Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Cancer. 2010 May 1;116(9):2132-9. doi: 10.1002/cncr.24973.
Preclinical data indicate that there is substantial antitumor activity and synergy between calcitriol and dexamethasone. On the basis of these data, the authors conducted a phase 2 trial of intravenous (iv) calcitriol at a dose of 74 microg weekly (based on a recent phase 1 trial) and dexamethasone in patients with castration-resistant prostate cancer (CRPC).
A 2-stage Kepner-Chang design was used. Oral dexamethasone at a dose of 4 mg was given weekly on Days 1 and 2, and iv calcitriol (74 microg over 1 hour) was administered weekly on Day 2 from 4 to 8 hours after the dexamethasone dose in patients with CRPC. Laboratory data were monitored weekly, and renal sonograms, computed tomography scans, and bone scans were obtained every 3 months. Disease response was assessed by using the Response Evaluation Criteria in Solid Tumors (RECIST) and standard criteria for prostate-specific antigen (PSA) response. The calcitriol dose was delineated by from the authors' recent phase 1 trial.
Of 18 evaluable patients, 15 patients were Caucasian (83%). No patients had a complete or partial response by either RECIST or PSA response criteria. Fourteen patients had progressive disease, 2 patients refused to continue treatment (after 64 days and 266 days), and 2 patients remain on the trial (for 306 days and 412 days).The median time to disease progression was 106 days (95% confidence interval, 80-182 days). Fourteen episodes of grade 3 or 4 toxicity were noted in 7 patients (hyperglycemia, hypocalemia, chest pain, dyspnea, hypercalcemia, hypophosphatemia, cardiac arrhythmia, and pain). Only 1 episode of grade 3/ 4 toxicity was related definitely to calcitriol (hypercalcemia). No treatment-related deaths were noted.
High-dose, iv calcitriol at a dose of 74 microg weekly in combination with dexamethasone was well tolerated but failed to produce a clinical or PSA response in men with CRPC.
临床前数据表明，钙三醇和地塞米松联合应用具有显著的抗肿瘤活性和协同作用。基于这些数据，作者开展了一项Ⅱ期临床试验，采用每周静脉注射钙三醇 74μg（基于最近的Ⅰ期临床试验）和地塞米松治疗去势抵抗性前列腺癌（CRPC）患者。
采用两阶段 Kepner-Chang 设计。CRPC 患者每周 1 和 2 日口服地塞米松 4mg，地塞米松剂量后 4 至 8 小时给予静脉注射钙三醇（74μg，1 小时内滴注完毕）。每周监测实验室数据，每 3 个月进行肾脏超声、计算机断层扫描和骨扫描。采用实体瘤反应评价标准（RECIST）和前列腺特异性抗原（PSA）反应标准评估疾病缓解情况。钙三醇剂量由作者最近的Ⅰ期临床试验确定。
18 例可评估患者中，15 例为白人（83%）。无患者通过 RECIST 或 PSA 缓解标准达到完全或部分缓解。14 例患者疾病进展，2 例患者拒绝继续治疗（分别在 64 天和 266 天后），2 例患者仍在试验中（分别治疗 306 天和 412 天）。中位疾病进展时间为 106 天（95%置信区间，80-182 天）。7 例患者（高血糖、低钙血症、胸痛、呼吸困难、高钙血症、低磷血症、心律失常和疼痛）发生 14 次 3 或 4 级毒性反应。仅 1 次 3/4 级毒性反应与钙三醇肯定相关（高钙血症）。无治疗相关死亡。
每周静脉注射钙三醇 74μg 联合地塞米松治疗剂量较高，患者可耐受，但未能使 CRPC 男性患者产生临床或 PSA 缓解。
