Dual-tracer PET/CT protocol with [18F]FDG and [68Ga]Ga-FAPI-46 outperforms single-tracer PET/CT with [18F]FDG in different cancer types, resulting in larger functional and gross tumor volume.

PURPOSE: Fibroblast activation protein (FAP) detected by positron-emission tomography (PET) using fibroblast activation protein inhibitor (FAPI) appears to be a promising target for cancer imaging, staging, and therapy, providing added value and strength as a complement to [18F]fluorodeoxyglucose (FDG) in cancer imaging. We recently introduced a combined single-session/dual-tracer protocol with [18F]FDG and [68Ga]Ga-FAPI for cancer imaging and staging. Malignant tissue visualization and target-to-background uptake ratios (TBRs) as well as functional tumor volume (FTV) and gross tumor volume (GTV) were assessed in the present study with single-tracer [18F]FDG PET/computed tomography (CT) and with dual-tracer [18F]FDG&[68Ga]Ga-FAPI-46 PET/CT. METHODS: A total of 19 patients with head and neck and gastrointestinal cancers received initial [18F]FDG-PET/CT followed by dual-tracer PET/CT after additional injection of [68Ga]Ga-FAPI-46 during the same medical appointment (on average 13.9 ± 12.3 min after injection of [18F]FDG). Two readers visually compared detection rate of malignant tissue, TBR, FTV, and GTV for tumor and metastatic tissue in single- and dual-tracer PET/CT. RESULTS: The diagnostic performance of dual-tracer compared to single-tracer PET/CT was equal in 13 patients and superior in 6 patients. The mean TBRs of tumors and metastases in dual-tracer PET/CTs were mostly higher compared to single-tracer PET/CT using maximal count rates (CRmax). GTV and FTV were significantly larger when measured on dual-tracer compared to single-tracer PET/CT. CONCLUSION: Dual-tracer PET/CT with [18F]FDG and [68Ga]Ga-FAPI-46 showed better visualization due to a generally higher TBR and larger FTV and GTV compared to [18F]FDG-PET/CT in several tumor entities, suggesting that [68Ga]Ga-FAPI-46 provides added value in pretherapeutic staging.

Patterns of PET-positive residual tissue at interim restaging and risk of treatment failure in advanced-stage Hodgkin's lymphoma: an analysis of the randomized phase III HD18 trial by the German Hodgkin Study Group.

PURPOSE: Response-adapted treatment using early interim functional imaging with PET after two cycles of chemotherapy (PET-2) for advanced-stage Hodgkin's lymphoma (AS-HL) is the standard of care in several countries. However, the distribution of residual metabolic disease in PET-2 and the prognostic relevance of multiple involved regions have not been reported to date. METHODS: We retrospectively analyzed data from all PET-2-positive patients included in HD18. Residual tissue was visually compared with reference regions according to the Deauville score (DS). PET-2 positivity was defined as residual tissue with uptake above the liver (DS4). PFS was defined as the time from staging until progression, relapse, or death from any cause, or to the day when information was last received on the patient's disease status and analyzed using Kaplan-Meier and Cox regressions. Comparisons were made between patients with 1-2 and >2 positive regions in PET-2 as well as patients without PET-2-positive regions randomized into comparator arms of HD18. RESULTS: Between 2008 and 2014, 1964 patients with newly diagnosed AS-HL were recruited in HD18 and randomized following their PET-2 scan. Of these, 480 patients had a positive PET-2 and were eligible for this analysis. Upper and lower mediastinum in almost half of all patients: 230 (47.9%) and 195 (40.6%), respectively. 372 (77.5%) of patients have 1-2 positive regions in PET-2. 5y-PFS for patients with 1-2 regions was 91.7% (CI95: 88.7-94.6) vs. 81.8% (CI95: 74.2-90.1) for those with >2 regions with a corresponding hazard ratio (HR) of 2.2 (CI95: 1.2-4.0). Compared with patients without PET-2-positive disease receiving 6-8 cycles of chemotherapy, patients with 1-2 had a higher risk for a PFS event (HR 1.35; CI95 0.81-2.28), but it was not statistically significant (p=0.25). Patients with >2 PET-2-positive lesions had a significantly higher risk (HR 2.95; CI95: 1.62-5.37; p<0.001). CONCLUSION: PET-2-positive residuals of AS-HL are mostly located in the mediastinum, and a majority of patients have few affected regions. The risk of progression was twofold higher in patients with more than two positive regions in PET-2.

Prognostic value of baseline metabolic tumor volume (MTV) for forecasting chemotherapy outcome in early-stage unfavorable Hodgkin lymphoma: Data from the phase III HD17 trial.

OBJECTIVES: The prognostic relevance of metabolic tumor volume (MTV) having recently been demonstrated in patients with early-stage favorable and advanced-stage Hodgkin lymphoma. The current study aimed to assess the potential prognostic value of 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in early-stage unfavorable Hodgkin lymphoma patients treated within the German Hodgkin Study Group HD17 trial. METHODS: 18 F-FDG PET/CT images were available for MTV analysis in 154 cases. We used three different threshold methods (SUV2.5 , SUV4.0 , and SUV41% ) to calculate MTV. Receiver-operating-characteristic analysis was performed to describe the value of these parameters in predicting an adequate therapy response. Therapy response was evaluated as PET negativity after 2 cycles of eBEACOPP followed by 2 cycles of ABVD. RESULTS: All three threshold methods analyzed for MTV showed a positive correlation with the PET response after chemotherapy. Areas under the curve (AUC) were 0.70 (95% CI 0.53-0.87) and 0.65 (0.50-0.80) using the fixed thresholds of SUV4.0 and SUV2.5 , respectively, for MTV- calculation. The calculation of MTV using a relative threshold of SUV41% showed an AUC of 0.63 (0.47-0.79). CONCLUSIONS: MTV does have predictive value after chemotherapy in early-stage unfavorable Hodgkin lymphoma, particularly when the fixed threshold of SUV4.0 is used for MTV calculation. TRIAL REGISTRATION: ClinicalTrials.gov NCT01356680.

Predictive value of baseline metabolic tumor volume in early-stage favorable Hodgkin Lymphoma - Data from the prospective, multicenter phase III HD16 trial.

BACKGROUND: 18F -fluorodeoxyglucose (FDG) positron emission tomography (PET) plays an important role in the staging and response assessment of lymphoma patients. Our aim was to explore the predictive relevance of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) in patients with early stage Hodgkin lymphoma treated within the German Hodgkin Study Group HD16 trial. METHODS: 18F-FDG PET/CT images were available for MTV and TLG analysis in 107 cases from the HD16 trial. We calculated MTV and TLG using three different threshold methods (SUV4.0, SUV41% and SUV140%L), and then performed receiver-operating-characteristic analysis to assess the predictive impact of these parameters in predicting an adequate therapy response with PET negativity after 2 cycles of chemotherapy. RESULTS: All three threshold methods analyzed for MTV and TLG calculation showed a positive correlation with the PET response after 2 cycles chemotherapy. The largest area under the curve (AUC) was observed using the fixed threshold of SUV4.0 for MTV- calculation (AUC 0.69 [95% CI 0.55-0.83]) and for TLG-calculation (AUC 0.69 [0.55-0.82]). The calculations for MTV and TLG with a relative threshold showed a lower AUC: using SUV140%L AUCs of 0.66 [0.53-0.80] for MTV and 0.67 for TLG [0.54-0.81]) were observed, while with SUV41% an AUC of 0.61 [0.45-0.76] for MTV, and an AUC 0.64 [0.49-0.80]) for TLG were seen. CONCLUSIONS: MTV and TLG do have a predictive value after two cycles ABVD in early stage Hodgkin lymphoma, particularly when using the fixed threshold of SUV4.0 for MTV and TLG calculation. TRIAL REGISTRATION: ClinicalTrials.gov NCT00736320 .

PET/CT Reconstruction and Its Impact on [Measures of] Metabolic Tumor Volume.

RATIONALE AND OBJECTIVES: In oncological imaging, the use of metabolic tumor volume (MTV) for further prognostic differentiation and the development of risk adapted strategies appears promising. The aim of this analysis was to evaluate ultra-high definition (UHD) and ordered subset expectation maximization (OSEM) PET/CT reconstructions for their potential impact on different methods of MTV measurement. MATERIALS AND METHODS: We analyzed positron emission tomography combined with computed tomography (PET/CT) scans of 40 Hodgkin lymphoma patients before first-line treatment who had undergone fluorodeoxyglucose (FDG) PET/CT. The MTVs were determined taking an SUV of 4.0 (MTV4.0) as a fixed threshold or 41% of the single hottest voxel (MTV41%) as an adaptive threshold for automated lymphoma delineation in both UHD and OSEM reconstructions. We then compared the absolute and relative differences between MTV4.0 and MTV41% in UHD and OSEM reconstructions. The relative distribution of MTV4.0 and MTV41% in relation to the reconstruction method applied was recorded and respective differences were tested for statistical significance using the paired sample t-test. RESULTS: A comparison of MTV4.0 and MTV41% showed smaller relative and absolute differences in MTV between different reconstruction settings for the MTV4.0 method. Conversely, the absolute as well as the relative differences between MTVs obtained from different reconstructions settings were significantly greater when the MTV41% method was applied (p < 0001). CONCLUSION: MTV4.0 brings higher robustness between different reconstruction settings, while with MTV41% the deviation between volumes obtained with different reconstruction settings is greater. For clinical routine and for multicenter settings, the MTV4.0 therefore appears most promising.

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.

Influences on PET Quantification and Interpretation.

Various factors have been identified that influence quantitative accuracy and image interpretation in positron emission tomography (PET). Through the continuous introduction of new PET technology-both imaging hardware and reconstruction software-into clinical care, we now find ourselves in a transition period in which traditional and new technologies coexist. The effects on the clinical value of PET imaging and its interpretation in routine clinical practice require careful reevaluation. In this review, we provide a comprehensive summary of important factors influencing quantification and interpretation with a focus on recent developments in PET technology. Finally, we discuss the relationship between quantitative accuracy and subjective image interpretation.

Dual-Tracer PET/CT Protocol with [18F]-FDG and [68Ga]Ga-FAPI-46 for Cancer Imaging: A Proof of Concept.

Imaging studies with PET tracers acting as fibroblast activation protein inhibitors (FAPIs) show promising results that could usefully complement [18F]-FDG in cancer imaging. Methods: All patients received [18F]-FDG PET/CT and dual-tracer PET/CT after an additional injection of [68Ga]Ga-FAPI-46 after the [18F]-FDG PET/CT. Two readers visually compared detection rate and analyzed target-to-background ratios for tumor and metastatic tissue in single- and dual-tracer PET/CT. Results: Detection rate in dual-tracer PET/CT was visually as good as that in single-tracer PET/CT in 4 patients and superior in 2 patients, whereas target-to-background ratios were significantly higher in dual-tracer PET/CT. Conclusion: Dual-tracer [18F]-FDG/[68Ga]Ga-FAPI-46 PET/CT within a single session is feasible and has potential. The dual-tracer approach may have superior sensitivity to [18F]-FDG PET/CT alone without compromising individual assessment of either scan.

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.

Avoidance of iodine deficiency/excess during pregnancy in Hashimoto's thyroiditis.

PURPOSE: Hashimoto's thyroiditis is a common disease that also affects pregnant women. We analyzed to what extent the inflammatory process of Hashimoto's thyroiditis changes with iodine prophylaxis in pregnant women. The target for immunologic activity was levels of thyroid antibodies (TPO). METHODS: The data were collected retrospectively from 20 consecutive, pregnant patients who had been diagnosed with Hashimoto's thyroiditis between 01.12.2012 and 01.12.2014 and had received iodine supplementation with 100 µg (n = 1) or 150 µg (n = 19). At least two measurements of TPO antibody levels taken during pregnancy and one after pregnancy were evaluated for each patient in the study group. RESULTS: At the end of pregnancy, the average TPO antibody level for the 20 patients studied was 137 IU/ml (+/-214 IU/ml), the lowest being 16 IU/ml and the highest 1000 IU/ml. Despite iodine prophylaxis, levels of TPO antibodies decreased in 18 patients during pregnancy, falling below the reference value of 35 IU/ml in 5 cases. However, in one patient TPO antibodies increased from 60 IU/ml to 237 IU/ml during pregnancy while in another, levels remained constant at 1000 IU/ml. CONCLUSION: Iodine prophylaxis in pregnant women, taken at a dose of 100 or 150 µg daily was shown to have no negative systemic effects on Hashimoto's thyroiditis in a group of pregnant women with increased TPO levels, and can therefore be recommended for expectant mothers, including those with this disease.

Pentixafor PET/CT for imaging of chemokine receptor 4 expression in esophageal cancer - a first clinical approach.

BACKGROUND: Expression of CXCR4, a chemokine (C-X-C motif) receptor that plays a central role in tumor growth and metastasis of circulating tumor cells, has been described in a variety of solid tumors. A high expression of CXCR4 has a prognostic significance with regard to overall and progression-free survival and offers a starting point for targeted therapies. In this context, [68]Ga-Pentixafor-Positron Emission Tomography/Computer Tomography (PET/CT) offers promising possibility of imaging the CXCR4 expression profile. We set out to compare a [18F] fluorodeoxyglucose (FDG)-PET/CT and a [68Ga]Pentixafor-PET/CT in (re-)staging and radiation planning of patients with localized esophageal cancer. MATERIALS AND METHODS: In this retrospective analysis, ten patients, with adeno- or squamous cell carcinoma of the esophagus (n = 3 and n = 7, respectively), which were scheduled for radio (chemo) therapy, were imaged using both Pentixafor and FDG PET/CT examinations. All lesions were visually rated as Pentixafor and FDG positive or negative. For both tracers, SUVmax was measured all lesions and compared to background. Additionally, immunohistochemistry of CXCR4 was obtained in patients undergoing surgery. RESULTS: FDG-positive tumor-suspicious lesions were detected in all patients and a total of 26 lesions were counted. The lesion-based analysis brought equal status in 14 lesions which were positive for both tracers while five lesions were FDG positive and Pentixafor negative and seven lesions were FDG negative, but Pentixafor positive. Histopathologic correlation was available in seven patients. The CXCR4 expression of four non-pretreated tumour lesion samples was confirmed immunohistochemically. CONCLUSION: Our data shows that additional PET/CT imaging with Pentixafor for imaging the CXCR4 chemokine receptor is feasible but heterogeneous in both newly diagnosed and pretreated recurrent esophageal cancer. In addition, the Pentixafor PET/CT may serve as complementary tool for radiation field expansion in radiooncology.

Early Response to First-Line Anti-PD-1 Treatment in Hodgkin Lymphoma: A PET-Based Analysis from the Prospective, Randomized Phase II NIVAHL Trial.

PURPOSE: A primary analysis of the ongoing NIVAHL trial demonstrated unexpectedly high interim complete response rates to nivolumab-based first-line treatment in early-stage unfavorable Hodgkin lymphoma. However, biomarkers such as metabolic tumor volume (MTV) or total lesion glycolysis (TLG) and their change under treatment (ΔMTV and ΔTLG), measured on PET, might provide additional relevant information for response assessment in this setting. Hence, the current analysis aimed to investigate early response to checkpoint inhibitor therapy beyond conventional criteria. PATIENTS AND METHODS: NIVAHL is a prospective, randomized phase II trial that recruited between April 2017 and October 2018. Patients in arms A and B were assessed for early treatment response after two courses of doxorubicin, vinblastine, and dacarbazine with two concomitant nivolumab infusions per cycle (2 × N-AVD) and 4 × nivolumab, respectively. In the current analysis, we included all 59 individuals with PET images available to the central review panel for quantitative analysis before April 30, 2019. RESULTS: At interim restaging, we determined a mean ΔMTV and ΔTLG of -99.8% each in arm A after 2 × N-AVD, compared with -91.4% and -91.9%, respectively, for treatment group B undergoing 4 × nivolumab. This high decrease in MTV and TLG was observed regardless of the initial lymphoma burden. CONCLUSIONS: Our study showed that nivolumab-based first-line treatment leads to rapid, near-complete reduction of tumor metabolism in early-stage unfavorable Hodgkin lymphoma. Thus, PET-derived biomarkers might allow reduction or even omission of chemotherapy and radiotherapy. Furthermore, MTV and TLG could be also used to optimize immune checkpoint-targeting treatments in other cancers.

Impact of different approaches to calculation of treatment activities on achieved doses in radioiodine therapy of benign thyroid diseases.

PURPOSE: Radioiodine has been used for the treatment of benign thyroid diseases for over 70 years. However, internationally, there is no common standard for pretherapeutic dosimetry to optimally define the individual therapy activity. Here, we analyze how absorbed tissue doses are influenced by different approaches to pretherapeutic activity calculation of varying complexity. METHODS: Pretherapeutic determination of treatment activity was retrospectively recalculated in 666 patients who had undergone radioiodine therapy for benign thyroid diseases (Graves' disease, non-toxic goiter, and uni- and multinodular goiter). Approaches considering none, some, or all of a set of individual factors, including target volume, maximum radioiodine uptake, and effective half-life, were applied. Assuming individually stable radioiodine kinetics, which had been monitored twice a day under therapy, hypothetically achieved tissue doses based on hypothetically administered activities resulting from the different methods of activity calculation were compared to intended target doses. RESULTS: The Marinelli formula yields the smallest deviations of hypothetically achieved doses from intended target doses. Approaches taking individual target volume into consideration perform better than fixed therapy activities, which lead to high variances in achieved doses and high deviations of hypothetically achieved doses from intended target doses. CONCLUSION: Elaborate pretherapeutic dose planning, taking individual radioiodine uptake, half-life, and target volume into consideration, should be used whenever possible. The use of disease-specific fixed activities cannot be recommended. Deviations of achieved tissue doses from target doses can already be significantly lowered by application of volume-adapted treatment activities if more elaborate means are not available.