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

描述（由申请人提供）：放射治疗很少用于治疗骨肉瘤。提供有效局部控制所需的剂量（80-100戈伊）对周围正常组织造成太大损伤，无法常规安全地输送。尽管引入了有效的全身化疗，骨肉瘤患者谁不能实现一个完整的手术切除是永远无法治愈的。因此，迫切需要为肿瘤不可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放射性药物153 Sm-EDTMP。这种药剂可以精确地将细胞毒性辐射传递到肿瘤，而不影响超过2毫米以外的正常组织。到目前为止，由于难以通过这种方式提供足够的辐射，疗效有限。在拟议的临床试验中，我们正在测试的假设，串联治疗与153 Sm-EDTMP可以提供足够的辐射，允许更耐受剂量的外照射放疗管理，如果生物等效剂量的组合治疗达到80-100戈伊，可以实现有效的局部控制。我们的项目也将测试假设，计算肿瘤吸收剂量后，管理 小放射性的153 Sm-EDTMP将使我们能够计算出更大的放射性，从而使我们能够精确地达到80-100戈伊的目标剂量。我们已发表的工作已经证明，在给予固定量的活性后，每个患者（尽管不是患者之间）的给药活性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，给予的活性将基于第一次治疗后的剂量测定计算。最后，在以前的临床试验中，我们发现肿瘤吸收剂量和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可变反应。低氧肿瘤对标准辐射的反应比含氧量正常的肿瘤低，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。我们将使用一种新的技术，[18 F]-MISO PET来测试缺氧使肿瘤对放射性药物产生抗性的假设，就像它有助于抵抗外部束放射治疗一样。总之，这项工作将建立在我们以前的经验，治疗骨肉瘤患者与153 Sm-EDTMP，使用个性化的剂量，结合放射性药物与标准的外照射放疗，并评估能力[18 F]-MISO PET预测治疗反应。这些结果将使我们能够继续开发这种有前途的药物，用于一组通常不接受放射治疗的患者。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射束放射治疗相结合提供基础。

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.