Survival Benefit and Safety of Bevacizumab in Combination with Erlotinib as Maintenance Therapy in Patients with Metastatic Colorectal Cancer: A Meta-Analysis.
BACKGROUND
Recently, the need for maintenance chemotherapy arose as a result of the significantly improved survival of patients with metastatic colorectal cancer (mCRC) without increasing adverse events. Currently used maintenance regimens are fluoropyrimidines, bevacizumab, and the combination of fluoropyrimidine with bevacizumab. A new combination with bevacizumab and erlotinib, a tyrosine kinase inhibitor of the epithelial growth factor receptor, has shown synergistic effects in preclinical tests and promising results in some clinical trials. Whether bevacizumab combined with erlotinib vs. bevacizumab alone as maintenance therapy will further improve the clinical outcomes in patients with mCRC is controversial. We conducted this meta-analysis to compare the survival benefit and safety of these two regimens in patients with mCRC.


METHODS
We searched PubMed, EMBASE, and the Central Registry of Controlled Trials of the Cochrane Library up to August 2016. We also searched the Proceedings of the American Society of Clinical Oncology (1986 to August 2016). Abstracts were manually searched to identify relevant trials. A total of three randomized controlled trials with 682 patients met the inclusion criteria.


RESULTS
Our results demonstrated that bevacizumab combined with erlotinib significantly improved overall survival (hazard ratio 0.78; 95 % confidence interval 0.66-0.93; p = 0.006) and progression-free survival (hazard ratio 0.79; 95 % confidence interval 0.68-0.92; p = 0.002). Significantly more grade 3 rash, diarrhea, infection total, and fatigue were observed in the bevacizumab combined with erlotinib arm, which were controllable and reversible.


CONCLUSIONS
Based on current evidence, the addition of erlotinib to bevacizumab as maintenance therapy significantly increases overall survival and progression-free survival with an increased but manageable toxicity in patients with mCRC. It should be considered as a treatment option for these patients under the premise of a reasonable selection of the target population.
Department of Oncology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, People's Republic of China.
Wei
W
Xu
Department of Oncology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, People's Republic of China.
Yang
Y
Gong
Department of Oncology, Liyang People's Hospital, Liyang, Jiangsu, People's Republic of China.
Meng
M
Kuang
Department of Oncology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, People's Republic of China.
Peng
P
Wu
Department of Radiation Oncology, The First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China.
Chunxiang
C
Cao
Department of Oncology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, People's Republic of China. jinfeichen@sohu.com.
Jinfei
J
Chen
Department of Oncology, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing, 210006, People's Republic of China. tangcuiju2016@163.com.
Cuiju
C
Tang
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D018572:Disease-Free Survival; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D006801:Humans; D009362:Neoplasm Metastasis; D016019:Survival Analysis
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D000068258:Bevacizumab; D000069347:Erlotinib Hydrochloride
Lancet. 2015 May 9;385(9980):1843-52
25862517
Int J Cancer. 2015 Mar 1;136(5):E359-86
25220842
Ann Oncol. 2015 Apr;26(4):709-14
25605741
Ann Oncol. 2013 Sep;24(9):2335-41
23788755
Genet Epidemiol. 2005 Feb;28(2):123-37
15593093
J Clin Oncol. 2006 Apr 20;24(12):1892-7
16622264
Biometrics. 1994 Dec;50(4):1088-101
7786990
Lancet Oncol. 2013 Jan;14(1):29-37
23168366
CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49
19474385
Biomed Rep. 2013 Jul;1(4):495-498
24648974
N Engl J Med. 2009 Feb 5;360(6):563-72
19196673
Endocr Relat Cancer. 2005 Jul;12 Suppl 1:S159-71
16113092
Lancet Oncol. 2014 Sep;15(10):1065-75
25088940
Lancet Oncol. 2015 Nov;16(15):1493-505
26474518
J Thorac Oncol. 2014 Sep;9(9):1411-7
25122437
Ann Oncol. 2016 Jan;27(1):140-7
26483047
J Clin Oncol. 2006 Jan 20;24(3):394-400
16421419
J Clin Oncol. 2013 Nov 1;31(31):3926-34
24101054
J Clin Oncol. 2012 May 1;30(13):1505-12
22412142
Lancet Oncol. 2011 Jul;12(7):642-53
21641867
J Clin Oncol. 2009 Feb 10;27(5):672-80
19114685
Clin Cancer Res. 2009 May 15;15(10):3495-502
19447871
J Clin Oncol. 2008 Nov 20;26(33):5326-34
18854571
Cancer Res. 2002 May 1;62(9):2554-60
11980649
N Engl J Med. 2013 Sep 12;369(11):1023-34
24024839
Oncol Res. 2013;21(4):181-91
24762224
Ann Oncol. 2007 Jul;18(7):1185-9
17483115
J Clin Oncol. 2009 Dec 1;27(34):5727-33
19786657
Br J Cancer. 2006 Apr 24;94(8):1136-43
16570047
BMJ. 1997 Sep 13;315(7109):629-34
9310563
Invest New Drugs. 2013 Aug;31(4):1035-43
23417697
N Engl J Med. 2009 Apr 2;360(14):1408-17
19339720
Clin Cancer Res. 2011 Oct 15;17 (20):6522-30
21880790
Lancet Oncol. 2015 Oct;16(13):1355-69
26361971
BMJ. 2011 Oct 18;343:d5928
22008217
N Engl J Med. 2014 Oct 23;371(17):1609-18
25337750
Pharmacol Ther. 2011 Jul;131(1):80-90
21439312