Quantitative implications of the updated EARL 2019 PET-CT performance standards

Purpose Recently, updated EARL specifications (EARL2) have been developed and announced. This study aims at investigating the impact of the EARL2 specifications on the quantitative reads of clinical PET-CT studies and testing a method to enable the use of the EARL2 standards whilst still generating quantitative reads compliant with current EARL standards (EARL1). Methods Thirteen non-small cell lung cancer (NSCLC) and seventeen lymphoma PET-CT studies were used to derive four image datasets-the first dataset complying with EARL1 specifications and the second reconstructed using parameters as described in EARL2. For the third (EARL2F6) and fourth (EARL2F7) dataset in EARL2, respectively, 6 mm and 7 mm Gaussian post-filtering was applied. We compared the results of quantitative metrics (MATV, SUVmax, SUVpeak, SUVmean, TLG, and tumor-to-liver and tumor-to-blood pool ratios) obtained with these 4 datasets in 55 suspected malignant lesions using three commonly used segmentation/volume of interest (VOI) methods (MAX41, A50P, SUV4). Results We found that with EARL2 MAX41 VOI method, MATV decreases by 22%, TLG remains unchanged and SUV values increase by 23-30% depending on the specific metric used. The EARL2F7 dataset produced quantitative metrics best aligning with EARL1, with no significant differences between most of the datasets (p>0.05). Different VOI methods performed similarly with regard to SUV metrics but differences in MATV as well as TLG were observed. No significant difference between NSCLC and lymphoma cancer types was observed. Conclusions Application of EARL2 standards can result in higher SUVs, reduced MATV and slightly changed TLG values relative to EARL1. Applying a Gaussian filter to PET images reconstructed using EARL2 parameters successfully yielded EARL1 compliant data

Quantitative implications of the updated EARL 2019 PET-CT performance standards

Purpose Recently, updated EARL specifications (EARL2) have been developed and announced. This study aims at investigating the impact of the EARL2 specifications on the quantitative reads of clinical PET-CT studies and testing a method to enable the use of the EARL2 standards whilst still generating quantitative reads compliant with current EARL standards (EARL1). Methods Thirteen non-small cell lung cancer (NSCLC) and seventeen lymphoma PET-CT studies were used to derive four image datasets-the first dataset complying with EARL1 specifications and the second reconstructed using parameters as described in EARL2. For the third (EARL2F6) and fourth (EARL2F7) dataset in EARL2, respectively, 6 mm and 7 mm Gaussian post-filtering was applied. We compared the results of quantitative metrics (MATV, SUVmax, SUVpeak, SUVmean, TLG, and tumor-to-liver and tumor-to-blood pool ratios) obtained with these 4 datasets in 55 suspected malignant lesions using three commonly used segmentation/volume of interest (VOI) methods (MAX41, A50P, SUV4). Results We found that with EARL2 MAX41 VOI method, MATV decreases by 22%, TLG remains unchanged and SUV values increase by 23-30% depending on the specific metric used. The EARL2F7 dataset produced quantitative metrics best aligning with EARL1, with no significant differences between most of the datasets (p>0.05). Different VOI methods performed similarly with regard to SUV metrics but differences in MATV as well as TLG were observed. No significant difference between NSCLC and lymphoma cancer types was observed. Conclusions Application of EARL2 standards can result in higher SUVs, reduced MATV and slightly changed TLG values relative to EARL1. Applying a Gaussian filter to PET images reconstructed using EARL2 parameters successfully yielded EARL1 compliant data

PET segmentation of bulky tumors:Strategies and workflows to improve inter-observer variability

Background PET-based tumor delineation is an error prone and labor intensive part of image analysis. Especially for patients with advanced disease showing bulky tumor FDG load, segmentations are challenging. Reducing the amount of user-interaction in the segmentation might help to facilitate segmentation tasks especially when labeling bulky and complex tumors. Therefore, this study reports on segmentation workflows/strategies that may reduce the inter-observer variability for large tumors with complex shapes with different levels of user-interaction. Methods Twenty PET images of bulky tumors were delineated independently by six observers using four strategies: (I) manual, (II) interactive threshold-based, (III) interactive threshold-based segmentation with the additional presentation of the PET-gradient image and (IV) the selection of the most reasonable result out of four established semi-automatic segmentation algorithms (Select-the-best approach). The segmentations were compared using Jaccard coefficients (JC) and percentage volume differences. To obtain a reference standard, a majority vote (MV) segmentation was calculated including all segmentations of experienced observers. Performed and MV segmentations were compared regarding positive predictive value (PPV), sensitivity (SE), and percentage volume differences. Results The results show that with decreasing user-interaction the inter-observer variability decreases. JC values and percentage volume differences of Select-the-best and a workflow including gradient information were significantly better than the measurements of the other segmentation strategies (p-value&lt;0.01). Interactive threshold-based and manual segmentations also result in significant lower and more variable PPV/SE values when compared with the MV segmentation. Conclusions FDG PET segmentations of bulky tumors using strategies with lower user-interaction showed less inter-observer variability. None of the methods led to good results in all cases, but use of either the gradient or the Select-the-best workflow did outperform the other strategies tested and may be a good candidate for fast and reliable labeling of bulky and heterogeneous tumors.</p

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

Evidence synthesis to inform model-based cost-effectiveness evaluations of diagnostic tests: a methodological systematic review of health technology assessments

Background: Evaluations of diagnostic tests are challenging because of the indirect nature of their impact on patient outcomes. Model-based health economic evaluations of tests allow different types of evidence from various sources to be incorporated and enable cost-effectiveness estimates to be made beyond the duration of available study data. To parameterize a health-economic model fully, all the ways a test impacts on patient health must be quantified, including but not limited to diagnostic test accuracy. Methods: We assessed all UK NIHR HTA reports published May 2009-July 2015. Reports were included if they evaluated a diagnostic test, included a model-based health economic evaluation and included a systematic review and meta-analysis of test accuracy. From each eligible report we extracted information on the following topics: 1) what evidence aside from test accuracy was searched for and synthesised, 2) which methods were used to synthesise test accuracy evidence and how did the results inform the economic model, 3) how/whether threshold effects were explored, 4) how the potential dependency between multiple tests in a pathway was accounted for, and 5) for evaluations of tests targeted at the primary care setting, how evidence from differing healthcare settings was incorporated. Results: The bivariate or HSROC model was implemented in 20/22 reports that met all inclusion criteria. Test accuracy data for health economic modelling was obtained from meta-analyses completely in four reports, partially in fourteen reports and not at all in four reports. Only 2/7 reports that used a quantitative test gave clear threshold recommendations. All 22 reports explored the effect of uncertainty in accuracy parameters but most of those that used multiple tests did not allow for dependence between test results. 7/22 tests were potentially suitable for primary care but the majority found limited evidence on test accuracy in primary care settings. Conclusions: The uptake of appropriate meta-analysis methods for synthesising evidence on diagnostic test accuracy in UK NIHR HTAs has improved in recent years. Future research should focus on other evidence requirements for cost-effectiveness assessment, threshold effects for quantitative tests and the impact of multiple diagnostic tests

FDG-PET as a biomarker for early response in diffuse large B-cell lymphoma as well as in Hodgkin lymphoma? Ready for implementation in clinical practice?

A short history Major changes have taken place in the staging and response assessment of malignant lymphoma in the last two decades. With the introduction of fluorodeoxyglucose-positron emission tomography (FDG-PET) and positron emission tomography-computed tomography (PET-CT), the criteria for staging and monitoring response have changed dramatically. In the revised Cheson criteria published in 2007, 1 staging with FDG-PET was still optional, and end-of treatment assessment using FDG-PET and CT was obligatory for Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma (DLBCL). In the Lugano criteria published in 2014, 2 PET-CT is recommended for staging as well as response assessment following therapy, as it is the most accurate imaging modality. However, one of the characteristics of (molecular) metabolic imaging is to be able to assess metabolic changes early in treatment. The question arises whether &apos;interim&apos; FDG-PET-CT (iPET) can be used as a biomarker to differentiate good and poor responders during treatment, in order to modify therapy and to improve outcome. Recent clinical trials have addressed these questions, and we discuss the results and the implications for clinical practice. Assessment of interim-PET scans International guidelines recommend the use of a 5-point scale [also called the Deauville score (DS)] for grading FDG-uptake in lymphoma, compared to physiological uptake in the mediastinum and liver, for response assessment in daily practice and clinical trials. Recently, the European Association of Nuclear Medicine (EANM) guidelines for FDG-PET in tumor imaging for trials and clinical practice have been up-dated, Interim-PET in Hodgkin lymphoma Hodgkin lymphoma is a lymphoma entity with cure rates of up to 90%. iPET predicts response early during treatment and PET-guided therapy is a new strategy in development for HL. The goal of current and recently completed clinical trials is to achieve optimal efficacy in terms of progression-free survival (PFS) and overall survival (OS), and to reduce long-term adverse effects. The first reports using iPET to de-escalate therapy in responding individuals with early-stage disease have been published. The UK RAPID study 8 and the EORTC H10 study In the RAPID trial, the 3-year PFS was 97.1% using RT versus 90.8% for NFT in a per-protocol analysis (HR 2.36; 1.13, 4.95). There was no significant difference in 3-year OS: 97.1% (RT) versus 99.0% (NFT). In the H10 study, 1-year PFS was 100% (favorable disease) and 97.3% (unfavorable disease) using RT versus 94.9% (favorable) and 94.7% (unfavorable) for NFT. The H10 study was halted early for patients with CMR as it was felt unlikely to demonstrate non-inferiority for the NFT option with a 10% decrease in 5-year PFS where the threshold for non-inferiority was set at a hazard ratio of respectively 3.2 and

FDG-PET as a biomarker for early response in diffuse large B-cell lymphoma as well as in Hodgkin lymphoma? Ready for implementation in clinical practice?

A short history Major changes have taken place in the staging and response assessment of malignant lymphoma in the last two decades. With the introduction of fluorodeoxyglucose-positron emission tomography (FDG-PET) and positron emission tomography-computed tomography (PET-CT), the criteria for staging and monitoring response have changed dramatically. In the revised Cheson criteria published in 2007, 1 staging with FDG-PET was still optional, and end-of treatment assessment using FDG-PET and CT was obligatory for Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma (DLBCL). In the Lugano criteria published in 2014, 2 PET-CT is recommended for staging as well as response assessment following therapy, as it is the most accurate imaging modality. However, one of the characteristics of (molecular) metabolic imaging is to be able to assess metabolic changes early in treatment. The question arises whether &apos;interim&apos; FDG-PET-CT (iPET) can be used as a biomarker to differentiate good and poor responders during treatment, in order to modify therapy and to improve outcome. Recent clinical trials have addressed these questions, and we discuss the results and the implications for clinical practice. Assessment of interim-PET scans International guidelines recommend the use of a 5-point scale [also called the Deauville score (DS)] for grading FDG-uptake in lymphoma, compared to physiological uptake in the mediastinum and liver, for response assessment in daily practice and clinical trials. Recently, the European Association of Nuclear Medicine (EANM) guidelines for FDG-PET in tumor imaging for trials and clinical practice have been up-dated, Interim-PET in Hodgkin lymphoma Hodgkin lymphoma is a lymphoma entity with cure rates of up to 90%. iPET predicts response early during treatment and PET-guided therapy is a new strategy in development for HL. The goal of current and recently completed clinical trials is to achieve optimal efficacy in terms of progression-free survival (PFS) and overall survival (OS), and to reduce long-term adverse effects. The first reports using iPET to de-escalate therapy in responding individuals with early-stage disease have been published. The UK RAPID study 8 and the EORTC H10 study In the RAPID trial, the 3-year PFS was 97.1% using RT versus 90.8% for NFT in a per-protocol analysis (HR 2.36; 1.13, 4.95). There was no significant difference in 3-year OS: 97.1% (RT) versus 99.0% (NFT). In the H10 study, 1-year PFS was 100% (favorable disease) and 97.3% (unfavorable disease) using RT versus 94.9% (favorable) and 94.7% (unfavorable) for NFT. The H10 study was halted early for patients with CMR as it was felt unlikely to demonstrate non-inferiority for the NFT option with a 10% decrease in 5-year PFS where the threshold for non-inferiority was set at a hazard ratio of respectively 3.2 and

Treatment of patients with MYC rearrangement positive large B-cell lymphoma with R-CHOP plus lenalidomide: results of a multicenter phase II HOVON trial

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