Phase I's, Photons, and Philosophies: New Tactics for Exploratory Clinical Trials of Concurrent Chemoradiation
Authors: Mitchell Machtay
Journal: Journal of Clinical Oncology (2003)

It is unusual for this journal to publish an editorial about a phase I protocol—particularly a phase I protocol that does not involve any elaborate new targeted agents. However, the article by Muler et al [1] introduces several innovative concepts in phase I clinical oncology trials that deserve some comments. The most obvious feature of the Michigan study is the use of a novel trial methodology called time-to-event continual reassessment methodology (TITE-CRM). A detailed discussion of this design is beyond the scope of this review, but one of its major goals is to accelerate the determination of the maximum tolerated dose (MTD) of a new regimen. If properly performed, it improves the confidence of the MTD calculation when compared with conventional phase I design (3/6 design) and minimizes the number of patients subjected to doses that are likely to be subtherapeutic. This design is particularly well suited to radiotherapy trials, given that dose-limiting toxicity may occur after (sometimes long after) the treatment is finished [2]. Conventional 3/6 radiotherapy phase I trials require lengthy periods of trial suspension, which has been problematic to the Radiation Therapy Oncology Group and others. The TITE-CRM design can speed up the phase I process, avoiding such delays. This is a positive step. However, this design could also result in a higher number of patients subjected to doses above MTD, particularly if there are delays in communicating toxicity data to the medical monitoring team. Therefore, does the TITE-CRM create an ethical dilemma in phase I clinical research? As stated in the article by Muler et al, this study was approved in its entirety by the University of Michigan institutional review board, and we must thus presume that its members closely scrutinized the TITE-CRM design and compared it with a conventional phase I design. I would concur that this particular study was designed and executed according to the Helsinki Declaration and other guidelines of human research. However, this should not be taken to mean that the TITE-CRM design should be used in all settings and without concern. Protocol features that are even more important in a TITE-CRM phase I than a conventional phase I design are as follows: (1) exceptionally strong background data to support the choice of doses; (2) a disease setting in which dose-intensity of multiple therapeutic agents is likely necessary to improve tumor control or palliation; (3) dose escalation increments that are relatively conservative; (4) an informed consent form that clearly describes the risks of a phase I study; (5) rapid, nearly real-time reporting and analysis of toxicities by physicianinvestigators and clinical research and nurse associates; (6) highly efficient medical monitoring, analogous to Data Monitoring Committees used in phase III studies; (7) scrutiny, approval, and frequent reapproval of the study by a very experienced academic institutional review board that often reviews early phase clinical trials; and (8) careful peer review and commentary by the journal(s) that ultimately referee this type of research. When these criteria can be met, as seems to have been done in the study by Muler et al, the TITE-CRM design does appear to be an improvement over classical 3/6 phase I design, at least for concurrent chemoradiotherapy studies. This methodology deserves testing, not just in the tense relationship between radiotherapy and gemcitabine, nor just in pancreatic cancer. It is very reasonable to explore this design for concurrent chemoradiotherapy trials in lung cancer, malignant brain tumors, and other inoperable malignancies, and the Michigan researchers should be congratulated for introducing this to the radiation oncology research community. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 2 JANUARY 15 2004