Adverse Effects of Bevacizumab During Treatment for Metastatic Colorectal Cancer
Keywords:Bevacizumab, colorectal cancer, bleeding, interstitial pneumonitis.
Objective:Bevacizumab has been increasingly used in combination chemotherapy for the treatment of metastatic or recurrent colorectal cancer.The aim of this report is to underline the possible risks associated with bevacizumab use.
Methods:Between July 2005 and March 2013, a total of 130 patients with metastatic colorectal cancer who received oxaliplatin as first-line chemotherapy were divided into 2 groups those treated with bevacizumab (group A) and those without (group B), and compared. The primary endpoint was to clarify the profile of bevacizumab - induced adverse effects. Secondary endpoints examined therapeutic effects, including overall survival (OS).
Results:The incidence of major side effects was almost equivalent, except for bleeding, between the 2 groups. With regard to the therapeutic effects, 1 patient in group A showed complete disappearance of multiple lung metastases without any evidence of recurrence. The median OS was 926 days (95% confidence interval [CI], 756 - 1257) in group A and 534 days (95% CI, 421 - 621) in group B (p < 0.01).
Conclusion:The results demonstrate that bevacizumab prolonged survival in these patients although there was an increased risk of clinically significant bleeding.
Willett CG, Boucher Y, di Tomaso E, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 2004; 10: 145-147. http://dx.doi.org/10.1038/nm988
Ranieri G, Patruno R, Ruggicri E, et al. Vascular endothelial growth factor (VEGF) as a target of bevacizumab in cancer: from the biology to the clinic [review]. Curr Med Chem 2006; 13: 1845-185. http://dx.doi.org/10.2174/092986706777585059
Melnyk O, Zimmerman M, Kim KJ, Shuman M. Neutralizing anti-vascular endothelial growth factor antibody inhibits further growth of established prostate cancer and metastases in a pre-clinical model. J Urol 1999; 161: 960-963. http://dx.doi.org/10.1016/S0022-5347(01)61829-9
Jain PK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 2005; 307: 58-62. http://dx.doi.org/10.1126/science.1104819
Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Eng J Med 2004; 350: 2335-2342. http://dx.doi.org/10.1056/NEJMoa032691
Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group study E3200. J Clin Oncol 2007; 25: 1539-1544. http://dx.doi.org/10.1200/JCO.2006.09.6305
Saltz LB, Clarke S, Diaz-Rubio, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randamized phase III study. J Clin Oncol 2008; 26: 2013-2019. http://dx.doi.org/10.1200/JCO.2007.14.9930
Bennouna J, Sastre J, Arnold D, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol 2013; 14: 29-37. http://dx.doi.org/10.1016/S1470-2045(12)70477-1
Kabbinavar F, Shah A. Guidelines for the management of side effects of bevacizumab in patients with colorectal cancer. Cancer ther 2008; 6: 327-340.
Hapani S, Chu D, Wu S. Risk of gastrointestinal perforation in patients with cancer treated with bevacizumab: a meta-analysis [Review]. Lancet Oncol 2009; 10: 559-568. http://dx.doi.org/10.1016/S1470-2045(09)70112-3
Khorana AA, Dalal M, Lin J, Connolly GC. Incidence and predictors of venous thromboembolism among ambulatory high-risk cancer patients undergoing chemotherapy in the United States. Cancer 2013; 119: 648-655. http://dx.doi.org/10.1002/cncr.27772
Kozloff M, Yood MU, Berlin J, et al. Clinical outcomes associated with bevacizumab-containing treatment of metastatic colorectal cancer: the BRiTE observational cohort study. Oncologist 2009; 14: 862-870. http://dx.doi.org/10.1634/theoncologist.2009-0071
Nakamura H, Satoh H, Kaburagi T, et al. Bevacizumab-containing chemotherapy for non-small cell lung cancer patients: a population-based observational study by the Ibaraki thoracic integratibe (POSITIVE) research group. Med Oncol 2012; 29: 3202-3206. http://dx.doi.org/10.1007/s12032-012-0318-5
Cassidy J, Tabernero J, Twelves C, et al. XELOX (capecitabine plus oxaliplatin): active first-line therapy for patients with metastatic colorectal cancer. J Clin Oncol 2004; 22: 2084-2091. http://dx.doi.org/10.1200/JCO.2004.11.069
Doi T, Boku N, Kato K, et al. Phase I/ II study of capecitabine plus oxaliplatin (XELOX) plus bevacizumab as first-line therapy in Japanese patients with metastatic colorectal cancer. Jpn J Clin Oncol 2010; 40: 913-920. http://dx.doi.org/10.1093/jjco/hyq069
Muro K, Boku N, Shimada Y, et al. Irinotecan plus S-1 (IRIS) versus fluorouracil and folinic acid plus irinotecan (FOLFIRI) as second-line chemotherapy for metastatic colorectal cancer: a randomised phase 2/ 3 non-inferiority (FIRIS study). Lancet Oncol 2010; 11: 853-860. http://dx.doi.org/10.1016/S1470-2045(10)70181-9
Komatsu Y, Yuki S, Sogabe S, et al. Phase II study of combined chemotherapy with irinotecan and S-1 (IRIS) plus bevacizumab in patients with inoperable recurrent or advanced colorectal cancer. Acta Oncol Early Online 2012; 51: 867-72. http://dx.doi.org/10.3109/0284186X.2012.682629
Aoki Y, Kojima S, Kataoka T, et al. A case of interstitial pneumonia induced by S-1/ irinotecan combination therapy. Jpn J Cancer Chemother 2008; 35: 975-977 (in Japanese).
Van Custem 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 2009; 20: 1842-1847. http://dx.doi.org/10.1093/annonc/mdp233
Johnson DH,Fehrenbacher L, Novotony WF. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small cell lung cancer. J Clin Oncol 2004; 22: 2184-2191. http://dx.doi.org/10.1200/JCO.2004.11.022
Hapani S, Sher A, Chu D, Wu S. Incresed risk of serious hemorrhage with bevacizumab in cancer patients: a meta-analysis. Oncology 2010; 79: 27-38. http://dx.doi.org/10.1159/000314980
Ferrara N, Gerber HP, Lecouter J. The biology of VEGF and its receptors. Nat Med 2003; 9: 669-676. http://dx.doi.org/10.1038/nm0603-669
Veheul HM, Pinedo HM. Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat Rev Cancer 2007; 7: 475-485. http://dx.doi.org/10.1038/nrc2152
Kamba T, McDonald DM. Mechanisms of adverse effects of anti-VEGF therapy of cancer. Br J Cancer 2007; 96: 1788-1795. http://dx.doi.org/10.1038/sj.bjc.6603813
Shamloo B, Chhabre P, Freedman AN, Potosky A, Malin J, Smith SW. Novel adverse events of bevacizumab in the US FDA adverse event reporting system database. Drud Saf 2012; 35: 507-518. http://dx.doi.org/10.2165/11597600-000000000-00000
Usui K, Katou Y, Furushima K, Tanaka Y, Tanai C, Ishihara T. Interstitial lung disease during chemotherapy combined with oxaliplatin and/ or bevacizumab in advanced colorectal cancer patients. Jpn J Clin Oncol 2011; 41: 498-502. http://dx.doi.org/10.1093/jjco/hyr006
Kang HJ, Park JS, Kim D-W, et al. Adverse pulmonary reactions associated with the use of monoclonal antibodies in cancer patients. Res Med 2012; 106: 443-450. http://dx.doi.org/10.1016/j.rmed.2011.11.009