Bevacizumab-Induced Nasal Septum Perforation

(齐康网)     Received September 15, 2005; accepted for publication October 4, 2005.

    A 53-year-old white male presented for evaluation and treatment after transverse colectomy for colon cancer. Postoperative computerized tomography and positron emission tomography scans confirmed synchronous liver metastases. The patient was started on 5-fluorouracil (5-FU), leucovorin, and oxaliplatin (Eloxatin®; Sanofi-Synthelabo Inc., New York) (mFOLFOX) in combination with bevacizumab (Avastin®; Genentech, Inc., South San Francisco, CA). His concurrent medications included metoprolol (Lopressor®; Novartis Pharmaceuticals Corporation, East Hanover, NJ and irbesartan (Avapro®; Bristol-Myers Squibb, Princeton, NJ) for hypertension and clopidogrel (Plavix®; Bristol-Myers Squibb), atorvastatin (Lipitor®; Pfizer Pharmaceuticals, New York), and aspirin for a history of single vessel coronary artery disease status post angioplasty. After three cycles of treatment with mFOLFOX/bevacizumab, the patient noted scabbing and irritation in the inferior part of the nasal septum associated with occasional bleeding. Physical examination revealed a small mucosal break. He denied any nasal instrumentation or manipulation, any history of cocaine abuse, or use of intranasal medications. After six cycles of chemotherapy, he complained of a "hole in the nose" in association with scant bloody discharge. Physical examination revealed a nasal septum perforation without any masses. A consultation with a head and neck specialist confirmed these findings on rhinoscopy. The mucosa was noted to be dry and scaly and slightly erythematous around the edges of the perforation. There were no visible masses or other abnormalities noted in the nasal vestibules. Figure 1 shows the nasal septal defect.

    Bevacizumab is a recombinant monoclonal immunoglobulin G1 antibody that selectively binds to vascular endothelial growth factor (VEGF), thus preventing its binding to the VEGF receptors VEGFR-1 and VEGFR-2 and inhibiting angiogenesis [1]. The combination of bevacizumab with irinotecan (Camptosar®; Pfizer Pharmaceuticals), 5-FU, and leucovorin has been shown to produce a superior response rate, time to progression, and overall survival in the first-line treatment of metastatic colon cancer [2]. Similarly, the combination of bevacizumab with FOLFOX has resulted in superior response rates, time to progression, and overall survival in the second-line treatment of metastatic colorectal cancer [3]. Bevacizumab has been associated with a 1% risk for bowel perforation when given as a single agent or in combination with FOLFOX [3]. Furthermore, a higher risk for wound healing complications and bleeding has been documented in patients who started treatment within 60 days from surgery [4]. Nasal bleeding is a common side effect of bevacizumab and is usually mild and intermittent. However, nasal septum perforation attributed to bevacizumab has not been previously reported. It is likely that nasal irritation occurs secondary to chemotherapy and/or bevacizumab. This nasal irritation may be associated with mucosal breaks and ulceration. Wound repair would normally require angiogenesis to provide nutrients, promote granulation tissue formation, and facilitate the clearance of debris. Bevacizumab inhibits VEGF-dependent angiogenesis, including endothelial cell proliferation and invasion migration, resulting in suboptimal wound healing [5]. The lack of appropriate wound repair in this case likely led to a vicious cycle of irritation, itching, and increasing nonhealing erosions in the nasal septum, ultimately leading to perforation. We believe that this side effect is attributable to bevacizumab only, especially because this patient underwent a subsequent hepatectomy (after an appropriate break from bevacizumab) without any wound healing complications.2995

    Nasal septum defect during bevacizumab therapy is self-limited and does not require treatment modification. Patients with nasal septum ulcerations should be advised to avoid manipulating their lesions and should be considered for local nasal wound care. These patients should be cautioned about the possibility of the development of a nasal septum perforation.

    AUTHORS’ NOTES

    The work was performed at Roswell Park Cancer Institute. The authors indicate no research support or disclaimers to be declared. The case has not been presented before.

    DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

    The authors indicate no potential conflicts of interest.

    REFERENCES

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    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.

    Giantonio B, Catalano P, Meropol N et al. High-dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: results from the Eastern Cooperative Oncology Group (ECOG) study E3200. Proc Am Soc Clin Oncol 2005;23:1s. Abstract 2.

    Hurwitz H, Fehrenbacher L, Cartwright T et al. Wound healing/bleeding in metastatic colorectal cancer patients who undergo surgery during treatment with bevacizumab. J Clin Oncol 2004;22(14s):3702.

    Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 2005;23:1011–1027. (文章出处：《肿瘤学家》)齐康网