Prediction of overall survival through circadian rest-activity monitoring during chemotherapy for metastatic colorectal cancer

Authors

  • Pasquale F. Innominato,

    1. INSERM, UMRS 776, «Biological Rhythms and Cancers», Villejuif, France
    2. Faculty of Medicine, Université Paris Sud, le Kremlin-Bicêtre, France
    3. APHP, Chronotherapy Unit, Department of Oncology, Paul Brousse Hospital, Villejuif, France
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  • Sylvie Giacchetti,

    1. INSERM, UMRS 776, «Biological Rhythms and Cancers», Villejuif, France
    2. Faculty of Medicine, Université Paris Sud, le Kremlin-Bicêtre, France
    3. APHP, Chronotherapy Unit, Department of Oncology, Paul Brousse Hospital, Villejuif, France
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  • Georg A. Bjarnason,

    1. Department of Medical Oncology, Sunnybrook Odette Cancer Centre, Toronto, Ontario, Canada
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  • Christian Focan,

    1. Department of Medical Oncology, Saint Joseph Clinics, Liège, Belgium
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  • Carlo Garufi,

    1. Department of Medical Oncology, Regina Elena Institute, Roma, Italy
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  • Bruno Coudert,

    1. Department of Medical Oncology, Centre Georges-François Leclerc, Dijon, France
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  • Stefano Iacobelli,

    1. Department of Oncology & Neurosciences, University G. d'Annunzio Medical School, Chieti, Italy
    2. Consorzio Interuniversitario Nazionale per la Bio-Oncologia (CINBO), Italy
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  • Marco Tampellini,

    1. Department of Medical Oncology, San Luigi Gonzaga Hospital, Orbassano, Italy
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  • Xavier Durando,

    1. Department of Medical Oncology, Centre Jean Perrin, Clermont-Ferrand, France
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  • Marie-Christine Mormont,

    1. INSERM, UMRS 776, «Biological Rhythms and Cancers», Villejuif, France
    2. APHP, Chronotherapy Unit, Department of Oncology, Paul Brousse Hospital, Villejuif, France
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  • Jim Waterhouse,

    1. Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, United Kingdom
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  • Francis A. Lévi

    Corresponding author
    1. INSERM, UMRS 776, «Biological Rhythms and Cancers», Villejuif, France
    2. Faculty of Medicine, Université Paris Sud, le Kremlin-Bicêtre, France
    3. APHP, Chronotherapy Unit, Department of Oncology, Paul Brousse Hospital, Villejuif, France
    • INSERM UMRS776 "Rythmes Biologiques et Cancers," Hôpital Paul Brousse, 14 Avenue P.V. Couturier, Villejuif Cedex 94807, France
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    • Tel.: [+33 1 45 59 38 55], Fax: +[33 1 45 59 36 02]


Abstract

The clinical relevance of circadian rhythm modifications in patients on chemotherapy is unknown. Even so, circadian parameter I<O before chemotherapy independently predicted overall survival. This study investigates the relevance of I<O measured during chemotherapy for survival and symptoms. The circadian rest-activity pattern was monitored for 3 days using a wristwatch actigraph while 77 patients were receiving a chemotherapy course within an international randomized Phase III trial. Treatment consisted of first-line chronomodulated or conventional delivery of 5-fluorouracil, leucovorin and oxaliplatin for metastatic colorectal cancer. I<O was computed as the percentage of minutes of activity counts in bed which were below the median of activity out of bed. Circadian disruption was defined by I<O equal to or less than 97.5%. Circadian disruption occurred in 39 patients (51%) on chemotherapy. It was associated with a significantly shorter overall survival, independently of other prognostic factors (multivariate Hazard Ratio: 2.12; p = 0.004). The median survival of patients with a robust circadian rhythm was 22.3 months as compared to 14.7 months in those with circadian disruption during chemotherapy. No toxicity was significantly associated with circadian disruption, but the incidence of grade ≥2 fatigue and of body weight loss ≥5% was two and threefold higher, respectively, in patients with disrupted circadian rhythm on chemotherapy. Chemotherapy disrupted circadian activity rhythm in nearly 50% of the patients. Circadian disruption on chemotherapy predicted for shorter overall survival. The prevention of chemotherapy-induced circadian disruption might reduce toxicity and improve efficacy in cancer patients.

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