Modulated radiotherapy with multileaf collimators is widely used to improve target conformity and normal tissue sparing. This introduced an additional degree of complexity, studied by multiple teams through different properties. Three categories of complexity metrics were considered in this review: fluence, deliverability and accuracy metrics. The first part of this review is dedicated to the inventory of these complexity metrics. Different applications of these metrics emerged. Influencing the optimizer by integrating complexity metrics into the cost function has been little explored and requires more investigations. In modern treatment planning system, it remains confined to MUs or treatment time limitation. A large majority of studies calculated metrics only for analysis, without plan modification. The main application was to streamline the patient specific quality assurance workload, investigating the capability of complexity metrics to predict patient specific quality assurance results. Additionally complexity metrics were used to analyze behaviour of TPS optimizer, compare TPS, operators and plan properties, and perform multicentre audit. Their potential was also explored in the context of adaptive radiotherapy and automation planning. The second part of the review gives an overview of these studies based on the complexity metrics.

Background. The tumor vasculature acts as an interface for the primary tumor. It regulates oxygenation, nutrient delivery, and treatment efficacy including radiotherapy. The response of the tumor vasculature to different radiation doses has been disparately reported. Whereas high single doses can induce endothelial cell death, improved vascular functionality has also been described in a various dose range, and few attempts have been made to reconcile these findings. Therefore, we aimed at comparing the effects of different radiation fractionation regimens on the tumor vascular microenvironment. Methods: Lewis lung and prostate PC3 carcinoma-derived tumors were irradiated with regimens of 10 × 2 Gy, 6 × 4 Gy, 3 × 8 Gy or 2 × 12 Gy fractions. The tumor vasculature phenotype and function was evaluated by immunohistochemistry for endothelial cells (CD31), pericytes (desmin, α-SMA), hypoxia (pimonidazole) and perfusion (Hoechst 33342). Results: Radiotherapy increased vascular coverage similarly in all fractionation regimens in both models. Vessel density appeared unaffected. In PC3 tumors, hypoxia was decreased and perfusion was enhanced in proportion with the dose per fraction. In LLC tumors, no functional changes were observed at t = 15 days, but increased perfusion was noticed earlier (t = 9–11 days). Conclusion: The vascular microenvironment response of prostate and lung cancers to radiotherapy consists of both tumor/dose-independent vascular maturation and tumor-dependent functional parameters.

In pre-clinical animal experiments, radiation delivery is usually delivered with kV photon beams, in contrast to the MV beams used in clinical irradiation, because of the small size of the animals. At this medium energy range, however, the contribution of the photoelectric effect to absorbed dose is significant. Accurate dose calculation therefore requires a more detailed tissue definition because both density (ρ) and elemental composition (Zeff) affect the dose distribution. Moreover, when applied to cone beam CT (CBCT) acquisitions, the stoichiometric calibration of HU becomes inefficient as it is designed for highly collimated fan beam CT acquisitions. In this study, we propose an automatic tissue segmentation method of CBCT imaging that assigns both density (ρ) and elemental composition (Zeff) in small animal dose calculation. The method is based on the relationship found between CBCT number and ρ*Zeff product computed from known materials. Monte Carlo calculations were performed to evaluate the impact of ρZeff variation on the absorbed dose in tissues. These results led to the creation of a tissue database composed of artificial tissues interpolated from tissue values published by the ICRU. The ρZeff method was validated by measuring transmitted doses through tissue substitute cylinders and a mouse with EBT3 film. Measurements were compared to the results of the Monte Carlo calculations. The study of the impact of ρZeff variation over the range of materials, from ρZeff = 2 g.cm− 3 (lung) to 27 g.cm− 3 (cortical bone) led to the creation of 125 artificial tissues. For tissue substitute cylinders, the use of ρZeff method led to maximal and average relative differences between the Monte Carlo results and the EBT3 measurements of 3.6% and 1.6%. Equivalent comparison for the mouse gave maximal and average relative differences of 4.4% and 1.2%, inside the 80% isodose area. Gamma analysis led to a 94.9% success rate in the 10% isodose area with 4% and 0.3 mm criteria in dose and distance. Our new tissue segmentation method was developed for 40kVp CBCT images. Both density and elemental composition are assigned to each voxel by using a relationship between HU and the product ρZeff. The method, validated by comparing measurements and calculations, enables more accurate small animal dose distribution calculated on low energy CBCT images.

Proton therapy (PRT) is an irradiation technique that aims at limiting normal tissue damage while maintaining the tumor response. To study its specificities, the ARRONAX cyclotron is currently developing a preclinical structure compatible with biological experiments. A prerequisite is to identify and control uncertainties on the ARRONAX beamline, which can lead to significant biases in the observed biological results and dose–response relationships, as for any facility. This paper summarizes and quantifies the impact of uncertainty on proton range, absorbed dose, and dose homogeneity in a preclinical context of cell or small animal irradiation on the Bragg curve, using Monte Carlo simulations. All possible sources of uncertainty were investigated and discussed independently. Those with a significant impact were identified, and protocols were established to reduce their consequences. Overall, the uncertainties evaluated were similar to those from clinical practice and are considered compatible with the performance of radiobiological experiments, as well as the study of dose–response relationships on this proton beam. Another conclusion of this study is that Monte Carlo simulations can be used to help build preclinical lines in other setups.