Clinical Evidence and Radiobiological Background of Particle Radiation Therapy

  • Walter TinganelliEmail author
  • Marco Durante
  • Alexander Helm
Part of the Current Clinical Pathology book series (CCPATH)


Charged particle therapy compared to the conventional radiotherapy offers many advantages. The particles’ peculiar inversed dose-depth profile characteristics provide the possibility, contrarily to photon irradiation, to deposit the energy more precisely to the tumour leading to a higher tumour local control, a lower probability to damage the surrounding healthy tissue and a lower risk of complications.

Particle therapy thus is helpful especially for the most radioresistant tumours or for those neoplasms prognosed too difficult to eradicate with surgery due to the position in anatomical sites where the access is limited.

The few clinical trials performed until now indicate that carbon ion treatment has the potential to completely replace conventional radiotherapy and in many cases surgery as well.

Furthermore, recent studies intend to elucidate the possibility to treat cancer using ions different from carbon and proton such as lithium or oxygen.

Increasing evidence prompts the promising potential of particle therapy; however, the cost-benefit ratio remains controversial and thus particle therapy still remains to be applied exclusively in a few states around the world. Current studies in radiobiology and medical physics focus on cost reduction as well as an increase in the benefit of this treatment.


Overall Survival Glioblastoma Multiforme Intensity Modulate Radiation Therapy Linear Energy Transfer Relative Biological Effectiveness 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Loeffler JS, Durante M. Charged particle therapy—optimization, challenges and future directions. Nat Rev Clin Oncol. 2013;10:411–24.CrossRefPubMedGoogle Scholar
  2. 2.
    Gilbert MR. New treatments for malignant gliomas: careful evaluation and cautious optimism required. Ann Intern Med. 2006;144(5):371–3.CrossRefPubMedGoogle Scholar
  3. 3.
    Durante M, Loeffler JS. Charged particles in radiation oncology. Nat Rev Clin Oncol. 2010;7(1):37–43.CrossRefPubMedGoogle Scholar
  4. 4.
    Kamiya-Matsuoka C, Gilbert MR. Treating recurrent glioblastoma: an update. CNS Oncol. 2015;4(2):91–104.CrossRefPubMedGoogle Scholar
  5. 5.
    Kamada T, Tsujii H, Blakely EA, Debus J, De Neve W, Durante M, Jäkel O, Mayer R, Orecchia R, Pötter R, Vatnitsky S, Chu WT. Carbon ion radiotherapy in Japan: an assessment of 20 years of clinical experience. Lancet Oncol. 2015;16(2):e93–100.CrossRefPubMedGoogle Scholar
  6. 6.
    Zhu X, El Fakhri G. Proton therapy verification with PET imaging. Theranostics. 2013;3(10):731–40.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Levin WP, Kooy H, Loeffler JS, DeLaney TF. Proton beam therapy. Br J Cancer. 2005;93(8):849–54.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Kraft G, Weber U. Tumor therapy with ion beams. In: Grupen C, Buvat I, editors. Handbook of particle detection and imaging. Berlin: Springer; 2012. p. 1179–205.CrossRefGoogle Scholar
  9. 9.
    Schlaff CD, Krauze A, Belard A, O’Connell JJ, Camphausen KA. Bringing the heavy: carbon ion therapy in the radiobiological and clinical context. Radiat Oncol. 2014;9(1):88.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Akino Y, Teshima T, Kihara A, Kodera-Suzumoto Y, Inaoka M, Higashiyama S, Furusawa Y, Matsuura N. Carbon-ion beam irradiation effectively suppresses migration and invasion of human non-small-cell lung cancer cells. Int J Radiat Oncol Biol Phys. 2009;75(2):475–81.CrossRefPubMedGoogle Scholar
  11. 11.
    Durante M, Reppingen N, Held KD. Immunologically augmented cancer treatment using modern radiotherapy. Trends Mol Med. 2013;19(9):565–82.CrossRefPubMedGoogle Scholar
  12. 12.
    Shannon AM, Bouchier-Hayes DJ, Condron CM, Toomey D. Tumour hypoxia, chemotherapeutic resistance and hypoxia-related therapies. Cancer Treat Rev. 2003;29(4):297–307.CrossRefPubMedGoogle Scholar
  13. 13.
    Bussink J, Kaanders JH, van der Kogel AJ. Tumor hypoxia at the micro-regional level: clinical relevance and predictive value of exogenous and endogenous hypoxic cell markers. Radiother Oncol. 2003;67(1):3–15.CrossRefPubMedGoogle Scholar
  14. 14.
    Collet G, El Hafny-Rahbi B, Nadim M, Tejchman A, Klimkiewicz K, Kieda C. Hypoxia-shaped vascular niche for cancer stem cells. Contemp Oncol (Pozn). 2015;19(1A):A39–43.Google Scholar
  15. 15.
    von Sonntag C. The basics of oxidants in water treatment. Part A: OH radical reactions. Water Sci Technol. 2007;55(12):19–23.CrossRefGoogle Scholar
  16. 16.
    Meesungnoen J, Jay-Gerin JP. High-LET ion radiolysis of water: oxygen production in tracks. Radiat Res. 2009;171(3):379–86.CrossRefPubMedGoogle Scholar
  17. 17.
    Tinganelli W, Ma NY, Von Neubeck C, Maier A, Schicker C, Kraft-Weyrather W, Durante M. Influence of acute hypoxia and radiation quality on cell survival. J Radiat Res. 2013;54 Suppl 1:i23–30.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Krämer M, Scholz M. Treatment planning for heavy-ion radiotherapy: calculation and optimization of biologically effective dose. Phys Med Biol. 2000;45(11):3319–30.CrossRefPubMedGoogle Scholar
  19. 19.
    Tinganelli W, Durante M, Hirayama R, Kraemer M, Maier A, Kraft-Weyrather W, Furusawa Y, Friedrich T, Scifoni E. Kill-painting of hypoxic tumours in charged particle therapy. Sci Rep. 2015;5:170–16.Google Scholar
  20. 20.
    Plaks V, Kong N, Werb Z. The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells? Cell Stem Cell. 2015;16(3):225–38.Google Scholar
  21. 21.
    Kunisaki Y. Cancer stem cells and the niches. Nihon Rinsho. 2015;73(5):739–44. Japanese.PubMedGoogle Scholar
  22. 22.
    Li L, Neaves WB. Normal stem cells and cancer stem cells: the niche matters. Cancer Res. 2006;66(9):4553–7.CrossRefPubMedGoogle Scholar
  23. 23.
    Saito S, Lin YC, Tsai MH, Lin CS, Murayama Y, Sato R, Yokoyama KK. Emerging roles of hypoxia-inducible factors and reactive oxygen species in cancer and pluripotent stem cells. Kaohsiung J Med Sci. 2015;31(6):279–86.CrossRefPubMedGoogle Scholar
  24. 24.
    Bloy N, Pol J, Manic G, Vitale I, Eggermont A, Galon J, Tartour E, Zitvogel L, Kroemer G, Galluzzi L. Trial watch: radioimmunotherapy for oncological indications. Oncoimmunology. 2014;3(9):e954929.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Kalbasi A, June CH, Haas N, Vapiwala N. Radiation and immunotherapy: a synergistic combination. J Clin Invest. 2013;123(7):2756–63.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Postow MA, Callahan MK, Barker CA, Yamada Y, Yuan J, Kitano S, Mu Z, Rasalan T, Adamow M, Ritter E, Sedrak C, Jungbluth AA, Chua R, Yang AS, Roman RA, Rosner S, Benson B, Allison JP, Lesokhin AM, Gnjatic S, Wolchok JDN. Immunologic correlates of the abscopal effect in a patient with melanoma. Engl J Med. 2012;366:925–31.CrossRefGoogle Scholar
  27. 27.
    Ivanov VN, Partridge MA, Huang SX, Hei TK. Suppression of the proinflammatory response of metastatic melanoma cells increases TRAIL-induced apoptosis. J Cell Biochem. 2011;112:463–75.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Kong LY, Gelbard A, Wei J, Reina-Ortiz C, Wang Y, Yang EC, Hailemichael Y, Fokt I, Jayakumar A, Qiao W, Fuller GN, Overwijk WW, Priebe W, Heimberger AB. Inhibition of p-STAT3 enhances IFN-a efficacy against metastatic melanoma in a murine model. Clin Cancer Res. 2010;16:2550–61.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Steiner HH, Bonsanto MM, Beckhove P, Brysch M, Geletneky K, Ahmadi R, Schuele-Freyer R, Kremer P, Ranaie G, Matejic D, Bauer H, Kiessling M, Kunze S, Schirrmacher V, Herold-Mende C. Antitumor vaccination of patients with glioblastoma multiforme: a pilot study to assess feasibility, safety, and clinical benefit. J Clin Oncol. 2004;22:4272–81.CrossRefPubMedGoogle Scholar
  30. 30.
    López-Larrea C, Suárez-Alvarez B, López-Soto A, López-Vázquez A, Gonzalez S. The NKG2D receptor: sensing stressed cells. Trends Mol Med. 2008;14:179–89.CrossRefPubMedGoogle Scholar
  31. 31.
    Ogbomo H, Cinatl Jr J, Mody CH, Forsyth PA. Immunotherapy in gliomas: limitations and potential of natural killer (NK) cell therapy. Trends Mol Med. 2011;17:433–41.CrossRefPubMedGoogle Scholar
  32. 32.
    Villalva C, Martin-Lannerée S, Cortes U, Dkhissi F, Wager M, Le Corf A, Tourani JM, Dusanter-Fourt I, Turhan AG, Karayan-Tapon L. STAT3 is essential for the maintenance of neurosphere-initiating tumor cells in patients with glioblastomas: a potential for targeted therapy? Int J Cancer. 2011;128:826–38.CrossRefPubMedGoogle Scholar
  33. 33.
    Teulings HE, Tjin EP, Willemsen KJ, Krebbers G, van Noesel CJ, Kemp EH, Nieuweboer-Krobotova L, van der Veen JP, Luiten RM. Radiation-induced melanoma-associated leucoderma, systemic antimelanoma immunity and disease-free survival in a patient with advanced-stage melanoma: a case report and immunological analysis. Br J Dermatol. 2013;168:733–8.CrossRefPubMedGoogle Scholar
  34. 34.
    Maes W, Gool SW. Experimental immunotherapy for malignant glioma: lessons from two decades of research in the GL261 model. Cancer Immunol Immunother. 2011;60:153–60.CrossRefPubMedGoogle Scholar
  35. 35.
    Newcomb EW, et al. The combination of ionizing radiation and peripheral vaccination produces long-term survival of mice bearing established invasive GL261 gliomas. Clin Cancer Res. 2006;12:4730–7.CrossRefPubMedGoogle Scholar
  36. 36.
    Lee Y, Auh SL, Wang Y, Burnette B, Wang Y, Meng Y, Beckett M, Sharma R, Chin R, Tu T, Weichselbaum RR, Fu YX. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood. 2009;114:589–95.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Demaria S, Formenti SC. Combining radiotherapy and cancer immunotherapy: a paradigm shift. J Natl Cancer Inst. 2013;105:256–65.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Krysko DV, Garg AD, Kaczmarek A, Krysko O, Agostinis P, Vandenabeele P. Immunogenic cell death and DAMPs in cancer therapy. Nat Rev Cancer. 2012;12:860–75.CrossRefPubMedGoogle Scholar
  39. 39.
    Panaretakis T, Kepp O, Brockmeier U, Tesniere A, Bjorklund AC, Chapman DC, Durchschlag M, Joza N, Pierron G, van Endert P, Yuan J, Zitvogel L, Madeo F, Williams DB, Kroemer G. Mechanisms of pre-apoptotic calreticulin exposure in immunogenic cell death. EMBO J. 2009;28:578–90.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Garg AD, Krysko DV, Verfaillie T, Kaczmarek A, Ferreira GB, Marysael T, Rubio N, Firczuk M, Mathieu C, Roebroek AJ, Annaert W, Golab J, de Witte P, Vandenabeele P, Agostinis P. A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death. EMBO J. 2012;31:1062–79.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJB, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Samuel RCJ, Ludwin K, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–96.CrossRefPubMedGoogle Scholar
  42. 42.
    Auffinger B, Spencer D, Pytel P, Ahmed AU, Lesniak MS. The role of glioma stem cells in chemotherapy resistance and glioblastoma multiforme recurrence. Expert Rev Neurother. 2015;31:1–12.Google Scholar
  43. 43.
    Thon N, Kreth S, Kreth FW. Personalized treatment strategies in glioblastoma: MGMT promoter methylation status. Onco Targets Ther. 2013;6:1363–72.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Lee SW, Kim HK, Lee NH, Yi HY, Kim HS, Hong SH, Hong YK. The synergistic effect of combination temozolomide and chloroquine treatment is dependent on autophagy formation and p53 status in glioma cells. Cancer Lett. 2015;360(2):195–204.CrossRefPubMedGoogle Scholar
  45. 45.
    Sotelo J, Briceño E, López-González MA. Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2006;144(5):337–43.CrossRefPubMedGoogle Scholar
  46. 46.
    van den Bent MJ, Carpentier AF, Brandes AA, Sanson M, Taphoorn MJ, Bernsen HJ, Frenay M, Tijssen CC, Grisold W, Sipos L, Haaxma-Reiche H, Kros JM, van Kouwenhoven MC, Vecht CJ, Allgeier A, Lacombe D, Gorlia T. Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. J Clin Oncol. 2006;24(18):2715–22.CrossRefPubMedGoogle Scholar
  47. 47.
    Mizumoto M, Oshiro Y, Tsuboi K. Proton beam therapy for intracranial and skull base tumors. Transl Cancer Res. 2013;2:2.Google Scholar
  48. 48.
    Fitzek MM, Thornton AF, Rabinov JD, Lev MH, Pardo FS, Munzenrider JE, Okunieff P, Bussiere M, Braun I, Hochberg FH, Hedley-Whyte ET, Liebsch NJ, Harsh 4th GR. Accelerated fractionated proton/photon irradiation to 90 cobalt gray equivalent for glioblastoma multiforme: results of a phase II prospective trial. J Neurosurg. 1999;91:251–60.CrossRefPubMedGoogle Scholar
  49. 49.
    Mizumoto M, Tsuboi K, Igaki H. Phase I/II trial of hyperfractionated concomitant boost proton radiotherapy for supratentorial glioblastoma multiforme. Int J Radiat Oncol Biol Phys. 2010;77:98–105.CrossRefPubMedGoogle Scholar
  50. 50.
    Mizumoto M, Yamamoto T, Takano S, Ishikawa E, Matsumura A, Ishikawa H, Okumura T, Sakurai H, Miyatake S, Tsuboi K. Long-term survival after treatment of glioblastoma multiforme with hyperfractionated concomitant boost proton beam therapy. Pract Radiat Oncol. 2015;5(1):e9–16.CrossRefPubMedGoogle Scholar
  51. 51.
    Matsuda M, Yamamoto T, Ishikawa E, Nakai K, Zaboronok A, Takano S, Matsumura A. Prognostic factors in glioblastoma multiforme patients receiving high-dose particle radiotherapy or conventional radiotherapy. Br J Radiol. 2011;84(Spec Iss 1): S054–060.Google Scholar
  52. 52.
    Yamamoto T, Tsuboi K. Particle radiotherapy for malignant gliomas. Brain Nerve. 2009;61(7):855–66.PubMedGoogle Scholar
  53. 53.
    Fitzek MM, Thornton AF, Harsh 4th G, Rabinov JD, Munzenrider JE, Lev M, Ancukiewicz M, Bussiere M, Hedley-Whyte ET, Hochberg FH, Pardo FS. Dose-escalation with proton/photon irradiation for Daumas-Duport lower-grade glioma: results of an institutional phase I/II trial. Int J Radiat Oncol Biol Phys. 2001;51(1):131–7.CrossRefPubMedGoogle Scholar
  54. 54.
    Hug EB, Muenter MW, Archambeau JO, DeVries A, Liwnicz B, Loredo LN, Grove RI, Slater JD. Conformal proton radiation therapy for pediatric low-grade astrocytomas. Strahlenther Onkol. 2002;178(1):10–7.CrossRefPubMedGoogle Scholar
  55. 55.
    Hauswald H, Rieken S, Ecker S, Kessel KA, Herfarth K, Debus J, Combs SE. First experiences in treatment of low-grade glioma grade I and II with proton therapy. Radiat Oncol. 2012;7:189.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Rieken S, Habermehl D, Haberer T, Jaekel O, Debus J, Combs SE. Proton and carbon ion radiotherapy for primary brain tumors delivered with active raster scanning at the Heidelberg Ion Therapy Center (HIT): early treatment results and study concepts. Radiat Oncol. 2012;7:41.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Freeman T. Treatments begin on HIT’s heavy ion gantry. Medicalphysicsweb. 2012.Google Scholar
  58. 58.
    Mizoe JE, Tsujii H, Hasegawa A, Yanagi T, Takagi R, Kamada T, Tsuji H, Takakura K. Phase I/II clinical trial of carbon ion radiotherapy for malignant gliomas: combined X-ray radiotherapy, chemotherapy, and carbon ion radiotherapy. Int J Radiat Oncol Biol Phys. 2007;69(2):390–6.CrossRefPubMedGoogle Scholar
  59. 59.
    Combs SE, Heeger S, Haselmann R, Edler L, Debus J, Schulz-Ertner D. Treatment of primary glioblastoma multiforme with cetuximab, radiotherapy and temozolomide (GERT)—phase I/II trial: study protocol. BMC Cancer. 2006;6:133.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Kantor G, Loiseau H, Vital A, Mazeron JJ. Gross tumor volume (GTV) and clinical target volume (CTV) in adult gliomas. Cancer Radiother. 2001;5(5):571–80.CrossRefPubMedGoogle Scholar
  61. 61.
    Combs SE, Bruckner T, Mizoe JE, Kamada T, Tsujii H, Kieser M, Debus J. Comparison of carbon ion radiotherapy to photon radiation alone or in combination with temozolomide in patients with high-grade gliomas: explorative hypothesis-generating retrospective analysis. Radiother Oncol. 2013;108(1):132–5.CrossRefPubMedGoogle Scholar
  62. 62.
    Combs SE, Burkholder I, Edler L, Rieken S, Habermehl D, Jäkel O, Haberer T, Haselmann R, Unterberg A, Wick W, Debus J. Randomised phase I/II study to evaluate carbon ion radiotherapy versus fractionated stereotactic radiotherapy in patients with recurrent or progressive gliomas: the CINDERELLA trial. BMC Cancer. 2010;10:533.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Walter Tinganelli
    • 1
    • 2
    Email author
  • Marco Durante
    • 1
    • 2
  • Alexander Helm
    • 1
    • 2
  1. 1.Helmholtzzentrum für Schwerionenforschung GmbH (GSI)DarmstadtGermany
  2. 2.Trento Institute for Fundamental Physics and Applications (TIFPA)TrentoItaly

Personalised recommendations