Gudrun Zahlmann

Quantitative imaging biomarkers: A review of statistical methods for technical performance assessment

Technological developments and greater rigor in the quantitative measurement of biological features in medical images have given rise to an increased interest in using quantitative imaging biomarkers to measure changes in these features. Critical to the performance of a quantitative imaging biomarker in preclinical or clinical settings are three primary metrology areas of interest: measurement linearity and bias, repeatability, and the ability to consistently reproduce equivalent results when conditions change, as would be expected in any clinical trial. Unfortunately, performance studies to date differ greatly in designs, analysis method, and metrics used to assess a quantitative imaging biomarker for clinical use. It is therefore difficult or not possible to integrate results from different studies or to use reported results to design studies. The Radiological Society of North America and the Quantitative Imaging Biomarker Alliance with technical, radiological, and statistical experts developed a set of technical performance analysis methods, metrics, and study designs that provide terminology, metrics, and methods consistent with widely accepted metrological standards. This document provides a consistent framework for the conduct and evaluation of quantitative imaging biomarker performance studies so that results from multiple studies can be compared, contrasted, or combined.

Response Assessment Criteria for Glioblastoma: Practical Adaptation and Implementation in Clinical Trials of Antiangiogenic Therapy

Since 1990, the primary criteria used for assessing response to therapy in high-grade gliomas were those developed by Macdonald and colleagues, which incorporated 2-dimensional area measurements of contrast-enhancing tumor regions, corticosteroid dosing, and clinical assessment to arrive at a designation of response, stable disease, or progression. Recent advances in imaging technology and targeted therapeutics, however, have exposed limitations of the Macdonald criteria and have highlighted the need for reevaluation of response assessment criteria. In 2010, the Response Assessment in Neuro-Oncology (RANO) Working Group published updated criteria to address this need and to standardize response assessment for high-grade gliomas. In 2009, prior to the publication of the RANO criteria, the randomized, placebo-controlled, multicenter, phase 3 AVAglio trial was designed and initiated to investigate the effectiveness of radiotherapy and temozolomide with or without bevacizumab in newly diagnosed glioblastoma. The AVAglio protocol enacted specific measures to adapt the Macdonald criteria to the frontline treatment setting and to antiangiogenic agent evaluation, including the incorporation of a T2/fluid-attenuated inversion recovery component, qualitative assessment of irregularly shaped contrast-enhancing lesions, and a decision tree for confirming or ruling out pseudoprogression. Moreover, the protocol outlines practical means by which these adapted response criteria can be implemented in the clinic. This article describes the evolution of radiographic response criteria for high-grade gliomas and highlights the similarities and differences between those implemented in the AVAglio study and those subsequently published by RANO.

Meta-analysis of the technical performance of an imaging procedure: Guidelines and statistical methodology

Medical imaging serves many roles in patient care and the drug approval process, including assessing treatment response and guiding treatment decisions. These roles often involve a quantitative imaging biomarker, an objectively measured characteristic of the underlying anatomic structure or biochemical process derived from medical images. Before a quantitative imaging biomarker is accepted for use in such roles, the imaging procedure to acquire it must undergo evaluation of its technical performance, which entails assessment of performance metrics such as repeatability and reproducibility of the quantitative imaging biomarker. Ideally, this evaluation will involve quantitative summaries of results from multiple studies to overcome limitations due to the typically small sample sizes of technical performance studies and/or to include a broader range of clinical settings and patient populations. This paper is a review of meta-analysis procedures for such an evaluation, including identification of suitable studies, statistical methodology to evaluate and summarize the performance metrics, and complete and transparent reporting of the results. This review addresses challenges typical of meta-analyses of technical performance, particularly small study sizes, which often causes violations of assumptions underlying standard meta-analysis techniques. Alternative approaches to address these difficulties are also presented; simulation studies indicate that they outperform standard techniques when some studies are small. The meta-analysis procedures presented are also applied to actual [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) test–retest repeatability data for illustrative purposes.

Response Assessment in Pediatric Neuro-Oncology: Implementation and Expansion of the RANO Criteria in a Randomized Phase II Trial of Pediatric Patients with Newly Diagnosed High-Grade Gliomas

SUMMARY: Determination of tumor response to treatment in neuro-oncology is challenging, particularly when antiangiogenic agents are considered. Nontumoral factors (eg, blood-brain barrier disruption, edema, and necrosis) can alter contrast enhancement independent of true tumor response/progression. Furthermore, gliomas are often infiltrative, with nonenhancing components. In adults, the Response Assessment in Neuro-Oncology (RANO) criteria attempted to address these issues. No such guidelines exist yet for children. The ongoing randomized phase II trial, A Study of Avastin (bevacizumab) in Combination With Temolozomide (TMZ) and Radiotherapy in Paediatric and Adolescent Patients With High-Grade Glioma (HERBY), will establish the efficacy and safety of the antiangiogenic agent bevacizumab for the first-line treatment of newly diagnosed high-grade glioma in children (n = 121 patients, enrollment complete). The primary end point is event-free survival (tumor progression/recurrence by central review, second primary malignancy, or death). Determination of progression or response is based on predefined clinical and radiographic criteria, modeled on the RANO criteria and supported by expert pseudoprogression review and the use of standardized imaging protocols. The HERBY trial will also compare conventional MR imaging (T1-weighted and T2/fluid-attenuated inversion recovery sequences) with conventional MR imaging plus diffusion/perfusion imaging for response assessment. It is anticipated that HERBY will provide new insights into antiangiogenic-treated pediatric brain tumors. HERBY will also investigate the practicality of obtaining adequate quality diffusion/perfusion scans in a trial setting, and the feasibility of implementing standard imaging protocols across multiple sites. To date, 61/73 (83.6%) patients with available data have completed diffusion-weighted imaging (uptake of other nonconventional techniques has been limited). Harmonization of imaging protocols and techniques may improve the robustness of pediatric neuro-oncology studies and aid future trial comparability.

Tumor volume measurement error using computed tomography imaging in a phase II clinical trial in lung cancer.

Abstract. To address the error introduced by computed tomography (CT) scanners when assessing volume and unidimensional measurement of solid tumors, we scanned a precision manufactured pocket phantom simultaneously with patients enrolled in a lung cancer clinical trial. Dedicated software quantified bias and random error in the X,Y, and Z dimensions of a Teflon sphere and also quantified response evaluation criteria in solid tumors and volume measurements using both constant and adaptive thresholding. We found that underestimation bias was essentially the same for X,Y, and Z dimensions using constant thresholding and had similar values for adaptive thresholding. The random error of these length measurements as measured by the standard deviation and coefficient of variation was 0.10 mm (0.65), 0.11 mm (0.71), and 0.59 mm (3.75) for constant thresholding and 0.08 mm (0.51), 0.09 mm (0.56), and 0.58 mm (3.68) for adaptive thresholding, respectively. For random error, however, Z lengths had at least a fivefold higher standard deviation and coefficient of variation than X and Y. Observed Z-dimension error was especially high for some 8 and 16 slice CT models. Error in CT image formation, in particular, for models with low numbers of detector rows, may be large enough to be misinterpreted as representing either treatment response or disease progression.

Implementing Adjusted Imaging Metrics Within Roche With the Metrics Champion Consortium Experiences and Outcome

Purpose: To implement adjusted performance imaging metrics on imaging clinical trials of a pharmaceutical company (Roche) in a business relationship with preferred imaging providers and to report on findings and lessons learned. Methods: In 2009 the Metrics Champion Consortium provided the first imaging metrics for use in clinical trials as industry consensus. Roche reviewed, adjusted, excluded, and extended these metrics and defined target values per metric in order to implement them in all clinical trials with 7 preferred providers. Results: Roche preferred providers were able to report on all 19 metrics (8 unchanged Metrics Champion Consortium, 7 adjusted, and 4 Roche defined). Seventy-three Roche studies over 27 months form the basis for reporting; data are provided as mean and standard deviation per disease area with number of studies and for all studies reported for the specific metric for all providers. Disease areas are oncology, central nervous system, and inflammation. Seventeen metrics have proven to be useful; 2 metrics did not provide sufficient information; and 4 metrics need adjustments of target values. Limitations: Imaging trial–related metrics are a new concept, and Roche and providers had to develop the same consistent understanding of content and how to report a specific metric. The 73 studies covered all phases and disease areas, which made it difficult at times to compare results. Conclusions: Imaging metrics in clinical trials are a useful tool in improving timeliness and quality of imaging data, enhancing trial processes, and governing sponsor/provider relationships. It increases the transparency in the business relationship and in the different clinical trial–related process steps. The use of metrics highlights critical topics, such as reading and adjudication, and enables parties to take actions to improve performance. Disease area–related reporting needs more data for specific improvements.

440TiPTHE HERBY STUDY: A PHASE 2 OPEN-LABEL, RANDOMIZED, MULTICENTER STUDY OF BEVACIZUMAB-BASED THERAPY IN PEDIATRIC PATIENTS WITH NEWLY DIAGNOSED HIGH-GRADE GLIOMA

ABSTRACT Background: Despite recent therapeutic advances, outcomes in pediatric high-grade glioma (HGG) remain poor. A phase 1 study (Glade-Bender et al., J Clin Oncol. 2008) indicated that bevacizumab (BEV) is well tolerated in children with refractory solid tumors and yielded pharmacokinetic data that support further studies of BEV in childhood cancer. Trial design: A total of 120 eligible patients aged 3 to 18 years with newly diagnosed, localized supratentorial or infratentorial cerebellar or peduncular, histologically confirmed World Health Organization grade 3 or 4 HGG (central independent histologic confirmation) will be randomized to 6 weeks of concomitant temozolomide (TMZ) and local radiotherapy, followed by a 4-week TMZ treatment break and 48 weeks of adjuvant TMZ ± BEV every other week. Children aged 6 months to 3 years with recurrent disease are eligible in a young patient cohort; at relapse, these patients will receive TMZ + BEV without radiotherapy. All patients/parents must provide written informed consent per the local institutional review boards. The primary end point is event-free survival, defined as the time to earliest occurrence of tumor progression/recurrence (by central independent assessment per Response Assessment in Neuro-Oncology criteria), secondary malignancy, or death. Secondary end points include overall survival, response rate, safety, feasibility, and tolerability. The usefulness of multimodal MRI will be explored with respect to the diagnosis of pseudoprogression and prognostication of tumor evolution. All randomized patients will be followed for ≥3 years. A futility analysis will be performed after the first 60 randomized patients have been followed for 1 year. The primary analysis will be performed after all patients have been followed for 1 year. Updated analyses will be performed 3 years after the last patient has been randomized. HERBY is being conducted at 87 clinical sites in 15 countries. The first patient was randomized in October 2011. Among 118 patients screened to date, 79 have been randomized, and 1 has been enrolled in the young patient cohort. Completion of the study is expected in 2016. Some content has been presented at ASCO 2012 (abs TPS9596), SNO 2013 (abs PC-007), and ISPN 2013 (abs P109). Disclosure: D. Hargrave: Advisory board: Roche; P. Varlet: Advisory board: Roche Other substantive relationships: Roche; T. Jaspan: Corporate sponsored research: Roche; C. Jones: Advisory board: Genentech Paediatric Oncology Advisory Board Corporate-sponsored research: Roche/Genentech - HERBY trial M. Massimino: Advisory board: Roche, present study; A.A. Azizi: Advisory board: Roche F. Saran: Advisory board: Roche; P. Morgan: Advisory board: Trial Steering Group for F Hoffmann‐La Roche sponsored HERBY study (BO25041) Corporate-sponsored research: Employing institution receives support for its role in the F Hoffmann‐La Roche sponsored HERBY study (BO25041); G. Zahlmann: Stock ownership: Roche employee program Corporate-sponsored research: Roche employee; M. Zheng: Stock ownership: Genentech/Roche; S. Fuerst-Recktenwald: Other substantive relationships: Roche employee C. Berger: Corporate sponsored research: Roche; E. Bouffet: Advisory board: Boehringer Ingelheim. All other authors have declared no conflicts of interest.