Dahut William L, Scripture Charity, Posadas Edwin, Jain Lokesh, Gulley James L, Arlen Philip M, Wright John J, Yu Yunkai, Cao Liang, Steinberg Seth M, Aragon-Ching Jeanny B, Venitz Jürgen, Jones Elizabeth, Chen Clara C, Figg William D
Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
Clin Cancer Res. 2008 Jan 1;14(1):209-14. doi: 10.1158/1078-0432.CCR-07-1355.
To determine if sorafenib is associated with a 4-month probability of progression-free survival, which is consistent with 50%, as determined by clinical, radiographic, and prostate-specific antigen (PSA) criteria in patients with metastatic androgen-independent prostate cancer (AIPC).
Patients with progressive metastatic AIPC were enrolled in an open-label, single-arm phase II study. Sorafenib was given continuously at a dose of 400 mg orally twice daily in 28-day cycles. Clinical assessment and PSA measurement were done every cycle whereas radiographic measurements were carried out every two cycles.
Twenty-two patients were enrolled in the study to date, completing a planned first stage of the trial. Baseline patient characteristics included a median age of 63.9 years (range, 50-77 years), Gleason score of 9 (range, 4-9.5), and PSA concentration of 53.3 ng/mL (range, 2-1,905 ng/mL). Fifty-nine percent of patients had received one prior chemotherapy regimen. Of the 21 patients with progressive disease, 13 progressed only by PSA criteria in the absence of evidence of clinical and radiographic progression. Two patients were found to have dramatic reduction of bone metastatic lesions as shown by bone scan, although they met PSA progression criteria at the time when scans were obtained. Toxicities likely related to treatment included one grade 3 hypertension; one grade 3 hand-foot syndrome; and grade 1/2 toxicities: fatigue, anorexia, hypertension, skin rash, nausea, and diarrhea. Results from in vitro studies suggested that PSA is not a good marker of sorafenib activity. The geometric mean exposure (AUC(0-12)) and maximum concentration (C(max)) were 9.76 h mg/L and 1.28 mg/L, respectively. The time to maximum concentration (t(max)) and accumulation ratio (after second dose) ranged from 2 to 12 h and 0.68 to 6.43, respectively.
Sorafenib is relatively well tolerated in AIPC with two patients showing evidence of improved bony metastatic lesions. Interpretation of this study is complicated by discordant radiographic and PSA responses. PSA may not be an adequate biomarker for monitoring sorafenib activity. Based on these observations, further investigation using only clinical and radiographic end points as progression criteria is warranted. Accrual to the second stage of trial is ongoing.
根据临床、影像学和前列腺特异性抗原（PSA）标准，确定索拉非尼是否与转移性去势抵抗性前列腺癌（AIPC）患者4个月无进展生存概率相关，该概率与50%一致。
将病情进展的转移性AIPC患者纳入一项开放标签、单臂II期研究。索拉非尼以400mg口服，每日两次的剂量持续给药，每28天为一个周期。每个周期进行临床评估和PSA测量，而影像学测量每两个周期进行一次。
截至目前，22例患者入组该研究，完成了试验计划的第一阶段。患者基线特征包括年龄中位数为63.9岁（范围50 - 77岁）， Gleason评分9分（范围4 - 9.5），PSA浓度53.3 ng/mL（范围2 - 1905 ng/mL）。59%的患者曾接受过一种先前的化疗方案。在21例病情进展的患者中，13例仅根据PSA标准进展，而无临床和影像学进展证据。2例患者骨扫描显示骨转移病灶显著减少，尽管在扫描时他们符合PSA进展标准。可能与治疗相关的毒性包括1例3级高血压；1例3级手足综合征；以及1/2级毒性：疲劳、厌食、高血压、皮疹、恶心和腹泻。体外研究结果表明，PSA不是索拉非尼活性的良好标志物。几何平均暴露量（AUC(0 - 12)）和最大浓度（C(max)）分别为9.76 h mg/L和1.28 mg/L。达峰时间（t(max)）和蓄积比（第二次给药后）分别为2至12小时和0.68至6.43。
索拉非尼在AIPC中耐受性相对良好，2例患者显示骨转移病灶改善迹象。本研究的解读因影像学和PSA反应不一致而复杂化。PSA可能不是监测索拉非尼活性的充分生物标志物。基于这些观察结果，有必要进一步仅使用临床和影像学终点作为进展标准进行研究。试验第二阶段的入组正在进行。
