Comparison of toxicity associated with early morning versus late afternoon radiotherapy in patients with head-and-neck cancer: a prospective randomized trial of the National Cancer Institute of Canada Clinical Trials Group (HN3).
OBJECTIVE
Based on our demonstration of a circadian rhythm in the human oral mucosa cell cycle, with most cells in the G(1) phase in the morning and M phase at night, we hypothesized that morning radiotherapy (RT) would lead to less oral mucositis than afternoon RT.


METHODS
A total of 216 patients were randomized to morning (8-10 AM) vs. afternoon (4-6 PM) RT and stratified by radiation dose, smoking status, and center. Patients receiving primary or postoperative RT alone were eligible. Oral mucositis was scored using the Radiation Therapy Oncology Group (RTOG) criteria and a validated scoring system.


RESULTS
Of 205 evaluable patients, 52.9% vs. 62.4% developed RTOG Grade 3 or greater mucositis after morning vs. afternoon RT, respectively (p = 0.17). Morning RT was also associated with significantly less weight loss after 5 months (p = 0.024). In a subgroup of 111 patients treated to a dose of 66-70 Gy in 33-35 fractions, exploratory analyses revealed a significant reduction in Grade 3 or greater mucositis with morning RT (44.6% vs. 67.3%, p = 0.022) and a longer interval to the development of Grade 3 or greater mucositis (median, >7.9 vs. 5.6 weeks, p = 0.033). In 53 patients, who smoked during therapy, a significant reduction was found in Grade 3 or greater mucositis with morning RT (42.9% vs. 76%, p = 0.025).


CONCLUSIONS
In this proof of principle study, morning RT was associated with significantly less weight loss after 5 months and an apparent reduction in oral mucositis in a subset of patients receiving >/=66 Gy and in patients who smoked during therapy.
Bjarnason
Georg A
GA
Department of Medical Oncology, Sunnybrook Odette Cancer Centre, Toronto, ON, Canada.
Mackenzie
Robert G
RG
Nabid
Abdenour
A
Hodson
Ian D
ID
El-Sayed
Samy
S
Grimard
Laval
L
Brundage
Michael
M
Wright
James
J
Hay
John
J
Ganguly
Pradip
P
Leong
Carson
C
Wilson
Jane
J
Jordan
Richard C K
RC
Walker
Melanie
M
Tu
Dongsheng
D
Parulekar
Wendy
W
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002940:Circadian Rhythm; D015897:Comorbidity; D018572:Disease-Free Survival; D005260:Female; D006258:Head and Neck Neoplasms / Q000453:epidemiology* / Q000532:radiotherapy*; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D011832:Radiation Injuries / Q000453:epidemiology* / Q000517:prevention & control; D011878:Radiotherapy / Q000379:methods* / Q000706:statistics & numerical data*; D018570:Risk Assessment / Q000379:methods*; D013280:Stomatitis / Q000453:epidemiology* / Q000517:prevention & control; D014481:United States / Q000453:epidemiology