PROTON RADIATION THERAPY RESEARCH

申请人的描述（Applicant's Description） 据估计，20%至80%的患者在当地接受治疗。 晚期上皮或间叶肿瘤将继发于治疗失败而死亡。 光子治疗和/或手术以实现局部控制。而且这些 积极的局部治疗本身通常与显著的 急性和晚期发病率。还有其他的肿瘤，特别是小儿肿瘤 肿瘤，局部控制通常令人满意，但与治疗相关 后期影响很大。本项目的主要目的是 利用质子束的上级剂量分布来改善临床 各种实体瘤患者的结果， 控制和治疗相关的发病率。 我们已经在哈佛用质子疗法治疗了5,000多名癌症患者 自1974年以来的回旋加速器实验室。我们在以下方面取得了重大进展： 包括软骨肉瘤在内的许多疾病部位的临床结果， 颅底和颈椎脊索瘤（95%和50 局部对照），鼻窦肿瘤（87%的局部 对照组）和眼黑色素瘤（97%局部控制）。我们建议 在其他肿瘤部位使用质子束进行临床试验， 光子疗法提供了次优的治疗结果。 本计划项目的两个基本假设是，使用上级 质子束的剂量分布，我们可以（在子项目5中）提高肿瘤剂量 并在不增加对非目标正常的损害的情况下改善局部控制 组织和（在子项目6中）保持高的局部控制率， 降低治疗相关的发病率。我们将评估临床收益， 5个终点：1）局部控制，2）无远处转移生存期，3） 总生存期，4）治疗相关发病率，和5）生活质量（QOL） 我们还假设质子照射将减少并发症， 放疗和化疗之间的关系，从而提高依从性， 治疗的强度。我们将使用精心设计的前瞻性I/II/III期 来检验这些假设。 该研究计划由三个密切相关的项目组成。在 子项目5我们将开展I/II/III期剂量递增研究， 前列腺癌、肺癌、鼻窦癌、鼻咽癌和肝细胞癌。的 这些试验的目的是改善局部控制和生存。次级项目6 我们将开展II/III期研究，旨在减少与治疗相关的 儿童癌症的发病率，包括髓母细胞瘤、视网膜母细胞瘤， 软组织肉瘤和成人肿瘤，包括直肠癌， 脉络膜黑素瘤在前列腺临床试验中， 洛马琳达大学医学中心在协议设计和患者 权责发生制。在子项目4中，我们将开发治疗提供和规划系统， 设计和实施剂量测定和质量保证计划， 拟议的临床试验。 东北质子治疗中心（NPTC），由NCI和 MGH，已建在MGH校园。NPTC将提供更多的 开展拟议临床试验所需的能力和新技术 在这个应用中。凭借我们在质子临床试验方面的经验， 以及NPTC提供的资源，我们拥有独特的能力， 提出的研究。我们希望这些临床试验 将显示出改善的癌症控制率，降低的治疗发病率， 改善QOL。

DESCRIPTION (Applicant's Description) It is estimated that between 20-80 percent of patients treated for locally advanced epithelial or mesenchymal tumors will die secondary to the failure of photon therapy and/or surgery to achieve local control. Furthermore, these aggressive local therapies are themselves often associated with significant acute and late morbidity. There are other tumors, particularly pediatric tumors, for which local control is often satisfactory but treatment-related late effects are high. It is the primary aim of this Program Project to exploit the superior dose distributions of proton beams to improve clinical outcomes for patients with a variety of solid tumors both in terms of cancer control and treatment-related morbidity. We have treated over 5,000 cancer patients with proton therapy at the Harvard Cyclotron Laboratory since 1974. We have achieved significant gains in clinical outcomes for a number of disease sites including chondrosarcomas and chordomas of the skull base and cervical spine (95 percent and 50 percent local control, respectively), paranasal sinus tumors (87 percent local control), and ocular melanomas (97 percent local control). We propose to carry out clinical trials using proton beams in additional tumor sites where photon therapy has provided suboptimal treatment outcomes. The two basic hypotheses for this Program Project are that, using the superior dose distributions of proton beams, we can (in subproject 5) escalate tumor dose and improve local control without increasing damage to non-target normal tissues and (in subproject 6) maintain high rates of local control while decreasing treatment related morbidity. We will assess clinical gains in terms of five endpoints: 1) local control, 2) distant metastasis-free survival, 3) overall survival, 4) treatment-related morbidity, and 5) quality-of-life (QOL) We also hypothesize that proton irradiation will decrease the comorbidity between radiation therapy and chemotherapy thus improving compliance and intensity of treatment. We will use well-designed prospective phase I/II/III trials to test these hypotheses. The proposed research program consists of three closely related projects. In subproject 5 we will carry out phase I/II/III dose escalation studies for prostate, lung, paranasal sinus, nasopharynx and hepatocellular cancers. The goals of these trials are to improve local control and survival. In subproject 6 we will carry out phase II/III studies designed to reduce treatment-related morbidity for pediatric cancers including medulloblastoma, retinoblastoma, and soft tissue sarcomas, and adult tumors including rectal carcinoma and choroidal melanoma. In the prostate clinical trial we will collaborate with the Loma Linda University Medical Center in protocol design and patient accrual. In subproject 4 we will develop treatment delivery and planning systems, and design and carry out dosimetry and quality assurance programs to support the proposed clinical trials. The Northeast Proton Therapy Center (NPTC), jointly funded by the NCI and the MGH, has been built on the MGH campus. The NPTC will provide the increased capacity and new technologies needed to conduct the clinical trials proposed in this application. With our experience in conducting proton clinical trials, and the resources offered by the NPTC, we have unique capabilities to carry out the proposed research. It is our expectation that these clinical trials will show improved cancer control rates, reduced treatment morbidity and improved QOL.