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Background: The purpose of this research was to assess agreement between four rating systems of cosmetic outcome measured in a subset of patients with early breast cancer participating in the randomised TARGIT-A trial. TARGIT-A compared risk-adapted single-dose intra-operative radiotherapy (TARGIT-IORT) to whole breast external beam radiotherapy (EBRT)., Methods: Patients, their Radiation Oncologist and Research Nurse completed a subjective cosmetic assessment questionnaire before radiotherapy and annually thereafter for five years. Objective data previously calculated by the validated BCCT.core software which utilizes digital photographs to score symmetry, colour and scar was also used. Agreement was assessed by the Kappa statistic and longitudinal changes were assessed by generalized estimating equations., Results: Overall, an Excellent-Good (EG) cosmetic result was scored more often than a Fair-Poor (FP) result for both treatment groups across all time points, with patients who received TARGIT-IORT scoring EG more often than those who received EBRT however this was statistically significant at Year 5 only. There was modest agreement between the four rating systems with the highest Kappa score being moderate agreement which was between nurse and doctor scores at Year 1 with Kappa = 0.46 (p < 0.001), 95% CI (0.24, 0.68)., Conclusion: Despite similar overall findings between treatment groups and rating systems, the inter-rater agreement was only modest. This suggests that the four rating systems utilized may not necessarily be used interchangeably and it is arguable that for an outcome such as cosmetic appearance, the patient's point of view is the most important., Trial Registration: TARGIT-A ISRCTN34086741 , Registered 21 July 2004, retrospectively registered.

Purpose: Given the paucity of available data concerning radiotherapy-induced urinary toxicity, it is important to ensure derivation of the most robust models with superior predictive performance. This work explores multiple statistical-learning strategies for prediction of urinary symptoms following external beam radiotherapy of the prostate., Methods: The performance of logistic regression, elastic-net, support-vector machine, random forest, neural network, and multivariate adaptive regression splines (MARS) to predict urinary symptoms was analyzed using data from 754 participants accrued by TROG03.04-RADAR. Predictive features included dose-surface data, comorbidities, and medication-intake. Four symptoms were analyzed: dysuria, haematuria, incontinence, and frequency, each with three definitions (grade ≥ 1, grade ≥ 2 and longitudinal) with event rate between 2.3% and 76.1%. Repeated cross-validations producing matched models were implemented. A synthetic minority oversampling technique was utilized in endpoints with rare events. Parameter optimization was performed on the training data. Area under the receiver operating characteristic curve (AUROC) was used to compare performance using sample size to detect differences of ≥0.05 at the 95% confidence level., Results: Logistic regression, elastic-net, random forest, MARS, and support-vector machine were the highest-performing statistical-learning strategies in 3, 3, 3, 2, and 1 endpoints, respectively. Logistic regression, MARS, elastic-net, random forest, neural network, and support-vector machine were the best, or were not significantly worse than the best, in 7, 7, 5, 5, 3, and 1 endpoints. The best-performing statistical model was for dysuria grade ≥ 1 with AUROC ± standard deviation of 0.649 ± 0.074 using MARS. For longitudinal frequency and dysuria grade ≥ 1, all strategies produced AUROC>0.6 while all haematuria endpoints and longitudinal incontinence models produced AUROC<0.6., Conclusions: Logistic regression and MARS were most likely to be the best-performing strategy for the prediction of urinary symptoms with elastic-net and random forest producing competitive results. The predictive power of the models was modest and endpoint-dependent. New features, including spatial dose maps, may be necessary to achieve better models.

Background and Purpose: This study aimed to compare urinary dose-symptom correlates after external beam radiotherapy of the prostate using commonly utilised peak-symptom models to multiple-event and event-count models which account for repeated events., Materials and Methods: Urinary symptoms (dysuria, haematuria, incontinence and frequency) from 754 participants from TROG 03.04-RADAR trial were analysed. Relative (R1-R75 Gy) and absolute (A60-A75Gy) bladder dose-surface area receiving more than a threshold dose and equivalent uniform dose using exponent a (range: a ∈[1 … 100]) were derived. The dose-symptom correlates were analysed using; peak-symptom (logistic), multiple-event (generalised estimating equation) and event-count (negative binomial regression) models., Results: Stronger dose-symptom correlates were found for incontinence and frequency using multiple-event and/or event-count models. For dysuria and haematuria, similar or better relationships were found using peak-symptom models. Dysuria, haematuria and high grade (⩾ 2) incontinence were associated to high dose (R61-R71 Gy). Frequency and low grade (⩾ 1) incontinence were associated to low and intermediate dose-surface parameters (R13-R41Gy). Frequency showed a parallel behaviour (a=1) while dysuria, haematuria and incontinence showed a more serial behaviour (a=4 to a ⩾ 100). Relative dose-surface showed stronger dose-symptom associations., Conclusions: For certain endpoints, the multiple-event and event-count models provide stronger correlates over peak-symptom models. Accounting for multiple events may be advantageous for a more complete understanding of urinary dose-symptom relationships., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Quality assurance methods are incorporated into multicentre radiotherapy clinical trials for ensuring consistent application of trial protocol and quantifying treatment uncertainties. The study's purpose was to determine whether post-treatment disease progression is associated with measures of the quality of radiotherapy treatment.Methods: The TROG 03.04 RADAR trial tested the impact of androgen deprivation on prostate cancer patients receiving dose-escalated external beam radiation therapy. The trial incorporated a plan-review process and Level III dosimetric intercomparison at each centre, from which variables suggestive of treatment quality were collected. Kaplan-Meier statistics and Fine and Gray competing risk modelling were employed to test for associations between quality-related variables and the participant outcome local composite progression.Results: Increased 'dose-difference' at the prostatic apex and at the anterior rectal wall, between planned and measured dose, was associated with reduced progression. Participants whose treatment plans included clinical target volume (CTV) to planning target volume (PTV) margins exceeding protocol requirements also experienced reduced progression. Other quality-related variables, including total accrual from participating centres, measures of target coverage and other variations from protocol, were not significantly associated with progression.Conclusions: This analysis has revealed the association of several treatment quality factors with disease progression. Increased dose and dose margin coverage in the prostate region can reduce disease progression. Extensive and rigorous monitoring has helped to maximise treatment quality, reducing the incidence of quality-indicator outliers, and thus reduce the chance of observing significant associations with progression rates. [ABSTRACT FROM AUTHOR]

Introduction: To investigate the accuracy of deriving dose-volume histogram (DVH) parameters from deformably registered data by comparing values with the simple addition of DVHs from each phase of a combined external beam radiotherapy (EBRT)/high-dose-rate (HDR-BT) brachytherapy prostate treatment.Methods: Eighty-two patients received EBRT in 23 fractions of 2 Gy and HDR-BT TG43 in three fractions of 6.5 Gy. The HDR-BT CT was deformably registered to the EBRT CT. The rectum D0.1cc , D1cc , D2cc and D10cc were calculated in two ways. (i) Parameter-adding: the EBRT DVH parameters (or the EBRT prescription dose) were added to the unregistered HDR-BT DVH parameters. (ii) Distribution-adding: the parameters were extracted after the EBRT doses were 3D-summed with the registered HDR-BT doses. Resulting differences between the parameters were investigated.Results: The D0.1cc , D1cc and D2cc from parameter-adding were 21.3% (P < 0.001), 6.3% (P < 0.001) and 3.5% (P < 0.001) smaller than those from distribution-adding. The D10cc was 2.2% (P = 0.015) larger for distribution-adding.Conclusion: Distribution-adding was confounded by unsystematic inter/intra-observer rectum-contouring errors and registration accuracy near the anterior rectal wall. Consequently, clinical use of distribution-adding to assess rectal doses requires careful contour and registration evaluation. [ABSTRACT FROM AUTHOR]

Background: Derivation of dose-volume correlated with toxicity for multi-modal treatments can be difficult due to the perceived need for voxel-by-voxel dose accumulation. With data available for a single-institution cohort with long follow-up, an investigation was undertaken into rectal dose-volume effects for gastrointestinal toxicities after deformably-registering each phase of a combined external beam radiotherapy (EBRT)/high-dose-rate (HDR) brachytherapy prostate treatment. Methods: One hundred and eighteen patients received EBRT in 23 fractions of 2 Gy and HDR (TG43 algorithm) in 3 fractions of 6.5 Gy. Results for the Late Effects of Normal Tissues - Subjective, Objective, Management and Analytic toxicity assessments were available with a median follow-up of 72 months. The HDR CT was deformably-registered to the EBRT CT. Doses were corrected for dose fractionation. Rectum dose-volume histogram (DVH) parameters were calculated in two ways. (1) Distribution-adding: parameters were calculated after the EBRT dose distribution was 3D-summed with the registered HDR dose distribution. (2) Parameter-adding: the EBRT DVH parameters were added to HDR DVH parameters. Logistic regressions and Mann-Whitney U-tests were used to correlate parameters with late peak toxicity (dichotomised at grade 1 or 2). Results: The 48-80, 40-63 and 49-55 Gy dose regions from distribution-adding were significantly correlated with rectal bleeding, urgency/tenesmus and stool frequency respectively. Additionally, urgency/tenesmus and anorectal pain were associated with the 25-26 Gy and 44-48 Gy dose regions from distribution-adding respectively. Parameteradding also indicated the low-mid dose region was significantly correlated with stool frequency and proctitis. Conclusions: This study confirms significant dose-histogram effects for gastrointestinal toxicities after including deformable registration to combine phases of EBRT/HDR prostate cancer treatment. The findings from distributionadding were in most cases consistent with those from parameter-adding. The mid-high dose range and near maximum doses were important for rectal bleeding. The distribution-adding mid-high dose range was also important for stool frequency and urgency/tenesmus. We encourage additional studies in a variety of institutions using a variety of dose accumulation methods with appropriate inter-fraction motion management. [ABSTRACT FROM AUTHOR]

Background: Registering CTs for patients receiving external beam radiotherapy (EBRT) with a boost dose from high-dose-rate brachytherapy (HDR) can be challenging due to considerable image discrepancies (e.g. rectal fillings, HDR needles, HDR artefacts and HDR rectal packing materials). This study is the first to comparatively evaluate image processing and registration methods used to register the rectums in EBRT and HDR CTs of prostate cancer patients. The focus is on the rectum due to planned future analysis of rectal dose-volume response.Methods: For 64 patients, the EBRT CT was retrospectively registered to the HDR CT with rigid registration and non-rigid registration methods in VelocityAI. Image processing was undertaken on the HDR CT and the rigidly-registered EBRT CT to reduce the impact of discriminating features on alternative non-rigid registration methods applied in the software suite for Deformable Image Registration and Adaptive Radiotherapy Research (DIRART) using the Horn-Schunck optical flow and Demons algorithms. The propagated EBRT-rectum structures were compared with the HDR structure using the Dice similarity coefficient (DSC), Hausdorff distance (HD) and average surface distance (ASD). The image similarity was compared using mutual information (MI) and root mean squared error (MSE). The displacement vector field was assessed via the Jacobian determinant (JAC). The post-registration alignments of rectums for 21 patients were visually assessed.Results: The greatest improvement in the median DSC relative to the rigid registration result was 35 % for the Horn-Schunck algorithm with image processing. This algorithm also provided the best ASD results. The VelocityAI algorithms provided superior HD, MI, MSE and JAC results. The visual assessment indicated that the rigid plus deformable multi-pass method within VelocityAI resulted in the best rectum alignment.Conclusions: The DSC, ASD and HD improved significantly relative to the rigid registration result if image processing was applied prior to DIRART non-rigid registrations, whereas VelocityAI without image processing provided significant improvements. Reliance on a single rectum structure-correspondence metric would have been misleading as the metrics were inconsistent with one another and visual assessments. It was important to calculate metrics for a restricted region covering the organ of interest. Overall, VelocityAI generated the best registrations for the rectum according to the visual assessment, HD, MI, MSE and JAC results. [ABSTRACT FROM AUTHOR]

Objectives To test the hypothesis that observation with early salvage radiotherapy ( SRT) is not inferior to 'standard' treatment with adjuvant RT ( ART) with respect to biochemical failure in patients with pT3 disease and/or positive surgical margins ( SMs) after radical prostatectomy ( RP). To compare the following secondary endpoints between the two arms: patient-reported outcomes, adverse events, biochemical failure-free survival, overall survival, disease-specific survival, time to distant failure, time to local failure, cost utility analysis, quality adjusted life years and time to androgen deprivation. Patients and Methods The Radiotherapy - Adjuvant Versus Early Salvage ( RAVES) trial is a phase III multicentre randomised controlled trial led by the Trans Tasman Radiation Oncology Group ( TROG), in collaboration with the Urological Society of Australia and New Zealand ( USANZ), and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group ( ANZUP). In all, 470 patients are planned to be randomised 1:1 to either ART commenced at ≤4 months of RP (standard of care) or close observation with early SRT triggered by a PSA level of >0.20 ng/mL (experimental arm). Eligible patients have had a RP for adenocarcinoma of the prostate with at least one of the following risk factors: positive SMs ± extraprostatic extension ± seminal vesicle involvement. The postoperative PSA level must be ≤0.10 ng/mL. Rigorous investigator credentialing and a quality assurance programme are designed to promote consistent RT delivery among patients. Results Trial is currently underway, with 258 patients randomised as of 31 October 2013. International collaborations have developed, including a planned meta-analysis to be undertaken with the UK Medical Research Council/National Cancer Institute of Canada Clinical Trials Group RADICALS (Radiotherapy and Androgen Deprivation In Combination with Local Surgery) trial and an innovative psycho-oncology sub-study to investigate a patient decision aid resource. Conclusion On the current evidence available, it remains unclear if ART is equivalent or superior to observation with early SRT. [ABSTRACT FROM AUTHOR]

Introduction The Trans- Tasman Radiation Oncology Group 03.04 'Randomised Androgen Deprivation and Radiotherapy' multicentre prostate cancer trial examined the optimal duration of androgen deprivation in combination with dose-escalated radiotherapy. Rigorous quality assurance ( QA) processes were undertaken to ensure the validity and reliability of the radiation therapy treatment plan data. Method QA processes included a planning benchmarking exercise and a periodic audit of target and normal tissue delineation. Centralised electronic review of digital plan data for external-beam radiotherapy was undertaken to detect protocol variations. The impact of clinical factors and feedback to submitting centres during the trial on variation rates was investigated. Results Twenty-three centres across Australia and New Zealand recruited 1071 participants to the trial. Treatment plans for 754 participants receiving external-beam treatment alone were reviewed. From these, 1185 minor and 86 major variations were identified, leading to feedback to treating centres to reduce variations for subsequent patients' treatment and plans, suggesting improvement in treatment quality through these QA programs. Participant anatomical factors (delineated clinical target volume and rectal volume) and treatment planning factors (beam energy, beam definition and patient position orientation) were found to significantly impact variation rates. The dummy run demonstrated disagreement in identification of the base of the prostate and the superior extent of the rectum. Feedback from the periodic audit led to a change of practice at five contributing centres. Conclusion The application of a suite of complementary QA activities allows the quality of trial data to be optimised and quantified, and can provide a catalyst for reforming treatment practices. [ABSTRACT FROM AUTHOR]

The article focuses on the phase three trial of the whole breast radiotherapy against targeted intraoperative radiotherapy on patients with breast cancer. It says that TARGIT-A trial was launched on March 24, 2000 applying the intraoperative intrabeam technique on women with invasive ductal breast carcinoma aged 45 years old and above, undergoing breast-conserving surgery. Meanwhile, patients from nine countries were enrolled on 28 centres with 1:1 ratio in order to obtain the whole breast radiotherapy or targeted intraoperative radiotherapy wherein local recurrence on conserved breast was the primary outcome. Results show that single dose of targeted radiotherapy for breast cancer patients may be used as substitute for external beam radiotherapy.

A new device, Intrabeam, is available for intraoperative radiotherapy. We have prospectively examined its feasibility and tolerability in delivering adjuvant breast cancer treatment.Thirty-five patients undergoing breast-conserving surgery received targeted tumour bed irradiation consisting of 5 Gy (at 10 mm) in a single fraction. This single intraoperative treatment was used to replace the external beam radiotherapy‘boost’ that would usually be given in 10 daily treatments following 5 weeks of whole breast irradiation. Patients later completed external beam radiotherapy as usual. Potential toxicities were prospectively assessed fortnightly prior to external beam radiotherapy, weekly during it, and 3 monthly subsequently.The intraoperative radiotherapy was able to be delivered without difficulty, either at time of initial cancer surgery or as a second procedure. When performed as a separate procedure the median operating time was 56 min. The treatment was well tolerated, with only one patient experiencing any grade 3 or 4 toxicities− this was acute grade three itch. There was an overall early breast infection rate of 17%. No unexpected toxicities were seen.This simple and well-tolerated treatment delivers a useful radiation dose to the area of highest risk of tumour recurrence. The early infection rate is similar to that reported in the literature, for treatments without intraoperative radiotherapy. Whether such a treatment may adequately replace the entire adjuvant radiation therapy treatment for low-risk patients is now being studied in a randomized trial. [ABSTRACT FROM AUTHOR]

SUMMARY The increased procedural demands of stereotactic localization techniques when compared with conventional treatment practices reduces machine efficiency, an outcome likely to be greatly magnified by the introduction of fractionation to stereotactic techniques. Currently in Australia and New Zealand there are no guidelines for the definition of efficiency. We sought to devise a system to simultaneously validate the accuracy and efficiency of the technique. The frameless relocation methods employed in the Medtronic Sofamor Danek (MSD) stereotactic radiotherapy (SRT) system were studied in the clinical setting. Accuracy has been determined according to the accumulation of errors throughout the planning and treatment process. The clinical demands of the system (staffing and resources) were analysed relative to conventional treatment approaches. Timing studies indicate a mean time of 19.7 min for treatment of a daily SRT fraction (4–5 arcs, single isocentre). Cost and staffing requirements are similar to those for conventional radiotherapy. It is concluded that with the system used, SRT is efficient for routine clinical implementation, with the level of efficiency increasing with increasing patient numbers. It is recommended that a common acceptance standard be developed to allow cross-institutional comparison of the clinical efficiency of new treatment techniques. [ABSTRACT FROM AUTHOR]

SUMMARY The increasing popularity of 3-D planning leads to procedural alterations as both workload and resource utilization increase. Although the complexity of the techniques has increased (as well as the set-up and treatment times), the workload statistics must still include the number of fields treated. It is commonly known that machine statistics of fields treated per day do not accurately represent workload because there are major differences between techniques. A mantle treatment technique and an opposed spine technique both have (statistically) two fields, although the set-up requirements and treatment times are very different. A basic treatment equivalent (BTE) formula was reported in early 1999 by Delaney et al. and incorporates a large number of variables inherent in patient treatment. The formula considers different factors that affect overall treatment time, and aims to represent a more accurate treatment time indicator. The aim of introducing the BTE into the Department of Radiation Oncology at Sir Charles Gairdner Hospital was to create a more accurate scheduling system and even out workloads on all treatment units. Therefore the BTE formula was used to assess accuracy of treatment times in order to determine if the values could be relied upon as accurate time indicators. Patients undergoing a variety of treatment techniques were timed for the duration of their treatment procedure, and their treatment times compared to the time estimated using the BTE formula. A few minor alterations were made to the equation for treatment units with multi-leaf collimation (MLC). A trial conducted at Sir Charles Gairdner Hospital found that, using the BTE formula (with a few modifications required for the MLC treatment units), of 60 patients timed for the duration of their set-up and treatment, 85% of values were in the range of ± 3 min, and 95% were in the range of ± 5 min of the estimated times. Through the routine use of the BTE equation a more... [ABSTRACT FROM AUTHOR]

Objective: TARGIT‐A randomised women with early breast cancer to receive external beam radiotherapy (EBRT) or intraoperative radiotherapy (TARGIT‐IORT). This study aimed to identify what extra risk of recurrence patients would accept for perceived benefits and risks of different radiotherapy treatments. Methods: Patient preferences were determined by self‐rated trade‐off questionnaires in two studies: Stage (1) 209 TARGIT‐A participants (TARGIT‐IORTn = 108, EBRTn = 101); Stage (2) 123 non‐trial patients yet to receive radiotherapy (pre‐treatment group), with 85 also surveyed post‐radiotherapy. Patients traded‐off risks of local recurrence in preference selection between TARGIT‐IORT and EBRT. Results: TARGIT‐IORT patients were more accepting of IORT than EBRT patients with 60% accepting the highest increased risk presented (4%–6%) compared to 12% of EBRT patients, and 2% not accepting IORT at all compared to 43% of EBRT patients. Pre‐treatment patients were more accepting of IORT than post‐treatment patients with 23% accepting the highest increased risk presented compared to 15% of post‐treatment patients, and 15% not accepting IORT at all compared to 41% of pre‐treatment patients. Conclusions: Breast cancer patients yet to receive radiotherapy accept a higher recurrence risk than the actual risk found in TARGIT‐A. Measured patient preferences are highly influenced by experience of treatment received. This finding challenges the validity of post‐treatment preference studies. [ABSTRACT FROM AUTHOR]

Klinefelter syndrome is a common cause of hypogonadism. Testosterone replacement therapy has beneficial effects on bone, muscle and psychosexual function. However, it may remove the relative protection from adenocarcinoma of prostate, which is otherwise rare in uncomplicated Klinefelter syndrome. We report the case of a 55-year-old man with Klinefelter syndrome who developed prostate cancer after only 7 years of androgen supplementation. Androgen deprivation therapy was complicated by the presence of testosterone implants. The patient was treated with androgen blockade followed by radiation therapy. We recommend that serum prostate specific antigen (PSA) and digital rectal examinations be carried out during, as well as before androgen replacement. [ABSTRACT FROM AUTHOR]

In vivo dosimetry is a proven reliable method of checking overall treatment accuracy, allowing verification of dosimetry and dose calculation as well as patient treatment setup. We conducted a pilot study to assess the clinical utility of in vivo dosimetry in our department. Diodes (calibrated for typical treatment conditions) were used to record entrance dose measurements on 62 patients representing a variety of treatment sites. Measurements were compared with predictions from the planning system, with results found to be in tolerance for the majority of treatment sites. However, large discrepancies were encountered for measurements performed during breast irradiation (up to 16% for lateral tangential fields). The sensitivity of the recorded entrance dose to the positioning error of the diode placement was examined. The sensitivity of diode signal to small changes in position were compared with feasible variations in other parameters (e.g., dosimetry, FSD at setup). For the breast irradiation technique considered, wedges are used for the majority of fields. It was found that a proportion of error was predominantly due to the use of wedges and the presence of significantly nonuniform patient contours. In combination with diode placement errors, this resulted in increased measurement error. Correct diode placement is critical to ensure accurate data collection. The results of this study indicate the importance of separating errors due to measurement technique from actual treatment/setup errors. [Copyright &y& Elsevier]

Background: Adjuvant radiotherapy has been shown to halve the risk of biochemical progression for patients with high-risk disease after radical prostatectomy. Early salvage radiotherapy could result in similar biochemical control with lower treatment toxicity. We aimed to compare biochemical progression between patients given adjuvant radiotherapy and those given salvage radiotherapy.Methods: We did a phase 3, randomised, controlled, non-inferiority trial across 32 oncology centres in Australia and New Zealand. Eligible patients were aged at least 18 years and had undergone a radical prostatectomy for adenocarcinoma of the prostate with pathological staging showing high-risk features defined as positive surgical margins, extraprostatic extension, or seminal vesicle invasion; had an Eastern Cooperative Oncology Group performance status of 0-1, and had a postoperative prostate-specific antigen (PSA) concentration of 0·10 ng/mL or less. Patients were randomly assigned (1:1) using a minimisation technique via an internet-based, independently generated allocation to either adjuvant radiotherapy within 6 months of radical prostatectomy or early salvage radiotherapy triggered by a PSA of 0·20 ng/mL or more. Allocation sequence was concealed from investigators and patients, but treatment assignment for individual randomisations was not masked. Patients were stratified by radiotherapy centre, preoperative PSA, Gleason score, surgical margin status, and seminal vesicle invasion status. Radiotherapy in both groups was 64 Gy in 32 fractions to the prostate bed without androgen deprivation therapy with real-time review of plan quality on all cases before treatment. The primary endpoint was freedom from biochemical progression. Salvage radiotherapy would be deemed non-inferior to adjuvant radiotherapy if freedom from biochemical progression at 5 years was within 10% of that for adjuvant radiotherapy with a hazard ratio (HR) for salvage radiotherapy versus adjuvant radiotherapy of 1·48. The primary analysis was done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT00860652.Findings: Between March 27, 2009, and Dec 31, 2015, 333 patients were randomly assigned (166 to adjuvant radiotherapy; 167 to salvage radiotherapy). Median follow-up was 6·1 years (IQR 4·3-7·5). An independent data monitoring committee recommended premature closure of enrolment because of unexpectedly low event rates. 84 (50%) patients in the salvage radiotherapy group had radiotherapy triggered by a PSA of 0·20 ng/mL or more. 5-year freedom from biochemical progression was 86% (95% CI 81-92) in the adjuvant radiotherapy group versus 87% (82-93) in the salvage radiotherapy group (stratified HR 1·12, 95% CI 0·65-1·90; pnon-inferiority=0·15). The grade 2 or worse genitourinary toxicity rate was lower in the salvage radiotherapy group (90 [54%] of 167) than in the adjuvant radiotherapy group (116 [70%] of 166). The grade 2 or worse gastrointestinal toxicity rate was similar between the salvage radiotherapy group (16 [10%]) and the adjuvant radiotherapy group (24 [14%]).Interpretation: Salvage radiotherapy did not meet trial specified criteria for non-inferiority. However, these data support the use of salvage radiotherapy as it results in similar biochemical control to adjuvant radiotherapy, spares around half of men from pelvic radiation, and is associated with significantly lower genitourinary toxicity.Funding: New Zealand Health Research Council, Australian National Health Medical Research Council, Cancer Council Victoria, Cancer Council NSW, Auckland Hospital Charitable Trust, Trans-Tasman Radiation Oncology Group Seed Funding, Cancer Research Trust New Zealand, Royal Australian and New Zealand College of Radiologists, Cancer Institute NSW, Prostate Cancer Foundation Australia, and Cancer Australia. [ABSTRACT FROM AUTHOR]

• To validate models published for late rectal bleeding after RT for prostate cancer. • The analysis was performed on a large international pooled population (1633 pts) • Clinical and dosimetric risk factors were confirmed on the validation set. • Best calibration plots are obtained for volume parameters pointing to medium–high dose. 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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

Purpose: We assessed the association of the spatial distribution of dose to the bladder surface, described using dose-surface maps, with the risk of urinary dysfunction.Methods and Materials: The bladder dose-surface maps of 754 participants from the TROG 03.04-RADAR trial were generated from the volumetric data by virtually cutting the bladder at the sagittal slice, intersecting the bladder center-of-mass through to the bladder posterior and projecting the dose information on a 2-dimensional plane. Pixelwise dose comparisons were performed between patients with and without symptoms (dysuria, hematuria, incontinence, and an International Prostate Symptom Score increase of ≥10 [ΔIPSS10]). The results with and without permutation-based multiple-comparison adjustments are reported. The pixelwise multivariate analysis findings (peak-event model for dysuria, hematuria, and ΔIPSS10; event-count model for incontinence), with adjustments for clinical factors, are also reported.Results: The associations of the spatially specific dose measures to urinary dysfunction were dependent on the presence of specific symptoms. The doses received by the anteroinferior and, to lesser extent, posterosuperior surface of the bladder had the strongest relationship with the incidence of dysuria, hematuria, and ΔIPSS10, both with and without adjustment for clinical factors. For the doses to the posteroinferior region corresponding to the area of the trigone, the only symptom with significance was incontinence.Conclusions: A spatially variable response of the bladder surface to the dose was found for symptoms of urinary dysfunction. Limiting the dose extending anteriorly might help reduce the risk of urinary dysfunction. [ABSTRACT FROM AUTHOR]

Purpose: To report the first comprehensive investigation of patient-reported cosmesis and breast-related quality of life (QOL) outcomes comparing patients randomized to risk-adapted single-dose intraoperative radiation therapy (TARGIT-IORT) versus external beam radiation therapy (EBRT) on the TARGIT-A trial.Methods and Materials: Longitudinal cosmesis and QOL data were collected from a subset of TARGIT-A participants who received TARGIT-IORT as a separate procedure (postpathology). Patients completed a cosmetic assessment before radiation therapy and annually thereafter for at least 5 years. Patients also completed the combined European Organization for Research and Treatment of Cancer (EORTC) core questionnaire and Breast-Specific Module in addition to the Body Image after Breast Cancer Questionnaire at baseline and annually thereafter. The combined EORTC questionnaires were also collected 3, 6, and 9 months after wide local excision.Results: An Excellent-Good cosmetic result was scored more often than a Fair-Poor result for both treatment groups across all time points. The TARGIT-IORT patients reported better breast-related QOL than EBRT patients. Statistically and clinically significant differences were seen at month 6 and year 1, with EBRT patients having moderately worse breast symptoms (a statistically significant difference of more than 10 in a 100-point scale) than TARGIT-IORT patients at these time points.Conclusion: Patients treated with TARGIT-IORT on the TARGIT-A trial have similar self-reported cosmetic outcome but better breast-related QOL outcomes than patients treated with EBRT. This important evidence can facilitate the treatment decision-making process for patients who have early breast cancer suitable for breast-conserving surgery and inform their clinicians. [ABSTRACT FROM AUTHOR]

Purpose/objective To identify dosimetry, clinical factors and medication intake impacting urinary symptoms after prostate radiotherapy. Material and methods Data describing clinical factors and bladder dosimetry (reduced with principal component (PC) analysis) for 754 patients treated with external beam radiotherapy accrued by TROG 03.04 RADAR prostate radiotherapy trial were available for analysis. Urinary symptoms (frequency, incontinence, dysuria and haematuria) were prospectively assessed using LENT-SOMA to a median of 72 months. The endpoints assessed were prevalence (grade ⩾1) at the end of radiotherapy (representing acute symptoms), at 18-, 36- and 54-month follow-ups (representing late symptoms) and peak late incidence including only grade ⩾2. Impact of factors was assessed using multivariate logistic regression models with correction for over-optimism. Results Baseline symptoms, non-insulin dependent diabetes mellitus, age and PC1 (correlated to the mean dose) impact symptoms at >1 timepoints. Associations at a single timepoint were found for cerebrovascular condition, ECOG status and non-steroidal anti-inflammatory drug intake. Peak incidence analysis shows the impact of baseline, bowel and cerebrovascular condition and smoking status. Conclusions The prevalence and incidence analysis provide a complementary view for urinary symptom prediction. Sustained impacts across time points were found for several factors while some associations were not repeated at different time points suggesting poorer or transient impact. [ABSTRACT FROM AUTHOR]

Purpose To use a high-quality multicenter trial dataset to determine dose-volume effects for gastrointestinal (GI) toxicity following radiation therapy for prostate carcinoma. Influential dose-volume histogram regions were to be determined as functions of dose, anatomical location, toxicity, and clinical endpoint. Methods and Materials Planning datasets for 754 participants in the TROG 03.04 RADAR trial were available, with Late Effects of Normal Tissues (LENT) Subjective, Objective, Management, and Analytic (SOMA) toxicity assessment to a median of 72 months. A rank sum method was used to define dose-volume cut-points as near-continuous functions of dose to 3 GI anatomical regions, together with a comprehensive assessment of significance. Univariate and multivariate ordinal regression was used to assess the importance of cut-points at each dose. Results Dose ranges providing significant cut-points tended to be consistent with those showing significant univariate regression odds-ratios (representing the probability of a unitary increase in toxicity grade per percent relative volume). Ranges of significant cut-points for rectal bleeding validated previously published results. Separation of the lower GI anatomy into complete anorectum, rectum, and anal canal showed the impact of mid-low doses to the anal canal on urgency and tenesmus, completeness of evacuation and stool frequency, and mid-high doses to the anorectum on bleeding and stool frequency. Derived multivariate models emphasized the importance of the high-dose region of the anorectum and rectum for rectal bleeding and mid- to low-dose regions for diarrhea and urgency and tenesmus, and low-to-mid doses to the anal canal for stool frequency, diarrhea, evacuation, and bleeding. Conclusions Results confirm anatomical dependence of specific GI toxicities. They provide an atlas summarizing dose-histogram effects and derived constraints as functions of anatomical region, dose, toxicity, and endpoint for informing future radiation therapy planning. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: To investigate the hypothesis that primary tumor volume is prognostic independent of T and N stages in patients with non-small cell lung cancer (NSCLC) treated by definitive radiotherapy. Materials and methods: Multicenter prospective observational study. Patient eligibility: pathologically proven stage I–III non-small cell lung cancer planned for definitive radiotherapy (minimum 50Gy in 20 fractions) using CT-based contouring. Volumes of the primary tumor and enlarged nodes were measured according to a standardized protocol. Survival was adjusted for the effect of T and N stage. Results: There were 509 eligible patients. Five-year survival rates for tumor volume grouped by quartiles were, for increasing tumor volume, 22%, 14%, 15% and 21%. Larger primary tumor volume was associated with shorter survival (HR=1.060 (per doubling); 95% CI 1.01–1.12; P =0.029). However, after adjusting for the effects of T and N stage, there was no evidence for an association (HR=1.029, 95% CI, 0.96–1.10, P =0.39). There was evidence, however, that larger primary tumor volume was associated with an increased risk of dying, independently of T and N stage, in the first 18months but not beyond. Conclusions: In patients treated by non-surgical means we were unable to show that lung tumor volume, overall, provides additional prognostic information beyond the T and N stage (TNM, 6th edition). There is evidence, however, that larger primary tumor volume adversely affects outcome only within the first 18months. Larger tumor size alone should not by itself exclude patients from curative (chemo)radiotherapy. [Copyright &y& Elsevier]

A previously developed method for achieving patient relocation in fractionated stereotactic radiotherapy (attachment of an infrared fiducial system to a bite tray) relies on the integrity of a bite tray system that incorporates moulding to the patient’s upper dentition. Reproducible and accurate patient positioning requires stability of the bite tray and mould during the full treatment process, both during the time the bite tray is inserted in the patient’s mouth, and between separate bite tray insertions. The optimum construction method for a stable reproducible tray has not been sufficiently investigated. We undertook a study to identify factors which might influence the integrity of the hard palate bite tray system. Reprosil Fast Set Putty was used to construct 3 impression conditions; teeth only; teeth and alveolar sulcus; and teeth, alveolar sulcus, and the hard palate. Reproducibility was assessed by volunteers inserting the impressions multiple times and recording the locations of 8 standard reference points. Our results showed the optimal impression technique (i.e., the one that led to the smallest ranges in positional and rotational errors) was that which incorporated the teeth, alveolar sulcus, and hard palate. [Copyright &y& Elsevier]

Purpose: To assess the potential for sucralfate administered rectally to reduce the risk of late rectal morbidity in patients undergoing nonconformal radiotherapy (RT) for carcinoma of the prostate and to study the variables potentially contributing to late rectal morbidity and particularly to explore the relationship between acute and late toxicity.Methods and Materials: Eighty-six patients with localized prostate carcinoma were randomized in a double-blind, placebo-controlled study to a daily enema of 3 g of sucralfate in a 15-mL suspension or the same suspension without sucralfate. The enema began the first day of RT and was continued for 2 weeks after treatment completion. The primary end point of the study was acute Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer (EORTC) toxicity; however, the patients were followed for an additional 5 years on a 6-month basis. The evaluation included late RTOG/EORTC toxicity and a patient self-assessment questionnaire.Results: With a median follow-up of 5 years, the Kaplan-Meier probability of late Grade 2 RTOG/EORTC toxicity was 12% (95% confidence interval [CI] 2–22%) for placebo and 5% (95% CI 0–12%) for sucralfate (p = 0.26). The probability of late rectal bleeding was 59% (95% CI 45–73%) for placebo and 54% (95% CI 40–68%) for sucralfate. No statistically significant difference was found between the treatment arms for the peak incidence of any of the other patient self-assessment variables. Cox proportional hazards modeling indicated acute RTOG/EORTC toxicity of Grade 2 or greater was associated with a hazard ratio of 2.74 (95% CI 1.31–5.73) for the development of late toxicity of Grade 1 or greater. Substituting the patient self-assessment variables for acute RTOG/EORTC toxicity revealed that rectal pain of a moderate or severe grade during RT was the best predictor of the subsequent development of late toxicity, with a hazard ratio of 3.44 (95% CI 1.68–7).Conclusion: The results of this study do not support the use of sucralfate administered rectally as a method for reducing the late toxicity of nonconformal RT for prostate cancer. There appears to be an association between the development of acute and subsequent late toxicity, although the nature of this association remains to be determined. [Copyright &y& Elsevier]