Hematological and renal toxicity in mice after three cycles of high activity [177Lu]Lu-PSMA-617 with or without human α1-microglobulin.

Radioligand therapy with [177Lu]Lu-PSMA-617 can be used to prolong life and reduce tumor burden in terminally ill castration resistant prostate cancer patients. Still, accumulation in healthy tissue limits the activity that can be administered. Therefore, fractionated therapy is used to lower toxicity. However, there might be a need to reduce toxicity even further with e.g. radioprotectors. The aim of this study was to (i). establish a preclinical mouse model with fractionated high activity therapy of three consecutive doses of 200 MBq [177Lu]Lu-PSMA-617 in which we aimed to (ii). achieve measurable hematotoxicity and nephrotoxicity and to (iii). analyze the potential protective effect of co-injecting recombinant α1-microglobulin (rA1M), a human antioxidant previously shown to have radioprotective effects. In both groups, three cycles resulted in increased albuminuria for each cycle, with large individual variation. Another marker of kidney injury, serum blood urea nitrogen (BUN), was only significantly increased compared to control animals after the third cycle. The number of white and red blood cells decreased significantly and did not reach the levels of control animals during the experiment. rA1M did reduce absorbed dose to kidney but did not show significant protection here, but future studies are warranted due to the recent clinical studies showing a significant renoprotective effect in patients.

Salivary toxicity from PSMA-targeted radiopharmaceuticals: What we have learned and where we are going.

Clinical trials of prostate-specific membrane antigen (PSMA) targeted radiopharmaceuticals have shown encouraging results. Some agents, like lutetium-177 [177Lu]Lu-PSMA-617 ([177Lu]Lu-PSMA-617), are already approved for late line treatment of metastatic castration-resistant prostate cancer (mCRPC). Projections are for continued growth of this treatment modality; [177Lu]Lu-PSMA-617 is being studied both in earlier stages of disease and in combination with other anti-cancer therapies. Further, the drug development pipeline is deep with variations of PSMA-targeting radionuclides, including higher energy alpha particles conjugated to PSMA-honing vectors. It is safe to assume that an increasing number of patients will be exposed to PSMA-targeted radiopharmaceuticals during the course of their cancer treatment. In this setting, it is important to better understand and mitigate the most commonly encountered toxicities. One particularly vexing side effect is xerostomia. In this review, we discuss the scope of the problem, inventories to better characterize and monitor this troublesome side effect, and approaches to preserve salivary function and effectively palliate symptoms. This article aims to serve as a useful reference for prescribers of PSMA-targeted radiopharmaceuticals, while also commenting on areas of missing data and opportunities for future research.

Dual FDG/PSMA PET imaging to predict lesion-based progression of mCRPC during PSMA-RLT.

Candidates for prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) of metastatic castration-resistant prostate cancer (mCRPC) frequently have "mismatch" lesions with pronounced 18-fluorodeoxyglucose ([18F]FDG) but attenuated PSMA ligand uptake on positron emission tomography (PET). However, no quantitative criteria yet exist to identify mismatch lesions and predict their response to RLT. To define such criteria, we retrospectively analyzed 267 randomly-selected glucometabolic mCRPC metastases from 22 patients. On baseline PET, we determined [18F]FDG and [68Ga]Ga-PSMA-11 maximum standardized uptake value (SUVmax), and calculated the [18F]FDG SUVmax/[68Ga]Ga-PSMA-11 SUVmax quotient (FPQ). From follow-up [18F]FDG PET after two lutetium-177-PSMA-617 RLT cycles, we evaluated the treatment response and categorized the lesions into three subgroups (partial remission, stable disease, progression) based on change in [18F]FDG SUVmax. Lastly, we compared the baseline PET variables in progressing versus non-progressing lesions. Variables differing significantly, and a score incorporating them, were assessed via receiver operator characteristic (ROC) curve analysis, regarding ability to predict lesional progression, with area under the curve (AUC) as metric. Cut-offs with optimal sensitivity and specificity were determined using the maximum value of Youden's index. Fifty-one of 267 lesions (19.1%) progressed, 102/267 (38.2%) manifested stable disease, and 114/267 (42.7%) partially responded after two RLT cycles. At baseline, median [68Ga]Ga-PSMA-11 SUVmax was significantly lower (p < 0.001), median FPQ significantly higher (p < 0.001), and median [18F]FDG SUVmax similar in progressing versus non-progressing lesions. [68Ga]Ga-PSMA-11 SUVmax and FPQ showed predictive power regarding progression (AUCs: 0.89, 0.90). An introduced clinical score combining both further improved predictive performance (AUC: 0.94). Optimal cut-offs to foretell progression were: [68Ga]Ga-PSMA-11 SUVmax < 11.09 (88.2% sensitivity, 81.9% specificity), FPQ ≥ 0.92 (90.2% sensitivity, 78.7% specificity), clinical score ≥ 6/9 points (88.2% sensitivity, 87.5% specificity). At baseline, a low [68 Ga]Ga-PSMA-11 SUVmax and a high FPQ predict early lesional progression under RLT; [18F]FDG SUVmax does not. A score combining [68 Ga]Ga-PSMA-11 SUVmax and FPQ predicts early lesional progression even more effectively and might therefore be useful to quantitatively identify mismatch lesions.

Preclinical Evaluation of HER2-Targeting DARPin G3: Impact of Albumin-Binding Domain (ABD) Fusion.

Designed ankyrin repeat protein (DARPin) G3 is an engineered scaffold protein. This small (14.5 kDa) targeting protein binds with high affinity to human epidermal growth factor receptor 2 (HER2). HER2 is overexpressed in several cancers. The use of the DARPin G3 for radionuclide therapy is complicated by its high renal reabsorption after clearance via the glomeruli. We tested the hypothesis that a fusion of the DARPin G3 with an albumin-binding domain (ABD) would prevent rapid renal excretion and high renal reabsorption resulting in better tumour targeting. Two fusion proteins were produced, one with the ABD at the C-terminus (G3-ABD) and another at the N-terminus (ABD-G3). Both variants were labelled with 177Lu. The binding properties of the novel constructs were evaluated in vitro and their biodistribution was compared in mice with implanted human HER2-expressing tumours. Fusion with the ABD increased the retention time of both constructs in blood compared with the non-ABD-fused control. The effect of fusion with the ABD depended strongly on the order of the domains in the constructs, resulting in appreciably better targeting properties of [177Lu]Lu-G3-ABD. Our data suggest that the order of domains is critical for the design of targeting constructs based on scaffold proteins.

Prompt gamma timing for proton range verification with TlBr and TlCl as pure Cherenkov emitters.

Objective. Prompt gamma timing (PGT) uses the detection time of prompt gammas emitted along the range of protons in proton radiotherapy to verify the position of the Bragg peak (BP). Cherenkov detectors offer the possibility of enhanced signal-to-noise ratio (SNR) due to the inherent physics of Cherenkov emission which enhances detection of high energy prompt gamma rays relative to other induced uncorrelated signals. In this work, the PGT technique was applied to 3 semiconductor material slabs that emit only Cherenkov light for use in a full scale system: a 3 × 3 × 20 mm3TlBr, a 12 × 12 × 12 mm3TlBr, and a 5 × 5 × 5 mm3TlCl.Approach. A polymethyl methacrylate (PMMA) target was exposed to a 67.5 MeV, 0.5 nA proton beam and shifted in 3 mm increments at the Crocker nuclear laboratory (CNL) in Davis, CA, USA. A fast plastic scintillator coupled to a photomultiplier tube (PMT) provided the start reference for the proton time of flight. Time of flight (TOF) distributions were generated using this reference and the gamma-ray timestamp in the Cherenkov detector.Main results. The SNR of the proton correlated peaks relative to the background was 20, 29, and 30 for each of the three samples, respectively. The upper limit of the position resolutions with the TlCl sample were 2 mm, 3 mm, and 5 mm for 30k, 10k, and 5k detected events, respectively. The time distribution of events with respect to the reference reproduced with clarity the periodicity of the beam, implying a very high SNR of the Cherenkov crystals to detect prompt gammas. Background presence from the neutron-induced continuum, prompt gammas from deuterium, or positron activation were not observed. Material choice and crystal dimensions did not seem to affect significantly the outcome of the results.Significance. These results show the high SNR of the pure Cherenkov emitters TlBr and TlCl for the detection of prompt gammas in a proton beam with current of clinical significance and their potential for verifying the proton range. The accuracy in determining shifts of the BP was highly dependent on the number of events acquired, therefore, the performance of these detectors are expected to vary with different beam conditions such as current, pulse repetition, and proton bunch width.

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.

Metastatic Lung Adenocarcinoma Received Combined 177 Lu-FAP-2286 Radiation Therapy and Targeted Therapy.

ABSTRACT: A 56-year-old man with metastatic lung adenocarcinoma received combined 177 Lu-FAP-2286 radiation therapy and targeted therapy. After 1 treatment cycle, improvement of symptoms and radiological remission was observed. Moreover, the patient did not report any adverse effects.

Radionuclide Therapy With 177 Lu-PSMA in a Patient With Hepatocellular Carcinoma.

ABSTRACT: A 69-year-old man diagnosed with progressive bone metastatic castration-resistant prostate adenocarcinoma and concurrent alcoholic cirrhosis with multiple hepatocellular carcinoma (HCC) nodules was referred to our nuclear medicine service for 177 Lu-PSMA-617 therapy. The patient's pretreatment screening using 68 Ga-PSMA-11 PET/CT revealed high prostate-specific membrane antigen expression in both prostatic and HCC lesions. The patient underwent 2 doses of 177 Lu-PSMA-617. Subsequent imaging assessments with 68 Ga-PSMA-11 PET/CT and hepatic MRI indicated progressive HCC nodules, while showing a partial response in prostatic bone metastases. Positive clinical and biological responses were observed only in prostatic disease, but not in HCC nodules.

Cutaneous, Subcutaneous, and Bilateral Adrenal Gland Metastases in Progressive Prostate Carcinoma: Theranostic Potential of 68 Ga-PSMA-11 PET/CT Imaging and 177 Lu-PSMA-617 Therapy.

ABSTRACT: Prostate carcinoma (PC) is the second most common malignant tumor in males globally. The metastatic spread of PC usually involves the pelvic and abdominal lymph nodes and the skeletal system. Cutaneous metastases are exceedingly uncommon and typically manifest themselves late in the disease course, considered as ominous sign with limited treatment options and a poor prognosis. We describe a patient wherein 68 Ga-PSMA-11 PET/CT detected multiple uncommon metastatic sites in the cutaneous region of the scrotum, penis, and thigh, as well as in the subcutaneous region of anterior abdominal wall, and in bilateral adrenal glands. These findings served as a theranostic tool for selecting 177 Lu-PSMA-617 treatment for these extremely rare metastatic sites.

[177Lu]Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): an open-label, multicentre, randomised, phase 2 trial.

BACKGROUND: Enzalutamide and lutetium-177 [177Lu]Lu-prostate-specific membrane antigen (PSMA)-617 both improve overall survival in patients with metastatic castration-resistant prostate cancer. Androgen and PSMA receptors have a close intracellular relationship, with data suggesting complementary benefit if targeted concurrently. In this study, we assessed the activity and safety of enzalutamide plus adaptive-dosed [177Lu]Lu-PSMA-617 versus enzalutamide alone as first-line treatment for metastatic castration-resistant prostate cancer. METHODS: ENZA-p was an open-label, randomised, controlled phase 2 trial done at 15 hospitals in Australia. Participants were men aged 18 years or older with metastatic castration-resistant prostate cancer not previously treated with docetaxel or androgen receptor pathway inhibitors for metastatic castration-resistant prostate cancer, gallium-68 [68Ga]Ga-PSMA-PET-CT (PSMA-PET-CT) positive disease, Eastern Cooperative Oncology Group performance status of 0-2, and at least two risk factors for early progression on enzalutamide. Participants were randomly assigned (1:1) by a centralised, web-based system using minimisation with a random component to stratify for study site, disease burden, use of early docetaxel, and previous treatment with abiraterone acetate. Patients were either given oral enzalutamide 160 mg daily alone or with adaptive-dosed (two or four doses) intravenous 7·5 GBq [177Lu]Lu-PSMA-617 every 6-8 weeks dependent on an interim PSMA-PET-CT (week 12). The primary endpoint was prostate-specific antigen (PSA) progression-free survival, defined as the interval from the date of randomisation to the date of first evidence of PSA progression, commencement of non-protocol anticancer therapy, or death. The analysis was done in the intention-to-treat population, using stratified Cox proportional hazards regression. This trial is registered with ClinicalTrials.gov, NCT04419402, and participant follow-up is ongoing. FINDINGS: 162 participants were randomly assigned between Aug 17, 2020, and July 26, 2022. 83 men were assigned to the enzalutamide plus [177Lu]Lu-PSMA-617 group, and 79 were assigned to the enzalutamide group. Median follow-up in this interim analysis was 20 months (IQR 18-21), with 32 (39%) of 83 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 16 (20%) of 79 patients in the enzalutamide group remaining on treatment at the data cutoff date. Median age was 71 years (IQR 64-76). Median PSA progression-free survival was 13·0 months (95% CI 11·0-17·0) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 7·8 months (95% CI 4·3-11·0) in the enzalutamide group (hazard ratio 0·43, 95% CI 0·29-0·63, p<0·0001). The most common adverse events (all grades) were fatigue (61 [75%] of 81 patients), nausea (38 [47%]), and dry mouth (32 [40%]) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and fatigue (55 [70%] of 79), nausea (21 [27%]), and constipation (18 [23%]) in the enzalutamide group. Grade 3-5 adverse events occurred in 32 (40%) of 81 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 32 (41%) of 79 patients in the enzalutamide group. Grade 3 events that occurred only in the enzalutamide plus [177Lu]Lu-PSMA-617 group included anaemia (three [4%] of 81 participants) and decreased platelet count (one [1%] participant). No grade 4 or 5 events were attributed to treatment on central review in either group. INTERPRETATION: The addition of [177Lu]Lu-PSMA-617 to enzalutamide improved PSA progression-free survival providing evidence of enhanced anticancer activity in patients with metastatic castration-resistant prostate cancer with risk factors for early progression on enzalutamide and warrants further evaluation of the combination more broadly in metastatic prostate cancer. FUNDING: Prostate Cancer Research Alliance (Movember and Australian Federal Government), St Vincent's Clinic Foundation, GenesisCare, Roy Morgan Research, and Endocyte (a Novartis company).

Enhanced Theranostic Efficacy of 89Zr and 177Lu-Labeled Aflibercept in Renal Cancer: A Viable Option for Clinical Practice.

Vascular endothelial growth factor (VEGF) targeted therapy serves as an important therapeutic approach for renal cancer, but its clinical effectiveness is unsatisfactory. Moreover, there is a lack of reliable biomarkers for preoperative assessment of tumor VEGF expression. This study aimed to explore the potential for further applications of 177Lu/89Zr-labeled aflibercept (Abe), a VEGF-binding agent, in imaging visualization of VEGF expression and therapy for renal cancer. To determine specificity uptake in renal cancer, BALB/c mice with VEGF-expressing Renca tumor were intravenously injected with [89Zr]Zr-Abe, [177Lu]Lu-Abe, or Cy5.5-Abe and the blocking group was designed as a control group. PET, SPECT, and fluorescence images were acquired, and the biodistribution of [89Zr]Zr-Abe and [177Lu]Lu-Abe was performed. Additionally, the [177Lu]Lu-Abe, [177Lu]Lu-Abe-block, 177Lu only, Abe only, and PBS groups were compared for evaluation of the therapeutic effect. To assess the safety, we monitored and evaluated the body weight, blood biochemistry analysis, and whole blood analysis and major organs were stained with hematoxylin and eosin after [177Lu]Lu-Abe treatment. DOTA-Abe was successfully labeled with 177Lu and Df-Abe with 89Zr in our study. The uptake in tumor of [89Zr]Zr-Abe was significantly higher than that of [89Zr]Zr-Abe-block (P < 0.05) and provided excellent tumor contrast in PET images. [177Lu]Lu-Abe demonstrated promising tumor-specific targeting capability with a high and persistent tumor uptake. The standardized tumor volume of [177Lu]Lu-Abe was significantly smaller than those of other treatment groups (P < 0.05). [177Lu]Lu-Abe also had smaller tumor volumes and reduced expression of VEGF and CD31 compared to those of the control groups. Fluorescence images demonstrate higher tumor uptake in the Cy5.5-Abe group compared to the Cy5.5-Abe-block group (P < 0.05). In conclusion, [89Zr]Zr-Abe enables noninvasive analysis of VEGF expression, serving as a valuable tool for assessing the VEGF-targeted therapy effect. Additionally, all of the findings support the enhanced therapeutic efficacy and safety of [177Lu]Lu-Abe, making it a viable option for clinical practice in renal cancer.

Genomic Correlates of Prostate-Specific Membrane Antigen Expression and Response to 177Lu-PSMA-617: A Retrospective Multicenter Cohort Study.

PURPOSE: While 177Lu-PSMA-617 (LuPSMA) is an effective therapy for many patients with metastatic castration-resistant prostate cancer (mCRPC), biomarkers associated with outcomes are not well defined. We hypothesized that prostate cancer mutational profile may associate with clinical activity of LuPSMA. We devised a study to evaluate associations between mCRPC mutational profile with LuPSMA clinical outcomes. METHODS: This was a multicenter retrospective analysis of patients with mCRPC with next-generation sequencing (NGS) who received LuPSMA. PSA50 response (ie, ≥50% decline in prostate-specific antigen [PSA]) rate, PSA progression free survival (PSA PFS), and overall survival (OS) were compared between genetically defined subgroups. RESULTS: One hundred twenty-six patients with NGS results who received at least one cycle of LuPSMA were identified. The median age was 73 (IQR, 68-78) years, 124 (98.4%) received ≥1 prior androgen receptor-signaling inhibitor, and 121 (96%) received ≥1 taxane-based chemotherapy regimen. Fifty-eight (46%) patients with a DNA damage repair gene mutation (DNA damage response group) and 59 (46.8%) with a mutation in TP53, RB1, or PTEN tumor suppressor genes (TSG group) were identified. After adjusting for relevant confounders, the presence of ≥1 TSG mutation was associated with shorter PSA PFS (hazard ratio [HR], 1.93 [95% CI, 1.05 to 3.54]; P = .034) and OS (HR, 2.65 [95% CI, 1.15 to 6.11]; P = .023). There was improved OS favoring the DNA damage response group (HR, 0.37 [95% CI, 0.14 to 0.97]; P = .044) on multivariable analysis. Univariate analysis of patients with ATM mutations had significantly higher rates of PSA50 response, PSA PFS, and OS. CONCLUSION: Outcomes on LuPSMA varied on the basis of mutational profile. Prospective studies to define the clinical activity of LuPSMA in predefined genomic subgroups are justified.

Targeting Breast Cancer Using 177 Lu-Labeled Trastuzumab and Trastuzumab Fragment : First-in-Human Clinical Experience.

PURPOSE: A monoclonal antibody, trastuzumab, is used for immunotherapy for HER2-expressing breast cancers. Large-sized antibodies demonstrate hepatobiliary clearance and slower pharmacokinetics. A trastuzumab fragment (Fab; 45 kDa) has been generated for theranostic use. PATIENTS AND METHODS: Fab was generated by papain digestion. Trastuzumab and Fab have been radiolabelled with 177 Lu after being conjugated with a bifunctional chelating. The affinity and target specificity were studied in vitro. The first-in-human study was performed. RESULTS: The bifunctional chelating agent conjugation of 1-2 molecules with trastuzumab and Fab was detected at the molar ratio 1:10 in bicarbonate buffer (0.5 M, pH 8) at 37°-40°C. However, 2-3 molecules of bifunctional chelating agent were conjugated when DMSO in PBS (0.1 M, pH 7) was used as a conjugation buffer at a molar ratio of 1:10. The radiolabelling yield of DOTA-conjugated Fab and trastuzumab at pH 5, 45°C to 50°C, with incubation time 2.5-3 hours was 80% and 41.67%, respectively. However, with DOTAGA-conjugated trastuzumab and Fab, the maximum radiolabelling yield at pH 5.5, 37°C, and at 2.5-3 hours was 80.83% and 83%, respectively. The calculated K d of DOTAGA Fab and trastuzumab with HER2-positive SKBR3 cells was 6.85 ± 0.24 × 10 -8 M and 1.71 ± 0.10 × 10 -8 M, respectively. DOTAGA-Fab and trastuzumab showed better radiolabelling yield at mild reaction conditions.177 Lu-DOTAGA-Fab demonstrated higher lesion uptake and lower liver retention as compared with 177 Lu-DOTAGA-trastuzumab. However, 177 Lu-DOTAGA-Fab as compared with 177 Lu-DOTAGA-trastuzumab showed a relatively early washout (5 days) from the lesion. CONCLUSIONS: 177 Lu-DOTAGA-Fab and trastuzumab are suitable for targeting the HER2 receptors.

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.

Advances in Radioligand Theranostics in Oncology.

Theranostics with radioligands (radiotheranostics) has played a pivotal role in oncology. Radiotheranostics explores the molecular targets expressed on tumor cells to target them for imaging and therapy. In this way, radiotheranostics entails non-invasive demonstration of the in vivo expression of a molecular target of interest through imaging followed by the administration of therapeutic radioligand targeting the tumor-expressed molecular target. Therefore, radiotheranostics ensures that only patients with a high likelihood of response are treated with a particular radiotheranostic agent, ensuring the delivery of personalized care to cancer patients. Within the last decades, a couple of radiotheranostics agents, including Lutetium-177 DOTATATE (177Lu-DOTATATE) and Lutetium-177 prostate-specific membrane antigen (177Lu-PSMA), were shown to prolong the survival of cancer patients compared to the current standard of care leading to the regulatory approval of these agents for routine use in oncology care. This recent string of successful approvals has broadened the interest in the development of different radiotheranostic agents and their investigation for clinical translation. In this work, we present an updated appraisal of the literature, reviewing the recent advances in the use of established radiotheranostic agents such as radioiodine for differentiated thyroid carcinoma and Iodine-131-labeled meta-iodobenzylguanidine therapy of tumors of the sympathoadrenal axis as well as the recently approved 177Lu-DOTATATE and 177Lu-PSMA for differentiated neuroendocrine tumors and advanced prostate cancer, respectively. We also discuss the radiotheranostic agents that have been comprehensively characterized in preclinical studies and have shown some clinical evidence supporting their safety and efficacy, especially those targeting fibroblast activation protein (FAP) and chemokine receptor 4 (CXCR4) and those still being investigated in preclinical studies such as those targeting poly (ADP-ribose) polymerase (PARP) and epidermal growth factor receptor 2.

A Case Series of Choroidal and Orbital Neuroendocrine Tumors: Metastasis: Two Patients Treated With Peptide Radionuclide Therapy.

ABSTRACT: Neuroendocrine tumors (NETs) are rare cancers with heterogeneous histologies, response to treatments, and prognoses. Majority of these cancers originate in the gastrointestinal tract and metastasize to the liver. We report the cases of 5 patients with low-grade NET disease with rare metastases to the choroids. Two of the patients were treated with peptide receptor radionuclide therapy (lutetium 177 [ 177 Lu]). This is the first report confirming peptide radionuclide therapy safety in patients with low-grade NET with ocular metastases.

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.

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.