Conformal Total Body and Marrow Irradiation for Leukemia

描述(由申请人提供)：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，原因是高剂量照射的疗效(即减少复发)和辐射毒性之间的内在冲突。更具体地说，研究表明，更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“适应性全身和骨髓照射”(适应性TBMI)的新技术的可行性。这一新方法有三个明显的优点：1)结合图像引导的放射治疗，使“集中的辐射”能够被传递到目标(骨髓和其他疾病部位)，从而不同地将辐射剂量输送到不同的器官；2)监测给患者的辐射剂量，并调整后续治疗(根据需要)，以达到规定的剂量，也称为适应过程；以及，3)在不增加毒性的情况下，允许更高的辐射剂量(剂量增加)，方法是提高对病变部位的剂量与对桨和软组织的剂量的治疗比率。这些优势将使进行临床试验以确定安全有效的TBMI在骨髓移植中的最大耐受量成为可能。我们将进行一项可行性试验，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了解；(Ii)通过自适应过程实现个体化治疗；以及(Iii)提高剂量递增的放射生物学精度。通过提高适应性TBMI的治疗比率而获得的剂量递增有望在不增加对健康器官的毒性的情况下提高疗效(即杀死白血病)。这项工作的中心假设是，适应性TBMI的剂量递增是安全有效的，并为高危血液系统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)通过执行I期剂量递增研究来确定TBMI的最大辐射剂量，并在II期研究中评估该方法的有效性；2)通过测量扫描仪内3D全身定位的精度、测量TBMI剂量传递的准确性以及建立自适应的TBMI治疗过程来优化TBMI传递。患有晚期难治性白血病的受试者(0-45岁)(那些未能完全缓解的人)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，通过更好地控制白血病，TBMI可能会提供比TBI更大的好处，因此，预计将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存活率的潜力，这与NIH确立的科学使命是一致的。 公共卫生相关性：复发是急性白血病和其他血液系统恶性肿瘤患者的主要死亡原因，然而传统的全身照射(TBI)不能提供足够的辐射来防止复发而不引起致命的毒性。我们建议评估一种新的全身和骨髓照射(TBMI)技术，该技术允许对疾病部位进行有针对性的和更高的辐射剂量，同时保留健康的器官并将毒性降至最低。我们的目标是使用TBMI更好地控制疾病，减少疾病复发，提高患者存活率。

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. PUBLIC HEALTH RELEVANCE: Relapse is the major cause of death for patients with acute leukemia and other hematological malignancies, yet conventional total body irradiation (TBI) cannot provide enough radiation to prevent relapse without inducing fatal toxicities. We propose to assess a novel total body and marrow irradiation (TBMI) technique that allows for targeted and elevated radiation doses to disease sites while sparing healthy organs and minimizing toxicities. Our goal is to use TBMI for better disease control, decreased disease recurrence and improved patient survival.