Faculty Bibliography

This retrospective analysis of the phase III GOYA study investigated the prognostic value of baseline metabolic tumor volume parameters and maximum standardized uptake values for overall and progression-free survival (PFS) in treatment-naïve diffuse large B-cell lymphoma. Baseline total metabolic tumor volume (determined for tumors >1 mL using a threshold of 1.5 times the mean liver standardized uptake value +2 standard deviations), total lesion glycolysis, and maximum standardized uptake value positron emission tomography data were dichotomized based on receiver operating characteristic analysis and divided into quartiles by baseline population distribution. Of 1,418 enrolled patients, 1,305 had a baseline positron emission tomography scan with detectable lesions. Optimal cut-offs were 366 cm3 for total metabolic tumor volume and 3,004 g for total lesion glycolysis. High total metabolic tumor volume and total lesion glycolysis predicted poorer PFS, with associations retained after adjustment for baseline and disease characteristics (high total metabolic tumor volume hazard ratio: 1.71, 95% confidence interval [CI]: 1.35- 2.18; total lesion glycolysis hazard ratio: 1.46; 95% CI: 1.15-1.86). Total metabolic tumor volume was prognostic for PFS in subgroups with International Prognostic Index scores 0-2 and 3-5, and those with different cell-of-origin subtypes. Maximum standardized uptake value had no prognostic value in this setting. High total metabolic tumor volume associated with high International Prognostic Index or non-germinal center B-cell classification identified the highest-risk cohort for unfavorable prognosis. In conclusion, baseline total metabolic tumor volume and total lesion glycolysis are independent predictors of PFS in patients with diffuse large B-cell lymphoma after first-line immunochemotherapy.

Image texture analysis (radiomics) uses radiographic images to quantify characteristics that may identify tumour heterogeneity and associated patient outcomes. Using fluoro-deoxy-glucose positron emission tomography/computed tomography (FDG-PET/CT)-derived data, including quantitative metrics, image texture analysis and other clinical risk factors, we aimed to develop a prognostic model that predicts survival in patients with previously untreated diffuse large B-cell lymphoma (DLBCL) from GOYA (NCT01287741). Image texture features and clinical risk factors were combined into a random forest model and compared with the international prognostic index (IPI) for DLBCL based on progression-free survival (PFS) and overall survival (OS) predictions. Baseline FDG-PET scans were available for 1263 patients, 832 patients of these were cell-of-origin (COO)-evaluable. Patients were stratified by IPI or radiomics features plus clinical risk factors into low-, intermediate- and high-risk groups. The random forest model with COO subgroups identified a clearer high-risk population (45% 2-year PFS [95% confidence interval (CI) 40%-52%]; 65% 2-year OS [95% CI 59%-71%]) than the IPI (58% 2-year PFS [95% CI 50%-67%]; 69% 2-year OS [95% CI 62%-77%]). This study confirms that standard clinical risk factors can be combined with PET-derived image texture features to provide an improved prognostic model predicting survival in untreated DLBCL.

Traumatic brain injury (TBI) is a risk factor for the later development of neurodegenerative diseases that may have various underlying pathologies. Chronic traumatic encephalopathy (CTE) in particular is associated with repetitive mild TBI (mTBI) and is characterized pathologically by aggregation of hyperphosphorylated tau into neurofibrillary tangles (NFTs). CTE may be suspected when behavior, cognition, and/or memory deteriorate following repetitive mTBI. Exposure to blast overpressure from improvised explosive devices (IEDs) has been implicated as a potential antecedent for CTE amongst Iraq and Afghanistan Warfighters. In this study, we identified biomarker signatures in rats exposed to repetitive low-level blast that develop chronic anxiety-related traits and in human veterans exposed to IED blasts in theater with behavioral, cognitive, and/or memory complaints. Rats exposed to repetitive low-level blasts accumulated abnormal hyperphosphorylated tau in neuronal perikarya and perivascular astroglial processes. Using positron emission tomography (PET) and the [¹⁸F]AV1451 (flortaucipir) tau ligand, we found that five of 10 veterans exhibited excessive retention of [¹⁸F]AV1451 at the white/gray matter junction in frontal, parietal, and temporal brain regions, a typical localization of CTE tauopathy. We also observed elevated levels of neurofilament light (NfL) chain protein in the plasma of veterans displaying excess [¹⁸F]AV1451 retention. These findings suggest an association linking blast injury, tauopathy, and neuronal injury. Further study is required to determine whether clinical, neuroimaging, and/or fluid biomarker signatures can improve the diagnosis of long-term neuropsychiatric sequelae of mTBI.

Interim 18F-fluorodeoxyglucose positron emission tomography (Interim-18F-FDG-PET, hereafter I-PET) has the potential to guide treatment of patients with diffuse large B-cell lymphoma (DLBCL) if the prognostic value is known. The aim of this study was to determine the optimal timing and response criteria for evaluating prognosis with I-PET in DLBCL. Individual patient data from 1692 patients with de novo DLBCL were combined and scans were harmonized. I-PET was performed at various time points during treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. Scans were interpreted using the Deauville score (DS) and change in maximum standardized uptake value (ΔSUVmax). Multilevel Cox proportional hazards models corrected for International Prognostic Index (IPI) score were used to study the effects of timing and response criteria on 2-year progression-free survival (PFS). I-PET after 2 cycles (I-PET2) and I-PET4 significantly discriminated good responders from poor responders, with the highest hazard ratios (HRs) for I-PET4. Multivariable HRs for a PET-positive result at I-PET2 and I-PET4 were 1.71 and 2.95 using DS4-5, 4.91 and 6.20 using DS5, and 2.93 and 4.65 using ΔSUVmax, respectively. ΔSUVmax identified a larger proportion of poor responders than DS5 did. For all criteria, the negative predictive value was >80%, and positive predictive values ranged from 30% to 70% at I-PET2 and I-PET4. Unlike I-PET1, I-PET3 discriminated good responders from poor responders using DS4-5 and DS5 thresholds (HRs, 2.94 and 4.67, respectively). I-PET2 and I-PET4 predict good response equally during R-CHOP therapy in DLBCL. Optimal timing and response criteria depend on the clinical context. Good response at I-PET2 is suggested for de-escalation trials, and poor response using ΔSUVmax at I-PET4 is suggested for randomized trials that are evaluating new therapies.

GOYA was a randomized phase 3 study comparing obinutuzumab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) vs standard-of-care rituximab plus CHOP in patients with previously untreated diffuse large B-cell lymphoma (DLBCL). This retrospective analysis of GOYA aimed to assess the association between progression-free survival (PFS) and overall survival (OS) with positron emission tomography (PET)-based complete response (CR) status. Overall, 1418 patients were randomly assigned to receive 8 21-day cycles of obinutuzumab (n = 706) or rituximab (n = 712) plus 6 or 8 cycles of CHOP. Patients received a mandatory fluoro-2-deoxy-d-glucose-PET/computed tomography scan at baseline and end of treatment. After a median follow-up of 29 months, the numbers of independent review committee-assessed PFS and OS events in the entire cohort were 416 (29.3%) and 252 (17.8%), respectively. End-of-treatment PET CR was highly prognostic for PFS and OS according to Lugano 2014 criteria (PFS: hazard ratio [HR], 0.26; 95% confidence interval [CI], 0.19-0.38; P < .0001; OS: HR, 0.12; 95% CI, 0.08-0.17; P < .0001), irrespective of international prognostic index score and cell of origin. In conclusion, the results from this prospectively acquired large cohort corroborated previously published data from smaller sample sizes showing that end-of-treatment PET CR is an independent predictor of PFS and OS and a promising prognostic marker in DLBCL. Long-term survival analysis confirmed the robustness of these data over time. Additional meta-analyses including other prospective studies are necessary to support the substitution of PET CR for PFS as an effective and practical surrogate end point. This trial was registered at www.clinicaltrials.gov as #NCT01287741.

Segmentation of lymphoma lesions in FDG PET/CT images is critical in both assessing individual lesions and quantifying patient disease burden. Simple thresholding methods remain common despite the large heterogeneity in lymphoma lesion location, size, and contrast. Here, we assess 11 automated PET segmentation methods for their use in two scenarios: individual lesion segmentation and patient-level disease quantification in lymphoma. Lesions on ¹⁸F-FDG PET/CT scans of 90 lymphoma patients were contoured by a nuclear medicine physician. Thresholding, active contours, clustering, adaptive region-growing, and convolutional neural network (CNN) methods were implemented on all physician-identified lesions. Lesion-level segmentation was evaluated using multiple segmentation performance metrics (Dice, Hausdorff Distance). Patient-level quantification of total disease burden (SUV_total) and metabolic tumor volume (MTV) was assessed using Spearman's correlation coefficients between the segmentation output and physician contours. Lesion segmentation and patient quantification performance was compared to inter-physician agreement in a subset of 20 patients segmented by a second nuclear medicine physician. In total, 1223 lesions with median tumor-to-background ratio of 4.0 and volume of 1.8 cm³, were evaluated. When assessed for lesion segmentation, a 3D CNN, DeepMedic, achieved the highest performance across all evaluation metrics. DeepMedic, clustering methods, and an iterative threshold method had lesion-level segmentation performance comparable to the degree of inter-physician agreement. For patient-level SUV_total and MTV quantification, all methods except 40% and 50% SUV_max and adaptive region-growing achieved a performance that was similar the agreement of the two physicians. Multiple methods, including a 3D CNN, clustering, and an iterative threshold method, achieved both good lesion-level segmentation and patient-level quantification performance in a population of 90 lymphoma patients. These methods are thus recommended over thresholding methods such as 40% and 50% SUV_max, which were consistently found to be significantly outside the limits defined by inter-physician agreement.

Introduction: Lugano 2014 criteria are the current standard for response assessment in lymphoma and incorporate ¹⁸F fludeoxyglucose (FDG)-positron emission tomography (PET)-computed tomography (CT) into standard staging of FDG-avid lymphomas (Cheson, et al. J Clin Oncol 2014); bi-dimensional tumor measurements of up to six CT target lesions are used for non-FDG avid lymphomas, and when PET is unavailable. The Response Evaluation Criteria in Lymphoma (RECIL), developed more recently, showed that uni-dimensional measurements of up to three target lesions could provide response assessment at a similar accuracy to the Lugano criteria (Younes, et al. Annals Oncol 2017). In the Phase III GOYA trial (NCT01287741), complete response (CR) status by RECIL criteria showed high concordance with Lugano criteria and was highly prognostic for survival outcome in previously untreated patients (pts) with CD20-positive diffuse large B-cell lymphoma treated with obinutuzumab (G) plus chemotherapy (G-chemo) or rituximab (R)-chemo. Here, we compared the prognostic and predictive performance of the Lugano and RECIL criteria in pts from the Phase III GALLIUM trial (NCT01332968).
Method(s): Pts were randomized 1:1 to receive G or R plus CHOP, CVP, or bendamustine (stratification factors: chemotherapy regimen, Follicular Lymphoma International Prognostic Index and geographic region). FDG-PET scans were mandatory in the first 170 pts where a PET scanner was available, and optional thereafter, and were performed at screening and end of induction (EOI). Response was assessed by the investigator (INV) and an independent review committee (IRC) using Cheson 2007 criteria, the IRC also assessed EOI response using Lugano 2014 criteria. Response and progression-free survival (PFS) by RECIL 2017 criteria were retrospectively evaluated via a programming algorithm based on IRC-assessed 5PS scores and the individual lesion measurements from INV assessment. Response categories at EOI by RECIL criteria were cross-tabulated against those by Lugano criteria. Estimates of the treatment effect for PFS were expressed as hazard ratios (HRs) with 95% confidence intervals (CIs) using stratified log-rank tests. Landmark analyses of PFS and overall survival (OS) from EOI, by EOI CR/non-CR status were performed. The impact of covariates on the prognostic value for PFS and OS were analyzed using multivariable Cox models.
Result(s): In GALLIUM, 1202 pts with follicular lymphoma (FL) were enrolled (601 per treatment arm), of which 595 had PET evaluable data (R-chemo, n=298; G-chemo, n=297). High concordance between Lugano and RECIL criteria for EOI CR was observed regardless of antibody received, with 416 pts classified as CR by RECIL among the 450 pts achieving complete metabolic response (CMR) by Lugano (416/450 [92.4%]; R-chemo, 199/216 [92.1%]; G-chemo, 217/234 [92.7%]) (Table). However, poor concordance was seen for progressive disease (PD), with 18/21 (85.7%) pts with progressive metabolic disease by Lugano classified as partial/minimal responders by RECIL. A strong correlation was observed between Cheson 2007 and RECIL PFS definitions, with a kappa estimate of 0.63 (95% CI: 0.58-0.69). EOI CR status by RECIL showed prognostic value by Cox multivariable regression analysis adjusted for stratification factors for PFS and OS; this prognostic value was similar with Lugano criteria (Figure). PFS rate by treatment arm for pts with a CR/CMR was higher by RECIL versus Lugano for both R-chemo and G-chemo (PFS rate at 3 years from EOI: RECIL: 86.0% and 89.7%; Lugano: 76.4% and 85.0%, respectively); similar results were seen with OS. G-chemo was associated with improved RECIL-PFS (from randomization) compared with R-chemo (HR, 0.72; 95% CI: 0.57-0.91; p=0.0069), similar to the GALLIUM 5-year updated analysis results by Cheson 2007 (HR, 0.76; 95% CI: 0.62-0.92; p=0.0043) (Townsend, et al. ASCO 2020).
Conclusion(s): RECIL 2017 criteria showed high concordance with Lugano 2014 criteria with EOI CR strongly prognostic for improved outcomes versus non-CR; however, a discordance was observed for PD. A similar treatment difference between arms for PFS was detected with RECIL and Cheson 2007 criteria. RECIL criteria (uni-dimensional assessment of up to three target lesions) may be a suitable alternative to Lugano criteria (bi-dimensional assessment of up to six target lesions) in pts with previously untreated advanced-stage FL. [Formula presented] Disclosures: Kostakoglu: F. Hoffmann-La Roche: Consultancy. Davies: Roche, Celgene, Kite Pharma, Acerta, Karyopharma, Regeneron, Incyte: Consultancy; Roche, Acerta Pharma, AstraZeneca, Celgene, Gilead, ADC Therapeutics, Gilead: Research Funding; Celegene, Roche, Kite Pharma, Celegene: Honoraria; Roche: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Herold: Helios Klinikum Erfurt: Current Employment; F. Hoffmann-La Roche: Research Funding. Hiddemann: F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Marcus: Gilead: Consultancy; F. Hoffmann-La Roche: Honoraria; Janssen: Honoraria, Speakers Bureau. Trotman: Celgene: Research Funding; F. Hoffmann-La Roche: Research Funding; BeiGene: Research Funding; Takeda: Research Funding; PCYC: Research Funding. Knapp: F. Hoffmann-La Roche: Current Employment. Mattiello: F. Hoffmann-La Roche: Current Employment. Nielsen: F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Sahin: F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Ward: F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Younes: AstraZeneca: Current Employment; MSKCC: Ended employment in the past 24 months; Janssen, Curis, Merck, Bristol-Myers Squibb, Syndax Pharmaceuticals, F. Hoffmann-La Roche, Curis (Inst), Johnson & Johnson (Inst), Novartis (Inst): Research Funding; Janssen, AbbVie, Merck, Curis, Epizyme, F. Hoffmann-La Roche, Takeda, Bristol-Myers Squibb, Bayer HealthCare Pharmaceuticals, Celgene, Incyte, Janssen Pharmaceuticals, Merck, Sanofi, Seattle Genetics, Takeda Millennium: Honoraria; BioPath, Xynomic, Epizyme, and F. Hoffmann-La Roche: Consultancy.
Copyright

PURPOSE/OBJECTIVE:F) fluorodeoxyglucose (FDG) PET/CT images using convolutional neural networks (CNNs). MATERIALS AND METHODS/METHODS:F-FDG PET/CT images (acquired between 2005 and 2011) by a nuclear medicine physician. An ensemble of three-dimensional patch-based, multiresolution pathway CNNs was trained using fivefold cross-validation. Performance was assessed using the true-positive rate (TPR) and number of false-positive (FP) findings. CNN performance was compared with agreement between physicians by comparing the annotations of a second nuclear medicine physician to the first reader in 20 of the patients. Patient TPR was compared using Wilcoxon signed rank tests. RESULTS:Across all 90 patients, a range of 0-61 nodes per patient was detected. At an average of four FP findings per patient, the method achieved a TPR of 85% (923 of 1087 nodes). Performance varied widely across patients (TPR range, 33%-100%; FP range, 0-21 findings). In the 20 patients labeled by both physicians, a range of 1-49 nodes per patient was detected and labeled. The second reader identified 96% (210 of 219) of nodes with an additional 3.7 per patient compared with the first reader. In the same 20 patients, the CNN achieved a 90% (197 of 219) TPR at 3.7 FP findings per patient. CONCLUSION/CONCLUSIONS:An ensemble of three-dimensional CNNs detected lymph nodes at a performance nearly comparable to differences between two physicians' annotations. This preliminary study is a first step toward automated PET/CT assessment for lymphoma.© RSNA, 2020.