Early metabolic response in sequential FDG-PET/CT under cetuximab is a predictive marker for clinical response in first-line metastatic colorectal cancer patients: results of the phase II REMOTUX trial.

BACKGROUND: To assess the predictive value of early metabolic response (ΔSUV) after short-term treatment with first-line cetuximab in patients (pts) with RAS-wt metastatic colorectal cancer (mCRC). METHODS: In this prospective phase II study, RAS-wt mCRC pts received a single-agent cetuximab run-in therapy of 2 weeks. ΔSUV was assessed with FDG-PET/CT on days 0 and 14. Early clinical response (ECR) was evaluated with CT on day 56 after treatment with FOLFIRI-cetuximab. Primary endpoint was the predictive significance of ΔSUV for ECR. Secondary endpoints were PFS (progression free survival), OS and the influence of ΔSUV on survival. RESULTS: Forty pts were enroled and 33 pts were evaluable for the primary endpoint. The CT response rate was 57.6%. For responders, ΔSUV was significantly higher (p = 0.0092). A significant association of ΔSUV with ECR was found (p = 0.02). Median PFS was 11.7 months and median OS was 33.5 months with a 1-year survival rate of 87.9%. ΔSUV was found to significantly impact the hazard for OS (p = 0.045). CONCLUSIONS: We demonstrate that cetuximab induces metabolic responses in mCRC pts. The study endpoint was met with the ΔSUV discriminating between responders and non-responders. However, these data should be validated in larger patient cohorts.

Comparison of lesion detection and quantitation of tracer uptake between PET from a simultaneously acquiring whole-body PET/MR hybrid scanner and PET from PET/CT.

PURPOSE: PET/MR hybrid scanners have recently been introduced, but not yet validated. The aim of this study was to compare the PET components of a PET/CT hybrid system and of a simultaneous whole-body PET/MR hybrid system with regard to reproducibility of lesion detection and quantitation of tracer uptake. METHODS: A total of 46 patients underwent a whole-body PET/CT scan 1 h after injection and an average of 88 min later a second scan using a hybrid PET/MR system. The radioactive tracers used were (18)F-deoxyglucose (FDG), (18)F-ethylcholine (FEC) and (68)Ga-DOTATATE (Ga-DOTATATE). The PET images from PET/CT (PET(CT)) and from PET/MR (PET(MR)) were analysed for tracer-positive lesions. Regional tracer uptake in these foci was quantified using volumes of interest, and maximal and average standardized uptake values (SUV(max) and SUV(avg), respectively) were calculated. RESULTS: Of the 46 patients, 43 were eligible for comparison and statistical analysis. All lesions except one identified by PET(CT) were identified by PET(MR) (99.2 %). In 38 patients (88.4 %), the same number of foci were identified by PET(CT) and by PET(MR). In four patients, more lesions were identified by PET(MR) than by PET(CT), in one patient PET(CT) revealed an additional focus compared to PET(MR). The mean SUV(max) and SUV(avg) of all lesions determined by PET(MR) were by 21 % and 11 % lower, respectively, than the values determined by PET(CT) (p < 0.05), and a strong correlation between these variables was identified (Spearman rho 0.835; p < 0.01). CONCLUSION: PET/MR showed equivalent performance in terms of qualitative lesion detection to PET/CT. The differences demonstrated in quantitation of tracer uptake between PET(CT) and PET(MR) were minor, but statistically significant. Nevertheless, a more detailed study of the quantitative accuracy of PET(MR) and the factors governing it is needed to ultimately assess its accuracy in measuring tissue tracer concentrations.

A phase II study for metabolic in vivo response monitoring with sequential 18FDG-PET-CT during treatment with the EGFR-monoclonal-antibody cetuximab in metastatic colorectal cancer: the Heidelberg REMOTUX trial.

BACKGROUND: The epidermal growth factor receptor monoclonal antibody cetuximab has proven activity in metastatic colorectal cancer. To date, the mechanisms of action are not completely understood. Especially the impact on tumor glucose metabolism, or tumor vascularization remains largely unclear. The understanding of mechanisms such as early changes in tumor metabolism is of clinical importance since there may be a substantial influence on choice and sequence of drug combinations. Early signals of response to cetuximab may prove useful to identify patients having a relevant clinical treatment benefit. The objective of this trial is to evaluate the predictive relevance of the relative change in (18)F-Fluorodeoxyglucose tumor uptake for early clinical response during short-term single agent treatment with cetuximab. Early clinical response will be routinely measured according to the response evaluation criteria in solid tumors. Accompanying research includes cytokine immune monitoring and analysis of tumor proteins and tumor genes. METHODS/DESIGN: The REMOTUX trial is an investigator-initiated, prospective, open-label, single-arm, single-center early exploratory predictive study. The first (18)F-FDG PET-CT is conducted at baseline followed by the run-in phase with cetuximab at days 1 and 8. At day 14, the second (18)F-FDG PET-CT is performed. Subsequently, patients are treated according to the Folfiri-cetuximab regimen as an active and approved first-line regimen for metastatic colorectal carcinoma. At day 56, clinical response is evaluated with a CT-scan compared to the baseline analysis. Tracer uptake is assessed using standardized uptake values (SUVs). The main hypothesis to be tested in the primary analysis is whether or not the relative change in the SUV from baseline to day 14 has any predictive relevance for early clinical response determined at day 56. Patients are followed until death from any cause or until 24 months after the last patient has ended trial treatment. DISCUSSION: The aim of this trial is to evaluate metabolic changes in metastatic colorectal cancer during short-term single agent treatment with cetuximab and to analyse their potential of predicting early clinical response. This could be helpful to answer the question if early identification of patients not responding to cetuximab is possible. TRIAL REGISTRATION: ClinicalTrials.gov NCT200811021020; EudraCT 200901327923.

Sequential FDG-PET and induction chemotherapy in locally advanced adenocarcinoma of the Oesophago-gastric junction (AEG): the Heidelberg Imaging program in Cancer of the oesophago-gastric junction during Neoadjuvant treatment: HICON trial.

BACKGROUND: 18-Fluorodeoxyglucose-PET (18F-FDG-PET) can be used for early response assessment in patients with locally advanced adenocarcinomas of the oesophagogastric junction (AEG) undergoing neoadjuvant chemotherapy. It has been recently shown in the MUNICON trials that response-guided treatment algorithms based on early changes of the FDG tumor uptake detected by PET are feasible and that they can be implemented into clinical practice. Only 40%-50% of the patients respond metabolically to therapy. As metabolic non-response is known to be associated with a dismal prognosis, metabolic non-responders are increasingly treated with alternative neoadjuvant chemotherapies or chemoradiation in order to improve their clinical outcome. We plan to investigate whether PET can be used as response assessment during radiochemotherapy given as salvage treatment in early metabolic non-responders to standard chemotherapy. METHODS/DESIGN: The HICON trial is a prospective, non-randomized, explorative imaging study evaluating the value of PET as a predictor of histopathological response in metabolic non-responders. Patients with resectable AEG type I and II according to Siewerts classification, staged cT3/4 and/or cN+ and cM0 by endoscopic ultrasound, spiral CT or MRI and FDG-PET are eligible. Tumors must be potentially R0 resectable and must have a sufficient FDG-baseline uptake. Only metabolic non-responders, showing a < 35% decrease of SUV two weeks after the start of neoadjuvant chemotherapy are eligible for the study and are taken to intensified taxane-based RCT (chemoradiotherapy (45 Gy) before surgery. 18FDG-PET scans will be performed before ( = Baseline) and after 14 days of standard neoadjuvant therapy as well as after the first cycle of salvage docetaxel/cisplatin chemotherapy (PET 1) and at the end of radiochemotherapy (PET2). Tracer uptake will be assessed semiquantitatively using standardized uptake values (SUV). The percentage difference ΔSUV = 100 (SUV Baseline - SUV PET1)/SUV Baseline will be calculated and assessed as an early predictor of histopathological response. In a secondary analysis, the association between the difference SUV PET1 - SUV PET2 and histopathological response will be evaluated. DISCUSSION: The aim of this study is to investigate the potential of sequential 18FDG-PET in predicting histopathological response in AEG tumors to salvage neoadjuvant radiochemotherapy in patients who do not show metabolic response to standard neoadjuvant chemotherapy.

Three-dimensional multiphase time-resolved low-dose contrast-enhanced magnetic resonance angiography using TWIST on a 32-channel coil at 3 T: a quantitative and qualitative comparison of a conventional gadolinium chelate with a high-relaxivity agent.

PURPOSE: To evaluate low-dose contrast-enhanced magnetic resonance angiography (CE-MRA) at high temporal and spatial resolution for imaging of abdominal vascular structures. MATERIALS AND METHODS: Contrast-enhanced magnetic resonance angiography (TWIST [time-resolved angiography with interleaved stochastic trajectories]) was performed in 8 male New Zealand white rabbits at 3 T using a prototype 32-channel coil. Gadoteridol (Gd-HP-DO3A, ProHance; Bracco Imaging SpA, Milan, Italy) and the high-relaxivity agent gadobenate dimeglumine (Gd-BOPTA, MultiHance; Bracco Imaging SpA), each at a dose of 0.04 mmol/kg body weight, were used in an intraindividual comparison. Quantitative analysis of contrast-to-noise ratio (CNR) was performed in regions of interest placed in the aorta and the adjacent tissues. The image quality in the aorta, external iliac artery, and vena cava was categorized by 2 independent blinded readers from excellent (1) to poor (3). RESULTS: A significantly (P < 0.001) higher CNR was obtained with gadobenate dimeglumine. The improved CNR led to a better delineation of the external iliac arteries. Qualitative rating showed the image quality to be excellent for gadobenate dimeglumine and adequate for gadoteridol. CONCLUSIONS: Time-resolved CE-MRA performed at 3 T with a 32-channel volume coil can be improved using the high-relaxivity agent gadobenate dimeglumine, which increases quality and quantity of vessel enhancement.

Assessment of diffusion-weighted MRI and 18F-fluoro-deoxyglucose PET/CT in monitoring early response to neoadjuvant chemotherapy in adenocarcinoma of the esophagogastric junction.

BACKGROUND & AIMS: To prospectively assess whether changes in apparent diffusion coefficient (ADC) values or standardized uptake value (SUV) changes in 18F-fluorodeoxyglucose (FDG) PET correlate with treatment response under neoadjuvant chemotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction (AEG). METHODS: Fifteen patients (median age, 64 years) with histologically proven AEG type I and II received 1.5 Tesla MRI including "diffusion-weighted imaging" and FDG PET/CT before and 14 days after neoadjuvant EOX chemotherapy. The FDG uptake of the tumor was quantified by calculating the SUV in static PET scans. ADC values within the tumor tissue were quantitatively assessed using a region-of-interest analysis excluding necrotic areas. Early metabolic response was defined as a decrease in the SUV(mean) >/= 35% in FDG PET two weeks following the start of neoadjuvant chemotherapy, which had been reported to be predictive of histopathological response and survival. Concordance between ADC and SUV changes, differences at first examination and overall survival were assessed. RESULTS: The ADC within the AEG tumors was significantly lower than in normal esophagus and increased following neoadjuvant chemotherapy by 16.0 +/- 1.1% (p=0.007). Tumor glucose SUV decreased by 29.1 +/- 23.2% (p=0.002). Initial ADC and SUV were comparable in both groups (p=0.65, p=0.82). ADC increase and metabolic PET-response were concordant in 73.3% of all patients. The median overall survival was 757 days for PET-responders and 623 days for PET-non-responders (p=0.138). CONCLUSION: The ADC increase in AEG tumors following chemotherapy is concordant in the majority of cases to PET-response, but not correlated to prognosis in this study.

Integrated whole-body PET/MR hybrid imaging: clinical experience.

OBJECTIVES: Integrated whole-body positron emission tomography (PET)/magnetic resonance (MR) scanners have recently been introduced and potentially offer new possibilities in hybrid imaging of oncologic patients. Integration of PET in a whole-body MR system requires new PET detector technology and new approaches to attenuation correction of PET data based on MR imaging. The aim of this study was to evaluate the clinical performance and image quality parameters of integrated whole-body PET/MR hybrid imaging in intraindividual comparison with PET/CT in oncologic patients. MATERIALS AND METHODS: Eighty patients underwent a single-injection, dual-imaging protocol including whole-body PET/computed tomography (CT) and subsequent whole-body PET/MR hybrid imaging. Positron emission tomography/computed tomography was performed after adequate resting time (73 ± 13 minutes post injectionem of 227 ± 52.7 MBq Fluor-18-Fluordesoxyglucose, 3 minutes of acquisition time for each of 7 bed positions), followed by PET/MR (172 ± 33 minutes post injectionem, 10 minutes acquisition time for each of 4 bed positions). Positron emission tomographic data for both modalities were reconstructed iteratively. Two observers evaluated the following parameters: qualitative correlation of tracer-avid lesions in PET/CT versus PET/MR and PET image quality of PET/CT versus PET/MR. Magnetic resonance image quality of standard sequences (T1-weighted, T2-weighted), performance of the Dixon sequence for MR-based attenuation correction in comparison with corresponding T1-weighted images, artifacts in PET/MR data, and spatial coregistration of PET and MR data were evaluated by another observer. RESULTS: In 70 of the 80 patients, both image data sets were complete. In these patients, 192 tracer-avid lesions were identified on PET/CT; 195, on PET/MR. A total of 187 lesions were identified concordantly by both modalities, and this corresponds to an agreement rate of 97.4%. The overall PET image quality was rated good to excellent for PET from PET/CT (12/28, excellent, 42.9%; 16/28, good, 57.1%; 0/28, poor, 0.0%) and slightly superior compared with PET from PET/MR, which was rated good (3/28, excellent, 10.7%; 20/28, good, 71.4%; 5/28, poor, 17.9%) in a subset of 28 patients. The overall image quality of the MR image data sets in all 70 of the 80 patients was rated excellent (260/280, excellent, 92.8%; 15/280, good, 5.4%; 5/280, poor, 1.8%). The Dixon sequence and conversion to µ-maps for MR-based attenuation correction provided robust tissue segmentation in all 280 bed positions of the acquired PET/MR data. No artifacts such as elevated noise and radiofrequency disturbances related to hardware cross talk between the PET and MR components in the hybrid system could be detected in the MR images. No major spatial mismatches between PET and MR data were detected. CONCLUSIONS: Integrated PET/MR hybrid imaging is feasible in a clinical setting with similar detection rates as those of PET/CT. Attenuation correction can be performed sufficiently with Dixon sequences, although bone is disregarded. The administration of specific radiotracers and dedicated imaging sequences will foster this hybrid imaging modality in various indications.