Changes In FDG Uptake Research Articles

P2.02-045 Prognostic Value of Metabolic FDG-PET Response in Locally Advanced NSCLC: A Literature Review

It is still a matter of debate whether metrics of metabolic imaging by 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) predict clinical outcome in non-small cell lung cancer (NSCLC). Pretreatment FDG uptake in the primary tumor has been shown to be a prognostic factor for survival. The prognostic role of FDG-PET in the evaluation of tumor response remains unclear and controversial. Hence, we conducted a comprehensive literature review to assess the prognostic value of FDG-PET/CT response monitoring along multimodality treatment in patients with locally advanced NSCLC. A systematic search of studies published in PubMed was performed using the keywords “positron emission tomography” or “PET”, “non-small cell lung cancer,” and “response” or “outcome.” References from adequate articles were checked for studies not retrieved by the search strategy. Inclusion criteria were: studies limited to locally advanced NSCLC containing >60% stage III patients, studies in which response monitoring with FDG-PET or PET/CT was performed, and studies that reported survival data. Twenty-two studies (median 47 patients, range 15-545) published between 1998 and 2016 were included in the analysis. Ten studies used PET alone while recent trials used integrated PET/CT. PET based response evaluation was performed either after neoadjuvant chemotherapy prior to surgery or radiotherapy either after radical treatment consisting of (chemo)radiotherapy. Eight studies specifically addressed the prognostic value of early metabolic response measurement, either during induction chemo(radio)therapy (n=2) either early in the course of radical (chemo)radiotherapy (n=6). A heterogeneity between the studies was observed regarding timing of the repeat PET, thresholds to define metabolic response, and metrics of metabolic FDG imaging such as MRglu (metabolic rate of glucose), Total Lesion Glycolysis (TLG), Standardized Uptake Value (SUV), SUVmax, SUVpeak, SUVmean or Metabolic Tumor Volume (MTV). All studies showed a significant correlation between either the change in FDG uptake or the residual FDG uptake within the primary tumor and survival. Posttreatment FDG-PET/CT has been considered as a useful tool in determining prognosis and guiding therapy for patients with locally advanced NSCLC. Before implementation in routine clinical practice, there is however a need for standardization of PET data acquisition and analysis and a validation of a single definition for metabolic tumor response.

The effect of isoflurane on 18F-FDG uptake in the rat brain: a fully conscious dynamic PET study using motion compensation.

BackgroundIn preclinical positron emission tomography (PET) studies an anaesthetic is used to ensure that the animal does not move during the scan. However, anaesthesia may have confounding effects on the drug or tracer kinetics under study, and the nature of these effects is usually not known.MethodWe have implemented a protocol for tracking the rigid motion of the head of a fully conscious rat during a PET scan and performing a motion compensated list-mode reconstruction of the data. Using this technique we have conducted eight rat studies to investigate the effect of isoflurane on the uptake of 18F-FDG in the brain, by comparing conscious and unconscious scans.ResultsOur results indicate that isoflurane significantly decreases the whole brain uptake, as well as decreasing the relative regional FDG uptake in the cortex, diencephalon, and inferior colliculi, while increasing it in the vestibular nuclei. No statistically significant changes in FDG uptake were observed in the cerebellum and striata.ConclusionThe applied event-based motion compensation technique allowed for the investigation of the effect of isoflurane on FDG uptake in the rat brain using fully awake and unrestrained rats, scanned dynamically from the moment of injection. A significant effect of the anaesthesia was observed in various regions of the brain.

The Place of FDG PET/CT in Renal Cell Carcinoma: Value and Limitations.

Unlike for most other malignancies, application of FDG PET/CT is limited for renal cell carcinoma (RCC), mainly due to physiological excretion of 18F-fluoro-2-deoxy-2-d-glucose (FDG) from the kidneys, which decreases contrast between renal lesions and normal tissue, and may obscure or mask the lesions of the kidneys. Published clinical observations were discordant regarding the role of FDG PET/CT in diagnosing and staging RCC, and FDG PET/CT is not recommended for this purpose based on current national and international guidelines. However, quantitative FDG PET/CT imaging may facilitate the prediction of the degree of tumor differentiation and allows for prognosis of the disease. FDG PET/CT has potency as an imaging biomarker to provide useful information about patient’s survival. FDG PET/CT can be effectively used for postoperative surveillance and restaging with high sensitivity, specificity, and accuracy, as early diagnosis of recurrent/metastatic disease can drastically affect therapeutic decision and alter outcome of patients. FDG uptake is helpful for differentiating benign or bland emboli from tumor thrombosis in RCC patients. FDG PET/CT also has higher sensitivity and accuracy when compared with bone scan to detect RCC metastasis to the bone. FDG PET/CT can play a strong clinical role in the management of recurrent and metastatic RCC. In monitoring the efficacy of new target therapy such as tyrosine kinase inhibitors (TKIs) treatment for advanced RCC, FDG PET/CT has been increasingly used to assess the therapeutic efficacy, and change in FDG uptake is a strong indicator of biological response to TKI.

Analysis of 18F-FDG PET/CT imaging characteristics and metabolism features of pancreatic solid pseudopapillary tumor

Objective To summarize the imaging features and metabolic characteristics of solid pseudopapillary tumors of the pancreas (SPTP) using 18F-FDG PET/CT in order to improve the diagnostic accuracy. Methods 18F-FDG PET/CT findings and clinical data of 16 patients (3 males, 13 females, average age 38.6 years) pathologically proved SPTP from August 2010 to June 2014 in Shanghai Changhai Hospital were analyzed retrospectively. The morphology, density and metabolic characteristics of the lesions were observed, and SUVmax and tumor size were measured and recorded. The difference between early SUVmax and delayed SUVmax was evaluated with paired t test in 10 patients underwent dual-time scans, and the retention index (RI) was also calculated. Results The lesions were all single with well delineated and exogenous growth. The long diameter of the tumors was about 1.2-10.4(4.0±2.7) cm, and the short diameter was 1.0-8.6(3.3±2.2) cm. Four tumors were nearly completely solid, in which 2 lesions showed high and uniform FDG accumulation, 1 inhomogeneous high metabolic lesion, and 1 with FDG uptake similar to normal pancreas. The other 12 cases demonstrated solid and cystic mixed structures which showed uneven high metabolic components in mural nodules mixed with mild metabolic and/or uptake defect. The early SUVmax of all patients was 7.3±6.8(2.4-29.1). For the 10 patients with dual-phase scans, no statistical difference was seen between the early SUVmax (6.0±3.4) and the delayed SUVmax(6.4±3.2)(t=-1.658, P>0.05); RI was 6.9%(-4.2%, 13.6%). Among the 16 patients, 5 were found to have invasion of pancreatic duct or surrounding organs of pancreas, with early SUVmax (6.7±4.1)(3.4-13.1), SUVmax of remaining 11 patients was 4.4(2.6, 7.6). Conclusions SPTP is mostly cystic-solid or solid lesions with big volumes, calcification, well-defined borders and outward swelling. On FDG PET images, there are diverse metabolic characteristics of lesions, with high uptake on the solid part, and few changes of FDG uptake on the delayed scan. Key words: Pancreatic neoplasms; Tomography, emission-computed; Tomography, X-ray computed; Deoxyglucose

Predictive and prognostic value of FDG-PET/CT imaging and different response evaluation criteria after primary systemic therapy of breast cancer.

(1) To predict pathological complete remission (pCR) and survival after primary systemic therapy (PST) in patients diagnosed with breast cancer by using two different PET/CT based scores: a simplified PERCIST-based PET/CT score (Method 1) and a combined PET/CT score supplemented with the morphological results of the RECIST system (Method 2) and (2) to assess the effect of different breast carcinoma subtypes on tumor response and its evaluation. Eighty-eight patients were enrolled in the study who underwent PET/CT imaging before and after PST. PET/CTs were evaluated by changes in maximum Standardized Uptake Value (SUVmax) and tumor size. Method 1 and 2 were applied to predict pathological complete remission (pCR). Kaplan-Meier analyses for survival were performed. Classification into biological subtypes was performed based on the pre-therapeutic tumor characteristics. A total of 30/88 patients showed pCR (34.1%). Comparing pCR/non-pCR patient groups, significant differences were detected by changes in SUVmax (p<0.001) and tumor size (p<0.001) regarding the primary breast lesions. To predict pCR, Method 2 had higher sensitivity (72.4% vs. 44.8%) and negative predictive value (57.9% vs. 45.8%) with lower false negativity rate (16 vs. 32) than Method 1. pCR rate was higher in Her2-positive and triple negative tumors. Despite the significant differences detected between the biological subtypes regarding changes in primary tumor SUVmax (p=0.007) and size (p=0.015), the subtypes only had significant impact on response evaluation with Method 2 and not with Method 1. In our study, neither clinical nor pathological CR were predictors of longer progression-free survival. Our results suggest that combined PET/CT criteria are more predictive of pCR. The effect of biological subtypes is significant on pCR rate as well as on the changes in FDG-uptake and morphological tumor response. Response evaluation with combined criteria was also able to reflect the differences between the biological behavior of breast tumor subtypes.

Serial Changes of FDG Uptake and Diagnosis of Suspected Lung Malignancy

This study prospectively evaluates the serial change of FDG uptake and its diagnostic value in malignant versus benign lung lesions in patients with suspected lung cancer. Patients with suspected lung malignancy underwent whole-body FDG PET/CT at 1, 2, and 3 hours after an IV injection of F-FDG. The SUVs of FDG in lung nodules and hilar/mediastinal nodes at each time point were correlated with biopsy/surgical pathologic findings. There were a total of 45 malignant lesions and 80 benign lesions from 43 patients with pathologic diagnosis that were included for analysis. The SUVmax had an average of 25.5% increase in all tumor-positive lesions from 1 to 2 hours (vs 1.6% decrease in all tumor-negative lesions, P < 0.0001) and an average of 39.1% increase from 1 to 3 hours (vs 4.5% increase in all tumor-negative lesions, P < 0.0001). The receiver operating characteristic analysis showed that the 2-hour and 3-hour SUVmax had similar area under the curve and outperformed the SUVmax on the 1-hour initial imaging or retention index (RI). The optimal cutoff values to differentiate malignancy from benign lesions were 3.24 for 1-hour SUVmax, 3.67 for 2-hour SUVmax, and 4.21 for 3-hour SUVmax, with 11.6% for 1- to 2-hour RI and 23.9% for 1- to 3-hour RI. The 3-hour delayed SUVmax of 4.21 provided the best overall performance (accuracy of 88.8%). The analysis of the lesion-to-background ratio revealed that delayed imaging improved the image quality significantly, leading to much easier detection of either malignant or benign lesions. Multiple time point FDG PET/CT imaging moderately improves the diagnostic accuracy of lung cancer and significantly improves the image quality.

Timing and intensity of changes in FDG uptake with symptomatic esophagitis during radiotherapy or chemo-radiotherapy

PurposeTo study whether esophageal FDG activity changes by time of mid-course of fractionated radiotherapy (RT), and whether these changes are associated with radiation esophagitis in patients with non-small cell lung cancer (NSCLC).MethodsFifty patients with stage I-III NSCLC were enrolled prospectively and, all received ≥60 Gy RT. FDG-PET/CT scans were acquired prior to, and during-RT after delivery of 45 Gy. Normalized standardized uptake values (NSUV), defined by the esophageal maximum SUV relative to intravascular background level in the aortic arch, were sampled in the esophagus at the level of the primary tumor, sternal notch, aortic arch, carina, and gastro-esophageal junction. Symptomatic radiation esophagitis was defined as an event.ResultsCompared to baseline, esophageal NSUV increased significantly during-RT at the level of the primary tumor (1.09 ± 0.05 vs.1.28 ± 0.06, p = 0.001), but did not change at other levels in the esophagus. 16 patients had radiation esophagitis events and these patients had significantly higher during-RT to baseline NSUV ratios than those without esophagitis (1.46 ± 0.12, 95% CI 1.20-1.71; vs. 1.11 ± 0.05, 95% CI 1.01-1.21, p = 0.002). Maximum esophageal dose (p = 0.029), concurrent chemotherapy (p = 0.022) and esophageal FDG PET NSUV ratio (during-RT to baseline, p = 0.007), were independent factors associated with esophagitis and area under curves (AUC) were 0.76, 0.70 and 0.78, respectively. Combining esophageal maximum dose and FDG PET NSUV Ratio at the tumor level increased AUC to 0.85 (p = 0.016).ConclusionFDG uptake increased in esophagus during-RT and this increase may predict radiation esphagitis during later course of treatment.

Monitoring tumour response during chemo-radiotherapy: a parametric method using FDG-PET/CT images in patients with oesophageal cancer

BackgroundThe objective of this study is to investigate the feasibility and the additional interest of a parametric imaging (PI) method to monitor the early tumour metabolic response in a prospective series of oesophageal cancer patients who underwent positron emission tomography with fluoro-2-deoxy-d-glucose (FDG-PET/CT) before and during curative-intent chemo-radiotherapy.MethodsFifty-seven patients with squamous cell carcinoma (SCC) of the oesophagus prospectively underwent FDG-PET/CT before chemo-radiotherapy (CRT) (PET1) and at 21 ± 3 days after the beginning of CRT (PET2). The outcome was assessed at 3 months and 1 year after the completion of CRT (clinical examination, CT scan or FDG-PET/CT, biopsy). For each patient, PET1 and PET2 were registered using CT images. The 2 PET image sets were subtracted, so the voxels with significant changes in FDG uptake were identified. A model-based analysis of this graph was used to identify the tumour voxels in which significant changes occurred between the two scans and yielded indices characterising these changes (green and red clusters). Quantitative parameters were compared with clinical outcome at 3 months and at 1 year.ResultsThe baseline tumour FDG uptake decreased significantly at PET2 (p < 0.0001). The tumour volume significantly decreased between PET1 and PET2 (p < 0.02). The initial functional volume of the lesion (TV1) was significantly lower (p < 0.02) in patients in clinical response (CR) at 3 months and 1 year. The volume of the lesion during the treatment (TV2) was significantly lower in patients identified as in CR at 3 months (p < 0.03), but did not predict the outcome at 1 year. Multivariate analyses of outcome at 3 months showed that the risk of failure/death increased with younger age (p = 0.001), larger metabolic volume on PET1 (p = 0.009) and larger volume with decreased FDG uptake (p = 0.047). As for outcome at 1 year, the risk of failure/death increased with younger age (p = 0.006), nodal involvement (p = 0.08) and larger volumes with increased uptake (p = 0.03).ConclusionA parametric method to assess tumour response on serial FDG-PET performed during chemo-radiotherapy was evaluated. Early metabolic changes, i.e. variations in FDG uptake, provided additional prognostic information in multivariate analyses ClinicalTrials.gov NCT 00934505.Trial registrationCurrent Controlled Trials ISRCTN7824458

A Phase I Study of an Agonist CD40 Monoclonal Antibody (CP-870,893) in Combination with Gemcitabine in Patients with Advanced Pancreatic Ductal Adenocarcinoma

This phase I study investigated the maximum-tolerated dose (MTD), safety, pharmacodynamics, immunologic correlatives, and antitumor activity of CP-870,893, an agonist CD40 antibody, when administered in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDA). Twenty-two patients with chemotherapy-naïve advanced PDA were treated with 1,000 mg/m(2) gemcitabine once weekly for three weeks with infusion of CP-870,893 at 0.1 or 0.2 mg/kg on day three of each 28-day cycle. CP-870,893 was well-tolerated; one dose-limiting toxicity (grade 4, cerebrovascular accident) occurred at the 0.2 mg/kg dose level, which was estimated as the MTD. The most common adverse event was cytokine release syndrome (grade 1 to 2). CP-870,893 infusion triggered immune activation marked by an increase in inflammatory cytokines, an increase in B-cell expression of costimulatory molecules, and a transient depletion of B cells. Four patients achieved a partial response (PR). 2-[(18)F]fluoro-2-deoxy-d-glucose-positron emission tomography/computed tomography (FDG-PET/CT) showed more than 25% decrease in FDG uptake within primary pancreatic lesions in six of eight patients; however, responses observed in metastatic lesions were heterogeneous, with some lesions responding with complete loss of FDG uptake, whereas other lesions in the same patient failed to respond. Improved overall survival correlated with a decrease in FDG uptake in hepatic lesions (R = -0.929; P = 0.007). CP-870,893 in combination with gemcitabine was well-tolerated and associated with antitumor activity in patients with PDA. Changes in FDG uptake detected on PET/CT imaging provide insight into therapeutic benefit. Phase II studies are warranted.

FDG Pulmonary Uptake Changes During and Post-Radiation Therapy Compared to Pretreatment in Predicting Radiation-Induced Lung Toxicity in Non-Small Cell Lung Cancer

We hypothesize that the 18F-fludeoxyglucose (18FDG) uptake changes during early radiation therapy reflect subclinical radiation lung injury that is predictive of post-treatment radiation induced lung toxicity (RILT). The primary aim of our study was to investigate the relationship between clinically significant RILT and pulmonary 18FDG uptake changes during and post-radiation therapy. We studied a prospectively recruited cohort of 84 NSCLC patients treated with chemoradiation therapy. All patients had 18FDG PET performed before and during RT and 49 patients also had post-RT PET images. Pulmonary 18FDG uptake were assessed using Hick's visual grading scale (0-3) by a physician blinded to clinical RILT results: Grade 0∼ no abnormality identified in normal tissues within the radiation treatment volume; Grade 1∼increased activity in the pleural reflections and soft tissues within the radiation treatment volume but no parenchymal lung changes; Grade 2 = increased parenchymal lung uptake in the radiation treatment volume of equal or lower intensity than normal soft tissues in the mediastinum or chest wall located outside the radiation field; Grade 3 = increased parenchymal lung uptake in the radiation treatment volume of greater intensity than normal soft tissues in the mediastinum or chest wall. Common Terminology Criteria for Adverse Events version 3.0 was used to score RILT and event was defined as grade 2 or higher. On during-RT PET images, 75 (89.3%), 5 (6.0%), 4 (4.7%) and 0 (0%) patients had grade 0, 1, 2, and 3 changes, respectively. At 3 months after completion of RT, 42.9% patients had visible changes: 12 (24.5%) grade 1, 3 (6.1%) grade 2, and 6 (12.2%) grade 3 on the post-RT PET images. Overall, 11 patients (13.1%) developed RILT and the median time to RILT after radiation therapy was 4.6 months (range, 2-10). Among patients developed clinical RILT, 3 patients (37.5%) grade 1-2, 4 (50%) had grade 3 FDG uptake on the post-RT PET images. In 9 patients with increased FDG uptake during-RT, 5 (55.6 %) developed RILT, and 3 of them had grade 3 and above. Among 8 RILT patients with post-RT PET images available for assessment, 7 (89%) had grade 1-3 changes on FDG uptake. There was a significant correlation between the incidence of severe RILT and FDG uptake changes on during-RT (p = 0.002) and post-RT (p < 0.001) PET images. FDG uptake is commonly increased at 3 months after RT, but infrequently increased on during-RT PET. Increase in FDG uptake in lung either during- or post-RT may be associated with increased risk of RILT. Increased uptake during-RT may identify patients at highest risk for RILT. Visual assessment of PET may identify patients at high risk for toxicity and guide individualized radiation plan to decrease RILT.

Differential Washout of FDG Activity in Two Different Inflammatory Lesions

We describe the changes of FDG uptake in different inflammatory lesions on multiple time point FDG PET/CT. FDG uptake in granulomatous lesions was more intense and focal, with higher intensity on delayed images. In contrast, FDG uptake in chronic arthritic joint inflammation was diffuse and mild, without significant change over time, while FDG uptake in nonarthritic joints was at near-background level with decreased activity on delayed images. The retention index was significantly higher in patients with granulomatous lesions than that in other groups. Our finding indicates differential FDG uptake and clearance in active granulomas versus chronic inflammation.

Abstract 4695: Predictive role of FDG PET-CT in monitoring locally advanced rectal cancer (LARC) during preoperative radiochemotherapy with an experimental bevacizumab schedule.

Abstract Objectives : We have shown that pathological regression of LARC and relapse free survival can be predicted by early changes in FDG uptake during preoperative radiochemotherapy. We have attempted to improve efficacy of our neo-adjuvant treatment by adding an experimental bevacizumab (BEV) schedule. FDG PETCT was utilized to monitor response and correlate with pathological outcome. Methods : Forty six patients with poor prognosis LARC received 3 biweekly courses of oxaliplatin/ raltitrexed (day 1) and FU/ folinic acid (day 2) during pelvic RT (45 Gy). BEV (5 mg/kg) was administered on day -4 for the first 2 courses. PET-CT was performed at baseline, on day 12 and prior to surgery and lesion TLG (mean SUV x volume) values determined. Pathologic response was defined using a modified Mandard tumor regression grade (TRG) scale. Responders were defined as TRG1-2, non-responders as TRG3-4. Results : Thirty-seven patients (80%) showed pathologic response (65% with previous scheme). Eight patients (17%, previously 35%) were non-responders. Responders showed significantly higher TLG reduction on day 12 PET-CT (median -72% range -90%+31%) compared to non-responders (TRG3-4, median -38%, range -45% +25%, p &amp;lt; 0.05), confirming previous findings. Preoperative PET-CT studies, on the other hand, were not predictive of pathologic response (responders TLG change median -92%, range -100% +4%, non-responders median 86%, range -94%-76%, p = ns). Ongoing studies to define a correlation between FDG uptake and biomarkers of angiogenesis such as Circulating endothelial cells (CEC) will be presented. Conclusions : Our findings indicate that the current scheme significantly increases pathologic response. PET-CT confirms to be a powerful early surrogate marker of treatment efficacy. PET-CT may be used to tailor more aggressive treatment for non-responsive patient Citation Format: Antonio Avallone, Paolo Delrio, Biagio Pecori, Fabiana Tatangelo, Elena Di Gennaro, Antonella Petrillo, Vincenzo Rosario Iaffaioli, Alessandra Leone, Corradina caracò, Alfredo Budillon, Secondo Lastoria, Luigi Aloj. Predictive role of FDG PET-CT in monitoring locally advanced rectal cancer (LARC) during preoperative radiochemotherapy with an experimental bevacizumab schedule. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4695. doi:10.1158/1538-7445.AM2013-4695

FDG PET/CT during neoadjuvant chemotherapy may predict response in ER-positive/HER2-negative and triple negative, but not in HER2-positive breast cancer

BackgroundResponse monitoring with MRI during neoadjuvant chemotherapy (NAC) in breast cancer is promising, but knowledge of breast cancer subtype is essential. The aim of the present study was to evaluate the relevance of breast cancer subtypes for monitoring of therapy response during NAC with 18F-FDG PET/CT. MethodsEvaluation included 98 women with stages II and III breast cancer. PET/CTs were performed before and after six or eight weeks of NAC. FDG uptake was quantified using maximum standardized uptake values (SUVmax). Tumors were divided into three subtypes: HER2-positive, ER-positive/HER2-negative, and triple negative. Tumor response at surgery was assessed dichotomously (presence or absence of residual disease) and ordinally (breast response index, representing relative change in tumor stage). Multivariate regression and receiver operating characteristic (ROC) analyses were employed to determine associations with pathological response. ResultsA (near) complete pathological response was seen in 19 (76%) of 25 HER2-positive, 7 (16%) of 45 ER-positive/HER2-negative, and 20 (71%) of 28 triple negative tumors. Multivariate regression of pathological response indicated a significant interaction between change in FDG uptake and breast cancer subtype. The area under the ROC curve was 0.35 (0.12–0.64) for HER2-positive, 0.90 (0.76–1.00) for ER-positive/HER2-negative, and 0.96 (0.86–1.00) for triple negative tumors. We found no association between age, stage, histology, or baseline SUVmax and pathological response. ConclusionResponse monitoring with PET/CT during NAC in breast cancer seems feasible, but is dependent on the breast cancer subtype. PET/CT may predict response in ER-positive/HER2-negative and triple negative tumors, but seems less accurate in HER2-positive tumors.

Fasting 2-Deoxy-2-[18F]fluoro-d-glucose Positron Emission Tomography to Detect Metabolic Changes in Pulmonary Arterial Hypertension Hearts over 1 Year

The development of tools to monitor the right ventricle in pulmonary arterial hypertension (PAH) is of clinical importance. PAH is associated with pathologic expression of the transcription factor hypoxia-inducible factor (HIF)-1α, which induces glycolytic metabolism and mobilization of proangiogenic progenitor (CD34(+)CD133(+)) cells. We hypothesized that PAH cardiac myocytes have a HIF-related switch to glycolytic metabolism that can be detected with fasting 2-deoxy-2-[(18)F]fluoro-d-glucose positron emission tomography (FDG-PET) and that glucose uptake is informative for cardiac function. Six healthy control subjects and 14 patients with PAH underwent fasting FDG-PET and echocardiogram. Blood CD34(+)CD133(+) cells and erythropoietin were measured as indicators of HIF activation. Twelve subjects in the PAH cohort underwent repeat studies 1 year later to determine if changes in FDG uptake were related to changes in echocardiographic parameters or to measures of HIF activation. FDG uptake in the right ventricle was higher in patients with PAH than in healthy control subjects and correlated with echocardiographic measures of cardiac dysfunction and circulating CD34(+)CD133(+) cells but not erythropoietin. Among patients with PAH, FDG uptake was lower in those receiving β-adrenergic receptor blockers. Changes in FDG uptake over time were related to changes in echocardiographic parameters and CD34(+)CD133(+) cell numbers. Immunohistochemistry of explanted PAH hearts of patients undergoing transplantation revealed that HIF-1α was present in myocyte nuclei but was weakly detectable in control hearts. PAH hearts have pathologic glycolytic metabolism that is quantitatively related to cardiac dysfunction over time, suggesting that metabolic imaging may be useful in therapeutic monitoring of patients.

Correlation between therapy response assessment using FDG PET/CT and histopathologic tumor regression grade in hepatic metastasis of colorectal carcinoma after neoadjuvant therapy

To evaluate the correlation between change in FDG uptake before and after chemotherapy in hepatic metastases of colorectal carcinoma (HCRC) and a histopathologic tumor regression grade (TRG). In patients with HCRC, PET/CT data prior to hepatic surgery were retrospectively analyzed under an IRB waiver. The maximum standard uptake value (SUVmax) was measured before and after chemotherapy. The relative change of FDG activity in the identified lesions was calculated (dSUV). Histopathological specimens of resected metastases were graded on a 5-score TRG scale. A TRG of 1-3 was rated as a responding to therapy, whereas TRG 4-5 were regarded as non-responding lesions. 31 lesions were identified in 23 patients. Mean SUVmax before and after therapy was 6.9 ± 3.7 and 3.5 ± 1.8, respectively. The area under the receiver operator characteristic curve revealed a conclusive correlation between TRG and dSUV (AUC 0.773; 95% confidence interval 0.599-0.946) with a cut off at 41% decrease in FDG activity yielding a sensitivity and specificity of 72 and 75%, respectively. A relative change in FDG activity (dSUV) of more than 41% decrease correlated significantly with histopathological tumor regression and might be a prognostic tool for response to chemotherapy in HCRC.

FDG-Positron Emission Tomography/Computerized Tomography for Monitoring the Response of Pelvic Lymph Node Metastasis to Neoadjuvant Chemotherapy for Bladder Cancer

We evaluated FDG-positron emission tomography/computerized tomography for monitoring the response of pelvic lymph node metastasis to neoadjuvant chemotherapy for bladder cancer. We compared this to contrast enhanced computerized tomography. Included in study were 19 consecutive patients with lymph node positive bladder cancer who underwent FDG-positron emission tomography/computerized tomography and contrast enhanced computerized tomography before and after a median of 4 cycles (range 2 to 4) of neoadjuvant chemotherapy between September 2011 and April 2012. Metabolic response was assessed according to EORTC (European Organisation for Research and Treatment of Cancer) recommendations based on the change in FDG uptake on FDG-positron emission tomography/computerized tomography. Radiological response was assessed on contrast enhanced computerized tomography according to RECIST (Response Evaluation Criteria in Solid Tumors) 1.1. All patients underwent pelvic lymph node dissection. Histopathological evaluation served as the gold standard for the nodal response. Before neoadjuvant chemotherapy, hypermetabolic FDG uptake was seen in all 19 patients, which matched the lymph node metastasis. Evaluating the nodal response with positron emission tomography/computerized tomography was feasible in all patients. On histopathology 16 patients were responders, including 14 with a complete pathological response of the lymph nodes. Positron emission tomography/computerized tomography and contrast enhanced computerized tomography correctly distinguished responders from nonresponders (18 of 19 patients or 94.7% and 15 of 19 or 78.9%) and complete responders from patients with residual disease (13 of 19 or 68.4% and 12 of 19 or 63.2%, respectively). Although no definitive conclusions can be drawn from these preliminary data, positron emission tomography/computerized tomography appears feasible for evaluating the nodal response to neoadjuvant chemotherapy and distinguishing responders from nonresponders.

1201P - 18F-FDG-PET Response During the Second Week of Concurrent or Sequential Chemo-Radiotherapy Significantly Correlates with 2-Year Survival in NSCLC Patients

ABSTRACT Purpose/Objective Assessment early during the course of treatment could identify prognostic groups, allowing treatment individualisation at a time when therapy changes are possible and before major toxicity occurred. We hypothesised that FDG-PET/CT imaging during the second week of chemo-radiotherapy would correlate with 2-year overall survival (OS). Methods We performed FDG-PET/CT imaging at two time points: One 4D PET/CT was performed prior to the start of radiotherapy, and a second 4D PET/CT during the second week of radiotherapy, sequential or concurrently with cisplatin-vinorelbine. In total 34 consecutive patients with NSCLC were successfully imaged. Images were analysed both for CT-based characteristics (volume of the primary tumour and, if present, involved lymph nodes), PET characteristics included the average, maximum and peak SUV (SUVmean, SUVmax, SUVpeak, resp.). The difference in these parameters between both time points were correlated to the 2-year overall survival. Results The change in FDG-uptake (SUVmean) of the primary tumour was significantly different (p = 0.007) between the group surviving more than 2 years (-20.2 ± 20.5%) compared to the group not surviving two years ( + 2.1 ± 21.9%). Using the EORTC criteria for partial response (decrease in signal of 15%), a sensitivity of 63% and a specificity of 93% in this population was found that separated the survival curves (p = 0.001). CT-based early response parameters were not associated with prediction of survival. Conclusions Decrease in FDG-uptake already in the second week of (chemo-) radiotherapy is correlated with overall survival in NSCLC. This opens avenues for individualized and optimized treatment based on early treatment response analysis. A prospective trial including 120 patients has just been terminated. Disclosure All authors have declared no conflicts of interest.

Early prediction of histopathological response of rectal tumors after one week of preoperative radiochemotherapy using 18 F-FDG PET-CT imaging. A prospective clinical study

BackgroundPreoperative radiochemotherapy (RCT) is standard in locally advanced rectal cancer (LARC). Initial data suggest that the tumor’s metabolic response, i.e. reduction of its 18 F-FDG uptake compared with the baseline, observed after two weeks of RCT, may correlate with histopathological response. This prospective study evaluated the ability of a very early metabolic response, seen after only one week of RCT, to predict the histopathological response to treatment.MethodsTwenty patients with LARC who received standard RCT regimen followed by radical surgery participated in this study. Maximum standardized uptake value (SUV-MAX), measured by PET-CT imaging at baseline and on day 8 of RCT, and the changes in FDG uptake (ΔSUV-MAX), were compared with the histopathological response at surgery. Response was classified by tumor regression grade (TRG) and by achievement of pathological complete response (pCR).ResultsAbsolute SUV-MAX values at both time points did not correlate with histopathological response. However, patients with pCR had a larger drop in SUV-MAX after one week of RCT (median: -35.31% vs −18.42%, p = 0.046). In contrast, TRG did not correlate with ΔSUV-MAX. The changes in FGD-uptake predicted accurately the achievement of pCR: only patients with a decrease of more than 32% in SUV-MAX had pCR while none of those whose tumors did not show any decrease in SUV-MAX had pCR.ConclusionsA decrease in ΔSUV-MAX after only one week of RCT for LARC may be able to predict the achievement of pCR in the post-RCT surgical specimen. Validation in a larger independent cohort is planned.

Lesion-based detection of early chemosensitivity using serial static FDG PET/CT in metastatic colorectal cancer

PurposeMedical oncology needs early identification of patients that are not responding to systemic therapy. 18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) performed before and early during treatment has been proposed for this purpose. However, the best way to assess the change in FDG uptake between two scans has not been identified. We studied cutoff thresholds to identify responding tumours as a function of the method used to measure tumour uptake.MethodsThe study included 28 metastatic colorectal cancer (mCRC) patients who underwent 2 FDG PET/CT scans (baseline and at day 14 of the first course of polychemotherapy). For 78 tumour lesions, 4 standardized uptake value (SUV) indices were measured: maximum SUV (SUVmax) and mean SUV in a region obtained using an isocontour (SUV40 %), with each of these SUV normalized either by the patient body weight (BW) or body surface area (BSA). The per cent change and absolute change in tumour uptake between the baseline and the early PET scans were measured based on these four indices. These changes were correlated to the RECIST 1.0-based response using contrast-enhanced CT at baseline and at 6–8 weeks on treatment.ResultsThe 78 tumours were classified as non-responding (NRL, n = 58) and responding lesions (RL, n = 20). Receiver-operating characteristic (ROC) curves characterizing the performance in NRL/RL classification using early FDG PET uptake had areas under the curve between 0.75 and 0.84, without significant difference between the indices. The cutoff threshold in FDG uptake per cent change to get a 95 % sensitivity of RL detection depended on the way uptake was measured: −14 % (specificity of 53 %) and −22 % (specificity of 64 %) for SUVmax and SUV40 %, respectively. Thresholds expressed as absolute SUV decrease instead of per cent change were less sensitive to the SUV definition: an SUV decline by 1.2 yielded a sensitivity of RL detection of 95 % for SUVmax and SUV40 %. For a given cutoff threshold, the sensitivity was the same whatever the normalization (by BSA or BW).ConclusionA 14 % drop of tumour FDG SUVmax, 22 % drop of SUV40 % or 1.2 drop of SUVmax or SUVmean after one single course of polychemotherapy predicts objective response in mCRC lesions with a high sensitivity, potentially allowing the early identification of non-responding patients.

FDG-PET is a good biomarker of both early response and acquired resistance in BRAFV600 mutant melanomas treated with vemurafenib and the MEK inhibitor GDC-0973

BackgroundThe BRAF inhibitor, vemurafenib, has recently been approved for the treatment of metastatic melanoma in patients harboring BRAFV600 mutations. Currently, dual BRAF and MEK inhibition are ongoing in clinical trials with the goal of overcoming the acquired resistance that has unfortunately developed in some vemurafenib patients. FDG-PET measures of metabolic activity are increasingly employed as a pharmacodynamic biomarker for guiding single-agent or combination therapies by gauging initial drug response and monitoring disease progression. However, since tumors are inherently heterogeneous, investigating the effects of BRAF and MEK inhibition on FDG uptake in a panel of different melanomas could help interpret imaging outcomes.Methods18 F-FDG uptake was measured in vitro in cells with wild-type and mutant (V600) BRAF, and in melanoma cells with an acquired resistance to vemurafenib. We treated the cells with vemurafenib alone or in combination with MEK inhibitor GDC-0973. PET imaging was used in mice to measure FDG uptake in A375 melanoma xenografts and in A375 R1, a vemurafenib-resistant derivative. Histological and biochemical studies of glucose transporters, the MAPK and glycolytic pathways were also undertaken.ResultsWe demonstrate that vemurafenib is equally effective at reducing FDG uptake in cell lines harboring either heterozygous or homozygous BRAFV600 but ineffective in cells with acquired resistance or having WT BRAF status. However, combination with GDC-0973 results in a highly significant increase of efficacy and inhibition of FDG uptake across all twenty lines. Drug-induced changes in FDG uptake were associated with altered levels of membrane GLUT-1, and cell lines harboring RAS mutations displayed enhanced FDG uptake upon exposure to vemurafenib. Interestingly, we found that vemurafenib treatment in mice bearing drug-resistant A375 xenografts also induced increased FDG tumor uptake, accompanied by increases in Hif-1α, Sp1 and Ksr protein levels. Vemurafenib and GDC-0973 combination efficacy was associated with decreased levels of hexokinase II, c-RAF, Ksr and p-MEK protein.ConclusionsWe have demonstrated that 18 F-FDG-PET imaging reflects vemurafenib and GDC-0973 action across a wide range of metastatic melanomas. A delayed post-treatment increase in tumor FDG uptake should be considered carefully as it may well be an indication of acquired drug resistance.Trial registrationClinicalTrials.gov NCT01271803