Dose distributions Proton minibeam radiation therapy plans for (left to right columns) metastases in the temporal lobe, the frontal lobe, the liver and the lung. The planning target volumes is outlined in yellow, organs-at-risk in other colours. (Courtesy: R Ortiz et al Med. Phys. 10.1002/mp.16203)
Treating cancer patients with spatially modulated radiation beams could destroy tumours while minimizing damage to nearby organs and healthy tissue. That’s the idea behind proton minibeam radiation therapy (pMBRT), an emerging treatment technique that uses an array of submillimetre-sized radiation beams to deliver therapeutic dose.
The minibeams comprise alternating high-dose peaks and low-dose valleys, a pattern that’s less harmful to healthy tissue at shallow depths. At greater depths, these beams gradually widen to create a homogeneous dose distribution within the target volume. Studies in small animals have shown that pMBRT can dramatically reduce normal tissue toxicity, with equivalent or superior tumour control, compared with conventional proton therapy.
“Proton minibeam radiation therapy has already shown a remarkable gain in the therapeutic index in preclinical studies,” says Ramon Ortiz from Institut Curie. “These promising results encourage the translation of this technique into the clinical domain.” With this aim, Ortiz (now at UC San Francisco) and colleagues at Institut Curie evaluated the benefits of pMBRT for treating cancer metastases, reported their findings in Medical Physics.
Simulating pMBRT scenarios
Metastatic disease accounts for up to 90% of cancer-related deaths. Metastases are commonly treated using stereotactic radiotherapy (SRT) techniques, but the dose required for local control is often limited by the risk of toxicity to nearby normal tissue. For brain metastases, for example, radiation-induced brain necrosis is reported in half of patients treated with SRT.
To determine whether pMBRT can reduce such complications, the team used Monte Carlo simulations to compute dose distributions for four patients who previously received SRT at Institut Curie. The patients had been treated for metastatic lesions in the brain’s temporal lobe, frontal lobe, the liver and the lung.
The researchers simulated single-fraction pMBRT plans, using one or two treatment fields to deliver the same biological equivalent dose (BED) to the tumour target as prescribed for the SRT. They modelled a brass minibeam collimator containing 400 μm × 5.6 cm slits at various centre-to-centre separations, to create both narrow- and wider-spaced minibeams. They then computed dose distributions for the four patient cases, for pMBRT, SRT and conventional proton therapy.
In the narrow-spaced pMBRT plans, which create a uniform dose distribution in the target volume, tumour coverage was similar to or slightly better than in the SRT plans. Plans using wider-spaced pMBRT beams, which deliver a quasi-uniform dose distribution to the target, had a lower tumour coverage.
Importantly, pMBRT significantly reduced the dose to critical structures compared with SRT. In the first brain case, pMBRT decreased the mean BED to organs-at-risk (OARs) by between 44% (right acoustic nerve) and 100% (left acoustic nerve). In the second brain treatment, pMBRT completely spared the OARs, including the optic tract, brainstem and chiasm.
In the liver case, the mean BED to the liver and ribs was reduced by 25% and 75%, respectively, while avoiding irradiation of the superior vena cava. And for the lung case, the dose to OARs was reduced by between 11% (ribs) and 100% (pulmonary artery and bronchi). The mean BED to OARs was mostly similar between pMBRT and conventional proton therapy.
The researchers also investigated possible adverse effects of pMBRT on normal tissues. For the two brain metastases cases, for example, they computed the dose delivered to healthy brain tissue. They considered the dose limits for standard fractionated irradiation, in which a normalized total dose at 2 Gy-fractions (NTD2.0) of 72 Gy leads to a 5% probability of radio-necrosis within five years.
For all pMBRT plans, the maximum valley NTD2.0 to the healthy brain (61 Gy(RBE) for the temporal lobe case and 47 Gy(RBE) for the frontal lobe case) remained below this dose tolerance threshold, in contrast to conventional proton therapy. For the patients with lung and liver metastases, the mean doses to lung and liver tissues in pMBRT plans were also well below the maximum tolerable mean doses.
The pMBRT treatments considered in this study were delivered using just one or two minibeam arrays. The use of fewer fields than in the SRT treatments (three or four arcs) requires less patient repositioning, reducing the fraction treatment time, as well as lowering the volume of normal tissue exposed to low doses. In addition, delivering pMBRT in one treatment fraction considerably reduces the total treatment time compared with the SRT plans, which used three to five fractions.
The researchers point out that the pMBRT plans evaluated in this work could be delivered clinically using the set-up already implemented at the Orsay Proton Therapy Center for preclinical trials, with target and organ motion during treatment controlled as in SRT and proton therapy.
Ortiz tells Physics World that Institut Curie is now discussing the possibility of Phase I/II clinical trials. “These would evaluate the neurotoxicity and tumour control rates in the treatment of recurrent glioblastoma multiforme with proton minibeams,” he explains. “This study aims to contribute to the preparation of those clinical investigations.”
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