As you know, intravenous bisphosphonates and to a lesser extent oral bisphosphonates like fosamax have been associated with an increased rick of osteonecrosis of the jaw (ONJ). Recently, Dr. Richard Wynn at the University of Maryland published on a human monoclonal antibody, bevacizumab (Avastin), used in treating metastatic carcinoma, that also appears to be associated with an increased incidence of ONJ.
About the Author
Dr. Richard L. Wynn is Professor of Pharmacology at the University of Maryland Dental School. He holds a BS degree in Pharmacy and a PhD degree in Pharmacology. He chaired the Department of Pharmacology at the University of Maryland Dental School from 1980 to 1995. He is the lead author of the Drug Information Handbook for Dentistry, a co-author on many other dental drug publications, an author of over 300 refereed scientific journal articles, a consultant to the Academy of General Dentistry, a featured columnist, and a featured speaker presenting more than 500 courses in continuing dental education. One of his primary interests continues to be keeping dental professionals informed of all aspects of drug use in dental practice.
Bevacizumab (Avastin®): Another Drug Associated With Osteonecrosis of the Jaw
First it was the intravenous bisphosphonates, zoledronic acid (Zometa®) and palmidronate (Aredia®), then the oral bisphosphonates (the Fosamax® family of drugs), then the anti-RANKL drug, denosumab (Prolia®, Xgeva®). Now it’s a human monoclonal antibody known as bevacizumab (Avastin) that is associated with osteonecrosis of the jaw (ONJ) syndrome.
Bevacizumab (Avastin) belongs to a class of drugs known as antiangiogenic agents, used with increasing frequency in treating cancer. Bevacizumab is indicated for the treatment of metastatic colorectal cancer, and metastatic nonsquamous, nonsmall cell lung cancer. Angiogenesis in tumor cells involves the formation and growth of new blood vessels which help tumor growth. Bevacizumab acts to block angiogenesis through inhibition of cell proliferation and vessel sprouting, as well as by decreasing circulating vascular endothelial growth factor (VEGF) levels. This action is similar to the antiangiogenic action ascribed to the bisphosphonates. There are literature reports on patients receiving bevacizumab who developed ONJ. These reports are described in this month’s newsletter.
A case of ONJ associated with bevacizumab exposure was reported in a letter to the editor in 2008 (Greuter S, Schmid F, Ruhstaller T, et al, “Bevacizumab Associated Osteonecrosis of the Jaw,” Ann Oncol, 2008, 19(12):2091-2).
A 63-year old woman was treated for breast cancer. Bone scans were normal and she had never taken bisphosphonates. While being treated with liposomal doxorubicin and bevacizumab, the patient experienced left-sided maxillary pain after one-month therapy. A tooth infection was diagnosed and numbers 25 and 26 were extracted. One month later, a mouth-antrum fistula was surgically revised and occluded. Soon afterward, the patient suffered from a trigeminal neuralgia. Imaging showed maxillary sinusitis and signs of ONJ. The jaw lesion was extirpated and the sinus drained. Histology verified the clinical diagnosis of ONJ and an infiltration from the cancer was excluded. At 3 months of follow-up, the patient remained free of lesions and symptoms.
The authors commented that bevacizumab acts to block angiogensis through inhibition of cell proliferation and vessel sprouting, as well as by decreasing circulating vascular endothelial growth factor (VEGF) levels. This action is similar to the antiangiogenic action described for the bisphosphonates.
The authors stated that this was the third published case of ONJ associated with bevacizumab therapy. The doxorubicin the patient was taking is an anthracycline antineoplastic agent that has been on the market for many years and has never been known for causing ONJ. The authors suspected that bevacizumab, which hampers wound healing and possibly bone remodeling, was the causative agent in this case.
The other two published cases were included in a report by Estilo, et al (Estilo CL, Fornier M, Farooki A, et al, “Osteonecrosis of the Jaw Related to Bevacizumab,” J Clin Oncol, 2008, 26(24):4037-8).
A 51-year-old female with a history of infiltrating ductal carcinoma of the right breast was diagnosed in late 2001 and treated with mastectomy in 2002. She subsequently underwent treatment with chemotherapy, doxorubicin, cyclophosphamide, and letrozole for various cycles over a 3-year period. Since 2006, she underwent additional chemotherapy, capecitabine therapy, and radiation. In late December 2006, she was started on bevacizumab at a dose of 15 mg/kg every 3 weeks for a total of 8 doses, the last dose given in May 2007. Six weeks after the last dose, the patient presented with a 2-month history of complaints of lower jaw discomfort and protruding bone in the lower jaw. Examination revealed an area of bone exposure in the left posterior lingual mandible approximately 1 X 1 mm in diameter. The area appeared necrotic. The surrounding tissue had no evidence of infection. The exposed bone was smoothed with a bone file and the patient prescribed chlorhexidine 0.12% oral rinse. The bevacizumab and capecitabine were then discontinued. The area of exposed bone had resolved within a few weeks. The overlying mucosa appeared normal. At that time, a new area of exposed bone appeared in the right posterior lingual mandible of 1 X 1mm in area. Histology showed devitalized necrotic bone with a scalloped “moth eaten” appearance. Bacterial colonies occupied the demineralized areas.
The other case was a 33-year-old woman with a history of glioblastoma multiforme diagnosed in November 2006. She underwent surgery followed by radiation therapy and temozolomide from December 2006 through January 2007. The patient started bevacizumab therapy in Feb 2007 at a dose of 10 mg/kg every 2 weeks. Thirteen weeks later, she was referred to the dental clinic for evaluation of a 2-week history of spontaneous mucosal breakdown overlying her right mandible. The patient complained of gingival pain. On examination, there appeared a 1 X 2 cm dehiscence at the junction of the unattached/attached gingiva in the mucobuccal fold overlying the lower right first and second premolar and first molar teeth. There was exposed necrotic bone visible through the dehiscence extending inferiorly and posteriorly. There was no evidence of infection. Other than that, the oral mucosa appeared healthy with intact dentition. The patient continued on biweekly bevacizumab. In August 2007, she returned with a small mucosal defect posterior to the original lesion. There was soft tissue dehiscence with no evidence of exposed bone.
The authors commented that the clinical features of bone exposure in the two cases were compatible with ONJ in patients exposed to bisphosphonate therapy. The two patients had no history of bisphosphonate use. The authors suggested that bevacizumab contributed to the oral mucosal breakdown with exposed necrotic mandibular bone in the two patients. The antiangiogenic property of bevacizumab could compromise microvessel integrity in the jaw and lead to subclinical compromise of the osteonecrosis. Trauma from tooth brushing or chewing could also increase the demand on this compromised bone to repair itself and result in localized bone necrosis, periosteal death, and eventual exposed necrotic bone.
Estilo et al went on to explain that angiogenesis is a critical step in tumor growth, invasion, and metastasis. VEGF is a family of cytokines that exert important functions in tumor angiogenesis. VEGF is overexpressed in various human tumors and overexpression of VEGF is associated with tumor progression. VEGF is also essential for osteogenic differentiation and bone formation. Thus bevacizumab, used as a VEGF inhibitor to suppress tumor progression, could also suppress the osteogenic differentiation and bone formation. This could result in failure to repair bone trauma.
In the two patients described, additional factors possibly contributing to the development of ONJ were the advanced cancer and chemotherapy. The authors cautioned that clinicians involved in the care of patients treated with bevacizumab should be aware of the potential complication of ONJ.
Antiangiogenic Agents and the Risk of ONJ
Christodoulou et al reported that a combination of bisphosphonates and antiangiogenic factors induces ONJ more frequently than bisphosphonates alone (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(3):209-11). Their introduction in the report stated that antiangiogenic agents may add to the risk of ONJ, especially when used in combination with bisphosphonates. The purpose of the study was to do a back review of data of patients receiving bisphosphonates with or without antiangiogenic factors for osseous metastases from various tumors between June 2007 and June 2008.
Among 116 patients being treated for various malignancies, 25 received concurrent treatment with antiangiogenic agents at some point. Twenty-two were taking bevacizumab, two were taking a drug called sunitinib, and one was taking a drug called sorafenib. The median duration to exposure to bisphosphonates was 28.5 months for the 25 patients taking the antiangiogenic drugs and 24 months for those not taking any antiangiogenic drugs. There were no significant differences between the two groups regarding treatment duration with the bisphosphonate.
Of the 25 patients receiving concurrent treatment with bisphosphonates and the antiangiogenic drug, 4 developed ONJ (incidence of 16%). Of the 91 patients receiving bisphosphonates without antiangiogenic factors, 1 developed ONJ (incidence 1.1%). This difference was statistically significant.
In this study, the diagnosis of ONJ was according to the clinical diagnoses made by dentists specializing in treating cancer patients and consisted of pain in the jaw with exposed, necrotic bone, some with purulent discharge. The authors commented that bisphosphonates have also been reported to possess antiangiogenic activity, particularly zoledronic acid (Zometa®) — a widely popular bisphosphonate used as an adjunct agent in cancer treatment.
Greuter et al (above) summed it up best by stating “if more cases of bevacizumab-associated ONJ are reported, special dental management (jaw x-ray, optimal dental health, and good oral hygiene) should become standard before patients start bevacizumab.”
Dental Management to Reduce the Risk of ONJ
The importance of special dental management to reduce the risk of ONJ in patients taking bevacizumab was shown in a recent report (Francini F, Pascucci FF, Francini E, et al, “Osteonecrosis of the Jaw in Patients with Cancer Who Received Zoledronic Acid and Bevacizumab,” J Am Dent Assoc, 2011, 142(5):506-13). They looked at cancer patients on zoledronic acid and chemotherapy combined with bevacizumab who underwent a dental exam before starting treatment. They found that none of the patients developed ONJ.
The study included 59 patients with either breast cancer or nonsmall cell lung cancer who received 4 mg zoledronic acid I.V. every 4 weeks and 15 mg per kg bevacizumab every 3 weeks. The median time of receiving zoledronic acid was 18 months and the median time of receiving bevacizumab was 16 months. All subjects received a dental exam and panoramic x-rays before starting treatment and every three months thereafter until the patient died or was lost to follow-up. If needed, patients received periodontal disease treatment and underwent tooth extraction before they received any drug.
None of the patients required dentoalveolar surgery while undergoing cancer treatment. After a median follow up of 19.7 months, none of the participants developed ONJ. The conclusion was that a bisphosphonate combined with an antiangiogenic drug did not predispose to ONJ in participants with cancer that metastasized to the bone, who underwent a baseline dental examination and preventive dental measures.
Indications for Bevacizumab (Avastin®) Approved by FDA:
Treatment of metastatic colorectal cancer; treatment of unresectable, locally advanced, recurrent or metastatic nonsquamous, nonsmall cell lung cancer; treatment of metastatic HER-2 negative breast cancer (who have not received chemotherapy for metastatic disease); treatment of progressive glioblastoma; treatment of metastatic renal cell cancer (not an approved use in Canada).
Note: For the treatment of metastatic breast cancer, effectiveness is based on improvement in progression-free survival; not indicated for the treatment of breast cancer with metastatic disease that has progressed following anthracycline and taxane treatment. For the treatment of glioblastoma, effectiveness is based on improvement in objective response rate.
Treatment of recurrent ovarian cancer; recurrent cervical cancer; soft tissue sarcomas (angiosarcoma or hemangiopericytoma/solitary fibrous tumor); age-related macular degeneration (AMD).