Circadian rhythm in rest and activity: a biological correlate of quality of life and a predictor of survival in patients with metastatic colorectal cancer

Abstract

The rest-activity circadian rhythm (CircAct) reflects the function of the circadian timing system. In a prior single-institution study, the extent of CircAct perturbation independently predicted for survival and tumor response in 192 patients receiving chemotherapy for metastatic colorectal cancer. Moreover, the main CircAct parameters correlated with several health-related quality of life (HRQoL) scales. In this prospective study, we attempted to extend these results to an independent cohort of chemotherapy-naive metastatic colorectal cancer patients participating in an international randomized phase III trial (European Organisation for Research and Treatment of Cancer 05963). Patients were randomized to receive chronomodulated or conventional infusion of 5-fluorouracil, leucovorin, and oxaliplatin as first-line treatment for metastatic colorectal cancer. Patients from nine institutions completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 and wore a wrist accelerometer (actigraph) for 3 days before chemotherapy delivery. Two validated parameters (I<O and r24) were used to estimate CircAct. Of 130 patients with baseline CircAct assessments, 96 had baseline HRQoL data. I<O was confirmed to correlate with global quality of life, physical functioning, social functioning, fatigue, and appetite loss (r > |0.25|; P < 0.01). I<O further independently predicted for overall survival with a hazard ratio of 0.94 (P < 0.0001). The associations between CircAct parameters, HRQoL, and survival, which were shown in this international study involving previously untreated metastatic colorectal cancer patients, confirm prior single-institution findings in mostly pretreated metastatic colorectal cancer patients. The circadian timing system constitutes a novel therapeutic target. Interventions that normalize circadian timing system dysfunction may affect quality of life and survival in cancer patients.

Figure 1

Boxplots illustrating the distribution of the CircAct parameters Ist and 3^rd quartiles; thin vertical bars denote range.

Figure 2

The difference in mean HRQoL scores (+ Standard Error of the Mean) between two subgroups of patients classified by CircAct parameters above median (black bars) vs below the median (gray bars) where the clinical relevance (Effect Size ≥ 0.4) was statistically significant (p < 0.01). Black boxes indicate CircAct parameters above median: I

Figure 3

Kaplan Meier survival curves according to r24 (A) and I<O (B) split by the quartiles of their distribution. 1^st quartile: thick solid line; 2^nd quartile: thin dashed line; 3^rd quartile: thick dotted line; 4^th quartile: thin solid line. Logrank test (df=3): p=0.002 for r24 (A); p=0.008 for I<O (B).