Long-Term Efficacy of Zolenronic Acid in Patients with Bone Metastases

Abstract & Commentary

Synopsis: In a randomized clinical trial involving 773 patients, 4mg or 8mg of zoledronate were compared with placebo in patients with bone metastases from solid tumors (other than breast or prostate cancer). Fewer patients treated with zoledronate developed 1 or more skeletal related events (pathologic fracture, spinal cord compression, radiation therapy to bone, and surgery to bone) at 21 months of treatment. A similar observation had been reported at 9 months of treatment, and this report indicates that such treatment remains effective over the long-haul.

Source: Rosen LS, et al. Cancer. 2004;100:2613-2621.

Bone is one of the most frequent sites of metastasis in patients with primary cancers, such as breast, prostate, thyroid, lung and kidney carcinomas. Metastasis to bone results in considerable skeletal morbidity, as tumor cells stimulate osteoclast and/or osteoblast activity resulting in osteolysis and potential excessive bone formation in the region of tumor cell deposits. Bisphosphonates have been shown to inhibit osteoclast-mediated bone resorption and prevent skeletal complications, including bone pain, spinal cord compression, symptomatic pathologic fractures and hypercalcemia of malignancy (HCM). Zoledronic acid is a potent third generation bisphosphonate that has demonstrated efficacy in the treatment of skeletal complications in patients with bone metastases secondary to breast and prostate carcinomas. However, there is limited data on the efficacy of bisphosphonates in the treatment of skeletal complications from solid tumors other than those of the breast or prostate. The efficacy and safety of zoledronic acid in patients with bone metastases secondary to advanced lung carcinoma and other solid tumors (except breast and prostate carcinomas) have been established previously in a Phase III randomized, placebo-controlled trial. Rosen and colleagues with the Cancer Institute Medical Group in Los Angeles conducted a Phase III, double-blind, placebo-controlled trial in attempt to report the long-term (21 months) efficacy and safety of zoledronic acid treatment.

Seven-hundred seventy-three patients with documented bone metastases secondary to lung carcinoma and other solid tumors, with the exception of breast and prostate carcinomas, were enrolled. Of these, 196 patients completed the 9-month core phase and 101 patients continued into the extension phase of treatment. At 21 months, fewer patients treated with zoledronic acid developed at least 1 SRE than those treated with placebo (39% with 4-mg dose [P = 0.127], 36% with 8/4-mg dose [P = 0.023] vs 46% with placebo). In addition, 4 mg of zoledronic acid reduced the median time to first SRE (236 days with 4 mg vs 155 days with placebo; P = 0.009) as well as the annual incidence of SREs (1.74 per year with 4-mg dose vs 2.71 per year with placebo). Patients treated with zoledronic acid reported bone pain less frequently than those on the placebo. Zoledronic acid given at a dose of 4 mg was well tolerated with long-term administration.

Comment by William B. Ershler, MD

The value of this well constructed clinical trial was the unequivocal demonstration of the efficacy and safety of zoledronic acid in patients with solid tumors involving bone, other than breast and prostate cancer and the extension of this conclusion to what must be considered long term treatment for these patients (21 months). Treated patients (at 4 mg) experienced fewer skeletal complications and had a significantly delayed onset of complications and a significantly reduced annual incidence of skeletal complications.

Zoledronate has inherent advantages over pamidronate, the alternative bisphosphonate used to treat skeletal complications of breast and prostate cancer. It is significantly more powerful and smaller doses are required. This allows a shorter infusion period, and may possibly even indicate that less frequent injections will be required. It is satisfying to note that over the long haul, the drug remains effective and safe. However, is there enough here for physicians to switch from pamidronate, if that is what they are accustomed to using? Certainly, the safety and toxicity profile is comparable. With regard to efficacy, data from a direct comparison is currently unavailable, and if a study were to be undertaken, it most likely would not be underwritten by the manufacturer (Novartis), inasmuch as they produce and distribute both compounds. Clinicians who practice evidence-based medicine are presented with strong evidence for the efficacy and safety of zoledronate, but similar or comparative data for the less expensive progenitor (pamidronate) is unlikely to be available anytime soon. Perhaps the payer (insurance companies or the government) would be interested in such a project.

William B. Ershler, MD INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC, is Editor of Clinical Oncology Alert.