Long‐term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors

Rosen and colleagues recently concluded that zoledronic acid demonstrated long-term safety and efficacy in cancer patients with skeletal metastases.1 They used Kaplan–Meier estimates to demonstrate that the incidence of renal dysfunction among patients who were receiving zoledronic acid did not differ statistically from the incidence among patients who were receiving a placebo. They also stated that zoledronic acid had “broad efficacy” in the treatment of bone metastases and that hypercalcemia was prevented completely, whereas it occurred in 4% of patients in the control arm. However, what also should have been addressed is the fact that the trial was not powered to detect the capability of zoledronic acid in causing renal dysfunction. With marketed use of the drug to a large number of patients, zoledronic acid clearly is associated with nephrotoxicity. Many patients require dialysis or die from this complication despite receiving the recommended dose and infusion time.2 Moreover, severe hypocalcemia, painful avascular necrosis of the jaws, and endophthalmitis have been reported.3-5 In an actual long-term setting, the agent does not appear to be as safe as the authors imply. Nor is it “highly effective,” as claimed. The inability of zoledronic acid to improve survival—the most important endpoint in a cancer trial—was addressed parsimoniously in a single sentence. In addition, its failure to improve the overall quality of life of patients was left unmentioned. Pain continued to increase throughout the trial period. The fact that zoledronic acid helped prevent hypercalcemia, indeed, should be considered with caution. It may be unwise to treat certain patients with terminal disease who develop hypercalcemia and somnolence, when they will wake up only to experience pain and suffering. Questionably safe and ambiguously effective, zoledronic acid also is burdensome. Despite a 15-minute infusion time, the patients have to wait for blood test results first, spending a good portion of their already limited days in our offices. At a cost of $795 per 4-mg dose—almost $300,000 for a single quality-adjusted life year when used in patients with prostate carcinoma—it is not cost effective, posing a great burden to our society.6 Finally, the authors should provide data to support that zoledronic acid should be administered at the first occurrence of skeletal metastases. Theoretically, patients with previous skeletal complications should derive a better risk-benefit ratio. In my view, serious consideration should be taken before subjecting a patient to this therapy. I believe that further studies are needed to identify an even lower dose and frequency that may be equally effective as the approved dosage. Tawee Tanvetyanon M.D.* , * Division of Hematology/Oncology, Cardinal Bernardin Cancer Center, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois, Edward Hines Jr. Veteran Administration Hospital, Hines, Illinois.