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Physics and biomedical challenges of cancer therapy with accelerated heavy ions


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.

Key points

  • 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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Fig. 1: Heavy ion physics.
Fig. 2: Dose-averaged linear energy transfer versus depth in tissue for a single spread-out Bragg peak of protons, He, C and O providing a uniform physical dose (2 Gy) in the target volume.
Fig. 3: Impact of lateral scattering on treatment planning.
Fig. 4: Accelerator technologies in heavy ion therapy.
Fig. 5: Biological advantages of heavy ions.
Fig. 6: The ‘best’ bullets are those providing the lowest relative biological effectiveness-weighted dose in the normal tissue at the same effect in the target.
Fig. 7: Biologically optimized multi-ion plan for a hypoxic skull base chordoma (hypoxia is assumed to be concentred in the central part of the tumour).


  1. 1.

    Wilson, R. R. Radiological use of fast protons. Radiology 47, 487–491 (1946).

    Article  Google Scholar 

  2. 2.

    Tobias, C. A. Failla Memorial lecture. The future of heavy-ion science in biology and medicine. Radiat. Res. 103, 1–33 (1985).

    ADS  Article  Google Scholar 

  3. 3.

    Durante, M. & Loeffler, J. S. Charged particles in radiation oncology. Nat. Rev. Clin. Oncol. 7, 37–43 (2010).

    Article  Google Scholar 

  4. 4.

    Castro, J. R. Results of heavy ion radiotherapy. Radiat. Environ. Biophys. 34, 45–48 (1995).

    Article  Google Scholar 

  5. 5.

    Colliez, F., Gallez, B. & Jordan, B. F. Assessing tumor oxygenation for predicting outcome in radiation oncology: a review of studies correlating tumor hypoxic status and outcome in the preclinical and clinical settings. Front. Oncol. 7, 10 (2017).

    Article  Google Scholar 

  6. 6.

    Blakely, E. A., Ngo, F., Curtis, S. & Tobias, C. A. Heavy-ion radiobiology: cellular studies. Adv. Radiat. Biol. 11, 295–389 (1984).

    Article  Google Scholar 

  7. 7.

    Tinganelli, W. & Durante, M. Carbon ion radiobiology. Cancers 12, 3022 (2020).

    Article  Google Scholar 

  8. 8.

    Tsujii, H. et al. Carbon-Ion Radiotherapy (Springer, 2014).

  9. 9.

    Kraft, G. Tumor therapy with heavy charged particles. Prog. Part. Nucl. Phys. 45, 473–544 (2000).

    ADS  Article  Google Scholar 

  10. 10.

    Thariat, J., Hannoun-Levi, J.-M., Sun Myint, A., Vuong, T. & Gérard, J.-P. Past, present, and future of radiotherapy for the benefit of patients. Nat. Rev. Clin. Oncol. 10, 52–60 (2012).

    Article  Google Scholar 

  11. 11.

    Lo, S. S. et al. Stereotactic body radiation therapy: a novel treatment modality. Nat. Rev. Clin. Oncol. 7, 44–54 (2010).

    Article  Google Scholar 

  12. 12.

    Pan, H. Y., Jiang, J., Shih, Y.-C. T. & Smith, B. D. Adoption of radiation technology among privately insured nonelderly patients with cancer in the United States, 2008 to 2014: a claims-based analysis. J. Am. Coll. Radiol. 14, 1027–1033.e2 (2017).

    Article  Google Scholar 

  13. 13.

    Waddle, M. R. et al. Photon and proton radiation therapy utilization in a population of more than 100 million commercially insured patients. Int. J. Radiat. Oncol. 99, 1078–1082 (2017).

    Article  Google Scholar 

  14. 14.

    Lievens, Y., Borras, J. M. & Grau, C. Provision and use of radiotherapy in Europe. Mol. Oncol. 14, 1461–1469 (2020).

    Article  Google Scholar 

  15. 15.

    Particle Therapy Co-Operative Group (PTCOG). Particle therapy facilities in clinical operation. PTCOG (2021).

  16. 16.

    Malouff, T. D. et al. Carbon ion therapy: a modern review of an emerging technology. Front. Oncol. 10, 82 (2020).

    Article  Google Scholar 

  17. 17.

    Beltran, C., Amos, R. A. & Rong, Y. We are ready for clinical implementation of carbon ion radiotherapy in the United States. J. Appl. Clin. Med. Phys. 21, 6–9 (2020).

    Article  Google Scholar 

  18. 18.

    Pompos, A., Durante, M. & Choy, H. Heavy ions in cancer therapy. JAMA Oncol. 2, 1539–1540 (2016).

    Article  Google Scholar 

  19. 19.

    Bortfeld, T. R. & Loeffler, J. S. Three ways to make proton therapy affordable. Nature 549, 451–453 (2017).

    ADS  Article  Google Scholar 

  20. 20.

    Jäkel, O., Smith, A. R. & Orton, C. G. The more important heavy charged particle radiotherapy of the future is more likely to be with heavy ions rather than protons. Med. Phys. 40, 090601 (2013).

    Article  Google Scholar 

  21. 21.

    Durante, M. & Debus, J. Heavy charged particles: does improved precision and higher biological effectiveness translate to better outcome in patients? Semin. Radiat. Oncol. 28, 160–167 (2018).

    Article  Google Scholar 

  22. 22.

    Rackwitz, T. & Debus, J. Clinical applications of proton and carbon ion therapy. Semin. Oncol. 46, 226–232 (2019).

    Article  Google Scholar 

  23. 23.

    Tessonnier, T. et al. Helium ions at the heidelberg ion beam therapy center: Comparisons between FLUKA Monte Carlo code predictions and dosimetric measurements. Phys. Med. Biol. 62, 6784–6803 (2017).

    Article  Google Scholar 

  24. 24.

    Kurz, C., Mairani, A. & Parodi, K. First experimental-based characterization of oxygen ion beam depth dose distributions at the Heidelberg Ion-Beam Therapy Center. Phys. Med. Biol. 57, 5017–5034 (2012).

    Article  Google Scholar 

  25. 25.

    Kopp, B. et al. Development and validation of single field multi-ion particle therapy treatments. Int. J. Radiat. Oncol. 106, 194–205 (2020).

    Article  Google Scholar 

  26. 26.

    Inaniwa, T. et al. Application of lung substitute material as ripple filter for multi-ion therapy with helium-, carbon-, oxygen-, and neon-ion beams. Phys. Med. Biol. 66, 055002 (2021).

    Article  Google Scholar 

  27. 27.

    Dokic, I. et al. Next generation multi-scale biophysical characterization of high precision cancer particle radiotherapy using clinical proton, helium-, carbon- and oxygen ion beams. Oncotarget 7, 56676–56689 (2016).

    Article  Google Scholar 

  28. 28.

    Inaniwa, T. et al. Experimental validation of stochastic microdosimetric kinetic model for multi-ion therapy treatment planning with helium-, carbon-, oxygen-, and neon-ion beams. Phys. Med. Biol. 65, 045005 (2020).

    Article  Google Scholar 

  29. 29.

    Sokol, O., Krämer, M., Hild, S., Durante, M. & Scifoni, E. Kill painting of hypoxic tumors with multiple ion beams. Phys. Med. Biol. 64, 045008 (2019).

    Article  Google Scholar 

  30. 30.

    Durante, M. & Paganetti, H. Nuclear physics in particle therapy: a review. Rep. Prog. Phys. 79, 096702 (2016).

    ADS  Article  Google Scholar 

  31. 31.

    Newhauser, W. D. & Zhang, R. The physics of proton therapy. Phys. Med. Biol. 60, R155 (2015).

    ADS  Article  Google Scholar 

  32. 32.

    Schardt, D., Elsässer, T. & Schulz-Ertner, D. Heavy-ion tumor therapy: physical and radiobiological benefits. Rev. Mod. Phys. 82, 383–425 (2010).

    ADS  Article  Google Scholar 

  33. 33.

    Bichsel, H. Stochastics of energy loss and biological effects of heavy ions in radiation therapy. Adv. Quantum Chem. 65, 1–38 (2013).

    Article  Google Scholar 

  34. 34.

    Kamakura, S., Sakamoto, N., Ogawa, H., Tsuchida, H. & Inokuti, M. Mean excitation energies for the stopping power of atoms and molecules evaluated from oscillator-strength spectra. J. Appl. Phys. 100, 064905 (2006).

    ADS  Article  Google Scholar 

  35. 35.

    Bär, E., Andreo, P., Lalonde, A., Royle, G. & Bouchard, H. Optimized I-values for use with the Bragg additivity rule and their impact on proton stopping power and range uncertainty. Phys. Med. Biol. 63, 165007 (2018).

    Article  Google Scholar 

  36. 36.

    Besemer, A., Paganetti, H. & Bednarz, B. The clinical impact of uncertainties in the mean excitation energy of human tissues during proton therapy. Phys. Med. Biol. 58, 887–902 (2013).

    Article  Google Scholar 

  37. 37.

    De Smet, V., Labarbe, R., Vander Stappen, F., Macq, B. & Sterpin, E. Reassessment of stopping power ratio uncertainties caused by mean excitation energies using a water-based formalism. Med. Phys. 45, 3361–3370 (2018).

    Article  Google Scholar 

  38. 38.

    Embriaco, A., Bellinzona, E. V., Fontana, A. & Rotondi, A. On Molière and Fermi–Eyges scattering theories in hadrontherapy. Phys. Med. Biol. 62, 6290–6303 (2017).

    Article  Google Scholar 

  39. 39.

    Ebrahimi Loushab, M., Mowlavi, A. A., Hadizadeh, M. H., Izadi, R. & Jia, S. B. Impact of various beam parameters on lateral scattering in proton and carbon-ion therapy. J. Biomed. Phys. Eng. 5, 169–176 (2015).

    Google Scholar 

  40. 40.

    Zeitlin, C. & La Tessa, C. The role of nuclear fragmentation in particle therapy and space radiation protection. Front. Oncol. 6, 65 (2016).

    Article  Google Scholar 

  41. 41.

    Lomax, A. J. Myths and realities of range uncertainty. Br. J. Radiol. 93, 20190582 (2020).

    Article  Google Scholar 

  42. 42.

    Paganetti, H. Range uncertainties in proton therapy and the role of Monte Carlo simulations. Phys. Med. Biol. 57, R99–R117 (2012).

    ADS  Article  Google Scholar 

  43. 43.

    Durante, M. & Flanz, J. Charged particle beams to cure cancer: strengths and challenges. Semin. Oncol. 46, 219–225 (2019).

    Article  Google Scholar 

  44. 44.

    Knopf, A.-C. & Lomax, A. In vivo proton range verification: a review. Phys. Med. Biol. 58, R131–R160 (2013).

    Article  Google Scholar 

  45. 45.

    Parodi, K. Vision 20/20: positron emission tomography in radiation therapy planning, delivery, and monitoring. Med. Phys. 42, 7153–7168 (2015).

    Article  Google Scholar 

  46. 46.

    Pönisch, F., Parodi, K., Hasch, B. G. & Enghardt, W. The modelling of positron emitter production and PET imaging during carbon ion therapy. Phys. Med. Biol. 49, 5217–5232 (2004).

    Article  Google Scholar 

  47. 47.

    Bauer, J. et al. Implementation and initial clinical experience of offline PET/CT-based verification of scanned carbon ion treatment. Radiother. Oncol. 107, 218–226 (2013).

    Article  Google Scholar 

  48. 48.

    Augusto, R. S. et al. An overview of recent developments in FLUKA PET tools. Phys. Med. 54, 189–199 (2018).

    Article  Google Scholar 

  49. 49.

    Durante, M. & Parodi, K. Radioactive beams in particle therapy: past, present, and future. Front. Phys. 8, 00326 (2020).

    Article  Google Scholar 

  50. 50.

    Durante, M., Golubev, A., Park, W.-Y. & Trautmann, C. Applied nuclear physics at the new high-energy particle accelerator facilities. Phys. Rep. 800, 1–37 (2019).

    ADS  MathSciNet  Article  Google Scholar 

  51. 51.

    Chacon, A. et al. Experimental investigation of the characteristics of radioactive beams for heavy ion therapy. Med. Phys. 47, 3123–3132 (2020).

    Article  Google Scholar 

  52. 52.

    Augusto, R. S. et al. New developments of 11C post-accelerated beams for hadron therapy and imaging. Nucl. Instrum. Methods Phys. Res. B 376, 374–378 (2016).

    ADS  Article  Google Scholar 

  53. 53.

    Chao, A. W. & Chou, W. Reviews of Accelerator Science and Technology. Volume 2: Medical Applications of Accelerators (World Scientific, 2009).

  54. 54.

    Farr, J. B., Flanz, J. B., Gerbershagen, A. & Moyers, M. F. New horizons in particle therapy systems. Med. Phys. 45, e953–e983 (2018).

    Article  Google Scholar 

  55. 55.

    Alonso, J. R. & Antaya, T. A. Superconductivity in medicine. Rev. Accel. Sci. Technol. 05, 227–263 (2012).

    Article  Google Scholar 

  56. 56.

    Jongen, Y. et al. Compact superconducting cyclotron C400 for hadron therapy. Nucl. Instrum. Methods Phys. Res. A 624, 47–53 (2010).

    ADS  Article  Google Scholar 

  57. 57.

    Syresin, E. M. et al. Superconducting synchrotron project for hadron therapy. Phys. Part. Nucl. Lett. 9, 202–212 (2012).

    Article  Google Scholar 

  58. 58.

    Noda, K. et al. Recent progress and future plans of heavy-ion cancer radiotherapy with HIMAC. Nucl. Instrum. Methods Phys. Res. B 406, 374–378 (2017).

    ADS  Article  Google Scholar 

  59. 59.

    Zlobin, A. V. & Schoerling, D. in Nb3Sn Accelerator Magnets. Designs, Technologies and Performance (eds. Schoerling, D. & Zlobin, A.) 3–22 (Springer, 2019).

  60. 60.

    Wan, W. et al. Alternating-gradient canted cosine theta superconducting magnets for future compact proton gantries. Phys. Rev. Spec. Top. Accel. Beams 18, 103501 (2015).

    ADS  Article  Google Scholar 

  61. 61.

    Baird, Y. T. E. & Li, Q. Optimized magnetic design of superconducting magnets for heavy ion rotating gantries. IEEE Trans. Appl. Supercond. 30, 1–8 (2020).

    Google Scholar 

  62. 62.

    Caporaso, G. J., Chen, Y.-J. & Sampayan, S. E. The dielectric wall accelerator. Rev. Accel. Sci. Technol. 02, 253–263 (2009).

    Article  Google Scholar 

  63. 63.

    Ma, W. J. et al. Laser acceleration of highly energetic carbon ions using a double-layer target composed of slightly underdense plasma and ultrathin foil. Phys. Rev. Lett. 122, 014803 (2019).

    ADS  Article  Google Scholar 

  64. 64.

    Higginson, A. et al. Near-100 MeV protons via a laser-driven transparency-enhanced hybrid acceleration scheme. Nat. Commun. 9, 724 (2018).

    ADS  Article  Google Scholar 

  65. 65.

    Ahmed, H. et al. High energy implementation of coil-target scheme for guided re-acceleration of laser-driven protons. Sci. Rep. 11, 699 (2021).

    ADS  Article  Google Scholar 

  66. 66.

    Wang, K. D. et al. Achromatic beamline design for a laser-driven proton therapy accelerator. Phys. Rev. Accel. Beams 23, 111302 (2020).

    ADS  Article  Google Scholar 

  67. 67.

    Karsch, L. et al. Towards ion beam therapy based on laser plasma accelerators. Acta Oncol. 56, 1359–1366 (2017).

    Article  Google Scholar 

  68. 68.

    Linz, U. & Alonso, J. Laser-driven ion accelerators for tumor therapy revisited. Phys. Rev. Accel. Beams 19, 124802 (2016).

    ADS  Article  Google Scholar 

  69. 69.

    Noda, K. Progress of radiotherapy technology with HIMAC. J. Phys. Conf. Ser. 1154, 012019 (2019).

    Article  Google Scholar 

  70. 70.

    Kubiak, T. Particle therapy of moving targets — the strategies for tumour motion monitoring and moving targets irradiation. Br. J. Radiol. 89, 20150275 (2016).

    Article  Google Scholar 

  71. 71.

    Bert, C. & Durante, M. Motion in radiotherapy: particle therapy. Phys. Med. Biol. 56, R113–R144 (2011).

    ADS  Article  Google Scholar 

  72. 72.

    Riboldi, M., Orecchia, P. R. & Baroni, P. G. Real-time tumour tracking in particle therapy: technological developments and future perspectives. Lancet Oncol. 13, e383–e391 (2012).

    Article  Google Scholar 

  73. 73.

    Czerska, K. et al. Clinical practice vs. state-of-the-art research and future visions: Report on the 4D treatment planning workshop for particle therapy–Edition 2018 and 2019. Phys. Med. 82, 54–63 (2021).

    Article  Google Scholar 

  74. 74.

    Graeff, C., Lüchtenborg, R., Eley, J. G., Durante, M. & Bert, C. A 4D-optimization concept for scanned ion beam therapy. Radiother. Oncol. 109, 419–424 (2013).

    Article  Google Scholar 

  75. 75.

    Iwata, Y. et al. Design of a superconducting rotating gantry for heavy-ion therapy. Phys. Rev. Spec. Top. Accel. Beams 15, 044701 (2012).

    ADS  Article  Google Scholar 

  76. 76.

    Rahim, S. et al. Upright radiation therapy — a historical reflection and opportunities for future applications. Front. Oncol. 10, 213 (2020).

    Article  Google Scholar 

  77. 77.

    Yang, J., Chu, D., Dong, L. & Court, L. E. Advantages of simulating thoracic cancer patients in an upright position. Pract. Radiat. Oncol. 4, e53–e58 (2014).

    Article  Google Scholar 

  78. 78.

    Zhang, X. et al. Development of an isocentric rotating chair positioner to treat patients of head and neck cancer at upright seated position with multiple nonplanar fields in a fixed carbon-ion beamline. Med. Phys. 47, 2450–2460 (2020).

    Article  Google Scholar 

  79. 79.

    Sheng, Y. et al. Performance of a 6D treatment chair for patient positioning in an upright posture for fixed ion beam lines. Front. Oncol. 10, 213 (2020).

    Article  Google Scholar 

  80. 80.

    Cornforth, M. N. Occam’s broom and the dirty DSB: cytogenetic perspectives on cellular response to changes in track structure and ionization density. Int. J. Radiat. Biol. 97, 1099–1108 (2020).

    Article  Google Scholar 

  81. 81.

    Stannard, C. et al. Malignant salivary gland tumours: can fast neutron therapy results point the way to carbon ion therapy? Radiother. Oncol. 109, 262–268 (2013).

    Article  Google Scholar 

  82. 82.

    Parker, C. et al. Targeted alpha therapy, an emerging class of cancer agents. JAMA Oncol. 4, 1765–1772 (2018).

    Article  Google Scholar 

  83. 83.

    Durante, M., Orecchia, R. & Loeffler, J. S. Charged-particle therapy in cancer: clinical uses and future perspectives. Nat. Rev. Clin. Oncol. 14, 483–495 (2017).

    Article  Google Scholar 

  84. 84.

    Blakely, E. A. The 20th Gray lecture 2019: health and heavy ions. Br. J. Radiol. 93, 20200172 (2020).

    Article  Google Scholar 

  85. 85.

    Fowler, J. F. 21 years of biologically effective dose. Br. J. Radiol. 83, 554–568 (2010).

    Article  Google Scholar 

  86. 86.

    Friedrich, T., Scholz, U., Elsässer, T., Durante, M. & Scholz, M. Systematic analysis of RBE and related quantities using a database of cell survival experiments with ion beam irradiation. J. Radiat. Res. 54, 494–514 (2013).

    ADS  Article  Google Scholar 

  87. 87.

    Wang, J. Z., Huang, Z., Lo, S. S., Yuh, W. T. C. & Mayr, N. A. A generalized linear-quadratic model for radiosurgery, stereotactic body radiation therapy, and high-dose rate brachytherapy. Sci. Transl. Med. 2, 39ra48 (2010).

    Article  Google Scholar 

  88. 88.

    Takahashi, Y. et al. Heavy ion irradiation inhibits in vitro angiogenesis even at sublethal dose. Cancer Res. 63, 4253–4257 (2003).

    Google Scholar 

  89. 89.

    Liu, Y. et al. Effects of carbon-ion beam irradiation on the angiogenic response in lung adenocarcinoma A549 cells. Cell Biol. Int. 38, 1304–1310 (2014).

    Article  Google Scholar 

  90. 90.

    Konings, K., Vandevoorde, C., Baselet, B., Baatout, S. & Moreels, M. Combination therapy with charged particles and molecular targeting: a promising avenue to overcome radioresistance. Front. Oncol. 10, 128 (2020).

    Article  Google Scholar 

  91. 91.

    Durante, M., Brenner, D. J. & Formenti, S. C. Does heavy ion therapy work through the immune system? Int. J. Radiat. Oncol. Biol. Phys. 96, 934–936 (2016).

    Article  Google Scholar 

  92. 92.

    Wulf, H. et al. Heavy-ion effects on mammalian cells: inactivation measurements with different cell lines. Radiat. Res. 104, 122–134 (1985).

    Article  Google Scholar 

  93. 93.

    ICRU Report 93: Prescribing, Recording, and Reporting Light Ion Beam Therapy. J. ICRU 16 (2016).

  94. 94.

    Inaniwa, T. et al. Treatment planning for a scanned carbon beam with a modified microdosimetric kinetic model. Phys. Med. Biol. 55, 6721–6737 (2010).

    Article  Google Scholar 

  95. 95.

    Grün, R. et al. Impact of enhancements in the local effect model (LEM) on the predicted RBE-weighted target dose distribution in carbon ion therapy. Phys. Med. Biol. 57, 7261–7274 (2012).

    Article  Google Scholar 

  96. 96.

    Tommasino, F. & Durante, M. Proton radiobiology. Cancers 7, 353–381 (2015).

    Article  Google Scholar 

  97. 97.

    Paganetti, H. Relative biological effectiveness (RBE) values for proton beam therapy. Variations as a function of biological endpoint, dose, and linear energy transfer. Phys. Med. Biol. 59, R419–R472 (2014).

    ADS  Article  Google Scholar 

  98. 98.

    Mutter, R. W. et al. Incorporation of biologic response variance modeling into the clinic: limiting risk of brachial plexopathy and other late effects of breast cancer proton beam therapy. Pract. Radiat. Oncol. 10, e71–e81 (2020).

    Article  Google Scholar 

  99. 99.

    Zhang, L., Wang, W., Hu, J., Lu, J. & Kong, L. RBE-weighted dose conversions for patients with recurrent nasopharyngeal carcinoma receiving carbon-ion radiotherapy from the local effect model to the microdosimetric kinetic model. Radiat. Oncol. 15, 277 (2020).

    Article  Google Scholar 

  100. 100.

    Wang, W. et al. RBE-weighted dose conversions for carbon ionradiotherapy between microdosimetric kinetic model and local effect model for the targets and organs at risk in prostate carcinoma. Radiother. Oncol. 144, 30–36 (2020).

    Article  Google Scholar 

  101. 101.

    Molinelli, S. et al. Dose prescription in carbon ion radiotherapy: How to compare two different RBE-weighted dose calculation systems. Radiother. Oncol. 120, 307–312 (2016).

    Article  Google Scholar 

  102. 102.

    Fossati, P., Matsufuji, N., Kamada, T. & Karger, C. P. Radiobiological issues in prospective carbon ion therapy trials. Med. Phys. 45, e1096–e1110 (2018).

    Article  Google Scholar 

  103. 103.

    Friedrich, T., Scholz, U., Durante, M. & Scholz, M. RBE of ion beams in hypofractionated radiotherapy (SBRT). Phys. Med. 30, 588–591 (2014).

    Article  Google Scholar 

  104. 104.

    Yoshida, Y. et al. Evaluation of therapeutic gain for fractionated carbon-ion radiotherapy using the tumor growth delay and crypt survival assays. Radiother. Oncol. 117, 351–357 (2015).

    Article  Google Scholar 

  105. 105.

    Chapman, J. D. Can the two mechanisms of tumor cell killing by radiation be exploited for therapeutic gain? J. Radiat. Res. 55, 2–9 (2014).

    ADS  Article  Google Scholar 

  106. 106.

    Laine, A. M. et al. The role of hypofractionated radiation therapy with photons, protons, and heavy ions for treating extracranial lesions. Front. Oncol. 5, 302 (2016).

    Article  Google Scholar 

  107. 107.

    Barker, H. E., Paget, J. T. E., Khan, A. A. & Harrington, K. J. The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat. Rev. Cancer 15, 409–425 (2015).

    Article  Google Scholar 

  108. 108.

    Strigari, L., Benassi, M., Sarnelli, A., Polico, R. & D’Andrea, M. A modified hypoxia-based TCP model to investigate the clinical outcome of stereotactic hypofractionated regimes for early stage non-small-cell lung cancer (NSCLC). Med. Phys. 39, 4502–4514 (2012).

    Article  Google Scholar 

  109. 109.

    Toma-Dasu, I., Sandström, H., Barsoum, P. & Dasu, A. To fractionate or not to fractionate? That is the question for the radiosurgery of hypoxic tumors. J. Neurosurg. 121, 110–115 (2014).

    Article  Google Scholar 

  110. 110.

    McKeown, S. R. Defining normoxia, physoxia and hypoxia in tumours — implications for treatment response. Br. J. Radiol. 87, 20130676 (2014).

    Article  Google Scholar 

  111. 111.

    Furusawa, Y. et al. Inactivation of aerobic and hypoxic cells from three different cell lines by accelerated (3)He-, (12)C- and (20)Ne-ion beams. Radiat. Res. 154, 485–496 (2000).

    ADS  Article  Google Scholar 

  112. 112.

    Tinganelli, W. et al. Kill-painting of hypoxic tumours in charged particle therapy. Sci. Rep. 5, 17016 (2015).

    ADS  Article  Google Scholar 

  113. 113.

    Grassberger, C., Ellsworth, S. G., Wilks, M. Q., Keane, F. K. & Loeffler, J. S. Assessing the interactions between radiotherapy and antitumour immunity. Nat. Rev. Clin. Oncol. 16, 729–745 (2019).

    Article  Google Scholar 

  114. 114.

    Durante, M. et al. X-rays vs. carbon-ion tumor therapy: cytogenetic damage in lymphocytes. Int. J. Radiat. Oncol. Biol. Phys. 47, 793–798 (2000).

    Article  Google Scholar 

  115. 115.

    Durante, M. & Formenti, S. Harnessing radiation to improve immunotherapy: better with particles? Br. J. Radiol. 93, 20190224 (2020).

    Article  Google Scholar 

  116. 116.

    Davuluri, R. et al. Lymphocyte nadir and esophageal cancer survival outcomes after chemoradiation therapy. Int. J. Radiat. Oncol. 99, 128–135 (2017).

    Article  Google Scholar 

  117. 117.

    Mohan, R. et al. Proton therapy reduces the likelihood of high-grade radiation-induced lymphopenia in glioblastoma patients: phase II randomized study of protons vs photons. Neuro. Oncol. 23, 284–294 (2021).

    Article  Google Scholar 

  118. 118.

    Kim, N. et al. Proton beam therapy reduces the risk of severe radiation-induced lymphopenia during chemoradiotherapy for locally advanced non-small cell lung cancer: a comparative analysis of proton versus photon therapy. Radiother. Oncol. 156, 166–173 (2021).

    Article  Google Scholar 

  119. 119.

    Takahashi, Y. et al. Carbon ion irradiation enhances the antitumor efficacy of dual immune checkpoint blockade therapy both for local and distant sites in murine osteosarcoma. Oncotarget 10, 633–646 (2019).

    Article  Google Scholar 

  120. 120.

    Helm, A. et al. Reduction of lung metastases in a mouse osteosarcoma model treated with carbon ions and immune checkpoint inhibitors. Int. J. Radiat. Oncol. 109, 594–602 (2021).

    Article  Google Scholar 

  121. 121.

    Marcus, D. et al. Charged particle and conventional radiotherapy: current implications as partner for immunotherapy. Cancers 13, 1468 (2021).

    Article  Google Scholar 

  122. 122.

    Friedrich, T., Henthorn, N. & Durante, M. Modeling radioimmune response — current status and perspectives. Front. Oncol. 11, 647272 (2021).

    Article  Google Scholar 

  123. 123.

    Wang, Z. et al. Charged particle radiation therapy for uveal melanoma: a systematic review and meta-analysis. Int. J. Radiat. Oncol. 86, 18–26 (2013).

    Article  Google Scholar 

  124. 124.

    Mishra, K. K. et al. Long-term results of the UCSF-LBNL randomized trial: charged particle with helium ion versus iodine-125 plaque therapy for choroidal and ciliary body melanoma. Int. J. Radiat. Oncol. Biol. Phys. 92, 376–383 (2015).

    Article  Google Scholar 

  125. 125.

    Kamada, T. et al. Carbon ion radiotherapy in Japan: an assessment of 20 years of clinical experience. Lancet Oncol. 16, e93–e100 (2015).

    Article  Google Scholar 

  126. 126.

    Shinoto, M. et al. Carbon ion radiation therapy with concurrent gemcitabine for patients with locally advanced pancreatic cancer. Int. J. Radiat. Oncol. Biol. Phys. 95, 498–504 (2016).

    Article  Google Scholar 

  127. 127.

    Kawashiro, S. et al. Multi-institutional study of carbon-ion radiotherapy for locally advanced pancreatic cancer: Japan Carbon-ion Radiation Oncology Study Group (J-CROS) study 1403 pancreas. Int. J. Radiat. Oncol. 101, 1212–1221 (2018).

    Article  Google Scholar 

  128. 128.

    Nevala-Plagemann, C., Hidalgo, M. & Garrido-Laguna, I. From state-of-the-art treatments to novel therapies for advanced-stage pancreatic cancer. Nat. Rev. Clin. Oncol. 17, 108–123 (2020).

    Article  Google Scholar 

  129. 129.

    Yamasaki, A., Yanai, K. & Onishi, H. Hypoxia and pancreatic ductal adenocarcinoma. Cancer Lett. 484, 9–15 (2020).

    Article  Google Scholar 

  130. 130.

    Ho, W. J., Jaffee, E. M. & Zheng, L. The tumour microenvironment in pancreatic cancer — clinical challenges and opportunities. Nat. Rev. Clin. Oncol. 17, 527–540 (2020).

    Article  Google Scholar 

  131. 131.

    Huart, C., Chen, J., Le Calvé, B., Michiels, C. & Wéra, A.-C. Could protons and carbon ions be the silver bullets against pancreatic cancer? Int. J. Mol. Sci. 21, 4767 (2020).

    Article  Google Scholar 

  132. 132.

    Liermann, J. et al. Carbon ion radiotherapy in pancreatic cancer: a review of clinical data. Radiother. Oncol. 147, 145–150 (2020).

    Article  Google Scholar 

  133. 133.

    Dreher, C., Habermehl, D., Jäkel, O. & Combs, S. E. Effective radiotherapeutic treatment intensification in patients with pancreatic cancer: higher doses alone, higher RBE or both? Radiat. Oncol. 12, 203 (2017).

    Article  Google Scholar 

  134. 134.

    Shinoto, M. et al. Carbon-ion radiotherapy for locally recurrent rectal cancer: Japan Carbon-ion Radiation Oncology Study Group (J-CROS) study 1404 rectum. Radiother. Oncol. 132, 236–240 (2019).

    Article  Google Scholar 

  135. 135.

    Cai, X. et al. The role of carbon ion radiotherapy for unresectable locally recurrent rectal cancer: a single institutional experience. Radiat. Oncol. 15, 209 (2020).

    Article  Google Scholar 

  136. 136.

    Habermehl, D. et al. Reirradiation using carbon ions in patients with locally recurrent rectal cancer at HIT: first results. Ann. Surg. Oncol. 22, 2068–2074 (2015).

    Article  Google Scholar 

  137. 137.

    Guren, M. G. et al. Reirradiation of locally recurrent rectal cancer: a systematic review. Radiother. Oncol. 113, 151–157 (2014).

    Article  Google Scholar 

  138. 138.

    Venkatesulu, B. P., Giridhar, P., Malouf, T. D., Trifletti, D. M. & Krishnan, S. A systematic review of the role of carbon ion radiation therapy in recurrent rectal cancer. Acta Oncol. 59, 1218–1223 (2020).

    Article  Google Scholar 

  139. 139.

    Imada, H. et al. Comparison of efficacy and toxicity of short-course carbon ion radiotherapy for hepatocellular carcinoma depending on their proximity to the porta hepatis. Radiother. Oncol. 96, 231–235 (2010).

    Article  Google Scholar 

  140. 140.

    Qi, W.-X., Fu, S., Zhang, Q. & Guo, X.-M. Charged particle therapy versus photon therapy for patients with hepatocellular carcinoma: a systematic review and meta-analysis. Radiother. Oncol. 114, 289–295 (2015).

    Article  Google Scholar 

  141. 141.

    Habermehl, D. et al. Hypofractionated carbon ion therapy delivered with scanned ion beams for patients with hepatocellular carcinoma–feasibility and clinical response. Radiat. Oncol. 8, 59 (2013).

    Article  Google Scholar 

  142. 142.

    Shibuya, K. et al. A feasibility study of high-dose hypofractionated carbon ion radiation therapy using four fractions for localized hepatocellular carcinoma measuring 3 cm or larger. Radiother. Oncol. 132, 230–235 (2019).

    Article  Google Scholar 

  143. 143.

    Chauvel, P. Osteosarcomas and adult soft tissue sarcomas: is there a place for high LET radiation therapy? Ann. Oncol. 3, S107–S110 (1992).

    Article  Google Scholar 

  144. 144.

    Strander, H., Turesson, I. & Cavallin-ståhl, E. A systematic overview of radiation therapy effects in soft tissue sarcomas. Acta Oncol. 42, 516–531 (2003).

    Article  Google Scholar 

  145. 145.

    Weber, D. C. et al. Profile of European proton and carbon ion therapy centers assessed by the EORTC facility questionnaire. Radiother. Oncol. 124, 185–189 (2017).

    Article  Google Scholar 

  146. 146.

    Matsunobu, A. et al. Impact of carbon ion radiotherapy for unresectable osteosarcoma of the trunk. Cancer 118, 4555–4563 (2012).

    Article  Google Scholar 

  147. 147.

    Kamada, T. et al. Efficacy and safety of carbon ion radiotherapy in bone and soft tissue sarcomas. J. Clin. Oncol. 20, 4466–4471 (2002).

    Article  Google Scholar 

  148. 148.

    Cuccia, F. et al. Outcome and toxicity of carbon ion radiotherapy for axial bone and soft tissue sarcomas. Anticancer Res. 40, 2853–2859 (2020).

    Article  Google Scholar 

  149. 149.

    Seidensaal, K. et al. The role of combined ion-beam radiotherapy (CIBRT) with protons and carbon ions in a multimodal treatment strategy of inoperable osteosarcoma. Radiother. Oncol. 159, 8–16 (2021).

    Article  Google Scholar 

  150. 150.

    Uhl, M. et al. Highly effective treatment of skull base chordoma with carbon ion irradiation using a raster scan technique in 155 patients: first long-term results. Cancer 120, 3410–3417 (2014).

    Article  Google Scholar 

  151. 151.

    Mattke, M. et al. High control rates of proton- and carbon-ion-beam treatment with intensity-modulated active raster scanning in 101 patients with skull base chondrosarcoma at the Heidelberg Ion Beam Therapy Center. Cancer 124, 2036–2044 (2018).

    Article  Google Scholar 

  152. 152.

    Nikoghosyan, A. V. et al. Randomised trial of proton vs. carbon ion radiation therapy in patients with low and intermediate grade chondrosarcoma of the skull base, clinical phase III study. BMC Cancer 10, 606 (2010).

    Article  Google Scholar 

  153. 153.

    Cramer, J. D., Burtness, B., Le, Q. T. & Ferris, R. L. The changing therapeutic landscape of head and neck cancer. Nat. Rev. Clin. Oncol. 16, 669–683 (2019).

    Article  Google Scholar 

  154. 154.

    Akbaba, S. et al. Bimodal radiotherapy with active raster-scanning carbon ion radiotherapy and intensity-modulated radiotherapy in high-risk nasopharyngeal carcinoma results in excellent local control. Cancers 11, 379 (2019).

    Article  Google Scholar 

  155. 155.

    Shirai, K. et al. Prospective observational study of carbon-ion radiotherapy for non-squamous cell carcinoma of the head and neck. Cancer Sci. 108, 2039–2044 (2017).

    Article  Google Scholar 

  156. 156.

    Högerle, B. A. et al. Primary adenoid cystic carcinoma of the trachea: clinical outcome of 38 patients after interdisciplinary treatment in a single institution. Radiat. Oncol. 14, 117 (2019).

    Article  Google Scholar 

  157. 157.

    Kong, L. et al. Phase I/II trial evaluating carbon ion radiotherapy for salvaging treatment of locally recurrent nasopharyngeal carcinoma. J. Cancer 7, 774–783 (2016).

    Article  Google Scholar 

  158. 158.

    Baumann, B. C. et al. Comparative effectiveness of proton vs photon therapy as part of concurrent chemoradiotherapy for locally advanced cancer. JAMA Oncol. 6, 237–246 (2020).

    Article  Google Scholar 

  159. 159.

    Li, X. et al. Toxicity profiles and survival outcomes among patients with nonmetastatic nasopharyngeal carcinoma treated with intensity-modulated proton therapy vs intensity-modulated radiation therapy. JAMA Netw. Open 4, e2113205 (2021).

    Article  Google Scholar 

  160. 160.

    Gondi, V., Yock, T. I. & Mehta, M. P. Proton therapy for paediatric CNS tumours — improving treatment-related outcomes. Nat. Rev. Neurol. 12, 334–345 (2016).

    Article  Google Scholar 

  161. 161.

    Newhauser, W. D. & Durante, M. Assessing the risk of second malignancies after modern radiotherapy. Nat. Rev. Cancer 11, 438–448 (2011).

    Article  Google Scholar 

  162. 162.

    Rieber, J. G. et al. Treatment tolerance of particle therapy in pediatric patients. Acta Oncol. 54, 1049–1055 (2015).

    Article  Google Scholar 

  163. 163.

    Mohamad, O. et al. Risk of subsequent primary cancers after carbon ion radiotherapy, photon radiotherapy, or surgery for localised prostate cancer: a propensity score-weighted, retrospective, cohort study. Lancet Oncol. 20, 674–685 (2019).

    Article  Google Scholar 

  164. 164.

    Ohno, T. & Okamoto, M. Carbon ion radiotherapy as a treatment modality for paediatric cancers. Lancet Child Adolesc. Health 3, 371–372 (2019).

    Article  Google Scholar 

  165. 165.

    Knäusl, B., Fuchs, H., Dieckmann, K. & Georg, D. Can particle beam therapy be improved using helium ions? – A planning study focusing on pediatric patients. Acta Oncol. 55, 751–759 (2016).

    Article  Google Scholar 

  166. 166.

    Horst, F. et al. Physical characterization of 3He ion beams for radiotherapy and comparison with 4He. Phys. Med. Biol. 66, 095009 (2021).

    Article  Google Scholar 

  167. 167.

    Tommasino, F., Scifoni, E. & Durante, M. New ions for therapy. Int. J. Part. Ther. 2, 428–438 (2015).

    Article  Google Scholar 

  168. 168.

    Scifoni, E. et al. Including oxygen enhancement ratio in ion beam treatment planning: model implementation and experimental verification. Phys. Med. Biol. 58, 3871–3895 (2013).

    Article  Google Scholar 

  169. 169.

    Sokol, O. et al. Oxygen beams for therapy: advanced biological treatment planning and experimental verification. Phys. Med. Biol. 62, 7798–7813 (2017).

    Article  Google Scholar 

  170. 170.

    Hagiwara, Y. et al. Influence of dose-averaged linear energy transfer on tumour control after carbon-ion radiation therapy for pancreatic cancer. Clin. Transl. Radiat. Oncol. 21, 19–24 (2020).

    Article  Google Scholar 

  171. 171.

    Matsumoto, S. et al. Unresectable chondrosarcomas treated with carbon ion radiotherapy: relationship between dose-averaged linear energy transfer and local recurrence. Anticancer Res. 40, 6429–6435 (2020).

    Article  Google Scholar 

  172. 172.

    Bassler, N. et al. LET-painting increases tumour control probability in hypoxic tumours. Acta Oncol. 53, 25–32 (2014).

    Article  Google Scholar 

  173. 173.

    Bassler, N., Jäkel, O., Søndergaard, C. S. & Petersen, J. B. Dose- and LET-painting with particle therapy. Acta Oncol. 49, 1170–1176 (2010).

    Article  Google Scholar 

  174. 174.

    Ebner, D. K., Frank, S. J., Inaniwa, T., Yamada, S. & Shirai, T. The emerging potential of multi-ion radiotherapy. Front. Oncol. 11, 624786 (2021).

    Article  Google Scholar 

  175. 175.

    Inaniwa, T., Kanematsu, N., Noda, K. & Kamada, T. Treatment planning of intensity modulated composite particle therapy with dose and linear energy transfer optimization. Phys. Med. Biol. 62, 5180–5197 (2017).

    Article  Google Scholar 

  176. 176.

    Horsman, M. R. et al. Imaging hypoxia to improve radiotherapy outcome. Nat. Rev. Clin. Oncol. 9, 674–687 (2012).

    Article  Google Scholar 

  177. 177.

    Mazal, A. et al. FLASH and minibeams in radiation therapy: the effect of microstructures on time and space and their potential application to protontherapy. Br. J. Radiol. 93, 20190807 (2020).

    Article  Google Scholar 

  178. 178.

    Favaudon, V. et al. Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice. Sci. Transl. Med. 6, 245ra93 (2014).

    Article  Google Scholar 

  179. 179.

    Vozenin, M. C. et al. The advantage of FLASH radiotherapy confirmed in mini-pig and cat-cancer patients. Clin. Cancer Res. 25, 35–42 (2019).

    Article  Google Scholar 

  180. 180.

    Montay-Gruel, P. et al. Hypofractionated FLASH-RT as an effective treatment against glioblastoma that reduces neurocognitive side effects in mice. Clin. Cancer Res. 27, 775–784 (2021).

    Article  Google Scholar 

  181. 181.

    Di Martino, F. et al. FLASH radiotherapy with electrons: issues related to the production, monitoring, and dosimetric characterization of the beam. Front. Phys. 8, 570697 (2020).

    Article  Google Scholar 

  182. 182.

    Jolly, S., Owen, H., Schippers, M. & Welsch, C. Technical challenges for FLASH proton therapy. Phys. Med. 78, 71–82 (2020).

    Article  Google Scholar 

  183. 183.

    Zakaria, A. M. et al. Ultra-high dose-rate, pulsed (FLASH) radiotherapy with carbon ions: generation of early, transient, highly oxygenated conditions in the tumor environment. Radiat. Res. 194, 587–593 (2020).

    Article  Google Scholar 

  184. 184.

    Vozenin, M.-C., Montay-Gruel, P., Limoli, C. & Germond, J.-F. All irradiations that are ultra-high dose rate may not be FLASH: the critical importance of beam parameter characterization and in vivo validation of the FLASH effect. Radiat. Res. 194, 571–572 (2020).

    Article  Google Scholar 

  185. 185.

    Rothwell, B. C. et al. Determining the parameter space for effective oxygen depletion for FLASH radiation therapy. Phys. Med. Biol. 66, 055020 (2021).

    Article  Google Scholar 

  186. 186.

    Chaudhary, P. et al. Radiobiology experiments with ultra-high dose rate laser-driven protons: methodology and state-of-the-art. Front. Phys. 9, 624963 (2021).

    Article  Google Scholar 

  187. 187.

    Bourhis, J. et al. Treatment of a first patient with FLASH-radiotherapy. Radiother. Oncol. 139, 18–22 (2019).

    Article  Google Scholar 

  188. 188.

    Pratx, G. & Kapp, D. S. A computational model of radiolytic oxygen depletion during FLASH irradiation and its effect on the oxygen enhancement ratio. Phys. Med. Biol. 64, 185005 (2019).

    Article  Google Scholar 

  189. 189.

    Labarbe, R., Hotoiu, L., Barbier, J. & Favaudon, V. A physicochemical model of reaction kinetics supports peroxyl radical recombination as the main determinant of the FLASH effect. Radiother. Oncol. 153, 303–310 (2020).

    Article  Google Scholar 

  190. 190.

    Jansen, J. et al. Does FLASH deplete oxygen? Experimental evaluation for photons, protons, and carbon ions. Med. Phys. 48, 3982–3990 (2021).

    Article  Google Scholar 

  191. 191.

    Boscolo, D., Scifoni, E., Durante, M., Krämer, M. & Fuss, M. C. May oxygen depletion explain the FLASH effect? A chemical track structure analysis. Radiother. Oncol. 162, 68–75 (2021).

    Article  Google Scholar 

  192. 192.

    Weber, U., Scifoni, E. & Durante, M. FLASH radiotherapy with carbon ion beams. Med. Phys. (2021).

    Article  Google Scholar 

  193. 193.

    Schültke, E. et al. Microbeam radiation therapy — grid therapy and beyond: a clinical perspective. Br. J. Radiol. 90, 20170073 (2017).

    Article  Google Scholar 

  194. 194.

    Lamirault, C. et al. Short and long-term evaluation of the impact of proton minibeam radiation therapy on motor, emotional and cognitive functions. Sci. Rep. 10, 13511 (2020).

    ADS  Article  Google Scholar 

  195. 195.

    Billena, C. & Khan, A. J. A current review of spatial fractionation: back to the future. Int. J. Radiat. Oncol. 104, 177–187 (2019).

    Article  Google Scholar 

  196. 196.

    Dilmanian, F. A. et al. Interlaced x-ray microplanar beams: a radiosurgery approach with clinical potential. Proc. Natl Acad. Sci. USA 103, 9709–9714 (2006).

    ADS  Article  Google Scholar 

  197. 197.

    Dilmanian, F. A. et al. Interleaved carbon minibeams: an experimental radiosurgery method with clinical potential. Int. J. Radiat. Oncol. Biol. Phys. 84, 514–519 (2012).

    Article  Google Scholar 

  198. 198.

    González, W. & Prezado, Y. Spatial fractionation of the dose in heavy ions therapy: an optimization study. Med. Phys. 45, 2620–2627 (2018).

    Article  Google Scholar 

  199. 199.

    Prezado, Y. et al. A potential renewed use of very heavy ions for therapy: neon minibeam radiation therapy. Cancers 12, 1356 (2021).

    Article  Google Scholar 

  200. 200.

    Kirkby, K. J. et al. Heavy charged particle beam therapy and related new radiotherapy technologies: the clinical potential, physics and technical developments required to deliver benefit for patients with cancer. Br. J. Radiol. 93, 20200247 (2020).

    Article  Google Scholar 

  201. 201.

    Kramer, M. et al. Helium ions for radiotherapy? Physical and biological verifications of a novel treatment modality. Med. Phys. 43, 1995–2004 (2016).

    Article  Google Scholar 

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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).

Review criteria

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 website with the keywords ‘heavy ions’, ‘carbon ions’, ‘comparative’, ‘randomized’ and ‘phase III’. The website was used for the latest statistics on particle therapy.

Author information




M.D. produced the first draft. J.D. and J.S.L. worked on the biological and clinical sections. All authors edited and modified the manuscript.

Corresponding author

Correspondence to Marco Durante.

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Competing interests

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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Nature Reviews Physics thanks Hywel Owen, Eleanor Blakely and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Track structure in biology.

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.

Differences in the DNA lesion distribution between X-rays and heavy ions.

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.

The principle of pencil beam scanning in particle therapy.

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).

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