Wendy Hayes

Repeatability of 18F-FDG PET in a Multicenter Phase I Study of Patients with Advanced Gastrointestinal Malignancies

18F-FDG PET is often used to monitor tumor response in multicenter oncology clinical trials. This study assessed the repeatability of several semiquantitative standardized uptake values (mean SUV [SUVmean], maximum SUV [SUVmax], peak SUV [SUVpeak], and the 3-dimensional isocontour at 70% of the maximum pixel value [SUV70%]) as measured by repeated baseline 18F-FDG PET studies in a multicenter phase I oncology trial. Methods: Double-baseline 18F-FDG PET studies were acquired for 62 sequentially enrolled patients. Tumor metabolic activity was assessed by SUVmean, SUVmax, SUVpeak, and SUV70%. The effect on SUV repeatability of compliance with recommended image-acquisition guidelines and quality assurance (QA) standards was assessed. Summary statistics for absolute differences relative to the average of baseline values and repeatability analysis were performed for all patients and for a subgroup that passed QA, in both a multi- and a single-observer setting. Intrasubject precision of baseline measurements was assessed by repeatability coefficients, intrasubject coefficients of variation (CV), and confidence intervals on mean baseline differences for all SUV parameters. Results: The mean differences between the 2 SUV baseline measurements were small, varying from −2.1% to 1.9%, and the 95% confidence intervals for these mean differences had a maximum half-width of about 5.6% across the SUV parameters assessed. For SUVmax, the intrasubject CV varied from 10.7% to 12.8% for the QA multi- and single-observer datasets and was 16% for the full dataset. The 95% repeatability coefficients ranged from −28.4% to 39.6% for the QA datasets and up to −34.3% to 52.3% for the full dataset. Conclusion: Repeatability results of double-baseline 18F-FDG PET scans were similar for all SUV parameters assessed, for both the full and the QA datasets, in both the multi- and the single-observer settings. Centralized quality assurance and analysis of data improved intrasubject CV from 15.9% to 10.7% for averaged SUVmax. Thresholds for metabolic response in the multicenter multiobserver non-QA settings were −34% and 52% and in the range of −26% to 39% with centralized QA. These results support the use of 18F-FDG PET for tumor assessment in multicenter oncology clinical trials.

Characterization of Pneumonitis in Patients with Advanced Non-small Cell Lung Cancer Treated with Everolimus (RAD001)

Purpose: To assess the incidence and radiographic and clinical presentation of pneumonitis associated with the mammalian target of rapamycin inhibitor everolimus in patients with advanced non-small cell lung cancer. Patients and Methods: A retrospective, centralized review of serial computed tomography scans and corresponding clinical data from patients with advanced non-small cell lung cancer treated with 10-mg oral once daily everolimus monotherapy in a phase II clinical study was conducted. Serial chest CT scans underwent a consensus read by two radiologists for presence of pneumonitis. These cases were then reviewed with corresponding clinical data by a pulmonologist to assess the suspected causality to everolimus and outcome. Results: Twenty-four of 64 patients reviewed were found to have radiographic evidence of pneumonitis. In 16 of these 24 patients, pneumonitis was suspected as either possibly (12) or probably (4) related to everolimus. The most common radiographic manifestations were focal areas of consolidation at the lung bases or ground-glass opacities. Pneumonitis evaluated with Common Terminology Criteria for Adverse Events (version 3) was grade 1 or 2 in 12 of 16 suspected cases, with 4 patients experiencing higher grades. In most of the patients, pneumonitis remained at the same or lower grade without discontinuation of therapy. Patients with evidence of interstitial lung disease at baseline had an increased risk of Common Terminology Criteria for Adverse Events grade more than or equal to 3 pneumonitis. Conclusion: Within the limitation of this retrospective study, results suggest that a mostly low-grade pneumonitis with a possible or probable relationship to everolimus was relatively frequent, occurring in 25% of evaluated patients. These results suggest a need for monitoring of pulmonary adverse events and the development of guidelines for managing pneumonitis in future studies with everolimus.

Measuring response to therapy using FDG PET: semi-quantitative and full kinetic analysis

PurposeImaging with positron emission tomography (PET) using 18F-2-fluoro-2-deoxy-D-glucose (FDG) plays an increasingly important role for response assessment in oncology. Several methods for quantifying FDG PET results exist. The goal of this study was to analyse and compare various semi-quantitative measures for response assessment with full kinetic analysis, specifically in assessment of novel therapies.MethodsBaseline and response dynamic FDG studies from two different longitudinal studies (study A: seven subjects with lung cancer and study B: six subjects with gastrointestinal cancer) with targeted therapies were reviewed. Quantification of tumour uptake included full kinetic methods, i.e. nonlinear regression (NLR) and Patlak analyses, and simplified measures such as the simplified kinetic method (SKM) and standardized uptake value (SUV). An image-derived input function was used for NLR and Patlak analysis.ResultsThere were 18 and 9 lesions defined for two response monitoring studies (A and B). In all cases there was excellent correlation between Patlak- and NLR-derived response (R2 > 0.96). Percentage changes seen with SUV were significantly different from those seen with Patlak for both studies (p < 0.05). After correcting SUV for plasma glucose, SUV and Patlak responses became similar for study A, but large differences remained for study B. Further analysis revealed that differences in responses amongst methods in study B were primarily due to changes in the arterial input functions.ConclusionUse of simplified methods for assessment of drug efficacy or treatment response may provide different results than those seen with full kinetic analysis.

Volumetric CT in Lung Cancer: An Example for the Qualification of Imaging as a Biomarker

RATIONALE AND OBJECTIVES New ways to understand biology as well as increasing interest in personalized treatments requires new capabilities for the assessment of therapy response. The lack of consensus methods and qualification evidence needed for large-scale multicenter trials, and in turn the standardization that allows them, are widely acknowledged to be the limiting factor in the deployment of qualified imaging biomarkers. MATERIALS AND METHODS The Quantitative Imaging Biomarker Alliance is organized to establish a methodology whereby multiple stakeholders collaborate. It has charged the Volumetric Computed Tomography (CT) Technical Subcommittee with investigating the technical feasibility and clinical value of quantifying changes over time in either volume or other parameters as biomarkers. The group selected solid tumors of the chest in subjects with lung cancer as its first case in point. Success is defined as sufficiently rigorous improvements in CT-based outcome measures to allow individual patients in clinical settings to switch treatments sooner if they are no longer responding to their current regimens, and reduce the costs of evaluating investigational new drugs to treat lung cancer. RESULTS The team has completed a systems engineering analysis, has begun a roadmap of experimental groundwork, documented profile claims and protocols, and documented a process for imaging biomarker qualification as a general paradigm for qualifying other imaging biomarkers as well. CONCLUSION This report addresses a procedural template for the qualification of quantitative imaging biomarkers. This mechanism is cost-effective for stakeholders while simultaneously advancing the public health by promoting the use of measures that prove effective.

Downregulation of 18F-FDG Uptake in PET as an Early Pharmacodynamic Effect in Treatment of Non–Small Cell Lung Cancer with the mTOR Inhibitor Everolimus

Everolimus downregulates glucose metabolism–associated genes in preclinical models. Inhibition of glucose metabolism measured by 18F-FDG PET was postulated to serve as a pharmacodynamic marker in everolimus-treated non–small cell lung cancer (NSCLC) patients. Methods: In 8 NSCLC patients treated with everolimus, the percentage change in 18F-FDG PET uptake (days 8 and 28 relative to baseline) was determined using a variety of summed standardized uptake value (SUV) measures. Both maximum and mean SUVs were used, with normalizations to body surface area and body weight and with and without correcting for plasma glucose levels. Results: In 5 patients, a reduction of 18F-FDG PET uptake on day 8 was observed with all methods, ranging from −12.8% to −72.2%. Conclusion: These observations demonstrate that inhibition of glucose metabolism is an early effect of everolimus treatment in NSCLC patients and can be assessed using 18F-FDG PET.

RECIST 1.1-Update and clarification : From the RECIST committee

The Response Evaluation Criteria in Solid Tumours (RECIST) were developed and published in 2000, based on the original World Health Organisation guidelines first published in 1981. In 2009, revisions were made (RECIST 1.1) incorporating major changes, including a reduction in the number of lesions to be assessed, a new measurement method to classify lymph nodes as pathologic or normal, the clarification of the requirement to confirm a complete response or partial response and new methodologies for more appropriate measurement of disease progression. The purpose of this paper was to summarise the questions posed and the clarifications provided as an update to the 2009 publication.

Repeatability of Metabolically Active Tumor Volume Measurements with FDG PET/CT in Advanced Gastrointestinal Malignancies: A Multicenter Study

PURPOSE To evaluate the feasibility and repeatability of various metabolically active tumor volume ( MATV metabolically active tumor volume ) quantification methods in fluorine 18 fluorodeoxyglucose ( FDG fluorine 18 fluorodeoxyglucose ) positron emission tomography (PET)/computed tomography (CT) in a multicenter setting and propose the optimal MATV metabolically active tumor volume method together with the minimal threshold for future response evaluation studies. MATERIALS AND METHODS The study was approved by the institutional review board of all four participating centers, and patients provided written informed consent. Thirty-four patients with advanced gastrointestinal malignancies underwent two FDG fluorine 18 fluorodeoxyglucose PET/CT examinations within 1 week. MATV metabolically active tumor volume s were defined semiautomatically with 27 variations of tumor delineation methods with different reference values. Feasibility was determined as the percentage of successful tumor segmentations per MATV metabolically active tumor volume method. Repeatability was determined with intraclass correlation coefficients, Bland-Altman plots, and limits of agreement ( LOA limit of agreement s) of the percentage difference between the test and repeat test measurements. In addition, LOA limit of agreement variability per center was investigated. RESULTS In total, 136 lesions were identified. Feasibility of tumor segmentation ranged from 54% to 100% (74-136 of 136 lesions); repeatability was evaluated for 19 MATV metabolically active tumor volume methods with feasibility of greater than 95%. The median MATV metabolically active tumor volume derived with 50% threshold of mean standardized uptake value ( SUV standardized uptake value ) of a sphere of 12-mm diameter with highest local intensity ( SUVhp mean SUV of a sphere of 12-mm diameter with highest local intensity ), which may not include the voxel with highest SUV standardized uptake value corrected for local background, was 5.7 and 6.1 mL for test and retest scans, respectively, with a relative LOA limit of agreement of 36.1%. Comparable repeatability was found between centers. A difference in uptake time between scan 1 and 2 of 15 minutes or longer had a minor negative influence on repeatability. CONCLUSION MATV metabolically active tumor volume measured with 50% of SUVhp mean SUV of a sphere of 12-mm diameter with highest local intensity corrected for local background is recommended in multicenter FDG fluorine 18 fluorodeoxyglucose PET/CT studies on the basis of a high feasibility (96%) and repeatability ( LOA limit of agreement of 36.1%).

Measurement of metabolic tumor volume: static versus dynamic FDG scans

BackgroundMetabolic tumor volume assessment using positron-emission tomography [PET] may be of interest for both target volume definition in radiotherapy and monitoring response to therapy. It has been reported, however, that metabolic volumes derived from images of metabolic rate of glucose (generated using Patlak analysis) are smaller than those derived from standardized uptake value [SUV] images. The purpose of this study was to systematically compare metabolic tumor volume assessments derived from SUV and Patlak images using a variety of (semi-)automatic tumor delineation methods in order to identify methods that can be used reliably on (whole body) SUV images.MethodsDynamic [18F]-fluoro-2-deoxy-D-glucose [FDG] PET data from 10 lung and 8 gastrointestinal cancer patients were analyzed retrospectively. Metabolic tumor volumes were derived from both Patlak and SUV images using five different types of tumor delineation methods, based on various thresholds or on a gradient.ResultsIn general, most tumor delineation methods provided more outliers when metabolic volumes were derived from SUV images rather than Patlak images. Only gradient-based methods showed more outliers for Patlak-based tumor delineation. Median measured metabolic volumes derived from SUV images were larger than those derived from Patlak images (up to 59% difference) when using a fixed percentage threshold method. Tumor volumes agreed reasonably well (< 26% difference) when applying methods that take local signal-to-background ratio [SBR] into account.ConclusionLarge differences may exist in metabolic volumes derived from static and dynamic FDG image data. These differences depend strongly on the delineation method used. Delineation methods that correct for local SBR provide the most consistent results between SUV and Patlak images.

Workshop on imaging science development for cancer prevention and preemption

The concept of intraepithelial neoplasm (IEN) as a near-obligate precursor of cancers has generated opportunities to examine drug or device intervention strategies that may reverse or retard the sometimes lengthy process of carcinogenesis. Chemopreventive agents with high therapeutic indices, well-monitored for efficacy and safety, are greatly needed, as is development of less invasive or minimally disruptive visualization and assessment methods to safely screen nominally healthy but at-risk patients, often for extended periods of time and at repeated intervals. Imaging devices, alone or in combination with anticancer drugs, may also provide novel interventions to treat or prevent precancer.

RECIST 1.1 – Standardisation and disease-specific adaptations: Perspectives from the RECIST Working Group

Radiologic imaging of disease sites plays a pivotal role in the management of patients with cancer. Response Evaluation Criteria in Solid Tumours (RECIST), introduced in 2000, and modified in 2009, has become the de facto standard for assessment of response in solid tumours in patients on clinical trials. The RECIST Working Group considers the ability of the global oncology community to implement and adopt updates to RECIST in a timely manner to be critical. Updates to RECIST must be tested, validated and implemented in a standardised, methodical manner in response to therapeutic and imaging technology advances as well as experience gained by users. This was the case with the development of RECIST 1.1, where an expanded data warehouse was developed to test and validate modifications. Similar initiatives are ongoing, testing RECIST in the evaluation of response to non-cytotoxic agents, immunotherapies, as well as in specific diseases. The RECIST Working Group has previously outlined the level of evidence considered necessary to formally and fully validate new imaging markers as an appropriate end-point for clinical trials. Achieving the optimal level of evidence desired is a difficult feat for phase III trials; this involves a meta-analysis of multiple prospective, randomised multicentre clinical trials. The rationale for modifications should also be considered; the modifications may be proposed to improve surrogacy, to provide a more mechanistic imaging technique, or be designed to improve reproducibility of the imaging biomarker. Here, we present the commonly described modifications of RECIST, each of which is associated with different levels of evidence and validation.