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Meta-Analysis
. 2011 Sep 7:(9):CD007930.
doi: 10.1002/14651858.CD007930.pub2.

Angiogenesis inhibitors for the treatment of ovarian cancer

Kezia Gaitskell  1 , Igor Martinek, Andrew Bryant, Sean Kehoe, Shibani Nicum, Jo Morrison
Affiliations
Meta-Analysis

Angiogenesis inhibitors for the treatment of ovarian cancer

Kezia Gaitskell et al. Cochrane Database Syst Rev. .

Update in

Abstract

Background: Many women with ovarian cancer eventually develop resistance to conventional chemotherapy drugs, and so novel agents are being developed to target specific molecular pathways. One such class of drugs inhibits angiogenesis (the development of new blood vessels), which is essential for tumour growth. It is important to establish whether the addition of these new drugs to conventional chemotherapy regimens improves survival, and what the side-effects may be.

Objectives: To compare the effectiveness and toxicities of angiogenesis inhibitors in the treatment of ovarian cancer.

Search strategy: We sought to identify completed randomised controlled trials (RCTs) by searching The Cochrane Gynaecological Cancer Review Group's Trial Register, The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 10), MEDLINE and EMBASE (1990 to October 2010). We also searched registers of clinical trials, and contacted investigators of completed and ongoing trials for further information.

Selection criteria: Randomised controlled studies comparing angiogenesis inhibitors with either standard chemotherapy or no treatment, in women with ovarian cancer.

Data collection and analysis: Two independent authors carried out data collection and extraction. We used a random-effects model for pooling data.

Main results: We did not find any fully-published, completed RCTs of angiogenesis inhibitors that met our inclusion criteria. We identified five abstracts of completed RCTs of four different angiogenesis-inhibiting agents, with a total of 3701 participants.Meta-analysis of two trials found no statistically significant difference in overall survival (OS) between women with newly-diagnosed advanced ovarian cancer who received concurrent and maintenance bevacizumab compared to those who received chemotherapy (carboplatin and paclitaxel) alone. However, women who received concurrent and maintenance bevacizumab had their risk of disease progression reduced by a quarter (hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.68 to 0.83; P < 0.001); they also had a significantly increased risk of severe gastrointestinal adverse events, moderate or severe hypertension and severe bleeding.One trial also compared chemotherapy to concurrent (but not maintenance bevacizumab), and found no statistically significant difference in OS or progression-free survival (PFS). However, the women who received bevacizumab had a significantly higher risk of moderate or severe hypertension.A three-armed RCT, of paclitaxel alone or with low- or high-dose AMG 386, in women with recurrent ovarian cancer, found no statistically significant difference in OS. However, women who received low-dose AMG 386 had a third less risk of disease progression than those who received placebo (HR 0.57, 95% CI 0.36 to 0.91; P = 0.02). The trial found no evidence of increased adverse events in the intervention arms.Two relatively small RCTs (one of VEGF-Trap, the other of BIBF 1120) found no evidence of either significant survival benefit or increased severe adverse events, compared to placebo, but they both lacked statistical power. All five trials had unclear risk of bias, largely because they have only been published in abstract form, and thus many methodological details are unclear. We identified twelve suitable ongoing trials.

Authors' conclusions: There is, as yet, no fully-published RCT evidence for the efficacy or safety of angiogenesis inhibitors for the treatment of ovarian cancer, but some preliminary results are available from five trials. There is some evidence from a meta-analysis of two trials that the addition of concurrent and maintenance bevacizumab to standard chemotherapy may reduce the risk of disease progression, in women with newly-diagnosed advanced ovarian cancer. There is also some evidence from a single trial that low-dose AMG 386 may reduce the risk of disease progression in women with recurrent ovarian cancer. However, there is currently no evidence that angiogenesis inhibitors improve OS, nor is there enough evidence to justify the routine use of angiogenesis inhibitors in treating women with ovarian cancer. We eagerly await both the more detailed results of these five completed trials, and the preliminary results of the several ongoing trials.

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Figures

Figure 1
Figure 1
(A) The VEGF-R is a transmembrane protein, found on cells, which line blood vessels (endothelial cells). (B) Following binding to its ligand, VEGF, the VEGF-R is stimulated and develops tyrosine kinase activity. (C) Tyrosine kinase activity sets off a sequence of downstream events that lead to stimulation of cell growth and new vessels grow in, to supply the growing tumour. (D) VEGF-R activity can be blocked by antibodies, which bind to VEGF, and so stop it binding to the receptor, or using chemicals, which inhibit the tyrosine kinase enzyme activity of the VEGF-R.
Figure 2
Figure 2
Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies
Figure 3
Figure 3. Risk of bias summary: review authors’ judgements about each risk of bias item for each included study
See this image and copyright information in PMC

References

References to studies included in this review

    1. Burger RA, Brady MF, Bookman MA, Monk BJ, Walker J, Homesley H, et al. Gynaecologic Oncology Group study Safety and subgroup efficacy analyses in GOG218, a phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC) or fallopian tube cancer (FTC) Annals of Oncology. 2010;21:8s:(Suppl):viii307. abstr 978PD.
    1. Burger RA, Brady MF, Bookman MA, Monk BJ, Walker JL, Homesley HD, et al. Gynecologic Oncology Group study Safety and subgroup efficacy analyses in GOG-0218, a Phase III trial of bevacizumab in the primary treatment of advanced epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer; Conference Poster from ESMO 2010.
    1. Burger RA, Brady MF, Bookman MA, Walker JL, Homesley HD, Fowler J, et al. Gynecologic Oncology Group (GOG) study Phase III trial of Bevacizumab in the Primary Treatment of Advanced Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer; Powerpoint Presentation from ASCO 2010 Conference.

    1. *

    2. Burger RA, Brady MF, Bookman MA, Walker JL, Homesley HD, Fowler J, et al. Gynecologic Oncology Group study Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC) Journal of Clinical Oncology (Meeting Abstracts) 2010;28:18s(Suppl) abstr LBA1.
    1. Amgen Phase 2, AMG 386 (20060342) in combination with paclitaxel for subjects with advanced recurrent epithelial ovarian or primary peritoneal cancer. MetaRegister of Controlled Trials. Protocol Registered. 2007 May 24;

References to studies excluded from this review

    1. Azad N, Annunziata CM, Greenberg L, Minasian L, Kotz H, Sarosy G, et al. Combination therapy with sorafenib and bevacizumab is active in epithelail ovarian cancer [abstract] Gynecologic Oncology. 2008;108(3 Suppl 1):S23.
    1. Burger RA. Role of vascular endothelial growth factor inhibitors in the treatment of gynecologic malignancies. Journal of Gynecologic Oncology. 2010;21(1):3–11. - PMC - PubMed
    1. Markman M. Antiangiogenic drugs in ovarian cancer. Expert Opinion on Pharmacotherapy. 2009;10(14):2269–77. - PubMed
    1. National Cancer Institute. Cytran . Combination chemotherapy plus IM-862 in treating patients with resected Stage III ovarian cancer or primary peritoneal cancer. MetaRegister of Controlled Trials Protocol Registered; Jun 6, 2001.
    1. Case Comprehensive Cancer Center. National Cancer Institute . BAY 43-9006 plus paclitaxel/carboplatin in women with GYN tumors. MetaRegister of Controlled Trials Protocol Registered; Nov 9, 2004.

References to studies awaiting assessment

    1. Exelixis . NCT00940225: study of cabozantinib (XL184) in adults with advanced malignancies. MetaRegister of Controlled Trials. Protocol Registered; Jul 12, 2009.
    1. Gordon MS, Edelman G, Galsky MD, Smith DC, Schoffski P, Houggy K, et al. An adaptive randomized discontinuation trial of XL184 (BMS-907351) in patients (pts) with advanced solid tumors. Journal of Clinical Oncology (Meeting Abstracts) 2010;28(15s)(Suppl) abstr TPS188.

References to ongoing studies

    1. Hoffmann-La Roche. AURELIA: A study of Avastin (bevacizumab) added to chemotherapy in patients with platinum-resistant ovarian cancer. MetaRegister of Controlled Trials. Protocol Registered; Sep 14, 2009.

    1. *

    2. Hainsworth JD, Numnum TM, Rao GG. A randomized phase II study of paclitaxel/carboplatin with or without sorafenib in the first-line treatment of patients with stage III/IV epithelial ovarian cancer. Journal of Clinical Oncology (Meeting Abstracts) 2010;28(15 Suppl):TPS257.
    1. Sarah Cannon Research Institute. Bayer . NCT00390611: Paclitaxel and Carboplatin with or without sorafenib in the first-line treatment of patients with ovarian cancer. MetaRegister of Controlled Trials. Protocol Registered; Oct 19, 2006.
    1. Gynecologic Cancer InterGroup A double-blind, placebo-controlled, three-arm, randomised, multi-centre Gynecologic Cancer InterGroup trial of cediranib (AZD2171), in combination with platinum-based chemotherapy and as a single agent maintenance therapy, in women with ovarian cancer relapsing more than 6 months following completion of first line platinum-based treatment. MetaRegister of Controlled Trials. ISRCTN Assigned. 2007 Aug 13;
    1. ImClone LLC . NCT00913835: a study of Liposomal Doxorubicin with or without IMC-3G3 in platinum-refractory or resistant advanced ovarian cancer. MetaRegister of Controlled Trials. Protocol Registered; Jun 2, 2009.

Additional references

    1. Abaid LN, Lopez KL, Micha JP, Rettenmaier MA, Brown III, JV, Goldstein BH. Bevacizumab, paclitaxel and carboplatin for advanced ovarian cancer: Low risk of gastrointestinal and cardiovascular toxicity. European Journal of Gynaecological Oncology. 2010;31(3):308–311. - PubMed
    1. Aflibercept AVE 0005, AVE 005, AVE0005, VEGF Trap - Regeneron, VEGF Trap (R1R2), VEGF Trap-Eye. Drugs in Research and Development. 2008;9(4):261–9. - PubMed
    1. Alberts DS, Liu PY, Wilczynski SP, Jang A, Moon J, Ward JH, et al. Phase II trial of imatinib mesylate in recurrent, biomarker positive, ovarian cancer (Southwest Oncology Group Protocol S0211) International Journal of Gynecological Cancer. 2007;17(4):784–8. - PubMed
    1. Asmane I, Guastalla JP, Meeus P, Moullet I, Ardisson P, Vincent L, et al. Feasibility of bevacizumab (BEV) plus chemotherapy in heavily pretreated ovarian cancer (OC) patients (pts): A retrospective study. Journal of Clinical Oncology (Meeting Abstracts) 2010;28(15 suppl):e15509.
    1. Bucher HC, Guyatt GH, Griffith LE, Walter SD. The Results of Direct and Indirect Treatment Comparisons in Meta-Analysis of Randomized Controlled Trials. Journal of Clinical Epidemiology. 1997;50(6):683–91. - PubMed

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