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

Nature Reviews Clinical Oncology volume 14, pages 483–495 (2017)Cite this article

Subjects

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

Abstract

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.

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Figure 1: Geographical distribution of centres delivering charged-particle therapy (CPT) to patients with cancer.
Figure 2: Nonmalignant tissue can be spared from radiation from charged particles owing to the physical properties of these particles.
Figure 3: Clinical trial design in charged-particle therapy (CPT).
Figure 4: Treatment plans using stereotactic body radiotherapy (SBRT) or charged-particle therapy (CPT) for two patients with NSCLC.
Figure 5: The biological effects of charged particles depend on ionization density (linear energy transfer (LET)).
Figure 6: Double opposed-field irradiation of an idealized geometry simulating a typical head and neck tumour using ionization from 1H, 4He, 12C, or 16O.

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References

  1. 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  PubMed  CAS  Google Scholar 

  2. Jermann, M. Particle therapy statistics in 2014. Int. J. Part. Ther. 2, 50–54 (2015).

    Article  Google Scholar 

  3. Durante, M. & Paganetti, H. Nuclear physics in particle therapy: a review. Rep. Prog. Phys. 79, 96702 (2016).

    Article  CAS  Google Scholar 

  4. Kooy, H. M. & Grassberger, C. Intensity modulated proton therapy. Br. J. Radiol. 88, 20150195 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Baumann, M. et al. Radiation oncology in the era of precision medicine. Nat. Rev. Cancer 16, 234–249 (2016).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  8. Lievens, Y. & Pijls-Johannesma, M. Health economic controversy and cost-effectiveness of proton therapy. Semin. Radiat. Oncol. 23, 134–141 (2013).

    Article  PubMed  Google Scholar 

  9. Paganetti, H. & Zietman, A. Why is proton beam therapy so controversial? J. Am. Coll. Radiol. 12, 1318–1319 (2015).

    Article  PubMed  Google Scholar 

  10. Loeffler, J. S. & Durante, M. Charged particle therapy — optimization, challenges and future directions. Nat. Rev. Clin. Oncol. 10, 411–424 (2013).

    Article  PubMed  Google Scholar 

  11. Loeffler, J. S. Technology assessment in radiation oncology: time for reassessment? Nat. Clin. Pract. Oncol. 5, 299–299 (2008).

    Article  PubMed  Google Scholar 

  12. Suit, H. et al. Should positive phase III clinical trial data be required before proton beam therapy is more widely adopted? No. Radiother. Oncol. 86, 148–153 (2008).

    Article  PubMed  Google Scholar 

  13. Sakurai, H., Robert Lee, W. & Orton, G. C. We do not need randomized clinical trials to demonstrate the superiority of proton therapy. Med. Phys. 39, 1685–1687 (2012).

    Article  PubMed  Google Scholar 

  14. Bentzen, S. M. Radiation oncology health technology assessment: the best is the enemy of the good. Nat. Clin. Pract. Oncol. 5, 563 (2008).

    Article  PubMed  Google Scholar 

  15. Jaffray, D. A. Image-guided radiotherapy: from current concept to future perspectives. Nat. Rev. Clin. Oncol. 9, 688–699 (2012).

    Article  CAS  PubMed  Google Scholar 

  16. Bentzen, S. M. Randomized controlled trials in health technology assessment: overkill or overdue? Radiother. Oncol. 86, 142–147 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Ferlay, J. et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 136, E359–E386 (2015).

    Article  CAS  PubMed  Google Scholar 

  18. Zagar, T. M., Cardinale, D. M. & Marks, L. B. Breast cancer therapy-associated cardiovascular disease. Nat. Rev. Clin. Oncol. 13, 172–184 (2016).

    Article  CAS  PubMed  Google Scholar 

  19. Darby, S. C. et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N. Engl. J. Med. 368, 987–998 (2013).

    Article  CAS  PubMed  Google Scholar 

  20. Mailhot Vega, R. B. et al. Establishing cost-effective allocation of proton therapy for breast irradiation. Int. J. Radiat. Oncol. Biol. Phys. 95, 11–18 (2016).

    Article  PubMed  Google Scholar 

  21. Dagan, R., Ho, M. W., Rutenberg, M. S., Li, Z. & Mendenhall, N. P. Two-year outcomes of a prospective study of proton therapy for breast cancer regional nodal irradiation [abstract]. J. Clin. Oncol. 33 (Suppl.), 65 (2015).

    Google Scholar 

  22. Verma, V., Shah, C. & Mehta, M. P. Clinical outcomes and toxicity of proton radiotherapy for breast cancer. Clin. Breast Cancer 16, 145–154 (2016).

    Article  PubMed  Google Scholar 

  23. Akamatsu, H. et al. First experience of carbon-ion radiotherapy for early breast cancer. Jpn J. Radiol. 32, 288–295 (2014).

    Article  CAS  PubMed  Google Scholar 

  24. Martin, N. E. & D'Amico, A. V. Progress and controversies: radiation therapy for prostate cancer. CA Cancer J. Clin. 64, 389–407 (2014).

    Article  Google Scholar 

  25. Zaorsky, N. G. et al. Evolution of advanced technologies in prostate cancer radiotherapy. Nat. Rev. Urol. 10, 565–579 (2013).

    Article  PubMed  Google Scholar 

  26. Wallis, C. J. D. et al. Surgery versus radiotherapy for clinically-localized prostate cancer: a systematic review and meta-analysis. Eur. Urol. 70, 21–30 (2015).

    Article  PubMed  Google Scholar 

  27. Roach, M., Ceron Lizarraga, T. L. & Lazar, A. A. Radical prostatectomy versus radiation and androgen deprivation therapy for clinically localized prostate cancer: how good is the evidence? Int. J. Radiat. Oncol. Biol. Phys. 93, 1064–1070 (2015).

    Article  PubMed  Google Scholar 

  28. Lennernäs, B. et al. Radical prostatectomy versus high-dose irradiation in localized/locally advanced prostate cancer: a Swedish multicenter randomized trial with patient-reported outcomes. Acta Oncol. 54, 875–881 (2015).

    Article  PubMed  CAS  Google Scholar 

  29. Yu, J. B. et al. Proton versus intensity-modulated radiotherapy for prostate cancer: patterns of care and early toxicity. J. Natl Cancer Inst. 105, 25–32 (2013).

    Article  CAS  PubMed  Google Scholar 

  30. Sheets, N. C. et al. Intensity-modulated radiation therapy, proton therapy, or conformal radiation therapy and morbidity and disease control in localized prostate cancer. JAMA 307, 1611–1620 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bryant, C. et al. Five-year biochemical results, toxicity, and patient-reported quality of life after delivery of dose-escalated image guided proton therapy for prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 95, 422–434 (2016).

    Article  PubMed  Google Scholar 

  32. Schiller, K. C., Habl, G. & Combs, S. E. Protons, photons, and the prostate — is there emerging evidence in the ongoing discussion on particle therapy for the treatment of prostate cancer? Front. Oncol. 6, 8 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Durante, M. Charged particles for liver cancer. Ann. Transl Med. 3, 2–5 (2015).

    Google Scholar 

  34. Hong, T. S. et al. Multi-institutional phase II study of high-dose hypofractionated proton beam therapy in patients with localized, unresectable hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J. Clin. Oncol. 34, 460–468 (2016).

    Article  CAS  PubMed  Google Scholar 

  35. Granovetter, M. Proton radiotherapy for primary liver cancers. Lancet Oncol. 17, e49 (2016).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  37. 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  CAS  PubMed  Google Scholar 

  38. Tanaka, S., Louis, D. N., Curry, W. T., Batchelor, T. T. & Dietrich, J. Diagnostic and therapeutic avenues for glioblastoma: no longer a dead end? Nat. Rev. Clin. Oncol. 10, 14–26 (2013).

    Article  CAS  PubMed  Google Scholar 

  39. Malvezzi, M. et al. European cancer mortality predictions for the year 2016 with focus on leukaemias. Ann. Oncol. 27, 725–731 (2016).

    Article  CAS  PubMed  Google Scholar 

  40. Durante, M., Tommasino, F. & Yamada, S. Modeling combined chemotherapy and particle therapy for locally advanced pancreatic cancer. Front. Oncol. 5, 145 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Hammel, P. et al. Effect of chemoradiotherapy versus chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: the LAP07 randomized clinical trial. JAMA 315, 1844–1853 (2016).

    Article  CAS  PubMed  Google Scholar 

  42. Crane, C. H. Hypofractionated ablative radiotherapy for locally advanced pancreatic cancer. J. Radiat. Res. 57, i53–i57 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Chadha, A. S. et al. Phase I trial of consolidative radiotherapy with concurrent bevacizumab, erlotinib and capecitabine for unresectable pancreatic cancer. PLoS ONE 11, 1–15 (2016).

    Article  CAS  Google Scholar 

  44. Krishnan, S. et al. Focal radiation therapy dose escalation improves overall survival in locally advanced pancreatic cancer patients receiving induction chemotherapy and consolidative chemoradiation. Int. J. Radiat. Oncol. Biol. Phys. 94, 755–765 (2016).

    Article  PubMed  Google Scholar 

  45. Terashima, K. et al. A phase I/II study of gemcitabine-concurrent proton radiotherapy for locally advanced pancreatic cancer without distant metastasis. Radiother. Oncol. 103, 25–31 (2012).

    Article  PubMed  Google Scholar 

  46. 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  CAS  PubMed  Google Scholar 

  47. Wang, X., Hu, C. & Eisbruch, A. Organ-sparing radiation therapy for head and neck cancer. Nat. Rev. Clin. Oncol. 8, 639–648 (2011).

    Article  CAS  PubMed  Google Scholar 

  48. Lukens, J. N., Lin, A. & Hahn, S. M. Proton therapy for head and neck cancer. Curr. Opin. Oncol. 27, 165–171 (2015).

    Article  CAS  PubMed  Google Scholar 

  49. Gregoire, V., Langendijk, J. A. & Nuyts, S. Advances in radiotherapy for head and neck cancer. J. Clin. Oncol. 33, 3277–3284 (2015).

    Article  CAS  PubMed  Google Scholar 

  50. Patel, S. H. et al. Charged particle therapy versus photon therapy for paranasal sinus and nasal cavity malignant diseases: a systematic review and meta-analysis. Lancet Oncol. 15, 1027–1038 (2014).

    Article  CAS  PubMed  Google Scholar 

  51. Jensen, A. D. et al. High-LET radiotherapy for adenoid cystic carcinoma of the head and neck: 15 years' experience with raster-scanned carbon ion therapy. Radiother. Oncol. 118, 272–280 (2016).

    Article  PubMed  Google Scholar 

  52. Jensen, A. D. et al. Combined intensity-modulated radiotherapy plus raster-scanned carbon ion boost for advanced adenoid cystic carcinoma of the head and neck results in superior locoregional control and overall survival. Cancer 121, 3001–3009 (2015).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  54. Maquilan, G. & Timmerman, R. Stereotactic body radiation therapy for early-stage lung cancer. Cancer J. 22, 274–279 (2016).

    Article  PubMed  Google Scholar 

  55. Bertolaccini, L., Terzi, A., Ricchetti, F. & Alongi, F. Surgery or stereotactic ablative radiation therapy: how will be treated operable patients with early stage not small cell lung cancer in the next future? Ann. Transl Med. 3, 25 (2015).

    PubMed  PubMed Central  Google Scholar 

  56. De Ruysscher, D. & Chang, J. Y. Clinical controversies: proton therapy for thoracic tumors. Semin. Radiat. Oncol. 23, 115–119 (2013).

    Article  PubMed  Google Scholar 

  57. Berman, A., James, S. & Rengan, R. Proton beam therapy for non-small cell lung cancer: current clinical evidence and future directions. Cancers (Basel). 7, 1178–1190 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Mauguen, A. et al. Surrogate endpoints for overall survival in chemotherapy and radiotherapy trials in operable and locally advanced lung cancer: a re-analysis of meta-analyses of individual patients' data. Lancet Oncol. 14, 619–626 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Machtay, M. et al. Higher biologically effective dose of radiotherapy is associated with improved outcomes for locally advanced non-small cell lung carcinoma treated with chemoradiation: an analysis of the Radiation Therapy Oncology Group. Int. J. Radiat. Oncol. Biol. Phys. 82, 425–434 (2012).

    Article  PubMed  Google Scholar 

  60. Bradley, J. D. et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 16, 187–199 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Eaton, B. R. et al. Institutional enrollment and survival among NSCLC patients receiving chemoradiation: NRG Oncology Radiation Therapy Oncology Group (RTOG) 0617. J. Natl. Cancer Inst. 108, djw034 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Tucker, S. L. et al. Impact of heart and lung dose on early survival in patients with non-small cell lung cancer treated with chemoradiation. Radiother. Oncol. 119, 495–500 (2016).

    Article  PubMed  Google Scholar 

  63. Hong, J. C. & Salama, J. K. Dose escalation for unresectable locally advanced non-small cell lung cancer: end of the line? Transl Lung Cancer Res. 5, 126–133 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Movsas, B. et al. Quality of life analysis of a radiation dose-escalation study of patients with non-small-cell lung cancer: a secondary analysis of the Radiation Therapy Oncology Group 0617 randomized clinical trial. JAMA Oncol. 2, 359–367 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Roelofs, E. et al. Results of a multicentric in silico clinical trial (ROCOCO): comparing radiotherapy with photons and protons for non-small cell lung cancer. J. Thorac. Oncol. 7, 165–176 (2012).

    Article  CAS  PubMed  Google Scholar 

  66. Chang, J. Y. et al. Consensus statement on proton therapy in early-stage and locally advanced non-small cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 95, 505–516 (2016).

    Article  PubMed  Google Scholar 

  67. Liao, Z. X. et al. Bayesian randomized trial comparing intensity modulated radiation therapy versus passively scattered proton therapy for locally advanced nonsmall cell lung cancer [abstract]. J. Clin. Oncol. 34 (Suppl.), 8500 (2016).

    Article  Google Scholar 

  68. 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  PubMed  Google Scholar 

  69. 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  PubMed  Google Scholar 

  70. Graeff, C., Constantinescu, A., Luchtenborg, R., Durante, M. & Bert, C. Multigating, a 4D optimized beam tracking in scanned ion beam therapy. Technol. Cancer Res. Treat. 13, 497–504 (2014).

    Article  PubMed  Google Scholar 

  71. Wölfelschneider, J. et al. Impact of fractionation and number of fields on dose homogeneity for intra-fractionally moving lung tumors using scanned carbon ion treatment. Radiother. Oncol. 118, 498–503 (2016).

    Article  PubMed  CAS  Google Scholar 

  72. Anderle, K. et al. In silico comparison of photons versus carbon ions in single fraction therapy of lung cancer. Phys. Med. 32, 1118–1123 (2016).

    Article  PubMed  Google Scholar 

  73. Nikoghosyan, A. V. et al. Randomised trial of proton versus carbon ion radiation therapy in patients with chordoma of the skull base, clinical phase III study HIT-1-Study. BMC Cancer 10, 607 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  74. 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  PubMed  Google Scholar 

  75. Wedenberg, M. & Toma-Dasu, I. Disregarding RBE variation in treatment plan comparison may lead to bias in favor of proton plans. Med. Phys. 41, 91706 (2014).

    Article  CAS  Google Scholar 

  76. Langendijk, J.A. et al. Selection of patients for radiotherapy with protons aiming at reduction of side effects: the model-based approach. Radiother. Oncol. 107, 267–273 (2013).

    Article  CAS  PubMed  Google Scholar 

  77. Durante, M. New challenges in high-energy particle radiobiology. Br. J. Radiol. 87, 20130626 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Schaue, D. & McBride, W. H. Opportunities and challenges of radiotherapy for treating cancer. Nat. Rev. Clin. Oncol. 12, 1–14 (2015).

    Article  Google Scholar 

  79. 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).

    Article  PubMed  Google Scholar 

  80. Sabin, N. D. et al. Imaging changes in very young children with brain tumors treated with proton therapy and chemotherapy. Am. J. Neuroradiol. 34, 446–450 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Gunther, J. R. et al. Imaging changes in pediatric intracranial ependymoma patients treated with proton beam radiation therapy compared to intensity modulated radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 93, 54–63 (2015).

    Article  PubMed  Google Scholar 

  82. Sethi, R. V. et al. Patterns of failure after proton therapy in medulloblastoma; linear energy transfer distributions and relative biological effectiveness associations for relapses. Int. J. Radiat. Oncol. Biol. Phys. 88, 655–663 (2014).

    Article  PubMed  Google Scholar 

  83. Yock, T. I. et al. Long-term toxic effects of proton radiotherapy for paediatric medulloblastoma: a phase 2 single-arm study. Lancet Oncol. 17, 287–298 (2016).

    Article  PubMed  Google Scholar 

  84. Peeler, C. R. et al. Clinical evidence of variable proton biological effectiveness in pediatric patients treated for ependymoma. Radiother. Oncol. 121, 395–401 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Buchsbaum, J. C. et al. Range modulation in proton therapy planning: a simple method for mitigating effects of increased relative biological effectiveness at the end-of-range of clinical proton beams. Radiat. Oncol. 9, 2 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Fager, M. et al. Linear energy transfer painting with proton therapy: a means of reducing radiation doses with equivalent clinical effectiveness. Int. J. Radiat. Oncol. Biol. Phys. 91, 1057–1064 (2015).

    Article  PubMed  Google Scholar 

  87. Unkelbach, J., Botas, P., Giantsoudi, D., Gorissen, B. & Paganetti, H. Reoptimization of intensity-modulated proton therapy plans based on linear energy transfer. Int. J. Radiat. Oncol. Biol. Phys. 96, 1097–1106 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  89. Castro, J. R. et al. Treatment of cancer with heavy charged particles. Int. J. Radiat. Oncol. Biol. Phys. 8, 2191–2198 (1982).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  91. No authors listed. Report of the Cancer Moonshot Task Force. https://obamawhitehouse.archives.gov/sites/default/files/docs/final_cancer_moonshot_task_force_report_1.pdf (2016).

  92. 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  PubMed  Google Scholar 

  93. 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  CAS  PubMed  PubMed Central  Google Scholar 

  94. Brown, J. M. & Wilson, W. R. Exploiting tumour hypoxia in cancer treatment. Nat. Rev. Cancer 4, 437–447 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. 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  CAS  PubMed  Google Scholar 

  96. 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 (Suppl.), 110–115 (2014).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  101. De Ruysscher, D., Haustermans, K. & Thorwarth, D. FDG and beyond. Recent Results Cancer Res. 198, 163–173 (2016).

    Article  CAS  PubMed  Google Scholar 

  102. Flynn, R. T., Bowen, S. R., Bentzen, S. M., Rockwell Mackie, T. & Jeraj, R. Intensity-modulated x-ray (IMXT) versus proton (IMPT) therapy for theragnostic hypoxia-based dose painting. Phys. Med. Biol. 53, 4153–4167 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  104. Formenti, S. & Demaria, S. Systemic effects of local radiotherapy. Lancet Oncol. 10, 718–726 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Weichselbaum, R. R., Liang, H., Deng, L. & Fu, Y.-X. Radiotherapy and immunotherapy: a beneficial liaison? Nat. Rev. Clin. Oncol. http://dx.doi.org/10.1038/nrclinonc.2016.211 (2017).

  106. Shaked, Y. Balancing efficacy of and host immune responses to cancer therapy: the yin and yang effects. Nat. Rev. Clin. Oncol. 13, 611–626 (2016).

    Article  CAS  PubMed  Google Scholar 

  107. 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  PubMed  Google Scholar 

  108. Yin, X. et al. Radiation quality-dependence of bystander effect in unirradiated fibroblasts is associated with TGF-β1-Smad2 pathway and miR-21 in irradiated keratinocytes. Sci. Rep. 5, 11373 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Shimokawa, T., Ma, L., Ando, K., Sato, K. & Imai, T. The future of combining carbon-ion radiotherapy with immunotherapy: evidence and progress in mouse models. Int. J. Part. Ther. 3, 61–70 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Yovino, S., Kleinberg, L., Grossman, S. A., Narayanan, M. & Ford, E. The etiology of treatment-related lymphopenia in patients with malignant gliomas: modeling radiation dose to circulating lymphocytes explains clinical observations and suggests methods of modifying the impact of radiation on immune cells. Cancer Invest. 31, 140–144 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  112. Pignalosa, D. et al. Chromosome inversions in lymphocytes of prostate cancer patients treated with X-rays and carbon ions. Radiother. Oncol. 109, 256–261 (2013).

    Article  CAS  PubMed  Google Scholar 

  113. Takagi, M. et al. Treatment outcomes of particle radiotherapy using protons or carbon ions as a single-modality therapy for adenoid cystic carcinoma of the head and neck. Radiother. Oncol. 113, 364–370 (2014).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  115. Rovituso, M. et al. Fragmentation of 120 and 200 MeV u−14 He ions in water and PMMA targets. Phys. Med. Biol. 62, 1310–1326 (2017).

    Article  CAS  PubMed  Google Scholar 

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

    Article  Google Scholar 

  117. 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  PubMed  CAS  Google Scholar 

  118. 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  CAS  PubMed  Google Scholar 

  119. 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  CAS  PubMed  Google Scholar 

  120. Hall, J. A., Salgado, R., Lively, T., Sweep, F. & Schuh, A. A risk-management approach for effective integration of biomarkers in clinical trials: perspectives of an NCI, NCRI, and EORTC working group. Lancet Oncol. 15, e184–e193 (2014).

    Article  PubMed  Google Scholar 

  121. O'Connor, J. P. B. et al. Imaging biomarker roadmap for cancer studies. Nat. Rev. Clin. Oncol. 14, 169–186 (2017).

    Article  CAS  PubMed  Google Scholar 

  122. Qutub, M. A. Z., Klein, S. B. & Buchsbaum, J. C. Rapid RBE-weighted proton radiation dosimetry risk assessment. Technol. Cancer Res. Treat. 15, NP1–NP7 (2016).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Pignalosa, D. & Durante, M. Overcoming resistance of cancer stem cells. Lancet Oncol. 13, e187–e188 (2012).

    Article  PubMed  Google Scholar 

  125. Laine, A. et al. International symposium on ion therapy: planning the first hospital-based heavy ion therapy center in the United States. Int. J. Part. Ther. 2, 468–471 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Roach, M. et al. New clinical and research programs in particle beam radiation therapy: the University of California San Francisco perspective. Int. J. Part. Ther. 2, 471–473 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Patel, S. et al. Recommendations for the referral of patients for proton-beam therapy, an Alberta Health Services report: a model for Canada? Curr. Oncol. 21, 251–262 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Shah, A., Ricci, K. I. & Efstathiou, J. A. Beyond a moonshot: insurance coverage for proton therapy. Lancet Oncol. 17, 559–561 (2016).

    Article  PubMed  Google Scholar 

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Acknowledgements

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.

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Authors and Affiliations

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

    Marco Durante

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

    Marco Durante

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

    Roberto Orecchia

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

    Roberto Orecchia

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

    Jay S. Loeffler

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

    Jay S. Loeffler

Authors
  1. Marco Durante
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  2. Roberto Orecchia
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  3. Jay S. Loeffler
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Contributions

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

Corresponding author

Correspondence to Marco Durante.

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Competing interests

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

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PowerPoint slides

Glossary

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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Durante, M., Orecchia, R. & Loeffler, J. Charged-particle therapy in cancer: clinical uses and future perspectives. Nat Rev Clin Oncol 14, 483–495 (2017). https://doi.org/10.1038/nrclinonc.2017.30

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