Annals of Oncology Advance Access originally published online on March 8, 2006
Annals of Oncology 2006 17(7):1177-1178; doi:10.1093/annonc/mdl025
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© 2006 European Society for Medical Oncology
letter to the editor |
Bevacizumab in metastatic colorectal cancer: a left intracardiac thrombotic event
In September 2005, a 44-year-old French woman was referred to our University Hospital for the etiological diagnosis and specific treatment of an intracardiac mass. Two weeks previously she had experienced a cardiac arrest in the 48 h following the first cycle of first-line 5-fluorouracil (5-FU), oxaliplatin and bevacizumab-based chemotherapy for metastatic rectal cancer. After resuscitation at home by the emergency team, she was admitted to a general hospital. A trans-oesophageal cardiac ultrasound was performed and showed a 20 x 30 mm hypoechogenic and exophytic tumor attached to the left ventricle (Figure 1). Left ventricular function was initially noted at about 35%. ECG and cardiac enzymes did not indicate myocardial infarction. Nevertheless, heparin treatment was then systematically initiated at a curative dose. Since being admitted to our department, we have observed a complete response to anticoagulant treatment without any residual image in the left ventricle on second trans-thoracic and -oesophageal cardiac ultrasound.
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The first hypothetical diagnosis of a rectal metastasis in the left ventricular cavity was then excluded. We were then convinced of a severe side-effect of the chemotherapy treatment. All initial symptoms corresponded to a grade 4 life-threatening cardiac arrhythmia and a grade 3 left ventricular systolic dysfunction according to the common toxicity criteria version 3.0 grading scale [1
]. The initial left ventricular dysfunction led us to perform a coronary artery angiography and methergin test. We then excluded coronary artery disease and a possible spasm related to the 5-FU, which could have been responsible for the cardiac arrest. We concluded that this had been a potent cardiac thrombotic adverse-event of the bevacizumab. At discharge, this patient had recovered a normal left ventricular function confirmed by cardiac ultrasound and SPECT without any myocardial necrosis. We initiated an oral anticoagulant treatment for at least 6 months in this context of neoplasia. When last seen in November 2005, the patient was well and there has been no sign of recurrent cardiac thrombosis. Oncologists decided to contraindicate bevacizumab in the therapeutic program and continued a 5-FU and oxaliplatin chemotherapy regimen until disease progression or new side-effects greater than grade 3.
Since vascular endothelial growth factor (VEGF) regulates vascular proliferation and permeability, vascular dysfunction is an area of concern with angiogenesis inhibitors such as bevacizumab [2]. Although the increased risk of bleeding and the increased risk of thrombosis may appear to be contradictory, two effects of bevacizumab on the vasculature have been suggested, such as (i) the decreased replenishment of endothelial cells, leading to an increase of bleeding and (ii) the exposure of the subendothelium activating tissue factors and then provoking thrombotic events [2]. In recent randomized trials, grade 3–4 thrombotic events (including deep-vein and intra-abdominal thrombosis) occurred more frequently in patients receiving bevacizumab in combination with chemotherapy compared with chemotherapy alone [3]. Although arterial thromboembolic events were not a concern in additional phase II and III trials in colorectal cancer patients, a recent meta-analysis by the manufacturer [4] found a two-fold higher frequency in the bevacizumab treated-patients. These events included transient ischemic attacks, angina, myocardial infarction and stroke. Patients who are older than 65 years of age and have had a prior arterial thromboembolic event are at greater risk. In contrast, we present here an intracardiac thrombosis in a young patient without any history of arterial disease. Up to now, cardiac death was noted as an adverse event secondary to bevacizumab; this case illustrated one mechanism of cardiac arrest.
Since bevacizumab has demonstrated a therapeutic benefit in patients with metastatic colorectal cancers [5], more data need to be collected to gain a full understanding of bevacizumab's effect on bleeding and thrombosis.
1 INSERM, U 586 and Cardiology Department, RANGUEIL University Hospital, Toulouse, France; 2 Department of Medical Oncology, Institut Claudius Régaud, Toulouse, France; 3 Cardiology Department, General Hospital, Auch, France; 4 INSERM, EMI 0227 and Department of Radiation Oncology, Val d'Aurelle Cancer Institute, Montpellier, France
* (E-mail: azria{at}valdorel.fnclcc.fr)
References
1. Trotti A, Colevas AD, Setser A et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 2003; 13: 176–181.[CrossRef][Web of Science][Medline]
2. Kilickap S, Abali H, Celik I. Bevacizumab, bleeding, thrombosis, and warfarin. J Clin Oncol 2003; 21: 3542.
3. Skillings JR, Johnson DH, Miller K et al. Arterial thromboembolic events (ATEs) in a pooled analysis of 5 randomized, controlled trials (RCTs) of bevacizumab (BV) with chemotherapy. J Clin Oncol 2005; 24: (Abstr 3019).
4. Motl S. Bevacizumab in combination chemotherapy for colorectal and other cancers. Am J Health Syst Pharm 2005; 62: 1021–1032.
5. Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350: 2335–2342.
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