BIOKINETIC AND DOSIMETRY OF 90Y-DOTATOC THERAPY FOR NEUROENDOCRINE TUMOURS

Biokinetic model is a mathematical model which desc ribes the behavior of the Y in human body during the treatment of neuroendocr ine tumours. This paper presents calculation of absorbed doses in human org ans in biokinetic model Y for DOTATOC therapy. For this purpose, the human body i s represented by five compartments: blood, kidneys, urinary bladder, tumo r and liver. The input file was developed and designed to calculate absorbed doses in human organs, when compartments, as kidneys, liver and tumour, are sou rces of Y. For this purpose, computer software MCNP5/X was used. To solve the sy stem of equations obtained from the model, one data must be taken from the measurem ents of Y in blood or urine. Results obtained, showed that highest absorbed dose is in tumour, compared to other organs in human body.


INTRODUCTION
Y-DOTATOC ([Y-DOTA0, Tyr3]-octreotide) is successfully used during last 15 years for the treatment of neuroendocrine tumours that are inoperable, or metastatic (ZAKNUN et al., 2013, CREMONESI et al., 2010).These tumours often have no symptoms and are discovered only when metastases occur.These tumours increased from 1.09 to 5.25 cases per 100 000 inhabitants per year in the period from 1994 to 2009 (SINGH et al., 2017). 90Y-DOTATOC in Peptide Receptor Radionuclide Therapy (PRRT) is used to treat the patient with neuroendocrine tumours (NET), as this kind of peptide provides quick concentration of radionuclide to tumour tissue, while the rest activity is excreted through the kidneys and bladder.Certain amount of radioactivity is accumulated in kidney which can cause the significant damages and reducing the kidney function (BARONE et al., 2005;OTTE et al., 1999).Due to this fact, there is a tendency to optimize the treatments by development of the personalized dosimetry in order to achieve the largest doses in tumour with smaller as possible dose in kidneys (BODEI et al., 2015;HINDORF et al., 2009).
The aim of this study was to calculate absorbed doses in organs and tumour tissue (YORIYAZ et al., 2001).This was based on the available methods for the measurement of 90 Y-DOTATOC distribution in the organs of the human body and on the solution of mathematical model which determines transfer coefficients for critical organs.

Application procedure and blood and urine sampling
As the results of biokinetic model, totally 11 equations and 12 unknown integration constants were obtained.Such system cannot be solved and one additional information is needed.This data is provided from the measurements of 90 Y -DOTATOC in blood or urine.
Measurements were performed on 10 patients which were treated by this therapy in Clinical Centre Kragujevac (MATOVIC, 2012).Patients received activity of 90 Y-DOTATOC between 2.7 and 5.4 GBq.Blood was sampled at the moment when the application of radiopharmaceutical was terminated, and later at each hour during first 6 hours and after in intervals of 6 h up to 72 h after application of the radiopharmaceutical.Urine was also collected and measured 72 h after application.Activities in urine and blood samples were measured in liquid scintillation counter RACKBETA, LKB-Wallac.Counter was calibrated with the known samples of 90 Y, and it is found that efficiency to 90 Y is 90.2%.

Details of the computational model
Radiation dose in different organs from beta radiation emitted by 90 Y -DOTATOC located in the kidneys were calculated for human ORNL phantom (KRSTIC and NIKEZIC, 2007).For this purpose, MCNP5/X software (X-TEAM, 2003), which performs simulation of transport of neutrons, photons and electron in different materials and geometries, was used.In this paper simulation of transport of electrons is performed in the adult male ORNL phantom.
MCNP code was used to calculate mean absorbed dose (in MeV/g per one particle of radiation) in organs and tissues of the human body (ICRP 1991).Analytical models of the human body were developed in publication (ECKERMAN et al., 1996).All organs of the human body were represented with analytical equations.Each kidney is an ellipsoid cut by a plane, given by the following equation: Parameter x0 is taken as positive for the left kidney, and negative for the right, the volume is 288 cm 3 for both kidneys; parameters (in cm) y0 and z0 are 6 and 32.5, respectively.Values (in cm) a, b and c are 2.5, 1.5 and 5.5.
The liver (volume is 1830 cm 3 ) is represented by an elliptical cylinder cut with a plane as follows: , and Parameters (in cm) a and b are 16.50 and 8, respectively.Values (in cm) for xm, ym, zm and z1 are: 35, 45 and 43 cm, respectively.
The tumour has a spherical shape and is located in the centre of the abdomen, between the kidneys and near the liver and pancreas.The diameter of tumour was 3 cm.
According to ORNL, human phantom consists of three types of tissues, skeletal, lung and soft, with different densities and elemental compositions.All equations for organs of ORNL phantom, with other relevant information (chemical compositions, volumes, masses etc), were programmed in input files for MCNP-4B code (KRSTIC and NIKEZIC, 2007).By combining surfaces through Bull algebra, MCNP-4B forms cells representing various organs.
To calculate doses in other organs when the source of radiation is located in the kidneys, liver and tumour, ORNL phantom of human body was used.This model does not give details of human kidneys, liver and tumour.In addition, uniform distribution of activity in these organs is assumed.
The intention was to calculate the mean absorbed dose in all organs of human body from the radioactivity located in the kidneys and liver of ORNL phantom, using MCNP software.The results obtained from MCNP in MeV• g -1 per one emitted particle.Since the kidneys appear in pair, they are presented in MCNP as the union of regions which contain left and right kidney.The number on histories must be increased to ensure low statistical error.As the calculation time in this case would be enormous, calculations were done separately.
For the calculations, a spectrum of electrons emitted by 90 Y is needed.Spectrum of beta (β) radiation for 90 Y (http://ie.lbl.gov/education/isotopes.htm) are presented in Fig. 1.Particle energy was sampled according to yields using random method incorporated in MCNP software.In order to simulate emission of whole spectrum of β -radiation, large number of histories was created (about 10 8 ) to ensure uncertainty lower than few percent.As a result of computation, mean absorbed dose per one particle of radiation (β) from kidney as a source was obtained for adult male ORNL phantom.

RESULTS AND DISCUSSION
MCNP software was applied to calculate the absorbed dose in organs of ORNL phantom in MeV/g per particle.Mean absorbed dose per particle of radiation from kidneys, liver and tumour (as sources) in ORNL human phantom presented in Table 1.In the first column are given the human organs, in the second, third and fourth are kidneys, liver, and tumour, respectively.
The table shows that the largest dose in tumour, which is the ultimate goal of this therapy.The values obtained in this work were 39, 2.8•10 3 and 9.06•10 6 aGy/particle where the source of radiation is located in the kidneys, liver, and the tumour, respectively.However, the kidneys received large dose, and before the application of this therapy, renal function must be tested.During the therapy to the patient intravenously administered the positively charged amino acids (L-arginine, L-lysine), which serve as the renal protective agents.It is recommended that the dose in the kidneys to limit to 23 Gy (BARONE et al., 2005).
Table1.Results of MCNP5/X calculations for absorbed dose per particle in organs of human body (kidneys, liver and tumour are the sources of irradiation).