Exploring the role of combined external beam radiotherapy and targeted radioligand therapy with [177Lu]Lu-PSMA-617 for prostate cancer - from bench to bedside.

Management of prostate cancer (PC) might be improved by combining external beam radiotherapy (EBRT) and prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) with lutetium-177 (177Lu)-labeled PSMA inhibitors. We hypothesized a higher efficacy of the combination due to augmentation of the radiation dose to the tumor and interactions of EBRT with PSMA expression potentially increasing radiopharmaceutical uptake. Therefore, this study analyzed the influence of radiation on PSMA expression levels in vitro. The results were translated to evaluate the efficacy of the combination of photon EBRT and [177Lu]Lu-PSMA-617 in a murine PC xenograft model. Finally, a clinical case report on a combined elective field EBRT with RLT dose escalation illustrates a proof-of-concept. Methods: PSMA gene and protein expression were assessed in human PSMA-overexpressing LNCaP cells after irradiation using reverse transcription quantitative polymerase chain reaction (RT-qPCR), flow cytometry and On-Cell Western assays. In the in vivo therapy study, LNCaP tumor-bearing BALB/c nu/nu mice were irradiated once with 2 Gy X-ray EBRT and injected with 40 MBq [177Lu]Lu-PSMA-617 after 4 h or received single or no treatment (n = 10 each). Tumor-absorbed doses by [177Lu]Lu-PSMA-617 were calculated according to the Medical Internal Radiation Dosimetry (MIRD) formalism after deriving time-activity curves using a gamma probe. An exemplified patient case is demonstrated where fractionated EBRT (54 Gy to prostate; 45 Gy to pelvic lymphatics) and three cycles of [177Lu]Lu-PSMA-617 (3.4-6.0 GBq per cycle) were sequentially combined under concurrent androgen deprivation for treating locally advanced PC. Results: At 4 h following irradiation with 2-8 Gy, LNCaP cells displayed a PSMA protein upregulation by around 18% relative to non-irradiated cells, and a stronger upregulation on mRNA level (up to 2.6-fold). This effect was reversed by 24 h when PSMA protein levels were downregulated by up to 22%. Mice treated with the combination therapy showed significantly improved outcomes regarding tumor control and median survival (p < 0.0001) as compared to single or no treatment. Relative to monotherapy with PSMA-RLT or EBRT, the tumor doubling time was prolonged 1.7- or 2.7-fold and the median survival was extended by 24% or 60% with the combination, respectively. Additionally, tumors treated with EBRT exhibited a 14% higher uptake of the radiopharmaceutical as evident from the calculated tumor-absorbed dose, albeit with high variability in the data. Concerning the patient case, the tri-modality treatment was well tolerated and the patient responded with a long-lasting complete biochemical remission for five years following end of PSMA-RLT. The patient then developed a biochemical relapse with oligo-recurrent disease on follow-up imaging. Conclusion: The present preclinical and clinical data demonstrate that the combination of EBRT with dose escalation by PSMA-RLT improves tumor control and potentially prolongs survival. This may pave the way for further clinical investigations of this approach to explore the curative potential of the combination therapy.

Determination of lutetium density in LYSO crystals: methodology and PET detector applications.

Objective. Lutetium yttrium oxyorthosilicate (LYSO) scintillation crystals are used in positron emission tomography (PET) due to their high gamma attenuation, fair energy resolution, and fast scintillation decay time. The enduring presence of the176Lu isotope, characterized by a half-life of 37.9 billion years, imparts a consistent radiation background (BG) profile that depends on the geometry and composition attributes of the LYSO crystals.Approach. In this work, we proposed a methodology for estimating the composition of LYSO crystals in cases where the exact Lutetium composition remains unknown. The connection between BG spectrum intensity and intrinsic radioactivity enables precise estimation of Lutetium density in LYSO crystal samples. This methodology was initially applied to a well-characterized LYSO crystal sample, yielding results closely aligned with the known composition. The composition estimation approach was extended to several samples of undisclosed LYSO crystals, encompassing single crystal and crystal array configurations. Furthermore, we model the background spectrum observed in the LYSO-based detector and validate the observed spectra via simulations.Main results. The estimated Lutetium composition exhibited adequate consistency across different samples of the same LYSO material, with variations of less than 1%. The result of the proposed approach coupled with the simulation successfully models the background radiation spectra in various LYSO-based detector geometries.Significance. The implications of this work extend to the predictive assessment of system behaviors and the autonomous configuration parameters governing LYSO-based detectors.

[161Tb]Tb-PSMA-617 radioligand therapy in patients with mCRPC: preliminary dosimetry results and intra-individual head-to-head comparison to [177Lu]Lu-PSMA-617.

Rationale: Evaluation of alternative radionuclides for use in prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) is currently focusing on 161Tb, which may provide advantages by emitting additional Auger and conversion electrons. In this pilot study, we present preliminary dosimetry data for [161Tb]Tb-PSMA-617 RLT in a direct comparison with [177Lu]Lu-PSMA-617. Method: Six patients with metastatic castration-resistant prostate cancer (mCRPC) underwent treatment with [177Lu]Lu-PSMA-617 and subsequently - after inadequate response - with [161Tb]Tb-PSMA-617. Whole-body planar and SPECT imaging-based dosimetry of organs at risk (kidneys and salivary glands) and tumor lesions were calculated using IDAC for 177Lu and OLINDA/EXM for 161Tb. The therapeutic index (TI) of mean tumor-absorbed doses over relevant organs at risk was calculated. Results: Mean absorbed doses to organs at risk of PSMA-RLT were slightly higher for [161Tb]Tb-PSMA-617 compared to [177Lu]Lu-PSMA-617 (kidneys: 0.643 ± 0.247 vs. 0.545 ± 0.231 Gy/GBq, factor 1.18; parotid gland: 0.367 ± 0.198 vs. 0.329 ± 0.180 Gy/GBq, factor 1.10), but markedly higher regarding tumor lesions (6.10 ± 6.59 vs 2.59 ± 3.30 Gy/GBq, factor 2.40, p < 0.001). Consequently, the mean TI was higher for [161Tb]Tb-PSMA-617 compared to [177Lu]Lu-PSMA-617 for both, the kidneys (11.54 ± 9.74 vs. 5.28 ± 5.13, p = 0.002) and the parotid gland (16.77 ± 13.10 vs. 12.51 ± 18.09, p = 0.008). Conclusion: In this intra-individual head-to-head pilot study, [161Tb]Tb-PSMA-617 delivered higher tumor-absorbed doses and resulted in superior TI compared to [177Lu]Lu-PSMA-617. This preliminary data support 161Tb as a promising radionuclide for PSMA-RLT in mCRPC.

Prognostic Performance of RECIP 1.0 Based on [18F]PSMA-1007 PET in Prostate Cancer Patients Treated with [177Lu]Lu-PSMA I&T.

In metastatic castration-resistant prostate cancer (mCRPC) patients treated with prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), the recently proposed criteria for evaluating response to PSMA PET (RECIP 1.0) based on 68Ga- and 18F-labeled PET agents provided prognostic information in addition to changes in prostate-specific antigen (PSA) levels. Our aim was to evaluate the prognostic performance of this framework for overall survival (OS) in patients undergoing RLT and imaged with [18F]PSMA-1007 PET/CT and compare the prognostic performance with the PSA-based response assessment. Methods: In total, 73 patients with mCRPC who were scanned with [18F]PSMA-1007 PET/CT before and after 2 cycles of RLT were retrospectively analyzed. We calculated the changes in serum PSA levels (ΔPSA) and quantitative PET parameters for the whole-body tumor burden (SUVmean, SUVmax, PSMA tumor volume, and total lesion PSMA). Men were also classified following the Prostate Cancer Working Group 3 (PCWG3) criteria for ΔPSA and RECIP 1.0 for PET imaging response. We performed univariable Cox regression analysis, followed by multivariable and Kaplan-Meier analyses. Results: Median OS was 15 mo with a median follow-up time of 14 mo. Univariable Cox regression analysis provided significant associations with OS for ΔPSA (per percentage, hazard ratio [HR], 1.004; 95% CI, 1.002-1.007; P < 0.001) and PSMA tumor volume (per unit, HR, 1.003; 95% CI, 1.000-1.005; P = 0.03). Multivariable Cox regression analysis confirmed ΔPSA (per percentage, HR, 1.004; 95% CI, 1.001-1.006; P = 0.006) as an independent prognosticator for OS. Kaplan-Meier analyses provided significant segregation between individuals with versus those without any PSA response (19 mo vs. 14 mo; HR, 2.00; 95% CI, 0.95-4.18; P = 0.04). Differentiation between patients with or without progressive disease (PD) was also feasible when applying PSA-based PCWG3 (19 mo vs. 9 mo for non-PD and PD, respectively; HR, 2.29; 95% CI, 1.03-5.09; P = 0.01) but slightly failed when applying RECIP 1.0 (P = 0.08). A combination of both response systems (PCWG3 and RECIP 1.0), however, yielded the best discrimination between individuals without versus those with PD (19 mo vs. 8 mo; HR, 2.78; 95% CI, 1.32-5.86; P = 0.002). Conclusion: In patients with mCRPC treated with RLT and imaged with [18F]PSMA-1007, frameworks integrating both the biochemical (PCWG3) and PET-based response (RECIP 1.0) may best assist in identifying subjects prone to disease progression.

Radiation levels outside a patient undergoing177Lu-PSMA radioligand therapy.

Understanding the spatial distribution of radiation levels outside of a patient undergoing177Lu radioligand therapy is not only helpful for conducting correct tests for patient release, but also useful for estimation of its potential exposure to healthcare workers, caregivers, family members, and the general public. In this study, by mimicking the177Lu-labeled prostate-specific membrane antigen radioligand therapy for prostate cancers in an adult male, the spatial distribution of radiation levels outside of the phantom was simulated based on the Monte Carlo software of Particle and Heavy Ion Transport System, and verified by a series of measurements. Moreover, the normalized dose rates were further formulized on the three transverse planes representing the heights of pelvis, abdomen and chest. The results showed that the distributions of radiation levels were quite complex. Multi-directional and multi-height measurements are needed to ensure the external dose rate to meet the release criteria. In general, the radiation level was higher at the horizontal plane where the source was located, and the levels in front and behind of the body were higher than those of the left and right sides at the same height. The ratio of simulated dose rates to measured ones ranged from 0.82 to 1.19 within 1 m away from the body surface in all directions. Based on the established functions, the relative root mean square deviation between the calculated and simulated values were 0.21, 0.25 and 0.23 within a radius of 1 m on the pelvis, abdomen and chest transverse planes, respectively. It is expected that the results of this study would be helpful for guiding the test of extracorporeal radiation to determine the patient's release, and of benefit to estimate the radiation exposure to others.

Dosing lutetium Lu 177-dotatate for a hemodialysis patient.

Lu177-dotatate (Lutathera™) is a radioactive drug approved for the treatment of adults with gastro-entero-pancreatic neuroendocrine tumors and is predominantly renally excreted. Currently all patients receive 7400 MBq (200 mCi), and there are no guidelines for treating hemodialysis patients. We measured radioactivity prior to and post administration of two cycles of Lu177-dotatate in a hemodialysis patient, and radiation exposure to staff. We reduced the standard 7400 MBq by 33% for the first cycle and patient radioactivity fell by 40% following postdilution hemodiafiltration started 6 h post dosing, and by 45% for the second cycle and radioactivity fell by 47% with postdilution hemodiafiltration started 5 h post administration. By reducing the initial administered radioactivity, coupled with early dialysis, and choosing postdilution hemodiafiltration we were able to achieve radioactivity retention curves similar to those from patients with normal renal function receiving the standard administration of 7400 MBq.

Extravasation After [ 177 Lu]Lu-HA-DOTATATE Therapy.

ABSTRACT: Extravasation of the radiopharmaceutical during peptide receptor radionuclide therapy infusion is an unwanted infrequently reported event. We present the case of a 74-year old woman with a neuroendocrine tumor who was referred for peptide receptor radionuclide therapy. During intravenous infusion of 7.4 GBq [ 177 Lu]Lu-HA-DOTATATE in the upper right arm, extravasation of the radiopharmaceutical occurred through a displaced intravenous catheter. Planar scintigraphy showed pooling of radioactivity in the right upper arm. After 24 hours, the swelling in the arm was decreased; however, erythema was increased. One week later, symptoms had disappeared, and the patient did not experience any complications during follow-up of 11 months.

177 Lu-FAP-2286 Therapy in a Metastatic Bone Malignant Solitary Fibrous Tumor.

ABSTRACT: A 57-year-old woman with a metastatic bone malignant solitary fibrous tumor received 177 Lu-FAP-2286 therapy. After 1 treatment cycle, 68 Ga-FAP-2286 PET/CT revealed remission of the lesions. Moreover, the patient did not report any adverse effects.

Crystal scatter effects in a large-area dual-panel Positron Emission Mammography system.

Positron Emission Mammography (PEM) is a valuable molecular imaging technique for breast studies using pharmaceuticals labeled with positron emitters and dual-panel detectors. PEM scanners normally use large scintillation crystals coupled to sensitive photodetectors. Multiple interactions of the 511 keV annihilation photons in the crystals can result in event mispositioning leading to a negative impact in radiopharmaceutical uptake quantification. In this work, we report the study of crystal scatter effects of a large-area dual-panel PEM system designed with either monolithic or pixelated lutetium yttrium orthosilicate (LYSO) crystals using the Monte Carlo simulation platform GATE. The results show that only a relatively small fraction of coincidences (~20%) arise from events where both coincidence photons undergo single interactions (mostly through photoelectric absorption) in the crystals. Most of the coincidences are events where at least one of the annihilation photons undergoes a chain of Compton scatterings: approximately 79% end up in photoelectric absorption while the rest (<1%) escape the detector. Mean positioning errors, calculated as the distance between first hit and energy weighted (assigned) positions of interaction, were 1.70 mm and 1.92 mm for the monolithic and pixelated crystals, respectively. Reconstructed spatial resolution quantification with a miniDerenzo phantom and a list mode iterative reconstruction algorithm shows that, for both crystal types, 2 mm diameter hot rods were resolved, indicating a relatively small effect in spatial resolution. A drastic reduction in peak-to-valley ratios for the same hot-rod diameters was observed, up to a factor of 14 for the monolithic crystals and 7.5 for the pixelated ones.

[The lacrimal apparatus as an organ at risk during radionuclide therapy].

Within the framework of the article, the authors analyzed the available information about the damage to the lacrimal apparatus during radionuclide therapy. In focus of article lesions of the lacrimal production system, the main and accessory lacrimal glands, as well as lacrimal drainage are considered. It was found that damage to the lacrimal apparatus is characteristic of 131I therapy for thyroid cancer, as well as for radioligand therapy using anti-PSMA antibodies labeled with 177Lu and 225Ac. 177Lu-PSMA and 225Ac-PSMA may damage the lacrimal gland with the formation of a clinically pronounced "dry eye syndrome". The pathogenesis of such lesions is associated with the accumulation of a radioisotope in the tissues of the lacrimal apparatus, while during therapy with 131I, accumulation is realized due to the expression of the sodium-iodine symporter in the nasolacrimal duct, and during therapy with 177Lu-PSMA and 225Ac-PSMA, the radiobiological effect is realized in connection with the expression PSMA by lacrimal tissue. An analysis of the available sources showed that to date there are no results of systematic studies on the problem, there is a lack of knowledge regarding the individual risks of developing these complications, methods for their prevention that have proven effectiveness have not been developed, and the treatment methods used, having relatively low efficiency, are not specialized. The authors concluded that the strengthening of interdisciplinary interaction, as well as the organization verification methodology and correct studies, can contribute to solving problems related to the study of the complications under consideration.

Single-Time-Point Renal Dosimetry Using Nonlinear Mixed-Effects Modeling and Population-Based Model Selection in [177Lu]Lu-PSMA-617 Therapy.

The aim of this study was to investigate the accuracy of single-time-point (STP) renal dosimetry imaging using SPECT/CT data, a nonlinear mixed-effects (NLME) model, and a population-based model selection (PBMS) in a large population for 177Lu-labeled prostate-specific membrane antigen therapy. Methods: Biokinetic data (mean ± SD) of [177Lu]Lu-PSMA-617 in kidneys at time points 1 (1.8 ± 0.8 h), 2 (18.7 ± 0.9 h), 3 (42.6 ± 1.0 h), 4 (66.3 ± 0.9 h), and 5 (160.3 ± 24.2 h) after injection were obtained from 63 patients with metastatic castration-resistant prostate cancer using SPECT/CT. Thirteen functions were derived from various parameterizations of 1- to 5-exponential functions. The function's parameters were fitted in the NLME framework to the all-time-point (ATP) data. The PBMS NLME method was performed using the goodness-of-fit test and Akaike weight to select the best function fitting the data. The best function from ATP fitting was used to calculate the reference time-integrated activity and absorbed doses. In STP dosimetry, the parameters of a particular patient with STP data were fitted simultaneously to the STP data at different time points of that patient with ATP data of all other patients. The parameters from STP fitting were used to calculate the STP time-integrated activity and absorbed doses. Relative deviations (RDs) and root-mean-square errors (RMSEs) were used to analyze the accuracy of the calculated STP absorbed dose compared with the reference absorbed dose obtained from the best-fit ATP function. The performance of STP dosimetry using PBMS NLME modeling was compared with the Hänscheid and Madsen methods. Results: The function [Formula: see text] was selected as the best-fit ATP function, with an Akaike weight of 100%. For STP dosimetry, the STP measurement by SPECT/CT at time point 3 (42.6 ± 1.0 h) showed a relatively low mean RD of -4.4% ± 9.4% and median RD of -0.7%. Time point 3 had the lowest RMSE value compared with those at the other 4 time points. The RMSEs of the absorbed dose RDs for time points 1-5 were 23%, 16%, 10%, 20%, and 53%, respectively. The STP dosimetry using the PBMS NLME method outperformed the Hänscheid and Madsen methods for all investigated time points. Conclusion: Our results show that a single measurement of SPECT/CT at 2 d after injection might be used to calculate accurate kidney-absorbed doses using the NLME method and PBMS.

Formulation of patient dose of [177Lu]Lu-Trastuzumab using in-house developed freeze-dried kit: A path forward for clinical translation.

Trastuzumab is a US-FDA-approved humanized monoclonal antibody used for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The aim of the present work is to optimize a freeze-dried formulation of DOTA-Trastuzumab conjugate for the preparation of patient doses of [177Lu]Lu-Trastuzumab for radioimmunotherapy of breast cancer. The formulation of [177Lu]Lu-Trastuzumab usually takes a long time, and thus, such a process is not suitable for the routine preparation of this agent in hospital radiopharmacies. To circumvent this, a pre-synthesized DOTA-Trastuzumab conjugate as a freeze-dried formulation is proposed. In the present work, DOTA-Trastuzumab conjugate was subjected to a freeze-drying process after the addition of optimized amounts of radioprotectant and cryoprotectant. [177Lu]Lu-DOTA-Trastuzumab was prepared by incubating the lyophilized powder of the kit vial with medium-specific activity 177LuCl3. The final radiochemical purity of [177Lu]Lu-DOTA-Trastuzumab, prepared using freeze-dried kit, was determined to be >95%. To ascertain the reproducibility of the procedure, six consecutive batches of the freeze-dried formulation were prepared, radiolabeled, and evaluated by carrying out both in vitro and ex vivo studies. The consistency of the results of all the six consecutive batches confirmed the robustness and utility of the in-house optimized freeze-dried formulation for the preparation of patient doses of [177Lu]Lu-Trastuzumab at hospital radiopharmacies.

Transformation of G1-G2 neuroendocrine tumors to neuroendocrine carcinomas following peptide receptor radionuclide therapy.

We observed that some patients with well-differentiated neuroendocrine tumors (NET) who received peptide receptor radionuclide therapy (PRRT) with Lutetium-177 (177Lu) DOTATATE developed rapid disease progression with biopsy-proven histologic transformation to neuroendocrine carcinoma (NEC), an outcome that has not been previously described. Therefore, we conducted a retrospective review of all patients with well-differentiated G1-G2 NET who received at least one cycle of PRRT with (177Lu) DOTATATE at our center from January 2019 to December 2020. Among 152 patients, we identified 7 patients whose NET transformed to NEC. Median time from start of PRRT to transformation was 8.2 months (range: 2.6-14.4 months). All patients whose tumors underwent transformation had pancreatic tail as the primary site and had prior chemotherapy with temozolomide. No differences in the incidence of transformation were observed according to gender, race, original tumor grade, or number of prior therapies. Six patients received treatment with platinum and etoposide after transformation with two patients having partial response as best response. All patients with transformation died from progressive disease with median overall survival (OS) after transformation of 3.3 months (95% CI 2.1-4.4). Molecular testing of transformed NEC identified mutation(s) in TP53 and/or ATM in all cases. Transformation of NET to NEC following PRRT is associated with aggressive course and dismal prognosis. Patients with pancreatic tail as the primary site who had prior therapy with temozolomide may be at a higher risk. Further investigation is necessary to determine the best treatment sequence in this patient population.

Clinical Internal Dosimetry and Biodistribution of 177 Lu-DOTA-Trastuzumab in HER2-Positive Metastatic and Locally Advanced Breast Carcinoma.

OBJECTIVE: The aim of this study was to assess the biodistribution and dosimetry of 177 Lu-DOTA-trastuzumab in patients with HER2-positive breast carcinoma using whole-body (WB) planar imaging at multiple time points. PATIENTS AND METHODS: This study was a prospective evaluation of HER2-positive metastatic/locally advanced breast carcinoma patients who underwent gamma camera imaging for dosimetry and biodistribution studies by using 177 Lu-DOTA-trastuzumab. The standard diagnostic dosimetry protocol was followed, which included cold trastuzumab injection followed by in-house produced 177 Lu-DOTA-trastuzumab. Serial WB planar images (anterior and posterior) were obtained on gamma camera after the infusion of 177 Lu-DOTA-trastuzumab at multiple time points. Whole-body and organ regions of interest were drawn, and the numbers of disintegrations were obtained. The mean absorbed doses for the liver, spleen, kidneys, heart, red marrow, and tumor were obtained from OLINDA EXM v2.1.1 and ORIGIN software. RESULTS: The study included a cohort of 21 female breast carcinoma patients. Tracer activity ( 177 Lu-DOTA-trastuzumab) was noted in the physiological organs such as the liver, spleen, kidneys, heart, as well as in the tumors. On visual analysis of 177 Lu-DOTA-trastuzumab biodistribution, the liver activity showed gradual clearance over time, and although spleen was comparatively faintly visualized than liver and similarly, kidneys were faintly visualized suggestive of the alternate route of tracer excretion. The maximum number of patients (n = 12) showed 2 components of clearance, namely, fast and slow. The average effective half-life of all the patients (including single and 2 components of clearance) was 106.25 ± 22.14 hours (84.11-128.39 hours). The mean absorbed dose for the liver, spleen, kidneys, heart, whole body, and red marrow was 1.0702 ± 0.731, 1.4114 ± 0.462, 1.4232 ± 0.364, 1.4719 ± 0.602, 0.2412 ± 0.0295, and 0.1485 ± 0.0213 mGy/MBq, respectively, by OLINDA EXM and 0.5741 ± 0.333, 0.8096 ± 0.224, 0.7943 ± 0.235, 1.8971 ± 0.713, and 0.09619 ± 0.0144 for liver, spleen, kidneys, heart and whole body respectively by ORIGIN. The absorbed radiation dose for tumor was 1.94E+2 by OLINDA EXM software and 1.78E+2 by ORIGIN software. In this study, during and after infusion of 177 Lu-DOTA-trastuzumab, no major adverse effects were noted in any patient except 1 patient who had grade 1 nausea and managed conservatively by antiemetic drug. CONCLUSIONS: The results of our study demonstrated expected and favorable biodistribution and dosimetry with 177 Lu-DOTA-trastuzumab in HER2-positive breast carcinoma patients. We noticed the mean absorbed dose to the normal organs within the limits of maximum tolerable dose, and also tumor dose was higher than the normal liver dose. Therefore, we conclude that 177 Lu-DOTA-trastuzumab radioimmunotherapy is feasible and a safe treatment option for treating HER2-positive breast carcinoma patients.

Cutaneous Metastasis From Prostate Cancer on Posttherapeutic 177 Lu-Prostate-Specific Membrane Antigen Scan.

ABSTRACT: In this note, we aim to present a patient with a known case of prostate cancer with widespread metastasis to the skeleton and liver who has undergone several cycles of chemoradiotherapy. The patient received 2 doses of 177 Lu-prostate-specific membrane antigen therapy, in which several zones of uptake were detected on the thoracic wall compatible with cutaneous metastatic lesions of prostate cancer.

Dual 177 Lu-Prostate-Specific Membrane Antigen and 177 Lu-DOTATATE Therapy in Metastatic Castration-Resistant Prostate Cancer With Neuroendocrine Differentiation.

ABSTRACT: We present an 87-year-old man diagnosed with prostate cancer and neuroendocrine differentiation, posttherapy results to consecutive 177 Lu-prostate-specific membrane antigen and 177 Lu-DOTATATE. Despite hormonal therapy and chemoradiotherapy, the patient progressed rapidly, and multiple liver and bone metastases showed regression after 177 Lu-prostate-specific membrane antigen and 177 Lu-DOTATATE treatment. Prostate cancer with neuroendocrine differentiation is resistant to treatments; however, treatment with the combination of 177 Lu-DOTATATE therapy may be promising.

177Lu-PSMA therapy in metastatic prostate cancer: An updated review of prognostic and predictive biomarkers.

177Lu-PSMA has been approved for the treatment of PSMA-positive metastatic castration-resistant (mCRPC) patients who progressed to androgen receptor pathway inhibitors (ARPIs) and taxane-based chemotherapy. However, a higher proportion of patients do not respond to this type of radioligand therapy (RLT). To date, there is a lack of validated prognostic and predictive biomarkers for 177Lu-PSMA therapy in prostate cancer. Several studies have investigated the prognostic and predictive role of clinical and molecular factors and also the metabolic features of PET imaging. In this review, we aim to take stock of the current scenario, focusing on new emerging data from retrospective/prospective series and clinical trials. Given the high costs and the possibility of primary resistance, it seems essential to identify clinical and molecular characteristics that could allow clinicians to choose the right patient to treat with 177Lu-PSMA. Biomarker-based clinical trials are urgently needed in this field.

Quadruplet Therapy in De Novo High-Volume Mixed Neuroendocrine Prostate Cancer Using 177Lu-PSMA: A Case Report.

ABSTRACT: We present a case of de novo high-volume metastatic prostate cancer with high PSMA expression, partially PSMA-negative, using quadruplet therapy (PROMISE ver. 2 miTNM; miT4N2M1aM1b(dmi) PRIMARY score: 5, PSMA-expression score: 0-3). Because of our patient's partial PSMA negativity and after a multidisciplinary tumor board discussion, we decided to use a modified protocol involving doublet hormonal therapy along with 177Lu-PSMA and radiation therapy to address the PSMA-negative disease. The patient responded well to this treatment, but recurrence was ultimately inevitable. This case represents a typical example of mixed neuroendocrine prostate carcinoma and highlights its resistant phenotype in response to quadruplet therapy.

A simple method to shorten the apparent dead time in the dosimetry of Lu-177 for targeted radionuclide therapy using a gamma camera.

BACKGROUND: The dead-time loss reportedly degrades the accuracy of dosimetry using a gamma camera for targeted radionuclide therapy with Lu-177; therefore, the dead-time loss needs to be corrected. However, the correction is challenging. In this study, we propose a novel and simple method to shorten the apparent dead time rather than correcting it through experiments and Monte Carlo simulations. METHODS: An energy window of 208 keV ± 10 % is generally used for the imaging of Lu-177. Lower-energy gamma photons and X-rays of Lu-177 do not contribute to image formation but lead to dead-time losses. In our proposed method, a thin lead sheet was used to shield gamma photons and X-rays with energies lower than 208 keV, while detecting 208 keV gamma photons that penetrated the thin sheet. We measured and simulated the energy spectra and count rate characteristics of a clinical gamma camera system using a cylindrical phantom filled with a Lu-177 solution. Lead sheets of 1.0- and 0.5-mm thicknesses were used as thin shields, and the dead-time losses in tumour imaging with consumed Lu-177 were simulated. RESULTS: The apparent dead times with lead sheets of 1.0- and 0.5-mm thicknesses and without a lead sheet were 1.7, 1.9, and 5.8 µs for an energy window of 208 keV ± 10 %, respectively. The dead-time losses could be reduced from 10 % to 1.3 % using the 1.0-mm thick lead sheet in the simulated imaging of tumour. CONCLUSION: Our method is promising in clinical situations and studies on Lu-177 dosimetry for tumours.

Diffuse Pneumonitis after Lutetium-177-PSMA-617 Treatment in a Patient with Metastatic Castration-Resistant Prostate Cancer.

We present the case of a patient with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC) who received lutetium Lu-177 vipivotide tetraxetan (also known as 177Lu-PSMA-617) due to progressive disease despite chemotherapy, hormonal therapy and radiation, including palliative mediastinal and central nervous system radiation. He was subsequently hospitalised for worsening acute onset dyspnoea despite clinically responding to therapy. Interval imaging revealed progressive multifocal ground-glass opacities superimposed on a background of underlying peribronchovascular fibrosis. Further workup, including an extensive workup to identify a possible infectious aetiology, ruled out most aetiologies leaving radiation pneumonitis (RP), radiation recall pneumonitis (RRP) and drug-induced pneumonitis as possible diagnoses secondary to 177Lu -PSMA-617. The associated imaging findings of ground-glass opacities and consolidation can be like other aetiologies such as acute infection and subsequently may be treated incorrectly. In the use of theragnostics like 177Lu -PSMA-617, it is fundamental to apply the practices of radioprotection learnt from radiotherapy, as well as to consider prior radiotherapy treatments and their possible side effects when used in conjunction.