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.

Rapid predictive dosimetry for radioembolization.

Economics of today's busy clinical practice demand both time and cost-efficient methods of predictive dosimetry for liver radioembolisation. A rapid predictive schema adapted from the Medical Internal Radiation Dose (MIRD) method i.e., Partition Model, has been devised that can be completed within minutes. This rapid schema may guide institutions that do not have access to software capable of comprehensive auto-segmentation of lung, tumour and non-tumorous liver, or where rigorous artery-specific tomographic predictive dosimetry is unfeasible for the routine clinical workflow. This rapid schema is applicable to any beta-emitting radiomicrosphere, although absorbed dose-response thresholds will differ according to device. Sampling errors in lung, tumour and non-tumorous liver will compound and propagate throughout this schema. This rapid schema achieves efficiency in lieu of accuracy. The user must be mindful of potentially large sampling errors and assumes all responsibility. Any suspicion of significant error requires the user to revert back to standard-of-care methods.

Rapid predictive dosimetry for Second Strike prescription based on whole body radioiodine kinetics in differentiated thyroid cancer.

Objectives: In systemic radionuclide therapy such as radioiodine (I-131) for differentiated thyroid cancer, post-therapy dosimetry is essential to verify pre-therapy predictions, which in turn informs the next treatment. However, post-therapy multi-time point dosimetry is resource intensive and unfeasible in many institutions. We devised a schema of rapid predictive dosimetry by circumventing post-First Strike multi-time point dosimetry with carefully assigned gestalt values of predicted kinetics to personalise the Second Strike prescription. Methods: Verification is performed after the First Strike. Patient-specific time-activity curve is plotted from serial measurements of whole body exposure rates to obtain its decay constant; its inverse is the whole body Time Integrated Activity Coefficient (TIAC). The percentage of whole body TIAC attributed to blood is carefully assigned by gestalt based on population kinetics tabulated in Part 1, adjusted by any metastasis on I-131 whole body scintigraphy. Marrow absorbed dose is calculated by EANM formularism. Lung safety threshold at 48h post-therapy is linearly scaled by height, where the patient's risk of lung radiotoxicity is revealed from the whole body time-activity curve value at 48h. Predictive prescription for the second I-131 fraction (Second Strike) is by careful gestalt assessment based on predicted kinetics, remaining marrow and lung tolerance, marrow dose rate constraint per fraction (0.265 Gy/h), local regulatory and facility requirements in relation to radiation protection. Tumour dosimetry is obviated under the assumption of severe tumour absorbed dose heterogeneity. The final prescription for the Second Strike is usually the lowest I-131 activity amongst all clinical, dosimetric and regulatory constraints. Results: This schema is incorporated into a Predictive Calculator spreadsheet for rapid predictive dosimetry, and is freely available. Calculations may be completed within minutes to generate personalised predictive prescriptions, making it feasible for routine clinical implementation. Conclusion: Our innovative schema of rapid verification and predictive dosimetry bridges the technological gap between empiric vs theranostic prescription to help institutions modernise. Its expeditious design makes this schema feasible to be integrated into the routine clinical workflow. Its predictive estimates provide invaluable dosimetric insight to inform the next I-131 fraction, allowing every prescription to be scientifically rationalised and personalised according to individual circumstances.

A simplified general schema for rapid single time-point marrow predictive dosimetry.

The red marrow is often the dose-limiting organ in systemic radionuclide therapy. However, multi-time-point personalised predictive dosimetry is resource intensive and impractical for routine clinical implementation. Single-time-point methods are a reasonable alternative for streamlining dosimetric workflows. However, there is a lack of single time-point methodology specific for the marrow. A simplified schema for rapid marrow predictive dosimetry is proposed based on direct image quantification of marrow radioconcentration, which may be generalised to most forms of systemic radionuclide therapy.

First Strike personalized predictive radioiodine prescription for inoperable metastatic differentiated thyroid cancer.

Objectives: The traditional practice of empiric radioiodine (I-131) prescription is scientifically obsolete and inappropriate for inoperable metastatic differentiated thyroid cancer. However, theranostically guided prescription is still years away for many institutions. A personalized predictive method of radioiodine prescription that bridges the gap between empiric and theranostic methods is presented. It is an adaptation of the "maximum tolerated activity" method, where serial blood sampling is replaced by population kinetics carefully chosen by the user. It aims to maximize crossfire benefits within safety constraints to overcome tumour absorbed dose heterogeneity for a safe and effective first radioiodine fraction i.e., the First Strike. Methods: The EANM method of blood dosimetry was incorporated with population kinetics, marrow and lung safety constraints, body habitus and clinical assessment of metastatic extent. Population data of whole body and blood kinetics in patients with and without metastases, prepared by recombinant human thyroid stimulating hormone or thyroid hormone withdrawal, and the maximum safe marrow dose rate were deduced from published data. For diffuse lung metastases, the lung safety limit was linearly scaled by height and separated into lung and remainder-of-body components. Results: The slowest whole body Time Integrated Activity Coefficient (TIAC) amongst patients with any metastases was 33.5±17.0 h and the highest percentage of whole body TIAC attributed to blood was 16.6±7.9%, prepared by thyroid hormone withdrawal. A variety of other average radioiodine kinetics is tabulated. Maximum safe marrow dose rate was deduced to be 0.265 Gy/h per fraction, where blood TIAC is normalised to administered activity. An easy-to-use calculator was developed which only requires height, weight and gender to populate recommendations for personalized First Strike prescription. The user decides by clinical gestalt whether the prescription is to be constrained by marrow or lung, then selects an activity depending on how extensive the metastases are likely to be. A Standard Female with oligometastasis and good urine output without diffuse lung metastasis is expected to safely tolerate 8.03 GBq of radioiodine as the First Strike. Conclusion: This predictive method will help institutions rationalise the First Strike prescription based on radiobiologically sound principles, personalised to individual circumstances.

Empiric radioiodine for hyperthyroidism: Outcomes, prescribing patterns, and its place in the modern era of theranostics.

BACKGROUND: The modern era of radioiodine (I-131) theranostics for metastatic differentiated thyroid cancer requires us to rationalize the role of traditional empiric prescription in nonmalignant thyroid disease. We currently practice empiric I-131 prescription for treatment of hyperthyroidism. This study aims to assess outcomes after treatment of hyperthyroidism by empiric I-131 prescription at our centre, evaluate factors that impact on outcomes and prescribing practice, and gain insight into whether there is a place for theranostically-guided prescription in hyperthyroidism. PATIENTS AND METHODS: A retrospective review was undertaken of all patients with Graves' disease, toxic multinodular goitre (MNG) and toxic adenoma treated with I-131 between 2016 and 2021. Associations between clinical or scintigraphic variables and remission (euthyroid or hypothyroid) or persistence of hyperthyroidism at follow-up were performed using standard t test as well as Pearson's product correlation. RESULTS: Of 146 patients with a mean follow-up of 13.6 months, 80.8% achieved remission of hyperthyroidism. This was highest in toxic nodules (90.1%), compared with Graves' disease (73.8%) and toxic MNG (75.5%). In patients with Graves' disease, higher administered activity was associated with remission (p = .035). There was a weak inverse correlation between the Tc-99m pertechnetate uptake vs prescribed activity in Graves' disease (r = -0.33; p = .009). Only one patient (0.7%) had an I-131 induced flare of thyrotoxicosis. CONCLUSION: Traditional empiric I-131 prescription is a safe and effective treatment of hyperthyroidism and suitable for most patients. However, there may be a role for personalized I-131 prescription by theranostic guidance in selected patients with high thyroid hyperactivity.

Indirect Lung Absorbed Dose Verification by 90Y PET/CT and Complete Lung Protection by Hepatic Vein Balloon Occlusion: Proof of Concept.

Postradioembolization lung absorbed dose verification was historically problematic and impractical in clinical practice. We devised an indirect method using 90Y PET/CT. Methods: Conceptually, true lung activity is simply the difference between the total prepared activity minus all activity below the diaphragm and residual activity within delivery apparatus. Patient-specific lung mass is measured by CT densitovolumetry. True lung mean absorbed dose is calculated by MIRD macrodosimetry. Results: Proof of concept is shown in a hepatocellular carcinoma patient with a high lung shunt fraction of 26%, where evidence of technically successful hepatic vein balloon occlusion for radioembolization lung protection was required. Indirect lung activity quantification showed the postradioembolization lung shunt fraction to be reduced to approximately 1% with a true lung mean absorbed dose of approximately 1 Gy, suggesting complete lung protection by hepatic vein balloon occlusion. Conclusion: We discuss possible clinical applications such as lung absorbed dose verification, refining the limits of lung tolerance, and the concept of massive activity radioembolization.

Brain hypometabolism in rare genetic neurodegenerative disease: Niemann-Pick disease type C, spinocerebellar ataxia and Huntington disease assessed by FDG PET.

Brain metabolic imaging using 18F-fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) with contemporaneous low-dose CT may be used to assess neurodegenerative diseases. In contrast to oncology whole-body FDG PET, qualitative assessment alone in brain FDG PET is subjective and vulnerable to visual interference due to high physiologic background activity. Therefore, mild changes in brain metabolism may be visually undetectable by qualitative interpretation alone, resulting in diagnostic inaccuracy. To overcome this, some institutions may employ an objective comparison to a normal reference database. To date, there is limited literature describing brain metabolic changes in rare genetic neurodegenerative diseases such as Niemann-Pick disease Type C, spinocerebellar ataxia and Huntington disease. In this case series, we illustrate the typical FDG PET findings in the cortex and deep grey matter for these rare diseases, utilising normal database comparison including three dimensional Stereotactic Surface Projection (3D-SSP) mapping. These comparisons can generate 3D-SSP maps where metabolic changes may be expressed in standard deviations from normal (z-score) and visually depicted in a scale of colours to improve diagnostic accuracy.

Dose-response for yttrium-90 resin microsphere radioembolisation.

The fundamental premise of yttrium-90 radioembolisation is to balance safety with efficacy. To achieve this, dose-response guidance must be provided. This is a tabulation of published data of key dose-response metrics for yttrium-90 resin microsphere radioembolisation of liver malignancies. Metrics are expressed in terms of mean radiation absorbed doses (Gy), dose-volume histograms, Biologically Effective Doses, Normal Tissue Complication Probability and Tumour Control Probability.

90Y PET for Qualitative and Quantitative Assessment of Residual Activity in Delivery Apparatus After Radioembolization.

Assessment of residual activity is critical for quality assurance after 90Y radioembolization. The resin microsphere manufacturer's indirect method of estimating the residual activity is laborious and vulnerable to inaccuracies. Furthermore, the method cannot localize the exact site of residual activity. 90Y PET/CT for qualitative and quantitative assessment of residual activity has not, to our knowledge, been described. We show an example of 90Y PET/CT of residual activity in the delivery apparatus and catheters packed inside the delivery box. Focally intense residual activity was clearly localized to the stopcock junction. Residual activity was directly quantified by setting the PET volume-of-interest isocontour threshold to 1%.

Recommendations for radioembolisation after liver surgery using yttrium-90 resin microspheres based on a survey of an international expert panel.

INTRODUCTION: Guidelines on how to adjust activity in patients with a history of liver surgery who are undergoing yttrium-90 radioembolisation (90Y-RE) are lacking. The aim was to study the variability in activity prescription in these patients, between centres with extensive experience using resin microspheres 90Y-RE, and to draw recommendations on activity prescription based on an expert consensus. METHODS: The variability in activity prescription between centres was investigated by a survey of international experts in the field of 90Y-RE. Six representative post-surgical patients (i.e. comparable activity prescription, different outcome) were selected. Information on patients' disease characteristics and data needed for activity calculation was presented to the expert panel. Reported was the used method for activity prescription and whether, how and why activity reduction was found indicated. RESULTS: Ten experts took part in the survey. Recommendations on activity reduction were highly variable between the expert panel. The median intra-patient range was 44 Gy (range 18-55 Gy). Reductions in prescribed activity were recommended in 68% of the cases. In consensus, a maximum DTarget of 50 Gy was recommended. CONCLUSION: With a current lack of guidelines, large variability in activity prescription in post-surgical patients undergoing 90Y-RE exists. In consensus, DTarget ≤50 Gy is recommended. KEY POINTS: • BSA method does not account for a decreased remnant liver volume after surgery. • In post-surgical patients, a volume-based activity determination method is recommended. • In post-surgical patients, a mean D Target of ≤ 50Gy should be aimed for.

Yttrium-90 hepatic radioembolization: clinical review and current techniques in interventional radiology and personalized dosimetry.

In recent years, yttrium-90 ((90)Y) microsphere radioembolization has been establishing itself as a safe and efficacious treatment for both primary and metastatic liver cancers. This extends to both first-line therapies as well as in the salvage setting. In addition, radioembolization appears efficacious for patients with portal vein thrombosis, which is currently a contraindication for surgery, transplantation and transarterial chemoembolization. This article reviews the efficacy and expanding use of (90)Y microsphere radioembolization with an added emphasis on recent advances in personalized dosimetry and interventional radiology techniques. Directions for future research into combination therapies with radioembolization and expansion into sites other than the liver are also explored.

Gender, Race, and Age at Diagnosis as Risk Factors for Metastasis or Recurrence among 1,657 Thyroid Cancer Patients Treated with Radioiodine across 40 Years in Singapore.

BACKGROUND: To obtain descriptive data on Singaporean thyroid cancer patients treated with radioiodine and to assess gender, race, and age at diagnosis as risk factors for metastasis or recurrence. METHODS: This is a retrospective study of all thyroid cancer patients treated with radioiodine of any prescribed activity at our institution. Data collected included: age at diagnosis, gender, race, histopathological type, duration of follow-up, and metastasis at diagnosis (locoregional or distant) or recurrence at any time. Gender, race, and age at diagnosis were analyzed for possible associations with metastasis or recurrence. RESULTS: A total of 1,657 thyroid cancer patients were treated with radioiodine across a 40-year period; mean follow-up 6.4 ± 6.9 years (median 4.2 years). 656 (39.6%) patients had metastasis or recurrence over the duration of their follow-up. Male gender (odds ratio (OR) 1.38; p = 0.006), Malay race (OR 1.71; p < 0.0001), and age at diagnosis of > 46 years (OR 1.31; p = 0.007) were significantly associated with metastasis or recurrence. CONCLUSION: Male gender, Malay race, and age at diagnosis of > 46 years were significant risk factors for metastasis or recurrence in Singaporean thyroid cancer patients treated with radioiodine.

Scientific basis of personalised tomographic radiation planning for radioembolisation: A form of brachytherapy planning.

Today's tomographic imaging techniques such as catheter-directed CT and single photon emission computed tomography with integrated computed tomography may be used for pre-therapy radiation planning for radioembolisation based on prospective calculation of tissue radiation absorbed doses. We outline the scientific concepts that underlie modern personalised tomographic radiation planning for radioembolisation and highlight its similarities to brachytherapy planning.

A gelatin liver phantom of suspended 90Y resin microspheres to simulate the physiologic microsphere biodistribution of a postradioembolization liver.

UNLABELLED: For phantom studies involving (90)Y PET/CT, homogeneous solutions of (90)Y, for example, (90)Y citrate, are commonly used. However, the microsphere biodistribution of a postradioembolization liver is never homogeneous; therefore, such phantoms are physiologically unrealistic for simulating clinical scenarios. The aim of this work was to develop a safe and practical phantom capable of simulating the heterogeneous microsphere biodistribution of a postradioembolization liver. METHODS: Gelatin (5%) was used to suspend (90)Y resin microspheres, poured into plastic containers to simulate a liver with 2 tumors. Microspheres were added while the gelatin was maintained in a liquid state on a hot plate and continuously stirred with magnetic stir bars. The liquid microsphere mixture was then rapidly cooled in an ice bath while being stirred, resulting in a heterogeneous suspension of microspheres. The completed phantom was serially scanned by (90)Y PET/CT over 2 wk. RESULTS: All scans demonstrated a heterogeneous microsphere distribution throughout the liver and tumor inserts. Serendipitously, magnetic stir bars left inside the phantom produced CT artifacts similar to those caused by embolization coils, whereas pockets of air trapped within the gelatin during its preparation mimicked gas within hollow viscus. The microspheres and tumor inserts remained fixed and suspended within the gelatin, with no evidence of breakdown or leakage. CONCLUSION: A gelatin phantom realistically simulating the physiologic microsphere biodistribution of a postradioembolization liver is feasible to construct in a radiopharmacy.

Personalized predictive lung dosimetry by technetium-99m macroaggregated albumin SPECT/CT for yttrium-90 radioembolization.

BACKGROUND: For yttrium-90 ((90)Y) radioembolization, the common practice of assuming a standard 1,000-g lung mass for predictive dosimetry is fundamentally incongruent with the modern philosophy of personalized medicine. We recently developed a technique of personalized predictive lung dosimetry using technetium-99m ((99m)Tc) macroaggregated albumin (MAA) single photon emission computed tomography with integrated CT (SPECT/CT) of the lung as part of our routine dosimetric protocol for (90)Y radioembolization. Its rationales are the technical superiority of SPECT/CT over planar scintigraphy, ease and convenience of lung auto-segmentation CT densitovolumetry, and dosimetric advantage of patient-specific lung parenchyma masses. METHODS: This is a retrospective study of our pulmonary clinical outcomes and comparison of lung dosimetric accuracy and precision by (99m)Tc MAA SPECT/CT versus conventional planar methodology. (90)Y resin microspheres (SIR-Spheres) were used for radioembolization. Diagnostic CT densitovolumetry was used as a reference for lung parenchyma mass. Pulmonary outcomes were based on follow-up diagnostic CT chest or X-ray. RESULTS: Thirty patients were analyzed. The mean lung parenchyma mass of our Southeast Asian cohort was 822 ± 103 g standard deviation (95% confidence interval 785 to 859 g). Patient-specific lung parenchyma mass estimation by CT densitovolumetry on (99m)Tc MAA SPECT/CT is accurate (bias -21.7 g) and moderately precise (95% limits of agreement -194.6 to +151.2 g). Lung mean radiation absorbed doses calculated by (99m)Tc MAA SPECT/CT and planar methodology are both accurate (bias <0.5 Gy), but (99m)Tc MAA SPECT/CT offers better precision over planar methodology (95% limits of agreement -1.76 to +2.40 Gy versus -3.48 to +3.31 Gy, respectively). None developed radiomicrosphere pneumonitis when treated up to a lung mean radiation absorbed dose of 18 Gy at a median follow-up of 4.4 months. CONCLUSIONS: Personalized predictive lung dosimetry by (99m)Tc MAA SPECT/CT is clinically feasible, safe, and more precise than conventional planar methodology for (90)Y radioembolization radiation planning.