Dynamic contrast-enhanced magnetic resonance imaging pharmacodynamic biomarker study of sorafenib in metastatic renal carcinoma
Dynamic contrast-enhanced magnetic resonance imaging pharmacodynamic biomarker study of sorafenib in metastatic renal carcinoma
复制标题
DOI：
10.1200/jco.2007.15.5655
复制
发表时间：
2008-10-01
影响因子：
45.3
通讯作者：
Stadler, Walter M.
中科院分区：
文献类型：
--
作者：
Hahn, Olwen M.;Yang, Cheng;Stadler, Walter M.
索拉非尼是一种抗肾癌血管生成药物。我们进行了一项随机试验，以研究动态对比磁共振成像（DCE-MRI）作为药效学生物标志物。患者和方法患者被随机分配接受安慰剂或200或400 mg索拉非尼，每天两次。在基线和4周时进行DCE-MRI。计算以盲法选择的转移部位的DCE-MRI参数、造影剂注射后90秒造影剂浓度-时间曲线下面积（IAUC（90））和造影剂的体积转移常数（K-transs）。主要终点是K-trans.ResultsOf 56评估患者的变化，48进行了两次MRI; 44 MRI评估研究终点。安慰剂、200 mg和400 mg队列的平均K-translog比值分别为0.131（标准差[SD]，0.315）、-0.148（SD，0.382）和-0.271（SD，0.499）（趋势P = 0.0077），对应于= 14%、-14%和-24%的变化。IAUC（90）对数比分别为0.041（SD，0.197）、-0.040（SD，0.132）、-0.356（SD，0.411）（趋势P = .0003），对应于+4%、-4%和-30%的变化。使用对数秩检验，IAUC（90）和K-transs变化与无进展生存期（PFS）无关。高基线K-transs的患者有一个更好的PFS（P = 0.027）。结论IAUC（90）和K-transs是索拉非尼的药效学生物标志物，但变异性高，效果的幅度小于以前报道的。索拉非尼治疗4周后DCE-MRI参数的变化不能预测PFS，这表明这些生物标志物不是替代终点。基线K-transs作为预后或预测生物标志物的价值需要进一步研究。
PurposeSorafenib is an antiangiogenic agent with activity in renal cancer. We conducted a randomized trial to investigate dynamic contrast magnetic resonance imaging (DCE-MRI) as a pharmacodynamic biomarker.Patients and MethodsPatients were randomly assigned to placebo or 200 or 400 mg twice per day of sorafenib. DCE-MRI was performed at baseline and 4 weeks. DCE-MRI parameters, area under the contrast concentration versus time curve 90 seconds after contrast injection (IAUC(90)), and volume transfer constant of contrast agent (K-trans) were calculated for a metastatic site selected in a blinded manner. Primary end point was change in K-trans.ResultsOf the 56 assessable patients, 48 underwent two MRIs; 44 MRIs were assessable for study end points. Mean K-trans log ratios were 0.131 (standard deviation [SD], 0.315), -0.148 (SD, 0.382),-0.271 (SD, 0.499) in placebo, 200-and 400-mg cohorts, respectively (P = .0077 for trend) corresponding to changes of = 14%,-14%, and-24%. IAUC(90) log ratios were 0.041 (SD, 0.197), -0.040 (SD, 0.132), -0.356 (SD, 0.411), respectively (P = .0003 for trend), corresponding to changes of + 4%, -4%, and -30%. Using a log-rank test, IAUC(90) and K-trans changes were not associated with progression-free survival (PFS). Patients with high baseline K-trans had a better PFS (P = .027).ConclusionIAUC(90) and K-trans are pharmacodynamic biomarkers for sorafenib, but variability is high and magnitude of effect is less than previously reported. Changes in DCE-MRI parameters after 4 weeks of sorafenib are not predictive of PFS, suggesting that these biomarkers are not surrogate end points. The value of baseline K-trans as a prognostic or predictive biomarker requires additional study.