Potential increased tumor-dose delivery with combined 131I-MIBG and 90Y-DOTATOC treatment in neuroendocrine tumors: a theoretic model.
(131)I-Metaiodobenzylguanidine (MIBG) and (90)Y-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 (131)I-MIBG or (90)Y-DOTATOC. The results obtained from these derivations were compared with direct dose calculations using published dosimetric organ values for (131)I-MIBG and (90)Y-DOTATOC along with critical organ-dose limits. Tumor dose was calculated as a function of the tumor-dose ratio, defined as the (90)Y-DOTATOC tumor dose per megabecquerel divided by the (131)I-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 (90)Y-DOTATOC activity supplemented with 76% of the maximum tolerated activity of (131)I-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.


CONCLUSIONS
Combining (131)I-MIBG and (90)Y-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.
Madsen
Mark T
MT
Department of Radiology, University of Iowa, 200 Hawkins Dr., Iowa City, 52242, USA. mark-madsen@uiowa.edu
Bushnell
David L
DL
Juweid
Malik E
ME
Menda
Yusuf
Y
O'Dorisio
M Sue
MS
O'Dorisio
Thomas
T
Besse
Ian M
IM
D019797:3-Iodobenzylguanidine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D006801:Humans; D007457:Iodine Radioisotopes / Q000627:therapeutic use; D008954:Models, Biological; D018358:Neuroendocrine Tumors / Q000532:radiotherapy*; D015282:Octreotide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011829:Radiation Dosage; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics / Q000627:therapeutic use; D015021:Yttrium Radioisotopes / Q000627:therapeutic use
D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D015021:Yttrium Radioisotopes; D019797:3-Iodobenzylguanidine; D015282:Octreotide; C106246:Edotreotide