Delft University Press is an imprint of IOS Press
the Peptide Receptor Radionuclide
Therapy with
177
Lu
177
Lu
Boxue Liu
Boxue Liu
RADIATION SCIENCE AND TECHNOLOGY, TU DELFT
ISBN 978-1-61499-364-3 (print)
IOS Press
Whole Body Activity Retentions in the Peptide
Delft University of Technology Faculty of Applied Sciences
Whole Body Activity Retentions in the Peptide
Receptor Radionuclide Therapy with
177
Lu
Proefschrift
ter verkrijging van de graad van doctor aan de Technische Universiteit Delft,
op gezag van de Rector Magnificus prof. ir. K.C.A.M. Luyben, voorzitter van het College voor Promoties,
in het openbaar te verdedigen op 16 december 2013 om 15:00 uur
door
Boxue LIU
Master of Science in Engineering, China Institute of Atomic Energy Geboren te Shaanxi, China
Samenstelling promotiecommissie:
Rector Magnificus voorzitter
Prof. dr. H.T. Wolterbeek Technische Universiteit Delft, promotor Prof. dr. E.H. Brück Technische Universiteit Delft
Prof. dr. P.H. Elsinga Universiteit of Groningen Prof. dr. ir. M. de Bruin Technische Universiteit Delft Prof. dr. F.M. Mulder Technische Universiteit Delft Dr. ir. P. Bode Technische Universiteit Delft Dr. W.A.P. Breeman Erasmus Universiteit Rotterdam
The work presented in this PhD thesis is financially supported by the NUTS-OHRA via the project 0804-047 and carried out at the Section Radiation and Isotopes for Health of the Department Radiation Science and Technology of the Delft University of Technology in collaboration with the Department of Nuclear Medicine of the Erasmus MC in Rotterdam.
© 2013 Boxue Liu and IOS Press
All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without prior permission from the publisher.
ISBN 978-1-61499-364-3
Keywords: PRRT, Whole-body dose, Activity in the excreted urine, Activity in the whole-body, Whole-body measurements, Uncertainty in measurement
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The publisher is not responsible for the use which might be made of the following information.
A quantitative result without any kind of uncertainty is not only useless; it is dangerous because it can be misused.
Chapter 1: Introduction 1 Chapter 2: Direct measurement of the activity of the excreted urine
in the toilet pot: I. Feasibility investigation 11 Chapter 3: Direct measurement of the activity of the excreted urine
in the toilet pot: II. Experiments with the mock-up voiding 27 Chapter 4: Whole-body measurements with external probes:
Principle and validation 45 Chapter 5: Whole-body measurements with external probes:
Comparison with the urine collection method 51 Chapter 6: Whole-body measurements with external probes:
Time-dependent detector responses 67 Chapter 7: Uncertainty estimation of the whole-body dose 91 Chapter 8: Discussion and concluding remarks 101 Appendix A: Measurements of the collected urine
with the whole-body measurement system 109 Appendix B: Equivalent point source in a uniform rectangular phantom 113 Appendix C: Measurement data of time-activity curves for 12 patients 129 Appendix D: Experimental conditions and spectra of 177Lu measurements 141
Summary 155
Samenvatting 159
Acknowledgements 163
Introduction
Whole-body dosimetry
Most neuroendocrine tumours have five highly specialized receptors that bind to the naturally occurring hormone somatostatin. DOTA-tateis an analogue of somatostatin that is able to attach to two of these five somatostatin receptors. Peptide receptor radionuclide therapy (PRRT) combines such compounds with a radionuclide like
177
Lu. These radiopeptides can be administered into a patient and will travel throughout the body binding to carcinoid tumour cells that have receptors for them. Once bound, these radiopeptides emit radiation and kill the tumour cells they are bound to.
The PRRT with 177Lu-DOTA-octreotate is carried out at the Erasmus MC in Rotterdam. Patients are typically hospitalized for about 24 hours at the Nuclear Medicine Department of the Erasmus MC to limit the radiation dose risk to their immediate environment. Estimation of the internal radiation dose and assessment of the effectiveness of the therapy requires a good estimate of the whole-body activity retention of 177Lu after administration.
Requirements for better patient measurements
The main clearance of the activity in the patient body is through the urinary pathway. The amount of activity in the excreted faeces and perspiration is negligible in the PRRT with 177Lu [1-2]. For estimation of the 177Lu excretion from the patient’s body, urine therefore is collected at the given interval after administration. The whole-body retention of the administered activity can then be estimated by measurement of the amount of activity in the excreted urine and subtracting from the administered activity [1-4].
For long, the excreted urine was collected by the patient himself in a flask and the amount of activity was measured in a subsample thereof using a dose calibrator. There are several disadvantages of this method:
• Risk of spill-over and radioactive contamination;
• Feminine unfriendliness and unacceptability amongst certain ethnic parts of the population;
• Enhanced radiation dose to analysts handling and processing the collected urine. This method has to be left for the radiological safety considerations. It is desirable to minimize and even replace manipulations with the excreted amounts of activity e.g. by another approach and to improve the patient-friendliness aspect of these measurements.
These considerations cornered the objective of a research project aiming at the reduction of the burden to radiotherapy patients and analysts in the assays of the amount of radionuclide activity in the body. This project was financially facilitated by NUTS-OHRA and carried out by the Section Radiation and Isotopes for Health of the Department Radiation Science and Technology of the Delft University of Technology, in collaboration with the Department of Nuclear Medicine of the Erasmus MC in Rotterdam.
Requirements for more accurate results
The consequence of spill-over during the collection is that the urine collection method may render an overestimated value of the whole-body activity; the trueness is thus affected.
On the other hand, the whole-body activity at the given time is estimated by subtraction of the activity of the accumulated urine until the given time from the administrated activity. Then the uncertainty of the whole-body activity is the sum of the squares of uncertainties of the activity of the collected urine by the propagation of uncertainty of this subtraction. Therefore, its relative uncertainty of the whole-body activity increases gradually with time. That is intrinsic for the urine collection method.
A method, replacing the urine collection method, should therefore also aim at a higher degree of accuracy (trueness + precision) of the estimation of the amount of activity remaining in the patient’s body.
Research strategy
Two methods have been developed with the potential to overcome the drawbacks of the urine collection method: (i) Direct measurement of the activity of the excreted urine in the toilet pot and (ii) Direct measurement of the remaining activity in the whole-body using external detectors.
Source conditions
Normally the 177Lu is prepared using the 176Lu(n,γ) reaction, therefore 177mLu is also produced. The activity ratio of 177mLu to 177Lu is 0.05±0.008 kBq/MBq (Mean ± SD) measured by Erasmus MC [5], which is not fully consistent with the value of 0.091±0.012 kBq/MBq (the coverage factor k=2) measured by PTB1 but rather low.
The decay schemes of 177mLu and 177Lu are shown in Figure 1 and 2 [6]. The beta particles with the maximum energy 498 keV are used to kill the tumour cells. The
177
Lu activity, whatever is remained in the patient body or in the excreted urine, can be measured by counting the 208 keV gamma-rays although there are some higher energy gamma-rays with very small yields. With respect to the activity ratio and their half lives, the contribution to the count rate of 208 keV from the 177mLu is very small and can not be estimated because the measurements are performed within 24 h after administration. An effective half live of 6.71 d [5-6] for 177Lu, taking into account of the contribution of the 177mLu, was applied in our measurements instead of the value of 6.647 d [6] in Figure 1.
Figure 1 Decay scheme of 177Lu [6]
1
Figure 2 Decay scheme of 177mLu [6]
The 177Lu is administered to the patients as 177Lu-DOTA-octreotate. It is still bound to DOTA in the excreted urine shortly after the administration, but it might be decomposed later. For the activity measurements by counting 208 keV gamma-rays, it does not matter if it is bound to DOTA.
Boundary conditions
The Erasmus MC formulated the performance indicators, boundary conditions and other constraints for new techniques replacing the urine collection method:
• The degree of trueness: the measurement estimate of the whole-body activity should be within ±10% from the estimate based on the urine collection method - the “Golden” standard;
• The expanded uncertainty of the 177Lu activity of the excreted urine should be less than ±10% (the coverage factor k=2, unless otherwise stated);
• Easy implementation in existing premises without reconstruction or modifications thereof;
• Robust instrumentation, patient friendly and easy operation.
Direct measurements in the toilet pot
Instead of having the patient collecting the urine -with all drawbacks- the excreted urine can also be collected in the toilet pot, and the activity can be measured before flushing
and in the absence of the patient. This requires (amongst others) a radiation measurement instrument to be implemented directly next to the toilet pot.
A literature search through the website of the PubMed [7] with keywords “radionuclide therapy”, “patient” and “urine” rendered 846 papers. Only 4 papers were found by keywords “radionuclide therapy”, “patient”, “urine” and “toilet”. However, there is no paper about the direct measurement of the activity of the excreted urine in the toilet pot.
Whole-body measurements with external detectors
The measurement of the activity in the excreted urine -by whatever method- is an indirect approach for estimating the activity retained in the patient body. As an alternative, the retained activity can be directly found by the whole-body measurement with external detectors. Whole-body dosimetry using external probes has been used in some targeted radionuclide therapy mostly for 131I mIBG and for 90Y-DOTA-octreotide [8-14]. This approach has been chosen in this project for estimating whole-body activities in the PRRT with 177Lu-DOTA-octreotate.
A baseline measurement is done before the first voiding immediately after administration. It serves as an individual patient calibration. Whole-body activities at subsequent measurements are then individually normalized to the administered activity. Geometric means of count rates from two opposite measurements in anterior and posterior views are used. The solid angle (relevant for the geometrical efficiency) is small since each detector is positioned at least 2 m from the patient. Both the small solid angle and the geometric mean result in a detection efficiency that, at first, seems to be almost independent of distributions of the 177Lu activity in the patient body [3-4, 9]. However, these assumptions could be challenged by the activity redistributions and attenuation due to different organ positions in the patient body in between subsequent measurements, if compared to the situation at the moment of the baseline measurement [9]. This applies especially to the bladder; it is filled fully during the baseline measurement before the first voiding but almost empty during subsequent measurements.
Thus it is important to account for the redistribution of the activity in view of the required degree of accuracy of the whole-body measurement.
Uncertainty estimation
The estimation of the measurement uncertainty is essential in the individual dosimetry of radionuclide therapy, especially for the escalated dose to the tumours in the targeted radionuclide therapy [15-16]. Generally the whole-body dose is calculated by using the MIRD schema [17], for instance by the program OLINDA [18]. Unfortunately, the uncertainty evaluation is not included in the OLINDA.
The whole body dose is calculated by:
0
( D) ( D) WB WB
D T = A a T Sɶ ← , (4)
where D(TD) is the whole body dose (mGy); TD is the dose-integrated period; SWB←WB
is S-value of the absorbed dose rate to the whole body per unit activity in the whole body (mGy·MBq-1·h-1) in the MIRD scheme; A0 is the administered activity; a Tɶ( D)is
the time-integrated activity coefficient (MBq·h·MBq-1), which is also denoted as the total number of disintegrations per unit activity administered in the OLINDA or the residence time in normal [17-18].
It is assumed that the uncertainty of S-value is negligible compared to the uncertainty of the time-integrated activity coefficient [16]. The measurement uncertainty of the administered activity follows directly from the specifications of the sources used. Therefore the key issue is the estimation of the uncertainty of the time-integrated activity coefficient.
Flux GD et al [16] developed a method estimating the uncertainty of the whole-body dose by a spectral analysis method calculating the accumulated activity in the whole-body. However, the spectral analysis method is a fitting process of multi-exponential functions using every four measurement points and therefore different from normal non-linear regression analysis.
The time-integrated activity coefficient a Tɶ( D)is normally calculated by the bi-exponential regression by using the whole-body fraction a t( )of the administered activity as a function of time after administration [3-4, 17-18]. The a t is calculated ( ) by: 0 ( ) ( ) A t a t A
= and A(t) is the whole-body activity at the given time t. According to
the nonlinear regression procedure the fitting error does not include the contribution from the uncertainties of the measurement data of the time-activity in the whole-body for instance the regression program Prism (GraphPad Software Inc., San Diego CA,
USA). The problem is therefore the estimation of the uncertainty from contributions of both the bi-exponential regression and the measurement data.
Outline of the thesis
The overall objective of the research described in this thesis is to develop patient friendly techniques for an accurate measurement of the time-activity in the whole-body of the patients undergoing the PRRT with 177Lu.
In chapter 2 simulations and mock-up voiding experiments using 177Lu are described to assess the feasibility of measuring the activity of the excreted urine in the toilet pot. The volume and activity of the excreted urine per voiding is investigated by the urine collection method. The detector position is optimized by Monte-Carlo simulations.
In chapter 3 is described how the overflow features of a wash-down toilet pot is (qualitatively) studied with the methylene blue solutions. The impact on the measurement results by the urine volume and the voiding flow rate is investigated with radioactive solutions.
In chapter 4 the principle of the whole-body measurement with external probes is introduced. The degree of accuracy is investigated experimentally with the uniform water phantom of rectangular parallelepiped.
In chapter 5 the effects of activity redistributions during subsequent measurements are discussed. To this end, the excreted urine is collected by a few patients also undergoing whole-body measurements with an external probe. The degree of accuracy of the estimates of whole-body activities is analyzed.
In chapter 6 a novel approach of a series of paired measurements before and after each voiding consecutively after administration is introduced to overcome the effects of activity redistributions. These paired measurements make possible to derive the time-dependent detector responses during subsequent measurements and from there, the accurate estimation of whole-body activities. The measurement results are validated by the collected first urine after administration.
In chapter 7 is described how a simple method is developed for evaluating the combined uncertainty of the time-integrated activity coefficient accounting for contributions from both the fitting curve and the measurement data.
The outcome of the research is discussed and reflected to the objectives in chapter 8, resulting in final conclusions and recommendations for future works.
References
1. Kwekkeboom DJ, Bakker WH, Kooij PP, Konijnenberg MW, Srinivasan A, Erion JL et al. [177Lu-DOTAOTyr3]octreotate: comparison with [111In-DTPAo]octreotide in patients. Eur J Nucl Med 2001; 28:1319-25.
2. Esser JP, Krenning EP, Teunissen JJM, Kooij PP, van Gameren ALH, Bakker WH et al. Comparison of [177Lu-DOTAOTyr3]octreotate and [177Lu-DOTAOTyr3]octreotide: which peptide is preferable for PRRT? Eur J Nucl Med 2006; 33:1346-51.
3. Siegel JA, Thomas SR, Stubbs JB, Stabin MG, Hays MT, Koral KF et al. MIRD pamphlet No. 16: Techniques for quantitative radiopharmaceutical biodistribution data acquisition and analysis for use in human radiation dose estimates. J Nucl Med 1999; 40:37S-61S.
4. Lassman M, Hanscheid H, Chiesa C, Hindorf C, Flux G, luster M. EANM Dosimetry Committee series on standard operational procedures for pre-therapeutic dosimetry I: blood and bone marrow dosimetry in differentiated thyroid cancer therapy. Eur J Nucl Med Mol Imaging 2008; 35:1405-1412.
5. Bakker WH, Breeman WAP, Kwekkeboom DJ, de Jong LC, Krenning EP. Practical aspects of peptide receptor radionuclide therpay with [177Lu][DOTA0,Tyr3]octreotate. QJ Nucl Med MOL IMAGING 2006; 50:265-71.
6. Kondev F.G. Nuclear Data Sheets for A = 177. Nuclear Data Sheets 2003; 98: 801–1095
7. http://www.ncbi.nlm.nih.gov/pubmed/
8. Sudbrock F, Schmidt M, Simon T, Eschner W, Berthold F and and Schicha H. Dosimetry for 131
I-MIBG therapies in metastatic neuroblastoma, phaeochromocytoma and paraganglioma. Eur J Nucl Med 2010; 37:1279-90.
9. Chittenden SJ, Pratt BE, Pomeroy K, Black P, Long C, Smith N et al. Optimization of equipment and methodology for whole-body activity activity measurements in children undergoing targeted radionuclide therapy. Cancer Biotherapy & Radiopharmaceuticals 2007; 22:243-9.
10. Buckley SE, Chittenden SJ, Saran FH, Meller ST and Flux GD. Whole-body dosimetry for individualized treatment planning of 131I-MIBG radionuclide therapy for Neuroblastoma. J Nucl Med 2009; 50:1518-24.
11. Hindorf C, Chittenden S, Causer L, Lewington VJ, Mäcke HR and Flux GD. Dosimetry for (90)Y-DOTATOC therapies in patients with neuroendocrine tumors. Cancer Biotherapy & Radiopharmaceuticals 2007; 22:130-5.
12. Buckley SE, Saran FH, Gaze MN, Chittenden S, Partridge M, Lancaster D, et al. Dosimetry for fractionated (131)I-mIBG therapies in patients with primary resistant high-risk neuroblastoma: preliminary results. Cancer Biotherapy & Radiopharmaceuticals 2007; 22:105-12.
13. Gaze MN, Chang YC, Flux GD, Mairs RJ, Saran FH and Meller ST. Feasibility of dosimetry-based high-dose 131I-meta-iodobenzylguanidine with topotecan as a radiosensitizer in children with metastatic neuroblastoma. Cancer Biotherapy & Radiopharmaceuticals 2005; 20:195-9. 14. Sudbrock F, Schmidt M, Simon T, Eschner W, F. Berthold and Schicha H. Dosimetry for 131
I-MIBG therapies in metastatic neuroblastoma, phaeochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging (2010) 37:1279-1290.
15. Lassmann M, Chiesa C, Flux G and Bardies M. EANM Dosimetry Committee guidance document: good practice of clinical dosimetry reporting. Eur J Nucl Med Mol Imaging 2010; DOI 10.1007/s00259-010-1549-3.
16. Flux GD, Guy MJ, Beddows R, Pryor M, Flower MA. Estimation and implications of random errors in whole-body Dosimetry for targeted radionuclide therapy. Phys Med Biol 2002; 47:3211-3223.
17. Bolch WE, Eckerman KF, Sgouros G and Thomas SR. MIRD Pamphlet No. 21: A generalized schema for radiopharmaceutical dosimetry – Standardization of nomenclature. J Nucl Med 2009; 50:477-484.
18. Stabin MG, Sparks RB, Crowe E. OLINDA/EXAM: The second-generation personal computer software for internal dose assessment in nuclear medicine. J Nucl Med 2005; 46:1023-1027.
Direct measurement of the activity of the
excreted urine in the toilet pot: I. Feasibility
investigation
1Abstract: The objective was to develop a patient friendly technique measuring the activity of the excreted urine in the toilet pot for the PRRT with 177Lu instead of collecting the excreted urine. The feasibility has been investigated by using MNCP5 simulations and the preliminary radioactive mock-up voiding experiments. The most optimized position of the detector is on the side wall and aligned to centre of the water in the toilet pot. The expanded uncertainty of the activity of the excreted urine is about ±9% under the typical voiding condition.
Introduction
The disadvantages of the urine collection method can largely be taken away by direct measurement of the amount of 177Lu activity of the excreted urine in the toilet pot and automation of such a method before flushing. The Erasmus MC formulated the following performance indicators, boundary conditions and other constraints
(i) The use of the existing toilet pot and sewer system without modifications.
(ii) Measurement results of the activity of the excreted urine should be within ±10% from the urine collection method.
(iii) The expanded uncertainty of the activity of the excreted urine should be less than ±10%.
The feasibility of measuring the activity of the excreted urine in the toilet pot directly is described in this chapter. Firstly, the volume and activity of the excreted urine per voiding is investigated by the urine collection method. Then the detector
1
position is optimized by Monte-Carlo simulations. Mock-up voiding experiments with a
177
Lu containing solution in the toilet pot are carried out to evaluate the feasibility.
Methods and experimental conditions
Volume and activity per voiding
The excreted urine was collected by patients themselves in two intervals of 0-1 h and 1-24 h after infusion by 4 patients and four intervals of 0-1 h, 1-4 h, 4-10 h and 10-1-24 h by another 5 patients [1]. All excreted urine within a given interval was combined. As a result, the voiding frequency in the given interval and the volume per voiding are unknown. Generally, the patients void once per hour during and shortly after 1.5 L amino infusion together with the 177Lu-DATA-tate administration. There were one voiding at least during the interval of 0-1 h, typically two to three during the interval of 1-4 h and even more within intervals of 4-10 h and 10-24 h. The volume per voiding commonly ranges between 90 to 270 mL with healthy people [2]. It could be a bit larger for the patients in the PRRT with 177Lu because 177Lu-DOTA-octreotate is administered to the patients together with amino-acid infusion and the patients are asked to drink ample. From professional opinion of medical biochemists and physicians in the Department of Nuclear Medicine of the Erasmus MC, the typical voiding condition was assumed that the volume per voiding is ca. 300 mL and the voiding flow rate is ca. 15 mL/s during the PRRT with 177Lu. It was also assumed that the maximum volume per voiding is 500 mL. Thus a median value of the volume per voiding was estimated from volumes of the collected urine in the interval of 0-1 h. Based on this median volume and the volume in the interval 0-1 h for the given patient, the voiding frequency within the given interval was estimated for this patient. The average activity of the excreted urine per voiding was estimated from the total activity of the collected urine and the estimated frequency in the given interval.
Direct measurement in a toilet pot
Activity remaining in the water in toilet pot
There is a certain volume of clean water (containing no activity) in the toilet pot before voiding. During voiding, the excretion (assumingly mainly urine) goes into three parts
in the toilet pot. Most urine flows into the water in the toilet pot and thus dilutes. And a very smaller amount may remain on the inner ceramic surface of the toilet pot, but this fraction can be negligible compared to the excreted urine volume. A small part of the excreted urine is carried immediately by the overflow into the sewer tank for radioactive wastes before flushing. This waste tank is located far away from the toilet. The overflowed activity can not be measured anymore. The accuracy of the measurement depends therefore on the residual fraction and geometrical distribution features of the excreted urine in the water in the toilet pot.
Detector position
A radiation detector can be positioned around the toilet pot where the risk of radioactive contamination is small but still allowing for de-contamination if necessary. One of toilets used in the hospital ward is a typical non-siphoning and wash-down toilet, as shown in Figure 1. The centre of the water in the toilet pot is at ca. 13 cm above the floor, 45 cm from the side wall and 25 cm from the back wall. The patients have to sit at the toilet pot in order to reduce the risk of radioactive contamination which, however, cannot entirely be avoided. As such, the detector cannot be put immediately next to the toilet pot. A small detector might be positioned on the side or back wall and as high as possible. For instance the contamination risk could be minimized when a detector is positioned on the ceiling.
CdZnTe detector 28 cm 2.2 m LaBr3 detector CdZnTe detector 28 cm 2.2 m LaBr3 detector CdZnTe detector 28 cm 2.2 m LaBr3 detector
a. Toilet pot and experimental setup b. Top view of the toilet pot Figure 1 Toilet pot used in the hospital ward in the Erasmus MC and the schematic setup of the mock-up voiding experiments. a. Toilet pot and experimental setup. b. Top view of the toilet pot (The water of the front part in the U tube can only be seen. The water of the back part which can not be seen has an almost same geometry as the front part.)
On the other hand, the detector response should be insensitive to the activity distribution in the water in the toilet pot. It is a very dynamic process during voiding, where the radioactive urine flows through the water in the toilet pot and dilutes and spreads out in it. The activity distribution thus depends not only on the voiding flow rate and the urine volume, but also on the U-shape geometry of the water in the toilet pot and even the interaction between voiding and the toilet pot, for instance the splashing position inside the pot or even if voiding with diarrhea.
The water in the toilet pot has a U-shaped geometry. This U-tube is separated by a middle ceramic plate into two parts of almost identical geometry. The activity concentration decreases gradually from the very front of the water, then the bottom and the very end before the drainpipe. The activity distribution is probably uniform on the transverse axis when the voiding splashes at the middle of the inner front surface because of the symmetric geometry of the U-tube on the transverse axis. The activity distribution, especially on the vertical and longitudinal axes, is not only patient-dependent, but also voiding style dependent for the given patient.
The detector response depends on the activity distribution in the water in the toilet pot and the degree of gamma-ray self attenuation. Having a detector positioned at the top or back-side of the toilet pot is less favourable due to the higher impact of the gamma-ray self-attenuation in the water. However, the activity distribution along the transversal axis is expected to be more uniform. The symmetric geometry of the U-shape of the water makes the detector response relative insensitive to the distribution on both vertical and longitudinal axes when the detector is positioned on the side and aligned to the equivalent centre of the activity in the water. In the practice, the best position for the detector seems to be installed on the side wall and aligned to the centre of the water in the toilet pot. This has been analysed by Monte-Carlo simulations.
Simulations for optimization detector position
Gamma-ray fluences of 208 keV of 177Lu in air at the given position around the toilet pot were calculated with the Monte Carlo code MCNP5 [3]. Only the ceramic wall and the water in the toilet pot were modelled. The drainpipe, floor, ceiling and walls around the toilet pot were not taken into account because their scattering effects can be compensated by spectrum analysis. The top view (in front of the separating plate) of the water is shown in Figure 1 (b). The simulation model is presented in Figure 2. The geometry of the water in the toilet pot was simplified as a polyhedron with the
trapezium side plane, where the ceramic plate in middle of the water was omitted. The water in the toilet pot was assumed having a density of 1 g·cm-3 without accounting for the small effect by the excreted urine, 177Lu-DOTA-tate, and probably decomposed
177
Lu. The ceramic wall was modelled as two parts, e.g. an upper and a lower part, the latter wrapping the water volume. The lower part was simplified as the same geometry as the model of the water. The upper part was simplified as a truncated cone layer. The material of the ceramic wall of the toilet pot was considered simply as the SiO2 with a
thickness of 1 cm and a density of 2.2 g·cm-3. The centre of the water was set at the coordinate’s origin and X, Y and Z axes are on transversal (left-right), longitudinal (front-back) and vertical (bottom-top) directions respectively. The potential detector positions on the side wall are shown in Figure 2 as well. Both the uniform and in-homogeneous distributions of 177Lu activity in the water were simulated. Total photon histories were 109 for each simulation and the statistical uncertainty of the photon fluence was less than 0.5% (1SD) at the position on the side at 40 cm and aligned to the water centre in the toilet pot.
Water in U tube Ceramic
Water in U tube Ceramic
Figure 2 The toilet pot model of MCNP5 simulations. The unit of geometric size is cm. Positions on the side are not presented with the real scale. The water geometry of solid polyhedron: height of 12 cm, top rectangular of 10 cm by 20 cm and bottom rectangular of 8 cm by 7.7 cm. The toilet pot geometry of a truncated cone: diameter of 28 cm on top and 18 cm on bottom and height of 20 cm. The thickness of the ceramic wall: 1 cm.
Mock-up voiding experiments with 177Lu solution
A 177Lu-DOTA-tate solution was used to mimic the urine containing the 177Lu activity. The solution was poured to the front inner surface of the toilet pot using a funnel, mimicking a flow rate of 16 mL·s-1. The volume of the mock-up urine was from 100 mL to 500 mL by increment of 100 mL.
In the first experiment, the measurement system consisted of an eV-CPGTM CdZnTe detector of 15 x 15 x 7.5 mm3 (eV Microelectronics, Saxonburg, PA, USA) with a DSA-1000 digital spectrum analyzer and Genie2000 spectrum analysis software (both the detector and DSA-1000 were made available by CANBERRA, Zelik, Belgium). The detector was placed on the side at 28 cm from the centre of the water, as shown in Figure 1. The 177Lu activity was 35 MBq for each solution.
In the second experiment, the measurement system was composed of a LaBr3
detector of 38 x 38 (diameter) mm with a UniSpec MCA (also were made available by CANBERRA, Zelik, Belgium). The detector was positioned on the ceiling at 2.2 m from centre of the water as shown in Figure 1. The 177Lu activity was 80 MBq in each mock-up urine solution.
For the measurement of 208 keV gamma-rays using CdZnTe or LaBr3 detector,
the energy resolutions (FWHM) were more or less the same as 5%. The count rates were derived over the energy window of 196-228 keV. The spectrum acquisition interval was thus chosen to keep the standard statistical uncertainty of the net count rate less than ±2%. The background spectrum was measured during 10 min and compensated for each mock-up voiding measurement. A few typical spectra were given in the Appendix D.
Results
Volume and activity of the excreted urine
Volumes of the collected urine within the given interval for 9 patients are given in Table 1. Total volumes of the collected urine within 24 h ranged from 1.22 to 4.42 L and the median value was 3.22 L. Amounts of activity in the collected urine are given in Table 2. Around 62-86% of the administered activity was excreted through the urine pathway up to 24 h amongst 5 patients in the second set. Most activity was excreted within 10 h, typically 57-80 % [1].
Table 1 Volumes (L) of the collected urine in the given interval (Expanded uncertainties of ±2.4%)
Patients Urine volume (L)
0-1 h 1-4 h 4-10 h 10-24 h Total No. 1-1 0.137 1.08a 1.22 No. 1-2 0.441 3.11a 3.55 No. 1-3 0.346 2.94a 3.28 No. 1-4 0.398 4.02a 4.42 No. 2-1 0.338 0.328 0.979 1.20 2.85 No. 2-2 0.589 0.647 0.819 1.34 3.39 No.2-3 0.986 0.553 0.784 0.838 3.16 No. 2-4 0.457 0.513 1.19 0.913 3.08 No. 2-5 0.305 0.449 0.604 1.91 3.27 a
The excreted urine was collected in the interval of 1-24 h.
Table 2 Activities (GBq) (corrected to at t=0 h after administration) in the collected urine within the given interval (The expanded uncertainty of ±3.7%) and the administered activity A0 (GBq) (The expanded uncertainty of ±3.4%)
Patient Administered activity Activity in the collected urine (GBq)
GBq 0-1 h 1-4 h 4-10 h 10-24 h No. 1-1 7.37 1.48 2.95a No. 1-2 7.32 1.23 3.18a No. 1-3 7.39 1.70 4.29a No. 1-4 7.37 1.55 4.54a No. 2-1 7.63 3.67 1.41 0.99 0.50 No. 2-2 7.45 2.95 1.46 0.84 0.53 No.2-3 7.55 1.84 1.66 0.82 0.34 No. 2-4 7.36 2.44 1.59 0.94 0.29 No. 2-5 7.76 0.92 2.32 1.45 0.79 a
The urine was collected in the interval of 1-24 h.
Amongst the data of volumes in the interval of 0-1 h in Table 1, the urine volumes larger than 500 mL were considered as resulting from more than one voiding. Therefore the urine volume per voiding ranged from 137 to 457 mL with the median value of 346 mL. Further as a rough estimation, the 177Lu activity per voiding ranged from 92 MBq to 3.7 GBq, as shown in Table 3. For instance, the maximum activity was 3.7 GBq at t=1 h for the patient No. 2-1 where only one voiding was assumed, and the minimum activity was 96 MBq in the interval of 10-24 h (corrected to at t=0 h after administration) for the patient No. 2-4 where the voiding frequency was estimated as 3.
Table 3 Estimation of activities (GBq) (corrected to at t=0 h after administration) of the excreted urine per voiding and the voiding frequencies (the number in the bracket) in the given interval. The estimation was based on the data in Table 1 and 2 in addition of the median volume per voiding of 346 mL.
Patient Activity per voiding (GBq)
0-1 h 1-4 h 4-10 h 10-24 h No. 1-1 1.48 (1) No. 1-2 1.23 (1) No. 1-3 1.70 (1) No. 1-4 1.55 (1) No. 2-1 3.67 (1) 1.41 (1) 0.331 (3) 0.125 (4) No. 2-2 1.47 (2) 0.729 (2) 0.279 (3) 0.133 (4) No.2-3 0.614 (3) 0.830 (2) 0.407 (2) 0.114 (3) No. 2-4 2.44 (1) 0.795 (2) 0.234 (4) 0.096 (3) No. 2-5 0.92 (1) 2.32 (1) 0.724 (2) 0.131 (6) Simulations
The fluences of 208 keV gamma-rays at different heights and at 40 cm from the centre on the side were calculated for the given distribution of 177Lu activity. The uniform activity distribution was considered as uniform on X, Y and Z axes respectively. The result of the uniform distribution was used as a reference value for other inhomogeneous distributions.
For inhomogeneous distributions, the activity concentration on the X axis was always uniform, and different gradients of the activity concentration were considered on Y and Z axes separately. The activity concentration on the Y axis (-10 to 10 cm) and Z axis (-6 to 6 cm) are shown in Figures 3a and 3b respectively. Calculated results of the fluence of the 208 keV gamma-rays at the given height on the side (see Figure 2) are given in Figure 3c. Variations of the calculated gamma-ray fluence at the given height for different activity distributions were less than 1% compared to the uniform distribution. The fluences at the given position changed slightly when the activity distribution on the Y axis varied, with a maximum of 5% at the height of 2 m. In contrary, variations of the fluence were relative larger when the activity distribution on the Z axis changed, up to about -20% at the height greater than 1 m.
A 0 1 2 3 4 5 6 -15 -10 -5 0 5 10 15 Y cm R e la ti v e a c ti v it y c o n c e n tr a ti o n Uniform Y-5 B 0 1 1 2 2 3 3 4 -8 -6 -4 -2 0 2 4 6 8 Z cm R e la ti v e a c ti v it y c o n c e n tr a ti o n Uniform Z-3 C 0.7 0.8 0.9 1.0 1.1 0 50 100 150 200 250
Height on side wall cm
R e la ti v e f lu e n c e Uniform Z-3 Y-5 Y-5Z-3
Figure 3 Relative fluences of 208 keV gamma-rays normalized to the uniform 177Lu activity distribution
at different heights at 40 cm aside. 177Lu activity concentrations (relative value) on Y and Z axes in the water of the toilet pot in MCNP5 simulations are shown in Figure 3A and 3B. “Uniform” refers to the uniform 177Lu activity distributions on three axes all. Y-5 stands for the activity concentration decreasing on the Y axis (front-back) from 5 to 1; Z-3 stands for the activity concentration decreasing on the Z axis (bottom-top) from 3 to 1; Y-5Z-3 stands for the combined distribution of the177Lu activity concentration on the Y axis as shown in Figure 3A and on the Z axis as shown in Figure 3B respectively.
Mock up voiding experiments
Detector on the side
Detector responses, e.g. the count rate per activity, are given in Figure 4 for the CdZnTe detector positioned on the side of the toilet pot. Referring to the mock-up urine volume of 300 mL, the detector response reduced by about 9% for 100 mL, increased by 1.2% for 200 and remained almost unchanged for 400 and 500 mL.
0.0 1.0 2.0 3.0 4.0 0 100 200 300 400 500 600 Volume mL R e s p o n s e c p s /M B q CZT LaBr3
Figure 4 Detector responses (cps/MBq) of 208 keV gamma-rays versus volumes of the mock-up voiding. (The CdZnTe detector was positioned aside at 28 cm and the LaBr3 detector on the ceiling at 2.2 m respectively from the centre of the water in the toilet pot.)
Detector on the ceiling
Results for the LaBr3 detector positioned on the ceiling are also given in Figure 4. The
detector response decreased with the volume increasing from 100 to 500 mL. Compared to the response at 300 mL, the detector responses reduced by 14% for 500 mL and increased by 19% for 100 mL.
Optimal detector position
The simulation results (see Figure 3) and experimental results with the mock-up voiding (see Figure 4) indicate that the optimized detector position is on the side wall and aligned to the centre of the water volume.
Voiding conditions of the calibration
The geometrical differences of toilet pots from different brands, especially in the geometries of the ceramic wall and the amount of water in the toilet pot, will result in different detector responses. Geometrical parameters could even vary amongst toilets of the same brand and model, for instance, in case of an in-homogenous thickness of the ceramic wall of the pot. It is necessary to perform a calibration for each individual toilet pot used in the hospital ward.
From volumes of the collected urine in the interval 0-1 h in Table 1, the volume per voiding was mostly in the range 300-400 mL (6 out 7 in Table 1). The change of detector responses between 300 and 400 mL in mock-up urine experiments was less than 1% as shown in Figure 4. The reference value of the voiding volume was chosen as 300 mL as outlined above in fair agreement with the median value of the urine volume (346 mL) in these experiments. The flow rate by using the funnel with stem diameter of 3 mm is 16 mL/s. So the flow rate of 16 mL/s and volume of 300 mL is used as reference parameters of the typical voiding for the calibration.
Uncertainty estimation
The activity in the toilet pot can be estimated using the calibration with the typical voiding of 300 mL and 16 mL/s. However, it has to be realized that this calibration differs from the calibration with a standard source in normal radioactive measurements. The activity of the mock-up solution of 300 mL was measured with a dose calibrator before added into the toilet pot and can be considered as a reference source. The problem is the activity remained in the toilet pot during the calibration measurement was not the total activity poured into the pot. A small part of the added activity has already overflowed to the waste sewer tank and can not be measured anymore as mentioned above. The overflowed activity might change with different volumes of the mock-up voiding, even for the repeated calibrations with the same volume and flow rate due to the very dynamic overflow. Therefore, the measurement uncertainty of the activity in the toilet pot can not be estimated simply using propagation of the uncertainties from the components of the calibration and count rates. As an alternative, the uncertainty of the activity in the toilet pot was estimated using the biases of the measured activities from the reference values of the mock-up solution [4]. The results are shown in Table 4. The expanded uncertainty of the activity in the toilet pot was
about ±9% (the coverage factor k=2) for the detector CdZnTe at side of the toilet pot and ±26% for the detector LaBr3 on the ceiling respectively.
Table 4 The measurement uncertainty of the activity in the toilet pot estimated from the biases of the reference activity of the mock-up urine poured in to the toilet pot
Volume Bias a CZT LaBr3 mL % % 100 -8.8 19.1 200 1.2 -12.7 300 0.0 0.0 400 0.2 -7.9 500 0.0 -14.1 Median 0.0 -7.9 Mean -1.5 -3.1 Standard deviation ±4.1 ±13.6 RMS b ±4.2 ±12.5 uref c ±1.7 ±1.7 u d ±4.5 ±13.0 U f ±9.0 ±26 a
the bias of the measured activity from the reference value of 35 MBq. b RMS is defined as 2 2 Bi RMS N
=
∑
, Bi is the bias of the i thmeasurement, i=1, …, N, here N=5 [4].
c
uref is the standard uncertainty of the reference activity of the mock-up solution. d
u is the standard uncertainty, u2 =uref2 +RMS2. e
U is the expanded uncertainty with the coverage factor k=2.
Discussion
Impacts of the detector position and activity distributions
Detector on the side
The detector response varied by 10% between mock-up urine volumes of 100 and 200 mL when the detector was positioned on the side in Figure 4. This variation was probably caused by the activity distribution in the water in the toilet pot. Comparing to
200 mL, most of the radioactive Lu for the 100 mL mock-up urine seems remaining in the front part and close to the ceramic surface of the water in the toilet pot, which caused a lower response. Considering the more overflowed activity for the volume of 200 mL, the effect caused by the in-homogeneous distribution of 177Lu activity between 100 and 200 mL could be more than 10%. That could imply that the activity distribution was not uniform in the transversal direction of the water.
Detector responses decreased by 1.2% with volumes from 200 to 500 mL for the detector aside in Figure 4. This probably meant that the effect caused by the activity overflow was compensated by the change of the activity distribution.
Detector on the ceiling
The detector response is 19% higher for the 100 mL mock-up urine compared to other volumes when the detector was positioned on the ceiling in Figure 4. That was also due to changes of the distribution of 177Lu activity in the water between 100 mL and other volumes. For 100 mL, more radioactive 177Lu in the front part and close to the ceramic surface caused a higher response for the detector on the ceiling instead of the lower response for the detector at the side. The shielding of the ceramic wall of the toilet pot on top of the back part of the U-shape water in the toilet pot was another reason. The gamma-rays from the activity remaining in the back part of the water can not reach the detector directly because of the attenuation from the ceramic layer on the top. More activity will go into the back part of the U tube when the urine volume increases. The attenuation from the water and the ceramic top will result in the response decreasing. It is not fully understood why the detector response of 200 mL was lower than that for 300 mL in Figure 4. That could be due to the dynamic fluid flow causing a big difference on the activity overflow and distribution. Variations of the detector response by 14% with volumes from 200 to 500 mL in Figure 4 indicated that positioning detector on the ceiling is not a good choice.
Volumes of the excreted urine
The patients were asked to void first and then a whole-body measurement was carried out. Therefore there probably was a normal voiding in addition of a small voiding within the interval of 0-1 h. Volumes per voiding (see the volumes less than 500 mL in the interval 0-1 h in Table 1) could be overestimated for some patients but the median value should be reasonable. The median value of 346 mL (amongst 7 patients) is
beyond the normal range of 90 – 270 mL [2] due to the amino infusion of 1.5 L together with the 177Lu infusion.
There are two values larger than 500 mL for the urine volume data in the interval 0-1 h in Table 1. The volume of 986 mL is tested as a significant outlier performing the Grubbs’ outlier test [5]. The median value of the urine volume amongst 8 patients is 372 mL when removing the outlier.
Detector selection
The available space in the toilet room in the Erasmus MC is about 90 cm (see Figure 1). The probe will be positioned on the side wall as mentioned above. The associated electronics can be mounted on the ceiling if necessary. The probe should also be robust and waterproof given to bathroom cleaning and eventual decontamination. Therefore it is wise to use a small size detector, but it should have a high detection efficiency so as to measure an activity level down to 92 MBq of the excreted urine in the second day after the administration. On the other hand, the detector should also have a high count rate capability to measure an activity level up to 3.7 GBq of the first urine.
The CdZnTe detector could be an optimal solution. The probe size of the eV-CPGTM CdZnTe of 15 x 15 x 7.5 mm3 (eV Microelectronics) used in this experiment is 160x38 (diameter) mm3. Considering the detector cost and the activity range of the excreted urine per voiding, it is better to use an even smaller detector, e.g., a size of 10x10x10 mm3. The estimated standard statistical uncertainties for different levels of the activity are given in Table 5. As an alternative, a small scintillation detector like a LaBr3 detector of 15x15 mm (diameter) with a small PMT could be a good solution as
well. The statistical uncertainties are also estimated and given in Table 5. With respect to the standard statistical uncertainty of the count better than 1%, both detectors are sufficient for measurement of the activity down to 100 MBq in 2 min.
Measurement procedures
Generally the activity remaining in the patient body is much higher than the activity in the excreted urine (see Table 2). The patient should leave the bath room immediately after voiding and only then the measurement can be started. This implies that the patient can use the toilet like normal way except for the immediate flushing. The current mechanical flushing should be replaced by a delayed flushing, to be triggered once the measurement has been completed. The door of the bathroom should be locked before
the measurement finishes so that the interference by the activity from the next patient entering can be avoided. The measurement procedure should also include a waiting period for the overflow completing and the activity distribution stabilizing after voiding. The controlling system identifies the patent, locks the door of the bathroom, carries out the measurement, flushes the toilet and unlocks the door for the next patient. There are no needs to modify the current toilet pot and sewer system. This will make the technique of the direct measurement in the toilet pot easier to be accepted and implemented.
Table 5 Estimation of standard statistical uncertainties (%) of CdZnTe (10x10x10 mm) and LaBr3 (15x15 (diameter) mm) detectors positioned at 40 cm from centre of the water in the toilet pot (the acquisition interval of 2 min)
Activity Standard statistical uncertainty
CdZnTea LaBr3 a MBq % % 100 1.0 0.83 370 0.52 0.43 3700 0.16 0.14 a
The responses of the CdZnTe (10x10x10 mm) and LaBr3 (15x15 mm) detectors were estimated as 0.83 and 1.2 cps/MBq respectively using the results in Figure 4, taking into account of the detector size and the distance from the centre of the water in the toilet pot.
Conclusion
Based on both simulations and experiments, the preferred detector position is on the right/left side of the toilet pot and aligned to the centre of the water in the toilet pot. The amount of activity per voiding can be measured without any big modifications to the current toilet and sewer system except of replacing the flushing mechanism as a delayed flushing. The expanded uncertainty of the activity of the excreted urine in the toilet pot is about ±9% under typical voiding conditions.
Patients could use the toilet in normal way except for a delayed flushing. It will be friendly and comfortable for patients. And there will be no radiological risk for the staff handling the collected urine.
Acknowledgements The project was funded by Fonds NutsOhra (project number: 0804-047). The LaBr3 and CdZnTe measurement systems were made available by CANBERRA, Zellik, Belgium.
References
1. Liu B, de Blois E, Breeman W.A.P. , Bode P and Konijnenberg M. Comparison between whole-body measurements and urine collection for determining retentions in 177Lu Peptide Receptor Radionuclide Therapy. Publication in progress.
2. Thomas SR, Stabin MG, Chen CT and Samaratunga RC. MIRD Pamphlet No. 14 Revised: A dynamic urinary bladder model for radiation dose calculations. J Nucl Med 1999; 40:102S-123S. 3. X-5 Monte Caro Team. MCNP - A General Monte Carlo N-Particle Transport Code, Version 5.
LA-UR-03-1987 (Revised 2/1/2008).
4. Magnusson B, Näykki T, Hovind H and Krysell M. Handbook for calculation of measurement uncertainty in environmental laboratories. NORDTEST TR 537 ed. 3 2011-11.
Direct measurement of the activity of the
excreted urine in the toilet pot: II. Experiments
with the mock-up voiding
1Abstract: A small CeBr3 detector was positioned on the side wall and aligned to centre of the water in the
toilet pot. Several aspects of direct measurement of the activity of the excreted urine in the toilet pot were studied with the experiments in which voiding was mocked using the non-radioactive methylene-blue and 177
Lu radioactive containing solutions. The effects on measurement results caused by the urine volume and voiding flow rate were investigated with the 177Lu solutions. The expanded uncertainty of the activity of the excreted urine in the toilet pot was ±5% for the mimicked normal voiding conditions.
Introduction
The measurement method of the activity of the excreted urine in the toilet pot has been further investigated using the experiments with mock-up urine solutions. The overflow features of a wash-down toilet pot require study as these effects have an impact to the trueness of the results. Similarly, the impact of the urine volume and voiding flow rate needed further investigation.
Methods and experimental conditions
Measurement method
The new method of measuring the activity of the excreted urine in the toilet pot implies that the patient goes to the toilet as normal but does not flush. The 177Lu activity in the excreted urine is determined by:
( ) /
u u b
A = n −n R, (1)
1
where Au is the activity of the excreted urine per voiding (MBq), nu and nb are count
rates (cps) of 208 keV gamma rays from the excreted urine in the toilet pot and background respectively, R is the reference response of the count rate per activity (cps/MBq) by the calibration.
The reference response is determined by: ( s bc) / s
R= n −n A , (2)
where As is the activity of the given mock-up urine solution (MBq), ns is the count rate
(cps) of 208 keV gamma rays of the mock-up urine in the toilet pot and nbc is the count
rate (cps) of the background during the calibration. The mock-up urine volume is 300 mL and the voiding flow rate is 16 mL/s in the calibration [1]. The reference response depends on the overflow features of the toilet pot, e.g., the residual fraction and the activity distribution of the excreted urine in the toilet pot. The residual fraction is the ratio of the urine remaining in the water in the toilet pot to the excreted urine.
Overflow experiments with the Methylene-blue solution
Referring to the ALARA principle of radiation protection, a methylene-blue solution instead of radioactive solution was used in the overflow experiments.
The toilet pot used in the ward in the Erasmus MC is a typical non-siphoning and wash-down toilet pot (see the Figure 1b in Chapter 2). It was not available to get another fully same toilet for the overflow experiments outside the ward. The toilet pot 2 of Plieger was used in the methylene-blue solution experiments in the lab at the Delft University of Technology. This toilet has a similar geometry but a slightly smaller water volume in the toilet pot, as presented in Table 1.
Table 1 Parameters of the water geometry seen from the top view. The width and length are the maximum value at the top water surface and the depth is the maximum value in the centre of the toilet pot.
Parameters Toilet pot Toilet pot 2a
Volume (L) 1.5 1.2
Width (cm) 10 10
Length (cm) 12 11
Depth (cm) 12 10
a
Generally speaking, the typical value of the voiding flow rate is about 15 mL/s [1]. It could be lower for elderly and weaker patients and higher for some patients like younger female patients. Three funnels with different stem diameters were used to mimic the flow rates of 8, 16 and 24 mL/s respectively. The funnel with the flow rate of 16 mL/s was used for the calibration, representing the typical voiding flow rate of 15 mL/s.
The methylene blue solutions with volume of 100 to 500 ml were poured into the toilet pot 2 by a given funnel, see Figure 1. During pouring into, the diffusion and convection of this coloured solution in the water in the toilet pot were observed so as to evaluate the distribution features qualitatively. Then the diluted water was pumped out and mixed uniformly when the overflow was completed. A sample was taken and the absorption fraction of the blue light (630 nm) was measured using a UV-VIS photo-spectrometer (Shimadzu Scientific Instruments Inc., USA). Concentrations of the methylene-blue in the water were determined. And the residual fractions of the added amount of the methylene-blue were derived then.
Figure 1 Setup for the experiments with the Methylene-blue solution.
Mock-up voiding experiments with 177Lu solution
With respect to the practice of designing and manufacturing a probe and measurement system, a small CeBr3 scintillation detector 15B15/0.75M-E1-X of 15x15 (diameter)
mm3 (Scionix, Bunnik, Netherlands) plus an Inspector 2000 digital spectrum analyzer (CANBERRA, Zellik, Belgium) and software Genie2000 was used instead of the CdZnTe and LaBr3 detectors used in the preliminary experiments [1]. The CeBr3
detector has a high count rate capability as well but is cheaper than CdZnTe and LaBr3
detectors. The probe size of the CeBr3 detector is 85x26 (diameter) mm3, which is even
smaller than the size of the previous CdZnTe probe (160x38 mm (diameter)).
The radioactive experiments were performed in the same toilet pot as previous experiments in the ward at the Erasmus MC [1]. The detector was positioned at 40cm from centre of the water in the toilet pot and on the side wall, as shown in Figure 2. The two sets of experiments were carried out with the 177Lu mock-up urine solution. Activities of stock solutions were measured by a dose calibrator VDC-505 (Veenstra, Joure, The Netherlands) at first. Specific activities were 38 and 37 MBq/mL for the first and second set experiments respectively. Then the activity in the mock-up solution was calculated by the specific activity of the stock solution and how much stock solution was pipetted.
40 cm
Detector
40 cm
Detector
Figure 2 Schematic setup of the mock-up voiding experiments in the toilet pot. The CeBr3 detector was positioned vertically at the right side (as shown in the figure) in the second experiment.
In the first set experiment the CeBr3 detector were positioned horizontally (the
anterior-posterior direction) at 40 cm from the centre of the water in the toilet pot on the opposite side. Activities of the mock-up urine solution varied from 38 MBq to 380 MBq for investigating the linearity of the detector response. Radioactive solutions were poured into the toilet pot against the front inner surface using two funnels mimicking voiding flow rates of 16 and 20 ml/s respectively. The solution volume varied from 100mL to 500mL by increment of 100 mL. The experimental procedure was:
- pouring the radioactive solution with the given funnel and volume; - waiting for up to 2 min (let the overflow complete);
- flushing the toilet pot.
Patients treated by the PRRT with 177Lu are often suffering from diarrhea. Yoghurt, used to mimic diarrhea, was poured into the toilet pot before the radioactive solution. Mock-up urine solutions were also poured at the front edge of the water instead of the front inner surface in two measurements in order to investigate the effects caused by the pouring position.
In the second set of the experiments the CeBr3 detector was put vertically at the
same position. The measurements for the mock-up radioactive solution with volumes of 200, 300 and 400 mL at flow rates of 16 and 8 mL/s were repeated for three times with the same activity of the 177Lu solution of 37 MBq. The waiting time before spectrum acquisition was strictly controlled as 2 min at least during the second set experiment.
The count rates of the 208 keV gamma-rays over the energy window of 186-243 keV were calculated using the live time, where the energy resolution (FWHM) was ca. 10%. The dead time was ca. 2% when the mock-up urine with 380 MBq (the maximum activity in the experiments) was poured in to the toilet pot. The spectrum acquisition interval was 3 min (the live time) resulting in the standard statistical uncertainties of the counts <±2%. The background was monitored (after toilet flushing) during measurements with the interval between 1 to 26 min and compensated for measurements of the mock-up voiding. See a few typical spectra in the Appendix D.
Uncertainty estimation
The measurement uncertainty can not be estimated using propagation of the uncertainty from Eq.1 and 2 because the overflowed activity and the activity distribution in the toilet pot are unknown. As an alternative, it was estimated statistically using the measurement uncertainties of the reference activity and the biases of the measured activity from the reference value [1-2]. Therefore, the measurement uncertainty was estimated by: 2 2 2 2 2 i ref ref B u u RMS u N = + = +
∑
, (3)Where u is the standard uncertainty of the activity of the excreted urine in the toilet pot; uref is the standard uncertainty of the reference activity of the mock-up urine; Bi is the
bias of the measured activity of the ith mock-up voiding from the reference value and N is the total samples of the mock-up voiding. RMS is the root mean of the squares of the biases [2]. Here the activity of the mock-up solution, which was determined from the
specific activity of the stock solution as mentioned above, was considered as the reference value.
Results
Overflow features
Overflow features
The methylene blue solution went down to the bottom of the U tube along the inner front surface at first and overflowed out into the drainpipe when pouring it into the toilet pot. The convection dominated the flow of the solution through the water in the U tube. Meanwhile the diffusion made the solution spread out, gradually from the front part to the back part (top view) of the water in the toilet pot.
The overflow did not happen at beginning of pouring the methylene-blue solution into. For the flow rate of 16 mL/s the delay was about 5 s more or less for different volumes. Then firstly “clean” water (visually not containing the methylene blue solution) was overflowing. The blue solution started overflowing ca. 9 s after pouring. There was a much longer tail of the blue solution of the overflow. The overflowing tail lasted about 2 min with a gradually decreasing flow rate, depending on the volume and the flow rate.
Residual fraction
Residual fractions remaining in the water in the toilet pot are given in Figure 3. For the flow rate of 16 mL/s, the measurements were repeated 4 or 5 times with blue solution volumes varying from 200 to 500 mL. The residual fractions decreased from 89% (the median value) at 200 mL to 78% at 500 mL as shown in Figure 3a. At the flow rate of 24 mL/s, residual fractions were within the range of that for the flow rate of 16mL/s. The blue colour spread out in the water more quickly and evenly at both flow rates of 16 and 24 mL/s.
70 80 90 100 0 100 200 300 400 500 600 Volume (mL) R e s id u a l p e rc e n ta g e (% ) 16 mL/s Median
Figure 3a Flow rate of 16 mL/s. There were 4 data sets for 200 and 500 mL and 5 data sets for 300 and 400 mL respectively. The line is the median value amongst the data set at the given volume.
70 80 90 100 0 100 200 300 400 500 600 Volume (mL) R e s id u a l p e rc e n ta g e (% ) 24 mL/s
Figure 3b Flow rate of 24 mL/s.
70 80 90 100 0 100 200 300 400 500 600 Volume (mL) R e s id u a l p e rc e n ta g e (% ) 8mL/s
Figure 3c Flow rate of 8 mL/s. Two data at 300 mL are overlapped. Figure 3 Residual percentages (%) remaining in the water in the toilet pot of the amount of the methylene blue solution poured into the toilet pot 2.
Generally the residual fraction and distribution features are dependent mainly on geometrical parameters of the water volume in the toilet pot, e.g. shape, depth, width and length as shown in Table 1. They are also dependent on the inner surface geometry of the toilet pot and the way pouring the blue solution against it. Any slight change of the setup pouring the methylene blue solution into the pot causes the residual fraction a relative large change because of the very dynamic fluid flow, especially for the lower flow rate. Residual fractions fluctuated between 84% and 92% for the flow rate of 8 mL/s (see figure 3c). The time, when the solution started overflowing out, varied from 19 s to 40 s. The higher the residual fraction, the later the colour solution came out. As observed in the experiment at the flow rate of 8 mL/s, the solution spread out wider on the front inner surface and that caused the solution overflowing out later and the residual fraction higher.
For a small volume of 100 mL the residual fraction was 94% at 16 mL/s, much higher compared to that for the volume of 200 mL (see Figure 3a). Meanwhile, the blue colour was distributed mostly in the front part and the bottom part of the water and spread out more slowly and unevenly.
Mock-up voiding with radioactive solutions
Background count rate
In the second set experiment, the background was measured for 26 min before the first mock-up solution and 7 min after the last solution, and monitored in between at intervals of 1 to 3 min. Count rates of the background are given in Figure 4. The background was increasing with time slightly due to the accumulation of 177Lu residual in the toilet pot. The contribution from the accumulation of residual activity was about 10% of the total background count rate. The effect of the activity residual in the toilet pot was relative small. Other activities within the nuclear medicine compound of the Erasmus MC contribute to the background radiation. The average count rate of the background was used to correct the count rates of the mock-up solutions.
10 12 14 16 18 20 11:00 12:00 13:00 14:00 15:00 16:00 Time C o u n t ra te c p s 9-Feb-11 2-Nov-10
Figure 4 Count rates of the background at the given time. Acquisition intervals for the first and last measurements were 26 and 7 min respectively but between 1 to 3 min for all others in the second set experiment (on 09 February 2011) and 13, 25 and 15 min respectively for measurements in the first set experiment (on 02 November 2010). The error bars are expanded statistical uncertainties (the coverage factor k=2).
Calibration
The measurements for the calibration under the 300 mL and 16 mL/s mock-up voiding condition were repeated 3 times and the results are given in Table 2. The standard deviations of the detector response were about ±2%.
Table 2 Reference responses (count rate per activity) of the calibration with the mock-up urine volume of 300 mL and the flow rate of 16 mL/s
Detector direction Measurement CeBr3
cps/MBq Horizontal 1 1.84 2 1.77 3 1.81 Mean 1.81 RSD (%) 1.9 Vertical 1 1.99 2 2.05 3 2.00 Mean 2.01 RSD (%) 1.6
