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Multi-ion cancer therapy tackles the LET trilemma
Cancer treatments using heavy ions offer several key advantages over conventional proton therapy: a sharper Bragg peak and small lateral scattering for precision tumour targeting, as well as high linear energy transfer (LET). High-LET radiation induces complex DNA damage in cancer cells, enabling effective treatment of even hypoxic, radioresistant tumours. A team at the National Institutes for Quantum Science and Technology (QST) in Japan is now exploring the potential benefits of multi-ion therapy combining beams of carbon, oxygen and neon ions.
“Different ions exhibit distinct physical and biological characteristics,” explains QST researcher Takamitsu Masuda. “Combining them in a way that is tailored to the specific characteristics of a tumour and its environment allows us to enhance tumour control while reducing damage to surrounding healthy tissues.”
The researchers are using multi-ion therapy to increase the dose-averaged LET (LETd) within the tumour, performing a phase I trial at the QST Hospital to evaluate the safety and feasibility of this LETd escalation for head-and-neck cancers. But while high LETd prescriptions can improve treatment efficacy, increasing LETd can also deteriorate plan robustness. This so-called “LET trilemma” – a complex trade-off between target dose homogeneity, range robustness and high LETd – is a major challenge in particle therapy optimization.
In their latest study, reported in Physics in Medicine & Biology, Masuda and colleagues evaluated the impact of range and setup uncertainties on LETd-optimized multi-ion treatment plans, examining strategies that could potentially overcome this LET trilemma.
Robustness evaluation
The team retrospectively analysed the data of six patients who had previously been treated with carbon-ion therapy. Patients 1, 2 and 3 had small, medium and large central tumours, respectively, and adjacent dose-limiting organs-at-risk (OARs); and patients 4, 5 and 6 had small, medium and large peripheral tumours and no dose-limiting OARs.
For each case, the researchers first generated baseline carbon-ion therapy plans and then incorporated oxygen- or neon-ion beams and tuned the plans to achieve a target LETd of 90 keV/µm to the gross tumour volume (GTV).
Particle therapy plans can be affected by both range uncertainties and setup variations. To assess the impact of these uncertainties, the researchers recalculated the multi-ion plans to incorporate range deviations of +2.5% (overshoot) and –2.5% (undershoot) and various setup uncertainties, evaluating their combined effects on dose and LETd distributions.
They found that range uncertainty was the main contributor to degraded plan quality. In general, range overshoot increased dose to the target, while undershoot decreased dose. Range uncertainties had the largest effect on small tumours and central tumours: patient #1 exhibited a deviation of around ±6% from the reference, while patient #3 showed a dose deviation of just ±1%. Robust target coverage was maintained in all large or peripheral tumours, but deteriorated in patient 1, leading to an uncertainty band of roughly 11%.
“Wide uncertainty bands indicate a higher risk that the intended dose may not be accurately delivered,” Masuda explains. “In particular, a pronounced lower band for the GTV suggests the potential for cold spots within the tumour, which could compromise local tumour control.”
The team also observed that range undershoot increased LETd and overshoot decreased it, although absolute differences in LETd within the entire target were small. Importantly, all OAR dose constraints were satisfied even in the largest error scenarios, with uncertainty bands comparable to those of conventional carbon-ion treatment plans.
Addressing the LET trilemma
To investigate strategies to improve plan robustness, the researchers created five new plans for patient 1, who had a small, central tumour that was particularly susceptible to uncertainties. They modified the original multi-ion plan (carbon- and oxygen-ion beams delivered at 70° and 290°) in five ways: expanding the target; altering the beam angles to orthogonal or opposing arrangements; increasing the number of irradiation fields to a four-field arrangement; and using oxygen ions for both beam ports (“heavier-ion selection”).
The heavier-ion selection plan proved the most effective in mitigating the effects of range uncertainty, substantially narrowing the dose uncertainty bands compared with the original plan. The team attribute this to the inherently higher LETd in heavier ions, making the 90 keV/µm target easier to achieve with oxygen-ion beams alone. The other plan modifications led to limited improvements.
These findings suggest that strategically employing heavier ions to enhance plan robustness could help control the balance among range robustness, uniform dose and high LETd – potentially offering a practical strategy to overcome the LET trilemma.
“Clinically, this strategy is particularly well-suited for small, deep-seated tumours and complex, variable sites such as the nasal cavity, where range uncertainties are amplified by depth, steep dose gradients and daily anatomical changes,” says Masuda. “In such cases, the use of heavier ions enables robust dose delivery with high LETd.”
The researchers are now exploring the integration of emerging technologies – such as robust optimization, arc therapy, dual-energy CT, in-beam PET and online adaptation – to minimize uncertainties. “This integration is highly desirable for applying multi-ion therapy to challenging cases such as pancreatic cancer, where uncertainties are inherently large, or hypofractionated treatments, where even a single error can have a significant impact,” Masuda tells Physics World.
The post Multi-ion cancer therapy tackles the LET trilemma appeared first on Physics World.
