Nowadays there is a rising interest towards exploiting new therapeutical beams beyond carbon ions and protons. In particular, ¹⁶ O ions are being widely discussed due to their increased LET distribution. In this contribution, we report on the first experimental verification of biologically optimized treatment plans, accounting for different biological effects, generated with the TRiP98 planning system with ¹⁶ O beams, performed at HIT and GSI. This implies the measurements of 3D profiles of absorbed dose as well as several biological measurements. The latter includes the measurements of relative biological effectiveness along the range of linear energy transfer values from ≈20 up to ≈750 keV μ m ⁻¹ , oxygen enhancement ratio values and the verification of the kill-painting approach, to overcome hypoxia, with a phantom imitating an unevenly oxygenated target. With the present implementation, our treatment planning system is able to perform a comparative analysis of different ions, according to any given condition of the target. For the particular cases of low target oxygenation, ¹⁶ O ions demonstrate a higher peak-to-entrance dose ratio for the same cell killing in the target region compared to ¹² C ions. Based on this phenomenon, we performed a short computational analysis to reveal the potential range of treatment plans, where ¹⁶ O can benefit over lighter modalities. It emerges that for more hypoxic target regions (partial oxygen pressure of ≈0.15% or lower) and relatively low doses (≈4 Gy or lower) the choice of ¹⁶ O over ¹² C or ⁴ He may be justified.

Hypoxia, which is associated with abnormal vessel growth, is a characteristic feature of many solid tumors that increases their metastatic potential and resistance to radiotherapy. Carbon-ion radiation therapy, either alone or in combination with other treatments, is one of the most promising treatments for hypoxic tumors because the oxygen enhancement ratio decreases with increasing particle LET. Nevertheless, current clinical practice does not yet fully benefit from the use of carbon ions to tackle hypoxia. Here, we provide an overview of the existing experimental and clinical evidence supporting the efficacy of C-ion radiotherapy in overcoming hypoxia-induced radioresistance, followed by a discussion of the strategies proposed to enhance it, including different approaches to maximize LET in the tumors.

We report on a novel method for simultaneous biological optimization of treatment plans for hypoxic tumors using multiple ion species. Our previously introduced kill painting approach, where the overall cell killing is optimized on biologically heterogeneous targets, was expanded with the capability of handling different ion beams simultaneously. The current version (MIBO) of the research treatment planning system TRiP98 has now been augmented to handle 3D (voxel-by-voxel) target oxygenation data. We present a case of idealized geometries where this method can identify optimal combinations leading to an improved peak-to-entrance effective dose ratio. This is achieved by the redistribution of particle fluences, when the heavier ions are preferentially forwarded to hypoxic target areas, while the lighter ions deliver the remaining dose to its normoxic regions. Finally, we present an in silico skull base chordoma patient case study with a combination of 4He and 16O beams, demonstrating specific indications for its potential clinical application. In this particular case, the mean dose, received by the brainstem, was reduced by 3%-5% and by 10%-12% as compared to the pure 4He and 16O plans, respectively. The new method allows a full biological optimization of different ion beams, exploiting the capabilities of actively scanned ion beams of modern particle therapy centers. The possible experimental verification of the present approach at ion beam facilities disposing of fast ion switch is presented and discussed.

Charged particle therapy with protons or heavier ions is one of the most effective radiotherapy techniques, but uncertainties in the beam range can limit its efficacy. Radioactive ion beams are ideal for image-guided particle therapy because isotopes that undergo β⁺ decay can be visualized with positron emission tomography. This allows spatial localization of the particle distribution in vivo, which can be correlated with the expected dose deposition for online beam range verification. Here we report the successful treatment of a mouse osteosarcoma using a radioactive ¹¹C-ion beam. The tumour was located in the neck, close to the spinal cord, where deviations of even a few millimetres in the beam range could lead to unintended dose deposition in the spine and radiation-induced myelopathy, an injury to the spinal cord. We achieved complete tumour control with the highest dose of 20 Gy while avoiding paralysis. Low-grade neurological side effects were correlated to the activity measured by positron emission tomography in the spine. The biological washout of the activity from the tumour volume was dependent on the dose, indicating a potential component of vascular damage at high doses. This experiment marks a step towards future clinical applications of radioactive ion beams.

In Glioblastoma Multiforme (GBM), hypoxia is associated with radioresistance and poor prognosis. Since standard GBM treatments are not always effective, new strategies are needed to overcome resistance to therapeutic treatments, including radiotherapy (RT). Our study aims to shed light on the biomarker network involved in a hypoxic (0.2% oxygen) GBM cell line that is radioresistant after proton therapy (PT). For cultivating cells in acute hypoxia, GSI’s hypoxic chambers were used. Cells were irradiated in the middle of a spread-out Bragg peak with increasing PT doses to verify the greater radioresistance in hypoxic conditions. Whole-genome cDNA microarray gene expression analyses were performed for samples treated with 2 and 10 Gy to highlight biological processes activated in GBM following PT in the hypoxic condition. We describe cell survival response and significant deregulated pathways responsible for the cell death/survival balance and gene signatures linked to the PT/hypoxia configurations assayed. Highlighting the molecular pathways involved in GBM resistance following hypoxia and ionizing radiation (IR), this work could suggest new molecular targets, allowing the development of targeted drugs to be suggested in association with PT.