Relative Biological Effectiveness of Neutrons for Cancer Induction and Other Late Effects: A Review of Radiobiological Data

  • H. Engels
  • A. Wambersie
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 150)

Abstract

The risk of secondary cancer induction after a therapeutic irradiation with conventional photon beams is well recognised and documented. However, in general, it is totally overwhelmed by the benefit of the treatment. The same is true to a large extent for the combinations of radiation and drug therapy. After fast neutron therapy, the risk of secondary cancer induction is greater than after photon therapy. This can be expected from the whole set of radiobiological data, accumulated so far, which shows systematically a greater relative biological effectiveness (RBE) for neutrons for all the biological systems which have been investigated. Furthermore, the neutron RBE increases with decreasing dose and there is extensive evidence that neutron RBE is greater for cancer induction and for other late effects relevant in radiation protection than for cell killing at high doses as used in therapy. Almost no reliable human epidemiological data are available so far, and the aim of this work is to derive the best risks estimate for cancer induction after neutron irradiation and in particular fast neutron therapy. Animal data on RBE for tumour induction are analysed. In addition, other biological effects are reviewed, such as life shortening, malignant cell transformation in vitro, chromosome aberrations, genetic effects. These effects can be related, directly or indirectly, to cancer induction to the extent that they express a “genomic” lesion. Since neutron RBE depends on the energy spectrum, the radiation quality has to be carefully specified. Therefore, the microdosimetric spectra are reported each time they are available. Lastly, since heavy-ion beam therapy is being developed at several centres worldwide, the available data on RBE at low doses are reviewed. It can be concluded from this review that the risk of induction of a secondary cancer after fast neutron therapy should not be greater than 10–20 times the risk after photon beam therapy. For heavy ions, and in particular for carbon ions, the risk estimate should be divided by a factor of about 3 due to the reduced integral dose. The risk has to be balanced against the expected improvement in cure rate when the indication for high-LET therapy has been correctly evaluated in well-selected patient groups.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Barendsen GW (1968) Responses of cultured cells, tumours and normal tissues to radiations of different linear energy transfer. Curr Top Radiat Res Q 4: 293–356Google Scholar
  2. Barendsen GW (1979) Influence of radiation quality on the effectiveness of small doses for induction of reproductive death and chromosome aberrations in mammalian cells. Int J Radiat Biol 36: 49–63CrossRefGoogle Scholar
  3. Barendsen GW (1996) RBE-LET relationships for lethal, potentially lethal and sublethal damage in mammalian cells: implications for fast neutron radiotherapy. Bull Cancer (Paris) 83 Suppl 1: 15s - 18sGoogle Scholar
  4. Bateman JL, Rossi HH, Kellerer AM, Robinson CV, Bond VP (1972) Dose-dependence of fast neutron RBE for lens opacification in mice. Radiat Res 51: 381–390PubMedCrossRefGoogle Scholar
  5. Bauchinger M, Koester L, Schmid E, Dresp J, Streng S (1984) Chromosome aberrations in human lymphocytes induced by fission neutrons. Int J Radiat Biol 45: 449–457CrossRefGoogle Scholar
  6. Boice JD Jr, Engholm G, Kleinerman RA et al (1988) Radiation dose and second cancer risk in patients treated for cancer of the cervix. Radiat Res 116: 3–55PubMedCrossRefGoogle Scholar
  7. Breteau N, Le Bourgeois J-P, Barendsen GW, Stannard CE, Rosenwald J-C, Wambersie A (1996) Hadrons in radiation therapy. Bull Cancer (Paris) 83 SupplGoogle Scholar
  8. Broerse JJ, Hennen LA, van Zwieten MJ (1985) Radiation carcinogenesis in experimental animals and its implications for radiation protection. Int J Radiat Biol 48: 167–187CrossRefGoogle Scholar
  9. Broerse JJ, Van Bekkum DW, Zurcher C (1989) Radiation carcinogenesis in experimental animals. Experientia 45: 60–69PubMedCrossRefGoogle Scholar
  10. Cox R, Thacker J, Goodhead DT (1977) Inactivation and mutation of cultured mammalian cells by aluminium characteristic ultrasoft X-rays. II. Dose-responses of Chinese hamster and human diploid cells to aluminium X-rays and radiations of different LET. Int J Radiat Biol 31: 561–576CrossRefGoogle Scholar
  11. Curtis RE, Boice JD Jr, Stovall M et al (1992) Risk of leukemia after chemotherapy and radiation treatment for breast cancer. N Engl J Med 326: 1745–1751PubMedCrossRefGoogle Scholar
  12. Day NE, Boice JD Jr (eds) Second cancers in relation to radiation treatment for cervical cancer. IARC Sci Publ 52Google Scholar
  13. De Vathaire F, Francois P, Hill C et al (1989) Role of radiotherapy and chemotherapy in the risk of second malignant neoplasms after cancer in childhood. Br J Cancer 59: 792–796PubMedCrossRefGoogle Scholar
  14. Dennis JA (1976) Somatic aberrations induction in Tradescantia occidentalis by neutrons, X and gamma radiations. II. Biological results, RBE and OER. Int J Radiat Biol 29: 323–342CrossRefGoogle Scholar
  15. Di Paola M, Coppola M, Baarli J, Bianchi M, Sullivan AH (1980) Biological responses to various neutron energies from 1 to 600 MeV. II. Lens opacification in mice. Radiat Res 84: 453–461PubMedCrossRefGoogle Scholar
  16. Dicello JF, Wasiolek M, Zaider M (1991) Measured microdosimetric spectra of energetic ion beams of Fe, Ar, Ne and C: limitations of LET distributions and quality factor in radiation effects and space research. IEEE Trans Nucl Sci 38: 1203–1209CrossRefGoogle Scholar
  17. Dobson RL, Straume T (1982) Cancer risk and neutron RBE’s from Hiroshima and Nagasaki. In: Broerse JJ, Gerber GB (eds) Neutron carcinogenesis. Commission of the European Communities, Luxembourg, pp 279–299. Radiation protection report EUR 8084 ENGoogle Scholar
  18. Dufrain RJ, Littlefield LG, Joiner EE, Frome EL (1979) Human cytogenetic dosimetry: a dose response relationship for alpha radiation from 241 Am. Health Phys 37: 279–290CrossRefGoogle Scholar
  19. Edwards AA (1997) RBE values for neutron radiations. National Radiological Protection Board, Chilton, pp 7–8, Bulletin 193Google Scholar
  20. Edwards AA, Lloyd DC, Purrott RJ, Prosser JS (1982) The dependence of chromosome aberration yields on dose rate and radiation quality. In: Research and development report, 1979–1981. National Radiological Protection Board, Chilton, pp 83–85Google Scholar
  21. Fabry L, Leonard A, Wambersie A (1985) Induction of chromosome aberrations in Go human lymphocytes by low doses of ionizing radiations of different quality. Radiat Res 103: 122–134PubMedCrossRefGoogle Scholar
  22. Fry RIM, Powers-Risius P, Alpen EL, Ainsworth EJ, Ullrich RL (1983) High LET radiation carcinogenesis. Adv Space Res 3 (8): 241–243PubMedCrossRefGoogle Scholar
  23. Furuse T, Noda Y, Otsu H, Ohara H (1997) High-LET induced tumours in mice: tumour spectrum and RBEs. In: National Institute of Radiological Sciences (ed) Annual report 1996. NIRS, Chiba, pp 48–49Google Scholar
  24. Geard CR (1996) Neutron induced recoil protons of restricted energy and range and biological effectiveness. Health Phys 70 (6): 804–811PubMedCrossRefGoogle Scholar
  25. Geard CR, Brenner DJ (1997) Chromosome aberrations induced by neutrons: implications for radiation protection. In: EDF (ed) Effects biologiques des neutrons: conséquences en radioprotection. Electricité de France, Paris, pp 31–43 (Report no 10)Google Scholar
  26. Grahn D, Fritz T (1984) Studies on chronic radiation injury with mice and dogs exposed to external whole body irradiation at ANL. In: Proceedings of the 22nd Symposium on Life Sciences, Batelle Pacific Northwest Laboratory, Hanford, 27–30 Sept 1983: US DOE Conf-830951Google Scholar
  27. Grahn D, Thomson JF, Williamson FS, Lombard LS (1983) Somatic and genetic effects of low doses of fission neutrons and Co-60 gamma rays. In: Proceedings of the 7th International Congress of Radiation Research, Amsterdam 3–10 July 1983. Abstract Book C. Nijhoff, Dordrecht, pp C2 - C5Google Scholar
  28. Gueulette J, Beauduin M, Grégoire V, Vynckier S, De Coster BM, Octave-Prignot M, Wambersie A, Strijkmans K, De Schrijver A, El-Akkad S, Böhm L, Slabbert JP, Jones DTL, Maughan R, Onoda J, Yudelev M, Porter AT, Powers WE, Sabattier R, Breteau N, Courdi A, Brassart N, Chauvel P (1996) RBE variation between fast neutron beams as a function of energy. Intercomparison involving 7 neutrontherapy facilities. Bull Cancer (Paris) 83 Suppl 1: 55s - 63sGoogle Scholar
  29. Hahn A, Hill CK, Elkind MM (1984) Repair processes and radiation quality in neoplastic transformation of mammalian cells. Radiat Res 199: 249–261CrossRefGoogle Scholar
  30. Hall EJ (1996) Neutrons and carcinogenesis: a cautionary tale. Bull Cancer (Paris) 83 Suppl 1: 43s - 46sGoogle Scholar
  31. Hall EJ, Novak JK, Kellerer AM, Rossi HH, Marino S, Goodman LJ (1975) RBE as function of neutron energy. I. Experimental observations. Radiat Res 64: 245–255PubMedCrossRefGoogle Scholar
  32. Hei TK, Hall EJ, Waldren CA (1988) Mutation induction and relative biological effectiveness of neutrons in mammalian cells. Radiat Res 115: 281–291PubMedCrossRefGoogle Scholar
  33. Hempelmann L, Lushbaugh C, Voelz G (1980) What happened to the survivors of the early Los Alamos nuclear accidents? In: Hubner K, Fry S (eds) The medical basis for radiation accident preparedness. Elsevier/North-Holland, New York, pp 17–32Google Scholar
  34. Hill CK, Carnes BA, Han A, Elkind MM (1985) Neoplastic transformation is enhanced by multiple low doses of fission-spectrum neutrons. Radiat Res 102: 404–410PubMedCrossRefGoogle Scholar
  35. Hollander CF, van Zwieten MJ, Broerse JJ (1982) Carcinogenesis studies in rhesus monkeys after fission neutron and X-irradiation. In: Broerse JJ, Gerber GB (eds) Neutron carcinogenesis. Commission of the European Communities, Luxembourg, pp 183–185 (Radiation protection report EUR 8084 EN)Google Scholar
  36. ICRP (1963) Report of the RBE Subcommittee to the International Commission of Radiological Protection and the International Commission on Radiation Units and Measurements. Health Phys 9: 357–386Google Scholar
  37. ICRP (1991) 1990 recommendations of the International Commission on Radiological Protection. Pergamon, Oxford (ICRP pubi 60)Google Scholar
  38. ICRP (1996) Conversion coefficients for use in radiological protection against external radiation. Report of a Joint Task Group of the International Commission on Radiological Protection (ICRP) and of the International Commission on Radiation Units and Measurements (ICRU). Pergamon, Oxford (ICRP pubi 74, vol 26 )Google Scholar
  39. ICRU (1977) Neutron dosimetry for biology and medicine. International Commission on Radiation Units and Measurements, Bethesda (ICRU report 26 )Google Scholar
  40. ICRU (1978) Dose specification for reporting external beam therapy with photons and electrons. International Commission on Radiation Units and Measurements, ( ICRU report 29 )Google Scholar
  41. ICRU (1980) Radiation quantities and units. International Commission on Radiation Units and Measurements, Bethesda (ICRU report 33 )Google Scholar
  42. ICRU (1983) Microdosimetry. International Commission on Radiation Units and Measurements, Bethesda (ICRU report 36 )Google Scholar
  43. ICRU (1992) Photon, electron, proton and neutron interaction data for body tissues. International Commission on Radiation Units and Measurements, Bethesda (ICRU report 46 )Google Scholar
  44. ICRU (1993a) Stopping powers and ranges for proton and alpha particles. International Commission on Radiation Units and Measurements, Bethesda (ICRU report 49 )Google Scholar
  45. ICRU (1993b) Quantities and units in radiation protection dosimetry. International Commission on Radiation Units and Measurements, Bethesda (ICRU report 51 )Google Scholar
  46. Karzmark CJ (ed) (1987) Total skin electron therapy: technique and dosimetry. American Institute of Physics, New York (American Association of Physicists in Medicine, report 23 )Google Scholar
  47. Karzmark CJ, Nunan S, Tanabe E (1993) Medical electron accelerators. McGraw-Hill, New YorkGoogle Scholar
  48. Kellerer AM, Rossi HH (1972) The theory of dual radiation action. Curr Top Radiat Res Q 8: 85Google Scholar
  49. Kliauga PJ, Dvorak R (1978) Microdosimetric measurements of ionization by monoenergetic photons. Radiat Res 73: 1PubMedCrossRefGoogle Scholar
  50. Léonard A, Gerber GB (1982) RBE and dose-effect relationships in mammalian somatic and germ cells. In: Broerse JJ, Gerber GB (eds) Neutron carcinogenesis. Commission of the European Communities, Luxembourg, pp 361–364 (Radiation protection, report EUR 8084 EN)Google Scholar
  51. Little JB, Kennedy AR, McGandy RB (1985) Effect of dose rate on the induction of experimental lung cancer in hamsters by alpha radiation. Radiat, Res 103: 293–299CrossRefGoogle Scholar
  52. Lundgren DL, Gillet NA, Hahn FF, Griffith WC, McClellan RO (1987) Effects of protraction of the alpha dose to the lungs of mice by repeated inhalation exposure to aerosols of Pu-239-oxide. Radiat Res 111: 201–224PubMedCrossRefGoogle Scholar
  53. Maisin JR, Wambersie A, Gerber GB, Gueulette J, Mattelin G, Lambiet-Collier M (1983) Life shortening and disease incidence in BALB/c mice following a single d(50)+Be neutron or gamma exposure. Radiat Res 94: 374–389PubMedCrossRefGoogle Scholar
  54. Maisin JR, Wambersie A, Gerber GB, Mattelin G, Lambiet-Collier M, De Coster B, Gueulette J (1988) Life shortening and disease incidence in C57 BI mice after single and fractionated y and high-energy neutron exposure. Radiat Res 113: 300–317PubMedCrossRefGoogle Scholar
  55. Maisin JR, Vankerkom J, De Saint-Georges L, Janowski M, Lambiet-Collier M, Mattelin G, Wambersie A (1995) Effects of neutrons alone or combined with diethylnitrosamine on tumour induction in the livers of infant C57BL mice. Radiat Res 142: 78–84PubMedCrossRefGoogle Scholar
  56. Maisin JR, Gerber GB, Vankerkom J, Wambersie A (1996) Survival and diseases in C57BL mice exposed to X rays or 3.1 MeV neutrons at an age of 7 or 21 days. Radiat Res 146: 453–460PubMedCrossRefGoogle Scholar
  57. Merriam GR, Worgul BV, Medvedovsky C, Zaider M, Rossi HH (1984) Accelerated heavy particles and the lens. I. Cataractogenic potential. Radiat Res 98: 129–140PubMedCrossRefGoogle Scholar
  58. Nath R, Epp ER, Laughlin JS, Swanson WP, Bond VP (1984) Neutrons from high-energy x-ray medical accelerators: an estimate of risk to the radiotherapy patient. Med Phys 11: 231–241PubMedCrossRefGoogle Scholar
  59. NCRP (1990) The relative biological effectiveness of radiations of different quality. National Council on Radiation Protection and Measurements. Bethesda (Report no 104 )Google Scholar
  60. Pihet P (1989) Etude microdosimétrique des faisceaux de neutrons de haute énergie. Appli-cations dosimétriques et radiobiologiques. PhD thesis, Catholic University of LouvainGoogle Scholar
  61. Pihet P, Menzel HG, Haut H, Garot PJ, Wambersie A (1985) Shape of the RBE dose relationship for fast neutrons at low doses for somatic mutations in Tradescantia. In: Schraube H, Burger G (eds) Proceedings of the 5 fth Symposium on Neutron Dosimetry, Munich 1984, vol 1. Commission of the European Communities, Luxembourg, pp 45–55 (Report no EUR 9762)Google Scholar
  62. Pohl-Ruling J, Fischer P, Lloyd DC, Edwards AA, Natarajan AC et al (1986) Chromosomal damage in human lymphocytes by low doses of D-T neutrons. Mutat Res 173: 267–272PubMedCrossRefGoogle Scholar
  63. Prasanna PGS, Kolanko CJ, Gerstenberg HM, Blakely WF (1997) Premature chromosome condensation assay for biodosimetry: studies with fission neutrons. Health Phys 72: 594–600PubMedCrossRefGoogle Scholar
  64. Rodgers RC, Gross W (1974) Microdosimetry of monoenergetic neutrons. In: Proceedings of the 4th Symposium on Microdosimetry. Booz J, Ebert H, Eickel R, Waker A (eds) Commission of the European Communities, Luxembourg, p 1027 (Report no EUR 5122)Google Scholar
  65. Rossi HH (1996) Radiation physics and radiobiology. Health Phys 70 (6): 828–831PubMedCrossRefGoogle Scholar
  66. Sabatier L, Al Achkar W, Hoffschir F, Luccioni C, Dutrillux B (1987) Qualitative study of chromosomal lesions induced by neutrons and neon ions in human lymphocytes at Go phase. Mutat Res 178: 91–97PubMedCrossRefGoogle Scholar
  67. Savage JRK (1982) RBE of neutrons for genetic effects. In: Broerse JJ, Gerber GB (eds) Neutron carcinogenesis. Commission of the European Communities, Luxembourg, pp 307–332 (Radiation protection, report EUR 8084 EN)Google Scholar
  68. Savage JRK, Holloway M (1988) Induction of sister-chromatid exchanges by d(42 MeV)-Be neutrons in unstimulated human-blood lymphocytes. Br J Radiol 61: 231–234PubMedCrossRefGoogle Scholar
  69. Shellabarger CJ, Chmelevsky D, Kellerer AM (1980) Induction of mammary neoplasms in the Sprague-Dawley rat by 430 keV neutrons and X-rays. J Natl Cancer Inst 64: 821–833PubMedGoogle Scholar
  70. Shellabarger CJ, Chmelevsky D, Kellerer AM, Stone JP, Holtzman S (1982) Induction of mammary neoplasms in the ACI rat by 430 keV neutrons, X-rays and diethylstilboestrol. J Natl Cancer Inst 69: 1135–1146PubMedGoogle Scholar
  71. Sinclair WK (1985) Experimental RBE values of high LET radiations at low doses and the implications for quality factor assigment. Radiat Protect Dosimetry 13 (1–4): 319–326Google Scholar
  72. Sinclair WK (1996) The present system of quantities and units for radiation protection. Health Phys 70 (6): 781–786PubMedCrossRefGoogle Scholar
  73. Sparrow AH, Underbrink AG, Rossi HH (1972) Mutations induced in Tradescantia by small doses of X-rays and neutrons: analysis of dose-response curve. Science 76: 916–918CrossRefGoogle Scholar
  74. Storer JB, Mitchell TJ (1984) Limiting values for the RBE of fission neutrons at low doses for life shortening in mice. Radiat Res 97: 396–406PubMedCrossRefGoogle Scholar
  75. Straume TS, Egbert SD, Woolson WA, Finckel RC, Kubik PW, Gove HE, Sharma P, Hoshi M (1992) Neutron discrepancies in the DS 86 Hiroshima dosimetry system. Health Phys 63 (4): 421–426PubMedCrossRefGoogle Scholar
  76. Thacker J, Stretch A, Goodhead DT (1982) The mutagenecity of alpha particles from 239 Plutonium. Radiat Res 92: 343–352PubMedCrossRefGoogle Scholar
  77. Thomson JF, Williamson FS, Grahn D (1985) Life shortening in mice exposed to fission neutrons and gamma-rays. Radiat Res 104: 420–428PubMedCrossRefGoogle Scholar
  78. Tucker MA, Coleman CN, Cox RS et al (1988) Risk of second cancers after treatment for Hodgkin’s disease. N Engl J Med 318 (2): 76–81PubMedCrossRefGoogle Scholar
  79. Tubiana M, Dutreix J, Wambersie A (1990) Neutrons and other heavy particles. In: Introduction to radiobiology. Taylor and Francis, London, pp 273–312Google Scholar
  80. Ullrich RL (1982) Lung tumor induction in mice: neutron RBE at low doses. In: Broerse JJ, Gerber GB (eds) Neutron carcinogenesis. Commission of the European Communities, Luxembourg, pp 43–55 (Radiation protection, report EUR 8084 EN)Google Scholar
  81. Ullrich RL (1983) Tumor induction in BALB/c female mice after fission neutron or gamma-irradiation. Radiat Res 93: 506–515PubMedCrossRefGoogle Scholar
  82. Ullrich RL (1984) Tumor induction in BALB/c mice after fractionated and protracted exposures to fission-spectrum neutrons. Radiat Res 97: 587–597PubMedCrossRefGoogle Scholar
  83. Underbrink AG, Sparrow AH, Sautkulis D, Mills RE (1975) An elusive factor affecting mutation frequency in Tradescantia stamen hairs: its influence on RBE. Int J Radial Biol 28: 527–538CrossRefGoogle Scholar
  84. Underbrink AG, Kellerer AM, Mills RE, Sparrow AH (1976) Comparison of x-ray and gamma-ray dose responses curves for pink somatic mutations in Tradescantia clone 02. Radiat Environ Biophys 13: 295–303PubMedCrossRefGoogle Scholar
  85. UNSCEAR (1982) Ionizing radiation: sources and biological effects. United Nations Scientific Committee on the Effects of Atomic Radiations, New York (1982 report to the General Assembly, with annexes)Google Scholar
  86. UNSCEAR (1993) Report to the General Assembly, with scientific annexes. United Nations Scientific Committee on the Effects of Atomic Radiations, New York (United Nations publication sales no E.94.IX. 2)Google Scholar
  87. Van Dam J, Bonte J, Dutreix A, Bouhnik H, Wambersie A (1982) RBE of californium-252 at low dose rate for growth inhibition in Vivia faba. J Eur Radiother 3: 109–120Google Scholar
  88. Van der Kogel AJ (1979) Late effects of radiation on the spinal cord: dose-effect relationships and pathogenesis. Thesis, University of AmsterdamGoogle Scholar
  89. Vogel HH, Dickson HW (1982) Mammary neoplasia in Sprague-Dawley rats following acute and protracted irradiation. In: Broerse JJ, Gerber GB (eds) Neutron carcinogenesis. Commission of the European Communities, Luxembourg, pp 135–168 (Radiation protection, report EUR 8084 EN)Google Scholar
  90. Vulpis N (1973) Chromosome aberrations induced in human peripheral blood lymphocytes using heavy particles from the 10 B(n,alpha)Li reaction. Mutat Res 18: 103–111PubMedCrossRefGoogle Scholar
  91. Wambersie A (1992) Neutron therapy: from radiobiological expectation to clinical reality. Radiat Protect Dosimetry 44: 379–395Google Scholar
  92. Wambersie A, Gahbauer RA (1996) Medical applications of electron linear accelerators. In: Turner S (ed) CERN Accelerator School (CAS): Cyclotrons, linacs and their applications. CERN 96–02, 4 March 1996. CERN, Geneva, pp 229–248Google Scholar
  93. Wambersie A, Menzel HG (1997) Specification of absorbed dose and radiation quality in heavy particle therapy (a review). Radiat Protect Dosimetry 70: 517–527Google Scholar
  94. Wambersie A, Grégoire V, Brucher J-M (1992) Potential clinical gain of proton (and heavy ion) beams for brain tumors in children. Int J Radiat Oncol Biol Phys 22: 275–286PubMedCrossRefGoogle Scholar
  95. Wolber G, Guibbaud Y, Dollo R (1996) Neutron dosimetry in French nuclear power plants. Problems and their solutions in 1995. Bull Cancer (Paris) 83 Suppl 1: 19s - 26sGoogle Scholar

Copyright information

© Springer-Verlag Berlin · Heidelberg 1998

Authors and Affiliations

  • H. Engels
    • 1
    • 2
  • A. Wambersie
    • 2
  1. 1.Department. of Radiation ProtectionStudiecentrum voor Kernergie (SCK/CEN)MolBelgium
  2. 2.Cliniques Universitaires St-LucUniversité Catholique de LouvainBrusselsBelgium

Personalised recommendations