In Vivo Microbeam Radiation Therapy at a Conventional Small Animal Irradiator.

Microbeam radiation therapy (MRT) is a still pre-clinical form of spatially fractionated radiotherapy, which uses an array of micrometer-wide, planar beams of X-ray radiation. The dose modulation in MRT has proven effective in the treatment of tumors while being well tolerated by normal tissue. Research on understanding the underlying biological mechanisms mostly requires large third-generation synchrotrons. In this study, we aimed to develop a preclinical treatment environment that would allow MRT independent of synchrotrons. We built a compact microbeam setup for pre-clinical experiments within a small animal irradiator and present in vivo MRT application, including treatment planning, dosimetry, and animal positioning. The brain of an immobilized mouse was treated with MRT, excised, and immunohistochemically stained against γH2AX for DNA double-strand breaks. We developed a comprehensive treatment planning system by adjusting an existing dose calculation algorithm to our setup and attaching it to the open-source software 3D-Slicer. Predicted doses in treatment planning agreed within 10% with film dosimetry readings. We demonstrated the feasibility of MRT exposures in vivo at a compact source and showed that the microbeam pattern is observable in histological sections of a mouse brain. The platform developed in this study will be used for pre-clinical research of MRT.

A novel electron source for a compact x-ray tube for microbeam radiotherapy with very high dose rates.

Microbeam radiotherapy (MRT) is a novel concept in radiation oncology with arrays of alternating micrometer-wide high-dose peaks and low-dose valleys. Preclinical experiments have shown a lower normal tissue toxicity for MRT with similar tumor control rates compared to conventional radiotherapy. A promising candidate for the demanded compact radiation source is the line-focus x-ray tube. Here, we present the setup of a prototype for an electron accelerator being able to provide a suitable x-ray beam for the tube. Several beam dynamic calculations and simulations were performed concerning particle tracking, thermal and electrostatic properties of the electron source, resulting in a proper beamline, including the cathode, the pierce electrode (PE) and the focusing magnets. These parts are discussed separately. The simulations showed that a rectangular cathode with a small width of 0.4mm is mandatory. To quickly shut down the electron beam, an additional voltage of -600V must be applied to the PE. Moreover, the electric field inside the vacuum chamber stays below 10MVm-1 to minimize the risk of field emission. The thermal simulation validates a small displacement of 0.1mm of the heated cathode with respect to the PE, which must be considered during manufacturing of the cathode-PE assembly. The simulations lead to an adequate choice of cathode, electrodes and beamline to achieve the required focal spot of 0.05×20mm2 with a beam current of 0.3A and an electron energy of 300keV. With this setup first MRT experiments with high dose rates up to 10Gys-1 can be executed.

Heat management of a compact x-ray source for microbeam radiotherapy and FLASH treatments.

BACKGROUND: Microbeam and x-ray FLASH radiation therapy are innovative concepts that promise reduced normal tissue toxicity in radiation oncology without compromising tumor control. However, currently only large third-generation synchrotrons deliver acceptable x-ray beam qualities and there is a need for compact, hospital-based radiation sources to facilitate clinical translation of these novel treatment strategies. PURPOSE: We are currently setting up the first prototype of a line-focus x-ray tube (LFxT), a promising technology that may deliver ultra-high dose rates (UHDRs) of more than 100 Gy/s from a table-top source. The operation of the source in the heat capacity limit allows very high dose rates with micrometer-sized focal spot widths. Here, we investigate concepts of effective heat management for the LFxT, a prerequisite for the performance of the source. METHODS: For different focal spot widths, we investigated the temperature increase numerically with Monte Carlo simulations and finite element analysis (FEA). We benchmarked the temperature and thermal stresses at the focal spot against a commercial x-ray tube with similar power characteristics. We assessed thermal loads at the vacuum chamber housing caused by scattering electrons in Monte Carlo simulations and FEA. Further, we discuss active cooling strategies and present a design of the rotating target. RESULTS: Conventional focal spot widths led to a temperature increase dominated by heat conduction, while very narrow focal spots led to a temperature increase dominated by the heat capacity of the target material. Due to operation in the heat capacity limit, the temperature increase at the focal spot was lower than for the investigated commercial x-ray tube. Hence, the thermal stress at the focal spot of the LFxT was considered uncritical. The target shaft and the vacuum chamber housing require active cooling to withstand the high heat loads. CONCLUSIONS: The heat capacity limit allows very high power densities at the focal spot of the LFxT and thus facilitates very high dose rates. Numerical simulations demonstrated that the heat load imparted by scattering electrons requires active cooling.

Treatment Planning Study for Microbeam Radiotherapy Using Clinical Patient Data.

Microbeam radiotherapy (MRT) is a novel, still preclinical dose delivery technique. MRT has shown reduced normal tissue effects at equal tumor control rates compared to conventional radiotherapy. Treatment planning studies are required to permit clinical application. The aim of this study was to establish a dose comparison between MRT and conventional radiotherapy and to identify suitable clinical scenarios for future applications of MRT. We simulated MRT treatment scenarios for clinical patient data using an inhouse developed planning algorithm based on a hybrid Monte Carlo dose calculation and implemented the concept of equivalent uniform dose (EUD) for MRT dose evaluation. The investigated clinical scenarios comprised fractionated radiotherapy of a glioblastoma resection cavity, a lung stereotactic body radiotherapy (SBRT), palliative bone metastasis irradiation, brain metastasis radiosurgery and hypofractionated breast cancer radiotherapy. Clinically acceptable treatment plans were achieved for most analyzed parameters. Lung SBRT seemed the most challenging treatment scenario. Major limitations comprised treatment plan optimization and dose calculation considering the tissue microstructure. This study presents an important step of the development towards clinical MRT. For clinical treatment scenarios using a sophisticated dose comparison concept based on EUD and EQD2, we demonstrated the capability of MRT to achieve clinically acceptable dose distributions.

Prognostic role of gamma-glutamyl transferase in metastatic melanoma patients treated with immune checkpoint inhibitors.

BACKGROUND: Hepatic immune-related adverse events (irAE) including elevated liver function tests (transaminases) occur in 1.4-22.3% of melanoma patients receiving immune checkpoint inhibitors (ICPI) and constitute a potentially serious toxicity that is challenging to treat. In contrast to the liver transaminases alanine aminotransferase (ALT) and aspartate aminotransferase (AST), only little is known about the frequency and impact of gamma-glutamyl transferase (GGT) elevations. METHODS: GGT determined prior to and during therapy of metastatic melanoma patients treated with ICPI were retrospectively assessed in two independent cohorts (PD-1: n = 218, Ipi + Nivo: n = 148). Overall survival (OS) and best objective response were analyzed according to baseline and immune-related GGT (irGGT) elevations during treatment. RESULTS: In multivariate analysis, OS was reduced in patients with elevated baseline GGT (PD-1 group: hazard ratio [HR] 1.76, p = .0073; Ipi + Nivo group: HR 1.77, p = .032). Immune-related GGT elevation was recorded in 17% (PD-1 group) and 38.5% (Ipi + Nivo group). Of these patients, the majority (81 and 68%, respectively) had normal ALT and AST and showed no clinical signs of hepatotoxicity. Patients who experienced irGGT elevation had superior response (PD-1 group: odds ratio [OR] 3.57, p = .00072; Ipi + Nivo group: OR 1.74, p = .12) and OS (PD-1 group: HR 0.37, p = .0016; Ipi + Nivo group: HR 0.33, p = .00050). CONCLUSIONS: The frequency of hepatic irAE is currently underestimated. The addition of the sensitive enzyme GGT to the laboratory panel before and during therapy with ICPI allows to detect two to three times more patients developing hepatic or hepatobiliary toxicity than known so far. Immune-related GGT elevations correlate with response and favorable survival. Precis for use in the Table of Contents The frequency of hepatotoxicity under immune checkpoint blockade is currently underestimated. We suggest the addition of gamma-glutamyl transferase to the laboratory panel in checkpoint inhibitor patients for the detection of hepatobiliary toxicity.

Analytical modeling of depth-dose degradation in heterogeneous lung tissue for intensity-modulated proton therapy planning.

BACKGROUND AND PURPOSE: Proton therapy may be promising for treating non-small-cell lung cancer due to lower doses to the lung and heart, as compared to photon therapy. A reported challenge is degradation, i.e., a smoothing of the depth-dose distribution due to heterogeneous lung tissue. For pencil beams, this causes a distal falloff widening and a peak-to-plateau ratio decrease, not considered in clinical treatment planning systems. MATERIALS AND METHODS: We present a degradation model implemented into an analytical dose calculation, fully integrated into a treatment planning workflow. Degradation effects were investigated on target dose, distal dose falloffs, and mean lung dose for ten patient cases with varying anatomical characteristics. RESULTS: For patients with pronounced range straggling (in our study large tumors, or lesions close to the mediastinum), degradation effects were restricted to a maximum decrease in target coverage (D 95 of the planning target volume) of 1.4%. The median broadening of the distal 80-20% dose falloffs was 0.5 mm at the maximum. For small target volumes deep inside lung tissue, however, the target underdose increased considerably by up to 26%. The mean lung dose was not negatively affected by degradation in any of the investigated cases. CONCLUSION: For most cases, dose degradation due to heterogeneous lung tissue did not yield critical organ at risk overdosing or overall target underdosing. However, for small and deep-seated tumors which can only be reached by penetrating lung tissue, we have seen substantial local underdose, which deserves further investigation, also considering other prevalent sources of uncertainty.

Clinical microbeam radiation therapy with a compact source: specifications of the line-focus X-ray tube.

BACKGROUND AND PURPOSE: Microbeam radiotherapy (MRT) is a preclinical concept in radiation oncology with arrays of alternating micrometer-wide high-dose peaks and low-dose valleys. Experiments demonstrated a superior normal tissue sparing at similar tumor control rates with MRT compared to conventional radiotherapy. Possible clinical applications are currently limited to large third-generation synchrotrons. Here, we investigated the line-focus X-ray tube as an alternative microbeam source. MATERIALS AND METHODS: We developed a concept for a high-voltage supply and an electron source. In Monte Carlo simulations, we assessed the influence of X-ray spectrum, focal spot size, electron incidence angle, and photon emission angle on the microbeam dose distribution. We further assessed the dose distribution of microbeam arc therapy and suggested to interpret this complex dose distribution by equivalent uniform dose. RESULTS: An adapted modular multi-level converter can supply high-voltage powers in the megawatt range for a few seconds. The electron source with a thermionic cathode and a quadrupole can generate an eccentric, high-power electron beam of several 100 keV energy. Highest dose rates and peak-to-valley dose ratios (PVDRs) were achieved for an electron beam impinging perpendicular onto the target surface and a focal spot smaller than the microbeam cross-section. The line-focus X-ray tube simulations demonstrated PVDRs above 20. CONCLUSION: The line-focus X-ray tube is a suitable compact source for clinical MRT. We demonstrated its technical feasibility based on state-of-the-art high-voltage and electron-beam technology. Microbeam arc therapy is an effective concept to increase the target-to-entrance dose ratio of orthovoltage microbeams.