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Sunitinib and Zoledronic Acid
Combination Therapy for Metastatic
Renal Cell Carcinoma: Alarming for Osteonecrosis of the Jaw

Introduction
As medical treatment of serious diseases such as cancer lengthens patient survival, the side effects of new drugs are beginning to present in community dentists’ patients. The most well-known example is probably bisphosphonate-related osteonecrosis of the jaw (ONJ), which was first reported in 36 patients in 2003 by Marx1; all 36 patients had been treated with zoledronic acid, an antiresorptive bisphosphonate typically used to treat osteopenia or osteoporosis or bone destruction due to cancer. In 2004, Ruggiero et al2 reported another 63 patients with osteonecrosis caused by zoledronic acid. Based on that evidence, in 2005, the United States Food and Drug Administration issued a warning for the entire bisphosphonate drug class for possible ONJ. More recently, with advancements in cancer treatment utilizing therapies such as RANK ligand inhibitors and angiogenesis inhibitors, the risk of ONJ appears to have been increased further still.

Angiogenesis inhibitors short-circuit cancer growth by inhibiting blood vessel formation in tumors. One way cancer cells grow is by releasing a protein called vascular endothelial growth factor (VEGF) to signal the need for blood vessel growth; sunitinib, a tyrosine kinase inhibitor (TKI) and antiangiogenic agent, binds to receptors on epithelial or endothelial cells to block VEGF activity. After several case reports described the occurrence of osteonecrosis in cancer patients who received targeted therapies, specifically TKIs and monoclonal antibodies tar- geting VEGF, the American Association of Oral and Maxillofacial Surgeons in 2014 expanded the concept of bisphosphonate-related ONJ to what is now termed medi- cation-related ONJ.3

Targeted therapies play an integral role in cancer care and can cause many types of oral complications. Therefore, patients should be aware of the potential complications caused by angiogenesis inhibitors in addition to bisphosphonates.

Here we present a case in which a patient receiving sunitinib with a history of zoledronic acid therapy developed extensive ONJ.

Case Descriptions
A 73-year-old woman presented to The University of Texas MD Anderson Cancer Center oral oncology clinic for evaluation of a large hard palate defect communicating into the nasal cavity and exposed bone on the left mandible. The patient had been diagnosed with metastatic renal cell carcinoma (RCC) and had been treated with sunitinib for the previous 2 years. The patient received sunitinib (37.5 mg) on a daily basis for 4 weeks before surgery to remove the RCC and did not receive sunitinib for 2 weeks after the surgery. After this 2-week period, the patient was treated with a maintenance dose of sunitinib (37.5 mg, 3 days a week). The patient also had zoledronic acid (4mg) IV infusions every 4 weeks for 3 months (Total of 3 infusions) owing to a left iliac osteolytic bone lesion.

Six months before presenting at our clinic, the patient saw her local dentist for a routine check-up. She developed a small laceration on her hard palate caused by the edge of the film used when the dentist performed routine radiography. The laceration progressed to a large non-healing wound. The bony hard palate became involved with deterioration, leading to sequestration of bone and tissue from the mouth. Intraoral examination revealed a large, 3-cm defect on the midline of the hard palate, communicating into the nasal cavity but not extending into the soft palate (Fig 1). The left posterior lingual mandibular area had 1.5 cm bone exposure under the 3-unit fixed dental prosthesis #18-20 (Figs 2, 3). An obturator prosthesis was fabricated to close the oral-nasal communication. The exposed left lingual mandibular necrotic bone eventually progressed to the midline and extended inferiorly to the floor of mouth. A new site of exposed bone was identified on the right mandible measuring 1cm.

Due to inability to control progression necrosis and pain of the jaw, the patient underwent a subtotal mandibulectomy and immediate fibula free flap reconstruction and placement of a reinforcing and stabilizing titanium reconstruction plate (Synthes TruMatch Proplan). (Fig 4, 5)  Following 6 months healing phase, removable mandibular resection prosthesis was fabricated. (Fig 6) This prosthesis will help with oral functional difficulties including poor lip support, drooling of saliva, poor bolus control and speech disturbance. The patient requires a mandibular resection prosthesis, which will help maintain functional positioning of the jaws, improve speech, mastication and deglutition.

Discussion
The case report describes a patient who developed extensive stage III medication-related ONJ on the hard palate and mandible, in which she underwent subtotal mandi-bulectomy with immediate fibula free flap reconstruction. Patients with advanced RCC with bone metastases are typically treated with a combination of TKIs, such as sunitinib, and zoledronic acid. This combination improves median overall survival and has better treatment efficacy than other regimens.4 However, several studies showed that the combination of sunitinib and zoledronic acid increases the incidence of ONJ in patients with metastatic renal cell carcinoma.4-7 Fusco et al7 conducted a multicenter study of metastatic renal cell cancer treated with bisphosphonates and targeted agents. They concluded that ONJ is not a rare occurrence and attributed its icrease to the increase in life expectancy due to use of new targeted cancer drugs, such as sunitinib, and therefore longer exposure to bisphosphonate treatments. The median duration of bisphosphonate administration was 12 months before developing medication-related ONJ. However, the 3 doses of zoledronic acid may have had some kind of an exacerbating effect.

Osteonecrosis can also occur with targeted therapy alone. Multiple case reports have reported the development of ONJ in patients who received targeted antiangiogenic therapies but who were bisphosphonate naïve.8-10

Although it has been more than a decade since the first case of bisphosphonate-related ONJ was reported, the pathophysiology of the disease is not fully understood. Santini D et al showed cancer patients treated with zoledronic acid had dramatic decreased circulating VEGF levels.11 Because VEGF is important in normal jawbone remodeling and wound repair, researchers have suggested that inhibition of VEGF activity could potentially lead to ONJ.9

Targeted therapies, such as TKIs, play integral roles in cancer care but result in a variety of oral complications and some long-term side effects of these drugs are still unknown. Although the risk of developing ONJ from TKIs or zoledronic acid are extremely rare, combination of the two may have a synergetic affect. As patients receiving such treatments are living longer and are returning to their community caregivers after their cancers have been cured or rendered stable, patients should be aware of the potential for serious complications and take appropriate precautions in their care.

References
1. Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg. 2003;61:1115–1117.
2. Ruggiero SL, Mehrotra B, Rosenberg TJ, et al. Osteonecrosis of the jaws associated with the use of bisphosphonates: A review of 63 cases. J Oral Maxillofac Surg. 2004;62:527–534.
3. Ruggiero SL, Dodson TB, Fantasia J, et al. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw—2014 update. J Oral Maxillofac Surg. 2014;72: 1938–56.
4. Beuselinck B, Wolter P, Karadimou A, et al. Concomitant oral tyrosine kinase inhibitors and bisphosphonates in advanced renal cell carcinoma with bone metastases. Br J Cancer. 2012;107:1665–1671.
5. Smidt-Hansen T, Folkmar TB, Fode K, et al. Combination of zoledronic acid and targeted therapy is active but may induce osteonecrosis of the jaw in patient with metastatic renal cell carcinoma. J Oral Maxillofac Surg. 2013;7:1532–1540.
6. Christodoulou C, Pervena A, Klouvas G, et al. Combination of bisphosphonates and antiangiogenic factors induces osteonecrosis of the jaw more frequently than bisphosphonates alone. Oncology. 2009;76: 209–211.
7. Fusco V, Porta C, Saia G, et al. Osteonecrosis of the jaw in patients with metastatic renal cell cancer treated With Bisphosphonates and Targeted Agents: Results of an Italian Multicenter Study and Review of the Literature. Clin Genitourin Cancer. 2015 Aug;13:287-94.
8. Koch FP, Walter C, Hansen T, et al. Osteonecrosis of the jaw related to sunitinib. Oral Maxillofac Surg. 2011;15:63–66.
9. Nicolatou-Galitis O, Migkou M, Psyrri A, et al. Gingival bleeding and jaw bone necrosis in patients with metastatic renal cell carcinoma receiving sunitinib: report of 2 cases with clinical implications. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;113:234–238.
10. Fleissig Y, Regev E, Lehman H. Sunitinib related osteonecrosis of jaw: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;113:e1–3.
11. Santini D, Vincenzi B, Dicuonzo G, et al: Zoledronic acid induces significant and long-lasting modifications of circulating angiogenic factors in cancer patients. Clin Cancer Res. 9:2893, 2003. KCJ

Keywords: Osteonecrosis, medication related osteonecrosis, jaw disease, bone necrosis

Corresponding Author: Alexander M. Won, DDS, Assistant Professor, Department of Head and Neck Surgery, Unit 1445, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Houston, Texas 77030; Phone: 713-745-8353; Fax: 713-794-4662 E-mail: amwon@mdanderson.org

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