Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Assessing the risk of second malignancies after modern radiotherapy

Nature Reviews Cancer volume 11, pages 438–448 (2011)Cite this article

Subjects

Key Points

  • The availability of high-energy beams of photons, protons and carbon ions has contributed to increases in tumour control and the sparing of normal tissues from acute radiation toxicity.

  • Advances in cancer therapies for children have produced impressive prospects for long-term survival. Approximately 80% of children and adolescents treated for cancer survive more than 5 years, but roughly 73% of them develop treatment-related complications. The complication of perhaps greatest concern is the risk for developing a radiogenic second malignant neoplasm (SMN), which can develop years or decades after treatment.

  • Although the patient receives a high dose of therapeutic radiation, which is focused at the diseased tissue, the entire body is exposed to comparatively low doses of unwanted radiation that are caused by radiation leaking from the treatment apparatus and by scattering of the therapeutic radiation within the body.

  • Mechanisms of therapy-related cancers are similar to those of sporadic tumorigenesis, but the carcinogenic potential of low doses of photons is not completely understood, and the uncertainty is much higher for cancer that is induced by charged particles.

  • Epidemiological studies have conclusively shown that some SMNs can develop in tissues that are located in-field (that is, in the path of the therapeutic beam) and out-of-field (outside the path of the therapeutic beam).

  • Recent models predict that particle therapy lowers the risk of SMNs compared with contemporary photon therapies.

  • Regardless of the type of radiation beams used, nascent approaches to personalized, risk-adapted radiotherapy seem to be likely to yield further reductions in risk from out-of-field exposures, and research in genetic susceptibility and radiobiology should help to identify biomarkers of long-term risk in cancer survivors.

Abstract

Recent advances in radiotherapy have enabled the use of different types of particles, such as protons and heavy ions, as well as refinements to the treatment of tumours with standard sources (photons). However, the risk of second cancers arising in long-term survivors continues to be a problem. The long-term risks from treatments such as particle therapy have not yet been determined and are unlikely to become apparent for many years. Therefore, there is a need to develop risk assessments based on our current knowledge of radiation-induced carcinogenesis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Treatment planning.
Figure 2: Secondary neutron dose in particle therapy.
Figure 3: Dose–response curve for carcinogenesis.
Figure 4: Dose and risk distribution for second cancer.

Similar content being viewed by others

References

  1. Smith, M. A. et al. Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J. Clin. Oncol. 28, 2625–2634 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Friedman, D. L. et al. Subsequent neoplasms in 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J. Natl. Cancer Inst. 102, 1083–1095 (2010). These are the most recent results of the CCSS, the most important epidemiological analysis of SMNs in children.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Oeffinger, K. C. et al. for the Childhood Cancer Survivor Study. Chronic health conditions in adult survivors of childhood cancer. N. Eng. J. Med. 355, 1572–1582 (2006).

    Article  CAS  Google Scholar 

  4. Robison, L. L. et al. The Childhood Cancer Survivor Study: a National Cancer Institute-supported resource for outcome and intervention research. J. Clin. Oncol. 27, 2308–2318 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  5. West, C. & Rosenstein, B. S. Establishment of a radiogenomics consortium. Radiother. Oncol. 94, 117–118 (2010).

    Article  PubMed  Google Scholar 

  6. Travis, L. B. et al. Cancer survivorship--genetic susceptibility and second primary cancers: research strategies and recommendations. J. Natl. Cancer Inst. 98, 15–25 (2006).

    Article  PubMed  Google Scholar 

  7. Tubiana, M. Can. we reduce the incidence of second primary malignancies occurring after radiotherapy? A critical review. Radiother. Oncol. 91, 4–15 (2009).

    Article  PubMed  Google Scholar 

  8. Meropol, N. J. & Schulman, K. A. Cost of cancer care: issues and implications. J. Clin. Oncol. 25, 180–186 (2007).

    Article  PubMed  Google Scholar 

  9. Terasawa, T. et al. Systematic review: charged-particle radiation therapy for cancer. Ann. Intern. Med. 151, 556–565 (2009).

    Article  PubMed  Google Scholar 

  10. Durante, M. & Loeffler, J. S. Charged particles in radiation oncology. Nature Rev. Clin. Oncol. 7, 37–43 (2010). A review of the open research topics in particle therapy, including both tumour control and the risk of complications.

    Article  Google Scholar 

  11. Schulz-Ertner, D. & Tsujii, H. Particle radiation therapy using proton and heavier ion beams. J. Clin. Oncol. 25, 953–964 (2007).

    Article  PubMed  Google Scholar 

  12. Hall, E. J. Intensity-modulated radiation therapy, protons, and the risk of second cancers. Int. J. Radiat. Oncol. Biol. Phys. 65, 1–7 (2006). This paper started the heated debate on the risk of secondary cancers using IMRT and proton therapy.

    Article  PubMed  Google Scholar 

  13. Brenner, D. J. & Hall, E. J. Secondary neutrons in clinical proton radiotherapy: a charged issue. Radiother. Oncol. 86, 165–170 (2008).

    Article  PubMed  Google Scholar 

  14. Newhauser, W. D. Complexity of advanced radiation therapy necessitates multidisciplinary inquiry into dose reconstruction and risk assessment. Phys. Med. Biol. 55, e01 (2010).

    Article  Google Scholar 

  15. Reulen, R. C. et al. Long-term cause-specific mortality among survivors of childhood cancer. JAMA 304, 172–179 (2010).

    Article  CAS  PubMed  Google Scholar 

  16. Yock, T. I. & Tarbell, N. J. Proton beam radiotherapy for treatment in pediatric brain tumors. Nature Clin. Pract. Oncol. 1, 97–103 (2004).

    Article  Google Scholar 

  17. Combs, S. E. et al. Carbon ion radiotherapy for pediatric patients and young adults treated for tumors of the skull base. Cancer 115, 1348–1355 (2009).

    Article  PubMed  Google Scholar 

  18. Merchant, T. E. Proton beam therapy in pediatric oncology. Cancer J. 15, 298–305 (2009).

    Article  PubMed  Google Scholar 

  19. Armstrong, G. T., Stovall, M. & Robison, L. L. Long-term effects of radiation exposure among adult survivors of childhood cancer: results from the Childhood Cancer Survivor Study. Radiat. Res. 174, 840–850 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lichter, A. S. & Lawrence, T. S. Recent advances in radiation oncology. N. Engl. J. Med. 332, 371–379 (1995).

    Article  CAS  PubMed  Google Scholar 

  21. Bernier, J., Hall, E. J. & Giaccia, A. Radiation oncology: a century of achievements. Nature Rev. Cancer 4, 737–747 (2004).

    Article  CAS  Google Scholar 

  22. Bucci, M. K., Bevan, A. & Roach, M. 3rd. Advances in radiation therapy: conventional to 3D, to IMRT, to 4D, and beyond. CA Cancer J. Clin. 55, 117–134 (2005).

    Article  PubMed  Google Scholar 

  23. Goodhead, D. T. et al. Direct comparison between protons and alpha-particles of the same LET: I. Irradiation methods and inactivation of asynchronous V79, HeLa and C3H 10T1/2 cells. Int. J. Radiat. Biol. 61, 611–624 (1992).

    Article  CAS  PubMed  Google Scholar 

  24. Edwards, A. A. RBE of radiations in space and the implications for space travel. Phys. Med. 17, S147–S152 (2001).

    Google Scholar 

  25. Webb, S. The physical basis of IMRT and inverse planning. Br. J. Radiol. 76, 678–689 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Bortfeld, T. IMRT: a review and preview. Phys. Med. Biol. 51, R363–R379 (2006).

    Article  PubMed  Google Scholar 

  27. Verellen, D. et al. Innovations in image-guided radiotherapy. Nature Rev. Cancer 7, 949–960 (2007).

    Article  CAS  Google Scholar 

  28. Hall, E. J. & Wuu, C. S. Radiation-induced second cancers: the impact of 3D-CRT and IMRT. Int. J. Radiat. Oncol. Biol. Phys. 56, 83–88 (2003).

    Article  PubMed  Google Scholar 

  29. Halperin, E. C. Particle therapy and treatment of cancer. Lancet Oncol. 7, 676–685 (2006).

    Article  CAS  PubMed  Google Scholar 

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

    Article  Google Scholar 

  31. Durante, M. & Cucinotta, F. A. Heavy ion carcinogenesis and human space exploration. Nature Rev. Cancer 8, 465–472 (2008).

    Article  CAS  Google Scholar 

  32. Xu, X. G., Bednarz, B. & Paganetti, H. A review of dosimetry studies on external-beam radiation treatment with respect to second cancer induction. Phys. Med. Biol. 53, 193–241 (2008). A comprehensive review that includes a careful comparison of the secondary radiation from different radiotherapy facilities.

    Article  Google Scholar 

  33. Krämer, M. & Durante, M. Ion beam transport calculations and treatment plans in particle therapy. Eur. Phys. J. D60, 195–202 (2010).

    Google Scholar 

  34. Howell, R. M. et al. Methodology for determining doses to in-field, out-of-field and partially in-field organs for late effects studies in photon radiotherapy. Phys. Med. Biol. 55, 7009–7023 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Stovall, M. et al. Dose reconstruction for therapeutic and diagnostic radiation exposures: use in epidemiological studies. Radiat. Res. 166, 141–157 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. Newhauser, W. D. et al. Can megavoltage computed tomography reduce proton range uncertainties in treatment plans for patients with large metal implants? Phys. Med. Biol. 53, 2327–2344 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Schneider, U. et al. Secondary neutron dose during proton therapy using spot scanning Int. J. Radiat. Oncol. Biol. Phys. 53, 244–251 (2002).

    Article  PubMed  Google Scholar 

  38. Gunzert-Marx, K. et al. Secondary beam fragments produced by 200 MeVu−112C ions in water and their dose contributions in carbon ion radiotherapy. New J. Phys. 10, 075003 (2008). A comprehensive set of measurements on neutrons produced by heavy ion therapy.

    Article  CAS  Google Scholar 

  39. Yonai, S. et al. Measurement of absorbed dose, quality factor, and dose equivalent in water phantom outside of the irradiation field in passive carbon-ion and proton radiotherapies. Med. Phys. 37, 4046–4055 (2010).

    Article  CAS  PubMed  Google Scholar 

  40. Münter, M. et al. Heavy ion radiotherapy during pregnancy. Fertil. Steril. 94, 2329.e5–7 (2010). Direct evidence from a pregnant patient that particle therapy produced low levels of stray radiation in distal organs.

    Article  Google Scholar 

  41. ICRU. Prescribing, recording, and reporting proton-beam therapy. ICRU Report No. 78. (J. ICRU, 2007).

  42. Wambersie, A. et al. The RBE issues in ion-beam therapy: conclusions of a joint IAEA/ICRU working group regarding quantities and units. Radiat. Prot. Dosim. 122, 463–470 (2006).

    Article  CAS  Google Scholar 

  43. Brenner, D. J. Effective dose: a flawed concept that could and should be replaced. Br. J. Radiol. 81, 521–523 (2008).

    Article  CAS  PubMed  Google Scholar 

  44. ICRP. Recommendations of the ICRP. ICRP Publication 103.) Ann. ICRP 37 2007).

  45. El Ghissassi, F. et al. A review of human carcinogens-part D: radiation. Lancet Oncol. 10, 751–752 (2009).

    Article  PubMed  Google Scholar 

  46. UNSCEAR. Effects of Ionizing Radiation. Volume I. Annex A: Epidemiological Studies of Radiation and Cancer. (United Nations Office, Vienna, 2006).

  47. Pawel, D. et al. Improved estimates of cancer site-specific risks for A-bomb survivors. Radiat. Res. 169, 87–98 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Mullenders, L. et al. Assessing cancer risks of low-dose radiation. Nature Rev. Cancer 9, 596–604 (2009).

    Article  CAS  Google Scholar 

  49. Schneider, U., Lomax, A. & Timmermann, B. Second cancers in children treated with modern radiotherapy techniques. Radiother. Oncol. 89, 135–140 (2008).

    Article  PubMed  Google Scholar 

  50. Sachs, R. K. & Brenner, D. J. Solid tumor risks after high doses of ionizing radiation. Proc. Natl Acad. Sci. USA 102, 13040–13045 (2005). An excellent model of risk at high doses, which is important for radiotherapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Allan, J. M. & Travis, L. B. Mechanisms of therapy-related carcinogenesis. Nature Rev. Cancer 5, 943–955 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. Little, M. P. Cancer after exposure to radiation in the course of treatment for benign and malignant disease. Lancet Oncol. 2, 212–220 (2001).

    Article  CAS  PubMed  Google Scholar 

  53. Malone, K. K. et al. Population-based study of the risk of second primary contralateral breast cancer associated with carrying a mutation in BRCA1 or BRCA2. J. Clin. Oncol. 28, 2404–2410 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Negrini, S., Gorgoulis, V. G. & Halazonetis, T. D. Genomic instability-an evolving hallmark of cancer. Nature Rev. Mol. Cell. Biol. 11, 220–228 (2010).

    Article  CAS  Google Scholar 

  55. Rosemann, M. et al. Multilocus inheritance determines predisposition to α-radiation induced bone tumourigenesis in mice. Int. J. Cancer 118, 2132–2138 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Gonzalez-Vasconcellos, I. et al. Differential effects of genes of the Rb1 signalling pathway on osteosarcoma incidence and latency in α-particle irradiated mice. Radiat. Environ. Biophys. 50, 135–141 (2011).

    Article  CAS  PubMed  Google Scholar 

  57. Brenner, D. J. et al. Cancer risks attributable to low doses of ionizing radiation: assessing what we really know. Proc. Natl Acad. Sci. USA 100, 13761–13766 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Mothersill, C. & Seymour, C. B. Radiation-induced bystander effects-implications for cancer. Nature Rev. Cancer 4, 158–164 (2004).

    Article  CAS  Google Scholar 

  59. Coussens, L. M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Barcellos-Hoff, M. H., Park, C. & Wright, E. G. Radiation and the microenvironment - tumorigenesis and therapy. Nature Rev. Cancer 5, 867–875 (2005).

    Article  CAS  Google Scholar 

  61. Ikushima, H. & Myazono, K. TGFβ signalling: a complex web in cancer progression. Nature Rev. Cancer 10, 415–424 (2010).

    Article  CAS  Google Scholar 

  62. Shuryak, I., Sachs, R. K. & Brenner, D. J. Cancer risks after radiation exposure in middle age. J. Natl. Cancer Inst. 102, 1628–1636 (2010). An important model of age-dependent cancer risk that suggests that promotion not initiation could be the most important factor in radiation carcinogenesis in adults.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Goss, P. E & Chambers, A. F. Does tumour dormancy offer a therapeutic target? Nature Rev. Cancer 10, 871–877 (2010).

    Article  CAS  Google Scholar 

  64. Prise, K. M. & O'Sullivan, J. M. Radiation-induced bystander signalling in cancer therapy. Nature Rev. Cancer 9, 351–360 (2009).

    Article  CAS  Google Scholar 

  65. Mancuso, M. et al. Oncogenic bystander radiation effects in Patched heterozygous mouse cerebellum. Proc. Natl Acad. Sci. USA 105, 12445–12450 (2008). Evidence from an animal model that cancer in distal organs can be caused by a non-targeted (bystander) effect and not low dose, stray radiation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Burr, K. L. et al. Radiation-induced delayed bystander-type effects mediated by hemopoietic cells. Radiat. Res. 173, 760–768 (2010).

    Article  CAS  PubMed  Google Scholar 

  67. Calabrese, E. J. & Baldwin, L. A. Toxicology rethinks its central belief. Nature 421, 691–692 (2003).

    Article  CAS  PubMed  Google Scholar 

  68. Dobbs, T. A. et al. Interplay of two major repair pathways in the processing of complex double-strand DNA breaks. DNA Repair 7, 1372–1383 (2008).

    Article  CAS  PubMed  Google Scholar 

  69. Jakob, B. et al. Live cell microscopy analysis of radiation-induced DNA double-strand break motion. Proc. Natl Acad. Sci. USA 106, 3172–3177 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Ritter, S. & Durante, M. Heavy-ion induced chromosomal aberrations: a review. Mutat. Res. 701, 38–46 (2010).

    Article  CAS  PubMed  Google Scholar 

  71. Cucinotta, F. A. & Durante, M. Cancer risk from exposure to galactic cosmic rays: implications for space exploration by human beings. Lancet Oncol. 7, 431–435 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Ding, L. H. et al. Gene expression changes in normal human skin fibroblasts induced by HZE-particle radiation. Radiat. Res. 164, 523–526 (2005).

    Article  CAS  PubMed  Google Scholar 

  73. Ding, L. H. et al. Gene expression profiles of normal human fibroblasts after exposure to ionizing radiation: a comparative study of low and high doses. Radiat. Res. 164, 17–26 (2005).

    Article  CAS  PubMed  Google Scholar 

  74. Wood, D. H. Long-term mortality and cancer risk in irradiated rhesus monkeys. Radiat. Res. 126, 132–140 (1991).

    Article  CAS  PubMed  Google Scholar 

  75. Paganetti, H. et al. Relative biological effectiveness (RBE) values for proton beam therapy. Int. J. Radiat. Oncol. Biol. Phys. 53, 407–421 (2002).

    Article  PubMed  Google Scholar 

  76. Alpen, E. L. et al. Tumorigenic potential of high-Z., high-LET charged particle radiations. Radiat. Res. 88, 132–143 (1993).

    Article  Google Scholar 

  77. Dicello, J. F. et al. In vivo mammary tumourigenesis in the Sprague-Dawley rat and microdosimetric correlates. Phys. Med. Biol. 49, 3817–3830 (2004).

    Article  CAS  PubMed  Google Scholar 

  78. Wolf, C. et al. Neutron RBE for induction of tumors with high lethality in Sprague-Dawley rats. Radiat. Res. 154, 412–420 (2000).

    Article  CAS  PubMed  Google Scholar 

  79. Grahn, D., Lombard, L. S. & Carnes, B. A. The comparative tumorigenic effects of fission neutrons and cobalt-60 gamma rays in the B6CF1 mouse. Radiat. Res. 129, 19–36 (1992).

    Article  CAS  PubMed  Google Scholar 

  80. Hollander, C. F., Zurcher, C. & Broerse, J. J. Tumorigenesis in high-dose total body irradiated Rhesus Monkeys – a life span study. Toxicol. Pathol. 31, 209–213 (2003).

    CAS  PubMed  Google Scholar 

  81. Kuhne, W. W. et al. Biological effects of high-energy neutrons measured in vivo using a vertebrate model. Radiat. Res. 172, 473–480 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Weil, M. M. et al. Incidence of acute myeloid leukemia and hepatocellular carcinoma in mice irradiated with 1 GeV/nucleon 56Fe ions. Radiat. Res. 172, 213–219 (2009).

    Article  CAS  PubMed  Google Scholar 

  83. Rola, R. et al. Hippocampal neurogenesis and neuroinflammation after cranial irradiation with 56Fe particles. Radiat. Res. 169, 626–632 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. NCRP. Uncertainties in fatal cancer risk estimates used in radiation protection. Report No. 126. (NCRP, Bethesda, USA, 1997).

  85. Suit, H. et al. Secondary carcinogenesis in patients treated with radiation: a review of data on radiation-induced cancers in human, non-human primate, canine and rodent subjects. Radiat. Res. 167, 12–42 (2007).

    Article  CAS  PubMed  Google Scholar 

  86. Hill, C. K. et al. Fission-spectrum neutrons at reduced dose rates enhance neoplastic transformation. Nature 298, 67–69 (1982).

    Article  CAS  PubMed  Google Scholar 

  87. Brenner, D. J. & Hall, E. J. Commentary 2 to Cox and Little: radiation-induced oncogenic transformation: the interplay between dose, dose protraction, and radiation quality. Adv. Radiat. Biol. 16, 167–179 (1992).

    Article  CAS  PubMed  Google Scholar 

  88. National Research Council. Health Risks from Low Levels of Ionizing Radiation: BEIR VII Phase 2. (National Academies Press, Washington, DC, 2006).

  89. Miralbell, R. et al. Potential reduction of the incidence of radiation-induced second cancers by using proton beams in the treatment of pediatric tumors. Int. J. Radiat. Oncol. Biol. Phys. 54, 824–829 (2002). The first model of secondary cancers in paediatric patients treated with protons, suggesting that risk should be lower than for X-rays.

    Article  PubMed  Google Scholar 

  90. Newhauser, W. D. et al. The risk of developing a second cancer after receiving craniospinal proton irradiation. Phys. Med. Biol. 54, 2277–2291 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Fontenot, J. D., Lee, A. K. & Newhauser, W. D. Risk of secondary malignant neoplasms from proton therapy and intensity-modulated X-ray therapy for early-stage prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 74, 616–622 (2009). A direct comparison of predicted SMN risk for IMRT and protons indicating that a lower risk is expected for particles.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Taddei, P. J. et al. Risk of second malignant neoplasm following proton versus intensity-modulated photon radiotherapies for hepatocellular carcinoma. Phys. Med. Biol. 55, 7055–7065 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Taddei, P. J. et al. Effective dose from stray radiation for a patient receiving proton therapy for liver cancer. AIP Conf. Proc. 1099, 445–449 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Taddei, P. J. et al. Predicted risks of second malignant neoplasm incidence and mortality due to secondary neutrons in a girl and boy receiving proton craniospinal irradiation. Phys. Med. Biol. 55, 7067–7080 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Taddei, P. J. et al. Reducing stray radiation dose for a pediatric patient receiving proton cranospinal irradiation. Nucl. Techn. 168, 108–112 (2009). Evidence that simple counter measures can effectively reduce the secondary dose in paediatric patients.

    Article  CAS  Google Scholar 

  96. Taddei, P. J. et al. Reducing stray radiation dose to patients receiving passively scattered proton radiotherapy for prostate cancer. Phys. Med. Biol. 53, 2131–2147 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Ottolenghi, A., Smyth, V. & Trott, K. R. The risk to healthy tissue from the use of existing and emerging techniques for radiation therapy. Radiat. Prot. Dosim. 143, 533–535 (2011).

    Article  Google Scholar 

  98. Brenner, D. J. Medical imaging in the 21st century — getting the best bang for the rad. N. Eng. J. Med. 362, 943–945 (2010).

    Article  CAS  Google Scholar 

  99. Brenner, D. J. & Hricak, H. Radiation exposure from medical imaging: time to regulate? JAMA 304, 208–209 (2010).

    Article  CAS  PubMed  Google Scholar 

  100. Green, S. & Aird, E. Imaging in radiotherapy. Br. J. Radiol. 80, 967–969 (2007).

    Article  CAS  PubMed  Google Scholar 

  101. Deng, J. et al. Kilovoltage imaging dose in the radiotherapy of pediatric patients. Int. J. Radiat. Oncol. Biol. Phys. 6 Apr 2011 [e-pub ahead of print].

  102. Chung, C. S. et al. Comparative analysis of secondary malignancy risk in patients treated with proton therapy versus conventional photon therapy. Int. J. Radiat. Oncol. Biol. Phys. 72, S8 (2008).

    Article  Google Scholar 

  103. 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  CAS  PubMed  Google Scholar 

  104. Hartel, C. et al. Chromosomal aberrations in peripheral blood lymphocytes of prostate cancer patients treated with IMRT and carbon ions. Radiother. Oncol. 95, 73–78 (2010).

    Article  CAS  PubMed  Google Scholar 

  105. Mole, R. H. Dose–response relationships in Radiation Carcinogenesis: Epidemiology and Biologic Significance (eds Boice, J. D. and Fraumeni, J. F.) 263–271 (Raven Press, New York, 1984).

    Google Scholar 

Download references

Acknowledgements

This work was supported in part by the US National Cancer Institute (awards 1R01CA131463-01A1) and by Northern Illinois University, USA, through a subcontract of the US Department of Defense (award W81XWH-08-1-0205). Research on particle therapy at GSI is partially supported by EU FP7 (ALLEGRO project), ESA (IBER-project) and Beilstein Stiftung (NanoBiC program). The authors would like to thank K. B. Carnes for her assistance in preparing this manuscript.

Author information

Authors and Affiliations

  1. MD Anderson Cancer Center Radiation Oncology, 1515 Holcombe Boulevard, Houston, 77030-4009, Texas, USA

    Wayne D. Newhauser

  2. Department of Biophysics, GSI Helmholtz Center for Heavy-Ion Research, Planckstrasse 1, and Darmstadt University of Technology, Darmstadt, 64291, Germany

    Marco Durante

Authors
  1. Wayne D. Newhauser
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marco Durante
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Glossary

Medulloblastoma

Malignant primary brain tumour that originates in the cerebellum or posterior fossa.

Atomic bomb survivors database

Survivors of the atomic bombs dropped in 1945 in Japan have been followed for cancers for more than 60 years, and represent the main source of epidemiological data on radiogenic cancers.

Stray radiation

Therapeutic beam radiation that is emitted through the accelerator housing and reaches the patient outside of the treatment volume.

Radiation quality

Ionizing radiation includes many different qualities: high-energy electromagnetic radiation (such as X-rays), neutrons, electrons, protons and heavy ions. Their different biological effectiveness is scaled using weighting factors (Box 1).

Relative biological effectiveness

The ratio of the dose, DR, of a reference radiation (typically γ-ray or X-rays) and Dt of a test radiation (for example, neutrons, protons and heavy ions) that produce the same biological effect. It depends on several factors including the dose, dose rate, biological end point, radiation test LET and tissue.

α-particles

Helium nuclei emitted by some heavy elements by a natural radioactive process known as α-decay. They represent the high-LET component of the natural radiation background for the general population, mostly caused by inhalation of Radon gas.

Intensity-modulated radiation therapy

Currently the most advanced type of photon radiotherapy. Accurate conformation to the target tumour is achieved by increasing the intensity of the rays to the target, and reducing the intensity of the beams that cross sensitive structures. The resulting inhomogenous dose distribution in the single field is compensated by cold and hot spots in the beams coming from other directions.

Monitor units

A monitor unit (MU) is a measure of the linear accelerator (Linac) output. The dose to the target is calibrated with a detector (monitor), and therefore MUs correspond to a given dose to the tumour.

Bragg peak

Region where charged particles release most of their energy in matter, before stopping.

Passive proton beam shaping

A technique that spreads the Bragg peak, using attenuators and collimators.

Magnetically scanned beams

Also known as spot scanning, a technique to deliver particle therapy. A small pencil beam is deflected by a magnet in two dimensions to cover a slice of the tumour, and the next slice is exposed by changing the energy in the accelerator. Unlike passive beam shaping, it does not require attenuators to modulate the Bragg peak, and therefore the production of neutrons outside the patient's body is negligible.

Linear-no-threshold

The model commonly adopted by the International Regulatory Agencies to extrapolate the radiation risk at low doses. It is assumed that the cancer risk is always directly proportional to the absorbed dose.

Sterilization effects

At high radiation doses, the cell killing (sterilization) overcomes the radiation transforming potential, and hence the neoplastic transformation per exposed cell decreases.

Fractionation

The therapeutic radiation dose is very high (up to 60–70 Gy), but is normally delivered in daily fractions of approximately 2 Gy for effective sparing of the normal tissue.

Ataxia telangectasia

A rare and severe neurodegenerative disease (also known as Boder–Sedgwick or Louis–Bar syndrome). It is caused by a defect in ATM, which encodes a serine/threonine protein kinase involved in DNA repair and cell cycle regulation.

Non-targeted effects

Radiation effect observed in cells, tissue or organs not directly exposed to radiation. It can be caused by cell-to-cell communication via gap junctions, release of cytokines in the body, or mediated by the immune or nervous system.

Bystander effect

A non-targeted effect generally observed in cellular experiments. The 'bystander' cell can receive radiation damage, although only the neighbouring target cell is exposed.

Abscopal effect

A radiation response in an organ not directly exposed to the radiation field.

Harderian gland

A subcutaneous accessory lacrimal gland found within the eye's orbit in many vertebrates (not in humans).

Sparing effect

When the same radiation dose is delivered in multiple fractions, at intervals of several hours (typically 1 day), the biological damage is generally reduced.

Fission-spectrum neutrons

Neutrons produced during the nuclear fission process, typically in nuclear reactors for energy production. The energy spectrum peaks at about 1 MeV.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Newhauser, W., Durante, M. Assessing the risk of second malignancies after modern radiotherapy. Nat Rev Cancer 11, 438–448 (2011). https://doi.org/10.1038/nrc3069

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc3069

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer