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Erasmus MC–Sophia Children's Hospital, Rotterdam, The Netherlands
Cincinnati Children's Hospital, Cincinnati, Ohio
In September 2005, more than 70 experts gathered in Chantilly, Virginia, for a 2-day workshop, "Imaging Endpoints for Cystic Fibrosis Clinical Trials," sponsored by the Cystic Fibrosis Foundation (CFF). The primary aim of the workshop was to identify areas needing further development to establish lung imaging, and specifically computed tomography (CT) scanning, as valid outcome measures for CF clinical trials. Among the participants were scientists, CF physicians, radiologists, physicists, statisticians, and representatives from the U.S. Food and Drug Administration, industry, and the CFF. The rationale for the workshop was clear. In the field of CF, a broad array of new therapies are in development. To test all these new therapies in clinical trials, a range of feasible, valid, and precise endpoints is urgently needed.
Lung function parameters traditionally have been used as the primary endpoint in many therapeutic studies in CF. Ironically, the improvements in lung function among patients with CF over the past decade have rendered these measurements less useful as clinical trial endpoints, since the average rate of decline has slowed and normal lung function is, on average, preserved until later ages. As a result of the use of endpoints of relatively poor sensitivity and precision, large numbers of study subjects are required in most studies. This clearly limits the number of trials that can be conducted in the CF population. In addition, large studies consume valuable resources and expose a large number of patients to the potential risks of investigational drugs. Fortunately, a large body of literature published in the last decade suggests that imaging endpoints are more sensitive to detecting the progression of CF lung disease than lung function–related parameters. The most extensive developments have been in the area of CT; interesting recent advances have occurred in magnetic resonance imaging (MRI), positron emission tomography (PET), and in chest radiography.
This symposium in the Proceedings reflects the contents of the workshop. Although the main focus is on CF, the articles are relevant for discussions of the role of imaging techniques in monitoring other lung diseases, such as asthma and chronic obstructive pulmonary disease.
In the article by Rosenfeld, the qualities of an ideal outcome measure are summarized and the advantages and limitations of currently used endpoints reviewed. She sets the stage for the subsequent articles by discussing the potential role for chest CT and other newer imaging modalities as potential surrogate endpoints.
Part I of this symposium contains state-of-the-art reviews of the role of each of the imaging modalities in the monitoring of CF lung disease. In the first article, Cleveland and colleagues discuss the role conventional chest radiographs may play in large longitudinal studies. They demonstrate that chest radiograph scores can be as sensitive as lung function to the progression of CF lung disease. CT is currently considered the most promising technique to monitor CF lung disease. However, standardized techniques need to be further established. Long discusses the most important technical factors in relation to CT scanning of the lung in young children and older patients. A key factor is the control of lung volume during the scanning procedure, which is especially important in young children. The most reliable technique for controlling lung volumes in infants and very young children is the controlled volume technique, discussed in detail by Long.
Multidetector CT scanners allow greater flexibility in the design of CT protocols to evaluate CF lung disease than prior scanners. The relation between the scanning protocol and the information obtained from the images is discussed by Robinson. Air trapping is an important feature of early lung disease that can be detected on CT when the appropriate protocol is used.
Radiation exposure is clearly an important topic in relation to the use of CT. To minimize the risk of radiation-induced cancers, the radiation dose should be kept to the absolute minimum required to achieve acceptable image quality. Patients undergoing chest CT examinations should derive a benefit that exceeds the (small) radiation risk. This complicated topic is discussed in the article by Huda.
The resolution of MRI is clearly inferior to that of CT. However, relevant structural changes in the lung can be identified with MRI, and, importantly, it is a radiation-free technique. Furthermore, MRI is a promising technique to study functional aspects of the lung. The role of MRI in lung imaging is discussed by Altes and colleagues.
PET can provide visual and quantitative information about the rate at which glucose is taken up by the lung, a process that relates to the presence of inflammation and reflects the extent of disease. PET can be combined with CT, allowing anatomical information to locate areas of inflammation seen on the PET scan and increasing the accuracy of the interpretation. The role of PET and PET-CT is discussed by Dolovich and Schuster.
Part II of this symposium focuses on how to conduct studies using imaging techniques and how to analyze the data. The factors that determine the power to detect treatment effects are discussed by Corey. It is important that the outcome measure reflects an important aspect of the disease. FEV1 has been an excellent surrogate for long-term survival. Now measures are needed to detect and monitor the events that initiate and establish initial lung disease in CF. The requirements that must be met by imaging endpoints before they can be used as surrogate endpoints are discussed by Emond in an online article, which may be accessed from this issue's table of contents at www.atsjournals.org (direct access at http://pats.atsjournals.org/cgi/content/full/4/4/DC1).
The information on images can be quantified using scoring systems. In the contribution by de Jong and Tiddens, the basic principles of CT scoring systems in CF are discussed. With proper training, the systems are reproducible. A great disadvantage of scoring systems is that they are time consuming for the scorers. In the article by Tiddens and de Jong, clinical studies that used CT scores as endpoints are summarized. These studies strongly suggest that CT scoring is more sensitive than pulmonary function tests for the detection of relevant disease progression in CF. Bronchiectasis, which is progressive and irreversible in CF, is probably the most relevant structural change on CT scans that can be scored in a reliable fashion.
Computerized analysis of CT images is an attractive alternative to standard scoring. In the article by Goris and colleagues, automated analysis of air trapping is discussed. This type of analysis is likely to be more sensitive than visual image analysis. However, it is more dependent on well-standardized data acquisition. It is likely that in the future both methods will be used in parallel.
In the contribution by Brody, the practical lessons from three CF trials in which CT scanning was used as an outcome measure are discussed. These studies show that CT scans can be used as surrogate endpoints in CF clinical trials.
Part III of this symposium focuses on how imaging endpoints could be used in future trials. Aziz describes the steps needed before CT can be used as a potential endpoint in the multidose gene therapy trial to be run by the U.K. Gene Therapy Consortium. During a "run-in" period, all potential imaging and nonimaging assays will be monitored over a period of 1 year before the cohort is randomized. The information on how CT characteristics fluctuate over time in individuals is vital to assess whether a potential effect of therapy is real or simply a reflection of underlying natural fluctuation. Finally, Ramsey discusses how imaging techniques may be useful biomarkers in the different study phases of drug development. It is important that such a technique is able to demonstrate the safety and efficacy of new therapeutic agents for registration with the U.S. Food and Drug Administration. It is recognized that CF investigators must begin to focus on structural as well as functional measures of disease status. However, there are still many steps required before imaging techniques such as chest CT become validated biomarkers in this population.
Relevant developments that occurred after the date of the workshop have been incorporated into the manuscripts. The workshop clearly was not the endpoint in the development of imaging-related endpoints in CF but rather a catalyst. Imaging-related endpoints will become increasingly important. The workshop underlined that lung function is no longer the "one size fits all" endpoint in clinical studies but that the emerging use of radiographic parameters, especially CT scan scoring, can be complementary to or may even replace more traditional endpoints.
FOOTNOTES
Conflict of Interest Statement: H.A.W.M.T. acted as a member of two ad hoc advisory boards for Novartis and received within the last 3 years honoraria and travel expenses for lectures and workshops from Hoffman-La-Roche and Genentech. The BV Kindergeneeskunde of Erasmus MC–Sophia Children's Hospital has in the last 3 years received research grants from Hoffman-La-Roche. A.S.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
This article has been cited by other articles:
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  B. W. Ramsey Outcome Measures for Development of New Therapies in Cystic Fibrosis: Are We Making Progress and What Are the Next Steps? Proceedings of the ATS, August 1, 2007; 4(4): 367 - 369. [Full Text] [PDF]
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