1、今天的主要内容,食管癌分期的争议与进展 (第六,七版)食管癌外科进展食管癌化疗进展,分期的变化与争议,6th Edition AJCC Cancer Staging -1977,食管癌分期（UICC/AJCC，1997）,M更明确的界定 MX, M1进一步分M1a、M1b部位 M1a M1b胸上段 颈部LNM 其余远处转移胸中段 不应用 非区域LNM或远处转移 胸下段 腹腔动脉LNM 其余远处转移,食管癌分期（UICC，1997）,Stage GroupingStage0 Tis N0 M0Stage T1 N0 M0StageA T2 N0 M0T3 N0 M0StageB T1 N1 M0
2、T2 N1 M0Stage T3 N1 M0T4 Any N M0Stage Any T Any N M1StageA Any T Any N M1aStageB Any T Any N M1b,AJCC/UICC分期的指导思想,强调肿瘤侵润深度（而非长度）对分期的影响强调非区域性淋巴结转移对分期的影响，将非区域性淋巴结转移归属于M1而非N2 （等同内脏器官转移）以日本食管癌临床研究资料为基础制订（颈、胸段食管鳞癌为主）,存在的主要争议,未将胃-食管连接部肿瘤包括在内，故受到以胃-食管连接部腺癌为主要食管癌的大部分欧美国家的质疑。 T3、T4同归为期，等于认同T3、T4对患者远期生存没有影响。
3、 区域性淋巴结的划分受质疑。 淋巴结转移数量对愈后的影响未纳入,KORST分期，1998,-二种分期区域淋巴结的比较,-Krost分期区域淋巴结划分,-T分期对愈后的影响（T3、T4）,-淋巴结转移数量与愈后的关系,-T分期与淋巴结转移的关系,-澳大利亚弗林德斯大学对不同分期食管腺癌与生存的研究（b）,7th Edition AJCC Cancer Staging -2009,修订的依据,2006年，AJCC主持 World wide Esophageal Cancer Collaboration（WECC)共13个机构参加收集7885例，最终入组4628例单纯手术患者,WECC协作单位,患者
4、临床病理资料,患者临床病理资料,修改要点,添加新元素： Histological Type Grade of Differenciation 修改旧元素： T：细分T1与T4 N：转移淋巴结个数 M：取消M1a和M1b Staging,T分期,N分期,M分期,H G,Staging,II期,III期,IIa,IIb,III,II,IIIa,IIIb,局限性,仅适用于单纯手术患者 不适用于非手术治疗患者 对T4b及M1患者的代表性差 不包括颈段食管癌未应用T1a与T1b 取消M1a,外科治疗进展,目前外科治疗效果,切除率 5892 并发症发生率 6.320.5 30日死亡率 2.35.0 5年生
5、存率 830 10年生存率 5.224,张汝刚：食管癌的综合治疗；2005；8,食管癌外科治疗结果,作者 年代 病例数 5-Sur (%) 手术死亡率 Earlam 1980 83783 15 29 Muller 1990 76911 10 13 邵令方 1993 60000 25-40 2.8-4.1 张汝刚 1998 4538 29.9 3.5 刘志才 1999 3867 33.7 0.78 戎铁华 2000 2041 25.2 1.2综述 *中国医科院肿瘤医院 # 林州市食管癌医院,早期食管癌的治疗,EEMR (1993, Makuuchi H et al, Japan) 1. 准确判定
6、是上皮内癌，无LNM 2. 术前准确判定病灶范围、术后判定切除彻底性 3. 可获得术后随访及辅助治疗但Yokoyama等认为，如侵犯粘膜肌层可EEMRRT/CT,早期食管癌的治疗EEMR,日本Makuuchi -H等(1999) 246例 5-y SR 100% 国内王国清等（1999）154例，穿孔2例，出血18例，3年生存率100%、1年内复发率10%，再次治疗满意。治疗原位癌、黏膜内癌、癌前病变的重要手段并发症：出血，穿孔,争议,50%变为 原位癌,25%变为 原位癌,10%变为 原位癌,轻度不典型增生,中度不典型增生,重度不典型增生,EMR,FOLLOW UP,延误治疗,治疗过度,早期
7、食管癌的治疗 食管切除及LND,作者 邵令方 常扶保 陆士新(1996) (1998) (1999) 例数 208 298 318 5 -y 92.6% 86.2% 89.9% 10-y 71.6% 72.6% 72.6% 15-y 62.7% 58.2% 58.2% 20-y 50.9% 38.6% 38.2%,结论,胸腔镜辅助下食管癌切除术是安全可行的对-期的患者其愈后是满意的手术时间及淋巴结清扫可以经过训练后改善仍需随机对照研究,化疗进展,单药对食管癌的疗效（Ajani 1994),食管癌联合化疗,PDD+5FU治疗食管癌,食管癌： Taxanes化疗,Single Agent Taxa
8、nes in Metastatic Esophageal Cancer,Author Drug/Dose #Pts. Prior Rx CR(%) PR(%) Med Surv.(mo),Kelsen P/80qw 65 Y 0 14.5 6.5 Ajani P/250 50 N 2 30 13.2 Ohtsu D/70 49 Y 0 25 NR,Taxanes 是由太平洋紫杉树或红豆杉的树干、树皮或针叶中提取或半合成的一类抗肿瘤植物药作用机理主要是促进微管聚合从而抑制了细胞分裂，导致癌细胞死亡目前在临床上应用的紫杉醇类药物主要有两种：Paclitaxel和Docetaxel,J Ajani
9、M. D. Anderson Cancer Center,J Ajani M. D. Anderson Cancer Center,1994首先报道单药Taxol治疗食管腺、鳞癌有效-J Natl Cancer Inst，1994;86(14):1086-911995报道Taxol单药对食管、贲门癌疗效突出，耐受性良好.RR：36% 。-Semin Oncol ，1995 ; 22(3 Suppl 6):35-401996报道联合方案：TPF方案Taxol 175mg/ m2，d1；PDD 20 mg/ m2/d，静滴，d1-5；5-Fu 750 mg/ m2/d，d1-5，28天/C .RR
10、：45% -Semin Oncol ，1996 ;23(5 Suppl 12):55-8,1996 Ilson TPF RR：48% Oncology (Huntingt)， 1996;10(9):1385-96. 1998 Petrasch TP RR：40%Br J Cancer ，1998;78(4):511-4. 1998 Kelsen TP RR：49% J Clin Oncol ，1998 ;16(5):1826-34,Phase II multicenter trial of docetaxel + oxaliplatin in stage IV gastroesophageal
11、 and/or stomach cancer,Richards DA et al.,Study design,PATIENT PROFILE: Median age=59.4 years 72% male patients, 76% white ECOG PS scores: 0 (45%); 1 ( 49%); 2 (6%) 32.8% of patients had distal gastric cancer,N=71 Eligibility: Patients with metastatic (Stage IV) AGEJ/S,ENDPOINTS: Primary: ORR, Secon
12、dary: time to response, duration of response, TTP, toxicity, 1- and 2-year survival,Docetaxel,60 mg/m2 1h IV D1; q3w,Oxaliplatin,130 mg/m2 2h IV D1; q3w,+,Results: efficacy,RR of 38% similar to TAX 325; OS of 9.2 months similar to TAX 325,Results: toxicity,Authors conclusions,The combination of oxal
13、iplatin and docetaxel is well tolerated in patients with Stage IV GEJ/gastric cancer The most frequent toxicity is haematological with 70% of the patients developing Grade 34 neutropenia. Febrile neutropenia episodes were infrequent, occurring in 7% of patients The combination of oxaliplatin and doc
14、etaxel produces an encouraging confirmed response rate of 38% and a clinical benefit rate of 42%, which are comparable to other standard front-line regimensThis combination deserves further study in Phase III investigations,Key messages,The median survival time (9.2 months) is consistent with the TA
15、X 325 results This study confirms: The safety of combining docetaxel and oxaliplatin Febrile neutropenia in 7% of patients The efficacy of this combination RR=38% Clinical benefit rate=42%,Combining docetaxel and oxaliplatin is a promising combination for gastric cancer,Randomised phase II study eva
16、luating weekly docetaxel in combination with cisplatin and 5FU or capecitabine in metastatic oesophago-gastric cancer,Tebbutt N, et al.,Study design,N=79 Evaluable N=68 Inclusion criteria Metastatic oesophageal or gastric (OG) carcinoma,measurabledisease PS 02,T C F,Docetaxel Cisplatin 5-FU,PATIENT
17、PROFILE: 100% PS 01, adequate organ function, no prior treatment, informed consent,30 mg/m2 D1, D8; qw 60 mg/m2 D1; q3w 200 mg/m2/D continuously q3w,wTCF,wTX,T X,Docetaxel Capecitabine,30 mg/m2 D1, D8; qw 1600 mg/m2/D D114 q3w,Results,*High dose of 5-FU (200 mg/m2/D continuous infusion for 21 days),
18、Authors conclusions,Both wTCF and wTX are active regimenswTCF achieves high response rates and progression-free survival times comparable to 3-weekly TCF. wTCF has a more favourable safety profile and a lower rate of febrile neutropeniawTX has significant activity with minimal grade 3/4 toxicity and
19、 may be ideal for patients who are not suitable for platinum-based regimensModification of wTCF by substitution of cisplatin with oxaliplatin (E) and 5-FU with capecitabine (X) to generate wTEX may further improve activity and safety. This combination is worthy of further study,Key messages,Toxicity
20、 is more manageable with the modified TCF regimen Taxotere-induced FN can be managed by either by adding G-CSF prophylaxis or by using a weekly regimen FN for TCF (q3w)=28% (TAX 325) FN for TCF (q3w) + G-CSF=12% (TAX 325) FN for wTCF=6% A Taxotere/Eloxatin-based triplet regimen is already under inve
21、stigation (GATE study),The results of this study confirm that Taxotere-based triplet therapy (wTCF) is superior to a Taxotere-based doublet (wTX) in the treatment of metastatic gastric carcinoma,紫杉类药物是最有效的单药之一联合PDD取得了实质性进展同时加入5-Fu未见更好受益，反而增加毒性与放疗联合应用有良好的前景,食管癌：Irinotecan 化疗,MAGIC,可切除胃癌(74%) 低位食管癌(14
22、%) 胃食管结合部(11%),R,ECF q213cs,ECF q213cs,N=250,N=253,手术,单纯手术,ECF: E 50mg/m2 C 60mg/m2 FU 200mg/m2/d civ,Cunningham D, et al. Perioperative Chemotherapy versus Surgery Alone for Resectable Gastroesophageal Cancer. N Engl J Med.2006;355(1):11-20.,MAGIC：无疾病进展生存率（PFS）,ECF+手术 vs.手术 hazard ratio = 0.66; 95%
23、 CI：0.53 to 0.81; P0.001,MAGIC：总体生存率（OS）,ECF+手术 vs.手术 hazard ratio = 0.75; 95% CI：0.60 to 0.93; P = 0.009; 5-year survival rate：36% vs. 23%,MAGIC：肿瘤大小与术后分期,MAGIC 结论,对于可手术胃癌和低位食管腺癌患者，ECF+手术与单纯手术相比: 缩小肿瘤大小 降低术后分期 显著提高PSF 显著提高OS,FFCD 9703,可切除胃癌(89%) 低位食管癌(11%),R,FP 2-3cs,FP 3-4cs,N=113,N=111,手术,单纯手术,FP
24、: F 800mg/m2 d1-5 P 100mg/m2 d1 q28,Final results of a randomized trial comparing preoperative 5-fluorouracil (F)/cisplatin (P) to surgery alone in adenocarcinoma of stomach and lower esophagus (ASLE): FNLCC ACCORD07-FFCD 9703 trial.2007 ASCO Annual Meeting Abstract No: 4510,FFCD 9703结果,MAGIC与FFCD 9
25、703比较,以ECF或FP方案进行围手术期化疗可以显著延长可切除胃癌和低位食管腺癌患者的无进展生存期和总体生存期。,V325,Phase III Study of Docetaxel and Cisplatin Plus Fluorouracil Compared With Cisplatin and Fluorouracil As First-Line Therapy for Advanced Gastric Cancer: A Report of the V325 Study Group. J Clin Oncol, 2006, 24:4991-4997.,未经治疗局部晚期或转移性胃癌患者
26、,R,Docetaxel 75 mg/m2 Cisplatin 75 mg/m2 d1 Fluorouracil 750 mg/m2/d (d1- 5) q3w,N=227,N=230,Cisplatin 100 mg/m2 (d1) Fluorouracil 1,000 mg/m2/d (d1 - 5) q4w,Median follow-up is 13.6ms.,DCF与CF治疗效果比较,Time to progression,Overall survival,DCF与CF毒性比较,V325 结论,对于未经治疗的晚期胃癌患者，DCF的疾病进展时间、总体中位生存期均优于CF。 2006年F
27、DA批准DCF（多西他赛/顺铂/5-FU）方案用于治疗以前未经化疗的晚期胃癌，包括胃食管结合部癌。 DCF方案的严重不良反应，尤其是3/4级粒细胞减少，导致患者难以耐受DCF方案化疗。DCF改良方案（DC或DF，紫杉醇替代多西紫杉醇）可减少不良反应，而疗效无差异。,+,靶向治疗,Erlotinib,食管癌病人EGFR超表达者3090 有EGFR超表达的病人预后差 以往单药疗效 12PR（ASCO 2004) 22例治疗结果 PR 9. SD 45.5 PD 45.5.（ASCO 2005),Fumikata H, Cancer Letters 226(2005) 37-47,Bevacizum
28、ab,贝伐单抗(bevacizumab，Avastin)为基因工程重组人源化抗VFGF单克隆抗体，主要通过抑制VEGF发挥作用。2004年本品在美国获准上市，是第一种抗肿瘤血管生成作用的抗癌新药，在转移性结肠、直肠癌中联合化疗作为一线药物。,Bevacizumab+DCF,入选患者 47例晚期转移性胃癌和胃食管结合部癌患者。 治疗方案 bevacizumab 15 mg/kg d1, irinotecan 65 mg/m2 cisplatin 30 mg/m2 day1/8, q21d.,Multicenter Phase II Study of Irinotecan, Cisplatin,
29、and Bevacizumab in Patients With Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma. J Clin Oncol 2006, 24:5201-5206.,治疗效果(n=47),Median TTP= 8.3 ms(95% CI, 5.5 to 9.9 ms),Median OS=12.3 ms (95% CI, 11.3 to 17.2 ms),可测量疾病与不可测量疾病疗效差异,可测量 vs. 不可测量 median survival 15.4 v 8.4ms log-rank P.04,
30、常见毒性反应发生率,BEV+DCF结论,贝伐单抗（抗VEGF抗体）联合伊立替康和顺铂对晚期胃癌或食管胃结合部腺癌有效，进展期为8.3月，而中位生存期为12.3月。该方案仍然存在安全问题，例如肠穿孔、高血压和血栓栓塞，仍需要进一步的III期临床试验评价化疗联合贝伐单抗的价值。,Cetuximab,西妥昔单抗(Cetuximab，Erbitux)是人鼠嵌合型IgG1抗EGFR单抗。 英国国家卫生与临床研究院目前已批准本品用于转移性结肠癌的治疗。 美国FDA批准本品与依立替康联合治疗表达EGFR的依立替康耐药性结肠癌，并批准其与放疗联用，治疗无法通过外科手术切除的头颈部鳞状细胞癌患者。,FOLCET
31、UX study,入选患者 38例晚期EGFR阳性转移性胃癌和胃食管结合部癌初治患者。 治疗方案 cetuximab weekly at 400 mg/m2 iv loading dose, then at 250 mg/m2 iv, CPT11 180 mg/m2 iv d1, LFA 100 mg/m2 iv followed by 5FU 400 mg/m2 iv bolus and 600 mg/m2 civ 22h d1-2 (FOLFIRI) every 2 weeks, for a maximum of 24 weeks, then cetuximab alone was all
32、owed in pts with CR/PR/SD.,Phase II study of cetuximab plus FOLFIRI as first-line treatment in patients with unresectable/metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma (FOLCETUX study). Annals of Oncology. 2007. 18(3):510-517.,FOLCETUX 结论,OR (RECIST) : 3 (12%) CR,11 (44%) PR,
33、56% CR + PR (95% CI: 37-75), 11 (44%) SD. PFS at 3 months ：80% (95% CI: 64-96). Survival data ：73.6% of the pts are alive; median follow-up 3 months, range 1-12. Grade 3-4 toxicity (CTC v3.0) : 15 (53.6%) neutropenia (1 pt died of febrile neutropenia), 1 (3.4%) thrombocytopenia, 2 (6.8%) hypertransaminasemia, 1 (3.4%) hyperbilirubinemia. Cutaneous toxicity was: 7 (25%) gr1, 11 (39.2%) gr2, 5 (17.8%) gr3.,西妥昔单抗与FOLFIRI方案联合治疗EFGR阳性晚期胃或胃食管结合部癌患者有效，其耐受性可，主要的不良反应是中性粒细胞减少。,今天的小结,分期手段的提高使分期更准确，分期进一步的深化为规范分期治疗及个体化治疗提供基础（分子分期）新的化疗方案（紫杉类药物）提高疗效靶向治疗有潜在的前景,THANKS,
