Meta-Analysis of the Test-Retest Repeatability of [18F]-Fluorodeoxyglucose Standardized Uptake Values: Implications for Assessment of Tumor Response.

PURPOSE: Currently, guidelines for PET with 18F-fluorodeoxyglucose (FDG-PET) interpretation for assessment of therapy response in oncology primarily involve visual evaluation of FDG-PET/CT scans. However, quantitative measurements of the metabolic activity in tumors may be even more useful in evaluating response to treatment. Guidelines based on such measurements, including the European Organization for Research and Treatment of Cancer Criteria and PET Response Criteria in Solid Tumors, have been proposed. However, more rigorous analysis of response criteria based on FDG-PET measurements is needed to adopt regular use in practice. EXPERIMENTAL DESIGN: Well-defined boundaries of repeatability and reproducibility of quantitative measurements to discriminate noise from true signal changes are a needed initial step. An extension of the meta-analysis from de Langen and colleagues (2012) of the test-retest repeatability of quantitative FDG-PET measurements, including mean, maximum, and peak standardized uptake values (SUVmax, SUVmean, and SUVpeak, respectively), was performed. Data from 11 studies in the literature were used to estimate the relationship between the variance in test-retest measurements with uptake level and various study-level, patient-level, and lesion-level characteristics. RESULTS: Test-retest repeatability of percentage fluctuations for all three types of SUV measurement (max, mean, and peak) improved with higher FDG uptake levels. Repeatability in all three SUV measurements varied for different lesion locations. Worse repeatability in SUVmean was also associated with higher tumor volumes. CONCLUSIONS: On the basis of these results, recommendations regarding SUV measurements for assessing minimal detectable changes based on repeatability and reproducibility are proposed. These should be applied to differentiate between response categories for a future set of FDG-PET-based criteria that assess clinically significant changes in tumor response.

The quantitative assessment of interstitial lung disease with positron emission tomography scanning in systemic sclerosis patients.

OBJECTIVES: The reversibility of interstitial lung disease (ILD) in SSc is difficult to assess by current diagnostic modalities and there is clinical need for imaging techniques that allow for treatment stratification and monitoring. 18F-Fluorodeoxyglucose (FDG) PET/CT scanning may be of interest for this purpose by detection of metabolic activity in lung tissue. This study aimed to investigate the potential role of 18F-FDG PET/CT scanning for the quantitative assessment of SSc-related active ILD. METHODS: 18F-FDG PET/CT scans and high resolution CT scans of eight SSc patients, including five with ILD, were analysed. For comparison, reference groups were included: eight SLE patients and four primary Sjögren's syndrome (pSS) patients, all without ILD. A total of 22 regions of interest were drawn in each patient at apical, medial and dorsobasal lung levels. 18F-FDG uptake was measured as mean standardized uptake value (SUVmean) in each region of interest. Subsequently, basal/apical (B/A) and medial/apical (M/A) ratios were calculated at patient level (B/A-p and M/A-p) and at tissue level (B/A-t and M/A-t). RESULTS: SUVmean values in dorsobasal ROIs and B/A-p ratios were increased in SSc with ILD compared with SSc without ILD (P = 0.04 and P = 0.07, respectively), SLE (P = 0.003 and P = 0.002, respectively) and pSS (P = 0.03 and P = 0.02, respectively). Increased uptake in the dorsobasal lungs and increased B/A-t ratios corresponded to both ground glass and reticulation on high resolution CT. CONCLUSION: Semi-quantitative assessment of 18F-FDG PET/CT is able to distinguish ILD from non-affected lung tissue in SSc, suggesting that it may be used as a new biomarker for SSc-ILD disease activity.

Assessment of Simplified Methods for Quantification of 18F-FDHT Uptake in Patients with Metastatic Castration-Resistant Prostate Cancer.

18F-fluorodihydrotestosterone (18F-FDHT) PET/CT potentially provides a noninvasive method for assessment of androgen receptor expression in patients with metastatic castration-resistant prostate cancer (mCRPC). The objective of this study was to assess simplified methods for quantifying 18F-FDHT uptake in mCRPC patients and to assess effects of tumor perfusion on these 18F-FDHT uptake metrics. Methods: Seventeen mCRPC patients were included in this prospective observational multicenter study. Test and retest 30-min dynamic 18F-FDHT PET/CT scans with venous blood sampling were performed in 14 patients. In addition, arterial blood sampling and dynamic 15O-H2O scans were obtained in a subset of 6 patients. Several simplified methods were assessed: Patlak plots; SUV normalized to body weight (SUVBW), lean body mass (SUVLBM), whole blood (SUVWB), parent plasma activity concentration (SUVPP), area under the parent plasma curve (SUVAUC,PP), and area under the whole-blood input curve (SUVAUC,WB); and SUVBW corrected for sex hormone-binding globulin levels (SUVSHBG). Results were correlated with parameters derived from full pharmacokinetic 18F-FDHT and 15O-H2O. Finally, the repeatability of individual quantitative uptake metrics was assessed. Results: Eighty-seven 18F-FDHT-avid lesions were evaluated. 18F-FDHT uptake was best described by an irreversible 2-tissue-compartment model. Replacing the continuous metabolite-corrected arterial plasma input function with an image-derived input function in combination with venous sample data provided similar Ki results (R2 = 0.98). Patlak Ki and SUVAUC,PP showed an excellent correlation (R2 > 0.9). SUVBW showed a moderate correlation to Ki (R2 = 0.70, presumably due to fast 18F-FDHT metabolism. When calculating SUVSHBG, correlation to Ki improved (R2 = 0.88). The repeatability of full kinetic modeling parameters was inferior to that of simplified methods (repeatability coefficients > 36% vs. < 28%, respectively). 18F-FDHT uptake showed minimal blood flow dependency. Conclusion:18F-FDHT kinetics in mCRPC patients are best described by an irreversible 2-tissue-compartment model with blood volume parameter. SUVAUC,PP showed a near-perfect correlation with the irreversible 2-tissue-compartment model analysis and can be used for accurate quantification of 18F-FDHT uptake in whole-body PET/CT scans. In addition, SUVSHBG could potentially be used as an even simpler method to quantify 18F-FDHT uptake when less complex scanning protocols and accuracy are required.

Assessment of target-mediated uptake with immuno-PET: analysis of a phase I clinical trial with an anti-CD44 antibody.

BACKGROUND: Ideally, monoclonal antibodies provide selective treatment by targeting the tumour, without affecting normal tissues. Therefore, antibody imaging is of interest, preferably in early stages of drug development. However, the imaging signal consists of specific, as well as non-specific, uptake. The aim of this study was to assess specific, target-mediated uptake in normal tissues, with immuno-PET in a phase I dose escalation study, using the anti-CD44 antibody RG7356 as example. RESULTS: Data from thirteen patients with CD44-expressing solid tumours included in an imaging sub-study of a phase I dose escalation clinical trial using the anti-CD44 antibody RG7356 was analysed. 89Zirconium-labelled RG7356 (1 mg; 37 MBq) was administered after a variable dose of unlabelled RG7356 (0 to 675 mg). Tracer uptake in normal tissues (liver, spleen, kidney, lung, bone marrow, brain and blood pool) was used to calculate the area under the time antibody concentration curve (AUC) and expressed as tissue-to-blood AUC ratios. Within the dose range of 1 to 450 mg, tissue-to-blood AUC ratios decreased from 10.6 to 0.75 ± 0.16 for the spleen, 7.5 to 0.86 ± 0.18 for the liver, 3.6 to 0.48 ± 0.13 for the bone marrow, 0.69 to 0.26 ± 0.1 for the lung and 1.29 to 0.56 ± 0.14 for the kidney, indicating dose-dependent uptake. In all patients receiving ≥ 450 mg (n = 7), tumour uptake of the antibody was observed. CONCLUSIONS: This study demonstrates how immuno-PET in a dose escalation study provides a non-invasive technique to quantify dose-dependent uptake in normal tissues, indicating specific, target-mediated uptake.

Quality assessment of positron emission tomography scans: recommendations for future multicentre trials.

BACKGROUND: Standardization protocols and guidelines for positron emission tomography (PET) in multicenter trials are available, despite a large variability in image acquisition and reconstruction parameters exist. In this study, we investigated the compliance of PET scans to the guidelines of the European Association of Nuclear Medicine (EANM). From these results, we provide recommendations for future multicenter studies using PET. MATERIAL AND METHODS: Patients included in a multicenter randomized phase II study had repeated PET scans for early response assessment. Relevant acquisition and reconstruction parameters were extracted from the digital imaging and communications in medicine (DICOM) header of the images. The PET image parameters were compared to the guidelines of the EANM for tumor imaging version 1.0 recommended parameters. RESULTS: From the 223 included patients, 167 baseline scans and 118 response scans were available from 15 hospitals. Scans of 19% of the patients had an uptake time that fulfilled the Uniform Protocols for Imaging in Clinical Trials response assessment criteria. The average quality score over all hospitals was 69%. Scans with a non-compliant uptake time had a larger standard deviation of the mean standardized uptake value (SUVmean) of the liver than scans with compliant uptake times. CONCLUSIONS: Although a standardization protocol was agreed on, there was a large variability in imaging parameters. For future, multicenter studies including PET imaging a prospective central quality review during patient inclusion is needed to improve compliance with image standardization protocols as defined by EANM.

Cost-effectiveness of response evaluation after chemoradiation in patients with advanced oropharyngeal cancer using 18F-FDG-PET-CT and/or diffusion-weighted MRI.

BACKGROUND: Considerable variation exists in diagnostic tests used for local response evaluation after chemoradiation in patients with advanced oropharyngeal cancer. The yield of invasive examination under general anesthesia (EUA) with biopsies in all patients is low and it may induce substantial morbidity. We explored four response evaluation strategies to detect local residual disease in terms of diagnostic accuracy and cost-effectiveness. METHODS: We built a decision-analytic model using trial data of forty-six patients and scientific literature. We estimated for four strategies the proportion of correct diagnoses, costs concerning diagnostic instruments and the proportion of unnecessary EUA indications. Besides a reference strategy, i.e. EUA for all patients, we considered three imaging strategies consisting of 18FDG-PET-CT, diffusion-weighted MRI (DW-MRI), or both 18FDG-PET-CT and DW-MRI followed by EUA after a positive test. The impact of uncertainty was assessed in sensitivity analyses. RESULTS: The EUA strategy led to 96% correct diagnoses. Expected costs were €468 per patient whereas 89% of EUA indications were unnecessary. The DW-MRI strategy was the least costly strategy, but also led to the lowest proportion of correct diagnoses, i.e. 93%. The PET-CT strategy and combined imaging strategy were dominated by the EUA strategy due to respectively a smaller or equal proportion of correct diagnoses, at higher costs. However, the combination of PET-CT and DW-MRI had the highest sensitivity. All imaging strategies considerably reduced (unnecessary) EUA indications and its associated burden compared to the EUA strategy. CONCLUSIONS: Because the combined PET-CT and DW-MRI strategy costs only an additional €927 per patient, it is preferred over immediate EUA since it reaches the same diagnostic accuracy in detecting local residual disease while leading to substantially less unnecessary EUA indications. However, if healthcare resources are limited, DW-MRI is the strategy of choice because of lower costs while still providing a large reduction in unnecessary EUA indications.

[18F]FDG PET/CT-based response assessment of stage IV non-small cell lung cancer treated with paclitaxel-carboplatin-bevacizumab with or without nitroglycerin patches.

PURPOSE: Nitroglycerin (NTG) is a vasodilating drug, which increases tumor blood flow and consequently decreases hypoxia. Therefore, changes in [18F] fluorodeoxyglucose positron emission tomography ([18F]FDG PET) uptake pattern may occur. In this analysis, we investigated the feasibility of [18F]FDG PET for response assessment to paclitaxel-carboplatin-bevacizumab (PCB) treatment with and without NTG patches. And we compared the [18F]FDG PET response assessment to RECIST response assessment and survival. METHODS: A total of 223 stage IV non-small cell lung cancer (NSCLC) patients were included in a phase II study (NCT01171170) randomizing between PCB treatment with or without NTG patches. For 60 participating patients, a baseline and a second [18F]FDG PET/computed tomography (CT) scan, performed between day 22 and 24 after the start of treatment, were available. Tumor response was defined as a 30 % decrease in CT and PET parameters, and was compared to RECIST response at week 6. The predictive value of these assessments for progression free survival (PFS) and overall survival (OS) was assessed with and without NTG. RESULTS: A 30 % decrease in SUVpeak assessment identified more patients as responders compared to a 30 % decrease in CT diameter assessment (73 % vs. 18 %), however, this was not correlated to OS (SUVpeak30 p = 0.833; CTdiameter30 p = 0.557). Changes in PET parameters between the baseline and the second scan were not significantly different for the NTG group compared to the control group (p value range 0.159-0.634). The CT-based (part of the [18F]FDG PET/CT) parameters showed a significant difference between the baseline and the second scan for the NTG group compared to the control group (CT diameter decrease of 7 ± 23 % vs. 19 ± 14 %, p = 0.016, respectively). CONCLUSIONS: The decrease in tumoral FDG uptake in advanced NSCLC patients treated with chemotherapy with and without NTG did not differ between both treatment arms. Early PET-based response assessment showed more tumor responders than CT-based response assessment (part of the [18F]FDG PET/CT); this was not correlated to survival. This might be due to timing of the [18F]FDG PET shortly after the bevacizumab infusion.

Imaging biomarker roadmap for cancer studies.

Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as useful tools for testing research hypotheses in clinical trials and research studies, or as clinical decision-making tools for use in healthcare, by crossing 'translational gaps' through validation and qualification. Important differences exist between IBs and biospecimen-derived biomarkers and, therefore, the development of IBs requires a tailored 'roadmap'. Recognizing this need, Cancer Research UK (CRUK) and the European Organisation for Research and Treatment of Cancer (EORTC) assembled experts to review, debate and summarize the challenges of IB validation and qualification. This consensus group has produced 14 key recommendations for accelerating the clinical translation of IBs, which highlight the role of parallel (rather than sequential) tracks of technical (assay) validation, biological/clinical validation and assessment of cost-effectiveness; the need for IB standardization and accreditation systems; the need to continually revisit IB precision; an alternative framework for biological/clinical validation of IBs; and the essential requirements for multicentre studies to qualify IBs for clinical use.

Summary of the UPICT Protocol for 18F-FDG PET/CT Imaging in Oncology Clinical Trials.

The Uniform Protocols for Imaging in Clinical Trials (UPICT) (18)F-FDG PET/CT protocol is intended to guide the performance of whole-body FDG PET/CT studies within the context of single- and multiple-center clinical trials of oncologic therapies by providing acceptable (minimum), target, and ideal standards for all phases of imaging. The aim is to minimize variability in intra- and intersubject, intra- and interplatform, interexamination, and interinstitutional primary or derived data. The goal of this condensed version of the much larger document is to make readers aware of the general content and subject area. The document has several main subjects: context of the imaging protocol within the clinical trial; site selection, qualification, and training; subject scheduling; subject preparation; imaging-related substance preparation and administration; imaging procedure; image postprocessing; image analysis; image interpretation; archiving and distribution of data; quality control; and imaging-associated risks and risk management.

Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group.

PURPOSE: Recent advances in imaging, use of prognostic indices, and molecular profiling techniques have the potential to improve disease characterization and outcomes in lymphoma. International trials are under way to test image-based response­adapted treatment guided by early interim positron emission tomography (PET)­computed tomography (CT). Progress in imaging is influencing trial design and affecting clinical practice. In particular, a five-point scale to grade response using PET-CT, which can be adapted to suit requirements for early- and late-response assessment with good interobserver agreement, is becoming widely used both in practice- and response-adapted trials. A workshop held at the 11th International Conference on Malignant Lymphomas (ICML) in 2011 concluded that revision to current staging and response criteria was timely. METHODS: An imaging working group composed of representatives from major international cooperative groups was asked to review the literature, share knowledge about research in progress, and identify key areas for research pertaining to imaging and lymphoma. RESULTS: A working paper was circulated for comment and presented at the Fourth International Workshop on PET in Lymphoma in Menton, France, and the 12th ICML in Lugano, Switzerland, to update the International Harmonisation Project guidance regarding PET. Recommendations were made to optimize the use of PET-CT in staging and response assessment of lymphoma, including qualitative and quantitative methods. CONCLUSION: This article comprises the consensus reached to update guidance on the use of PET-CT for staging and response assessment for [18F]fluorodeoxyglucose-avid lymphomas in clinical practice and late-phase trials.

Assessment of simplified methods to measure 18F-FLT uptake changes in EGFR-mutated non-small cell lung cancer patients undergoing EGFR tyrosine kinase inhibitor treatment.

UNLABELLED: 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET/CT provides a noninvasive assessment of proliferation and, as such, could be a valuable imaging biomarker in oncology. The aim of the present study was to assess the validity of simplified quantitative parameters of (18)F-FLT uptake in non-small cell lung cancer (NSCLC) patients before and after the start of treatment with a tyrosine kinase inhibitor (TKI). METHODS: Ten patients with metastatic NSCLC harboring an activating epidermal growth factor receptor mutation were included in this prospective observational study. Patients underwent (15)O-H2O and (18)F-FLT PET/CT scanning on 3 separate occasions: within 7 d before treatment, and 7 and 28 d after the first therapeutic dose of a TKI (gefitinib or erlotinib). Dynamic scans were acquired and venous blood samples were collected during the (18)F-FLT scan to measure parent fraction and plasma and whole-blood radioactivity concentrations. Simplified measures (standardized uptake value [SUV] and tumor-to-blood ratio [TBR]) were correlated with fully quantitative measures derived from kinetic modeling. RESULTS: Twenty-nine of thirty (18)F-FLT PET/CT scans were evaluable. According to the Akaike criterion, a reversible 2-tissue model with 4 rate constants and blood volume parameter was preferred in 84% of cases. Relative therapy-induced changes in SUV and TBR correlated with those derived from kinetic analyses (r(2) = 0.83-0.97, P < 0.001, slope = 0.72-1.12). (18)F-FLT uptake significantly decreased at 7 and 28 d after the start of treatment compared with baseline (P < 0.01). Changes in (18)F-FLT uptake were not correlated with changes in perfusion, as measured using (15)O-H2O. CONCLUSION: SUV and TBR could both be used as surrogate simplified measures to assess changes in (18)F-FLT uptake in NSCLC patients treated with a TKI, at the cost of a small underestimation in uptake changes or the need for a blood sample and metabolite measurement, respectively.

Assessment of tumour size in PET/CT lung cancer studies: PET- and CT-based methods compared to pathology.

BACKGROUND: Positron emission tomography (PET) may be useful for defining the gross tumour volume for radiation treatment planning and for response monitoring of non-small cell lung cancer (NSCLC) patients. The purpose of this study was to compare tumour sizes obtained from CT- and various more commonly available PET-based tumour delineation methods to pathology findings. METHODS: Retrospective non-respiratory gated whole body [18F]-fluoro-2-deoxy-D-glucose PET/CT studies from 19 NSCLC patients were used. Several (semi-)automatic PET-based tumour delineation methods and manual CT-based delineation were used to assess the maximum tumour diameter. RESULTS: 50%, adaptive 41% threshold-based and contrast-oriented delineation methods showed good agreement with pathology after removing two outliers (R2=0.82). An absolute SUV threshold of 2.5 also showed a good agreement with pathology after the removal of 5 outliers (R2: 0.79), but showed a significant overestimation in the maximum diameter (19.8 mm, p<0.05). Adaptive 50%, relative threshold level and gradient-based methods did not show any outliers, provided only small, non-significant differences in maximum tumour diameter (<4.7 mm, p>0.10), and showed fair correlation (R2>0.62) with pathology. Although adaptive 70% threshold-based methods showed underestimation compared to pathology (36%), it provided the best precision (SD: 14%) together with good correlation (R2=0.81). Good correlation between CT delineation and pathology was observed (R2=0.77). However, CT delineation showed a significant overestimation compared with pathology (3.8 mm, p<0.05). CONCLUSIONS: PET-based tumour delineation methods provided tumour sizes in agreement with pathology and may therefore be useful to define the (metabolically most) active part of the tumour for radiotherapy and response monitoring purposes.

Cost-effectiveness of adding FDG-PET or CT to the diagnostic work-up of patients with stage III melanoma.

OBJECTIVE: The aim of this prospective study was to assess predictive value of fludeoxyglucose-positron emission tomography (FDG-PET) and computed tomography (CT) and to analyze their cost-effectiveness in several diagnosis-treatment combinations. BACKGROUND: The incidence of melanoma continues to rise. A proportion will present or recur with lymph node metastases (American Joint Committee on Cancer/Union for International Cancer Control stage III). To detect distant metastases, CT and/or FDG-PET are available. However, few studies have assessed their value and costs in stage III. METHODS: All consecutive patients with melanoma with palpable, proven lymph node metastases (2003-2008) referred for examination with FDG-PET and CT were prospectively included. Sensitivity, specificity, and accuracy, and positive predictive value (PPV) and negative predictive value (NPV) were calculated. In economic evaluation, the costs of diagnostic work-up with and without FDG-PET and CT were compared. RESULTS: Overall, 253 patients with melanoma were included. FDG-PET showed a higher sensitivity than CT: 86.1% compared with 78.2%. Specificity was higher for CT (93.7%) compared with FDG-PET (93.1%). Overall, FDG-PET showed a higher PPV and NPV. Cost-consequence analysis showed that adding CT (True-Positive upstaging in 61 patients) to diagnostic work-up decreased cost by 5.5%, adding FDG-PET (True-Positive upstaging in 68 patients) increased cost by 7.2%, and adding both (True-Positive upstaging in 78 patients) increased cost by 15.1%. CONCLUSIONS: In this study, FDG-PET had higher sensitivity and predictive value, whereas CT had a higher specificity. Adding one of these diagnostic tools improved the staging of stage III patients with less than 10% cost increase. A proposal for stage-specific use of imaging modalities for clinicians caring for patients with melanoma is presented.

¹8F-fluoro-deoxyglucose positron emission tomography in assessment of myeloma-related bone disease: a systematic review.

BACKGROUND: The goal of this study was to conduct a comparative analysis of whole body X-ray (WBXR) and (18) F-fluoro-deoxyglucose positron emission tomography ((18) FDG PET) in staging and response assessment of multiple myeloma. METHODS: We performed a systematic review of studies comparing (18) FDG PET with WBXR and/or magnetic resonance imaging in terms of sensitivity for myeloma-related bone disease at staging and during follow-up. RESULTS: Eighteen studies involving 798 patients met the inclusion criteria. The mean Quality Assessment of Diagnostic Accuracy Studies (QUADAS) score, expressed as a percentage of the maximum score, was 61%. In 7 studies (n = 242 patients), concordance assessment between WBXR and (18) FDG PET scan was possible, showing a higher sensitivity of the (18) FDG PET in the detection of myeloma bone lesions in 6 studies. The only study reporting on the prognostic value of (18) FDG PET at staging found that the number of FDG-avid focal lesions was an independent prognostic parameter. In addition, the limited studies on response monitoring showed that normalization of (18) FDG PET during treatment correlated with a superior clinical outcome. CONCLUSIONS: In general, (18) FDG PET has a superior sensitivity for myeloma bone lesions compared with WBXR. Future studies have to validate the additive value of myeloma-related bone disease detected on (18) FDG PET-computed tomography (CT) in predicting outcome. Response monitoring with the use of (18) FDG PET-CT during treatment is promising, allowing more precise prediction of prognosis compared with the standard response monitoring. In view of the expanding treatment options for multiple myeloma, this may provide important information for treatment decisions in the future.

Effects of image characteristics on performance of tumor delineation methods: a test-retest assessment.

UNLABELLED: PET can be used to monitor response during chemotherapy and assess biologic target volumes for radiotherapy. Previous simulation studies have shown that the performance of various automatic or semiautomatic tumor delineation methods depends on image characteristics. The purpose of this study was to assess test-retest variability of tumor delineation methods, with emphasis on the effects of several image characteristics (e.g., resolution and contrast). METHODS: Baseline test-retest data from 19 non-small cell lung cancer patients were obtained using (18)F-FDG (n = 10) and 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) (n = 9). Images were reconstructed with varying spatial resolution and contrast. Six different types of tumor delineation methods, based on various thresholds or on a gradient, were applied to all datasets. Test-retest variability of metabolic volume and standardized uptake value (SUV) was determined. RESULTS: For both tracers, size of metabolic volume and test-retest variability of both metabolic volume and SUV were affected by the image characteristics and tumor delineation method used. The median volume test-retest variability ranged from 8.3% to 23% and from 7.4% to 29% for (18)F-FDG and (18)F-FLT, respectively. For all image characteristics studied, larger differences (≤10-fold higher) were seen in test-retest variability of metabolic volume than in SUV. CONCLUSION: Test-retest variability of both metabolic volume and SUV varied with tumor delineation method, radiotracer, and image characteristics. The results indicate that a careful optimization of imaging and delineation method parameters is needed when metabolic volume is used, for example, as a response assessment parameter.

Quantitative imaging test approval and biomarker qualification: interrelated but distinct activities.

UNLABELLED: Quantitative imaging biomarkers could speed the development of new treatments for unmet medical needs and improve routine clinical care. However, it is not clear how the various regulatory and nonregulatory (eg, reimbursement) processes (often referred to as pathways) relate, nor is it clear which data need to be collected to support these different pathways most efficiently, given the time- and cost-intensive nature of doing so. The purpose of this article is to describe current thinking regarding these pathways emerging from diverse stakeholders interested and active in the definition, validation, and qualification of quantitative imaging biomarkers and to propose processes to facilitate the development and use of quantitative imaging biomarkers. A flexible framework is described that may be adapted for each imaging application, providing mechanisms that can be used to develop, assess, and evaluate relevant biomarkers. From this framework, processes can be mapped that would be applicable to both imaging product development and to quantitative imaging biomarker development aimed at increasing the effectiveness and availability of quantitative imaging. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100800/-/DC1.

Chest CT and whole-body 18F-FDG PET are cost-effective in screening for distant metastases in head and neck cancer patients.

UNLABELLED: The aim of the study was to define the cost-effectiveness of whole-body (18)F-FDG PET, as compared with chest CT, in screening for distant metastases in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: In a multicenter prospective study, 145 consecutive patients with high risk factors for distant metastases and scheduled for extensive treatment underwent chest CT and whole-body (18)F-FDG PET for screening of distant metastases. The cost data of 80 patients in whom distant metastases developed or who had a follow-up of at least 12 mo were analyzed. Cost-effectiveness analysis, including sensitivity analysis, was performed to compare the results of (18)F-FDG PET, CT, and a combination of CT and (18)F-FDG PET (CT + (18)F-FDG PET). RESULTS: Pretreatment screening identified distant metastases in 21% of patients. (18)F-FDG PET had a higher sensitivity (53% vs. 37%) and positive predictive value (80% vs. 75%) than did CT. CT + (18)F-FDG PET had the highest sensitivity (63%). The average costs in the CT, (18)F-FDG PET, and CT + (18)F-FDG PET groups amounted to euro38,558 (approximately $57,705), euro38,355 (approximately $57,402), and euro37,954 (approximately $56,801), respectively, in the first year after screening. CT + (18)F-FDG PET resulted in savings between euro203 (approximately $303) and euro604 (approximately $903). Sensitivity analysis showed that the dominance of CT + (18)F-FDG PET was robust. CONCLUSION: In HNSCC patients with risk factors, pretreatment screening for distant metastases by chest CT is improved by (18)F-FDG PET. The combination of (18)F-FDG PET with CT is the most effective, without leading to additional costs.

The cost-effectiveness of 18FDG-PET in selecting patients with suspicion of recurrent laryngeal carcinoma after radiotherapy for direct laryngoscopy.

The aim of this study was to estimate the cost-effectiveness of (18)FDG-PET in the selection for direct laryngoscopy in patients with suspicion of recurrent laryngeal carcinoma after radiotherapy. The direct medical costs of 30 patients with suspicion of a recurrence were calculated from the first visit where suspicion was raised until one year after. A conventional strategy, in which all these patients underwent direct laryngoscopy, was compared to an (18)FDG-PET strategy in which only patients with a positive or equivocal (18)FDG-PET underwent direct laryngoscopy. A sensitivity analysis was performed to examine the influence of the type of camera and 'setting'. The mean costs of an (18)FDG-PET strategy were 399 euros less than a direct laryngoscopy strategy. The type of camera and setting had no influence. In patients with suspicion for recurrent laryngeal carcinoma after radiotherapy, (18)FDG-PET seems to be effective and less costly in selecting patients for direct laryngoscopy.

NEOadjuvant therapy monitoring with PET and CT in Esophageal Cancer (NEOPEC-trial).

BACKGROUND: Surgical resection is the preferred treatment of potentially curable esophageal cancer. To improve long term patient outcome, many institutes apply neoadjuvant chemoradiotherapy. In a large proportion of patients no response to chemoradiotherapy is achieved. These patients suffer from toxic and ineffective neoadjuvant treatment, while appropriate surgical therapy is delayed. For this reason a diagnostic test that allows for accurate prediction of tumor response early during chemoradiotherapy is of crucial importance. CT-scan and endoscopic ultrasound have limited accuracy in predicting histopathologic tumor response. Data suggest that metabolic changes in tumor tissue as measured by FDG-PET predict response better. This study aims to compare FDG-PET and CT-scan for the early prediction of non-response to preoperative chemoradiotherapy in patients with potentially curable esophageal cancer. METHODS/DESIGN: Prognostic accuracy study, embedded in a randomized multicenter Dutch trial comparing neoadjuvant chemoradiotherapy for 5 weeks followed by surgery versus surgery alone for esophageal cancer. This prognostic accuracy study is performed only in the neoadjuvant arm of the randomized trial. In 6 centers, 150 consecutive patients will be included over a 3 year period. FDG-PET and CT-scan will be performed before and 2 weeks after the start of the chemoradiotherapy. All patients complete the 5 weeks regimen of neoadjuvant chemoradiotherapy, regardless the test results. Pathological examination of the surgical resection specimen will be used as reference standard. Responders are defined as patients with < 10% viable residual tumor cells (Mandard-score).Difference in accuracy (area under ROC curve) and negative predictive value between FDG-PET and CT-scan are primary endpoints. Furthermore, an economic evaluation will be performed, comparing survival and costs associated with the use of FDG-PET (or CT-scan) to predict tumor response with survival and costs of neoadjuvant chemoradiotherapy without prediction of response (reference strategy). DISCUSSION: The NEOPEC-trial could be the first sufficiently powered study that helps justify implementation of FDG-PET for response-monitoring in patients with esophageal cancer in clinical practice. TRIAL REGISTRATION: ISRCTN45750457.

Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma.

PURPOSE: To develop guidelines for performing and interpreting positron emission tomography (PET) imaging for treatment assessment in patients with lymphoma both in clinical practice and in clinical trials. METHODS: An International Harmonization Project (IHP) was convened to discuss standardization of clinical trial parameters in lymphoma. An imaging subcommittee developed consensus recommendations based on published PET literature and the collective expertise of its members in the use of PET in lymphoma. Only recommendations subsequently endorsed by all IHP subcommittees were adopted. RECOMMENDATIONS: PET after completion of therapy should be performed at least 3 weeks, and preferably at 6 to 8 weeks, after chemotherapy or chemoimmunotherapy, and 8 to 12 weeks after radiation or chemoradiotherapy. Visual assessment alone is adequate for interpreting PET findings as positive or negative when assessing response after completion of therapy. Mediastinal blood pool activity is recommended as the reference background activity to define PET positivity for a residual mass > or = 2 cm in greatest transverse diameter, regardless of its location. A smaller residual mass or a normal sized lymph node (ie, < or = 1 x 1 cm in diameter) should be considered positive if its activity is above that of the surrounding background. Specific criteria for defining PET positivity in the liver, spleen, lung, and bone marrow are also proposed. Use of attenuation-corrected PET is strongly encouraged. Use of PET for treatment monitoring during a course of therapy should only be done in a clinical trial or as part of a prospective registry.