Retrospective analysis on the clinical efficacy of bevacizumab combined with FOLFOX4 in the first line treatment of metastatic colorectal cancer

Article information

Kosin Med J. 2017;32(2):170-178
Publication date (electronic) : 2017 January 19
doi :
Department of Internal Medicine, College of Medicine, Kosin University, Busan, Korea
Corresponding Author: Yang Soo Kim, Department of Internal Medicine, College of Medicine, Kosin University, 262, Gamcheon-ro, Seo-gu, Busan 49267, Korea Tel: +82-51-990-5820 Fax: +82-51-990-5820 E-mail:
Received 2015 April 08; 2015 April 28; Accepted 2015 September 09.



The addition of bevacizumab to standard chemotherapy has been improved survival outcomes in patients with metastatic colorectal cancer. However, the combination of bevacizumab with oxaliplatin-based chemotherapy as first-line treatment showed limited survival benefit. The purpose of this study was to investigate the clinical efficacy and toxicity of the combination of bevacizumab to oxaliplatin and leucovorin (FOLFOX4) in the first-line treatment of patient with metastatic colorectal cancer.


Between December 2004 and September 2009, medical records of patients who were diagnosed with metastatic colorectal cancer and received the first line chemotherapy with bevacizumab and FOLFOX4, were retrospectively reviewed.


A total of forty patients were analyzed. The median age of the patients was 55 years (range, 33-80), and 55% was male. The patients received a total of 206 cycles of therapy (median 4 cycles per patient; range 1 – 15 cycles). Of these 40 patients, none achieved complete response (CR) and 15 achieved a partial response (PR), for the overall response rate (ORR) 37.5% (95% CI, 22.5-52.5). Median progression free survival (PFS) was 6.9 months (95% CI, 3.4-10.5) and median overall survival (OS) was 22.6 months (95% CI, 17.3-27.8The most common grade 3 or 4 hematologic toxicity and non-hematologic toxicity were neutropenia (10.0%) and diarrhea (10.0%), respectively. Two patients experienced gastrointestinal perforation.


In this study, the combination bevacizumab with FOLFOX4 was associated with favorable OS, but did not showed favorable PFS and ORR.

Fig. 1.

Survival curves by the Kaplan–Meier method.

Patient characteristics (n = 40)

Toxicity profile (According to NCI-CTCAE1)version3.0)

Tumor responses and results of treatment


1. de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000;18:2938–47.
2. Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000;355:1041–7.
3. Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, et al. Irinotecan plus Fluorouracil and Leucovorin for Metastatic Colorectal Cancer. Irinotecan Study Group. N Engl J Med 2000;343:905–14.
4. Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004;22:23–30.
5. Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008;26:2013–9.
6. Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009;360:1408–17.
7. Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol 2010;28:4697–705.
8. Kabbinavar F, Hurwitz HI, Fehrenbacher L, Meropol NJ, Novotny WF, Lieberman G, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 2003;21:60–5.
9. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335–42.
10. Kabbinavar FF, Schulz J, McCleod M, Patel T, Hamm JT, Hecht JR, et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol 2005;23:3697–705.
11. Macedo LT, da Costa Lima AB, Sasse AD. Addition of bevacizumab to first-line chemotherapy in advanced colorectal cancer: a systematic review and meta-analysis, with emphasis on chemotherapy subgroups. BMC cancer 2012;12:89.
12. Meyerhardt JA, Li L, Sanoff HK, Carpenter W 4th, Schrag D. Effectiveness of bevacizumab with first-line combination chemotherapy for Medicare patients with stage IV colorectal cancer. J Clin Oncol 2012;30:608–15.
13. Grothey A, Sargent D, Goldberg RM, Schmoll HJ. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 2004;22:1209–14.
14. Petrelli F, Coinu A, Ghilardi M, Cabiddu M, Zaniboni A, Barni S. Efficacy of oxaliplatin-based chemotherapy + bevacizumab as first-line treatment for advanced colorectal cancer: a systematic review and pooled analysis of published trials. Am J Clin Oncol 2015;38:227–33.
15. Petrelli F, Borgonovo K, Cabiddu M, Ghilardi M, Lonati V, Maspero F, et al. FOLFIRI-bevacizumab as first-line chemotherapy in 3500 patients with advanced colorectal cancer: a pooled analysis of 29 published trials. Clin Colorectal Cancer 2013;12:145–51.
16. Dvorak HF. Discovery of vascular permeability factor (VPF). Exp Cell Res 2006;312:522–6.
17. Gressett SM, Shah SR. Intricacies of bevacizumab-induced toxicities and their management. Ann Pharmacother 2009;43:490–501.
18. Ranpura V, Hapani S, Wu S. Treatment-related mortality with bevacizumab in cancer patients: a meta-analysis. JAMA 2011;305:487–94.
19. Hapani S, Chu D, Wu S. Risk of gastrointestinal perforation in patients with cancer treated with bevacizumab: a meta-analysis. Lancet Oncol 2009;10:559–68.
20. Heinzerling JH, Huerta S. Bowel perforation from bevacizumab for the treatment of metastatic colon cancer: incidence, etiology, and management. Curr Surg 2006;63:334–7.
21. Saif MW, Elfiky A, Salem RR. Gastrointestinal perforation due to bevacizumab in colorectal cancer. Ann Surg Oncol 2007;14:1860–9.
22. Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL, et al. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol 2008;26:3523–9.

Article information Continued

Fig. 1.

Survival curves by the Kaplan–Meier method.

Table 1.

Patient characteristics (n = 40)

Characteristic Data
Age, years [median (range)] 55 (33-80)
≤ 60 years 28 (70.0)
> 60 years 12 (30.0)
Gender [n (%)]
Male 22 (55.0)
Female 18 (45.0)
Site of primary tumor [n (%)]
Colon 21 (52.5)
Rectum 19 (47.5)
ECOG PS [n(%)]
0-1 31 (77.5)
≥ 2 9 (22.5)
Number of metastatic site [n (%)]
1 site 21 (52.5)
≥ 2 sites 19 (47.5)
Site of metastasis [n (%)]
Liver 27 (67.5)
Lung 13 (32.5)
Peritoneum 3 (7.5)
Lymph nodes 7 (17.5)
Bone 12 (30.0)
Prior resection of primary tumor [n (%)] 25 (62.5)
Prior adjuvant treatment [n (%)] 18 (45.0)
Initial CEA level(ng/mL) [median(range)] 29.5 (0.8-2359.0)
< 3.5 ng/mL 4 (10.0)
≥ 3.5 ng/mL 36 (90.0)

ECOG: Eastern Cooperative Oncology Group

PS: performance status

CEA: carcinoembryonic antigen

Table 2.

Toxicity profile (According to NCI-CTCAE1)version3.0)

Grade III or IV [n(%)]
Anemia 0
Neutropenia 4(10.0)
Thrombocytopenia 0
Febrile neutropenia 0
Nausea 0
Anorexia 1(2.5)
Diarrhea 4(10.0)
Peripheral neuropathy 0
GI bleeding 0
GI perforation 2(5.0)
Hypertension 0
Proteinuria 1(2.5)

NCI-CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events

GI: gastrointestinal

Table 3.

Tumor responses and results of treatment

Responses [n %)] 95% CI
Complete response 0 (0) -
Partial response 15 (37.5) 22.5-52.5
Stable disease 18 (45.5) 30.0-62.5
Progressive disease 7 (17.5) 7.5-30.0
Overall response rate 15 (37.5) 22.5-52.5
Disease control rate 33 (82.5) 70.0-92.5

CI: confidence interval