Phase 3 multicenter randomized trial of PSMA PET/CT prior to definitive radiation therapy for unfavorable intermediate-risk or high-risk prostate cancer [PSMA dRT]: study protocol.

BACKGROUND: Definitive radiation therapy (dRT) is an effective initial treatment of intermediate-risk (IR) and high-risk (HR) prostate cancer (PCa). PSMA PET/CT is superior to standard of care imaging (CT, MRI, bone scan) for detecting regional and distant metastatic PCa. PSMA PET/CT thus has the potential to guide patient selection and the planning for dRT and improve patient outcomes. METHODS: This is a multicenter randomized phase 3 trial (NCT04457245). We will randomize 312 patients to proceed with standard dRT (control Arm, n = 150), or undergo a PSMA PET/CT scan at the study site (both 18F-DCFPyL and 68Ga-PSMA-11 can be used) prior to dRT planning (intervention arm, n = 162). dRT will be performed at the treating radiation oncologist facility. In the control arm, dRT will be performed as routinely planned. In the intervention arm, the treating radiation oncologist can incorporate PSMA PET/CT findings into the RT planning. Androgen deprivation therapy (ADT) is administered per discretion of the treating radiation oncologist and may be modified as a result of the PSMA PET/CT results. We assume that approximately 8% of subjects randomized to the PSMA PET arm will be found to have M1 disease and thus will be more appropriate candidates for long-term systemic or multimodal therapy, rather than curative intent dRT. PET M1 patients will thus not be included in the primary endpoint analysis. The primary endpoint is the success rate of patients with unfavorable IR and HR PCa after standard dRT versus PSMA PET-based dRT. Secondary Endpoints (whole cohort) include progression free survival (PFS), metastasis-free survival after initiation of RT, overall survival (OS), % of change in initial treatment intent and Safety. DISCUSSION: This is the first randomized phase 3 prospective trial designed to determine whether PSMA PET/CT molecular imaging can improve outcomes in patients with PCa who receive dRT. In this trial the incorporation of PSMA PET/CT may improve the success rate of curative intent radiotherapy in two ways: to optimize patient selection as a biomarker and to personalizes the radiotherapy plan. CLINICAL TRIAL REGISTRATION: UCLA IND#147591 ○ Submission: 02.27.2020 ○ Safe-to-proceed letter issued by FDA: 04.01.2020 UCLA IRB #20-000378 ClinicalTrials.gov Identifier NCT04457245 . Date of Registry: 07.07.2020. Essen EudraCT 2020-003526-23.

Impact of 18F-FDG PET/CT, CT and EBUS/TBNA on preoperative mediastinal nodal staging of NSCLC.

BACKGROUND: Staging of non-small-cell lung cancer (NSCLC) is a multidisciplinary process involving imaging, endoscopic and surgical techniques. This study aims at investigating the diagnostic accuracy of 18F-FDG PET/CT, CT scan, and endobronchial ultrasound/transbronchial needle aspirate (EBUS/TBNA) in preoperative mediastinal lymph nodes (MLNs) staging of NSCLC. METHODS: We identified all patients who were diagnosed with NSCLC at the King Hussein Cancer Center in Amman, Jordan, between July 2011 and December 2017. We collected their relevant clinical, radiological, and histopathological findings. The per-patient analysis was performed on all patients (N = 101) and then on those with histopathological confirmation (N = 57), followed by a per-lymph-node-station basis overall, and then according to distinct N-stage categories. RESULTS: 18F-FDG PET/CT, in comparison to CT, had a better sensitivity (90.5% vs. 75%, p = 0.04) overall and in patients with histopathological confirmation (83.3% vs. 54.6%), and better specificity (60.5% vs. 43.6%, p = 0.01) overall and in patients with histopathological confirmation in MLN staging (60.6% vs. 38.2%). Negative predictive value of mediastinoscopy, EBUS/TBNA, and 18F-FDG PET/CT were (87.1%), (90.91%), and (83.33%) respectively. The overall accuracy was highest for mediastinoscopy (88.6%) and EBUS/TBNA (88.2%), followed by 18F-FDG PET/CT (70.2%). Dividing patients into N1 disease vs. those with N2/N3 disease yielded similar findings. Comparison between 18F-FDG PET/CT and EBUS/TBNA in patients with histopathological confirmation shows 28 correlated true positive and true negative findings with final N-staging. In four patients, 18F-FDG PET/CT detected metastatic MLNs that would have otherwise remained undiscovered by EBUS/TBNA alone. Lymph nodes with a maximal standardized uptake value (SUVmax) more than 3 were significantly more likely to be true-positive. CONCLUSION: Multimodality staging of the MLNs in NSCLC is essential to provide accurate staging and the appropriate treatment. 18F-FDG PET/CT has better overall diagnostic utility when compared to the CT scan. The NPV of 18F-FDG PET/CT in MLNs is reliable and comparable to the NPV of EBUS/TBNA. SUVmax of MLNs can help in predicting metastases, but nevertheless, a positive 18F-FDG PET/CT MLNs particularly if such a result would change the treatment plan, should be verified histopathologically.

Evaluation of improved attenuation correction in whole-body PET/MR on patients with bone metastasis using various radiotracers.

PURPOSE: This study evaluates the quantitative effect of improved MR-based attenuation correction (AC), including bone segmentation and the HUGE method for truncation correction in PET/MR whole-body hybrid imaging specifically of oncologic patients with bone metastasis and using various radiotracers. METHODS: Twenty-three patients that underwent altogether 28 whole-body PET/MR examinations with findings of bone metastasis were included in this study. Different radiotracers (18F-FDG, 68Ga-PSMA, 68Ga-DOTATOC, 124I-MIBG) were injected according to appropriate clinical indications. Each of the 28 whole-body PET datasets was reconstructed three times using AC with (1) standard four-compartment µ-maps (background air, lung, muscle, and soft tissue), (2) five-compartment µ-maps (adding bone), and (3) six-compartment µ-maps (adding bone and HUGE truncation correction). The SUVmax of each detected bone lesion was measured in each reconstruction to evaluate the quantitative impact of improved MR-based AC. Relative difference images between four- and six-compartment µ-maps were calculated. MR-based HUGE truncation correction was compared with the PET-based MLAA truncation correction method in all patients. RESULTS: Overall, 69 bone lesions were detected and evaluated. The mean increase in relative difference over all 69 lesions in SUVmax was 5.4 ± 6.4% when comparing the improved six-compartment AC with the standard four-compartment AC. Maximal relative difference of 28.4% was measured in one lesion. Truncation correction with HUGE worked robust and resulted in realistic body contouring in all 28 exams and for all 4 different radiotracers. Truncation correction with MLAA revealed overestimations of arm tissue volume in all PET/MR exams with 18F-FDG radiotracer and failed in all other exams with radiotracers 68Ga-PSMA, 68Ga-DOTATOC, and 124I- MIBG due to limitations in body contour detection. CONCLUSION: Improved MR-based AC, including bone segmentation and HUGE truncation correction in whole-body PET/MR on patients with bone lesions and using various radiotracers, is important to ensure best possible diagnostic image quality and accurate PET quantification. The HUGE method for truncation correction based on MR worked robust and results in realistic body contouring, independent of the radiotracers used.

Inferior vena cava involvement in children with Wilms tumor.

OBJECTIVES: Retrospective review of children with WT thrombus involving the IVC. METHODS: We reviewed the charts of 123 patients with WT diagnosed between January 2006 and December 2015. Patients with caval tumor thrombus were identified, demographic data, radiological images, extent of thrombus, chemo- and radiotherapy, surgical approach, pathology reports and outcomes were analyzed. RESULTS: IVC involvement was identified in 11 patients (9%). Left-sided tumors were more common (55%). Sensitivity of CT scan in thrombus identification was 64%. Neoadjuvant chemotherapy was the primary mode of treatment with 19% reduction of primary tumor size, thrombus resolution in four and regression in six patients. No thrombus progression was observed. Delayed surgical treatment was either nephro-ureterectomy (nine patients) or partial nephrectomy in patients with bilateral WT (two patients). During surgery, thrombectomy and intimal stripping achieved local control in patients with persistent caval tumor. Cardiopulmonary bypass was not needed in patients with initial atrial involvement (five patients). Despite adherence and invasion of tumor thrombus to IVC wall, only one patient required segmental vein resection. All patients eventually achieved CR, none had local relapse. One patient had lung relapse treated to complete remission. The 3-year EFS is 85.7 ± 13.2% and the 3-year OS is 100%. CONCLUSION: IVC tumor thrombus in patients with WT was managed successfully using preoperative chemotherapy followed by surgery with minimal aggressive approach. Luminal thrombus removal and intimal stripping supplanted by local radio boost when indicated seem to be adequate tools for local control with documented good overall outcomes.

Approach to Non-Neutropenic Fever in Pediatric Oncology Patients-A Single Institution Study.

BACKGROUND: Pediatric oncology patients with fever, even when not neutropenic, are known to be at an increased risk of bloodstream infections. However, there are no standard guidelines for management of fever in non-neutropenic patients, resulting in variability in practice across institutions. PROCEDURE: We retrospectively analyzed the clinical characteristics, management, and outcome of all febrile non-neutropenic episodes in pediatric oncology patients at a single institution over the two-year period 2011-2012, to identify predictors of bloodstream infections. We assessed the efficacy of a uniform approach to outpatient management of a defined subset of patients at low risk of invasive infections. RESULTS: A total of 254 episodes in 83 patients were identified. All patients had implanted central venous catheters (port). Sixty-two episodes (24%) were triaged as high-risk and admitted for inpatient management; five (8%) had positive blood cultures. The remaining 192 episodes were triaged as low risk and managed with once daily outpatient intravenous ceftriaxone; three (1.6%) were associated with bacteremia, and 10% required eventual inpatient management. Of all the factors analyzed, only signs of sepsis (lethargy, chills, hypotension) were associated with positive bloodstream infection. CONCLUSIONS: Treatment of a defined subset of patients with outpatient intravenous ceftriaxone was safe and effective. Signs of sepsis were the only factor significantly associated with bloodstream infection. This study provides a baseline for future prospective studies assessing the safety of withholding antibiotics in this subset of patients.

Shifting the Paradigm: The Transformative Role of Neoadjuvant Therapy in Early Breast Cancer.

The use of neoadjuvant systemic therapy (NST) has become increasingly important in the treatment of breast cancer because of its various advantages. These include the ability to downstage tumors without compromising locoregional control and the potential to obtain valuable information about clinical and biological response to therapy with implications for individual prognoses. Surgical response assessment paves the way for response-adapted therapy, and pathological complete response (pCR; defined as ypT0/is ypN0) serves as an additional endpoint for drug development trials. Recommended NST regimens commonly consist of anthracyclines and taxane, with dose-dense anthracyclines and weekly paclitaxel often preferred, whenever feasible. For patients with human epidermal growth factor receptor-2 (HER2)-positive tumors, dual anti-HER2 therapy (trastuzumab and pertuzumab) is indicated together with NST in case of elevated risk of recurrence. For patients with triple-negative breast cancer (TNBC), adding carboplatin to NST correlates with improved pCR and survival rates, as does the addition of immune checkpoint inhibitors. For hormone receptor (HR)-positive/HER2-negative cancers, emerging data on NST including immune checkpoint inhibitors may elevate the significance of NST in high-risk luminal breast cancer. Here, we present a synthesis of the results from neoadjuvant clinical trials that aim at optimizing treatment options for patients with high-risk breast cancer.

68Ga-Fibroblast Activation Protein Inhibitor PET/CT Improves Detection of Intermediate and Low-Grade Sarcomas and Identifies Candidates for Radiopharmaceutical Therapy.

Fibroblast activation protein-α (FAP) is often highly expressed by sarcoma cells and by sarcoma-associated fibroblasts in the tumor microenvironment. This makes it a promising target for imaging and therapy. The level of FAP expression and the diagnostic value of 68Ga-FAP inhibitor (FAPI) PET for sarcoma subtypes are unknown. We assessed the diagnostic performance and accuracy of 68Ga-FAPI PET in various bone and soft-tissue sarcomas. Potential eligibility for FAP-targeted radiopharmaceutical therapy (FAP-RPT) was evaluated. Methods: This prospective observational trial enrolled 200 patients with bone and soft-tissue sarcoma who underwent 68Ga-FAPI PET/CT and 18F-FDG PET/CT (186/200, or 93%) for staging or restaging. The number of lesions detected and the uptake (SUVmax) of the primary tumor, lymph nodes, and visceral and bone metastases were analyzed. The Wilcoxon test was used for semiquantitative assessment. The association of 68Ga-FAPI uptake intensity, histopathologic grade, and FAP expression in sarcoma biopsy samples was analyzed using Spearman r correlation. The impact of 68Ga-FAPI PET on clinical management was investigated using questionnaires before and after PET/CT. Eligibility for FAP-RPT was defined by an SUVmax greater than 10 for all tumor regions. Results: 68Ga-FAPI uptake was heterogeneous among sarcoma subtypes. The 3 sarcoma entities with the highest uptake (mean SUVmax ± SD) were solitary fibrous tumor (24.7 ± 11.9), undifferentiated pleomorphic sarcoma (18.8 ± 13.1), and leiomyosarcoma (15.2 ± 10.2). Uptake of 68Ga-FAPI versus 18F-FDG was significantly higher in low-grade sarcomas (10.4 ± 8.5 vs. 7.0 ± 4.5, P = 0.01) and in potentially malignant intermediate or unpredictable sarcomas without a World Health Organization grade (not applicable [NA]; 22.3 ± 12.5 vs. 8.5 ± 10.0, P = 0.0004), including solitary fibrous tumor. The accuracy, as well as the detection rates, of 68Ga-FAPI was higher than that of 18F-FDG in low-grade sarcomas (accuracy, 92.2 vs. 80.0) and NA sarcomas (accuracy, 96.9 vs. 81.9). 68Ga-FAPI uptake and the histopathologic FAP expression score (n = 89) were moderately correlated (Spearman r = 0.43, P < 0.0002). Of 138 patients, 62 (45%) with metastatic sarcoma were eligible for FAP-RPT. Conclusion: In patients with low-grade and NA sarcomas, 68Ga-FAPI PET demonstrates uptake, detection rates, and accuracy superior to those of 18F-FDG PET. 68Ga-FAPI PET criteria identified eligibility for FAP-RPT in about half of sarcoma patients.

Randomized Trial of Prostate-Specific Membrane Antigen PET/CT Before Definitive Radiotherapy for Unfavorable Intermediate- and High-Risk Prostate Cancer (PSMA-dRT Trial).

This multicenter randomized phase III trial (NCT04457245) evaluated the effect of performing prostate-specific membrane antigen (PSMA) PET/CT before definitive radiotherapy. Methods: Men with unfavorable intermediate- or high-risk prostate cancer were randomized 1.08:1 between receiving and not receiving a PSMA PET/CT scan before definitive radiotherapy. All other imaging modalities were allowed in the control arm. The primary endpoint was 5-y progression-free survival. Results: Fifty-four men were randomized between November 2020 and December 2021 (PSMA PET/CT, n = 25; control, n = 29). The trial closed early after approval and insurance coverage of PSMA PET/CT. In the PSMA PET/CT arm, 14 patients had localized disease (miT2b-cN0M0), 6 had locally advanced disease (miT3a-bN0M0), 3 had regional metastasis (miN1M0), and 1 had distant metastasis (miM1b). Four patients were upstaged. Conclusion: PSMA PET/CT upstaged 17% of patients, which allowed for more accurate radiotherapy planning. Unfortunately, this trial closed early before completion of target enrollment (54/316, 17%) and was underpowered to assess the effect of PSMA PET/CT on progression-free survival.

Prognostic Implications of 68Ga-FAPI-46 PET/CT-Derived Parameters on Overall Survival in Various Types of Solid Tumors.

Tumoral fibroblast activation protein expression is associated with proliferation and angiogenesis and can be visualized by PET/CT. We examined the prognostic value of [68Ga]Ga-fibroblast activation protein inhibitor (FAPI) (68Ga-FAPI)-46 PET/CT for different tumor entities in patients enrolled in 2 prospective imaging studies (NCT05160051, n = 30; NCT04571086, n = 115). Methods: Within 4 wk, 145 patients underwent 68Ga-FAPI-46 and [18F]FDG (18F-FDG) PET/CT. The association between overall survival (OS) and sex, age, tumor entity, total lesion number, highest SUVmax, and the presence of each nodal, visceral, and bone metastasis was tested using univariate Cox regression analysis. Multivariate analyses were performed for prognostic factors with P values of less than 0.05. Results: In the univariate analysis, shorter OS was associated with total lesion number and the presence of nodal, visceral, and bone metastases on 68Ga-FAPI-46 PET/CT (hazard ratio [HR], 1.06, 2.18, 1.69, and 2.05; P < 0.01, < 0.01, = 0.04, and = 0.02, respectively) and 18F-FDG PET/CT (HR, 1.05, 2.31, 1.76, and 2.30; P < 0.01, < 0.01, = 0.03, and < 0.01, respectively) and with SUVmax on 68Ga-FAPI-46 PET/CT (HR, 1.03; P = 0.03). In the multivariate analysis, total lesion number on 68Ga-FAPI-46 PET/CT was an independent risk factor for shorter OS (HR, 1.05; P = 0.02). In patients with pancreatic cancer, shorter OS was associated with total lesion number on 68Ga-FAPI-46 PET/CT (HR, 1.09; P < 0.01) and bone metastases on 18F-FDG PET/CT (HR, 31.39; P < 0.01) in the univariate analysis and with total lesion number on 68Ga-FAPI-46 PET/CT (HR, 1.07; P = 0.04) in the multivariate analyses. In breast cancer, total lesion number on 68Ga-FAPI-46 PET/CT (HR, 1.07; P = 0.02), as well as bone metastases on 18F-FDG PET/CT (HR, 9.64; P = 0.04), was associated with shorter OS in the univariate analysis. The multivariate analysis did not reveal significant prognostic factors. In thoracic cancer (lung cancer and pleural mesothelioma), the univariate and multivariate analyses did not reveal significant prognostic factors. Conclusion: Disease extent on 68Ga-FAPI-46 PET/CT is a predictor of short OS and may aid in future risk stratification by playing a supplemental role alongside 18F-FDG PET/CT.

Head-to-head comparison of 68 Ga-FAPI-46 PET/CT, 18F-FDG PET/CT, and contrast-enhanced CT for the detection of various tumors.

OBJECTIVE: FAPI-PET/CT exhibits high tumor uptake and low background accumulation, enabling high-sensitivity tumor detection. We compared the diagnostic performance of 68 Ga-FAPI-46 PET/CT plus contrast-enhanced CT (CE-CT), 18F-FDG PET/CT plus CE-CT, and standalone CE-CT in patients with various malignancies. METHODS: 232 patients underwent 68 Ga-FAPI-46 PET/CT,18F-FDG PET/CT, and CE-CT each within 4 weeks. Detection rates were assessed by a blinded reader, with ≥ 2 weeks between scans of the same patient to avoid recall bias. A sub-analysis of diagnostic performance was performed for 490 histopathologically validated lesions. Detection rates were compared using McNemar's test. RESULTS: Lesion-based detection rates in 68 Ga-FAPI-46 PET/CT plus CE-CT, 18F-FDG PET/CT plus CE-CT, and CE-CT alone were 91.2% (1540/1688), 82.5% (1393/1688) and 60.2% (1016/1688). The detection rates were significantly higher for 68 Ga-FAPI-46 PET/CT plus CE-CT than for 18F-FDG PET/CT plus CE-CT (p < 0.02 for primary lesions and p < 0.001 for total, abdominopelvic nodal, liver and other visceral lesions) and CE-CT (p < 0.0001 for total, primary, cervicothoracic nodal, abdominopelvic nodal, liver, other visceral, and bone lesions). In the sub-analysis, sensitivity, specificity, positive and negative predictive value, and accuracy were 61.3%, 96.7%, 81.4%, 91.4% and 90.0% for 68 Ga-FAPI-46 PET/CT plus CE-CT, 57.0%, 95.7%, 75.7%, 90.5% and 88.4% for 18F-FDG PET/CT plus CE-CT, and 51.6%, 97.2%, 81.4%, 89.6% and 88.6% for CECT, respectively. CONCLUSIONS: 68 Ga-FAPI-46 PET/CT plus CE-CT demonstrates a higher tumor detection rate than 18F-FDG PET/CT plus CE-CT and CE-CT in a diverse spectrum of malignancies, especially for primary, abdominopelvic nodal, liver, and other visceral lesions. Further studies on which entities draw particular benefit from 68 Ga-FAPI-46 PET/CT are warranted to aid appropriate diagnostic workup. TRIAL REGISTRATION: A total of N = 232 patients were analyzed. Of these, N = 50 patients were included in a prospective interventional trial (NCT05160051), and N = 175 in a prospective observational trial (NCT04571086) for correlation and clinical follow-up of PET findings; N = 7 patients were analyzed retrospectively.

Diagnostic Accuracy of 68Ga-FAPI Versus 18F-FDG PET in Patients with Various Malignancies.

To assess the diagnostic accuracy of 68Ga-labeled fibroblast activation protein inhibitor (FAPI) and 18F-labeled FDG PET for the detection of various tumors, we performed a head-to-head comparison of both imaging modalities across a range of tumor entities as part of our ongoing 68Ga-FAPI PET observational trial. Methods: The study included 115 patients with 8 tumor entities who received imaging with 68Ga-FAPI for tumor staging or restaging between October 2018 and March 2022. Of those, 103 patients received concomitant imaging with 68Ga-FAPI and 18F-FDG PET and had adequate lesion validation for accuracy analysis. Each scan was evaluated for the detection of primary tumor, lymph nodes, and visceral and bone metastases. True or false positivity and negativity to detected lesions was assigned on the basis of histopathology from biopsies or surgical excision, as well as imaging validation. Results: 68Ga-FAPI PET revealed higher accuracy than 18F-FDG PET in the detection of colorectal cancer (n = 14; per-patient, 85.7% vs. 78.6%; per-region, 95.6% vs. 91.1%) and prostate cancer (n = 22; per-patient, 100% vs. 90.9%; per-region, 96.4% vs. 92.7%). 68Ga-FAPI PET and 18F-FDG PET had comparable per-patient accuracy in detecting breast cancer (n = 16, 100% for both) and head and neck cancers (n = 10, 90% for both modalities). 68Ga-FAPI PET had lower per-patient accuracy than 18F-FDG PET in cancers of the bladder (n = 12, 75% vs. 100%) and kidney (n = 10, 80% vs. 90%), as well as lymphoma (n = 9, 88.9% vs. 100%) and myeloma (n = 10, 80% vs. 90%). Conclusion: 68Ga-FAPI PET demonstrated higher diagnostic accuracy than 18F-FDG PET in the diagnosis of colorectal cancer and prostate cancer, as well as comparable diagnostic performance for cancers of the breast and head and neck. Accuracy and impact on management will be further assessed in an ongoing prospective interventional trial (NCT05160051).

Predictive value of highly sensitive basal versus stimulated thyroglobulin measurement in long-term follow-up of thyroid cancer.

Objective: Recurrence of differentiated thyroid cancer (DTC) is associated with reduced quality of life, and therefore, early identification of patients at risk is urgently needed.Here we investigated the predictive power of various cut-off values of single stimulated thyroglobulin (s-Tg) and single highly sensitive measured, unstimulated thyroglobulin (u-hsTg) measurements close to the end of primary therapy for recurrence-free survival (RFS) in long-term follow-up (>10 years) of patients with DTC. Methods: In DTC patients with adjuvant radioiodine therapy, we assessed retrospectively u-hsTg (6 ± 3 months before s-Tg measurement) and s-Tg measurements (≤24 months after last radioiodine therapy). Positive predictive (PPV)/negative predictive values (NPV) of various cut-off values (s-Tg: 0.5/1.0 ng/mL; u-hsTg: 0.09/0.2 ng/mL) for patient outcomes as well as additional factors associated with disease development were analyzed. Results: In total, 175 patients were retrospectively reviewed (tumor recurrence: n = 14/complete remission: n = 161). Examined cut-off values for s-Tg and u-hsTg showed significant predictive power for RFS (log-rank: all P < 0.001). NPV/PPV for s-Tg were 98.6%/36.4%, respectively (0.5 ng/mL cut-off) and 96.7%/42.9%, respectively (1.0 ng/mL cut-off); those for u-hsTg were 97.3%/35.7%, respectively (0.09 ng/mL cut-off) and 95.2%/85.7%, respectively (0.2 ng/mL cut-off). U-hsTg (P < 0.001) and patient age (P < 0.05) were significantly associated with tumor recurrence. One-third of patients with tumor recurrence in the course initially showed undetectable u-hsTg after completion of primary therapy. Conclusion: With >10 years of follow-up, both s-Tg and u-hsTg have a comparably high predictive power for RFS, while only u-hsTg was significantly associated with a recurrence event.Serial u-hsTg measurements seem warranted since patients with tumor recurrence during follow-up may have an undetectable tumor marker at baseline.

Anti-hormonal maintenance treatment with the CDK4/6 inhibitor ribociclib after 1st line chemotherapy in hormone receptor positive / HER2 negative metastatic breast cancer: A phase II trial (AMICA).

PURPOSE: This phase II study evaluated the impact of adding ribociclib to maintenance endocrine therapy (ET) treatment of physicians' choice following the first palliative chemotherapy in pre- and post-menopausal women with hormone receptor positive (HR+)/human epidermal growth factor 2 negative (HER2-) metastatic breast cancer (mBC). PATIENTS AND METHODS: The initial randomized study design was later amended into a single-arm study, and all subsequent patients received ribociclib and ET. The primary end point was locally assessed progression-free survival (PFS). Secondary end points included overall survival (OS), clinical benefit rate (CBR), safety, compliance, and quality of life (QoL). RESULTS: A total of 43 patients received ribociclib + ET and 10 patients received ET only. Median PFS was 12.4 months [95% CI 8.7-24.4] for patients who received ribociclib + ET and 4.75 months [95% CI 1.0-10.3] for those who received ET only. Median OS was not reached for patients who received ribociclib + ET, and 28 (65.1%) patients experienced clinical benefit [95% CI 49.1-79.0]. For patients who received ribociclib + ET, grade 3-4 hematological adverse events (AEs) occurred in 25 (58.1%) patients, and grade 3-4 non-hematological AEs occurred in 17 (39.5%) patients. During the study, 15 patients died - 14 of whom due to tumor-related reasons, and one patient due to pneumonia, which was not treatment-related. CONCLUSION: The results of the AMICA study show a promising efficacy and safety of maintenance treatment with ribociclib added to ET after at least stable disease following the first metastatic chemotherapy in patients with HR+/HER2-mBC. TRIAL REGISTRATION: Anti-hormonal Therapy With Ribociclib in HR-positive/HER2- Negative Metastatic Breast Cancer (AMICA), NCT03555877, https://clinicaltrials.gov/ct2/show/NCT03555877.

Superior Tumor Detection for 68Ga-FAPI-46 Versus 18F-FDG PET/CT and Conventional CT in Patients with Cholangiocarcinoma.

Management of cholangiocarcinoma is among other factors critically determined by accurate staging. Here, we aimed to assess the accuracy of PET/CT with the novel cancer fibroblast-directed 68Ga-fibroblast activation protein (FAP) inhibitor (FAPI)-46 tracer for cholangiocarcinoma staging and management guidance. Methods: Patients with cholangiocarcinoma from a prospective observational trial were analyzed. 68Ga-FAPI-46 PET/CT detection efficacy was compared with 18F-FDG PET/CT and conventional CT. SUVmax/tumor-to-background ratio (Wilcoxon test) and separately uptake for tumor grade and location (Mann-Whitney U test) were compared. Immunohistochemical FAP and glucose transporter 1 (GLUT1) expression of stromal and cancer cells was analyzed. The impact on therapy management was investigated by pre- and post-PET/CT questionnaires sent to the treating physicians. Results: In total, 10 patients (6 with intrahepatic cholangiocarcinoma and 4 with extrahepatic cholangiocarcinoma; 6 with grade 2 tumor and 4 with grade 3 tumor) underwent 68Ga-FAPI-46 PET/CT and conventional CT; 9 patients underwent additional 18F-FDG PET/CT. Immunohistochemical analysis was performed on the entire central tumor plain in 6 patients. Completed questionnaires were returned in 8 cases. Detection rates for 68Ga-FAPI-46 PET/CT, 18F-FDG PET/CT, and CT were 5, 5, and 5, respectively, for primary tumor; 11, 10, and 3, respectively, for lymph nodes; and 6, 4, and 2, respectively, for distant metastases. 68Ga-FAPI-46 versus 18F-FDG PET/CT SUVmax for primary tumor, lymph nodes, and distant metastases was 14.5 versus 5.2 (P = 0.043), 4.7 versus 6.7 (P = 0.05), and 9.5 versus 5.3 (P = 0.046), respectively, and tumor-to-background ratio (liver) was 12.1 versus 1.9 (P = 0.043) for primary tumor. Grade 3 tumors demonstrated a significantly higher 68Ga-FAPI-46 uptake than grade 2 tumors (SUVmax, 12.6 vs. 6.4; P = 0.009). Immunohistochemical FAP expression was high on tumor stroma (∼90% of cells positive), whereas GLUT1 expression was high on tumor cells (∼80% of cells positive). Overall, average expression intensity was estimated as grade 3 for FAP and grade 2 for GLUT1. Positive 68Ga-FAPI-46 PET findings led to a consequent biopsy workup and diagnosis of cholangiocarcinoma in 1 patient. However, patient treatment was not adjusted on the basis of 68Ga-FAPI-46 PET. Conclusion: 68Ga-FAPI-46 demonstrated superior radiotracer uptake, especially in grade 3 tumors, and lesion detection in patients with cholangiocarcinoma. In line with this result, immunohistochemistry demonstrated high FAP expression on tumor stroma. Accuracy is under investigation in an ongoing investigator-initiated trial.

68Ga-Labeled Fibroblast Activation Protein Inhibitor (68Ga-FAPI) PET for Pancreatic Adenocarcinoma: Data from the 68Ga-FAPI PET Observational Trial.

The fibroblast activation protein (FAP) is highly expressed on carcinoma-associated fibroblasts in the stroma of pancreatic cancer and thus is a promising target for imaging and therapy. Preliminary data on PET imaging with radiolabeled FAP inhibitors (FAPIs) demonstrate superior tumor detection. Here we assess the accuracy of FAP-directed PET in patients with pancreatic cancer. Methods: Of 64 patients with suspected or proven pancreatic cancer, 62 (97%) were included in the data analysis of the 68Ga-FAPI PET observational trial (NCT04571086). All of these patients underwent contrast-enhanced CT, and 38 patients additionally underwent 18F-FDG PET. The primary study endpoint was the association of 68Ga-FAPI PET uptake intensity and histopathologic FAP expression. Secondary endpoints were detection rate, diagnostic performance, interreader reproducibility, and change in management. Datasets were interpreted by 2 masked readers. Results: The primary endpoint was met: The association between 68Ga-FAPI SUVmax and histopathologic FAP expression was significant (Spearman r, 0.48; P = 0.04). For histopathology-validated lesions, 68Ga-FAPI PET showed high sensitivity and positive predictive values (PPVs) on per-patient (sensitivity, 100%; PPV, 96.3%) and per-region (sensitivity, 100%; PPV, 97.0%) bases. In a head-to-head comparison versus 18F-FDG or contrast-enhanced CT, 68Ga-FAPI detected more tumor on a per-lesion (84.7% vs. 46.5% vs. 52.9%), per-patient (97.4% vs. 73.7% vs. 92.1%), or per-region (32.6% vs. 18.8% vs. 23.7%) basis, respectively. 68Ga-FAPI PET readers showed substantial overall agreement on the basis of the Fleiss κ: primary κ, 0.77 (range, 0.66-0.88). Minor and major changes in clinical management occurred in 5 patients (8.4%) after 68Ga-FAPI PET. Conclusion: We confirmed an association of 68Ga-FAPI PET SUVmax and histopathologic FAP expression in pancreatic cancer patients. Additionally, we found high detection rate and diagnostic accuracy, superior to those of 18F-FDG PET/CT. 68Ga-FAPI might become a powerful diagnostic tool for pancreatic cancer work-up.

Fibroblast-Activation Protein PET and Histopathology in a Single-Center Database of 324 Patients and 21 Tumor Entities.

We present an overview of our prospective fibroblast-activation protein inhibitor (FAPI) registry study across a 3-y period, with head-to-head comparison of tumor uptake in 68Ga-FAPI and 18F-FDG PET, as well as FAP immunohistochemistry. Methods: This is an interim analysis of the ongoing 68Ga-FAPI PET prospective observational trial at our department. Patients who underwent clinical imaging with 68Ga-FAPI PET between October 2018 and October 2021 were included. Tracer uptake was quantified by SUVmax for tumor lesions and by SUVmean for normal organs. PET tumor volume (40% isocontour) and tumor-to-background ratios were calculated. Correlation between SUVmax and FAP staining in tissue samples was analyzed. Results: In total, 324 patients with 21 different tumor entities underwent 68Ga-FAPI imaging; 237 patients additionally received 18F-FDG PET. The most common tumor entities were sarcoma (131/324, 40%), pancreatic cancer (67/324, 21%), and primary tumors of the brain (22/324, 7%). The mean primary tumor SUVmax was significantly higher for 68Ga-FAPI than 18F-FDG among pancreatic cancer (13.2 vs. 6.1, P < 0.001) and sarcoma (14.3 vs. 9.4, P < 0.001), and the same was true for mean SUVmax in metastatic lesions of pancreatic cancer (9.4 vs. 5.5, P < 0.001). Mean primary tumor maximum tumor-to-background ratio was significantly higher for 68Ga-FAPI than 18F-FDG across several tumor entities, most prominently pancreatic cancer (14.7 vs. 3.0, P < 0.001) and sarcoma (17.3 vs. 4.7, P < 0.001). Compared with 18F-FDG, 68Ga-FAPI showed superior detection for locoregional disease in sarcoma (52 vs. 48 total regions detected) and for distant metastatic disease in both sarcoma (137 vs. 131) and pancreatic cancer (65 vs. 57), respectively. Among 61 histopathology samples, there was a positive correlation between 68Ga-FAPI SUVmax and overall FAP immunohistochemistry score (r = 0.352, P = 0.005). Conclusion: 68Ga-FAPI demonstrates higher absolute uptake in pancreatic cancer and sarcoma, as well as higher tumor-to-background uptake along with improved tumor detection for pancreatic cancer, sarcoma, and other tumor entities when compared with 18F-FDG. 68Ga-FAPI is a new tool for tumor staging with theranostic potential.

Pitfalls and Common Findings in 68Ga-FAPI PET: A Pictorial Analysis.

Fibroblast activation protein inhibitor (FAPI) PET/CT is a new tool in the diagnostic workup of cancer. With a growing volume of applications, pitfalls and common findings need to be considered for 68Ga-FAPI PET/CT image interpretation. The aim of this study was to summarize common findings and report pitfalls in 68Ga-FAPI PET/CT. Methods: Ninety-one patients underwent whole-body PET/CT with either FAPI-04 (n = 25) or FAPI-46 (n = 66). Findings were rated in a consensus session of 2 experienced readers. Pitfalls and common findings were defined as focal or localized uptake above the background level and categorized as unspecific or nonmalignant and grouped into degenerative, muscular, scarring/wound-healing, uterine, mammary gland, and head-and-neck findings. The frequency of findings was reported on a per-patient and per-group basis, and SUVmax, SUVmean, and SUVpeak were measured. Results: Non-tumor-specific uptake was found in 81.3% of patients. The most frequent finding was uptake in degenerative lesions (51.6%), with a mean SUVmax of 7.7 ± 2.9, and head-and-neck findings (45.1%). Except for the salivary glands, the uptake values did not differ between 10 and 60 min after injection in most findings. Uterine uptake was found in most women (66.7%), with a mean SUVmax of 12.2 ± 7.3, and uptake correlated negatively with age (SUVmax, r = -0.6, P < 0.01; SUVpeak, r = -0.57, P < 0.01; SUVmean, r = -0.58, P < 0.01). Conclusion: Pitfalls include non-tumor-specific 68Ga-FAPI uptake in degenerative lesions, muscle, the head and neck, scarring, the mammary glands, or the uterus. Here, we summarize the findings to help readers avoid common mistakes at centers introducing 68Ga-FAPI PET/CT.

68Ga-FAPI as a Diagnostic Tool in Sarcoma: Data from the 68Ga-FAPI PET Prospective Observational Trial.

Bone and soft-tissue sarcomas express fibroblast activation protein (FAP) on tumor cells and associated fibroblasts. Therefore, FAP is a promising therapeutic and diagnostic target. Novel radiolabeled FAP inhibitors (e.g., 68Ga-FAPI-46) have shown high tumor uptake on PET in sarcoma patients. Here, we report the endpoints of the 68Ga-FAPI PET prospective observational trial. Methods: Forty-seven patients with bone or soft-tissue sarcomas undergoing clinical 68Ga-FAPI PET were eligible for enrollment into the 68Ga-FAPI PET observational trial. Of these patients, 43 also underwent 18F-FDG PET. The primary study endpoint was the association between 68Ga-FAPI PET uptake intensity and histopathologic FAP expression analyzed with Spearman r correlation. Secondary endpoints were detection rate, positive predictive value (PPV), interreader reproducibility, and change in management. Datasets were interpreted by 2 masked readers. Results: The primary endpoint was met, and the association between 68Ga-FAPI PET uptake intensity and histopathologic FAP expression was significant (Spearman r = 0.43; P = 0.03). By histopathologic validation, PPV was 1.00 (95% CI, 0.87-1.00) on a per-patient and 0.97 (95% CI, 0.84-1.00) on a per-region basis. In cases with histopathologic validation, 27 of 28 (96%) confirmed patients and 32 of 34 (94%) confirmed regions were PET-positive, resulting in an SE of 0.96 (95% CI, 0.82-1.00) on a per-patient and 0.94 (95% CI, 0.80-0.99) on a per-region basis. The detection rate on a per-patient basis in 68Ga-FAPI and 18F-FDG PET was 76.6% and 81.4%, respectively. In 8 (18.6%) patients, 68Ga-FAPI PET resulted in an upstaging compared with 18F-FDG PET. 68Ga-FAPI PET readers showed substantial to almost perfect agreement for the defined regions (Fleiss κ: primary κ = 0.78, local nodal κ = 0.54, distant nodal κ = 0.91, lung κ = 0.86, bone κ = 0.69, and other κ = 0.65). Clinical management changed in 13 (30%) patients after 68Ga-FAPI PET. Conclusion: We confirm an association between tumoral 68Ga-FAPI PET uptake intensity and histopathologic FAP expression in sarcoma patients. Further, with masked readings and independent histopathologic validation, 68Ga-FAPI PET had a high PPV and sensitivity for sarcoma staging.

Initial Clinical Experience with 90Y-FAPI-46 Radioligand Therapy for Advanced-Stage Solid Tumors: A Case Series of 9 Patients.

Fibroblast activation protein (FAP) is overexpressed in several solid tumors and therefore represents an attractive target for radiotheranostic applications. Recent investigations demonstrated rapid and high uptake of small-molecule inhibitors of FAP (68Ga-FAPI-46) for PET imaging. Here, we report our initial experience of the feasibility and safety of 90Y-FAPI-46 for radioligand therapy of extensively pretreated patients with solid tumors. Methods: Patients were considered for 90Y-FAPI-46 therapy if they showed both an exhaustion of all approved therapies based on multidisciplinary tumor board decision, and high FAP expression, defined as SUVmax greater than or equal to 10 in more than 50% of all lesions. If tolerated, 90Y-FAPI-46 bremsstrahlung scintigraphy was performed after therapy to confirm systemic distribution and focal tumor uptake, and 90Y-FAPI-46 PET scans were performed at multiple time points to determine absorbed dose. Blood-based dosimetry was used to determine bone marrow absorbed dose. Adverse events were graded using Common Terminology Criteria for Adverse Events (version 5.0). Results: Nine patients either with metastatic soft-tissue or bone sarcoma (n = 6) or with pancreatic cancer (n = 3) were treated between June 2020 and March 2021. Patients received a median of 3.8 GBq (interquartile range [IQR], 3.25-5.40 GBq) for the first cycle, and 3 patients received subsequent cycles with a median of 7.4 GBq (IQR, 7.3-7.5 GBq). Posttreatment 90Y-FAPI-46 bremsstrahlung scintigraphy demonstrated sufficient 90Y-FAPI-46 uptake in tumor lesions in 7 of 9 patients (78%). Mean absorbed dose was 0.52 Gy/GBq (IQR, 0.41-0.65 Gy/GBq) in the kidney, 0.04 Gy/GBq (IQR, 0.03-0.06 Gy/GBq) in bone marrow, and less than 0.26 Gy/GBq in the lung and liver. Measured tumor lesions received up to 2.28 Gy/GBq (median, 1.28 Gy/GBq). New laboratory G3 or G4 toxicities were noted in 4 patients (44%, n = 2 patients with thrombocytopenia only, n = 2 patients with new onset of thrombocytopenia and anemia). Other G3 or G4 laboratory-based adverse events occurred in 2 patients or fewer. No acute toxicities attributed to 90Y-FAPI-46 were noted. Radiographic disease control was noted in 4 patients (50%). Conclusion: FAP-targeted radioligand therapy with 90Y-FAPI-46 was well tolerated, with a low rate of attributable adverse events. Low radiation doses to at-risk organs suggest feasibility of repeat cycles of 90Y-FAPI-46. We observed signs of tumor response, but further studies are warranted to determine efficacy and the toxicity profile in a larger cohort.

Molecular Subgroup Is the Strongest Predictor of Medulloblastoma Outcome in a Resource-Limited Country.

PURPOSE: Medulloblastoma is composed of four clinically and prognostically distinct molecular subgroups (WNT, SHH, group 3, and group 4). However, the clinical implications of these subgroups in the context of the unique challenges of low- to middle-income countries are rarely reported. METHODS: We assembled an institutional cohort of children (3-18 years) diagnosed with medulloblastoma and treated in Jordan between 2003 and 2016. Tumors were subgrouped by NanoString and correlated with clinical and radiologic characteristics. RESULTS: Eighty-eight patients were identified (63% male); median age was 6.9 years (interquartile range 4.8-9.2) and median symptom duration was 6 weeks (interquartile range 4-11). Radiotherapy was implemented as standard-risk in 41 patients (47%) and high-risk in 47 patients (53%). Subgrouping revealed 17 WNT (19%), 22 SHH (25%), 21 group 3 (24%), and 28 group 4 tumors (32%). Median time between craniotomy and radiotherapy was 45 days (17-155); 44% of them > 49 days. Median duration of radiotherapy was 44 days (36-74). Seventy-two patients (82%) received chemotherapy afterward. With a median follow-up of 4.6 years (0.2-14.9), 5-year progression-free survival (PFS) and overall survival were 73.5% and 69.4%, respectively, with no statistically significant survival difference between standard-risk and high-risk patients. Metastasis was significant for overall survival (P = .011). Patients with SHH and group 4 tumors had very good PFS (83.4% and 87.0%, respectively) and those with group 3 tumors had dismal outcomes (PFS 44.9%), whereas WNT tumors had less-than expected PFS (70.5%). PFS was statistically significant in patients with nonmetastatic tumors receiving radiotherapy ≤ 49 days (P = .011), particularly group 3 tumors. CONCLUSION: Patients with SHH and group 4 medulloblastoma had excellent survival comparable with high-income countries. Compliance with treatment protocols and avoiding radiotherapy delays are important in achieving adequate survival in low- to middle-income country settings. Subgroup-driven treatment protocols should be considered in countries with limited resources.