Breast cancer patient perspective on opportunities and challenges of a genetic test aimed to predict radio-induced side effects before treatment: Analysis of the Italian branch of the REQUITE project.

AIM: To explore breast cancer patient's perspective on future genetic testing for prediction of toxicity after breast radiotherapy (RT). MATERIALS AND METHODS: The study involved patient enrolled in the Italian branch of the REQUITE project conducted at the National Cancer Institute in Milan. Semi-structured interviews were conducted within one month from the end of radiotherapy treatment by two radiation oncologists and a radiotherapy technician previously trained by a clinical psychologist with experience in the oncology field. Semi-structured interviews are characterized by a set of pre-defined questions and developed ad hoc by researchers in Leicester within the REQUITE project. The interview questions investigated interest in undergoing the genetic test and expectations on its usefulness and disadvantages. RESULTS: Eighteen interviews were conducted and analysed. Forty-five initial codes were combined into nine themes which were then clustered in two main macro-areas (i) Opportunities and (ii) Challenges. Overall, all patients understand the aim of the genetic test and considered its intrinsic opportunity to make the physician more confident with the treatment. Regarding side effects, most of patients felt prepared to RT but not without fear. Many women considered important to have the largest and reliable information, also about negative experiences. Prevailing emotions were anxiety and fear but not connected to genetic test's result. CONCLUSIONS: A genetic test could be an opportunity because generate knowledge and give patients a dynamic role in the decision-making approach. Prediction of single patient radiosensitivity before RT could prompt suggestion to entail a more and more tailored radiation treatment in the era of personalized approach.

Patterns in ano-rectal dose maps and the risk of late toxicity after prostate IMRT.

Purpose: The aim of this work was to determine how the spatial pattern of dose in the ano-rectal wall is related to late gastro-intestinal toxicity for prostate cancer patients treated with mainly IMRT.Patients and methods: Patients from the DUE-01 multicentre study with patient-reported (prospective) follow-up and available dosimetric data were included. Conventionally fractionated patients received 74-80 Gy and hypofractionated patients received 65-75.2 Gy. A large majority of the patients were treated with intensity-modulated radiotherapy (IMRT). Dose-surface maps (DSMs) for the anal canal and rectum as a single structure, and for the anal canal and the rectum separately, were co-registered rigidly in two dimensions and, for the patients with and without toxicity, respectively, the mean value of the dose in each pixel was calculated. A pixel-wise t-test was used to highlight the anatomical areas where there was a significant difference between the 'mean dose maps' of each group. Univariate models were also fitted to a range of spatial parameters. The endpoints considered were a mean grade ≥1 late fecal incontinence and a maximum grade ≥2 late rectal bleeding.Results: Twenty-six out of 213 patients had fecal incontinence, while 21/225 patients had rectal bleeding. Incontinence was associated with a higher dose in the caudal region of the anal canal; the most relevant spatial parameter was the lateral extent of the low and medium isodoses (5-49 Gy in EQD2). Bleeding was associated with high isodoses reaching the posterior rectal wall. The spatial dose parameters with the highest AUC value (.69) were the lateral extent of the 60-70 Gy isodoses.Conclusions: To avoid fecal incontinence it is important to limit the portion of the anal canal irradiated. Our analysis confirms that rectal bleeding is a function of similar spatial dose parameters for patients treated with IMRT, compared to previous studies on patients treated with three-dimensional conformal radiotherapy.

Baseline status and dose to the penile bulb predict impotence 1 year after radiotherapy for prostate cancer.

AIM: To assess the predictors of the onset of impotence 1 year after radiotherapy for prostate cancer. PATIENTS AND METHODS: In a multi-centric prospective study, the International Index of Erectile Function (IIEF) questionnaire-based potency of 91 hormone-naïve and potent patients (IIEF1-5 > 11 before radiotherapy) was assessed. At the time of this analysis, information on potency 1 year after treatment was available for 62 of 91 patients (42 treated with hypofractionation: 2.35-2.65 Gy/fr, 70-74.2 Gy; 20 with conventional fractionation: 74-78 Gy). Prospectively collected individual information and Dmax/Dmean to the penile bulb were available; the corresponding 2 Gy-equivalent values (EQD2_max/EQD2_mean) were also considered. Predictors of 1­year impotency were assessed through uni- and multi-variable backward logistic regression: The best cut-off values discriminating between potent and impotent patients were assessed by ROC analyses. The discriminative power of the models and goodness-of-fit were measured by AUC analysis and the Hosmer-Lemeshow (H&L) test. RESULTS: At 1­year follow-up, 26 of 62 patients (42 %) became impotent. The only predictive variables were baseline IIEF1-5 values (best cut-off baseline IIEF1-5 ≥ 19), Dmax ≥ 68.5 Gy and EQD2_max ≥ 74.2 Gy. The risk of 1­year impotence may be predicted by a two-variable model including baseline IIEF1-5 (OR: 0.80, p = 0.003) and EQD2_max ≥ 74.2 Gy (OR: 4.1, p = 0.022). The AUC of the model was 0.77 (95% CI: 0.64-0.87, p = 0.0007, H&L: p = 0.62). The 1­year risk of impotency after high-dose radiotherapy in potent men depends on the EQD2_max to the penile bulb and on baseline IIEF1-5 values. CONCLUSION: A significant reduction in the risk may be expected mainly when sparing the bulb in patients with no/mild baseline impotency (IIEF1-5 > 17).

Radiation dose from multidetector CT studies in children: results from the first Italian nationwide survey.

BACKGROUND: Multidetector CT (MDCT) scanners have contributed to the widespread use of CT in paediatric imaging. However, concerns are raised for the associated radiation exposure. Very few surveys on radiation exposure from MDCT studies in children are available. OBJECTIVE: The aim of this study was to outline the status of radiation exposure in children from MDCT practice in Italy. MATERIALS AND METHODS: In this retrospective multicentre study we asked Italian radiology units with an MDCT scanner with at least 16 slices to provide dosimetric and acquisition parameters of CT examinations in three age groups (1-5, 6-10, 11-15 years) for studies of head, chest and abdomen. The dosimetric results were reported in terms of third-quartile volumetric CT dose index (CTDIvol) (mGy), size-specific dose estimate (SSDE) (mGy), dose length product (DLP) (mGy cm), and total DLP for multiphase studies. These results were compared with paediatric European and adult Italian published data. A multivariate analysis assessed the association of CTDIvol with patient characteristics and scanning modalities. RESULTS: We collected data from 993 MDCT examinations performed at 25 centres. For age groups 1-5 years, 6-10 years and 11-15 years, the CTDIvol, DLP and total DLP values were statistically significantly below the values observed in our analogous national survey in adults, although the difference decreased with increasing age. CTDIvol variability among centres was statistically significant (variance = 0.07; 95% confidence interval = 0.03-0.16; P < 0.001). CONCLUSIONS: This study reviewed practice in Italian centres performing paediatric imaging with MDCT scanners. The variability of doses among centres suggests that the use of standardised CT protocols should be encouraged.

Adult exposures from MDCT including multiphase studies: first Italian nationwide survey.

OBJECTIVES: To evaluate the radiation dose in routine multidetector computed tomography (MDCT) examinations in Italian population. METHODS: This was a retrospective multicentre study included 5,668 patients from 65 radiology departments who had undergone common CT protocols: head, chest, abdomen, chest­abdomen­pelvis (CAP), spine and cardiac. Data included patient characteristics, CT parameters, volumetric CT dose index (CTDIvol) and dose length product (DLP) for each CT acquisition phase. Descriptive statistics were calculated, and a multi-regression analysis was used to outline the main factors affecting exposure. RESULTS: The 75th percentiles of CTDIvol (mGy) and DLP (mGy cm) for whole head were 69 mGy and 1,312 mGy cm, respectively; for chest, 15 mGy and 569 mGy cm; spine, 42 mGy and 888 mGy cm; cardiac, 7 mGy and 131 mGy cm for calcium score, and 61 mGy and 1,208 mGy cm for angiographic CT studies. High variability was present in the DLP of abdomen and CAP protocols, where multiphase examinations dominated (71 % and 73 % respectively): for abdomen, 18 mGy, with 555 and 920 mGy cm in abdomen and abdomen­pelvis acquisitions respectively; for CAP, 17 mGy, with 508, 850 and 1,200 mGy cm in abdomen, abdomen­pelvis and CAP acquisitions respectively. CONCLUSION: The results of this survey could help in the definition of updated diagnostic reference levels (DRL). KEY POINTS: • Radiation dose associated with multidetector CT (MDCT) is an important health issue. • This national survey assessed dose exposures of 5,668 patients undergoing MDCT. • Dose indices correlate with BMI, voltage, rotation time, pitch and tube current. • These results may contribute to an update of national diagnostic reference levels.

Local dose analysis to predict acute and late urinary toxicities after prostate cancer radiotherapy: Assessment of cohort and method effects.

PURPOSE: To perform bladder dose-surface map (DSM) analysis for (1) identifying symptom-related sub-surfaces (Ssurf) and evaluating their prediction capability of urinary toxicity, (2) comparing DSM with dose-volume map (DVM) (method effect), and (3) assessing the reproducibility of DSM (cohort effect). METHODS AND MATERIALS: Urinary toxicities were prospectively analyzed for 254 prostate cancer patients treated with IMRT/IGRT at 78/80 Gy. DSMs were generated by unfolding bladder surfaces in a 2D plane. Pixel-by-pixel analysis was performed to identify symptom-related Ssurf. Likewise, voxel-by-voxel DVM analysis was performed to identify sub-volumes (Svol). The prediction capability of Ssurf and Svol DVHs was assessed by logistic/Cox regression using the area under the ROC curve (AUC). The Ssurf localization and prediction capability were compared to (1) the Svol obtained by DVM analysis in the same cohort and (2) the Ssurf obtained from other DSM studies. RESULTS: Three Ssurf were identified in the bladder: posterior for acute retention (AUC = 0.64), posterior-superior for late retention (AUC = 0.68), and inferior-anterior-lateral for late dysuria (AUC = 0.73). Five Svol were identified: one in the urethra for acute incontinence and four in the posterior bladder part for acute and late retention, late dysuria, and hematuria. The overlap between Ssurf and Svol was moderate for acute retention, good for late retention, and bad for late dysuria, and AUCs ranged from 0.62 to 0.81. The prediction capabilities of Ssurf and Svol models were not significantly different. Among five symptoms comparable between cohorts, common Ssurf was found only for late dysuria, with a good spatial agreement. CONCLUSION: Spatial agreement between methods is relatively good although DVM identified more sub-regions. Reproducibility of identified Ssurf between cohorts is low.

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.

Texture analysis of T1-w and T2-w MR images allows a quantitative evaluation of radiation-induced changes of internal obturator muscles after radiotherapy for prostate cancer.

PURPOSE: To investigate the potential of texture analysis applied on T2-w and postcontrast T1-w images acquired before radiotherapy for prostate cancer (PCa) and 12 months after its completion in quantitatively characterizing local radiation effect on the muscular component of internal obturators, as organs potentially involved in urinary toxicity. METHODS: T2-w and postcontrast T1-w MR images were acquired at 1.5 T before treatment (MRI1) and at 12 months of follow-up (MRI2) in 13 patients treated with radiotherapy for PCa. Right and left internal obturator muscle contours were manually delineated upon MRI1 and then automatically propagated on MRI2 by an elastic registration method. Planning CT images were coregistered to both MRIs and dose maps were deformed accordingly. A high-dose region receiving >55 Gy and a low-dose region receiving <55 Gy were identified in each muscle volume. Eighteen textural features were extracted from each region of interest and differences between MRI1 and MRI2 were evaluated. RESULTS: A signal increase was highlighted in both T2-w and T1-w images in the portion of the obturators near the prostate, i.e., in the region receiving medium-high doses. A change in the spatial organization was identified, as an increase in homogeneity and a decrease in contrast and complexity, compatible with an inflammatory status. In particular, the region receiving medium-high doses presented more significant or, at least, stronger differences. CONCLUSIONS: Texture analysis applied on T1-w and T2-w MR images has demonstrated its ability in quantitative evaluating radiation-induced changes in obturator muscles after PCa radiotherapy.

Development of a Ready-to-Use Graphical Tool Based on Artificial Neural Network Classification: Application for the Prediction of Late Fecal Incontinence After Prostate Cancer Radiation Therapy.

PURPOSE: This study was designed to apply artificial neural network (ANN) classification methods for the prediction of late fecal incontinence (LFI) after high-dose prostate cancer radiation therapy and to develop a ready-to-use graphical tool. MATERIALS AND METHODS: In this study, 598 men recruited in 2 national multicenter trials were analyzed. Information was recorded on comorbidity, previous abdominal surgery, use of drugs, and dose distribution. Fecal incontinence was prospectively evaluated through self-reported questionnaires. To develop the ANN, the study population was randomly split into training (n = 300), validation (n = 149), and test (n = 149) sets. Mean grade of longitudinal LFI (ie, expressed as the average incontinence grade over the first 3 years after radiation therapy) ≥1 was considered the endpoint. A suitable subset of variables able to better predict LFI was selected by simulating 100,000 ANN configurations. The search for the definitive ANN was then performed by varying the number of inputs and hidden neurons from 4 to 5 and from 1 to 9, respectively. A final classification model was established as the average of the best 5 among 500 ANNs with the same architecture. An ANN-based graphical method to compute LFI prediction was developed to include one continuous and n dichotomous variables. RESULTS: An ANN architecture was selected, with 5 input variables (mean dose, previous abdominal surgery, use of anticoagulants, use of antihypertensive drugs, and use of neoadjuvant and adjuvant hormone therapy) and 4 hidden neurons. The developed classification model correctly identified patients with LFI with 80.8% sensitivity and 63.7% ± 1.0% specificity and an area under the curve of 0.78. The developed graphical tool may efficiently classify patients in low, intermediate, and high LFI risk classes. CONCLUSIONS: An ANN-based model was developed to predict LFI. The model was translated in a ready-to-use graphical tool for LFI risk classification, with direct interpretation of the role of the predictors.

Evaluation of Mediators Associated with the Inflammatory Response in Prostate Cancer Patients Undergoing Radiotherapy.

A recent "hot topic" in prostate cancer radiotherapy is the observed association between acute/late rectal toxicity and the presence of abdominal surgery before radiotherapy. The exact mechanism is unclear. Our working hypothesis was that a previous surgery may influence plasma level of inflammatory molecules and this might result in enhanced radiosensitivity. We here present results on the feasibility of monitoring the expression of inflammatory molecules during radiotherapy. Plasma levels of a panel of soluble mediators associated with the inflammatory response were measured in prostate cancer patients undergoing radical radiotherapy. We measured 3 cytokines (IL-1b, IL-6, and TNF alpha), 2 chemokines (CCL2 and CXCL8), and the long pentraxin PTX3. 20 patients were enrolled in this feasibility evaluation. All patients were treated with IMRT at 78 Gy. 3/20 patients reported grade 2 acute rectal toxicity, while 4/20 were scored as grade 2 late toxicity. CCL2 was the most interesting marker showing significant increase during and after radiotherapy. CCL2 levels at radiotherapy end could be modelled using linear regression including basal CCL2, age, surgery, hypertension, and use of anticoagulants. The 4 patients with late toxicity had CCL2 values at radiotherapy end above the median value. This trial is registered with ISRCTN64979094.

Understanding urinary toxicity after radiotherapy for prostate cancer: first steps forward.

One of the most relevant achievements of Professor Gianni Bonadonna was the implementation of the methodology of controlled clinical trials in medical oncology. It is valid for all cancer types, oncological disciplines and clinical endpoints, both survival and toxicity. This narrative review reports on the status of the current knowledge of the radiation-induced urinary syndrome after external-beam radiotherapy for prostate cancer. In recent years, the syndrome has been the object of large-scale prospective observational trials specifically devoted to investigating the association of patient and treatment features with acute/late urinary toxicity. The first results of these trials allow initial attempts at predictive modeling, which can serve as a basis for the optimization of patient selection and treatment planning.

Patient-reported urinary incontinence after radiotherapy for prostate cancer: Quantifying the dose-effect.

BACKGROUND AND PURPOSE: Urinary incontinence following radiotherapy (RT) for prostate cancer (PCa) has a relevant impact on patient's quality of life. The aim of the study was to assess the unknown dose-effect relationship for late patient-reported urinary incontinence (LPRUI). METHODS AND MATERIALS: Patients were enrolled within the multi-centric study DUE01. Clinical and dosimetry data including the prescribed 2Gy equivalent dose (EQD2) were prospectively collected. LPRUI was evaluated through the ICIQ-SF questionnaire filled in by the patients at RT start/end and therefore every 6months. Patients were treated with conventional (74-80Gy, 1.8-2Gy/fr) or moderately hypo-fractionated RT (65-75.2Gy, 2.2-2.7Gy/fr) in 5 fractions/week with intensity-modulated radiotherapy. Six different end-points of 3-year LPRUI, including or not patient's perception (respectively, subjective and objective end-points), were considered. Multivariable logistic models were developed for each end-point. RESULTS: Data of 298 patients were analyzed. The incidence of the most severe end-point (ICIQ-SF>12) was 5.1%. EQD2 calculated with alpha-beta=0.8Gy showed the best performance in fitting data: the risk of LPRUI markedly increased for EQD2>80Gy. Previous abdominal/pelvic surgery and previous TURP were the clinical factors more significantly predictive of LPRUI. Models showed excellent performances in terms of goodness-of-fit and calibration, confirmed by bootstrap-based internal validation. When included in the analyses, baseline symptoms were a major predictor for 5 out of six end-points. CONCLUSIONS: LPRUI after RT for PCa dramatically depends on EQD2 and few clinical factors. Results are consistent with a larger than expected impact of moderate hypo-fractionation on the risk of LPRUI. As expected, baseline symptoms, as captured by ICIQ-SF, are associated to an increased risk of LPRUI.

Eleven-year management of prostate cancer patients on active surveillance: what have we learned?

PURPOSE: To evaluate the outcomes of active surveillance (AS) on patients with low-risk prostate cancer (PCa) and to identify predictors of disease reclassification. METHODS: In 2005, we defined an institutional AS protocol (Sorveglianza Attiva Istituto Nazionale Tumori [SAINT]), and we joined the Prostate Cancer Research International: Active Surveillance (PRIAS) study in 2007. Eligibility criteria included clinical stage ≤T2a, initial prostate-specific antigen (PSA) <10 ng/mL, and Gleason Pattern Score (GPS) ≤3 + 3 (both protocols); ≤25% positive cores with a maximum core length containing cancer ≤50% (SAINT); and ≤2 positive cores and PSA density <0.2 ng/mL/cm3 (PRIAS). Switching to active treatment was advised for a worsening of GPS, increased positive cores, or PSA doubling time <3 years. Active treatment-free survival (ATFS) was assessed using the Kaplan-Meier method. Factors associated with ATFS were evaluated with a multivariate Cox proportional hazards model. RESULTS: A total of 818 patients were included: 200 in SAINT, 530 in PRIAS, and 88 in personalized AS monitoring. Active treatment-free survival was 50% after a median follow-up of 60 months. A total of 404/818 patients (49.4%) discontinued AS: 274 for biopsy-related reclassification, 121/404 (30%) for off-protocol reasons, 9/404 (2.2%) because of anxiety. Biopsy reclassification was associated with PSA density (hazard ratio [HR] 1.8), maximum percentage of core involvement (HR 1.5), positive cores at diagnostic biopsy (HR 1.6), older age (HR 1.5), and prostate volume (HR 0.6) (all p<0.01). Patients from SAINT were significantly more likely to discontinue AS than were the patients from PRIAS (HR 1.65, p<0.0001). CONCLUSIONS: Five years after diagnosis, 50% of patients with early PCa were spared from active treatment. Wide inclusion criteria are associated with lower ATFS. However, at preliminary analysis, this does not seem to affect the probability of unfavorable pathology.

First application of a pixel-wise analysis on bladder dose-surface maps in prostate cancer radiotherapy.

PURPOSE: To develop a method for investigating local dose effects on the bladder after prostate cancer radiotherapy based on dose-surface maps (DSMs). BACKGROUND AND PURPOSE: DSMs of patients included in a prospective study (DUE01) were generated by virtually cutting bladder contours at the points intersecting the sagittal plane passing through its center-of-mass: maps were laterally normalized and aligned at the posterior inferior point. The average DSMs of patients with/without toxicity, the DSMs of differences and t statistic were used to select regions better discriminating patients with toxicity. A total of 72 patients with no/mild urinary symptoms before radiotherapy and who were treated with moderate hypo-fractionation (2.5-2.65Gy/fr, 70-74Gy) were considered, and the endpoint was an International Prostate Symptoms Score (IPSS)⩾15 at the end of therapy (IPSSend⩾15, n=25/72). RESULTS: The DSMs of patients with/without toxicity were significantly different (p<0.05). The percentage of bladder circumference receiving >50-70Gy at 5-7mm from the base was associated with an IPSSend⩾15 (odds ratios: 1.03-1.07). Different patterns were recognized for specific symptoms. With frequency/urgency, a quasi-threshold effect on the absolute posterior dose at 5-12mm from the base (2Gy equivalent doses=80-82Gy, α/ß=3-5Gy) was observed. CONCLUSIONS: Local-dose effects for acute symptoms were detected in a group of patients treated within a moderately hypo-fractionated protocol. The results for frequency/urgency were consistent with a threshold effect on the trigone.

Multi-variable models of large International Prostate Symptom Score worsening at the end of therapy in prostate cancer radiotherapy.

PURPOSE/OBJECTIVE: Prospectively assessing clinical/dosimetry factors affecting the acute worsening of urinary functionality after radiotherapy for prostate cancer. MATERIAL/METHODS: DUE01 population was considered, including patients treated with conventional or moderate hypo-fractionation (2.2-2.7 Gy/fr). Relevant clinical factors were collected, urinary symptoms were self-reported through the International Prostate Symptom Score (IPSS) before and at the end of radiotherapy; while absolute weekly dose-surface histograms (DSHw) were chosen as dosimetry descriptors. An IPSS increase of at least 10 and 15 points (ΔIPSS ⩾ 10 and ΔIPSS ⩾ 15) were chosen as endpoints. Patients with baseline IPSS>20 were excluded. Relevant factors were chosen through a bootstrap-based in silico methodology. RESULTS: Complete information was available for 380 patients: 77/380 (20%) and 28/380 (7%) with ΔIPSS ⩾ 10 and ΔIPSS ⩾ 15, respectively. Neoadjuvant hormone was protective (OR=0.49 and 0.69). DSHw at 8.5 Gy/week and 12 Gy/week were risk factors, with additional risk for patients who use cardiovascular drugs and anti-hypercholesterolemia drugs. In the hypo-fractionated subgroup (n=209) the role of cardiovascular drugs (OR=2.16) for ΔIPSS ⩾ 10 and anti-hypercholesterolemia drugs (OR=2.80) for ΔIPSS⩾15, together with DSHw (10 Gy/week and 12.5 Gy/week, respectively), was confirmed. CONCLUSION: Current study shows a dose-surface/volume effect for acute large worsening of urinary functionality; several clinical variables largely impact the risk and especially all the factors related with vascular diseases.

Predicting the 5-Year Risk of Biochemical Relapse After Postprostatectomy Radiation Therapy in ≥PT2, pN0 Patients With a Comprehensive Tumor Control Probability Model.

PURPOSE: To fit the individual biochemical recurrence-free survival (bRFS) data from patients treated with postprostatectomy radiation therapy (RT) with a comprehensive tumor control probability (TCP) model. METHODS AND MATERIALS: Considering pre-RT prostate-specific antigen (PSA) as a surrogate of the number of clonogens, bRFS may be expressed as a function of dose-per-fraction-dependent radiosensitivity (αeff), the number of clonogens for pre-RT PSA = 1 ng/mL (C), and the fraction of patients who relapse because of clonogens outside the treated volume (K), assumed to depend (linearly or exponentially) on pre-RT PSA and Gleason score (GS). Data from 894 node-negative, ≥pT2, pN0 hormone-naive patients treated with adjuvant (n=331) or salvage (n=563) intent were available: 5-year bRFS data were fitted grouping patients according to GS (<7:392, =7:383, >7:119). RESULTS: The median follow-up time, pre-RT PSA, and dose were 72 months, 0.25 ng/mL, and 66.6 Gy (range 59.4-77.4 Gy), respectively. The best-fit values were 0.23 to 0.26 Gy(-1) and 10(7) for αeff and C for the model considering a linear dependence between K and PSA. Calibration plots showed good agreement between expected and observed incidences (slope: 0.90-0.93) and moderately high discriminative power (area under the curve [AUC]: 0.68-0.69). Cross-validation showed satisfactory results (average AUCs in the training/validation groups: 0.66-0.70). The resulting dose-effect curves strongly depend on pre-RT PSA and GS. bRFS rapidly decreases with PSA: the maximum obtainable bRFS (defined as 95% of the maximum) declined by about 2.7% and 4.5% for each increment of 0.1 ng/mL for GS <7 and ≥7, respectively. CONCLUSIONS: Individual data were fitted by a TCP model, and the resulting best-fit parameters were radiobiologically consistent. The model suggests that relapses frequently result from clonogens outside the irradiated volume, supporting the choice of lymph-node irradiation, systemic therapy, or both for specific subgroups (GS <7: PSA >0.8-1.0 ng/mL; GS ≥7: PSA >0.3 ng/mL). Early RT should be preferred over delayed RT; the detrimental effect of PSA increase can never be fully compensated by increasing the dose, especially for patients with GS ≥7.

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.

Insensitivity of leptogenesis with flavor effects to low energy leptonic CP violation.

If the baryon asymmetry of the Universe is produced by leptogenesis, CP violation is required in the lepton sector. In the seesaw extension of the standard model with three hierarchical right-handed neutrinos, we show that the baryon asymmetry is insensitive to the Pontecorvo-Maki-Nagakawa-Sakata phases: thermal leptogenesis can work for any value of the observable phases. This result was well known when there were no flavor effects in leptogenesis; we show that it remains true when flavor effects are included.