Comb External Beam Radiotherapy with 153Sm-EDTMP to Treat High Risk Osteosarcoma

153Sm-EDTMP 梳状外照射治疗高危骨肉瘤

• 批准号: 8826062
• 负责人: David M. Loeb
• 金额: $ 35.47万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8826062
• 关键词: Accounting; Aftercare; Avidity; Biological; Biological Markers; Characteristics; Clinical; Clinical Trials; Comb animal structure; Computer software; Data; Development; Dose; Excision; External Beam Radiation Therapy; Foundations; Generations; Goals; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Health; Hypoxia; Individual; Intensity-Modulated Radiotherapy; Lesion; Measures; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Operative Surgical Procedures; Organ; Patients; Phase II Clinical Trials; Positron-Emission Tomography; Publishing; Radiation; Radiation therapy; Radiopharmaceuticals; Resistance; Samarium SM 153 lexidronam; Stable Disease; Techniques; Testing; Therapeutic; Toxic effect; Tracer; Treatment Efficacy; Treatment Protocols; Unresectable; Variant; Work; base; cancer cell; chemotherapy; combinatorial; cytotoxic radiation; cytotoxicity; dosage; dosimetry; experience; free radical oxygen; high risk; indexing; novel; osteosarcoma; phase 2 study; radioresistant; response; treatment planning; treatment strategy; tumor

DESCRIPTION (provided by applicant): Radiation therapy is rarely used in the treatment of osteosarcoma. The dose required to provide effective local control (80-100 Gy) causes too much damage to surrounding normal tissue to be delivered routinely and safely. Despite the introduction of effective systemic chemotherapy, osteosarcoma patients who cannot achieve a complete surgical resection are never cured. Thus, there is an urgent need for the development of effective local control measures for patients whose tumors are unresectable. Our group has been studying a radiopharmaceutical, 153Sm-EDTMP, for this purpose. This agent can deliver cytotoxic radiation to tumors with exquisite precision, sparing surrounding normal tissue more than 2 mm away. So far, efficacy has been limited because of difficulties delivering sufficient radiation by this means. In the proposed clinical trial, we are testing the hypothesis that tandem treatments with 153Sm-EDTMP can deliver sufficient radiation to allow more tolerable doses of external beam radiotherapy to be administered, and that if the biological equivalent dose of the combination treatment reaches 80-100 Gy, effective local control can be accomplished. Our project will also test the hypothesis that calculating the tumor absorbed dose after administration of a small activity of 153Sm-EDTMP will allow us to calculate a larger activity to administer that will allow us to precisely reach our target dose of 80-100 Gy. Our published work has demonstrated a linear relationship between administered activity and absorbed dose in each patient (though not between patients) after administration of fixed amounts of activity. Our current treatment plan will allow variation in the second administration, with the administered activity to be based on dosimetry calculations after the first treatment. Finally, in previous clincal trials we found little correlation between tumor absorbed dose and clinical response. It is not clear what characteristics account for this variable response to treatment. Hypoxic tumors are less responsive to standard radiation than normoxic tumors, probably because part of the cytotoxicity of radiation therapy involves the generation of oxygen free radicals. We will use a novel technique, [18F]-MISO PET to test the hypothesis that hypoxia makes tumors resistant to radiopharmaceuticals, just as it contributes to resistance to external beam radiotherapy. In summary, this work will build on our prior experience treating osteosarcoma patients with 153Sm-EDTMP, using individualized dosing, combining the radiopharmaceutical with standard external beam radiotherapy, and evaluating the ability of [18F]-MISO PET to predict response to therapy. These results will allow us to continue to develop this promising agent for a group of patients not normally treated with radiation. In addition, this treatment approach can provide the basis for combining radiopharmaceuticals with external beam radiotherapy for other tumor types as well.

描述（由申请人提供）：放射疗法很少用于治疗骨肉瘤。提供有效局部控制所需的剂量（80-100 Gy）会对周围正常组织造成太大损害，无法常规、安全地输送。尽管引入了有效的全身化疗，但无法实现完全手术切除的骨肉瘤患者始终无法治愈。因此，迫切需要为肿瘤无法切除的患者制定有效的局部控制措施。为此，我们小组一直在研究一种放射性药物153Sm-EDTMP。该试剂能够以极高的精度向肿瘤发射细胞毒性辐射，从而避免周围 2 毫米外的正常组织受到伤害。到目前为止，由于难以通过这种方式提供足够的辐射，功效受到限制。在拟议的临床试验中，我们正在测试这样的假设：153Sm-EDTMP串联治疗可以提供足够的辐射，以允许进行更耐受剂量的外照射放疗，并且如果联合治疗的生物等效剂量达到80-100Gy，则可以实现有效的局部控制。我们的项目还将测试计算给药后肿瘤吸收剂量的假设 153Sm-EDTMP 的小活性将允许我们计算要施用的更大活性，这将使我们能够精确地达到 80-100 Gy 的目标剂量。我们发表的工作已经证明，在给予固定量的活动后，每位患者（尽管不是在患者之间）的给予活动和吸收剂量之间存在线性关系。我们目前的治疗计划将允许第二次给药的变化，给药活动将基于第一次治疗后的剂量测定计算。最后，在之前的临床试验中，我们发现肿瘤吸收剂量与临床反应之间几乎没有相关性。目前尚不清楚是什么特征导致了这种对治疗的不同反应。缺氧肿瘤对标准放射的反应不如含氧量正常的肿瘤，可能是因为放射治疗的部分细胞毒性涉及氧自由基的产生。我们将使用一种新技术，[18F]-MISO PET 来检验缺氧使肿瘤对放射性药物产生抵抗力的假设，就像它有助于抵抗外照射放射治疗一样。总之，这项工作将建立在我们之前用 153Sm-EDTMP 治疗骨肉瘤患者的经验的基础上，使用个体化剂量，将放射性药物与标准外照射放射治疗相结合，并评估 [18F]-MISO PET 预测治疗反应的能力。这些结果将使我们能够继续为一组通常不接受放射治疗的患者开发这种有前景的药物。此外，这种治疗方法也可以为其他肿瘤类型的放射性药物与外照射放射治疗相结合提供基础。