A new radiation therapy technique for the treatment of high-grade brain cancer using personalized microbeam radiation therapy (MRT)

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A new radiation therapy technique pioneered by scientists from the University of Wollongong’s Centre for Medical Radiation Physics (CMRP) has shown promise for improving treatment outcomes in patients with brain cancer.

Working at the Australian Synchrotron facility in Melbourne, the scientists tested a technique for the treatment of high-grade brain cancer using personalized microbeam radiation therapy (MRT), combining it with an innovative assessment of tumor dose-coverage.

MRT uses ultra-fine X-rays – each smaller in diameter than a human hair – to destroying the cancerous tissue while not harming the surrounding healthy tissue.

Precise targeting also enables much higher dosages to be delivered to the tumor in a very short time.

The researchers used CT scans, performed at Monash Biomedical Imaging, to map individual brain tumors in rats, and then used MRT to deliver high dose to the cancer cells with pinpoint precision.

The synchrotron is able to produce much more powerful X-rays than conventional hospital X-ray machines.

The MRT treated rats survived for significantly longer than non-irradiated rats with the same aggressive brain tumors. No long-term adverse effects were observed following MRT, and there was no noticeable decline in cognition, vision, mobility, or behavior in the treated rats.

The study, which included researchers from the Illawarra Health and Medical Research Institute (IHMRI), Australian Synchrotron—Australia’s Nuclear Science and Technology Organisation (ANSTO), Central Coast Cancer Centre and Prince of Wales Hospital, is published in Scientific Reports.

It is the first long-term Australian MRT brain cancer survival study, and the first in the world to look at optimisation of personalized pre-clinical MRT of high-grade brain cancer.

The results and methods investigated MRT from multiple points of view including radiation and medical physics, radiobiology, diagnostic imaging, and preclinical survival.

Lead author and UOW Ph.D. student Elette Engels said brain tumors were among the most difficult cancers to treat.

“Brain cancers require more rigorous and novel treatment strategies to overcome their radiation resistance,” she said.

“This new MRT technique treats tumors with very narrow wafer-like X-ray blades to deliver very high doses of synchrotron radiation delivered in a very short time.

“This is not feasible with conventional radiotherapy X-ray machines in hospitals. Our research shows that the treatment of tumor cells is much more effective when the radiation dose is delivered using MRT.

“Our work aims to optimize this technique and personalize the entire procedure, from diagnosis to treatment, for each patient.”

Treating brain cancers in children and young adults is especially difficult. Over the past 30 years, treatment outcomes for brain cancer in children and young adults have remained at a stand-still.

Corresponding author Dr. Moeava Tehei said that despite advances in surgical techniques, radiotherapy and chemotherapeutics, brain tumors remain difficult to remove surgically and can be resistant to radiation and drug treatments.

“A breakthrough in the treatment of brain cancer is well overdue,” Dr. Tehei said.

“Many brain cancer survivors suffer from cognitive and somatic side effects of the treatment, with increased risks in children.

“Sparing normal tissue from damage is key to improved quality of life for brain cancer survivors.”

Personalized synchrotron MRT holds the promise of quicker, more effective treatment of brain cancers.

Current radiation therapy for a brain tumor is typically delivered over several weeks with daily radiation treatments. Instead of hitting a larger area of the brain with lower doses of X-rays, repeated numerous times, the new technique would involve a single dose of ultra high dose rate X-rays, precisely targeted at the cancerous cells.

“A single dose of this personalized synchrotron MRT treatment could be more effective than multiple radiation treatments as they are delivered now. Waiting times and toxic dosage could be eliminated if this technology was available in hospitals,” Ms Engels said

While more research needs to be done, with the aim of moving towards clinical trials on human patients, the evidence to date suggests that the techniques trialled in this study will be transferable to human patients.

Ms Engels also wished to thank all co-authors, especially Professor Michael Lerch, head of UOW’s School of Physics, and Associate Professor Stephanie Corde, Deputy Director of Radiation Oncology Medical Physics at Prince of Wales Hospital in Sydney, for their significant contribution to the study.


In the last 30 years, treatment outcomes for brain cancer in children and young adults have remained at a stand-still. Despite significant progress in brain cancer treatment involving surgical resection, radiotherapy and chemotherapeutics, the inherent resistance of these cancers challenge treatment success1.

The prognosis is even poorer for high-grade gliosarcomas and glioblastoma multiformes (GBMs), and treatments must balance the risk of neurological deficits2.

Consequently, there has been little improvement in brain and CNS cancer survival between 1990 and 2016 (only −2.2% difference in mortality) despite a 17% increase in incidence3. Due to the extremely invasive nature of high-grade brain cancers, treatments remain challenging and research into novel therapies with improved outcomes are still needed.

Synchrotron microbeam radiation therapy (MRT) is an innovative cancer treatment technique proposed in 19924. MRT implements spatially fractionated beams of kilovoltage radiation that are tens of microns in width and spaced hundreds of micrometers apart.

The synchrotron radiation source is extremely brilliant and non-divergent, capable of producing a high-flux of photons leading to irradiation dose-rates upwards of thousands of Gray (Gy) per second5.

The synchrotron microbeam array contains micron-sized beamlets that promote radiosurgical treatment of cancers (with in-beam, or peak doses, of hundreds of Gray).

Further, normal tissue sparing is observed, due to the biologically tolerable dose between microbeams (defined as the valley dose). Numerous pre-clinical studies support the reduction in normal tissue damage with MRT, while effectively treating the cancer5–8.

Amongst the synchrotron facilities that provide the technical pre-requisites to explore MRT, there is significant variation between treatment techniques including beam dimensions and spacing, beam filtration, image guidance, dose rates and doses.

A major uncertainty in prescribing MRT is relating these parameters to systematic tumor control. Early studies4,9–12 use skin entrance doses as a standard, providing insufficient knowledge of the tumor dose coverage at depth.

A few recent studies6,12–15 describe the valley and peak dose in the brain at depth, however, there is scarce individualized tumor volume coverage, as typically used in clinics. Image guidance in MRT is necessary to ensure tumor coverage but is not implemented in all studies.

Le Duc et al.16 is among the few studies to consider co-registration of images and positioning animals accordingly to better target brain tumors. Spatially fractionated MRT doses are challenging to compare with existing modalities. Studies such as Smyth et al.17 have surmised that the MRT valley dose is the most relatable parameter to standard broad beam treatments, yet the effect of the dose spatial modulation is not well understood.

Furthermore, direct relationships between in vitro and in vivo MRT studies are scarce. While in vitro studies are performed to discern the response of cells to MRT18,19, they are not correlated directly to in vivo studies. Ideally, as the current focus of clinical practice is personalization, patterns in in vitro studies should be used to predict in vivo responses in an effort to personalize MRT for better patient specificity.

MRT could also benefit from more clinically oriented approaches to treatment planning. The MRT dose coverage of the tumor volume and organs at risk (OAR) must be further investigated. This requires knowledge of the peak and valley dose distribution in the anatomy, and MRT related normal tissue toxicities.

Normal tissue responses to MRT show good tolerance to valley doses greater than 18 Gy5–7,10,20–24. However, clinical signs in animals following MRT are not well documented. Brain tumor treatment in human patients can cause adverse effects, including tiredness, skin reactions, headaches, nausea, seizures and hair loss22.

Previous pre-clinical MRT studies have few reports of early radiation symptoms, and there is no standard for symptom management for brain MRT to-date. No long-term side effects are typically found however, in terms of cell functionality20, memory loss23, motor function and behavior24.

The future of MRT therefore requires the correlation of dosimetry and treatment planning, accurate imaging of brain tumors and image guidance, and reporting of clinical signs and symptom management.

To date, there are no pre-clinical studies in MRT that combine the necessary dosimetry, image guidance, treatment planning and short- and long-term follow-up. This study is designed to demonstrate the necessary steps for optimization of personalized pre-clinical MRT of high grade brain cancer: treatment planning, radiobiological insights, image-guidance, and symptom management strategies.

References

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More information: Elette Engels et al. Toward personalized synchrotron microbeam radiation therapy, Scientific Reports (2020). DOI: 10.1038/s41598-020-65729-z

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