【作者】 张烨；

【导师】 肖建平； 李晔雄； 易俊林；

【作者基本信息】 中国协和医科大学 ， 肿瘤学， 2010， 博士

【摘要】 第一部分肺转移瘤的体部立体定向放射治疗预后因素分析目的分析大分割体部立体定向放射治疗治疗肺转移瘤的临床疗效和毒性。方法与材料回顾性分析从2000年1月1日到2006年12月31日,71例不可手术和／或化疗失败的肺转移瘤患者,共172个病灶接受大分割体部立体定向放射治疗。最常见的原发灶部位分别是肺13例和结直肠11例。单纯肺转移患者24例(33.8%),伴有其他部位转移的患者47例(66.2%)。接受一程治疗59例,二程治疗9例,三、四、六程治疗各1例。中位总剂量48 Gy(范围,30-60 Gy),中位分割次数为4次(范围,2-12次)。结果全组病人随访率97.2%,2例失访。中位随访时间24.0个月(范围,3-84.5个月)。中位病灶最大径2.1 cm(范围,0.9-7.9 cm),中位靶体积1.8 cm3(范围,0.18-35.3cm3)。中位生存时间为24.0个月。1年、3年和5年的局部控制率分别为96.6%、89.2%和89.2%。1年、3年和5年的总体生存率分别为77.5%、42.0%和21.1%,1年、3年和5年的无疾病进展生存率分别为53.5%、13.7%和6.3%。单因素分析显示大于1.5 cm的病灶局部控制率差于≤1.5 cm(100%Vs.90.6%,P=0.048),年轻人(≤35岁)和老年人(≥65岁)预后好于中年人(36-64岁)(P=0.04),一般情况好(KPS 90分)预后好于一般情况欠佳的患者(KPS 70-80分)(P=0.023),DFI≥12月的患者疗效优于DFI在0-12月的患者(P=0.028),肺转移诊断时无肺外转移的患者预后好于肺转移诊断时伴有肺外转移的患者(P=0.035),并且软组织来源的肿瘤中位生存时间高于上皮来源肿瘤(50个月Vs.20个月,P=0.159)。多因素分析显示：非中年人是独立的预后良好因素(P=-0.044),而KPS 90分有显著性差异的趋势。无3级以上大分割体部立体定向放射治疗相关并发症。结论大分割体部立体定向放射治疗对肺转移瘤是安全有效的,长期生存好且并发症可接受。第二部分剂量分割模式照射人肺腺癌移植瘤后基因表达谱差异的初步研究目的研究总相同照射剂量、不同剂量分割方案对BALB/c-nu裸鼠移植瘤(人肺腺癌细胞系Anip973)肿瘤抑制和基因表达的差异。方法将移植瘤种鼠的肿瘤组织制备成肿瘤组织块,选择裸鼠右后肢外侧小腿腓肠肌处接种,建立移植瘤裸鼠模型。待肿瘤直径达1.0 cm时将48只裸鼠分成4个组：未照射空白对照组、2 Gy 30次常规照射组(2 Gy组)、6 Gy 10次大分割组(6 Gy组)、10 Gy 6次大分割组(10 Gy组)。大分割组均在2周内完成,所有照射完成后继续观察裸鼠1个月。连续测量瘤体最大基底径并采用基因谱芯片技术检测4个组移植瘤细胞的基因表达差异,并进行实时PCR验证。结果2 Gy组、6 Gy和10 Gy组肿瘤抑制率分别为12.4%、60.3%、56.2%。6、10 Gy组较2 Gy组上调了抑制细胞增殖和诱导凋亡的基因如Bax和BCL2L10,下调了促进细胞增殖基因如c-myc和EGF、抗凋亡基因以及XRCC4、RAD21、RAD23B等DNA损伤修复基因。PCR证实6 Gy 10次组c-myc基因表达丰度明显低于2 Gy 30次组和10 Gy 6次组,分别为2.9%、5.6%、4.8%(P=0.000；P=0.002)；10 Gy 6次组c-myc基因水平相对于2 Gy 30次组也有下降(P=0.069)。结论两个大分割方案较常规分割方案对BALB/c-nu裸鼠移植瘤(人肺腺癌细胞系Anip973)在基因水平上生长抑制显著,6 Gy 10次分割方案较10 Gy 6次分割方案有更强的生长抑制作用。更多还原

【Abstract】 Part I Prognostic factors of Stereotactic body radiotherapy for lung metastatsesObjective To analyze the clinical outcome and toxicity of patients with lung metastases.Methods and Materials From January 2000 to December 2006,71 lung metastases patients with total 172 lesions treated with fractionated stereotactic body radiotherapy (SBRT) were retrospectively reviewed. All patients were unfit for surgery and/or resisted to chemotherapy. The most primary diagnosis was lung cancer in 13 patients and colorectal cancer in 11. Twenty-four patients had lung metastases in the lung alone and 47 metastases in other sites. Fifty-nine patients received one course of SBRT,9 two courses and 1 three、four and six courses respectively. The median total dose was 48 (range,30-60) Gy in 4 (range,2-12) fractions. Results All patients except two were followed up. The median follow up was 24.0 months (range,3-84.5 months). The median size of irradiated lesion was 2.1 cm (range,0.9-7.9 cm) and the target volume 1.8 cm3 (range,0.18-35.3 cm3). The 1-,3-and 5-year local control、overall survival and progression-free survival were 96.6%,89.2% and 89.2%,77.5%,42.0% and 21.1%, 53.5%,13.7% and 6.3%, respectively. In the univariate analysis, lesions small than 1.5 cm had better control than large lesions (100% vs.90.6%, P=0.048). Patients younger than 35 and older than 65 (P=0.04), good KPS (P=0.023), disease free interval more than 12 months (P=0.028), without extrapulmonary metastases (P=0.035) and primary soft tissue tumor (P=0.159) were good prognostic factors. Multivariate analysis showed patients younger than 35 and older than 65 was independent prognosis factor (P=0.044). No grade 3 or more SBRT treatment related toxicity occurred. Conclusions SBRT is an effective and safe treatment for lung metastases, with high long term survival and tolerable complications. Part II Initial microarray analysis on different fractionated radiation regimens in xenografts with human lung adenocarcinomaObjective To identify the tumor growth inhibition and the gene expression on different fractionated radiation regimens with the same total radiation dose in xenografts with human lung adenocarcinoma. Methods Forty-eight BALB/c-nu mice, implanted with human lung adenocarcinoma (Anip973), were randomized into 4 groups:normal control group,60 Gy in 30 fractions conventional radiation group (2 Gy group),60 Gy in 10 fractions successive hypofractionated radiation group within 2 weeks (6 Gy group),60 Gy in 6 fractions intermittent hypofractionaed radiation group within 2 weeks (10 Gy group). The size of the xenografts was measured as the longest diameter. Gene alterations were investigated with the microchip analytical procedures covering the entire genome. Genes with significantly different expression were further measured by the quantitative real-time polymerase chain reaction (RT-PCR). Results The tumor inhibition rate in 2 Gy、6 Gy and 10 Gy group is 12.4%,60.3% and 56.2%. Compared to the 2 Gy group, the expression of the genes related with the cell growth inhibition and apoptosis increased, while the genes related with the cell proliferation, anti-apoptosis and DNA damage repair decreased in the 6 Gy and 10 Gy groups. Confirmed by RT-PCR, c-myc gene was distinctly suppressed in the 6 Gy group (2.9%) than 2 Gy (5.6%) group and 10 Gy (4.8%) group (P=0.000, P=0.002), and was slightly suppressed in the 10 Gy group than 2 Gy group (P=0.069). Conclusions In the BALB/c-nu mice implanted with human lung adenocarcinoma, the hypofractionated radiation regimens clearly inhibit the tumor growth more than conventional fractionation group, though with the same total dose. The 6 Gy group seem to be more effective than 10 Gy group in the inhibition of tumor growth.更多还原