雷替曲塞一线治疗大肠癌综述

1、翻译第1页Review article 1审查第1条A systematic review of raltitrexed-based first-linechemotherapy in advanced colorectal cancerSandro Barnia, Antonio Ghidinib, Andrea Coinua, Karen Borgonovoa andFausto Petrellia雷替曲塞为基础的一线的系统评价 化疗在晚期大肠癌 桑德罗Barnia，安东尼奥Ghidinib，安德烈Coinua，卡伦Borgonovoa和 福斯托PetrelliaRaltitrexed i

2、s a thymidylate synthase inhibitor belonging tothe antimetabolite class of cytotoxic drugs. It is alsoeffective in colorectal cancer (CRC) both as a single agentand in combination with other drugs, in particular in thosepatients with cardiologic risk factors or previouscardiotoxicity. The efficacy o

3、f first-line raltitrexed-basedchemotherapy containing oxaliplatin (TOMOX) andirinotecan (TOMIRI) was investigated in this systematicreview. Studies that enrolled advanced CRC patients forfirst-line therapy with TOMOX/TOMIRI combinations wereidentified using electronic databases (Pubmed, SCOPUS,Web o

4、f Science, EMBASE, and the Cochrane Library). Asystematic analysis was carried out using ComprehensiveMeta Analysis (version 2.2.064) software to calculate thepooled response rate and 95% confidence limits. Themedian pooled overall survival and progression-freesurvival were also calculated. Results

5、for TOMOX andTOMIRI studies were compared using the two-sidedStudents t-test. We tested for significant heterogeneityusing Cochrans 2-test and I2 index. Twelve studiespublished between 2001 and 2012 were eligible for thisanalysis and a total of 735 patients were enrolled in thesestudies. The overall

6、 response rate was 40% (95%confidence interval 3446%): 43.9% for TOMOX and 34.1%for TOMIRI arms. The weighted median overall survival and雷替曲塞是属于胸苷酸合成酶抑制剂抗代谢物类的细胞毒性药物。它也有效的结直肠癌（CRC）既作为一个单一的代理并与其他药物，尤其是在那些组合患者的心源性危险因素或以前心脏毒性。一线的雷替曲塞为基础的疗效含奥沙利铂化（TOMOX）和伊立替康（TOMIRI）在本系统进行了研究审查。该研究入选晚期CRC患者一线治疗TOMOX/ TOM

7、IRI组合为使用电子数据库（考研，SCOPUS确定， 科学，医学文摘，和Cochrane图书馆的网络）。一 系统的分析进行了使用综合 Meta分析（2.2.064版）软件计算汇集响应速度和95置信区间。该 汇集中位数总生存期和无进展生存也被计算出来。结果TOMOX和使用双面TOMIRI研究进行比较 学生氏t检验。我们测试了显著异质性使用科克伦的2检验和I2指数。 12个研究2001年至2012年间出版的有资格获得此分析，共有735例患者参加了这些 研究。整体回应率为40（95可信区间34-46）：43.9TOMOX和34.1为TOMIRI武器。加权中位总生存期和IntroductionChem

8、otherapy is the primary treatment of advancedcolorectal cancer (CRC) and 5-fluorouracil (5-FU) is thecornerstone agent of any combination in first-line che-motherapy. 5-FU plus oxaliplatin or irinotecan-basedchemotherapy (alone or with monoclonal antibodies) isthe preferred treatment in healthy pati

9、ents with meta-static disease, amenable or not to surgery. However,5-FU, used mainly as a bolus administration, is poten-tially associated with severe gastrointestinal toxicity (e.g.diarrhea and mucositis), and, especially if infused con-tinuously, with cardiovascular events in the form ofangina-lik

10、e symptoms (because of coronary vasospasm),cardiac rhythm abnormalities, and ischemia. In particular,patients with dihydropyrimidine dehydrogenase deficitdevelop adverse toxic events because of impaired 5-FUmetabolism. Finally, 5-FU requires a central line forcontinuous infusion regimens.介绍 化疗是晚期的主要

11、治疗方法结肠直肠癌（CRC）和5 - 氟尿嘧啶（5-FU）是在一线化疗任意组合的基石剂。 5-FU+奥沙利铂和伊立替康化疗（单独或与单克隆抗体）是 在健康治疗转移性疾病，服从或不手术的首选治疗方法。但是，5-FU，主要用作推注给药，则可能有严重的胃肠道毒性（如相关腹泻和粘膜炎），和，特别是，如果连续输注，以下列形式的心血管事件心绞痛样症状（因为冠状动脉痉挛），心脏节律异常，缺血。特别是，患者二氢嘧啶脱氢酶赤字发展，因为受损的5-FU的毒性不良事件 新陈代谢。最后，5-FU需要的中心线为持续输注治疗方案。progression-free survival times were 14.6 and

12、6.7 months,respectively. Neutropenia and liver toxicity were morefrequent with TOMOX, whereas neutropenia and diarrheawere more frequent with TOMIRI. However, compared withhistorical FOLFOX and FOLFIRI trials, raltitrexed-baseddoublets are associated with less neutropenia andgastrointestinal toxicit

13、y and uncommon cardiotoxicity.TOMOX and TOMIRI doublets are active as first-linechemotherapy for advanced CRC and seem useful inparticular when the use of 5-fluorouracil is contraindicatedfor cardiac comorbidity. Anti-Cancer Drugs 00:000000 2014 Wolters Kluwer Health | Lippincott Williams &Wilkins.无

14、进展生存期分别为14.6和6.7个月。中性粒细胞减少和肝毒性更经常与TOMOX，而中性粒细胞减少和腹泻 更频繁的与TOMIRI。然而，与比较历史FOLFOX和FOLFIRI方案试验中，雷替曲塞为基础的双峰是用更少的中性粒细胞减少有关，胃肠道毒性和心脏毒性少见。 TOMOX和TOMIRI双峰是积极作为一线化疗对晚期CRC，似乎有用特别是当使用5 - 氟尿嘧啶是禁忌心脏合并症。抗癌药物00:000-000 2014威科健康| Lippincott威廉斯威尔金斯。Anti-Cancer Drugs 2014, 00:000000Keywords: colorectal cancer, combina

15、tion chemotherapy, first line,metastatic, overall survival, raltitrexed, toxicity Medical Oncology Unit, Oncology Department, Treviglio Hospital, Treviglio (BG)and bMedical Oncology, Casa di Cura Igea, Milan, ItalyCorrespondence to Fausto Petrelli, MD, Medical Oncology Unit, OncologyDepartment, Trev

16、iglio Hospital, Piazzale Ospedale 1, 24047 Treviglio(BG), ItalyTel: + 39 0363424420; fax: + 39 0363424380; e-mail: faupelibero.itReceived 11 March 2014 Revised form accepted 23 April 2014抗癌药物2014年，00:000-000 关键词：结直肠癌，联合化疗，第一行， 转移性，总生存期，雷替曲塞，毒性 肿瘤医学部，肿瘤科，特雷维格里奥医院，特雷维格里奥（BG）和bMedical肿瘤，卡萨帝库拉伊格，米兰，意大利对

17、应福斯托彼得雷利，医学博士，肿瘤内科部肿瘤科系，特雷维格里奥医院，广场Ospedale1，24047特雷维格里奥（BG），意大利 电话：+390363424420;传真：+390363424380;电子邮件：faupelibero.it 收到2014年3月11日修订的形式接受2014年4月23日Raltitrexed is chemically similar to folic acid and belongsto the antimetabolites class of cytotoxic drugs (http:/www.hospira.ca/english/raltitrexed.asp

18、x) 1. It inhibits selectivelythe thymidylate synthase enzyme (TS), leading to DNAinhibition. Raltitrexed also has a convenient 3-weeklyschedule of administration because of its long-lastinginhibition of TS. In contrast to 5-FU, folate analogues areneither subjected to rapid catabolism nor require me

19、ta-bolic activation or a modulating agent, such as folinicacid. In addition, they are not incorporated into nucleicacids and their inhibition of TS cannot be overcome bythe accumulation of dUMP that is converted from 5-FU.About two decades ago, raltitrexed was launched into theclinical setting and w

20、as directly compared with 5-FU in arandomized-controlled trial. The first phase III study toreport clinical results randomized 439 patients withuntreated CRC to raltitrexed at the dose of 3 mg/m2every 21 days or 5-FU + folinic acid (Mayo Clinic regi-men) 2. The response rate (RR) was similar for the

21、 twoarms. There were no statistically significant differences in雷替曲塞是化学上类似于叶酸和属于 在抗代谢类细胞毒药物上（http:/www。 hospira.ca/英语/ raltitrexed.aspx）1。它选择性地抑制 胸苷酸合成酶（TS），导致DNA 抑制。雷替曲塞也有一个方便的3周 管理由于其持久的时间表 抑制TS的。在对比5-FU，叶酸类似物是 既不进行快速分解，也不需要代谢活化或调节剂，如亚叶酸。此外，它们不结合到核酸 酸和它们抑制TS的不能被克服 转储的积累是从5-FU的转化。 大约二十年前，雷替曲塞被射入 临床

22、上，并直接与5-FU在一个较 随机对照试验。第III期研究，以 报告临床效果随机439例 未经处理的CRC雷替曲塞在3 mg/m2剂量 每21天或5-FU+亚叶酸（梅奥诊所的方案）2。有效率（RR）为相近的两个 怀抱。有在统计学上无显著差异。0959-4973 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/CAD.0000000000000133 Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this a

23、rticle is prohibited科健康| Lippincott威廉斯威尔金斯 版权所有Lippincott威廉斯威尔金斯。未经授权，不得复制本文章。翻译第2页2 Anti-Cancer Drugs 2014, Vol 00 No 002抗癌药物2014年，00卷00号the overall survival (OS) between the two groups.However, the time to progression (TTP) was in favor of5-FU. Patients who received raltitrexed spen

24、t less time inthe hospital for drug administration and had significantlylower rates of grade 3 and 4 toxicities such as leukopenia,diarrhea, and mucositis. Subsequently, raltitrexed wasassociated with oxaliplatin (TOMOX) and irinotecan(TOMIRI) 3,4, and these combinations were associatedwith similar

25、efficacy and good safety compared withconventional 5-FU-based regimens. In 2012, TOMOXwas compared with the standard FOLFOX with betterRR for TOMOX schedule (45 vs. 36%). The OS andprogression-free survival (PFS) were similar 5.Raltitrexed was also associated with a potentially lowerrisk of cardioto

26、xicity in patients with cardiac disease or inthose who experienced a cardiac event with 5-FU 6.两组之间的总生存率（OS）。 然而，到进展时间（TTP），当时是赞成 5-FU。谁收到雷替曲塞花更少的时间在患者 医院药品管理和显著有 3级和4级毒性反应，如白细胞减少率较低， 腹泻，黏膜炎。随后，雷替曲塞是 奥沙利铂（TOMOX）和伊立替康相关 （TOMIRI）3,4，并且这些组合被相关 与同类相比，疗效和良好的安全性 传统的5-FU为基础的方案。 2012年，TOMOX 用标准FOLFOX方案具有更好的

27、比较 RR为TOMOX时间表（45与36）。操作系统和 无进展生存期（PFS）相似5。 雷替曲塞也有可能降低相关 心脏毒性患者的心脏疾病或中的风险 那些谁经历了心脏事件与5-FU6。There are several relevant reasons for considering ralti-trexed as an effective and easier alternative to 5-FU inpatients with advanced CRC, in particular, in terms ofcardiac effects and activity. We performed

28、 a systematicliterature review of studies including raltitrexed-baseddoublets or triplets as a first-line treatment for metastaticCRC to describe the activity and outcomes associatedwith these regimens.有几个相关的理由足以认为雷替曲塞为有效，更容易替代5-FU晚期患者的CRC，特别是在以下方面强心作用和活动。我们进行了系统的的研究，包括雷替曲塞为基础的文献综述双峰或三胞胎作为一线治疗转移性CRC

29、校验来形容活动和结果相关这些方案。Materials and methodsLiterature searchPubMed, EMBASE, Web of Science, SCOPUS, and theCochrane Library were systematically searched inDecember 2013, to identify relevant publications.Keywords included in the search were colon neoplasmMesh and raltitrexed Mesh and recurrent orrelapsed

30、 or advanced or metastatic. The literature searchwas limited to human studies published in English. Wealso reviewed conference abstracts to identify unpub-lished papers. All potentially relevant studies wereretrieved, and their references were checked to deter-mine whether there were any more eligib

31、le studies.材料和方法 文献检索 考研，文摘，科学，SCOPUS，Web和的 Cochrane图书馆是在系统检索 2013年12月，以确定有关的出版物。 包括在搜索关键字为“结肠肿瘤 网眼和雷替曲塞网“和”经常性或 复发或晚期或转移性。文献检索 仅限于以英文出版的人体研究。我们 还审查会议摘要，以确定结果未 已发表的论文。所有可能相关的研究是 检索，以及它们的引用进行了检查以确定 矿井是否有任何更多的符合条件的研究。Study selectionTo summarize the efficacy of raltitrexed-based che-motherapy, only stu

32、dies that fulfilled all of the followingcriteria were considered eligible for inclusion in thepresent review: (a) patients with advanced CRC (meta-static disease); (b) those who were treated with TOMOXor TOMIRI combinations as first-line chemotherapy formetastatic disease; (c) at least one of the fo

33、llowing datawere available: overall RR (the number of completeresponse and partial response, PFS or TTP, and OS); (d)single-arm retrospective series or prospective clinicaltrials, which means that the raltitrexed-containing arms ofrandomized-controlled trials were also eligible; and (e) atleast 20 p

34、atients were enrolled in the study. Studies wereexcluded if they included fewer than 20 patients, if thepatients included were treated after first-line选择研究 总结的雷替曲塞为主的化疗方案的疗效，即满足下列所有条件的只有研究标准被认为有资格列入 本次审查：（一）治疗晚期CRC（元静态疾病）; （二）那些谁是与TOMOX治疗或TOMIRI组合作为一线化疗 转移性疾病; （c）至少以下数据之一是可利用的：总RR（完整数反应和局部反应，PFS或TTP

35、和OS）; （四） 单臂回顾系列或前瞻性临床试验中，这意味着的含雷替曲塞武器随机对照试验也符合申请资格;及（e）在 至少有20名患者参加了这项研究。研究是排除在外，如果他们包括少于20名患者，如果患者包括后处理的第一线.chemotherapy, and if they did not report outcome datafor raltitrexed-containing combinations.化疗，如果他们没有报告的结果数据 含雷替曲塞组合。When the same population was studied in more than onepublication, only t

36、he one with most relevant data wasincluded in this review. Two investigators (A.G. and F.P.) independently reviewed the potentially eligiblestudies and then crosschecked their results.Disagreements between the investigators were resolvedby consensus after discussion with a third specialist (S.B.)for

37、 a final decision.当相同的人口研究了在一个以上的 出版，只有一个与最相关的数据是 列入本次审查。两位调查员（A.G.和F。 P.）独立审查可能成为合格“研究，然后交叉检查及其结果。 研究者之间的分歧得到解决 通过与第三方专家（SB）的讨论后达成共识 作最后决定。Data extractionThe following data were extracted from the includedstudies independently by two investigators: first authorsname, year of publication, study desi

38、gn, number ofpatients treated by raltitrexed combinations, age (med-ian) of the patients, regimen type and dose, rate of pre-vious 5-FU adjuvant chemotherapy and time elapsedfrom adjuvant chemotherapy, rate of objective responses,median PFS or TTP, median OS, and main grade (G) 34hematological and n

39、onhematological toxicities.数据提取 以下数据来自包括提取 研究由两个独立的调查：第一作者 名，出版，研究设计，数年 用雷替曲塞组合患者，治疗方案的类型和剂量，年龄（中位数）治疗的患者，以前的5-FU辅助化疗和时间流逝速度从辅助化疗，客观反应率，中位PFS或TTP，中位OS，和主级（G）3-4血液学和非血液学毒性。When available, data on the first-line chemotherapyalone were abstracted if more pretreated patients wereincluded. The median PFS

40、, TTP, and OS were sum-marized descriptively because of insufficient data for aformal meta-analysis.当可用时，在一线化疗数据单独进行抽象，如果更多的预处理患者包括在内。中位PFS，TTP和OS进行描述性概括，因为资料不足的一个正式的荟萃分析。Statistical analysisThe objective RRs were meta-analyzed usingComprehensive Metanalysis software v.2.2.64 (releasedon 27 July 201

41、1; Biostat, Englewood, NJ, USA) with arandom-effects or a fixed-effects model. The statisticalheterogeneity among studies was assessed usingCochrans Q-test and the I2 statistic. A P value of lessthan 0.10 for the Q-test or an I2 value of greater than 50%was suggestive of considerable interstudy hete

42、rogeneityand so a random-effect model was chosen. Analysis wascarried out according to the intention-to-treat analysisreported in each paper. The PFS/TTP and OS weresummarized descriptively because of the lack of com-parison arms for meta-analysis. The weighted medianPFS and OS were calculated. Subg

43、roup analysis wascarried out according to the type of doublet (TOMOX vs.TOMIRI) and the time elapsed by the end of adjuvanttherapy. Differences in TOMIRI and TOMOX armsresults were calculated using the t-test.统计分析 客观的RR分别使用meta-分析 综合Metanalysis软件v.2.2.64（发布 于2011年7月27日;抗生素的，恩格尔伍德，NJ，USA）与随机效应或固定效应模型

44、。统计 用研究的异质性进行了评估科克伦的Q-检验和I2统计。少P值大于0.10为Q-检验或大于50的I 2值 是暗示相当interstudy学科研讨国际结合会异质性 所以随机效应模型被选中。分析是 根据意向性治疗分析进行 报道中的每个文件。该PFS/ TTP和OS分别为 描述性的总结，因为缺乏比较臂荟萃分析。加权平均 PFS和OS进行了计算。亚组分析是 根据双峰的类型进行（TOMOX对比 TOMIRI）和佐剂的结束所经过的时间 治疗。在TOMIRI和TOMOX武器的差异 结果用t-检验计算。ResultsOf the 1290 studies surveyed, 16 studies publ

45、ishedbetween 2000 and 2012 were identified as potentiallyeligible for this analysis. On the basis of the predefinedeligibility criteria, we selected 12 studies 35,715 thatfulfilled the qualitative and quantitative requirements ofthe systematic analysis. A total of 735 patients wereenrolled across th

46、e selected trials (range, 3794). Twowere randomized phase II trials and 10 were prospective结果 接受调查的1290项研究中，16项研究发表2000年至2012年被认定为潜在获此分析。在预定义的基础 资格标准，我们选择了12个研究3-5,7-15认为满足的定性和定量要求该系统的分析。共有735例患者参加在选定的试验（范围37-94）。二被随机II期试验和10项前瞻性.Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of

47、this article is prohibited.版权所有Lippincott威廉斯威尔金斯。未经授权，不得复制本文章。翻译第3页Raltitrexed-based first-line chemotherapy Barni et al. 3雷替曲塞为基础的一线化疗旅游Barni等。 3Fig. 1 图1Scheithauer et al. 14Scheithauer等。 14 Seitz et al. 15塞茨等人。 15 Santini et al. 13Neri et al. 12, nonrespondersNeri et al. 12, respondersMartoni et

48、al. 11Gravalos et al. 5Feliu et al. 9 TOMIRIFeliu et al. 9 TOMOXFeliu et al. 10Chiara et al. 8Cascinu et al. 3Carnaghi et al. 4桑蒂尼等。 13 内里等人。 12，无反应 内里等人。 12，反应 Martoni等。 11 Gravalos等。 5 费利等人等。 9 TOMIRI 费利等人等。 9 TOMOX 费利等人等。 10 Chiara酒店等。 8 Cascinu等。 3 CARNAGHI等。 4Median PFS (gray) and median OS (bl

49、ack) of included trials. OS, overall survival; PFS, progression-free survival.中位PFS（灰色）和中位OS（黑色）纳入试验。OS，PFS总生存率，无进展生存期。single-arm trials. Eight TOMOX and five TOMIRI armswere analyzed. Response data were available across allstudies. Pooled OS and PFS data from eight and 11 dif-ferent studies were al

50、so obtained (Fig. 1). Details ofpatient demographics and study designs are included inTable 1.单臂试验。八TOMOX五TOMIRI武器 进行了分析。响应数据是可用在所有 研究。从8和11个不同的研究中汇集的OS和PFS数据中也获得（图1）。详情 病人的人口统计资料和研究设计都包含在 表1中。Overall RR and pooled median PFS and OSThe overall RR for all arms was 40% (95% confidenceinterval, 3446%)

51、according to the random-effect model(Fig. 2). The RR was 43.9% for TOMOX arms and 34.1%for TOMIRI arms. This difference was not statisticallydifferent according to the t-test (P = 0.1937).总体RR和汇集中位PFS和OS 所有武器的总体RR为40（95可信 间隔34-46）根据随机效应模型 （图2）。 RR分别为43.9TOMOX武器和34.1 为TOMIRI武器。这种差异无统计学 不同，根据t-检验（P =0

52、.1937）。The weighted median OS time was 14.6 months (range,815 months). The weighted median PFS was6.7 months (range, 511.1 months). The results of thePFS/OS were 6.5/14.8 months for TOMOX and 6.7/14.2for TOMIRI arms.加权中位OS为14.6个月（范围，8-15个月）。加权中位PFS为6.7个月（范围5-11.1个月）。的结果PFS/ OS分别为6.5/14.8个月TOMOX和6.7/

53、14.2为TOMIRI武器。Only four studies reported time elapsed from the end ofadjuvant chemotherapy. The RR was similar according todisease-free interval (12 vs. 12与12个月）：48对比51。中位PFS和OS也类似总体结果两组。Toxicity of G34 severityOverall, the most frequent G34 hematological toxicitywas neutropenia (mean 12%; range 030

54、%). Grade 34anemia and thrombocytopenia were less common (mean3% for both toxicities). Among nonhematological G34toxicities, the incidence of nausea/vomiting was 9%; thatG3-4毒性严重程度总的来说,最常见的G3-4血液毒性是中性粒细胞减少(平均12%,范围0 - 12%)。3 - 4年级贫血和血小板减少症并不常见(的意思3%为毒性)。在非血液学G3-4毒性,恶心/呕吐的发生率是9%,of diarrhea, was 13.7

55、%; stomatitis 2%; asthenia 7%; andliver function toxicity 16%. In the Feliu phase II rando-mized study that compared TOMOX and TOMIRI, alltoxicities were similar in frequency, except for a higherincidence of diarrhea (mainly G12) in the TOMIRI arm.腹泻的13.7%;性口炎2%;衰弱7%;肝功能毒性16%。在Feliu TOMOX和TOMIRI相比二期

56、随机研究,毒性在频率相似,除了高腹泻的发病率(主要是G1-2)TOMIRI手臂。The main nonhematological and hematological toxicitiesin TOMIRI doublets were diarrhea (mean G34, 22.8%)and neutropenia (mean G34, 11%), whereas elevation ofliver enzymes (mean G34, 20%) and neutropenia (meanG34 11%) were more frequently encountered inTOMOX schedules.主