奥曲肽治疗化疗相关性腹泻最终版

Octreotide 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 assessing 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 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.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: 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.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 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 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 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).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 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).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（(Dukes 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 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 patients 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).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、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 Criteria for assessing the severity of chemotherapy-induced diarrhoeaGrades of CID Frequency of Diarrhoea Stoma output Need for intravenous fluidresuscitationInterfering with dailyActivities1 4 times/day Mild None None2 4-6 times/day Moderate 24 hrs None3 7 times/day severe 24 hrs Yes4 Diarrhoea resulting into life threatening consequences like haemodynamic collapse or shock.5 Death 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1 4 次/天 轻 无 无2 4-6 次/天 中度 24 小时 无3 7 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 in adjuvant settingChemotherapy-induced diarrhea in colorectal cancer in adjuvant settingNo Chemotherapy/Regimens Incidence of CID NCI grade3Reference/Trial/Citation1 FOLFOX 4 11% MOSAIC trial, AndreT., et al. N.Engl.J.Med.,20042 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%5 Mayo Clinic Regimen(FU/LV) 16%6 Roswell Park Regimen(FU/LV) 29%Schmoll et al.Journal of Clinical of Oncology,2007.January;25(1)Reference-(10)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泻编号 化疗/方案 CID 发生率 参考文献 /试验/引文NCI 等级31 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.,20042 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 卡培他滨+奥沙利铂(XELOXA) 19%5 Mayo Clinic Regimen(FU/LV) 16%6 Roswell Park Regimen(FU/LV) 29%Schmoll et al.Journal of Clinical of Oncology,2007.January;25(1)Reference-(10)Fig.3. Chemotherapy-induced diarrhea in advanced/metastatic colorectal cancerChemotherapy-induced diarrhea in advanced/metastatic colorectal cancerNo. Chemotherapy/Regimens Incidence of CIDNIC grade3Reference/Trial/Citation1 Capecitabine/Oxaliplatin 16%2 5-FU+Oxaliplatin 12.5%Cao Y.,et al. Journal of Colouectal Disease, 2009 Reference-(11)3 OxMdG Fegimen 6%4 OxMdG+Cetuximab 13%5 XELOX 15%6 XELOX+ Cetuximab 25%Adams R.A.,et al.British Journal of Cancer (2009) 100,251-8Reference-(12)7 FOLFIRI 14%8 FOLFOX 6 11%Tournigand C., et al. GERCOR study. Journal of Clinical Oncology, Jan 2004,24(2)Reference-(6)9 FOLFOX 4+Bevacizumab 7.8% 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%2 5-氟尿嘧啶+奥沙利铂 12.5%Cao Y.,et al. Journal of Colouectal Disease, 2009 Reference-(11)3 OxMdG Fegimen 6%4 OxMdG+西妥昔单抗 13%5 XELOX 15%6 XELOX+西妥昔单抗 25%Adams R.A.,et al.British Journal of Cancer (2009) 100,251-8Reference-(12)7 氟尿嘧啶、亚叶酸和伊立替康联合用药14%8 奥沙利铂、氟尿嘧啶和甲酰四氢叶酸钙方案（FOLFOX 6）11%Tournigand C., et al. GERCOR study. Journal of Clinical Oncology, Jan 2004,24(2)Reference-(6)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 assessing 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 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. 我们检索了从 1984 到 2009 年 25 年间 PubMed，MEDLINE 和循证医学图书馆中的有关文献。检索用词有“octreotide CID”以及“colorectal cancer CID and octreotide”、 “chemotherapy induced diarrhea in colorectal cancer and octreotide（结直肠癌患者化疗相关性腹泻和奥曲肽）”。入选文献均用英文撰写而且样本人群中至少大部分是结直肠癌患者。综述包括了两组随机对照临床试验、四组非随机对照研究和两篇系列病例报道。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.排除了仅使用化疗治疗癌症的非结直肠癌患者、使用奥曲肽治疗的单个病例报告以及其他控制 CID 的用药方案。本文也从药物经济学的角度审视了单独使用奥曲肽治疗 CID 时的推荐安全剂量和副作用。Results 结果1) Octreotide VS other medications in CID 奥曲肽和其他药物治疗 CID 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)(P0.005).在 41 个患者的队列研究（68.3% 的结直肠癌患者）(P 0.005)的随机临床试验（22 ）中，证明了奥曲肽相对比洛哌丁胺在控制严重 CID（NIC 级别 2 级和以上）的效果。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). Gebbia 等进行了类似的随机试验（23） ，证明患者使用奥曲肽比使用洛哌丁胺效果更好（见表 4） 。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. 在一个前瞻性研究中（26） ，报道了奥曲肽在治疗一个对阿片样物质有抗药性的 CID患者队列的有效性为 94%，且没有严重的副作用。Cascinu et al.(27)在一个 27 名患者(其中 21 名患者有晚期直肠癌，其余的是晚期胰腺癌)的队列中报道了更高的有效率（在开始治疗 72 小时完全有效率达到了 96.3%） 。当我们将所有的随机研究的结果综合起来，发现在一个 88 名严重 CID（NCI 级别为三家或者以上）患者（79 名为结直肠癌患者）的队列中，61 名患者（69.32%）为阿片样物质或者洛哌丁胺抵抗性 CID 患者使用奥曲肽，在至少 4 天之内有 54 名患者（88.52%）有效控制腹泻。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.在一个前瞻性非随机研究中（24） ，3-4 级、对洛哌丁胺有抗药性的结直肠癌患者，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。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.Zidan 等(25)以对洛哌丁胺有严重抗药性的 CID 患者群（大多数为结直肠癌患者）为研究对象，进行了一个类似的前瞻性多中心试验，将奥曲肽作为一种特效药，发现94%的患者腹泻痊愈且没有任何严重副作用。该研究没有给出痊愈患者中直结肠癌患者的确切百分比。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.一项前瞻性研究报道了奥曲肽对具有阿片样物质抗药性的 CID 患者群的作用（26 ）证实了其治愈率为 94%，且没有严重副作用。Cascinu 等(27)对 27 名患者（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）用奥曲肽治疗，获得了更高的治愈率（在 72 小时的治疗时间内 96.3%完全有效） 。综合所有这些非随机研究的结果，在 88 名患有严重 CID（ NCI 评级为 3 以上）的患者（其中结直肠癌患者为 79 例）中，61 名具有鸦片样物质或洛哌丁胺抗药性的 CID 患者（ 69.32%）使用奥曲肽治疗，54 名患者（88.52%）在 4 天内腹泻得到有效控制。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 patients quality of life and tolerance towards chemotherapy. No serious adverse effects were reported in either of them.Rosenoff (28,29)发表的两个病例系列报道了使用长效奥曲肽治愈对洛哌丁胺和/或地芬诺脂阿托品有抗药性的严重的 CID（NCI 级别 3 以上）患者。这两篇论文都表明，奥曲肽治疗改善了患者的生活质量，提高了对化疗的耐受能力，均未报道严重的不良反应。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). 由于没有固定剂量的相关指导，奥曲肽治疗 CID 完全凭经验。加拿大 CID 工作小组对抗洛哌丁胺或鸦片的 CID2 级患者（NCI 分级）和 3 或 4 级 CID 患者的推荐剂量是皮下注射奥曲肽 100-150 微克，一天三次。对顽固性腹泻患者，剂量可以增加到 500 微克，一天三次（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).该小组还推荐使用长效奥曲肽 30mg（肌肉注射，每 28 天一次）对任何接受化疗的在以前的疗程中有 CID 病史的结直肠癌患者进行预防性的治疗（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 (p0.001). 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. Rosenoff 及其同事在一项多中心随机标签公开的研究中已对长效奥曲肽（长效 40mg 对比 30mg）的剂量效果进行了评价（31） ，发现奥曲肽组治疗腹泻所需的平均时间周期更短。两项结果都具有显著的统计学意义(p0.001) 。在该项试验中，尽管相对于30mg 组，40mg 组患有严重腹泻（34 级）症状和得到额外健康护理支持的患者均少，这些差别没有显著的统计学意义。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 (p0.05) (30). In a phase 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).但是这个试验提出了奥曲肽对于 CID 二级预防的可能性。正如 Goumas 等指出，奥曲肽对 CID 患者具有正性的剂量响应效果。在一项随机研究中，每天三次 100ug 或 500ug奥曲肽（皮下注射）治疗严重的、对洛哌丁胺抗药患者的 CID。结果显示，500mg 剂量组患者的治愈率为 90.32%，100mg 患者组的治愈率为 60.71%(p0.05) (30)。在 35 名患者参加的 I 期临床试验中证明奥曲肽治疗氟嘧啶诱导的腹泻的安全剂量，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).大量的文献检索结果显示，奥曲肽是安全和耐受良好的药物，在有效浓度