Waterfall plots provide detailed information on magnitude of response to conventional chemotherapy in advanced colorectal cancer (ACRC) - lessons learned from N9741

Abstract

4080 Background: Waterfall plots have been used to capture the anti-tumor efficacy of both biologic agents (Ratain JCO 2006), which mainly exhibit a cytostatic effect, but also of chemotherapeutic agents. We are not aware of an application to therapeutic studies in CRC. We conducted waterfall plot analyses on the data of N9741 which compared IFL, FOLFOX4, and IROX as first-line therapy in ACRC (Goldberg JCO 2004). Methods: 634 (IFL 215, FOLFOX 215, IROX 204) of the 795 pts presented in the published analysis had measurable disease, and are included. The percentage change in tumor measurements from baseline to 12 wks was calculated, allowing for a time window of assessment from 6 to 20 wks for those without a 12 wk measurement. Pts with progression before the 12 wk assessment were assigned a 100% increase. The average reduction in tumor burden (ARTB) was calculated as difference in waterfall AUC divided by the number of pts. ARTB captures the average percentage reduction in tumor measurements at 12 wks for a patient entering the trial. Results: Waterfall plot analysis demonstrated some tumor growth at 12 wks in 23.7% (IFL), 15.8% (FOLFOX), and 26.9% (IROX) of pts. In contrast, tumor shrinkage was observed in 67.9% (IFL), 71.6% (FOLFOX), and 61.4% (IROX) of pts. Total differential AUC was -34.4 (IFL), -61.6 (FOLFOX), and -30.4 (IROX) resulting in an ARTB of 16.0% (95% Confidence Interval (CI) (23.7%, 8.2%)) for IFL, 28.7% (35.1%, 22.2%) for FOLFOX, and 14.9% (22.5%, 7.3%) for IROX. Conclusions: Waterfall plot analyses are feasible in this and likely other CRC trials using conventional chemotherapy. Our analysis confirms the published results of N9741, but suggests a larger degree of benefit for individuals based on anti-tumor activity than captured by conventional response analysis. Waterfall plots provide a potentially useful new efficacy metric, the average reduction of tumor burden per pt, which should be validated in future trials. No significant financial relationships to disclose.