Introducing longitudinal cumulative dose to describe chemotherapy patterns over time: Case study of a colon cancer trial

Abstract

Adjuvant chemotherapy regimens take months to complete. Despite this, studies evaluate chemotherapy adherence via measures assessed at the end of treatment (eg, number of patients missing any dose, relative dose intensity [RDI]). This approach ignores information like the timing of treatment delays. We propose longitudinal cumulative dose (LCD) to integrate impacts of dose reductions, missed doses and dose delays over time. We obtained data from the 2246 participants in the MOSAIC trial randomized to FOLFOX (all three agents) or 5-FU/LV (only 5-fluorouracil and leucovorin). We evaluated proportions of patients stopping treatment early and reducing, missing or delaying a dose in each arm for each chemotherapy agent at each cycle. We calculated LCD, the fraction of the final standard dose a participant reached by a given day, for each participant and each agent and compared it over time and at 24 weeks between treatment arms. Participants randomized to FOLFOX were more likely to stop treatment, reduce doses, miss doses or delay cycles; these differences increased over time. Median LCD for oxaliplatin in the FOLFOX arm at 24 weeks was 77%. The LCD for 5-fluorouracil differed between arms (FOLFOX arm median: 81%; 5-FU/LV arm median: 96%). Visualizing LCD highlighted the timing of deviations from standard administration in a way RDI could not, with major differences in 5-fluorouracil LCD across treatment arms beginning after the sixth dose. Further evaluation of LCD and its impacts on clinical outcomes may clarify mechanisms for heterogeneous patient outcomes.

Keywords: adherence; chemotherapy; colon cancer; oncology; randomized controlled trial.