title: Does chronomodulated radiotherapy improve pathological response in locally advanced rectal cancer?
abstract: The predominant mode of radiation-induced cell death for solid tumours is mitotic catastrophe, which is in part dependent on sublethal damage repair being complete at around 6 h. Circadian variation appears to play a role in normal cellular division, and this could influence tumour response of radiation treatment depending on the time of treatment delivery. We tested the hypothesis that radiation treatment later in the day may improve tumour response and nodal downstaging in rectal cancer patients treated neoadjuvantly with radiation therapy. Recruitment was by retrospective review of 267 rectal cancer patients treated neoadjuvantly in the Department of Radiation Oncology at the Canberra Hospital between January 2010 and November 2015. One hundred and fifty-five patients met the inclusion criteria for which demographic, pathological and imaging data were collected, as well as the time of day patients received treatment with each fraction of radiotherapy. Data analysis was performed using the Statistical Package R with nonparametric methods of significance for all tests set at p < 0.05. Of the 45 female and 110 male patients, the median age was 64. Seventy-three percent had cT3 disease and there was a mean tumour distance from the anal verge of 7 cm. Time to surgical resection following radiotherapy ranged from 4 to 162 days with a median of 50 days, with a complete pathological response seen in 21% of patients. Patients exhibiting a favourable pathological response had smaller median pre- and postradiotherapy tumour size and had a greater change in tumour size following treatment (p < 0.01). Patients who received the majority of their radiotherapy fractions after 12:00 pm were more likely to show a complete or moderate pathological response (p = 0.035) and improved nodal downstaging. There were also more favourable responses amongst patients with longer time to surgical resection postradiotherapy (p < 0.004), although no relationship was seen between response and tumour distance from the anal verge. Females were less likely to exhibit several of the above responses. Neoadjuvant radiotherapy for locally advanced rectal cancer performed later in the day coupled with a longer time period to surgical resection may improve pathological tumour response rates and nodal downstaging. A prospective study in chronomodulated radiotherapy in this disease is warranted.
authors.affiliation: a The Canberra Hospital , Department of Radiation Oncology , Garran , Australian Capital Territory , Australia.|d University of Notre Dame Australia, School of Medicine , Darlinghurst , New South Wales , Australia.
authors.forename: Tim
authors.initials: T
authors.lastname: Squire
authors.affiliation: a The Canberra Hospital , Department of Radiation Oncology , Garran , Australian Capital Territory , Australia.|e University of Adelaide, School of Medical Sciences , Adelaide , South Australia , Australia.
authors.forename: Grant
authors.initials: G
authors.lastname: Buchanan
authors.affiliation: b The Canberra Hospital , Department of Surgery , Garran , Australian Capital Territory , Australia.|f Australian National University, College of Medicine, Biology and Environment , Canberra , Australian Capital Territory , Australia.
authors.forename: David
authors.initials: D
authors.lastname: Rangiah
authors.affiliation: b The Canberra Hospital , Department of Surgery , Garran , Australian Capital Territory , Australia.|f Australian National University, College of Medicine, Biology and Environment , Canberra , Australian Capital Territory , Australia.
authors.forename: Ian
authors.initials: I
authors.lastname: Davis
authors.affiliation: c The Canberra Hospital , Department of Medical Oncology , Garran , Australian Capital Territory , Australia.|f Australian National University, College of Medicine, Biology and Environment , Canberra , Australian Capital Territory , Australia.
authors.forename: Desmond
authors.initials: D
authors.lastname: Yip
authors.affiliation: c The Canberra Hospital , Department of Medical Oncology , Garran , Australian Capital Territory , Australia.|f Australian National University, College of Medicine, Biology and Environment , Canberra , Australian Capital Territory , Australia.
authors.forename: Yu Jo
authors.initials: YJ
authors.lastname: Chua
authors.affiliation: g Hampton University Proton Therapy Institute , Hampton , Virginia , USA.|h University of Virginia School of Medicine , Department of Radiation Oncology , Charlottesville , Virginia , USA.
authors.forename: Tyvin
authors.initials: T
authors.lastname: Rich
authors.affiliation: a The Canberra Hospital , Department of Radiation Oncology , Garran , Australian Capital Territory , Australia.|f Australian National University, College of Medicine, Biology and Environment , Canberra , Australian Capital Territory , Australia.
authors.forename: Hany
authors.initials: H
authors.lastname: Elsaleh
mesh_terms: D000230:Adenocarcinoma / Q000532:radiotherapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002940:Circadian Rhythm / Q000502:physiology*; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D012004:Rectal Neoplasms / Q000473:pathology / Q000532:radiotherapy* / Q000628:therapy; D012007:Rectum / Q000187:drug effects / Q000473:pathology*; D012189:Retrospective Studies
chemical_list: D005472:Fluorouracil
keywords: chemotherapy; chronomodulated therapy; pathological response. radiotherapy; rectal cancer; surgical resection; treatment time