Aim: The effect of KRAS status on response to bevacizumab plus chemotherapy in metastatic colorectal cancer is still unclear. We aimed to evaluate the overall clinical response to such a therapy in clinical practice and assess the role of KRAS status on therapy response. Patients & methods: This was a retrospective study enrolling 108 metastatic colorectal cancer patients. KRAS mutation analysis was performed by PCR. Results: Overall, 41.7% of patients had stable disease, 39.8% a partial response, 3.7% a complete response and 14.8% disease progression. Both clinical benefit and objective response rate tended to be higher in patients with only hepatic metastases than those with extrahepatic or multiple metastases. Response to therapy would appear to be independent of KRAS status, but larger studies are needed. Conclusion: Bevacizumab plus chemotherapy provides clinical benefit and objective response rate in patients with metastatic colorectal cancer independently of KRAS expression, especially in those patients with only liver metastases.

Keywords:

Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

References

1 Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil and leucoverin for metastatic colorectal cancer. N. Engl. J. Med.350,2335–2342 (2004).▪▪ Main study of bevacizumab in metastatic colorectal cancer.
Medline CASGoogle Scholar
2 Saltz LB, Clarke S, Diaz-Rubio E 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.26(12),2013–2019 (2008).
Medline CASGoogle Scholar
3 Fuchs CS, Marshall J, Mitchell E et al. Randomized controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C study. J. Clin. Oncol.25(30),4779–4786 (2007).
Medline CASGoogle Scholar
4 Van Cutsem E, Kohne CH, Lang I et al. Cetuximab plus irinotecan, fluorouracil and leucoverin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J. Clin. Oncol.29(15),2011–2019 (2011).
Medline CASGoogle Scholar
5 Bokemeyer C, Bondarenkob I, Hartman JT et al. Efficacy according to biomarker status of cetuximab plus FOLOX-4 as first-line treatment for metastatic colorectal cancer. The OPUS study. Ann. Oncol.22(7),1535–1546 (2011).
Medline CASGoogle Scholar
6 Amado RG, Wolf M, Peeters M et al. Wild-type KRAS is required for Panitumumab efficacy in patients with metastatic colorectal cancer. J. Clin. Oncol.26(10),1626–1634 (2008).
Medline CASGoogle Scholar
7 Karapetis CS, Khambata-Ford S, Jonker DJ et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N. Engl. J. Med.359(17),1757–1765 (2008).
Medline CASGoogle Scholar
8 Andreyev HJ, Norman AR, Cunningham D et al. Kirsten ras mutations in patients with colorectal cancer: the “RESCAL II” study. Br. J. Cancer85(5),692–696 (2001).
Medline CASGoogle Scholar
9 Roth AD, Tejpar S, Delorenzi M et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 Trial. J. Clin. Oncol.28(3),466–474 (2010).
Medline CASGoogle Scholar
10 Ciardiello F, Troiani T, Bianco R et al. Interaction between the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) pathways: a rational approach for multitarget anticancer therapy. Ann. Oncol.17(Suppl. 7),vii109–vii114 (2006).▪ Molecular mechanism of interaction between VEGF and EGF receptor pathways.
MedlineGoogle Scholar
11 Ince WL, Jubb AM, Holden SN et al. Association of K-ras, b-raf and p53 status with the treatment effect of Bevacizumab. J. Natl Cancer Inst.97(13),981–989 (2005).
Medline CASGoogle Scholar
12 Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer45(2),228–247 (2009).
Medline CASGoogle Scholar
13 Sanger F, Nicklen F, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc. Natl Acad. Sci. USA74(12),5463–5467 (1977).
Medline CASGoogle Scholar
14 Kabbinavar FF, Schulz J, McCleod M et al. Addition of bevacizumab to bolus fluorouracil and leucoverin in first-line metastatic colorectal cancer: results of a randomized Phase II trial. J. Clin. Oncol.23(16),3697–3704 (2005).▪▪ Main studies of bevacizumab in metastatic colorectal cancer.
Medline CASGoogle Scholar
15 Sobrero A, Ackland S, Clarke S et al. Phase IV study of Bevacizumab in combination with infusional Fluorouracil, Leucoverin and Irinotecan (FOLFIRI) in first-line metastatic colorectal cancer. Oncology77(2),113–119 (2009).
Medline CASGoogle Scholar
16 Grothey A, Sugrue MM, Purdie DM et al. Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: results from a large observation cohort study (BRiTE). J. Clin. Oncol.26(33),5326–5334 (2008).
Medline CASGoogle Scholar
17 Tol J, Koopman M, Cats A et al. Chemotherapy, bevacizumab and cetuximab in metastatic colorectal cancer. N. Engl. J. Med.360(6),563–572 (2009).
Medline CASGoogle Scholar
18 Hecht JR, Mitchell E, Chidiac T et al. A randomized Phase IIIb trial of chemotherapy, bevacizumab and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J. Clin. Oncol.27(5),672–680 (2009).
Medline CASGoogle Scholar
19 Reinacher-Schick AC, Kubicka S, Freier W et al. Activity of the combination of bevacizumab (Bev) with capecitabine/irinotecan (CapIri/Bev) or capecitabine/oxaliplatin (CapOx/Bev) in advanced colorectal cancer (ACRC): a randomized Phase II study of the AIO Colorectal Study Group (AIO trial 0604). Presented at: 8th Annual Meeting American Society of Clinical Oncology. Chicago, IL, USA, 30 May–3 June 2008.
Google Scholar
20 Tebbutt NC, Wilson K, Gebski VJ et al. Capecitabine, bevacizumab and mitomycin in first-line treatment of metastatic colorectal cancer: results of the Australasian Gastrointestinal Trials Group randomized Phase III MAX study. J. Clin. Oncol.28(19),3191–3198 (2010).
Medline CASGoogle Scholar
21 Giantonio BJ, Catalano PJ, Meropol NJ et al. Bevacizumab in combination with oxaliplatin, fluorouracil and leucoverin (FolFoX4) for previously treated metastasic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J. Clin. Oncol.25(12),1539–1544 (2007).
Medline CASGoogle Scholar
22 Diaz-Rubio E, Gomez-Espana A, Massuti B et al. First-line XELOX plus bevacizumab followed by XELOX plus bevacizumab or single-agent bevacizumab as maintenance therapy in patients with metastatic colorectal cancer: the Phase III MACRO TTD study. Oncologist17(1),15–25 (2012).
Medline CASGoogle Scholar
23 Schmoll H, Cunningham D, Sobrero A et al. mFolFoX6 + cediranib vs mFolFoX6 + bevacizumab in previously untreated metastatic colorectal cancer (MCRC): a randomized, double-blind, Phase II/III study (HORIZON III). Presented at: 35th European Society of Medical Oncology. Milan, Italy, 8–12 October 2010.
Google Scholar
24 Van Cutsem E, Rivera F, Berry S et al. Safety and efficacy of first-line bevacizumab with FOLFOX, XELOX, FOLFIRI and fluoropyrimidines in metastatic colorectal cancer: the BEAT study. Ann. Oncol.20(11),1842–1847 (2009).▪▪ Initial promising results of bevacizumab in neoadjuvant treatment of colorectal liver metastases.
Medline CASGoogle Scholar
25 Gruenberger B, Tamandl D, Schueller J et al. Bevacizumab, capecitabine, and oxaliplatin as neoadjuvant therapy for patients with potentially curable metastatic colorectal cancer. J. Clin. Oncol.26(11),1830–1835 (2008).
Medline CASGoogle Scholar
26 Blazer DG 3rd, Kishi Y, Maru DM et al. Pathologic response to prospective chemotherapy: a new outcome end point after resection of hepatic colorectal metastases. J. Clin. Oncol.26(33),5344–5350 (2008).
MedlineGoogle Scholar
27 Wong R, Cunningham D, Barbachano Y et al. A multicentre study of capecitabine, oxaliplatin plus bevacizumab as perioperative treatment of patients with poor-risk colorectal liver-only metastases not selected for up-front resection. Ann. Oncol.22(9),2042–2048 (2011).
Medline CASGoogle Scholar
28 Hurwitz HI, Yi J, Ince W, Novotny WF, Rosen O. The clinical benefit of bevacizumab in metastatic colorectal cancer is independent of K-ras mutation status: analysis of Phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer. Oncologist14(1),22–28 (2009).▪▪ Main studies of correlation between bevacizumab and KRAS status.
Medline CASGoogle Scholar
29 Price TJ, Hardingham JE, Lee CK et al. Impact of K-ras and BRAF gene mutation status on outcomes from the Phase III AGITG MAX trial of capecitabina alone or in combination with bevacizumab and mitomycin in advanced colorectal cancer. J. Clin. Oncol.29(10),2675–2682 (2011).
Medline CASGoogle Scholar

Vol. 8, No. 9

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Published online 3 October 2012

Published in print September 2012

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Acknowledgements

The authors thank Anselmo Papa, for his valuable review of this article and Erika Giordani, Monica Verrico and Enrico Basso for their input into the manuscript.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

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Bevacizumab plus chemotherapy in metastatic colorectal cancer patients treated in clinical practice

Abstract

References