Baseline PET Research Articles

Putaminal dopamine turnover in de novo Parkinson disease predicts later motor complications.

To investigate the predictive value of striatal dopamine turnover in patients with de novo Parkinson disease (PD) for the onset of later motor complications. This retrospective, observer-blinded cohort study followed up 31 patients with early PD who completed quantitative (18)F-dopa PET imaging to measure striatal (18)F-dopa uptake (Kocc) and effective distribution volume ratio (EDVR) as the inverse of dopamine turnover prior to antiparkinsonian treatment. The onset of wearing-off and dyskinesias was determined based on blinded clinical assessments and patient records. The predictive value of baseline PET measures for motor complications was evaluated using Cox proportional hazard models. During a mean follow-up time of 6.8 years, 18 (58.1%) patients developed wearing-off, 11 (35.5%) dyskinesia, and 20 (64.5%) any motor complication. Patients with dyskinesia and any motor complication showed lower baseline EDVR (higher dopamine turnover) in the putamen than those without dyskinesias and any motor complication, with differences most markedly present in the posterior putamen. Baseline EDVR in the whole and the posterior putamen predicted development of motor complications with an increasing risk with lower EDVR (higher dopamine turnover), whereas EDVR in other regions and Kocc did not correlate with motor complications. Correspondingly, Kaplan-Meier curves showed reduced survival from motor complications in patients with lower baseline EDVR (higher dopamine turnover) in the posterior putamen with ongoing levodopa treatment and disease duration. Elevated putaminal dopamine turnover in de novo PD is associated with an increased risk for later motor complications and comprises a disease-intrinsic predisposing factor for their development.

Assessment of Total Lesion Glycolysis and Metabolic Tumor Volume Improve the Clinical Value of Focal Lesion Assessment By FDG PET/CT in Myeloma

Introduction: Focal lesions are important anatomical features seen in the bone marrow of multiple myeloma patients that contribute to drug resistance and disease relapse. Fluroine-18 fluorodexyglucose positron emission tomography with CT attenuation correction ( 18 F-FDG PET/CT) is useful in the detection and enumeration of focal lesions and in semi-quantitative characterization of metabolic activity by calculation of glucose uptake reported as a standardized uptake value (SUV). Lesion count and SUV are predictors of outcome. Two additional variables, total lesion glycolysis (TLG) and metabolic tumor volume (MTV) can also be assessed and have the potential to improve the value of this approach. The purpose of this study was to determine whether TLG and MTV can predict progression free survival (PFS) and overall survival (OS), and to determine whether they are superior to traditional assessment methods. Materials and Methods: 191 patients underwent whole body PET/CT in the Total Therapy 3A trial and were evaluated using 3 dimensional region of interest analysis with TLG, MTV, and standard measurement parameters derived for all focal lesions with peak SUV above the background red marrow signal. Survival analysis was performed using Kaplan-Meier and log-rank tests. Univariate and multivariate analyses were performed using Cox proportional hazards regression . Results: Baseline characteristics show that 43/191 patients (23%) had no detectable lesions by PET. 1-3 lesions were present in 55/191 (28%) of patients and over 3 lesions in 93/191 (49%) of patients. A baseline TLG >205g was seen in 18% (34/191) of patients, with a TLG >620g being seen in 7% (14/191). A baseline MTV >210cm 3 was seen in 7% (14/191). The distribution of patients with high TLG scores between molecular subgroups was not even with patients in the PR, MF and HY subgroups having higher scores. The 3 year PFS and OS for patients with no PET focal lesions was 83.1% and 88.3%, for patients with 1-3 lesions was 83.9%, and 85.5%, and for patients with >3 lesions 59.6% and 63.5% (p 3 at 81.4% and 84.7%, compared to patients with a baseline MTV of greater than 210cm 3 of 21.4% and 28.6% (p On univariate analysis baseline PET/CT with >3 focal lesions (HR 1.92, 95% CI 1.22-3.04, p=0.004), TLG >205g (HR 2.99, 95% CI 1.83-4.88, p 620g (HR 6.90, 95% CI 3.67-12.97, p 210cm 3 (HR 6.20, 95% CI 3.33-11.54, p 620g retained prognostic significance for predicting PFS and OS together with high B2M, LDH and GEP based proliferation. Importantly baseline TLG >620g and baseline MTV >210cm 3 were statistically more predictive of poor PFS and OS than baseline PET with >3 focal lesions in both univariate and multivariate models. Conclusion : TLG assessment is superior to counting the number of focal lesions. It is the optimum method for evaluating the extent of focal lesions and to predict clinical outcome. As this measurement can be standardized using FDA approved software, it should be utilized clinically and in trials going forward. Disclosures McDonald: University of Arkansas for Medical Sciences: Employment. Waheed: University of Arkansas for Medical Sciences: Employment. Ntambi: University of Arkansas for Medical Sciences: Employment. van Rhee: University of Arkansa for Medical Sciences: Employment. Zangari: University of Arkansas for Medical Sciences: Employment; Novartis: Research Funding; Onyx: Research Funding; Millennium: Research Funding. Heuck: Janssen: Other: Advisory Board; Millenium: Other: Advisory Board; Foundation Medicine: Honoraria; Celgene: Consultancy; University of Arkansas for Medical Sciences: Employment. Petty: University of Arkansas for Medical Sciences: Employment. Schinke: University of Arkansas for Medical Sciences: Employment. Thanendrarajan: University of Arkansas for Medical Sciences: Employment. Mitchell: Cancer Research and Biostatistics: Employment. Hoering: Cancer Research and Biostatistics: Employment. Barlogie: International Workshop on Waldenstrom9s Macroglobulinemia: Other: Travel Stipend; ComtecMed- World Congress on Controversies in Hematology: Other: Travel Stipend; European School of Haematology- International Conference on Multiple Myeloma: Other: Travel Stipend; Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Myeloma Health, LLC: Patents & Royalties: Co-inventor of patents and patent applications related to use of GEP in cancer medicine licensed to Myeloma Health, LLC; Dana Farber Cancer Institute: Other: Travel Stipend; Multiple Myeloma Research Foundation: Other: Travel Stipend. Morgan: Weisman Institute: Honoraria; CancerNet: Honoraria; MMRF: Honoraria; University of Arkansas for Medical Sciences: Employment; Bristol Myers Squibb: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Takeda-Millennium: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding. Davies: Array-Biopharma: Membership on an entity9s Board of Directors or advisory committees; Takeda-Millennium: Membership on an entity9s Board of Directors or advisory committees; University of Arkansas for Medical Sciences: Employment; Onyx-Amgen: Membership on an entity9s Board of Directors or advisory committees; Celgene: Membership on an entity9s Board of Directors or advisory committees.

Randomized Phase III Study Comparing an Early PET Driven Treatment De-Escalation to a Not PET-Monitored Strategy in Patients with Advanced Stages Hodgkin Lymphoma: Interim Analysis of the AHL2011 Lysa Study

BACKGROUNDEscalated BEACOPP (BEAesc) demonstrated a better disease control than ABVD but no overall survival (OS) improvement in patients with advanced Hodgkin Lymphoma (HL) (Federico et al , J Clin Oncol 2009, Viviani et al, N Engl J Med 2011, Mounier et al, Ann Oncol 2014). The superior efficiency of BEAesc is associated to a substantially higher immediate hematological toxicity, and an increased risk of secondary myelodysplasia/leukemia and infertility. So, to better manage HL treatment there is a need to identify early responding patients able to benefit from a strategy of dose intensity de-escalation after upfront BEAesc, without impairing the disease control. PET performed after 2 cycles of chemotherapy (PET2) might identify such a population suitable for receiving ABVD after 2 cycles of upfront BEAesc, and was implemented in the present study.METHODSThe AHL 2011 trial (NCT01358747) was designed to evaluate in 16 to 60 years old HL patients with Ann Arbor stage III, IV or high risk IIB, a treatment strategy driven by PET after 2 BEAesc cycles (PET2), delivering 4 cycles of ABVD for PET2 negative patients and 4 cycles of BEAesc for PET2 positive patients. This PET-driven strategy was randomly compared to a standard treatment not monitored by PET and delivering 6 cycles of BEAesc. A baseline PET was mandatory before treatment and PET2 were centrally reviewed and interpreted according to Deauville criteria within 48 hours. The allocation of treatment in the experimental arm was based on the PET2 central review results. PFS was the primary endpoint of the study with a hypothesis of non-inferiority of the PET driven arm compared to the standard arm with a margin of 10% (85% 5y-PFS in the standard arm vs >75% in the PET driven arm). An interim analysis of the primary endpoint was planned after 50% (n = 49) of the 97 scheduled events needed for the final analysis.RESULTSFrom May 2011 to May 2014, 823 patients were registered and 782 were eligible for the interim analysis including 401 patients in the arm A, and 381 in arm B. Patients characteristics were well balanced in both arms: median age was 30 years (16 - 60), 64% were male, 81% had nodular sclerosis and 12% mixed cellularity HL, 12% had stage IIB, 28% stage III, 60% stage IV, and 58% had an international prognosis score ≥3.After 2 cycles of BEAesc PET was positive in 97 (12%) patients and PET2 positivity was similar in the standard and experimental arms (n = 48, 12% and n = 49, 13% respectively). Based on PET2 results, 319 (84%) patients received 4 cycles of ABVD and 49 (13%) 4 additional cycles of BEAesc in the experimental arm.Grade ≥3 toxicity was significantly higher in patients receiving 6 cycles of BEAesc compared to those who received 2 cycles of BEAesc + 4 cycles of ABVD with more frequent anemia (11% vs 2%), leukopenia (85% vs 72%), thrombocytopenia (44% vs 13%), febrile neutropenia (6% vs 3%), and sepsis (7% vs 4%). 182 serious adverse events (SAE) related to treatment occurred in 108 (24%) patients treated with 6 cycles of BEAesc (leading to death in 4 cases), compared to 72 SAE (leading to death in 1 case) in 50 (15%) patients treated with 2 x BEAesc + 4 x ABVD (p<0.002). In these latter patients most of SAE (67%) occurred during the 2 first cycles of chemotherapy.With a median follow up of 16.3 months, in an intent to treat basis, the estimated 2y-PFS was similar in the standard (91.6%) and the PET driven arms (88.3%; p = 0.79). PET2 positivity was related to a significantly lower 2y-PFS compared to PET2 negative patients in the whole population (72.9% vs 92.8%; p<0.0001) and in both randomization arms (75.1% vs 94% and 70.8% vs 91.6% in the standard and PET driven arms, respectively; p<0.0001 for both). Overall survival was similar in both randomization arms and in PET2 positive or negative subsets of patients.CONCLUSIONSThis interim analysis suggests that PET performed after 2 cycles of BEAesc can be safely used to guide subsequent treatment and supports the response-adapted strategy delivering 4 cycles of ABVD for patients with negative PET2 (84%) without impairing the disease control. This approach allows to significantly reduce the treatment-related immediate toxicity in most patients and provides similar patients' outcome compared to standard BEAesc treatment. Still, PET positivity after 2 cycles of BEAesc is related to a higher risk of disease progression, encouraging to develop new treatment options in patients with PET2 positive advanced stage HL. DisclosuresCasasnovas:Roche: Consultancy, Research Funding; Takeda: Consultancy; Gilead: Consultancy. Salles:Celgene Corporation; Roche and Gilead Sciences: Research Funding; Calistoga Pharmaceuticals, Inc.; Celgene Corporation; Genentech, Inc.; Janssen Pharmaceutica Products, L.P.; Roche: Consultancy; Celgene Corporation; Roche: Speakers Bureau. Dupuis:ABBVIE: Membership on an entity's Board of Directors or advisory committees; ROCHE: Speakers Bureau. Morschhauser:Genentech Inc./Roche: Other: Advisory boards. Tempescul:Gilead: Other: Export Board Committee.

Molecular Profile and FDG-PET/CT Metabolic Tumor Volume Improve Risk Classification at Diagnosis for Patients with Diffuse Large B Cell Lymphoma

Introduction: The addition of rituximab to the CHOP backbone has improved the outcome of patients with diffuse large B-cell lymphoma (DLBCL). However, over 30% of patients still have a high risk of treatment failure or relapses and cannot be selected accurately by the classic prognostic factors. Molecular profiling has individualized categories with different outcomes. Baseline total metabolic tumor volume seems also to be an important tool to predict outcome in DLBCL, as demonstrated by Casasnovas (Casasnovas et al Hematol Oncol 2015:33,suppl 1) but has not been associated with molecular data. Our study investigated the prognostic impact of baseline PET metrics, including total metabolic tumor volume (TMTV0) and their added value to molecular characteristics (ABC/GCB status, MYC overexpression).Methods: From 2003 to 2009, 81 patients with newly diagnosed DLBCL were retrospectively included. They were treated with rituximab associated with CHOP or ACVBP regimen. All had a baseline FDG-PET/CT. TMTV0 was computed by summing the metabolic volumes of all nodal and extranodal lesions obtained using the 41% SUVmax thresholding method. According to the gene expression profile (GEP), determined using DASL (cDNA-mediated Annealing, Selection, Ligation and extension), a subset of 57 patients was classified in GCB or ABC subtypes. An exploratory analysis was done on MYC expression. Optimal cut points for binary outcome were determined by X-tile" and ROC analysis.Results: 81 patients with a median age of 66 years were enrolled: 80% were stage III/IV, 73% had elevated LDH, 67% IPIaa>1. Median pre-therapy TMTV0 was 320 cm3 (25th-75th percentiles 106-668 cm3). With a median follow-up of 64 months, the 5y-PFS was 60% and the 5y-OS was 63% in the whole population. Using a cut off of 300 cm3, patients with a high TMTV0 (n=43, 53%) had a significantly shorter PFS and OS than those with a low TMTV0 (5y-PFS: 76% vs. 43%, p=0.0023, HR=3.0 and 5y-OS: 78% vs. 46%, p=0.0047, HR=3.0). Patients with a high TMTV0 had a more aggressive disease, with significantly more advanced stage (100%) and higher frequency of IPIaa>1 (93%) than patients with a low TMTV0 (p<0.0001 and p<0.0001 respectively). As expected, ABC status (n=27) was associated with a worse outcome (5y-PFS: 38% vs. 70%, p=0.019, HR=2.4; 5y-OS:37% vs 73%, p=0.0046, HR=3.1). In multivariate analysis, TMTV0 and cells of origin were independent prognostic factors for PFS (p=0.028 and p=0.038 respectively) and OS (p=0.035 and p=0.013). Combining these two factors, TMTV0 allowed a better sub-stratification of ABC/GCB patients (p=0.013 for PFS and p=0.0036 for OS). GCB patients with small TMTV0(n=15) had a 87% 5y-PFS and 86% 5y-OS compared to 53% and 60% for GCB with high TMTV0 (n=15); ABC patients with small TMTV0 (n=11) 50% and 60% compared to 30% and 23% for ABC with high TMTV (n=16) (figure 1). Patients with overexpression of MYC (n=26) had an increased risk of relapse or progression (p=0.0032, HR=3.08) and a reduced survival rates (p=0.0004, HR=4.25). Combining MYC with TMTV0 gave an added prognostic value by splitting the population in 3 risk groups: MYC negative and low TMTV0 (n=16, 5y-PFS of 93% and 5y-OS 93%) ; MYC negative and high TMTV0 (n=15, 45% and 55%) ; MYC positive whatever TMTV0 (n=26, 30% and 30%), p=0.0011 and p=0.0005 respectively.Conclusion: The addition of TMTV0 improved the risk stratification of ABC/GCB subtypes and MYC expression. The combination of molecular and imaging characteristicts at diagnosis could lead to a more accurate selection of patients, in order to increase tailor therapy. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Utility of Interim and Post-Therapy PET/CT in T-Cell and NK-Cell Lymphoma: A Single Institutional Analysis over 9 Years

Introduction: Positron emission tomography combined with computed tomography (PET-CT) is functional imaging test and has been widely used in malignant lymphoma (ML) for initial staging and monitoring response to treatment. Interim PET-CT (iPET) and post-therapy PET-CT (ePET) is also used to assess the early response and guide subsequent treatment, although its role is still controversial other than in Hodgkin's disease and diffuse large B cell lymphoma. Peripheral T cell lymphoma (PTCL) and natural killer (NK) cell lymphomas are relatively rare and heterogeneous types of ML. The prognosis of T and NK (T/NK) cell lymphoma is poor and no standard treatment is available. Therefore, there is a need to find better prognostic factors or tools for these patients. PET-CT is both sensitive and specific for initial staging of T/NK cell lymphoma, although there have been few studies using i- and ePET in these lymphomas. We investigated the prognostic value of i- and ePET in T/NK cell lymphoma in a retrospective single-center study.Methods: Between June 2006 and June 2015, 79 patients with T/NK cell lymphomas had iPET after 2 to 4 courses of treatment and at the end of treatment at Kameda Medical Center, Japan. iPET was performed just before the next cycle of treatment. Treatment responses were scored according to the Deauville score using a 5-point scale (DS). We defined DS scores 1 - 3 as complete metabolic response (CMR). Standardized uptake value (SUV) measurement was normalized relative to the injected dose and lean body mass. The SUV was measured for all lesions and the highest value for each scan was recorded as maximum SUV (SUVmax). These lesions were identified as indicator lesions. For mid- and end-treatment scans, we recorded the change in SUVmax (DSUV), comparing the index lesion and the highest SUVmax in the scan regardless of the index lesion. Differences in overall survival (OS) and progression-free survival (PFS) were calculated by two-sided log-rank test. PET-CT status was assessed for its ability to predict PFS and OS.Results: The study population consisted of 48 men and 31 women with a median age of 70 years. The most frequent lymphoma diagnoses were peripheral T cell lymphoma-not otherwise specified (PTCL-NOS) (n = 29), angioimmunoblastic T cell lymphoma (AITL) (n = 21), anaplastic large cell lymphoma (ALCL) (n = 6), adult T cell leukemia/lymphoma (ATLL) (n = 12), enteropathy-associated T cell lymphoma (EATL) (n = 2), and NK/T cell lymphoma (NKTCL) (n = 9). Most patients except for ATLL and NK cell lymphoma were instituted with the CHOP-like regimen. Baseline PET scan was positive in all cases and median SUVmax was 13.7 (range, 2.6 - 37.4). iPET results were negative in 17 cases (26%), and ePET results were negative in 22 of 46 (48%) cases. With a median follow up of 30 months, 5-year PFS rate was 66% for obtaining CMR vs. 9.2% for not obtaining CMR (P < 0.001). The percentages of patients that obtained CMR were 48% (14/29), 62% (13/21), 67% (4/6), 33% (3/9), 50% (1/2), and 56% (5/9) for those with PTCL-NOS, AITL, ALCL, ATLL, EATL, and NKTCL, respectively. The patients who obtained CMR showed significantly longer PFS and OS compared to those who did not. We also analyzed DSUVmax. Using the ROC curve, DSUVmax values between baseline and iPET of > 62% and > 85% were predictive of better PFS and OS (sensitivity 96%, specificity 67%, area under the curve (AUC) 0.89, 95% confidence interval (CI) = 0.82 - 0.97 and sensitivity 49%, specificity 97%, AUC 0.80, 95% CI = 0.70 - 0.90, respectively). We examined the positive and negative predictive values (PPV and NPV) and accuracy in predicting PFS and OS in 66 patients who underwent iPET. Of 35 iPET-positive patients, 31 (89%) showed progression, and 26 (74%) died during the follow-up. On multivariate Cox regression analysis, obtaining CMR at iPET emerged as an independent prognostic factor for PFS and OS (P<0.001 and P<0.001, respectively).Conclusions: Our data suggest that patients with positive results on i- or ePET should be considered candidates for intensive therapeutic strategies to improve their clinical outcome. Large prospective studies of patients with tumors of a homogeneous histological subtype within the T/NK cell lymphoma, treated with a uniform protocol, and evaluated on the basis of standardized criteria are warranted. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Prognostic value of early response assessment using 18F-FDG PET/CT in chemotherapy-treated patients with non-small-cell lung cancer.

We aimed to evaluate the prognostic value of early response assessment using a volumetric fluorine-18-fluorodeoxyglucose (F-FDG) PET analysis in chemotherapy-treated patients with non-small-cell lung cancer (NSCLC). We retrospectively reviewed 33 patients with NSCLC who received first-line chemotherapy and performed F-FDG PET/computed tomography before (baseline PET) and after two cycles of chemotherapy (interim PET). The maximum standardized uptake value (SUVmax) and metabolic tumor volume (MTV) of the total malignant lesion were measured in baseline (SUV1 and MTV1) and interim (SUV2 and MTV2) PET images, and percentage changes in SUVmax (ΔSUV) and MTV (ΔMTV) were calculated between the two images. We compared PET parameters and clinicopathologic variables in terms of the 2-year overall survival (OS). The median follow-up period was 14.3 months and the 2-year OS was 31%. In PET images, the mean SUV1, MTV1, SUV2, MTV2, ΔSUV, and ΔMTV were 13.1±4.5, 307.9±340.0 cm, 9.5±5.1, 180.4±29.6 cm, 27±28%, and 42±65%, respectively. In univariable analysis, M stage, TNM stage, and all six PET parameters associated significantly with OS. Both the MTV1 and the ΔMTV were tested against OS controlling for M stage, one at time, and the effect remained significant in multivariable analyses. A smaller baseline MTV and greater decrease in MTV between baseline and interim PET images are associated with a significantly prolonged OS. A volume-based F-FDG PET analysis would facilitate prediction of clinical outcome and identification of treatment-resistant patients early during chemotherapy and could thus be used in personalized treatment approaches for patients with NSCLC.

RECIST criteria: our experience in daily practice

Content organisation Our cases will be presented in a pictorial essay mode. Key differential diagnostic points will be highlighted in the discussion of each case. It is important to consider: Complete knowledge of clinical-oncologic status and treatments time points. Recognition of smallest measured value (NADIR) between time points for adequate selection of comparative review. Sum of target lesions (baseline and current time points) including percentage of change. Select no more than two target lesions by sector. Complete knowledge of actinic extension field which often could present different behavior than other lesional sites. Local tumour growth over vital organs regardless strict RECIST criteria in exceptional cases. Further criteria utilization in line with oncological disease being studied (mRECIST criteria for hepatocellular carcinoma or CHOI criteria for GIST). Use of SUL on baseline PET CT studies with greater accuracy in assessing response on further evaluations (PERCIST criteria).

Utility of baseline 18FDG-PET/CT functional parameters in defining prognosis of primary mediastinal (thymic) large B-cell lymphoma

AbstractThe International Extranodal Lymphoma Study Group (IELSG) 26 study was designed to evaluate the role of 18F-fluorodeoxyglucose (18FDG) positron emission tomography/computed tomography (PET/CT) in the management of primary mediastinal (thymic) large B-cell lymphoma (PMBCL). We examined the prognostic impact of functional PET parameters at diagnosis. Metabolic activity defined by the maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) was measured on baseline 18FDG PET/CT following a standard protocol in a prospectively enrolled cohort of 103 PMBCL patients. All received combination chemoimmunotherapy with doxorubicin- and rituximab-based regimens; 93 had consolidation radiotherapy. Cutoff values were determined using the receiver-operating characteristic curve. At a median follow-up of 36 months, progression-free survival (PFS) and overall survival (OS) were 87% and 94%, respectively. In univariate analysis, elevated MTV and TLG were significantly associated with worse PFS and OS. Only TLG retained statistical significance for both OS (P = .001) and PFS (P < .001) in multivariate analysis. At 5 years, OS was 100% for patients with low TLG vs 80% for those with high TLG (P = .0001), whereas PFS was 99% vs 64%, respectively (P < .0001). TLG on baseline PET appeared to be a powerful predictor of PMBCL outcomes and warrants further validation as a biomarker. The IELSG 26 study was registered at www.clinicaltrials.gov as #NCT00944567.

Variability of Hepatic 18F-FDG Uptake at Interim PET in Patients With Hodgkin Lymphoma.

When evaluating response of Hodgkin lymphoma (HL) to chemotherapy on interim (18)F-FDG-PET/CT, physiological liver uptake is used as reference. Hodgkin lymphoma sites with uptake greater than liver are interpreted as positive. We aimed at examining factors that might influence liver uptake as reference organ. Fifty patients with HL who received baseline (18)F-FDG-PET/CT (PET1) and interim PET (PET2), usually after 2 cycles of adriamycin bleomycin, vinblastine, and dacarbazine chemotherapy, were included retrospectively. SUVmean normalized for body weight (SUVmean) and for lean body mass (SULmean) were obtained from regions of interest in the right lobe of the liver. On univariate analysis, liver SUVmean on interim PET increased with increasing body mass index (BMI) (P = 0.0453) and were higher in women (P = 0.0401). These factors remained significant on multivariate analysis (P = 0.009 and P = 0.008, respectively). No significant correlation was found with postinjection delay, blood glucose level, and age. Liver SULmean were not affected by the studied variables. Average liver SUVmean in the 50 patients were similar at baseline and interim PET. In 11 patients (22%), however, there was 30% or greater variation in liver SUVmean between PET1 and PET2. No factors explaining intrapatient variation in hepatic uptake between PET1 and PET2 were found on correlation analysis. At interim PET in patients with HL, liver SUVmean depends on BMI and sex, but not liver SULmean. Furthermore, our study, conducted with standard clinical procedure, also confirmed the high range of liver uptake values from one patient to another. Caution is required when using liver SUV as reference in patients with high BMI. Intrapatient fluctuation in liver SUVmean should also be expected.

SU‐E‐J‐124: 18F‐FDG PET Imaging to Improve RT Treatment Outcome for Locally Advanced Lung Cancer

Purpose:To investigate spatial correlation between high uptake regions of pre‐ and 10‐days‐post therapy1 8F‐FDG PET in recurrent lung cancer and to evaluate the feasibility of dose escalation boosting only regions with high FDG uptake identified on baseline PET.Methods:Nineteen patients with stages II– IV inoperable lung cancer were selected. Volumes of interest (VOI) on pre‐therapy FDG‐PET were defined using an isocontour at ≥50% of SUVmax. VOI of pre‐ and post‐therapy PET images were correlated for the extent of overlap. A highly optimized IMRT plan to 60 Gy prescribed to PTV defined on the planning CT was designed using clinical dose constraints for the organs at risk. A boost of 18 Gy was prescribed to the VOI defined on baseline PET. A composite plan of the total 78 Gy was compared with the base 60 Gy plan. Increases in dose to the lungs, spinal cord and heart were evaluated. IMRT boost plan was compared with proton RT and SBRT boost plans.Results:Overlap fraction of baseline PET VOI with the VOI on 10 days‐post therapy PET was 0.8 (95% CI: 0.7 – 0.9). Using baseline VOI as a boosting volume, dose could be escalated to 78 Gy for 15 patients without compromising the dose constraints. For 4 patients, the dose limiting factors were V20Gy and Dmean for the total lung, and Dmax for the spinal cord. An increase of the dose to OARs correlated significantly with the relative size of the boost volume.Conclusion:VOI defined on baseline 18F‐FDG PET by the SUVmax‐≥50% isocontour may be a biological target volume for escalated radiation dose. Dose escalation to this volume may provide improved tumor control without breaching predefined dose constraints for OARs. The best treatment outcome may be achieved with proton RT for large targets and with SBRT for small targets.

Biological tumor volume (BTV) as a predictor for local control in nasopharyngeal carcinoma (NPC).

e17045 Background: Treatment of NPC is mainly guided by TNM stage. This study aims to evaluate if the active tumor volume delineated as BTV on PET scan is a predictor of local disease control. Methods: This is a retrospective review of all patients who had baseline PET scan performed before treatment in our center from Aug., 2010 to Mar., 2013. Patients with distant metastases at diagnosis were excluded. Total 77 patients were included. The BTV were automatically delineated by a signal to background ratio method we reported before. All patients completed radiotherapy (RT) with intensity modulated radiotherapy to at least 70Gy to primary tumor. 7 patients had RT alone and 70 patients had chemotherapy (cisplatin or carboplatin) concurrent with RT with either additional induction or adjuvant chemotherapy. Local control was assessed by endoscopy and biopsy at 10 weeks after completion of RT. Local failure include patients with persistent disease in NP after RT and those who had local relapse after initial dis...

Improved power for characterizing longitudinal amyloid-β PET changes and evaluating amyloid-modifying treatments with a cerebral white matter reference region.

In this article, we describe an image analysis strategy with improved power for tracking longitudinal amyloid-β (Aβ) PET changes and evaluating Aβ-modifying treatments. Our aims were to compare the power of template-based cerebellar, pontine, and cerebral white matter reference regions to track 24-mo florbetapir standardized uptake value (SUV) ratio (SUVR) changes; to relate those changes to 24-mo clinical declines; and to evaluate Aβ-modifying treatments in Aβ-positive (Aβ+) and Aβ-negative (Aβ-) patients with probable Alzheimer dementia (pAD), in patients with mild cognitive impairment (MCI), in cognitively normal controls (NCs), and in cognitively normal apolipoprotein E4 (APOE4) carriers and noncarriers. We used baseline and follow-up (∼24 mo) florbetapir PET scans from 332 Aβ+ and Aβ- subjects participating in the multicenter Alzheimer's Disease Neuroimaging Initiative. Each of the proposed analyses included 31 pAD patients, 187 MCI patients, and 114 NCs. Cerebral-to-white matter, cerebellar, and pontine SUVRs were characterized in terms of their longitudinal variability; their power to track longitudinal fibrillar Aβ increases in Aβ+ and Aβ- subgroups and cognitively normal APOE4 carriers and noncarriers; the sample sizes needed to detect attenuated accumulation of or clearance of fibrillar Aβ accumulation in randomized clinical trials; and their ability to relate 24-mo fibrillar Aβ increases to clinical declines. As predicted, cerebral-to-white matter SUVR changes were significantly less variable and had significantly greater power to detect 24-mo fibrillar Aβ increases and evaluate Aβ-modifying treatment effects in Aβ+ pAD, MCI, and NC subjects and cognitively normal APOE4 carriers. They were also distinguished by the ability to detect significant associations between 24-mo Aβ increases and clinical declines. A cerebral white matter reference region may improve the power to track longitudinal fibrillar Aβ increases, to characterize their relationship to longitudinal clinical declines, and to evaluate Aβ-modifying treatments in randomized clinical trials.

Regorafenib assessment in refractory advanced colorectal cancer: RegARd-C study protocol

IntroductionRegorafenib was recently approved for patients with pretreated advanced colorectal cancer (aCRC), despite a moderate improvement of the patients’ outcome, and significant toxicities. Based on previous studies showing that early...

Multiparameteric PET-MR Assessment of Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer: PET, MR, PET-MR and Tumor Texture Analysis: A Pilot Study

Purpose: Patients with locally advanced rectal cancer (LARC) achieving pathologic complete response (pCR) to neoadjuvant chemoradiotherapy (CRT) have significantly improved long term survival. Preoperative detection of pCR may enable a conservative therapeutic approach in some patients. The purpose of the current prospective pilot study was to assess multiparametric qualitative and quantitative MR, PET, PET-MR and tumor texture features in predicting pCR to CRT in patients with LARC. Material and Methods: Eighteen LARC patients underwent staging with FDG-PET and MR-rectum and 15 had post-CRT restaging. Response was assessed qualitatively and quantitatively. SUV (tumor/background), SUV/ADC, and tumor texture parameters derived via machine learning algorithms (MLA) from PET and multiple MR sequences and were correlated with histopathology. Results: A third of patients had pCR. Sensitivity, specificity & accuracy of PET, MR and combined PET-MR were 90, 60, & 80; 90, 20 & 66.7; 90, 80 & 86.7, respectively. Differences did not reach statistical significance. Quantitatively, only tumor-muscle (SUV/ADC) ratio improved prediction of pCR. Of all texture features assessed using MLA, only the classifier trained on pre-treatment PET was significant (p = 0.034; accuracy, 92.8%). Combined PET and MR texture features did not improve performance. Conclusion: Combined PET-MR may improve specificity compared with PET or MR alone, although this needs to be validated in a larger cohort. Tumor to muscle SUV/ADC ratios post-therapy and texture features on baseline PET show promise in improving prediction of pCR post-CRT in LARC.

332PD - Prediction of Axillary Lymph Node Response to Neoadjuvant Chemotherapy (Nac) By Changes in Maximum Standard Uptake Values (Suvmax) with 18Fdg-Pet (Pet) Imaging of the Primary Breast Tumour

ABSTRACT Aim: The aim of this study was to investigate the effect of NAC (Fluorouracil, epirubicin, cyclophosphamide (FEC100) or docetaxel) in predicting pathological complete response in axillary nodes (pCRA) based on changes in SUVmax on PET in the primary tumour in locally advanced breast cancer (LABC). Methods: Women with node positive LABC were randomized to receive 4 cycles of FEC100 followed by four cycles of docetaxel (Arm A), or the regimen in reverse order (Arm B). FDG-PET studies were performed at baseline, after 4 and 8 cycles of NAC. pCRA to NAC was assessed in surgical specimens. Receiver operating characteristic analysis (ROC) was performed to determine a cut-off value Δ% SUV 1-2 and SUV 1-3 for prediction of nodal status after NAC. Association between SUVmax changes and pCRA was analysed by Mann Whitney U test. Results: One hundred women with node positive LABC were enrolled into the study, 52 (%) were treated on Arm A and 48 (%) on Arm B. Ninty five (95%) had invasive ductal cancers, 64(%) were ER + , 32(%) were HER2 + , while 23(%) were triple negative subtype. Baseline characteristics and PET SUVmax values were similar in two Arms. Baseline PET SUVmax correlated with tumour grade (P = 0.003), triple negative phenotype (P = 0.014) and Ki67 index (P = 0.005). All women had axillary lymph node dissection with fifty one (51%) undergoing breast conserving surgery. pCRA was seen in 46 (%) women. Overall there was no significant difference in pCRA rates between the two drug regimens. PET SUV reduction after four cycles of FEC was a strong predictor of pCRA. In Arm A, pCRA was associated with median PET SUVmax reduction of 81% after 4 cycles of FEC, in contrast to only 39% reduction after 4 cycles of docetaxel in Arm B (P Conclusions: PET SUV response in the primary tumour, after 4 cycles of FEC100 accurately predicts the axillary status. By contrast assessment of PET response with docetaxel resulted in higher rates of false positive and negative. This methodology may allow for selection of patients for less aggressive axillary surgery after NAC. Disclosure: All authors have declared no conflicts of interest.

18F]fluorothymidine-positron emission tomography in patients with locally advanced breast cancer under bevacizumab treatment: Usefulness of different quantitative methods of tumor proliferation

ObjectivesTo investigate quantitative methods of tumor proliferation using 3′-[18F]fluoro-3′-deoxythymidine ([18F]FLT) PET in patients with breast cancer (BC), studied before and after one bevacizumab administration, and to correlate the [18F]FLT-PET uptake with the Ki67 index. Material and methodsThirty patients with newly diagnosed, untreated BC underwent a [18F]FLT-PET before and 14 days after bevacizumab treatment. A dynamic scan centered over the tumor began simultaneously with the injection of [18F]FLT (385±56MBq). Image derived input functions were obtained using regions of interest drawn on the left ventricle (LV) and descending aorta (DA). Metabolite corrected blood curves were used as input functions to obtain the kinetic Ki constant using the Patlak graphical analysis (time interval 10–60min after injection). Maximum SUV values were derived for the intervals 40–60min (SUV40) and 50–60min (SUV50). PET parameters were correlated with the Ki67 index obtained staining tumor biopsies. Results[18F]FLT uptake parameters decreased significantly (p<0.001) after treatment: SUV50=3.09±1.21 vs 2.22±0.96; SUV40=3.00±1.18 vs 2.14±0.95, Ki_LV(10–3)=52[22–116] vs 38[13–80] and Ki_DA(10–3)=49[15–129] vs 33[11–98]. Consistency interclass correlation coefficients within SUV and within Ki were high. Changes of SUV50 and Ki_DA between baseline PET and after one bevacizumab dose PET correlated with changes in Ki67 index (r-Pearson=0.35 and 0.26, p=0.06 and 0.16, respectively). Conclusions[18F]FLT-PET is useful to demonstrate proliferative changes after a dose of bevacizumab in patients with BC. Quantification of tumor proliferation by means of SUV and Ki has shown similar results, but SUV50 obtained better results. A correlation between [18F]FLT changes and Ki67 index was observed.

Regorafenib assessment guided by metabolic imaging in refractory advanced colorectal cancer (aCRC): REGARD-C study.

Background: Regorafenib, an oral multi-tyrosine kinase inhibitor that shares with sorafenib several targets on tumor angiogenesis, oncogenesis, and tumor microenvironment, was recently approved for patients (pts) with pretreated advanced colorectal cancer (aCRC). The drug improves the pts’ outcome, but with significant toxicities, underscoring the need to identify those who will not benefit. A previous study (SoMore trial) showed that early FDGPET-based metabolic response assessment (MRA) may adequately discriminate pts with chemorefractory aCRC unlikely to benefit from a sorafenib-capecitabine combination. RegARd-C aims to explore early MRA in pts treated with regorafenib as a clinical tool to spare pts from needless toxicity from a drug that gives them little or no benefit and as a translational tool to guide comprehensive genomic and epigenetic research on the determinants of drug resistance. Methods: RegARd-C’s (EUDRACT 2012-005655-16) is a multi-centric prospective study. Its primary objective is to identify in a population of pts with pretreated aCRC, those who will not benefit from regorafenib given at 160 mg/day, three weeks/4. Baseline PET is repeated at D14 of the first treatment course. MRA results are blinded for the investigators. Tumor tissues, optionally obtained from a PET-measurable lesion, and blood samples (at baseline; after the first chemotherapy course; and every two months) are collected. Overall survival (OS) is the primary endpoint and will be correlated with metabolic parameters, and genetic, epigenetic and molecular aberrations assessed from tumor biopsies and blood samples using gene expression and methylation profiling, RNA and exome sequencing. As the study is exploratory, no formal hypothesis was formulated. We arbitrarily decided to have a sample size of 105 evaluable pts with 70 pts as a derivation set and 35 pts as a validation set. Taking into account an expected 20-25% drop-out rate, between 124 and 140 pts will be accrued.This sample size is, however, sufficient to validate the hypothesis generated by the SoMore study, which found a prognostic impact of homogeneous metabolic response on OS, with an estimated HR of 0.59. RegARd-C has accrued 76 pts since August 2013. Clinical trial information: NCT01929616.

Phosphodiesterase 10A PET Radioligand Development Program: From Pig to Human

Four novel phosphodiesterase 10A (PDE10A) PET tracers have been synthesized, characterized in preclinical studies, and compared with the previously reported (11)C-MP-10. On the basis of in vitro data, IMA102, IMA104, IMA107, and IMA106 were identified as potential PDE10A radioligand candidates and labeled with either (11)C via N-methylation or with (18)F through an SN2 reaction, in the case of IMA102. These candidates were compared with (11)C-MP-10 in pilot in vivo studies in the pig brain. On the basis of these data, (11)C-IMA106 and (11)C-IMA107 were taken into further evaluation and comparison with (11)C-MP-10 in the primate brain. Finally, the most promising radioligand candidate was progressed into human evaluation. All 5 tracers were produced with good radiochemical yield and specific activity. All candidates readily entered the brain and demonstrated a heterogeneous distribution consistent with the known expression of PDE10A. Baseline PET studies in the pig and baboon showed that (11)C-IMA107 and (11)C-MP-10 displayed the most favorable tissue kinetics and imaging properties. The administration of selective PDE10A inhibitors reduced the binding of (11)C-IMA107 and (11)C-MP-10 in the PDE10A-rich brain regions, in a dose-dependent manner. In the nonhuman primate brain, the tissue kinetics of (11)C-IMA107 and (11)C-MP-10 were well described by a 2-tissue-compartment model, allowing robust estimates of the regional total volume of distribution. Blockade with unlabeled MP-10 confirmed the suitability of the cerebellum as a reference tissue and enabled the estimation of regional binding potential as the outcome measure of specific binding. (11)C-IMA107 was identified as the ligand with the highest binding potential while still possessing reversible kinetics. The first human administration of (11)C-IMA107 has demonstrated the expected regional distribution and suitably fast kinetics, indicating that (11)C-IMA107 will be a useful tool for the investigation of PDE10A status in the living human brain.

Interim 18F-FDG PET SUVmax Reduction Is Superior to Visual Analysis in Predicting Outcome Early in Hodgkin Lymphoma Patients

PET performed after 2 cycles of chemotherapy (PET2) allows prediction of outcome in most patients with Hodgkin lymphoma (HL). Visual analysis using a 5-point scale was proposed to assess PET response, but a semiquantitative approach using maximum standardized uptake value (SUVmax) reduction between baseline and interim PET was shown to be superior to the 5-point scale in patients with diffuse large B-cell lymphoma and may also improve the accuracy of interim PET interpretation in HL. To compare the clinical usefulness of both methods in HL patients, we analyzed PET2 according to visual and ΔSUVmax criteria in a retrospective single-center study. From 2007 to 2010, 59 consecutive patients with a first diagnosis of HL were treated with 4-8 cycles of anthracycline-based chemotherapy. Radiotherapy was performed in 19 responding patients with localized disease. PET was done at baseline (PET0) and after 2 cycles of chemotherapy, and treatment was not modified according to the PET2 result. PET2 was interpreted using the 5-point scale (positivity for score 4 or 5). The SUVmax reduction between PET0 and PET2 (ΔSUVmax) was computed for all patients, and patients with a ΔSUVmax greater than 71% were considered good responders. When the 5-point scale was used, 46 patients (78%) achieved a negative PET2 result, 7 of whom failed treatment (negative predictive value, 85%). Forty-nine patients (83%) had a ΔSUVmax greater than 71%, 6 of whom failed treatment (negative predictive value, 88%). The PET2 positive predictive value was significantly better for ΔSUVmax (70%) than for the 5-point scale (46%). When ΔSUVmax was used, 6 (46%) of the 13 PET2-positive patients could be reclassified as good responders. Although visual PET2 positivity was related to a lower 4-y progression-free survival (45%) compared with PET2 negativity (81%, P < 0.002), ΔSUVmax (>71 vs ≤71%) was more accurate for identifying patients with different 4-y progression-free survivals (82% vs. 30%; P < 0.0001). In multivariate analysis using the international prognosis score and ΔSUVmax as covariates, ΔSUVmax remained the unique independent predictor for progression-free survival (P = 0.0001; relative risk, 8.1). Semiquantitative analysis was more accurate than visual analysis based on the 5-point scale to interpret PET2 and predict the outcome of HL patients. These encouraging results warrant further confirmation in larger and prospective series.

Abstract 212: In Vivo Molecular Imaging of Thrombosis and Thrombolysis Using a Fibrin-binding PET Probe

Background and purpose: Thrombus formation plays a critical role in cardiovascular diseases, but thrombus imaging is still challenging. Fibrin is a major component of both arterial and venous thrombi, and represents an ideal candidate for molecular imaging of thrombosis. Here, we describe imaging properties and target uptake of a new fibrin-specific PET probe for thrombus detection in two rat models of thrombosis and stroke. Materials and methods: The fibrin-binding probe FBP7 was synthesized by conjugation of the cyclic peptide FHCHypY(3-CI)DLCHIL to a cross-bridge chelator (CB-TE2A), followed by labeling with copper-64. Wistar rats (4-6/group) underwent carotid crush, as a non-occlusive, mural thrombosis model, or embolic stroke as an occlusive clot model followed by thrombolysis. Results: FBP7 clearly detected thrombus location in both animal models, with a high PET target:background ratio that increased over time (&gt;5-fold at 30-90’, &gt;15-fold at 240-300’, Fig. A-B). Biodistribution confirmed the high thrombus uptake (~0.5 %ID/g), which was &gt;5-10 folds greater than blood and other tissues of the head and thorax (C). Similar results were obtained from ex vivo autoradiography of ipsilateral vs. controlateral carotid arteries (D). PET/CT imaging allowed clot localization in the internal carotid/middle cerebral artery (ICA/MCA) segment of all stroke rats. After baseline PET acquisition, animals were infused with tPA (10 mg/kg, i.v.) or vehicle (saline) and imaged again for 90’. Time-dependent reduction of activity at the level of the thrombus was clearly detected in treated rats, but not in vehicle group (E). Brain autoradiography confirmed clot dissolution in tPA-treated animals, but enduring high thrombus activity in ipsilateral ICA/MCA of control rats (F-G). Conclusions: We demonstrated that FBP7 is suitable for molecular imaging of thrombosis and thrombolysis in vivo, and represents a very promising candidate for bench-to-bedside translation.