Cancer Bone Mets Therapy: One in 40 Patients at Risk for ONJ

Liam Davenport

June 05, 2019

CHICAGO — New data highlight the risk for osteonecrosis of the jaw (ONJ) in cancer patients who take bone-modifying agents to reduce the risk for skeletal events associated with bone metastases.

One of the studies, S0702, was a prospective observational analysis of nearly 3500 cancer patients who had metastatic bone disease that was treated with bone-modifying agents, including zoledronic acid (multiple brands).

Catherine H. Van Poznak, MD, University of Michigan Comprehensive Cancer Center, Ann Arbor, showed that after 3 years, the cumulative incidence of ONJ in all cancer patients was 2.8%.

However, the risk was higher in patients with multiple myeloma. For those patients, the cumulative incidence was 4.3%, or 1 in 40 patients, during a 3-year period.

More frequent dosing of zoledronic acid (every 3–4 weeks) was associated with an almost fivefold increased risk for ONJ.

The risk was highest for patients who wore dentures, particularly removable dentures, for patients who had previously undergone dental surgery, and for current smokers.

Approached for comment, Silke Gillessen, MD, Kantonsspital St. Gallen, Switzerland, said that ONJ in cancer patients who receive bone-targeted agents is "a reality" and that clinicians "should be aware of it."

She also noted that other drugs are associated with an increased risk for ONJ, such as steroids and antiangiogenic drugs, and clinicians need to be careful when using these for patients who are already taking bone-modifying agents.

She noted that it is unclear how these drugs should best be used: "We have to admit that despite 2 decades of experience, the optimal use of bone-targeted agents remains unknown," Gillessen said.

The second study, S0307, was a phase 3 trial of bisphosphonates as adjuvant therapy for breast cancer. In that trial, more than 6000 women were randomly assigned to receive either zoledronic acid, clodronate (multiple brands), or ibandronate (Boniva, Hoffmann–La Roche).

After 3 years, Darya Kizub, MD, Everett Clinic, Washington, and colleagues found that the incidence of ONJ was highest in women who received zoledronic acid, at 1.26% vs <1% for the other drugs.

The median time to onset, at 25 months, was also shorter for zoledronic acid than for clodronate. Multivariate analysis indicated that the choice of bisphosphonate was significantly associated with ONJ incidence.

The results expand on those from a study presented last year at the annual meeting of the European Society for Medical Oncology. In that study, more than 1500 older women with metastatic breast cancer received bone-modifying agents.

The results indicated an overall 2-year incidence rate of ONJ of 1.7%, or 0.9% for bisphosphonate users, and 2.7% for patients given denosumab (multiple brands).

Kizub told Medscape Medical News that it is recommended that women with early-stage breast cancer who have undergone the menopause "see a dentist and undergo any dental procedures" before they begin treatment with a bisphosphonate.

Giilessen agreed, emphasizing, "Since it is not an emergency treatment, you should always have time for a dental exam" and "you should try to collaborate with a dentist and oral surgeon."

Kizub noted that the findings are also "really encouraging," inasmuch as the incidence rates are lower than the 3% to 5% that has been reported from retrospective studies, "before people knew to undergo any dental procedures" before beginning treatment with bisphosphonates.

Kizub commented that her data suggest that patients use clodronate and ibandronate rather than zoledronic acid to reduce the risk for ONJ. She pointed out that of these three drugs, only zolendronic acid is available in the United States.

Clodronate and ibandronate "are available in Canada and Europe, but not here, so there's some work being with the Food and Drug Administration to make clodronate available," she explained.

"Maybe in a couple of years we'll have it, and then I do think that clodronate would be more appropriate with patients with poor dental health," she said.

However, there are other considerations: zolendronic acid is administered via an injection once every 3 months, whereas clodronate is an oral drug that is taken daily and is associated with a higher risk for adverse gastrointestinal events. Thus, it's a case of "balancing all of those together," Kizub said.

When she and her colleagues surveyed their patients as to which drug they would prefer to take, "over half said that they would prefer to have an oral drug instead of the IV drug, if it was available."

Prospective, Observational Study

Van Poznak began her presentation by noting that case reports of ONJ in cancer patients who received intravenous bisphosphonates started to emerge in 2003. Estimates of the risk have ranged from <1% to 18% in cancer patients.

However, because those estimates were based on small cohorts and the range of percentages is broad, there is question as to their usefulness.

To investigate further, Van Poznak and colleagues conducted a prospective, observational study of US patients with metastatic bone disease from any malignancy.

Participants were required to have had limited or no prior exposure to bone-modifying agents and that their clinical care plan included the use of zoledronic acid within 30 days of study entry.

All cancer treatments, bone-modifying agents, and dental care were administered as clinically indicated. Dental examinations were recommended at baseline and every 6 months.

Medical, dental, and patient-reported outcomes were collected every 6 months unless ONJ was diagnosed, at which point the interval became every 3 months.

Among the 3491 patients for whom analyzable data were available, the median age was 63.1 years, 51.7% were women, and a minority were black (10.9%) or hispanic (5.6%).

Most of the patients had private medical insurance (43.7%); others were insured by Medicare (38.0%) or Medicaid (9.1%).

The most common cancer types were cancer of the breast (32.1%), prostate (20.1%), and lung (19.1%), as well as multiple myeloma (16.6%).

Antiangiogenic therapy had been used in 12.1% of patients, 5.6% received an osteoclast inhibitor within 6 months of study entry, and 12.3% were current smokers.

At baseline, a dental examination was performed in 64.8% of patients; 22.1% were found to have complete or partial dentures, and 5% to 7% were found to have poor oral health because of severe dental plaque or other causes.

ONJ was defined as the presence of exposed bone in the maxillofacial region for a period of at least 8 weeks in a patient who had been exposed to a bisphosphonate but who had not undergone radiotherapy to the craniofacial region.

Three years after study registration, the researchers identified 87 cases of ONJ, giving a cumulative incidence of 2.8%.

The highest incidence of ONJ was in patients with multiple myeloma, at a cumulative incidence at 3 years of 4.3%; the lowest was in patients with breast cancer, at 2.4%.

The majority of patients with ONJ (56%) had asymptomatic disease. The lesion was <1 cm in size in 62% of patients; 63% of patients had no signs or symptoms of infection.

At the time of ONJ diagnosis, the patients' average pain score on the 10-point Brief Pain Inventory was 2.72, compared with 0.81 at baseline. The most common problems were interference with eating (2.80) and interference with quality of life (2.22).

Van Poznak said that rinses were used to treat the ONJ in 61% of cases; 42% of patients received antibiotics; 18% underwent debridement; and 5% underwent invasive procedures.

ONJ resolved in 12% of patients; 14% showed improvement; 60% had stable disease; and 17% experienced disease progression.

Further analysis revealed that a zoledronic acid dosing interval of 3–4 weeks was associated with a significantly increased risk for ONJ, vs an interval of 5 weeks or longer (hazard ratio [HR], 4.80; P = .008).

In addition, ONJ was associated with the wearing of dentures (HR, 1.99; P = .007) and the use of removable dentures (HR, 2.19; P = .01).

The researchers found that any prior oral surgery was significantly associated with the incidence of ONJ (HR, 1.89; P = .05), as was being a current smoker (HR, 2.19; P = .01).

In contrast, patients who had more than 25 teeth were less likely to develop ONJ (HR, 0.48; P = .003), as were patients with more mandibular teeth than the median (HR, 0.61; P = .05),

Study in Breast Cancer Patients

In the second study (SO307), Kizub and colleagues examined the factors associated with provoked and unprovoked ONJ in 6097 breast cancer patients who had undergone surgery and were receiving adjuvant systemic therapy.

The patients were randomly assigned to receive either intravenous zoledronic acid 4 mg for 6 months and then every 3 months, oral clodronate 1600 mg per day, or oral ibandronate 50 mg daily for 3 years.

Patients with poor dental health at baseline were discouraged from entering the study until any invasive dental procedures had been completed. These patients were monitored with dental examinations every 6–12 months.

Among 5836 women for whom data were complete, 48 (0.8%) developed ONJ after a mean of 27.0 months. Infection was present in 43.8% of patients.

For women who took zoledronic acid, the incidence of ONJ was significantly higher than for those women who took the other bisphosphonates, at 1.32% vs 0.79% for ibandronate and 0.37% for clodronate (P = .002).

The time to onset was also shorter with zoledronic acid than with the other drugs, at 24.9 months for zoledronic acid, 41.2 months for clodronate, and 23.9 months for ibandronate (P = .0447).

ONJ was considered to have been provoked by dental extraction in 41.7% of cases, periodontal disease in 29.2%, dental trauma in 12.5%, and other dental surgery in 6.3%. It was thought to be unprovoked in 41.7%.

Factors associated with ONJ were moderate to severe dental calculus, gingivitis, periodontal disease, and periodontitis of more than 4 mm, but only the type of bisphosphonate was significantly associated on multivariate analysis (P = .0386).

The researchers acknowledge that their results are limited by the small number of patients with ONJ and by the lack of information on other potential ONJ risk factors, such as smoking, diabetes, and corticosteroid use.

SWOG S0702 was sponsored by Southwest Oncology Group Collaborators, the National Cancer Institute (NCI), and Novartis. SWOG S0307 was sponsored by the Southwest Oncology Group, the NCI, the North Central Cancer Treatment Group, the Eastern Cooperative Oncology Group, the NSABP Foundation Inc, Cancer and Leukemia Group B, and the NCIC Clinical Trials Group. Van Poznak has received research funding from Bayer (inst) and has patents, royalties, or other intellectual property in UpToDate. Kizub has disclosed no relevant financial relationships. Kizub's coauthors have disclosed numerous relevant financial relationships, as listed in the abstract. Gillessen has received honoraria from Janssen; has a consulting or advisory role with Active Biotech (inst), Advanced Accelerator Applications, Astellas Pharma (inst), Bayer (inst), Bristol-Myers Squibb (inst), Clovis Oncology (inst), CureVac (inst), Curevac (inst), Ferring (inst), Innocrin Pharma (inst), Janssen (inst), MaxiVax, Menarini Silicon Biosystems (inst), Novartis (inst), Orion Pharma GmbH, Roche, and Sanofi; has patents, receives royalties from, or has other intellectual property related to a biomarker; and has relationships with Nektar and ProteoMediX.

American Society of Clinical Oncology (ASCO) 2019 Annual Meeting: Abstract 552, presented June 2, 2019, and abstract 1150, presented June 3, 2019.

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