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

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 'interim' 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 'interim' 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

Contains fulltext : 228586.pdf (publisher's version ) (Open Access

Predictive value of interim positron emission tomography in diffuse large B-cell lymphoma : a systematic review and meta-analysis

Purpose: Diffuse large B-cell lymphoma (DLBCL) represents the most common subtype of non-Hodgkin lymphoma. Most relapses occur in the first 2 years after diagnosis. Early response assessment with 18F-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET) may facilitate early change of treatment, thereby preventing ineffective treatment and unnecessary side effects. We aimed to assess the predictive value of visually-assessed interim 18F-FDG PET on progression-free survival (PFS) or event-free survival (EFS) in DLBCL patients treated with first-line immuno-chemotherapy regimens. Methods: For this systematic review and meta-analysis Pubmed, Embase, and the Cochrane Library were searched until July 11, 2017. Prospective and retrospective studies investigating qualitative interim PET response assessment without treatment adaptation based on the interim PET result were eligible. The primary outcome was two-year PFS or EFS. Prognostic and diagnostic measures were extracted and analysed with pooled hazard ratios and Hierarchical Summary Receiver Operator Characteristic Curves, respectively. Meta-regression was used to study covariate effects. Results: The pooled hazard ratio for 18 studies comprising 2,255 patients was 3.13 (95%CI 2.52–3.89) with a 95% prediction interval of 1.68–5.83. In 19 studies with 2,366 patients, the negative predictive value for progression generally exceeded 80% (64–95), but sensitivity (33–87), specificity (49–94), and positive predictive values (20–74) ranged widely. Conclusions: These findings showed that interim 18F-FDG PET has predictive value in DLBCL patients. However, (subgroup) analyses were limited by lack of information and small sample sizes. Some diagnostic test characteristics were not satisfactory, especially the positive predictive value should be improved, before a successful risk stratified treatment approach can be implemented in clinical practice

Interobserver agreement of interim and end-of-treatment18F-FDG PET/CT in diffuse large B-cell lymphoma : Impact on clinical practice and trials

We aimed to assess the interobserver agreement of interim PET (I-PET) and end-of-treatment PET (EoT-PET) using the Deauville score (DS) in first-line diffuse large B-cell lymphoma (DLBCL) patients. Methods: I-PET and EoT-PET scans of DLBCL patients were performed in the HOVON84 study (2007–2012), an international multicenter randomized controlled trial. Patients received R-CHOP14 and were randomized to receive rituximab intensification in the first 4 cycles or not. I-PET was performed after 4 cycles (for observational purposes), and EoT-PET after 6 or 8 cycles. Two independent central reviewers retrospectively scored all scans according to the DS system, masked to clinical outcomes. Results were dichotomized as negative (DS of 1–3) or positive (DS of 4–5). Besides percentage overall agreement (OA), we calculated agreement for positive and negative scores, expressed as positive agreement (PA) and negative agreement (NA), respectively. Results: 465 I-PET and 457 EoT-PET scans were centrally reviewed; baseline18F-FDG PET or PET/CT was available in 75%–77%, and CT in the remaining cases. Percentage OA for I-PET and EoT-PET were 87.7% and 91.7% (P 5 0.049), with NA of 92.0% and 95.0% (P 5 0.091), and PA of 73.7% and 76.3% (P 5 0.656), respectively. Conclusion: Interobserver agreement using DS in DLBCL patients in I-PET and EoT-PET yields high OA and NA. The lower PA suggests that EoT-PET/CT treatment evaluation in daily practice and I-PET–adapted trials may benefit from dual reads and central review, respectively

Interobserver agreement of interim and end-of-treatment F-FDG PET/CT in diffuse large B-cell lymphoma (DLBCL): impact on clinical practice and trials

We aimed to assess the interobserver agreement of interim PET (I-PET) and end-of-treatment PET (EoT-PET) using the Deauville score (DS) in first-line diffuse large B-cell lymphoma (DLBCL) patients. Methods: I-PET and EoT-PET scans of DLBCL patients were performed in the HOVON84 study (2007–2012), an international multicenter randomized controlled trial. Patients received R-CHOP14 and were randomized to receive rituximab intensification in the first 4 cycles or not. I-PET was performed after 4 cycles (for observational purposes), and EoT-PET after 6 or 8 cycles. Two independent central reviewers retrospectively scored all scans according to the DS system, masked to clinical outcomes. Results were dichotomized as negative (DS of 1–3) or positive (DS of 4–5). Besides percentage overall agreement (OA), we calculated agreement for positive and negative scores, expressed as positive agreement (PA) and negative agreement (NA), respectively. Results: 465 I-PET and 457 EoT-PET scans were centrally reviewed; baseline18F-FDG PET or PET/CT was available in 75%–77%, and CT in the remaining cases. Percentage OA for I-PET and EoT-PET were 87.7% and 91.7% (P 5 0.049), with NA of 92.0% and 95.0% (P 5 0.091), and PA of 73.7% and 76.3% (P 5 0.656), respectively. Conclusion: Interobserver agreement using DS in DLBCL patients in I-PET and EoT-PET yields high OA and NA. The lower PA suggests that EoT-PET/CT treatment evaluation in daily practice and I-PET–adapted trials may benefit from dual reads and central review, respectively

Automated Segmentation of Baseline Metabolic Total Tumor Burden in Diffuse Large B-Cell Lymphoma: Which Method Is Most Successful? A Study on Behalf of the PETRA Consortium

Metabolic tumor volume (MTV) is a promising biomarker of pretreatment risk in diffuse large B-cell lymphoma (DLBCL). Different segmentation methods can be used that predict prognosis equally well but give different optimal cutoffs for risk stratification. Segmentation can be cumbersome; a fast, easy, and robust method is needed. Our aims were to evaluate the best automated MTV workflow in DLBCL; determine whether uptake time, compliance or noncompliance with standardized recommendations for 18F-FDG scanning, and subsequent disease progression influence the success of segmentation; and assess differences in MTVs and discriminatory power of segmentation methods. Methods: One hundred forty baseline 18F-FDG PET/CT scans were selected from U.K. and Dutch studies on DLBCL to provide a balance between scans at 60 and 90 min of uptake, parameters compliant and noncompliant with standardized recommendations for scanning, and patients with and without progression. An automated tool was applied for segmentation using an SUV of 2.5 (SUV2.5), an SUV of 4.0 (SUV4.0), adaptive thresholding (A50P), 41% of SUVmax (41%), a majority vote including voxels detected by at least 2 methods (MV2), and a majority vote including voxels detected by at least 3 methods (MV3). Two independent observers rated the success of the tool to delineate MTV. Scans that required minimal interaction were rated as a success; scans that missed more than 50% of the tumor or required more than 2 editing steps were rated as a failure. Results: One hundred thirty-eight scans were evaluable, with significant differences in success and failure ratings among methods. The best performing was SUV4.0, with higher success and lower failure rates than any other method except MV2, which also performed well. SUV4.0 gave a good approximation of MTV in 105 (76%) scans, with simple editing for a satisfactory result in additionally 20% of cases. MTV was significantly different for all methods between patients with and without progression. The 41% segmentation method performed slightly worse, with longer uptake times; otherwise, scanning conditions and patient outcome did not influence the tool's performance. The discriminative power was similar among methods, but MTVs were significantly greater using SUV4.0 and MV2 than using other thresholds, except for SUV2.5. Conclusion: SUV4.0 and MV2 are recommended for further evaluation. Automated estimation of MTV is feasible