Background and Aims

Over 30 years of preclinical research have proven the outstanding potential of synchrotron Microbeam Radiation Therapy (MRT) in increasing the therapeutic ratio of brain tumor treatment. MRT has recently entered a clinical transfer phase in which dog brain tumor patients are treated under clinical conditions to determine the safety and feasibility of clinical MRT.

Methods

Four pet dogs received MRT for brain tumor treatment (suspected glioma). Ultra-high dose rate synchrotron x-rays, spatially fractionated into arrays of microbeams (50µm-wide, 400µm-spaced), were delivered through 5 conformal incidences. A minimal cumulated valley dose (diffusing between microbeams) of 2.8Gy to the PTV was prescribed, corresponding to ~25Gy peak dose (within microbeams) for each incidence. Additionally, 4 dogs were exposed at the hospital (ConvRT) to 10 Gy of 6MV x-rays. All dogs underwent monthly MRI and veterinary controls.

Results

During the first 3 months after ConvRT, quality of life (QoL) improved to scores from 7.1/10 to 8.4/10. The tumor volume reduced by 57% (±15%) at 1 month and 76% (±14%) at 3 months. One animal was euthanized 3 months post exposure, presumably related to radiation side effects. In contrast, clinical follow-up after MRT did not indicate radiotoxicity; a considerable improvement of the dogs’ QoL scores (from 6.8/10 to 8.8/10) and disappearance of tumor-induced seizures were noted. A tumor volume reduction of 59% (±19%) was seen at 1 month and reached 75% (±19%) at 3 months. The follow-up is currently ongoing.

Conclusions

This is the first neuro-oncologic veterinary trial of 3D-conformal synchrotron MRT for spontaneous intracranial tumors in large pet animals. The absence of acute to subacute radiotoxicity in normal brain tissues proves that MRT is a safe tool for brain tumor treatment. This trial is an essential last step towards the clinical transfer of MRT in the near future for the treatment of deep seated human brain tumors.

Background and Aims

Mini-beam irradiation is an innovative radiotherapy method utilizing spatial fractionation in order to reduce healthy tissue toxicity while controlling the tumor. To investigate this until yet not fully understood mechanism further, an adjustable collimator with variable peak-widths (PW) and valley-widths (VW) as well as customizable source to collimator distance (SCD) is needed. Generally, mini-beam collimators are expensive, require demanding production and cannot be easily adapted. Therefore, this study aims to design a customizable and adjustable low-cost mini-beam collimator which dosimetric parameters were evaluated.

Methods

A mini-beam holder skeleton was designed and 3D printed (80mmx80mm) to arrange successive tungsten plates (40mmx10mmx1mm) and 3D printed plastic plates (40mmx10mmx0.25mm-2mm) creating valley and peak regions, respectively. These plates can easily be exchanged and reproducibly stacked with three screws. Additionally, it is possible to vary the SCD by 3D printed angled plastic plates that perfectly fit the convergence at a certain distance. Thereby dose rates were varied from 4Gy/min to 216Gy/min. For the dosimetric characterization of the different configurations, EBT-XD films were irradiated with a Faxitron MultiRad 225.

Results

We created a collimator with exchangeable leaves to generate dose profiles with PW between 0.25mm and 2mm. For all setups, FWHM remains constant over the irradiated area and deviates by at most 10% relative to the collimator size. Peak and valley doses behave linearly to the applied doses and the peak to valley dose ratio (PVDR) for each of the different collimator setups remains constant up to 9.1 for the different setups.

Conclusions

To summarize, our novel adjustable collimator achieved dose profiles that are in accordance with the geometry, as well as homogeneity in peak and valley doses over the irradiated area. The next step will be to perform in vitro experiments for the different collimator parameters to investigate cell response for different peak widths, PVDR and dose rates.

Background and Aims

Radiotherapeutic treatments of ocular tumours are often challenging due to nearby radiosensitive structures (macula, optic nerve, lachrymal gland etc.) and the high doses required to treat radioresistant cancers such as uveal melanomas [1]. Proton therapy and stereotactic radiosurgery can provide excellent outcomes, however, such modalities are not always accessible to patients (high costs, low availability) and side effects in structures like the lens, eye lids or ciliary body remain an issue. Minibeam radiation therapy (MBRT) with orthovoltage X-rays (as implemented in previous studies [2,3]) could represent a cost-effective and easily implementable alternative in this regard.

In this proof-of-concept study, we evaluate orthovoltage X-ray MBRT as a potential treatment modality for ocular tumours.

Methods

As a first step, Monte Carlo simulations were performed with the TOPAS toolkit [4] to assess the dose distributions in human and rat CT images, considering in particular the dose depositions in the skull and brain. In a second step, in vivo studies will be performed to assess the dose tolerances of rat eyes to orthovoltage X-ray minibeams.

Results

Through the Monte Carlo simulations, the feasibility of irradiating ocular targets with collimator-generated orthovoltage X-ray minibeams could be demonstrated and first dose distributions could be obtained. A high degree of spatial fractionation could be maintained in the brain with peak-to-valley dose ratios of 2-10 (depending on the minibeam configuration), suggesting that an effective target irradiation at a decreased risk for adverse effects may be possible. Complementary in vivo experiments are ongoing.

Conclusions

To our knowledge, this is the first study considering MBRT with orthovoltage X-rays as a cost-effective alternative for the treatment of ocular tumours.

References:

[1] Stannard et al., Camb. Opht. Symp., 2013.

[2] Sotiropoulos et al., Clin. Transl. Radiat. Oncol., 2021.

[3] Prezado et al., Sci. Rep., 2017.

[4] Perl et al., Med. Phys., 2012.

Background and Aims

Proton minibeam radiation therapy (pMBRT) is a novel radiotherapy technique that has shown a significant reduction in normal tissue toxicity and equivalent or superior tumor control, compared to standard proton therapy. The treatment of metastasis situated close to critical structures seems to be a suitable candidate to benefit from this technique. In this study, the potential of pMBRT for treating brain, lung, and liver metastases was evaluated by comparison with stereotactic radiotherapy (SRT) treatments, a technique currently used in clinics for this type of indications.

Methods

Four clinical cases, initially treated with SRT, were selected for this study. pMBRT treatments consisted of one fraction and one or two fields, as proposed for phase I/II clinical trials. The use of different centre-to centre distances between minibeams to obtain different levels of heterogeneity at the target was evaluated. Three criteria were used to compare SRS and pMBRT treatments: (i) the tumor coverage, (ii) the dose to organs-at-risk, and (iii) the possible adverse effects in normal tissues by considering valley doses as the responsible for tissue sparing, as also done in microbeam radiotherapy. Dose calculations were computed by means of Monte Carlo simulations.

Results

pMBRT treatments provide a similar or superior target coverage than SRT, even using fewer fields. This approach also significantly reduces the biologically effective dose (BED) to organs-at-risk, while valley and mean doses to normal tissues remain under tolerance limits when treatments are delivered in a single fraction.

Conclusions

This works provides a first insight into the possibility of treating metastases with pMBRT. More favorable dose distributions and treatment delivery regimes may be expected from this new approach than in SRT. This work aims to guide upcoming evaluations of the clinical implementation of pMBRT and future clinical trials.

Background and Aims

Proton minibeam radiation therapy (pMBRT) is a novel therapeutic approach which employs narrow (< 1 mm), spatially modulated proton beams [Prezado et al, 2013]. pMBRT has shown a remarkable reduction in neurotoxicity [Lamirault et al, 2020], and equivalent or superior tumor control [Prezado et al, 2018; Bertho et al, 2020] over conventional proton therapy (PT).

While the majority of pMBRT studies focused on brain or skin irradiations [Sammer et al, 2020; Girts et al, 2015; Bertho et al, 2020], this work reports on the first evaluation of the pulmonary response to pMBRT. Pulmonary irradiations are challenging as cardiorespiratory motion can blur the spatial fractionation of the dose. We compared the radiopathological consequences of pulmonary pMBRT versus conventional PT in mice.

Methods

Pulmonary irradiations, delivering a mean dose of 17Gy in both modalities, were performed in C57BL/6 mice. The development of radiation-induced pulmonary fibrosis was monitored thanks to the on-board cone-beam computed tomography (CBCT) system of the Small Animal Radiation Research Platform.

Results

CBCT images revealed a significant increase in lung density following conventional PT, corresponding to the development of radiation-induced lung fibrosis which ultimately impacted the survival of the animals (6/8 reached the endpoints 5 months post-irradiation). Comparatively, the increase in lung tissue density observed in the CBCT images of the pMBRT group was only mild 6 months post-irradiation. All the animals of this group survived until the end of the study without clinical symptoms. Histopathological analysis is ongoing and will be used to characterize the response of the lung parenchyma and cellular actors involved in the development of radiation-induced fibrosis.

Conclusions

These preliminary results suggest that the gain of normal tissue tolerance after pMBRT is also present in lung irradiation. Indeed, compared to conventional PT, pMBRT minimizes the development of radiation-induced lung fibrosis. This opens the door for pMBRT in moving targets.