十二指肠癌治疗进展课件

Recent Advances in the Management of Adenocarcinoma of the duodenum,安徽医科大学第一附属医院肿瘤内科 吴红阳 副主任医师 Feb 22, 2011,原发性十二指肠恶性肿瘤发病率较低。 仅占胃肠系统恶性肿瘤的1%-3%。美国2008年新发包含所有小肠肿瘤6110例， 其中十二指肠肿瘤1992例。 缺乏典型症状、体征 无特异的检查方法 预后较差，病死率较高。,5年生存率单纯手术者淋巴结阴性38%-83%，淋巴结阳性15%-53% 。 文献表明二者差异可能与检出15个或更多的区域淋巴结有关。,与十二指肠肿瘤相关的临床报道较少，绝大部分为外科医生所写。 化疗疗效不够确切，尚缺乏标准的治疗方案。联合5-Fu和铂类药物被证明有效，反应率29%-50% 。,首发症状以腹痛、消化道出血、贫血、腹部肿块、黄疸最为常见 多数患者出现多个伴随症状，极少数患者因单一症状就诊。,120 例患者中， 腹痛75 例（62.5%），多为反复发作的脐周或上腹痛，进食后加重，其中急性消化道穿孔3 例（2.5%）。 消化道出血或贫血71 例（59.1%），多数患者反复出现黑便、血便，部分患者以贫血就诊，其中7 例（5.8%）因消化道大出血急诊入院。 腹部肿块43 例（35.8%），以空、回肠活动性肿块多见，其中消化道梗阻13 例（10.8%）。 黄疸38 例（31.7%），全部发生于十二指肠肿瘤患者， 部分患者伴有高热、皮肤搔痒、尿黄、大便呈白陶土样等症状。 其他不典型症状，如乏力、恶心、呕吐、消瘦、腹胀、腹泻等。 全部患者发病至确诊时间1-6个月。,刘哲峰，南方医科大学学报。2010;30(3)：602-605,腹部X线、消化道钡剂造影 CT、MRI 纤维内镜等 肿瘤标记物检查如CEA、CA19-9 、NSE等。,十二指肠肿瘤包含：腺癌、间质瘤、类癌、淋巴瘤、黑色素瘤等。,Of newly diagnosed small-bowel cancers： approximately 40% are adenocarcinomas. Another 40% are carcinoids, 15% are sarcomas, and less than 5% are lymphomas.,Martin RG. Malignant tumors of the small intestine. Surg Clin North Am. 1986; 66:779-785.,刘哲峰，南方医科大学学报。2010;30(3)：602-605,History,In the first report of chemotherapy for the treatment of small bowel carincoma, published in 1965, 4 of 11 patients responded to single-agent 5-FU. Since then, a number of primarily retrospective studies have been conducted to evaluate various chemotherapy combinations for this cancer.,小肠恶性肿瘤治疗首选根治性切除术及区域淋巴结清扫，若无法根治性切除，则行姑息性手术以减少肿瘤负荷，提高患者生活质量。 由于原发性小肠腺癌发病率低，国内外均未见前瞻性多中心随机对照研究，因此至今尚缺乏小肠腺癌的标准化疗方案。 多数文献报道小肠腺癌的化疗并未延长生存期，目前常用方案包括5-FU 联合铂类（顺铂、卡铂或草酸铂）、5-FU 联合伊立替康等。,小肠腺癌化疗与生存期的关系,67 例小肠腺癌患者具有完整病例资料者49 例。期-期患者中 接受化疗者17 例（期4 例，期7 例，期6 例），中位生存期23.2 个月，1年 生存率61.3%； 未接受化疗者28 例（期4 例，期19 例，期5 例)，中位生存期20.1 个月，1年 生存率分别为58.4%。接受化疗者与未接受化疗者的生存期比较无统计学意义（P=0.842)。,刘哲峰，南方医科大学学报。2010;30(3)：602-605,A number of single institution retrospective studies have evaluated the role of adjuvant chemotherapy for small bowel adenocarcinoma, but none of these studies have shown a statistically significant benefit favoring its use.,Agrawal S, et al. Ann Surg Oncol， 2007;14:2263-9.,Dabaja BS, et al. Cancer， 2004;101:518-26.,Wu TJ, et al, World J Surg，2006;30:391-8; Discussion 399.,Bauer RL, et al. Ann Surg Oncol,1994;1:183-8.,Separate retrospective studies have evaluated the role of adjuvant chemoradiation following resection of adenocarcinoma of the duodenum, but none have demonstrated a clear benefit for adjuvant treatment. Bakaeen FG, Murr MM, Sarr MG, et al. What prognostic factors are important in duodenal adenocarcinoma? Arch Surg 2000;135:63541. Barnes G, Jr., Romero L, Hess KR, Curley SA. Primary adenocarcinoma of the duodenum: Management and survival in 67 patients. Ann Surg Oncol 1994;1:738. Swartz MJ, Hughes MA, Frassica DA, et al. Adjuvant concurrent chemoradiation for node-positive adenocarcinoma of the duodenum. Arch Surg 2007;142:2858. Kelsey CR, Nelson JW, Willett CG, et al. Duodenal adenocarcinoma: Patterns of failure after resection and the role of chemoradiotherapy. Int J Radiat Oncol Biol Phys 2007;69:143641.,Radiotherapy & adjuvant therapy,The role of radiotherapy as a component of adjuvant therapy for duodenal adenocarcinoma has been studied in a limited fashion. One prospective phase-III study conducted by the European Organization for Research and Treatment of Cancer (EORTC) evaluated the role of concurrent 5-FU and radiotherapy as adjuvant therapy in patients with pancreatic and periampullary carcinoma, which was defined as adenocarcinoma of the distal common bile duct, ampulla of Vater, or duodenum.,Klinkenbijl JH, et al Ann Surg. 1999;230:776784.,A total of 93 patients with periampullary cancer were randomized to either observation or concurrent 5-FU and radiotherapy. Five-year overall survival between the two groups was equal.,Klinkenbijl JH, et al Ann Surg. 1999;230:776784.,Radiotherapy & adjuvant therapy,Despite the lack of evidence supporting the delivery of adjuvant chemotherapy for small bowel adenocarcinoma, an analysis of the National Cancer Database has shown an increase in use from 8% in 1985 to 24% in 2005. Bilimoria KY, et al. Small bowel cancer in the United States:Changes in epidemiology, treatment, and survival over the last 20 years. Ann Surg 2009;249:6371.,Clinical Behavior and Prognostic Factors of Periampullary Adenocarcinoma,A retrospective review was performed of 15 clinical and pathologic variables encountered among 60 patients with periampullary tumors. According to the Cox analysis, absence of neural invasion and use of adjuvant chemotherapy were significant factors for longer survival of patients with ampullary tumors. Lymphatic invasion was related to a shorter survival in patients with pancreatic carcinoma.,ANNALS OF SURGERY 1995,222(5): 632-637,ANNALS OF SURGERY 1995,222(5): 632-637,预后,年龄、肿瘤部位、组织学类型、淋巴结转移情况以及临床分期等。 其中年轻者预后较年老者差； 十二指肠肿瘤预后最差，空肠肿瘤预后较好； 腺癌预后最差，平滑肌肉瘤预后较好； 淋巴结阳性者5年总生存期明显短于淋巴结阴性者； 临床分期中、期的5年生存率达到36%-48%，而期则降至5%-6%。,Five year survival rate of small intestine adenocarcinoma based on disease stage,Stage I 55% Stage IIA 49% Stage IIB 35% Stage IIIA 31% Stage IIIB 18% Stage IV 5%,Cancer Facts & Figures 2009. Atlanta: American Cancer Society 2009.,In a recent series from Duke University, no difference in 5-year overall survival was seen between patients who did or did not receive concurrent 5-FU and radiotherapy as adjuvant or neoadjuvant therapy. However, in the subgroup of patients who had a margin-negative resection (n = 25), 5-year overall survival was 53% in the surgery-alone group and 83% in the chemoradiotherapy group (P = .07).,Radiotherapy & adjuvant therapy,Kelsey CR, et al. Duodenal adenocarcinoma: patterns of failure after resection and the role of chemoradiotherapy. Int J Radiat Oncol Biol Phys. 2007;69:14361441.,Radiotherapy & adjuvant therapy,Adjuvant Concurrent Chemoradiation for Node-Positive Adenocarcinoma of the Duodenum。 The Johns Hopkins Hospital between 1994 and 2003. Fourteen cases of node-positive duodenal adenocarcinoma were identified.,Arch Surg. 2007;142(3):285-288,Method,All patients received adjuvant external beam radiation therapy, and all were offered fluorouracil-based concurrent and maintenance chemotherapy. Eight patients received concurrent fluorouracil, leukovorin, and mitomycin C, followed by maintenance chemotherapy with the same agents as part of an institutional study investigating those agents in periampullary carcinomas. Two patients received concurrent fluorouracil with no maintenance therapy; 2 received concurrent fluorouracil and leucovorin, followed by maintenance with the same agents; 1 patient received concurrent fluourouracil and cisplatin; 1 patient refused chemotherapy.,Arch Surg. 2007;142(3):285-288,The median follow-up was 12 months for patients who died and 42 months for those who lived. Death occurred in 7 of 14 patients (50%) during the follow-up period. Median survival for all patients was 41 months, and the 5-year survival rate was 44%. Of the 7 patients who experienced disease recurrence, 6 experienced distant metastasis as first recurrence. One of these 7 patients experienced both local recurrence and distant metastasis.,Compared with historical controls treated with surgery alone, patients who received adjuvant chemoradiation therapy had an improved median survival (21 months vs 41 months, respectively). Overall 5-year survival, however, was not improved (44% vs 43%, respectively).,Median follow-up was 12 months for patients who died and 42 months for those who survived. The median survival for all patients was 41 months, with a 5-year survival rate of 44%,Median survival appears to be improved with the use of adjuvant therapy (41 months vs 21 months). Overall survival at 5 years, however, was not different between the 2 groups.,Compared with historical controls from our own institution, the use of adjuvant chemoradiation therapy in such patients seems to improve median survival, but does not improve overall survival at 5 years. This finding is consistent with a previously published retrospective analysis of 48 patients treated at our institution from 1984 to 1996.,辅助化放疗,One multicenter study conducted by the Eastern Cooperative Oncology Group (ECOG) reported on the combination of 5-FU, doxorubicin, and mitomycin C (FAM) in 39 patients with adenocarcinoma of the small bowel or ampulla of Vater. The overall response rate was 18%, with a median overall survival of 8 months.,Gibson MK, et al. Phase II study of 5-fluorouracil, doxorubicin, and mitomycin C for metastatic small bowel adenocarcinoma. Oncologist. 2005;10:132137.,辅助化放疗,Overman MJ等报道1990-2008年间Anderson Cancer Center 54例手术切除切缘阴性患者。 Median radiation dose was 5000 cGy (range, 4000-5760 cGy). Concurrent fluorouracil-based chemotherapy was given with radiation therapy, followed by maintenance chemotherapy. DFS和OS。,Overman MJ.Acta Oncol. 2010;49(4):474-479.,中位年龄55岁。 原发灶十二指肠67% 、空肠20% 、回肠13%。 30例(56%)接受系统辅助化疗，28例伴或不伴放疗，2例仅接受放疗。,At a median follow-up of 4.7 years, 14 patients (26%)have relapsed and 12 patients (22%) have died. When stratifi ed by stage, the 5-year OS for patients with stage I, II, and III disease were 100% (95% CI: 100100%), 87% (95% CI: 2998%), and 59% (95%CI: 2581%).,Multivariate analysis: For both OS and DFS, a lymph node ratio of 10% and poorly differentiated histology were associated with worse outcomes. For DFS, adjuvant therapy was associated with an improved outcome, with a hazard ratio of 0.27. For OS, no benefit from adjuvant therapy was seen, with a hazard ratio of 0.47.,To better evaluate the role of systemic chemotherapy as adjuvant therapy, two separate multivariate analyses were conducted. In the first analysis we compared patients who had received systemic adjuvant chemotherapy with or without additional radiation (n = 25) to patients who received no adjuvant therapy. Adjuvant therapy improved DFS, but not OS .,In the second analysis patients treated with adjuvant systemic chemotherapy alone (n = 18) were compared to patients who received no adjuvant therapy. Though the hazard ratios were similar in this analysis, adjuvant chemotherapy was not a statistically significant factor for either DFS (HR 0.33, 95% CI: 0.081.27, p = 0.11) or OS (HR 0.53, 95% 0.142.06, p = 0.36).,In the subgroup of Lymph node ratio10%, OS was improved, but not DFS,In multivariate analysis, the use of adjuvant therapy was associated with improved DFS (HR 0.27; 95% CI 0.07-0.98, P = 0.05) but not OS (HR 0.47; 95% CI 0.13-1.62, P = 0.23). In patients with a high risk of relapse (defined as a lymph node ratio or=10%), adjuvant therapy appeared to improve OS, P = 0.04, but not DFS, P = 0.15.,Role of adjuvant chemoradiation therapy in adenocarcinomas of the ampulla of vater. Concurrent chemotherapy included primarily 5-fluorouracil (52%) and capecitabine (43%). Median follow-up was 31 months.,Int J Radiat Oncol Biol Phys. 2008 Mar 1;70(3):735-43.,Among these patients (n = 34), those who received adjuvant CRT had a trend toward improved OS (median, 35.2 vs. 16.5 months; p = 0.06).,Int J Radiat Oncol Biol Phys. 2008 Mar 1;70(3):735-43.,neoadjuvant chemoradiotherapy,The role of neoadjuvant chemoradiotherapy for duodenal adenocarcinoma has been studied in small numbers. An initial report from Fox Chase Cancer Center reported complete pathologic responses in four of four patients treated with radiotherapy and concurrent 5-FU and mitomycin-C.,Yeung RS, et al. Neoadjuvant chemoradiation in pancreatic and duodenal carcinoma. A phase II study Cancer. 1993;72:21242133.,However, a larger report from Duke University noted complete pathologic responses in only 2 of 11 patients treated with neoadjuvant 5-FUbased chemoradiotherapy. Kelsey CR, et al. Duodenal adenocarcinoma: patterns of failure after resection and the role of chemoradiotherapy. Int J Radiat Oncol Biol Phys. 2007;69:14361441. Interestingly, none of these patients had lymph node involvement at the time of surgical resection, though no description of pretreatment radiographic staging was reported.,Palliative chemotherapy,The largest published study investigating chemotherapeutic measures for small bowel AC involved 14 subjects with metastatic small bowel AC and involved a chemotherapeutic regiment containing 5-fluorouracil (5-FU). Patients had a median survival of 9 months.,Jigyasu D, et al. Chemotherapy for primary adenocarcinoma of the small bowel. Cancer 1984, 53(1):23-25.,A more recent investigation reported advanced small bowel AC treated with infusional 5-FU-based regimens had a response rate of 37.5% and a median survival of 13 months.,Crawley C, et al. The Royal marsden experience of a small bowel adenocarcinoma treated with protracted venous infusion 5-fluorouracil. Br J Cancer 1998, 78(4):508-510.,Chemotherapy with 5-fluorouracil and a platinum compound improves outcomes in metastatic small bowel adenocarcinoma.,The authors identified 80 patients with metastatic SBA who were treated with chemotherapy at the University of Texas M. D. Anderson Cancer Center between 1978 and 2005. 29/80 patients (36%) received 5-FU + a platinum compound, 41 patients (51%) received 5-FU - a platinum compound, 10 patients (13%) received non-5-FU-based treatment.,Cancer. 2008 Oct 15;113(8):2038-45.,Compared with other chemotherapy regimens, treatment with 5-FU and a platinum agent resulted in a higher response rate (46% vs 16% with other regimens; P = .01) and longer median PFS (8.7 months vs 3.9 months; P or = .01) but not better OS (14.8 months vs 12 months; P = .1).,Cancer. 2008 Oct 15;113(8):2038-45.,In multivariate analysis, treatment with 5-FU and a platinum compound was a significant predictor of response and PFS but only reached borderline significance for OS.,Cancer. 2008 Oct 15;113(8):2038-45.,Prior Studies of Chemotherapy for Advanced Small Bowel Adenocarcinoma,M. D. Anderson Cancer Center evaluated the combination of capecitabine and oxaliplatin (CAPOX) in 30 patients with either metastatic or locally advanced small bowel or ampullary adenocarcinoma. The overall response rate was 50%, with a median time to progression of 9.8 months and a median overall survival of 20.3 months.,Overman MJ, et al. Phase II study of capecitabine and oxaliplatin for advanced adenocarcinoma of the small bowel and ampulla of Vater. J Clin Oncol. 2009,For the 25 patients with metastatic disease, the response rate was 52%, with a median overall survival of 15.5 months. In the 18 patients who had small bowel adenocarcinoma, the response rate was 61%, with a median time to progression of 9.8 months and median overall survival of 20.4 months. Of note, 10% of treated patients had a complete radiographic response to CAPOX.,Overman MJ, et al. Phase II study of capecitabine and oxaliplatin for advanced adenocarcinoma of the small bowel and ampulla of Vater. J Clin Oncol. 2009,capecitabine and oxaliplatin,The combination of capecitabine and oxaliplatin is reportedly highly effective.,Gan To Kagaku Ryoho. 2010 Aug;37(8):1454-7.,S-1(case report),A case report using onastat, tegafur, and gimestat (otherwise known as S-1chemotherapy) showed remission of primary AC of the duodenum. We reported that S-1 and UFT/LV therapy was effective with the two cases as an oral chemotherapy for the primary small intestinal cancer.,Katakura Y, et al.Remission of primary duodenal adenocarcinoma with liver metastases with s-1 chemotherapy. Dig Dis Sci 2007, 52(4):1121-1124.,Gan To Kagaku Ryoho. 2010 Nov;37(12):2789-91.,Case report,A case of successful control for primary duodenal cancer with combined CPT-11, CDDP and DOC chemotherapy. Combined CPT-11, CDDP and DOC chemotherapy were performed. After two courses, endoscopic examination and biopsy showed primary lesion of the duodenum had disappeared. Metastatic lymph nodes were reduced from CT scan after three courses, and successfully controlled until nine courses. Then regimen was changed to S-1 alone and S-1/CPT-11. The patient remained alive for two years after the operation without tumor progression.,Gan To Kagaku Ryoho. 2008 Oct;35(10):1753-6.,Small number report,A case of peritoneal dissemination from mucinous carcinoma of the duodenum, which was associated with tumor thrombosis in the accessory pancreatic duct and successfully treated by chemotherapy. A 72-year-old woman was admitted with an abdominal tumor, which had been detected by CT scanning.,Okumura F,et al. Nippon Shokakibyo Gakkai Zasshi. 2009;106(12):1736-43.,Endoscopic examination of the upper gastrointestinal tract revealed a type 3 tumor in the descending limb of the duodenum. A diagnosis of adenocarcinoma was made on the basis of the histological analysis of the biopsy sample.,Okumura F,et al. Nippon Shokakibyo Gakkai Zasshi. 2009;106(12):1736-43.,Pancreatoduodenectomy was performed, and peritoneal dissemination was confirmed at surgery. The pathological findings indicated primary duodenal cancer (mucinous carcinoma) associated with tumor thrombosis in the accessory pancreatic duct.,FOLFOX 4,Complete response of an initially non-surgical adenocarcinoma of the duodenum to chemotherapy with the FOLFOX 4 regimen. We report here the case of a young patient with an initially non-surgical adenocarcinoma of the duodenum treated in a palliative setting with the FOLFOX 4 chemotherapy regimen.,J Gastrointest Surg. 20