Independent prognostic value of the rest/activity circadian rhythm on overall survival (OS) in patients (pts) with metastatic colorectal cancer (MCC) receiving first line chemotherapy with 5-fluorouracil, leucovorin and oxaliplatin: A companion study to EORTC 05963

Abstract

3553 Background: In tumor bearing rodents, disruption of the rest/activity rhythm (RAR) results in faster tumor growth and a shorter OS (Cancer Res 64:7879, JNCI 94:690, Cell 111:41). In single institution prospective trials on pts with metastatic breast cancer (JNCI 92:994) and MCC (Clin Cancer Res 6:3038), a disrupted circadian rhythm also results in a shorter OS. In this multicenter prospective trial, we studied the prognostic value of the RAR in MCC patients receiving first line FOLFOX-2 vs. 4-day chronomodulated infusion of the same drugs. Methods: To assess the RAR, 130 pts out of 564 pts in 9 centers wore a wrist-watch (actigraph), which recorded the number of wrist movements per minute for 3 days before starting therapy. Two RAR parameters, validated in previous clinical studies, were calculated: the autocorrelation coefficient at 24h (r24), indicating the robustness of the activity pattern over a period of 24 hours, and the dichotomy index (I<O), quantifying the differences in activity distribution between the rest phase and the active phase. The prognostic values of r24 and I<O were assessed by the logistic regression model for response and toxicity and by the Cox Proportional Hazard model for OS. Results: RAR parameters were not predictive for response or toxicity. When RAR parameters were categorized into quartiles, r24 and I<O were detected as potential prognostic factors for OS in a univariate analysis. The relative risk of death was 1.31 fold larger in the lowest vs highest I<O quartile. In a Cox Proportional Hazard model, I<O was confirmed as an independent predictor of OS (p < 0.0003) along with CEA ≥ 50 ng/ml (p = <0.0001), WHO PS 1 or 2 (P = 0.0129) and number of metastatic sites ≥ 2 (p = 0.039). Using the bootstrap technique, I<O had a 70% probability of inclusion in the Cox model, making it one of the strongest prognostic factors for OS. Conclusions: This multicenter prospective study establishes the strong and independent prognostic value of the rest/activity circadian rhythm for the overall survival of patients with metastatic colorectal cancer. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sanofi research funding for the EORTC 05963 trial