值。
方法：回顾性分析2006年1月至2008年6月在河北医科大学第四医院治疗的73例小细胞肺癌患者临床及病理资料，所有病例均经病理学证实，男性54例（74.0%）、女性19例（26.0%），中位年龄53岁（范围27~73岁），治疗前肿瘤中位体积100.0cm~3（范围6.0~489.0cm~3）。接受手术治疗者38例（52.1%），其中楔形切除1例、段切除3例、叶切除21例、全肺切除13例；接受局部放疗者35例（47.9%），对肺部原发肿瘤及转移的纵隔、锁上淋巴结进行照射，中位剂量54.0Gy（范围42.0~66.0Gy）。调取73例患者病理石蜡块，常规切片，用免疫组化方法检测NSE、GRP、GRPR的蛋白表达，结合肿瘤体积重新分级。采用Kaplan-Meier法计算生存率、远处转移率，采用Log-rank法进行预后与远处转移的单因素分析。P＜0.05判定为具有统计学意义。
结果：NSE、GRP、GRPR蛋白在小细胞肺癌组织中的阳性表达率分别为71.2%、79.5%、75.3%，GRP与GRPR的表达存在相关性（P=0.000）。GRP、GRPR蛋白不同表达水平患者间的预后及远处转移均存在明显差异（P＜0.05）。肿瘤体积结合GRPR蛋白表达，以及结合GRP/GRPR蛋白表达重新分级，不同级别患者间的远处转移存在明显差异（P＜0.05）。GRP与GRPR蛋白表达预测小细胞肺癌远处转移的灵敏度均为71.4%，特异度分别为83.9%、90.3%。
结论：GRP、GRPR是灵敏度及特异度均较好的预测小细胞肺癌的侵袭性及远处转移的重要指标，有可能成为以GRPR为靶点靶向治疗小细胞肺癌的依据。
Small cell lung cancer (SCLC) is one special kind of undifferentiatedcarcinoma of the lung. It is characterized by more malignance, specificbiologic behavior and poor prognosis. The cancer cell originate fromKulchitsky cell of the lung, and belongs to neuroendocrine tumor. Afterdiagnosis, the median survival time is less than3months and the2-yearsurvival rate is not more than1%if there is no treatment policy. BecauseSCLC can relapse rapidly and metastasize widely at early stage,approximately30to40percent of it is limited-stage (LS) at clinical diagnosis.
SCLC is sensitive to chemotherapy and radiotherapy, so it is necessary toadopt combined therapy. It is not clear that which modality of combinedtherapy could be chosen to improve the prognosis for LS-SCLC and it becomethe hot issue for oncologist. Consequently, the purpose of this study is toinvestigate the outcome of patients with LS-SCLC after combined therapy andto evaluate the prognostic factors.
SCLC belongs to neuroendocrine tumor and has specific biologic behavior,which is probably relevant to some tumor marker. Recently, gastrin-releasingpeptide (GRP) and its receptor (GRPR) are tumor marker studied frequentlyand express highly in SCLC. The combination of GRP and GRPR canaccelarate the growth and metastasis of SCLC. So the purpose of the study isto investigate the relationship between tumor marker and local control,prognosis and metastasis of patients with SCLC and to evaluate the value oftumor marker forecasting the metastasis.
Part1：A prognostic analysis for patients with limited-stage small-celllung cancer treated by combined therapy
Objective: The aim of this study was to analyze the outcome of patients with limited-stage small-cell lung cancer (LS-SCLC) treated by combinedtherapy and to evaluate the prognostic factors.
Methods: Data from158patients with SCLC after combined therapybetween January2006and June2008were retrospectively analyzed. Allpatients had histological or cytological confirmation of SCLC, and wereclassified as limited-stage disease. There were120(75.9%) male and38(24.1%) female. The median age was55years old (range,24~78years). Themedian volume of primary tumor before therapy were95.0cubic centimetre(range,3.2~3600.0cubic centimetre). One hundred and forty-six patientsreceived chemotherapy, and the median chemotherapy cycle was5(range,1~17cycles). One hundred and twenty patients received radiotherapy, and themedian radiotherapy dose was54Gy (range,30.0~70.0Gy). Forty-ninepatients received surgery. The combined therapy included radiotherapy＋/－chemotherapy, surgery＋/－chemotherapy and surgery＋radiotherapy＋/－chemotherapy. The method of Kaplan-Meier was used for survival ratesanalysis.
Results: The overall response rate (CR+PR) was86.7%. The mediansurvival time (MST) was24months, and the1-,2-and3-year survival rateswere76.3%,48.9%and39.1%, respectively. The1-,2-and3-year survivalrates of patients receiving radiotherapy＋/－chemotherapy, surgery＋/－chemotherapy and surgery＋radiotherapy＋/－chemotherapy were73.0%,41.4%,30.3%and79.0%,60.5%,54.4%and90.9%,81.8%,71.6%,respectively. The difference was not statistically significant in the analysisafter stratification by clinical stage. In univariate analyses, the clinical stage,short-term clinical effect, chemotherapy, radiotherapy, radiotherapy dose andsurgery were significantly associated with prognosis. The multivariate analysisshowed that short-term clinical effect, chemotherapy, and radiotherapy dosewere independent factors influencing prognosis.
Conclusion: The combined therapy of radiotherapy, surgery andchemotherapy may obtain good outcome without significant difference forpatients with LS-SCLC. We need a further study to choose the best modality of combined therapy.
Part2：A study of patients with limited-stage small-cell lung cancer afterthoracic radiotherapy combined with systemic chemotherapy
Objective: The aim of this study was to evaluate the effect of patients withlimited-stage small-cell lung cancer (LS-SCLC) treated by thoracicradiotherapy combined with systemic chemotherapy.
Methods: Data from107patients with SCLC after radiotherapy combinedwith chemotherapy between January2006and June2008were retrospectivelyanalyzed. All patients had histological or cytological confirmation of SCLC,and were classified as limited-stage disease. There were82(76.6%) male and25(23.4%) female. The median age was54years old (range,24~73years).The median volume of primary tumor before therapy were135.0cubiccentimetre (range,3.2~489.0cubic centimetre). All patients receivedradiotherapy. There were82patients (76.6%) received radiotherapy ofinvolved field, and the median radiotherapy dose was56.0Gy (range,36.0~66.0Gy). In another25patients (23.4%), the involved field receivedradiotherapy of median dose56.0Gy (range,50.0~70.0Gy), and the lymphaticdrainage area of ipsilateral hilum and mediastinum received prophylacticradiotherapy of median dose40.0Gy (range,30.0~52.0Gy). Ninety-ninepatients received chemotherapy, and the median chemotherapy cycle was5(range,1~10cycles). There were25patients receiving radiotherapysequentially to chemotherapy,25receiving radiotherapy consolidated withchemotherapy, and49receiving radiotherapy concurrently with chemotherapy.The method of Kaplan-Meier was used for local control rates, survival rates,and metastasis rates analysis.
Results:(1) The overall response rate (CR+PR) was87.9%. The1-,2-and3-year local control rates were83.1%,70.0%and64.0%, respectively. Inunivariate analyses, short-term clinical effect and chemotherapy weresignificantly associated with local control. But in multivariate analysis, thevolume of primary tumor, T stage, short-term clinical effect, radiotherapy dose,GTVD_(mean), and PTVCI were independent factors for the local control.(2) The median survival time (MST) was19months and the1-,2-and3-year survivalrates were73.8%,38.8%and27.6%, respectively. In univariate analyses, thevolume of primary tumor, chemotherapy, and PTVD_(95)were significantlyassociated with prognosis. The multivariate analysis showed that pleuraleffusion，the volume of primary tumor, T stage, chemotherapy, target range ofradiotherapy, radiotherapy dose, GTVHI, PTVD_(mean), and PTVD_(95)wereindependent factors influencing the prognosis.(3) The1-,2-and3-yearmetastasis rates were44.2%,67.4%and70.3%, respectively. In univariateanalyses, the volume of primary tumor, T stage, short-term clinical effect,local control, chemotherapy and target range of radiotherapy weresignificantly associated with metastasis. But in multivariate analysis, age, thevolume of primary tumor, T stage, target range of radiotherapy, and PTVCIwere independent factors influencing metastasis.
Conclusion: In LS-SCLC, the modality of radiotherapy combined withsystemic chemotherapy does not affect the local control, prognosis, andmetastasis. The volume of primary tumor and T stage is significantlyassociated with not only local control, but also prognosis and metastasis ofpatients with LS-SCLC.
Part3：A study of tumor marker associated with small-cell lung cancer
Objective: The aim of this study was to investigate the relationshipbetween tumor marker and local control, prognosis and metastasis of patientswith small-cell lung cancer and to evaluate the value of tumor markerforecasting the metastasis.
Methods: Data from73patients with SCLC between January2006andJune2008were retrospectively analyzed. All patients had histologicalconfirmation of SCLC. There were54(74.0%) male and19(26.0%) female.The median age was53years old (range,27~73years). The median volume ofprimary tumor before therapy were100.0cubic centimetre (range,6.0~489.0cubic centimetre). Thirty-eight (52.1%) patients received surgery, and35(47.9%) patients received radiotherapy. All patients’ paraffin-embedded tumortissues were obtained from the Pathology Department, and were cut in4-μm sections. The expression of NSE, GRP, and GRPR were checked byimmunohistochemistry. The method of Kaplan-Meier was used for survivalrates and metastasis rates analysis. The Log-rank test was used for correlationbetween antibody expression and prognosis and metastasis.
Results: NSE, GRP, and GRPR were detected in71.2%,79.5%, and75.3%,respectively, of all tumor specimens. The expression of GRP was correlated tothat of GRPR significantly (P=0.000). The expression of GRP and GRPRwere associated with patients’ prognosis and metastasis significantly (P＜0.05). The sensitivity of the expression of GRP and GRPR forecasting themetastasis were both71.4%, and the specificity of them were83.9%and90.3,respectively.
Conclusion: GRP and GRPR may play an important role in the small-celllung cancer process, and may be an important tumor marker forecasting theinvasion and metastasis of SCLC. The study may provide a molecular basisfor exploiting target of immunotherapeutic purposes in SCLC.
引文
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