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Purpose Recent reports personalizing the administered activity (AA) of each cycle of peptide receptor radionuclide therapy based on the predicted absorbed dose (AD) to the kidneys (dose-limiting organ) have been promising. Assuming identical renal pharmacokinetics for each cycle is pragmatic, however it may lead to over- or under-estimation of the optimal AA. Here, we investigate the influence that earlier cycles of [177Lu]Lu-DOTATATE had on the biokinetics and AD of subsequent cycles in a recent clinical trial that evaluated the safety and activity of [177Lu]Lu-DOTATATE in pediatric neuroblastoma (NBL). We investigated whether predictions based on an assumption of unchanging AD per unit AA (Gy/GBq) prove robust to cyclical changes in biokinetics. Methods A simulation study, based on dosimetry data from six children with NBL who received four-cycles of [177Lu]Lu-DOTATATE in the LuDO trial (ISRCTN98918118), was performed to explore the effect of variable biokinetics on AD. In the LuDO trial, AA was adapted to the patient’s weight and SPECT/CT-based dosimetry was performed for the kidneys and tumour after each cycle. The largest tumour mass was selected for dosimetric analysis in each case. Results The median tumour AD per cycle was found to decrease from 15.6 Gy (range 8.12–26.4) in cycle 1 to 11.4 Gy (range 9.67–28.8), 11.3 Gy (range 2.73–32.9) and 4.3 Gy (range 0.72–20.1) in cycles 2, 3 and 4, respectively. By the fourth cycle, the median of the ratios of the delivered AD (ADD) and the predicted (or “expected”) AD (ADE) (which was based on an assumption of stable biokinetics from the first cycle onwards) were 0.16 (range 0.02–0.92, p = 0.013) for the tumour and 1.08 (range 0.84–1.76, p > 0.05) for kidney. None of the patients had an objective response at 1 month follow up. Conclusion This study demonstrates variability in Gy/GBq and tumour AD per cycle in children receiving four administrations of [177Lu]Lu-DOTATATE treatment for NBL. NBL is deemed a radiation sensitive tumour; therefore, dose-adaptive treatment planning schemes may be appropriate for some patients to compensate for decreasing tumour uptake as treatment progresses. Trial registration ISRCTN ISRCTN98918118. Registered 20 December 2013 (retrospectively registered).

Purpose Selective internal radiotherapy (SIRT) is administered to treat tumors of the liver and is generally well tolerated. While widely adopted for its therapeutic benefits, SIRT is rarely combined with external beam radiotherapy (EBRT) due to the complexity of the dosimetry resulting from the combination of treatments with distinct radiobiological effects. The purpose of this study was to establish a dosimetric framework for combining SIRT and EBRT using clinical experience derived from representative hepatocellular carcinoma (HCC) patients who received both therapies. Methods and Materials Treatments from ten patients with HCC given EBRT either before or after SIRT were analyzed. The dosimetry framework used here considered differences in the radiobiological effects and fractionation schemes of SIRT versus EBRT, making use of the concepts of biological effective dose (BED) and equivalent dose (EQD). Absorbed dose from SIRT was calculated, converted to BED, and summed with BED from EBRT dose plans. Two of these patients were further explored in a virtual planning exercise to investigate the feasibility of combining stereotactic body radiotherapy (SBRT) and SIRT. Results The combination of EBRT and SIRT in ten patients with HCC showed no major toxicity. No Child-Pugh scores went above 8 and ALBI scores from only one patient worsened to grade 3 (>-1.39) from treatment through 3-months follow-up. A framework with radiobiological modelling was developed to manage the combined treatments in terms of their sum BED. The exploratory SIRT plus SABR inverse dose plans for two patients, incorporating radiobiologically-informed 90Y SIRT dosimetry, achieved dose distributions comparable to SBRT-alone. Conclusions Treatment with both EBRT and SIRT can be given safely to patients with HCC. The BED and EQD concepts should be used in combined dosimetry to account for the differing radiobiological effects of EBRT and SIRT. Inverse dose planning of EBRT following SIRT could provide improved dose distributions and flexibility to the clinical workflow. Further research into combination therapy is needed through prospective trials.

CERVOXY; International audience

CERVOXY; International audience

Molecular radiotherapy using177Lu-DOTATATE is a most effective treatment for somatostatin receptor–expressing neuroendocrine tumors. Despite its frequent and successful use in the clinic, little or no radiobiologic considerations are made at the time of treatment planning or delivery. On positive uptake on octreotide-based PET/SPECT imaging, treatment is usually administered as a standard dose and number of cycles without adjustment for peptide uptake, dosimetry, or radiobiologic and DNA damage effects in the tumor. Here, we visualized and quantified the extent of DNA damage response after177Lu-DOTATATE therapy using SPECT imaging with111In-anti-γH2AX-TAT. This work was a proof-of-principle study of this in vivo noninvasive biodosimeter with β-emitting therapeutic radiopharmaceuticals.Methods:Six cell lines were exposed to external-beam radiotherapy (EBRT) or177Lu-DOTATATE, after which the number of γH2AX foci and the clonogenic survival were measured. Mice bearing CA20948 somatostatin receptor–positive tumor xenografts were treated with177Lu-DOTATATE or sham-treated and coinjected with111In-anti-γH2AX-TAT,111In-IgG-TAT control, or vehicle.Results:Clonogenic survival after external-beam radiotherapy was cell-line–specific, indicating varying levels of intrinsic radiosensitivity. Regarding in vitro cell lines treated with177Lu-DOTATATE, clonogenic survival decreased and γH2AX foci increased for cells expressing high levels of somatostatin receptor subtype 2. Ex vivo measurements revealed a partial correlation between177Lu-DOTATATE uptake and γH2AX focus induction between different regions of CA20948 xenograft tumors, suggesting that different parts of the tumor may react differentially to177Lu-DOTATATE irradiation.Conclusion:111In-anti-γH2AX-TAT allows monitoring of DNA damage after177Lu-DOTATATE therapy and reveals heterogeneous damage responses.

CERVOXY COLL; International audience

Compared to external beam radiotherapy, targeted radionuclide therapy (TRT) allows for systemic radiation treatment of metastatic lesions. Published work on recent strategies to improve patient management and response to TRT through individualising patient treatment, modifying treatment pharmacokinetics and increasing anticancer potency are discussed in this review, with a special focus on the application of clinically evaluated radiolabelled ligands and peptides in the treatment of neuroendocrine and prostate cancers.

CERVOXY/OXFORD COLL; International audience

Metastasis of breast cancer to the brain presents a pressing therapeutic challenge. Vascular cell adhesion molecule 1 (VCAM‐1) is upregulated on brain endothelial cells during the early stages of metastasis and provides a target for the detection and treatment of early brain metastases. We have developed a Monte Carlo model representing brain vasculature to evaluate the efficacy of a variety of potential therapeutic nuclides; alpha‐emitters: 149Tb, 211At, 212Pb, 213Bi and 225Ac; beta and Auger electron‐emitters: 90Y, 161Tb and 177Lu, 67Ga, 89Zr, 111In and 124I for targeted radionuclide therapy (TRT).

Brain metastases develops frequently in patients with lung and breast cancers, however treatment is mainly palliative and commonly comprises whole-brain irradiation. The pressing therapeutic challenge presented by brain metastases is the need to treat the whole brain in a molecularly targeted manner at an early stage when relatively few metastatic tumour cells have invaded the brain parenchyma. The aim of this preliminary study is to develop a geometric model of early brain metastasis to evaluate the theoretical efficacy of α- and β-emitting radionuclides for molecular radiotherapy (MRT).

Neuroblastoma is the most frequent extra-cranial tumour in younger childhood. The current treatment of high-risk (stage 4) inoperable neuroblastoma includes a combination of chemotherapy and/or total irradiation with either autologous bone marrow transplantation or peripheral blood stem cell reinfusion. Despite these treatments the 4-year overall survival for high-stage neuroblastoma is still low (69%). Targeted/molecular radiotherapy (MRT) where the overexpressed noradrenaline transporter is targeted with 131I-MIBG (Meta-iodobenzylguanidine) an analogue of noradrenaline is an effective treatment for relapsed or refractory neuroblastoma. The aim of this study is to investigate whether in vivo imaging could be used to inform scheduling of MRT with 131I-MIBG in a human neuroblastoma xenograft model (SK-N-SH) to optimize and enhance the efficacy of external beam irradiation (EBRT).

The spatial distribution of radiopharmaceuticals that emit short-range high linear-energy-transfer electrons greatly affects absorbed dose and biological effectiveness. The purpose of this study was to investigate the effect of heterogeneous radionuclide distribution on tumor control probability (TCP) in a micrometastasis model. Methods: The cancer cell lines MDA-MB-468, SQ20B, and 231-H2N were grown as spheroids to represent micrometastases. The intracellular distribution of a representative radiopeptide (111In-labeled epidermal growth factor) and radioimmunotherapeutic (111In-labeled trastuzumab) was determined in cell internalization experiments. The intratumoral distribution was evaluated by microautoradiography of spheroids. γH2AX staining was performed on spheroid sections to correlate DNA damage with radionuclide distribution. Experimental surviving fractions were obtained using clonogenic assays. A random close-packed algorithm, which models the random packing behavior of cells and reflects variation in the radii of cells and nuclei, was used to simulate 3-dimensional spheroids. Calculated survival fractions were generated using an iterative modeling method based on Monte Carlo–determined absorbed dose with the PENELOPE code and were compared with experimental surviving fraction. Radiobiologic parameters deduced from experimental results and Monte Carlo simulations were used to predict the TCP for a 3-dimensional spheroid model. Results: Calculated survival fractions agreed well with experimental data, particularly when an increased value for relative biological effectiveness was applied to self-dose deposited by sources located in the nucleus and when radiobiologic parameters were adjusted to account for dose protraction. Only in MDA-MB-468 spheroids treated with 111In-epidermal growth factor was a TCP of more than 0.5 achieved, indicating that for this cell type the radiopeptide would be curative when targeting micrometastases. This ability is attributed to the relative radiosensitivity of MDA-MB-468 cells, high nuclear uptake of the radiopeptide, and uniform distribution of radioactivity throughout the spheroid. Conclusion: It is imperative to include biologic endpoints when evaluating the distribution of radionuclides in models emulating micrometastatic disease. The spatial distribution of radioactivity is a clear determinant of biological effect and TCP as demonstrated in this study.

Brain metastases develop frequently in patients with breast cancer, and present a pressing therapeutic challenge. Expression of vascular cell adhesion molecule 1 (VCAM-1) is upregulated on brain endothelial cells during the early stages of metastasis and provides a target for the detection and treatment of early brain metastases. The aim of this study was to use a model of early brain metastasis to evaluate the efficacy of α-emitting radionuclides, 149Tb, 211At, 212Pb, 213Bi and 225Ac; β-emitting radionuclides, 90Y, 161Tb and 177Lu; and Auger electron (AE)-emitters 67Ga, 89Zr, 111In and 124I, for targeted radionuclide therapy (TRT). METHODS: Histologic sections and two photon microscopy of mouse brain parenchyma were used to inform a cylindrical vessel geometry using the Geant4 general purpose Monte Carlo (MC) toolkit with the Geant4-DNA low energy physics models. Energy deposition was evaluated as a radial function and the resulting phase spaces were superimposed on a DNA model to estimate double-strand break (DSB) yields for representative β- and α-emitters, 177Lu and 212Pb. Relative biological effectiveness (RBE) values were determined by only evaluating DNA damage due to physical interactions. RESULTS: 177Lu produced 2.69 ± 0.08 DSB per GbpGy, without significant variation from the lumen of the vessel to a radius of 100 μm. The DSB yield of 212Pb included two local maxima produced by the 6.1 MeV and 8.8 MeV α-emissions from decay products, 212Bi and 212Po, with yields of 7.64 ± 0.12 and 9.15 ± 0.24 per GbpGy, respectively. Given its higher DSB yield 212Pb may be more effective for short range targeting of early micrometastatic lesions than 177Lu. CONCLUSION: MC simulation of a model of early brain metastases provides invaluable insight into the potential efficacy of α-, β- and AE-emitting radionuclides for TRT. 212Pb, which has the attributes of a theranostic radionuclide since it can be used for SPECT imaging, showed a favorable dose profile and RBE.

Purpose: To assess the efficacy of different schedules for combining external beam radiotherapy (EBRT) with molecular radiotherapy (MRT) using 131I-mIBG in the management of neuroblastoma. Materials and Methods: Balb/c nu/nu mice bearing SK-N-SH neuroblastoma xenografts were assigned to five treatment groups: 131I-mIBG 24h after EBRT, EBRT 6 days after 131I-mIBG, EBRT alone, 131I-mIBG alone and control (untreated). A total of 56 mice were assigned to 3 studies. Study 1: Vessel permeability was evaluated using dynamic contrast-enhanced (DCE)-MRI (n=3). Study 2: Tumour volume and overall survival were assessed by longitudinal MR imaging (n=25). Study 3: Tumour uptake of 131I-mIBG in excised lesions was evaluated by -counting and autoradiography (n=28). Tumour dosimetry was performed using Monte Carlo simulations of absorbed fractions with the radiation transport code PENELOPE. Results: Given alone, both 131I-mIBG and EBRT resulted in a seven-day delay in tumour regrowth. Following EBRT, vessel permeability was evaluated by DCE-MRI and showed an increase at 24h post irradiation that correlated with an increase in 131I-mIBG tumour uptake, absorbed dose and overall survival in the case of combined treatment. Similarly, EBRT administered seven days after MRT to coincide with tumour regrowth, significantly decreased the tumour volume and increased overall survival. Conclusions: This study demonstrates that combining EBRT and MRT has an enhanced therapeutic effect and emphasizes the importance of treatment scheduling according to pathophysiological criteria such as tumour vessel permeability and tumour growth kinetics.

Radiolabelled antibodies and peptides hold promise for molecular radiotherapy but are often limited by low payload resulting in delivery of inadequate amounts of radioactivity to tumour tissue and, therefore, modest therapeutic effect. We have developed PEGylated epidermal growth factor (EGF)-gold nanoparticles (NP) with a high indium-111 (111In) payload (111In-EGF-Au-PEG NPs) as a prototypic NP-based theranostic radiopharmaceutical.

Breast cancer patients frequently develop brain metastases. Conventional treatment is palliative and often involves whole-brain radiotherapy. There is a pressing unmet therapeutic need to treat brainmetastasis at an early stage, when relatively few tumor cells have invaded the brain parenchyma. However, to evaluate the efficacy of new therapeutic treatments, preclinical models of early stage brain metastases and tools to monitor response to treatment are needed. The aim of this study was to develop a model in which early brain metastases can be tracked by MRI using microparticles of iron oxide (MPIO).

Auger-electron (AE) emitting radionuclides could be exploited for therapeutic purposes due to the high local energy deposition by low-energy Auger electrons or may deliver an unintentional mean absorbed dose burden when used as medical imaging agents. Emission spectra of AE emitting radionuclides are essential for dosimetric calculations to quantify the biological damage to the target. The BrIccEmis code, a Monte Carlo model of the Auger cascade is used here to provide radiation spectra data for 14 AE emitting radionuclides. The aim of this study is to compare MIRD single cell Svalues with S-values derived from BrIccEmis generated radiation spectra.

Background: Yttrium-90 selective internal radiotherapy (90Y SIRT) is a treatment aimed at improving tumour control within the liver, from which the disease burden is the most common cause of death. FOXFIRE, SIRFLOX, SARAH and other phase 3 clinical trials of SIRT indicated response in the liver but not increased overall survival. The present work aims to address this phenomenon and hypothesises that optimising treatment around absorbed dose to the liver would result in improved patient outcomes. In addition, the present work hypothesises that treatment planning could be further optimised by considering the factors of radiosensitivity, perfusion, and treatment paradigms to enhance uncomplicated tumour control in the liver and therefore overall survival. Materials and Methods: Clonogenic assays of cancer cell lines were used to assess radiosensitivity from exposure to 90Y SIRT and EBRT (LINAC and 137Cs). Radiobiological parameters from the survival curves were adapted to a biological effective dose (BED) model useful to compare radiation response between 90Y SIRT and EBRT. In a group of colorectal carcinoma (CRC) patients treated with 90Y SIRT, tumour volumes were contoured and absorbed dose was measured to assess the dose-response relationship. An additional subcohort was analysed based on clinical imaging of perfusion in the liver from dynamic contrast enhanced magnetic resonance imaging (DCE MRI) and perfusion CT (pCT). Perfusion modelling parameter maps in the tumours were used to assess possible associations with dose deposition and response to 90Y SIRT. Additional BED models were applied to a second cohort of ten hepatocellular carcinoma (HCC) patients that received both 90Y SIRT and EBRT to assess tumour volumes, dose, and radiobiological endpoints. Finally, stereotactic ablative radiotherapy (SABR) treatments were planned considering prior 90Y SIRT through radiobiological modelling. Results: Radiation response from clonogenic assays of CRC cell lines yielded radiobiological fit parameters for 90Y SIRT. These findings suggested greater resistance to 90Y therapy than to either 137Cs or LINAC exposures. A mixed statistical model combining these findings resulted in BED parameters for 90Y SIRT. A dose-response relationship was demonstrated in the CRC patient cohort. Perfusion imaging from the subcohort generally revealed statistically significant relationships between perfusion parameters and dose or response for pCT but not for DCE MRI. In the HCC patient cohort, a methodology was demonstrated to combine doses from different LINAC and 90Y SIRT treatments. Exploratory SABR plans, considering equivalent dose deposition from 90Y SIRT, achieved treatment profiles comparable to those of SABR alone. Conclusions: The clonogenic assay results extend the BED model and provide a framework for general consideration of 90Y SIRT radiobiology. This work established a framework for such future analyses and identified several hypotheses which could have clinical application for additional radiotherapy in 90Y SIRT patients. Biological response in vitro and in patients suggests there could be clinical utility for radiobiological modelling of 90Y SIRT. Biological response to 90Y SIRT is complex and future clinical trials are necessary to definitively appreciate the clinical response to radiation dose.

Recently, there has been a growth in using post-treatment dosimetry after the first treatment cycle to plan the prescription for subsequent administrations to achieve an acceptable safe dose to kidneys and therapeutic dose to tumour. This level of personalisation recognises inter-patient variability in the uptake and clearance of 177Lu-DOTATATE by the kidneys and tumours. Increasingly, studies are showing additional variation in pharmacokinetics between cycles in an individual patient which may be particularly relevant in NETs cases in paediatric cases like NBL. The central goals for this work were to characterise variability in the spatial and temporal patterns of renal and tumour biokinetics and dose during a four cycle course of 177Lu-DOTATATE and investigate relationships between these variabilities and patient response. To accomplish this, an open-source software platform was written to facilitate calculation of per cycle pharmacokinetics of organs at risk and lesions using published clinical protocols. Subsequently, we applied these protocols on a single pretherapy Ga68-DOTATATE PET/CT and intra-therapy longitudinal SPECT/CT image sets acquired in six children with NBL after each cycle to understand the temporal change in physical dose and effective half life over a course of treatment in two anatomical and one functional region. The kinetics of radiobiological dose in the tumour was explored using parameters derived from in-vitro experiments. The effective half life of 177Lu-DOTATATE in the tumour showed the greatest variation between cycles. Overall, the temporal and spatial variability in renal and tumour pharmacokinetics and dose showed no clear relationship with response in this small cohort. This thesis is a significant step towards further understanding intra-cycle variability during a course of treatment which may impact dosimetry based treatment planning aimed at delivering a set dose per cycle.

Targeted radiotherapy (TRT) is a technique which allows for individual cancer cells to be targeted by radiation. However, there is variation in uptake at the whole body, organ, cellular and subcellular levels. This distribution affects the biological efficacy of the TRT agents. To address this problem, novel techniques have been developed and demonstrated. These aim to provide quantitative information about the spatial distribution of Auger electron (AE) emitting radiopharmaceuticals at the subcellular level. Two methods have been developed. The first, photoresist autoradiography (PAR), uses photoresists as an autoradiography substrate, and the second uses microautoradiography (MAR) and a transmission electron microscope (TEM). The techniques have been demonstrated using the AE emitter indium-111. Firstly, PAR is demonstrated using poly (methyl methacrylate) (PMMA). Photoresists were exposed to indium-111 which had been internalised into cells, and the photoresists were analysed using atomic force microscopy (AFM). The technique has a theoretical resolution in the nanometre range and was able to demonstrate cellular patterns on the micron scale. To gain quantitative information, the photoresist response (depth of pattern) was calibrated as a function of electron fluence and a model of the patterns was created. Combining the calibration data with the point source model allowed the position and intensity of the internalised source terms to be estimated using the PAR method. Secondly, a technique for electron microscope-microautoradiography (EM-MAR) was developed. The processing conditions of the MAR technique were determined and staining techniques developed, to produce high quality TEM micrographs. A time course experiment showed the distribution and variation in the uptake of the radiopharmaceutical at the cellular level. Both techniques are able to provide information about the subcellular distribution of the radioactivity at a higher resolution than current techniques. Both enable the collection of information which can be used in microdosimetric calculations.