Estimates of Alpha/Beta (alpha/beta) Ratios for Individual Late Rectal Toxicity Endpoints: An Analysis of the CHHiP Trial

Purpose: Changes in fraction size of external beam radiation therapy exert nonlinear effects on subsequent toxicity. Commonly described by the linear-quadratic model, fraction size sensitivity of normal tissues is expressed by the α/β ratio. We sought to study individual α/β ratios for different late rectal effects after prostate external beam radiation therapy. Methods and Materials: The CHHiP trial (ISRCTN97182923) randomized men with nonmetastatic prostate cancer 1:1:1 to 74 Gy/37 fractions (Fr), 60 Gy/20 Fr, or 57 Gy/19 Fr. Patients in the study had full dosimetric data and zero baseline toxicity. Toxicity scales were amalgamated to 6 bowel endpoints: bleeding, diarrhea, pain, proctitis, sphincter control, and stricture. Lyman-Kutcher-Burman models with or without equivalent dose in 2 Gy/Fr correction were log-likelihood fitted by endpoint, estimating α/β ratios. The α/β ratio estimate sensitivity was assessed using sequential inclusion of dose modifying factors (DMFs): age, diabetes, hypertension, inflammatory bowel or diverticular disease (IBD/diverticular), and hemorrhoids. 95% confidence intervals (CIs) were bootstrapped. Likelihood ratio testing of 632 estimator log-likelihoods compared the 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) to sphincter control (G1 + α/β = 3.1 Gy; 95% CI, 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 = .00041) and proctitis G1+ (P = .00046). However, the α/β ratios were similar in these no-DMF versus 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 adverse effects of rectal radiation therapy. When comparing dose-fractionation schedules, we suggest using late a rectal α/β ratio ≤ 3 Gy

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

Evaluation of erectile potency and radiation dose to the penile bulb using image guided radiotherapy in the CHHiP trial

Background and purpose: The penile bulb (PB) dose may be critical in development of post prostate radiotherapy erectile dysfunction (ED). This study aimed to generate PB dose constraints based on dose-volume histograms (DVHs) in patients treated with prostate radiotherapy, and to identify clinical and dosimetric parameters that predict the risk of ED post prostate radiotherapy. / Materials and methods: Penile bulb DVHs were generated for 276 patients treated within the randomised IGRT substudy of the multicentre randomised trial, CHHiP. Incidence of ED in relation to dose and randomised IGRT groups were evaluated using Wilcoxon rank sum, Chi-squared test and atlases of complication incidence. Youden index was used to find dose-volume constraints that discriminated for ED. Multivariate analysis (MVA) of effect of dosimetry, clinical and patient-related variables was performed. / Results: Reduced treatment margins using IGRT (IGRT-R) produced significantly reduced mean PB dose compared with standard margins (IGRT-S) (median: 25 Gy (IGRT-S) versus 11 Gy (IGRT-R); p < 0.0001). Significant difference in both mean (median: 23 Gy (ED) vs. 18 Gy (no ED); p = 0.011) and maximum (median: 59 Gy (ED) vs. 52 Gy (no ED); p = 0.018) PB doses between those with and without clinician reported ED were identified. Mean PB dose cut-point for ED was derived at around 20 Gy. On MVA, PB mean dose and age predicted for impotence. / Conclusion: PB dose appears predictive of post-radiotherapy ED with calculated threshold mean dose of around 20 Gy, substantially lower than published recommendations. IGRT-R enables favourable PB dosimetry and can be recommended provided prostate coverage is not compromised

Evaluation of erectile potency and radiation dose to the penile bulb using image guided radiotherapy in the CHHiP trial

Background and purpose The penile bulb (PB) dose may be critical in development of post prostate radiotherapy erectile dysfunction (ED). This study aimed to generate PB dose constraints based on dose-volume histograms (DVHs) in patients treated with prostate radiotherapy, and to identify clinical and dosimetric parameters that predict the risk of ED post prostate radiotherapy. Materials and methods Penile bulb DVHs were generated for 276 patients treated within the randomised IGRT substudy of the multicentre randomised trial, CHHiP. Incidence of ED in relation to dose and randomised IGRT groups were evaluated using Wilcoxon rank sum, Chi-squared test and atlases of complication incidence. Youden index was used to find dose-volume constraints that discriminated for ED. Multivariate analysis (MVA) of effect of dosimetry, clinical and patient-related variables was performed. Results Reduced treatment margins using IGRT (IGRT-R) produced significantly reduced mean PB dose compared with standard margins (IGRT-S) (median: 25 Gy (IGRT-S) versus 11 Gy (IGRT-R); p < 0.0001). Significant difference in both mean (median: 23 Gy (ED) vs. 18 Gy (no ED); p = 0.011) and maximum (median: 59 Gy (ED) vs. 52 Gy (no ED); p = 0.018) PB doses between those with and without clinician reported ED were identified. Mean PB dose cut-point for ED was derived at around 20 Gy. On MVA, PB mean dose and age predicted for impotence. Conclusion PB dose appears predictive of post-radiotherapy ED with calculated threshold mean dose of around 20 Gy, substantially lower than published recommendations. IGRT-R enables favourable PB dosimetry and can be recommended provided prostate coverage is not compromised

Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial

SummaryBackgroundProstate cancer might have high radiation-fraction sensitivity that would give a therapeutic advantage to hypofractionated treatment. We present a pre-planned analysis of the efficacy and side-effects of a randomised trial comparing conventional and hypofractionated radiotherapy after 5 years follow-up.MethodsCHHiP is a randomised, phase 3, non-inferiority trial that recruited men with localised prostate cancer (pT1b–T3aN0M0). Patients were randomly assigned (1:1:1) to conventional (74 Gy delivered in 37 fractions over 7·4 weeks) or one of two hypofractionated schedules (60 Gy in 20 fractions over 4 weeks or 57 Gy in 19 fractions over 3·8 weeks) all delivered with intensity-modulated techniques. Most patients were given radiotherapy with 3–6 months of neoadjuvant and concurrent androgen suppression. Randomisation was by computer-generated random permuted blocks, stratified by National Comprehensive Cancer Network (NCCN) risk group and radiotherapy treatment centre, and treatment allocation was not masked. The primary endpoint was time to biochemical or clinical failure; the critical hazard ratio (HR) for non-inferiority was 1·208. Analysis was by intention to treat. Long-term follow-up continues. The CHHiP trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN97182923.FindingsBetween Oct 18, 2002, and June 17, 2011, 3216 men were enrolled from 71 centres and randomly assigned (74 Gy group, 1065 patients; 60 Gy group, 1074 patients; 57 Gy group, 1077 patients). Median follow-up was 62·4 months (IQR 53·9–77·0). The proportion of patients who were biochemical or clinical failure free at 5 years was 88·3% (95% CI 86·0–90·2) in the 74 Gy group, 90·6% (88·5–92·3) in the 60 Gy group, and 85·9% (83·4–88·0) in the 57 Gy group. 60 Gy was non-inferior to 74 Gy (HR 0·84 [90% CI 0·68–1·03], pNI=0·0018) but non-inferiority could not be claimed for 57 Gy compared with 74 Gy (HR 1·20 [0·99–1·46], pNI=0·48). Long-term side-effects were similar in the hypofractionated groups compared with the conventional group. There were no significant differences in either the proportion or cumulative incidence of side-effects 5 years after treatment using three clinician-reported as well as patient-reported outcome measures. The estimated cumulative 5 year incidence of Radiation Therapy Oncology Group (RTOG) grade 2 or worse bowel and bladder adverse events was 13·7% (111 events) and 9·1% (66 events) in the 74 Gy group, 11·9% (105 events) and 11·7% (88 events) in the 60 Gy group, 11·3% (95 events) and 6·6% (57 events) in the 57 Gy group, respectively. No treatment-related deaths were reported.InterpretationHypofractionated radiotherapy using 60 Gy in 20 fractions is non-inferior to conventional fractionation using 74 Gy in 37 fractions and is recommended as a new standard of care for external-beam radiotherapy of localised prostate cancer.FundingCancer Research UK, Department of Health, and the National Institute for Health Research Cancer Research Network

A randomised assessment of image guided radiotherapy within a phase 3 trial of conventional or hypofractionated high dose intensity modulated radiotherapy for prostate cancer.

Background and purpose Image-guided radiotherapy (IGRT) improves treatment set-up accuracy and provides the opportunity to reduce target volume margins. We introduced IGRT methods using standard (IGRT-S) or reduced (IGRT-R) margins in a randomised phase 2 substudy within CHHiP trial. We present a pre-planned analysis of the impact of IGRT on dosimetry and acute/late pelvic side effects using gastrointestinal and genitourinary clinician and patient-reported outcomes (PRO) and evaluate efficacy.Materials and methods CHHiP is a randomised phase 3, non-inferiority trial for men with localised prostate cancer. 3216 patients were randomly assigned to conventional (74 Gy in 2 Gy/fraction (f) daily) or moderate hypofractionation (60 or 57 Gy in 3 Gy/f daily) between October 2002 and June 2011. The IGRT substudy included a second randomisation assigning to no-IGRT, IGRT-S (standard CTV-PTV margins), or IGRT-R (reduced CTV-PTV margins). Primary substudy endpoint was late RTOG bowel and urinary toxicity at 2 years post-radiotherapy.Results Between June 2010 to July 2011, 293 men were recruited from 16 centres. Median follow-up is 56.9(IQR 54.3-60.9) months. Rectal and bladder dose-volume and surface percentages were significantly lower in IGRT-R compared to IGRT-S group; (p < 0.0001). Cumulative proportion with RTOG grade ≥ 2 toxicity reported to 2 years for bowel was 8.3(95% CI 3.2-20.7)%, 8.3(4.7-14.6)% and 5.8(2.6-12.4)% and for urinary 8.4(3.2-20.8)%, 4.6(2.1-9.9)% and 3.9(1.5-9.9)% in no IGRT, IGRT-S and IGRT-R groups respectively. In an exploratory analysis, treatment efficacy appeared similar in all three groups.Conclusion Introduction of IGRT was feasible in a national randomised trial and IGRT-R produced dosimetric benefits. Overall side effect profiles were acceptable in all groups but lowest with IGRT and reduced margins.Isrctn 97182923

Fragmentation of single-particle strength around the doubly-magic nucleus 132Sn and the position of the 0f5/2 proton-hole state in 131In

Spectroscopic factors of neutron-hole and proton-hole states in 131Sn and 131In, respectively, were measured using one-nucleon removal reactions from doubly magic 132Sn at relativistic energies. For 131In, a 2910(50)-keV γ ray was observed for the first time and tentatively assigned to a decay from a 5=2− state at 3275(50) keV to the known 1=2− level at 365 keV. The spectroscopic factors determined for this new excited state and three other single-hole states provide first evidence for a strong fragmentation of singlehole strength in 131Sn and 131In. The experimental results are compared to theoretical calculations based on the relativistic particle-vibration couplin

Quasi-free neutron and proton knockout reactions from light nuclei in a wide neutron-to-proton asymmetry range

The quasi-free scattering reactions 11C(p,2p) and 10,11,12C(p,pn) have been studied in inverse kinematics at beam energies of 300–400 MeV/u at the R3B-LAND setup. The outgoing proton-proton and proton-neutron pairs were detected in coincidence with the reaction fragments in kinematically complete measurements. The efficiency to detect these pairs has been obtained from GEANT4 simulations which were tested using the 12C(p,2p) and 12C(p,pn) reactions. Experimental cross sections and momentum distributions have been obtained and compared to DWIA calculations based on eikonal theory. The new results reported here are combined with previously published cross sections for quasi-free scattering from oxygen and nitrogen isotopes and together they enable a systematic study of the reduction of single-particle strength compared to predictions of the shell model over a wide neutron-to-proton asymmetry range. The combined reduction factors show a weak or no dependence on isospin asymmetry, in contrast to the strong dependency reported in nucleon-removal reactions induced by nuclear targets at lower energies. However, the reduction factors for (p,2p) are found to be 'significantly smaller than for (p,pn) reactions for all investigated nuclei.German Federal Ministry of Education and Research | Ref. BMBF 05P2015RDFN1German Federal Ministry of Education and Research | Ref. 05P15WOFNAEuropean Commission | Ref. FP7, ENSAR, n. 262010Comisión Interministerial de Ciencia y Tecnología (CICYT) | Ref. FPA2012-32443Comisión Interministerial de Ciencia y Tecnología (CICYT) | Ref. FPA2015-64969-07387Comisión Interministerial de Ciencia y Tecnología (CICYT) | Ref. FPA2015-69640-C2-1-PSwedish Research Council | Ref. 621-2011-5324National Science Foundation, EE. UU. | Ref. n. 1415656Department of Energy, EE. UU. | Ref. n. DE-FG02-08ER41533Fundação para a Ciência e a Tecnologia | Ref. PTDC/FIS/ 103902/200