【作者】 陈妹琼；

【导师】 申洪；

【作者基本信息】 南方医科大学 ， 病理学， 2008， 硕士

【摘要】 肺癌是最常见的死亡率最高的恶性肿瘤之一,其中非小细胞肺癌(NSCLC)占80%以上。由于80%的肺癌患者在确诊时已属晚期,失去手术机会,化疗为其治疗的主要手段之一。然而,系统化疗在NSCLC治疗中的作用至今仍是肿瘤学中有争议的问题,有关化疗延长NSCLC患者生存期的报告结论不一,且化疗带来的毒副作用可能令病人难以承受。许多医生认为,晚期肺癌的化疗,其毒性作用可能超过其治疗的益处。患者也面临着是否选择或接受化疗的抉择。因此,化疗对晚期肺癌的意义究竟如何?是否应该进行化疗尚需探讨和进一步研究证实,为此我们对这一问题进行了实验研究。目的和意义:本课题旨在探讨化疗能否延长晚期肺癌患者的生存期及改善生活质量,为临床治疗方案的选择和疗效评价提供实验依据。并了解肺癌患者的基本特征,为肺癌的防治和流行病学研究提供资料。材料和方法一、C57BL/6小鼠晚期Lewis肺腺癌化疗疗效评价实验分组:将小鼠随机分成化疗组(20只)、对照组(20只)和空白组(12只)实验方法:建立C57BL/6小鼠晚期肺癌模型,实验组采用临床常用的紫杉醇/顺铂联合化疗方案,对照组给予等量生理盐水,空白组不予处理,观察各组小鼠的生存期、一般状态及体重变化。统计学分析:采用SPSS13.0统计软件,对不同组别小鼠生存期的变化采用单向方差分析(One-way ANOVA);对不同组别小鼠精神状态分值变化的比较采用Kruskal-Wallis H检验;对不同组别小鼠体重的变化采用重复测量数据的方差分析(repeated—measures ANOVA)及One-way ANOVA;采用Dunnett T3法进行两两比较:以P＜0.05为差异有统计学意义。二、肺癌住院患者的基本特征分析收集南方医院2000年—2005年部分临床确诊为肺癌的住院患者资料1012例,其中男性730例,女性282例。分析肺癌患者的首发症状、确诊前症状及体征;确诊时患者的吸烟史、年龄分布、一般行为状态、组织学类型及累及器官,并比较男女两性在这些方面的差异。统计学分析:采用SPSS13.0统计软件,对数据进行R×C表资料的x~2检验,以P＜0.05(双侧)为差异有统计学意义。三、晚期肺癌患者化疗疗效随访研究材料:本研究为回顾性研究,收集南方医院2000年～2005年符合诊断与纳入标准的患者237例,平均年龄57.18±12.983(20～87岁);其中化疗组142例,平均年龄53.82±12.047(20～82岁);支持治疗组95例,平均年龄62.20±12.764(29～87岁)。因两组经均衡性检验,发现年龄及KPS评分(卡氏行为状态评分)分布不均衡,化疗组年龄较支持治疗组轻,KPS评分高于支持治疗组。因此先根据两组患者不同年龄段所占比例的差异,化疗组剔除31～40岁年龄段患者5例,支持治疗组剔除70岁以上患者12例;再根据两组患者KPS评分所占比例的差异,化疗组剔除评分为90分者4例,支持治疗组剔除70分者4例。共剔除25例后两组分布均衡,化疗组133例,平均年龄54.17±11.753(20～82岁);支持治疗组79例,平均年龄59.96±12.289(29～87岁)。方法:根据患者的治疗情况将病例分为化疗组及支持治疗组。化疗组133例,为接受临床常规的化疗方案的患者,化疗药物不限;支持治疗组79例,为拒绝化疗或不能坚持完成化疗的患者,采用支持对症治疗。统计学分析:采用SPSS13.0统计软件,对两组患者性别、年龄分布、吸烟史、一般状况、临床分期、病理类型、累及器官的比较采用x~2检验;对化疗组男女间近期疗效的比较采用x~2检验,对化疗组男女间化疗药物毒性反应的比较采用Mann-Whitney Test;采用Kaplan—Meier方法进行生存率计算,显著性检验采用Log rank法,对预后因素进行COX回归分析;生存期计算自确诊之日至死亡或末次随访时间;两组间1年、2年、3年生存率的比较采用x~2检验。以P＜0.05为差异有统计学意义。实验结果一、C57BL/6小鼠晚期Lewis肺腺癌化疗疗效评价1、化疗组较对照组及空白组能延长小鼠的生存期,差异有统计学意义(P=0.000)。2、在一般状态方面,治疗后第2天三组间差异无统计学意义(P=0.636),治疗后第3～7天,化疗组一般状态明显优于对照组及空白组,差异有统计学意义(P＜0.05)。3、在小鼠体重变化方面,化疗体重减轻程度较对照组及空白组明显,差异有统计学意义(P=0.017);但在治疗后第4～7天,三组间体重减轻差异无统计学意义(P＞0.05)。二、肺癌住院患者的基本特征分析1、肺癌患者确诊前无任何症状者占7.91%;咳嗽是最常见的首发症状,约占58.89%,其次为咳痰,约占24.51%;以咯血、胸背痛、胸闷、气促为初发症状者分别占15.61%、17.39%、9.19%、9.98%;以声嘶、发热、呼吸困难、消瘦为初发症状者约占1.38%、3.56%、0.89%、1.98%;以皮下结节或肿块、肢体麻木或无力、腰痛为首发症状者约占4.46%、3.46%、4.47%;以头晕呕吐、吞咽困难、语言障碍、下肢疼痛、脸颈浮肿为初发症状者较少见,分别占0.99%、0%、0.2%、0.79%、0.79%。2、肺癌患者男女比例约为2.5:1,平均年龄58.5岁(20～93岁);其中男性730人,平均年龄59.06岁(20～83岁),女性282人,平均年龄57.05岁(27～93岁)。在31岁以前发病者甚少,约0.89%,51～70岁间发病者所占比例最高,约57.9%,随后有所下降;患者的行为状态评分,以80分最多,占46.84%;患者的组织学类型均以腺癌最多见,占41.40%(男性中腺癌占37.12%,女性中占52.48%),其次为鳞癌,占28.75%(男性中占32.98%,女性中占18.09%),小细胞肺癌占7.91%(男性中占9.32%,女性中占4.26%),另外未给出明确病理分型者占15.12%(男性中占13.70%,女性中占19.15%);早期肺癌约占14.43%(男性中占15.62%,女性中占11.35%),以ⅢB/Ⅳ期患者最多见,占73.71%(男性中占71.10%,女性中占80.49%);确诊时肺癌的远处转移以骨最多见(25.30%),其次为脑(9.19%)。3、不同性别肺癌患者确诊时年龄构成比,行为状态得分及累及器官差异均无统计学意义(P值分别为0.057,0.346,0.078);而在病理组织学类型及TNM分期方面,两组构成比差异有统计学意义(P值分别为0.000,0.017)。女性中腺癌明显多于鳞癌(P=0.000);而男性中,腺癌鳞癌所占比例差异无统计学意义(P=0.170)。确诊时晚期肺癌患者占73.71%,但女性Ⅳ期肺癌患者所占比例明显高于男性(P=0.017)。两性KPS评分均以80分最为多见,差异有统计学意义(P=0.000)。三、晚期肺癌患者化疗疗效随访研究1、化疗组和支持治疗组的病例在性别、年龄、吸烟史、KPS评分、临床分期、病理类型及累及器官方面的分布均衡,差异无统计学意义(P值分别为0.946、0.143、0.176、0.095、0.184、0.586、0.218)。2、化疗组患者合计化疗497个周期,中位化疗周期为5.52周期。化疗药物以顺铂/卡铂及第三代化疗药物最为常用。化疗组总体有效率为36.1%,病情无变化者占45.1%,病情进展者占18.8%。男性女性之间近期疗效差异无统计学意义(x~2=1.609,v=3,P=0.657)。3、化疗药物的血液毒性反应以白细胞降低为主,占53.4%;白细胞,血小板,血红蛋白下降Ⅲ～Ⅳ度者分别占19.5%、9.8%、1.5%;恶心呕吐Ⅲ～Ⅳ度者占6.8%。男女两性之间毒性反应差异均无统计学意义(P值均大于0.05)。4、化疗组的中位生存期为16个月(95%可信区间为13.576-18.424),有效率为36.1%,1年、2年及3年生存率分别为65.41%、17.29%、5.26%;支持治疗组的中位生存期为8个月(95%可信区间为6.922-9.078),1年、2年及3年生存率分别为27.85%、7.59%、5.06%。化疗组较支持治疗组生存时间延长,差异有统计学意义(P=0.000);化疗组1年生存率优于支持治疗组,差异有统计学意义(P=0.000);两组间2年及3年生存率差异均无统计学意义(P值分别为0.075、0.949)。5、化疗组及支持治疗组中男女间1年、2年及3年生存率差异均无统计学意义(P＞0.05);支持治疗组中女性中位生存期大于男性(P=0.037)。6、Cox回归分析显示KPS评分、治疗方式为影响生存的独立预后因素(P=0.000)。KPS分值越高,死亡风险越小(P=0.000);对于治疗方式,支持治疗较化疗的危险性高(P=0.000)。结论:一、对于一般状态较好的C57BL/6小鼠晚期肺癌,紫杉醇/顺铂联合化疗能延长其生存期,改善生存质量。二、虽然确诊时约73.71%的患者已属晚期,失去手术机会,但其中大多数患者一般状况尚可,行为状态评分≥80,仍有机会通过化疗延长生命,改善生活质量。三、化疗较支持治疗能延长一般状态较好的晚期肺癌患者的生存期,化疗组一年生存率优于支持治疗组,但化疗对患者的长期生存率并无显著影响。男女两性对化疗的耐受性及反应性方面差异均无统计学意义。四、KPS评分、治疗方式为影响生存的独立预后因素:KPS分值越高,死亡风险越小;对于治疗方式,支持治疗较化疗的危险性高。因此对于一般状态较好的患者,即KPS评分较高的晚期肺癌应采用化疗。更多还原

【Abstract】 Lung cancer continues to be the leading cause of cancer-related mortality. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for approximately 80% of cases. Systemic chemotherapy is the main treatment for the majority of patients with NSCLC because most are diagnosed with advanced inoperable disease. However, the role of chemotherapy is controversial for patients with advanced NSCLC. There are conflicting data on the contribution to survival of chemotherapy ,and the side reaction maybe aggravate patient’s condition, many physicians consider that advanced stage patients don’t tolerate chemotherapy well and maybe have a poorer prognosis than patients not chemotherapy. So it’s important to study and research the significance of chemotherapy for advanced lung cancer.OBJECTIVE AND SIGNIFICANCE: The objective of this study is to investigate whether chemotherapy can increase the survival time and improve quality of life of patience with advanced-lung cancer. Provide experiment evidence for clinician in applying therapeutic regimen and evaluating curative effect. And investigate the characteristics of lung cancer cases to offer fundamental data of lung cancer for preventing and controlling the disease.METERLAILS AND METHODS:Ⅰ、Assessment of the use of paclitaxel and cisplatin in advanced Lewis lung carcinoma in C57BL/6 miceExperimental groups: The animals were randomly divided into 3 groups, a chemotherapy arm (n=20), a control arm (n=20) and a blank arm (n=12).Methods: An advanced lung cancer model was established in C57BL/6 mice. One group was treated with the standard therapeutic regimen of paclitaxel and cisplatin. The control group was injected only with 0.9% NaCl and a blank group received no injection .Survival time, mental state and weight of each group were recorded .Statistical analysis: the statistical significance of differences in survival and mental state among the groups were determined by One-way ANOVA and Kruskal-Wallis H. the method of repeated—measures ANOVA and One-way ANOVA were used to determine differences in weight loss among the groups. Multiple comparisons were determined by Dunnett T3. All statistical analyses were performed with SPSS 13.0 software. The value of P≤0.05 was defined as significant.Ⅱ、A Study on the Characteristics of Lung Cancer CasesCollected 1012 cases of lung cancer from Nan fang hospital diagnosed from 2000 to 2005. The cases include 730 males and 282 females. The first symptom and the symptom and physical sign before final diagnosis were recorded. Histories of smoking, age, gender, performance status, organ involvement, histological type were recorded too. And compare those between the males and females.Statistical analysis: statistical analyses were performed with SPSS 13.0 software. The statistical significance differences between the groups were determined by x~2 test. The value of P≤0.05 was defined as significant.Ⅲ、clinical follow-up study of patients with advanced-lung cancer on assessment of chemotherapyThis is a retrospective study of patients with advanced lung cancer admitted for treatment in Nanfang hospital. Clinical data were reviewed in the records of these patients from 2000 to 2005. All the patients meet the criteria and divided into 142 cases of chemotherapy group, 99 cases of supportive care group, according to the therapeutic methods. There were significance differences in age and KPS score between the two groups, so applied paired way to keep balance between the two groups. 25 cases were been deleted. 133 cases belong to chemotherapy group, and average age was 54.17±11.753 (20～82) . Supportive care group included 79 cases, and 59.96±12.289 (29～87) .Statistical analysis: statistical analyses were performed with SPSS 13.0 software. The x~2 tests were used to determine differences in gender, age, smoking, performance status, clinical stage, histological type and organ involvement between the groups. The statistical significance differences in curative effect and toxicity between both sexes in chemotherapy group were determined by x~2 test and Mann-Whitney Test. The method of Kaplan—Meier was used to determine actuarial survival. Differences in survival were determined by Log rank analysis. Cox regression proportional hazard model was used in analysis of the risk factors influencing the prognosis. Overall survival time was defined as the interval between initial diagnoses and the date of last consultation or until death. The value of P≤0.05 was defined as significant.RESULTS:Ⅰ、Assessment of the use of paclitaxel and cisplatin in advanced Lewis lung carcinoma in C57BL/6 mice1、The survival time of the experimental group was significantly greater than the control group and the blank group (P= 0.000) .2、On the second day after treatment there was no significant difference among the groups in their mental state (P=0.636) . On days three to seven after treatment, the experimental group had significantly better mental score index than the control group and the blank group (P<0.05 ) .3、On the second and third days after treatment, the experimental group had significant greater percent weight loss than the control group (P=0.030) and the blank group (P=0.003 ) . On days four to seven after treatment, the three groups were not significantly different in weight loss (P>0.05 ) .Ⅱ、A Study on the Characteristics of Lung Cancer Cases1、The rate of no symptom before final diagnosis was 7.91% in patients withlung cancer. Cough was the most common first symptom, account for58.89%; next was expectoration, 24.51%. The rate of anorexia, chest pain,chest distress, breathlessness as first symptom were 15.61 %, 17.39%, 9.19%, 9.98%, respectively. The rate of hoarseness, fever, dyspnea, emaciated asfirst symptom were 1.38%、3.56%、0.89%、1.98%. The rate ofsubcutaneous nodule or tumor, limbs numbness or asthenia, lumbodynia asfirst symptom were 4.46%, 3.46%, 4.47%, respectively. The rate ofdizziness and vomitus, acataposis, allolalia, pelvic limb pain, face and neckpuffiness were 0.99%、0%、0.2%、0.79%、0.79%, respectively.2、The ratio of male and female was 5 to 2 in patients with lung cancer, andaverage age was 58.5 (20～93) . The number of patients was low before 31years old, about 0.89%. The number reach peak in the fifth to seventh decades of life, and then begins to descent. The performance status was determined according to clinical data available in the records. The rate of patients with PS score of 80 was at most, about 45.62%. Adenocarcinoma was the predominant histological type, about 40.22 %( male 37.12, female 52.48). The second was squamous carcinoma, about 28.75% (male 32.88%, female 18.09). The ratio of small cell lung cancer was 7.91% (male 9.32%, female 4.26%). In addition, the rate of no histological type was 15.12%(male 13.7%,female 19.15%). Classification of clinical staging was obtained from the records, based on clinical motes or reports of imaging exams. The ratio of patients in earlier stage was about 14.13% (male 15.62%, female 11.35%). The ratio of patients in advanced stage was at most, about 71.71% (male 71.10%, female 80.49%). When diagnosis, the most common site of metastasis was bone (25.30%), then was brain (9.19%).3、There were not significantly different between male and female in constituent ratio of age (P=0.057) , PS score (P= 0.346) and organs involved (P=0.078) . But histological type (P=0.000) and TNM stage (P=0.017) had significant difference between both sexes.Ⅲ、clinical follow-up study of patients with advanced-lung cancer on assessment of chemotherapy1、There were no significant difference in constituent ratio of sex, age, smoking, KPS score, clinical stage, histological type and organ involvement between chemotherapy group and supportive care group (P>0.05) .2、For all patients in chemotherapy were given 497 cycles of therapy and the median number of cycles was 5.52, ranging from 1 to 14. cisplatin or carboplatin were the most common drugs employed, other frepuent drugs are paclitaxel, Gemcitabine, Navelbine, etoposide. In chemotherapy group, the overall response rate was 36.1% and the rate of no change, progressive disease were 45.1%, 18.8%, respectively. There was no significant difference in curative effect between both sexes (P=0.657) .3、The main blood toxicity was leucopenia, about 53.4%. Grade 3 or 4 leucopenia occurred in 26 patients (19.5%). The rates of grade 3/4 thrombocytopenia and anemia were 9.8%, 1.5%. Grade 3 or 4 nausea and vomiting occurred in 9 patients (6.8%). Toxicity could be tolerant. And there was no significant difference in toxicity between both sexes (P>0.05) .4、In chemotherapy group, the median survival was 16 months (95%CI: 13.576-18.424); response rate was 36.1%; one-year, two-year and three-year survival were 65.41%, 17.29%, 5.26%, respectively. In supportive care group, the median survival was 8 months (95%CI: 6.922-9.078) and one-year, two-year, three-year survival were 27.85%, 7.59%, 5.06%, respectively. The overall survival was significantly better for patients treated with chemotherapy compared to patients that only received supportive care (P=0.000). There were significantly different in one-year survival between two groups (P=0.000). But the two-year and three-year survival were no significant difference between two groups (P=0.075, P=0.949).5、There were no significant difference in median survival, one-year survival, two-year survival and three-year survival between male and female in chemotherapy group and supportive care group (P>0.05) .6、Cox regression prognostic analysis showed that KPS scores and therapy method were independent predictors of overall survival (P=0.000). The prognosis was well in the patients with advanced lung cancer at good performance and chemotherapy. CONCLUSIONS:1、The combination of paclitaxel and ciplatin can prolong the survival time andimprove quality of life of mice with advanced lung cancer.2、At present, adenocarcinoma was the most common histological type. Approximately 80% patients were in advanced stage, and have no chance to operate, but most of them have good performance status with PS score greater than 80. so they have chance to prolong survival time and improve quality of life through chemotherapy.3、The overall survival was significantly better for patients treated with chemotherapy compared to patients that only received supportive care, but chemotherapy could not improve long term survival compared to supportive care. There were no significant difference in tolerance and response to chemotherapy drugs between male and female.4、KPS scores and therapy method were independent predictors of overall survival. The prognosis was well in the patients with advanced lung cancer at good performance and chemotherapy. So patients with advanced lung cancer at good performance should treat with chemotherapy.更多还原