Radiation therapy is a time-tested technique for controlling solid tumours in patients. Intensity modulated radiation therapy was a huge leap forward for radiation oncology, allowing for the precise delivery of radiation to tumour targets, sparing healthy tissue.
A linear accelerator (linac) delivers a carefully calibrated beam of radiation from one position, rotates around the patient, and delivers another beam, repeating the process hundreds of time to build up a dose distribution that converges on the tumour, while spreading out the burden to healthy tissue. Intensity-modulated radiation therapy is now the standard of care within Ontario. However, the tumour can change shape between radiation fractions, or move between imaging and treatment, so some healthy tissue must be sacrificed to create margins-of-safety.
Adding imaging capabilities in the form of a cone beam CT (CBCT) to create image guided radiation therapy (IGRT) allows the treatment team to identify the tumour in its exact position while the patient lies on the treatment bed. Therapy can be made even more conformal, ensuring that no tumour is missed and minimizing the damage to healthy tissue. The Princess Margaret Cancer Centre has been a leader in the research, development, and clinical adoption of IGRT. Researchers there have been optimizing this technique for clinical use for over a decade.
For research purposes, it would be ideal to mimic the clinical situation—including IGRT techniques—as closely as possible in preclinical models, to get the best results in understanding the mechanism of cancer control and to test novel therapies. However, preclinical radiation therapy simulation was limited to large box irradiators that delivered whole-body radiation fields to test specimens. This limited the scope of radiation therapy experiments.
That all changed in 2006, when Dr. David Jaffray and Dr. Dick Hill at The Princess Margaret Cancer Centre and The Techna Institute in Toronto combined with Precision X-Ray Inc. (PXI) of North Branford, CT to design a system that could deliver IGRT in preclinical experiments. Combining the expertise at Princess Margaret in IGRT, radiobiological basic research, and preclinical research with PXI’s vast experience in designing and manufacturing cabinet irradiators for preclinical studies allowed the team to design the X-RAD 225Cx.
The X-RAD 225Cx employs a dual focal spot X-ray tube, capable of both imaging and delivering ionizing radiation for treatment scenarios. With a flat panel detector the system can image a 10x10x10 cm volume with a maximum resolution of 0.1 mm3. A robust gantry system, capable of a full 360° rotation, provides consistent geometry thanks to a reinforcing gantry ring. A stage with three axes of translation can place a sample in 3 dimensions with positional accuracy of 0.25 mm. The system’s collimators can modulate the irradiation from large 20 x 20 cm fields down to precise 1 mm beams. This allows for a large variation in possible dose patterns, including irradiating multiple targets within one specimen, with fractionated treatments over many days; just as patients would experience in the clinical IGRT situation. The system cabinet is lead lined and fully self-shielded, allowing it to be installed anywhere without the need for a specific shielded room. This also enables users to quickly make small changes to their experiments, as they can operate it within the same room as the operating PC and experimental preparation work.
Techna and PXI enjoy a synergistic relationship, where the hardware is designed, manufactured and assembled by PXI, while the software is developed by research staff at the Princess Margaret Cancer Centre. The software is licensed to PXI by the Techna team, who in turn use the funds obtained from sales royalties to further develop the software and add new features. The first X-RAD 225Cx unit was installed at The Princess Margaret Cancer Centre in 2008, and since then 13 more units have been installed worldwide. The most recent was installed at Memorial Sloan-Kettering Cancer Center in New York.
Researchers at the Princess Margaret Cancer Centre are not just involved in the development of the system, but are also frequent users. There are two systems installed at facilities in Toronto (one at Princess Margaret Cancer Centre and another at the STTARR laboratory), which have been involved in a multitude of radiobiological studies. “At the STTARR Innovation Centre (www.sttarr.ca), this is a powerful tool for over 35 research projects ranging from dose calibration in phantoms to analyzing radiation sensitizers in cells to evaluating new treatment plans in tumour-bearing models,” says Dr. Justin Grant, facility manager. “Researchers come from hospitals, universities and industry. With minimal training and support, they can operate the system themselves to achieve their research goals.”
New features are constantly being added to the X-RAD 225Cx IGRT platform, and the platform’s flexible design allows for easy upgrades to existing systems. Last year, in collaboration with the Netherlands Cancer Institute (NKI), a special version of their X-Ray Volume Imaging software (XVI) was integrated to allow for multi-modality image guidance. Additionally, a new option is available enabling the on-board acquisition of bioluminescent images on the system, delivering functional imaging that supplements the already available anatomical information given by CBCT. Current research is ongoing into the development of dose painting techniques using the system, where a specific target volume is determined using functional imaging, then precisely targeted using conformal irradition.
More recently, a robust Monte-Carlo based treatment planning system (SmART-Plan) was developed at Maastro Radiotherapy Clinic in the Netherlands, and is also integrated into the software. This software enables the user to plan a complex, multi beam/arc treatment on a scanned specimen and calculate the dose distribution in under five minutes.
This tool effectively grants the preclinical researchers the same treatment planning capabilities as the clinical physicists enjoy in the hospital setting. “Smart-Plan renders planning pre-clinical irradiation studies easy;” says Dr. Frank Verhaegen, whose group developed the treatment planning software, “it offers unprecedented accuracy and an intuitive workflow.”
This Canadian success story is a valuable advancement for preclinical radiation oncology research, closely simulating clinical IGRT. As of this writing, 10 peer reviewed articles have been published in scientific journals on research conducted using the X-RAD 225Cx, and many more ongoing studies have presented preliminary data at conferences.
The system’s ability to deliver precise IGRT to a variety of preclinical models in a research setting has provided a solid platform for the future of radiobiological research.
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