title: Prostate cancer treated with brachytherapy; an exploratory study of dose-dependent biomarkers and quality of life.
abstract: BACKGROUND
  Low-dose-rate permanent prostate brachytherapy (PPB) is an attractive treatment option for patients with localised prostate cancer with excellent outcomes. As standard CT-based post-implant dosimetry often correlates poorly with late treatment-related toxicity, this exploratory (proof of concept) study was conducted to investigate correlations between radiation - induced DNA damage biomarker levels, and acute and late bowel, urinary, and sexual toxicity.
  
  
  METHODS
  Twelve patients treated with125I PPB monotherapy (145Gy) for prostate cancer were included in this prospective study. Post-implant CT based dosimetry assessed the minimum dose encompassing 90% (D90%) of the whole prostate volume (global), sub-regions of the prostate (12 sectors) and the near maximum doses (D0.1cc, D2cc) for the rectum and bladder. Six blood samples were collected from each patient; pre-treatment, 1 h (h), 4 h, 24 h post-implant, at 4 weeks (w) and at 3 months (m). DNA double strand breaks were investigated by staining the blood samples with immunofluorescence antibodies to γH2AX and 53BP1 proteins (γH2AX/53BP1). Patient self-scored quality of life from the Expanded Prostate Cancer Index Composite (EPIC) were obtained at baseline, 1 m, 3 m, 6 m, 9 m, 1 year (y), 2y and 3y post-treatment. Spearman's correlation coefficients were used to evaluate correlations between temporal changes in γH2AX/53BP1, dose and toxicity.
  
  
  RESULTS
  The minimum follow up was 2 years. Population mean prostate D90%was 144.6 ± 12.1 Gy and rectal near maximum dose D0.1cc= 153.0 ± 30.8 Gy and D2cc= 62.7 ± 12.1 Gy and for the bladder D0.1cc= 123.1 ± 27.0 Gy and D2cc= 70.9 ± 11.9 Gy. Changes in EPIC scores from baseline showed high positive correlation between acute toxicity and late toxicity for both urinary and bowel symptoms. Increased production of γH2AX/53BP1 at 24 h relative to baseline positively correlated with late bowel symptoms. Overall, no correlations were observed between dose metrics (prostate global or sector doses) and γH2AX/53BP1 foci counts.
  
  
  CONCLUSIONS
  Our results show that a prompt increase in γH2AX/53BP1foci at 24 h post-implant relative to baseline may be a useful measure to assess elevated risk of late RT - related toxicities for PPB patients. A subsequent investigation recruiting a larger cohort of patients is warranted to verify our findings.
authors.affiliation: Centre of Cancer Research and Cell Biology, Queen's University Belfast, BT7 1NN, Belfast, UK. s.osman@qub.ac.uk.
authors.forename: Sarah O S
authors.initials: SO
authors.lastname: Osman
authors.affiliation: Centre of Cancer Research and Cell Biology, Queen's University Belfast, BT7 1NN, Belfast, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Horn
authors.affiliation: Centre of Cancer Research and Cell Biology, Queen's University Belfast, BT7 1NN, Belfast, UK.
authors.forename: Darren
authors.initials: D
authors.lastname: Brady
authors.affiliation: Centre of Cancer Research and Cell Biology, Queen's University Belfast, BT7 1NN, Belfast, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: McMahon
authors.affiliation: Radiotherapy Physics, Northern Ireland Cancer Centre, Belfast Health and Social Care Trust, Belfast, UK.
authors.forename: Ahamed B Mohamed
authors.initials: AB
authors.lastname: Yoosuf
authors.affiliation: Clinical Oncology, Northern Ireland Cancer Centre, Belfast Health and Social Care Trust, Belfast, UK.
authors.forename: Darren
authors.initials: D
authors.lastname: Mitchell
authors.affiliation: Radiotherapy Physics, Northern Ireland Cancer Centre, Belfast Health and Social Care Trust, Belfast, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Crowther
authors.affiliation: Centre of Cancer Research and Cell Biology, Queen's University Belfast, BT7 1NN, Belfast, UK.
authors.forename: Ciara A
authors.initials: CA
authors.lastname: Lyons
authors.affiliation: Centre of Cancer Research and Cell Biology, Queen's University Belfast, BT7 1NN, Belfast, UK.|Radiotherapy Physics, Northern Ireland Cancer Centre, Belfast Health and Social Care Trust, Belfast, UK.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Hounsell
authors.affiliation: Centre of Cancer Research and Cell Biology, Queen's University Belfast, BT7 1NN, Belfast, UK.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Prise
authors.affiliation: Centre of Cancer Research and Cell Biology, Queen's University Belfast, BT7 1NN, Belfast, UK.|Radiotherapy Physics, Northern Ireland Cancer Centre, Belfast Health and Social Care Trust, Belfast, UK.
authors.forename: Conor K
authors.initials: CK
authors.lastname: McGarry
authors.affiliation: Centre of Cancer Research and Cell Biology, Queen's University Belfast, BT7 1NN, Belfast, UK.|Clinical Oncology, Northern Ireland Cancer Centre, Belfast Health and Social Care Trust, Belfast, UK.
authors.forename: Suneil
authors.initials: S
authors.lastname: Jain
authors.affiliation: Centre of Cancer Research and Cell Biology, Queen's University Belfast, BT7 1NN, Belfast, UK.|Clinical Oncology, Northern Ireland Cancer Centre, Belfast Health and Social Care Trust, Belfast, UK.
authors.forename: Joe M
authors.initials: JM
authors.lastname: O'Sullivan
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood*; D001918:Brachytherapy; D005500:Follow-Up Studies; D006657:Histones / Q000097:blood*; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D011379:Prognosis; D011446:Prospective Studies; D011471:Prostatic Neoplasms / Q000097:blood* / Q000473:pathology / Q000532:radiotherapy; D011788:Quality of Life; D011879:Radiotherapy Dosage; D015996:Survival Rate; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000097:blood*
chemical_list: D015415:Biomarkers; C468783:H2AX protein, human; D006657:Histones; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1
keywords: DNA damage biomarkers (γH2AX and 53BP1); EPIC; Permanent prostate brachytherapy; Sector analysis