Proton therapy is an increasingly popular cancer treatment that offers superior dose shaping to conventional photon radiotherapy. This high-precision dose delivery, however, means that target margins are needed to account for range uncertainties, exposing more healthy tissue to radiation. In addition, uncertainties in linear energy transfer (LET) and relative biological effectiveness (RBE) at the end of the beam range can increase irradiation of healthy tissue behind the target.
A team from the GROW School for Oncology and Reproduction at Maastricht University in the Netherlands has now shown, through an in silico planning study, that proton therapy using shoot-through proton FLASH beams could avoid these uncertainties. Furthermore, the technique provides adequate target coverage and at least as good normal tissue sparing as clinical proton therapy.
Conventional clinical proton therapy uses a series of Bragg peaks (the depth at which the beam deposits most of its dose) to irradiate the tumour volume. The shoot-through technique, on the other hand, employs high-energy proton beams that travel straight through the patient, depositing dose along their entire track, with the Bragg peaks positioned outside of the body.
This approach removes uncertainties on LET and proton range. However, it also eliminates the favourable dose deposition characteristics of protons. To compensate for this loss, the researchers turned to FLASH radiotherapy, in which radiation delivered at ultrahigh dose rates – 40 Gy/s or more – offers potential to destroy tumours while sparing surrounding normal tissue. In particular, they investigated the FLASH protective effect in neurological tumours, where proton therapy has been observed to cause radiation-induced contrast enhancements (RICE) in the brain.
“In the follow-up of patients with neurological tumours there is a concern about the potential effect of high LET on brain tissue,” explains first author Esther Kneepkens. “RICE in the brain, as visible on MRI scans, has shown correlation to areas with increased LET values.”
While RICE lesions are often asymptomatic, they cause stress for the patient and treatment team since they mimic tumour progression. Kneepkens notes that higher LET has also been seen to cause brainstem toxicity in paediatric patients, albeit a minor effect. “Although the correlations reported are not strong enough to establish the risk of high LET in the treatment of brain tumours, they certainly warrant further research,” she says.
To test their hypothesis, Kneepkens and colleagues – in collaboration with RaySearch Laboratories – created shoot-through proton FLASH plans for five patients with neurological cancer who had previously received intensity-modulated proton therapy (IMPT). To ensure that the beam travelled straight through the patient, they used a proton energy of 227 MeV, the highest produced by the Mevion Hyperscan S250i.
Assuming a FLASH protective factor (FPF) of 1.5 for normal tissues outside the target, the shoot-through plans delivered comparable target coverage to the original IMPT plans and met the same number of clinical goals. Doses to many organs-at-risk (OARs) including brainstem, hippocampi, pituitary and optical nerves were lower in the shoot-through than the IMPT plans.
In clinical proton therapy, RBE – the ratio of the dose of photons to the dose of protons that causes the same level of damage – is generally assumed to be 1.1 along the entire proton track. But RBE actually depends on a number of parameters, including the LET, which is highest at the end of the beam range. Kneepkens notes that, in addition to brain toxicities, researchers have seen a possible correlation between high LET and end-of-range rib fractures in breast cancer patients. “This indicates that the currently assumed fixed RBE of 1.1 could be insufficient to understand the full impact of proton therapy, as is recognized by the community,” she explains.
As a computable surrogate for RBE, the researchers calculated dose-averaged LET (LETD) distributions for all plans. The IMPT plans showed large variations in LETD around the clinical target volume (CTV) compared with the shoot-through plans, which also had lower average LETD for all structures. In the brainstem, for example, the average LETD was 4.0 keV/µm for IMPT and 0.9 keV/µm for shoot-through proton FLASH.
The team also examined how a 3% variation in density affected the dose distributions. The FLASH shoot-through plans were more robust, with a maximum variation in D2% dose to OARs of 0.57 Gy and a maximum drop in D98% dose to the CTV of 0.20 Gy. For the IMPT plans, the maximum drop in CTV dose was 0.56 Gy, while changes in OAR doses varied, with the highest differences in the hippocampus (3.04 Gy) and cochlea (5.72 Gy).
Shoot right through: FLASH protons could eliminate Bragg peak constraints
This robustness to density uncertainties demonstrates how dose distributions for shoot-through proton beams are less dependent on the tissues they pass through. This is particularly important for patients with brain tumours, the researchers explain, as tumours close to sinuses and cavities could be deemed ineligible for proton therapy, due to changes in sinus filling or the need for time-consuming imaging and adaptation.
The researchers are now looking to install equipment for preclinical FLASH research in rodents. “We believe that the FLASH phenomenon is very complex – and has, up to now, not been explained fully – and that many parameters need to be investigated in preclinical models first,” team leader Frank Verhaegen tells Physics World. “Once we have the novel equipment, we will start an extensive preclinical research program.”
The researchers report their findings in Physics in Medicine & Biology.
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- Source: https://physicsworld.com/a/shoot-through-proton-flash-a-robust-approach-to-brain-tumour-treatment/
