Predicting Liver Function After Irradiation

描述（由申请人提供）：大约三分之二的肝癌患者存在不可切除的疾病。我们之前的研究表明，高剂量适形放疗联合化疗似乎可以延长不可切除的肝内癌患者的生存期。然而，进一步增加辐射剂量的尝试受到辐射性肝病（RILD）发展的限制。RILD的病理是静脉闭塞性疾病，其特征是肝脏中央静脉内血栓形成，产生“后”肝充血。在过去，开发模型来估计发生RILD的可能性的努力主要是基于正常肝脏的计划辐射剂量分布。这些分析表明，增加平均肝脏剂量与发生RILD的可能性相关。虽然这些模型允许安全提供比以前可能的高得多的辐射剂量，但它们也表明，单独根据物理剂量分布或一般临床特征作出的预测不能反映个体患者敏感性的广泛范围。由于RILD的基本病理生理是静脉闭塞，我们提出假设，早期监测门静脉灌注和肝胆功能将有可能预测照射后的肝功能，从而允许安全地向肿瘤提供更高的剂量，而不会增加并发症。我们的初步数据为支持这一假设提供了证据。在本R01申请中，我们建议根据放疗计划，以及放疗前和放疗中DCE MRI和SPECT评估门静脉灌注和肝胆功能的值，建立一个预测放疗完成后肝功能的模型。此外，我们还利用我们开发的肝剂量反应函数来评估放射治疗期间个体和区域的辐射敏感性，以预测放射后的肝功能。我们提出的方法是高度创新的，代表了研究肝脏辐射毒性的新范式。它有可能成为个体化治疗的工具。

DESCRIPTION (provided by applicant): Approximately two thirds of patients with intrahepatic cancer present with unresectable disease. Our previous studies show that high dose conformal radiation combined with chemotherapy appears to prolong the survival of patients with unresectable intrahepatic cancers. However, attempts to increase radiation dose still further have been limited by the development of radiation-induced liver disease (RILD). The pathology of RILD is veno-occlusive disease, which is characterized by thrombosis within the central veins of the liver producing "post" hepatic congestion. In the past, efforts to develop models to estimate the likelihood of developing RILD have been based primarily on the planned radiation dose distribution for the normal liver. These analyses have demonstrated that increasing mean liver dose correlates with the likelihood of developing RILD. While these models have permitted the safe delivery of far higher doses of radiation than have previously been possible, they also suggest that there is a broad range of individual patient sensitivity that is not reflected by predictions made solely based on the physical dose distribution or general clinical features. As the basic pathophysiology of RILD is venous occlusion, we develop the hypothesis that early monitoring of portal venous perfusion and hepatobiliary function would have the potential to predict liver function after irradiation, thereby permitting to safely deliver the higher dose to the tumor without an increase of complications. Our preliminary data provide evidence to support this hypothesis. In this R01 application, we propose to develop a model to predict liver function after the completion of radiation therapy based upon the radiation treatment plan, and the values of portal venous perfusion and hepatobiliary function assessed by DCE MRI and SPECT prior to and during radiation therapy. Also, we assess individual and regional radiation sensitivity during radiation therapy using the liver dose response function that we have developed, for prediction of liver function after irradiation. Our proposed approach is highly innovative and represents a new paradigm to investigate radiation toxicity in the liver. It has potential to be a tool for individualized therapy. PUBLIC HEALTH RELEVANCE: Our previous studies show that high dose conformal radiation combined with chemotherapy appears to prolong the survival of patients with unresectable intrahepatic cancers. However, attempts to increase radiation dose still further have been limited by radiation-induced liver injury. Our long term goal is to develop a new imaging approach for prediction of radiation-induced syptomatic liver injury. Therefore, higher dose of radiation can be safely delivered to tumor in patients who can be better tolerant to radiation, thereby improving survival.