177Lu-DOTA-0-Tyr3-octreotate infusion modeling for real-time detection and characterization of extravasation during PRRT

Abstract

Purpose: Given the recent and rapid development of peptide receptor radionuclide therapy (PRRT), increasing emphasis should be placed on the early identification and quantification of therapeutic radiopharmaceutical (thRPM) extravasation during intravenous administration. Herein, we provide an analytical model of ¹⁷⁷Lu-DOTA0-Tyr3-octreotate (Lutathera^®) infusion for real-time detection and characterization of thRPM extravasation.

Methods: For 33 Lutathera^®-based PRRT procedures using the gravity infusion method, equivalent dose rates (EDRs) were monitored at the patient's arm. Models of flow dynamics for nonextravasated and extravasated infusions were elaborated and compared to experimental data through an equivalent dose rate calibration. Nonextravasated infusion was modeled by assuming constant volume dilution of ¹⁷⁷Lu activity concentration in the vial and Poiseuille-like laminar flow through the tubing and patient vein. Extravasated infusions were modeled according to their onset times by considering elliptically shaped extravasation region with different aspect ratios.

Results: Over the 33 procedures, the peak of the median EDR was reached 14 min after the start of the infusion with a value of 450 µSv h^-1. On the basis of experimental measurements, 1 mSv h^-1 was considered the empirical threshold for Lutathera^® extravasation requiring cessation of the infusion and start again with a new route of injection. According to our model, the concentration of extravascular activity was directly related to the time of extravasation onset and its duration, a finding inherent in the gravity infusion method. This result should be considered when planning therapeutic strategy in the case of RPM extravasation because the local absorbed dose for β-emitters is closely linked to activity concentration. For selected EDR values, charts of extravasated activity, volume, and activity concentration were computed for extravasation characterization.

Conclusion: We proposed an analytical model of Lutathera^® infusion and extravasation (gravity method) based on EDR monitoring. This approach could be useful for the early detection of thRPM extravasation and for the real-time assessment of activity concentration and volume accumulation in the extravascular medium.

Keywords: 177Lu; Equivalent dose rate; Extravasation; Gravity infusion method; Lutathera; Neuroendocrine tumors; Peptide receptor radionuclide therapy; Radioprotection.

Fig. 1

Illustration of the gravity infusion device (A) and equivalent dose rate measurements on the patient's arm (B)

Fig. 2

Simplified geometry used to model the infusion process

Fig. 3

Illustration of the time delay ($T_{\mathrm{delay}}$) between the vial concentration and the fluid element concentration as a function of time $t$ and the position of the fluid element in cylindrical coordinates $(s,r)$. A For $t<T_1$, the fluid element traveled the distance $s$ at the velocity $\overrightarrow{v_1}(r)$. $T_{\mathrm{delay}}$ is thus expressed as the ratio between the fluid element curvilinear abscissa $s$ and the velocity $\overrightarrow{v_1}(r)(T_{\mathrm{delay}}=\frac{s}{\overrightarrow{v_1}\left(r\right)})$. B For $T_1<\mathrm{t}\le T_2$, there are two cases depending on the curvilinear abscissa s of the fluid element: Case 1. $s{\le D}_2(r,t)$, the fluid element has traveled the distance $s$ at the velocity $\overrightarrow{v_2}(r)(T_{\mathrm{delay}}=\frac{s}{\overrightarrow{v_2}\left(r\right)})$. Case 2. $s>D_2(r,t)$, the fluid element has traveled the distance $D_2(r,t)$ at the velocity $\overrightarrow{v_2}(r)$ and the distance $s-D_2(r,t)$ at the velocity $\overrightarrow{v_1}(r)$ $(T_{\mathrm{delay}}=\frac{D_2(r,t)}{\overrightarrow{v_2}(r)}+\frac{s-D_2(r,t)}{\overrightarrow{v_1}(r)})$. C For $t>T_2$, there are three cases depending on the curvilinear abscissa $s$ of the fluid element. The mathematical expression of $T_{\mathrm{delay}}$ is obtained by following the same method as for $T_1<t\le T_2$

Fig. 4

A Illustration of the calibration procedure of the AT1123 survey meter according to the position of an 11.01 MBq point source along the axis of the tubing(s) and for a fixed tubing-survey meter distance of 1 cm. B Result of the calibration that provides the relationship between EDR measurements and positions of the point source (circular symbols) with the corresponding regression (dashed line)

Fig. 5

Box-plot representation of the evolution of experimental EDR at the patients’ arm (A) and abdomen (B) for the 33 Lutathera-based PRRT infusion procedures with the associated median value for each time point (black curve). The evolution of simulated EDR at the patient's arm with the proposed infusion modeling is also depicted (A, blue curve)

Fig. 6

Evolution of simulated activity in the vial (red curve), arm (blue curve) and abdomen (black curve) for nonextravasated infusion (A). Evolution at the patient’s arm of simulated activity (B), volume (C) and activity concentration (D) for infusions that extravasate with onset times ranging from 1 to 40 min with 1-min sampling (gray curves)

Fig. 7

Evolution of simulated EDR at the patient’s arm for infusions that extravasate with onset times ranging from 1 to 40 min with 1-min sampling (gray curves) and for four elliptical aspect ratios (2, 3, 4 and 5)

Fig. 8

Range of extravasated activity (A), volume (B), and activity concentration (C) versus time for 4 aspect ratios (AR = 2, 3, 4, 5) that leads to the same EDR and for 8 representative EDR values (1, 2, 3, 4, 5, 6, 8 and 10 mSv/h)