title: Bevacizumab and osteonecrosis of the jaw: incidence and association with bisphosphonate therapy in three large prospective trials in advanced breast cancer.
abstract: Long-term bisphosphonate therapy is associated with increased risk of osteonecrosis of the jaw (ONJ). In a retrospective analysis, a 16% ONJ incidence was reported in patients receiving bisphosphonates with anti-angiogenic therapy (bevacizumab or sunitinib) for bone metastases from breast, colon, or renal cell cancers. To assess ONJ incidence with bevacizumab, we analysed data from 3,560 patients receiving bevacizumab-containing therapy for locally recurrent or metastatic breast cancer (LR/MBC) in two double-blind, randomised trials (AVADO and RIBBON-1) and a large, non-randomised safety study (ATHENA). The overall incidence of ONJ with bevacizumab was 0.3% in the blinded phase of the two randomised trials and 0.4% in the single-arm study. There was a trend towards increased ONJ incidence in patients who received bisphosphonate therapy versus those with no bisphosphonate exposure (0.9 vs. 0.2%, respectively, in the pooled analysis of the randomised trials; 2.4 vs. 0%, respectively, in ATHENA). In conclusion, this is the largest analysis of ONJ in patients receiving bevacizumab for LR/MBC. The 0.3-0.4% incidence is considerably lower than previously suggested with anti-angiogenic therapy in a small retrospective analysis. The risk of ONJ appeared to be increased in patients exposed to bisphosphonates, a pattern consistent with observations before the introduction of anti-angiogenic therapy to breast cancer management. The 0.9-2.4% incidence seen in bisphosphonate-exposed patients receiving bevacizumab is within the 1-6% range reported for bisphosphonates alone. Good oral hygiene, dental examination, and avoidance of invasive dental procedures remain important in patients receiving bisphosphonates, irrespective of bevacizumab administration.
authors.affiliation: Department of Oncology, Hematology and Respiratory Diseases, University of Modena and Reggio Emilia, University Hospital, Via del Pozzo 71, 41100 Modena, Italy. guarneri.valentina@unimore.it
authors.forename: Valentina
authors.initials: V
authors.lastname: Guarneri
authors.forename: David
authors.initials: D
authors.lastname: Miles
authors.forename: Nicholas
authors.initials: N
authors.lastname: Robert
authors.forename: Véronique
authors.initials: V
authors.lastname: Diéras
authors.forename: John
authors.initials: J
authors.lastname: Glaspy
authors.forename: Ian
authors.initials: I
authors.lastname: Smith
authors.forename: Christoph
authors.initials: C
authors.lastname: Thomssen
authors.forename: Laura
authors.initials: L
authors.lastname: Biganzoli
authors.forename: Tanya
authors.initials: T
authors.lastname: Taran
authors.forename: PierFranco
authors.initials: P
authors.lastname: Conte
mesh_terms: D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000068258:Bevacizumab; D001943:Breast Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004164:Diphosphonates / Q000009:adverse effects*; D000077143:Docetaxel; D004311:Double-Blind Method; D004357:Drug Synergism; D005260:Female; D018734:Genes, erbB-2; D006801:Humans; D015994:Incidence; D007571:Jaw Diseases / Q000139:chemically induced* / Q000453:epidemiology / Q000517:prevention & control; D008875:Middle Aged; D015337:Multicenter Studies as Topic / Q000706:statistics & numerical data*; D009362:Neoplasm Metastasis; D009910:Oral Hygiene; D010020:Osteonecrosis / Q000139:chemically induced* / Q000453:epidemiology / Q000517:prevention & control; D017239:Paclitaxel / Q000008:administration & dosage; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data*; D043823:Taxoids / Q000008:administration & dosage; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077235:Vinorelbine
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004164:Diphosphonates; D043823:Taxoids; D000077143:Docetaxel; D000068258:Bevacizumab; D014747:Vinblastine; D017239:Paclitaxel; D000077235:Vinorelbine