Grkovski Milan, Lee Nancy Y, Schöder Heiko, Carlin Sean D, Beattie Bradley J, Riaz Nadeem, Leeman Jonathan E, O'Donoghue Joseph A, Humm John L
Department of Medical Physics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Eur J Nucl Med Mol Imaging. 2017 Sep;44(10):1682-1691. doi: 10.1007/s00259-017-3720-6. Epub 2017 May 24.
There is growing recognition that biologic features of the tumor microenvironment affect the response to cancer therapies and the outcome of cancer patients. In head and neck cancer (HNC) one such feature is hypoxia. We investigated the utility of F-fluoromisonidazole (FMISO) dynamic positron emission tomography (dPET) for monitoring the early microenvironmental response to chemoradiotherapy in HNC.
Seventy-two HNC patients underwent FMISO dPET scans in a customized immobilization mask (0-30 min dynamic acquisition, followed by 10 min static acquisitions starting at ∼95 min and ∼160 min post-injection) at baseline and early into treatment where patients have already received one cycle of chemotherapy and anywhere from five to ten fractions of 2 Gy per fraction radiation therapy. Voxelwise pharmacokinetic modeling was conducted using an irreversible one-plasma two-tissue compartment model to calculate surrogate biomarkers of tumor hypoxia (k and Tumor-to-Blood Ratio (TBR)), perfusion (K ) and FMISO distribution volume (DV). Additionally, Tumor-to-Muscle Ratios (TMR) were derived by visual inspection by an experienced nuclear medicine physician, with TMR > 1.2 defining hypoxia.
One hundred and thirty-five lesions in total were analyzed. TBR, k and DV decreased on early response scans, while no significant change was observed for K . The k -TBR correlation decreased substantially from baseline scans (Pearson's r = 0.72 and 0.76 for mean intratumor and pooled voxelwise values, respectively) to early response scans (Pearson's r = 0.39 and 0.40, respectively). Both concordant and discordant examples of changes in intratumor k and TBR were identified; the latter partially mediated by the change in DV. In 13 normoxic patients according to visual analysis (all having lesions with TMR = 1.2), subvolumes were identified where k indicated the presence of hypoxia.
Pharmacokinetic modeling of FMISO dynamic PET reveals a more detailed characterization of the tumor microenvironment and assessment of response to chemoradiotherapy in HNC patients than a single static image does. In a clinical trial where absence of hypoxia in primary tumor and lymph nodes would lead to de-escalation of therapy, the observed disagreement between visual analysis and pharmacokinetic modeling results would have affected patient management in <20% cases. While simple static PET imaging is easily implemented for clinical trials, the clinical applicability of pharmacokinetic modeling remains to be investigated.
人们越来越认识到肿瘤微环境的生物学特征会影响癌症治疗的反应以及癌症患者的预后。在头颈癌（HNC）中，缺氧就是这样一种特征。我们研究了F-氟米索硝唑（FMISO）动态正电子发射断层扫描（dPET）在监测HNC患者对放化疗的早期微环境反应中的效用。
72例HNC患者在基线期和治疗早期接受了FMISO dPET扫描，扫描时使用定制的固定面罩（0 - 30分钟动态采集，随后在注射后约95分钟和160分钟开始进行10分钟静态采集），此时患者已经接受了一个周期的化疗以及每次2Gy、共5至10次的放射治疗。使用不可逆的单血浆双组织室模型进行体素水平的药代动力学建模，以计算肿瘤缺氧（k和肿瘤与血液比值（TBR））、灌注（K）和FMISO分布容积（DV）的替代生物标志物。此外，由经验丰富的核医学医师通过视觉检查得出肿瘤与肌肉比值（TMR），TMR > 1.2定义为缺氧。
总共分析了135个病灶。在早期反应扫描中，TBR、k和DV降低，而K未观察到显著变化。从基线扫描（平均瘤内和体素水平合并值的Pearson相关系数r分别为0.72和0.76）到早期反应扫描（Pearson相关系数r分别为0.39和0.40），k - TBR相关性大幅下降。同时发现了瘤内k和TBR变化的一致和不一致实例；后者部分由DV的变化介导。在视觉分析判定为正常氧合的13例患者中（所有患者的病灶TMR = 1.2），发现了k显示存在缺氧的亚体积区域。
与单一静态图像相比，FMISO动态PET的药代动力学建模揭示了HNC患者肿瘤微环境更详细的特征以及对放化疗反应的评估。在一项临床试验中，如果原发肿瘤和淋巴结不存在缺氧会导致治疗降级，那么观察到的视觉分析与药代动力学建模结果之间的差异在不到20%的病例中会影响患者管理。虽然简单的静态PET成像易于在临床试验中实施，但药代动力学建模的临床适用性仍有待研究。
