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Sunitinib related osteonecrosis of jaw: a case report
Vol. 113 No. 3 March 2012
Sunitinib related osteonecrosis of jaw: a case report Yoram Fleissig, DMD,a Eran Regev, DMD, MD,b and Hadas Lehman, DMD, MSc,c Jerusalem, Israel HADASSAH-HEBREW UNIVERSITY MEDICAL CENTER
A 58-year-old woman presented to the Oral and Maxillofacial Surgery Clinic experiencing severe limited mouth opening and exposed bone in the socket of the right mandibular third molar 8 months following the extraction of the tooth. The patient had been treated during the year before her presentation with sunitinib, an antiangiogenic drug, for renal cell carcinoma. The clinical, radiographic, and histologic picture of a chronic nonhealing extraction socket was consistent with osteonecrosis of the jaw (ONJ), although she had never been treated with bisphosphonates or corticosteroids. The treatment with sunitinib was discontinued and the patient was treated with antibiotics and physiotherapy for 12 weeks with complete recovery. Sunitinib may cause osteonecrosis of the jaw after oral surgical interventions with no previous exposure to bisphosphonates. The pathogenesis may be related to its antiangiogenic mechanism and impaired wound healing. Full recovery may require long-term cessation of the insulting drug combined with prolonged antibiotic treatment. (Oral Surg Oral Med Oral Pathol Oral Radiol 2012;113:e1-e3)
Osteonecrosis of the jaw (ONJ), a chronic nonhealing and painful wound, may be the result of radiotherapy,1 chemotherapy,2 and a complication of osteomyelitis.3 As a unique phenomena to the jawbones, the main predisposing factors to develop ONJ in all these conditions are oral surgical intervention and oral mucosa breakdown. Although treatment modalities vary from extensive resection to conservative treatment, depending on the cause, the prevention of such a complication is preferred. In recent years, there has been a growing clinical and basic research interest in the entity of bisphosphonate-related osteonecrosis of the jaw (BRONJ). Although clinically and histologically it may resemble other conditions of ONJ, the pathogenesis of BRONJ has not yet been elucidated.4 Nevertheless, several potential factors have been suggested that increase the risk of developing BRONJ in combination with bisphosphonates (BPs). One such drug group is the antiangiogenic drugs.4 We present here a patient who was treated with sunitinib for renal cell carcinoma and developed osteonecrosis of the mandible with no history of bisphosphonate treatment.
a
Resident, Department of Oral and Maxillofacial Surgery, HadassahHebrew University Medical Center, Jerusalem, Israel. b Senior Lecturer, Department of Oral and Maxillofacial Surgery, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. c Attending, Department of Oral and Maxillofacial Surgery, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. Received for publication Mar 20, 2011; returned for revision Jun 15, 2011; accepted for publication Jun 23, 2011. © 2012 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter doi:10.1016/j.tripleo.2011.06.023
CASE REPORT A 58-year-old woman presented to the Oral and Maxillofacial Surgery Clinic at Hadassah-Hebrew University Faculty of Dental Medicine, complaining of limited mouth opening and pain on the right lower jaw of 2 months’ duration. Eight months before her presentation she had her right lower third molar extracted because of deep caries and recurrent episodes of pericoronitis (Fig. 1). The patient was diagnosed with renal cell carcinoma 12 years before her initial presentation for which she underwent a left total nephrectomy followed by right partial nephrectomy 3 times because of recurrences. In the past year she had been treated with cycles of 50 mg sunitinib once a day for 4 weeks followed by 2 weeks drug-free. The rest of her medical history was positive for hypothyroidism treated with thyroxine sodium. She also had osteoporosis but had never been treated with bisphosphonates or corticosteroids and had never received radiotherapy to the head and neck region. Review of the clinic record revealed that the extraction took place on the 14th day of the treatment-free period, which was extended by another 14 days after the extraction. Therefore, she had a total of 4 weeks without sunitinib before resuming the drug. On follow-up visits several weeks after the extraction, there was partial healing in the socket, but she failed to return for further appointments. On presentation, the patient stated that she experienced episodes of limited mouth opening, apparently correlated with the sunitinib treatment courses, following but also before the extraction. On extraoral examination on the admission day, she had a slight right submandibular swelling and local redness without skin fistula. Maximal mouth opening was 5 mm between the incisors. Intraoral examination revealed local inflammation around the socket of the right lower third molar, slight pus excretion, and a small area of exposed bone. A panorex taken on admission revealed incomplete bone remodeling of the right lower third molar socket (Fig. 2). A computed tomography (CT) scan demonstrated
e1
ORAL AND MAXILLOFACIAL SURGERY e2 Fleissig et al.
Fig. 1. Preoperative panorex with mandibular right third molar vertically impacted.
Fig. 2. Panorex taken 8 months after extraction. Note the unsatisfactory bone remodeling of the extraction socket and cortex disappearance.
Fig. 3. CT scan coronal reconstruction showing irregular remodeling and cortical bone disappearance after extraction of the mandibular right third molar. irregularity of the alveolar cortical margin in the location of the lower third molar (Fig. 3) and moderate inflammatory changes of the subcutaneous adipose tissue adjacent to the right side of the mandible and the submental region, suggestive of cellulitis. There were also several enlarged lymph nodes, up to 16 mm in diameter, in the right submandibular region.
OOOO March 2012 With the differential diagnosis of osteomyelitis or metastasis, the patient was admitted for intravenous (IV) antibiotics (amoxicillin and clavulanate) and a biopsy of the exposed bone was performed. Sunitinib was discontinued. The histopathology examination revealed necrotic bone and colonies of gram-positive bacteria, morphologically consistent with Actinomyces; however, the microbiology culture could not confirm Actinomyces species. The patient was discharged for home IV therapy with penicillin-G 16 million U every 24 hours for 6 weeks followed by 6 weeks of oral antibiotics (amoxicillin) and physiotherapy for the limited mouth opening. The patient returned for weekly follow-up visits. The extraoral signs resolved after 3 weeks of antibiotic treatment. The intraoral wound was healing and her mouth opening improved progressively until complete recovery after 6 weeks.
DISCUSSION Since its approval by the Food and Drug Administration in 2006 and the introduction for the treatment of advanced kidney cancer, sunitinib has shown improved survival rate over the previous cytokine treatment.5,6 Sunitinib is an orally administered multitargeted receptor tyrosine kinase (RTK) inhibitor, including vascular endothelial growth factor receptor (VEGFR) and plateletderived growth factor receptor (PDGFR), which are overexpressed in tumors.5,6 RTKs are cell surface receptors that initiate growth, differentiation, and survival of various cell types, including endothelial and tumor cells. Inhibition of these receptors impairs proliferation, migration, differentiation, neoangiogenesis, and invasion of cancer cells, thus providing an attractive target for cancer therapy.7 The common sunitinib treatment protocol consists of 6-week cycles of 50 mg/d for 4 weeks followed by 2 weeks off treatment. Following a single oral dose, peak plasma sunitinib levels are reached after 6 to 12 hours. Sunitinib and its primary metabolite, SU12662, have half-lives of 40 and 80 hours, respectively.5 In contrast to conventional chemotherapy, which is given in courses over a defined period, treatment with sunitinib may be given as a maintenance drug over a longer period, sometimes for years.8 Previous reports have already highlighted the hazardous potential for osteonecrosis of the jaw when combining bisphosphonates and antiangiogenic drugs. It is assumed that the incidence of ONJ in antiangiogenic-treated patients who are exposed to bisphosphonates is 0.9% to 2.4%.9 Several case reports indicated that sunitinib specifically may increase the risk of BRONJ or worsen it.8,10-12 It was suggested that the additive toxic effect of antiangiogenic drugs in patients receiving bisphosphonates causes ONJ because of oral mucosa breakdown, impaired angiogenesis, and bone remodeling.13 Mucositis, another side effect of sunitinib,
OOOO Volume 113, Number 3
may also be a contributing factor of BRONJ when combined with bisphosphonates.8 Review of the English literature14 revealed only 1 similar case report of ONJ in a patient treated with sunitinib with no previous exposure to bisphosphonates. These 2 cases, in addition to the reports on the association of bisphosphonates and antiangiogenic drugs, may raise the possibility that sunitinib, independently, can cause ONJ. Unlike BRONJ, in which the pathogenesis is not yet clear, the role of antiangiogenic drugs in ONJ seems intuitive. Because VEGF and PDGF are well-known factors in normal jawbone remodeling and wound repair, inhibition of their activity could lead to ONJ. Other antiangiogenic drugs have already been suspected of having a similar effect. For example, bevacizumab (Avastin), a monoclonal antibody that binds to VEGF and inhibits angiogenesis, was reported to cause wound-healing complications,15 as well as ONJ, with a calculated risk of up to 0.2%.9,16,17 The current literature suggests a treatment window of bevacizumab of 6 to 8 weeks before and 4 weeks after surgery to lower the risk of surgical wound-healing complications.15 The perioperative treatment holiday of 4 weeks that was done in our case was based on the experience with bevacizumab and on the half-life of sunitinib. Apparently this treatment protocol may not be sufficient. According to sunitinib clinical outcome success, it is anticipated that its use will increase and encompass other cancers as well, potentially resulting in more cases of ONJ. In conclusion, there is emerging evidence that sunitinib is independently related to osteonecrosis of the jaw, and that discontinuation may lead to clinical improvement; however, more research is needed to support these findings. Because long-term side effects of sunitinib are still not known, these first reports of ONJ should raise a red flag, and oncologists as well as dentists and oral and maxillofacial surgeons should be aware of the potential for development of ONJ as a result of surgical intervention under sunitinib treatment. REFERENCES 1. Marx RE. Osteoradionecrosis: a new concept of its pathophysiology. J Oral Maxillofac Surg 1983;41:283-8. 2. Sung EC, Chan SM, Sakuri K, Chung E. Osteonecrosis of the maxilla as a complication to chemotherapy: a case report. Spec Care Dentist 2002;22:142-6. 3. Lew DP, Waldvogel FA. Osteomyelitis. N Engl J Med 1997;336:999-1007.
Fleissig et al. e3 4. Allen MR, Burr DB. The pathogenesis of bisphosphonate-related osteonecrosis of the jaw: so many hypotheses, so few data. J Oral Maxillofac Surg 2009;67(Suppl 1):61-70. 5. Oudard S, Beuselinck B, Decoene J, Albers P. Sunitinib for the treatment of metastatic renal cell carcinoma. Cancer Treat Rev 2011;37:178-84. 6. Patyna S, Laird AD, Mendel DB, O’Farrell AM, Liang C, Guan H, et al. SU14813: a novel multiple receptor tyrosine kinase inhibitor with potent antiangiogenic and antitumor activity. Mol Cancer Ther 2006;5:1774-82. 7. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115-24. 8. Hoefert S, Eufinger H. Sunitinib may raise the risk of bisphosphonate-related osteonecrosis of the jaw: presentation of three cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010;110:463-9. 9. Guarneri V, Miles D, Robert N, Diéras V, Glaspy J, Smith I, et al. Bevacizumab and osteonecrosis of the jaw: incidence and association with bisphosphonate therapy in three large prospective trials in advanced breast cancer. Breast Cancer Res Treat 2010;122;181-8. 10. Brunello A, Saia G, Bedogni A, Scaglione D, Basso U. Worsening of osteonecrosis of the jaw during treatment with sunitinib in a patient with metastatic renal cell carcinoma. Bone 2009;44:173-5. 11. Bozas G, Roy A, Ramasamy V, Maraveyas A. Osteonecrosis of the jaw after a single bisphosphonate infusion in a patient with metastatic renal cancer treated with sunitinib. Onkologie 2010;33:321-3. 12. Christodoulou C, Pervena A, Klouvas G, Galani E, Falagas ME, Tsakalos G et al. Combination of bisphosphonates and antiangiogenic factors induces osteonecrosis of the jaw more frequently than bisphosphonates alone. Oncology 2009;76:209-11. 13. Ayllon J, Launay-Vacher V, Medioni J, Cros C, Spano JP, Oudard S. Osteonecrosis of the jaw under bisphosphonate and antiangiogenic therapies: cumulative toxicity profile? Ann Oncol 2009;20;600-1. 14. Koch FP, Walter C, Hansen T, Jäger E, Wagner W. Osteonecrosis of the jaw related to sunitinib. Oral Maxillofac Surg 2011;15:63-6. 15. Gordon CR, Rojavin Y, Patel M, Zins JE, Grana G, Kann B, et al. A review on bevacizumab and surgical wound healing: an important warning to all surgeons. Ann Plast Surg 2009; 62:707-9. 16. Estilo CL, Fornier M, Farooki A, Carlson D, Bohle G, Huryn JM, et al. Osteonecrosis of the jaw related to bevacizumab. J Clin Oncol 2008;26:4037-8. 17. Salort-Llorca C, Mínguez-Serra MP, Silvestre-Donat FJ. Maxillary osteonecrosis associated to antiangiogenic drugs. Med Oral Patol Oral Cir Bucal 2011;16:e137-8. Reprint requests: Yoram Fleissig, DMD Department of Oral and Maxillofacial Surgery Hebrew University-Hadassah School of Dental Medicine Jerusalem 91129, Israel [email protected]
Sunitinib related osteonecrosis of jaw: a case report Yoram Fleissig, DMD,a Eran Regev, DMD, MD,b and Hadas Lehman, DMD, MSc,c Jerusalem, Israel HADASSAH-HEBREW UNIVERSITY MEDICAL CENTER
A 58-year-old woman presented to the Oral and Maxillofacial Surgery Clinic experiencing severe limited mouth opening and exposed bone in the socket of the right mandibular third molar 8 months following the extraction of the tooth. The patient had been treated during the year before her presentation with sunitinib, an antiangiogenic drug, for renal cell carcinoma. The clinical, radiographic, and histologic picture of a chronic nonhealing extraction socket was consistent with osteonecrosis of the jaw (ONJ), although she had never been treated with bisphosphonates or corticosteroids. The treatment with sunitinib was discontinued and the patient was treated with antibiotics and physiotherapy for 12 weeks with complete recovery. Sunitinib may cause osteonecrosis of the jaw after oral surgical interventions with no previous exposure to bisphosphonates. The pathogenesis may be related to its antiangiogenic mechanism and impaired wound healing. Full recovery may require long-term cessation of the insulting drug combined with prolonged antibiotic treatment. (Oral Surg Oral Med Oral Pathol Oral Radiol 2012;113:e1-e3)
Osteonecrosis of the jaw (ONJ), a chronic nonhealing and painful wound, may be the result of radiotherapy,1 chemotherapy,2 and a complication of osteomyelitis.3 As a unique phenomena to the jawbones, the main predisposing factors to develop ONJ in all these conditions are oral surgical intervention and oral mucosa breakdown. Although treatment modalities vary from extensive resection to conservative treatment, depending on the cause, the prevention of such a complication is preferred. In recent years, there has been a growing clinical and basic research interest in the entity of bisphosphonate-related osteonecrosis of the jaw (BRONJ). Although clinically and histologically it may resemble other conditions of ONJ, the pathogenesis of BRONJ has not yet been elucidated.4 Nevertheless, several potential factors have been suggested that increase the risk of developing BRONJ in combination with bisphosphonates (BPs). One such drug group is the antiangiogenic drugs.4 We present here a patient who was treated with sunitinib for renal cell carcinoma and developed osteonecrosis of the mandible with no history of bisphosphonate treatment.
a
Resident, Department of Oral and Maxillofacial Surgery, HadassahHebrew University Medical Center, Jerusalem, Israel. b Senior Lecturer, Department of Oral and Maxillofacial Surgery, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. c Attending, Department of Oral and Maxillofacial Surgery, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. Received for publication Mar 20, 2011; returned for revision Jun 15, 2011; accepted for publication Jun 23, 2011. © 2012 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter doi:10.1016/j.tripleo.2011.06.023
CASE REPORT A 58-year-old woman presented to the Oral and Maxillofacial Surgery Clinic at Hadassah-Hebrew University Faculty of Dental Medicine, complaining of limited mouth opening and pain on the right lower jaw of 2 months’ duration. Eight months before her presentation she had her right lower third molar extracted because of deep caries and recurrent episodes of pericoronitis (Fig. 1). The patient was diagnosed with renal cell carcinoma 12 years before her initial presentation for which she underwent a left total nephrectomy followed by right partial nephrectomy 3 times because of recurrences. In the past year she had been treated with cycles of 50 mg sunitinib once a day for 4 weeks followed by 2 weeks drug-free. The rest of her medical history was positive for hypothyroidism treated with thyroxine sodium. She also had osteoporosis but had never been treated with bisphosphonates or corticosteroids and had never received radiotherapy to the head and neck region. Review of the clinic record revealed that the extraction took place on the 14th day of the treatment-free period, which was extended by another 14 days after the extraction. Therefore, she had a total of 4 weeks without sunitinib before resuming the drug. On follow-up visits several weeks after the extraction, there was partial healing in the socket, but she failed to return for further appointments. On presentation, the patient stated that she experienced episodes of limited mouth opening, apparently correlated with the sunitinib treatment courses, following but also before the extraction. On extraoral examination on the admission day, she had a slight right submandibular swelling and local redness without skin fistula. Maximal mouth opening was 5 mm between the incisors. Intraoral examination revealed local inflammation around the socket of the right lower third molar, slight pus excretion, and a small area of exposed bone. A panorex taken on admission revealed incomplete bone remodeling of the right lower third molar socket (Fig. 2). A computed tomography (CT) scan demonstrated
e1
ORAL AND MAXILLOFACIAL SURGERY e2 Fleissig et al.
Fig. 1. Preoperative panorex with mandibular right third molar vertically impacted.
Fig. 2. Panorex taken 8 months after extraction. Note the unsatisfactory bone remodeling of the extraction socket and cortex disappearance.
Fig. 3. CT scan coronal reconstruction showing irregular remodeling and cortical bone disappearance after extraction of the mandibular right third molar. irregularity of the alveolar cortical margin in the location of the lower third molar (Fig. 3) and moderate inflammatory changes of the subcutaneous adipose tissue adjacent to the right side of the mandible and the submental region, suggestive of cellulitis. There were also several enlarged lymph nodes, up to 16 mm in diameter, in the right submandibular region.
OOOO March 2012 With the differential diagnosis of osteomyelitis or metastasis, the patient was admitted for intravenous (IV) antibiotics (amoxicillin and clavulanate) and a biopsy of the exposed bone was performed. Sunitinib was discontinued. The histopathology examination revealed necrotic bone and colonies of gram-positive bacteria, morphologically consistent with Actinomyces; however, the microbiology culture could not confirm Actinomyces species. The patient was discharged for home IV therapy with penicillin-G 16 million U every 24 hours for 6 weeks followed by 6 weeks of oral antibiotics (amoxicillin) and physiotherapy for the limited mouth opening. The patient returned for weekly follow-up visits. The extraoral signs resolved after 3 weeks of antibiotic treatment. The intraoral wound was healing and her mouth opening improved progressively until complete recovery after 6 weeks.
DISCUSSION Since its approval by the Food and Drug Administration in 2006 and the introduction for the treatment of advanced kidney cancer, sunitinib has shown improved survival rate over the previous cytokine treatment.5,6 Sunitinib is an orally administered multitargeted receptor tyrosine kinase (RTK) inhibitor, including vascular endothelial growth factor receptor (VEGFR) and plateletderived growth factor receptor (PDGFR), which are overexpressed in tumors.5,6 RTKs are cell surface receptors that initiate growth, differentiation, and survival of various cell types, including endothelial and tumor cells. Inhibition of these receptors impairs proliferation, migration, differentiation, neoangiogenesis, and invasion of cancer cells, thus providing an attractive target for cancer therapy.7 The common sunitinib treatment protocol consists of 6-week cycles of 50 mg/d for 4 weeks followed by 2 weeks off treatment. Following a single oral dose, peak plasma sunitinib levels are reached after 6 to 12 hours. Sunitinib and its primary metabolite, SU12662, have half-lives of 40 and 80 hours, respectively.5 In contrast to conventional chemotherapy, which is given in courses over a defined period, treatment with sunitinib may be given as a maintenance drug over a longer period, sometimes for years.8 Previous reports have already highlighted the hazardous potential for osteonecrosis of the jaw when combining bisphosphonates and antiangiogenic drugs. It is assumed that the incidence of ONJ in antiangiogenic-treated patients who are exposed to bisphosphonates is 0.9% to 2.4%.9 Several case reports indicated that sunitinib specifically may increase the risk of BRONJ or worsen it.8,10-12 It was suggested that the additive toxic effect of antiangiogenic drugs in patients receiving bisphosphonates causes ONJ because of oral mucosa breakdown, impaired angiogenesis, and bone remodeling.13 Mucositis, another side effect of sunitinib,
OOOO Volume 113, Number 3
may also be a contributing factor of BRONJ when combined with bisphosphonates.8 Review of the English literature14 revealed only 1 similar case report of ONJ in a patient treated with sunitinib with no previous exposure to bisphosphonates. These 2 cases, in addition to the reports on the association of bisphosphonates and antiangiogenic drugs, may raise the possibility that sunitinib, independently, can cause ONJ. Unlike BRONJ, in which the pathogenesis is not yet clear, the role of antiangiogenic drugs in ONJ seems intuitive. Because VEGF and PDGF are well-known factors in normal jawbone remodeling and wound repair, inhibition of their activity could lead to ONJ. Other antiangiogenic drugs have already been suspected of having a similar effect. For example, bevacizumab (Avastin), a monoclonal antibody that binds to VEGF and inhibits angiogenesis, was reported to cause wound-healing complications,15 as well as ONJ, with a calculated risk of up to 0.2%.9,16,17 The current literature suggests a treatment window of bevacizumab of 6 to 8 weeks before and 4 weeks after surgery to lower the risk of surgical wound-healing complications.15 The perioperative treatment holiday of 4 weeks that was done in our case was based on the experience with bevacizumab and on the half-life of sunitinib. Apparently this treatment protocol may not be sufficient. According to sunitinib clinical outcome success, it is anticipated that its use will increase and encompass other cancers as well, potentially resulting in more cases of ONJ. In conclusion, there is emerging evidence that sunitinib is independently related to osteonecrosis of the jaw, and that discontinuation may lead to clinical improvement; however, more research is needed to support these findings. Because long-term side effects of sunitinib are still not known, these first reports of ONJ should raise a red flag, and oncologists as well as dentists and oral and maxillofacial surgeons should be aware of the potential for development of ONJ as a result of surgical intervention under sunitinib treatment. REFERENCES 1. Marx RE. Osteoradionecrosis: a new concept of its pathophysiology. J Oral Maxillofac Surg 1983;41:283-8. 2. Sung EC, Chan SM, Sakuri K, Chung E. Osteonecrosis of the maxilla as a complication to chemotherapy: a case report. Spec Care Dentist 2002;22:142-6. 3. Lew DP, Waldvogel FA. Osteomyelitis. N Engl J Med 1997;336:999-1007.
Fleissig et al. e3 4. Allen MR, Burr DB. The pathogenesis of bisphosphonate-related osteonecrosis of the jaw: so many hypotheses, so few data. J Oral Maxillofac Surg 2009;67(Suppl 1):61-70. 5. Oudard S, Beuselinck B, Decoene J, Albers P. Sunitinib for the treatment of metastatic renal cell carcinoma. Cancer Treat Rev 2011;37:178-84. 6. Patyna S, Laird AD, Mendel DB, O’Farrell AM, Liang C, Guan H, et al. SU14813: a novel multiple receptor tyrosine kinase inhibitor with potent antiangiogenic and antitumor activity. Mol Cancer Ther 2006;5:1774-82. 7. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115-24. 8. Hoefert S, Eufinger H. Sunitinib may raise the risk of bisphosphonate-related osteonecrosis of the jaw: presentation of three cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010;110:463-9. 9. Guarneri V, Miles D, Robert N, Diéras V, Glaspy J, Smith I, et al. Bevacizumab and osteonecrosis of the jaw: incidence and association with bisphosphonate therapy in three large prospective trials in advanced breast cancer. Breast Cancer Res Treat 2010;122;181-8. 10. Brunello A, Saia G, Bedogni A, Scaglione D, Basso U. Worsening of osteonecrosis of the jaw during treatment with sunitinib in a patient with metastatic renal cell carcinoma. Bone 2009;44:173-5. 11. Bozas G, Roy A, Ramasamy V, Maraveyas A. Osteonecrosis of the jaw after a single bisphosphonate infusion in a patient with metastatic renal cancer treated with sunitinib. Onkologie 2010;33:321-3. 12. Christodoulou C, Pervena A, Klouvas G, Galani E, Falagas ME, Tsakalos G et al. Combination of bisphosphonates and antiangiogenic factors induces osteonecrosis of the jaw more frequently than bisphosphonates alone. Oncology 2009;76:209-11. 13. Ayllon J, Launay-Vacher V, Medioni J, Cros C, Spano JP, Oudard S. Osteonecrosis of the jaw under bisphosphonate and antiangiogenic therapies: cumulative toxicity profile? Ann Oncol 2009;20;600-1. 14. Koch FP, Walter C, Hansen T, Jäger E, Wagner W. Osteonecrosis of the jaw related to sunitinib. Oral Maxillofac Surg 2011;15:63-6. 15. Gordon CR, Rojavin Y, Patel M, Zins JE, Grana G, Kann B, et al. A review on bevacizumab and surgical wound healing: an important warning to all surgeons. Ann Plast Surg 2009; 62:707-9. 16. Estilo CL, Fornier M, Farooki A, Carlson D, Bohle G, Huryn JM, et al. Osteonecrosis of the jaw related to bevacizumab. J Clin Oncol 2008;26:4037-8. 17. Salort-Llorca C, Mínguez-Serra MP, Silvestre-Donat FJ. Maxillary osteonecrosis associated to antiangiogenic drugs. Med Oral Patol Oral Cir Bucal 2011;16:e137-8. Reprint requests: Yoram Fleissig, DMD Department of Oral and Maxillofacial Surgery Hebrew University-Hadassah School of Dental Medicine Jerusalem 91129, Israel [email protected]