Liver Radioprotection by Systemic of Regional Amifostine

描述(申请人提供)：尽管大剂量三维计划放射治疗改善了局灶性肝内癌患者的局部控制，并可能提高患者的存活率，但许多患者有弥漫性疾病。氨磷汀已经在随机试验中被证明可以保护腮腺、肺和食道免受辐射。我们建议优化使用氨磷汀作为正常肝脏的辐射保护剂，这将允许局灶性和弥漫性疾病患者安全地提供更高剂量的辐射。在具体目标1中，我们将对弥漫性肝内癌患者进行全身氨磷汀剂量递增放射治疗的I期试验。我们的临床前数据表明，全身性应用氨磷汀在正常肝脏比在肝内肿瘤中产生更多的WR-1065，这导致对肝脏(而不是肿瘤)的辐射保护。因此，我们假设全身性氨磷汀将允许有意义的选择性保护正常肝脏，允许辐射剂量增加。在具体目标2中，我们将开展临床前研究，以优化选择性(目标2A)，并估计区域氨磷汀的适当剂量(目标2B)。我们的初步数据表明，全身和门静脉氨磷汀都保护正常肝脏而不保护肿瘤，门静脉氨磷汀产生的活性代谢物WR-1065的正常组织/肿瘤比显著高于全身氨磷汀。我们假设，区域氨磷汀在产生更高的WR-1065肝肿瘤比方面优于全身氨磷汀，与肿瘤相比，对正常肝脏的选择性保护更大。在具体目标3中，我们将对弥漫性肝内癌患者进行区域氨磷汀剂量递增放射治疗的I期试验。我们假设，与全身给药相比，区域给药对正常肝脏的保护作用更强(或相等)，且全身毒性相同(或更小)。我们的初步数据、研究团队和将临床前研究结果转化为临床的记录表明，这项建议可能会改善弥漫性肝内癌患者的治疗结果。

DESCRIPTION (provided by applicant): Although high dose three dimensionally planned radiation therapy improves local control and, possibly, survival for patients with focal intrahepatic cancers, many patients have diffuse disease. Amifostine has been shown in randomized trials to protect the parotid gland, lung, and esophagus from radiation. We propose to optimize the use of amifostine as a radiation protector of normal liver, which will permit the safe delivery of higher doses of radiation for patients with both focal and diffuse disease. In Specific Aim 1 we will conduct a phase I trial of dose escalating radiation therapy with systemic amifostine for patients with diffuse intrahepatic cancer. Our preclinical data demonstrate that systemic administration of amifostine produces more WR-1065 in the normal liver than in intrahepatic tumor, and that this leads to radioprotection of the liver (and not the tumor). Therefore, we hypothesize that systemic amifostine will permit meaningful selective protection of the normal liver, permitting radiation dose escalation. In Specific Aim 2 we will carry out preclinical studies to optimize selectivity (Aim 2A) and estimate the appropriate dose of regional amifostine (Aim 2B). Our preliminary data demonstrate that both systemic and portal venous amifostine protect normal liver without protecting tumor, and that portal venous amifostine produces significantly higher normal tissue/tumor ratios of the active metabolite WR-1065 than systemic amifostine. We hypothesize that regional amifostine will be superior to systemic amifostine in producing a higher liver to tumor ratio of WR-1065, causing greater selective protection of normal liver compared to tumor. In Specific Aim 3 we will conduct a phase I trial of dose escalating radiation therapy with regional amifostine for patients with diffuse intrahepatic cancer. We hypothesize that regional administration of amifostine will permit greater (or equal) protection of normal liver than is possible by systemic administration, with equal (or less) systemic toxicity. Our preliminary data, research team, and record for translating preclinical findings to the clinic suggest that this proposal is likely to improve the outcome of treatment of patients with diffuse intrahepatic cancer.