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AME专刊|肿瘤勾画的影像学技术和肺癌异质性量化: 当前可能性概述

Published at: 2015年第1卷第S1期

Wouter van Elmpt 1 , Catharina M.L. Zegers 1 , Marco Das 2 , Dirk De Ruysscher 3
1 Department of Radiation Oncology (MAASTRO)
2 Department of Radiology, GROW, School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands
3 Radiation Oncology, University Hospitals Leuven/KU Leuven, Leuven, Belgium

摘要

描述和勾画原发肺肿瘤和淋巴结的影像学技术是恰当放疗的前提条件。针对这个目标已经提出了大量的影像学模式,但是只有计算机断层(CT)和FDG-PET已经常规应用于临床。 乏氧PET、动态增强CT (DCE-CT)、双能CT (DECT)和 (功能性)磁共振影像(MRI)将来有应用前景。除了原发肿瘤方面的信息,这些技术能用于定量组织异质性和评价疗效。将来,治疗分类可能会按影像学技术设计以佳化个体化治疗


Correspondence to: Wouter van Elmpt, Ph。D。 Department of Radiation Oncology (MAASTRO), GROW, School for Oncology and Developmental Biology, Maastricht University Medical Centre, Dr。 Tanslaan 12, NL-6229 ET Maastricht, The Netherlands。 Email: wouter。vanelmpt@maastro。nl。

Submitted Aug 05, 2013。 Accepted for publication Aug 21, 2013。

前言

肺癌是所有发达国家最重要的一个癌症死亡原因(1)。在将来的数十年后中国这些国家的肺癌预期会愈演愈烈 (2)。放疗在所有肺癌分期中的起着越来越重要的作用: I 期非小细胞肺癌 (NSCLC) 应用立体定向体部放疗(SBRT) (3), 也称为立体定向消融放射治疗或SABR,它们的结果等效于手术。III 期NSCLC和小细胞肺癌 (SCLC)通常应用化疗联合放疗,而寡转移灶的患者应用包括放疗在内的治疗后可能有很长的无病生存期(4,5)。

然而,明确界定需要照射的肿瘤是成功放疗的前提条件。应用计算机断层(CT)或磁共振(MRI)等形态学影像使肿瘤边界可视化是很重要的,如今应用正电子发射断层(PET)等分子影像技术也能使癌症的生物学特征和危及器官(OAR)达到可视化。应用这些影像评价肿瘤生物学异质性可能设计出更个体化的治疗。应用关于肿瘤和危及器官特征方面的知识能使治疗比最优化。虽然看起来很明显,但是事实证明要达到这个目的很困难。因为缺乏经认证的自动化系统,这类系统应该能很好地合并被OAR包绕且密度相似的体积,所以很难高度准确地且内部外部观察变异都很低地确定肿瘤边界。生物学特征可以成像,但它们应用于标准实践需要改善疗效的前瞻性临床实验。

本文将重点放在应用最新的影像学技术勾画和描述肺癌患者原发肿瘤和受侵淋巴结。某些这类技术已经应用于临床实践而部份仍然处于研究水平。此外,还给出这些方法的前景,将来如何应用个体化治疗肺癌和如何佳化局部肿瘤控制和器官毒性之间的平衡。

靶区勾画和量化的影像学模式

FDG-PET/CT

晚期肺癌纵隔淋巴结分期方面,FDG-PET的准确性优于CT。因而,在放疗治疗计划过程中加入PET是合理的。在多个 NSCLC的计划研究中,应用FDG-PET能减少受照射OAR体积,这将减少副反应或使以提高局部控制率为目标的放疗剂量增加成为可能(6,7)。NSCLC和SCLC的前瞻性研究确实都表明,基于FDG-PET扫描的选择性纵隔淋巴结照射并不使孤立淋巴结复发率增高 (8-10)。

放疗计划中应用FDG-PET可以减少肿瘤学家勾画的变异并允许如果需要可以手动编辑的肿瘤自动勾画(11-13)。为了直接把PET/CT设备应用于放疗计划,必需考虑新的标准。Thorwarth 详细地概述了基本技术现状和放疗计划推荐 (14)。在标准的3D PET/CT捕获中,小病灶可能难以检测,这是因为固有的呼吸运动伪影所致,而且与呼吸关联的4D捕获比较可能导致标准摄取值(SUV)定量不准确 (15)。PET/CT有获取呼吸校正(4D)模式选项以抵消胸部呼吸运动。此外,多个报导显示4D PET确实可以改善病灶检出率 (16,17)。 The 4D扫描通常由代表呼吸周期不同时相的一套5、8或10个3DPET/CT扫描重建而成(18)。获得这样一个4D PET 扫描与4D CT合并,但实践中并未应泛应用。获取4D影像的缺点是在某种程度上延长了扫描时间,这可能限制的PET/CT的工作量而且并不是所有软件系统都能处理这么大量的影像学数据。然而应用更先进的重建程序,只使用没有呼吸运动部份 (如呼气时相) (19,20) 或 (非刚性) 配准PET的不同呼吸时相成为单一的影像(21) 从而可能改善工作流。

以肿瘤放射治疗为目的的肿瘤勾画是一个费时的手工过程,且存在观察者间和观察者变异(22)。虽然应用严格的勾画方案减少变异 (23), 但是仍然存在时间投入同时限制的自适应方案。因为放射治疗中CT扫描作为初始数据集,(电子)密度的准确定量是放射治疗计划剂量计算所必需的,基于CT扫描的自动分野是合理的。此外,4D-CT扫描已经用于日常实践中,这些运动信息可以在自动勾画方案中得到解释。另一方面,如果肿瘤被肺组织包绕,FDG-PET 与解剖边界的关联确实优于CT(24)。因而联合CT 和FDG-PET是合理的,而自动分野的方案能减少勾画时间。然而,只有少数研究用病理学来证实他们的自动分野方法(22,25-28)因为缺乏技术验证以及准确性(29,30)。因而完全自动肿瘤分野还没有应用于常规临床实践。

乏氧PET

肿瘤细胞乏氧是一个实体瘤已知的特片, 它对治疗效果起着负面影响(31)。准确地确定肿瘤乏氧对选择哪些病人将从特异的抗乏氧治疗中获益具有重要性。应用Eppendorf的电极是评价肿瘤乏氧的金标准,然而这个方法的缺点在于它是侵袭性的, 局限用于容易进入的浅表肿瘤(32)。乏氧PET影像允许肿瘤乏氧的非侵袭性检测和定量并提供显示乏氧分布的机会,重要的是它能整合到放射剂量分布中。检测肿瘤乏氧的最常见机制是应用2-硝基咪唑PET示踪剂,它能选择性结合并保留在乏氧肿瘤细胞中。

多个氟-18 [18F]的2-硝基咪唑,已经应用于患者中以确定乏氧。第一个而且是最常用的乏氧PET示踪剂是[18F]MISO, 然而,在乏氧病灶中累积缓慢和有限的正常组织清除率限制了它的临床应用(33)。因而,开发了新的替代示踪剂,通过增强示踪剂的亲水性和清除率以改善乏氧示踪剂的药代动力学属性,如 [18F]AZA, [18F]ETNIM, [18F]EF3, [18F]HX4 和Cu-ATSM核苷缀合物。

基于PET影像的肿瘤乏氧定量可以在静态影像上进行,在注射后的某个时间点采集;或基于动态获取,它也考虑到病灶的灌注 (34)。 图 1所示的是肺癌患者例子,同时有FDG-PET/CT扫描和乏氧[18F]HX4-PET/CT扫描。在NSCLC 患者中,乏氧PET表现出与预后的相关性而且给出与FDG摄取不同的信息(35,36)。s乏氧PET成像的研究显示,多数NSCLC病灶存在肿瘤细胞乏氧 (37-40)。肿瘤乏氧的范围与肿瘤反应和放疗后复发的危险相关 (41,42)。最近的理论研究表明根据乏氧成像的推量或数字剂量绘画是可行的,对辐射抵抗/乏氧的区域增加放射剂量可能会提高局部控制率 (43-45)。

图 1. NSCLC患者的FDG-PET/CT 扫描 (左) 和乏氧HX4-PET/CT 扫描范例。代谢(FDG) 和乏氧(HX4) PET影像中肿瘤异质性均清晰可见。

MRI

MRI提供了高分辨率且有良好软组织对比的解剖学信息。已经研究了它在肿瘤和淋巴结勾画方面的应用。肿瘤的运动可能导致明显伪影,这显然是一个重要的问题。为了解决运动问题,两个特殊序列是有用的: 快速小角度激发成像序列(FLASH) 和真实稳态进动快速成像(TrueFISP) (46,47)。两种技术都显示出质量上有诊断价值的膈肌和胸壁有规律且同步的运动。因为可以对完整的呼吸周的整个肺进行成像,所以动态MRI可以用于确定内靶区(ITV)。但是,肺的动态MRI扫描仍然容易产生伪影,这会影响配准的准确性。

就我们所知道的,肺癌患者没有对比MRI、CT或FDG-PET/CT勾画的研究, 也没有病理学证实的研究。然而,如果要鉴别良性与恶性淋巴结,弥散加权MRI(DW-MRI) 的准确性可能与FDG-PET 扫描相似(48)。

动态对比增强CT(DCE-CT)

DCE-CT (或灌注CT) 影像是肿瘤鉴别比较新的方法。它提供了一种评价肺癌患者功能参数的便捷方法。迄今为止DCE-CT仍然是一种研究工具,但是研究的初始结果显示将来有应用前景。 DCE-CT扫描给出了血流 (BF), 血流容量(BV) 和血管通透性的信息 (49-52)。然而文献中某些DCE-CT研究受扫描器头尾方向视野大小(如3-5 cm)限制,现在的技术结构有能力使DCE-CT扫描器大小达12cm。重现DCE-CT扫描提取参数也在可接受的范围 (49,50,53) 并允许更大的患者研究以寻找疗效的预后因子。这些参数与化疗或抗血管生成药物的亲和性相关 (54)且治疗有反应者与无反应者之间显示有差异 (53)。在某些研究中, DCE-CT提取值与预后及NSCLC亚型相关 (55)。 DCE-CT值能给出FDG摄取之外的信息,两者在鉴定肿瘤方面起着互补作用。临床和预后方面的内涵尚未得到充分的理解而DCE-CT研究的患者例数仍然很少。因而需要进一步的临床研究以评价DCE-CT在未来个体化治疗和预后中的价值。最近 Mandeville等的研究评价了DCE-CT参数,认为与乏氧标志存在关联(56)。研究表明BV和BF与乏氧的免疫组化标志负相关。最近Lee 等的研究显示这个现象在DCE-CT中重复性很高(57)。如果应用DCE-CT测量随时间变化的增强曲线, Hwang 等的研究显示增强模式对应着肿瘤分期 (58)。有趣的是,研究其他部位时DCE-CT参数或许能预测生存,如 Koh等研究结直肠癌患者时就有这样的发现(59)。 Spira等评价DCE-CT参数与组织病理学的关系时发现,两者存在很好的相关性特别是与微血管密度(MVD)的相关性更明显 (60)。 Fraioli等证实治疗后灌注参数的改变与治疗反应之间的相关性 (61)。

双能CT (DECT)

最新的CT扫描技术有能力同时或紧跟着应用两套不同的kV系统。不同的两个扫描结果可以用于组织鉴定和碘成像。某些研究试图应用碘成像鉴别肺肿瘤,初步显示有希望的结果 (62-64)。初步区分良性与恶性肺部结节看来是可能的,但是研究的病例数仍然较少而且临床上真正需要的是<8 mm 的肺部小结切当前仍然不能满意地解决(65-67)。

正常组织鉴别的影像学模式

放射治疗通常推动最佳的肿瘤控制以及可以接受(低)副反应。放疗诱发的肺部毒性 (RILT)是推高肺部肿瘤剂量的主要剂量限制因素之一;因而评价肺功能在设计治疗计划中起着潜在的重要作用。多种影像学技术能用于肺功能定量以及局部肺功能定量,而常规肺功能检测只能给予整体肺功能评价。

SPECT/CT

虽然SPECT的空间分辨能力有限应用,但是SPECT/CT定量分析肺部灌注和通气损伤是常用于评估肺功能的影像学模式。研究表明放疗能引起肺灌注改变 (68-70)。关于肺部区域敏感性和区域功能的知识可以指导计划设计以避开肺内高功能区(71-74)。然而减少肺毒性的假设仍需临床研究的验证。

CT

放疗后的CT密度出现改变而且患者之间差别明显(75,76)。深度分析肺部CT特征可以确定放射性肺损伤的危险人群。

PET/CT

肺部FDG的摄取可以反应了炎症状态。研究表明放疗前肺部高FDG摄取是合并放射性肺炎的独立危险因素(77)。肺部嗜FDG区是肺炎高易感区。在根据FDG摄取模式用上述知识改变肺部放射剂量分布前,需要进一步的研究说明这些结果。

MRI

患者吸入惰性超极化的氦-3气体后MRI扫描能显示肺部通气区域(78)。非通气区域不显示MRI信号。理论研究中,考虑到这些因素能显著降低肺V20 (78)。然而这个策略从未进行前瞻性研究,因而仍在研究中。

DECT

DECT肺灌注显影经常用于检测肺栓塞(PE) (79-83)。注射碘造影剂(CM)后应用两种能量的CT扫描器(通常 80/140 kV) 这使肺内碘分布的可视化成为可能。 CT是排除急性PE的可选择方法,可以很好地显示亚段水平的栓子。应用DECT后不只是显示栓塞成为可能,而且可以显示相应有灌注缺损。这有临床重要性,如早前的研究所示,单个亚段的栓塞(未导致显著的灌注缺损)可以不处理(84)。基于肺部放疗可能也会改变肺部CM灌注的假设,这个技术提供了进一步评价肺癌放疗患者的可能。 图 2 所示是一例右下叶PE导致一个大的灌注缺损。

2.段动脉栓塞导致大面积右下叶灌注缺损患者的范例。

而DECT最初用于肺部碘成像, 氙通气因而加入了患者通气成像这个缺失部份。最近几年某些研究团队证明应用氙通气是可行而且安全的,也能显示通气成像,这将增加在重症监护患者甚至是儿童不同病理状态下的额外应用价值,如哮喘 (85-93)。

应用影像的治疗个体化

下一个重要进步是当前临床试验正在验证的剂量绘画假说(94,95)。该假说的理论基础是肿瘤的异质性。整块肿瘤的生物学特性不一致导致治疗反应的不均一性(96)。因而整块肿瘤中部份出现治疗抗拒与当前均匀照射治疗技术不是最佳治疗有关。通过应用影像学信息引导或确定准确的剂量效应关系达到个性化治疗是下一阶段个体化治疗的任务(97)。一个当前正在进行的多中心NSCLC研究正在检验这个假设,均一的剂量和对高代谢活性区域追加剂量两者哪个有更好的局部控制率(98)。

在个体化治疗中应用影像学信息的方式是疗效评估。治疗过程中重复采集影像可能提供治疗成功的预测信息。 乏氧 (如HX4、FAZA、 FMISO),代谢 (如FDG) 或增殖 [如FLT (99)] PET示踪剂允许治疗过程中早期进行治疗评价 (100)。放疗过程中MRI扫描也能用于评价肿瘤的改变 (101)。 DW-MRI 衍生的ADC (表观弥散系数)值的改变与生存相关。然而, ADC和FDG 的改变也明显相关。仍不清楚的是这些预测参数有什么临床价值。

在当前肺癌4-6周的分次放疗方案中,治疗仍然还有改进的空间。 如前所述,这些治疗方案的改进可以是减少副反应也可以是增加局部肿瘤控制的机会。

结论

当前临床实践中影像是靶区勾画不可或缺的一部份。接着需要研究的是肿瘤鉴定。减少正常组织毒性也是全面优化治疗的重要方面。个体化治疗优化中应该应用影像学特征评价组织功能。

致谢

One of the authors (W.v.E.) would like to acknowledge funding (KWF MAC 2011-4970) from the Dutch Cancer Society.

Disclosure: The authors declare no conflict of interest.

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Cite this article as: van Elmpt W, Zegers CM, Das M, De Ruysscher D. Imaging techniques for tumour delineation and heterogeneity quantification of lung cancer: overview of current possibilities. J Thorac Dis 2014;6(4):319-327. doi: 10.3978/j.issn.2072-1439.2013.08.62

 

编译|蔡文杰,福建医科大学附属泉州第一医院放疗科副主任医师,福建省抗癌协会肿瘤放射治疗专业委员会青年委员会副主任委员。

 

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Doi:10.3978/kysj.2014.1.458
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