奥曲肽治疗化学疗法导致的腹泻直肠癌病人：一篇综述（翻译）

Octreotide in chemotherapy induced diarrhoea in colorectal cancer: a review article 奥曲肽治疗化学疗法导致的腹泻直肠癌病人：一篇综述 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 assessing the role of octreotide in CID through an extensive literature search. 背景：化学疗法导致的腹泻(CID)在癌症治疗中比较常见。当原发癌是直肠癌时风险更大。这篇综述的目的在于通过大量广泛的文献调查评价奥曲肽在治疗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 and 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. ：在通过PUBMED,MEDLIN和循证医学文库搜索之后，仅挑选出在近20年用英文发表的，并且所选的队列为结肠病人的研究。两个随机对比临床试验，四个非随机研究和两案例系列出版物在考虑的范围之内。 Results: 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 maximum of 96 hours, octreotide reduced CID by ≥ 2 grades in 91% of 88 patients and in 88.52% patients with drug-resistant CID. 效果：从两个随机研究中都可以看出，在治疗严重的CID时，奥曲肽比咯哌丁胺有更好的笑料。在从非随机法选择的88个病人中，原发癌是结肠癌的有79个病人。61个病人有CID抗药性。在最多96个小时内，奥曲肽降低了88个患者中的91%的患者，CID抗药性患者中的88.52%患者至少两级。 Conclusion: Octreotide is 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：奥曲肽在治疗严重的CID患者比较有效，能抵抗其他方式的治疗，且不良反应较少。尽管价格比较昂贵，奥曲肽 Key words: octreotide, chemotherapy induced diarrhoea, octreotide in diarrhoea. 关键词：奥曲肽，化学疗法导致的腹泻， Abbreviations缩写 CID = Chemotherapy induced diarrhoea化学疗法诱导的腹泻 5FU = 5 Fluorouracil5-氟尿嘧啶 UFT=Uracil优福定 NCI=National Cancer 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 which are Dukes C or Stage Ⅲ 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. Bowel Cancer Statistics. Cancer Research UK; 2004). All Dukes C, high risk Dukes B and metastatic colorectal 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 frequently 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). Capecitabine, irinotecan, cetuximab and 5FU bolus regimens are often associated with higher incidences of diarrhea(8-12). Primary colorectal 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 glucoronyl 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 patient’s 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 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 7 days. 32.3% cases in this study needed hospitalization and their median length of hospital stay was 8 days (21). 结直肠癌是英国和威尔士第二常见的癌症致死的病种，是美国的第三常见的病种（1）。在英国，每年有30000例新患者，目前四分之一的患者是杜克斯C或第三阶段。（请查阅（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）2004年在英国和欧盟癌症导致死亡率和存活率癌症论文专著。肠癌统计资料，癌症调查，英国；2004）所有的杜克斯C，高危的杜克斯B和转移的结直肠癌都有可能被当做post operativ？(杜克斯B/C)或缓解化疗杜克斯D/转移疾病）(2,3)。都有CID病症而且高达82%。这些患者中大约三分之一患有比较严重的3-4级腹泻（见表1），这是由住院，化学疗法剂量改变和最初的治疗结束的数据统计出来的。辅助以化学-食物疗法(4,5)和转移（6,7）性的结直肠癌疾病和CID相关的发病率已经在图表中概括了（表2,3）。卡培他滨，伊立替康，西妥昔单抗和5-氟尿嘧啶丸剂疗法通常导致高腹泻率(8-11)。大部分的结直肠癌是CID的不独立的危险因素。在一些文献中提到的其他的独立的危险因素有早期循环中化学疗法导致的腹泻，在夏天运用化学疗法，老年组女性（14,15），缺乏双氢嘧啶脱氢酶（DPD），缺乏尿苷二磷酸glucorony？转移酶（UGT）(16-20)和被形容为环节疗法的辅助化学疗法（16）。腹泻能导致脱水，电解质失衡，肾病损，营养缺乏，并且有对癌症治疗本身有负面影响。严重的腹泻降低患者对于化学疗法的忍受能力，这通常会导致剂量的减少和治疗结束过早。增加的发病率增加了治疗的成本，并且导致不良的治疗结果。腹泻加上化学疗法诱发嗜中性白血球减少症，这是很危险甚至致命。NCI划分了CID的严重性等级。Dranitsaris和同业者的回溯性研究中，在化学疗法的第一次循环后的腹泻发生率为54.2%，这导致20%平均的剂量的减少量和治疗过程中平均7天的延误。在这个研究中32.3%的病例需要住院治疗，并且平均住院期为8天。 National Cancer Institute Criteria for assessing the severity of chemotherapy-induced diarrhoea Grades of CID Frequency of Diarrhoea Stoma output Need for intravenous fluid resuscitation Interfering with daily Activities 1 ＜4 times/day Mild None None 2 4-6 times/day Moderate ＜24 hrs None 3 ≥7 times/day severe ＞24 hrs Yes 4 Diarrhoea resulting into life threatening consequences like haemodynamic collapse or shock. 5 Death due to consequences of diarrhoea Fig.1.—NCI grading of diarrhea 国家癌症研究所评估化学疗法导致的腹泻的严重性的 CID等级 腹泻的频率 排气量 静脉输入溶液复苏术的需求 日常活动的干扰 1 ＜4次/天 2 4-6次/天 3 ≥7 次/天 4 腹泻导致生命危险，例如血液动力的崩溃或休克 5 腹泻导致死亡 表1.国家癌症研究所腹泻等级划分 Chemotherapy-induced diarrhea in colorectal cancer in adjuvant setting No Chemotherapy/Regimens Incidence of CID NCI grade≤3 Reference/Trial/Citation 1 FOLFOX 4 11% MOSAIC trial, AndreT., et al. N.Engl.J.Med.,2004 2 FLOX 38% NSABP trial,Kuebler J.P., et al,.J.Clin.Oncol.,2007 Reference-(5) 3 CapO/OxCap 11% X-ACT Trial.Twelves C.,et al.Clin.Colorectal Cancer,2006 Reference-(9) 4 Capecitabine+Oxaliplatin(XELOXA) 19% Schmoll et al.Journal of Clinical of Oncology,2007.January;25(1) Reference-(10) 5 Mayo Clinic Regimen(FU/LV) 16% 6 Roswell Park Regimen(FU/LV) 29% Fig.2.—Chemotherapy-induced diarrhea in colorectal cancer in adjuvant setting 结直肠癌患者中CID的辅助疗法？ 编号 化学疗法/食物疗法 CID发生率 NCI等级≤3 参照/实验/引文 1 奥沙利铂‘氟尿嘧啶和甲酰四氢叶酸钙 11% MOSAIC trial, AndreT., et al. N.Engl.J.Med.,2004 2 氟氧剂 38% NSABP trial,Kuebler J.P., et al,.J.Clin.Oncol.,2007 Reference-(5) 3 加拿大社会心理肿瘤协会/ OxCap? 11% 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 of Clinical of Oncology,2007.January;25(1) Reference-(10) 5 16% 6 29% 表2.- 结直肠癌患者中CID的辅助疗法？ Chemotherapy-induced diarrhea in advanced/metastatic colorectal cancer No. Chemotherapy/Regimens Incidence of CID NIC grade≤3 Reference/Trial/Citation 1 Capecitabine/Oxaliplatin 16% Cao Y.,et al. Journal of Colouectal Disease, 2009 Reference-(11) 2 5-FU+Oxaliplatin 12.5% 3 OxMdG Fegimen 6% Adams R.A.,et al.British Journal of Cancer (2009) 100,251-8 Reference-(12) 4 OxMdG+Cetuximab 13% 5 XELOX 15% 6 XELOX+ Cetuximab 25% 7 FOLFIRI 14% Tournigand C., et al. GERCOR study. Journal of Clinical Oncology, Jan 2004,24(2) Reference-(6) 8 FOLFOX 6 11% 9 FOLFOX 4+Bevacizumab 7.8% Emmanouilides C.,et al. BMC Cancer,2007,7(91) Reference-(7) Fig.3. – Chemotherapy-induced diarrhea in advanced/metastatic colorectal cancer 化学疗法诱导腹泻/转化为结直肠癌 编号 化学疗法/食物疗法 CID发生率 NCI等级≤3 参照/实验/引文 1 卡培他滨/奥沙利铂 16% Cao Y.,et al. Journal of Colouectal Disease, 2009 Reference-(11) 2 5-氟尿嘧啶+Oxaliplatin 12.5% 3 OxMdG Fegimen 6% Adams R.A.,et al.British Journal of Cancer (2009) 100,251-8 Reference-(12) 4 OxMdG+Cetuximab 13% 5 XELOX 15% 6 XELOX+ Cetuximab 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 FOLFOX 6 11% 9 氟尿嘧啶。亚叶酸和伊立替康联合用药4+贝伐单抗 7.8% Emmanouilides C.,et al. BMC Cancer,2007,7(91) Reference-(7) Fig.3. –化学疗法诱导腹泻/转化为结直肠癌 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 assessing the role of octreotide in CID through an extensive literature search. 奥曲肽经常被用来治疗CID。在缺少固定的方案时，完全是凭经验来进行治疗。这篇综述的目的在于通过广泛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 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 review. The articles related to patients having chemotherapy solely for cancers other than colorectal carcinoma and solitary case reports regarding use of octretide or other modes of medications to control CID were excluded. We have also looked at the pharmaco-economic aspects relating to octreotide, its recommended safe dose and its adverse effects in the treatment of CID only. 我们通过PubMed，MEDLINE和询证医学图书馆来查询从1984到2009年这近25年有关的文献。关键词像“奥曲肽 CID”，“结直肠癌CID和奥曲肽”，“结直肠癌患者应用化学疗法导致腹泻和奥曲肽”被用来搜索相关的文献。我们归纳了这些文献，这些式用英文撰写的，而且抽样中整群至少大部分是结直肠癌患者。在综述中，归纳了两组随机对比临床试验，四组非随机控制研究和两个病例系列的文献。这些文献是关于患者仅使用化学疗法来治疗癌症，而不仅仅是直肠癌和单一的关于奥曲肽的作用或者其他用来控制CID用药的病例被排除在外。我们也要考虑关于单独使用奥曲肽时在治疗CID时的药学经济学因素，他的推荐安全剂量和副作用。 Results结果 1) Octreotide VS other medications in CID治疗CID时奥曲肽和其他用药的对比 A randomized trial (22) established the effectiveness of octreotide , against loperamide in controlling severe CID (NIC grades 2 and above) in a cohort of 41patients(68.3% colorectal cancer)(P＜0.005). Gebbia et al. performed a similar randomized trial(23), where the group of patients receiving octreotide had much better results, compared to those receiving loperamide (Fig.4). In a prospective non-randomized study(24), colorectal cancer patients with grade 3-4, loperamide resistant CID were treated with octreotide. In this cohort, nearly 16% of patients had complete resolution of diarrhea and about 29% experienced reduction of diarrhea by at least two grades. In the remaining 25% of cases, diarrhea ,was reduced by one grade. A similar prospective multicentre trial by Zidan et al.(25) in a cohort of patients, (the majority of which were colorectal cancer patients) with severe loperamide resistant CID, octreotide was used as a failsafe and complete resolution of diarrhea was noted in 94% cases without any major adverse effects. This study did not specify the exact percentage of colorectal cancer patients who were among this complete resolution group. A prospective study (26) reporting the effects of octreotide in a cohort with opioid-resistant CID, demonstrated 94% success rate with no serious side effects. Cascinu et al.(27) has reported a better success rate (96.3% complete response within 72hours of onset of treatment) with octreotide in a cohort of 27 patients (21 patients with advanced colorectal cancer and rest with advanced pancreatic cancer). When we combined the results of all these non-randomized studies, in a cohort of 88 patients (colorectal cancer in 79 out of 88 cases) with severe CID (NCI grades 3 and above), 61 patients (69.32%) with opioids or loperamide resistant CID were treated with octreotide, which was effective in controlling diarrhea in 54(88.52%) patients within a maximum of 4 days. 在41个患者的病例群中（68.3%的结直肠癌患者）(P＜0.005)随机对比临床试验（22）中，证明了奥曲肽相对比洛哌丁胺在控制严重的CID（NIC级别2级和以上）的效用。Gebbia et al.进行相似的随机对比试验（23），在这个试验中，患者使用奥曲肽比使用洛哌丁胺效果更好（见表4）。在一个预期的非随机研究中（24），3-4级结直肠癌患者，对洛哌丁胺有抗药性使用奥曲肽来治疗CID。在这个队列中，大约16%的患者的腹泻症状完全消退，大约29%的患者症状减轻了至少两个级别。剩下的25%的病例中，腹泻减轻了1个级别。以一个有严重的洛哌丁胺抗药性的CID患者群（大多数为结直肠癌患者）为研究对象，Zidan et al.(25)进行的一个相似的预期的多中心试验，记载的事奥曲肽是一种破损安全和完全消退腹泻能达到94%，且没有任何大的副作用的药品。这个研究没有详细指出在完全消退群中直结肠癌患者的确切概率。一个关于奥曲肽对阿片样物质具有抗药性的CID患者群的影响的预测性研究（26）例证了其成功率为94%，没有严重副作用。Cascinu et al.(27)报道了用奥曲肽治疗一个27名患者群（21名患者为比较严重的结直肠癌，其余为比较严重的胰腺癌患者）得到了更高的成功率（在72小时的治疗时间内有96.3%完全有效）。当我们结合所有这些非随机研究的结果，在一个88名有严重CID（NCI级别为3和更高）的患者群中（这88名患者中结直肠癌患者为79个），61名有鸦片和洛哌丁胺抗药性的CID患者（69.32）使用奥曲肽来治疗，在最多4天内有效控制腹泻的有54名患者（88.52%）。 Two case series publications by Rosenoff (28,29) reported successful treatment of severe CID (NCI grades 3 and above), refractory to loperamide and/or diphenoxylate atropine, by octreotide LAR(long acting release preparation). Both these publications demonstrated improvement in patient’s quality of life and tolerance towards chemotherapy. No serious adverse effects were reported in either of them. Rosenoff (28,29)发表的两个案例系列中提到使用奥曲肽LAR（长效释放药剂）成功治愈严重的CID（NCI级别在3级和以上），抗洛哌丁胺和/或地芬诺脂阿品脱的患者。这两篇论文都证明了提高了患者的生命质量和对化学疗法的耐受能力。这两篇论文中都没有提到严重的不良反应。 2) Dose of octreotide in CID治疗CID时奥曲肽的剂量 In the absence of fixed dose related guidelines, the use of octreotide in CID has been purely empirical. The Canadian Working Group on CID has recommended that patients with grade 2 CID (NCI grading) refractory to loperamide or opioids and grade 3 or 4 CID should have octreotide at a dose of 100-150 micrograms subcutaneously thrice daily. In refractory diarrhea, doses may be increased up to 500 micrograms thrice daily (16,30). The Canadian working group also recommends that octreotide LAR 30 mg (intramuscularly, once every 28 days) can be used prophylactically in any patient with colorectal cancer receiving chemotherapy who had experienced CID with the previous cycles(16). Dose efficacy of octreotide LAR（Long acting 40 mg VS 30mg）has been assessed by Rosenoff and colleagues in a multicentre, randomized, open-label study (31). The mean duration of anti-diarrhoeal treatment was found to be shorter for octreotide. Statistical significance was reached with both these results (p＜0.001). In this trial, although fewer patients in the 40 mg group experienced severe (grades 3-4) diarrhea and unscheduled healthcare support as compared to the 30 mg group, none of these differences were statistically significant. But this trial introduced the possibility of secondary prevention of CID by octreotide. Octreotide has a positive dose- response effect in CID, as shown by Goumas et al. in a randomized study, where patients with severe, loperamide resistant, CID were treated by thrice daily doses of either 100ug or 500ug of (subcutaneous) octreotide. Complete resolution was reported in 90.32% patients in the 500-microgram arm as compared to 60.71% in the 100-microgram arm (p＜0.05) (30). In a phase Ⅰ trial performed to demonstrate the safe dose of octreotide in fluoropyrimidine-induced diarrhea in 35 patients, the maximum tolerated dose was found to be 2000 micrograms (subcutaneous) thrice daily (32). 由于缺乏固定剂量的指导，使用奥曲肽治疗CID完全凭经验。加拿大某CID研究机构对2级抗洛哌丁胺或鸦片的CID患者（NCI分级）和3或4级CID患者的推荐剂量是100-150微克皮下注射，一天三次。顽固性腹泻患者，剂量增加到500微克一天三次（16,30）。这个加拿大研究机构也推荐使用奥曲肽长效释放药剂30mg（肌肉注射，每28天一次）来预防性的治疗任何接受化学疗法的有早期CID病史的结直肠癌患者（16）。奥曲肽长效释放药剂（长效40mg对比30mg）的剂量功效已经被Rosenoff和他的同事在一个多中心随机标签公开的研究中进行了评估（31）。发现使用奥曲肽抗痢疾治疗的平均耐受时间更短。两个结果的统计意义都已经达到(p＜0.001)。在这个试验中，尽管相对于30mg组，在40mg组很少患者有严重腹泻（3—4级）症状，并且得到了不在计划内的健康护理支持，这些差别不具有统计学的意义。但是这个试验提出了奥曲肽对于治疗CID的二级预防的可能性。Goumas et al指出，奥曲肽对CID患者有积极地剂量响应反应。在一个随机法的研究中，严重的，抗洛哌丁胺的患者的CID的治疗法是每天三次100ug或500ug奥曲肽（皮下注射）。显示使用500mg的患者的完全消退率为90.32%，使用100mg的患者的完全消退率为60.71%(p＜0.05) (30)。在阶段1，用治疗氟嘧啶诱导的腹泻的35名患者的试验证明奥曲肽安全剂量，发现最大耐量是每天三次2000mg（皮下注射）（32）。 3) Adverse effects related to the use of octreotide in CID治疗CID时奥曲肽的副作用 An extensive literature search has revealed that octreotide is safe, well-tolerated drug and effective with minimal adverse effects within the therapeutic range when used in CID (26,32)(Fig.5). Local pain at the injection site was reported by Gebbia et al.(23) and Barbounis et al.(24)(incidences of 15% and 38%) in their respective studies. But none of these were severe enough for cessation of therapy. Local pain was short lived and no longer than 15 minutes. This can be avoided if the vial is warmed prior to drug administration(33). Symptoms like increased diarrhea or looseness of stools, vitamin B12 deficiency and potential risk of gallstone formation (12-60%) are associated with long-term octreotide use in CID, because of the short duration of therapy in the latter. However, Rosenhoff et al.(31) has reported an incidence of gallstones in 3% patients being treated for CID. But this study did not mention whether these patients with gallstones has ultrasound scans prior to their treatment with octreotide, and hence may be a coincidental finding. Diarrhoea or the looseness of stools in long-term treatment with octreotide is possibly because of its increase in fecal fat excretion (36). Mild abdominal pain (15%)(23) at the onset of treatment, fatigue (48%), weakness (33%), nausea (28%), flatulence (21%) and constipation(13%) are some of the other non-specific adverse effects associated with use of octreotide in CID but none were serious enough and most of them disappeared on further treatment with octreotide(31). 大量的文献调查揭示了奥曲肽是安全和耐受良好的药物，用来治疗CID时在有效浓度范围内事有效的而且副作用极少。Gebbia et al.(23) 和 Barbounis et al.(24)在他们各自的研究中提到了注射部门的局部疼痛（发生率为15%和38%）。但是他们都没有指出严重到中断治疗。局部疼痛的时间短暂，不超过15分钟。而且可以通过在药物管理之前进行加热来避免（33）。长期使用奥曲肽治疗CID会导致腹泻加重，或looseness of stools？维生素B12缺乏和胆结石形成的潜在风险(12-60%)，因为在随后的治疗中治疗时期比较短。然而Rosenhoff et al.(31)报道了在治疗CID时胆结石的发病率为3%。但是这个研究并没有指明在胆结石患者使用奥曲肽之前是否进行过超声波扫描。长期使用奥曲肽治疗的患者发生腹泻或looseness of stools？是可能的，因为它增加了分辩证脂肪排泄物（36）。使用奥曲肽治疗CID其他的不良反应有治疗初期轻微的腹痛（15%）（23）、疲劳（48%），虚弱（33%），恶心（28%），肠胃气胀（21%）和便秘（13%），但是都不够严重，而且在进一步的使用奥曲肽之后，大部分症状会消失。 No. Author and ref. Year Type Journal Patients Study on Results and significance 1 Casinu S.et al.(22) 1993 Randomised study J.Clin.Oncol 41 Octreotid VS loperamide Oct:Lop=90.5%:15%, p＜0.005 2 Gebbia V.et al.(23) 1993 Randomised study Anticancer Drugs 40 Octreotid VS loperamide Oct:Lop=80%:30%, p＜0.001 3 Barbounis V.et al.(25) 2001 Nonrandomised study Support Care Cancer 13 Oct response in Drug resistant CID Response in 12 patients 4 Zidan J.et al.(25) 2001 Nonrandomised study Annals of Oncology 32 Oct response in Drug resistant CID CR in 30 cases in 3 days 5 Petrelli N.J.et al.(26) 1993 Nonrandomised study Cancer 16 Oct response in Drug resistant CID CR in 15 cases in 3-4 days 6 Cascinu S.et al.(27) 1992 Nonrandomised study Eur.J.Cancer. 27 Oct response in Drug resistant CID CR in 26 cases in 3 days Abbreviations: Oct Octreotide Lop Loperamide CR Complete response CID Chemotherapy induced diarrhea Ref reference Fig.4.—Octreotide VS other drugs in CID 编号 作者和参考 年份 类型 期刊 患者 研究对象 结果和意义 1 Casinu S.et al.(22) 1993 Randomised study J.Clin.Oncol 41 奥曲肽 VS 洛哌丁胺 奥曲肽：洛哌丁胺=90.5%:15%, p＜0.005 2 Gebbia V.et al.(23) 1993 Randomised study Anticancer Drugs 40 奥曲肽 VS 洛哌丁胺 奥曲肽：洛哌丁胺=80%:30%, p＜0.001 3 Barbounis V.et al.(25) 2001 Nonrandomised study Support Care Cancer 13 抗药性CID患者的奥曲肽反应 12个患者有反应 4 Zidan J.et al.(25) 2001 Nonrandomised study Annals of Oncology 32 抗药性CID患者的奥曲肽反应 3天30个案例完全有效 5 Petre