BACKGROUNDThe authors previously reported the efficacy of a dose of 4 mg of zoledronic acid in reducing skeletal complications in patients with bone metastases secondary to lung carcinoma and other solid tumors (except carcinomas of the breast and prostate). In the current study, they update these results and report the long‐term efficacy and safety of 21 months of treatment with zoledronic acid in a randomized, placebo‐controlled trial.METHODSA total of 773 patients were randomized to receive zoledronic acid (4 mg or 8 mg) or placebo via a 15‐minute infusion every 3 weeks for 21 months. The 8‐mg dose later was reduced to 4 mg (8/4‐mg group). The primary efficacy endpoint was the percentage of patients at 21 months with ≥ 1 skeletal‐related event (SRE) (pathologic fracture, spinal cord compression, radiation therapy to bone, or surgery to bone). Secondary analyses (time to first SRE, annual incidence of SREs, and multiple‐event analysis) included hypercalcemia of malignancy.RESULTSFewer patients treated with zoledronic acid developed at least 1 SRE at 21 months compared with patients treated with placebo (39% of those treated at the 4‐mg dose [P =0.127] and 36% of those treated at the 8/4‐mg dose [P = 0.023], compared with 46% of those treated with placebo). Furthermore, 4 mg of zoledronic acid significantly delayed the median time to first SRE (236 days with 4 mg vs. 155 days with placebo; P = 0.009) and significantly reduced the annual incidence of SREs (1.74 per year with the 4‐mg dose vs. 2.71 per year with placebo; P = 0.012). Moreover, the 4‐mg dose of zoledronic acid was found to reduce the risk of developing a skeletal event by 31% (hazard ratio of 0.693; P = 0.003). Zoledronic acid was found to be well tolerated with long‐term use; the most commonly reported adverse events in all treatment groups included bone pain and the transient, acute‐phase reactions of nausea, anemia, and emesis.CONCLUSIONSTo the authors' knowledge, zoledronic acid is the first bisphosphonate to demonstrate long‐term safety and efficacy in this patient population. Cancer 2004. © 2004 American Cancer Society.

Purpose: Blockade of the T-cell inhibitory receptor CTL-associated antigen-4 (CTLA-4) augments and prolongsT-cell responses and is a strategy to elicit antitumor immunity. The objectives of this pilot study were to establish the pharmacokinetic and safety profile for a single dose of 3 mg/kg of the anti-CTLA-4 antibody Ipilimumab (MDX-010, BMS-734016) and to assess if this therapy resulted in prostate-specific antigen (PSA) modulation and the development of polyclonal T-cell activation and/or clinical autoimmunity in patients with hormone-refractory prostate cancer treated with Ipilimumab. Experimental Design: Patients with metastatic hormone-refractory prostate cancer received a single 3 mg/kg i.v. dose of Ipilimumab. Serologic measures of autoimmunity were obtained, and T-cell activation was evaluated by flow cytometry. Pharmacokinetic sampling of plasma for MDX-CTLA-4, PSA measurement, and diagnostic imaging were also undertaken. Results: Fourteen patients were treated: 12 patients received a single dose of Ipilimumab, and 2 patients were re-treated with a second dose upon PSA progression. Two patients showed PSA declines of z50%. Treatment was well tolerated with clinical autoimmunity limited to one patient who developed grade 3 rash/pruritis requiring systemic corticosteroids. The mean F SD Ipilimumab terminal elimination half-life was 12.5 F 5.3 days. Conclusions: A single dose of 3 mg/kg Ipilimumab, an anti-CTLA-4 antibody, given to patients with prostate cancer is safe and does not result in significant clinical autoimmunity. PSA-modulating effects observed warrant further investigation.

Exatecan plus gemcitabine was not superior to gemcitabine alone with respect to overall survival in the first-line treatment of advanced pancreatic cancer.