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Kidney Cancer Journal 51 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 Figure 6a. Figure 6b. CABOSUN trial is viewed at a regulatory level and how these other IO combinations come forward. Take-home on treating kidney cancer. The key to kidney cancer treatment is to tailor a patient’s therapy and the schedule. In patients who can receive full doses, you want to be sensitive to their co-morbidities, because comorbidities limit our ability to give full doses. You want to make sure you address the toxicities associated with targeted therapy—persistently and throughout their course. I tell my patients when I first see them that the beginning of the treatment will be a bit more difficult until we get a handle on toxicity specific to them. Over time, we manage it quite well—we change schedule, we try not to modify dose, we pick patients appropriately and try to match the patient, regimen and the opportunity for best outcome. Robert A.Figlin, MD Editor-in-Chief EDITOR’S MEMO (continued from page 34)


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