Radiotherapy should have low toxicity in the entrance channel (normal tissue) and be very effective in cell killing in the target region (tumour). In this regard, ions heavier than protons have both physical and radiobiological advantages over conventional X-rays. Carbon ions represent an excellent combination of physical and biological advantages. There are a dozen carbon-ion clinical centres in Europe and Asia, and more under construction or at the planning stage, including the first in the USA. Clinical results from Japan and Germany are promising, but a heated debate on the cost-effectiveness is ongoing in the clinical community, owing to the larger footprint and greater expense of heavy ion facilities compared with proton therapy centres. We review here the physical basis and the clinical data with carbon ions and the use of different ions, such as helium and oxygen. Research towards smaller and cheaper machines with more effective beam delivery is necessary to make particle therapy affordable. The potential of heavy ions has not been fully exploited in clinics and, rather than there being a single ‘silver bullet’, different particles and their combination can provide a breakthrough in radiotherapy treatments in specific cases.
Charged particle therapy is the most advanced radiotherapy technique.
Most of the patients are treated with protons, but heavy ions present additional biological advantages.
Carbon-ion therapy is ongoing in 12 centres worldwide and clinical results are promising, whereas new ions (like 4He and 16O) will be used in the future.
Heavy ion therapy is much more expensive than X-ray therapy and level 1 evidence of superiority is missing.
Radiobiology suggests that heavy ions can be exquisitely effective against hypoxic tumours and improve the effects of immunotherapy.
Rather than a ‘silver bullet’, different particles and their combination can provide optimal results in specific cases.
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The authors thank Uli Weber, Emanuele Scifoni, Olga Sokol, Daria Boscolo, Burkhard Jakob, Anastasiia Quarz, Koji Noda and Elena Benedetto for their precious assistance in the preparation of the figures. The research activities at GSI and Heidelberg Ion Beam Therapy Center (HIT) are partly supported by the EU Horizon 2020 research and innovation programme under grant agreement no. 101008548 (HITRIplus). Projects on innovative beam delivery at GSI are supported by ERC advanced grant 2020 number 883425 (BARB).
The authors searched PubMed and Scopus using the keywords ‘heavy ions’, ‘carbon ions’, ‘clinical trials’ and ‘comparative’, and selected the period from 2016, considering our previous reviews on the topic21,83. We also searched the ClinicalTrials.gov website with the keywords ‘heavy ions’, ‘carbon ions’, ‘comparative’, ‘randomized’ and ‘phase III’. The website www.ptcog.ch was used for the latest statistics on particle therapy.
M.D. has no conflict of interest. J.S.L. is co-chair of the medical advisory board at Mevion. J.D. received grants from several companies and attended advisory board meetings of Merck KGaA (Darmstadt).
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Supplementary video 1 | A heavy ion track (uranium 750 MeV/n), simulated with the Monte Carlo code TRAX, is overlaid to a live cell imaging movie of U2OS osteosarcoma cells labeled with NBS1-GFP protein. NBS1 (Nijmegen breakage syndrome) is a gene involved in DNA double strand break (DSB) repair. While in the simulation every dot correspond to a ionization event, in the movie the accumulation of the fluorescent protein (time lapse 0-15 min) correspond to the protein recruitment to sites of DNA DSBs, clearly along the track- However, high-energy electrons (δ-rays) are also produced by high-energy heavy ions, and they can hit neighboring cells, as shown in the bottom nucleus, where sporadic DSBs are evident. Movie from the GSI collection, distributed with permission.
Supplementary video 2 | The live cell imaging movies show human osteosarcoma U2OS cells irradiated labelled with (A) 53BP1-GFP or (B) NBS1-GFP and exposed to (A) X-rays or (B) heavy ions (two separate iron ions 1 GeV/n). Both 53BP1 and NBS1 are involved in DNA DSB repair. The movie shows the fast recruitment of the repair proteins to the DNA DSB sites that are uniformly distributed in the nucleus after X-rays (A), but mostly distributed along the tracks for heavy ions (B). Movie from the GSI collection, distributed with permission.
Supplementary video 3 | The therapy is divided in thin slices, and every slice is scanned with a small pencil beam using magnetic deflection in the XY plane. Changing the energy, the beam is moved to the next slice on the Z-axis, and scanned again. Movie produced by GSI press office, distributed with permission.
Reduced oxygen supply in a tissue compared with the normal level (normoxia or physioxia). Tumours are typically hypoxic.
- Linear energy transfer
Energy loss of charged particles per unit track length (see Eq. 1).
- Entrance channel
The normal tissue volume traversed by the therapeutic beam before reaching the target region (tumour).
- Spread-out Bragg peak
The monoenergetic beam Bragg peak is too narrow to cover a tumour volume. It must, therefore, be enlarged to provide a uniform biological dose to the target volume.
- Track structure
The complete set of ionizations and excitation events caused by a charged particle traversing a medium. Energy is deposited either directly by the traversing ion or by the high-energy electrons emitted by target atom ionization (δ-rays — see Supplementary Video 1).
- Conformal radiotherapy
A delivery system that shapes the radiation beams to match the shape of the tumour.
Variation in the range of a particle beam caused by the stochastic nature of the energy loss process.
- Dose halo
Energy deposited due to scattering in the volume immediately surrounding the target.
- Treatment planning
The calculation of the optimal beam directions, energies and intensities to achieve the highest possible dose to the tumour while sparing organs at risk and reducing unnecessary dose to the normal tissue.
Reduction of the number of fractions and increase of the dose per fraction compared with the conventional radiotherapy scheme (2 Gy per fraction in 20–30 fractions, one fraction per day).
Radius of the circular motion of a charged particle in the presence of a uniform magnetic field.
Impact of the magnetic field on the trajectory of a charged particle (Eq. 5).
- Passive modulation systems
Systems to produce spread-out Bragg peak from a monoenergetic beam using passive scatterers with different techniques, such as a rotating wheel of different techniques or a scatterer with a collimator and a patient-specific compensator.
- Targeted radioimmunotherapy
Cancer therapy that uses a targeting construct (e.g. antibody, peptides or nanoparticles), attached to a radionuclide, to deliver a systemic cytotoxic dose of radiation to malignant tissue.
Hypoxic sub-volumes in cancers are radioresistant. During the interval between fractions, the blood can reach the hypoxic niches that survived the previous fraction, making them radiosensitive.
- Second cancers
Malignant neoplasias induced by the treatment to a primary tumour.
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Durante, M., Debus, J. & Loeffler, J.S. Physics and biomedical challenges of cancer therapy with accelerated heavy ions. Nat Rev Phys (2021). https://doi.org/10.1038/s42254-021-00368-5