SFRT not only brings a different radiobiology, but it also requires distinct dosimetry protocols, and a different mindset when prescribing the dose and performing treatment planning. This section will critically review those important aspects in SFRT both for clinical and preclinical use.

The dosimetry protocol to be used for the different SFRT techniques is typically determined by the shape and size of the beamlets and the dose distributions they create. We may separate GRID and LRT on one hand and MRT and MBRT on the other.

Dosimetry of GRID and LRT techniques is relatively straightforward as the high dose regions are typically on the order of 1 cm or more in diameter (Li et al 2023). Any quality assurance device or dosimeter with resolution sufficient to resolve those regions is appropriate for those cases. The size of these high dose regions is similar to SRS and SBRT treatments, and accordingly, the same dosimeters could be used (Grams and Zhang 2023, Grams et al 2023). Treatment planning systems (TPS) are generally quite capable of accurate dose calculations at this length scale, and therefore a TPS which has been commissioned for use in stereotactic body radiation therapy (SBRT) or stereotactic radiosurgery (SRS) treatments should also be suitable for either GRID or LRT. Published guidelines for SBRT/SRS (Smilowitz et al 2015, Halvorsen et al 2017) treatment planning and delivery should also be followed for GRID and LRT dosimetry.

Concerning GRID, the collimator should be incorporated within the user's TPS (Grams et al 2022, Grams and Zhang 2023, Grams et al 2023). If this is not feasible, reference lookup tables can be used for estimation of relevant dosimetric parameters (Grams et al 2022). Details on the commissioning and dosimetric characterization of physical blocks for SFRT treatment can be found in the literature (Nobah et al 2015, Zhang et al 2020).

Several different LRT planning methods have been used clinically (Wu et al 2020, Grams et al 2021, Duriseti et al 2022). Although the high dose regions in LRT plans are not usually small enough to pose challenges for dose calculations, these plans can be quite complex to deliver and therefore verification that planned and delivered doses agree is warranted. As all SFRT techniques involve steep dose gradients, including GRID and LRT, a dosimeter having adequate spatial resolution is required. A variety of such detectors are available including high resolution diode arrays, electronic portal imaging devices (EPIDs) (Duriseti et al 2021), and radiochromic films (Ha et al 2006).

What is lacking in current treatment planning software is the incorporation and reporting of SFRT-specific dosimetry parameters. This will be discussed in section hereafter. This is perhaps understandable, since at the present time the underlying biology behind the effectiveness of SFRT is not well understood which makes it difficult to determine what dose metrics would be clinically relevant.

Future versions of TPS software which can incorporate the unique biologic features of SFRT such as immunomodulation into dose calculations in order to accurately predict tumor response would represent a significant and welcome innovation (Asperud et al 2021).

On the other hand, the narrow beams employed in MBRT and MRT (50–1000 μm in their narrowest direction) come with several challenges and place them in the small-field dosimetry domain. Yet, the size of such beams is considerably smaller than the beamlets employed in conventional small-field RT techniques (e.g. stereotactic radiosurgery (SRS)), which are of the order of centimetres. Consequently, additional considerations from the ones stated in the small-field dosimetry codes of practice, i.e. the TRS-483 report for Dosimetry of Small Static Fields Used in External Beam Radiotherapy (IAEA 2017), are required.

The first consideration applies to the lack of lateral charged particle equilibrium (LCPE) on the beam axis for such narrow fluence profiles and high dose gradients. The availability of detectors that possess tissue equivalence and that can cope with these dosimetry characteristics is rather limited (Bräuer-Krisch et al 2010). Radiochromic films have been the gold standard for MRT and MBRT relative dose measurements, since they provide a wide dose range and a high spatial resolution when combined with adequate reading systems (Martínez-Rovira et al 2012, Peucelle et al 2015). Some commercial solid state detectors such as the PTW microdiamond detector have been also proven suitable for dose measurements both in MRT (Livingstone et al 2018) and MBRT (Guardiola et al 2020). Some other commercial solid state detectors, such as nanoRazor diode, with a spatial resolution of 60 μm, deemed to be suitable for minibeams (De Marzi et al 2018).

Despite their good performance, both types of detectors come with their own limitations. Measurements with solid-state detector are arduous and time-consuming since the dose needs to be measured at numerous points to accurately resolve the high dose gradients. Regarding film measurements, they need post-processing, not allowing real-time dose measurements. In addition, the dynamic dose range of some of these dosimeters may be not enough to measure accurately and simultaneously the high (peak) and low (valley) doses within the regions of interest in all configurations. For instance, in MRT, where doses range from nearly 0 to 300–600 Gy, two radiochromic films might be needed to be used to measure peak and valley doses independently (Sammer et al 2019). Additionally, the film reading process is subject to various source of uncertainty as reported elsewhere (Sorriaux et al 2013), amounting up to 5% to 10%. In addition, the high dose rate in MRT limits the use of other real-time high spatial resolution detectors such as MOSFET sensors since the saturation of their dose response. Systems, such as X-Tream, consisting of a single strip of silicon able to resolve microbeam widths of 50–100 μm and measure the instantaneous dose rates in MRT applications (Petasecca et al 2012).

Ideal dosimeters for MRT and MBRT should allow the measurement of dose distributions in real-time and 2D measurements. First advances towards this end are reported in the work by Flynn et al (2023), which employs a high temporal and spatial resolution CMOS detector, whose suitability to assist with quality assurance tests for proton MBRT has been already reported. Other alternatives would also be 2D arrays of high-resolution detectors, such as the microdiamond detector.

The second consideration is the high susceptibility to geometric imprecisions in collimated beams. As reported in the work by Ortiz et al (2022), small uncertainties or variations in setup parameters, not relevant in other RT techniques, may significantly affect proton MBRT dose distributions. A representative example is the reduction in the PVDR by up to 20% for a tilt angle between the beamline and pMBRT multi-slit collimator of 0.25 degrees, as it is illustrated in figure 3.

Figure 3. Impact of a tile angle between the collimator and beamline of 0.25 degrees in pMBRT lateral dose profiles.

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Equivalent conclusions are expected to be drawn when applying this type of sensitivity studies to other MBRT and MRT techniques due to the similar collimation methods and dose distributions.

Taking all these considerations into account, preclinical dosimetry protocols have been proposed (Prezado et al 2011, Prezado et al 2012, Ortiz et al 2022). Those are two-steps protocols and could be extended to the future clinical trials. First, the reference dosimetry is performed in a seamless irradiation field with an ionization chamber. Then, output factors, previously assessed with high-spatial resolution detectors, enable the determination of peak and valley doses. These dosimetry protocols have been successfully used for MRT and MBRT dosimetry in preclinical experiences to ensure the reproducibility of irradiations. Further developments towards standardized SFRT dosimetry protocols and codes of practice could imply an absolute dosimetry protocol in SFRT conditions, traceable to primary standards such as small-core calorimeters, as first attempted Flynn et al (2023).

MRT and MBRT dose computation requires the development of adapted dose calculation engines since the irradiation conditions differ significantly from those in conventional radiotherapy. This implies (i) adequate physics parameters to consider the effects of the lack of LCPE and (ii) high resolution scoring grids to resolve the small beamlet sizes and high dose gradients. As reported in various studies (Ortiz et al 2022, Ortiz 2022), simulation parameters that are more likely to lead to miscalculation of dose distributions in MRT and MBRT are the threshold for production of secondary particles and scoring voxels dimensions. Values for default in conventional RT for these parameters may lead to an underestimation of peak valleys and related quantities (e.g. PVDR), and volume-averaging effects within the scoring grid, respectively. Whereas the modification of those parameters is straightforward in Monte Carlo (MC) codes, currently most clinical TPS may not allow adapting physics and scoring parameters to the requirements for correct MRT and MBRT dose calculations. However, MC calculations, although being very precise when used properly, are excessively time-consuming for clinical routine. One possibility to overcome this difficulty is to use fast calculation algorithms with hybrid dose calculation algorithms employing micro and minibeam kernels as an input in TPS (Donzelli et al 2018, Day et al 2021), variance-reduction techniques (Martinez-Rovira et al 2012), parallelization methods or graphical processing units.

In addition, MC codes typically used in MRT and MBRT research do not allow treatment plan optimization which considers the characteristics of MRT and MBRT dose distributions. Current published practices for the calculation of dose distributions in examples of clinical patients are based on, first, optimizing dose distributions in seamless conditions with current clinical TPS and, then, calculating the dose distributions of the optimized treatment plan using MC simulations which include collimator devices at the end of the beam path and appropriate simulation parameters (Ortiz 2022).

Micro and minibeam production and the irradiator geometries differ significantly in many cases from those in conventional RT. For instance, such submillimeter beamlets are typically created by mechanical collimators placed in the beam path, and in MRT, the beam generated from a wiggler tuned by tens of meters of beam modifiers is highly linearly polarized (Martínez-Rovira et al 2012), modifying the distributions of dose deposition. Simplifications in the source modeling may lead to inaccuracies in the assessment of MRT (Nettelbeck et al 2009) and MBRT (De Marzi et al 2018) dosimetry parameters. Therefore, the characterization of the source and the development of an accurate beam model are essential components of dose computation engines (Martínez-Rovira et al 2012, De Marzi et al 2018, Dipuglia et al 2019). Whereas reproducing these unconventional beam characteristics and production methods is relatively straightforward in several MC codes, it is very limited in commercially available TPS. Only a few of them currently allow the implementation of collimators with the submillimeter apertures typically used in these techniques. Part of these difficulties were shared by the TPS of small animal irradiators. At the time of writing this manuscript, some commercial TPS were already available offering research modules able to perform accurate calculations in MBRT.

SFRT requires a new mindset in terms of dose prescription and planning. SFRT comes in different scales (GRID/LRT, minibeam, and microbeam) and different forms (peak dose in planes, pencil beams, or vertices). See table 1. Different dosimetric and geometric parameters may lead to differences in treatment response, and thus, should be considered in the planning and dose prescription. Currently, two different approaches are used to assess the dose distributions of SFRT:

(1)  

The first approach uses dosimetry parameters associated with conventional RT. These include organ specific dose-volume histograms (DVHs) or specific points on the DVH curve, e.g. lung V20Gy (lung dose tolerance) and minimum dose to the planning target volume (PTV).

(2)  

The second one employs distinct dosimetry parameters that specifically characterize the spatial distribution of the delivered SFRT dose. These include peak width, valley width, peak dose, valley dose, and peak dose to valley dose ratio, etc.

Regarding dose prescription, the most frequently used method, both clinically and preclinically and, with the exception of LRT, is to prescribe in terms of peak dose at the entrance or at the depth of maximum dose deposition (Billena and Khan 2019). This method is based on historical reasons coming from the beginning of GRID and the use of orthovoltage machines. However, and despite the lack of solid scientific reasons, it continues to be recommended in recent published guidelines (Mayr et al 2022). The latter also recommend the use of equivalent uniform dose (EUD) (Niemierko 1997). However, EUD models currently used are based on the linear-quadratic model, which assumes radiation-induced clonogenic cell death is only affected by the radiation dose the cell receives. None of the bystander effect, abscopal effect, vascular effect, and immune modulation that have been considered unique aspects of SFRT irradiations is modeled in the EUD model and thus it may not be suitable for SFRT application (Guardiola et al 2018). Alternative radiobiological models considering the above are needed. Whether a modified EUD model would be enough to describe the complexity of SFRT is yet to be experimentally determined.

A step forward is a recent paper on radio-immune response modeling for SFRT by Cho et al (2023), in which a mathematical model of immune response during and after radiation for Immune response of host body and immune suppression of tumor cells has been used. The model suggests that SFRT can make a significant difference in tumor cell killing compared to the homogeneous dose distribution. SFRT might increase or moderate the cell killing depending on the immune response triggered by many factors such as dose prescription parameters, tumor volume at the time of treatment and tumor characteristics.

Certainly, widespread and potential mainstream use of SFRT would be benefit from the identification of dosimetry parameter(s) in SFRT which correlated directly with treatment response or organ toxicity, the development of novel and efficient multi-objective optimization delivering a SFRT pareto front or the conceptualization of a new metric able to encapsulate the multiparametric and multiscale nature of SFRT. Some attempts have been made in that last direction. Anderson et al (2012) proposed to use a new quantity called percentage volume below 10% (percentage volume of normal tissue, within the volume traversed by the microbeam array path, receiving a dose below 10% of the peak entrance dose) to characterize normal tissue dose distributions. However, no experimental evidence was provided. Lansonneur et al (2020) proposed the concept of dose prominence to overcome the challenge of evaluating and reporting the PVDR in a patient due to the marked inhomogeneity of the 3D dose distribution. This concept, defined here as the dose difference between a peak and its lowest contour line, is extensively used in topography, where it measures how much a peak stands out from the surrounding signal baseline. However, none of those new proposals address all the existing challenges regarding dose prescription in SFRT.

In this context there is an urgent need to both increase the number and prioritize the investigations aimed at either finding the best correlation between the individual dosimetry parameters and the biological response in SFRT or defining a new metric and experimentally validating it. One way of shedding some light in that direction, would be to perform retrospective data analysis. In this regard and concerning current existing published clinical data (section 2.1), the task is challenging. This is primarily a consequence that SFRT is often not used as a monotherapy, but as a priming therapy followed by a conventional course of RT, or is temporally interlaced with conventional RT (Duriseti et al 2022). Moreover, most of the clinical trials are monocentric with no real consensus or standardization among different centers. Additionally, most clinical studies have been prescribed in peak dose at the entrance or at the Dmax, implying that tumors having very different volumes or depth will get very different valleys doses or PVDR. A recent attempt to standardize the dose prescriptions has been made (Zhang et al 2020) but the recommendation continues being to prescribe in peak dose, which as previously discussed has a historical rather than scientific rationale. On the other hand, preclinical studies, whose design is more flexible as it is not limited by strict clinical constraints, are better suited to shed light on the aforementioned critical questions. In recent years the SFRT research community has focused their efforts on better understanding the correlations between the physical parameters and the biological response in SFRT.

One of the first attempts in that direction was the work of Regnard et al (2008). They assessed the impact of different ctc distances on the balance between sparing and curing and concluded that larger ctc (200 μm instead of 100 μm) provided a larger widening of the therapeutic window. In a continuation study, Serduc et al (2009) attempted to assess the influence of the microbeam width at constant valley dose. However, since the same ctc was used in all the several configurations, the valley width was very different in all groups, and, thus, no clean conclusions can be extracted from this study since several parameters were varied at the same time.

In a carefully designed study by Rivera et al (2020), Fischer 344 rats with fibrosarcoma tumor allografts were irradiated with kV x-rays using a small animal irradiator with different configuration SFRT collimators to assess the impact on tumor control of a large range of radiation spatial fractionation parameters (e.g. peak, valley doses, PVDR, etc). The dosimetry parameters most closely associated with tumor response were tumor EUD, valley dose and percentage tumor directly irradiated. Average dose and peak dose showed the weakest associations to tumor response. Only the uniform radiation group did not gain weight post-radiation, indicative of treatment toxicity; however, body weight change in general shows weak association with all dosimetry parameters except for valley (minimum) dose, valley width, and peak width. The finding that peak dose lacks correlation with treatment response in the rat model study directly challenges the clinical practice of using peak dose to prescribe SFRT treatment. The question is whether the finding is specific to one study or can be generalized to single-fraction preclinical SFRT studies? To answer this important question Fernadez, Chang, and Prezado reviewed all SFRT preclinical studies available up to 2022 including some unpublished data (Fernandez-Palomo et al 2022). Of the 16 preclinical studies that met the review criteria (single SFRT treatment, adequate dosimetry data, and having a control group) there is a large variety of SFRT types (microbeams, minibeams, x-rays and protons) and tumor types (different brain tumors and fibrosarcoma). Increased life span (ILS) from the SFRT treatment compared to the life span of the untreated control group is used to evaluate treatment response. No strong correlation was found between ILS and any of the dosimetry parameters when all data were included in the analysis, regardless of the preclinical SFRT mode used. However, strong correlations appeared when MRT and MBRT were analyzed separately, which might suggest potentially different modes of action in both techniques. In both cases, and despite the heterogeneity of the data, valley doses stand out as one of the key parameters in terms of ILS, whereas peak dose was only weakly correlated. Nevertheless, we need to exercise caution in translating preclinical findings to clinical applications. The peak dose may be an important clinical and preclinical SFRT dosimetry parameter for cytotoxic cell killing and for triggering important secondary radiobiological processes, such as vascular permeability or immune cell infiltration, all of which merit further investigation. There are also important differences between preclinical SFRT studies and clinical SFRT applications. The size of the peak and valley width (in cm) is significantly larger in clinical SFRT than in preclinical studies (10–100 s microns); the PVDR is significantly lower (~5) in clinical SFRT than in preclinical studies (>10 in MBRT and 20–50 in MRT). More importantly, clinical SFRT is often followed by a course of conventional RT, whereas animal studies often have a single SFRT regime. Additionally, the fact that cancer patients may respond very differently to the same treatment compared to animal models is also a well-known limitation of preclinical studies.