【作者】 张芳；

【导师】 程玉峰；

【作者基本信息】 山东大学 ， 临床医学（专业学位）， 2014， 博士

【摘要】 第一部分贫血、吸烟、饮酒与放疗的食管鳞癌初治患者预后关系的临床研究研究背景及目的：根据全球流行病学资料统计,食管癌是世界上最常见的癌症之一,发病率位于第八位,是世界癌症相关死亡的第六大病因。食管癌的发病率和死亡率有明显的地域性差异,除了日本以外发达国家食管癌的发病率都比较低,而我国发生的食管癌病例占全球的一半左右,是世界上食管癌发病率和死亡率最高的国家,是我国癌症相关死亡的第四大病因。食管癌主要分为两种组织学类型：食管鳞状细胞癌和食管腺癌。食管鳞状细胞癌仍然是中国和其他东亚国家食管癌的主要类型,而食管腺癌主要发生在美国和欧洲国家的白种人。目前食管癌的治疗中,手术治疗仍为首选治疗,具有重要的地位。不能手术和局部晚期患者,放射治疗为标准治疗,目前多主张同步放化疗。手术切除可以根治早期食管癌,对于局部进展期食管癌,仍然具有切除临床病灶、缓解梗阻、延长生存期的作用。但以手术为主的治疗模式,局部复发及远处转移率较高,总体预后差。治疗失败的主要原因在于局部复发和远处转移。由于食管在纵隔中与重要组织器官相邻,影响了肿瘤的完整切除,同时在确诊食管癌时常已存在微转移病灶,这为肿瘤的局部复发和远处转移创造了条件,从而影响了手术的疗效。食管癌,尤其是食管鳞癌对射线中度敏感,放疗可控制食管癌的局部复发,而同步应用的化疗既可以加强放疗控制局部肿瘤病灶,也可以消灭全身的微转移病灶,可减少肿瘤的复发和转移,为食管癌的治疗带来了希望。近来研究发现手术联合放化疗可延长可切除食管癌患者的长期生存率。放疗作为食管癌主要的治疗手段之一,提高放疗疗效,增加局部控制率,从而提高生存率。肿瘤细胞是否乏氧及乏氧克隆细胞所占的比例是影响放射敏感性的主要因素。有研究证明贫血可以引起肿瘤组织乏氧,通过一些肿瘤基因的活动,如基因不稳定性,基因突变,紊乱增生；X射线对哺乳动物细胞DNA的损伤,约三分之二是由氢氧自由基所致；肿瘤组织乏氧时由于氧气的缺乏导致自由基产生下降,从而减少肿瘤细胞DNA损伤,产生放射抗拒。Fein等报道在T12期声门鳞癌患者中,血红蛋白正常组的2年局部控制率明显优于贫血组。然而,在贫血与食管鳞癌预后关系方面的研究却罕见报道。吸烟、饮酒早已经被认为是食管鳞癌发病的主要危险因素,然而,却很少有研究报道吸烟、饮酒是否会影响食管鳞癌患者的预后。本研究的目的是评价贫血、吸烟、饮酒在初治的食管鳞癌放疗患者中的预后价值及与其他预后因子的关系。研究方法：本研究收集了2009年1月至2010年12月山东大学齐鲁医院放疗科收治的经病理证实、有完整随访资料的79例初次治疗的食管癌患者的临床资料,经病理学检查证实均为鳞癌,且都接受了放疗。采用直线加速器,技术为三维适形放疗,照射靶区主要包括原发灶和区域淋巴结,术前或术后一般剂量为50Gy,未行手术治疗的患者一般剂量为60-70Gy。化疗方案为紫杉类药物联合铂类方案。贫血的定义：男性血红蛋白<120g/L,女性血红蛋白<110g/L。用SPSS17.0统计软件进行分析。患者2年总生存率和2年无复发生存率情况用Kaplan-Meier方法进行分析；生存率比较用log-rank检验。临床指标(年龄、性别、是否吸烟、TNM分期、治疗方式、肿瘤部位等)和贫血对2年总生存率和无复发生存率的分析采用Cox回归进行单因素、多因素分析；P<0.05为有统计学意义。研究结果：在79例放疗的食管鳞癌初治患者中,治疗前贫血的发病率为29.1%,贫血组和血红蛋白正常组两组患者在临床资料、肿瘤特征、治疗方面没有统计学差异。血红蛋白正常组2年总生存率和2年无复发生存率分别为36%、25%,贫血组2年总生存率和2年无复发生存率分别为17%、13%,两者差异有统计学意义(总生存率P=0.019；无复发生存率P=0.029)。是否吸烟组和是否饮酒组2年总生存率和2年无复发生存率,两者差异无统计学意义。单因素分析发现贫血可影响患者的2年总生存率(风险比=1.897；P＝0.024)和2年无复发生存率(风险比=1.776；P=0.036)。多因素分析提示贫血可影响患者的2年总生存率(风险比=2.125；P=0.011)和2年无复发生存率(风险比=1.898；P=0.025)。单因素和多因素分析发现是否吸烟和是否饮酒对2年总生存率和2年无复发生存率的影响均无统计学意义。研究结论：放疗前的贫血是影响放疗的食管鳞癌初治患者2年总生存率和2年无复发生存率的一个独立预后因素,可增加复发的风险。血常规是一项常规检查,在临床中可简单而快速的判断是否贫血。第二部分体重指数与放化疗的食管鳞癌初治患者预后关系的临床研究研究背景及目的：根据全球流行病学资料统计,食管癌是全球最常见肿瘤之一其发病率居第八位、病死率居第六位。食管癌主要分为两种组织学类型：食管鳞状细胞癌和食管腺癌。中国和其他亚洲国家以食管鳞癌为主,而在美国和欧洲国家,腺癌更常见。目前在中国,随着经济的发展,肥胖的人数也在不断增加。有些研究发现体重指数的增加明显增加了乳腺癌、胰腺癌、结直肠癌和食管癌的发病风险。Carmichael A. R等发现无论是绝经期前还是绝经期后,肥胖的女性乳腺癌患者预后较低/正常体重的乳腺癌患者差。在一项4288例结肠癌患者的研究中,在诊断结肠癌时体重指数大于35.0kg/m2患者更容易出现肿瘤的复发,预后较差。Pelucchi C等发现在诊断胰腺癌时体重指数大于25.0kg/m2的患者较体重指数小于等于25.0kg/m2的患者生存率明显下降。然而,也有一些学者证明体重指数与癌症患者的预后无明显相关性。Hayashi Y等的研究显示,超重/肥胖体重指数的患者与正常/低体重指数的患者相比,超重/肥胖体重指数患者的5年总生存率和5年无复发生存率更高的原因是超重/肥胖体重指数的患者在诊断食管癌时临床分期较早。Ravi Shridhar等报道在放化疗的食管腺癌患者中,体重指数与患者的生存无明显相关性。目前体重指数与食管鳞癌预后关系的临床研究尚少。本实验的目的是评估治疗前的体重指数在放化疗的食管鳞癌初治患者中预后的价值。研究方法：本研究收集了2009年1月至2010年12月山东大学齐鲁医院放疗科和淄博市第一医院肿瘤科收治的经病理证实、有完整随访资料的60例初次治疗的食管癌患者的临床资料,经病理学检查证实均为鳞癌,且都接受了同步放化疗,化疗方案为多西紫杉醇+顺铂(21天为一周期,共2周期),同时给予三维适形放疗,DT54-60Gy/2Gy/27-30F,同步放化疗结束后继续原方案化疗3-4周期。我们根据体重指数将病人分成体重指数小于24.00kg/m2和体重指数大于等于24.00kg/m2两组,对比两组患者2年总生存率和无复发生存率情况；P<0.05为有统计学意义。研究结果：共有60例食管鳞癌患者进入本研究,其中41例患者在低/正常体重组(体重指数小于24.00kg/m2),19例患者在超重/肥胖体重组(体重指数大于等于24.00kg/m2)。两组患者在临床资料、肿瘤特征、治疗方面没有统计学差异。我们应用Kaplan-Meier生存函数分析发现低/正常体重组和超重/肥胖体重组的2年总生存率和2年无复发生存率无统计学意义(P=0.763for OS;P=0.818for DFS)。 Cox单因素分析发现临床分期可影响患者的2年总生存率和2年无复发生存率,淋巴结状态可影响患者的2年无复发生存率,远处转移情况可影响患者的2年总生存率,而年龄、性别、是否吸烟、是否饮酒、肿瘤部位和体重指数与患者的2年总生存率和2年无复发生存率无相关性。Cox多因素分析显示,体重指数与患者的2年总生产率的风险比为1.117,2年无复发生存率的风险比为1.161,无统计学意义。Cox多因素分析显示,临床分期、性别、T分期为放化疗的食管鳞癌初治患者独立的预后因素(P<0.04)。研究结论：体重指数与放化疗的食管鳞癌初治患者的2年总生存率和2年无复发生存率无明显相关性,体重指数不是一个放化疗食管鳞癌初治患者的预后指标。结论：放疗前贫血是影响放疗的食管鳞癌初治患者2年总生存率和无复发生存率的一个独立预后因素,体重指数不是一个放化疗食管鳞癌初治患者的预后指标。更多还原

【Abstract】 Part1A retrospective study:the prognostic value of anemia, smoking and drinking in esophageal squamous cell carcinoma with primary radiotherapyObjective:Esophageal cancer is the eighth most common cancer and the sixth mortality in the world. The distribution of esophageal cancer is heterogenous. Developed countries except for Japan have low rates, while China has a high rate of esophageal cancer, the fourth mortality in China. Esophageal squamous cell carcinoma (ESCC) continues to be the major type of esophageal cancer in Asia, in contrast, esophageal adenocarcinoma predominately affects the whites. Tobacco smoking and alcohol are well established causes of ESCC; however, there are few reports that directly evaluate these factors as prognostic factors for esophageal cancer. Currently, surgery remains an important treatment choice in esophageal cancer, while concurrent chemoradiotherapy is the standard treatment in inoperable and locally advanced esophageal cancer. The main reason for treatment failure is recurrence and distant metastasis. Radiotherapy is one of the main treatment for esophageal cancer and can control local recurrence of esophageal cancer. Anaemia is known to produce rumour hypoxia, tumour hypoxia confers radio-resistance through the hypoxia-associated reduction in free-radical production and consequent radiotherapy-induced DNA damage. Fein et al reported that the2-year local control rates in the non-anaemic group were significantly better than those in the anaemic group (p<0.0018) in T1-T2squamous cell carcinoma of the glottic larynx. However, few studies have investigated the relation between anemia and survival in patients with ESCC. The objective of this study was to evaluate the prognostic value of anaemia, smoking and drinking in patients receiving primary radiotherapy for ESCC and its relationship with other prognostic factors.Methods:A total of79patients who underwent radiotherapy during initial treatment for ESCC were included in this study. The2-year overall survival rate and disease-free survival rate were analyzed between the anemic and non-anemic groups, non-smokers and smokers groups, non-drinkers and drinkers groups using the Kaplan-Meier method and the Cox proportional hazards model.Results:There were79patients (10female) of median age of63(range38-84) years. The2-year overall survival rate and disease-free survival rate were36%and25%, respectively, in the non-anemic group, and17%and13%, respectively, in the anemic group(P=0.019for overall survival rate; P=0.029for disease-free survival rate) using the Kaplan-Meier method. Survival analysis using the Kaplan-Meier method show that the2-year overall survival rate and disease-free survival rate were no statistical difference between smoking, drinking and survival. In a univariate analysis, anemia was identified as a significant prognostic factor for2-year overall survival rate (haz-ard ratio1.897; P=0.024) and2-year disease-free survival rate (hazard ratio1.776; P=0.036), independent of TNM stage. In a multivariate analysis, anemia was identified as a highly significant prognostic factor for2-year overall survival rate (hazard ratio2.125; P=0.011) and2-year disease-free survival rate (hazard ratio1.898; P=0.025), independent of TNM stage and initial treatment. We found no statistical difference in the2-year overall survival rate and disease-free survival rate associated with smoking(P>0.2) and drinking (P>0.6) in univariate and multivariate analysis.Conclusions:Smoking and drinking were not prognostic for2-year overall survival rate or disease-free survival rate. Anemia before radiotherapy was associated with poor prognosis and an increased risk of relapse, which may serve as a new prognostic characteristic in ESCC treated with primary radiotherapy. Hemoglobin is a routine examination, therefore Anemia is simple and quick to determine.Part2Prognostic Value of Body Mass Index for Patients Undergoing Chemoradiotherapy for Esophageal Squamous Cell CarcinomaObjective:Esophageal cancers are among the most prevalent malignancies worldwide, with high rates of incidence and mortality. There are two major histological types of esophageal carcinoma:esophageal squamous cell carcinoma (ESCC) and adenocarcinoma with considerably varied epidemiological features. ESCC continues to be the major type of esophageal cancer in Asia, whereas esophageal adenocarcinoma predominately affects the whites. In China, the ratio of obesity is increasing. In some studies increased the body mass index(BMI) has been shown to correlate with increased risk for breast, pancreatic, colorectal, and esophageal cancers. Carmichael A.R showed that obesity was associated with worse prognosis in both pre-and post-menopausal women with breast cancer. Among4288colon cancer patients, a BMI greater than35.0kg/m2at diagnosis was associated with an increased risk for recurrence of and death from colon cancer. Pelucchi C et al. found that a BMI greater than25.0kg/m2at diagnosis was associated with reduced survival after pancreatic cancer. However, others have shown that the body mass index was not of prognostic value. Hayashi Y et al. have shown that the better5-year overall survival (OS) and disease-free survival (DFS) noted in patients with a high BMI compared with those with a normal/low BMI is because of the diagnosis of a low baseline clinical stage. Ravi Shridhar et al. reported that BMI was not associated with survival in patients with esophageal adenocarcinoma treated with chemoradiotherapy (CRT). The impact of obesity on survival of ESCC has only been minimally addressed. The aim of the present study was to examine whether BMI was of the prognostic value in patients with ESCC who underwent CRT as primary treatment.Methods:Sixty patients with ESCC were retrospectively reviewed in this study. Patients’ overall survival(OS)and disease-free survival(DFS) were compared between the two groups (BMI<24.00kg/m2and BMI≥24.00kg/m2). Results:There were41patients in the low/normal BMI group (BMI<24.00kg/m2) and19patients in the high BMI group (BMI>24.00kg/m2). No significant differences were observed in patient characteristics between groups. We found no difference in2-year OS and DFS associated with BMI (p=0.763for OS; p=0.818for DFS) using the Kaplan-Meier method. Univariate analysis revealed that higher clinical stage was prognostic for worse2-year OS and DFS, metastasis for2-year OS, Lymph node status for2-year DFS, while age, gender, smoking, drinking, tumor location and BMI were not prognostic. There were no differences in the2-year OS (hazard ratio=1.117; p=0.789) and DFS(hazard ratio=1.161; p=0.708) between BMI groups in multivariate analysis. In a multivariate analysis, We found statistical differences in the2-year OS and DFS associated with clinical stage, gender and tumor infiltration (P<0.04), independent of age, smoking, drinking, tumor location, the status of Lymph node, metastases and BMI.Conclusions:BMI was not associated with survival in patients with ESCC treated with CRT as primary therapy. BMI should not be considered a prognostic factor for Patients undergoing CRT for ESCC.Conclusion of the study:Anemia before radiotherapy may serve as a new prognostic characteristic in ESCC treated with primary radiotherapy. BMI should not be considered a prognostic factor for Patients undergoing CRT for ESCC.更多还原