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Journal of Clinical Oncology, Vol 26, No 24 (August 20), 2008: pp. 4037-4038 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.5424
Osteonecrosis of the Jaw Related to BevacizumabMemorial Sloan-Kettering Cancer Center, New York, NY A 51-year-old female with history of infiltrating ductal carcinoma of the right breast was diagnosed in late 2001 and treated with mastectomy in February 2002. She was subsequently treated with adjuvant chemotherapy with doxorubicin and cyclophosphamide for four cycles followed by hormonal therapy with letrozole for three years. She was diagnosed with a chest wall recurrence, involving the soft tissues in the right axillary and supra-clavicular areas in early 2006 and underwent six cycles of chemotherapy with albumin-bound nanoparticle-paclitaxel. She subsequently underwent a chest wall resection in September 2006, followed by radiation to the chest wall. She started capecitabine at the dose of 1000 mg twice a day, two weeks on and one week off, in October 2006 (in concurrence with radiation therapy to the chest wall). In December 2006, the dose of capecitabine was increased to 1500 mg AM and 1000 mg PM, also two weeks on and one week off. Bevacizumab was also started in late December 2006 at the dose of 15 mg/kg for 3 weeks for a total of 8 doses, the last one in May 2007. Six weeks following the last dose of bevacizumab, the patient presented with a 2-month history of complaints of lower jaw discomfort and what the she described as protruding bone in the lower jaw. The patient denied any recent history of dental or oral surgery. Examination revealed a small area of bone exposure in the left posterior lingual mandible, measuring approximately 1 x 1 mm in diameter. The bone appeared necrotic. The surrounding soft tissue appeared normal with no evidence of infection. The rest of the oral and dental examination was unremarkable. The exposed bone was smoothed with a bone file. The patient was prescribed chlorhexidine 0.12% oral rinse. Bevacizumab and capecitabine were discontinued. A few weeks later, the area of exposed bone had resolved. The overlying mucosa appeared normal. However, there was now a new area of 1 x 1 mm exposed bone in the right posterior lingual mandible (Fig 1A). The bone was mobile and was easily removed. Histological examination of the bony specimen (Fig 1B) showed devitalized, necrotic bone (NB, black arrowhead) demonstrating a scalloped, "moth-eaten" appearance. Bacterial colonies occupied those areas in which there was loss of mineralized bone. Also present are colonies of bacteria (B, black arrows) suggestive of Actinomyces and inflammatory cells at the edges of the necrotic bone. Another patient, a 33–year-old woman had a history of glioblastoma multiforme diagnosed in November 2006. She underwent subtotal resection of a left frontal mass in November 19, 2006, followed by radiation therapy with concurrent temozolomide, from December 4, 2006, to January 23, 2007. The total radiation dose was 5940 Gy/33 fractions. The radiation port did not include the oral cavity and jaw. The patient started bevacizumab therapy on February 20, 2007, at the dose of 10 mg/kg for 2 weeks. Thirteen weeks later, she was referred by a local medical oncologist for evaluation of 2-week history of spontaneous mucosal breakdown overlying her right mandible. The patient complained of gingival pain. On examination, there was a 1 x 2 cm dehiscence (Fig 1C), black arrow) at the junction of the unattached/attached gingiva in the mucobuccal fold overlying the lower right first and second premolar and first molar teeth. There was exposed necrotic bone visible through the dehiscence extending inferiorly and posteriorly. There was no evidence of acute infection. The rest of the oral mucosa appeared healthy; the dentition was intact. The patient continued on biweekly bevacizumab. On August 16, 2007, she returned with a small mucosal defect (Fig 1D, black arrow) posterior to the original lesion. There is a soft tissue dehiscence with no evidence of exposed bone. However, the original lesion appeared less deep, was asymptomatic, and displayed evidence of epithelial growth up the posterior wall of the defect.
The clinical features of bone exposure in the jaw in the two patients are compatible with osteonecrosis of the jaw (ONJ) in patients treated with bisphosphonate therapy. Beginning in 2003, there has been an increasing number of cases of ONJ reported in the dental and medical literature. ONJ is an oral lesion in which there is exposed necrotic bone. The lesions are often preceded by a dental surgical procedure; however, ONJ can also occur spontaneously. The etiology of ONJ is unknown. The incidence in patients with cancer receiving bisphosphonate therapy for metastatic bone disease has been estimated to range between 1% and 10%.1 A review found that 94% of reported cases of ONJ-involved patients receiving nitrogen-containing bisphosphonate (pamidronate and/or zoledronic acid) therapy intravenously for metastatic bone disease.2 Our two patients had no history of oral or intravenous bisphosphonate therapy. Angiogenesis is a critical step in tumor growth, invasion, and metastasis.3,4 Vascular endothelial growth factor (VEGF) is a family of cytokines that exert important functions in tumor angiogenesis. VEGF is overexpressed in various human tumors; furthermore, overexpression of VEGF has been shown to be associated with tumor progression.4 VEGF is essential for osteogenic differentiation and bone formation.5 Bevacizumab is a recombinant, humanized monoclonal antibody that binds to VEGF, thus inhibiting angiogenesis. Bevacizumab was approved by the US Food and Drug Administration in 2004 for the treatment of metastatic colorectal cancer. Bevacizumab, in combination with other agents, has also demonstrated clinical efficacy in many other cancers, including breast and lung cancer.6,7 Observed toxicities associated with bevacizumab include hypertension, proteinuria, mild to moderate hemorrhage, wound healing complications, thromboembolic events, and gastrointestinal perforation.8,9 Two separate cases of nasal septum perforation in patients treated with bevacizumab have been reported; impaired angiogenesis-dependent wound healing was hypothesized.10,11 We suggest that bevacizumab contributed to the oral mucosal breakdown/exposed necrotic mandibular bone in the two patients described in this report. The antiangiogenic property of bevacizumab might compromise microvessel integrity at the jaw and lead to subclinical compromise of the osteon. Trauma from tooth brushing or chewing could increase the demand on this compromised bone to repair itself, thus resulting in localized bone necrosis, periosteal death, and eventual exposed necrotic bone. Alternatively, inhibiting VEGF could have direct deleterious effects on bone cell differentiation and function and thereby cause a failure to repair physiologic trauma. Additional factors possibly contributing to the development of ONJ in these two patients include advanced cancer and chemotherapy. Neither patient had a history of medical conditions known to affect the vasculature, and neither patient smoked. To our knowledge, these are the first reports of ONJ in patients treated with bevacizumab alone without other antiangiogenic agents or bisphosphonates. Clinicians involved in the care of patients treated with bevacizumab should be aware of this potential complication. It is also important to note that patients with advanced breast cancer are often treated with both bevacizumab and bisphosphonate therapy. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES 1. Van Poznak C, Estilo C: Osteonecrosis of the jaw in cancer patients receiving IV bisphosphonates. Oncology (Williston Park) 20:1053-1062, 2006[Medline] 2. Woo S-B, Hellstein JW, Kalmar JR: Systematic review: Bisphosphonates and osteonecrosis of the jaw. Ann Intern Med 144:753-761, 2006 3. Kerbel R, Folkman J: Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2:727-739, 2002[CrossRef][Medline] 4. Dvorak HF: Vascular permeability factor/vascular endothelial growth factor: A critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 20:4368-4380, 2002 5. Cher ML, Towler DA, Rafii S, et al: Cancer interaction with the bone microenvironment: A workshop of the National Institutes of Health Tumor Microenvironment Study Section. Am J Pathol 168:1405-1412, 2006 6. Miller KD, Chap LI, Holmes FA, et al: Randomized phase III trial of capecitabine compared with bevacizumab and capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23:792-799, 2005 7. Herbst RS, O'Neill VJ, Fehrenbacher L, et al: Phase II study of efficacy and safety of bevacizumab in combination with chemotherapy or erlotinib compared with chemotherapy alone for treatment of recurrent or refractory non–small-cell lung cancer. J Clin Oncol 25:4743-4750, 2007 8. Saif MW, Elfiky A, Salem RR: Gastrointestinal perforation due to bevacizumab in colorectal cancer. Ann Surg Oncol 14:1860-1869, 2007[CrossRef][Medline] 9. Shih T, Lindley C: Bevacizumab: An angiogenesis inhibitor for the treatment of solid malignancies. Clin Ther 28:1779-1802, 2006[CrossRef][Medline] 10. Fakih MG, Lombardo JC: Bevacizumab-induced nasal septum perforation. The Oncologist 11:85-86, 2006 11. Traina TA, Norton L, Drucker K, et al: Nasal septum perforation in a bevacizumab-treated patient with metastatic breast cancer. The Oncologist 11:1070-1071, 2006
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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