Treatment planning in PRRT with ¹⁷⁷Lu-DOTATATE considering optimization of the amount, schedule and affinity of a preload substance

Objectives: A method to maximize tumor dose by optimizing the amount and activity of injected peptide for a fixed kidney biologically effective dose (BED) and a maximum red bone marrow BED was recently developed by Kletting et al. (J. Nucl. Med., 2016) for peptide receptor radionuclide therapy (PRRT) with ⁹⁰Y-DOTATATE. The aim of this simulation study was to improve this method by also including the optimization of the amount, schedule and affinity of a preload substance at the example of PRRT with ¹⁷⁷Lu-DOTATATE.

Methods: A whole-body physiologically based pharmacokinetic (PBPK) model for ¹¹¹In-DOTATATE, developed with data from 9 patients (12 series) with meningioma or neuroendocrine tumors (NETs), was adapted for ¹⁷⁷Lu-DOTATATE and implemented in MATLAB/Simulink. For adapting the PBPK model and dose calculations to ¹⁷⁷Lu-DOTATATE, the physical decay, dose factors and affinity of ¹⁷⁷Lu-DOTATATE were considered while the other parameters for ¹¹¹In-DOTATATE remained unchanged in the model. The PBPK model for ¹⁷⁷Lu-DOTATATE was used to estimate the optimal treatment characteristics for the 12 datasets by simulating different injected activities and amounts of ¹⁷⁷Lu-DOTATATE as well as different amounts, schedules and affinities of a preload substance. The activities used in the simulations were determined by calculating the maximum allowed activities within constraints for the kidney BED (<20 Gy_2.5), red bone marrow BED (<1 Gy₁₅) and the theoretical maximum specific activity for ¹⁷⁷Lu-DOTATATE (720 MBq/nmol) for every combination of ¹⁷⁷Lu-DOTATATE and preload substance. The DOTATATE amount was varied from 4 nmol to 256 nmol while the amount of preload substance was varied from 0 nmol to 128 nmol. The infusion time of the ¹⁷⁷Lu-DOTATATE was kept constant (60 min). The preload infusion time was changed between 0.25 min and 120 min. The difference between the start of the preload infusion and the start of the ¹⁷⁷Lu-DOTATATE infusion was varied from 0 min to 60 min. The dissociation constant (K_D) used for the preload was changed between 2 nmol/L and 0.2 nmol/L while the K_D used for ¹⁷⁷Lu-DOTATATE was 2 nmol/L. The tumor equivalent uniform BED (EUBED) was calculated for every combination of parameters considering one or two metastases. The combination of the investigated parameters which produced the maximum tumor EUBED under the specified constraints was considered as optimal treatment. Results obtained with and without a preload substance were compared.

Results: An automated treatment planning for PRRT was implemented in MATLAB/Simulink. The simulations show that including a preload substance yields an improvement of (5±5) % (range: 0 - 13 %) in the maximum tumor EUBED, which represents a decrease of (31±27) % (range: 0 - 75 %) for the tumor survival fraction (SF). The optimal amount of preload for the different patients ranged from 0 to 16 nmol (mean (8±5) nmol) while the optimal preload affinity was 0.2 nmol/L for all cases. Co-infusion of ¹⁷⁷Lu-DOTATATE and a high affinity substance yielded the best results. The optimal infusion period for the preload was (15±36) min (range: 0.25 - 120 min). The optimal amount of ¹⁷⁷Lu-DOTATATE was (64±25) nmol (range: 32 - 128 nmol). The optimal activity was (33±8) GBq (range: 18 - 44 GBq).

Conclusion: An optimization method simultaneously considering activity and amount of radiopharmaceutical as well as preload characteristics, maximum specific activity and multiple metastases was developed and implemented in MATLAB/Simulink. Including a preload substance may improve the outcome of the treatment but it could also worsen it, therefore individualized treatment planning is required to determine the optimal amount and activity of radiopharmaceutical as well as the optimal type, amount and schedule of a preload substance. The maximum specific activity was the dominating constraint for the treatment optimization with ¹⁷⁷Lu-DOTATATE. Research Support: www.mitigate-project.eu