Cetuximab and cancers of the head and neck: tapping the circadian rhythm.

Proteins in tissue obtained from human skin and oral mucosa have shown a significant circadian rhythm, with the peak expression of p27 at 6:00 AM (early G1-phase marker), p53 at 10:50 AM (late G1-phase marker) and cyclin-E at 2:50 PM (S-phase marker). Patients irradiated in late afternoon/evening have shown a higher grade of mucositis and dermatitis. Studies evaluating the effect of EGFR blockade on cell cycle progression in several human cell types, including A431 squamous epithelial carcinoma cells, suggest that cetuximab leads to cell cycle arrest in G1 phase. On concurrent administration with radiation, mucositis and dermatitis are its main side-effects. So we can hypothesize that cetuximab administration after 11:00 AM would decrease these toxicities. In addition, its administration prior to late afternoon/evening (3:00 PM) can further reduce the radiation associated mucositis and dermatitis due to the occurrence of S-phase during this time and thus increase the therapeutic benefit.