Early Average Change in Tumor Size in a Phase 2 Trial: Efficient Endpoint or False Promise?
Authors: L. V. Rubinstein, J. E. Dancey, E. L. Korn, M. A. Smith, J. J. Wright
Journal: JNCI Journal of the National Cancer Institute (2007)

that the authors evaluated to design the trial they propose had a range of results for early tumor size change and clinical benefi t. The variability in the results may refl ect the extrapolations that were required for the authors to estimate mean change in tumor size in these studies; they may also refl ect variability in the mechanisms of action of the agents studied in the trials, in the proportions of patients with sensitive versus insensitive disease, and in the overall level of effi cacy of the agents in patients. These results do not directly address how early changes in tumor size may be predictive of clinical benefi t because clinical benefi t to the patient or study population likely relates to the type and magnitude of the antitumor effect as well as to its duration. Defi ning a potentially clinically meaningful difference in the early change in tumor size would require analysis of many more studies over many more disease subgroups and different classes of agents because the endpoint may prove to be predictive only in certain settings. Even then, this endpoint would be most useful in situations in which median progression-free survival is relatively long (at least 6 – 12 months); otherwise, the progression-free survival endpoint in a randomized trial would be both feasible and preferable as an endpoint, as described below. In any event, when early tumor size changes are small, it may be useful to incorporate some measure of their durability. Adapting a suggestion by the authors, we suggest that it may be useful to average tumor size changes over some period of time. Second, substantial care is needed to avoid bias in assessing tumor size because even a small bias could result in a statistically signifi cant, but spurious, apparent treatment-related difference. Avoiding this bias might require blinded assessments or external review of assessments. Third, the approach does not adequately accommodate detection of new disease. It is not suffi cient to add the size of a new lesion to the sum total of the size of existing lesions because the implications of a new lesion are generally worse than those of a comparable increase in existing lesions. Indeed, the Response Evaluation Criteria in Solid Tumors guidelines ( 5 ) treat any new disease as unequivocal evidence of progression. It might be possible to accommodate new disease in the same way that the authors propose to accommodate early death, that is, by making Advances in our understanding of tumor biology, in pharmaceutical development, and in imaging technology have led to vigorous discussions about the most appropriate designs and endpoints for phase 2 trials ( 1 ). The need for these discussions is occasioned in part by novel agents whose predominant effect is to delay tumor progression and new imaging technologies that have increased the accuracy with which tumor size can be assessed and have introduced new ways of assessing tumor metabolism, perfusion, and necrosis. Further grounds for reassessment of trial design is the fact that it has long been acknowledged that tumor objective response, as defined by traditional response criteria, may sometimes be a poor surrogate for predicting patient benefit. The proposal by Karrison et al. ( 2 ) in this issue of the Journal is a novel and intriguing solution to some of the problems facing investigators designing phase 2 trials involving new anticancer agents in this current environment. The authors propose the use of a randomized design with average change in tumor size (at 8 weeks, in their central example) as the endpoint and describe a trial that they will undertake using this design. As the authors state, it is now relatively common for new, molecularly targeted agents to be tested early in their development in combination with established chemotherapy regimens. The effects of such agents may be primarily cytostatic, which presents investigators with new challenges that make the standard one-armed phase 2 design — which uses an objective response endpoint — inadequate ( 3 , 4 ). That is, the new agent may not be expected to increase the objective response rate associated with the standard chemotherapy but may, nevertheless, increase progression-free or overall survival. The authors suggest that an early small difference in average change in tumor size between the treatment arms with and without the experimental agent may be predictive of a clinically meaningful difference in progression-free or overall survival. Furthermore, they assert, and we agree, that such a difference in change in tumor size cannot be assessed adequately using historical control subjects. Finally, the authors correctly point out the statistical effi ciency of using a continuous endpoint as opposed to the dichotomous tumor response endpoint, noting that tumor size changes that are clinically unimportant at the individual level can, with moderate sample sizes, yield statistically signifi cant differences between treatment groups. As do Karrison et al. ( 2 ), we see potential problems with their proposed approach, and some additional factors relevant to the eventual utility of the design should be considered. First, small differences in early tumor size changes (modestly increased shrinkage or decreased expansion) offer no clinical benefi t of their own and, therefore, must be shown to be predictive of the clinically meaningful outcomes of progression-free and overall survival before such differences can be considered a useful endpoint. The trials