Review Article | Published:

Charged-particle therapy in cancer: clinical uses and future perspectives

Nature Reviews Clinical Oncology volume 14, pages 483495 (2017) | Download Citation


Radiotherapy with high-energy charged particles has become an attractive therapeutic option for patients with several tumour types because this approach better spares healthy tissue from radiation than conventional photon therapy. The cost associated with the delivery of charged particles, however, is higher than that of even the most elaborate photon-delivery technologies. Reliable evidence of the relative cost-effectiveness of both modalities can only come from the results of randomized clinical trials. Thus, the hurdles that currently limit direct comparisons of these two approaches in clinical trials, especially those related to insurance coverage, should be removed. Herein, we review several randomized trials of charged-particle therapies that are ongoing, with results that will enable selective delivery to patients who are most likely to benefit from them. We also discuss aspects related to radiobiology, including the immune response and hypoxia, which will need to be taken into consideration in future randomized trials to fully exploit the potential of charged particles.

Key points

  • Owing to their physical properties, the therapeutic use of charged particles in radiotherapy is advantageous over photon-based radiotherapy

  • The delivery of charged particles is more costly than that of X-rays, with no level 1 evidence currently indicating clinical superiority of either approach

  • Randomized trials are essential to establish the clinical benefit derived from charged-particle therapy; several studies are currently ongoing worldwide

  • The design of clinical trials for the comparison of different radiotherapy modalities is very complex; careful patient selection is essential to obtaining meaningful results

  • The criteria for patient selection for radiotherapy trials need to take dosimetric and radiobiological considerations into account

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We thank Kristjan Anderle, Annabelle Becker, Anthony Magliari, and Emanuele Scifoni for their assistance with figures. We are also grateful to Noah Chan Choi and David Grosshans for providing useful information on the clinical trials on lung.

Author information


  1. Trento Institute for Fundamental Physics and Applications (TIFPA), National Institute of Nuclear Physics (INFN), University of Trento, Via Sommarive 14, 38123 Povo, Trento, Italy.

    • Marco Durante
  2. Department of Physics, University Federico II, Monte S. Angelo, Via Cintia, 80126 Naples, Italy.

    • Marco Durante
  3. National Center of Oncological Hadrontherapy (CNAO), Strada dei Campeggi 53, 27100 Pavia, Italy.

    • Roberto Orecchia
  4. European Institute of Oncology (IEO), Via Ripamonti 435, 20141 Milan, Italy.

    • Roberto Orecchia
  5. Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA.

    • Jay S. Loeffler
  6. Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA.

    • Jay S. Loeffler


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M.D. researched data for the article. M.D., R.O. and J.S.L. wrote, reviewed, and edited the manuscript before submission.

Competing interests

J.S.L. declares an association with ProCure Proton Therapy. R.O. and M.D. declare no competing interests.

Corresponding author

Correspondence to Marco Durante.


Bragg peak

Bragg peak is the peak in the curve representing the energy loss of charged particles plotted against the depth in the material. The peak occurs immediately before the particle stops. If beams of different energies are used to irradiate a target volume, the narrow Bragg peak will be enlarged to cover the whole volume (spread-out-Bragg-peak, SOBP).

Passive scattering

Passive scattering is a dose-delivery system in particle therapy in which a broad monoenergetic beam is used to treat a tumour. The energy variation is obtained with compensating filters of different depths and the shape is controlled with patient-specific collimators.

Pencil-beam scanning

Pencil-beam scanning (PBS) is a dose-delivery system in particle therapy in which the beam is concentrated in spots of a few millimeters of diameter, and scanned through a 2D tumour slice. By changing the energy, a new slice can be scanned.

Intensity-modulated proton therapy

Intensity-modulated proton therapy (IMPT) is a dose-delivery system in proton therapy in which the intensity of each pencil beam is modified to achieve a better target coverage. Intensity modulation is also used in X-ray-therapy.

Tumour-control probability

Tumour-control probability (TCP) is the probability to sterilize a localized tumour volume. The tumour-control probability is generally higher than that of survival, which is affected by the occurrence of distant metastasis.

Relative biological effectiveness

Relative biological effectiveness (RBE) is the ratio of the dose of reference radiation (generally X-rays or γ-rays) to test radiation (for example, protons or heavy ions) that produces the same biological effect. Higher RBE values are associated with increased effectiveness.

Physical dose distribution

Physical dose distribution is the pattern of energy deposition in the body after exposure to ionizing radiation.

Stereotactic body radiation therapy

Stereotactic body radiation therapy (SBRT) is a type of radiotherapy in which special equipment is used to position a patient and precisely deliver the dose to an extracranial tumour. The method requires high-quality imaging and can be delivered in much fewer fractions than conventional radiotherapy.

Target volume

Target volume is the volume to be irradiated in radiotherapy. Several target volumes are considered in treatment planning. The gross tumour volume (GTV) corresponds to the visible tumour; the clinical target volume (CTV) includes the visible tumour and subclinical malignant extensions (GTV + margin); the internal target volume (ITV) includes the region where the CTV is moving (for example, during breathing); and the planning target volume (PTV) includes additional margins required to compensate for set-up uncertainties.

Water-equivalent path length

Water-equivalent path length (WEPL) is the distance in centimeters that a proton beam in a nonhomogeneous tissue (with different densities) would have traversed in water.

Dose painting

Dose painting is a heterogenous dose-delivery method used to increase the dose delivered to resistant tumour subvolumes.

Dose halo

Dose halo is the peripheral dose around the pencil beam caused by scattering of the primary particles.

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