A scoping review of small animal image-guided radiotherapy research: Advances, impact and future opportunities in translational radiobiology

Abstract

Background and purpose: To provide a scoping review of published studies using small animal irradiators and highlight the progress in preclinical radiotherapy (RT) studies enabled by these platforms since their development and commercialization in 2007.

Materials and methods: PubMed searches and manufacturer records were used to identify 907 studies that were screened with 359 small animal RT studies included in the analyses. These articles were classified as biology or physics contributions and into subgroups based on research aims, experimental models and other parameters to identify trends in the preclinical RT research landscape.

Results: From 2007 to 2021, most published articles were biology contributions (62%) whilst physics contributions accounted for 38% of the publications. The main research areas of physics articles were in dosimetry and calibration (24%), treatment planning and simulation (22%), and imaging (22%) and the studies predominantly used phantoms (41%) or in vivo models (34%). The majority of biology contributions were tumor studies (69%) with brain being the most commonly investigated site. The most frequently investigated areas of tumor biology were evaluating radiosensitizers (33%), model development (30%) and imaging (21%) with cell-line derived xenografts the most common model (82%). 31% of studies focused on normal tissue radiobiology and the lung was the most investigated site.

Conclusions: This study captures the trends in preclinical RT research using small animal irradiators from 2007 to 2021. Our data show the increased uptake and outputs from preclinical RT studies in important areas of biology and physics research that could inform translation to clinical trials.

Keywords: Preclinical models; Preclinical radiotherapy; Radiotherapy; Small animal irradiators.

Fig. 1

Overview of article screening and the analysis of small animal image-guided radiotherapy publications by year according to study area. Panel A: A flow chart of the article process used to identify a total of 359 articles from 2007 to 2021 and those that were excluded in the analysis; Panel B: Classification of articles in areas of physics & biology research from 2007 to 2021. In total there are 38% physics contributions and 62% biology contributions.

Fig. 2

Analysis of physics papers according to the main research areas and experimental models reported from 2007 to 2021. Panel A: Breakdown of physics studies into main research aims or area of interest of the published studies. Panel B: The percentage contribution of different experimental approaches used in physics articles. Studies reported the use of phantom (41%), in vivo (34%) and in silico (25%) approaches. Panel C: The distribution of the experimental approaches according to the main areas of physics research. From a total of 138 papers, we identified 7 main research areas reported in the literature with 3 main research focuses of dosimetry & calibration (24%), treatment planning & simulations (22%) and imaging (22%).

Fig. 3

Classification of biology papers based on normal tissue site and tumor indications from 2007 to 2021. Panel A: Percentage breakdown of the tissue types reported from a total of 69 normal tissue articles. Panel B: Distribution of tumor models reported from a total of 152 studies. Multiple includes studies which reported more than 1 tumor model. Panel C: Analysis of biology papers based on the main research areas. From a total of 221 papers, we identified 6 main research areas reported in the literature with 3 main research focuses of radiosensitizers (33%), model development (30%) and imaging (21%).Panel D: The percentage of tumor studies which combine RT with therapeutic agents reported from 2013 to 2021. We identified 4 main groups of immunotherapy, nanoparticles, chemotherapy, and other molecular targeted agents from a total of 96 tumours studies. Other molecular targeted agents encompass hypoxic agents, viral agents and cannabinoids.

Fig. 4

Further analysis of tumor radiobiology papers based on the main tumor sites and experimental models reported in studies from 2007 to 2021. Panel A: Percentage of different tumor types in all analysed tumor studies. From a total of 152 papers, we identified the main tumor sites reported in the literature in the brain, pancreas, liver, GI & oesophagus and lung. Panel B: Schematic representing the percentage of tumor experimental models reported in biology contributions using small animal irradiators. 4 main approaches of cell-line derived (82.2%), and genetical engineered mouse models (GEMM) (7.9%), patient-derived xenograft (PDX) (9.2%) and environmentally induced models (0.7%) were reported. Panel C: The relative distribution of experimental tumor models reported for each tumour type.

Fig. 5

Overview of treatment delivery methods reported in biology studies. Panel A: Collimator sizes reported for targeting orthotopic tumor studies (n = 50) on the SARRP, XRAD-SmART or other small animal irradiator platforms. From a total of 152 tumor studies, 75 were conducted in orthotopic models (49%) of which 25 studies did not report the treatment field sizes used or the details could not be accessed. 82% of orthotopic tumor models were treated using collimators ≥ 5 mm. Panel B: The measured radiochromic film (RCF) output for circular collimators of 1 mm (C1), 2 mm (C2) and 3 mm (C3) diameter. Results shown are in comparison to a 5 mm diameter field using a Precision X-ray Inc platform. Collimators with a size of<5 mm are at risk of dose overestimation (therefore, of underdosing) which could impact study performance.

Fig. 6

Tumor and normal tissue studies reporting the use of fractionation. The total number of biology studies per year which reported the use of a fractionated dose delivery for both tumor and normal tissue studies. Fractionation was first implemented in preclinical RT tumour studies in 2012.