Anti-angiogenic therapies for metastatic colorectal cancer

  • Review
  • Intervention


  • Anna Dorothea ADW Wagner,

    Corresponding author
    1. Centre Hospitalier Universitaire Vaudois, Fondation du Centre Pluridisciplinaire d'Oncologie, Lausanne, Switzerland
    • Anna Dorothea ADW Wagner, Fondation du Centre Pluridisciplinaire d'Oncologie, Centre Hospitalier Universitaire Vaudois, Rue du Bugnon 46, Lausanne, 1011, Switzerland.

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  • Dirk Arnold,

    1. Martin Luther University Halle Wittenberg, Department of Medicine IV, Halle/Saale, Sachsen Anhalt, Germany
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  • Axel AG Grothey,

    1. Mayo Clinic College of Medicine, Division of Medical Oncology, Rochester, USA
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  • Johannes Haerting,

    1. Martin Luther University Halle Wittenberg, Institute of Medical Epidemiology, Biostatistics and Informatics, Halle (Saale), Sachsen Anhalt, Germany
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  • Susanne Unverzagt

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


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.



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





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。






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




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










Cochrane Central Register of Controlled Trials、MEDLINEのほか、2008年11月までのECCO、ESMOおよびASCOの予稿集を検索した。さらに、試験の参考文献リストをスキャンし、この分野の専門家および製薬会社にも問い合わせて詳細な情報を得た。






現時点で、本メタアナリシスに適格な初回化学療法に関する試験はベバシズマブ(患者3,101例を含む5試験)およびバタラニブ(患者1168例を含む1試験)について入手できた。ベバシズマブを併用する、または併用しない初回化学療法の比較で、PFS(0.61、95%CI0.45~0.83)およびOS(0.81、95%CI 0.73~0.90)のHRから、ベバシズマブで治療された患者に有意な利益があることが確認された。しかし、PFSに対する効果には有意な異質性があった。セカンドライン化学療法については、ベバシズマブを併用した場合も併用しない場合もPFS(HR0.61、95%CI0.51~0.73)およびOS(HR 0.75、95%CI 0.63~0.89)のいずれにも利益があることが、ランダム化試験1件で実証された。治療に関連した死亡および60日間死亡率に有意差はなかったが、ベバシズマブで治療された患者でグレードIII/IVの高血圧、動脈血栓塞栓症および胃腸穿孔の発現率が高かった。バタラニブについては、現在入手可能なデータからPFSおよびOSに有意ではないが利益があることが示された。




監  訳: 柴田 実,2009.11.16

実施組織: 厚生労働省委託事業によりMindsが実施した。

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Plain language summary

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.