Case Report Mandibular fracture in a patient treated with long-term antiangiogenic therapy and previous bisphosphonate exposure Tyler Davis, MD,1 Don-John Summerlin, MD,2 Michael Moore, MD,3 Anne Younger, RN,4 and E. Gabriela Chiorean, MD1,4 Departments of 1 Medicine, 2 Pathology, and 3 Otolaryngology, 4 Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, IN isphosponate-related osteonecrosis a mandibular fracture while he was off zoledronic of the jaw (ONJ) has been reported acid for 15 months but undergoing treatment with in the literature since 2003,1,2 with paclitaxel and bevacizumab plus sorafenib on a more than 90% of the events attribut- clinical trial. The case may help explain the tempo- ed to treatment with bisphosphonate ral relationship between therapy and the occurrence agents, such as zoledronic acid (Zometa) and pami- of jaw fracture, as well as the link between ONJ and dronate, which are used to treat hypercalcemia of the risk of fractures with sequential use of bisphos- malignancy and to reduce the risk of skeletal-related phonates and antiangiogenic agents. B 3 –5 events due to bone metastases. Patients with ONJ Case presentation generally present with exposed necrotic bone that does not heal for 6–8 weeks, often leading to signifi- A 65-year-old man was diagnosed with stage cant morbidity. The pathogenic mechanism for os- IIB (T2cN0M0) prostate cancer and initially teonecrosis is unclear, but, in addition to inhibiting treated with prostatectomy in 1997. He devel- bone resorption, preclinical data have demonstrated oped a biochemical recurrence, with a rise in pros- thrombotic microangiopathy and potent inhibition tate-specific antigen (PSA) level, in 2000 and was of angiogenesis,6 which may lead to avascular necro- treated with local radiotherapy followed by bi- sis and poor wound healing after dental procedures. calutamide. In February 2004, he had another re- Angiogenesis is a critical step in tumor growth, currence, this time with bone metastases, and was and agents that block neovascularization by target- treated with six cycles of docetaxel plus estramus- ing vascular endothelial growth factor (VEGF) or tine and started on zoledronic acid, 4 mg IV every its receptor (VEGFR) have been used successfully 4 weeks, until December 2004, when a bone scan for a variety of solid tumors. Bevacizumab (Avastin) showed no evidence of disease and treatment with is a monoclonal antibody that inhibits angiogenesis zoledronic acid was stopped. Subsequently, he de- by binding to VEGF,7 and sorafenib (Nexavar) is a veloped PSA elevations and was treated with ke- multiple-kinase inhibitor that inhibits several intra- toconazole, followed by pemetrexed (Alimta). cellular and cell-surface kinases, including VEGFR.8 Zoledronic acid therapy was resumed in Novem- Osteonecrosis of the jaw or femoral heads has been ber 2005, when a bone scan showed progressive me- increasingly recognized in patients treated with an- tastases. At that point, he received multiple lines of tiangiogenic therapies, even without concurrent therapy on clinical trials, including paclitaxel with bisphosphonate use.9–12 Previous data on combining PTK787 (vatalanib, a pan-VEGFR/tyrosine ki- bisphosphonates with antiangiogenic agents are con- nase inhibitor), given between April 2006 and May flicting, with some reports indicating a similar risk 2007; a pan-PI3K/mTOR inhibitor SF1126, given of ONJ compared with the use of bisphosphonates Manuscript received June 27, 2011; accepted September 8, 2011. alone13,14 and others showing significantly higher 15.16 Correspondence to: E. Gabriela Chiorean, MD, Indiana Univer- rates (18% vs 1% with bisphosphonates alone). sity Melvin and Bren Simon Cancer Center, 535 Barnhill Drive, In this paper, we describe the case of a patient RT 473, Indianapolis, IN 46202; e-mail, [email protected]. with metastatic prostate cancer and a history of Disclosures: The authors have no conflicts of interest to disclose. ONJ from use of zoledronic acid who developed Commun Oncol 2011;8:415–417 © 2011 Elsevier Inc. All rights reserved. Volume 8/Number 9 September 2011 ■ COMMUNITY ONCOLOGY 415 CASE REPORT Davis et al FIGURE 1 Panoramic radiograph of the jaw showing a fracture of the left FIGURE 2 Slide illustrating bone necrosis (arrow). In this 40× im- mandible (arrow). Note the loss of bone mineralization and dentition, support- age, all visualized bone is dead. The basophilic areas between ing the diagnosis of osteonecrosis of the jaw. bony trabeculae represent bacterial colonies. FIGURE 3 Medium-power (200×) image illustrating dead bone and FIGURE 4 Medium-power (200×) image of mandibular resection show- areas of inflammation, with neutrophil infiltration (thick arrow) and ing obliterative endarteritis. The vessel in the center (arrow) demonstrates bacterial colonies (thin arrow). medial and intimal thickening and is almost occluded. Inflammation, in the form of lymphocytes and plasma cells, is also evident. between July and December 2007; was withheld for 3 weeks before the quire any dental procedures. Because and paclitaxel 80 mg/m2 three times procedure, and bevacizumab was with- of the patient’s overall response of his a week every 4 weeks, bevacizumab 5 held for an additional 4 weeks after metastatic disease to the study treat- mg/kg every 2 weeks, and sorafenib the tooth extraction. Although dental ment, he continued on protocol cou- 200 mg/day orally 5 days/week, given notes indicate slow healing, the patient pled with frequent dental follow-ups. from May 2008 to June 2010. had no residual discomfort, but with a Repeat bone scans every 2 months In May 2008, baseline CT scans clinical diagnosis of ONJ, treatment showed stable radiotracer uptake in showed evidence of mediastinal ad- with zoledronic acid was discontinued. the left mandible through June 2010, enopathy; and the bone scan showed In September 2009, a routine bone and he remained asymptomatic. diffuse metastases in the thoracolum- scan identified increased radiotracer On July 2, 2010, the patient devel- bar spine, bilateral ribs, distal left fe- uptake in the left mandible and, coin- oped left jaw pain, which was self-treat- mur, proximal left humerus, and the ciding with another left molar infec- ed with antibiotics. Nine days later, the calvarium, with no uptake in the man- tion, the patient developed an erosion pain acutely exacerbated, and he devel- dibles. In December 2008, the patient of the left mandibular area. He was oped jaw swelling, prompting him to required the extraction of an infected treated with oral antibiotics (amoxi- go to the hospital emergency room. A left mandibular molar. All treatment cillin/clavulanic acid) but did not re- panoramic x-ray demonstrated a non- 416 COMMUNITY ONCOLOGY ■ September 2011 www.CommunityOncology.net Jaw fracture related to bisphosphonate/antiangiogenesis therapy CASE REPORT teonecrosis of the jaw and bisphosphonates. displaced comminuted fracture of the aIn our patient, the ONJ occurred b N Engl J Med 2005;353:99–102; discussion mid-left mandible (Figure 1). His last 3 years after starting bisphosphonate 199–102. study treatment with paclitaxel and therapy, and after zoledronic acid was 5. Woo SB, Hellstein JW, Kalmar JR. Nar- bevacizumab was on June 29 and for discontinued, he remained on treat- rative [corrected] review: bisphosphonates and sorafenib, on July 2. In September 2010, ment with antiangiogenic agents and osteonecrosis of the jaws. Ann Intern Med 2006;144:753–761. after pain control and optimization of chemotherapy for another 18 months. 6. Wood J, Bonjean K, Ruetz S, et al. Novel his nutritional status via a gastroesoph- This treatment very likely exacerbated antiangiogenic effects of the bisphosphonate ageal tube, the patient underwent seg- his ONJ and caused the mandibular compound zoledronic acid. J Pharmacol Exp mental mandibular resection, with re- fracture more than 2 years from start- Ther 2002;302:1055–1061. 7. Presta LG, Chen H, O’Connor SJ, et al. construction with a fibular free flap and ing study treatment and 18 months af- Humanization of an anti-vascular endotheli- microvascular anastomosis. The length ter stopping the use of zoledronic acid. al growth factor monoclonal antibody for the of the mandible defect was estimated We reviewed the jaw resection patho- therapy of solid tumors and other disorders. at 3.5 cm. The pathology report indi- logic specimen and identified bone Cancer Res 1997;57:4593–4599. 8. Wilhelm SM, Carter C, Tang L, et al. cated devitalized, thickened, sclerotic necrosis and obliterative endarteritis BAY 43-9006 exhibits broad spectrum oral an- bony trabeculae with empty lacunes, (Figure 4), and although the surgical titumor activity and targets the RAF/MEK/ and soft tissue with mixed inflamma- specimen dated from 2 months after he ERK pathway and receptor tyrosine kinases in- volved in tumor progression and angiogenesis. tory response accompanied by necrosis, had stopped anti-VEGF therapy, it is Cancer Res 2004;64:7099–7109. but no evidence of malignancy (Figures consistent with the profound effects of 9. Koch FP, Walter C, Hansen T, et al. Os- 2 and 3). There was evidence of isolated antiangiogenic agents, which may have teonecrosis of the jaw related to sunitinib. Oral obliterative endarteritis (Figure 4). The precluded long-term bone healing. Maxillofac Surg 2011;15:63–66. 10. Greuter S, Schmid F, Ruhstaller T, et al. patient recovered well from surgery and The jaw fracture we describe in Bevacizumab-associated osteonecrosis of the remained off any cancer therapy, but our patient with a previous diagnosis jaw. Ann Oncol 2008;19:2091–2092. suffered rapid disease progression in of ONJ, despite discontinuing treat- 11. Estilo CL, Fornier M, Farooki A, et al. December 2010 and died from meta- ment with bisphosphonates, represents Osteonecrosis of the jaw related to bevacizum- ab. J Clin Oncol 2008;26:4037–4038. static disease in May 2011. an alarming complication of VEGF 12. Guillet M, Walter T, Scoazec JY, et al.