食管癌同步放化疗【治疗】课件.ppt

陕西肿瘤放疗年会2008年12月,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,食管癌同步放化疗西安交通大学医学院第二附属医院肿瘤中心放疗专业马红兵 王西京 任宏涛 王宝峰,1,肠道相关,概述药物临床进展,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,2,肠道相关,Cancer statistics, 2008. CA Cancer J Clin. 2008 Mar-Apr;58(2):71-96. Epub 2008 Feb 20,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,3,肠道相关,2004年全国40个观察点统计分析，食管癌发病率居第四位。全世界每年新发食管癌病例约万;我国的食管癌发病率居世界之首，发病人数占世界发病总数的60%, 13/10万/年，男性的发病率是女性的二倍。 。接受手术的5年生存率为15%39%而接受放疗者为8%15%,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,概述,我国食管癌,4,肠道相关,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,Surgical OncologyRadiation OncologyMedical OncologyBiological and Target TherapyThe traditional Chinese medicine,治疗手段,概述,5,肠道相关,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,目前，食管癌还是一个需多学科部门联合综合治疗以提高临床疗效的恶性肿瘤。,放射治疗 局部病变药物治疗 微小转移,肿瘤治愈,一个美好的设想：,概述,6,肠道相关,近年，综合治疗显示优势 先进的放疗技术新的化疗药物精确放疗、药物、生物靶向治疗 肿瘤综合治疗的希望,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,概述,7,肠道相关,离体细胞研究、分子生物学机制的研究有助于阐明综合治疗的生物学机制，对探讨临床最佳综合治疗方案有着重要的意义。,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,机制,概述,8,肠道相关,Spatial cooperationTemporal cooperationSelecting toxicity depending on cell cycle phaseDecrease in tumor mass and reoxygenationSelecting toxicity for hypoxic cellsCytokinetic cooperationDNA damage Cell apoptosis,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,机制,概述,9,肠道相关,药物,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,10,肠道相关,一线药物（90年代以前的 ）顺铂、5Fu、阿霉素 二线药物（90年代以后）泰素、泰索蒂、诺维本、健择、 半合成的喜树碱衍生物、新一代铂类生物靶向药物,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,药物,11,肠道相关,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,5Fu,抗代谢药2. 在体内转变为5氟尿嘧啶脱氧核苷 抑制胸腺嘧啶核甙合成酶，影响DNA的生物合成3、能掺入RNA中干扰蛋白质合成4. 对有氧和乏氧细胞有相同的杀伤作用,药物,12,肠道相关,5Fu增敏机制作用于放射抗拒的S期细胞干扰S期调控点实验室证实，放疗期间持续给药可以增敏,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,药物,13,肠道相关,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,甲酰四氢叶酸,顺铂,加强,5Fu,生化调节机制,4 用药时间,放疗后5min8h,5 用药量,200375mg/m2,5Fu特点：,药物,14,肠道相关,特点：吸收后在体内逐渐变为氟尿嘧啶而起作用 其作用机理与氟尿嘧啶相同， 在体内能干扰、阻断DNA、RNA及蛋白质的合成 其毒性只有氟尿嘧啶的1/41/7 化疗指数为氟尿嘧啶的2倍 血液中半衰期为5h 用药量，一般5001000mg/day慢性毒性试验中未见到严重的骨髓抑制，对免疫的影响较为轻微。,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,新一代 替加氟 Tegafur Injection,药物,15,肠道相关,卡莫氟(Carmofure)特点：不需经过肝脏的药物代谢而释放出5-Fu在血液、淋巴液、腹腔积液以及肿瘤组织中保持高浓度。,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,药物,16,肠道相关,卡培他滨(Caoecitabine)希罗达由于最后催化后形成5-Fu的胸苷磷酸化酶在瘤组织中的浓度为正常组织中的4倍，口服后瘤组织中的5-Fu浓度是静脉给予相同剂量的127倍。,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,药物,17,肠道相关,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,顺铂 Cisplatin,PDD，DDP,1 铂的金属络合物，作用似烷化剂,2 主要作用靶点为DNA,作用于DNA链间及链内交链，形成DDPDNA复合物,干扰DNA复制，或与核蛋白及胞浆蛋白结合。,3 属周期非特异性药,药物,18,肠道相关,用药量顺铂的抗肿瘤作用,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,浓度依赖性,时间依赖性,顺铂小剂量长期用药抑制肿瘤细胞对放疗所致亚致死性损伤修复抑制和潜在致死性损伤的修复,药物,顺铂最低临床应用剂量 6mg/m2/d,19,肠道相关,顺铂与放疗的相互作用阳离子与DNA链碱基作用改变DNA修复辐射增加DNA单链的修复,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,药物,20,肠道相关,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,5Fu,顺铂,二者对放射增敏有协同作用,增敏效果与给药时间有关,顺铂在放疗前16h,5Fu持续给药,增敏效果最佳,药物,21,肠道相关,卡铂 Carboplatin在乏氧的条件下卡铂的增敏作用高于顺铂奥沙利铂（乐沙定, 草酸铂）L-OHP复合体DDP复合体 靶分子和作用机制不同 抗瘤谱不同萘达铂 肾毒性、胃肠道反应及骨髓抑制均较DDP轻,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,药物,22,肠道相关,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,紫杉类醇药物(taxanes),泰素、紫素、特素、紫脘素，Paclitaxel, Taxol, PTX,机制,使微管不可逆的聚集干扰细胞的有丝分裂,主要作用于G2晚期和M期，具有显著的放射增敏作用,药物,23,肠道相关,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,是微管解聚抑制剂，其作用于微管/微管蛋白系统，通过促进微管双聚体装配成微管，且通过防止去多聚化过程而使微管稳定，阻滞细胞于G2和M期，从而抑制癌细胞的有丝分裂和增殖。,多西紫杉醇,泰索帝、多西他赛、Docetaxel/TXT,机制,特点,稳定微管的作用比紫杉醇强2倍,药物,24,肠道相关,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,健择,gemcitabine hydrochloride,盐酸吉西他滨,细胞周期特异性抗代谢类药物,作用于DNA合成期（S期）的肿瘤细胞在一定的条件下，可以阻止G1期向S期的进展,药物,25,肠道相关,分子靶向药物EGFRI (EGFR抑制剂）放射激活EGFR 抗拒放射EGFRI增加肿瘤细胞的放射敏感性机制阻止细胞进入S期增加放射诱导的细胞凋亡抑制放射诱导的EGFR磷酸化抑制放射损伤的修复,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,药物,26,肠道相关,临床进展,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,临床进展,27,肠道相关,N Engl J Med. 1992 Jun 11;326(24):1629-31. （RTOG8501）Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus.,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,METHODS. This phase III prospective, randomized, and stratified trial was undertaken to evaluate the efficacy of four courses of combined fluorouracil (1000 mg per square meter of body-surface area daily for four days) and cisplatin (75 mg per square meter on the first day) plus 5000 cGy of radiation therapy, as compared with 6400 cGy of radiation therapy alone, in patients with squamous-cell carcinoma or adenocarcinoma of the thoracic esophagus. RESULTS. The median survival was 8.9 months in the radiation-treated patients, as compared with 12.5 months in the patients treated with chemotherapy and radiation therapy. In the former group, the survival rates at 12 and 24 months were 33 percent and 10 percent, respectively, whereas they were 50 percent and 38 percent in the patients receiving combined therapy (P less than 0.001). Seven patients in the radiotherapy group and 25 in the combined-therapy group were alive at the time of the analysis. Severe and life-threatening side effects occurred in 44 percent and 20 percent, respectively, of the patients who received combined therapy, as compared with 25 percent and 3 percent of those treated with radiation alone.,28,肠道相关,RTOG85-01随机对照试验首次证明同步放化疗生存期明显优于单纯放疗这一篇文章被认为是食管癌非手术治疗中，具有里程碑意义的重要论文。本文的发表使得同期放化疗成为食管癌的标准治疗方案。同步放化疗已被美国NCCN推荐治疗不可切除的食管癌患者。,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,29,肠道相关,1: JAMA. 1999 May 5;281(17):1623-7. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group.,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,PATIENTS: Patients had squamous cell or adenocarcinoma of the esophagus, T1-3 N0-1 M0( stage), adequate renal and bone marrow reserve, and a Karnofsky score of at least 50. MethodsInterventions Combined modality therapy (n = 134): 50 Gy in 25 fractions over 5 weeks, plus cisplatin 75 mg/m2 intravenously on the first day of weeks 1, 5, 8, and 11, and fluorouracil, 1 g/m2 per day by continuous infusion on the first 4 days of weeks 1, 5, 8, and 11. In the randomized study, combined therapy was compared with RT only (n = 62): 64 Gy in 32 fractions over 6.4 weeks.RESULTS:at 5 years of follow-up the overall survival for combined therapy was 26% (95% confidence interval CI, 15%-37%) compared with 0% following RT. In the succeeding nonrandomized part, combined therapy produced a 5-year overall survival of 14% (95% CI, 6%-23%). Severe acute toxic effects also were greater in the combined therapy groups. There were no significant differences in severe late toxic effects between the groups. CONCLUSION: Combined therapy increases the survival of patients who have squamous cell or adenocarcinoma of the esophagus, T1-3 N0-1 M0, compared with RT alone.,1级NCCN,30,肠道相关,J Clin Oncol. 2002 Mar 1;20(5):1167-74. INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy.,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,PURPOSE: To compare the local/regional control, survival, and toxicity of combined-modality therapy using high-dose (64.8 Gy) versus standard-dose (50.4 Gy) radiation therapy for the treatment of patients with esophageal cancer. PATIENTS AND METHODS: A total of 236 patients with clinical stage T1 to T4, N0/1, M0 squamous cell carcinoma or adenocarcinoma four monthly cycles of fluorouracil (5-FU) (1,000 mg/m(2)/24 hours for 4 days) and cisplatin (75 mg/m(2) bolus day 1) with concurrent 64.8 Gy versus the same chemotherapy schedule but with concurrent 50.4 Gy. The trial was stopped after an interim analysis.RESULTS: For the 218 eligible patients, there was no significant difference in median survival (13.0 v 18.1 months), 2-year survival (31% v 40%), or local/regional failure and local/regional persistence of disease (56% v 52%) between the high-dose and standard-dose arms. CONCLUSION: The higher radiation dose did not increase survival or local/regional control.,RTOG 94 05,31,肠道相关,RTOG 0113.试验fluorouracil, cisplatin, and paclitaxel 诱导化疗然后 fluorouracil paclitaxel50.4 Gy RT (arm A) (37/41)paclitaxel plus cisplatin诱导化疗然后 fluorouracil paclitaxel50.4 Gy RT (arm B) (35/43). 结果中位生存时间 28.7 months (arm A)，14.9 months (arm B) 1 年生存率75.7% (arm A)，2年生存率56%(arm A)37%(arm B) 3级毒性(armA=54%,armB=43%) 4级毒性(armA=27%,armB=40%) 死亡(arm A = 3%, arm B =6%) 但没有达到 77.5%目标.,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,J Clin Oncol. 2008 Oct 1;26(28):4551-6. Epub 2008 Jun 23 Phase II randomized trial of two nonoperative regimens of induction chemotherapy followed by chemoradiation in patients with localized carcinoma of the esophagus: RTOG 0113.,32,肠道相关,第49届ASTRO年会 RTOG 0246试验初步结果:根治性放化疗联合选择性手术挽救治疗局部晚期食管癌可行 RTOG 0246试验(2003年9月5日-2006年3月17日),先给予以紫杉醇为基础的诱导化疗然后采用以紫杉醇为基础的同步放化疗联合选择性手术治疗可以切除的局部晚期食管癌初步结果：研究纳入43例无转移食管癌患者,其中40例可分析,治疗前分期为T3-4N1。结果显示,40例完成了诱导化疗,37例完成同步放化疗,发生度、度血液学毒性及度非血液学毒性的患者分别有28例、7例和7例。18例接受了手术,其中17例经胸腹CT、超声内镜或PET证实为复发或残留,1例为患者自己选择了手术。剩余22例没有接受手术的患者中,15例未复发,1例为医学原因不能手术,3例转移,3例死亡。预计1年总生存(OS)率为72%,预计1年无病生存(DFS)率为39%。这项多中心前瞻性期研究提示,根治性放化疗联合选择性外科手术挽救治疗局部晚期食管癌是可行的,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,33,肠道相关,OBJECTIVE: 评价大野加局部小野推高剂量照射联合同期放化疗治疗胸部食管癌的可行性。. METHODS: 病人： T1 -4N0-1M0 (UICC 1997) 胸部鳞状细胞食管癌. 大野：锁骨上窝至纵隔39.6 Gy 小野：推量至66.6 Gy (1.8 Gy/day, 5/ week). 2小时 cisplatin (80 mg/m(2) on day 连续 5-fluorouracil (800 mg/m(2)/day on days 2-6) every 3-4 weeks, for two cycles. RESULTS: 30例 (stage I, 3; stage II, 11; stage III, 16) 纳入观察. 21例 (70%) 完成计划. or = 70 years老年病人, 4 / 6退出. 3级 (NCI-CTC)毒性反应20 (67%) 例，4级毒性反应3(10%)例 . 主要表现为血液、消化道和肺损伤. 没有5级毒性反应. 中位生存期 27 months (range: 9-49 months). 平均生存时间 21 months. 1-、 2-year 生存率是 65 % and 49% . 食管狭窄 (grade 1-2: RTOG) was 21%. 没有食管穿孔. 结论：大野加局部小野推高剂量照射联合同期放化疗治疗胸部食管癌的可行 。,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,1: Jpn J Clin Oncol. 2001 Aug;31(8):375-81. LinksConcurrent chemoradiotherapy for squamous cell carcinoma of thoracic esophagus: feasibility and outcome of large regional field and high-dose external beam boost irradiation.,34,肠道相关,复旦大学附属肿瘤医院后程加速超分割(LCAF)与联合同步化疗(LCAF +CT)治疗原发性食管癌的期随机对照研究(患者111名)先予常规放疗DT41.4Gy/23f, 4 5 W,(1.8Gy/次, 1次/天) 缩野行加速超分割, DT27Gy/18次(1.5Gy/次,2次/日) 累积放疗总量6814 Gy/41f,44d完成。54例患者FP方案化疗4个周期(顺铂25mg/m2,d1d3, 5-FU600mg/m2, d1d3,28天为1周期) 中位生存期:30.8月vs. 23.9月(LCAF + CT vs. LCAF) LCAF + CT组与LCAF组1、3、5 年生存率分别为67%、44%、40% , 77%、39%、28% , ( P = 0.310) 结论：认为后程加速超分割结合同步化疗有延长生存期的趋势。,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,Zhao KL, Shi XH, J iang G, et al. Late course accelerated hyperfractionated radiotherapy plus concurrent chemotherapy for squamous cell carcinoma of the esophagus: a phase randomized study J . Int J Radiat Oncol Biol Phys, 2005, 62 ( 4 ) : 1014- 1020.,35,肠道相关,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,目的：评价联合放疗和化疗与单独放疗治疗局部食管癌的疗效，从总生存率、 cause-specific生存、局部复发、吞咽困难缓解、生活质量以及急性和慢性毒性反应方面予以评估。 药物为cisplatin or 5-fluorouracil 方法： 检索相关的MeSH主题词、Cochrane图书馆、国际肿瘤文献文摘数据库（Cancer LIT）、联机医学文献分析与检索系统（MEDLINE）, 医学文摘数据库（ EMBASE） 主要结果：19个随机试验被纳入，11个联合放化疗和8个续贯放化疗联合放化疗死亡风险比(HR) 0.73 (95% (CI) 0.64 to 0.84)，明显下降. 绝对生存受益率为1年9% (95% CI 5 to 12%) ，2年4% (95% CI 3 to 6%)，局部复发率（NNT需治数为9）为 12% ，(95% CI 3 to 22%) 单放组为68%. 严重毒性和生命威胁毒性（NNH致成危害需要的人数为6）较显著。续贯放化疗对于局部控制和生存率方面没有益处。结论：对于非手术的局部食管癌病人，相对单纯放疗同步放化疗应该优选，但有毒性风险。,Cochrane Database Syst Rev,36,肠道相关,CONCLUSIONS: Based on the available data, when a non-operative approach is selected then concomitant RTCT is superior to RT alone for patients with localized esophageal cancer but with significant toxicities. In patients who are in good general condition, and the risk benefit has been thoroughly discussed with the patient, concomitant RTCT should be considered for the management of esophageal cancer compared with radiotherapy alone.,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,Cochrane Database Syst Rev. 2001;(2):CD002092.Combined chemotherapy and radiotherapy (without surgery) compared with radiotherapy alone in localized carcinoma of the esophagus.,Cochrane Database Syst Rev. 2003;(1):CD002092. Combined chemotherapy and radiotherapy (without surgery) compared with radiotherapy alone in localized carcinoma of the esophagus.,1: Cochrane Database Syst Rev. 2006 Jan 25;(1):CD002092.Combined chemotherapy and radiotherapy (without surgery) compared with radiotherapy alone in localized carcinoma of the esophagus.Wong R, Malthaner R.,37,肠道相关,Philip进行多中心前瞻随机试验比较了标准食管癌切除术与放化疗的疗效。80例患者中36例接受了同步放化疗化疗采用连续灌注5-FU(200mg/m2,d1d42)、顺铂(60mg/m2,d1、d22),对肿瘤区和区域淋巴结同时照射,总剂量5060Gy44例接受标准手术,手术死亡率618% ,术后并发症发生率达38.6%。放化组与手术组的早期生存率没有区别, 2年生存率分别为58.3%、54.5%。提示同步放化疗与手术治疗疗效相当,该试验还提示手术组纵隔复发率高于放化组,而放化组则在颈部及腹部复发率偏高。,西安交通大学医学院第二附属医院,SECOND AFFILIATED HOSPITAL OF MEDICAL COLLEGE OF XIAN JIAOTONG UNIVERSITY,Chiu PW, Chan AC, Leung SF, et al. Multicenter prospective randomized trial comparing standard esophagectomywith chemoradiotherapy for treatment of squamous esophageal cancer: early results from the chinese university research group for esophageal cancer J . Gastrointest Surg, 2005, 9 (6) : 794 - 802.,38,肠道相关,同步放化疗后是否可以延缓手术,也是目前研究的热点法国Bedenne 法国BedenneFFCD9102试验,Eligible patients had operable T3N0-1M0 thoracic esophageal cancer. Patients received two cycles of fluorouracil (FU) and cisplatin (days 1 to 5 and 22 to 26) and either conventional (46 Gy in 4.5 weeks) or split-course (15 Gy, days 1 to 5 and 22 to 26) concomitant radiotherapy. 然后 randomly assigned to surgery (arm A) or continuation of chemoradiation (arm B; three c