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dc.contributor.authorBrand, DH
dc.contributor.authorBrüningk, SC
dc.contributor.authorWilkins, A
dc.contributor.authorNaismith, O
dc.contributor.authorGao, A
dc.contributor.authorSyndikus, I
dc.contributor.authorDearnaley, DP
dc.contributor.authorvan As, N
dc.contributor.authorHall, E
dc.contributor.authorGulliford, S
dc.contributor.authorTree, AC
dc.contributor.authorCHHiP Trial Management Group,
dc.identifier.citationInternational Journal of Radiation: Oncology - Biology - Physics,
dc.description.abstractPURPOSE: Moderately hypofractionated external beam intensity modulated radiation therapy (RT) for prostate cancer is now standard-of-care. Normal tissue toxicity responses to fraction size alteration are nonlinear: the linear-quadratic model is a widely used framework accounting for this, through the α/β ratio. Few α/β ratio estimates exist for human late genitourinary endpoints; here we provide estimates derived from a hypofractionation trial. METHODS AND MATERIALS: The CHHiP trial randomized 3216 men with localized prostate cancer 1:1:1 between conventionally fractionated intensity modulated RT (74 Gy/37 fractions (Fr)) and 2 moderately hypofractionated regimens (60 Gy/20 Fr and 57 Gy/19 Fr). RT plan and suitable follow-up assessment was available for 2206 men. Three prospectively assessed clinician-reported toxicity scales were amalgamated for common genitourinary endpoints: dysuria, hematuria, incontinence, reduced flow/stricture, and urine frequency. Per endpoint, only patients with baseline zero toxicity were included. Three models for endpoint grade ≥1 (G1+) and G2+ toxicity were fitted: Lyman Kutcher-Burman (LKB) without equivalent dose in 2 Gy/Fr (EQD2) correction [LKB-NoEQD2]; LKB with EQD2-correction [LKB-EQD2]; LKB-EQD2 with dose-modifying-factor (DMF) inclusion [LKB-EQD2-DMF]. DMFs were age, diabetes, hypertension, pelvic surgery, prior transurethral resection of prostate (TURP), overall treatment time and acute genitourinary toxicity (G2+). Bootstrapping generated 95% confidence intervals and unbiased performance estimates. Models were compared by likelihood ratio test. RESULTS: The LKB-EQD2 model significantly improved performance over LKB-NoEQD2 for just 3 endpoints: dysuria G1+ (α/β = 2.0 Gy; 95% confidence interval [CI], 1.2-3.2 Gy), hematuria G1+ (α/β = 0.9 Gy; 95% CI, 0.1-2.2 Gy) and hematuria G2+ (α/β = 0.6 Gy; 95% CI, 0.1-1.7 Gy). For these 3 endpoints, further incorporation of 2 DMFs improved on LKB-EQD2: acute genitourinary toxicity and prior TURP (hematuria G1+ only), but α/β ratio estimates remained stable. CONCLUSIONS: Inclusion of EQD2-correction significantly improved model fitting for dysuria and hematuria endpoints, where fitted α/β ratio estimates were low: 0.6 to 2 Gy. This suggests therapeutic gain for clinician-reported GU toxicity, through hypofractionation, might be lower than expected by typical late α/β ratio assumptions of 3 to 5 Gy.
dc.relation.ispartofInternational Journal of Radiation: Oncology - Biology - Physics
dc.titleThe Fraction Size Sensitivity of Late Genitourinary Toxicity: Analysis of Alpha/Beta (α/β) Ratios in the CHHiP Trial.
dc.typeJournal Article
rioxxterms.typeJournal Article/Review
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Trials & Statistics Unit
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Stereotactic and Precision Body Radiotherapy
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/17/18 Starting Cohort
icr.researchteamClin Trials & Stats Unit
icr.researchteamStereotactic Radiother
dc.contributor.icrauthorBrand, Douglas
dc.contributor.icrauthorCorbett, Anna
dc.contributor.icrauthorGao, Annie
dc.contributor.icrauthorDearnaley, David
dc.contributor.icrauthorHall, Emma
icr.provenanceDeposited by Dr Doug Brand on 2022-08-18. Deposit type is initial. No. of files: 1. Files: MANUSCRIPT_FINAL_Blinded_rv1_NoMarkup.docx
icr.provenanceDeposited by Mr Arek Surman (impersonating Dr Doug Brand) on 2022-08-18. Deposit type is subsequent. No. of files: 2. Files: MANUSCRIPT_FINAL_Blinded_rv1_NoMarkup (1).pdf; Supplement_rv1.pdf

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