Zoledronic Acid Reduces SREs in Solid Tumors

ORLANDO—Zoledronic acid (Zo-meta) reduces the incidence of skeletal-related events (SREs) such as bone pain and pathologic fractures in patients with bone metastases from prostate and other solid tumors, researchers reported at two major medical meetings.

In a study of patients with non-small-cell lung cancer (NSCLC) and other solid tumor metastases, zoledronic acid reduced by nearly 20% the proportion of patients who had SREs, Lee Rosen, MD, reported at the 38th Annual Meeting of the American Society of Clinical Oncology (abstract 1179). Fred Saad, MD, reported at the 97th Annual Meeting of the American Urological Association (abstract 703) that the drug had similar effects in prostate cancer patients with bone metastases. Both studies were sponsored by Novartis Oncology.

Solid Tumor Study

Dr. Rosen, formerly of UCLA’s Jonsson Comprehensive Cancer Center and currently director of developmental therapeutics, Cancer Institute Medical Group, Santa Monica, California, described a phase III study that compared placebo with two different doses of zoledronic acid in patients with bone metastasis from solid tumors other than breast or prostate cancer.

"We are all aware of the skeletal complications of advanced solid tumors, and of the vicious cycle of bone destruction, morbidity, and mortality often seen in these patients," Dr. Rosen said. "The bisphosphonates preferentially bind to bone, shorten the natural life of osteoclasts, and reduce the interactions between osteoclasts and tumors. The aminobisphosphonates—pamidronate [Aredia] and zoledronic acid—also inhibit tumor invasion and adhesion to the bone matrix, as well as inducing apoptosis in tumor cell lines."

The trial had been designed as a three-arm study to include randomization to placebo, 4 mg, or 8 mg of zoledronic acid given as a 5-minute infusion every 3 weeks for 9 months. Because of renal toxicity, the infusion period was lengthened to 15 minutes and infusion volume was increased from 50 mL to 100 mL. Because this did not completely solve the problem, the 8-mg zoledronic acid arm was reduced to 4 mg.

All 773 patients enrolled had at least one documented bone metastasis. Patients were stratified by whether they had lung cancer (51%, primarily non-small cell) or other solid tumors (including renal, unknown primary, and bladder cancer). An SRE was defined as a pathologic fracture, spinal cord compression, need for radiation therapy to bone to relieve pain, surgery to bone, or hypercalcemia of malignancy.

Dr. Rosen’s analysis included the proportion of patients with at least one SRE, time to first SRE, and number of events per patient per year (skeletal morbidity rate). Due to the protocol amendments, efficacy analysis did not include patients on the original 8-mg arm.

"There was a 19% reduction between zoledronic acid 4 mg and placebo in the proportion of patients who had at least one SRE (P = .039)," Dr. Rosen said. "Zoledronic acid also significantly prolonged the time before first SRE [by approximately 2 months], compared with placebo (P = .007)." The number of SREs per patient per year was also significantly lower for patients treated with zoledronic acid 4 mg (P = .017).

"Zoledronic acid is the first bisphos-phonate to show efficacy in the treatment of bone metastases from a wide variety of solid tumors. It caused a 20% relative reduction in the proportion of patients with SREs. It delayed by approximately 2 months the occurrence of the first event—a significant benefit in a group of patients whose average survival is only 6 or 7 months," Dr. Rosen said.

There was no significant difference between groups in bone pain (51% zoledronic acid vs 59% placebo), nausea (46% vs 34%), anemia (37% vs 33%), or vomiting (36% vs 29%). "Renal toxicity, once the amendments were put in place, did not appear to cause permanent damage," Dr. Rosen said.

Metastatic Prostate Cancer

In a study in patients with hormone-refractory prostate cancer metastatic to bone, Dr. Saad reported that, at 15 months, treatment with zoledronic acid 4 mg resulted in a 25% reduction in the proportion of patients having an SRE—44% for placebo vs 33% for zoledronic acid (P = .021). The proportion of patients with a pathologic fracture decreased from 22% with placebo to 13% with zoledronic acid.

The study included 643 patients with at least one bone metastasis. Patients were randomized to placebo or zoledronic acid 4 mg given via a 15-minute infusion every 3 weeks for 15 months. As in Dr. Rosen’s study, an 8-mg-dose arm was reduced to 4 mg during the study due to concerns about nephrotoxicity.

"The majority of SREs were fractures and radiation to bone, but the effect of zoledronic acid was consistent across all types of SREs," said Dr. Saad, director of Urologic Oncology, Montreal Cancer Center, University of Montreal.

Time to first SRE was significantly prolonged with zoledronic acid, as was the time to first pathologic fracture. Patients taking zoledronic acid also had a significantly slower rate of progression of pain, compared with placebo, at months 3 and 9. [The study has been published in the Journal of the National Cancer Institute (94:1422-1423, 1458-1468, 2002).]