Bevacizumab as Salvage Treatment for Her-2 Negative Breast Cancer: A Systematic Review_Chinese Journal of Evidence-Based Medicine

Authors：

XU Long ^1,2 , ZHANG Guojing ¹ ,  XIE Xiaodong ¹

1. Cancer Diagnosis and Treatment Center of PLA, The General Hospital of Shenyang Military Area Command, Shenyang 110840, China;2. Graduate Management Battalion, Fourth Military Medical University, Xi’an 710032, China;

Corresponding author：

XIE Xiaodong, Email: xiexiaodong@CSCO.org.cn

Keywords：

Breast cancer; Her-2; Bevacizumab; Randomized controlled trial; Systematic review; Meta-analysis

DOI：

10.7507/1672-2531.20120210

Video：

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Objective 　To systematically review the effect and safety of bevacizumab as salvage treatment for Her-2 negative recurrent or metastatic breast cancer.
Methods 　The stage III randomized controlled trials (RCTs) on chemotherapy plus bevacizumab vs. chemotherapy alone for Her-2 negative recurrent or metastatic breast cancer were collected from PubMed, EMbase, The Cochrane Library, SCI citation database and CBM. Conference abstracts in ASCO and ESMO during last three years, NCCN guideline (2012), as well as relevant Chinese journals were also retrieved manually. The retrieved literature was published from the inception of databases to February 2012. Two reviewers independently screened the literature according to inclusion and exclusion criteria, evaluated and cross-checked methodological quality, and resolved discrepancy by discussion or according to expert opinion. Then meta-analysis was conducted using STATA SE 12.0 software.
Results 　Of 132 articles collected, a total of 4 RCTs involving 3 131 patients were included. The results of meta-analyses showed that: compared with chemotherapy alone, bevacizumab plus chemotherapy could improve the progression-free survival (PFS) for patients with Her-2 negative breast cancer (HR=0.67, 95%CI 0.57 to 0.79, P=0.001), but it could not prolong the overall survival (OS) (HR=0.92, 95%CI 0.82 to 1.02, P=0.121). Adverse effects such as hypertension, proteinuria and bleeding significantly increased in the bevacizumab group, but no statistical significance was found in thrombo-embolic event, neutropenia and sensory neuropathy between the two groups.
Conclusion 　Bevacizumab can improve PFS rather than OS for patients with Her-2 negative recurrent or metastatic breast cancer, and it increases the Grade 3 to 4 adverse effects. It is necessary to identify the best indications of bevacizumab as salvage treatment for breast cancer.

Citation： XU Long,ZHANG Guojing,XIE Xiaodong. Bevacizumab as Salvage Treatment for Her-2 Negative Breast Cancer: A Systematic Review. Chinese Journal of Evidence-Based Medicine, 2012, 12(11): 1347-1353. doi: 10.7507/1672-2531.20120210 Copy

1.	Simon-Yarza T, Formiga FR, Tamayo E, et al. Vascular endothelial growth factor-delivery systems for cardiac repair: an overview. Theranostics, 2012, 2(6): 541-552.
2.	Konno H, Yamamoto M, Ohta M. Recent concepts of antiangiogenic therapy. Surg Today, 2010, 40(6): 494-500.
3.	Ferrara N, Hillan KJ, Gerber HP, et al. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov, 2004, 3(5): 391-400.
4.	Miller KD, Chap LI, Holmes FA, et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol, 2005, 23(4): 792-799.
5.	Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med, 2007, 357(26): 2666-2676.
6.	Miles DW, Chan A, Dirix L Y, et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol, 2010, 28(20): 3239-3247.
7.	Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol, 2011, 29(10):1252-1260.
8.	Brufsky AM, Hurvitz S, Perez E, et al. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol, 2011, 29(32): 4286-4293.
9.	Tanne JH. FDA cancels approval for bevacizumab in advanced breast cancer. BMJ, 2011, 343: d7684.
10.	Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med, 1998, 17(24): 2815-2834.
11.	DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials, 1986, 7(3): 177-188.
12.	Gray R, Bhattacharya S, Bowden C, et al. Independent review of E2100: a phase III trial of bevacizumab plus paclitaxel versus paclitaxel in women with metastatic breast cancer. J Clin Oncol, 2009, 27(30): 4966-4972.
13.	Spruance SL, Reid JE, Grace M, et al. Hazard ratio in clinical trials. Antimicrob Agents Chemother, 2004, 48(8): 2787-2792.
14.	Carpenter D, Kesselheim AS, Joffe S. Reputation and precedent in the bevacizumab decision. N Engl J Med, 2011, 365(2): e3.
15.	Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer, 2008, 8(8): 592-603.
16.	Smith IE, Pierga JY, Biganzoli L, et al. First-line bevacizumab plus taxane-based chemotherapy for locally recurrent or metastatic breast cancer: safety and efficacy in an open-label study in 2,251 patients. Ann Oncol, 2011, 22(3): 595-602.
17.	Lee JB, Woo OH, Park KH, et al. Bevacizumab for salvage treatment of metastatic breast cancer: a systemic review and meta-analysis of randomized controlled trials. Invest New Drugs, 2011, 29(1): 182-188.
18.	Cuppone F, Bria E, Vaccaro V, et al. Magnitude of risks and benefits of the addition of bevacizumab to chemotherapy for advanced breast cancer patients: Meta-regression analysis of randomized trials. J Exp Clin Cancer Res, 2011, 30: 54.
19.	Yang SX. Bevacizumab and breast cancer: current therapeutic progress and future perspectives. Expert Rev Anticancer Ther, 2009, 9(12): 1715-1725.

1. Simon-Yarza T, Formiga FR, Tamayo E, et al. Vascular endothelial growth factor-delivery systems for cardiac repair: an overview. Theranostics, 2012, 2(6): 541-552.
2. Konno H, Yamamoto M, Ohta M. Recent concepts of antiangiogenic therapy. Surg Today, 2010, 40(6): 494-500.
3. Ferrara N, Hillan KJ, Gerber HP, et al. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov, 2004, 3(5): 391-400.
4. Miller KD, Chap LI, Holmes FA, et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol, 2005, 23(4): 792-799.
5. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med, 2007, 357(26): 2666-2676.
6. Miles DW, Chan A, Dirix L Y, et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol, 2010, 28(20): 3239-3247.
7. Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol, 2011, 29(10):1252-1260.
8. Brufsky AM, Hurvitz S, Perez E, et al. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol, 2011, 29(32): 4286-4293.
9. Tanne JH. FDA cancels approval for bevacizumab in advanced breast cancer. BMJ, 2011, 343: d7684.
10. Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med, 1998, 17(24): 2815-2834.
11. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials, 1986, 7(3): 177-188.
12. Gray R, Bhattacharya S, Bowden C, et al. Independent review of E2100: a phase III trial of bevacizumab plus paclitaxel versus paclitaxel in women with metastatic breast cancer. J Clin Oncol, 2009, 27(30): 4966-4972.
13. Spruance SL, Reid JE, Grace M, et al. Hazard ratio in clinical trials. Antimicrob Agents Chemother, 2004, 48(8): 2787-2792.
14. Carpenter D, Kesselheim AS, Joffe S. Reputation and precedent in the bevacizumab decision. N Engl J Med, 2011, 365(2): e3.
15. Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer, 2008, 8(8): 592-603.
16. Smith IE, Pierga JY, Biganzoli L, et al. First-line bevacizumab plus taxane-based chemotherapy for locally recurrent or metastatic breast cancer: safety and efficacy in an open-label study in 2,251 patients. Ann Oncol, 2011, 22(3): 595-602.
17. Lee JB, Woo OH, Park KH, et al. Bevacizumab for salvage treatment of metastatic breast cancer: a systemic review and meta-analysis of randomized controlled trials. Invest New Drugs, 2011, 29(1): 182-188.
18. Cuppone F, Bria E, Vaccaro V, et al. Magnitude of risks and benefits of the addition of bevacizumab to chemotherapy for advanced breast cancer patients: Meta-regression analysis of randomized trials. J Exp Clin Cancer Res, 2011, 30: 54.
19. Yang SX. Bevacizumab and breast cancer: current therapeutic progress and future perspectives. Expert Rev Anticancer Ther, 2009, 9(12): 1715-1725.

Chinese Journal of Evidence-Based Medicine

Bevacizumab as Salvage Treatment for Her-2 Negative Breast Cancer: A Systematic Review

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