Pharmacodynamic study using FLT PET/CT in patients with renal cell cancer and other solid malignancies treated with sunitinib malate.
Pharmacodynamic study using FLT PET/CT in patients with renal cell cancer and other solid malignancies treated with sunitinib malate.
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DOI：
10.1158/1078-0432.ccr-11-1677
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发表时间：
2011-12-15
期刊：
影响因子：
--
通讯作者：
Wilding G
中科院分区：
文献类型：
--
作者：
Liu G;Jeraj R;Vanderhoek M;Perlman S;Kolesar J;Harrison M;Simoncic U;Eickhoff J;Carmichael L;Chao B;Marnocha R;Ivy P;Wilding G
使用3′-脱氧-3 ′-[18 F]氟胸苷（FLT）PET/CT成像表征苹果酸舒尼替尼暴露/停药期间肿瘤的增殖变化。入组了既往无抗VEGF暴露的晚期实体恶性肿瘤患者。所有患者的转移性病灶均适合FLT PET/CT成像。舒尼替尼的起始剂量为标准剂量50 mg PO每日一次，采用4/2或2/1方案。在基线、舒尼替尼暴露期间和治疗周期#1内舒尼替尼停药后进行FLT PET/CT扫描。在相同的时间点评估VEGF水平和舒尼替尼药代动力学数据。16例患者（8例患者接受4/2方案; 8例患者接受2/1方案）完成了所有3次计划的FLT PET/CT扫描，可进行药效学成像评价。在舒尼替尼停药期间（从扫描2变为3），4/2方案的中位FLT PET SUV均值增加+15%（范围-14%至277%）（p=0.047），2/1方案增加+19%（范围-5.3%至200%）（p=0.047）。舒尼替尼暴露期间，舒尼替尼PK和VEGF配体水平升高，停药期间恢复至基线水平。在肾细胞癌和其他实体恶性肿瘤患者中，舒尼替尼停药期间细胞增殖增加与VEGFR TKI停药发作一致。单变量和多变量分析表明，血浆VEGF与这种发作相关，探索性分析表明，临床获益较少的患者戒断发作更大。这可能表明，对VEGFR TKI治疗有强烈代偿反应的患者经历了早期“血管生成逃逸”。
To characterize proliferative changes in tumors during the sunitinib malate exposure/withdrawal using 3′-Deoxy-3′-[18F]fluorothymidine (FLT) PET/CT imaging. Patients with advanced solid malignancies and no prior anti-VEGF exposure were enrolled. All patients had metastatic lesions amenable to FLT PET/CT imaging. Sunitinib was initiated at the standard dose of 50 mg PO daily either on a 4/2 or 2/1 schedule. FLT PET/CT scans were obtained at baseline, during sunitinib exposure, and after sunitinib withdrawal within cycle #1 of therapy. VEGF levels and sunitinib pharmacokinetic data were assessed at the same time points. 16 patients (8 pts on 4/2 schedule; 8 pts on 2/1 schedule) completed all three planned FLT PET/CT scans, and were evaluable for pharmacodynamic imaging evaluation. During sunitinib withdrawal (change from scan 2 to 3), median FLT PET SUVmean increased +15% (range −14% to +277%) (p=0.047) for the 4/2 schedule and +19% (range −5.3% to +200%) (p=0.047) for the 2/1 schedule. Sunitinib PK and VEGF ligand levels increased during sunitinib exposure, and returned towards baseline during the treatment withdrawal. The increase of cellular proliferation during sunitinib withdrawal in patients with renal cell carcinoma and other solid malignancies is consistent with a VEGFR TKI withdrawal flare. Univariate and multivariate analysis suggest that plasma VEGF is associated with this flare, with an exploratory analysis implying that patients who experience less clinical benefit have a larger withdrawal flare. This might suggest that patients with a robust compensatory response to VEGFR TKI therapy experience early “angiogenic escape”.