Somatostatin receptor-directed molecular imaging for therapeutic decision-making in patients with medullary thyroid carcinoma

BACKGROUND: Somatostatin receptor (SSTR) positron emission tomography/computed tomography (PET/CT) is increasingly deployed in the diagnostic algorithm of patients affected with medullary thyroid carcinoma (MTC). We aimed to assess the role of SSTR-PET/CT for therapeutic decision making upon restaging. METHODS: 23 pretreated MTC patients underwent SSTR-PET/CT and were discussed in our interdisciplinary tumor board. Treatment plans were initiated based on scan results. By comparing the therapeutic regimen before and after the scan, we assessed the impact of molecular imaging on therapy decision. SSTR-PET was also compared to CT portion of the SSTR-PET/CT (as part of hybrid imaging). RESULTS: SSTR-PET/CT was superior in 9/23 (39.1%) subjects when compared to conventional CT and equivalent in 14/23 (60.9%). Those findings were further corroborated on a lesion-based level with 27/73 (37%) metastases identified only by functional imaging (equivalent to CT in the remaining 46/73 (63%)). Investigating therapeutic decision making, no change in treatment was initiated after PET/CT in 7/23 (30.4%) patients (tyrosine kinase inhibitor (TKI), 4/7 (57.2%); surveillance, 3/7 (42.8%)). Imaging altered therapy in the remaining 16/23 (69.6%). Treatment prior to PET/CT included surgery in 6/16 (37.5%) cases, followed by TKI in 4/16 (25%), active surveillance in 4/16 (25%), and radiation therapy (RTx) in 2/16 (12.5%) subjects. After SSTR-PET/CT, the therapeutic regimen was changed as follows: In the surgery group, 4/6 (66.7%) patients underwent additional surgery, and 1/6 (16.7%) underwent surveillance and TKI, respectively. In the TKI group, 3/4 (75%) individuals received another TKI and the remaining subject (1/4, 25%) underwent peptide receptor radionuclide therapy. In the surveillance group, 3/4 (75%) underwent surgery (1/4, (25%), RTx). In the RTx group, one patient was switched to TKI and another individual was actively monitored (1/2, 50%, respectively). Moreover, in the 16 patients in whom treatment was changed by molecular imaging, control disease rate was achieved in 12/16 (75%) during follow-up. CONCLUSIONS: In patients with MTC, SSTR-PET/CT was superior to CT alone and provided relevant support in therapeutic decision-making in more than two thirds of cases, with most patients being switched to surgical interventions or systemic treatment with TKI. As such, SSTR-PET/CT can guide the referring treating physician towards disease-directed treatment in various clinical scenarios

Comparison of PET/CT-based eligibility according to VISION and TheraP trial criteria in end-stage prostate cancer patients undergoing radioligand therapy

Background Two randomized clinical trials demonstrated the efficacy of prostate-specific membrane antigen (PSMA) radioligand therapy (PSMA RLT) in metastatic castration-resistant prostate cancer (mCRPC). While the VISION trial used criteria within PSMA PET/CT for inclusion, the TheraP trial used dual tracer imaging including FDG PET/CT. Therefore, we investigated whether the application of the VISION criteria leads to a benefit in overall survival (OS) or progression-free survival (PFS) for men with mCRPC after PSMA RLT. Methods Thirty-five men with mCRPC who had received PSMA RLT as a last-line option and who had undergone pretherapeutic imaging with FDG and [68Ga]Ga-PSMA I&T or [18F]PSMA-1007 were studied. Therapeutic eligibility was retrospectively evaluated using the VISION and TheraP study criteria. Results 26 of 35 (74%) treated patients fulfilled the VISION criteria (= VISION+) and only 17 of 35 (49%) fulfilled the TheraP criteria (= TheraP+). Significantly reduced OS and PFS after PSMA RLT was observed in patients rated VISION− compared to VISION+ (OS: VISION−: 3 vs. VISION+: 12 months, hazard ratio (HR) 3.1, 95% confidence interval (CI) 1.0–9.1, p < 0.01; PFS: VISION−: 1 vs. VISION+: 5 months, HR 2.7, 95% CI 1.0–7.8, p < 0.01). For patients rated TheraP−, no significant difference in OS but in PFS was observed compared to TheraP+ patients (OS: TheraP−: 5.5 vs. TheraP+: 11 months, HR 1.6, 95% CI 0.8–3.3, p = 0.2; PFS: TheraP−: 1 vs. TheraP+: 6 months, HR 2.2, 95% CI 1.0–4.5, p < 0.01). Conclusion Retrospective application of the inclusion criteria of the VISION study leads to a benefit in OS and PFS after PSMA RL, whereas TheraP criteria appear to be too strict in patients with end-stage prostate cancer. Thus, performing PSMA PET/CT including a contrast-enhanced CT as proposed in the VISION trial might be sufficient for treatment eligibility of end-stage prostate cancer patients

Associations between normal organs and tumor burden in patients imaged with fibroblast activation protein inhibitor-directed positron emission tomography

Several radiolabeled fibroblast activation protein targeted inhibitors (FAPI) have been developed for molecular imaging and therapy. A potential correlation of radiotracer uptake in normal organs and extent of tumor burden may have consequences for a theranostic approach using ligands structurally associated with [68Ga]Ga-FAPI, as one may anticipate decreased doses to normal organs in patients with extensive tumor load. In the present proof-of-concept study investigating patients with solid tumors, we aimed to quantitatively determine the normal organ biodistribution of [68Ga]Ga-FAPI-04, depending on the extent of tumor. Except for a trend towards significance in the myocardium, we did not observe any relevant associations between PET-based tumor burden and normal organs. Those preliminary findings may trigger future studies to determine possible implications for theranostic approaches and FAP-directed drugs, as one may expect an unchanged dose for normal organs even in patients with higher tumor load. Abstract (1) Background: We aimed to quantitatively investigate [68Ga]Ga-FAPI-04 uptake in normal organs and to assess a relationship with the extent of FAPI-avid tumor burden. (2) Methods: In this single-center retrospective analysis, thirty-four patients with solid cancers underwent a total of 40 [68Ga]Ga-FAPI-04 PET/CT scans. Mean standardized uptake values (SUVmean) for normal organs were established by placing volumes of interest (VOIs) in the heart, liver, spleen, pancreas, kidneys, and bone marrow. Total tumor burden was determined by manual segmentation of tumor lesions with increased uptake. For tumor burden, quantitative assessment included maximum SUV (SUVmax), tumor volume (TV), and fractional tumor activity (FTA = TV × SUVmean). Associations between uptake in normal organs and tumor burden were investigated by applying Spearman’s rank correlation coefficient. (3) Results: Median SUVmean values were 2.15 in the pancreas (range, 1.05–9.91), 1.42 in the right (range, 0.57–3.06) and 1.41 in the left kidney (range, 0.73–2.97), 1.2 in the heart (range, 0.46–2.59), 0.86 in the spleen (range, 0.55–1.58), 0.65 in the liver (range, 0.31–2.11), and 0.57 in the bone marrow (range, 0.26–0.94). We observed a trend towards significance for uptake in the myocardium and tumor-derived SUVmax (ρ = 0.29, p = 0.07) and TV (ρ = −0.30, p = 0.06). No significant correlation was achieved for any of the other organs: SUVmax (ρ ≤ 0.1, p ≥ 0.42), TV (ρ ≤ 0.11, p ≥ 0.43), and FTA (ρ ≤ 0.14, p ≥ 0.38). In a sub-analysis exclusively investigating patients with high tumor burden, significant correlations of myocardial uptake with tumor SUVmax (ρ = 0.44; p = 0.03) and tumor-derived FTA with liver uptake (ρ = 0.47; p = 0.02) were recorded. (4) Conclusions: In this proof-of-concept study, quantification of [68Ga]Ga-FAPI-04 PET showed no significant correlation between normal organs and tumor burden, except for a trend in the myocardium. Those preliminary findings may trigger future studies to determine possible implications for treatment with radioactive FAP-targeted drugs, as higher tumor load or uptake may not lead to decreased doses in the majority of normal organs

Training on reporting and data system (RADS) for somatostatin-receptor targeted molecular imaging can reduce the test anxiety of inexperienced readers

PURPOSE: For somatostatin receptor (SSTR)-positron emission tomography/computed tomography (PET/CT), a standardized framework termed SSTR-reporting and data system (RADS) has been proposed. We aimed to elucidate the impact of a RADS-focused training on reader’s anxiety to report on SSTR-PET/CT, the motivational beliefs in learning such a system, whether it increases reader’s confidence, and its implementation in clinical routine. PROCEDURES: A 3-day training course focusing on SSTR-RADS was conducted. Self-report questionnaires were handed out prior to the course (Pre) and thereafter (Post). The impact of the training on the following categories was evaluated: (1) test anxiety to report on SSTR-PET/CT, (2) motivational beliefs, (3) increase in reader’s confidence, and (4) clinical implementation. To assess the effect size of the course, Cohen’s d was calculated (small, d = 0.20; large effect, d = 0.80). RESULTS: Of 22 participants, Pre and Post were returned by 21/22 (95.5%). In total, 14/21 (66.7%) were considered inexperienced (IR,  1 year). Applying SSTR-RADS, a large decrease in anxiety to report on SSTR-PET/CT was noted for IR (d =  − 0.74, P = 0.02), but not for ER (d = 0.11, P = 0.78). For the other three categories motivational beliefs, reader’s confidence, and clinical implementation, agreement rates were already high prior to the training and persisted throughout the course (P ≥ 0.21). CONCLUSIONS: A framework-focused reader training can reduce anxiety to report on SSTR-PET/CTs, in particular for inexperienced readers. This may allow for a more widespread adoption of this system, e.g., in multicenter trials for better intra- and interindividual comparison of scan results. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11307-022-01712-6

Predicting microenvironment in CXCR4- and FAP-positive solid tumors - a pan-cancer machine learning workflow for theranostic target structures

Simple Summary Imaging based on positron emission tomography (PET) is a crucial part of up-to-date cancer care. For this purpose, PET employs and marks target structures at the cellular surface. Recently, C-X-C Motif Chemokine Receptor 4 (CXCR4) and Fibroblast Activation Protein Alpha (FAP) emerged as clinically relevant PET targets. However, it is unclear whether high levels of CXCR4 and FAP represent distinct cancer states—especially in solid tumors. Therefore, we established a machine learning model based on 9242 samples from 29 different cancer entities. Our analysis revealed that—in most solid tumors—high levels of CXCR4 were associated with immune cells infiltrating these tumors. Instead, FAP-positive tumors were characterized by high amounts of tumor vessels. Our machine learning approach potentially can identify the Achilles’ heel of tumors in a non-invasive manner—by performing PET without having to obtain tumor tissue beforehand. Abstract (1) Background: C-X-C Motif Chemokine Receptor 4 (CXCR4) and Fibroblast Activation Protein Alpha (FAP) are promising theranostic targets. However, it is unclear whether CXCR4 and FAP positivity mark distinct microenvironments, especially in solid tumors. (2) Methods: Using Random Forest (RF) analysis, we searched for entity-independent mRNA and microRNA signatures related to CXCR4 and FAP overexpression in our pan-cancer cohort from The Cancer Genome Atlas (TCGA) database—representing n = 9242 specimens from 29 tumor entities. CXCR4- and FAP-positive samples were assessed via StringDB cluster analysis, EnrichR, Metascape, and Gene Set Enrichment Analysis (GSEA). Findings were validated via correlation analyses in n = 1541 tumor samples. TIMER2.0 analyzed the association of CXCR4 / FAP expression and infiltration levels of immune-related cells. (3) Results: We identified entity-independent CXCR4 and FAP gene signatures representative for the majority of solid cancers. While CXCR4 positivity marked an immune-related microenvironment, FAP overexpression highlighted an angiogenesis-associated niche. TIMER2.0 analysis confirmed characteristic infiltration levels of CD8+ cells for CXCR4-positive tumors and endothelial cells for FAP-positive tumors. (4) Conclusions: CXCR4- and FAP-directed PET imaging could provide a non-invasive decision aid for entity-agnostic treatment of microenvironment in solid malignancies. Moreover, this machine learning workflow can easily be transferred towards other theranostic targets

Impact of tumor burden on normal organ distribution in patients imaged with CXCR4-targeted [68Ga]Ga-PentixaFor PET/CT

BACKGROUND: CXCR4-directed positron emission tomography/computed tomography (PET/CT) has been used as a diagnostic tool in patients with solid tumors. We aimed to determine a potential correlation between tumor burden and radiotracer accumulation in normal organs. METHODS: Ninety patients with histologically proven solid cancers underwent CXCR4-targeted [(68)Ga]Ga-PentixaFor PET/CT. Volumes of interest (VOIs) were placed in normal organs (heart, liver, spleen, bone marrow, and kidneys) and tumor lesions. Mean standardized uptake values (SUV(mean)) for normal organs were determined. For CXCR4-positive tumor burden, maximum SUV (SUV(max)), tumor volume (TV), and fractional tumor activity (FTA, defined as SUV(mean) x TV), were calculated. We used a Spearman's rank correlation coefficient (ρ) to derive correlative indices between normal organ uptake and tumor burden. RESULTS: Median SUV(mean) in unaffected organs was 5.2 for the spleen (range, 2.44 – 10.55), 3.27 for the kidneys (range, 1.52 – 17.4), followed by bone marrow (1.76, range, 0.84 – 3.98), heart (1.66, range, 0.88 – 2.89), and liver (1.28, range, 0.73 – 2.45). No significant correlation between SUV(max) in tumor lesions (ρ ≤ 0.189, P ≥ 0.07), TV (ρ ≥ -0.204, P ≥ 0.06) or FTA (ρ ≥ -0.142, P ≥ 0.18) with the investigated organs was found. CONCLUSIONS: In patients with solid tumors imaged with [(68)Ga]Ga-PentixaFor PET/CT, no relevant tumor sink effect was noted. This observation may be of relevance for therapies with radioactive and non-radioactive CXCR4-directed drugs, as with increasing tumor burden, the dose to normal organs may remain unchanged

Chemokine receptor–targeted PET/CT provides superior diagnostic performance in newly diagnosed marginal zone lymphoma patients: a head-to-head comparison with [18F]FDG

Background In patients with marginal zone lymphoma (MZL), [18F]FDG PET/CT provided inconsistent diagnostic accuracy. C-X-C motif chemokine receptor 4 (CXCR4) is overexpressed in MZL and thus, may emerge as novel theranostic target. We aimed to evaluate the diagnostic performance of CXCR4-targeting [68Ga]Ga-PentixaFor when compared to [18F]FDG PET/CT in MZL. Methods Thirty-two untreated MZL patients (nodal, n = 17; extranodal, n = 13; splenic, n = 2) received [68Ga]Ga-PentixaFor and [18F]FDG PET/CT within median 2 days. We performed a visual and quantitative analysis of the total lymphoma volume by measuring maximum/peak standardized uptake values (SUVmax/peak), and calculating target-to-background ratios (TBR, defined as lesion-based SUVpeak divided by SUVmean from blood pool). Visual comparisons for both radiotracers were carried out for all target lesions (TL), and quantitative analysis of concordant TL evident on both scans. Last, MZL subtype analyses were also conducted. Results On a patient-based level, [68Ga]Ga-PentixaFor identified MZL manifestations in 32 (100%) subjects (vs. [18F]FDG, 25/32 [78.1%]). Of the 256 identified TL, 127/256 (49.6%) manifestations were evident only on CXCR4-directed imaging, while only 7/256 (2.7%) were identified on [18F]FDG but missed by [68Ga]Ga-PentixaFor. In the remaining 122/256 (47.7%) concordant TL, [68Ga]Ga-PentixaFor consistently provided increased metrics when compared to [18F]FDG: SUVmax, 10.3 (range, 2.53–37.2) vs. 5.72 (2.32–37.0); SUVpeak, 6.23 (1.58–25.7) vs. 3.87 (1.54–27.7); P < 0.01, respectively. Concordant TL TBR on [68Ga]Ga-PentixaFor (median, 3.85; range, 1.05–16.0) was also approximately 1.8-fold higher relative to [18F]FDG (median, 2.08; range, 0.81–28.8; P < 0.01). Those findings on image contrast, however, were driven by nodal MZL (P < 0.01), and just missed significance for extranodal MZL (P = 0.06). Conclusions In newly diagnosed MZL patients, [68Ga]Ga-PentixaFor identified more sites of disease when compared to [18F]FDG, irrespective of MZL subtype. Quantitative PET parameters including TBR were also higher on [68Ga]Ga-PentixaFor PET/CT, suggesting improved diagnostic read-out using chemokine receptor-targeted imaging

In-vivo somatostatin-receptor expression in small cell lung cancer as a prognostic image biomarker and therapeutic target

Background: Given the dismal prognosis of small cell lung cancer (SCLC), novel therapeutic targets are urgently needed. We aimed to evaluate whether SSTR expression, as assessed by positron emission tomography (PET), can be applied as a prognostic image biomarker and determined subjects eligible for peptide receptor radionuclide therapy (PRRT). Methods: A total of 67 patients (26 females; age, 41–80 years) with advanced SCLC underwent SSTR-directed PET/computed tomography (somatostatin receptor imaging, SRI). SRI-avid tumor burden was quantified by maximum standardized uptake values (SUVmax) and tumor-to-liver ratios (T/L) of the most intense SCLC lesion. Scan findings were correlated with progression-free (PFS) and overall survival (OS). In addition, subjects eligible for SSTR-directed radioligand therapy were identified, and treatment outcome and toxicity profile were recorded. Results: On a patient basis, 36/67 (53.7%) subjects presented with mainly SSTR-positive SCLC lesions (>50% lesions positive); in 10/67 patients (14.9%), all lesions were positive. The median SUVmax was found to be 8.5, while the median T/L was 1.12. SRI-uptake was not associated with PFS or OS, respectively (SUVmax vs. PFS, ρ = 0.13 with p = 0.30 and vs. OS, ρ = 0.00 with p = 0.97; T/L vs. PFS, ρ = 0.07 with p = 0.58 and vs. OS, ρ = −0.05 with p = 0.70). PRRT was performed in 14 patients. One patient succumbed to treatment-independent infectious complications immediately after PRRT. In the remaining 13 subjects, disease control was achieved in 5/13 (38.5%) with a single patient achieving a partial response (stable disease in the remainder). In the sub-group of responding patients, PFS and OS were 357 days and 480 days, respectively. Conclusions: SSTR expression as detected by SRI is not predictive of outcome in patients with advanced SCLC. However, it might serve as a therapeutic target in selected patient