The Clinical Viewpoint: Definitions, Limitations of RECIST, Practical Considerations of Measurement

Abstract

In selecting an endpoint in clinical trial design, it is important to consider that the endpoint is both reliably measured and clinically meaningful. As such, overall survival (OS) has traditionally been considered the most clinically relevant and convincing endpoint in clinical trial design as long as it is accompanied by preservation in quality of life. However, progression-free survival (PFS) is increasingly more prominent in clinical trial design because of feasibility issues (smaller sample sizes and shorter follow-up). PFS has the advantage of taking into account not only responsive disease, but stable disease as well, an issue of particular importance in the relapsed and refractory setting in which therapies are often associated with a minimal to nil response but may still confer a survival advantage. Finally, PFS has a significant advantage in molecularly selected populations, in whom OS advantages are difficult to detect due to the effects of crossover. With an understanding of the limitations and biases that are introduced with PFS as a primary endpoint, we believe that PFS is not only a viable but also a necessary alternative to OS in assessing the efficacy of selected novel-targeted therapies in molecularly defined cancer populations. Ultimately, the selection of a clinical trial endpoint should not be based on a one-size-fits all approach; rather, it should be based on the specifics of the therapeutic strategy being tested and the population under study.

A Population Pharmacodynamic Model for Lactate Dehydrogenase and Neuron Specific Enolase to Predict Tumor Progression in Small Cell Lung Cancer Patients

“…Figure 4a(1-3) shows the drug exposure effect, where typical profile indicates that drug effect is reduced to 50% of its initial value after three to four chemotherapy cycles (3). Figure 4b(1-4) shows that had the model only included terms for drug and/or radiotherapy effects without resistance effects, we would have incorrectly predicted a steady monotonic decline in the disease level (2 and 3), whereas the incorporation of the resistance effect enabled the adequate prediction of a disease nadir level, at approximately the fourth cycle of chemotherapy (4).…”

“…2 and the estimates of model parameters shown in Table I. a Effect of chemotherapy exposure (1), the level of resistance corresponding to AUC CT (2), and drug effects in the presence of resistance (3). b Predicted disease dynamics in different scenarios: (1) disease level in the absence of any treatment, (2) disease level in presence of chemotherapy, (3) disease level under radiotherapy and chemotherapy, and (4) disease progression as it is described in our model (in the presence of radiotherapy, chemotherapy, and resistance) Fig.…”

“…For some patients, additional samples were collected between cycles. A total of 369 LDH observations were included in the analysis, where each patient contributed a mean of six samples (range [3][4][5][6][7][8][9][10][11][12][13][14][15][16]. A total of 152 NSE concentrations were included in the dataset, where each patient contributed four samples on average (range 1-7).…”

“…The Response Evaluation Criteria in Solid Tumors (RECIST) [1] defines current practice to categorize response to treatment, which has limited utility for prediction due to its nonquantitative nature [2,3]. A proposed solution is the use of quantitative tumor assessment measure.…”

Minimising the impact of errors in the interpretation of CT images for surveillance and evaluation of therapy in cancer

“…Changing the quality of investigations can have a radical effect on the interpretation of clinical trial data, and rules to ensure consistency in scanning and measurement are important. However, rigid application of these rules can reduce trial recruitment 66 and cause data loss through protocol violations, serving to make the study less relevant to the "real world" 67,68 . It is beyond the scope of this article to document the myriad ways of failing to report clinical research scans, except to say that getting the baseline pre-treatment scan correct makes follow-up considerably easier.…”