Conformal Total Body and Marrow Irradiation for Leukemia

描述（由申请人提供）：由于高剂量照射的疗效（即减少复发）和辐射诱导毒性之间的内在冲突，用于骨髓移植方案的常规全身照射（TBI）的进展已经停滞了50年。更具体地说，研究表明，高剂量的辐射可以减少复发，但会增加对危险器官（OAR）的毒性，包括肺、心脏、眼睛、肝脏和肾脏。我们建议研究一种名为“适应性全身骨髓照射”（adaptive total body and骨髓irradiation）的新技术的可行性。这种新方法有三个明显的优点：1)结合图像引导的断层治疗，允许“聚焦辐射”传递到目标（骨髓和其他疾病部位），从而不同剂量的辐射传递到不同的器官；2)监测给予患者的辐射剂量，并根据需要调整后续治疗，以达到规定的剂量，也称为适应过程；3)允许更高的辐射剂量（剂量递增），而不增加毒性，方法是提高对疾病部位的剂量与对桨叶和软组织的剂量的治疗比例。这些优势将使进行临床试验以确定骨髓移植环境中TBMI的安全有效的最大耐受剂量（MTD）成为可能。我们将进行可行性试验，使用自适应TBMI技术：(i)提供对身体运动和剂量传递准确性的理解；（ii）通过适应过程进行个体化治疗；（三）提高剂量递增的放射生物学精度。通过提高适应性TBMI的治疗比例而获得的剂量递增有望提高疗效（即白血病杀伤），而不会增加对健康器官的毒性。本研究的中心假设是，适应性TBMI的剂量递增是安全有效的，为高危血液恶性肿瘤患者提供了一种治疗选择。我们将通过两个目标来验证这一假设：1)通过进行I期剂量升级研究来确定TBMI的最大辐射剂量，并在II期研究中估计该方法的有效性；2)通过测量扫描仪内3D全身定位的准确性来优化TBMI传递，测量TBMI剂量传递的准确性，并建立适应性TBMI治疗过程。晚期化疗难治性白血病（未能完全缓解）的受试者（0-45岁）将符合条件。这些患者的存活率非常低，大多数人在几周到几个月内死于疾病。如果成功，TBMI可能通过更好的白血病控制提供比TBI显著的益处，因此，有望对晚期白血病和其他血液病患者产生重大影响。适应性TBMI具有更好的疾病控制、减少疾病复发和提高患者生存率的潜力，这与NIH确立的科学使命是一致的。

DESCRIPTION (provided by applicant): Advances in conventional total body irradiation (TBI) used for bone marrow transplant regimens have been stalled for five decades due to the inherent conflict between the efficacy of high dose irradiation (i.e., reduced relapse) and radiation induced toxicity. More specifically, studies show that higher doses of radiation reduce relapse, but increase toxicity to organs at risk (OAR) including the lungs, heart, eyes, liver, and kidneys. We propose to study the feasibility of a novel technique called "adaptive total body and marrow irradiation" (adaptive TBMI). This new approach has three clear advantages: 1) Incorporation of image guided tomotherapy that allows "focused radiation" to be delivered to the target (bone marrow and other disease sites), thereby differentially delivering doses of radiation to various organs; 2) Monitoring of radiation dose delivered to the patients and adjustment of subsequent treatments (as needed) to achieve the prescribed dose, also known as the adaptive process; and, 3) Allowance for higher radiation doses (dose escalation) without increasing toxicity by using an enhanced therapeutic ratio of dose to disease sites versus dose to OARs and soft tissues. These advantages will make it possible to conduct clinical trials to determine a safe and efficacious maximum tolerated dose (MTD) of TBMI in the setting bone marrow transplant. We will conduct a feasibility trial, using adaptive TBMI techniques to: (i) provide an understanding of body motion and the accuracy of dose delivery; (ii) individualize treatment through the adaptive processes; and, (iii) improving radiobiological precision of dose escalation. The dose escalation available through the enhanced therapeutic ratio of adaptive TBMI is expected to increase efficacy (i.e. leukemia kill) without increased toxicity to healthy organs. The central hypothesis of this work is that the dose escalation of adaptive TBMI is safe and efficacious, and provides a treatment option to patients with high risk hematological malignancies. We will test this hypothesis through two aims: 1) To Determine the maximum radiation dose of TBMI by performing a phase I dose escalation study and to estimate the efficacy of this approach in a phase II study, and 2) To optimize TBMI delivery by measuring the accuracy of 3D whole body localization within the scanner, measuring the accuracy of the TBMI dose delivery, and establishing an adaptive TBMI therapy process. Subjects (0-45 years of age) with advanced, chemotherapy refractory leukemia (those who fail to achieve complete remission) will be eligible. These patients have very poor survival, with most dying from their disease within weeks to months. If successful, TBMI may offer significant benefits over TBI through better leukemia control and thus, is expected to have a significant impact on patients with advanced leukemia and other hematologic diseases. Adaptive TBMI has the potential for better disease control, reduced disease recurrence and increased patient survival, consistent with the well-established NIH scientific mission.