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1、泰欣生治疗食管癌临床研究进展,医学部 吕慧 2011-6,目录,疾病概述 治疗现状 国内外试验概述 公司立项的试验概述,中国中国恶性肿瘤发病率 (信息来源：中国2009年肿瘤登记年报),中国恶性肿瘤死亡率 (信息来源：中国2009年肿瘤登记年报),4,中国食管癌高发区域地理分布,(信息来源：Hu SP. Chin Oncol,11(2):171174,2001 ),南部沿海潮汕地区和内陆太行山区是两大食管癌高发区 (信息来源：中国2009年肿瘤登记年报 1973-1975),食管癌的病理学特征,按发病率高低分别是： 胸中段胸下段胸上段颈段 食管癌的组织学类型: 鳞癌/腺癌/鳞腺癌/癌肉瘤/未分
2、化癌 我国:鳞癌为主 97.6% ;中1/3段 65.9%;西方国家:以下段食管为主、主要为腺癌（60以上） H. Li, British Journal of Surgery 1997; 84: 855-857 食管癌的扩散与转移: 1.食管壁内扩散; 2.直接浸润邻近器官; 3淋巴转移; 4.血行转移,临床特点： 就诊时：7080%为中晚期，少数为早期 预后：5年生存率只有30%左右。 治疗手段：以早期诊断和手术为主的综合治疗。以提高5年生存率为临床治疗努力的方向。 治疗原则：,TNM分期（AJCC，2002）,临床分期（cTNM）方法 - 综合,全身体检 影像学方法 EUS CT FDG
3、-PET 胸腔镜、腹腔镜 食管镜、支气管镜 细针穿刺、活检,* 汤终明 医学综述 2011.1.17卷。第2期,可手术切除 （期，或T1-3, N0-1 或 NX）,手术切除 （Tis，T1a，T1bN0， T1bNx， 隆突水平以下或累及胃食管连接部的肿瘤；）,放化疗（颈部食管癌首选：50.4Gy的放疗和同步进行的5-FU+DDP化疗）+手术,病理无淋巴结转移 R0切除术者,病理无淋巴结转移 R1/R2切除术者,T1N0患者：随访,T2N0患者：随访；低分化、年轻患者应放化疗,T3N0患者：放化疗,放疗和5-FU+DDP为主的化疗,手术切除后,化放后评价CR：腺癌- 手术或随访； 鳞癌：随访
4、或手术 化放后评价PR/SD ：手术,2010 NCCN食管癌诊断和治疗指南,食管远端或胃食管连接部的腺癌：放/化疗,淋巴结转移,中、上段腺癌及任何部位的鳞癌：随访或放化疗（国内主张放/化疗）,（T4期）不可手术切除/未接受手术,转移/局部晚期：5-FU+DDP为主的化疗+多烯/表柔+单抗,最佳支持治疗（食管内支架、肠外营养、镇痛药等）,常用的化疗药物,单药治疗食管鳞癌方案的反应率（RR）20%，药物包括5-FU、顺铂（DDP）、阿霉素、紫杉醇、多西他赛、奥沙利铂等。 食管癌被广泛认可联合化疗方案是DDP和5- FU的联合，有效率25%50%。 三药联合（ PTX+ DDP+ 5-FU ）被认
5、为对食管鳞癌和腺癌都有效，也有观点认为疗效不高于二药联合，增加5-FU会增加毒性。紫杉类过敏反应、血液毒发生率高。 伊立替康（CPT-11）单药及联合甲酰四氢叶酸钙（CF）、5-FU治疗部分食管鳞癌/胃癌有一定的疗效，和DDP联合的疗效更好。伊立替康毒副反应：延迟性腹泻（用药后5天发生持续均4天，严重者可致死）常见严重(3-4度)骨髓抑制（中性粒细胞、血小板 ）。 Kroep等报道健择（GEM）联合DDP治疗食管癌可能有好疗效。健择毒副作用：常见轻中度血液毒，25%皮疹，10%瘙痒，2/3肝脏转氨酶的异常。,食管癌：EGFR蛋白过度表达,EGFR蛋白过度表达在食管癌的发生率为*73%,而在正常
6、食管粘膜上皮则未见该蛋白过度表达 ,提示EGFR 与食管癌癌前病变的发生、发展密切相关。 因食管癌诊断迟、发现晚，多数治疗都是姑息性。国内外研究的重点都寄希望于许多新的化疗药物包括抗体药物，疫苗，基因治疗和抗血管生成药物等。,* Herbst RS, Shin DM. Cancer. 2002;1593-1611.,靶向药物-单抗类在联合化疗中的地位,局部晚期食管癌和食管胃交接处腺癌，Her-2阳性患者：单抗类+联合化疗是标准方案,S. Lorenzen, et al. Cetuximab plus cisplatin5-fluorouracil versus cisplatin5-fluor
7、ouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol (2009) 20(10): 1667-1673.,Metastatic squamous cell carcinoma of the esophagus,Initial dose 400mg/m2 Then 250mg/m2 weekly,Chemoth
8、erapy alone a maximum of six 29-day cycles, patients received cisplatin 100 mg/m2, day 1, plus 5-FU 1000 mg/m2, days 15 (CF),Tumor Response Tumor material was obtained for analysis of KRAS mutation status.,Chemotherapy + Cetuximab a maximum of six 29-day cycles, patients received cisplatin 100 mg/m2
9、, day 1, plus 5-FU 1000 mg/m2, days 15 (CF),靶向药物-Cetuximab 的临床试验 1 Cetuximab Combination with Chemotherapy,Safety 试验组VS对照组: 皮疹 (6% vs 0%) 腹泻 (16% vs 0%). Efficacy,中位随访期：21.5 月 KRAS 基因突变与疗效与预后的无关（ 37例可评估病例）,C. R. Thomas Jr 2010 ASCO Cetuximab plus cisplatin, irinotecan, and thoracic radiotherapy (TRT
10、) as definitive treatment for locally advanced, unresectable esophageal cancer,Pts cT4M0 stage or medically unresectable,biopsy-proven, EC (squamous cell or adenocarcinoma),Cetuximab 400 mg/m2 was given day (d) 1, then 250 mg/m2,weekly*3*2cycles; cisplatin 30 mg/m2 was given d1, 8 each C; irinotecan
11、 65 mg/m2 was given d1, 8 each C. TRT :1.8 Gy/d x 28 fxs, 5 d/wk to total dose 50.4 Gy.,靶向药物-Cetuximab 临床试验 2 A SWOG (S0414) phase II trial (Cetuximab+ irinotecan ),Safety Efficacy,Pts 17 No significant associations between marker expression and outcome were observed.,Eligibility criteria,resectable
12、, locally advanced (uT3 or uN1, T4 if deemed resectable) squamous cell carcinoma (SCC) or adenocarcinoma (AC) of the esophagus; staged by EUS, CT and PET scan; age 1870y; PS 2; normal organ functions.,Chemotherapy,4 cycles of FOLFOX-4 （奥沙利铂+5-FU+甲酰四氢叶酸）every two weeks,Radiotherapy,pts without PD wer
13、e given daily RT (1.8Gy fractions to 50.4Gy) with concurrent (4 weeks ),Cetuximab,Initial dose 400mg/m2 Then 250mg/m2 weekly,histopathological response rate,F. De Vita， A multicenter phase II study of induction CT with FOLFOX-4 and cetuximab followed by RT and cetuximab in locally advanced esophagea
14、l cancer (LAEC), Journal of Clinical Oncology, 2009 ASCO Annual Meeting,Vol 27, No 15S (May 20 Supplement), 2009: 4546,18weeks, pts without PD had esophagectomy,靶向药物-Cetuximab 的临床试验 3 Cetuximab combination with Chemo-radio,F.F De Vita， A multicenter phase II study of induction CT with FOLFOX-4 and c
15、etuximab followed by RT and cetuximab in locally advanced esophageal cancer (LAEC), Journal of Clinical Oncology, 2009 ASCO Annual Meeting,Vol 27, No 15S (May 20 Supplement), 2009: 4546,Safety The most frequent grade 3/4 toxicity of chemoradiotherapy,Efficacy 10 pts had no resection (9 progressive d
16、isease,1 patients refusal). Of 22 operated pts, 17 pts (77%) had RO-resection, 5 pts had palliative Surgery . 2 pts died due to complications after surgery (1 after 30 days) The pathological response rate was 68 %, with a complete histopathological remission recorded in 6 pts (27%); 17 pts (53%) are still alive without residual or recurrent disease,Restaged between weeks 9-11,J. C. Bendell, 2010
