Pretreatment Metabolic Tumor Volume Research Articles

Tumor burden quantified by Soluble B-Cell Maturation Antigen and Metabolic Tumor Volume determine myeloma CAR-T outcomes.

Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a breakthrough treatment for relapsed and refractory multiple myeloma (RRMM). However, these products are complex to deliver and alternative options are now available. Identifying biomarkers that can predict therapeutic outcomes is crucial for optimizing patient selection. There is a paucity of data evaluating the utility of both serum soluble B-cell maturation antigen (sBCMA) levels and metabolic tumor volume (MTV) at baseline in patients with RRMM undergoing CAR-T therapy. We identified a cohort of 183 patients with available serum to measure sBCMA and/or pre-treatment MTV, derived from positron emission tomography-computed tomography (PET-CT) scans obtained per standard of care. Expectedly, high pre-treatment levels of sBCMA correlated with other established markers of tumor burden (e.g., bone marrow plasma cells/BMPCs, beta2 microglobulin) and inflammation, and were highly prognostic for CAR-T related toxicities and inferior progression free survival (PFS). High MTV values were also associated with shorter PFS and inferior overall survival (OS). The poor correlation observed between these two measures prompted evaluation of those with discordant results, identifying that those with low sBCMA and high MTV frequently had low/absent BCMA expression on plasma cells and suboptimal response. Our findings highlight the potential utility of sBCMA and MTV to facilitate more personalized treatment strategies in the management of RRMM eligible for BCMA directed CAR-T.

Prognostic Role of Pretreatment Tumor Burden and Dissemination Features From 2-[18F]FDG PET/CT in Advanced Mantle Cell Lymphoma.

Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma with poor prognosis. The usefulness of fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (2-[18F]FDG PET/CT) and its parameters in the evaluation of treatment response and prognosis is not yet clear. The aim of this study was to investigate the prognostic role of tumor burden and tumor dissemination features derived by 2-[18F]FDG PET/CT in advanced MCL. We retrospectively included 120 patients with advanced MCL who underwent baseline 2- 2-[18F]FDG PET/CT and end-of-treatment (eot) PET/CT. The baseline-PET images were analyzed visually and semi-quantitatively by measuring the maximum standardized uptake value body weight (SUVbw), lean body mass (SUVlbm), body surface area (SUVbsa), metabolic tumor volume (MTV), total lesion glycolysis (TLG) and dissemination features (Dmax and Dmax-bsa). EotPET/CT was judged according to the Lugano classification. Progression-free survival (PFS) and overall survival (OS) were plotted according to the Kaplan-Meier method. At a median follow-up of 59months, relapse/progression occurred in 68 patients while death in 38 patients with a median PFS and OS of 27.2 and 57.6months, respectively. MIPI score, Bulky disease, Ki-67 index, metabolic response, pretreatment MTV and TLG were significantly associated with PFS at univariate analysis, but only metabolic response, MTV and TLG were confirmed to be independent prognostic factors. Considering OS, only dissemination features were demonstrated to be prognostic features. In conclusions, metabolic response and metabolic tumor burden parameters (MTV and TLG) are strongest predictor of PFS, while dissemination features may have a significant role for predicting OS.

PET/CT Biomarkers Enable Risk Stratification of Patients with Relapsed/Refractory Diffuse Large B-cell Lymphoma Enrolled in the LOTIS-2 Clinical Trial.

Significant progress has occurred in developing quantitative PET/CT biomarkers in diffuse large B-cell lymphoma (DLBCL). Total metabolic tumor volume (MTV) is the most extensively studied, enabling assessment of FDG-avid tumor burden associated with outcomes. However, prior studies evaluated the outcome of cytotoxic chemotherapy or chimeric antigen receptor T-cell therapy without data on recently approved FDA agents. Therefore, we aimed to assess the prognosis of PET/CT biomarkers in patients treated with loncastuximab tesirine. We centrally reviewed screening PET/CT scans of patients with relapsed/refractory DLBCL enrolled in the LOTIS-2 (NCT03589469) study. MTV was obtained by computing individual volumes using the SUV ≥4.0 threshold. Other PET/CT metrics, clinical factors, and the International Metabolic Prognostic Index (IMPI) were evaluated. Logistic regression was used to assess the association between biomarkers and treatment response. Cox regression was used to determine the effect of biomarkers on time-to-event outcomes. We estimated biomarker prediction as continuous and binary variables defined by cutoff points. Across 138 patients included in this study, MTV with a cutoff point of 96 mL was the biomarker associated with the highest predictive performance in univariable and multivariable models to predict failure to achieve complete metabolic response (OR, 5.42; P = 0.002), progression-free survival (HR, 2.68; P = 0.002), and overall survival (HR, 3.09; P < 0.0001). IMPI demonstrated an appropriate performance, however, not better than MTV alone. Pretreatment MTV demonstrated robust risk stratification, with those patients demonstrating high MTV achieving lower responses and survival to loncastuximab tesirine in relapsed/refractory DLBCL.

Optimization of Metabolic Tumor Volume as a Prognostic Marker in CAR T-Cell Therapy for Aggressive Large B-cell NHL

BackgroundCD19-targeted chimeric antigen receptor (CAR) T-cell therapy has become a standard of care in relapsed/refractory (R/R) aggressive large B-cell non-Hodgkin lymphomas (B-NHL) though the majority of recipients do not receive durable disease benefit, prompting the need to better define risk factors for relapse/progression. ObjectivesWe performed a single-center, retrospective analysis of patients treated with commercial CAR T-cell therapy to evaluate the impact of tumor burden, as measured by whole-body metabolic tumor volume (MTV) from 18F fluorodeoxyglucose PET imaging, on treatment outcomes. Study DesignSixty-one patients treated with CAR T-cell therapy for R/R B-NHL between May 2016 and November 2021 were included. ResultsUsing a receiver operating characteristic curve-based MTV optimization cutoff of 450 mL, 1-year progression-free survival (PFS) was 22% for high MTV versus 54% for low MTV (P < .01), and 1-year overall survival (OS) was 37% and 73%, respectively (P = .01). In a subset of 46 patients, residual MTV of less than 106 mL at the day 30 (D30) disease assessment was associated with significantly improved outcomes (1-year OS 85% vs. 13%, P < .01). Incorporation of pretreatment MTV to the International Prognostic Index (IPI) scoring system significantly distinguished 2-year PFS and OS outcomes by 3 risk groups. ConclusionsOur findings suggest that both pretreatment and D30 MTV are predictive of outcomes among R/R B-NHL patients treated with CAR T-cell therapy. These data indicate that efforts to reduce pretreatment tumor burden may improve longitudinal clinical outcomes. Furthermore, D30 postinfusion MTV quantification may aid clinicians in optimally identifying patients at high-risk for progression, and in whom closer disease monitoring should be considered. MTV also adds prognostic value to patients with high-risk IPI and holds promise for incorporation in novel risk scoring systems which can identify patients prior to CAR T-cell therapy at highest risk of adverse outcomes.

Prognostic significance of 18F-FDG PET/CT indices in metastatic renal cell cancer and evaluation of revised IMDC risk model by including 18F-FDG PET-CT parameters.

Prognostic markers in metastatic renal cell cancer (mRCC) are still insufficient. Any prognostic model objectively determines disease burden. To investigate the relationship between 18-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) parameters and outcomes in mRCC, and to define a revised International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model for the intermediate-risk group. A retrospective study of mRCC was conducted. To investigate the prognostic significance of 18F-FDG PET/CT parameters, maximum standardized uptake value (SUVmax), total lesion glycolysis (TLG), and metabolic tumor volume (MTV) were determined in pre-treatment images. Cutoff values were defined by ROC curve analyses and their association with outcomes was analyzed. Additionally, a TLG-adjusted IMDC model was created by stratifying intermediate-risk group patients according to TLG levels. The study included 52 patients. The disease control rate (DCR) was 61.5% and median overall survival (OS) was 18 months (95% confidence interval=9.2-25.8). In the univariate analyses, IMDC score, MTV, and TLG were prognostic factors for Disease Control Rate (DCR), and Eastern Cooperative Oncology Group (ECOG)-Performance Status (PS), IMDC score, lactate dehydrogenase (LDH), treatment option, MTV, and TLG were prognostic factors for OS (P < 0.05 each). In the multivariate analyses, MTV was an independent prognostic factor for DCR, and ECOG-PS, LDH, IMDC score, and TLG were independent prognostic factors for OS. According to the revised-IMDC model, the intermediate-favorable group showed longer OS than the intermediate-unfavorable group. Pretreatment MTV was independent prognostic factor for DCR and ECOG-PS, LDH, IMDC score, and TLG were independent prognostic factors for OS. Revised-IMDC model could identify patients with a worse prognosis among the IMDC intermediate-risk group.

Pre-treatment FLT-PET parameters as a prognostic tool for patients with locally advanced recurrent nasopharyngeal carcinoma salvaged by carbon-ion radiotherapy: a pilot study

Although carbon-ion radiotherapy (CIRT) may improve outcome for patients with locoregionally recurrent nasopharyngeal carcinoma (LR-NPC), local progression still remains one of the major failure patterns. This suggests an unmet need of markers for predicting disease control after re-irradiation and potentially guiding tailored treatment. The purpose of this study was to explore the predictive value of pre-treatment 3'-deoxy-3'-[18F]fluorothymidine (FLT)-positron emission tomography (PET) for patients with locally advanced LR-NPC. In this retrospective analysis, LR-NPC patients with locally advanced stage (stage III/IV) who received pre-treatment FLT-PET between June, 2015, and August, 2017, were retrospective reviewed and included in this study. OS and local progression-free survival (LPFS) were calculated using the Kaplan-Meier method. Univariable and multivariable Cox regression analyses of LPFS were performed. FLT-derived parameters, including SUVmax, metabolic tumor volume (MTV), and total lesion thymidine (TLT) were examined. The relationship between FLT-derived parameters and mucosal necrosis was tested by the Wilcoxon test. A total of 27 patients with a median follow-up of 31.3 months were included in this analysis. The 2-year OS and LPFS rates were 85.2% and 47.9%, respectively. In multivariable analysis, except for TLT-40% (P=0.059), all pre-treatment MTVs (P=0.040 for MTV-40%; P=0.021 for MTV-50%; P=0.026 for MTV-60%) and TLTs (P=0.043 for TLT-50%; P=0.048 for TLT-60%) were significantly related to LPFS. Moreover, MTVs and TLTs with various boundaries (except for MTV-40%) were also associated with the development of mucosal necrosis after CIRT. In the current study, a significant association between pre-treatment FLT-PET and LPFS was observed in patients with locally advanced LR-NPC. Further investigations are warranted to confirm the predictive role of FLT-PET.

Prognostic Value of Primary Tumor and Nodal FDG-PET Sub-Volumes in Cervical Cancer Patients Treated with Definitive Chemoradiation

<h3>Purpose/Objective(s)</h3> The prognostic value of total disease burden FDG-PET metabolic tumor volume (MTV) and total lesion glycolysis (TLG) in cervical cancer has previously been demonstrated. These parameters in the independent analysis of primary cervical tumor (PT), pelvic nodal disease (PND), and para-aortic nodal disease (PAND) sub-volumes are not known. We evaluated PET characteristics of these sub-volumes as a potential predictor of patient outcomes. <h3>Materials/Methods</h3> This retrospective study included cervical cancer patients who received definitive chemoradiation (CRT). Lesions in pre- and post-treatment FDG-PET scans were segmented with a fixed SUVmax threshold of 2.5 to calculate MTV and TLG for PT, PND, and PAND sub-volumes. SUV, MTV, and TLG were treated as continuous variables for analysis. <h3>Results</h3> Between 2015-2021, 100 patients treated with definitive CRT had PET scans available for analysis. Median age was 50 years and 72% had squamous cell carcinomas. 33% had localized disease (FIGO I, II), 15% were locally advanced (IIIA, IIIB, IVA), and 52% had lymph node positive disease (IIIC1, IIIC2). Most (85%) received 4 or more cycles of weekly concurrent chemotherapy. One- and five-year OS were 89.5% and 70.2%, respectively. Age, histology, HPV status, grade, stage, and receipt of chemotherapy were not associated with DFS. Bilateral parametrial involvement was statistically significant for DFS (HR 3.1, p = 0.01). On pre-treatment PET, the SUVmax of the PT, PND, and PAND was not significant predictors for DFS. Higher PT TLG and MTV were associated with poorer DFS (p = 0.007 and <0.001, respectively). Higher PND MTV was associated with poorer DFS (p = 0.022) but TLG did not reach significance (p = 0.058). Higher PAND TLG and MTV were not associated with DFS. Characteristics associated with worse OS included age >50 years, negative HPV status, stage, bilateral parametrial involvement, radiation treatment time >49 days, and lack of concurrent chemotherapy (all p < 0.05). Pre-treatment SUVmax of the PT, PND, and PAND were not significant predictors for OS. Higher PT TLG and MTV were associated with poorer OS (p = 0.023 and <0.01, respectively). Higher PND MTV was associated with poorer OS (p = 0.047) but not TLG (p = 0.129). Higher PAND TLG and MTV were not associated with OS. Among 28 pts with recurrence, 82% had distant metastases, 7% had out-of-field nodal relapse, and 11% relapsed within the radiation field. The percent change in pre- to post-treatment PT SUVmax was associated with development of distant metastases (p = 0.034). Percent change of TLG or MTV were not predictive of recurrence. <h3>Conclusion</h3> Pre-treatment FDG-PET PT TLG and MTV and PND MTV were predictive of DFS and OS in patients undergoing CRT for cervical cancer. Percent change in pre- to post-treatment PT SUVmax was predictive of distant metastases. Further study is needed to characterize the utility of these variables in informing treatment paradigms for cervical cancer.

Pretreatment [18F]FDG PET/CT and MRI in the prognosis of nasopharyngeal carcinoma.

The present study aimed to assess the prognostic interest of metabolic and anatomic parameters derived from 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography ([18F]FDG PET/CT) and head and neck magnetic resonance imaging (HN-MRI) for better management of nasopharyngeal carcinoma (NPC). In this study, pre-treatment [18F]FDG PET/CT and HN-MRI parameters of NPC patients diagnosed between January 2017 and December 2018, were prospectively investigated. Correlation between those parameters and 4-year patient's survival outcomes was evaluated using Kaplan-Meier and Cox-regression analyses. Our results revealed a significant association between pre-treatment nodal-maximum standardized uptake value (N-SUV max) and N categories (p = 0.01), between pre-treatment node-to-tumor SUV ratio (NTR) and both tumor size (p = 0.01) and N categories (p = 0.009), as well as between metabolic tumor volume (MTV) and both tumor size and NPC overall stage (p < 0.000). In multivariate analyses, pre-treatment N-SUV max, NTR and MTV were significant independent predictors of overall survival, distant metastasis-free survival, and progression-free survival (PFS) (p < 0.05). N-SUV max and MTV were also found to be significant independent predictors of loco-regional recurrence-free survival (p < 0.05), whereas HN-MRI detection of skull-base bone invasion was an independent factor associated with worse PFS in NPC (p = 0.03). The present study highlights N-SUV max, NTR and MTV derived from [18F]FDG PET/CT, and skull-base bone invasion defined by HN-MRI, as promising metabolic and anatomic prognosis biomarkers for NPC.

The prognostic effect of pretreatment 18F-FDG PET/CT metabolic parameters in locally advanced Esophageal Squamous Cell Carcinoma treated with definitive chemoradiotherapy

IntroductionIn this study, we aimed to examine the relation between pre-treatment 18F-FDG PET/CT metabolic parameters [(including the maximum standard uptake value (SUVmax), metabolic tumor volume (MTV), and tumor lesion glycolysis (TLG)] and treatment response and survival in locally-advanced Esophageal Squamous Cell Cancer (ESCC) treated with definitive chemoradiotherapy (dCRT). MethodsA total 76 patients with locally-advanced ESCC who received dCRT between June 2015 and December 2019 were included in this retrospective study. Patients were divided into two groups as complete response (CR) or non-complete response (Non-CR) according to response to treatment. AUC was obtained as 0.749 (p < 0.001) in the ROC curve drawn by MTV for the CR. The MTV value was ≤12 cm3, with 72.1% sensitivity and 73.0% specificity. ResultsOf the 76 patients, 38 (50%) were male and 38 (50%) were female. The median age was 62 (39–84) years. The treatment response in 35 (46%) patients was CR. MTV value was >12cm3 in 41(54%) patients. Median follow-up time was 14.5 months. In patients with MTV>12cm3, median progression-free survival(mPFS) and median overall survival(mOS) were 9 months and 11 months, respectively, whereas mPFS and OS could not be reached in those with MTV≤12 cm3 (p < 0.001 and p < 0.001, respectively). In patients with non-CR, mPFS and mOS were 8 months and 9 months, respectively, whereas mPFS and OS could not be reached in patients with CR (p < 0.001 and p < 0.001, respectively). In multivariate analysis, age (odds ratio [OR], 1.07), ECOG PS (OR, 11.1), and MTV (OR, 4.73) were found to be the factors affecting treatment response. ConclusionIn our study, treatment response and MTV were found to be the factors associated with survival in patients treated with dCRT, showing the pre-treatment MTV value as a predictor of treatment response.

Early Toxicity and Patient Reported Outcomes From a Phase 2 Trial of FDG-PET Response-Based De-Escalated Definitive Radiotherapy for p16+ Oropharynx Cancer

<h3>Purpose/Objective(s)</h3> Pre- and mid-treatment FDG-PET parameters are prognostic of treatment response in p16+ oropharynx cancer (OPC). Our prospective Phase 2 de-escalation study utilizes FDG-PET response criteria to select patients eligible for de-escalated radiotherapy and hypothesizes that early swallow function and quality of life will improve with lower dose radiation. <h3>Materials/Methods</h3> Eligibility criteria stipulated stage I-II (AJCC 8) p16+ OPC with FDG-avid disease. Patients with matted lymph nodes or history of head and neck surgery were excluded. All patients received concurrent weekly carboplatin/paclitaxel. FDG-PET was obtained at baseline and at fraction 10. Patients were de-escalated to 54 Gy in 27 fractions if both pretreatment metabolic tumor volume (MTV) 50% of SUVmax was ≤22cc and interval MTV above SUV 2.5 decreased ≥50% from baseline. Those not meeting FDG-PET response criteria received 70 Gy in 35 fractions. Planned interim analysis examined early toxicity and patient-reported outcomes (PROs: xerostomia questionnaire, UWash QoL, FACT-HN, PRO-CTCAE) after accrual of 48 of 75 evaluable patients. Change from baseline scores of PROs was assessed with a mixed-effects model regarding +/- 0.5 standard deviations as clinically significant, consistent with prior work. <h3>Results</h3> Overall population (n=48) characteristics were: median age 59.5 years, 85% male, 44% ever smoker with 20 pack-year median, 90% T1-2, and 81% N1 and similar between cohorts. Pre-treatment GTV size was not different (30.8 cc 54 Gy vs 33.1 cc 70 Gy cohort, p=0.54). Exactly 50% of patients (n=24) met the de-escalation cohort criteria with median decrease in interval MTV_2.5 of 63% (IQR 56-82%) vs median decrease of 26% (IQR 4-40%) among the 70 Gy cohort. The dose to the larynx, constrictors, oral cavity, and salivary glands in the 54 Gy cohort was 70-78% of that received by the 70 Gy cohort (all comparisons p<0.01). De-escalated patients lost significantly less weight as percent of baseline (7.0% vs 11.5%, p<0.001) and fewer required feeding tube placement during treatment (1 vs 5, p=0.08). The 70 Gy cohort also had significantly worse videofluoroscopic swallowing function at 3 months compared to baseline with average increase in Penetration Aspiration Scale of 2 points (vs 0 points in the 54 Gy cohort, p=0.023). Across all 4 PRO surveys, while 54 Gy patients reported faring numerically better than the 70 Gy patients at 1 month post-treatment, this did not reach clinical or statistical significance. <h3>Conclusion</h3> Mid-treatment FDG-PET response adaptation allows for approximately half of stage I-II p16+ OPC patients to be de-escalated to 54 Gy. This results in an approximately 25% reduction in dose delivered to organs known to affect toxicity and quality of life with significantly better objective measures of toxicity and numerically improved PROs.

Prognostic Value of Pretherapeutic Primary Tumor MTV from [18F]FDG PET in Radically Treated Cervical Cancer Patients.

The aim of this study was to assess the usefulness of pretherapeutic primary tumor metabolic tumor volume (MTV) in the prognosis of radically treated cervical cancer patients. Retrospective, single-centre analysis was performed on a group of 508 cervical cancer patients. All patients underwent a pretreatment [18F]FDG PET/CT study for the assessment of the disease stage. Several PET-derived parameters—namely, maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), total lesion glycolysis (TLG) and MTV, as well as the clinical parameters, were analysed in terms of the overall survival (OS), event-free survival (EFS), locoregional control (LRC) and freedom from distant metastases (FFDM). Hyperthermia and brachytherapy were prognostic for EFS, OS, and LRC.FIGO stage > II showed a significant effect on EFS, OS, and FFDM. Moreover, hysterectomy was prognostic for OS and histology was prognostic for FFDM. From the PET-derived parameters only MTV of the primary tumor had a significant influence on OS (cutoff point: >12.7 mL, HR: 2.8, 1.75–4.48 95% CI, p < 0.001), LRC (cutoff point: >13.7 mL, HR 2.82, 1.42–5.61 95% CI, p = 0.003), EFS (cutoff point: >10.4 mL, HR: 2.57, 1.67–3.97 95% CI, p < 0.001) and FFDM (cutoff point: >10.4 mL, HR: 5.04, 1.82–13.99 95% CI, p = 0.002). Pretreatment MTV from the primary tumor is the only independent prognostic parameter in OS, LRC, EFS, and FFDM in radically treated cervical cancer patients and should be used in clinical practice in assessing prognosis in these patients.

The role of pre-treatment and mid-treatment 18F-FDG PET/CT imaging in evaluating prognosis of peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS)

BackgroundIt has been reported the prognostic value of MTV in predicting the disease prognosis of peripheral T-cell lymphoma (PTCL) through pre-treatment PET/CT imaging. However, these are limited data on pretreatment evaluation and prognosis assessments of peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS). This study aimed to determine the prognostic values of pre-treatment and mid-treatment total metabolic tumor volume (MTV), total lesion glycolysis (TLG), and Deauville 5-Point Scale (D-5PS) in accessing the prognosis of PTCL-NOS.MethodsA retrospective analysis was conducted in 31 patients with pathologically diagnosed PTCL-NOS. These patients have undergone positron emission PET/CT scanning before and during chemotherapy. Follow-ups were also done to investigate the 2-year progression-free survival (PFS) and Overall Survival (OS) of these patients. During {}^{18}F-fluorodeoxyglucose ({}^{18}F-FDG) PET/CT scans, the MTV and TLG were recorded. Meanwhile, bigtriangleupMTV and bigtriangleupTLG were calculated. Furthermore, the receiver operating characteristic (ROC) curve was employed to classify and to define the threshold values. On the other hand, the mid-chemotherapy assessment and staging of these 31 patients were done by utilizing D-5PS. Subsequently, based on the D-5PS scores obtained, these patients were grouped into two categories: a group of patients with a score of <4 and another group with ge4 points. For these two groups of patients, the survival analysis was done by Kaplan–Meier analysis and a multivariate COX regression model. Moreover, Pearson’s chi-square test (chi ^{2} test) and Spearman rank correlation coefficient were used to comparing the collected data, respectively.ResultsDuring the 2-year follow-up period, 15 out of the 31 patients experienced disease progression. The optimal threshold values for both baseline MTV and TLG were 158.16 cm^{3} and 677.40.Additionally, the difference in 2-year PFS between the progressive and non-progressive groups was statistically significant (chi ^{2}=8.193, P=0.004<0.05; chi ^{2}=8.872, P=0.003<0.05), significant between-group difference was detected for MTV and for TLG (chi ^{2}=6.494, P=0.011<0.05; chi ^{2}=4.687, P=0.03<0.05). On the other hand, when these patients were classified into two groups according to the mid-chemotherapy Deauville score of <4 and ge4, the statistical difference of 2-year PFS between these two groups was significant, too (chi ^{2}=14.966, P=0.001<0.05),but there is no significant between-group difference in OS (chi ^{2}=3.337, P=0.068<0.05). COX analysis revealed that D-5PS are the independent factors influencing PFS, while MTV is the independent influencing factor of OS.ConclusionThe baseline total MTV obtained by PET/CT scanning, and D-5PS are crucial prognostic factors in evaluating the prognosis of PTCL-NOS.

Circulating Tumor DNA Is a Reliable Measure of Tumor Burden at Diagnosis of Diffuse Large B Cell Lymphoma: An International Reproducibility Study

▪Background: Pretreatment tumor burden is a known prognostic factor in diffuse large B cell lymphoma (DLBCL). Components of the International Prognostic Index (IPI), including lactate dehydrogenase (LDH) and clinical stage, attempt to capture tumor burden but lack specificity. Tumor volume is an alternative metric for disease burden, but requires specialized radiographic interpretation. We recently described circulating tumor DNA (ctDNA) levels as a novel quantitative biomarker for disease burden in DLBCL (Scherer F and Kurtz DM, Sci Transl Med 2016). To validate the performance of ctDNA across a diverse cohort of patients and medical centers, we assessed pretreatment ctDNA levels in patients with DLBCL from six centers around the world.Methods: We performed Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) on pretreatment cell-free and germline DNA from patients undergoing curative-intent anthracycline-based therapy. Somatic mutations were identified and variant allele fractions were determined. Levels of ctDNA were determined using the mean tumor allele fraction and the total concentration of cell-free DNA; absolute concentration of ctDNA was expressed as haploid genome equivalents per mL (hGE/mL). Finally, we correlated levels of ctDNA with clinical factors including stage, IPI, pretreatment metabolic tumor volume (MTV), and patient outcomes.Results: A total of 183 patients from six centers were enrolled (Stanford University, n=52; University of Eastern Piedmont, n=36; MD Anderson Cancer Center, n=21; Hospital Le Bocage, Dijon, n=25; the National Cancer Institute, n=33; and University Hospital Essen, n=16). Pretreatment cell-free DNA was sequenced deeply; ctDNA was detectable prior to therapy in 97% of patients. The performance of ctDNA detection was consistent across cohorts, with >90% of patients from each center having detectable ctDNA. Concentration of ctDNA was not significantly different across cohorts, with a median of 295 hGE of tumor DNA / mL (one-way ANOVA, P=0.62; Fig 1A). Using pretreatment plasma, all but 5 patients had mutations identifiable via non-invasive genotyping without knowledge of tumor genotype. In 88 patients with tumor samples available, a median of 81% (interquartile range: 34-92%) of variants identified via non-invasive genotyping were confirmed by tumor sequencing on a per-patient basis.We next sought to correlate levels of ctDNA with independent measures of tumor burden. We found a significant difference in ctDNA levels between patients in different IPI risk groups (one-way ANOVA, P<0.0001; Fig 1B). We also found that patients with higher-stage disease had higher ctDNA levels (P<0.0001); ctDNA levels also correlated with LDH (P<0.0001). We demonstrated a robust correlation between MTV and ctDNA level (P<0.0001; Fig 1C). This correlation was consistent across all three cohorts with MTV available (Essen: P=0.0005, r=0.80; Dijon: P<0.0001, r=0.73; Stanford: P=0.006, r=0.50). Finally, pretreatment ctDNA concentration was continuously associated with EFS and OS (P<0.0001 and P=0.0014). Using the median to divide patients into groups with high or low ctDNA, we found patients with high ctDNA levels had significantly inferior EFS compared to those with low ctDNA (P=0.005, HR 2.7, 95% CI 1.4-4.6; Fig 1D).Conclusions: Circulating tumor DNA is a robust biomarker of disease burden in DLBCL in patients from multiple medical centers across North America and Europe. Patients from different centers have similar levels of ctDNA despite pre-analytical variation. Concentrations of ctDNA correlate with stage, IPI, and tumor volume; furthermore, ctDNA level prior to therapy is prognostic of clinical outcome. This study validates previous findings and provides evidence that ctDNA is a reliable biomarker in aggressive lymphomas that could be used to refine clinical estimates of disease burden including stage.Figure 1: Reproducibility and clinical significance of pretreatment ctDNA. A) A stacked scatter plot compares ctDNA levels from patients across 6 cohorts. B) A stacked scatter plot shows ctDNA levels from patients with different IPI risk categories. C) A scatter plot compares metabolic tumor volume to ctDNA level. D) A Kaplan Meier estimate demonstrates event-free survival from the start of therapy for patients with pretreatment ctDNA level above and below the median value. (ND: Not detected). [Display omitted] DisclosuresHüttmann:Bristol-Myers Squibb, Takeda, Celgene, Roche: Honoraria; Gilead, Amgen: Other: Travel cost. Casasnovas:Roche: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Westin:Apotex: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees. Gaidano:Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Diehn:Roche: Consultancy; Novartis: Consultancy; Quanticel Pharmaceuticals: Consultancy; Varian Medical Systems: Research Funding. Alizadeh:Gilead: Consultancy; CiberMed: Consultancy; Roche: Consultancy; Genentech: Consultancy; Celgene: Consultancy.

Adding value to tumor staging in head and neck cancer: The role of metabolic parameters as prognostic factors.

Validated biomarkers in head and neck squamous cell carcinoma (HNSCC) are scarce. We retrospectively analyzed 62 patients with HNSCC treated with radiotherapy +/- concurrent chemotherapy. Pretreatment metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were measured in a 18 F-FDG positron emission tomography using a liver dependent standardized uptake value threshold. Cox regression analyses were performed to find associations with disease-free survival (DFS) and overall survival (OS). High values of MTV (>37 ml) were independently associated with a worse DFS (hazard ratio [HR] = 3.45; 95% confidence interval [CI], 1.52-7.84) and OS (HR = 3.27; 95% CI, 1.41-7.57). Similar results were found for high values of TLG (>247 g) for DFS (HR = 3.32; 95% CI, 1.44-7.65) and OS (HR = 3.42; 95% CI, 1.45-8.07). MTV and TLG can be considered as independent prognostic factors for DFS and OS in patients with HNSCC. Considering how easily obtainable they are, they may be useful for predicting clinical outcomes in these patients.

The predictive role of metabolic tumor volume on no response to neoadjuvant chemotherapy in patients with breast cancer.

To evaluate the predictive significance of pretreatment metabolic tumor volume on pathologic response in patients who received neoadjuvant chemotherapy for breast cancer. Seventy patients who received neoadjuvant chemotherapy between 2013 and 2017 years were enrolled in the study. Pathologic responses and 18-fluorodeoxyglucose positron emission tomography/computed tomography metabolic dates of patients were obtained from archive files. Forty-six (65.7%) patients were in stage II and 24 (34.3%) patients were in stage III; 25 (35.7%) patients were human epidermal growth factor receptor 2 positive, 46 (65.7%) patients were estrogen receptor-positive, 26 (37.1%) patients were progesterone receptor-positive. According to the Miller-Payne grading system, 24 (34.3%) patients constituted 100% pathological response; patients with 91-99% pathological response were 12 (17.1%), the number of patients with non-pathologic response was 6 (8.6%). Median metabolic tumor volume was 7.3 cm3 (7.1 ± 3.5), 8.8 (11.4 ± 9.4), 7.7 (8.3 ± 4.6) and 22 cm3 (19.8 ± 11.0) in patients with stages IIA, IIB, IIIA, and IIIB, respectively (p = 0.032). In Miller-Payne grading, the median metabolic tumor volume value was higher in patients with no pathologic response group than 100% response group (p = 0.003). The cut-off metabolic tumor volume value determining no pathologic response was calculated as higher than 13.62 cm3 (sensitivity 83.3% and specificity 82.8%). Our study results suggest that higher pretreatment metabolic tumor volume values are predictive on no pathologic response in patients treated with neoadjuvant chemotherapy for breast cancer.

Pretreatment Metabolic Tumor Volume of Primary Tumor and Total Lesion Glycolysis of Lymph Nodes are Predictive in Nasopharyngeal Cancer

Pretreatment Metabolic Tumor Volume of Primary Tumor and Total Lesion Glycolysis of Lymph Nodes are Predictive in Nasopharyngeal Cancer

Short Diagnosis-to-Treatment Interval Is Associated with Higher Levels of Circulating Tumor DNA in Aggressive B-Cell Non-Hodgkin Lymphoma

BACKGROUND Selection biases can impair the generalizability of clinical trials. Studies investigating aggressive diseases such as Diffuse Large B-cell Lymphoma (DLBCL) can be particularly affected by such biases since clinical urgency and need for therapy may not allow the requisite extensive screening and consent processes for trials. Diagnosis-to-Treatment Interval (DTI) has recently been proposed as a novel metric to capture this phenomenon (Maurer et al, JCO, 2018), and short DTI is associated with both adverse clinical factors and adverse clinical outcomes. Intriguingly, DTI was independent of clinical risk factors like the International Prognostic Index (IPI) suggesting that widely applied prognostic scores do not adequately reflect risk factors considered for clinical decision making. In this study, we aim to assess whether pretreatment levels of circulating tumor DNA (ctDNA) are associated with shorter DTI and may constitute an objective measure of clinical urgency. METHODS We quantified pretreatment ctDNA levels in plasma samples from 178 patients treated in 5 US and European centers for large cell lymphoma (DLBCL, Follicular lymphoma grade 3b, or High-grade-B-cell-lymphoma) using Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq) as previously described (Kurtz, JCO 2018; Scherer, STM 2016). Pretreatment ctDNA levels were correlated with DTI, clinical factors and treatment outcome. RESULTS Pretreatment ctDNA was detectable in 175/178 cases. Median number of single nucleotide variants (SNV) detected per patient was 129 (range 0-628). Pretreatment ctDNA levels ranged from 0 - 1.4 x105 haploid genome equivalents per milliliter of plasma (hGE/ml, median 239). Median DTI was 19 days (range 0-141, Figure 1A) and was similar in distribution to 2 previously described cohorts from the US and Europe (Maurer et al, JCO 2018). Shorter DTI was associated with higher ctDNA levels (RS=-0.39, P= 1.4 x10-7, Figure 1B). Patients with longer DTI had improved Event-Free Survival (EFS, Hazard Ratio (HR) for DTI: 0.9/week, P= 0.03). However, this association was lost when adjusting for pretreatment ctDNA levels (HR for DTI: 0.95/week, P= 0.39; HR for log10(ctDNA): 1.7, P= 5.8 x10-5). In a multivariate analysis including DTI, ctDNA and IPI, only ctDNA levels were significantly associated with EFS (HR for log10(ctDNA): 1.6, P= 0.002, n=178, Figure 1C). Pretreatment ctDNA levels remained the only prognostic factor for EFS in a second multivariate analysis also considering pretreatment metabolic tumor volume (MTV, HR for log10(ctDNA): 1.8, P= 0.01, n=93, Figure 1D). DISCUSSION Shorter DTI is associated with higher pretreatment ctDNA levels in patients with aggressive B-cell lymphomas. When comparing to established factors (DTI, IPI, MTV), pretreatment ctDNA levels appear to best predict clinical outcomes. This suggests that quantification of ctDNA better reflects disease burden and treatment urgency than existing clinical biomarkers. Pretreatment ctDNA level may therefore be a valuable metric for disease aggressiveness of patients included in clinical trials, and may help identify studies suffering from selection bias. This may be particularly useful for noncontrolled Phase I/II single arm trials, but also for stratification in randomized trials. Disclosures Kurtz: Roche: Consultancy. Dührsen:Alexion: Honoraria; Novartis: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Honoraria; Takeda: Consultancy, Honoraria; Celgene: Research Funding; CPT: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Teva: Honoraria; Roche: Honoraria, Research Funding. Hüttmann:Takeda: Honoraria; Gilead: Honoraria; University Hospital Essen: Employment. Westin:Juno: Other: Advisory Board; Novartis: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; Unum: Research Funding; MorphoSys: Other: Advisory Board; Genentech: Other: Advisory Board, Research Funding. Gaidano:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra-Zeneca: Consultancy, Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesys: Consultancy, Honoraria. Rossi:Abbvie: Honoraria, Other: Scientific advisory board; Janseen: Honoraria, Other: Scientific advisory board; Roche: Honoraria, Other: Scientific advisory board; Astra Zeneca: Honoraria, Other: Scientific advisory board; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Diehn:Novartis: Consultancy; BioNTech: Consultancy; AstraZeneca: Consultancy; Quanticell: Consultancy; Roche: Consultancy. Alizadeh:Pfizer: Research Funding; Chugai: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Pharmacyclics: Consultancy; Janssen: Consultancy; Genentech: Consultancy; Roche: Consultancy.

Prognostic utility of pre- and post-treatment FDG-PET parameters in anal squamous cell carcinoma

Background and purposeWe prospectively assessed the contributions of PET to initial staging, early detection of treatment failures, and prognostication in patients with anal squamous cell carcinoma (ASCC). Materials and methodsConsecutive patients with ASCC referred for radical chemoradiotherapy (CRT) consented to undergo FDG-PET imaging pre-treatment and at 3 and 6 months post-treatment. Clinicopathologic data were collected and CT and PET imaging reviewed for contribution to staging and recurrence detection. Maximum standardized uptake value (SUVmax), peak standardized uptake value (SUVpeak), metabolic tumour volume (MTV), and total lesion glycolysis (TLG) were assessed for association with progression-free survival (PFS), cause-specific survival (CSS), and overall survival (OS) using the Kaplan–Meier and Cox regression models. ResultsBetween 2009 and 2016, 73 patients with clinical stages I-IIIB ASCC completed curative-intent CRT. Median follow-up was 48 months. 14 patients died and 18 patients experienced disease progression. 4-year PFS, CSS, and OS were 73%, 87%, and 84%, respectively. A pre-treatment MTV >35 cm3 predicted for worse PFS (p = 0.011) and CSS (p = 0.024) on univariate and multivariate analyses, employing an MTV definition of voxels ≥25% of SUVmax. Higher 6-month post-treatment SUVmax and SUVpeak predicted for worse PFS and OS (p ≤ 0.011). Pre-treatment SUVmax, SUVpeak, and TLG, and 3-month post-treatment SUVmax and SUVpeak did not significantly correlate with survival outcomes. ConclusionsOur findings support that pre-treatment MTV provides meaningful prognostic information, with suggestion that an MTV delineation threshold of voxels ≥25% of SUVmax is appropriate in the anal region. Post treatment, the combination of clinical examination and PET effectively detected all treatment failures. Higher 6-month post-treatment SUVmax and SUVpeak predicted worse PFS and OS; however, the optimal timing of post-treatment PET imaging remains unclear.

PET-derived tumor metrics predict DLBCL response and progression-free survival

[18F] fluorodeoxyglucose (FDG) – positron emission tomography (PET)/computed tomography (CT) is used to stage and assess response in diffuse large B-cell lymphoma (DLBCL), though the prognostic value of tumor metrics calculated from interim scans remains unsolved. We investigated the predictive value of interim and end-of-treatment (EOT) metabolic tumor volume (MTV), and total lesion glycolysis (TLG) on progression-free survival (PFS) at 24 months in patients with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Controlling for pretreatment MTV, a positive interim MTV was highly correlated with (0.86) and a significant predictor of a positive EOT MTV (p = .03). Interim MTV > 0 (HR 5.51, CI 1.13, 26.79) and EOT MTV > 4.68 (HR 10.75, CI 1.31, 105.48) were significant predictors of PFS24. Our data show PET-derived metrics of pretreatment and interim MTV offer significant predictive value for EOT response and PFS, and can guide future response-adapted treatment approaches for DLBCL patients that build on the R-CHOP backbone.

Prognostic significance of metabolic tumor volume and total lesion glycolysis in patients with advanced cervical carcinoma.

18-Fluoro-2-deoxy-d-glucose positron emission tomography (18F-FDG PET/CT) is considered to be the most accurate image method of detection of node or distant metastases in cervical cancer. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) of 18F-FDG PET/CT are volumetric measurements of tumor cells with increased 18F-FDG uptake. The prognostic value of MTV and TLG in patients with advanced cervical cancer (ACC) were evaluated. 38 patients with ACC from one tertiary university hospital underwent 18F-FDG PET/CT between June 2009 and December 2015. Clinicopathologic factors and various PET parameters were analyzed to evaluate their relationship with recurrence-free survival (RFS) and overall survival (OS). These parameters were: maximum standardized uptake value (SUVmax), mean standardized uptake value (SUV mean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the primary tumor, of the pelvic nodes, of the paraaortic nodes and the metabolic volume of the metastases if any. A total of 38 patients with ACC fulfilled the inclusion criteria. All of them underwent a 18F-FDG PET/CT before definitive chemoradiotherapy. In the univariate analyses higher tumor size, pelvic lymph node metastasis and both MTV and TLG showed a significant association with OS and with RFS (MTV HR=1.55, p=0.011 and TLG HR=1.43, p=0.017 for RFS and MTV HR=1.82, p=0.006 and TLG HR=1.67, p=0.007 for OS). Pretreatment TLG sum and MTV sum seem to be independent prognostic factors for OS and RFS in patients with advanced cervical cancer treated with definitive chemoradiotherapy and they are better than the classic measurement of SUVmax.