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Potential Increased Tumor-Dose Delivery with Combined ¹³¹I-MIBG and ⁹⁰Y-DOTATOC Treatment in Neuroendocrine Tumors: A Theoretic Model

¹ Department of Radiology, University of Iowa, Iowa City, Iowa; ² Department of Pediatrics, University of Iowa, Iowa City, Iowa; ³ Department of Internal Medicine, University of Iowa, Iowa City, Iowa; and ⁴ Department of Mathematics, University of Iowa, Iowa City, Iowa

Correspondence: For correspondence or reprints contact: Mark T. Madsen, PhD, Department of Radiology, University of Iowa, 200 Hawkins Dr., Iowa City, IA 52242. E-mail: mark-madsen{at}uiowa.edu

¹³¹I-Metaiodobenzylguanidine (MIBG) and ⁹⁰Y-DOTA-D-Phe1-Tyr3-octreotide (DOTATOC) have been used as radiotherapeutic agents for treating neuroendocrine tumors. The tumor dose delivered by these agents is often insufficient to control or cure the disease. However, these 2 agents used together could potentially increase tumor dose without exceeding the critical organ dose because the dose-limiting tissues are different. In this paper, we investigate the conditions in which combined-agent therapy is advantageous and we quantify the expected tumor-dose gain. Methods: A series of equations was derived that predicted the optimal combination of agents and the fractional increase in tumor dose available from combined-agent therapy with respect to either ¹³¹I-MIBG or ⁹⁰Y-DOTATOC. The results obtained from these derivations were compared with direct dose calculations using published dosimetric organ values for ¹³¹I-MIBG and ⁹⁰Y-DOTATOC along with critical organ-dose limits. Tumor dose was calculated as a function of the tumor-dose ratio, defined as the ⁹⁰Y-DOTATOC tumor dose per megabecquerel divided by the ¹³¹I-MIBG tumor dose per megabecquerel. Comparisons were made between the dose delivered to tumor with single-agent therapy and the dose delivered to tumor with combined-agent therapy as a function of the tumor-dose ratio and the fraction of activity contributed by each agent. Results: The dose model accurately predicted the optimal combination of agents, the range at which combined-agent therapy was advantageous, and the magnitude of the increase. For the published organ dosimetry and critical organ-dose limits, combined-agent therapy increased tumor dose when the tumor-dose ratio was greater than 0.67 and less than 5.93. The maximum combined-agent tumor-dose increase of 68% occurred for a tumor-dose ratio of 2.57, using 92% of the maximum tolerated ⁹⁰Y-DOTATOC activity supplemented with 76% of the maximum tolerated activity of ¹³¹I-MIBG. Variations in organ dose per megabecquerel and dose-limiting values altered both the magnitude of the increase and the range at which combined-agent therapy was advantageous. Conclusion: Combining ¹³¹I-MIBG and ⁹⁰Y-DOTATOC for radiotherapy of neuroendocrine tumors can significantly increase the delivered tumor dose over the dose obtained from using either agent alone. Prior knowledge of the normal-organ and tumor dosimetry of both agents is required to determine the magnitude of the increase.

Key Words: radionuclide therapy • neuroendocrine cancer • combined-agent therapy • ¹³¹I-MIBG • ⁹⁰Y-DOTATOC

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