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Osteonecrosis of the jaw during sorafenib therapy for hepatocellular carcinoma

Abstract

Introduction

Sorafenib is an oral multiple tyrosine kinase inhibitor and is currently the only evidence-based treatment recommended for advanced hepatocellular carcinoma. We report a case of osteonecrosis of the jaw that occurred during sorafenib therapy in a patient with advanced hepatocellular carcinoma not treated with bisphosphonates or other antiangiogenic drugs.

Methods

A systematic search in PubMed yielded some cases of osteonecrosis of the jaw in patients treated with antiangiogenic agents, alone or in combination with bisphosphonates, for metastatic renal cell carcinoma. The only case of osteonecrosis observed during sorafenib therapy not combined with other predisposing agents was described by Guillet et al.

Results

A 74-year-old man diagnosed with hepatocellular carcinoma ensuing in hepatitis C virus infection, who was treated with sorafenib at a daily dose of 400 mg, developed osteonecrosis of the right mandibular body. The lesion was documented by a dental CT scan and surgical evaluation did not lead to an indication for curettage treatment. Sorafenib was discontinued because of the radiological and laboratory features of hepatocellular carcinoma progression and the high risk of jaw fracture.

Conclusions

To our knowledge, this is the first description of osteonecrosis of the jaw detected in a cirrhotic patient on sorafenib therapy not combined with bisphosphonates.

Tumori 2016; 102(Suppl. 2): e69 - e70

Article Type: CASE REPORT

DOI:10.5301/tj.5000504

Authors

Francesca Garuti, Vittoria Camelli, Luca Spinardi, Laura Bucci, Franco Trevisani

Article History

Disclosures

Financial support: None.
Conflict of interest: All the authors declare that they do not have any conflict of interest or financial interest regarding the subject of the article.

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Introduction

Sorafenib is an oral multiple tyrosine kinase inhibitor and currently represents the only evidence-based treatment recommended for advanced hepatocellular carcinoma (HCC) (1). The main adverse events related to this drug are fatigue (in 22%-73% of cases), diarrhea (39%-58%), skin rash (40%), anemia (27%), hand-foot skin reaction (21%-30%), and hypertension (5%-17%) (2).

Case presentation

A 74-year-old man was diagnosed with a single unresectable HCC in segment VII-VIII in 2013 ensuing in hepatitis C virus infection; severe stenosis of the aortic valve was also present. He underwent 3 transcatheter arterial chemoembolizations (TACE) and 2 percutaneous ethanol injections. In March 2015, magnetic resonance imaging showed neoplastic thrombosis of the left portal branch with recurrent HCC in segment II. In May 2015, a percutaneous aortic valvuloplasty was performed, and 10 days later sorafenib (Nexavar®; Bayer Pharmaceuticals Group) was started at a daily dose of 400 mg, with a ramp-up strategy. The full dosage (800 mg/day) was not reached because of the occurrence of marked fatigue. The patient’s treatment also included furosemide, potassium canrenoate, bisoprolol, allopurinol, tamsulosin, hydroxychloroquine, vitamin D and sertraline. He was not given bisphosphonates or other antiangiogenic drugs. Despite sorafenib therapy, serum alpha-fetoprotein levels rose progressively from 200 ng/mL to 450 ng/mL. In August, a multiphase computed tomography (CT) scan of the liver showed HCC progression with enlargement of the tumor nodules and portal thrombosis. In the same period, the patient contacted his dentist for a gingival lesion with bone exposure in the left mandibular body. A dental CT scan showed only the presence of a lytic area of the contralateral (right) mandibular body, at the site of a previous tooth extraction (October 2014) (Fig. 1). The case was discussed in a multidisciplinary meeting comprising a hepatologist, neuroradiologist, periodontologist and surgeon. The width of the lesion and its peripheral sclerosis were judged compatible with osteonecrosis of the jaw (ONJ) rather than a tooth extraction sequela which, however, could have been a risk factor for ONJ. Surgical maxillofacial evaluation did not lead to an indication for curettage treatment because there were no signs of local infection or bone sequestration. Sorafenib was discontinued because of the radiological and laboratory features of HCC progression and the high risk of jaw fracture. The adverse event was communicated to the Italian Agency of Pharmacovigilance, Bologna branch, in September 2015. Second-line therapy with capecitabine was started on October 10th, 2015. The patient died on November 8th due to HCC progression.

Axial CT (A) and multiplanar reformatting reconstructed lateral view (B) demonstrate the osseous sclerosis (arrows) surrounding a large lytic area of osteonecrosis close to the right mandibular canal.

Discussion

A systematic search in PubMed yielded some cases of ONJ arising in patients treated with antiangiogenic agents, alone or in combination with bisphosphonates, for metastatic renal cell carcinoma (3-4-5). The only case of osteonecrosis observed during sorafenib therapy not combined with other predisposing agents was described by Guillet et al (6). In their patient, who presented with HCC and mediastinal and vertebral metastases, bilateral osteonecrosis of the femoral heads was observed. Instead, no cases of ONJ occurring during sorafenib therapy have been reported so far.

The pathogenesis of sorafenib-induced ONJ has not yet been clarified, but a multifactorial origin may be hypothesized, including 1) ischemic injury caused by the drug; 2) low bone turnover due to vitamin D deficiency (the vitamin level of our patient was 12 ng/mL, which is well below the lower limit of normal range); 3) low chemotaxis of immunocompetent cells activated by several mediators, such as vitamin D itself, M-CSF, VEGF and RANKL (7). Therefore, it may be assumed that sorafenib and vitamin D deficiency, which is a very common finding in liver cirrhosis, concurred in the development of ONJ in our patient.

To the best of our knowledge, this is the first description of ONJ in a cirrhotic patient on sorafenib therapy not combined with bisphosphonates. Oncologists and gastroenterologists should be aware of this dangerous, although uncommon, adverse event, which may represent a previously unreported cause of interruption of sorafenib therapy. It can be hypothesized that early correction of vitamin D deficiency has a protective effect against this risk.

Disclosures

Financial support: None.
Conflict of interest: All the authors declare that they do not have any conflict of interest or financial interest regarding the subject of the article.
References
  • 1. Llovet JM Ricci S Mazzaferro V et al; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008 359 4 378 390 Google Scholar
  • 2. Blanchet B Billemont B Barete S et al. Toxicity of sorafenib: clinical and molecular aspects. Expert Opin Drug Saf 2010 9 2 275 287 Google Scholar
  • 3. Yarom N Elad S Madrid C Migliorati CA Osteonecrosis of the jaws induced by drugs other than bisphosphonates - a call to update terminology in light of new data. Oral Oncol 2010 46 1 e1 Google Scholar
  • 4. 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 13 4 287 294 Google Scholar
  • 5. 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 10 1665 1671 Google Scholar
  • 6. Guillet M Walter T Scoazec JY Vial T Lombard-Bohas C Dumortier J Sorafenib-induced bilateral osteonecrosis of femoral heads. J Clin Oncol 2010 28 2 e14 Google Scholar
  • 7. Troeltzsch M Woodlock T Kriegelstein S Steiner T Messlinger K Troeltzsch M Physiology and pharmacology of nonbisphosphonate drugs implicated in osteonecrosis of the jaw. J Can Dent Assoc 2012 78 c85 Google Scholar

Authors

Affiliations

  • Department of Medical and Surgical Sciences, Alma Mater Studiorum-University of Bologna, Bologna - Italy
  • Department of Head and Neck and Sense Organs, Neuroradiology Unit, S. Orsola-Malpighi Hospital, University of Bologna, Bologna - Italy

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