Derivation of dose/volume constraints for the anorectum from clinician and patient-reported outcomes in the CHHiP trial of radiotherapy fractionation.

BACKGROUND:The CHHiP trial randomised 3216 men with localised prostate cancer (1:1:1) to three radiotherapy fractionation schedules: 74Gy/37 fractions (f) over 7.4 weeks, 60Gy/20f/4 weeks and 57Gy/19f/3.8 weeks. Literature-based dose constraints were applied with arithmetic adjustment for the hypofractionated arms. This study aimed to derive anorectal dose constraints using prospectively-collected clinician-reported outcomes (CRO) and patient-reported outcomes (PRO) and to assess the added predictive value of spatial dose metrics. METHODS:A case-control study design was used, seven CRO and five PRO bowel symptoms were evaluated. Cases experienced a moderate or worse symptom 1-5 years post-radiotherapy, and did not have the symptom pre-radiotherapy. Controls did not experience the symptom at baseline, or between 1-5 years post-radiotherapy. The anorectum was re-contoured from the anal verge to the recto-sigmoid junction; dose/volume parameters were extracted. Univariate logistic regression, atlases of complication indices and bootstrapped receiver-operating-characteristic (ROC) analysis (1000 replicates, balanced outcomes) were used to derive dose constraints for the whole cohort (hypofractionated schedules were converted to 2Gy equivalent schedules using α/β=3Gy) and separate hypofractionated/conventional fractionation cohorts. Only areas under the curve (AUC) with 95% confidence interval lower limits >0.5 were considered statistically significant. Any constraint derived in <95-99% of bootstraps was excluded. RESULTS:Statistically significant dose constraints were derived for CRO, but not PRO. Intermediate to high doses were important for rectal bleeding whereas intermediate doses were important for increased bowel frequency, faecal incontinence and rectal pain. Spatial dose metrics did not improve prediction of CRO or PRO. A new panel of dose constraints for hypofractionated schedules to 60Gy or 57Gy are V20Gy<85%, V30Gy<57%, V40Gy<38%, V50Gy<22% and V60Gy<0.01%. CONCLUSIONS:Dose constraints differed between symptoms, indicating potentially different pathogenesis of radiation-induced side effects. Derived dose constraints were stricter than those used in CHHiP and may reduce bowel symptoms post-radiotherapy

Gastrointestinal Toxicity Prediction Not Influenced by Rectal Contour or Dose-Volume Histogram Definition.

PURPOSE: Rectal dose delivered during prostate radiation therapy is associated with gastrointestinal toxicity. Treatment plans are commonly optimized using rectal dose-volume constraints, often whole-rectum relative-volumes (%). We investigated whether improved rectal contouring, use of absolute-volumes (cc), or rectal truncation might improve toxicity prediction. METHODS AND MATERIALS: Patients from the CHHiP trial (receiving 74 Gy/37 fractions [Fr] vs 60 Gy/20 Fr vs 57 Gy/19 Fr) were included if radiation therapy plans were available (2350/3216 patients), plus toxicity data for relevant analyses (2170/3216 patients). Whole solid rectum relative-volumes (%) dose-volume-histogram (DVH), as submitted by treating center (original contour), was assumed standard-of-care. Three investigational rectal DVHs were generated: (1) reviewed contour per CHHiP protocol; (2) original contour absolute volumes (cc); and (3) truncated original contour (2 versions; ±0 and ±2 cm from planning target volume [PTV]). Dose levels of interest (V30, 40, 50, 60, 70, 74 Gy) in 74 Gy arm were converted by equivalent-dose-in-2 Gy-Fr (EQD2α/β= 3 Gy) for 60 Gy/57 Gy arms. Bootstrapped logistic models predicting late toxicities (frequency G1+/G2+, bleeding G1+/G2+, proctitis G1+/G2+, sphincter control G1+, stricture/ulcer G1+) were compared by area-undercurve (AUC) between standard of care and the 3 investigational rectal definitions. RESULTS: The alternative dose/volume parameters were compared with the original relative-volume (%) DVH of the whole rectal contour, itself fitted as a weak predictor of toxicity (AUC range, 0.57-0.65 across the 8 toxicity measures). There were no significant differences in toxicity prediction for: (1) original versus reviewed rectal contours (AUCs, 0.57-0.66; P = .21-.98); (2) relative- versus absolute-volumes (AUCs, 0.56-0.63; P = .07-.91); and (3) whole-rectum versus truncation at PTV ± 2 cm (AUCs, 0.57-0.65; P = .05-.99) or PTV ± 0 cm (AUCs, 0.57-0.66; P = .27-.98). CONCLUSIONS: We used whole-rectum relative-volume DVH, submitted by the treating center, as the standard-of-care dosimetric predictor for rectal toxicity. There were no statistically significant differences in prediction performance when using central rectal contour review, with the use of absolute-volume dosimetry, or with rectal truncation relative to PTV. Whole-rectum relative-volumes were not improved upon for toxicity prediction and should remain standard-of-care

Genitourinary α/β Ratios in the CHHiP Trial the Fraction Size Sensitivity of Late Genitourinary Toxicity: Analysis of Alpha/Beta (α/β) Ratios in the CHHiP Trial

PURPOSE: Moderately hypofractionated external beam intensity-modulated radiotherapy (IMRT) for prostate cancer is now standard-of-care. Normal tissue toxicity responses to fraction size alteration are non-linear: 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 XXXXXX trial randomised 3216 men with localised prostate cancer 1:1:1 between conventionally fractionated IMRT (74Gy/37 fractions (Fr)) and two moderately hypofractionated regimens (60Gy/20Fr & 57Gy/19Fr). Radiotherapy 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, Haematuria, Incontinence, Reduced flow/Stricture, 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 2Gy/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 three endpoints: Dysuria G1+ (α/β=2.0 Gy, 95%CI 1.2-3.2Gy), Haematuria G1+ (α/β=0.9 Gy, 95%CI 0.1-2.2Gy) and Haematuria G2+ (α/β=0.6Gy, 95%CI 0.1-1.7Gy). For these three endpoints, further incorporation of two DMFs improved on LKB-EQD2: acute genitourinary toxicity and Prior TURP (Haematuria G1+ only), but α/β ratio estimates remained stable. CONCLUSIONS: Inclusion of EQD2-correction significantly improved model fitting for Dysuria and Haematuria endpoints, where fitted α/β ratio estimates were low: 0.6-2 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 3-5 Gy

Estimates of Alpha/Beta (α/β) Ratios for Individual Late Rectal Toxicity Endpoints: An Analysis of the CHHiP trial.

Purpose Changes in fraction size of external beam radiotherapy (EBRT) exert non-linear impacts on subsequent toxicity. Commonly described by the linear-quadratic model, fraction size sensitivity of normal tissues is expressed by the α/β ratio. Here we study individual α/β ratios for different late rectal side effects after prostate EBRT.Methods and materials The XXXXXXX trial (XX-REGISTRATION-NUMBER-XX) randomised men with non-metastatic prostate cancer 1:1:1 to 74Gy/37 fractions (Fr), 60Gy/20Fr or 57Gy/19Fr. Patients included had full dosimetric data and zero baseline toxicity. Toxicity scales were amalgamated to 6 bowel endpoints: bleeding, diarrhoea, pain, proctitis, sphincter control and stricture. Lyman-Kutcher-Burman models +/- equivalent dose in 2 Gy/fraction correction were log-likelihood fitted by endpoint, estimating α/β ratios. α/β ratio estimate sensitivity was assessed by sequential inclusion of dose modifying factors (DMFs): age, diabetes, hypertension, inflammatory bowel or diverticular disease (IBD/diverticular), and haemorrhoids. 95% confidence intervals (95% CIs) were bootstrapped. Likelihood ratio testing of 632 estimator log-likelihoods compared models.Results Late rectal α/β ratio estimates (without DMF) ranged from: bleeding G1+ α/β = 1.6 Gy (95% CI 0.9-2.5 Gy), up to sphincter control G1+ α/β = 3.1 Gy (1.4-9.1 Gy). Bowel pain modelled poorly (α/β 3.6 Gy, 95% CI 0.0 - 840 Gy). Inclusion of IBD/diverticular disease as a DMF significantly improved fits for stool frequency G2+ (p=0.00041) & proctitis G1+ (p=0.00046). However, the α/β ratios were similar in these no-DMF vs DMF models for both stool frequency G2+ (α/β 2.7 Gy vs 2.5 Gy) and proctitis G1+ (α/β 2.7 Gy vs 2.6 Gy). Frequency-weighted averaging of endpoint α/β ratios produced: G1+ α/β ratio=2.4 Gy; G2+ α/β ratio=2.3 Gy.Conclusions We estimated α/β ratios for several common late rectal radiotherapy side effects. When comparing dose-fractionation schedules we suggest using late rectal α/β ratio ≤ 3 Gy

The Fraction Size Sensitivity of Late Genitourinary Toxicity: Analysis of Alpha/Beta (α/β) Ratios in the CHHiP Trial

Purpose: 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.ISSN:0360-3016ISSN:1879-355