High-, moderate- and low-LET ion beams for treatment of radioresistant tumors: Impact of beam quality, tumor grading and hypoxic status on radiation response

离子束放射治疗已成为治疗光子治疗后治愈率不理想的放射耐药肿瘤的一种有前途的方式。离子的深度剂量分布（布拉格峰）允许增加剂量到肿瘤剂量，同时仍然尊重邻近正常组织的耐受性。除此之外，与光子相比，离子束表现出更高的相对生物有效性（RBE），这取决于离子类型，并随着线性能量转移（LET）而上升。离子的LET可分为低（质子）、中（4he -离子）和高（12C-或16o -离子）。除了质子外，一些中心还提供4He、12C或16o离子，作为对抗癌症的额外策略。与质子相比，4he离子提供了更高的物理选择性，只有适度增加的RBE。12C-和16o -离子被认为是有吸引力的，特别是对于低氧肿瘤的治疗，因为高let辐射有望降低氧增强比（OER）。目前，由于缺乏临床和生物学数据，决定哪种离子类型最适合哪种肿瘤。特别是对于4he离子作为一种中等let模式，治疗不同类型肿瘤的潜力尚不清楚。作为我们之前项目（DFG, GL 893/1-1, KA 2679/3-1）的延续，我们提出了一项临床前研究，以量化内在缺氧（由肿瘤分级给出）的影响，以及急性缺氧（由肿瘤供应动脉夹紧引起）对临床设想的离子束照射后肿瘤反应的作用。该项目包括质子、4He-、12C-或16o -离子束辐照后三种不同肿瘤亚系大鼠前列腺肿瘤模型的剂量反应研究。在300天内，以50%局部肿瘤控制概率（TCD50）确定剂量，计算每种离子种类和肿瘤类型的RBE（光子与离子束）和OER（夹持与非夹持条件）值。为了表征肿瘤在照射前后的缺氧状态和灌注，将进行18F-MISO PET、光声成像和t1加权DCE-MRI测量并定量评估。影像学研究将辅以血管结构（CD31、SMA）、缺氧（吡莫硝唑、CCI103F、CAIX）、灌注（Hoechst 33342）、增殖（BrdU）和辐射诱导免疫反应（巨噬细胞、CD4+和CD8+ t细胞以及nk细胞）的组织学调查。该项目将提供验证和改进患者使用的rbe模型急需的全面生物学数据。扩大质子和12c离子以外的离子范围，可以通过优化对肿瘤的剂量构象，最大限度地减少肿瘤异质性和辐射耐药性的影响，从而在副作用最小的情况下提高临床疗效，从而开辟新的治疗策略。

Ion beam radiotherapy has emerged as a promising modality to treat radioresistant tumors with unsatisfying cure rates after photon therapy. The depth dose profile (Bragg-Peak) of ions allows for increasing the dose to the tumor dose while still respecting the tolerance of the adjacent normal tissue. Besides this, ion beams exhibit an increased relative biological effectiveness (RBE) compared to photons, which depends on the ion type and rises with linear energy transfer (LET). The LET of ions may be classified as low (protons), moderate (4He-ions) or high (12C- or 16O-ions). Besides protons, a few centers provide 4He-, 12C- or 16O-ions as additional strategy to fight cancer. Compared to protons, 4He-ions offer an increased physical selectivity with only a moderately increased RBE. 12C- and 16O-ions are considered attractive, especially for the treatment of hypoxic tumors as high-LET radiation is expected to reduce the oxygen enhancement ratio (OER). A decision on which ion type is suited best for which tumor is currently prevented by the lack of clinical and biological data. Especially for 4He-ions as a moderate-LET modality, the potential of treating different tumor types is only poorly understood.As continuation of our previous project (DFG, GL 893/1-1, KA 2679/3-1), we propose a preclinical study to quantify the impact of intrinsic hypoxia (given by the grading of the tumor) as well as the role of acute hypoxia (induced by clamping of the tumor-supplying artery) on the tumor response after irradiation with clinically envisaged ion beams. The project includes dose-response studies for three different tumor-sublines of a rat prostate tumor model after irradiation with proton, 4He-, 12C- or 16O-ion beams. Determining the doses at 50% local tumor control probability (TCD50) at 300 days, the RBE (photon vs. ion beams) and OER (clamping vs. non-clamping condition) values will be calculated for each ion species and tumor type. To characterize the hypoxic status and perfusion of the tumors prior and after irradiation, 18F-MISO PET, photoacoustic imaging and T1-weighted DCE-MRI measurements will be performed and evaluated quantitatively. Imaging studies will be supplemented by histological investigations of the vascular architecture (CD31, SMA), hypoxia (pimonidazole, CCI103F, CAIX), perfusion (Hoechst 33342), proliferation (BrdU) and on the radiation induced immune response (macrophages, CD4+ and CD8+ T-cells as well as NK-cells).This project will deliver comprehensive biological data urgently needed to validate and improve the RBE-models used in patients. Extending the range of ions beyond protons and 12C-ions could open new treatment strategies by optimizing the dose conformation to tumors, minimizing the impact of tumor heterogeneity and radiation resistance and thereby to increase the clinical outcome with a minimum of side effects.