High-LET radiation, however, also increases RBE in surrounding tissue, while increased fragmentation can damage normal tissue surrounding the target. To investigate these trade-offs, researchers from the GSI Helmholtz Centre for Heavy Ion Research and the Trento Institute for Fundamental Physics and Application have performed experimental verification of biologically optimized treatment plans, and determined the range of plans where 16O ions could provide benefit over lighter particle beams (Phys. Med. Biol. 62 7798).

"At GSI, the first studies of radiobiological properties of oxygen ions started in the 1990s, in search of the 'best' ion for an upcoming radiotherapy pilot project. At that time, carbon won," explained Olga Sokol, a PhD student in GSI's biophysics department. "We returned to the idea of using oxygen ions a few years ago, when we started to consider hypoxia explicitly in treatment planning (Phys. Med. Biol. 58 3871). With various new facilities offering therapeutic ions from protons to oxygen, this is a natural thing to do."

Plan validation

To create 16O treatment plans, Sokol and colleagues used GSI's in-house treatment planning system TRiP98, updated with recent 16O beam attenuation measurements and fragmentation data for lighter ions. They verified the generated plans by measuring absorbed dose inside a water phantom using pinpoint ionization chambers.

The researchers created plans for a target at 82 mm depth, first optimizing a plan for a uniform RBE-weighted (biological) target dose of 6.5 Gy. The calculated and measured dose profiles differed by about 1.3% in the entrance channel and 2.5% in the target region. In a second plan, optimized for a flat absorbed (physical) dose of 4 Gy, measured and calculated dose profiles differed by about 1.5% in the entrance channel, 3.3% in the target and 9.2% at the distal fall-off.

Next, the team examined the survival of Chinese hamster ovary cells after irradiation with 16O ions, under normoxic (21% pO2) and anoxic (0% pO2) conditions. Measurements in normoxia agreed well with the TRiP98 predictions, while in the anoxic case, there was a slight deviation between calculated and experimental survival data. However, the difference between doses leading to 10% survival was below 5%.

The researchers also determined OER10, the oxygen enhancement ratio at 10% survival level, defined as the dose under hypoxia divided by the isoeffective dose under normoxia. Using this definition, the experimental OER10 value of 1.33±0.05 agreed well with the TRiP98 prediction of 1.27.

Applying an only RBE-weighted plan to an unevenly oxygenated target will result in different survival levels throughout the target. Thus, the team is investigating the use of kill-painting, where the optimized quantity is not RBE-weighted dose, but a specified uniform survival level in the target.

To test this approach for oxygen beams, they created a phantom with a target containing three oxygenation levels (21%, 0.5% and 0%) and used TRiP98 to perform inverse planning aimed at a uniform survival fraction in the target. The prescribed RBE-weighted target dose for the equivalent normoxic plan was 6.5 Gy, corresponding to a target survival of 10%.

Experiments confirmed the TRiP98 survival predictions in both the target and entrance channel regions, with a slight deviation seen in the intermediate hypoxic region. Comparison with a previous 12C study using the same plan parameters showed that, in this scenario, damage in the entrance channel produced by 16O ions was only slightly lower than for 12C ions for the same target cell kill.

The biggest benefit

To reveal cases where 16O may provide greater benefit over lighter ions, the team used computational analysis to compare entrance channel survival rates for different sized hypoxic regions, for 4He, 12C and 16O ions. They examined target survival levels of 6.5%, 10% and 30%, corresponding to target doses of 4, 6.5 and 7.5 Gy for normoxic plans.

In normoxic cases, entrance channel damage was lowest for 4He ions, which deliver the lowest physical dose and produce less fragments. For higher target doses, 16O increased entrance channel survival by less than 4%, and only when most of the tumour was hypoxic. Switching to heavier ions is not justified in such cases.

With a lower target dose (4 Gy), as the size of the hypoxic region grew and oxygenation decreased, the benefit of 16O ions over lighter ions increased. Here, the reduced OER outweighs the negative effect of nuclear fragmentation.

"In clinics, the doses used for fractionated therapy are around 1–3 Gy. Thus, our comparison shows that for patient treatments, [16O] could be promising," explained Sokol. "However, this analysis was performed for idealized conditions and thus we cannot say that it is generally true for any case."

The team is now performing in silico studies with patient plans for different tumours, as well as planning more verification experiments. "We are also developing a multiple-ion approach combining the benefits of several different ions in one treatment plan, to further improve healthy tissue sparing during irradiation of hypoxic tumours," said Sokol. "In our view, there is no unique choice of ion type, due to the varying geometries, tissue sensitivities and field configurations."