Annals of Oncology Advance Access originally published online on June 15, 2006
Annals of Oncology 2006 17(12):1851-1852; doi:10.1093/annonc/mdl140
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© 2006 European Society for Medical Oncology
letters to the editor |
Chemotherapy with bevacizumab, irinotecan, 5-fluorouracil and leucovorin (IFL) associated with a large, embolizing thrombus in the thoracic aorta
1 Department of Medicine, Kantonales Spital Sursee, Luzern, Switzerland
2 Division of Cardiology, Kantonsspital Luzern, Switzerland
* (E-mail: adrian.schmassmann{at}kssw.ch)
We read with interest the studies [1–3] and the review by Midgley and Kerr [4] on the role of bevacizumab in the therapy of metastatic cancers. We report on a new presentation of arterial thrombo-embolism that occurred during chemotherapy with bevacizumab and irinotecan, 5-fluorouracil and leucovorin (IFL). A 57-year-old man with a history of rectal amputation from distal rectum cancer stage I (pT2NoMoG1) 6 years ago, was admitted with respiratory symptoms. Thoracic CT scan (including CT-guided biopsies) showed three lung metastases of the previous rectal cancer. This otherwise healthy patient was a non-smoker without cardiovascular risk factors. The laboratory work-up showed normal values. Palliative first-line chemotherapy with bevacizumab (5 mg/kg every 2 weeks) and IFL was started (irinotecan 125 mg/m2 i.v., 5-fluoruracil 500 mg/m2 i.v. and leucovorin 20 mg/m2 i.v. given once a week for 4 weeks every 6 weeks) [1]. Six weeks later, the patient developed an ischemic left foot and angiography showed embolic distal occlusions of the anterior and posterior tibial artery. Percutaneous transluminal angioplasty and local fibrinolysis led to partial improvement in the ischaemic symptoms; histological analysis from the embolus showed thrombotic material. Transoesophageal colour echocardiography revealed the source of thrombo-embolism as a pedunculated thrombus in the descending aorta (Figure 1). The aorta was otherwise normal without atherosclerosis. Bevacizumab was stopped while IFL therapy was continued. Therapeutic long-term dalteparin was started. Despite this therapy, the left big toe became necrotic and finally had to be amputated. Six weeks later, control echocardiography showed a complete disappearance of the thrombus. Ten weeks after initiating chemotherapy, thoracic CT showed significant reduction in the size of all three lung lesions. Clotting analysis showed normal values for antithrombin, protein C, protein S and plasminogen; negative results for lupus anticoagulant and anticardiolipin antibodies; no factor V Leiden or prothrombin G20210A mutation and normal homocystein serum levels. Thereafter, dalteparin was replaced by oral anticoagulation with phenprocoumon.
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Incorporation of vascular endothelial growth factor (VEGF) blockade by bevacizumab has improved the outcome of patients with different metastatic cancers [1–4]. However, several adverse events have been described [1–4]. VEGF is the key factor in tumour angiogenesis and regulates vascular proliferation and permeability. Furthermore, VEGF has important roles in mature vessels to maintain endothelial function. However, bevacizumab does not only inhibit tumour angiogenesis, but also decreases the renewal capacity of the endothelial cell in mature blood vessels. This endothelial dysfunction may cause defects in the interior vascular lining and may thereby cause arterial thrombosis [1–4]. Interestingly, VEGF was specifically expressed in aortic endothelial cells in mice where VEGF receptor 2 was found to be phosphorylated, indicating an autocrine loop [5].
To our knowledge, this is the first case report in which a large pedunculated thoracic aortic thrombus developed after therapy with IFL plus bevacizumab. It is important to emphasise that contrast-enhanced CT-scan before therapy with IFL and bevacizumab showed a non-atherosclerotic normal aorta. Clinical oncologists using bevacizumab therapy (especially those with metastatic colorectal cancer treated with IFL) should be aware of this potentially severe adverse side-effect.
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1. Hurwitz H, Fehrenbacher L, Novotny W, et al. (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342.
2. Yang JC, Haworth L, Sherry RM, et al. (2003) A randomized trial of bevacizumab, an anti–vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427–434.
3. Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al. (2003) Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 21:60–65.
4. Midgley R and Kerr D. (2005) Bevacizumab—current status and future directions. Ann Oncol 16:999–1004.
5. Maharaj AS, Saint-Geniez M, Maldonado AE, D'Amore PA. (2006) Vascular endothelial growth factor localization in the adult. Am J Pathol 168:639–648.
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