Validation of prediction models for radiation-induced late rectal bleeding: Evidence from a large pooled population of prostate cancer patients.

PURPOSE: To validate published models for the risk estimate of grade ≥ 1 (G1+), grade ≥ 2 (G2+) and grade = 3 (G3) late rectal bleeding (LRB) after radical radiotherapy for prostate cancer in a large pooled population from three prospective trials. MATERIALS AND METHODS: The external validation population included patients from Europe, and Oceanian centres enrolled between 2003 and 2014. Patients received 3DCRT or IMRT at doses between 66-80 Gy. IMRT was administered with conventional or hypofractionated schemes (2.35-2.65 Gy/fr). LRB was prospectively scored using patient-reported questionnaires (LENT/SOMA scale) with a 3-year follow-up. All Normal Tissue Complication Probability (NTCP) models published until 2021 based on the Equivalent Uniform Dose (EUD) from the rectal Dose Volume Histogram (DVH) were considered for validation. Model performance in validation was evaluated through calibration and discrimination. RESULTS: Sixteen NTCP models were tested on data from 1633 patients. G1+ LRB was scored in 465 patients (28.5%), G2+ in 255 patients (15.6%) and G3 in 112 patients (6.8%). The best performances for G2+ and G3 LRB highlighted the importance of the medium-high doses to the rectum (volume parameters n = 0.24 and n = 0.18, respectively). Good performance was seen for models of severe LRB. Moreover, a multivariate model with two clinical factors found the best calibration slope. CONCLUSION: Five published NTCP models developed on non-contemporary cohorts were able to predict a relative increase in the toxicity response in a more recent validation population. Compared to QUANTEC findings, dosimetric results pointed toward mid-high doses of rectal DVH. The external validation cohort confirmed abdominal surgery and cardiovascular diseases as risk factors.

Predicting Late Fecal Incontinence Risk After Radiation Therapy for Prostate Cancer: New Insights From External Independent Validation.

PURPOSE: This study aimed to validate a previously published predictive model for late fecal incontinence (FI) in a contemporary population of prostate cancer patients treated with radical radiation therapy. METHODS AND MATERIALS: The validation included patients treated with intensity-modulated radiation therapy (IMRT) (2010-2014). Prescribed dose range was 65-80 Gy, including conventional and moderate hypo-fractionated treatments. Rectal toxicity was scored using LENT/SOMA, a minimum 2-year follow up was considered. We chose to validate the model published by Rancati et al for predicting chronic FI, developed on a 3-dimensional conformal radiation therapy (3DCRT) population. It considered a longitudinal endpoint defined as the average toxicity grade during the follow up. This continuous endpoint was dichotomized using a cut-off value of mean FI grade >1. The model included mean rectal dose (Dmean), previous diseases of the colon (COLO) and previous abdominal surgery (SURG). Doses were corrected to 2 Gy/fraction using the linear-quadratic model and applying alpha/beta ratio = 4.8 Gy. RESULTS: 228 patients constituted the validation population. A mean FI grade >1 was scored in 25 patients (11%). Logistic regression confirmed risk factors reported in the literature, with similar odds ratios (ORs) for Dmean (1.04 ± 0.03 vs 1.06 ± 0.04) and SURG (1.9 ± 1.7 vs 1.6 ± 1.45); COLO was not confirmed. Consequently, the predictive models including Dmean/Dmean + SURG were evaluated using calibration plots. Both showed a clear discriminative trend, but the absolute observed toxicity rates were underestimated (ie, absolute predicted rates were always lower than corresponding absolute observed rates). This result was consistent with an unexpected effect of hypofractionation (OR = 2.20, conventional = 8.1% vs hypofractionated = 17.4%) beyond the standard correction using linear-quadratic model. Nevertheless, the FI rate in the conventionally treated group was almost double the rate observed in the previously studied cohort (4.3% vs 8.1%). CONCLUSIONS: The study confirms previously published results indicating that abdominal surgery and rectal mean dose are risk factors for late FI. Calibration plots highlight a possible role of hypofractionation beyond linear-quadratic correction.

Multi-variable models predicting specific patient-reported acute urinary symptoms after radiotherapy for prostate cancer: Results of a cohort study.

PURPOSE: A prospective trial started in 2010, aiming at developing models for urinary toxicity and erectile dysfunction after radiotherapy for prostate cancer. This analysis is finalised at highlighting correlations between clinical/dosimetric factors and acute urinary specific symptoms, as measured by single questions of the International Prostate Symptom Score (IPSS). MATERIALS/METHODS: IPSS was prospectively collected before and at the end of radiotherapy; absolute weekly bladder dose-surface histograms (DSHw) were chosen as dosimetric descriptors. Relevant clinical factors were prospectively gathered. Backward feature selection was used to identify variables to be included in logistic models for moderate-severe (scores⩾4) urinary symptoms. RESULTS: Complete data of 262 patients (120 conventional fractionation, 142 hypofractionation) were available. Smoking was a strong predictor for feeling of incomplete emptying, frequency, intermittency, urgency and straining; neoadjuvant hormonal therapy and use of antihypertensive drugs were risk factors for intermittency and weak stream, respectively. The baseline score was a major predictor for all symptoms with the exception of intermittency. DSHw were correlated to increased risk of frequency, intermittency, urgency and nocturia. Most models showed moderate-high discrimination (AUC≈0.60-0.79). CONCLUSIONS: Smoking and other clinical and dosimetric factors predict for specific moderate-severe acute urinary symptoms; baseline condition heavily modulated the risk in most endpoints.

Relationships between bladder dose-volume/surface histograms and acute urinary toxicity after radiotherapy for prostate cancer.

BACKGROUND AND PURPOSE: DUE01 is an observational study aimed at developing predictive models of genito-urinary toxicity of patients treated for prostate cancer with conventional (1.8-2Gy/fr, CONV) or moderate hypo-fractionation (2.35-2.7Gy/fr, HYPO). The current analysis focused on the relationship between bladder DVH/DSH and the risk of International Prostate Symptoms Score (IPSS)⩾15/20 at the end of radiotherapy. MATERIALS AND METHODS: Planning and relevant clinical parameters were prospectively collected, including DVH/DSH, LQ-corrected (DVHc/DSHc) and weekly (DVHw/DSHw) histograms. Best parameters were selected by the differences between patients with/without IPSS⩾15/20 at the end of radiotherapy. Logistic uni- and backward multi-variable (MVA) analyses were performed. RESULTS: Data of 247 patients were available (CONV: 116, HYPO: 131). Absolute DVHw/DSHw and DVHc/DSHc predicted the risk of IPSS⩾15 at the end of radiotherapy (n=77/247); an MVA model including baseline IPSS, anti-hypertensive, T stage, the absolute surface receiving ⩾8.5Gy/week and ⩾12.5Gy/week was developed (AUC=0.78, 95% CI: 0.72-0.83). Similar AUC values were found if replacing DSHw with DVHw/DVHc/DSHc parameters. The impact of dose-volume/surface parameters remained when excluding patients with baseline IPSS⩾15 and in HYPO. IPSS⩾20 at the end of radiotherapy (n=27/247) was mainly correlated to baseline IPSS and T stage. CONCLUSIONS: Although the baseline IPSS was the main predictor, constraining v8.5w<56cc and v12.5w<5cc may significantly reduce acute GU toxicity.

Sub-Doppler millimetre-wave spectroscopy of DBS and HBS: accurate values of nuclear electric and magnetic hyperfine structure constants.

The unstable thioborine molecule and its deuterated variant have been produced by a high-temperature reaction between hydrogen sulfide and crystalline boron at 1100 degrees C in a flow system. Five rotational transitions from J = 2 <-- 1, to J = 6 <-- 5 have been recorded with sub-Doppler resolution for the vibrational ground state of H10/11BS and D10/11BS using the Lamb-dip technique. The hyperfine structure due to the electric quadrupole interaction of deuterium nucleus has been resolved yielding the first experimental determination of the deuterium quadrupole coupling constant in thioborine, which is 0.1403(75) MHz in D11 BS and 0.1360(38) MHz in D10BS. Fairly accurate values of 10/11B spin-rotation coupling constants and of the hydrogen-boron spin-spin coupling constants have also been determined. Additionally, the hyperfine structure of the rotational lines for the nu2 = 1 excited state has been investigated, thus obtaining information on the asymmetry of the electric field gradient at the B nucleus in the bending state.