© The Author 2007. Published by Oxford University Press.
CORRESPONDENCE |
Bevacizumab-Induced Cardiovascular Events: A Consequence of Cholesterol Emboli Syndrome?
Affiliations of authors: Departments of Oncology (OM, JA, FG) and Internal Medicine (LM, LG), Faculty of Medicine, Assistance Publique–Hôpitaux de Paris, Hôpital Cochin, Université Paris V, Paris, France; Department of Internal Medicine and Cardiology, C.H.R.U. de Grenoble, Grenoble, France (JMM); Departments of Nephrology, Faculty of Medicine, Assistance Publique–Hôpitaux de Paris, Hôpital Pitié-Salpétrière, Université Paris VI, Paris, France (GD)
Correspondence to: Olivier Mir, MD, Unité d'Oncologie Médicale, Assistance Publique–Hôpitaux de Paris, Hôpital Cochin, Université Paris V, 27 rue du faubourg Saint-Jacques, 75679 Paris Cedex 14, France (e-mail: olivier.mir{at}cch.aphp.fr).
Bevacizumab (Avastin; Genentech, Inc, South San Francisco, CA) is a recombinant monoclonal antibody against vascular endothelial growth factor (VEGF) that is used to treat metastatic cancers of the colon, rectum, kidney, and breast. Its side effects include proteinuria (35% of patients), hypertension (15%–30% of patients), gastrointestinal perforations (5%–7% of patients), and arterial emboli (0.5%–1% of patients) (1–3). Although these toxic effects are more frequent in patients with atherosclerosis, their pathophysiology remains unresolved.
We observed that patients treated with bevacizumab who developed hypertension had similar clinical presentations and biologic features, leading us to propose a unique mechanism for the vascular side effects of bevacizumab. From June to October 2005, we prospectively observed 22 consecutive patients (six renal cancer patients and 16 colorectal cancer patients) who were being treated with bevacizumab at the Cochin University Hospital (Paris, France). All patients were instructed how to assess their blood pressure according to the current guidelines (4) and were asked to do so twice daily. All characteristics of this patient population (Table 1) were similar to those of other populations of patients treated with bevacizumab in previously published trials (1,2), except for performance status, which was 1 for most of our patients and 0 for patients in the previous studies.
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A total of 114 cycles of bevacizumab were administered, 25 cycles as single-agent and 89 cycles with 5-fluorouracil–based chemotherapy. The median number of cycles per patient was 6 (range = 2–9).
Three (13.5%) patients developed grade 1 or 2 hypertension (according to the National Cancer Institute Common Toxicity Criteria, version 3.0) (Table 1). Hypertension was not associated with proteinuria [as previously reported by Yang et al. (2)] and was easily managed with antihypertensive monotherapy, as previously described (1,2).
All three patients who developed hypertension had the following characteristics (Table 1): atherosclerosis risk factors (either a history of smoking or hypercholesterolemia), an increased heart rate (>90 beats per minute) at the onset of hypertension, and eosinophilia (>500/mm3) at the onset of hypertension. None of the patients who did not develop hypertension had an increased eosinophil count. None of the three patients who developed hypertension exhibited clinical symptoms that would require a skin biopsy.
Hypertension with concomitant eosinophilia is a well-known feature of cholesterol emboli syndrome (CES) (5). This syndrome is observed in patients undergoing arterial endovascular procedures (e.g., angiography, coronarography, and stenting) and spontaneously in patients with severe atherosclerosis (5).
VEGF is a well-known antihypertensive agent (6). Thus, inhibition of the VEGF pathway with bevacizumab could in theory lead to hypertension. However, in patients treated with sorafenib, another anti-VEGF agent, there was no correlation between the development of hypertension and serum VEGF level (7). Moreover, serum catecholamine, rennin, and aldosterone levels did not change during anti-VEGF therapy, lessening the likelihood that the onset of hypertension had an adrenergic or a renovascular etiology (7).
We hypothesize that bevacizumab-induced VEGF inhibition could be responsible for CES. In the subset of patients with atherosclerosis, CES may account for all bevacizumab-induced acute complications, including hypertension, arterial emboli, gastrointestinal perforations (related to mesenteric ischemia), and late-onset renal dysfunction (5).
In view of this observation, a prospective follow-up of atherosclerotic patients receiving bevacizumab seems warranted.
REFERENCES
(1) 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.
(2) Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzenruber DJ, Topalian SL, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003;349:427–34.
(3) Ramaswamy B, Elias AD, Kelbick NT, Dodley A, Morrow M, Hauger M, et al. Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients. Clin Cancer Res 2006;12:3124–9.
(4) O'Brien E, Asmar R, Beilin L, Imai Y, Mallion JM, Mancia G, et al. European Society of Hypertension recommendations for conventional, ambulatory and home blood pressure measurement. J Hypertens 2003;21:821–48.[CrossRef][Web of Science][Medline]
(5) Meyrier A. Cholesterol crystal embolism: diagnosis and treatment. Kidney Int 2006;69:1308–12.[Web of Science][Medline]
(6) Sane DC, Anton L, Brosnihan KB. Angiogenic growth factors and hypertension. Angiogenesis 2004;7:193–201.[CrossRef][Medline]
(7) Veronese ML, Mosenkis A, Flaherty KT, Gallagher M, Stevenson JP, Townsend RR, et al. Mechanisms of hypertension associated with BAY 43-9006. J Clin Oncol 2006;24: 1363–9.
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