ABSTRACT
Title
Findings of osteonecrosis of the jaw under combined bisphosphonate and antiangiogenic therapies: an emergent problem?
Authors
I. Morreale1, A. Alaimo1, O. Di Fede2, A. Musciotto2, V. Fusco3, N. D’Alessandro1, G. Campisi2
1 Sezione di Farmacologia “P. Benigno”, Dipartimento di Scienze per la Promozione della Salute “G. D’Alessandro” - Università degli Studi di Palermo
2 Centro P.R.O.M.A.B. . (Prevenzione e Ricerca sull’Osteonecrosi dei Mascellari da Bifosfonati) .A.O.U.P. “P. Giaccone”-palermo
3 SC Oncologia, ASO Alessandria
1 Sezione di Farmacologia “P. Benigno”, Dipartimento di Scienze per la Promozione della Salute “G. D’Alessandro” - Università degli Studi di Palermo
2 Centro P.R.O.M.A.B. . (Prevenzione e Ricerca sull’Osteonecrosi dei Mascellari da Bifosfonati) .A.O.U.P. “P. Giaccone”-palermo
3 SC Oncologia, ASO Alessandria
Abstract
Background Osteonecrosis of the jaw (ONJ) is a serious adverse effect of bisphosphonates (BPs). It is deļ¬ned as exposed necrotic bone in the maxillofacial region that has persisted for more than 8 weeks, in the context of a current or previous treatment with BPs and no history of radiotherapy to jaws. Antiangiogenic agents, which are frequently used together with BPs in cancer patients, might enhance the risk of ONJ. The mechanism of this effect is not completely understood yet, but ONJ can result from loss of the blood supply to bone. Recent notices of EMA and AIFA underline the suspect that bevacizumab or sunitinib may increase the risk of ONJ when administered simultaneously or sequentially to BPs. On March 8th 2011, the Italian Pharmacovigilance Database contained 14 reports of ONJ associated with administration of both BPs and antiangiogenic drugs (only bevacizumab or sunitinib):7 of patients treated with BPs and bevacizumab (in 3 bevacizumab was a suspected drug) and 7 of patients treated with BPs and sunitinib (in 1 case sunitinib was a suspected drug). We present 3 own patients with renal cell carcinoma treated with BPs and who developed ONJ during or after medication with antiangiogenic agents, in particular with sunitinib.
1 A 58 year-old male patient underwent nephrectomy and adrenalectomy in 2006. After disease progression following therapy with IL-2, in 2007 he was enrolled in a clinical trial and treated with IL-2 and sorafenib. From July to August 2008, due to disease progression, the patient was givensunitinib and intravenous ibandronic acid. In January 2009 the patient complained of left hemi-mandible pain so that CT was performed revealing areas of necrotic bone which were treated by curettage. Treatment with ibandronic acid and sunitinib was discontinued. However, sunitinib was administered again, from March to September 2009, when it was discontinued due to disease progression. The patient was lost to follow up in September 2009.
2 A 61 year-old male patient underwent right radical nephrectomy in 2002. In 2004 he underwent right hepatectomy due to presence of liver metastases and was treated with IL-2 and capecitabine until October 2005. In 2006 he was enrolled in a clinical trial and treated with sorafenib, which was discontinued after 5 months owing to disease progression. In 2007 he was treated with everolimus. In 2008, owing to bone metastases, he was given sunitinib combined with zoledronic acid for 3 cycles and with pamidronate for 2 cycles. In 2009 edema of the right mandible with purulent discharge and spontaneous teeth loss occurred; in the maxillofacial region there were areas of exposed bone. Sunitinib was discontinued after 14 months due to the occurrence of ONJ.
3 A 56 year-old male patient, affected by RCC with bone metastases, underwent nephrectomy in 2007. In addition he was treated with zoledronic acid and sunitinib. In September 2007 oral examination performed by a dental unit specialized in ONJ showed only plaque and tartar and no other local risk factor for ONJ. In May 2009 the patient complained of persistent right mandibular pain which had appeared 6-8 months before. Oral examination revealed areas of exposed necrotic bone (right second and third molars) of the mandible associated with purulent discharge and mobility of the molars. Systemic antibiotics and local antiseptic therapy were prescribed. In June 2009 dental examination showed exposed necrotic bone with diffuse swelling of the extraoral tissues and purulent discharge. The diagnosis was:ONJ of the right hemi-mandible in a patient exposed to zoledronic acid and sunitinib.
Conclusions In light of these findings, the risk of ONJ associated with both BPs and antiangiogenic therapies has to be evaluated in large cohorts of patients and in prospective studies.
References
Aragon-Ching JB et al. (2009) Cancer Invest. 27, 221-226.
Christodolou C et al. (2009) Oncology. 76, 209-211.
Guarneri V et al. (2010) Breast Cancer Res Treat.122, 181-188
1 A 58 year-old male patient underwent nephrectomy and adrenalectomy in 2006. After disease progression following therapy with IL-2, in 2007 he was enrolled in a clinical trial and treated with IL-2 and sorafenib. From July to August 2008, due to disease progression, the patient was givensunitinib and intravenous ibandronic acid. In January 2009 the patient complained of left hemi-mandible pain so that CT was performed revealing areas of necrotic bone which were treated by curettage. Treatment with ibandronic acid and sunitinib was discontinued. However, sunitinib was administered again, from March to September 2009, when it was discontinued due to disease progression. The patient was lost to follow up in September 2009.
2 A 61 year-old male patient underwent right radical nephrectomy in 2002. In 2004 he underwent right hepatectomy due to presence of liver metastases and was treated with IL-2 and capecitabine until October 2005. In 2006 he was enrolled in a clinical trial and treated with sorafenib, which was discontinued after 5 months owing to disease progression. In 2007 he was treated with everolimus. In 2008, owing to bone metastases, he was given sunitinib combined with zoledronic acid for 3 cycles and with pamidronate for 2 cycles. In 2009 edema of the right mandible with purulent discharge and spontaneous teeth loss occurred; in the maxillofacial region there were areas of exposed bone. Sunitinib was discontinued after 14 months due to the occurrence of ONJ.
3 A 56 year-old male patient, affected by RCC with bone metastases, underwent nephrectomy in 2007. In addition he was treated with zoledronic acid and sunitinib. In September 2007 oral examination performed by a dental unit specialized in ONJ showed only plaque and tartar and no other local risk factor for ONJ. In May 2009 the patient complained of persistent right mandibular pain which had appeared 6-8 months before. Oral examination revealed areas of exposed necrotic bone (right second and third molars) of the mandible associated with purulent discharge and mobility of the molars. Systemic antibiotics and local antiseptic therapy were prescribed. In June 2009 dental examination showed exposed necrotic bone with diffuse swelling of the extraoral tissues and purulent discharge. The diagnosis was:ONJ of the right hemi-mandible in a patient exposed to zoledronic acid and sunitinib.
Conclusions In light of these findings, the risk of ONJ associated with both BPs and antiangiogenic therapies has to be evaluated in large cohorts of patients and in prospective studies.
References
Aragon-Ching JB et al. (2009) Cancer Invest. 27, 221-226.
Christodolou C et al. (2009) Oncology. 76, 209-211.
Guarneri V et al. (2010) Breast Cancer Res Treat.122, 181-188