Prediction of Survival by Neutropenia According To Delivery Schedule of Oxaliplatin–5-Fluorouracil–Leucovorin for Metastatic Colorectal Cancer in a Randomized International Trial (EORTC 05963)

Abstract

Circadian clocks control cellular proliferation and drug metabolism over the 24 h. However, circadian chronomodulated chemotherapy with 5-fluorouracil, leucovorin, and oxaliplatin (chronoFLO4) offered no survival benefit as compared with the non–time-stipulated FOLFOX2, in an international randomized trial involving patients with previously untreated metastatic colorectal cancer (EORTC 05963). The authors hypothesized that treatment near maximum tolerated dose could disrupt circadian clocks thus impairing the efficacy of chronoFLO4 but not of FOLFOX2. Patients with available data (N = 556) were categorized into three subgroups according to the worst grade (G) of neutropenia experienced during treatment. Distinct multivariate models with time-dependent covariates were constructed for each treatment schedule. Neutropenia incidence (all grades) was 33% on chronoFLO4 and 61% on FOLFOX2 (p < .0001), and G3–4 were 7% and 25%, respectively (p < .0001). Neutropenia was significantly more frequent in women than men on either schedule (FOLFOX2, p = .003; chronoFLO4, p = .04). Median survival was 20.7 mo in patients with G3–4 neutropenia versus 12.5 mo in neutropenia-free patients on FOLFOX2 (p < .0001). Corresponding figures were 13.7 and 19.4 mo, respectively, on chronoFLO4 (p = .36). Multivariate analysis confirmed occurrence of severe neutropenia independently predicted for better overall survival on FOLFOX2 (HR = 0.56; p = .015), and worse survival on chronoFLO4 (HR = 1.77, p = .06), with a significant interaction test (p < .0001). Prediction of better survival in neutropenic patients on FOLFOX2 supports the administration of conventional chemotherapy near maximum tolerated dose. The opposite trend shown here for chronoFLO4 supports the novel concept of jointly optimized hematologic tolerability and efficacy through personalized circadian-timed therapy. (Author correspondence: [email protected])

Keywords:

• Chemotherapy
• Chronotherapy
• Circadian
• Colorectal cancer
• Neutropenia
• Prognostic factor

ACKNOWLEDGMENTS

The clinical trial EORTC 05963, whose data were used for the current study, was supported in part by a grant from Sanofi Pharma, which also provided oxaliplatin for patients until approval of the drug. The current study was supported by the Association Internationale pour la Recherche sur le Temps Biologique et la Chronotherapie (ARTBC International). None of these sources were involved in the study design, in the collection, analysis, and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication.

We are sincerely thankful to the other investigators who enrolled patients in the EORTC 05963 trial, to Antoine Poncet and Pierre-Antoine Dugué for their paramount help in updating the database, and to Marie-Ange Lentz, from the EORTC Data Center, for her excellent data managing efforts.

Declaration of Interest: The authors confirmed report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.