Bonekamp David, Mouridsen Kim, Radbruch Alexander, Kurz Felix T, Eidel Oliver, Wick Antje, Schlemmer Heinz-Peter, Wick Wolfgang, Bendszus Martin, Østergaard Leif, Kickingereder Philipp
1 Department of Neuroradiology, University of Heidelberg Medical Center, Heidelberg, Germany.
2 Department of Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
J Cereb Blood Flow Metab. 2017 Feb;37(2):485-494. doi: 10.1177/0271678X16630322. Epub 2016 Jul 21.
Antiantiogenic therapy with bevacizumab in recurrent glioblastoma is currently understood to both reduce microvascular density and to prune abnormal tumor microvessels. Microvascular pruning and the resulting vascular normalization are hypothesized to reduce tumor hypoxia and increase supply of systemic therapy to the tumor; however, the underlying pathophysiological changes and their timing after treatment initiation remain controversial. Here, we use a novel dynamic susceptibility contrast MRI-based method, which allows simultaneous assessment of tumor net oxygenation changes reflected by the tumor metabolic rate of oxygen and vascular normalization represented by the capillary transit time heterogeneity. We find that capillary transit time heterogeneity, and hence the oxygen extraction fraction combine with the tumoral blood flow (cerebral blood flow) in such a way that the overall tumor oxygenation appears to be worsened despite vascular normalization. Accordingly, hazards for both progression and death are found elevated in patients with a greater reduction of tumor metabolic rate of oxygen in response to bevacizumab and patients with higher intratumoral tumor metabolic rate of oxygen at baseline. This implies that tumors with a higher degree of angiogenesis prior to bevacizumab-treatment retain a higher level of angiogenesis during therapy despite a greater antiangiogenic effect of bevacizumab, hinting at evasive mechanisms limiting bevacizumab efficacy in that a reversal of their biological behavior and relative prognosis does not occur.
目前认为，贝伐单抗用于复发性胶质母细胞瘤的抗血管生成治疗既能降低微血管密度，又能修剪异常肿瘤微血管。微血管修剪及由此导致的血管正常化被认为可减轻肿瘤缺氧并增加全身治疗对肿瘤的供应；然而，治疗开始后潜在的病理生理变化及其发生时间仍存在争议。在此，我们使用一种基于动态对比增强磁共振成像的新方法，该方法能够同时评估由肿瘤氧代谢率反映的肿瘤净氧合变化以及由毛细血管通过时间异质性表示的血管正常化情况。我们发现，毛细血管通过时间异质性以及氧摄取分数与肿瘤血流（脑血流量）相结合，使得尽管血管正常化，但总体肿瘤氧合似乎仍恶化。相应地，在对贝伐单抗治疗反应时肿瘤氧代谢率降低幅度更大的患者以及基线时肿瘤内氧代谢率较高的患者中，进展和死亡风险均升高。这意味着，在贝伐单抗治疗前血管生成程度较高的肿瘤，尽管贝伐单抗具有更强的抗血管生成作用，但在治疗期间仍保持较高水平的血管生成，这暗示了限制贝伐单抗疗效的逃避机制，即其生物学行为和相对预后并未发生逆转。
