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目前越来越多的针对恶性肿瘤血管的分子靶向药物在临床治疗中发挥着日益重要的作用。但由于分子靶向药物与传统细胞毒类药物药理机制的差异,导致传统药物临床试验体系已不能很好地适应分子靶向药物研发的需求,这在药效评价方面表现得尤为突出。在抗肿瘤药物的Ⅰ期、Ⅱ期临床试验中,传统上对于药效的评价主要基于肿瘤体积的改变,但基于形态学的判断标准尚不能准确评价抗肿瘤血管分子靶向药物的疗效; 而目前针对恶性肿瘤生成的靶向药物越来越多,如果这些药物没有接受准确的药效评价就进入Ⅲ期临床试验,则必然大幅增加新药的研发成本。所以,许多研究者建议在Ⅰ、Ⅱ期临床试验中采用生物标志物作为药物有效性的证据,以决定其是否进入Ⅲ期临床试验[1]。
现今,大量的新技术、新方法被引入抗肿瘤血管分子靶向药物的临床试验。其中,动态增强磁共振成像(dynamic contrast-enhanced magnetic resonance imaging,DCE-MRI)已被广泛应用并逐渐显示出传统技术、方法无可比拟的优势。DCE-MRI是基于对比剂注射前后肿瘤内部信号强度的变化,通过对比剂浓度-时间曲线及一系列能够反映肿瘤内部血液动力学特征的参数来评价抗肿瘤血管分子靶向药物药效。DCE-MRI最常用的3种血流动力学模型分别是Patlak[2]、Tofts-Kermode[3]和St.Lawrence-Lee[4]模型。目前广泛采用的是Tofts双室动力学模型,其公式表示为:
$ C_{t}(t)=V_{p} C_{p}(t)+C_{p}(t) \cdot K_{\mathrm{trans}} \cdot \mathrm{e}^{\left(-K_{\mathrm{tans}} \cdot t / V_{e}\right)} $ 双室分别代表微血管管腔和细胞外血管外间隙(extracellular extravascular space,EES),式中,t为注射对比剂后的某一时间点; Ct(t)为该时间点EES中对比剂浓度; Cp(t)为该时间点微血管管腔内对比剂浓度; Vp为血浆容积; 通过静脉注射的对比剂以时间依赖性的渗漏方式漏至EES; Ktrans为对比剂由血管内转移至EES的速度常数; Ve为对比剂在EES的分布容积。Kep是对比剂由EES转移至血浆的速度常数,其与Ktrans和Ve的关系为: Kep= Ktrans/Ve[5]。定量分析通常需要通过测量器官或肿瘤解剖学位置附近动脉的信号变化获得动脉流入函数,以弥补因注射速率或心输出量引起的差异[6]。
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由于DCE-MRI参数理论上可以反映血管功能变化,且已有的研究已经证实用药后肿瘤组织内DCE-MRI参数与微血管密度[15-16]和血清VEGF、血管表皮生长因子受体(vascular endothelial growth factor receptor,VEGFR)浓度[17]等反映抗血管作用的传统指标相关; 另有研究表明,DCE-MRI参数具有良好的重复性,各参数的变异系数均<15%[18]。所以,DCE-MRI技术自2002年Dowlati等[19]与Galbraith等[20]分别在考布他汀-A4-磷酸(combretastatin A4 phosphate,CA4P)[19]和5, 6-二甲黄嘌呤-4-乙酸(5, 6-dimethylxanthenone-4-acetic acid,DMXAA)[20]的早期临床试验中被引入后,其相关参数便逐渐成为抗肿瘤血管分子靶向药物早期临床试验的评价指标之一。
目前,由于药物的种类不同,因此,最佳的DCE-MRI评价参数尚无定论。对于抗VEGF/VEGFR类药物,Ktrans和60 s曲线下起始面积(initial area under curve at 60 s,IAUC60)使用较多,并且在试验中二者通常联合使用[21]。在Tofts血流动力学模型中,Ktrans描述对比剂从血管内透过内皮细胞弥散入EES的速率。由于血管通透表面积(permeability surface area product,PS)和灌注量均可限制对比剂从血管内向EES弥散的速率,故Ktrans取决于二者之中较小者。即在灌注不足或者通透性远大于灌注量的肿瘤内部,Ktrans决定于灌注量,这种情况多见于颅外肿瘤; 若肿瘤内部血液灌注充足而通透性较低时,血管内对比剂未能全部透过内皮进入EES,则Ktrans决定于PS,这种情况多见于颅内肿瘤或者颅外经过治疗后的肿瘤[10]。IAUC60则是对比剂浓度-时间曲线到第60 s时曲线下面积,代表对比剂注射之后60 s进入ROI内的对比剂总量[22]。对于酪氨酸激酶抑制剂(tyrosine kinase inbibitor,TKI)或者血管破坏药物(vascular disrupting agents,VDA)而言,Ktrans和IAUC60在用药后的变化并不显著[23],而DCE-MRI的ETV、肿瘤增强分数(tumor enhancing fraction,EF)和血浆容积等可以更好地反映该类药物的药效动力学特征[24-25]。
迄今大约有近百项抗肿瘤血管分子靶向药物的早期临床试验使用了DCE-MRI参数作为确定药物抗血管作用的指标,表 1仅列举了其中具有代表性的7项。如表 1中所示,对于抗VEGFR药物、TKI与VDA,用药后每项临床研究中仅有一部分患者出现病灶退缩,而与此同时,DCE-MRI参数出现的改变差异均具有统计学意义。可见,DCE-MRI技术可以更早地确定药物的抗肿瘤血管作用。
药物名称 入组病例数 肿瘤类型 年份 DCE-MRI参数变化 缓解例数 抗VEGFR药物 贝伐单抗[35] 31 间变性星型细胞瘤 2011 Ktrans下降逸30%(化疗第4日至28日),ETV下降>40%(化疗第4日) 13例 阿柏西普[36] 47 多种肿瘤 2010 Ktrans下降20%~97%(化疗第1日至第5日) 3例 酪氨酸激酶抑制剂 舒尼替尼[37] 34 原发性肝癌 2009 Ktrans下降50%(化疗第14日) 18例 阿西替尼[38] 36 多种肿瘤 2005 Ktrans下降>50%(化疗第2日至28日) 2例 索拉非尼[33] 56 转移性肾癌 2008 Ktrans下降14%,IAUC90下降4%(化疗第4周,200 mg组);Ktrans下降24%,IAUC90下降30%(化疗第4周,400 mg组) 4例 血管破坏药物 DMXAA[20] 16 多种肿瘤 2002 IAUC24h下降66% - CA4P[19] 25 多种肿瘤 2002 Gpeak下降(P<0.03) 1例 注:表中,DCE-MRI:动态增强磁共振成像;VEGFR:血管内皮生长因子受体;Ktrans:容量转移常数;ETV:增强肿瘤体积;IAUC:对比剂浓度曲线下的初始面积;Gpeak:梯度峰值;DMXAA:5,6-二甲黄嘌呤-4-乙酸;CA4P:考布他汀- A4-磷酸;“-”表示无此项数据。 表 1 DCE-MRI参与的抗VEGFR、酪氨酸激酶抑制剂和血管破坏药物临床试验
Table 1. Clinial trials of anti-VEGFR medicine and tyrosine kinase inhibitor with application of DCE-MRI
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DCE-MRI参数不仅参与确定药物抗血管作用,还可以明确有效生物剂量。Galbraith等[26]在CA4P的剂量提升试验研究中,对入组患者分别接受从5 mg/m2至114 mg/m2剂量的药物治疗,结果发现,Ktrans只有在剂量大于52 mg/m2之后才会出现显著下降,即在用药后第4小时和第24小时较基线Ktrans分别下降37%和29%,而此时肿瘤尚未出现明显退缩。同时通过临床观察患者的不良反应,发现68 mg/m2为其最大耐受剂量,故而确定了介于有效生物剂量(52 mg/m2)和临床最大耐受剂量(68 mg/m2)之间的治疗时间,并为Ⅱ期临床试验确定了剂量范围。Gregorc等[27]在天冬酰氨-甘氨酸-精氨酸联合肿瘤坏死因子的剂量提升试验研究中,将患者分为4组: 0.2、0.4、0.8、1.6 mg组,其中1.6 mg为毒性限制剂量。用药后,4个组Ktrans变化程度分别为: -27%、-18%、-37%、+17%,其中,0.8 mg组Ktrans下降程度最大,故而确定了0.8 mg为最佳生物剂量从而进入Ⅱ期临床试验。
另外,DCE-MRI参数还可以用于优化给药方式。例如,Jonker等[28]在关于Brivanib的Ⅰ期临床试验中利用DCE-MRI测量Ktrans下降程度变化,比较了不同给药方式带来的药效差异。即在前期试验证实800 mg为Brivanib最大耐受剂量的前提下,给药前先行DCE-MRI的基线Ktrans测量,然后将受试者分成3组予以不同方式给药: 800 mg持续给药、800 mg间断给药、400 mg一日两次给药。在给药后第2、8、26日进行DCE-MRI扫描,结果表明,800 mg持续给药组在第2、8、26日的Ktrans下降程度分别为31%、45%、51%;400 mg一日两次组Ktrans下降程度分别为31%、64%、59%,均与给药前基线Ktrans差异有统计学意义; 而800 mg间断给药组的Ktrans下降程度分别为44%、31%、34%,与给药前基线Ktrans差异无统计学意义。因而认为800 mg持续给药组以及400 mg一日两次组有显著药效,为Ⅱ期临床试验确定了合理的给药方式。
动态增强磁共振成像在抗肿瘤血管药物早期临床试验中的应用
The application of dynamic contrast-enhanced magnetic resonance imaging in early-phase clinical trials of antivascular medicine for malignant tumors
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摘要: 动态增强磁共振成像(DCE-MRI)正逐渐被应用于抗肿瘤血管药物的早期临床试验。该文将对传统临床试验药效评价体系应用于抗肿瘤血管分子靶向药物研发中所存在的问题、DCE-MRI的相应技术原理、DCE-MRI临床应用现状与其在临床试验中的优势、存在的问题与展望做一综述,并列举一些近年来应用DCE-MRI技术进行抗肿瘤血管分子靶向药物临床试验的典型案例。Abstract: The development and research of antivascular medicine has already exerted challenges for traditional clinical trials and its evaluation system.Dynamic contrast-enhanced magnetic resonance imaging(DCE-MRI), as an uninvasive method to visualize and assess vascular structure and function, has been gradually utilized in clinical trials of antivascular medicine and improving stepwise with a view to further detecting angiogenesis of tumor and effects of medicine.This review will articulate on defects of traditional evaluation system in clinical trials of antivascular medicine, technological characteristics of DCE-MRI as well as pros and cons of its application in clinical trials.The detailed utilization of DCE-MRI in some early phase clinical trials during recent years will also be orchestrated in this review.
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Key words:
- Magnetic resonance imaging /
- Dynamic contrast-enhanced /
- Tumors /
- Antivasculra therapy /
- Drug evaluation
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表 1 DCE-MRI参与的抗VEGFR、酪氨酸激酶抑制剂和血管破坏药物临床试验
Table 1. Clinial trials of anti-VEGFR medicine and tyrosine kinase inhibitor with application of DCE-MRI
药物名称 入组病例数 肿瘤类型 年份 DCE-MRI参数变化 缓解例数 抗VEGFR药物 贝伐单抗[35] 31 间变性星型细胞瘤 2011 Ktrans下降逸30%(化疗第4日至28日),ETV下降>40%(化疗第4日) 13例 阿柏西普[36] 47 多种肿瘤 2010 Ktrans下降20%~97%(化疗第1日至第5日) 3例 酪氨酸激酶抑制剂 舒尼替尼[37] 34 原发性肝癌 2009 Ktrans下降50%(化疗第14日) 18例 阿西替尼[38] 36 多种肿瘤 2005 Ktrans下降>50%(化疗第2日至28日) 2例 索拉非尼[33] 56 转移性肾癌 2008 Ktrans下降14%,IAUC90下降4%(化疗第4周,200 mg组);Ktrans下降24%,IAUC90下降30%(化疗第4周,400 mg组) 4例 血管破坏药物 DMXAA[20] 16 多种肿瘤 2002 IAUC24h下降66% - CA4P[19] 25 多种肿瘤 2002 Gpeak下降(P<0.03) 1例 注:表中,DCE-MRI:动态增强磁共振成像;VEGFR:血管内皮生长因子受体;Ktrans:容量转移常数;ETV:增强肿瘤体积;IAUC:对比剂浓度曲线下的初始面积;Gpeak:梯度峰值;DMXAA:5,6-二甲黄嘌呤-4-乙酸;CA4P:考布他汀- A4-磷酸;“-”表示无此项数据。 -
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