Dec 14 2008
New data released demonstrates that the addition of Zometa (zoledronic acid) injection to standard chemotherapy before breast cancer surgery reduces the size of breast tumors more effectively than chemotherapy alone in women with early-stage disease.
These neo-adjuvant subset results from the retrospective exploratory analysis of the international AZURE (Adjuvant Zoledronic acid to redUce REcurrence) trial are the first to show the direct effect of Zometa in combination with chemotherapy to help shrink cancerous breast tumors, potentially resulting in less radical surgery for some women. The data were presented at the 31st Annual CTRC-AACR San Antonio Breast Cancer Symposium.
"These results support a potential anti-tumor benefit of combining Zometa with chemotherapy in the neoadjuvant treatment of breast cancer," said Matthew Winter, MBChB MSc, Clinical Research Fellow, University of Sheffield, UK, a lead investigator of this subset analysis. "Adding Zometa to chemotherapy prior to surgery increased tumor shrinkage in this analysis. When breast cancer treatment is given prior to surgery, the goal is to reduce the size of the tumor and in doing so potentially improve breast conservation rates and longer-term outcomes."
In the analysis, pre- and postmenopausal women who received Zometa in addition to chemotherapy before surgery (neo-adjuvant use) experienced a significant 33% reduction in the size of their primary tumor (14.1 mm reduction in tumor size) compared with patients who received chemotherapy alone (P=0.002)(1). The proportion of patients requiring mastectomy was higher (77.9%) in the chemotherapy-alone group than in the Zometa group (65.3%).
"Clinical evidence continues to demonstrate that Zometa may play a role in protecting patients from the return and spread of early-stage breast cancer," said David Epstein, President and CEO, Novartis Oncology. "We are encouraged by these latest results, which show Zometa may help some women avoid mastectomies, and we remain committed to further exploring the benefit of Zometa as an anticancer treatment."
Zometa is the world's leading treatment to reduce or delay bone complications in patients with advanced cancer that has spread to the bones across a broad range of solid tumors, including breast cancer.
The potential anticancer properties of Zometa were previously observed in premenopausal women with early-stage breast cancer from the Austrian Breast & Colorectal Cancer Study Group-12 (ABCSG-12) study, which was presented at the American Society of Clinical Oncology annual meeting (ASCO) earlier this year. Final results from the AZURE trial are expected in the next two to three years.
Novartis is further exploring the anticancer effect of Zometa in a broad clinical program in breast, lung and prostate cancers with the results expected over the next two to three years. Laboratory research has suggested that Zometa may help protect patients with early-stage breast cancer from the return or spread of the cancer to other parts of the body (distant metastatic sites) through several different pathways, including inhibiting angiogenesis (formation of blood vessels that grow and feed cancer cells), stimulating cancer-fighting T-cells, inducing tumor cell apoptosis (programmed cell death) and increasing the activity of anticancer agents that target tumor cell metastases(2).
AZURE is a randomized, open-label, multicenter, parallel group trial with a five-year treatment phase and a subsequent five-year follow-up phase designed to determine whether Zometa, added to standard therapy (chemotherapy and/or hormonal therapy) before (neo-adjuvant) or after (adjuvant) surgery, is superior to each therapy alone in improving disease-free survival in pre- and post-menopausal women with early-stage breast cancer. The trial includes 3,360 patients from 174 centers in seven countries and is coordinated by the Cancer Research Centre, Weston Park Hospital, Sheffield, England with support from Novartis(1).
The neo-adjuvant subset in the current analysis included 205 participants who received either chemotherapy alone or in combination with Zometa once every three to four weeks for six months prior to breast cancer surgery. Following adjustment for other prognostic factors, the adjusted mean tumor size after treatment was 28.2 millimeters in the Zometa group and 42.4 millimeters in the chemotherapy group, a significant reduction of 33%(1). The pathologic complete response rate (no evidence of residual cancer in the breast or lymph nodes) increased to 10.9% in the Zometa group from 5.8% in the chemotherapy group (P=0.033). The proportion of women needing a mastectomy was reduced by 16% in patients taking Zometa (65.3% in the Zometa group versus 77.9% in the chemotherapy-alone group)(1).
Zometa is indicated for patients with multiple myeloma and documented bone metastases from solid tumors in conjunction with standard antineoplastic therapy; prostate cancer should have progressed after treatment with at least one hormonal therapy.
Safety information
Zometa is contraindicated in patients with hypersensitivity to zoledronic acid or other bisphosphonates, or any of the excipients in the formulation of Zometa. Hypersensitivity reactions, including rare cases of urticaria and angioedema and very rare cases of anaphylactic reaction/shock, have been reported.
Due to the risk of clinically significant deterioration in renal function, which may progress to renal failure, single doses of Zometa should not exceed 4 mg, and the duration of infusion should be no less than 15 minutes. Risk factors for the deterioration of renal function include impaired baseline renal function and multiple cycles of bisphosphonate treatment.
Zometa is not recommended in patients with bone metastases with severe renal impairment. In patients with mild to moderate renal impairment at baseline, lower doses of Zometa are recommended based on calculated creatinine clearance. Before each Zometa dose, serum creatinine should be measured and treatment should be withheld for renal deterioration until serum creatinine has returned to within 10% of the baseline value.
Zometa should not be used during pregnancy. Women of childbearing potential should be advised to avoid becoming pregnant. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus.
Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including Zometa. Many of these patients were also receiving chemotherapy and corticosteroids, which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma) and dental status (dental extraction, periodontal disease, local trauma, including poorly fitting dentures). Many reports of ONJ involved patients with signs of local infection, including osteomyelitis. Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates. While on treatment, these patients should avoid invasive dental procedures, if possible. No data are available as to whether discontinuation of bisphosphonate therapy reduces the risk of ONJ in patients requiring dental procedures. A causal relationship between bisphosphonate use and ONJ has not been established. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.
In postmarketing experience, severe and occasionally incapacitating bone, joint and/or muscle pain has been reported infrequently in patients taking bisphosphonates.
The most common adverse events (greater than or equal to 15%) in bone metastases clinical trials, regardless of causality, with Zometa 4 mg (n=1031) were as follows: bone pain (55%), nausea (46%), fatigue (39%), anemia (33%), pyrexia (32%), vomiting (32%), constipation (31%), dyspnea (27%), diarrhea (24%), weakness (24%), myalgia (23%), anorexia (22%), cough (22%), arthralgia (21%), lower-limb edema (21%), malignant neoplasm aggravated (20%), headache (19%), dizziness (excluding vertigo) (18%), insomnia (16%), decreased weight (16%), back pain (15%) and paresthesia (15%).
Caution is advised when bisphosphonates are administered with aminoglycosides, loop diuretics and potentially nephrotoxic drugs.
Zometa contains the same active ingredient as found in Reclast(R) (zoledronic acid). Patients being treated with Zometa should not be treated with Reclast.
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