Interobserver variability in interim PET assessment in Hodgkin lymphoma-reasons and solutions.

INTRODUCTION: Interim PET (iPET) assessment is important for response adaptation in Hodgkin lymphoma (HL). The current standard for iPET assessment is the Deauville score (DS). The aim of our study was to evaluate the causes of interobserver variability in assigning the DS for iPET in HL patients and to make suggestions for improvement. METHODS: All evaluable iPET scans from the RAPID study were re-read by two nuclear physicians, blinded to the results and patient outcomes in the RAPID trial. The iPET scans were assessed visually according to the DS and, thereafter, quantified using the qPET method. All discrepancies of more than one DS level were re-evaluated by both readers to find the reason for the discordant result. RESULTS: In 249/441 iPET scans (56%) a concordant visual DS result was achieved. A "minor discrepancy" of one DS level occurred in 144 scans (33%) and a "major discrepancy" of more than one DS level in 48 scans (11%). The main causes for major discrepancies were 1) different interpretation of PET-positive lymph nodes-malignant vs. inflammatory; 2) lesions missed by one reader and 3) different assessment of lesions in activated brown fat tissue. In 51% of the minor discrepancy scans with residual lymphoma uptake, additional quantification resulted in a concordant quantitative DS result. CONCLUSION: Discordant visual DS assessment occurred in 44% of all iPET scans. The main reason for major discrepancies was the different interpretation of PET positive lymph nodes as malignant or inflammatory. Disagreements in evaluation of the hottest residual lymphoma lesion can be solved by the use of semi-quantitative assessment.

A Phase II, Open-label study to assess safety and management change using 68Ga-THP PSMA PET/CT in patients with high risk primary prostate cancer or biochemical recurrence after radical treatment: The PRONOUNCED study.

Objectives: To assess the safety and clinical impact of a novel, kit-based formulation of 68Ga-THP PSMA positron emission tomography/computed tomography (PET/CT) when used to guide the management of patients with prostate cancer (PCa). Methods: Patients were prospectively recruited in to one of: Group A: high-risk untreated prostate cancer; Gleason score >4+3, or PSA >20 ng/mL or clinical stage >T2c. Group B: biochemical recurrence (BCR) and eligible for salvage treatment after radical prostatectomy with two consecutive rises in prostate specific antigen (PSA) with a three month interval in between reads and final PSA >0.1 ng/mL or a PSA level >0.5 ng/mL. Group C: BCR with radical curative radiotherapy or brachytherapy at least three months prior to enrolment, and an increase in PSA level >2.0 ng/mL above the nadir level after radiotherapy or brachytherapy. Patients underwent evaluation with PET/CT 60 minutes following intravenous administration of 160±30 MBq of 68Ga-THP PSMA. Safety was assessed by means including vital signs, cardiovascular profile, serum haematology, biochemistry, urinalysis, PSA, and Adverse Events (AEs). A change in management was reported when the predefined clinical management of the patient altered as a result of 68Ga-THP PSMA PET/CT findings. Results: Forty-nine patients were evaluated with PET/CT; 20 in Group A, 21 in Group B and 8 in Group C. No patients experienced serious AEs discontinued the study due to AEs, or died during the study. Two patients had Treatment Emergent AEs attributed to 68Ga-THP-PSMA (pruritus in one patient and intravenous catheter site rash in another). Management change secondary to PET/CT occurred in 42.9% of all patients; 30% in Group A, 42.9% in Group B and 75% in Group C. Conclusion: 68Ga-THP PSMA was safe to use with no serious AE and no AE resulting in withdrawal from the study. 68Ga-THP PSMA PET/CT changed the management of patients in 42.9% of the study population, comparable to studies using other PSMA tracers. These data form the basis of a planned Phase III study of 68Ga-THP PSMA in patients with prostate cancer.

Quantitative assessment of interim PET in Hodgkin lymphoma: An evaluation of the qPET method in adult patients in the RAPID trial.

AIM: qPET is a quantitative method used to assess FDG-PET response in lymphoma. qPET was developed using 898 scans from children with Hodgkin Lymphoma (HL) in the EuroNet-PHL-C1 (C1) trial. The aim of this study was to determine if qPET could be applied as an alternative response method in adults in the RAPID trial. METHODS: PET-CT scans performed after 3 cycles of ABVD in RAPID were re-evaluated by an independent reader, blinded to PET results and outcome in RAPID. All initially involved regions were assessed visually and by qPET. The distribution of qPET measurements was compared for RAPID and C1 patients. Previously published qPET thresholds corresponding to visual DS (vDS) of 1-5 in C1 were used to derive quantitative DS (qDS) for RAPID patients. RESULTS: PET-CT scans were available for 450 patients from RAPID. vDS were 1 (171 scans), 2 (153 scans), 3 (72 scans), 4 (31 scans) and 5 (23 scans) respectively. The distribution of qPET values was similar to C1 patients, with a unimodal 'normal' distribution and a long tail to the right, suggestive of favorable response in the majority and less favorable response in the minority with outlying values. qPET thresholds from C1 applied in RAPID patients gave 86% concordance for vDS and qDS. There was 97% concordance for complete metabolic response (CMR; DS 1-3) vs. no-CMR using the Lugano classification. CONCLUSION: qPET which was developed in pediatric patients receiving more intensive OEPA chemotherapy, was a suitable quantitative method for assessing response in adult patients treated with ABVD in a response-adapted setting in the RAPID trial.

Effect of 18F-Fluciclovine Positron Emission Tomography on the Management of Patients With Recurrence of Prostate Cancer: Results From the FALCON Trial.

PURPOSE: Early and accurate localization of lesions in patients with biochemical recurrence (BCR) of prostate cancer may guide salvage therapy decisions. The present study, 18F-Fluciclovine PET/CT in biochemicAL reCurrence Of Prostate caNcer (FALCON; NCT02578940), aimed to evaluate the effect of 18F-fluciclovine on management of men with BCR of prostate cancer. METHODS AND MATERIALS: Men with a first episode of BCR after curative-intent primary therapy were enrolled at 6 UK sites. Patients underwent 18F-fluciclovine positron emission tomography/computed tomography (PET/CT) according to standardized procedures. Clinicians documented management plans before and after scanning, recording changes to treatment modality as major and changes within a modality as other. The primary outcome measure was record of a revised management plan postscan. Secondary endpoints were evaluation of optimal prostate specific antigen (PSA) threshold for detection, salvage treatment outcome assessment based on 18F-fluciclovine-involvement, and safety. RESULTS: 18F-Fluciclovine was well tolerated in the 104 scanned patients (median PSA = 0.79 ng/mL). Lesions were detected in 58 out of 104 (56%) patients. Detection was broadly proportional to PSA level; ≤1 ng/mL, 1 out of 3 of scans were positive, and 93% scans were positive at PSA >2.0 ng/mL. Sixty-six (64%) patients had a postscan management change (80% after a positive result). Major changes (43 out of 66; 65%) were salvage or systemic therapy to watchful waiting (16 out of 66; 24%); salvage therapy to systemic therapy (16 out of 66; 24%); and alternative changes to treatment modality (11 out of 66, 17%). The remaining 23 out of 66 (35%) management changes were modifications of the prescan plan: most (22 out of 66; 33%) were adjustments to planned brachytherapy/radiation therapy to include a 18F-fluciclovine-guided boost. Where 18F-fluciclovine guided salvage therapy, the PSA response rate was higher than when 18F-fluciclovine was not involved (15 out of 17 [88%] vs 28 out of 39 [72%]). CONCLUSIONS: 18F-Fluciclovine PET/CT located recurrence in the majority of men with BCR, frequently resulting in major management plan changes. Incorporating 18F-fluciclovine PET/CT into treatment planning may optimize targeting of recurrence sites and avoid futile salvage therapy.

The management impact of 68gallium-tris(hydroxypyridinone) prostate-specific membrane antigen (68Ga-THP-PSMA) PET-CT imaging for high-risk and biochemically recurrent prostate cancer.

PURPOSE: To determine the impact on clinical management of patients with high-risk (HR) prostate cancer at diagnosis and patients with biochemical recurrence (BCR) using a new kit form of 68Ga-prostate-specific membrane antigen (PSMA), namely tris(hydroxypyridinone) (THP)-PSMA, with positron emission tomography-computed tomography (PET-CT). METHODS: One hundred eighteen consecutive patients (50 HR, 68 BCR) had management plans documented at a multidisciplinary meeting before 68Ga-THP-PSMA PET-CT. Patients underwent PET-CT scans 60-min post-injection of 68Ga-THP-PSMA (mean 159 ± 21.2 MBq). Post-scan management plans, Gleason score, prostate-specific antigen (PSA) and PSA doubling time (PSAdt) were recorded. RESULTS: HR group: 12/50 (24%) patients had management changed (9 inter-modality, 3 intra-modality). Patients with PSA < 20 µg/L had more frequent management changes (9/26, 34.6%) compared with PSA > 20 µg/L (3/24, 12.5%). Gleason scores > 8 were associated with detection of more nodal (4/16, 25% vs 5/31, 16.1%) and bone (2/16, 12.5% vs 2/31, 6.5%) metastases. BCR group: Clinical management changed in 23/68 (34%) patients (17 inter-modality, 6 intra-modality). Forty out of 68 (59%) scans were positive. Positivity rate increased with PSA level (PSA < 0.5 µg/L, 0%; PSA 0.5-1.0 µg/L, 35%; PSA 1.0-5.0 µg/L, 69%; PSA 5.0-10.0 µg/L, 91%), PSAdt of < 6 months (56% vs 45.7%) and Gleason score > 8 (78.9% vs 51.2%). CONCLUSIONS: 68Ga-THP-PSMA PET-CT influences clinical management in significant numbers of patient with HR prostate cancer pre-radical treatment and is associated with PSA. Management change also occurs in patients with BCR and is associated with PSA and Gleason score, despite lower scan positivity rates at low PSA levels < 0.5 µg/L.

UK guidelines on 18F-fluciclovine PET/CT in prostate cancer imaging.

The purpose of these guidelines is to assist specialists in Nuclear Medicine and Radionuclide Radiology in recommending, performing, interpreting and reporting F-fluciclovine PET/computed tomography. It should be recognised that adherence to the guidance in this document will not assure an accurate diagnosis or a successful outcome. These guidelines will assist individual departments in the formulation of their own local protocols. The guidelines apply to studies on adults. All that should be expected is that the practitioner will follow a reasonable course of action based on current knowledge, available resources and the needs of the patient in order to deliver effective and safe medical care.

Characterisation of malignant peripheral nerve sheath tumours in neurofibromatosis-1 using heterogeneity analysis of 18F-FDG PET.

PURPOSE: Measurement of heterogeneity in 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) images is reported to improve tumour phenotyping and response assessment in a number of cancers. We aimed to determine whether measurements of 18F-FDG heterogeneity could improve differentiation of benign symptomatic neurofibromas from malignant peripheral nerve sheath tumours (MPNSTs). METHODS: 18F-FDG PET data from a cohort of 54 patients (24 female, 30 male, mean age 35.1 years) with neurofibromatosis-1 (NF1), and clinically suspected malignant transformation of neurofibromas into MPNSTs, were included. Scans were performed to a standard clinical protocol at 1.5 and 4 h post-injection. Six first-order [including three standardised uptake value (SUV) parameters], four second-order (derived from grey-level co-occurrence matrices) and four high-order (derived from neighbourhood grey-tone difference matrices) statistical features were calculated from tumour volumes of interest. Each patient had histological verification or at least 5 years clinical follow-up as the reference standard with regards to the characterisation of tumours as benign (n = 30) or malignant (n = 24). RESULTS: There was a significant difference between benign and malignant tumours for all six first-order parameters (at 1.5 and 4 h; p < 0.0001), for second-order entropy (only at 4 h) and for all high-order features (at 1.5 h and 4 h, except contrast at 4 h; p < 0.0001-0.047). Similarly, the area under the receiver operating characteristic curves was high (0.669-0.997, p < 0.05) for the same features as well as 1.5-h second-order entropy. No first-, second- or high-order feature performed better than maximum SUV (SUVmax) at differentiating benign from malignant tumours. CONCLUSIONS: 18F-FDG uptake in MPNSTs is higher than benign symptomatic neurofibromas, as defined by SUV parameters, and more heterogeneous, as defined by first- and high-order heterogeneity parameters. However, heterogeneity analysis does not improve on SUVmax discriminative performance.

The effect of post-injection 18F-FDG PET scanning time on texture analysis of peripheral nerve sheath tumours in neurofibromatosis-1.

BACKGROUND: Texture features are being increasingly evaluated in 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) as adjunctive imaging biomarkers in a number of different cancers. Whilst studies have reported repeatability between scans, there have been no studies that have specifically investigated the effect that the time of acquisition post-injection of 18F-FDG has on texture features. The aim of this study was to investigate if texture features change between scans performed at different time points post-injection. RESULTS: Fifty-four patients (30 male, 24 female, mean age 35.1 years) with neurofibromatosis-1 and suspected malignant transformation of a neurofibroma underwent 18F-FDG PET/computed tomography (CT) scans at 101.5 ± 15.0 and 251.7 ± 18.4 min post-injection of 350 MBq 18F-FDG to a standard clinical protocol. Following tumour segmentation on both early and late scans, first- (n = 37), second- (n = 25) and high-order (n = 31) statistical features, as well as fractal texture features (n = 6), were calculated and a comparison was made between the early and late scans for each feature. Of the 54 tumours, 30 were benign and 24 malignant on histological analysis or on clinical follow-up for at least 5 years. Overall, 25/37 first-order, 9/25 second-order, 13/31 high-order and 3/6 fractal features changed significantly (p < 0.05) between early and late scans. The corresponding proportions for the 30 benign tumours alone were 22/37, 7/25, 8/31 and 2/6 and for the 24 malignant tumours, 11/37, 6/25, 8/31 and 0/6, respectively. CONCLUSIONS: Several texture features change with time post-injection of 18F-FDG. Thus, when comparing texture features in intra- and inter-patient studies, it is essential that scans are obtained at a consistent time post-injection of 18F-FDG.

[18F]FDG PET/CT in the diagnosis of malignant peripheral nerve sheath tumours in neurofibromatosis type-1.

PURPOSE: The detection of malignant peripheral nerve sheath tumours (MPNSTs) in patients with neurofibromatosis 1 (NF1) remains a clinical challenge. The purpose of this study was to evaluate the use of [(18)F]2-fluoro-2-deoxy-D-glucose PET/CT (FDG PET/CT with early and delayed imaging) in patients with symptomatic neurofibromas, to revalidate current cut-off values for identification of malignant change within neurofibromas and to examine the relationship between SUV and tumour grade. METHODS: Patients with symptomatic neurofibromas underwent FDG PET/CT imaging at 90 and 240 min. Semiquantitative analysis using maximum standardized uptake value (SUVmax) was performed and correlated with histology. RESULT: In 69 patients, 85 lesions were identified for analysis, including 10 atypical neurofibromas and 21 MPNSTs. Sensitivity of FDG PET/CT in diagnosing NF1-associated MPNST was 0.97 (95% CI 0.81-0.99) and the specificity was 0.87 (CI 0.74-0.95). There was a significant difference in SUVmax between early and delayed imaging and in SUVmax between tumours identified as benign and malignant on PET/CT. There was also a significant difference in SUVmax between tumour grades. CONCLUSION: FDG PET/CT is a highly sensitive and specific imaging modality for the diagnosis of MPNST in NF1 patients. We recommend performing early (90 min) and delayed imaging at 4 h for accurate lesion characterization and using a cut-off SUVmax of 3.5 on delayed imaging to achieve maximal sensitivity.

Neuroendocrine tumors: role of interventional radiology in therapy.

The management of neuroendocrine tumors (NETs) is complex. Although NETs can affect a variety of organ systems, hepatic metastatic disease in particular lends itself to a wide range of interventional treatment options. Prior detailed radiologic assessment and careful patient selection are required. Curative surgery should always be considered but is rarely possible. Embolization, radionuclide therapy, or ablative techniques may then be undertaken. Transcatheter arterial embolization (TAE) may be used alone or in combination with transcatheter arterial chemoembolization (TACE). NET type and extent of hepatic involvement are factors that can help predict the success of either TAE or TACE. Embolization techniques can also be useful in patients with nonhepatic NETs. Radionuclide therapy is emerging as a valuable adjunct and is dependent on positive somatostatin receptor status. Therapeutic radiopeptides may be delivered arterially. Ablative techniques have been shown to play a role in the palliation of symptoms and principally involve radiofrequency ablation. Hepatic cryotherapy and percutaneous ethanol injection have also been used. A multidisciplinary approach to treatment and follow-up is important. Imaging should involve dual-phase multidetector computed tomography and contrast material-enhanced magnetic resonance imaging. The role of the interventional radiologist will continue to expand as imaging techniques become more refined.

The role of 99mTc-depreotide in the management of neuroendocrine tumours.

BACKGROUND: In-pentetreotide scan (OctreoScan) is a widely available agent with high sensitivity for imaging neuroendocrine tumours. Negative In-pentetreotide poses diagnostic as well as therapeutic problems in terms of staging and consideration of targeted radionuclide therapy. AIM: To assess the role of Tc-depreotide in patients with negative or weakly positive OctreoScan (Krenning score< or =1; measured on a scale range 0-4). To determine the usefulness of Tc-depreotide scintigraphy for highlighting lesions that may be missed by OctreoScan and/or CT/MRI imaging. STUDY DESIGN: Prospective analysis of 25 patients with neuroendocrine tumours, with negative or weakly positive In-pentetreotide scans, who were consecutively enrolled to undergo In-pentetreotide and Tc-depreotide imaging. The results were compared with either CT or MRI scans. RESULTS: Histology was available for 20 of 25 patients: of these 40% had high-grade tumours (cellular proliferation marker Ki-67 score >20%), a further 35% had intermediate-grade tumours (Ki-67 2-20%), and the remaining 25% had low-grade tumours (Ki-67 <2%). Fifty-two percent of patients had completely negative and 48% had weakly positive OctreoScan results. Thirty-two percent of these same patients had significantly positive Tc-depreotide scans (Krenning score> or =2), with the histology demonstrating intermediate-grade or high-grade tumours. CONCLUSION: Tc-depreotide imaging has low sensitivity but is useful in a one-third of OctreoScan-negative patients, displaying significantly better uptake than In-pentetreotide in this patient group. It aids diagnosis by highlighting lesions not seen by OctreoScan and/or CT/MRI imaging, and can possibly identify a group of patients amenable to therapy with radionuclide agents, such as SOM230, targeting somatostatin receptor subtypes 2, 3 and 5.