Secondary Carcinogenesis in Patients Treated with Radiation: A Review of Data on Radiation-Induced Cancers in Human, Non-human Primate, Canine and Rodent Subjects

Abstract Suit, H., Goldberg, S., Niemierko, A., Ancukiewicz, M., Hall, E., Goitein, M., Wong, W. and Paganetti, H. 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). Concern for risk of radiation-induced cancer is growing with the increasing number of cancer patients surviving long term. This study examined data on radiation transformation of mammalian cells in vitro and on the risk of an increased cancer incidence after irradiation of mice, dogs, monkeys, atomic bomb survivors, occupationally exposed persons, and patients treated with radiation. Transformation of cells lines in vitro increased linearly with dose from ∼1 to ∼4–5 Gy. At <0.1 Gy, transformation was not increased in all studies. Dose–response relationships for cancer incidence varied with mouse strain, gender and tissue/organ. Risk of cancer in Macaca mulatta was not raised at 0.25–2.8 Gy. From the atomic bomb survivor study, risk is accepted as increasing linearly to 2 Sv for establishing exposure standards. In irradiated patients, risk of cancer increased significantly from 1 to 45 Gy (a low to a high dose level) for stomach and pancreas, but not for bladder and rectum (1–60 Gy) or kidney (1–15 Gy). Risk for several organs/tissues increased substantially at doses far above 2 Gy. There is great heterogeneity in risk of radiation-associated cancer between species, strains of a species, and organs within a species. At present, the heterogeneity between and within patient populations of virtually every parameter considered in risk estimation results in substantial uncertainty in quantification of a general risk factor. An implication of this review is that reduced risks of secondary cancer should be achieved by any technique that achieved a dose reduction down to −0.1 Gy, i.e. dose to tissues distant from the target. The proportionate gain should be greatest for dose decrement to less than 2 Gy.

[1]  K. Mossman Extrapolation of Radiation-Induced Cancer Risks from Nonhuman Experimental Systems to Humans , 2006 .

[2]  Division on Earth Health Risks from Exposure to Low Levels of Ionizing Radiation: BEIR VII Phase 2 , 2006 .

[3]  B. Asselain,et al.  Radiation‐induced sarcomas after radiotherapy for breast carcinoma , 2005, Cancer.

[4]  G. Gulis,et al.  Risk of cancer after low doses of ionising radiation: retrospective cohort study in 15 countries , 2005, BMJ : British Medical Journal.

[5]  S. Ashley,et al.  Risk of second brain tumor after conservative surgery and radiotherapy for pituitary adenoma: update after an additional 10 years. , 2005, The Journal of clinical endocrinology and metabolism.

[6]  C. Rubino,et al.  Radiation dose and risk of soft tissue and bone sarcoma after breast cancer treatment , 2005, Breast Cancer Research and Treatment.

[7]  S. Molloi,et al.  Neoplastic Transformation In Vitro after Exposure to Low Doses of Mammographic-Energy X Rays: Quantitative and Mechanistic Aspects , 2004, Radiation research.

[8]  Yukiko Shimizu,et al.  Effect of Recent Changes in Atomic Bomb Survivor Dosimetry on Cancer Mortality Risk Estimates , 2004, Radiation research.

[9]  G. Heyes,et al.  The Neoplastic Transformation Potential of Mammography X Rays and Atomic Bomb Spectrum Radiation , 2004, Radiation research.

[10]  G. Hortobagyi,et al.  What is the prognosis of patients with operable breast cancer (BC) five years after diagnosis , 2004 .

[11]  E. Hall Henry S. Kaplan Distinguished Scientist Award 2003The crooked shall be made straight; dose–response relationships for carcinogenesis , 2004, International journal of radiation biology.

[12]  B. Goh,et al.  Eighteen‐year results in the treatment of early breast carcinoma with mastectomy versus breast conservation therapy , 2004, Cancer.

[13]  Andrew K. Lee,et al.  Mortality after cure of testicular seminoma. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  Charles Mw,et al.  Studies of mortality of atomic bomb survivors. Report 13: Solid cancer and noncancer disease mortality: 1950-1997. , 2003 .

[15]  R. Doll,et al.  Cancer risks attributable to low doses of ionizing radiation: Assessing what we really know , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[16]  J. Kaiser Sipping From a Poisoned Chalice , 2003, Science.

[17]  N. Wolmark,et al.  The incidence of lung carcinoma after surgery for breast carcinoma with and without postoperative radiotherapy , 2003, Cancer.

[18]  R. Renner Hormesis. Nietzsche's toxicology. , 2003, Scientific American.

[19]  Tsuneya Matsumoto,et al.  No Lengthening of Life Span in Mice Continuously Exposed to Gamma Rays at Very Low Dose Rates , 2003, Radiation research.

[20]  R. Renner Nietzsche's Toxicology. , 2003 .

[21]  S. Steinberg,et al.  Eighteen‐year results in the treatment of early breast carcinoma with mastectomy versus breast conservation therapy , 2003, Cancer.

[22]  B. Carnes,et al.  Mortality of Atomic Bomb Survivors Predicted from Laboratory Animals , 2003, Radiation research.

[23]  M. Stovall,et al.  Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease. , 2003, JAMA.

[24]  B. Emami,et al.  Risk of second primary cancer in the contralateral breast in women treated for early-stage breast cancer: a population-based study. , 2003, International journal of radiation oncology, biology, physics.

[25]  M. Hauptmann,et al.  Cancer incidence in the U.S. radiologic technologists health study, 1983–1998 , 2003 .

[26]  A. Niemierko,et al.  Second Tumors after Radiosurgery: Tip of the Iceberg or a Bump in the Road? , 2003, Neurosurgery.

[27]  A. Neugut,et al.  Lung carcinoma after radiation therapy in women treated with lumpectomy or mastectomy for primary breast carcinoma , 2003, Cancer.

[28]  J. Broerse,et al.  Tumorigenesis in High-Dose Total Body Irradiated Rhesus Monkeys—A Life Span Study , 2003, Toxicologic pathology.

[29]  Edward J Calabrese,et al.  The hormetic dose-response model is more common than the threshold model in toxicology. , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

[30]  S. Molloi,et al.  Low doses of diagnostic energy X-rays protect against neoplastic transformation in vitro , 2003, International journal of radiation biology.

[31]  Tom Pickles,et al.  The risk of second malignancy in men with prostate cancer treated with or without radiation in British Columbia, 1984-2000. , 2002, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[32]  A. Vortmeyer,et al.  Induction of glioblastoma multiforme in nonhuman primates after therapeutic doses of fractionated whole-brain radiation therapy. , 2002, Journal of neurosurgery.

[33]  Umberto Veronesi,et al.  Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. , 2002, The New England journal of medicine.

[34]  B. E. F. Isher,et al.  Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. , 2002 .

[35]  Erik Holmberg,et al.  Radiation Effects on Breast Cancer Risk: A Pooled Analysis of Eight Cohorts , 2002, Radiation research.

[36]  C. Land,et al.  Malignant Neoplasms after Radiation Therapy for Peptic Ulcer , 2002, Radiation research.

[37]  W. Mackillop,et al.  Increased risk of soft tissue sarcoma after radiotherapy in women with breast carcinoma , 2001, Cancer.

[38]  R. Doll,et al.  100 years of observation on British radiologists: mortality from cancer and other causes 1897-1997. , 2001, The British journal of radiology.

[39]  D. Brenner,et al.  The Bystander Effect in Radiation Oncogenesis: I. Transformation in C3H 10T½ Cells In Vitro can be Initiated in the Unirradiated Neighbors of Irradiated Cells , 2001, Radiation research.

[40]  A. Nademanee,et al.  Solid cancers after bone marrow transplantation. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[41]  A. Upton Radiation Hormesis: Data and Interpretations , 2001, Critical reviews in toxicology.

[42]  D A Pierce,et al.  Radiation-Related Cancer Risks at Low Doses among Atomic Bomb Survivors , 2000, Radiation research.

[43]  Dale L Preston,et al.  Longevity of atomic-bomb survivors , 2000, The Lancet.

[44]  D. Fischer,et al.  Second malignancies after treatment of early-stage breast cancer: lumpectomy and radiation therapy versus mastectomy. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[45]  J. J. Broerse,et al.  The carcinogenic risk of high dose total body irradiation in non-human primates. , 2000, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[46]  D. Brenner,et al.  Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery , 2000, Cancer.

[47]  N. Fukuda,et al.  Dose-response relationship for induction of solid tumors in female B6C3F1 mice irradiated neonatally with a single dose of gamma rays. , 1999, Journal of radiation research.

[48]  Arthur C. Lee,et al.  Mortality in beagles irradiated during prenatal and postnatal development. II. Contribution of benign and malignant neoplasia. , 1998, Radiation research.

[49]  H. Planel,et al.  Effect of a Continuous Gamma Irradiation at a Very Low Dose on the Life Span of Mice , 1998, Gerontology.

[50]  P. Hall,et al.  Risk of second malignant neoplasms among long-term survivors of testicular cancer. , 1997, Journal of the National Cancer Institute.

[51]  W. Heidenreich,et al.  No evidence for increased tumor rates below 200 mSv in the atomic bomb survivors data , 1997, Radiation and environmental biophysics.

[52]  Pierce Da,et al.  on: 'No evidence for increased tumor rates below 200 mSv in the atomic bomb survivors' data'. , 1997 .

[53]  A. Neugut,et al.  Bladder carcinoma and other second malignancies after radiotherapy for prostate carcinoma , 1997, Cancer.

[54]  A. Wambersie,et al.  Survival and diseases in C57BL mice exposed to X rays or 3.1 MeV neutrons at an age of 7 or 21 days. , 1996, Radiation research.

[55]  S. Toledo,et al.  Low-dose ionizing radiation decreases the frequency of neoplastic transformation to a level below the spontaneous rate in C3H 10T1/2 cells. , 1996, Radiation research.

[56]  D. Fairclough,et al.  Second malignancies after Ewing's sarcoma: radiation dose-dependency of secondary sarcomas. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[57]  D A Pierce,et al.  Studies of the mortality of atomic bomb survivors. Report 12, Part I. Cancer: 1950-1990. , 1996, Radiation research.

[58]  Hancock,et al.  Long-Term Complications of Treatment and Causes of Mortality After Hodgkin's Disease. , 1996, Seminars in radiation oncology.

[59]  T. Kinsella,et al.  Tumors in dogs exposed to experimental intraoperative radiotherapy. , 1996, International journal of radiation oncology, biology, physics.

[60]  B. Hankey,et al.  Lung cancer after Hodgkin's disease. , 1995, Journal of the National Cancer Institute.

[61]  P. Sparén,et al.  Second primary cancer after treatment for cervical cancer. An international cancer registries study , 1995, Cancer.

[62]  R. Doll,et al.  Cancer mortality following X‐ray treatment for ankylosing spondylitis , 1994, International journal of cancer.

[63]  K. Hardy,et al.  Head and neck tumors after energetic proton irradiation in rats. , 1994, Advances in space research : the official journal of the Committee on Space Research.

[64]  R. Doll,et al.  Mortality in a cohort of women given X‐ray therapy for metropathia haemorrhagica , 1994, International journal of cancer.

[65]  J. Gueulette,et al.  Life-shortening and disease incidence in mice after exposure to gamma rays or high-energy neutrons. , 1991, Radiation research.

[66]  D. Wood Long-term mortality and cancer risk in irradiated rhesus monkeys. , 1991, Radiation research.

[67]  B. Modan,et al.  Radiation-induced skin carcinomas of the head and neck. , 1991, Radiation research.

[68]  T. Nakano,et al.  Second cancer after radiation therapy for cancer of the uterine cervix , 1991, Cancer.

[69]  S. Rebessi,et al.  The dose-response relationships for myeloid leukemia and malignant lymphoma in BC3F1 mice. , 1989, Radiation research.

[70]  B. Modan,et al.  Tumors of the brain and nervous system after radiotherapy in childhood. , 1988, The New England journal of medicine.

[71]  R. Fry,et al.  Extrapolation of the relative risk of radiogenic neoplasms across mouse strains and to man. , 1988, Radiation research.

[72]  H. Storm Second primary cancer after treatment for cervical cancer. Late effects after radiotherapy , 1988, Cancer.

[73]  J. Gueulette,et al.  Life-shortening and disease incidence in C57Bl mice after single and fractionated gamma and high-energy neutron exposure. , 1988, Radiation research.

[74]  R. Ullrich,et al.  Radiation carcinogenesis: time-dose relationships. , 1987, Radiation research.

[75]  G. Matanoski,et al.  Does radiation exposure produce a protective effect among radiologists? , 1987, Health physics.

[76]  F. S. Williamson,et al.  Life shortening in mice exposed to fission neutrons and gamma rays. VI. Studies with the white-footed mouse, Peromyscus leucopus. , 1986, Radiation research.

[77]  A. Saran,et al.  Radiation-induced mouse liver neoplasms and hepatocyte survival. , 1986, Journal of the National Cancer Institute.

[78]  R. Griffiths,et al.  Radiation‐induced soft‐tissue sarcoma , 1986, The British journal of surgery.

[79]  F. S. Williamson,et al.  Life shortening in mice exposed to fission neutrons and gamma rays. IV. Further studies with fractionated neutron exposures. , 1985, Radiation research.

[80]  D. Wood,et al.  Seventeen-year mortality experience of proton radiation in Macaca mulatta. , 1985, Radiation research.

[81]  F. S. Williamson,et al.  Life shortening in mice exposed to fission neutrons and gamma rays II. Duration-of-life and long-term fractionated exposures. , 1981, Radiation research.

[82]  F. S. Williamson,et al.  Life shortening in mice exposed to fission neutrons and gamma rays I. Single and short-term fractionated exposures. , 1981, Radiation research.

[83]  M. M. Elkind,et al.  Repair of Cell Killing and Neoplastic Transformation at Reduced Dose Rates of 60Co γ-Rays , 1980 .

[84]  R. Ullrich Effects of split doses of x rays or neutrons on lung tumor formation in RFM mice. , 1980, Radiation research.

[85]  S P Azen,et al.  OBTAINING CONFIDENCE INTERVALS FOR THE RISK RATIO IN COHORT STUDIES , 1978 .

[86]  K. Rothman,et al.  Time distributions of recurrences of immunogenic and nonimmunogenic tumors following local irradiation. , 1978, Radiation research.

[87]  R. Doll,et al.  Mortality among patients with ankylosing spondylitis not given X-ray therapy. , 1977, The New England journal of medicine.

[88]  R. Ullrich,et al.  The influence of dose and dose rate on the incidence of neoplastic disease in RFM mice after neutron irradiation. , 1976, Radiation research.

[89]  E. Hall,et al.  Transformation of Mammalian Cells in vitro by Low Doses of X-rays , 1973, Nature.

[90]  C. Congdon,et al.  Long-term effects of acute and chronic irradiation in mice. I. Survival and tumor incidence following chronic irradiation of 0.11 r per day. , 1955, Journal of the National Cancer Institute.

[91]  L. Adler Treatment of Cervical Cancer , 1947, Acta radiologica.

[92]  E. K.,et al.  American Martyrs to Science through the Roentgen Rays , 1936, Annals of Medical History.

[93]  E. Hall,et al.  Radiobiology for the Radiologist, 6th Edition , 2006 .

[94]  John Maindonald,et al.  Data Analysis and Graphics Using R: Contents , 2006 .

[95]  L E Feinendegen,et al.  Evidence for beneficial low level radiation effects and radiation hormesis. , 2005, The British journal of radiology.

[96]  E. Calabrese,et al.  The effects of gamma rays on longevity , 2004, Biogerontology.

[97]  J. Kaiser Hormesis. Sipping from a poisoned chalice. , 2003, Science.

[98]  D. Brenner,et al.  Mortality patterns in British and US radiologists: what can we really conclude? , 2003, The British journal of radiology.

[99]  S. Pazzaglia,et al.  Carcinogenesis in Laboratory Mice after Low Doses of Ionizing Radiation , 2003, Radiation research.

[100]  Alicia Samuels,et al.  Cancer Statistics, 2003 , 2003, CA: a cancer journal for clinicians.

[101]  M. Frankenberg-Schwager,et al.  Enhanced Neoplastic Transformation by Mammography X Rays Relative to 200 kVp X Rays: Indication for a Strong Dependence on Photon Energy of the RBEM for Various End Points , 2002, Radiation research.

[102]  Jong-Hyeon Jeong,et al.  Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. , 2002, The New England journal of medicine.

[103]  D. Brenner,et al.  Oncogenic transformation in C3H10T1/2 cells by low-energy neutrons. , 2000, International journal of radiation biology.

[104]  D. Brenner,et al.  Commentary 2 to Cox and Little: radiation-induced oncogenic transformation: the interplay between dose, dose protraction, and radiation quality. , 1992, Advances in radiation biology.

[105]  A. Auquier,et al.  Long-term risk of sarcoma following radiation treatment for breast cancer. , 1991, International journal of radiation oncology, biology, physics.

[106]  B. Powers,et al.  Radiation-induced osteosarcoma in dogs after external beam or intraoperative radiation therapy. , 1990, Cancer research.

[107]  D. Brenner,et al.  Neutron-energy-dependent oncogenic transformation of C3H 10T1/2 mouse cells. , 1989, Radiation research.

[108]  C D Naylor,et al.  Meta-analysis of controlled clinical trials. , 1989, The Journal of rheumatology.

[109]  R. Ullrich,et al.  Myeloid leukemia in male RFM mice following irradiation with fission spectrum neutrons or gamma rays. , 1987, Radiation research.

[110]  C. Hill,et al.  Repair of cell killing and neoplastic transformation at reduced dose rates of 60Co gamma-rays. , 1980, Cancer research.

[111]  M. M. Elkind,et al.  Transformation of mouse C3H/10T1/2 cells by single and fractionated doses of X-rays and fission-spectrum neutrons. , 1979, Cancer research.

[112]  E. Hall,et al.  Radiobiology for the radiologist , 1973 .

[113]  R. Fry,et al.  Analysis of survival and cause of death statistics for mice under single and duration-of-life gamma irradiation. , 1972, Life sciences and space research.

[114]  P. Wichmann Radium in der Heilkunde , 1911 .