Elsevier

Seminars in Nuclear Medicine

Volume 38, Issue 5, September 2008, Pages 347-357
Seminars in Nuclear Medicine

Risks to Normal Tissues From Radionuclide Therapy

https://doi.org/10.1053/j.semnuclmed.2008.05.001Get rights and content

The development of radionuclide therapies during the past few decades provides a growing body of data on radiobiologic effects, including normal tissue toxicities and antitumor efficacy. Information on normal tissue toxicity from radionuclides is more limited than that from external beam radiation and appears to be more variable. Much of the increased variability is attributed to heterogeneous distribution, which complicates the potential for whole-organ toxicity, and the differences in dosimetry methodology. Although new tools are becoming available, quantitation of heterogeneous dose for radionuclides is usually less precise than dosimetry that is used in external beam radiation practice. The correlation between reported dose estimates and toxicity has improved during the past 2 decades, partly as the result of increased accuracy and standardization of dosimetry techniques and to adjustment for biologic effects. This review provides an updated compendium of dose–response relationships and consideration of dosimetry as well as radiobiologic factors that influence the reported results. Data presented are mainly derived from studies involving deliver of radiation to adults with malignancies, with most experience from radionuclides that predominantly emit beta radiation.

Section snippets

Theoretical Radiobiologic Models for Radionuclide Therapy

The linear quadratic (LQ) model that is now used extensively in clinical radiobiology was outlined by Fowler and Stern in 1960.12, 13 The model is based on a single-hit cell kill (Type A event), which corresponds to a lethal single-ionization event and is thus independent of dose rate. A second (Type B) event can only be induced by 2 separate ionization interactions and is thus a function of dose rate. The LQ equation for the surviving fraction (SF) of cells after an instantaneously delivered

Toxicity Monitoring

There are accepted standard toxicity scoring criteria that have been applied to various therapeutic agents, including cytotoxic chemotherapy agents, biologics, gene therapy, external beam radiation, and radionuclides. The most common types of toxicity may vary with modality, such as fibrosis associated with radiation and peripheral neuropathy that may result from chemotherapy. Because chemotherapy or other agents (such as biologics or radiation sensitizers/protectors) are frequently used with

Whole and Partial Organ Tolerance

In most instances, tolerance information is useful to avoid irreversible organ compromise, whereas in some instances dysfunction is the desired effect, such as 131I for thyroid ablation. The concept of minimal and maximal tissue tolerance dose was introduced by Rubin and Caserett and applied to whole or partial organ volume that received a uniform dose of external beam radiation at conventional high dose rate (>100 cGy/min) daily fractionations of 1.8 to 2Gy.48 Data were compiled from

Conclusion

Some principles can be concluded from data reviewed here and other studies of radionuclide effects on normal tissues:

  • 1

    Dose rate affects tolerance.

  • 2

    Fractionation increases tolerance of cumulative radionuclide dose.

  • 3

    Small doses may have more carcinogenic effects compared with higher doses that may compromise organ function.

  • 4

    Heterogeneous distribution affects whole organ tolerance.

  • 5

    Subunits of organs such as kidney and central nervous system have different tolerance.

  • 6

    Tolerance varies among individuals

Acknowledgments

We are grateful to Roger Dale for a major contribution to the Theoretical Radiobiologic Models section, Hazel Breitz for discussion and Tracey Cotton-Young for manuscript preparation assistance.

References (136)

  • C. Rubino et al.

    Radiation exposure and familial aggregation of cancers as risk factors for colorectal cancer after radioiodine treatment for thyroid carcinoma

    Int J Radiat Oncol Biol Phys

    (2005)
  • C. Bal et al.

    High-dose radioiodine treatment for differentiated thyroid carcinoma is not associated with change in female fertility or any genetic risk to the offspring

    Int J Radiat Oncol Biol Phys

    (2005)
  • J.M. Bennett et al.

    Assessment of treatment-related myelodysplastic syndromes and acute myeloid leukemia in patients with non-Hodgkin lymphoma treated with tositumomab and iodine I131 tositumomab

    Blood

    (2005)
  • B. Emami et al.

    Tolerance of normal tissue to therapeutic irradiation

    Int J Radiat Oncol Biol Phys

    (1991)
  • J.T. Lyman et al.

    Optimization of radiation therapy, IV: A dose-volume histogram reduction algorithm

    Int J Radiat Oncol Biol Phys

    (1989)
  • M.T. Milano et al.

    Normal tissue tolerance dose metrics for radiation therapy of major organs

    Semin Radiat Oncol

    (2007)
  • L.A. Dawson et al.

    Use of principal component analysis to evaluate the partial organ tolerance of normal tissues to radiation

    Int J Radiat Oncol Biol Phys

    (2005)
  • E. Glatstein

    Personal thoughts on normal tissue tolerance, or, what the textbooks don't tell you

    Int J Radiat Oncol Biol Phys

    (2001)
  • J.C. Cheng et al.

    Inclusion of biological factors in parallel-architecture normal-tissue complication probability model for radiation-induced liver disease

    Int J Radiat Oncol Biol Phys

    (2005)
  • R.K. Bodey et al.

    Application of the linear-quadratic model to combined modality radiotherapy

    Int J Radiat Oncol Biol Phys

    (2004)
  • A.S. Kennedy et al.

    Pathologic response and microdosimetry of (90)Y microspheres in man: Review of four explanted whole livers

    Int J Radiat Oncol Biol Phys

    (2004)
  • S.E. Order et al.

    Selective tumor irradiation by infusional brachytherapy in nonresectable pancreatic cancer: A phase I study

    Int J Radiat Oncol Biol Phys

    (1996)
  • T.E. Schefter et al.

    A phase I trial of stereotactic body radiation therapy (SBRT) for liver metastases

    Int J Radiat Oncol Biol Phys

    (2005)
  • E. Shaw et al.

    Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: Final report of RTOG protocol 90-05

    Int J Radiat Oncol Biol Phys

    (2000)
  • T. Korytko et al.

    12 Gy gamma knife radiosurgical volume is a predictor for radiation necrosis in non-AVM intracranial tumors

    Int J Radiat Oncol Biol Phys

    (2006)
  • A.N. Gutierrez et al.

    Whole brain radiotherapy with hippocampal avoidance and simultaneously integrated brain metastases boost: A planning study

    Int J Radiat Oncol Biol Phys

    (2007)
  • J.C.K.D. Flickinger et al.

    Dose and diameter relationships for facial, trigeminal and acoustic neuropathies following acoustic neuroma radiosurgery

    Radiother Oncol

    (1996)
  • G. Akabani et al.

    Dosimetry and dose-response relationships in newly diagnosed patients with malignant gliomas treated with iodine-131-labeled anti-tenascin monoclonal antibody 81C6 therapy

    Int J Radiat Oncol Biol Phys

    (2000)
  • C. Nieder et al.

    Update of human spinal cord reirradiation tolerance based on additional data from 38 patients

    Int J Radiat Oncol Biol Phys

    (2006)
  • R. Meredith

    Clinical trial design and scoring of radionuclide therapy endpoints: Normal organ toxicity and tumor response

    Cancer Biother Radiopharm

    (2002)
  • S.J. Knox et al.

    Determinants of the antitumor effect of radiolabeled monoclonal antibodies

    Cancer Res

    (1990)
  • S. Verwijnen et al.

    Low-dose-rate irradiation by 131I versus high-dose-rate external-beam irradiation in the rat pancreatic tumor cell line CA20948

    Cancer Biother Radiopharm

    (2004)
  • P.V. Neti et al.

    Log normal distribution of cellular uptake of radioactivity: Implications for biologic responses to radiopharmaceuticals

    J Nucl Med

    (2006)
  • J. Carlsson et al.

    Requirements regarding dose rate and exposure time for killing of tumour cells in beta particle radionuclide therapy

    Eur J Nucl Med Mol Imaging

    (2006)
  • L. Bodei et al.

    Receptor radionuclide therapy with 90Y-[DOTA]0-Tyr3-octreotide (90Y-DOTATOC) in neuroendocrine tumours

    Eur J Nucl Med Mol Imaging

    (2004)
  • P.G. Abrams et al.

    Radioimmunotherapy of Cancer

    (2000)
  • A. Hagenbeek

    Radioimmunotherapy for NHL: Experience of 90Y-ibritumomab tiuxetan in clinical practice

    Leuk Lymphoma

    (2003)
  • R.D. Blumenthal et al.

    Plasma FLT3-L levels predict bone marrow recovery from myelosuppressive therapy

    Cancer

    (2000)
  • S. Martin et al.

    Targeted alpha radiation and gamma rays induce significantly different molecular responses in human leukemic lymphocytes as revealed by gene expression profiling

    J Nucl Med

    (2005)
  • G. Sgouros et al.

    MIRD continuing education: Bystander and low dose-rate effects: are these relevant to radionuclide therapy?

    J Nucl Med

    (2007)
  • J.F. Fowler et al.

    Dose-rate effects: Some theoretical and practical considerations

    Br J Radiol

    (1960)
  • H.D. Thames

    An ‘incomplete-repair’ model for survival after fractionated and continuous irradiations

    Int J Radiat Biol Relat Stud Phys Chem Med

    (1985)
  • V.K. Langmuir et al.

    Radiobiology of radiolabeled antibody therapy as applied to tumor dosimetry

    Med Phys

    (1993)
  • R.G. Dale

    Dose-rate effects in targeted radiotherapy

    Phys Med Biol

    (1996)
  • J.A. O'Donoghue

    Optimal therapeutic strategies for radioimmunotherapy

    Recent Results Cancer Res

    (1996)
  • R.W. Howell et al.

    Proliferation and the advantage of longer-lived radionuclides in radioimmunotherapy

    Med Phys

    (1998)
  • E.D. Yorke et al.

    Absorbed dose averages and dose heterogeneities in Radioimmunotherapy

    Antibody Immunoconjugates and Radiopharmaceuticals

    (1991)
  • H. Thames et al.

    Fractionation in Radiotherapy

    (1987)
  • A.I. Kassis et al.

    Radiobiologic principles in radionuclide therapy

    J Nucl Med

    (2005)
  • G. Sgouros

    Dosimetry of internal emitters

    J Nucl Med

    (2005)
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