177 Lu-PSMA With Olaparib Radiosensitization Potentiates Response and Toxicity in Extensive Castration-Resistant Metastatic Prostate cancer.

ABSTRACT: A patient with widespread intensely prostate-specific membrane antigen-expressing, BRCA gene mutation-positive bone metastases at the time of prostate cancer diagnosis had progressed on multiple lines of standard therapy. He received 177 Lu-prostate-specific membrane antigen 8.5 GBq augmented by a short course of olaparib radiosensitization and achieved 90% decrease in serum PSA level after a single treatment. His tumor response was much better than expected by predictive dosimetry. However, his marrow radiotoxicity was worse than anticipated and required hospitalization. This suggests radiosensitizing agents to be a double-edged sword that must be carefully considered and balanced during activity prescription.

First-Strike Rapid Predictive Dosimetry and Dose Response for 177Lu-PSMA Therapy in Metastatic Castration-Resistant Prostate Cancer.

We devised and clinically validated a schema of rapid personalized predictive dosimetry for 177Lu-PSMA-I&T in metastatic castration-resistant prostate cancer. It supersedes traditional empiric prescription by providing clinically meaningful predicted absorbed doses for first-strike optimization. Methods: Prostate-specific membrane antigen PET was conceptualized as a simulation study that captures the complex dosimetric interplay between tumor, marrow, and kidneys at a single time point. Radiation principles of fractionation, heterogeneity, normal-organ constraints (marrow, kidney), absorbed dose, and dose rate were introduced. We created a predictive calculator in the form of a free, open-source, and user-friendly spreadsheet that can be completed within minutes. Our schema achieves speed and accuracy by sampling tissue radioconcentrations (kBq/cm3) to be analyzed in conjunction with clinical input from the user that reflect dosimetric preconditions. The marrow-absorbed dose constraint was 0.217 Gy (dose rate, ≤0.0147 Gy/h) per fraction with an interfraction interval of at least 6 wk. Results: Our first 10 patients were analyzed. The first-strike mean tumor-absorbed dose threshold for any prostate-specific antigen (PSA) response was more than 10 Gy (dose rate, >0.1 Gy/h). The metastasis with the lowest first-strike tumor-absorbed dose correlated the best with the percentage decrease of PSA; its threshold to achieve hypothetical zero PSA was 20 Gy or more. Each patient's PSA doubling time can be used to personalize their unique absorbed dose-response threshold. The predicted mean first-strike prescription constrained by marrow-absorbed dose rate per fraction was 11.0 ± 4.0 GBq. Highly favorable conditions (tumor sink effect) were dosimetrically expressed as the combination of tumor-to-normal-organ ratios of more than 150 for marrow and more than 4 for kidney. Our schema obviates the traditional role of the SUV as a predictive parameter. Conclusion: Our rapid schema is feasible to implement in any busy real-world theranostics unit and exceeds today's best practice standards. Our dosimetric thresholds and predictive parameters can radiobiologically rationalize each patient's first-strike prescription down to a single becquerel. Favorable tumor-to-normal-organ ratios can be prospectively exploited by predictive dosimetry to optimize the first-strike prescription. The scientific framework of our schema may be applied to other systemic radionuclide therapies.

Deep Hybrid Learning Prediction of Patient-Specific Quality Assurance in Radiotherapy: Implementation in Clinical Routine.

BACKGROUND: Arc therapy allows for better dose deposition conformation, but the radiotherapy plans (RT plans) are more complex, requiring patient-specific pre-treatment quality assurance (QA). In turn, pre-treatment QA adds to the workload. The objective of this study was to develop a predictive model of Delta4-QA results based on RT-plan complexity indices to reduce QA workload. METHODS: Six complexity indices were extracted from 1632 RT VMAT plans. A machine learning (ML) model was developed for classification purpose (two classes: compliance with the QA plan or not). For more complex locations (breast, pelvis and head and neck), innovative deep hybrid learning (DHL) was trained to achieve better performance. RESULTS: For not complex RT plans (with brain and thorax tumor locations), the ML model achieved 100% specificity and 98.9% sensitivity. However, for more complex RT plans, specificity falls to 87%. For these complex RT plans, an innovative QA classification method using DHL was developed and achieved a sensitivity of 100% and a specificity of 97.72%. CONCLUSIONS: The ML and DHL models predicted QA results with a high degree of accuracy. Our predictive QA online platform is offering substantial time savings in terms of accelerator occupancy and working time.

Impact of cyclic changes in pharmacokinetics and absorbed dose in pediatric neuroblastoma patients receiving [177Lu]Lu-DOTATATE.

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).

Radioimmunotherapy for Brain Metastases: The Potential for Inflammation as a Target of Choice.

Brain metastases (BM) are frequently detected during the follow-up of patients with malignant tumors, particularly in those with advanced disease. Despite a major progress in systemic anti-cancer treatments, the average overall survival of these patients remains limited (6 months from diagnosis). Also, cognitive decline is regularly reported especially in patients treated with whole brain external beam radiotherapy (WBRT), due to the absorbed radiation dose in healthy brain tissue. New targeted therapies, for an earlier and/or more specific treatment of the tumor and its microenvironment, are needed. Radioimmunotherapy (RIT), a combination of a radionuclide to a specific antibody, appears to be a promising tool. Inflammation, which is involved in multiple steps, including the early phase, of BM development is attractive as a relevant target for RIT. This review will focus on the (1) early biomarkers of inflammation in BM pertinent for RIT, (2) state of the art studies on RIT for BM, and (3) the importance of dosimetry to RIT in BM. These two last points will be addressed in comparison to the conventional EBRT treatment, particularly with respect to the balance between tumor control and healthy tissue complications. Finally, because new diagnostic imaging techniques show a potential for the detection of BM at an early stage of the disease, we focus particularly on this therapeutic window.

Stereotactic Inverse Dose Planning After Yttrium-90 Selective Internal Radiation Therapy in Hepatocellular Cancer.

PURPOSE: Selective internal radiation therapy (SIRT) is administered to treat tumors of the liver and is generally well tolerated. Although widely adopted for its therapeutic benefits, SIRT is rarely combined with external beam radiation therapy (EBRT) owing 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 patients with hepatocellular carcinoma (HCC) who received both therapies. METHODS AND MATERIALS: Treatments from 10 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 used in a virtual planning exercise to investigate the feasibility of combining stereotactic body radiation therapy and SIRT. RESULTS: The combination of EBRT and SIRT in 10 patients with HCC showed no major toxicity. No Child-Pugh scores went above 8 and albumin-bilirubin scores from only 1 patient worsened to grade 3 (> -1.39) from treatment through 3-months follow-up. A framework with radiobiological modeling was developed to manage the combined treatments in terms of their sum BED. The exploratory SIRT plus SABR inverse dose plans for 2 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 after SIRT could provide improved dose distributions and flexibility to the clinical workflow. Further research into combination therapy is needed through prospective trials.

Real-World Data Analysis of Efficacy and Survival After Lutetium-177 Labelled PSMA Ligand Therapy in Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: Lutetium-177 prostate-specific membrane antigen (177Lu-PSMA) radioligand therapy is emerging as a promising treatment for metastatic castration-resistant prostate cancer refractory to established therapies. While there is an increasing body of survival and other data from retrospective analyses and prospective trials, there is no clear understanding of how best to predict therapy response and survival outcomes. OBJECTIVE: In this retrospective cohort analysis, we aimed to identify features that are associated with response to radioligand therapy and greater survival based on analysis of real-world data. PATIENTS AND METHODS: 191 patients aged 70 ± 8 years with metastatic castration-resistant prostate cancer treated with radioligand therapy from November 2015 to February 2019 were included for analysis. Eligible patients had PSMA-expressing metastatic castration-resistant prostate cancer (confirmed by a 68Ga-PSMA-ligand positron emission tomography (PET)/computed tomography (CT) scan), an Eastern Cooperative Oncology Group performance status score ≤ 2 and no significant kidney, liver or bone marrow dysfunction (as characterised by kidney and liver function tests and a full blood count). Patients received one to five cycles of intravenous 177Lu-PSMA-ligand therapy. Endpoints included biochemical [prostate-specific antigen (PSA)] and radiologic (PSMA PET/CT) response, progression-free survival and overall survival, defined according to the Prostate Cancer Working Group 3 guidelines. Survival analysis was conducted by Kaplan-Meier estimation. RESULTS: Most individuals (89.5%) previously underwent first- and second-line systematic therapy. Of the 191 men treated with 452 cycles with mean injected activity of 6.1 ± 1.0 GBq per cycle, 159 patients were assessed for a biochemical response defined as a PSA decline ≥ 50% from baseline. A ≥ 50% PSA decline was observed in 89 (56%) patients, while any PSA decline occurred in 120 (75%) men. For the entire cohort, median values (interquartile range) of overall survival [n = 191], PSA progression-free survival [n = 132] and PET/CT progression-free survival were 12 (5-18), 4 (3-8) and 6 (3-10) months, respectively. Survival analysis confirmed better outcomes in individuals who had demonstrated therapy response. Predominantly lymph node metastatic disease and chemotherapy-naïve status were significant pre-therapy factors associated with longer survival. Baseline PSA was significantly linked to survival outcomes: lower levels predicted a lower risk of death and disease progression. Treatment-related adverse events included grade 3 or 4 haematological (12%), grade 1 or 2 renal (4.5%), and grade 3 or 4 clinical events (5.7%). CONCLUSIONS: Our findings suggest that 177Lu-PSMA radioligand therapy provides a significant response rate with a low toxicity profile. The evidence promotes greater efficacy of radioligand therapy in predominantly lymph node metastatic castration-resistant prostate cancer, and in individuals with chemotherapy-naïve status and lower levels of baseline PSA.

The Impact of Resampling and Denoising Deep Learning Algorithms on Radiomics in Brain Metastases MRI.

BACKGROUND: Magnetic resonance imaging (MRI) is predominant in the therapeutic management of cancer patients, unfortunately, patients have to wait a long time to get an appointment for examination. Therefore, new MRI devices include deep-learning (DL) solutions to save acquisition time. However, the impact of these algorithms on intensity and texture parameters has been poorly studied. The aim of this study was to evaluate the impact of resampling and denoising DL models on radiomics. METHODS: Resampling and denoising DL model was developed on 14,243 T1 brain images from 1.5T-MRI. Radiomics were extracted from 40 brain metastases from 11 patients (2049 images). A total of 104 texture features of DL images were compared to original images with paired t-test, Pearson correlation and concordance-correlation-coefficient (CCC). RESULTS: When two times shorter image acquisition shows strong disparities with the originals concerning the radiomics, with significant differences and loss of correlation of 79.81% and 48.08%, respectively. Interestingly, DL models restore textures with 46.15% of unstable parameters and 25.96% of low CCC and without difference for the first-order intensity parameters. CONCLUSIONS: Resampling and denoising DL models reconstruct low resolution and noised MRI images acquired quickly into high quality images. While fast MRI acquisition loses most of the radiomic features, DL models restore these parameters.

The Impact of Radiobiologically Informed Dose Prescription on the Clinical Benefit of 90Y SIRT in Colorectal Cancer Patients.

The purpose of this study was to establish the dose-response relationship of selective internal radiation therapy (SIRT) in patients with metastatic colorectal cancer (mCRC), when informed by radiobiological sensitivity parameters derived from mCRC cell lines exposed to 90Y. Methods: Twenty-three mCRC patients with liver metastases refractory to chemotherapy were included. 90Y bremsstrahlung SPECT images were transformed into dose maps assuming the local dose deposition method. Baseline and follow-up CT scans were segmented to derive liver and tumor volumes. Mean, median, and D70 (minimum dose to 70% of tumor volume) values determined from dose maps were correlated with change in tumor volume and volumetric RECIST response using linear and logistic regression, respectively. Radiosensitivity parameters determined by clonogenic assays of mCRC cell lines HT-29 and DLD-1 after exposure to 90Y or external beam radiotherapy (EBRT; 6 MV photons) were used in biologically effective dose (BED) calculations. Results: Mean administered radioactivity was 1,469 ± 428 MBq (range, 847-2,185 MBq), achieving a mean absorbed radiation dose to tumor of 35.5 ± 9.4 Gy and mean normal liver dose of 26.4 ± 6.8 Gy. A 1.0 Gy increase in mean, median, and D70 absorbed dose was associated with a reduction in tumor volume of 1.8%, 1.8%, and 1.5%, respectively, and an increased probability of a volumetric RECIST response (odds ratio, 1.09, 1.09, and 1.10, respectively). Threshold mean, median and D70 doses for response were 48.3, 48.8, and 41.8 Gy, respectively. EBRT-equivalent BEDs for 90Y are up to 50% smaller than those calculated by applying protraction-corrected radiobiological parameters derived from EBRT alone. Conclusion: Dosimetric studies have assumed equivalence between 90Y SIRT and EBRT, leading to inflation of BED for SIRT and possible undertreatment. Radiobiological parameters for 90Y were applied to a BED model, providing a calculation method that has the potential to improve assessment of tumor control.

OpenDose: Open-Access Resource for Nuclear Medicine Dosimetry.

Radiopharmaceutical dosimetry depends on the localization in space and time of radioactive sources and requires the estimation of the amount of energy emitted by the sources deposited within targets. In particular, when computing resources are not accessible, this task can be performed using precomputed tables of specific absorbed fractions (SAFs) or S values based on dosimetric models. The aim of the OpenDose collaboration is to generate and make freely available a range of dosimetric data and tools. Methods: OpenDose brings together resources and expertise from 18 international teams to produce and compare traceable dosimetric data using 6 of the most popular Monte Carlo codes in radiation transport (EGSnrc/EGS++, FLUKA, GATE, Geant4, MCNP/MCNPX, and PENELOPE). SAFs are uploaded, together with their associated statistical uncertainties, in a relational database. S values are then calculated from monoenergetic SAFs on the basis of the radioisotope decay data presented in International Commission on Radiological Protection Publication 107. Results: The OpenDose collaboration produced SAFs for all source region and target combinations of the 2 International Commission on Radiological Protection Publication 110 adult reference models. SAFs computed from the different Monte Carlo codes were in good agreement at all energies, with SDs below individual statistical uncertainties. Calculated S values were in good agreement with OLINDA/EXM 2.0 (commercial) and IDAC-Dose 2.1 (free) software. A dedicated website (www.opendose.org) has been developed to provide easy and open access to all data. Conclusion: The OpenDose website allows the display and downloading of SAFs and the corresponding S values for 1,252 radionuclides. The OpenDose collaboration, open to new research teams, will extend data production to other dosimetric models and implement new free features, such as online dosimetric tools and patient-specific absorbed dose calculation software, together with educational resources.

Imaging DNA Damage Repair In Vivo After 177Lu-DOTATATE Therapy.

Molecular radiotherapy using 177Lu-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 after 177Lu-DOTATATE therapy using SPECT imaging with 111In-anti-γH2AX-TAT. This work was a proof-of-principle study of this in vivo noninvasive biodosimeter with ß-emitting therapeutic radiopharmaceuticals. Methods: Six cell lines were exposed to external-beam radiotherapy (EBRT) or 177Lu-DOTATATE, after which the number of γH2AX foci and the clonogenic survival were measured. Mice bearing CA20948 somatostatin receptor-positive tumor xenografts were treated with 177Lu-DOTATATE or sham-treated and coinjected with 111In-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 with 177Lu-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 between 177Lu-DOTATATE uptake and γH2AX focus induction between different regions of CA20948 xenograft tumors, suggesting that different parts of the tumor may react differentially to 177Lu-DOTATATE irradiation. Conclusion:111In-anti-γH2AX-TAT allows monitoring of DNA damage after 177Lu-DOTATATE therapy and reveals heterogeneous damage responses.

VCAM-1 targeted alpha-particle therapy for early brain metastases.

BACKGROUND: Brain metastases (BM) develop frequently in patients with breast cancer. Despite the use of external beam radiotherapy (EBRT), the average overall survival is short (6 months from diagnosis). The therapeutic challenge is to deliver molecularly targeted therapy at an early stage when relatively few metastatic tumor cells have invaded the brain. Vascular cell adhesion molecule 1 (VCAM-1), overexpressed by nearby endothelial cells during the early stages of BM development, is a promising target. The aim of this study was to investigate the therapeutic value of targeted alpha-particle radiotherapy, combining lead-212 (212Pb) with an anti-VCAM-1 antibody (212Pb-αVCAM-1). METHODS: Human breast carcinoma cells that metastasize to the brain, MDA-231-Br-GFP, were injected into the left cardiac ventricle of nude mice. Twenty-one days after injection, 212Pb-αVCAM-1 uptake in early BM was determined in a biodistribution study and systemic/brain toxicity was evaluated. Therapeutic efficacy was assessed using MR imaging and histology. Overall survival after 212Pb-αVCAM-1 treatment was compared with that observed after standard EBRT. RESULTS: 212Pb-αVCAM-1 was taken up into early BM with a tumor/healthy brain dose deposition ratio of 6 (5.52e108 and 0.92e108) disintegrations per gram of BM and healthy tissue, respectively. MRI analyses showed a statistically significant reduction in metastatic burden after 212Pb-αVCAM-1 treatment compared with EBRT (P < 0.001), translating to an increase in overall survival of 29% at 40 days post prescription (P < 0.01). No major toxicity was observed. CONCLUSIONS: The present investigation demonstrates that 212Pb-αVCAM-1 specifically accumulates at sites of early BM causing tumor growth inhibition.

Radionuclide spatial distribution and dose deposition for in vitro assessments of 212 Pb-αVCAM-1 targeted alpha therapy.

PURPOSE: Targeted alpha therapy (TAT) takes advantage of the short-range and high-linear energy transfer of α-particles and is increasingly used, especially for the treatment of metastatic lesions. Nevertheless, dosimetry of α-emitters is challenging for the very same reasons, even for in vitro experiments. Assumptions, such as the uniformity of the distribution of radionuclides in the culture medium, are commonly made, which could have a profound impact on dose calculations. In this study we measured the spatial distribution of α-emitting 212 Pb coupled to an anti-VCAM-1 antibody (212 Pb-αVCAM-1) and its evolution over time in the context of in vitro irradiations. METHODS: Two experimental setups were implemented without cells to measure α-particle count rates and energy spectra in culture medium containing 15 kBq of 212 Pb-α-VCAM-1. Silicon detectors were placed above and below cell culture dishes for 20 h. One of the dishes had a 2.5-µm-thick mylar-base allowing easy detection of the α-particles. Monte Carlo simulations were performed to analyze experimental spectra. Experimental setups were modeled and α-energy spectra were simulated in the silicon detectors for different decay positions in the culture medium. Simulated spectra were then used to deconvolute experimental spectra to determine the spatial distribution of 212 Pb-αVCAM-1 in the medium. This distribution was finally used to calculate the dose deposition in cell culture experiments. RESULTS: Experimental count rates and energy spectra showed differences in measurements taken at the top and the bottom of dishes and temporal variations that did not follow 212 Pb decay. The radionuclide spatial distribution was shown to be composed of a uniform distribution and concentration gradients at the top and the bottom, which were subjected to temporal variations that may be explained by gravity and electrostatic attraction. The absorbed dose in cells calculated from this distribution was compared with the dose expected for a uniform and static distribution and found to be 1.75 times higher, which is highly significant to interpret biological observations. CONCLUSIONS: This study demonstrated that accurate dosimetry of α-emitters requires the experimental determination of radionuclide spatial and temporal distribution and highlighted that in vitro assessment of dose for TAT cannot only rely on a uniform distribution of activity in the culture medium. The reliability and reproducibility of future experiments should benefit from specifically developed dosimetry tools and methods.

Radiosensitivity of colorectal cancer to 90Y and the radiobiological implications for radioembolisation therapy.

Approximately 50% of all colorectal cancer (CRC) patients will develop metastasis to the liver. 90Y selective internal radiation therapy (SIRT) is an established treatment for metastatic CRC. There is still a fundamental lack of understanding regarding the radiobiology underlying the dose response. This study was designed to determine the radiosensitivity of two CRC cell lines (DLD-1 and HT-29) to 90Y ß - radiation exposure, and thus the relative effectiveness of 90Y SIRT in relation to external beam radiotherapy (EBRT). A 90Y-source dish was sandwiched between culture dishes to irradiate DLD-1 or HT-29 cells for a period of 6 d. Cell survival was determined by clonogenic assay. Dose absorbed per 90Y disintegration was calculated using the PENELOPE Monte Carlo code. PENELOPE simulations were benchmarked against relative dose measurements using EBT3 GAFchromic™ film. Statistical regression based on the linear-quadratic model was used to determine the radiosensitivity parameters [Formula: see text] and [Formula: see text] using R. These results were compared to radiosensitivity parameters determined for 6 MV clinical x-rays and 137Cs γ-ray exposure. Equivalent dose of EBRT in 2 Gy ([Formula: see text]) and 10 Gy ([Formula: see text]) fractions were derived for 90Y dose. HT-29 cells were more radioresistant than DLD-1 for all treatment modalities. Radiosensitivity parameters determined for 6 MV x-rays and 137Cs γ-ray were equivalent for both cell lines. The [Formula: see text] ratio for 90Y ß --particle exposure was over an order of magnitude higher than the other two modalities due to protraction of dose delivery. Consequently, an 90Y SIRT absorbed dose of 60 Gy equates to an [Formula: see text] of 28.7 and 54.5 Gy and an [Formula: see text] of 17.6 and 19.3 Gy for DLD-1 and HT-29 cell lines, respectively. We derived radiosensitivity parameters for two CRC cell lines exposed to 90Y ß --particles, 6 MV x-rays, and 137Cs γ-ray irradiation. These radiobiological parameters are critical to understanding the dose response of CRC lesions and ultimately informs the efficacy of 90Y SIRT relative to other radiation therapy modalities.

Clinical trials in molecular radiotherapy-Tribulations and Triumphs Report of the NCRI CTRad meeting held at the Lift Islington, 8 June 2018.

It has been almost a decade since the commentary Molecular radiotherapy - the radionuclide raffle? by Gaze and Flux (2010) . The overarching feeling then was that no individual or organisation has taken up the challenge, nationally or internationally, of championing molecular targeted radionuclide therapy in all its aspects. Here, we report on the recent NCRI-CTRad (Clinical Trials in Molecular Radiotherapy-Tribulations and Triumphs) meeting, held in London on the 8 June 2018. The meeting was organized by the NCRI-CTRad to review the challenges and opportunities for clinical trials in molecular radiotherapy, particularly focussing on investigator-led trials that incorporate imaging and dosimetry, and to discuss how the community can move forward. This meeting was organised in conjunction with the British Nuclear Medicine Society and reflects the progress of Nuclear Medicine in the UK.

Targeted Radionuclide Therapy: New Advances for Improvement of Patient Management and Response.

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.

Subcellular Targeting of Theranostic Radionuclides.

The last decade has seen rapid growth in the use of theranostic radionuclides for the treatment and imaging of a wide range of cancers. Radionuclide therapy and imaging rely on a radiolabeled vector to specifically target cancer cells. Radionuclides that emit ß particles have thus far dominated the field of targeted radionuclide therapy (TRT), mainly because the longer range (µm-mm track length) of these particles offsets the heterogeneous expression of the molecular target. Shorter range (nm-µm track length) α- and Auger electron (AE)-emitting radionuclides on the other hand provide high ionization densities at the site of decay which could overcome much of the toxicity associated with ß-emitters. Given that there is a growing body of evidence that other sensitive sites besides the DNA, such as the cell membrane and mitochondria, could be critical targets in TRT, improved techniques in detecting the subcellular distribution of these radionuclides are necessary, especially since many ß-emitting radionuclides also emit AE. The successful development of TRT agents capable of homing to targets with subcellular precision demands the parallel development of quantitative assays for evaluation of spatial distribution of radionuclides in the nm-µm range. In this review, the status of research directed at subcellular targeting of radionuclide theranostics and the methods for imaging and quantification of radionuclide localization at the nanoscale are described.

Targeting Micrometastases: The Effect of Heterogeneous Radionuclide Distribution on Tumor Control Probability.

The spatial distribution of radiopharmaceuticals that emit short-range high linear-energy-transfer electrons greatly affects the absorbed dose and their biological effectiveness. The purpose of this study was to investigate the effect of heterogeneous radionuclide distribution on tumor control probability (TCP) in a micrometastases model. Methods: 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-labelled epidermal growth factor, EGF) and radioimmunotherapeutic (111In-labelled 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 (SFexp ) were obtained using clonogenic assays. A random closed-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-D spheroids. Calculated survival fractions (SFcal ) were generated using an iterative modelling method based on Monte Carlo determined absorbed dose with the PENELOPE code and were compared to (SFexp ). Radiobiological parameters deduced from experimental results and MC simulations were used to predict the TCP for a 3-D spheroid model. Results: Calculated SFs were in good agreement with experimental data, particularly when an increased value for relative biological effectiveness (RBE) was applied to self-dose deposited by sources located in the nucleus and when radiobiological parameters were adjusted to account for dose protraction. Only in MDA-MB-468 spheroids treated with 111In-EGF was a TCP>0.5 achieved, indicating that for this cell type the radiopeptide would be curative when targeting micrometastases. This 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 biological 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.

Targeted alpha therapy with 212Pb or 225Ac: Change in RBE from daughter migration.

Targeted α-therapy (TAT) could be delivered early to patients who are at a high-risk for developing brain metastases, targeting the areas of the vasculature where tumor cells are penetrating into the brain. We have utilized a Monte Carlo model representing brain vasculature to calculate physical dose and DNA damage from the α-emitters 225Ac and 212Pb. The micron-scale dose distributions from all radioactive decay products were modeled in Geant4, including the eV-scale interactions using the Geant4-DNA models. These interactions were then superimposed on an atomic-scale DNA model to estimate strand break yields. In addition to 225Ac having a higher dose per decay than 212Pb, it also has a double strand break yield per decay that is 4.7 ±â€¯0.5 times that of 212Pb. However, the efficacy of both nuclides depends on retaining the daughter nuclei at the target location in the brain vasculature. The relative biological effectiveness (RBE) of 225Ac and 212Pb are similar when the entire decay chains are included, with maxima of 2.7 ±â€¯0.6 and 2.5 ±â€¯0.5 (respectively), and RBE values of about 2 to a depth of 80 µm. If the initial daughter is lost, the RBE of 212Pb is completely reduced to 1 or lower and the RBE of 225Ac is approximately 2 only for the first 40 µm.