Chronotherapeutic administration of neoadjuvant chemotherapy reduces cancer-related fatigue-like behavior

Circadian rhythms are ∼24-h oscillations in physiology and behavior and can be used to optimally time treatment, a practice known as chronotherapy. Chronotherapy for cancer treatment was first successfully utilized >50 years ago and has been demonstrated to improve anti-tumor efficacy and reduce toxic effects of chemotherapy. However, to our knowledge, no study has assessed chrono-chemotherapy for cancer-related fatigue (CRF). The most commonly reported side effect of chemotherapy is CRF, which peaks during treatment but can last up to a decade or longer in some patients. Although not specific to one cancer type, CRF is especially prevalent in patients undergoing treatment for breast cancer. We hypothesized that chronotherapy could reduce CRF in a mouse model of primary breast cancer. Female C57Bl/6 mice were orthotopically injected with the syngeneic EO771 mammary tumor cell line and housed individually with running wheels to assess fatigue-like behavior. Two doses of chemotherapy (paclitaxel or doxorubicin/cyclophosphamide [AC]) spaced 14 days apart were administered intraperitoneally at either the mid-inactive (Zeitgeber time [ZT] 6) or mid-active phase (ZT18). Mice receiving paclitaxel or AC at ZT6 demonstrated reduced fatigue-like behavior following the first dose compared to those receiving chemotherapy at ZT18. Central inflammatory markers were assessed following the second doses. Inflammatory profiles (composite z-scores) were higher in mice treated at ZT18 with paclitaxel but not AC. These data provide evidence that chronomodulation of neoadjuvant chemotherapy can reduce fatigue-like behavior in a mouse model of primary breast cancer and may inform clinical research to reduce adverse events in patients.