Impact of FAPI-46/dual-tracer PET/CT imaging on radiotherapeutic management in esophageal cancer.

BACKGROUND: Fibroblast activation protein (FAP) is expressed in the tumor microenvironment (TME) of various cancers. In our analysis, we describe the impact of dual-tracer imaging with Gallium-68-radiolabeled inhibitors of FAP (FAPI-46-PET/CT) and fluorodeoxy-D-glucose (FDG-PET/CT) on the radiotherapeutic management of primary esophageal cancer (EC). METHODS: 32 patients with EC, who are scheduled for chemoradiation, received FDG and FAPI-46 PET/CT on the same day (dual-tracer protocol, 71%) or on two separate days (29%) We compared functional tumor volumes (FTVs), gross tumor volumes (GTVs) and tumor stages before and after PET-imaging. Changes in treatment were categorized as "minor" (adaption of radiation field) or "major" (change of treatment regimen). Immunohistochemistry (IHC) staining for FAP was performed in all patients with available tissue. RESULTS: Primary tumor was detected in all FAPI-46/dual-tracer scans and in 30/32 (93%) of FDG scans. Compared to the initial staging CT scan, 12/32 patients (38%) were upstaged in nodal status after the combination of FDG and FAPI-46 PET scans. Two lymph node metastases were only visible in FAPI-46/dual-tracer. New distant metastasis was observed in 2/32 (6%) patients following FAPI-4 -PET/CT. Our findings led to larger RT fields ("minor change") in 5/32 patients (16%) and changed treatment regimen ("major change") in 3/32 patients after FAPI-46/dual-tracer PET/CT. GTVs were larger in FAPI-46/dual-tracer scans compared to FDG-PET/CT (mean 99.0 vs. 80.3 ml, respectively (p < 0.001)) with similar results for nuclear medical FTVs. IHC revealed heterogenous FAP-expression in all specimens (mean H-score: 36.3 (SD 24.6)) without correlation between FAP expression in IHC and FAPI tracer uptake in PET/CT. CONCLUSION: We report first data on the use of PET with FAPI-46 for patients with EC, who are scheduled to receive RT. Tumor uptake was high and not depending on FAP expression in TME. Further, FAPI-46/dual-tracer PET had relevant impact on management in this setting. Our data calls for prospective evaluation of FAPI-46/dual-tracer PET to improve clinical outcomes of EC.

Efficacy and Toxicity of Robotic Stereotactic Body Radiotherapy of Lung Metastases in Patients With Oligometastatic Disease.

BACKGROUND: Stereotactic body radiotherapy is a locally effective treatment for lung metastases in patients with oligometastatic disease, a modern variant of which is robotic (rSBRT). Since it is unclear which factors determine the success of rSBRT, we investigated a cohort of patients with lung metastases treated with rSBRT. PATIENTS AND METHODS: In our retrospective single-center analysis, we included patients with oligometastatic disease of different cancer types who underwent SBRT of lung metastases using an Accuray Cyberknife® device between 2012 and 2019. We evaluated local control rate (LC), progression-free (PFS) and overall (OS) survival, and toxicity. Multivariate analysis was performed to identify independent factors associated with the efficacy and toxicity of rSBRT. RESULTS: A total of 70 lung metastases of 54 patients were evaluated. The 4-year Kaplan-Meier estimate for LC, PFS and OS were 72.0%, 12.4% and 49.7%, respectively. Cox regression showed that LC of metastases of colorectal carcinoma and metastases treated with a biological effective dose at an α/ß-ratio of 10 (BED10) of <100 Gy was significantly worse than for other metastases. Patients suffered from grade I-II pneumonitis in 21.4% of cases treated with rSBRT (grade I: 20.0%; grade II: 1.4%). CONCLUSION: rSBRT is an effective and safe therapy for lung metastases. A BED10 of >100 Gy should be aimed for, especially for potentially radioresistant histologies such as colorectal carcinoma.

First Clinical Experience With [68Ga]Ga-FAPI-46-PET/CT Versus [18F]F-FDG PET/CT for Nodal Staging in Cervical Cancer.

INTRODUCTION: In several solid tumors, fibroblast activation protein (FAP) is overexpressed by cancer-associated fibroblasts in the tumor microenvironment. Preliminary evidence suggests that detection and staging are feasible with PET/CT imaging using [68Ga]-radiolabeled inhibitors of FAP also in cervical cancer (CC). Our study aims to explore the accuracy of [68Ga]Ga-fibroblast activation protein inhibitor (FAPI)-46 PET/CT and [18F]F-FDG PET/CT compared with histopathological results of surgical lymph node (LN) staging before primary chemoradiation. METHODS: Seven consecutive women with treatment-naive and biopsy-proven locally advanced CC underwent both whole-body [68Ga]Ga-FAPI-46- and [18F]F-FDG PET/CT, for imaging nodal staging before systematic laparoscopic lymphadenectomy of the pelvic and para-aortic region. Location and number of suspicious LNs in PET imaging were recorded and compared with the results of histopathological analysis, including immunohistochemical staining for FAP. RESULTS: All 7 patients had focal uptake above background in their tumor lesions in [68Ga]Ga-FAPI-46 PET/CT. [68Ga]Ga-FAPI-46 PET/CT showed a higher tumor-to-background ratio (TBR) in primary tumor as well as in LN metastasis. Median TBRmax values using liver were 32.02 and 5.15 for [68Ga]Ga-FAPI-46 PET/CT and [18F]F-FDG PET/CT, respectively. Median TBRmax using blood pool was 18.45 versus 6.85 for [68Ga]Ga-FAPI-46 PET/CT and [18F]F-FDG PET/CT, respectively. Higher TBR also applies for nodal metastasis: TBRmax was 14.55 versus 1.39 (liver) and 7.97 versus 1.8 (blood pool) for [68Ga]Ga-FAPI-46 PET/CT and [18F]F-FDG PET/CT, respectively. Overall, [68Ga]Ga-FAPI-46 PET/CT detected more lesions compared with [18F]F-FDG PET/CT. Following surgical staging, a total of 5 metastatic LNs could be pathologically confirmed, of which 2 and 4 were positive by [18F]F-FDG PET/CT and [68Ga]Ga-FAPI-46 PET/CT, respectively. CONCLUSION: [68Ga]Ga-FAPI-46 PET/CT seems useful to improve detection of nodal metastasis in patients with CCs. Future studies should aim to compare [68Ga]Ga-FAPI-46 PET/CT to surgical staging of pelvic and para-aortic LNs in patients with locally advanced CC.

Head-to-Head Comparison of [68 Ga]Ga-FAPI-46-PET/CT and [18F]F-FDG-PET/CT for Radiotherapy Planning in Head and Neck Cancer.

INTRODUCTION: In head and neck cancers (HNCs), fibroblast activation protein (FAP) is expressed by cancer-associated fibroblasts (CAFs) in the tumor microenvironment. Preliminary evidence suggests that detection and staging is feasible with positron emission tomography (PET/CT) imaging using [68 Ga]-radiolabeled inhibitors of FAP ([68 Ga]Ga-FAPI-46) in HNCs. This study aims to compare [68 Ga]Ga-FAPI-46 PET/CT and [18F]-fluorodeoxy-D-glucose ([18F]F-FDG) PET/CT with a focus on improved target volume definition and radiotherapy planning in patients with HNC referred for chemoradiation. METHODS: A total of 15 patients with HNCs received both [68 Ga]Ga-FAPI-46 PET/CT and [18F]F-FDG PET/CT with a thermoplastic mask, in addition to initial tumor staging by conventional imaging with contrast-enhanced CT and/or MRI. Mean intervals between FAPI/FDG and FAPI/conventional imaging were 4 ± 20 and 17 ± 18 days, respectively. Location and number of suspicious lesions revealed by the different procedures were recorded. Subsequently, expert-generated gross tumor volumes (GTVs) based on conventional imaging were compared to those based on [18F]F-FDG and [68 Ga]Ga-FAPI-46 PET/CT to measure the impact on subsequent radiation planning. RESULTS: All patients had focal FAPI uptake above background in tumor lesions. Compared to FDG, tumor uptake (median SUVmax 10.2 vs. 7.3, p = 0.008) and tumor-to-background ratios were significantly higher with FAPI than with FDG (SUVmean liver: 9.3 vs. 3.2, p < 0.001; SUVmean bloodpool: 6.9 vs. 4.0, p < 0.001). A total of 49 lesions were recorded. Of these, 40 (82%) were FDG+ and 41 (84%) were FAP+. There were 5 (10%) FAP+/FDG- lesions and 4 (8%) FAP-/FDG+ lesions. Volumetrically, a significant difference was found between the GTVs (median 57.9 ml in the FAPI-GTV, 42.5 ml in the FDG-GTV, compared to 39.2 ml in the conventional-GTV). Disease stage identified by FAPI PET/CT was mostly concordant with FDG PET/CT. Compared to conventional imaging, five patients (33%) were upstaged following imaging with FAPI and FDG PET/CT. CONCLUSION: We demonstrate that [68 Ga]Ga-FAPI-46 -PET/CT is useful for detecting tumor lesions in patients with HNCs. There is now a need for prospective randomized studies to confirm the role of [68 Ga]Ga-FAPI-46 PET/CT in relation to [18F]F-FDG PET/CT in HNCs and to evaluate its impact on clinical outcome.

Knowledge-based intensity-modulated proton planning for gastroesophageal carcinoma.

PURPOSE: To investigate the performance of a narrow-scope knowledge-based RapidPlan (RP) model, for optimisation of intensity-modulated proton therapy (IMPT) plans applied to patients with locally advanced carcinoma in the gastroesophageal junction. METHODS: A cohort of 60 patients was retrospectively selected; 45 were used to 'train' a dose-volume histogram predictive model; the remaining 15 provided independent validation. The performance of the RP model was benchmarked against manual optimisation. Quantitative assessment was based on several dose-volume metrics. RESULTS: Manual and RP-optimised IMPT plans resulted dosimetrically similar, and the planning dose-volume objectives were met for all structures. Concerning the validation set, the comparison of the manual vs RP-based plans, respectively, showed for the target (PTV): the homogeneity index was 6.3 ± 2.2 vs 5.9 ± 1.2, and V98% was 89.3 ± 2.9 vs 91.4 ± 2.2% (this was 97.2 ± 1.9 vs 98.8 ± 1.1 for the CTV). Regarding the organs at risk, no significant differences were reported for the combined lungs, the whole heart, the left anterior descending artery, the kidneys, the spleen and the spinal canal. The D0.1 cm3 for the left ventricle resulted in 40.3 ± 3.4 vs 39.7 ± 4.3 Gy(RBE). The mean dose to the liver was 3.4 ± 1.3 vs 3.6 ± 1.5 Gy(RBE). CONCLUSION: A narrow-scope knowledge-based RP model was trained and validated for IMPT delivery in locally advanced cancer of the gastroesophageal junction. The results demonstrate that RP can create models for effective IMPT. Furthermore, the equivalence between manual interactive and unattended RP-based optimisation could be displayed. The data also showed a high correlation between predicted and achieved doses in support of the valuable predictive power of the RP method.

Circulating CXCL10 in cirrhotic portal hypertension might reflect systemic inflammation and predict ACLF and mortality.

BACKGROUND & AIMS: CXCR% ligands play an important role in hepatic injury, inflammation and fibrosis. While CXCL9 and CXCL11 are associated with survival in patients receiving transjugular intrahepatic portosystemic shunt (TIPS), the role of CXCL10 in severe portal hypertension remains unknown. METHODS: A total of 89 cirrhotic patients were analysed. CXCL10 protein levels were measured in portal and hepatic blood at TIPS insertion and 2 weeks later in 24 patients. CXCL10 and IL8 levels were assessed in portal, hepatic, cubital vein and right atrium blood in a further 25 patients at TIPS insertion. Furthermore, real-time PCR determined hepatic CXCL10-mRNA in 40 cirrhotic patients. RESULTS: Hepatic CXCL10 showed no association with decompensation. By contrast, circulating CXCL10-levels were higher in portal than in hepatic vein blood, suggesting an extrahepatic source of CXCL10 in cirrhosis. However, CXCL10 protein in blood samples from portal, hepatic, cubital veins and right atrium correlated excellently with each other and with IL-8 levels. Higher CXCL10 circulating levels were associated with presence of ascites and higher Child scores. Higher CXCL10 circulating protein levels were associated with acute decompensation, acute-on-chronic liver failure (ACLF) and independently with mortality. Moreover, a decrease in CXCL10 protein levels after TIPS insertion was associated with better survival in each cohort and analysed together. DISCUSSION: Circulating CXCL10 possibly reflects systemic inflammation and it is correlated with acute decompensation, ACLF and complications in patients with severe portal hypertension receiving TIPS. CXCL10 predicts survival in these patients and a decrease in CXCL10 after TIPS may be considered a good prognostic factor.