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First published online October 16, 2008, 10.2967/jnumed.108.053173
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Journal of Nuclear Medicine Vol. 49 No. 11 1884-1899
© 2008 by Society of Nuclear Medicine
doi: 10.2967/jnumed.108.053173

Special Contribution

MIRD Pamphlet No. 20: The Effect of Model Assumptions on Kidney Dosimetry and Response—Implications for Radionuclide Therapy*

Barry W. Wessels1, Mark W. Konijnenberg2, Roger G. Dale3, Hazel B. Breitz4, Marta Cremonesi5, Ruby F. Meredith6, Alan J. Green7, Lionel G. Bouchet8, A. Bertrand Brill9, Wesley E. Bolch10, George Sgouros11 and Stephen R. Thomas12

1 Department of Radiation Oncology, Case Western Reserve University School of Medicine, Cleveland, Ohio; 2 Research and Development, Mallinckrodt Medical BV, Covidien, Petten, The Netherlands; 3 Radiation Physics and Radiobiology, Imperial Healthcare NHS Trust, London, United Kingdom; 4 Poniard Pharmaceuticals, Seattle, Washington; 5 Medical Physics Division, European Institute of Oncology, Milan, Italy; 6 University of Alabama at Birmingham, Birmingham, Alabama; 7 CRC Targeting and Imaging Group, Department of Oncology, Royal Free and University College Medical School, University College London, London, United Kingdom; 8 Still Rivers Systems, Inc., Littleton, Massachusetts; 9 Department of Radiology, Vanderbilt University, Nashville, Tennessee; 10 Department of Nuclear and Radiological Engineering, University of Florida, Gainesville, Florida; 11 Department of Radiology and Radiological Sciences, School of Medicine, Johns Hopkins University, Baltimore, Maryland; and 12 Department of Radiology, University of Cincinnati, Cincinnati, Ohio

Correspondence: For correspondence or reprints contact: Barry W. Wessels, Department of Radiation Oncology, B-181 Lerner Tower, University Hospitals Case Medical Center, 11100 Euclid Ave., Cleveland, OH 44106. E-mail: barry.wessels{at}uhhospitals.org

Renal toxicity associated with small-molecule radionuclide therapy has been shown to be dose-limiting for many clinical studies. Strategies for maximizing dose to the target tissues while sparing normal critical organs based on absorbed dose and biologic response parameters are commonly used in external-beam therapy. However, radiopharmaceuticals passing though the kidneys result in a differential dose rate to suborgan elements, presenting a significant challenge in assessing an accurate dose–response relationship that is predictive of toxicity in future patients. We have modeled the multiregional internal dosimetry of the kidneys combined with the biologic response parameters based on experience with brachytherapy and external-beam radiation therapy to provide an approach for predicting radiation toxicity to the kidneys. Methods: The multiregion kidney dosimetry model of MIRD pamphlet no. 19 has been used to calculate absorbed dose to regional structures based on preclinical and clinical data. Using the linear quadratic model for radiobiologic response, we computed regionally based surviving fractions for the kidney cortex and medulla in terms of their concentration ratios for several examples of radiopharmaceutical uptake and clearance. We used past experience to illustrate the relationship between absorbed dose and calculated biologically effective dose (BED) with radionuclide-induced nephrotoxicity. Results: Parametric analysis for the examples showed that high dose rates associated with regions of high activity concentration resulted in the greatest decrease in tissue survival. Higher dose rates from short-lived radionuclides or increased localization of radiopharmaceuticals in radiosensitive kidney subregions can potentially lead to greater whole-organ toxicity. This finding is consistent with reports of kidney toxicity associated with early peptide receptor radionuclide therapy and 166Ho-phosphonate clinical investigations. Conclusion: Radionuclide therapy dose–response data, when expressed in terms of biologically effective dose, have been found to be consistent with external-beam experience for predicting kidney toxicity. Model predictions using both the multiregion kidney and linear quadratic models may serve to guide the investigator in planning and optimizing future clinical trials of radionuclide therapy.

Key Words: dosimetry • kidney toxicity • radionuclide therapy • BED

* In collaboration with the MIRD Committee of the SNM: Stephen R. Thomas (Chair), Wesley E. Bolch, A. Bertrand Brill, Darrell R. Fisher, Ruby F. Meredith, George Sgouros, Barry W. Wessels (Task Group Leader), and Pat B. Zanzonico

COPYRIGHT © 2008 by the Society of Nuclear Medicine, Inc.


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