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

描述(申请人提供)：放射治疗很少用于骨肉瘤的治疗。提供有效的局部控制所需的剂量(80-100Gy)会对周围正常组织造成太大的损害，无法常规和安全地提供。尽管引入了有效的全身化疗，但无法完全手术切除的骨肉瘤患者永远不会被治愈。因此，迫切需要开发有效的局部控制措施来治疗无法切除的肿瘤患者。为此，我们小组一直在研究放射性药物153Sm-EDTMP。这种试剂可以精确地将细胞毒性辐射传递到肿瘤，避免超过2毫米远的正常组织。到目前为止，由于难以通过这种方式提供足够的辐射，疗效一直受到限制。在拟议的临床试验中，我们正在测试这样一个假设，即153Sm-EDTMP串联治疗可以提供足够的辐射，以允许进行更多可耐受的外照射剂量，并且如果联合治疗的生物等效剂量达到80-100GY，就可以实现有效的局部控制。我们的项目还将检验这样一种假设，即计算给药后的肿瘤吸收剂量 153Sm-EDTMP的小活度将使我们能够计算出要管理的更大的活度，从而使我们能够精确地达到我们的目标剂量80-100Gy.我们发表的研究表明，在每个患者(尽管不是患者之间)中，在给予固定剂量的活动后，给予的活度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在第二次给药中进行变化，所用活动将基于第一次治疗后的剂量计算。最后，在以前的临床试验中，我们发现肿瘤吸收剂量与临床反应之间几乎没有相关性。目前还不清楚是什么特征导致了对治疗的这种可变反应。低氧肿瘤对标准辐射的反应不如常氧肿瘤，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。我们将使用一种新的技术，[18F]-MISO PET来检验低氧使肿瘤对放射药物产生抗药性的假设，就像它对体外放射治疗的抗药性一样。综上所述，这项工作将建立在我们以前使用153Sm-EDTMP治疗骨肉瘤患者的经验的基础上，使用个性化剂量，将放射药物与标准外照射相结合，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开发这种有希望的药物，用于一组通常不接受放射治疗的患者。此外，该治疗方法也可为放射药物联合外照射治疗其他类型肿瘤提供依据。

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.