Intervention Review

Anti-angiogenic therapies for metastatic colorectal cancer

  1. Anna Dorothea ADW Wagner1,*,
  2. Dirk Arnold2,
  3. Axel AG Grothey3,
  4. Johannes Haerting4,
  5. Susanne Unverzagt5

Editorial Group: Cochrane Colorectal Cancer Group

Published Online: 8 JUL 2009

Assessed as up-to-date: 12 MAY 2009

DOI: 10.1002/14651858.CD005392.pub3


How to Cite

Wagner ADADW, Arnold D, Grothey AAG, Haerting J, Unverzagt S. Anti-angiogenic therapies for metastatic colorectal cancer. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD005392. DOI: 10.1002/14651858.CD005392.pub3.

Author Information

  1. 1

    Centre Hospitalier Universitaire Vaudois, Fondation du Centre Pluridisciplinaire d'Oncologie, Lausanne, Switzerland

  2. 2

    Martin Luther University Halle Wittenberg, Department of Medicine IV, Halle/Saale, Sachsen Anhalt, Germany

  3. 3

    Mayo Clinic College of Medicine, Division of Medical Oncology, Rochester, USA

  4. 4

    Martin Luther University Halle Wittenberg, Institute of Medical Epidemiology, Biostatistics and Informatics, Halle (Saale), Sachsen Anhalt, Germany

  5. 5

    Martin Luther University Halle-Wittenberg, Institute of Medical Epidemiology, Biostatistics and Informatics, Halle (Saale), Germany

*Anna Dorothea ADW Wagner, Fondation du Centre Pluridisciplinaire d'Oncologie, Centre Hospitalier Universitaire Vaudois, Rue du Bugnon 46, Lausanne, 1011, Switzerland. Anna-Dorothea.Wagner@gmx.de.

Publication History

  1. Publication Status: New
  2. Published Online: 8 JUL 2009

SEARCH

 

Abstract

  1. Top of page
  2. Abstract
  3. Plain language summary
  4. 摘要

Background

Angiogenesis inhibitors have been developed to block tumour angiogenesis and target vascular endothelial cells. While some of them have already been approved by the health authorities and are successfully integrated into patient care, many others are still under development, and the clinical value of this approach has to be established.

Objectives

To assess the efficacy and toxicity of targeted anti-angiogenic therapies, in addition to chemotherapy, in patients with metastatic colorectal cancer. Primary endpoints are both progression-free and overall survival. Response rates, toxicity and secondary resectability were secondary endpoints. Comparisons were first-line chemotherapy in combination with angiogenesis inhibitor, to the same chemotherapy without angiogenesis inhibitor; and second-line chemotherapy, to the same chemotherapy without angiogenesis inhibitor.

Search methods

We searched the Cochrane Central Register of Controlled Trials, MEDLINE, as well as proceedings from ECCO, ESMO and ASCO until November 2008. In addition, reference lists from trials were scanned, experts in the field and drug manufacturers were contacted to obtain further information.

Selection criteria

Randomized controlled trials on targeted anti-angiogenic drugs in metastatic colorectal cancer (MCRC).

Data collection and analysis

Data collection and analysis was performed, according to a previously published protocol. Because individual patient data was not provided, aggregate data had to be used for the analysis. Summary statistics for the primary endpoints were hazard ratios (HR's) and their 95% confidence intervals.

Main results

At present, eligible first line trials for this meta-analysis were available for bevacizumab (5 trials including 3101 patients) and vatalanib (1 trial which included 1168 patients). The overall HR´s for PFS (0.61, 95% CI 0.45 - 0.83) and OS (0.81, 95% 0.73 - 0.90) for the comparison of first-line chemotherapy, with or without bevacizumab, confirms significant benefits in favour of the patients treated with bevacizumab. However, the effect on PFS shows significant heterogeneity. For second-line chemotherapy, with or without bevacizumab, a benefit in both PFS (HR 0.61, 95% CI 0.51 - 0.73) and OS (HR 0.75, 95% CI 0.63-0.89) was demonstrated in a single, randomized trial. While differences in treatment-related deaths and 60-day mortality were not significant, higher incidences in grade III/IV hypertension, arterial thrombembolic events and gastrointestinal perforations were observed in the patients treated with bevacizumab. For valatanib, currently available data showed a non-significant benefit in PFS and OS.

Authors' conclusions

The addition of bevacizumab to chemotherapy of metastatic colorectal cancer prolongs both PFS and OS in first-and second-line therapy.

 

Plain language summary

  1. Top of page
  2. Abstract
  3. Plain language summary
  4. 摘要

The addition of bevacizumab to chemotherapy of metastatic colorectal cancer prolongs both progression-free survival as well as overall survival in first- and second line therapy.

Angiogenesis refers to the development of new blood vessels from the pre-existing vascular bed. Tumours are dependent on the formation of new blood vessels for their growth. Agents which inhibit the formation of new blood vessels are commonly referred to as "anti-angiogenic therapies". They are a new class of molecular designed drugs, among which one (bevacizumab) is already routinely used in clinical practice. Data from 5 randomized trials, which included a total of 3101 patients and evaluated the effect of bevacizumab, are currently available. Furthermore, data from one study, which included a total of 1168 patients and evaluated the effect of valatinib is published. The addition of bevacizumab to chemotherapy prolongs both progression-free survival from about 7.1 to 9.7 months when used as primary treatment and overall survival from about 17.7 to 20.5 months after prior use of chemotherapy (so called "second-line therapy") for metastatic colorectal cancer. However, the magnitude of the effect on progression-free survival is variable and probably depends on the type of chemotherapy to which it is associated. Vatalanib has no significant effect on progression-free and overall survival. Adverse effects of bevacizumab include increased frequencies of high blood pressure, arterial thromboembolic events and bowel perforations.

 

摘要

  1. Top of page
  2. Abstract
  3. Plain language summary
  4. 摘要

背景

使用抗血管新生治療方法(Antiangiogenic therapie)來治療移轉性大腸直腸癌

血管新生抑制劑已經被用來阻擋腫瘤細胞血管新生並且會附著在血管內皮細胞,當部分血管新生抑制劑已經受到健康當局的支持並且成功的參與了病患治療,也其他更多的血管新生抑制劑仍在開發中,目前也在陸續建置有關於這個方法的臨床數據

目標

本研究的主要目的在於評估除了化學治療外,使用標靶性的抗血管新生治療針對移轉性大腸直腸癌患者進行治療的毒性和有效性,主要試驗終止點為無病存活率和整體存活率,反應速度、毒性和第二次可切除性則是次要試驗終止點的評估依據,比試驗中係比較將第一線化學治療藥物與血管新生抑制劑併用,和使用相同化學治療藥物但沒有併用血管新生抑制劑、使用第二線化學治療藥劑或使用相同化學治療藥物但沒有併用血管新生抑制劑的治療效果

搜尋策略

我們檢索了Cochrane Central Register of Controlled Trials、MEDLINE、ECCO、ESMO、ASCO等資料庫,檢索一直持續到2008年11月,此外,也會針對試驗中的參考文獻清單進行檢索,並且連絡相關領域的專家、藥商以取得更多的資訊。

選擇標準

針對使用標靶性抗血管新生藥物治療移轉性大腸直腸癌(MCRC)的隨機性對照試驗都會被納入本研究中

資料收集與分析

研究中會根據先前公開的方法針對數據進行蒐集及分析,因為沒有取得個別患者的數據,所以必須使用整合性的數據進行分析,針對主要試驗終止點的統合分析是以風險比例(HR)和95%的信心區間表示。

主要結論

適合用來進行後設分析的第一線試驗是使用bevacizumab(5個包含有3101位患者的試驗)和使用vatalanib(1個包含有1168位受試者的試驗)進行試驗的結果。比較使用第一線化學治療藥物併用或不併用bevacizumab進行治療的整體HR值,對於PFS來說為0.61(95%的信心區間介於0.45至0.83之間)和對於OS來說為0.81(95%的信心區間介於0.73至0.90之間),表示併用bevacizumab對患者具有較明顯的好處,但是,在PFS的試驗結果上各試驗之間距有明顯的異質性,經由一單一的隨機性試驗結果可以證明,使用第二線化學治療藥物併用或不併用bevacizumab進行治療,對於PFS(HR值為.61,95%的信心區間介於0.51至0.73之間)和OS(HR值為.75,95%的信心區間介於0.63至0.89之間)都有所幫助,但是不同治療方法對於因為治療而死亡和60天死亡比例來說並沒有統計顯著的差異,當患者併用bevacizumab時,會具有較高的第III/IV型高血壓發生率、動脈阻塞事件和腸胃道穿孔(gastrointestinal perforations)的發生率,對於使用vatalanib來說,近期的可用數據顯示對於PFS和OS來說並沒有顯著的改善

作者結論

添加bevacizumab至移轉性大腸直腸直的化學治療藥物中可以在進行第一線治療和第二線治療上延長患者的PFS和OS數值

翻譯人

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌

總結

血管新生係只由已經存在的血管上形成心血管的現象,腫瘤細胞係平藉著形成新生血管來維持其生長,抑制心血管生成的藥劑通常會被當作「抗血管新生治療劑」,抗血管新生治療劑是一種新式的分子治療藥物,其中有一種(bevacizumab)已經被用在臨床實務上,由5個隨機性試驗、3101位受試者,評估bevacizumab藥劑效用的數據已經被使用於進行分析,此外,有一個包含有1168位患者、並且評估valatinib功效的試驗已經被發表,將bevacizumab藥物添加至化學治療藥物中作為主要治療方法可以使患者的無惡化存活率由7.2個月延長至9.7個月,即使患者先前已經進行過移轉性大腸直腸癌化學治療(所以被稱為第二線治療),患者的整體存活率也可以由17.7個月延長至20.5個月,但是,不同試驗中所得到對於無惡化存活率的影響各有所不同,並且可能與所使用的化學藥劑種類有關,Vatalanib對於患者的無惡化存活率及整體存活率並沒有明顯的影響,使用bevacizumab會出現的不良事件包括有增加高血壓發生頻率、發生動脈拴塞事件以及大腸穿孔等現象