The role of patient-based treatment planning in peptide receptor radionuclide therapy
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Accurate treatment planning is recommended in peptide-receptor radionuclide therapy (PRRT) to minimize the toxicity to organs at risk while maximizing tumor cell sterilization. The aim of this study was to quantify the effect of different degrees of individualization on the prediction accuracy of individual therapeutic biodistributions in patients with neuroendocrine tumors (NETs).
A recently developed physiologically based pharmacokinetic (PBPK) model was fitted to the biokinetic data of 15 patients with NETs after pre-therapeutic injection of 111In-DTPAOC. Mathematical phantom patients (MPP) were defined using the assumed true (true MPP), mean (MPP 1A) and median (MPP 1B) parameter values of the patient group. Alterations of the degree of individualization were introduced to both mean and median patients by including patient-specific information as a priori knowledge: physical parameters and hematocrit (MPP 2A/2B). Successively, measurable individual biokinetic parameters were added: tumor volume V tu (MPP 3A/3B), glomerular filtration rate GFR (MPP 4A/4B), and tumor perfusion f tu (MPP 5A/5B). Furthermore, parameters of MPP 5A/5B and a simulated 68Ga-DOTATATE PET measurement 60 min p.i. were used together with the population values used as Bayesian parameters (MPP 6A/6B). Therapeutic biodistributions were simulated assuming an infusion of 90Y-DOTATATE (3.3 GBq) over 30 min to all MPPs. Time-integrated activity coefficients were predicted for all MPPs and compared to the true MPPs for each patient in tumor, kidneys, spleen, liver, remainder, and whole body to obtain the relative differences RD.
The large RD values of MPP 1A [RDtumor = (625 ± 1266)%, RDkidneys = (11 ± 38)%], and MPP 1B [RDtumor = (197 ± 505)%, RDkidneys = (11 ± 39)%] demonstrate that individual treatment planning is needed due to large physiological differences between patients. Although addition of individual patient parameters reduced the deviations considerably [MPP 5A: RDtumor = (−2 ± 27)% and RDkidneys = (16 ± 43)%; MPP 5B: RDtumor = (2 ± 28)% and RDkidneys = (7 ± 40)%] errors were still large. For the kidneys, prediction accuracy was considerably improved by including the PET measurement [MPP 6A/MPP 6B: RDtumor = (−2 ± 22)% and RDkidneys = (−0.1 ± 0.5)%].
Individualized treatment planning is needed in the investigated patient group. The use of a PBPK model and the inclusion of patient specific data, e.g., weight, tumor volume, and glomerular filtration rate, do not suffice to predict the therapeutic biodistribution. Integrating all available a priori information in the PBPK model and using additionally PET data measured at one time point for tumor, kidneys, spleen, and liver could possibly be sufficient to perform an individualized treatment planning.
KeywordsPRRT PBPK modeling Treatment planning PET
The authors gratefully acknowledge grants by “Direktorat Jendral Pendidikan Tinggi” (Directorate General of Higher Education DIKTI of Ministry for Research, Technology and Higher Education, Republic Indonesia. Grant Number: 2644/E4.4/K/2013) for DH, funding received for MITIGATE from the European Community’s Seventh Framework Programme (FP7/2007-20013) under grant agreement no 602306 and M2OLIE (Research Campus funded by the German Federal Ministry of Education and Research (BMBF) within the Framework “Forschungscampus: public–private partnership for Innovations”) and Perspektivförderung “Translationale Radiochemie und Radiopharmazie” (Land Baden–Württemberg) and by the “Bundesministerium für Bildung und Forschung” (Federal Ministry of Education and Research, BMBF 02NUK008F) and “Bundesamt für Strahlenschutz” (Federal Office for Radiation Protection, BfS 3608S04001) for the establishment of the endowed professorship “Medizinische Strahlenphysik/Strahlenschutz” (Medical Radiation Physics/Radiation Protection). The authors also gratefully acknowledge the “Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) for support (GL 236/11-1 and KL 2742/2-1).
DH and GG conceived and designed the experiments.
DH performed the experiments.
DH, PK and GG analyzed the data.
FM and BM contributed reagents/materials/analysis tools.
DH, CM, AAA, BM, PK, FMM, GG contributed to the writing of the manuscript.
Compliance with ethical standards
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.
The authors declare that they have no competing interests.
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