Tumor bed implant for simultaneous heat and radiation of resectable brain tumors

摘要/概要 多形性胶质母细胞瘤（GBM）是一种侵袭性脑肿瘤，通常局部复发， 生存期<18个月。治疗通常包括手术，然后是放疗和化疗， 挑战仍然是提供足够的辐射剂量来消毒肿瘤床而没有不可接受的毒性， 正常的大脑周围。一项随机临床试验，研究近距离放射治疗对瘤床的辐射增强， 没有连续应用局部加热的GBM患者的两年生存率是对照组的两倍。 近距离放射治疗尽管31%的两年生存率高于目前最先进的治疗方法， 对于GBM，以前的热近距离治疗研究使用大学原型加热系统， 从未商业化，因此该方法被中断。替代疗法仍然无法 匹配先前的结果，时间已经到了优化热近距离放射治疗。随后的体内研究表明， 当应用两种疗法时，热（HT）和辐射（RT）之间的协同作用最大化 同步为了满足提高脑肿瘤手术后生存率的迫切需要，我们提出了一种 双模式热近距离治疗（TBT）球囊植入物，以填充切除腔，并进一步增加 在先前的研究中观察到的存活益处是：i）将HT和RT更均匀地递送至肿瘤床; ii）提供 通过同时结合HT和RT，在肿瘤床中将RT响应增强高达5倍; iii）在手术后肿瘤细胞迁移之前立即开始肿瘤床的RT;以及 通过将治疗时间从3-6周的每日体外放射治疗减少到<5周， 总治疗天数。我们的前提是，通过同时应用局部加热和近距离放射治疗， 在肿瘤细胞迁移之前， 我们可以显著增强局部反应和生存，同时最大限度地减少外周毒性， 改善临床结果。我们的第一阶段开发有三个具体目标：i）制造双重治疗， 球囊器械; ii）评价器械HT和RT组件的兼容性，并表征热 实验室研究中的辐射剂量测定;以及iii）证明符合以下条件的适当热分布： 在体内动物灌注组织研究中使用计算机治疗计划。在展示了安全性和 在II期随访临床试验中，我们预计神经外科医生和肿瘤学家 大约有250家脑外科中心已经拥有HDR后装设备， 在美国，每年超过52，000例切除的脑肿瘤明显需要改进治疗，令人印象深刻的临床 在GBM中使用较差的热近距离放射治疗方法的先例，并建立了用于 组件技术。虽然这一发展的重点是脑肿瘤治疗， 该方法有望应用于其它肿瘤切除部位，包括头颈部，乳房，肺， 和肉瘤（在美国每年可能有约600，000例患者）。

Abstract / Summary Glioblastoma multiforme (GBM) is an aggressive brain tumor that generally recurs locally and has a median survival <18 months. Treatment typically involves surgery followed by radiation and chemotherapy but the challenge remains to provide sufficient radiation dose to sterilize tumor bed without unacceptable toxicity in surrounding normal brain. A randomized clinical trial studying brachytherapy radiation boost to tumor bed with and without sequentially applied local heat showed a doubling of two-year survival in GBM compared to brachytherapy alone. Although that 31% two-year survival rate is higher than current state of the art treatment approaches for GBM, previous thermobrachytherapy studies used University prototype heating systems that were never commercialized, and thus the approach was discontinued. With alternative treatments still failing to match prior results, the time has come to optimize thermobrachytherapy. Ensuing in vivo studies have shown that synergy between heat (HT) and radiation (RT) is maximized when the two therapies are applied simultaneously. To meet the urgent need for improved survival following brain tumor surgery, we propose a dual-modality thermobrachytherapy (TBT) balloon implant to fill the resection cavity and further increase the survival benefit seen in prior studies by: i) delivering HT and RT more uniformly to tumor bed; ii) providing potent thermal enhancement of RT response up to 5X in tumor bed by combining HT and RT simultaneously; iii) beginning RT of tumor bed immediately after surgery before tumor cell migration; and iv) improving patient satisfaction and reducing cost by decreasing treatment time from 3-6 weeks of daily external beam RT to <5 days total therapy. Our premise is that by applying local heat and brachytherapy simultaneously for maximum synergy and uniformly to the resection cavity wall for effective localization of effect before tumor cells migrate, we can significantly enhance local response and survival while minimizing peripheral toxicity and thereby improve clinical outcomes. Our Phase I development has three specific aims: i) to fabricate a dual-therapy balloon device; ii) to evaluate the device for compatibility of HT and RT components and characterize thermal and radiation dosimetry in laboratory studies; and iii) demonstrate appropriate heat distributions that coincide with computer treatment plans in in vivo animal perfused tissue studies. After demonstrating safety and effectiveness in followup clinical trials in Phase II, we anticipate neurosurgeons and oncologists associated with ~250 brain surgery centers already owning HDR afterloaders will embrace this new technology due to obvious need for improved therapy in >52,000 resected brain tumors annually in the US, impressive clinical precedent in GBM with inferior thermobrachytherapy approaches, and established regulatory pathway for component technologies. While this development is focused towards brain tumor therapy, the TBT balloon procedure is expected to find application in other tumor resection sites including head and neck, breast, lung, and sarcoma (with potentially ~600,000 patients annually in US) following successful launch in brain tumors.