Lioe-Fee de Geus-Oei

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.

A prospective multi-centre study of the value of FDG-PET as part of a structured diagnostic protocol in patients with fever of unknown origin.

PurposeSince 18F-fluorodeoxyglucose (FDG) accumulates in neoplastic cells and in activated inflammatory cells, positron emission tomography (PET) with FDG could be valuable in diagnosing patients with fever of unknown origin (FUO). The aim of this study was to validate the use of FDG-PET as part of a structured diagnostic protocol in the general patient population with FUO.MethodsFrom December 2003 to July 2005, 70 patients with FUO were recruited from one university hospital (n=38) and five community hospitals (n=32). A structured diagnostic protocol including FDG-PET was used. A dedicated, full-ring PET scanner was used for data acquisition. FDG-PET scans were interpreted by two staff members of the department of nuclear medicine without further clinical information. The final clinical diagnosis was used for comparison with the FDG-PET results.ResultsOf all scans, 33% were clinically helpful. The contribution of FDG-PET to the final diagnosis did not differ significantly between patients diagnosed in the university hospital and patients diagnosed in the community hospitals. FDG-PET contributed significantly more often to the final diagnosis in patients with continuous fever than in patients with periodic fever. FDG-PET was not helpful in any of the patients with normal erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP).ConclusionFDG-PET is a valuable imaging technique as part of a diagnostic protocol in the general patient population with FUO and a raised ESR or CRP.

Predictive and prognostic value of FDG-PET in nonsmall-cell lung cancer : A Systematic Review

For several years, molecular imaging with 18F‐fluorodeoxyglucose positron emission tomography (FDG‐PET) has become part of the standard of care in presurgical staging of patients with nonsmall‐cell lung cancer (NSCLC), focusing on the detection of malignant lesions at early stages, early detection of recurrence, and metastatic spread. Currently, there is an increasing interest in the role of FDG‐PET beyond staging, such as the evaluation of biological characteristics of the tumor and prediction of prognosis in the context of treatment stratification and the early assessment of tumor response to therapy. In this systematic review, the literature on the value of the evolving applications of FDG‐PET as a marker for prediction (ie, therapy response monitoring) and prognosis in NSCLC is addressed, divided in sections on the predictive value of FDG‐PET in locally advanced and advanced disease, the prognostic value of FDG‐PET at diagnosis, after induction treatment, and in recurrent disease. Furthermore, the background and recommendations for the application of FDG‐PET for these indications will be discussed. Cancer 2007.

Chemotherapy Response Evaluation with 18F-FDG PET in Patients with Non-Small Cell Lung Cancer

The aim of this prospective study was to evaluate the value of 18F-FDG PET for the assessment of chemotherapy response in patients with non–small cell lung cancer. Furthermore, part of the objective of this study was to compare 2 methods to quantify changes in glucose metabolism. Methods: In 51 patients, dynamic 18F-FDG PET was performed before and at 5–8 wk into treatment. Simplified methods to measure glucose metabolism (standardized uptake value [SUV]) and quantitative measures (metabolic rate of glucose [MRGlu]), derived from Patlak analysis, were evaluated. The overall survival and progression-free survival with respect to MRGlu and SUV were calculated using Kaplan–Meier estimates. Fractional changes in tumor glucose use were stratified by the median value and also the predefined EORTC (European Organization for Research and Treatment of Cancer) metabolic response criteria, and criteria applying cutoff levels similar to those of RECIST (Response Evaluation Criteria in Solid Tumors) were evaluated. Results: When stratifying at the median value of ΔMRGlu and ΔSUV, the difference in overall survival (P = 0.017 for ΔMRGlu, P = 0.018 for ΔSUV) and progression-free survival (P = 0.002 for ΔMRGlu, P = 0.0009 for ΔSUV) was highly significant. When applying the predefined criteria for metabolic response, the cutoff levels as also used for size measurement (RECIST) showed significant differences for ΔSUV between response categories in progression-free survival (P = 0.0003) as well as overall survival (P = 0.027). Conclusion: The degree of chemotherapy-induced changes in tumor glucose metabolism as determined by 18F-FDG PET is highly predictive for patient outcome, stratifying patients into groups with widely differing overall survival and progression-free survival probabilities. The use of 18F-FDG PET for therapy monitoring seems clinically feasible, because simplified methods to measure tumor glucose use (SUV) are sufficiently reliable and can replace more complex, quantitative measures (MRGlu) in this patient population.

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.

18F-FDG PET Early Response Evaluation of Locally Advanced Non–Small Cell Lung Cancer Treated with Concomitant Chemoradiotherapy

The potential of 18F-FDG PET changes was evaluated for prediction of response to concomitant chemoradiotherapy in patients with locally advanced non–small cell lung cancer (NSCLC). Methods: For 28 patients, 18F-FDG PET was performed before treatment, at the end of the second week of treatment, and at 2 wk and 3 mo after the completion of treatment. Standardized uptake value (SUV), maximum SUV, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were obtained. Early metabolic changes were defined as fractional change (ΔTLG) when 18F-FDG PET at the end of the second week was compared with pretreatment 18F-FDG PET. In-treatment metabolic changes, as measured by serial 18F-FDG PET, were correlated with standard criteria of response evaluation of solid tumors by means of CT imaging (Response Evaluation Criteria In Solid Tumors 1.1). Parameters were analyzed for stratification in progression-free survival (PFS). Results: When compared with early metabolic nonresponders, a ΔTLG decrease of 38% or more was associated with a significantly longer PFS (1-y PFS 80% vs. 36%, P = 0.02). Pretreatment TLG was found to be a prognostic factor for PFS. Conclusion: The degree of change in TLG was predictive for response to concomitant chemoradiotherapy as early as the end of the second week into treatment for patients with locally advanced NSCLC. Pretreatment TLG was prognostic for PFS.

Scintigraphic Techniques for Early Detection of Cancer Treatment–Induced Cardiotoxicity

New antitumor agents have resulted in significant survival benefits for cancer patients. However, several agents may have serious cardiovascular side effects. Left ventricular ejection fraction measurement by 99mTc multigated radionuclide angiography is regarded as the gold standard to measure cardiotoxicity in adult patients. It identifies left ventricular dysfunction with high reproducibility and low interobserver variability. A decrease in left ventricular ejection fraction, however, is a relatively late manifestation of myocardial damage. Nuclear cardiologic techniques that visualize pathophysiologic processes at the tissue level could detect myocardial injury at an earlier stage. These techniques may give the opportunity for timely intervention to prevent further damage and could provide insights into the mechanisms and pathophysiology of cardiotoxicity caused by anticancer agents. This review provides an overview of past, current, and promising newly developed radiopharmaceuticals and describes the role and recent advances of scintigraphic techniques to measure cardiotoxicity. Both first-order functional imaging techniques (visualizing mechanical [pump] function), such as 99mTc multigated radionuclide angiography and 99mTc gated blood-pool SPECT, and third-order functional imaging techniques (visualizing pathophysiologic and neurophysiologic processes at the tissue level) are discussed. Third-order functional imaging techniques comprise 123I-metaiodobenzylguanidine scintigraphy, which images the efferent sympathetic nervous innervations; sympathetic neuronal PET, with its wide range of tracers; 111In-antimyosin, which is a specific marker for myocardial cell injury and necrosis; 99mTc-annexin V scintigraphy, which visualizes apoptosis and cell death; fatty-acid-use scintigraphy, which visualizes the storage of free fatty acids in the lipid pool of the cytosol (which can be impaired by cardiotoxic agents); and 111In-trastuzumab imaging, to study trastuzumab targeting to the myocardium. To define the prognostic importance and clinical value of each of these functional imaging techniques, prospective clinical trials are warranted.New antitumor agents have resulted in significant survival benefits for cancer patients. However, several agents may have serious cardiovascular side effects. Left ventricular ejection fraction measurement by (99m)Tc multigated radionuclide angiography is regarded as the gold standard to measure cardiotoxicity in adult patients. It identifies left ventricular dysfunction with high reproducibility and low interobserver variability. A decrease in left ventricular ejection fraction, however, is a relatively late manifestation of myocardial damage. Nuclear cardiologic techniques that visualize pathophysiologic processes at the tissue level could detect myocardial injury at an earlier stage. These techniques may give the opportunity for timely intervention to prevent further damage and could provide insights into the mechanisms and pathophysiology of cardiotoxicity caused by anticancer agents. This review provides an overview of past, current, and promising newly developed radiopharmaceuticals and describes the role and recent advances of scintigraphic techniques to measure cardiotoxicity. Both first-order functional imaging techniques (visualizing mechanical [pump] function), such as (99m)Tc multigated radionuclide angiography and (99m)Tc gated blood-pool SPECT, and third-order functional imaging techniques (visualizing pathophysiologic and neurophysiologic processes at the tissue level) are discussed. Third-order functional imaging techniques comprise (123)I-metaiodobenzylguanidine scintigraphy, which images the efferent sympathetic nervous innervations; sympathetic neuronal PET, with its wide range of tracers; (111)In-antimyosin, which is a specific marker for myocardial cell injury and necrosis; (99m)Tc-annexin V scintigraphy, which visualizes apoptosis and cell death; fatty-acid-use scintigraphy, which visualizes the storage of free fatty acids in the lipid pool of the cytosol (which can be impaired by cardiotoxic agents); and (111)In-trastuzumab imaging, to study trastuzumab targeting to the myocardium. To define the prognostic importance and clinical value of each of these functional imaging techniques, prospective clinical trials are warranted.

Differences in metabolism between adeno- and squamous cell non-small cell lung carcinomas: spatial distribution and prognostic value of GLUT1 and MCT4.

BACKGROUND Hypoxia leads to changes in tumor cell metabolism such as increased glycolysis. In this study, we examined the spatial distribution of the glycolysis and hypoxia related markers glucose transporter 1 (GLUT1) and monocarboxylate transporter 4 (MCT4) expression in relation to the vasculature in stage I, II and resectable stage IIIA NSCLC. Furthermore, associations of these markers with survival were investigated. METHODS GLUT1 and MCT4 expression were determined in 90 NSCLC fresh frozen biopsies using immunohistochemical techniques and a computerized image analysis system. Markers were analyzed for adenocarcinomas (n=41) and squamous cell carcinomas (n=34) separately. Eighty-four patients were retrospectively evaluated for relapse and survival. RESULTS Squamous cell carcinomas demonstrated higher GLUT1 expression, relative to adenocarcinomas. Also, in squamous cell carcinomas, GLUT1 and MCT4 expression increased with increasing distance from the vasculature, whereas in adenocarcinomas upregulation of MCT4 was already found at closer distance from vessels. In adenocarcinomas, high GLUT1 expression correlated with a poor differentiation grade and positive lymph nodes at diagnosis. High GLUT1 plus high MCT4 expression was associated with a poor disease-specific survival in only adenocarcinomas (p=0.032). CONCLUSION Analysis of GLUT1 and MCT4 expression on the histological level suggested a different metabolism for adenocarcinomas and squamous cell carcinomas. Likely, adenocarcinomas rely mainly on aerobic glycolysis for ATP production, whereas the behavior of squamous cell carcinomas is more physiologically, i.e. mitochondrial oxidation with anaerobic glycolysis under hypoxic conditions. High GLUT1 plus high MCT4 expression indicated an aggressive tumor behavior in adenocarcinomas. This subgroup of tumors may benefit from new treatment approaches, such as MCT4 inhibitors. Since this study has an exploratory character, our results warrant further investigation and need independent validation.

Tumour response prediction by diffusion-weighted MR imaging: Ready for clinical use?

BACKGROUND The efficacy of anticancer therapy is usually evaluated by anatomical imaging. However, this method may be suboptimal for the evaluation of novel treatment modalities, such as targeted therapy. Theoretically, functional assessment of tumour response by diffusion weighted imaging (DWI) is an attractive tool for this purpose and may allow an early prediction of response. The optimal use of this method has still to be determined. METHOD We reviewed the published literature on clinical DWI in the prediction of response to anticancer therapy, especially targeted therapy. Studies investigating the role of DWI in patients with cancer either for response prediction and/or response monitoring were selected for this analysis. RESULTS We identified 24 studies that met our criteria. Most studies showed a significant correlation between (changes in) apparent diffusion coefficient (ADC) values and treatment response. However, in different tumours and studies, both high and low pretreatment ADC were found to be associated with response rate. In the course of treatment, an increase in ADC was associated with response in most cases. CONCLUSION The potential of DWI for (early) response monitoring of anticancer therapies has been demonstrated. However, validation is hampered by the lack of reproducibility and standardisation. We recommend that these issues should be properly addressed prior to further testing the clinical use of DWI in the assessment of treatments.

Predictive and prognostic value of FDG-PET.

Abstract The predictive and prognostic value of fluorodeoxyglucose (FDG)-positron emission tomography (PET) in non-small-cell lung carcinoma, colorectal carcinoma and lymphoma is discussed. The degree of FDG uptake is of prognostic value at initial presentation, after induction treatment prior to resection and in the case of relapse of non-small cell lung cancer (NSCLC). In locally advanced and advanced stages of NSCLC, FDG-PET has been shown to be predictive for clinical outcome at an early stage of treatment. In colorectal carcinoma, limited studies are available on the prognostic value of FDG-PET, however, the technique appears to have great potential in monitoring the success of local ablative therapies soon after intervention and in the prediction and evaluation of response to radiotherapy, systemic therapy, and combinations thereof. The prognostic value of end-of treatment FDG-PET for FDG-avid lymphomas has been established, and the next step is to define how to use this information to optimize patient outcome. In Hodgkins lymphoma, FDG-PET has a high negative predictive value, however, histological confirmation of positive findings should be sought where possible. For non-Hodgkins lymphoma, the opposite applies. The newly published standardized guidelines for interpretation formulates specific criteria for visual interpretation and for defining PET positivity in the liver, spleen, lung, bone marrow and small residual lesions. The introduction of these guidelines should reduce variability among studies. Interim PET offers a reliable method for early prediction of long-term remission, however it should only be performed in prospective randomized controlled trials. Many of the diagnostic and management questions considered in this review are relevant to other tumour types. Further research in this field is of great importance, since it may lead to a change in the therapeutic concept of cancer. The preliminary findings call for systematic inclusion of FDG-PET in therapeutic trials to adequately position FDG-PET in treatment time lines.