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Therapeutic efficacy of heterogeneously distributed radiolabelled peptides: Influence of radionuclide choice

  • Giulia Tamborino
    Affiliations
    Research in Dosimetric Application, Belgian Nuclear Research Centre (SCK CEN), Boeretang 200, Mol, Belgium

    Department of Radiology and Nuclear Medicine, Erasmus University Medical Center, Doctor Molewaterplein 40, Rotterdam 3000 CA, the Netherlands
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  • Julie Nonnekens
    Affiliations
    Department of Radiology and Nuclear Medicine, Erasmus University Medical Center, Doctor Molewaterplein 40, Rotterdam 3000 CA, the Netherlands

    Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center, Doctor Molewaterplein 40, Rotterdam 3000 CA, the Netherlands
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  • Lara Struelens
    Affiliations
    Research in Dosimetric Application, Belgian Nuclear Research Centre (SCK CEN), Boeretang 200, Mol, Belgium
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  • Marijke De Saint-Hubert
    Affiliations
    Research in Dosimetric Application, Belgian Nuclear Research Centre (SCK CEN), Boeretang 200, Mol, Belgium
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  • Frederik A. Verburg
    Affiliations
    Department of Radiology and Nuclear Medicine, Erasmus University Medical Center, Doctor Molewaterplein 40, Rotterdam 3000 CA, the Netherlands
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  • Mark W. Konijnenberg
    Correspondence
    Corresponding author at: Department of Radiology and Nuclear Medicine, ERASMUS MC, Room Ns-561, PO box 2040, Rotterdam 3000 CA, The Netherlands.
    Affiliations
    Department of Radiology and Nuclear Medicine, Erasmus University Medical Center, Doctor Molewaterplein 40, Rotterdam 3000 CA, the Netherlands
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Open AccessPublished:March 01, 2022DOI:https://doi.org/10.1016/j.ejmp.2022.02.021

      Abstract

      Purpose

      To model dose-response relationships for in vivo experiments with radiolabelled peptides enabling maximum therapeutic efficacy while limiting toxicity to kidney and bone marrow.

      Methods

      A multiregional murine kidney phantom, with a kinetic model for cortex and outer medulla distribution, were used to predict renal toxicity.
      Maximum tolerated activities to avoid nephrotoxicity (at 40 Gy Biological Effective Dose BED) and hematologic toxicity (at 2 Gy) were compared.
      The therapeutic efficacy of 90Y, 161Tb, 177Lu and 213Bi was assessed at their respective maximum tolerated activities based on cellular-level dosimetry accounting for activity and tumor heterogeneity. These results were compared with average tumor-dosimetry-based predictions.

      Results

      The kidney was found to be the dose-limiting organ for all radionuclides, limiting the administered activity to 44 MBq 177Lu, 34 MBq 161Tb, 19 MBq 90Y and 13 MBq 213Bi , respectively.
      The average S-values for the initial heterogeneous activity distribution in the tumor volume are not significantly different from the homogeneous ones. The in vivo tumor cell survivals predicted by assuming uniform dose rate-distributions are not significantly different from those for heterogeneous dose rate-based predictions.
      The lowest in vivo survival was found for 213Bi (2%) followed by 161Tb (30%), 177Lu (37%) and 90Y (60%). The minimal effective dose rate for cell kill is 13–14 mGy/h for β-emitters and 2.2 mGy/h for the α-particle emitter 213Bi, below these values proliferation takes over.

      Conclusions

      Radionuclides emitting α-particles have the highest potential for improving therapeutic efficacy in tumors and metastases with uniform receptor expression, after careful evaluation of their burden to the healthy organs.

      Keywords

      Introduction

      Peptide receptor radionuclide therapy (PRRT) employs receptor-mediated binding to deliver a cytotoxic dose to neuroendocrine tumors (NETs). Somatostatin analogues radiolabelled with β-emitting radionuclides (i.e., [177Lu]Lu-DOTA-[Tyr3]octreotate or 177Lu-DOTATATE and [90Y] Y-DOTA-[Tyr3]octreotide or 90Y-DOTATOC) were proven highly efficacious in treatment of patients bearing inoperable or metastatic NETs overexpressing the somatostatin receptor type-2 (SSTR2) [
      • Strosberg J.
      • Wolin E.
      • Chasen B.
      • Kulke M.
      • Bushnell D.
      • Caplin M.
      • et al.
      Health-related quality of life in patients with progressive midgut neuroendocrine tumors treated with 177Lu-DOTATATE in the phase III netter-1 trial.
      ,
      • Kwekkeboom D.J.
      • Mueller-Brand J.
      • Paganelli G.
      • Anthony L.B.
      • Pauwels S.
      • Kvols L.K.
      • et al.
      Overview of results of peptide receptor radionuclide therapy with 3 radiolabeled somatostatin analogs.
      ]. However, despite their success in improving patient’s quality of life while mitigating adverse events, patients invariably relapse on average 2–3 years after starting treatment. In this respect, the use of dosimetry-guided treatment planning and alternative radionuclides may lead to improvement of progression free survival.
      Optimization of clinical PRRT by dosimetry-guided treatment planning relies on the evaluation of absorbed dose-effect relationships in preclinical experiments in order to assess treatment efficacy and toxicity. Regarding treatment efficacy, tumor size and targeted receptor expression may guide the radionuclide choice in terms of physical characteristics. For instance, simulations show that a low energy β-emitting radionuclide, such as 177Lu (Eβmean = 133 keV) yields a high probability of cure in the 1–3-mm tumor size range. Instead, the higher energy β-emitter (Eβmean = 933 keV) 90Y shows optimal tumor control in the 28–42-mm range [
      • O’Donoghue J.A.
      • Bardies M.
      • Wheldon T.E.
      • Sgouros G.
      Relationships between tumor size and curability for uniformly targeted therapy with beta-emitting radionuclides.
      ]. These results were confirmed in rats with subcutaneously implanted somatostatin receptor-positive tumors [
      • De Jong M.
      • Breeman W.A.P.
      • Bernard B.F.
      • Bakker W.H.
      • Visser T.J.
      • Kooij P.P.M.
      • et al.
      Tumor response after [90Y-DOTA0, Tyr3]-octreotide radionuclide therapy in a transplantable rat tumor model is dependent on tumor size.
      ,
      • De Jong M.
      • Breeman W.A.P.
      • Bernard B.F.
      • Bakker W.H.
      • Schaar M.
      • Van Gameren A.
      • et al.
      [177Lu-DOTA0, Tyr3]octreotate for somatostatin receptor-targeted radionuclide therapy.
      ]. Moreover, on one hand, the use of these medium-to-long range β particle-emitting radionuclides might overcome heterogeneous activity distributions by cross-irradiation; on the other hand, the relatively large loss of radiation in surrounding tissue and low linear energy transfer (LET) characterizing β-particles might reduce treatment efficacy. In this respect, a promising alternative to 177Lu is 161Tb, because of its additional release of low energy (up to 50 keV per decay) conversion and Auger electrons compared to 177Lu. Octreotate internalizes into the cells and possibly accumulates into the Golgi apparatus, making only the conversion electron energy high enough to reach the cell nucleus [
      • Tamborino G.
      • De Saint-Hubert M.
      • Struelens L.
      • Seoane D.C.
      • Ruigrok E.A.M.
      • Aerts A.n.
      • et al.
      Cellular dosimetry of [177Lu]Lu-DOTA-[Tyr3]octreotate radionuclide therapy: the impact of modeling assumptions on the correlation with in vitro cytotoxicity.
      ]. Indeed, theoretical dose calculations demonstrated that 161Tb may outperform 177Lu in treating small metastatic lesions [
      • Uusijärvi H.
      • Bernhardt P.
      • Rösch F.
      • Maecke H.R.
      Forssell-Aronsson E.
      ,

      Champion C, Quinto MA, Morgat C, Zanotti-Fregonara P, Hindié E. Comparison between three promising β-emitting radionuclides, 67Cu, 47Sc and 161Tb, with emphasis on doses delivered to minimal residual disease. Theranostics 2016;6. https://doi.org/10.7150/thno.15132.

      ,
      • Hindié E.
      • Zanotti-Fregonara P.
      • Quinto M.A.
      • Morgat C.
      • Champion C.
      Dose deposits from90Y,177Lu,111In, and161Tb in micrometastases of various sizes: Implications for radiopharmaceutical therapy.
      ]. Furthermore, studies with cells and mice bearing small tumor xenografts confirmed this finding [
      • Müller C.
      • Umbricht C.A.
      • Gracheva N.
      • Tschan V.J.
      • Pellegrini G.
      • Bernhardt P.
      • et al.
      Terbium-161 for PSMA-targeted radionuclide therapy of prostate cancer.
      ]. Finally, a more potent option, suitable for treatment of small tumor clusters and metastases, are higher LET particles, such as the α-emitter 213Bi, as shown in mice [
      • Nayak T.K.
      • Norenberg J.P.
      • Anderson T.L.
      • Prossnitz E.R.
      • Stabin M.G.
      • Atcher R.W.
      Somatostatin-receptor-targeted α-emitting 213Bi is therapeutically more effective than β−-emitting 177Lu in human pancreatic adenocarcinoma cells.
      ] and, more recently, in clinical trials [
      • Kratochwil C.
      • Giesel F.L.
      • Bruchertseifer F.
      • Mier W.
      • Apostolidis C.
      • Boll R.
      • et al.
      213Bi-DOTATOC receptor-targeted alpha-radionuclide therapy induces remission in neuroendocrine tumours refractory to beta radiation: a first-in-human experience.
      ].
      Once a clear dose-response relationship between tumor volume reduction and tumor absorbed dose is found, the challenge is to deliver the highest dose to the tumor while sparing healthy tissues. Therefore, the establishment of absorbed dose-effect relationships for healthy organs, as well, is a fundamental step to limit toxicity while maximizing treatment efficacy. In PRRT for NETs the main dose-limiting tissues are the bone marrow, populated by the highly radiosensitive hematopoietic cells, and the kidneys, since radiolabeled somatostatin analogs are reabsorbed in the renal proximal tubules via the endocytic megalin/cubilin receptor complex [
      • Melis M.
      • Krenning E.P.
      • Bernard B.F.
      • Barone R.
      • Visser T.J.
      • de Jong M.
      Localisation and mechanism of renal retention of radiolabelled somatostatin analogues.
      ].
      In more detail, kidneys have been shown to be a major critical organ for PRRT with 90Y-DOTATOC [
      • Barone R.
      • Borson-Chazot F.
      • Valkema R.
      • Walrand S.
      • Chauvin F.
      • Gogou L.
      • et al.
      Patient-specific dosimetry in predicting renal toxicity with (90)Y-DOTATOC: relevance of kidney volume and dose rate in finding a dose-effect relationship.
      ], whilst the main tissue at risk identified in the phase III study for 177Lu-DOTATATE was the red bone marrow, with about 10% of the patients undergoing grade-3 or −4 lymphopenia [
      • Strosberg J.
      • El-Haddad G.
      • Wolin E.
      • Hendifar A.
      • Yao J.
      • Chasen B.
      • et al.
      Phase 3 trial of 177Lu-DOTATATE for midgut neuroendocrine tumors.
      ].
      The co-emitted Auger/conversion electrons of 161Tb raised the concern of a potentially higher probability of renal toxicity than 177Lu-DOTATATE due to a higher dose to the cortex [

      Haller S, Pellegrini G, Vermeulen C, van der Meulen NP, Köster U, Bernhardt P, et al. Contribution of Auger/conversion electrons to renal side effects after radionuclide therapy: preclinical comparison of 161Tb-folate and 177Lu-folate. EJNMMI Res 2016;6. https://doi.org/10.1186/s13550-016-0171-1.

      ], even though a very recent first-in-human application of 161Tb-DOTATOC showed that the treatment was well tolerated and no related adverse events were reported [
      • Baum R.P.
      • Singh A.
      • Kulkarni H.R.
      • Bernhardt P.
      • Rydén T.
      • Schuchardt C.
      • et al.
      First-in-Human Application of Terbium-161: A Feasibility Study Using 161 Tb-DOTATOC.
      ].
      Moderate toxicity was instead observed in a clinical trial of 213Bi- DOTATOC administered with a renal protection solution in patients’ refractory to 177Lu-DOTATATE and 90Y-DOTATOC treatment, while acute haematotoxicity was even less pronounced than with the preceding β therapies [
      • Kratochwil C.
      • Giesel F.L.
      • Bruchertseifer F.
      • Mier W.
      • Apostolidis C.
      • Boll R.
      • et al.
      213Bi-DOTATOC receptor-targeted alpha-radionuclide therapy induces remission in neuroendocrine tumours refractory to beta radiation: a first-in-human experience.
      ].
      The aim of this work is to evaluate the relative therapeutic potential of 90Y, 177Lu, 161Tb and 213Bi for treatment of solid tumors, adopting our previously developed dosimetric model using the SSTR2 levels to account for tumor (cancer/healthy cells) and activity heterogeneity at cellular scale [
      • Tamborino G.
      • Nonnekens J.
      • De Saint-Hubert M.
      • Struelens L.
      • Feijtel D.
      • de Jong M.
      • et al.
      Dosimetric evaluation of receptor-heterogeneity on the therapeutic efficacy of peptide receptor radionuclide therapy: correlation with DNA damage induction and in vivo survival.
      ]. The comparison was carried out preventing kidney and bone marrow toxicity, thereby modeling the spatial and temporal distribution of radioactivity in kidney sub-regions and accounting for dose rate and fractionation of treatment delivery. The same biodistribution profiles were used for all radiolabelled analogues [
      • Tamborino G.
      • Nonnekens J.
      • De Saint-Hubert M.
      • Struelens L.
      • Feijtel D.
      • de Jong M.
      • et al.
      Dosimetric evaluation of receptor-heterogeneity on the therapeutic efficacy of peptide receptor radionuclide therapy: correlation with DNA damage induction and in vivo survival.
      ].

      Material and Methods

      Limiting organ dosimetry: Red bone marrow

      In order to determine the administered activity corresponding to a maximum tolerated dose (MTD) in the bone marrow of 2 Gy, simulation of self- and cross- S-values were combined with cumulated activities extrapolated from 177Lu-DOTATATE data [
      • Feijtel D.
      • Doeswijk G.N.
      • Verkaik N.S.
      • Haeck J.C.
      • Chicco D.
      • Angotti C.
      • et al.
      Inter and intra-tumor somatostatin receptor 2 heterogeneity influences peptide receptor radionuclide therapy response.
      ].

      Self- and cross-absorbed dose rate S-values for bone marrow dosimetry

      The Moby program [
      • Segars W.P.
      • Tsui B.M.W.
      • Frey E.C.
      • Johnson G.A.
      • Berr S.S.
      Development of a 4D-digital mouse phantom for molecular imaging research.
      ] was used to generate a voxel phantom of 128×128×432 elements, with cubic voxels of 234 μm. The original phantom was re-scaled to represent a mouse with body weight of about 25 g and its lungs were simulated in full exhaled condition. The mouse image was then expanded with voxels of zero value (i.e., empty) in order to allow for the addition of a spherical subcutaneous tumor xenograft on one of the flanks (Fig. 1) using Python [

      Python Softw Found 2017 https://doi.org/https://www.python.org/.

      ]. The tumor did not invade the tissue beneath the skin, resulting in a half sphere-like geometry. The phantom consists of 30 tissues, including the tumor, serving as both source and target in the absorbed dose rate S-value calculations. The compositions of each organ was taken from ICRP 23 [

      Report of the task group on reference man ICRP Publication 23 (1975). Ann ICRP 1980;4. https://doi.org/10.1016/0146-6453(80)90047-0.

      ]. The skeleton was subdivided in ribs, spine, skull, humeri, femurs, tibiae and others (i.e., radii, ulnae, fibulae, patellae and reminder) and assumed to be made of soft tissue (1 g/cm3 vs. 1.2 g/cm3) in order to evaluate the bone marrow S-values by rescaling for the marrow cellularity of each bone [
      • Colvin G.A.
      • Lambert J.-F.
      • Abedi M.
      • Hsieh C.-C.
      • Carlson J.E.
      • Stewart F.M.
      • et al.
      Murine marrow cellularity and the concept of stem cell competition: Geographic and quantitative determinants in stem cell biology.
      ]. The material of voxels outside the phantom was air. Density and volume of organs is detailed in Table 1. The activity was assumed to be homogeneously distributed in each source region.
      Figure thumbnail gr1
      Fig. 1MOBY phantom. A) Three-dimensional view of the murine phantom including the tumor xenograft on the left flank. B) Top view section highlighting the segmented tissues.
      Table 1Organ volumes and tissue densities of the murine model MOBY. Percentage of total marrow cellularity
      • Colvin G.A.
      • Lambert J.-F.
      • Abedi M.
      • Hsieh C.-C.
      • Carlson J.E.
      • Stewart F.M.
      • et al.
      Murine marrow cellularity and the concept of stem cell competition: Geographic and quantitative determinants in stem cell biology.
      for each bone is reported in parenthesis. The bones are solid structures made of soft tissue.
      TissueVolume (mm3)Density (g/cm3)
      Heart wall68.111.05
      Body17124.551.05
      Liver1649.891.06
      Lungs414.010.3
      Stomach wall64.561.04
      Stomach content401.971.04
      Pancreas322.901.04
      Kidneys302.631.05
      Spleen94.931.06
      Small intestine939.691.03
      Large intestine293.741.03
      Bladder59.251.04
      Vascular defense22.011.06
      Testis296.321.04
      Ribs205.99 (8 %)1
      Spine413.11 (52 %)1
      Skull477.82 (11 %)1
      Brain449.761.04
      Thyroid12.241.04
      Large intestine air276.640.00129
      Small intestine air706.210.00129
      Humeri33.08 (5 %)1
      Femurs96.80 (10 %)1
      Tibiae89.87 (4 %)1
      Other bones300.62 (10 %)1
      Gall bladder13.071.04
      Heart content181.601.06
      Airways76.341.03
      Tumor118.511
      The Gate MC toolkit version 9.0 [
      • Jan S.
      • Santin G.
      • Strul D.
      • Staelens S.
      • Assié K.
      • Autret D.
      • et al.
      GATE: A simulation toolkit for PET and SPECT.
      ] was used to perform simulations and score the average absorbed dose for target tissues with the DoseByRegion actor (locally deposited energy per dose voxel mass).
      The radioactive source for the β-emitting radionuclides was sampled using the predefined ion source definition (ENSDF database), which includes all the spectral components of 177Lu, 90Y and 161Tb. The 4 radionuclides involved in the decay chain of 213Bi were instead sampled by means of user defined spectra, accounting for the emission of all particle types, described in 11 separate macro-sources. The definition of the spectral components of 213Bi were taken from ICRP 107 and the probability of an event coming from each macro-source and the energy emitted per decay is reported in Table 2, together with the relative branching ratio, taken into account in the source sampling. Recoil energy associated with 213Bi and 213Po was ignored.
      Table 2Particles and energy (E) per decay (Bq s) emitted by the 213Bi decay chain. The branching ratios (BR) of each radionuclide is reported in the last row.
      Particle type213Bi (yield)E (MeV)213Po (yield)E (MeV)209Tl (yield)E (MeV)209Pb (yield)E(MeV)
      γ + x9.63E-011.28E-017.13E-053.75E-056.622.14E + 000
      β9.79E-014.25E-01016.55E-0111.97E-01
      e6.26E-011.92E-022.12E-051.23E-063.463.22E-020
      α2.09E-021.22E-011.00E + 008.38E + 0000
      BR19.79E-012.09E-021
      The Livermore physics list, including a low-energy electromagnetic model based on publicly available evaluated data tables from the Livermore data library and with a production cut-off of 20 μm, was adopted for simulations with 177Lu, 161Tb and 90Y. Whilst the results for 213Bi simulations were obtained using the QGSP_BIC_EMY physics list and adding a maximum step size of 100 μm. The transportation of secondary particles was included, as well.
      The total number of particles (10–50 million) was chosen to ensure an error below 3% for all the simulations.

      Cumulated activity in source organs

      The time-integrated activity concentration coefficients (TIACs) from a previously published work [
      • Feijtel D.
      • Doeswijk G.N.
      • Verkaik N.S.
      • Haeck J.C.
      • Chicco D.
      • Angotti C.
      • et al.
      Inter and intra-tumor somatostatin receptor 2 heterogeneity influences peptide receptor radionuclide therapy response.
      ] were corrected for the organ masses of MOBY and, after incorporating the 177Lu, 90Y, 161Tb and 213Bi physical decay functions (Table 3), combined with the S-values determined above. For the bone marrow calculations, a blood based approach with a red-marrow-to-blood ratio (RMBLR) = 1 [
      • Forrer F.
      • Krenning E.P.
      • Kooij P.P.
      • Bernard B.F.
      • Konijnenberg M.
      • Bakker W.H.
      • et al.
      Bone marrow dosimetry in peptide receptor radionuclide therapy with [177Lu-DOTA0, Tyr3]octreotate.
      ] was adopted assuming muscle as a surrogate for the whole body distribution (i.e., TIACmuscleTIACbloodTIACBM). The TIACs of the bone marrow contained in the 7 segmented bones was then calculated accounting for the cellularity [
      • Colvin G.A.
      • Lambert J.-F.
      • Abedi M.
      • Hsieh C.-C.
      • Carlson J.E.
      • Stewart F.M.
      • et al.
      Murine marrow cellularity and the concept of stem cell competition: Geographic and quantitative determinants in stem cell biology.
      ].
      Table 3Time integrated activity coefficient (TIAC) per gram of tissue in organs with physiologic uptake and in tumor, following a single (1-exp) or a double exponential (2-exp) clearance pattern.
      TIAC (h/g)SpleenPancreasKidneyLiverStomachDuodenum + intestineMuscleTumor
      Decay1-exp2-exp2-exp2-exp2-exp1-exp1-exp1-exp
      177Lu0.110.341.310.080.650.170.053.64
      161Tb0.100.341.280.080.630.160.043.43
      90Y0.050.281.030.050.440.090.032.02
      213Bi2.04E-030.030.063.11E-030.024.65E-031.70E-030.06
      Assuming an absorbed-dose threshold of 2 Gy to hypothetically reduce the probability of severe marrow depression [

      Kwekkeboom DJ, Bakker WH, Kam BL, Teunissen JJM, Kooij PPM, Herder WW, et al. Treatment of patients with gastro-entero-pancreatic (GEP) tumours with the novel radiolabelled somatostatin analogue [177Lu-DOTA0,Tyr3]octreotate. Eur J Nucl Med Mol Imaging 2003;30. https://doi.org/10.1007/s00259-002-1050-8.

      ], the maximum safe administered activity was computed as described below. Both self- and cross- absorbed doses to each bone marrow region were accounted for when dealing with β-emitting radionuclides, while the cross-dose was neglected for the 213Bi scenario. A relative biological effectiveness (RBE) of 2 [
      • Sgouros G.
      • Bolch W.
      • Watchman C.
      • Jurcic J.
      • Scheinberg D.
      Relative biological effectiveness (RBE) of the alpha-particle emitter 213Bi vs 90Y for hematologic toxicity and efficacy in patients with leukemia.
      ] was used to determine the RBE-weighted absorbed dose for α-particles to the bone marrow.

      Limiting organ dosimetry: Kidney

      A biological effective dose (BED) based treatment planning was performed to determine the MTD for nephrotoxicity. A regional kidney dosimetry model was used to determine the outer medulla and cortex S-value for β-emitting radionuclides. The uptake in outer medulla and cortex was modelled to determine the biodistribution profiles at regional level. Within the cortex most (95 %) of the activity was assumed to be located in the proximal tubes [
      • Melis M.
      • Krenning E.P.
      • Bernard B.F.
      • Barone R.
      • Visser T.J.
      • de Jong M.
      Localisation and mechanism of renal retention of radiolabelled somatostatin analogues.
      ].

      Regional kidney dosimetry model

      A multiregional mathematical kidney model of 0.15 ml (as in MOBY) was developed in order to perform separate detailed Monte Carlo simulations accounting for the inhomogeneous distribution of the activity and the relatively long range of β-emitting radionuclides. The kidney was divided into several regions: cortex, outer stripe (outer medulla), inner stripe (outer medulla), inner medulla, pelvis and papilla. These regions were modelled as prolate ellipsoids, except for the renal pelvis (cone) in MCNP6 (Fig. 2, Table 4). Volumes and densities are detailed in Table 4. Materials were defined as in ICRU report 46.
      Figure thumbnail gr2
      Fig. 2Regional kidney model. The kidney region corresponding to each identification number in the picture is reported in . The numbers indicate the cell tally (i.e., scorers) numbers used in MCNP to determine the absorbed energy.
      Table 4Dimensions and geometrical characteristics of the mouse kidney model defined in MCNP, the numbers in column ID refer to the kidney regions shown in Fig. 2.
      IDRegionDensity (g/cm3)Volume (cm3)External surfaceInternal surface
      R (cm)H (cm)R (cm)H (cm)
      10Cortex1.047.28E-020.2680.5000.2140.400
      20Outer stripe medulla1.042.86E-020.2140.4000.1780.360
      30Inner stripe medulla1.032.21E-020.1780.3600.1500.270
      40Inner medulla1.032.06E-020.1500.2700.0850.150
      50Papilla & Pelvis1.044.48E-030.0850.15000
      Conical surfaceEllipsoidal surface
      R (cm)H (cm)
      60Papilla1.042.26E-040.0800.2680.1340.201
      70Pelvis1.041.58E-030.0800.2680.1340.201
      0.2680.5
      Ellipsoidal surfaces of equation: xR2+yR2+zH2=1 contour kidney regions.
      The renal pelvis is modeled as a conical surface between two ellipsoidal surfaces.
      The radionuclides were located uniformly either in the cortex or in the outer medulla region and the absorbed fractions of energy for the emitted radiation of 177Lu, 90Y and 161Tb were simulated. From the absorbed fractions, the absorbed dose rate S-values to the cortex were derived.
      The decay data for these radionuclides were taken from ICRP 107. A cut off value of 1 keV was used in the energy transport calculations for electrons.
      For 213Bi calculations the S-values reported at nephron level by Hobbs et al. [
      • Hobbs R.F.
      • Song H.
      • Huso D.L.
      • Sundel H.M.
      • Sgouros G.
      A nephron-based model of the kidneys for macro-to-micro α-particle dosimetry.
      ] were adopted.

      Biodistribution modeling and biological effective dose (BED) calculations

      The Linear-Quadratic (LQ) model is an empirical relation between the cell survival S and absorbed dose D following a linear and quadratic exponential function: S = exp (-αD-βD2). Both the cell survival and the renal damage dose response curves for α-particle radiation follow only a linear exponential relation, reflecting that the repair of cellular damage is reduced favoring single event cell kill, expressed in the linear radiation sensitivity parameter α [
      • Strosberg J.
      • Wolin E.
      • Chasen B.
      • Kulke M.
      • Bushnell D.
      • Caplin M.
      • et al.
      Health-related quality of life in patients with progressive midgut neuroendocrine tumors treated with 177Lu-DOTATATE in the phase III netter-1 trial.
      ]. In general the Biological Effective Dose BED is defined for a dose given in N fractions as:
      BED=D1+GD/Nα/β,
      (1)


      with G the Lea-Catcheside factor, expressing the dose rate and DNA-damage repair function over time.
      The kidney absorbed-dose limit of 23 Gy determined for external beam radiotherapy (EBRT) [
      • Emami B.
      • Lyman J.
      • Brown A.
      • Cola L.
      • Goitein M.
      • Munzenrider J.E.
      • et al.
      Tolerance of normal tissue to therapeutic irradiation.
      ] was adjusted to the PRRT-equivalent via the BED formalism derived with the LQ model [
      • Dale Roger
      Use of the linear-quadratic radiobiological model for quantifying kidney response in targeted radiotherapy.
      ]. First, assuming α/β = 2.6 Gy and an absorbed dose per fraction of 2 Gy for EBRT, the equivalent BED was found. The BED was converted into the maximum absorbed dose in the renal cortex (Eq. (1)) per therapy cycle of PRRT, assuming 4 therapy cycles for all radionuclides. The G-factor was evaluated for 2 source regions (i.e., outer medulla and cortex) following a bi-exponential time-activity curve, according to the formula by Baechler et al. [
      • Baechler Sébastien
      • Hobbs Robert F.
      • Prideaux Andrew R.
      • Wahl Richard L.
      • Sgouros George
      Extension of the biological effective dose to the MIRD schema and possible implications in radionuclide therapy dosimetry.
      ].
      For this purpose, a differential clearance between cortex and outer medulla was assumed based on renal clearance data of female and male mice by Melis et al. [
      • Melis Marleen
      • Krenning Eric P.
      • Bernard Bert F.
      • de Visser Monique
      • Rolleman Edgar
      • de Jong Marion
      Renal uptake and retention of radiolabeled somatostatin, bombesin, neurotensin, minigastrin and CCK analogues: species and gender differences.
      ]. The ratio of activity in the cortex relative to the outer medulla was modelled with an exponential build-up curve followed by a plateau after 96 h and the sum of cortex and outer medulla activity was set equal to the whole-kidney activity (Table 3). A summary of the bi-exponential fitting parameters for the biological renal clearance is reported in Table 5. Fig. 3 shows a plot of the fractional activity in the whole kidney, outer medulla, and cortex versus time, used as input together with the regional S-values to evaluate the G-factor. Within the G-factor formula, a repair half-life for the renal cortex of 2.8 h [
      • Barone R.
      • Borson-Chazot F.
      • Valkema R.
      • Walrand S.
      • Chauvin F.
      • Gogou L.
      • et al.
      Patient-specific dosimetry in predicting renal toxicity with (90)Y-DOTATOC: relevance of kidney volume and dose rate in finding a dose-effect relationship.
      ] was used for the β-emitting radionuclides.
      Table 5Bi-exponential fitting parameters for outer medulla and cortex region of female and male mouse models, including whole kidney parameters.
      ParametersWhole kidneyMale mouse modelFemale mouse model
      CortexOuter medullaCortexOuter medulla
      Initial fraction1.000.440.560.230.77
      Plateau0.040.000.000.000.00
      %Fast76.1071.1682.1789.3679.83
      T1/2FAST (h)89.357.4519.886.48
      T1/2SLOW (h)47.9061.4547.2115551.23
      Figure thumbnail gr3
      Fig. 3Fractional activity vs. time after injection for outer medulla and cortex of kidney. The biodistributions differ for the female and male mouse model.
      The MTD per therapy cycle (total number of cycles: N) was evaluated by the following formula with the aforementioned parameters:
      DCORTEX=α/β2G/N1+4G/NBEDα/β-1


      For the 213Bi-DOTATATE scenario, only α-particles were assumed to cause nephrotoxicity. The time-integrated activity was evaluated at nephron level, assuming most of the radioactivity (95%) to be retained in the proximal tubules with respect to the glomeruli cells [
      • Melis M.
      • Krenning E.P.
      • Bernard B.F.
      • Barone R.
      • Visser T.J.
      • de Jong M.
      Localisation and mechanism of renal retention of radiolabelled somatostatin analogues.
      ]. The BED formula, in this case, was corrected with an RBE [
      • Dale Roger
      Use of the linear-quadratic radiobiological model for quantifying kidney response in targeted radiotherapy.
      ] of 2 and the G-factor was approximated to 1. Hence, the maximum absorbed dose was evaluated as follows:
      DGLOMERULI=-RBE+RBE2+4BED(α/β)2(α/β)


      The maximum injected activity was then evaluated from the absorbed dose determined by either Eq. (1) or Eq. (2), knowing TIACs and S-values for the corresponding compartments.
      It should be noticed that the same radiosensitivity parameters (α/β) were used for all radionuclides, except for 213Bi.

      Therapeutic efficacy: Tumor dosimetry and in vivo survival correlation

      The SSTR2 expression of NCI-H69 xenografts assessed by immunofluorescent stainings in previous experiments [
      • Feijtel D.
      • Doeswijk G.N.
      • Verkaik N.S.
      • Haeck J.C.
      • Chicco D.
      • Angotti C.
      • et al.
      Inter and intra-tumor somatostatin receptor 2 heterogeneity influences peptide receptor radionuclide therapy response.
      ] was used to assess the heterogeneity in the absorbed dose distribution over the tumor volume and the average absorbed dose S-value, as reported previously solely for 177Lu-DOTATATE [
      • Tamborino G.
      • Nonnekens J.
      • De Saint-Hubert M.
      • Struelens L.
      • Feijtel D.
      • de Jong M.
      • et al.
      Dosimetric evaluation of receptor-heterogeneity on the therapeutic efficacy of peptide receptor radionuclide therapy: correlation with DNA damage induction and in vivo survival.
      ]. Briefly, square tissue sections with 3.2×3.2 mm side and resolution of 0.625 μm/pixel from 4 independent mice before injection were used to reconstruct 16 voxelized computational models (heterogeneous tumor cell distribution) and the corresponding 16 voxelized sources (heterogeneous radionuclide distribution). The input data for the Monte Carlo (MC) simulations is represented by 507x507x289 voxels of 5.7×5.7×10 μm size.
      For comparison, the S-value and absorbed dose rate distribution calculations, assuming an equivalent uniform spherical phantom (representing the tumor) were also performed.
      The Gate MC toolkit version 9.0 was used to perform simulations and score 3-dimensional absorbed dose maps (resolution: 5.7×5.7×10 μm) within the defined geometry. The average dose was also calculated for tumorous and healthy cells with the DoseByRegion actor (deposited energy per dose voxel mass). The radioactive source definition and the physics list adopted for these calculations were the same as reported for the bone marrow S-value calculations. However, in order to display the absorbed dose distribution at voxel level, the production cut-off was lowered to 1 μm for 177Lu, 161Tb and 90Y, whilst a step size of 1 μm was added for the 213Bi-case.
      The in vivo survival was determined either accounting for the heterogeneous absorbed dose rate distribution or by means of a single averaged S-value (i.e., average approach) over the tumor volume as described previously [
      • Tamborino G.
      • Nonnekens J.
      • De Saint-Hubert M.
      • Struelens L.
      • Feijtel D.
      • de Jong M.
      • et al.
      Dosimetric evaluation of receptor-heterogeneity on the therapeutic efficacy of peptide receptor radionuclide therapy: correlation with DNA damage induction and in vivo survival.
      ] for both uniform (spherical) and heterogeneous scenario.
      The radiobiological parameters used to describe the in vivo tumor cell survival according to the LQ model for the β-emitting radionuclides (177Lu, 90Y, 161Tb) are: α = 0.14 Gy−1, α/β = 100 Gy or 10 Gy, Tμ = 60 h and TD = 14.5 d, where Tμ and TD are used to indicate repair and tumor repopulation half-life, respectively.
      A linear dose-response was assumed for 213Bi-DOTATATE exposure with an RBE of 3.4 [
      • Nayak T.K.
      • Norenberg J.P.
      • Anderson T.L.
      • Prossnitz E.R.
      • Stabin M.G.
      • Atcher R.W.
      Somatostatin-receptor-targeted α-emitting 213Bi is therapeutically more effective than β−-emitting 177Lu in human pancreatic adenocarcinoma cells.
      ].

      Results

      Bone marrow dosimetry

      The absorbed dose per administered activity for the bone marrow is reported in Fig. 4, distinguishing among the segmented bone marrow regions. The major contribution to the self- bone marrow dose is delivered by the bone marrow region with the highest cellularity (i.e., spine), regardless of the radionuclide used. Most of the cross-dose to the bone marrow for 177Lu and 161Tb is delivered by the total body (Fig. 4A and B), whilst the cross-dose for 90Y is more diverse including a significant contribution from tumor to lower limbs (i.e., tibiae and femurs), from stomach and liver to ribs and finally, from kidneys and stomach to spine (Fig. 4C). The electrons and photons contribution to the bone marrow absorbed dose is negligible (≈ 2 %) compared to the α-particle component.
      Figure thumbnail gr4
      Fig. 4Absorbed dose per administered activity to the bone marrow. The bar plots are used to distinguish either the contribution of self- and cross-dose (for β-emitters) or radiation type (for 213Bi) to the bone marrow absorbed dose.
      Finally, limiting the absorbed dose to the bone marrow to 2 Gy, the maximum administered activities are 231 MBq, 181 MBq, 22 MBq and 250 MBq for 177Lu, 161Tb, 90Y and 213Bi, respectively.

      Kidney dosimetry

      The simulated absorbed energy fractions and S-values for outer medulla and cortex activity are summarized in Table 6 and Table 7, respectively.
      Table 6Absorbed energy fractions in several target regions as defined in Table 4. Each radionuclide is emitted either from the cortex or from the outer medulla. The radiation types emitted by each radionuclide are defined by the subscripts. AE and IE indicate Auger electrons and internal conversion electrons, respectively.
      Target regionSource region: cortexSource region: outer medulla
      90Y(β)177Lu(β)177Lu(AE+IE)161Tb(β)161Tb (β)161Tb(AE)90Y(β)177Lu(β)177Lu(AE+IE)161Tb(β)161Tb(AE)161Tb(IE)
      1023.49%79.22%94.32%77.13%99.88%98.87%17.91%18.32%5.54%19.78%0.11%1.10%
      207.02%7.19%2.17%7.79%0.05%0.43%15.62%67.41%90.25%64.61%99.79%98.07%
      304.37%0.67%0.00%0.83%0.00%0.00%8.70%12.23%4.10%13.06%0.09%0.81%
      403.44%0.04%0.00%0.07%0.00%0.00%6.25%1.16%0.00%1.42%0.00%0.00%
      500.67%0.00%0.00%0.00%0.00%0.00%1.18%0.00%0.00%0.01%0.00%0.00%
      600.03%0.00%0.00%0.00%0.00%0.00%0.06%0.00%0.00%0.00%0.00%0.00%
      700.27%0.16%0.05%0.18%0.00%0.01%0.40%0.28%0.08%0.30%0.00%0.01%
      Total kidney39.29%87.27%96.55%85.99%99.93%99.32%50.12%99.41%99.97%99.19%100.00%99.99%
      Table 7S-values for 90Y, 177Lu and 161Tb distributed in the renal cortex or in the outer medulla.
      Target regionAbsorbed dose rate per unit activity S-value (mGy MBq −1 s −1)
      Source region: cortexSource region: outer medulla
      90Y177Lu161Tb90Y177Lu161Tb
      100.472.53E-013.47E-013.54E-015.34E-026.47E-02
      200.355.35E-026.50E-027.88E-015.56E-017.80E-01
      300.296.26E-038.92E-035.72E-011.19E-011.42E-01
      400.244.27E-047.83E-044.40E-011.17E-021.63E-02
      500.223.01E-061.79E-053.79E-011.84E-043.93E-04
      600.213.72E-074.82E-063.73E-012.77E-034.41E-03
      700.242.11E-022.64E-023.62E-013.70E-024.57E-02
      Total kidney0.380.130.180.480.150.20
      Assuming the cortex region as target, only a small fraction of the β-particles emitted from 90Y localized in the cortex reaches the target (23%) if compared to 177Lu (80%) and 161Tb (99%) (Table 6). On the contrary, when the radionuclides are assumed to be located in the outer medulla, similar energy fractions are absorbed in the cortex.
      The calculated factors leading to translate a BED of 41 Gy to PRRT-equivalent absorbed dose and the corresponding maximum injected activity are reported in Table 8.
      Table 8Comparison of G-factor, maximum tolerated dose to the cortex (Max D), TIACs in cortex (TIACC) and outer medulla (TIACOM), dose to the cortex per injected activity (D/IA) and maximum tolerated administered activity (Max A) for each radionuclide, using the female or male mouse model. The most restrictive result is reported in bold.
      177Lu161Tb90Y
      FemaleMaleFemaleMaleFemaleMale
      G-factor0.1030.0990.1040.1000.1490.144
      Max D (Gy)31.1131.3531.0331.2628.8129.02
      TIACC (s)2062.282129.421985.632082.371286.711563.21
      TIACOM (s)3199.342237.933137.102197.692425.831729.35
      D/IA (Gy/MBq)0.690.660.890.871.461.34
      Max A (MBq)44.9447.6534.7736.1219.7721.67
      The maximum tolerated absorbed dose to renal cortex (i.e., glomeruli cells) for 213Bi-DOTATATE is 8 Gy, corresponding to 13.74 MBq and 23.45 MBq of injected activity for male and female mice, respectively. The female mouse biodistribution results in the highest dose per injected activity because of the higher residence time estimated in the outer medulla for this mouse model.

      Tumor dosimetry

      Significant differences are found in the absorbed dose rate distributions caused by each radionuclide depending on the range of its particles and physical half-life. The dose rate map for the same tissue section (one of the 4 available tissue sections) theoretically treated with longer range radionuclides (177Lu and 90Y) and the corresponding cumulative dose volume histograms (cDVH, a graphical summary of the absorbed dose distribution by indicating the volumes with absorbed dose exceeding equi-spaced dose intervals in a histogram) are reported in Fig. 5A. The distributions of shorter-range radionuclides (161Tb and 213Bi) are shown in Fig. 5B. The equivalent spherical distributions are reported for comparison in both figures (Fig. 5A and B). The distributions corresponding to the other 3 tissue sections stained for the SSTR2 are reported in the Supplemental Material (Supplemental Material).
      Figure thumbnail gr5
      Fig. 5Graphical dosimetric evaluation of the impact of receptor heterogeneity on the absorbed dose distribution over the tumor volume compared to an equivalent uniform spherical scenario. The absorbed dose rate for the same initial SSTR2 expression image and the corresponding cumulative DVH for heterogeneous and uniform PRRT-exposures are shown for longer (A) and shorter (B) range radionuclides.
      The absorbed dose rate maps of 177Lu and 161Tb are very similar; however, the cDVH shows a longer tail corresponding to a greater presence of localized absorbed dose spots for 161Tb with respect to 177Lu. The absorbed dose rate map of 90Y is not significantly different from that of the spherical homogenous case scenario; however, a significant portion of the absorbed dose is delivered outside the tumor volume. The radionuclide with the most heterogeneous absorbed dose distribution is 213Bi, which shows a similar distribution pattern as 161Tb, with absorbed dose rate spots 2 times higher than the respective average values.
      The average S-values for the initial heterogeneous dose-distributions (Shet; SLu = 3.36 ± 0.32 μGyBq−1h−1, STb = 4.84 ± 0.48 μGyBq−1h−1, SY = 6.35 ± 0.47 μGyBq−1h−1, SBi = 218 ± 0.22 μGyBq−1h−1) are not significantly different from the corresponding uniform one (Shom;Shet-ShomShom<0.04), regardless of the type of radionuclide. The average absorbed doses to the tumor corresponding to an administered activity of 44 MBq of 177Lu, 34 MBq of 161Tb, 19 MBq of 90Y and 13.74 MBq of 213Bi are 12.9 Gy, 14.8 Gy, 5.9 Gy and 4.2 Gy (corresponding to 14 GyRBE3.4), respectively. It should be noticed that the calculated absorbed doses are limited by the toxicity to healthy organs and by the physical half-life characterizing each radionuclide (i.e., the cumulated activity of shorter lived radionuclides, such as 90Y and 213Bi, is smaller than longer lived ones), as well.
      The in vivo survival results, using the uniform (spherical) S-values for the dose calculations, are reported in Fig. 6A, as no significant difference has been found between the uniform and heterogeneous dose distribution assumption (Supplemental Material), as indicated for illustration purposes for one radionuclide (213Bi) in Fig. 6B.
      Figure thumbnail gr6
      Fig. 6In vivo survival comparison. A) In vivo survival curves for the analyzed radionuclides reported with dashed or continuous lines for an α/β = 100 Gy and α/β = 10 Gy, respectively. The other radiobiological parameters used to describe the in vivo survival according to the LQ model are: α = 0.14 Gy−1, Tμ = 60 h and TD = 14.5 d. A RBE = 3.4 is used for 213Bi calculations. B) Box plots indicating the in vivo survival distribution over time on different excised tissue sections (T1-T4) and uniform spherical phantom. The red “X” indicates the in vivo survival obtained by using a single average dose rate S-value. The whiskers correspond to 1.5 times the interquartile range.
      The minimal effective dose rate for cell kill, below which proliferation takes over, are reported in Table 9, together with the lowest survival rate.
      Table 9Minimal effective dose rate and corresponding survival value.
      RadionuclideDose rate (mGy/h)Lowest survival
      177Lu – α/β = 100 Gy13.6137.05%
      177Lu – α/β = 10 Gy10.7718.60%
      161Tb – α/β = 100 Gy13.6230.36%
      161Tb – α/β = 10 Gy10.8612.43%
      90Y – α/β = 100 Gy13.2960.10%
      90Y – α/β = 10 Gy9.9047.89%
      213Bi – RBE = 3.42.182.42%

      Discussion

      In this study, the potential of PRRT planning for various therapeutic radionuclides to control tumor growth has been assessed accounting for dose-limiting kidney and bone marrow toxicity. The results reported in this study, for a tumor diameter of about 3 mm, are of particular relevance for adjuvant or consolidation therapy in which tumor targets are smaller than the detectable size with positron emission tomography.
      PRRT efficacy in patients depends on several factors, including the efficiency of targeting the SSTR2, renal clearance, perfusion, and tumor mass. High specific activities are required to deliver an absorbed dose able to eradicate the tumor cells. In this respect, the assumption of the same biodistribution for all radionuclides should be taken with caution, as pharmacokinetic profiles might change depending on the mass of the injected peptide, thus influencing the absorbed dose to the target tissues [
      • Kletting Peter
      • Müller Berthold
      • Erentok Bahar
      • Schmaljohann Jörn
      • Behrendt Florian F.
      • Reske Sven N.
      • et al.
      Differences in predicted and actually absorbed doses in peptide receptor radionuclide therapy.
      ]. Furthermore, the activity labelled to peptides depends on the way the radionuclide is produced [

      Breeman WAP, De Jong M, Visser TJ, Erion JL, Krenning EP. Optimising conditions for radiolabelling of DOTA-peptides with 90Y, 111In and 177Lu at high specific activities. Eur J Nucl Med Mol Imaging 2003;30. https://doi.org/10.1007/s00259-003-1142-0.

      ]. High specific activities can be reached for 90Y and 213Bi compared to 177Lu and 161Tb, indicating that those radionuclides might have a more favorable pharmacokinetic profile [
      • Gracheva Nadezda
      • Müller Cristina
      • Talip Zeynep
      • Heinitz Stephan
      • Köster Ulli
      • Zeevaart Jan Rijn
      • et al.
      Production and characterization of no-carrier-added 161Tb as an alternative to the clinically-applied 177Lu for radionuclide therapy.
      ]. Overall, the receptor affinity and hence the biokinetics of the radiopharmaceutical during PRRT is influenced by the radionuclide used [
      • Reubi Jean Claude
      • Schär Jean-Claude
      • Waser Beatrice
      • Wenger Sandra
      • Heppeler Axel
      • Schmitt Jörg S.
      • et al.
      Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use.
      ].
      In more detail, since 161Tb and 177Lu are both lanthanides similar pharmacokinetics can be expected for both tumor and healthy organs [
      • Borgna Francesca
      • Barritt Patrick
      • Grundler Pascal V.
      • Talip Zeynep
      • Cohrs Susan
      • Zeevaart Jan Rijn
      • et al.
      Simultaneous visualization of 161Tb-and 177Lu-Labeled somatostatin analogues using dual-isotope SPECT imaging.
      ]. An absorbed dose threshold for the kidney of 24 Gy has been assumed (based on external beam therapy data), analyzing morphological changes in kidney structure of nude mice treated with 177Lu-DOTATATE [
      • Svensson Johanna
      • Mölne Johan
      • Forssell-Aronsson Eva
      • Konijnenberg Mark
      • Bernhardt Peter
      Nephrotoxicity profiles and threshold dose values for [177Lu]-DOTATATE in nude mice.
      ]. This value is in good agreement with the maximum absorbed dose evaluated in our work for the β-emitting radionuclides (29 Gy – 31 Gy). Interestingly, the MTD in patients falls also in a similar range (23 – 28 Gy) [
      • Bodei Lisa
      • Cremonesi Marta
      • Ferrari Mahila
      • Pacifici Monica
      • Grana Chiara M.
      • Bartolomei Mirco
      • et al.
      Long-term evaluation of renal toxicity after peptide receptor radionuclide therapy with 90Y-DOTATOC and 177Lu-DOTATATE: The role of associated risk factors.
      ]. It should be noted, however, that similar average absorbed doses to the cortex region do not cause similar pattern of damage because of the inherent physical difference (i.e., half-life and particle range) characterizing the analyzed radionuclides. As evident from the dose rate maps calculated for the resected tumor sections, the shorter the range of the emitted particle and the half-life of the mother nuclide, the more pronounced would be the damage in localized area with high radiosensitivity as the cortex region. For this reason, the maximum administered activity resulted to be lower for 161Tb (34 MBq) if compared to 177Lu (44 MBq).
      On the other hand, demonstration of the existence of an absorbed dose-response relationship for bone marrow toxicity from PRRT has proven elusive. For this reason, the 2 Gy safety limit usually assumed for 131I therapy, was chosen as limiting value to prevent myelotoxicity in this work. This limit, however, does not prevent induction of late hematologic toxicity such as induction of leukemia, which is another well-known, though fortunately rare late adverse event [
      • Bergsma Hendrik
      • van Lom Kirsten
      • Raaijmakers Marc H.G.P.
      • Konijnenberg M.
      • Kam B.L. Boen L.R.
      • Teunissen Jaap J.M.
      • et al.
      Persistent hematologic dysfunction after peptide receptor radionuclide therapy with 177Lu-DOTATATE: Incidence, course, and predicting factors in patients with gastroenteropancreatic neuroendocrine tumors.
      ].
      The tumor uptake of 177Lu-DOTATATE (5.4 ± 1.2 %IA/g) used in this study is comparable with the data of Chan et. al on H69 tumor-bearing mice treated with 213Bi-DOTATATE (7.5 ± 2.2 %IA/g), as well [
      • Chan Ho Sze
      • Konijnenberg Mark W.
      • de Blois Erik
      • Koelewijn Stuart
      • Baum Richard P.
      • Morgenstern Alfred
      • et al.
      Influence of tumour size on the efficacy of targeted alpha therapy with 213Bi-[DOTA0, Tyr3]-octreotate.
      ]. However, 177Lu-DOTATATE is not a good surrogate to determine kidney (44.0 ± 9.6 %IA/g vs 5.4 ± 0.87 %IA/g) and muscle uptake (2.1 ± 0.8 %IA/g vs 0.16 ± 0.17 %IA/g) of 213Bi-DOTATATE. Indeed, the difference in complexation chemistry of 213Bi in the DOTA-chelator compared to 177Lu and the binding of free 213Bi3+ to metallothionein in the kidneys are plausible causes of higher kidney uptake (12 ± 3.7 min/g compared to 3.5 min/g derived from 177Lu-DOTATATE). This threefold reduction in renal uptake could be justified only by the administration of a renal protection solution immediately prior to the treatment [

      Emma Y. Song Syed M.A. Rizvi Chang F Qu Chand Raja Martin W Brechbiel Alfred Morgenstern et al. 6 6 2007 898 904.

      ], which was not accounted for in this work. Nonetheless, our calculations resulted in a maximum safe activity of 13.74 MBq and are thus in line with earlier results of 13.0 ± 1.6 MBq (without renal protection) by Chan et al. [
      • Chan Ho Sze
      • Konijnenberg Mark W.
      • Daniels Tamara
      • Nysus Monique
      • Makvandi Mehran
      • de Blois Erik
      • et al.
      Improved safety and efficacy of 213Bi-DOTATATE-targeted alpha therapy of somatostatin receptor-expressing neuroendocrine tumors in mice pre-treated with l-lysine.
      ]. This might be related to the different dosimetric approach used for the calculations. Adopting the nephron model of Hobbs et al [
      • Hobbs R.F.
      • Song H.
      • Huso D.L.
      • Sundel H.M.
      • Sgouros G.
      A nephron-based model of the kidneys for macro-to-micro α-particle dosimetry.
      ] and assuming 95% of the radioactivity retained in the proximal tubules results in a sparing effect to the glomeruli dose in comparison to whole organ dosimetry calculations, assuming homogenous uptake in the mouse cortex. Interestingly, comparing the regional dosimetry approach accounting for the differential kinetics of outer medulla and cortex with the results evaluated at nephron level, no significant difference was found in the MTD to the cortex. While the regional S-values account for both β- and α-radiations, the S-values adopted at nephron level neglects the β-radiation contribution. Given that most of the radioactivity is retained in the proximal tubules, one could argue that longer range radiation might have a greater impact than shorter range radiation, whose dose deposition would be confined to the proximal tubules. Hence, the higher cross-dose from the proximal tubules to the radiation-sensitive glomeruli may even make the average dose concept not suitable for understanding radiation effects for β-emitter radionuclides. Moreover, a synergistic effect might be expected when dealing with a mixed radiation field.
      For this reason, a more complex description of the absorbed dose distribution at functional level, including different radiosensitivities of the sub-units in the cortex would be beneficial. Another reason to further characterize the kidney structure is the unusual response of kidney to PPRT with respect to EBRT. Early tubular damage is known to lead to nephritis (glomeruli damage) because of the glomeruli obstruction caused by the induction of fibrosis after radiation-induced inflammation [
      • Rolleman Edgar J.
      • Krenning Eric P.
      • Bernard Bert F.
      • de Visser Monique
      • Bijster Magda
      • Visser Theo J.
      • et al.
      Long-term toxicity of [177Lu-DOTA0, Tyr 3]octreotate in rats.
      ]. In PRRT this morphological change is not seen and tubular damage (hydronephrosis) is predominant with respect to nephritis.
      Only a direct comparative study would unambiguously characterize RBE, radiosensitivity and pharmacokinetic profiles of 213Bi, 90Y and 177Lu-labeled peptides in the kidneys and its sub-units. Such analysis is beyond the aim of this study, focused primarily on tumor efficacy comparison of different radionuclides.
      The bone marrow was not identified as the limiting organ in the current analysis, in agreement with many studies in mice showing myelotoxicity as generally mild and transient for PRRT with β-emitters [
      • Sandström Mattias
      • Garske-Román Ulrike
      • Granberg Dan
      • Johansson Silvia
      • Widström Charles
      • Eriksson Barbro
      • et al.
      Individualized dosimetry of kidney and bone marrow in patients undergoing 177Lu-DOTA-octreotate treatment.
      ,

      Pach D, Sowa-Staszczak A, Kunikowska J, Królicki L, Trofimiuk M, Stefańska A, et al. Repeated cycles of peptide receptor radionuclide therapy (PRRT) - Results and side-effects of the radioisotope 90Y-DOTA TATE, 177Lu-DOTA TATE or 90Y/177Lu-DOTA TATE therapy in patients with disseminated NET. Radiother Oncol 2012;102. https://doi.org/10.1016/j.radonc.2011.08.006.

      ].
      Using the cumulated activity in the blood as surrogate for the bone marrow assumes no specific binding in the marrow itself. The blood-to-bone-marrow activity ratio was measured to be unity in patients after PRRT [
      • Jan S.
      • Santin G.
      • Strul D.
      • Staelens S.
      • Assié K.
      • Autret D.
      • et al.
      GATE: A simulation toolkit for PET and SPECT.
      ], conforming the prior assumption. Unfortunately, none of the bone marrow dosimetry models for PRRT show a clear correlation between bone marrow dose and toxicity data. Our findings agree with data of patients treated with 177Lu-DOTATATE, for which the contribution of the cross-dose from source organs and tumors to the bone marrow dose is significant [
      • Forrer F.
      • Krenning E.P.
      • Kooij P.P.
      • Bernard B.F.
      • Konijnenberg M.
      • Bakker W.H.
      • et al.
      Bone marrow dosimetry in peptide receptor radionuclide therapy with [177Lu-DOTA0, Tyr3]octreotate.
      ]. This implies that the variability of body masses and tumor burdens should be taken into account carefully.
      The unrealistically high maximum safe activity found for myelotoxicity when using 213Bi-DOTATATE is certainly caused by the significantly lower TIAC when extrapolating data from 177Lu-DOTATATE. Assuming a TIAC of 0.033 h/g instead of 0.0017 h/g, obtained by fitting the data of Chan et al. [
      • Chan Ho Sze
      • Konijnenberg Mark W.
      • de Blois Erik
      • Koelewijn Stuart
      • Baum Richard P.
      • Morgenstern Alfred
      • et al.
      Influence of tumour size on the efficacy of targeted alpha therapy with 213Bi-[DOTA0, Tyr3]-octreotate.
      ], would lead to a maximum tolerated activity of 6 MBq and 11 MBq with an RBE of 2 and 1, respectively, compared to 250 MBq, found in this study. It should be noticed that for longer range α-particles, such as the ones emitted by 213Po (Eα = 5.8 MeV), the main contributor to the 213Bi absorbed dose, an RBE <2 could be postulated. The assumption of a solid bone structure for bone marrow calculations is not realistic and accounting for a more complex bone structure would lead to reduced absorbed doses [
      • Pacilio Massimiliano
      • Ventroni Guido
      • Basile Chiara
      • Ialongo Pasquale
      • Becci Domenico
      • Mango Lucio
      Improving the dose-myelotoxicity correlation in radiometabolic therapy of bone metastases with 153Sm-EDTMP.
      ] and RBE for α-emitters bound in proximity of the bone marrow regions [
      • Hobbs Robert F
      • Song Hong
      • Watchman Christopher J
      • Bolch Wesley E
      • Aksnes Anne-Kirsti
      • Ramdahl Thomas
      • et al.
      A bone marrow toxicity model for 223Ra alpha-emitter radiopharmaceutical therapy.
      ]. Modelling the bone structure is a complex task considering that even the simple determination of the bone marrow mass is virtually impossible, especially for mice. The EBRT derived MTD should be taken with caution because the biological response to exposures with different dose rates is not yet understood. Nonetheless, identifying the bone marrow as the non-limiting organ for 213Bi-DOTATATE is in agreement with the MTD found for PC3-tumor bearing mice treated with 213Bi-DOTA-AMBA (25 MBq corresponding to 4 Gy in the blood). Therefore, restricting the maximum injected activity to 13.7 MBq, as in this paper based on kidney dosimetry, is actually a conservative choice.
      The therapeutic efficacy of the radionuclides analyzed is then evaluated accounting for the toxicity in healthy organs (i.e., kidneys). In this study, we confirm the considerable potential of α-emitting radionuclides for small tumors or micrometastases characterized by a rather uniform receptor expression [
      • Kratochwil C.
      • Giesel F.L.
      • Bruchertseifer F.
      • Mier W.
      • Apostolidis C.
      • Boll R.
      • et al.
      213Bi-DOTATOC receptor-targeted alpha-radionuclide therapy induces remission in neuroendocrine tumours refractory to beta radiation: a first-in-human experience.
      ]. The high potency (i.e., high LET and short half-life) of 213Bi warrants high dose rates even in low receptor expression areas, eradicating most of the tumor cells. Even if this finding is limited to preclinical therapy tumor models, characterized by a more uniform receptor expression than corresponding clinical tumor models, the use of multiple fractions of therapy in combination with 90Y- and 177Lu-DOTATATE [

      Pach D, Sowa-Staszczak A, Kunikowska J, Królicki L, Trofimiuk M, Stefańska A, et al. Repeated cycles of peptide receptor radionuclide therapy (PRRT) - Results and side-effects of the radioisotope 90Y-DOTA TATE, 177Lu-DOTA TATE or 90Y/177Lu-DOTA TATE therapy in patients with disseminated NET. Radiother Oncol 2012;102. https://doi.org/10.1016/j.radonc.2011.08.006.

      ,
      • De Jong M.
      • Breeman W.A.P.
      • Valkema R.
      • Bernard B.F.
      • Krenning E.P.
      Combination radionuclide therapy using 177Lu and 90Y-labeled somatostatin analogs.
      ] might overcome the limitations of 213Bi-DOTATATE treatment when administered for larger or more heterogeneous tumors. It is evident that either 177Lu or 161Tb would provide a more uniform dose delivery in smaller (1 to 3 mm) tumors, as analyzed in this study, whilst larger tumors (28 to 32 mm) would benefit from the longer 90Y-particles range [
      • O’Donoghue J.A.
      • Bardies M.
      • Wheldon T.E.
      • Sgouros G.
      Relationships between tumor size and curability for uniformly targeted therapy with beta-emitting radionuclides.
      ]. In particular, the absorbed dose per decay of 161Tb is 44% higher than that of 177Lu, indicating a superior therapeutic potential for smaller tumor sizes. Despite accounting for the absorbed dose heterogeneity at microscale level (cell dimension), the in vivo survival is well predicted by average calculations assuming uniform dose distributions, as also postulated in clinical practice. This result may not come as a surprise considering that uniform radionuclide distributions are usually considered as acceptable model for internalized molecules via receptor mediated endocytosis [
      • Hindié E.
      • Zanotti-Fregonara P.
      • Quinto M.A.
      • Morgat C.
      • Champion C.
      Dose deposits from90Y,177Lu,111In, and161Tb in micrometastases of various sizes: Implications for radiopharmaceutical therapy.
      ].
      It should be noted, however, that the lack of difference between heterogeneous and uniform in vivo survival could be caused by the use of a single SSTR2 image, at the beginning of treatment, to perform calculations. Indeed, a significant reduction of receptor expression along treatment may vary the outcome of the calculations [
      • Tamborino G.
      • Nonnekens J.
      • De Saint-Hubert M.
      • Struelens L.
      • Feijtel D.
      • de Jong M.
      • et al.
      Dosimetric evaluation of receptor-heterogeneity on the therapeutic efficacy of peptide receptor radionuclide therapy: correlation with DNA damage induction and in vivo survival.
      ]. Moreover, cells may show an adaptive response and somatostatin induced vasoconstriction may results in regional hypoxia and therefore radionuclides emitting high-LET radiations, such as 213Bi may be recommended in the later therapy cycles.
      The fast re-growth observed in the in vivo survival curves (TD = 14 days) is also not representative of clinical models characterized by lower proliferation rates.
      In order to achieve tumor control each and every cell should be eradicated. To do so the dose rate variation at the cellular level should be analyzed against biological phenomena such as DNA repair capacity, cell cycle progression and proliferation in order to further improve biophysical modeling of PRRT.
      On the other hand, PRRT is acknowledged to be a palliative treatment with minimal adverse events. Dosimetry-guided treatment planning based on maximum tolerated absorbed dose to nontargeted organs obtained by modulating the activity per cycle while limiting the number of administrations can contribute to further reduce the tumor load, thus prolonging the life of patients with metastasized disease through repeated therapy cycles.

      Conclusion

      Out of the radionuclides studied, our results indicate that 213Bi has the highest potential for further improving therapeutic efficacy in tumors and metastases with mostly uniform (even if low) receptor expression after 177Lu or 90Y-DOTATATE therapies.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgements

      In memory of our beloved Professor Marion de Jong, who we miss dearly. Marion passed away during preparation of the manuscript. She was involved in the financing, development and main supervision of the project.

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

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