Dennis Vriens

Monitoring and Predicting Response to Therapy with 18F-FDG PET in Colorectal Cancer: A Systematic Review

Molecular imaging with 18F-FDG PET has been proven useful in the management of colorectal cancer. 18F-FDG PET plays a pivotal role in staging before surgical resection of recurrent colorectal cancer and metastases, in the localization of recurrence in patients with an unexplained rise in serum carcinoembryonic antigen levels, and in the assessment of residual masses after treatment. Currently, there is increasing interest in the role of 18F-FDG PET beyond staging. The technique appears to have significant potential for the characterization of tumors and for the prediction of prognosis in the context of treatment stratification and early assessment of tumor response to therapy. This systematic review provides an overview of the literature on the value of 18F-FDG PET for monitoring and predicting the response to therapy in colorectal cancer. The review covers chemotherapy response monitoring in advanced colorectal cancer, monitoring of the effects of local ablative therapies, and preoperative radiotherapy and multimodality treatment response evaluation in primary rectal cancer. Given the added value of 18F-FDG PET for these indications, implementation in clinical practice and systematic inclusion in therapeutic trials to exploit the potential of 18F-FDG PET are warranted.

Methodological considerations in quantification of oncological FDG PET studies.

PurposeThis review aims to provide insight into the factors that influence quantification of glucose metabolism by FDG PET images in oncology as well as their influence on repeated measures studies (i.e. treatment response assessment), offering improved understanding both for clinical practice and research.MethodsStructural PubMed searches have been performed for the many factors affecting quantification of glucose metabolism by FDG PET. Review articles and references lists have been used to supplement the search findings.ResultsBiological factors such as fasting blood glucose level, FDG uptake period, FDG distribution and clearance, patient motion (breathing) and patient discomfort (stress) all influence quantification. Acquisition parameters should be adjusted to maximize the signal to noise ratio without exposing the patient to a higher than strictly necessary radiation dose. This is especially challenging in pharmacokinetic analysis, where the temporal resolution is of significant importance. The literature is reviewed on the influence of attenuation correction on parameters for glucose metabolism, the effect of motion, metal artefacts and contrast agents on quantification of CT attenuation-corrected images. Reconstruction settings (analytical versus iterative reconstruction, post-reconstruction filtering and image matrix size) all potentially influence quantification due to artefacts, noise levels and lesion size dependency. Many region of interest definitions are available, but increased complexity does not necessarily result in improved performance. Different methods for the quantification of the tissue of interest can introduce systematic and random inaccuracy.ConclusionsThis review provides an up-to-date overview of the many factors that influence quantification of glucose metabolism by FDG PET.

A Curve-Fitting Approach to Estimate the Arterial Plasma Input Function for the Assessment of Glucose Metabolic Rate and Response to Treatment

For the quantification of dynamic 18F-FDG PET studies, the arterial plasma time–activity concentration curve (APTAC) needs to be available. This can be obtained using serial sampling of arterial blood or an image-derived input function (IDIF). Arterial sampling is invasive and often not feasible in practice; IDIFs are biased because of partial-volume effects and cannot be used when no large arterial blood pool is in the field of view. We propose a mathematic function, consisting of an initial linear rising activity concentration followed by a triexponential decay, to describe the APTAC. This function was fitted to 80 oncologic patients and verified for 40 different oncologic patients by area-under-the-curve (AUC) comparison, Patlak glucose metabolic rate (MRglc) estimation, and therapy response monitoring (ΔMRglc). The proposed function was compared with the gold standard (serial arterial sampling) and the IDIF. Methods: To determine the free parameters of the function, plasma time–activity curves based on arterial samples in 80 patients were fitted after normalization for administered activity (AA) and initial distribution volume (iDV) of 18F-FDG. The medians of these free parameters were used for the model. In 40 other patients (20 baseline and 20 follow-up dynamic 18F-FDG PET scans), this model was validated. The population-based curve, individually calibrated by AA and iDV (APTACAA/iDV), by 1 late arterial sample (APTAC1sample), and by the individual IDIF (APTACIDIF), was compared with the gold standard of serial arterial sampling (APTACsampled) using the AUC. Additionally, these 3 methods of APTAC determination were evaluated with Patlak MRglc estimation and with ΔMRglc for therapy effects using serial sampling as the gold standard. Results: Excellent individual fits to the function were derived with significantly different decay constants (P < 0.001). Correlations between AUC from APTACAA/iDV, APTAC1sample, and APTACIDIF with the gold standard (APTACsampled) were 0.880, 0.994, and 0.856, respectively. For MRglc, these correlations were 0.963, 0.994, and 0.966, respectively. In response monitoring, these correlations were 0.947, 0.982, and 0.949, respectively. Additional scaling by 1 late arterial sample showed a significant improvement (P < 0.001). Conclusion: The fitted input function calibrated for AA and iDV performed similarly to IDIF. Performance improved significantly using 1 late arterial sample. The proposed model can be used when an IDIF is not available or when serial arterial sampling is not feasible.

Chemotherapy Response Monitoring of Colorectal Liver Metastases by Dynamic Gd-DTPA–Enhanced MRI Perfusion Parameters and 18F-FDG PET Metabolic Rate

In this study, we examined the in vivo relationship between functional tumor vasculature, determined by dynamic contrast-enhanced (DCE-) MRI, and tumor metabolism, determined by dynamic 18F-FDG PET, during cytotoxic treatment of patients with colorectal liver metastases. Methods: Twenty-three patients underwent DCE-MRI (using gadolinium dimeglumine) and dynamic 18F-FDG PET at baseline and after 3 treatment cycles, unless treatment was terminated because of toxicity. Parameters for vasculature (rate constant between extravascular extracellular space and blood plasma [kep] and volume transfer constant [Ktrans]), extracellular space (ve), tumor size (the maximal axial diameter of each included lesion [MAD]), and metabolism (glucose metabolic rates [MRglc]) were derived, and changes during treatment were correlated. Overall survival (OS) and progression-free survival (PFS) served as outcome measures for the predictive abilities of pretreatment parameters and of treatment-related parameter changes. Results: Pretreatment MRglc and MAD were individually predictive for OS and PFS. During treatment, Ktrans increased significantly, but this increase could not be confirmed in a lesion-by-lesion analysis. MRglc decreased significantly (P < 0.001). No correlations were found for changes in DCE-MRI parameters and ΔMRglc. No relationship was found between changes in DCE-MRI parameters and OS or PFS. ΔMRglc was able to predict OS (P = 0.008) after correction for confounders. Conclusion: The efficacy of cytotoxic chemotherapy assessed by reduction in tumor metabolism does not depend on pretreatment properties of the tumor vasculature determined by DCE-MRI. Cytotoxic chemotherapy does not alter DCE-MRI–derived properties of tumor vasculature but decreases glucose consumption of tumor cells.

The role of 18 F-FDG PET in the differentiation between lung metastases and synchronous second primary lung tumours

PurposeIn lung cancer patients with multiple lesions, the differentiation between metastases and second primary tumours has significant therapeutic and prognostic implications. The aim of this retrospective study was to investigate the potential of 18F-FDG PET to discriminate metastatic disease from second primary lung tumours.MethodsOf 1,396 patients evaluated by the thoracic oncology group between January 2004 and April 2009 at the Radboud University Nijmegen Medical Centre, patients with a synchronous second primary lung cancer were selected. Patients with metastatic disease involving the lungs served as the control group. Maximum standardized uptake values (SUVs) measured with 18F-FDG PET were determined for two tumours in each patient. The relative difference between the SUVs of these tumours (∆SUV) was determined and compared between the second primary group and metastatic disease group. Receiver-operating characteristic (ROC) curve analysis was performed to determine the sensitivity and specificity of the ∆SUV for an optimal cut-off value.ResultsA total of 37 patients (21 metastatic disease, 16 second primary cancer) were included for analysis. The ∆SUV was significantly higher in patients with second primary cancer than in those with metastatic disease (58 vs 28%, respectively, p < 0.001). The area under the ROC curve was 0.81 and the odds ratio for the optimal cut-off was 18.4.ConclusionSUVs from 18F-FDG PET images can be helpful in differentiating metastatic disease from second primary tumours in patients with synchronous pulmonary lesions. Further studies are warranted to confirm the consistency of these results.

Serum FGF21 levels in adult m.3243A>G carriers Clinical implications

Objectives: To determine the value of fibroblast growth factor 21 (FGF21), a recently discovered biomarker for mitochondrial disease, in predicting clinical disease severity and disease progression in adult carriers of the m.3243A>G mutation. Methods: In the context of a national inventory, the heteroplasmy levels of the m.3243A>G mutation were measured in leukocytes and urinary epithelial cells. The Newcastle Mitochondrial Disease Adult Scale score was determined and blood was drawn for measuring FGF21 concentration. Twenty-five of the included initial patients studied were then selected randomly for a follow-up study. Results: This prognostic study included 99 adult carriers of the m.3243A>G mutation. Our analysis revealed a moderate, significant correlation between FGF21 concentration and disease severity (r = 0.49; p = <0.001). No significant correlations were found between disease severity and the heteroplasmy percentage determined in urinary epithelial cells or the heteroplasmy percentage determined in leukocytes. Weak but significant correlations were also found between FGF21 concentration and the severity of the myopathy (r = 0.38; p = <0.001) and between the concentration of FGF21 and the severity of the encephalopathy (r = 0.30; p = <0.001). Repeated measurements following 25 subjects for 2 years revealed no significant correlation between FGF21 concentration and disease progression. Conclusions: Measuring FGF21 concentration had little added value in monitoring and predicting the disease course in this specific patient group.

Cost-Effectiveness of FDG-PET/CT for Cytologically Indeterminate Thyroid Nodules: A Decision Analytic Approach

CONTEXT Patients with thyroid nodules of indeterminate cytology undergo diagnostic surgery according to current guidelines. In 75% of patients, the nodule is benign. In these patients, surgery was unnecessary and unbeneficial because complications may occur. Preoperative fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) was found to have a very high negative predictive value (96%) and might therefore avoid futile surgery, complications, and costs. In the United States, two molecular tests of cytology material are routinely used for this purpose. OBJECTIVE Five-year cost-effectiveness for routine implementation of FDG-PET/CT was evaluated in adult patients with indeterminate fine-needle aspiration cytology and compared with surgery in all patients and both molecular tests. DESIGN A Markov decision model was developed to synthesize the evidence on cost-effectiveness about the four alternative strategies. The model was probabilistically analyzed. One-way sensitivity analyses of deterministic input variables likely to influence outcome were performed. SETTING AND SUBJECTS The model was representative for adult patients with cytologically indeterminate thyroid nodules. MAIN OUTCOME MEASURES The discounted incremental net monetary benefit (iNMB), the efficiency decision rule containing outcomes as quality-adjusted life-years and (direct) medical cost, of implementation of FDG-PET/CT is displayed. RESULTS Full implementation of FDG-PET/CT resulted in 40% surgery for benign nodules, compared with 75% in the conventional approach, without a difference in recurrence free and overall survival. The FDG-PET/CT modality is the more efficient technology, with a mean iNMB of €3684 compared with surgery in all. Also, compared with a gene expression classifier test and a molecular marker panel, the mean iNMB of FDG-PET/CT was €1030 and €3851, respectively, and consequently the more efficient alternative. CONCLUSION Full implementation of preoperative FDG-PET/CT in patients with indeterminate thyroid nodules could prevent up to 47% of current unnecessary surgery leading to lower costs and a modest increase of health-related quality of life. Compared with an approach with diagnostic surgery in all patients and both molecular tests, it is the least expensive alternative with similar effectiveness as the gene-expression classifier.

Serum GDF15 Levels Correlate to Mitochondrial Disease Severity and Myocardial Strain, but Not to Disease Progression in Adult m.3243A>G Carriers

In this observational cohort study, we examined the prognostic value of growth and differentiation factor 15 (GDF15) in indicating and monitoring general mitochondrial disease severity and progression in adult carriers of the m.3243A>G mutation.Ninety-seven adult carriers of the m.3243A>G mutation were included in this study. The Newcastle mitochondrial disease adult scale was used for rating mitochondrial disease severity. In parallel, blood was drawn for GDF15 analysis by ELISA. Forty-nine carriers were included in a follow-up study. In a small subset of subjects of whom an echocardiogram was available from general patient care, myocardial deformation was assessed using two-dimensional speckle-tracking strain analysis.A moderate positive correlation was found between the concentration of GDF15 and disease severity (r = 0.59; p < 0.001). The concentration of serum GDF15 was higher in m.3243A>G carriers with diabetes mellitus, cardiomyopathy, and renal abnormalities. After a 2-year follow-up, no significant correlation was found between the change in disease severity and the change in the concentration of GDF15 or between the GDF15 level at the first assessment and the change in disease severity. In the subcohort of patients of whom an echocardiogram was available, the concentration of GDF15 correlated moderately to longitudinal global strain (r = 0.55; p = 0.006; n = 23) but not to circumferential or radial strain.Our results indicate that serum GDF15 is not a strong surrogate marker for general mitochondrial disease severity. Its value in indicating myocardial deformation should be confirmed in a prospective longitudinal study.

FDG-PET/CT based response-adapted treatment

Abstract It has been shown that [18F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) provides robust and reproducible data for early metabolic response assessment in various malignancies. This led to the initiation of several prospective multicenter trials in malignant lymphoma and adenocarcinoma of the esophagogastric junction, in order to investigate whether the use of PET-guided treatment individualization results in a survival benefit. In Hodgkin lymphoma and aggressive non-Hodgkin lymphoma, several trials are ongoing. Some studies aim to investigate the use of PET in early identification of metabolic non-responders in order to intensify treatment to improve survival. Other studies aim at reducing toxicity without adversely affecting cure rates by safely de-escalating therapy in metabolic responders. In solid tumors the first PET response-adjusted treatment trials have been realized in adenocarcinoma of the esophagogastric junction. These trials showed that patients with an early metabolic response to neoadjuvant chemotherapy benefit from this treatment, whereas metabolic non-responders should switch early to surgery, thus reducing the risk of tumor progression during chemotherapy and the risk of toxic death. The trials provide a model for designing response-guided treatment algorithms in other malignancies. PET-guided treatment algorithms are the promise of the near future; the choice of therapy, its intensity, and its duration will become better adjusted to the biology of the individual patient. Today’s major challenge is to investigate the impact on patient outcome of personalized response-adapted treatment concepts.

Evaluation of different normalization procedures for the calculation of the standardized uptake value in therapy response monitoring studies

ObjectivesThe aim of this prospective study was to assess the influence of different normalization procedures on relative changes in standardized uptake values (SUV) of 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) for the assessment of chemotherapy response in patients with colorectal carcinoma (CRC) and nonsmall cell lung carcinoma (NSCLC). MethodsIn 97 patients with CRC (n = 48) and NSCLC (n = 49), FDG-PET was performed before and during the course of chemotherapy. Relative changes in SUV (ΔSUV) were determined after correction for injected dose and bodyweight, lean body mass, body surface area or a combination of bodyweight and plasma glucose. The predictive value for overall and progression-free survival with respect to the different normalized ΔSUVs was assessed. ResultsIn both CRC and NSCLC, no differences were seen in the degree of change between the four SUV-normalizations during chemotherapy. Cox regression analysis for overall survival showed significant hazard ratios of 1.14–1.16 per 10% SUV change in CRC and 1.10–1.13 in NSCLC and for progression-free survival hazard ratios of 1.15 per 10% ΔSUV change in CRC and 1.10–1.12 in NSCLC. ConclusionRelative changes in SUV is a strong predictor for survival in both CRC and NSCLC. None of the four normalization methods showed statistical advantage over the other. Therefore, simplifying the methods for analysis of FDG-PET data can improve the incorporation of FDG-PET in clinical treatment–response monitoring and may facilitate application in multicentre trials.