奥曲肽治疗化疗相关性腹泻最终版doc.docx

1、奥曲肽治疗化疗相关性腹泻最终版docOctreotide in chemotherapy induced diarrhoea in colorectal cancer: a review article奥曲肽治疗直肠癌患者化疗相关性诱发腹泻：综述Abstract摘要Background: Chemotherapy-induced diarrhea(CID)is well known in cancer management. The risk is greater when the primary cancer is colorectal. The article aims towards a

2、ssessing the role of octreotide in CID through an extensive literature search.背景：化疗相关性诱发腹泻(CID)在癌症治疗中比较常见。特别是原发灶位于直肠的癌症则风险更大。本文旨在通过全面的文献检索评价奥曲肽治疗CID的作用。Methods：After searching through PUBMED,MEDLINE and the Cochrane library, only those studies which were published over the last 20 years in English a

3、nd where at least the majority of the cohort were colorectal patients, were included. Two randomized trials, four non-randomized studies and two case-series publications were thus considered.方法：检索PUBMED,MEDLIN和循证医学图书馆，选出最近20年用英文发表的、并且至少所选的主要观察队列为结肠病人的研究论文。符合条件的共有两项随机对照试验，四项非随机研究和两篇系列案例研究文献。Results:

4、It was seen in both the randomized studies, that octreotide had much better outcome as compared to loperamide in treating severe CID. Among 88 patients from the non-randomized studies with severe CID, the primary cancer was colorectal in 79 patients.61 patients had drug-resistant CID. Within a maxim

5、um of 96 hours, octreotide reduced CID by 2 grades in 91% of 88 patients and in 88.52% patients with drug-resistant CID.结果：随机对照试验研究结果显示，奥曲肽治疗严重CID的疗效比咯哌丁胺好很多。非随机研究结果显示，88例严重CID病人中，原发是结肠癌的有79例。其中61例病人有CID抗药性。用奥曲肽治疗最长时间为96个小时后，88例严重CID病人中，抗药性降低的患者为91%，抗药性患者中88.52%患者的CID评分至少2级。Conclusion: Octreotide is

6、 effective in treating severe CID, resistant to other modes of treatment. It is associated with a few minor adverse effects. Though expensive, octreotide could be considered as first line medication in CID of grades 3 or above. Its use in lower grades of CID would not be cost effective.结论：奥曲肽对其他治疗方式

7、无效的严重CID患者有效，且不良反应较少。尽管价格比较昂贵，奥曲肽仍可考虑作为CID评分级以上患者的一线药物。在低级别的CID治疗中，奥曲肽的作用并不是很大。Key words: octreotide, chemotherapy induced diarrhoea, octreotide in diarrhoea.关键词：奥曲肽，化疗导致的腹泻，奥曲肽治疗腹泻Abbreviations缩写CID = Chemotherapy induced diarrhoea化疗相关性诱发腹泻5FU = 5 Fluorouracil5-氟尿嘧啶UFT=Uracil优福定NCI=National Cancer

8、Institute国际肿瘤研究所NICE=National Institute of Clinical Excellence 国家临床优化研究所Introduction介绍Colorectal cancer is the second commonest cause for cancer related mortality in England and Wales and the third commonest cause in the United States(1). In the UK, there are 30000 new cases each year, a quarter of

9、which are Dukes C or Stage at presentation. (please refer to (a) NICE Guidance on Cancer Service: Improving Outcomes in Colorectal Cancer, Manual Improving Outcomes in Colorectal Cancers, Manual Update 2000 and (b) Cancer Stats monograph 2004 cancer incidence survival and mortality in the UK and EU.

10、 Bowel Cancer Statistics. Cancer Research UK; 2004).在英国和威尔士，结、直肠癌的死亡率是位居所有癌症死亡率的第二位，在美国是所有癌症死亡率的第三位（1）。英国每年新增30000例结直肠癌患者，其中四分之一是Dukes期或肿瘤III期。（请参考（a）NICE癌症服务指导原则：提高结直肠癌病愈率，提高结直肠癌病愈率手册，2000补充资料手册和（b）英国和欧盟2004年癌症死亡率和生存率统计专题论文集。肠癌统计资料，癌症研究，英国；2004）All Dukes C, high risk Dukes B and metastatic colorect

11、al cancers are likely to be considered for either post operative (Dukes B/C) or palliative chemotherapy (Dukes D/ metastatic disease)(2,3). Chemotherapy induced diarrhea(CID) is common and could be as high as 82%.Nearly a third of these patients have severe grade 3-4 diarrhoea(Fig.1), which is frequ

12、ently responsible for hospitalization, chemotherapy dose modification and early termination of treatment. Chemotherapy regimens used in adjuvant(4,5) and metastatic(6,7) colorectal disease and respective incidences of CID are summarized in the charts(Fig.2.3).所有的杜克斯C期，高危的杜克斯B期和转移的结直肠癌似乎都可考虑手术后化疗（(Du

13、kes B/C期)或姑息性化疗（杜克斯D期/癌转移）(2,3)。化疗相关性诱发腹泻（CID）非常普遍，可能高达82%。其中大约三分之一患有比较严重的3-4级腹泻（见表1），这往往是由于住院治疗、化疗剂量改变和治疗较早结束引起的。辅助化疗方案(4,5)和转移性结直肠癌疾病（6,7）及其CID发病率请见图表（表2,3）中的汇总。Capecitabine, irinotecan, cetuximab and 5FU bolus regimens are often associated with higher incidences of diarrhea(8-12). Primary colorec

14、tal cancer is an independent risk factor for CID. Other independent risk factors reported in the literature are diarrhea with chemotherapy in earlier cycles, chemotherapy in summer months(13), older age group females(14,15), dihydropyrimidine dehydrogenase (DPD) deficiency, uridine diphosphate gluco

15、ronyl transferase (UGT) deficiency(16-20) and adjuvant chemotherapy as compared to palliative therapy(16). Diarrhoea can cause dehydration, electrolyte imbalance, renal impairment ,nutritional deficiency and can have negative impact on the management of cancer itself. Severe diarrhea decreases patie

16、nts tolerance towards chemotherapy often resulting in dose reduction or early termination of the treatment. Increased morbidity increases the cost of care and leads to poorer clinical outcomes. Diarrhoea can be associated with chemotherapy induced neutropenia, which can be serious or even fatal. The

17、 severity of the CID is assessed by the National Cancer Institute(NCI) criteria(16).Dranitsaris and colleagues reported an incidence of 54.2% diarrhoea after the first cycle of chemotherapy in a retrospective study and this resulted in a median dose reduction by 20% and median delay in treatment by

18、7 days. 32.3% cases in this study needed hospitalization and their median length of hospital stay was 8 days (21).卡培他滨，伊立替康，西妥昔单抗和5-氟尿嘧啶推注方案通常导致高腹泻率(8-12)。原发性结直肠癌是CID的独立的危险因素。文献报道的其他的独立的危险因素有化疗早期疗程导致的腹泻、夏季化疗相关性诱发腹泻以及老年组女性（14,15）、双氢嘧啶脱氢酶（DPD）缺乏，尿苷二磷酸葡萄糖醛酸基转移酶缺乏（UGT）(16-20)以及与姑息性治疗相比较的辅助化疗（16）。腹泻会导致脱水

19、、电解质失衡、肾损害、营养缺乏，并且对癌症治疗本身有负面影响。严重的腹泻降低患者对于化疗的耐受能力，从而导致剂量的减少和治疗结束过早。发病率增加提高了治疗成本，并且导致不良的治疗结果。腹泻可能与化疗诱发的嗜中性白血球减少症有关，可能非常严重甚至致命。NCI划分了CID的严重性等级。Dranitsaris及其同事在一项回溯性研究中报道，第一个疗程后腹泻发生率为54.2%，这导致治疗剂量平均降低20%，治疗时间平均延长7天。此项研究中32.3%的患者需要住院治疗，并且平均住院期为8天。 Fig.1.NCI grading of diarrheaNational Cancer Institute C

20、riteria for assessing the severity of chemotherapy-induced diarrhoeaGrades of CIDFrequency of DiarrhoeaStoma outputNeed for intravenous fluidresuscitationInterfering with dailyActivities14 times/dayMildNoneNone24-6 times/dayModerate 24 hrsNone37 times/daysevere24 hrsYes4Diarrhoea resulting into life

21、 threatening consequences like haemodynamic collapse or shock.5Death due to consequences of diarrhoea表1.美国国立癌症研究所（NCI） 腹泻分级美国国立癌症研究所评价化疗相关性腹泻严重性的标准CID等级腹泻频率造瘘病人排泄量需要静脉输液复苏日常活动干扰14次/天轻无无24-6次/天中度 24小时无37 次/天严重24 小时有4腹泻导致生命危险，例如血液动力学衰竭或休克5腹泻导致死亡Fig.2.Chemotherapy-induced diarrhea in colorectal cancer

22、in adjuvant settingChemotherapy-induced diarrhea in colorectal cancer in adjuvant settingNoChemotherapy/RegimensIncidence of CID NCI grade3Reference/Trial/Citation1FOLFOX 411%MOSAIC trial, AndreT., et al. N.Engl.J.Med.,20042FLOX38%NSABP trial,Kuebler J.P., et al,.J.Clin.Oncol.,2007 Reference-(5)3Cap

23、O/OxCap11%X-ACT Trial.Twelves C.,et al.Clin.Colorectal Cancer,2006 Reference-(9)4Capecitabine+Oxaliplatin(XELOXA)19%Schmoll et al.Journal of Clinical of Oncology,2007.January;25(1)Reference-(10)5Mayo Clinic Regimen(FU/LV)16%6Roswell Park Regimen(FU/LV)29%表2.采用辅助疗法的结直肠癌患者的化疗相关性腹泻 采用辅助疗法的结直肠癌患者的化疗相关性腹

24、泻编号化疗/方案CID发生率NCI等级3参考文献/试验/引文1奥沙利铂、氟尿嘧啶和甲酰四氢叶酸钙方案11%MOSAIC trial, AndreT., et al. N.Engl.J.Med.,20042FLOX38%NSABP trial,Kuebler J.P., et al,.J.Clin.Oncol.,2007 Reference-(5)3CapO/OxCap11%X-ACT Trial.Twelves C.,et al.Clin.Colorectal Cancer,2006 Reference-(9)4卡培他滨+奥沙利铂(XELOXA)19%Schmoll et al.Journal

25、 of Clinical of Oncology,2007.January;25(1)Reference-(10)5Mayo Clinic Regimen(FU/LV)16%6Roswell Park Regimen(FU/LV)29%Fig.3. Chemotherapy-induced diarrhea in advanced/metastatic colorectal cancerChemotherapy-induced diarrhea in advanced/metastatic colorectal cancerNo.Chemotherapy/RegimensIncidence o

26、f CID NIC grade3Reference/Trial/Citation1Capecitabine/Oxaliplatin16%Cao Y.,et al. Journal of Colouectal Disease, 2009 Reference-(11)25-FU+Oxaliplatin12.5%3OxMdG Fegimen6%Adams R.A.,et al.British Journal of Cancer (2009) 100,251-8Reference-(12)4OxMdG+Cetuximab13%5XELOX15%6XELOX+ Cetuximab25%7FOLFIRI1

27、4%Tournigand C., et al. GERCOR study. Journal of Clinical Oncology, Jan 2004,24(2)Reference-(6)8FOLFOX 611%9FOLFOX 4+Bevacizumab7.8%Emmanouilides C.,et al. BMC Cancer,2007,7(91)Reference-(7)表3. 晚期/转移性结直肠癌患者的化疗相关性腹泻晚期/转移性结直肠癌患者化疗相关性腹泻编号化疗/方案CID发生率NCI等级3参考文献/试验/引文1卡培他滨/奥沙利铂16%Cao Y.,et al. Journal of

28、Colouectal Disease, 2009 Reference-(11)25-氟尿嘧啶+奥沙利铂12.5%3OxMdG Fegimen6%Adams R.A.,et al.British Journal of Cancer (2009) 100,251-8Reference-(12)4OxMdG+西妥昔单抗13%5XELOX15%6XELOX+西妥昔单抗25%7氟尿嘧啶、亚叶酸和伊立替康联合用药14%Tournigand C., et al. GERCOR study. Journal of Clinical Oncology, Jan 2004,24(2)Reference-(6)8奥

29、沙利铂、氟尿嘧啶和甲酰四氢叶酸钙方案（FOLFOX 6）11%9氟尿嘧啶、亚叶酸和伊立替康联合用药（FOLFOX 4）+贝伐单抗7.8%Emmanouilides C.,et al. BMC Cancer,2007,7(91)Reference-(7)Aim of the study 研究目的Octreotide has often been used to treat CID. In the absence of a fixed protocol, treatment has been purely empirical. This review article aims towards as

30、sessing the role of octreotide in CID through an extensive literature search.奥曲肽经常被用来治疗CID。由于没有固定的方案，完全是凭经验来进行治疗。本综述的目的在于通过全面的文献研究来评估奥曲肽治疗CID的作用。Methods and materials方法和材料We have searched PUBMED, MEDLINE and Cochrane library for relevant published articles over the last 25years from 1984 to 2009.The

31、 phrases like “octreotide CID”, “colorectal cancer CID and octreotide” and “chemotherapy induced diarrhea in colorectal cancer and octreotide” were used to search for relevant articles . We included those studies, which were published in English and where the whole cohort or at least a major proportion of it were colorectal cancer patients. We have included two randomized trials, four non-randomized controlled studies and two case series publications in our re