Citations

AbstractBackgroundFor men with prostate cancer, radiographic progression may occur without a concordant rise in prostate‐specific antigen (PSA). Our study aimed to assess the prevalence of radiographic progression using C‐11 choline positron emission tomography (PET) imaging in patients achieving ultra‐low PSA values and to evaluate clinical outcomes in this patient population.MethodsIn a single institution study, we reviewed the prospectively maintained Mayo Clinic C‐11 Choline PET metastatic prostate cancer registry to identify patients experiencing radiographic disease progression (rDP) on C‐11 choline PET scan while the PSA value was less than 0.5 ng/mL. Disease progression was confirmed by tissue biopsy or response to subsequent therapy. Clinicopathologic variables were abstracted by trained research personnel. Overall survival was estimated using the Kaplan–Meier method. Intergroup differences were assessed using the log‐rank test. A univariate and multivariate Cox regression model was performed to investigate variables associated with poor survival after rDP.ResultsA total of 1323 patients within the registry experienced rDP between 2011 and 2021, including 220 (16.6%) men with rDP occurring at low PSA level. A median (interquartile range [IQR]) of 54.7 (19.7–106.9) months elapsed between the time of prostate cancer diagnosis and low PSA rDP, during which 173 patients (78%) developed castration‐resistant prostate cancer (CRPC). Sites of low PSA rDP included local recurrence (n = 17, 8%), lymph node (n = 90, 41%), bone (n = 94, 43%) and visceral metastases (n = 19, 9%). Biopsy at the time of rDP demonstrated small‐cell or neuroendocrine features in 21% of patients with available tissue. Over a median (IQR) follow‐up of 49.4 (21.3–95.1) months from the time of low PSA rDP, 46% (n = 102) of patients died. Factors associated with poorer survival outcomes include advanced age at rDP, CRPC status, bone and visceral metastasis (p value <0.05). Visceral metastases were associated with decreased overall survival (p = 0.009 by log‐rank) as compared with other sites of rDP.ConclusionsMen with prostate cancer commonly experience metastatic progression at very low or even undetectable PSA levels. Periodic imaging, even at low absolute PSA values, may result in more timely identification of disease progression.

Introduction: As interest in metastasis-directed therapy (MDT) for prostate cancer (PCa) grows, exploring indications and patient selection is increasingly more important. Thus far, few studies have described long-term outcomes after surgical MDT in those with disease recurrence involving the lung. The objective of our study was to compare the cumulative incidence of cancer-related death by treatment modality in men with metachronous pulmonary metastases from PCa. Methods: In a single-institution retrospective study, we identified 75 men from the prospectively maintained Mayo Clinic C-11 Positron Emission Tomography Choline PCa registry with recurrent prostate cancer involving the lung but no other visceral organs. Patients were categorized into 3 groups based on treatment modalities: wedge resection ± hormonal therapy, chemohormonal therapy, and hormonal therapy alone. The risk of cancer-related death after treatment at the time of lung metastases was reported as cumulative incidence estimates. Non–cancer-related deaths were treated as a competing risk of death. A univariate Cox regression model was conducted to assess the impact of treatment modality on the risk of cancer-related death. Results: At the time of lung metastasis, the median age was 69.5 years, and the median (IQR) prostate-specific antigen was 4 (1.3-8.6) ng/ml. Forty-seven patients (62.7%) had hormone-sensitive disease, and 28 patients (37.3%) had hormone-resistant disease. A total of 26 patients (34.7%) were treated with wedge resection ± hormonal therapy, 27 (36%) with chemohormonal therapy, and 22 (29.3%) with hormonal therapy alone. The median (IQR) follow-up time was 50.3 (31.1-78.4) months, and 21 patients (28%) died. Patients who were treated with wedge resection ± hormonal therapy had lower rated of cancer-related death compared with those who received chemohormonal therapy (Hazard Ratio [HR]: 4.14, 95% CI: 1.01-16.96, P = .048) or hormonal therapy alone (HR: 6.37, 95% CI: 1.72-23.54, P = .005). Conclusion: This exploratory analysis supports the safety and feasibility of surgical metastasis-directed therapy in select patients with recurrent prostate cancer involving the lung. Favorable long-term survival provides justification for further evaluation of this approach.

Radiopharmaceuticals are rapidly developing as a field, with the successful use of targeted beta emitters in neuroendocrine tumors and prostate cancer serving as catalysts. Targeted alpha emitters are in current development for several potential oncologic indications. Herein, we review the three most prevalently studied conjugated/chelated alpha emitters (225actinium, 212lead, and 211astatine) and focus on contemporary clinical trials in an effort to more fully appreciate the breadth of the current evaluation. Phase I trials targeting multiple diseases are now underway, and at least one phase III trial (in selected neuroendocrine cancers) is currently in the initial stages of recruitment. Combination trials are now also emerging as alpha emitters are integrated with other therapies in an effort to create solutions for those with advanced cancers. Despite the promise of targeted alpha therapies, many challenges remain. These challenges include the development of reliable supply chains, the need for a better understanding of the relationships between administered dose and absorbed dose in both tissue and tumor and how that predicts outcomes, and the incomplete understanding of potential long-term deleterious effects of the alpha emitters. Progress on multiple fronts is necessary to bring the potential of targeted alpha therapies into the clinic.

e17057 Background: Results from the VISION trial (NCT03511664) led to the approval of lutetium-177 (177Lu)–PSMA-617 for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This trial excluded patients with baseline cytopenias, thus safety in this frequently encountered patient population is unknown. We aimed to use real-world data to describe the tolerability of radioligand therapy in those with poorer bone marrow reserve. Methods: We retrospectively reviewed the records of all patients, who received a first dose of 177Lu–PSMA-617 at Mayo Clinic in the interval of April 26, 2022, to December 1, 2022. Patients were categorized as having poor marrow reserve on the basis of pre-treatment hematologic parameters, including: (1) an anemia cohort with hemoglobin (Hg) less than 9 g/dL, (2) a thrombocytopenia cohort with platelets (Plt) less than 100 x 109/L, (3) a leukopenia cohort with white blood cell count (WBC) less than 2.5 x 109/L, and (4) a multiple cytopenia cohort. These were exclusionary parameters from the VISION trial. Longitudinal laboratory data and clinical outcomes were collected and analyzed using descriptive statistics. Results: At data cutoff, 185 patients had received one or more doses of 177Lu, including 26 (14%) with at least one baseline cytopenia prior to their first cycle of treatment. In total, there were 19 (73%) patients with anemia, 3 (12%) with thrombocytopenia, 2 (8%) with leukopenia, and 2 (8%) with multiple cytopenias at baseline. The median number of cycles received thus far is 3, including 14 (54%) who are still receiving therapy and 12 (46%) who have permanently discontinued treatment. Median longitudinal changes in blood counts for the anemia cohort are presented in Table 1. Reasons for treatment discontinuation include: toxicity (n = 2), disease progression (n = 5), death (n = 4), or other (n = 1). Dose reductions or treatment delays for worsening myelosuppression were utilized in 3 (12%) and 5 (19%) patients, respectively. Transfusions of packed red blood cells or platelets were required for 16 (62%) patients. A total of 6 (23%) received care in the emergency department or were hospitalized. Conclusions: Treatment discontinuation for toxicity was rare among men with mCRPC and baseline cytopenias, while receiving 177Lu; however, these patients have an overall poor prognosis. [Table: see text]

Abstract Purpose: Melanocortin 1 receptor (MC1R) has been shown in animal models to be a target for effective radionuclide therapy. This first-in-human clinical trial studied the safety and biodistribution of two novel MC1R-targeted imaging tracers designed to support the development of MC1R-targeted alpha particle therapy through image-based identification of MC1R and radiation dosimetry. Imaging was compared to MC1R expression by immunohistochemistry (IHC) of subjects’ melanoma tumors. Methods: Subjects with stage IV melanoma were randomized to receive either [203Pb]VMT01 SPECT/CT imaging followed by [68Ga]VMT02 PET/CT imaging approximately 1 month later, or vice versa in a cross-over design during their normal melanoma treatment course. Patient selection included a positive [18F]FDG PET/CT within 30 days of imaging tracer injection. 555 - 925 mBq of [203Pb]VMT01 was injected IV with imaging performed at 1, 4, and 24 hours. 74 - 277 mBq [68Ga]VMT02 was injected IV and imaging performed dynamically up to 1 hour, and at 2 and 3 hours. Due to an interruption in drug supply, only 3 subjects received [203Pb]VMT01 imaging. Key FDG-avid melanoma lesions were marked and presented to three experienced Radiologists serving as blinded reviewers. The blinded reviewers compared [18F]FDG PET/CT to experimental imaging and scored scans and key lesions on multiple metrics. Imaging positivity was defined as tumor uptake and retention of tracer in ≥ 1 melanoma tumors above background liver activity. Melanoma biopsy tissue was obtained and MC1R IHC performed as available. Results: 7 subjects were enrolled; 6 were imaged and 5 had available pathology. 3 of 6 imaged subjects had MC1R positive tumors via experimental imaging tracers. [68Ga]VMT02 PET/CT at 3 hours led to the best tumor to background ratio, and [203Pb]VMT01 SPECT/CT showed tumor retention at 24 hours. 4 of 5 subjects had positive MC1R staining by IHC. Of the 3 subjects with negative imaging, 2 had positive staining by IHC. Of the 3 subjects with positive imaging, 2 had available biopsies and all stained positive for MC1R by IHC. Conclusion: A subgroup of advanced melanoma patients were identified to express MC1R using new MC1R-targeted imaging agents. Full concordance between imaging and IHC of positive scans, but not with negative scans, suggests that IHC is a more sensitive biomarker detection method. Additional testing is needed to establish frequency of positive MC1R imaging in stage IV melanoma and its correlation to histological findings and treatment outcomes. Preferential tumor retention provides proof-of-concept that the MC1R-targeting therapy trial for [212Pb]VMT01 alpha-emitting therapy will deliver localized radiation to high MC1R expressing tumors as screened by [203Pb]VMT01 or [68Ga]VMT02. Imaging quality is sufficient for subject selection and dosimetry but may exclude subjects with MC1R receptor expression only detectable by IHC. Citation Format: Brenna M. Marks, Matthew Block, Geoffrey B. Johnson, Carrie B. Hruska, Mukesh K. Pandey, Andrew Paulsen, Michael K. Schultz, Michael A. McDonald, Edwin A. Sagastume, Frances L. Johnson. MC1R imaging and histology in the targeted imaging of melanoma for alpha-particle radiotherapy (TIMAR1) trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT104.

60 Background: Recent studies, including a post-hoc analysis of the ARCHES trial, highlight radiographic disease progression (rDP) occurring without concordant rise in prostate specific antigen (PSA). In a previous study by our group, we reported that almost 40% of patients on 2nd generation hormone therapy experience rDP with non-rising PSA and have poor survival outcomes. The current analysis more specifically focuses on the subgroup of patients with rDP occurring at low PSA (<0.5 ng/dL) and describes factors associated with poorer survival outcomes in this patient population. Methods: In a single institution study, we reviewed the prospectively maintained Mayo Clinic C-11 Choline PET registry for patients treated between 2011 and 2021, who experienced rDP at low PSA (value < 0.5 ng/mL). Disease progression on C-11 choline PET was confirmed by either tissue biopsy or subsequent response to therapy. We investigated factors associated with poor cancer-specific survival outcomes in univariable and multivariable cox regression analyses. Results: In total, 220 (16%) patients experiencing rDP at low PSA were identified. Median (IQR) age at rDP was 67.91 (61.10 – 73.87) yrs., median (IQR) primary Gleason score was 9 (7-9), and median (IQR) PSA was 0.17 (0 – 0.32) ng/ml. 75% of the patients (n=166) had CRPC disease status at time of rDP. Prior systemic treatments included 2nd generation HT in 18% (n= 40) and chemotherapy in 31% (n=70). Sites of rDP were divided into 7% local (n=16), 42% lymph nodes (n=91), 43% bone (n=95), and 8% visceral metastases (n=18). Over a median follow-up duration of 55 months, 46% of patients (n=100) reported death. Factors associated with poor survival outcomes are demonstrated in the table and include age at rDP, CRPC status, and disease location (P-value <0.05). Conclusions: We found that radiographic disease progression commonly occurs at low PSA (<0.5 ng/mL). CRPC-disease status and the development of visceral metastases are associated with particularly poor survival outcomes. To identify early progression, monitoring with imaging may be warranted, even in the patients with low PSA. [Table: see text]

269 Background: Metastatic visceral involvement in prostate cancer patients conveys a poor prognosis. Survival patterns of site-specific visceral metastasis are poorly understood. Here, we sought to investigate survival patterns in prostate cancer patients according to their first detected site of visceral metastasis. Methods: Retrospectively, we identified 200 patients with visceral metastatic prostate cancer. Patients were divided into three groups according to first site detected with visceral metastases; first-site lung metastases, first-site brain metastases, and first-site liver metastases. Visceral metastases were detected on either conventional imaging (CT/MRI), metabolic imaging (C-11 choline), or PSMA PET-CT scan. Follow up duration of our study was 80 months. Results: Clinicopathological variables are shown. The K-M curve of overall survival of the entire cohort suggests better survival patterns in patients with first-site lung metastases compared to patients with first-site brain or liver metastases (p<0.0001). In subset analysis of patients with CRPC, the K-M curve of overall survival, which demonstrates better survival outcomes in patients with first-site lung metastases in comparison with patients with first-site brain or liver metastases (p<0.0001). Conclusions: Our data suggests that prostate cancer patients with visceral metastatic disease have different survival patterns according to the first site detected with visceral metastasis. In our cohort, patients with first-site lung metastasis demonstrated better survival outcomes than patients with first-site brain or liver metastasis. Further studies are warranted. [Table: see text]

Evaluate the quantitative, subjective (Deauville score [DS]) and reader agreement differences between standard ordered subset expectation maximization (OSEM) and Bayesian penalized likelihood (BPL) positron emission tomography (PET) reconstruction methods. A retrospective review of 104 F-18 fluorodeoxyglucose PET/computed tomography (CT) exams among 52 patients with diffuse large B-cell lymphoma. An unblinded radiologist moderator reviewed both BPL and OSEM PET/CT exams. Four blinded radiologists then reviewed the annotated cases to provide a visual DS for each annotated lesion. Significant (P < .001) differences in BPL and OSEM PET methods were identified with greater standard uptake value (SUV) maximum and SUV mean for BPL. The DS was altered in 25% of cases when BPL and OSEM were reviewed by the same radiologist. Interobserver DS agreement was higher for OSEM (>1 cm lesion = 0.89 and ≤1 cm lesion = 0.84) compared to BPL (>1 cm lesion = 0.85 and ≤1 cm lesion = 0.81). Among the 4 readers, average intraobserver visual DS agreement between OSEM and BPL was 0.67 for lesions >1cm and 0.4 for lesions ≤1 cm. F-18 Fluorodeoxyglucose PET/CT of diffuse large B-cell lymphoma reconstructed with BPL has higher SUV values, altered DSs and reader agreement when compared to OSEM. This report finds volumetric PET measurements such as metabolic tumor volume to be similar between BPL and OSEM PET reconstructions. Efforts such as adoption of European Association Research Ltd accreditation should be made to harmonize PET data with an aim at balancing the need for harmonization and sensitivity for lesion detection.

641 Background: Tumors of neuroendocrine origin are a rare, heterogenous group of neoplasms. Neuroendocrine neoplasms (NENs) are categorized by site of origin, differentiation status, and by grade (Ki-67 expression and/or mitotic rate), with prognostic variability accordingly. These tumors frequently metastasize to bone, with reported incidence between 6-12% by older SSTR imaging. Our study evaluates patients with well-differentiated tumors of neuroendocrine origin to determine the incidence of osseous metastases when evaluated with higher-sensitivity Ga68 DOTATATE PET scans. The study characterizes the clinical features. Methods: This study was performed at a single, 3-site, US tertiary-care institution. IRB approval was obtained. An automated data extraction tool was used to mine the electronic medical record by searching all positron emission tomography (PET) studies for keywords. Identified scans had to include a combination of the following keywords: “Dotatate” AND “met*” or “lesion” AND “bone” or “osse*” or “skel*”. The individual medical records from the generated report were reviewed to include only patients with 1) well-differentiated NETs of GI and pancreatic origin, lung carcinoid, paraganglioma/pheochromocytoma, or other/unknown primary site, and 2) patients with confirmed osseous metastatic disease. Patient data was entered into a database and evaluated in aggregate. Results: 1,948 PET scans of 1,473 patients were extracted from the EMR, from which 424 patients were identified for inclusion; scans were performed between 5/2018 and 5/2021. Calculated incidence of bone metastasis by Ga68 DOTATATE PET was 28.8%. Median age of included population was 61 years (range 14-92), 49.5% being male. Site of origin was 47.2% bowel NET, 18.9% pancreatic NET, 10.8% lung carcinoid, 10.6% paraganglioma/pheochromocytoma, 2.1% other site, and 10.4% unknown primary. Majority of patients were asymptomatic (64.0%), had sclerotic appearance (76.7%), Krenning 4 (71.4%), and >3 sites (68.3%) of osseous disease. 94.6% of the population had disease of the axial skeleton; 65.6% appendicular. Only 57 patients (13.4%) with osseous disease suffered a fracture, despite metastases at high-risk sites. Fracture occurred at disproportionately low rates in NETs originating in bowel (22.8% of fractures), with proportionately higher rates among pancreatic NETS and paragangliomas/pheochromocytomas (31.6% and 22.8%, respectively). Fractures occurred at proportionately higher rates in higher-grade disease compared to low-grade. Conclusions: Osseous metastatic disease in well-differentiated NENs is evident at much higher rates when imaging with Ga68 DOTATATE PET compared with previously reported data. Nevertheless, fracture occurred at a low rate, suggesting that these patients are at a relatively low risk for skeletal-related events.