ASCO Update on Bone-Modifying Drugs in Metastatic Breast Cancer

Zosia Chustecka

March 02, 2011

March 2, 2011 — An updated guideline on the use of bone-modifying agents in patients with metastatic breast cancer have been issued by the American Society of Clinical Oncology (ASCO). The guideline now includes the novel drug denosumab (Xgeva, Amgen), which was approved late last year, in addition to the bisphosphonates zoledronic acid and pamidronate.

The update was published online February 22 in the Journal of Clinical Oncology.

Previous versions of this guideline (which was last updated in 2003) referred specifically to the use of bisphosphonates in breast cancer, which were the only bone-active drugs indicated in this patient population. Now that denosumab, an anti-RANKL monoclonal antibody, is also available, the guideline refers to "bone-modifying agents."

In addition, the scope of the guideline has been narrowed to consider only metastatic breast cancer, the authors explain. A separate update will cover the use of bone-modifying agents as adjuvant treatment for breast cancer and in managing treatment-associated bone loss.

Start Therapy When There is Bone Destruction

The updated guideline recommends that bone-modifying agents be used in patients with metastatic breast cancer who have evidence of bone destruction on plain radiographs.

In cases where the plain radiographs are normal but there is an abnormal bone scan, and bone destruction can be seen on an abnormal computed tomography or magnetic resonance imaging scan, the panel consensus is that "starting bisphosphonates is considered reasonable."

Once initiated, the panel recommends that bone-modifying agents be continued "until evidence of substantial decline in a patient's general performance status." However, the panel emphasizes that clinical judgement must be used to decide what constitutes a "general decline," and notes that there is no evidence that addresses the consequences of stopping bone-modifying agents after 1 or more skeletal-related events have occurred.

Three Drugs to Choose From

Three choices of therapies is outlined: denosumab 120 mg subcutaneously every 4 weeks; pamidronate 90 mg intravenously over no less than 2 hours every 3 to 4 weeks; and zoledronic acid (Zometa, Novartis) 4 mg intravenously over no less than 15 minutes every 3 to 4 weeks.

"There is insufficient evidence relating to efficacy to support one bone-modifying agent over another," the authors state.

When asked about this in an interview with Medscape Medical News, lead author Catherine Van Poznak, MD, breast medical oncologist at the University of Michigan, Ann Arbor, said that the panel of experts had chosen these words very carefully. She acknowledged that there have been head-to-head clinical trials comparing denosumab and zoledronic acid that have shown some superior outcomes at some end points for denosumab, but when all of the available data were taken into consideration, the panel felt that the evidence was insufficient to recommend any one agent over another, she explained.

For each individual patient, there are a number of factors that should be taken into consideration in addition to efficacy, Dr. Van Poznak emphasized; these include mode of administration, toxicity profile, patients preference, and cost.

Denosumab is administered by subcutaneous injection, whereas zoledronic acid and pamidronate are administered by intravenous infusion, she noted. In addition, the toxicity profiles are different — for example, denosumab is associated with a risk for hypocalcemia, and zoledronic acid and pamidronate are associated with a risk for renal toxicity and require renal function monitoring.

Renal Monitoring With Bisphosphonates

The requirements for renal monitoring with the 2 bisphosphonates are outlined in detail in the updated guideline; although they are new to the guideline, they are not new to physicians.

"Our knowledge of renal toxicity is not really new," because before the updates to the guideline, there were US Food and Drug Administration (FDA) changes to the labeling (in 2005), Dr. Van Poznak explained.

Pamidronate and zoledronic acid are associated with renal deterioration, particularly in patients with preexisting renal impairment and in those who receive multiple cycles of bisphosphonate therapy, the authors write.

The 2 drugs can be used without dosage modification in patients with a calculated serum creatinine clearance above 60 mL/min, but lower levels require dosage modification (details are outlined in the product labels). In addition, serum creatinine levels should be monitored before each dose of pamidronate or zoledronic acid, in accordance with FDA-approved labeling, the panel writes.

Renal monitoring is not required with denosumab, which offers a clear advantage over the bisphosphonates, clinicians reporting the comparative clinical trials have emphasized.

Osteonecrosis of the Jaw

Another new item in the update, but again not new to clinicians, is the association of these drugs with "the uncommon but potentially serious" condition of osteonecrosis of the jaw (ONJ).

The first reports of ONJ associated with intravenous bisphosphonates appeared in 2003; since then, a body of data has built up on this adverse event, with recent reports linking it to oral bisphosphonates and denosumab.

Dr. Van Poznak noted that the risk for ONJ in cancer patients treated with denosumab appears to be comparable to that with zoledronic acid. A meta-analysis of 3 pivotal clinical trials that compared denosumab with zoledronic acid head to head for the treatment of bone metastases in advanced myeloma patients found that ONJ occurred as an adverse event with both drugs at a rate that was not statistically significantly different. The rates were 1.8% with denosumab and 1.3% with zoledronic acid (P = .13), according to data reported last year at the Cancer and Bone Society 10th International Conference (Brown JE, et al. Abstract OC-9).

The update committee concurs with the FDA labeling, which recommends that all cancer patients in whom the use of bone-modifying agents are being considered should receive a dental examination and undergo necessary preventive dentistry prior to initiating therapy. While taking these drugs, patients should maintain optimal oral hygiene and, if possible, avoid invasive dental procedures that involve manipulation of the jaw bone or periosteum.

Other Modalities Needed For Bone Pain

The update also has a change in the timing of the management of bone pain; the new recommendation is that treatment of bone pain should be initiated at the onset of pain, and this should be done in concert with the use of bone-modifying agents. "This is required by good clinical practice," the experts write.

Bone-modifying agents have been shown to reduce pain scores and analgesic use in clinical trials. They are helpful in controlling bone pain, "but they should not supplant established practices in managing bone pain," Dr. Van Poznak emphasized.

The standard of care for pain management includes the use of nonsteroidal anti-inflammatory drugs, opioid and nonopioid analgesics, corticosteroids, adjuvant agents, interventional procedures, systemic radiopharmaceuticals, local radiation therapy, and surgery, the panel notes.

"Bone-modifying agents are an adjunctive therapy for cancer-related bone pain control and are not recommended as first-line treatment for cancer-related pain," the panel concludes.

Dr. Van Poznak reports acting as a consultant to Amgen, and receiving research funding from Amgen and Novartis. Coauthor Gary Yee, PharmD, FCCP, BCOP, from the University of Nebraska Medical Center in Omaha, reports acting as a consultant to Amgen and Roche. Coauthor Linda Bosserman, MD, from Rancho Cucamonga, California, reports acting as a consultant to Amgen and Roche, and receiving honoraria from Abraxis BioScience, Amgen, and Roche.

J Clin Oncol. Published online February 22, 2011. Abstract


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