Daniel C. Sullivan

Progress and promise of FDG-PET imaging for cancer patient management and oncologic drug development

2-[18F]Fluoro-2-deoxyglucose positron emission tomography (FDG-PET) assesses a fundamental property of neoplasia, the Warburg effect. This molecular imaging technique offers a complementary approach to anatomic imaging that is more sensitive and specific in certain cancers. FDG-PET has been widely applied in oncology primarily as a staging and restaging tool that can guide patient care. However, because it accurately detects recurrent or residual disease, FDG-PET also has significant potential for assessing therapy response. In this regard, it can improve patient management by identifying responders early, before tumor size is reduced; nonresponders could discontinue futile therapy. Moreover, a reduction in the FDG-PET signal within days or weeks of initiating therapy (e.g., in lymphoma, non–small cell lung, and esophageal cancer) significantly correlates with prolonged survival and other clinical end points now used in drug approvals. These findings suggest that FDG-PET could facilitate drug development as an early surrogate of clinical benefit. This article reviews the scientific basis of FDG-PET and its development and application as a valuable oncology imaging tool. Its potential to facilitate drug development in seven oncologic settings (lung, lymphoma, breast, prostate, sarcoma, colorectal, and ovary) is addressed. Recommendations include initial validation against approved therapies, retrospective analyses to define the magnitude of change indicative of response, further prospective validation as a surrogate of clinical benefit, and application as a phase II/III trial end point to accelerate evaluation and approval of novel regimens and therapies.

American Cancer Society lung cancer screening guidelines

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The Progress and Promise of Molecular Imaging Probes in Oncologic Drug Development

As addressed by the recent Food and Drug Administration Critical Path Initiative, tools are urgently needed to increase the speed, efficiency, and cost-effectiveness of drug development for cancer and other diseases. Molecular imaging probes developed based on recent scientific advances have great potential as oncologic drug development tools. Basic science studies using molecular imaging probes can help to identify and characterize disease-specific targets for oncologic drug therapy. Imaging end points, based on these disease-specific biomarkers, hold great promise to better define, stratify, and enrich study groups and to provide direct biological measures of response. Imaging-based biomarkers also have promise for speeding drug evaluation by supplementing or replacing preclinical and clinical pharmacokinetic and pharmacodynamic evaluations, including target interaction and modulation. Such analyses may be particularly valuable in early comparative studies among candidates designed to interact with the same molecular target. Finally, as response biomarkers, imaging end points that characterize tumor vitality, growth, or apoptosis can also serve as early surrogates of therapy success. This article outlines the scientific basis of oncology imaging probes and presents examples of probes that could facilitate progress. The current regulatory opportunities for new and existing probe development and testing are also reviewed, with a focus on recent Food and Drug Administration guidance to facilitate early clinical development of promising probes.

How experience and training influence mammography expertise

RATIONALE AND OBJECTIVES The authors evaluated the influence of perceptual and cognitive skills in mammography detection and interpretation by testing three groups representing different levels of mammography expertise in terms of experience, training, and talent with a mammography screening-diagnostic task. MATERIALS AND METHODS One hundred fifty mammograms, composed of unilateral cranial-caudal and mediolateral oblique views, were displayed in pairs on a digital workstation to 19 radiology residents, three experienced mammographers, and nine mammography technologists. One-third of the mammograms showed malignant lesions; two-thirds were malignancy-free. Observers interacted with the display to indicate whether each image contained no malignant lesions or suspicious lesions indicating malignancy. Decision time was measured as the lesions were localized, classified, and rated for decision confidence. RESULTS Compared with performance of experts, alternative free response operating characteristic performance for residents was significantly lower and equivalent to that of technologists. Analysis of overall performance showed that, as level of expertise decreased, false-positive results exerted a greater effect on overall decision accuracy over the time course of image perception. This defines the decision speed-accuracy relationship that characterizes mammography expertise. CONCLUSION Differences in resident performance resulted primarily from lack of perceptual-learning experience during mammography training, which limited object recognition skills and made it difficult to determine differences between malignant lesions, benign lesions, and normal image perturbations. A proposed solution is systematic mentor-guided training that links image perception to feedback about the reasons underlying decision making.

Clinical and Biological Effects of Valproic Acid as a Histone Deacetylase Inhibitor on Tumor and Surrogate Tissues: Phase I/II Trial of Valproic acid and Epirubicin/FEC

Purpose: The aim was to study the biological and molecular effects of the histone deacetylase (HDAC) inhibitor, valproic acid, in patients with solid tumor malignancies. Experimental Design: A phase I dose escalation of valproic acid given on days 1 to 3 followed by epirubicin (day 3) was followed by a dose expansion of valproic acid combined with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC100). Pharmacodynamic and pharmacokinetic studies entailed valproic acid and epirubicin plasma levels and their interaction, the effects of valproic acid on histone acetylation in peripheral blood mononuclear cells (PBMC) and tumor cells at baseline and day 3, and baseline expression of HDAC2 and HDAC6 as therapeutic targets. Results: Forty-four patients were enrolled in the phase I part, with a disease-specific cohort expansion of 15 breast cancer patients (median age, 55 years; range, 28-66 years) receiving 120 mg/kg/day valproic acid followed by FEC100. Partial responses were seen in 9 of 41 (22%) patients during the phase I part. Objective responses were seen in 9 of 14 (64%) evaluable patients at the dose expansion with a median number of 6 administered cycles. Predominant toxicities were valproic acid–associated somnolence and epirubicin-induced myelosuppression. Valproic acid plasma levels were associated with short-term, reversible depletion of WBC and neutrophils within 48 hours. Histone acetylation in tumor samples and in PBMCs correlated with valproic acid levels and was further linked to baseline HDAC2 but not to HDAC6 expression. Conclusion: Valproic acid is a clinically relevant HDAC inhibitor, and PBMCs may serve as a surrogate for tumor histone acetylation in solid tumor malignancies. HDAC2 should be further considered as a relevant therapeutic target.

The emerging science of quantitative imaging biomarkers terminology and definitions for scientific studies and regulatory submissions

The development and implementation of quantitative imaging biomarkers has been hampered by the inconsistent and often incorrect use of terminology related to these markers. Sponsored by the Radiological Society of North America, an interdisciplinary group of radiologists, statisticians, physicists, and other researchers worked to develop a comprehensive terminology to serve as a foundation for quantitative imaging biomarker claims. Where possible, this working group adapted existing definitions derived from national or international standards bodies rather than invent new definitions for these terms. This terminology also serves as a foundation for the design of studies that evaluate the technical performance of quantitative imaging biomarkers and for studies of algorithms that generate the quantitative imaging biomarkers from clinical scans. This paper provides examples of research studies and quantitative imaging biomarker claims that use terminology consistent with these definitions as well as examples of the rampant confusion in this emerging field. We provide recommendations for appropriate use of quantitative imaging biomarker terminological concepts. It is hoped that this document will assist researchers and regulatory reviewers who examine quantitative imaging biomarkers and will also inform regulatory guidance. More consistent and correct use of terminology could advance regulatory science, improve clinical research, and provide better care for patients who undergo imaging studies.

Breast tissue density quantification via digitized mammograms

Studies reported in the literature indicate that breast cancer risk is associated with mammographic densities. An objective, repeatable, and a quantitative measure of risk derived from mammographic densities will be of considerable use in recommending alternative screening paradigms and/or preventive measures. However, image processing efforts toward this goal seem to be sparse in the literature, and automatic and efficient methods do not seem to exist. Here, the authors describe and validate an automatic and reproducible method to segment dense tissue regions from fat within breasts from digitized mammograms using scale-based fuzzy connectivity methods. Different measures for characterizing mammographic density are computed from the segmented regions and their robustness in terms of their linear correlation across two different projections-cranio-caudal and medio-lateral-oblique-are studied. The accuracy of the method is studied by computing the area of mismatch of segmented dense regions using the proposed method and using manual outlining. A comparison between the mammographic density parameter taking into account the original intensities and that just considering the segmented area indicates that the former may have some advantages over the latter.

Expanding the Use of Magnetic Resonance in the Assessment of Tumor Response to Therapy: Workshop Report

Although dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and magnetic resonance spectroscopy (MRS) have great potential to provide routine assessment of cancer treatment response, their widespread application has been hampered by a lack of standards for use. Thus, the National Cancer Institute convened a workshop to assess developments and applications of these methods, develop standards for methodology, and engage relevant partners (drug and device industries, researchers, clinicians, and government) to encourage sharing of data and methodologies. Consensus recommendations were reached for DCE-MRI methodologies and the focus for initial multicenter trials of MRS. In this meeting report, we outline the presentations, the topics discussed, the ongoing challenges identified, and the recommendations made by workshop participants for the use of DCE-MRI and 1H MRS in the clinical assessment of antitumor therapies.

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.

Effect of human variability on independent double reading in screening mammography

RATIONALE AND OBJECTIVES To demonstrate the range of gains and losses that radiologists might experience from independent double reading in screening mammography. METHODS From a national random sample of radiologists, the authors formed 131 pairs. For each radiologist, the authors analyzed the increase relative to his or her individual true-positive rate (TPR) or false-positive rate (FPR), number of additional cancers detected, and change to negative biopsy rate that would result from independent double reading after pairing. RESULTS The average radiologist can expect an 8%-14% gain in TPR and a 4%-10% increase in FPR with pairing. For some radiologists, double reading increased the TPR with a small concomitant increase in FPR. Other radiologists, however, realized small gains in TPR with large increases in FPR. Adding the reading from a more experienced radiologist did not necessarily improve the TPR of a radiologist with less experience. CONCLUSION Radiologists can form complementary and noncomplementary pairs for double reading. Use of this procedure must be decided on an individual basis.