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¹⁶⁶Ho-DOTMP Radiation-Absorbed Dose Estimation for Skeletal Targeted Radiotherapy

¹ NeoRx Corp., Seattle, Washington; ² University of Texas M.D. Anderson Cancer Center, Houston, Texas; ³ Vanderbilt University, Nashville, Tennessee; ⁴ University of Alabama Comprehensive Cancer Center, Birmingham, Alabama; and ⁵ University of Washington, Seattle, Washington

Correspondence: For correspondence or reprints contact: Hazel B. Breitz, MD, NeoRx Corp., 300 Elliott Ave. West, No. 500, Seattle, WA 98119-4115. E-mail: hbreitz{at}neorx.com

¹⁶⁶Ho-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene-phosphonate (DOTMP) is a tetraphosphonate molecule radiolabeled with ¹⁶⁶Ho that localizes to bone surfaces. This study evaluated pharmacokinetics and radiation-absorbed dose to all organs from this ß-emitting radiopharmaceutical. Methods: After two 1.1-GBq administrations of ¹⁶⁶Ho-DOTMP, data from whole-body counting using a -camera or uptake probe were assessed for reproducibility of whole-body retention in 12 patients with multiple myeloma. The radiation-absorbed dose to normal organs was estimated using MIRD methodology, applying residence times and S values for ¹⁶⁶Ho. Marrow dose was estimated from measured activity retained after 18 h. The activity to deliver a therapeutic dose of 25 Gy to the marrow was determined. Methods based on region-of-interest (ROI) and whole-body clearance were evaluated to estimate kidney activity, because the radiotracer is rapidly excreted in the urine. The dose to the surface of the bladder wall was estimated using a dynamic bladder model. Results: In clinical practice, -camera methods were more reliable than uptake probe–based methods for whole-body counting. The intrapatient variability of dose calculations was less than 10% between the 2 tracer studies. Skeletal uptake of ¹⁶⁶Ho-DOTMP varied from 19% to 39% (mean, 28%). The activity of ¹⁶⁶Ho prescribed for therapy ranged from 38 to 67 GBq (1,030–1,810 mCi). After high-dose therapy, the estimates of absorbed dose to the kidney varied from 1.6 to 4 Gy using the whole-body clearance–based method and from 8.3 to 17.3 Gy using the ROI-based method. Bladder dose ranged from 10 to 20 Gy, bone surface dose ranged from 39 to 57 Gy, and doses to other organs were less than 2 Gy for all patients. Repetitive administration had no impact on tracer biodistribution, pharmacokinetics, or organ dose. Conclusion: Pharmacokinetics analysis validated -camera whole-body counting of ¹⁶⁶Ho as an appropriate approach to assess clearance and to estimate radiation-absorbed dose to normal organs except the kidneys. Quantitative -camera imaging is difficult and requires scatter subtraction because of the multiple energy emissions of ¹⁶⁶Ho. Kidney dose estimates were approximately 5-fold higher when the ROI-based method was used rather than the clearance-based model, and neither appeared reliable. In future clinical trials with ¹⁶⁶Ho-DOTMP, we recommend that dose estimation based on the methods described here be used for all organs except the kidneys. Assumptions for the kidney dose require further evaluation.

Key Words: ¹⁶⁶Ho-DOTMP • skeletal targeted radiotherapy • radiotherapeutic • dosimetry

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