Oral Maxillofac Surg (2011) 15:63–66 DOI 10.1007/s10006-010-0224-y

CASE REPORT

Osteonecrosis of the jaw related to sunitinib Felix P. Koch & Christian Walter & Torsten Hansen & Elke Jäger & Wilfried Wagner

Published online: 18 April 2010 # Springer-Verlag 2010

Abstract Case Report A 59-year-old male patient was referred to the hospital with exposed bone measuring 10 mm in diameter in the posterior, left-side region of the lower jaw. Two months previous, the first molar had been extracted. The patient had contracted renal cell carcinoma and had been treated by nephrectomy in 2003. Soft tissue metastases occurred. After initial therapy with interferon and vinblastine, a relapse occurred and the therapy was changed to sorafenib, followed by sunitinib. Osteonecrosis of the lower jaw appeared 1 year after initial and exclusive therapy with sunitinib. Conclusions Bisphosphonates had never been applied. With increasing application of multi-kinase inhibitors, complications due to osteonecrosis could occur more frequently. Keywords Osteonecrosis . Sunitinib . Multi-kinase inhibitor . Side effect . Tooth extraction . Cancer therapy

F. P. Koch (*) : C. Walter : W. Wagner Oral and Maxillofacial Surgery, University Medical Centre of the Johannes Gutenberg University, Mund-, Kiefer-und Gesichtschirurgie, Augustusplatz 2, 55131 Mainz, Germany e-mail: [email protected] T. Hansen Institute of Pathology, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany E. Jäger Clinic for Oncology and Haematology, Krankenhaus Nordwest, Frankfurt a.M., Germany

Introduction Sunitinib was introduced in the USA in 2006, and its longterm side effects are not yet known. This new class of anticancer therapeutics is a rationally designed small molecule that inhibits members of the split-kinase domain family of receptor tyrosine kinases, including the vascular endothelial growth factor receptors (VEGFRs) types 1 and 2, the platelet-derived growth factor receptors (PDGFR-α and PDGFR-β), as well as the stem cell factor c-KIT, FLT3, colony-stimulating factor1 (CSF-1) and RET [1–4]. By inhibition of the VEGF and PDGF signalling pathway, sunitinib affects the induction of angiogenesis and tumour progression by inhibiting surrounding fibroblasts and endothelial cells [5]. Sunitinib was 10% to 30% more potent against VEGFR2 and PDGF-β in biochemical and cell-based assays than the known indolin-2-one structural analogues [3]. The long-term side effects of this recently available anticancer therapeutic is currently under investigation. To the authors’ knowledge, this case presents the first occurrence of osteonecrosis of the jaw without an association with bisphosphonate medication [6–8].

Case report A 59-year-old male patient was referred to the clinic of Oral and Maxillofacial Surgery, University Medical Centre of the Johannes Gutenberg University in Mainz, with exposed bone measuring 10 mm in diameter in the posterior, leftside region of the lower jaw. Pus or inflammatory swelling of the soft tissue was not evident. The lesion was painless and did not show any signs of hyperaemia or bleeding (Fig. 1). Two months previous, the first molar had been extracted using local anaesthesia. The alveolar socket was

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Fig. 1 Clinical aspect of the left lower jaw 2 months after tooth extraction

Fig. 2 Cone beam CT image of hypodense bone in the region of the extracted first molar in the left lower jaw without signs of sequestration, marked by an arrow

left uncovered by the gingiva. In the general anamnesis, the patient had contracted renal cell carcinoma and had been treated by nephrectomy in 2003. Soft tissue metastases occurred in the dorsal, cervical muscles and others in the mediastinal, paravertebral region a short time afterwards. Initially, an adjuvant therapy with interferon and vinblastine was started. After a relapse occurring in January 2005, the therapy was changed to sorafenib, a multi-kinase inhibitor. During the first 4 weeks of June 2007, chemotherapy by sunitinib 50 mg/day was applied, followed by a continuous oral dosage of 37.5 mg/day. Concerning the personal anamnesis and written medical records, the patient had never been treated with bisphosphonates or corticosteroids. After the adjuvant chemotherapy began, hypertension and hypothyroidism occurred, resulting in the administration of ramipril 2.5 mg/day, hydrochlorothiazid 12.5/day, metoprolol 47,5 mg and l-thyroxin 50 μg/day. In May 2007, he was hospitalised because the left ventricular ejection fraction had decreased. In February 2008, regression of all metastases was documented by CT scan. For the diagnosis of osteonecrosis of the jaw, the digital volume tomography showed a hypodense bone area in the left, posterior region of the lower jaw without sequestration (Fig. 2). Surgical revision and ablation of necrosis was performed under general anaesthesia in April 2009. The bony extraction alveole did not macroscopically show any signs of bone remodelling processes after the tooth extraction that had been performed 3 months before. After necrosis ablation, the surrounding cancellous bone was found to have a physiological blood supply (Fig. 3). The wound was closed by a local gingival flap and tight sutures, which healed uneventfully. The histopathology showed necrotic bone with little invasion of polymorphonuclear cells. Furthermore, actinomyces could be found (Fig. 3).

Discussion Osteonecrosis of the jaw is a well-known complication after temporary or permanent loss of blood supply [9]. This could be caused by a traumatic event, or iatrogenically after radiation or chemotherapy in the oncologic setting [10]. Recently, osteonecrosis caused by bisphosphonates has been frequently discussed [11–13]. The described lesion was macroscopically very similar to bisphosphonateinduced enoral necrosis of the jaw. The patient, however, has never received bisphosphonate medication, but was chemotherapeutically treated with sorafenib and sunitinib, a tyrosine kinase inhibitor. Tyosine kinase inhibitors have anticancer potency to treat solid tumours, including gastrointestinal stromal tumours, small cell lung cancer, thyroid carcinoma and hematologic malignancies [4, 14,

Fig. 3 Histology of osteonecrosis and actinomyces, marked by an arrow (magnification of ×50)

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15]. Clinical phase II tumour trials attested the anticancer potency and the regression of renal cell carcinoma by sunitinib [16]. Known side effects of sunitinib are pain, hypertension, gastrointestinal toxicity, proteinuria, neurotoxicity, coagulation disorders with epistaxis, mucositis and hypothyroidism, the latter of which also occurring in this case [17–19]. Other adverse events described in clinical trials were fatigue, nausea, diarrhoea, skin discoloration, anorexia, dyspepsia and constipation [20]. A decrease in left ventricular ejection fraction is a rare but potentially life-threatening side effect [21]. In the presented case, 6 days of hospitalisation were necessary for the treatment of cardiomyopathia. By inhibiting the growth factor receptors and affecting the revascularisation process, sunitinib could have been responsible for the osteonecrosis and the unsatisfactory wound healing after tooth extraction. Similar to bisphosphonateinduced osteonecrosis of the jaw, risk factors such as tooth extraction or periodontal diseases should be discussed [22]. In addition to the macroscopic aspect, which is similar to that of bisphosphonate-induced osteonecrosis, the histopathology revealed an infiltration of actinomyces in this case, which has also been previously described in bisphosphonate-associated osteonecrosis [23]. In this case, however, bisphosphonates had never been applied, as is described elsewhere [6–8]. Furthermore, additional corticosteroid therapy was not performed as this medication is known to enhance osteonecrosis, especially an avascular necrosis of the femoral head [24]. The initially applied interferon alpha and vinblastine therapy had been stopped 3 years before the osteonecrosis of the jaw occurred. Since these medications do not remain in the tissue after several years, they should not be active 3 years after application [25, 26]. Therefore, in this case, the highly potent multikinase inhibitors were the only agents that could have been responsible for the development of an osteonecrosis of the jaw. If the single use of tyrosine kinase inhibitors, solely through high potent inhibitors such as sunitinib or in combination with different chemotherapeutic agents, can induce osteonecrosis of the jaw, the condition will become more frequent as use of this new therapeutic class increases.

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