Background and objective Delivering radiotherapy to the bladder is challenging as it is a mobile, deformable structure. Dose-escalated adaptive image-guided radiotherapy could improve outcomes. RAIDER aimed to demonstrate the safety of such a schedule. Methods RAIDER is an international phase 2 noncomparative randomised controlled trial (ISRCTN26779187). Patients with unifocal T2-T4a urothelial bladder cancer were randomised (1:1:2) to standard whole bladder radiotherapy (WBRT), standard-dose adaptive radiotherapy (SART), or dose-escalated adaptive radiotherapy (DART). Two fractionation (f) schedules recruited independently. WBRT and SART dose was 55 Gy/20f or 64 Gy/32f, and DART dose was 60 Gy/20f or 70 Gy/32f. For SART and DART, a radiotherapy plan (small, medium, or large) was chosen daily. The primary endpoint was the proportion of patients with radiotherapy-related late Common Terminology Criteria for Adverse Events grade ≥3 toxicity; the trial was designed to rule out >20% toxicity with DART. Key findings and limitations A total of 345 patients were randomised between October 2015 and April 2020: 41/46 WBRT, 41/46 SART, and 81/90 DART patients in the 20f/32f cohorts, respectively. The median age was 72/73 yr; 78%/85% had T2 tumours, 46%/52% had neoadjuvant chemotherapy, and 70%/71% had radiosensitising therapy. The median follow-up was 42.1/38.2 mo. Sixty-six of 77 (86%) 20f and 74 of 82 (90%) 32f participants planned for DART met the mandatory medium plan dose constraints. Radiotherapy-related grade ≥3 toxicity was reported in one of 58 patients (90% confidence interval [CI] 0.1, 7.9) with 20f DART and zero of 56 patients with 32f DART. Two-year overall survival was 77% (95% CI 69, 82) for WBRT + SART and 80% (95% CI 73, 85) for DART (hazard ratio = 0.84, 95% CI 0.59, 1.21, p = 0.4). Thirteen of 345 (3.8%) participants had salvage cystectomy. Conclusions and clinical implications Grade ≥3 late toxicity was low. DART was safe and feasible to deliver, meeting preset toxicity thresholds. Disease-related outcomes are promising for dose-escalated treatments, with a low salvage cystectomy rate and overall survival similar to that seen in cystectomy cohorts.

AimsAdding concurrent (chemo)therapy to radiotherapy improves outcomes for muscle-invasive bladder cancer patients. A recent meta-analysis showed superior invasive locoregional disease control for a hypofractionated 55 Gy in 20 fractions schedule compared with 64 Gy in 32 fractions. In the RAIDER clinical trial, patients undergoing 20 or 32 fractions of radical radiotherapy were randomised (1:1:2) to standard radiotherapy or to standard-dose or escalated-dose adaptive radiotherapy. Neoadjuvant chemotherapy and concomitant therapy were permitted. We report exploratory analyses of acute toxicity by concomitant therapy-fractionation schedule combination.Materials and methodsParticipants had unifocal bladder urothelial carcinoma staged T2-T4a N0 M0. Acute toxicity was assessed (Common Terminology Criteria for Adverse Events) weekly during radiotherapy and at 10 weeks after the start of treatment. Within each fractionation cohort, non-randomised comparisons of the proportion of patients reporting treatment emergent grade 2 or worse genitourinary, gastrointestinal or other adverse events at any point in the acute period were carried out using Fisher's exact tests.ResultsBetween September 2015 and April 2020, 345 (163 receiving 20 fractions; 182 receiving 32 fractions) patients were recruited from 46 centres. The median age was 73 years; 49% received neoadjuvant chemotherapy; 71% received concomitant therapy, with 5-fluorouracil/mitomycin C most commonly used: 44/114 (39%) receiving 20 fractions; 94/130 (72%) receiving 32 fractions. The acute grade 2+ gastrointestinal toxicity rate was higher in those receiving concomitant therapy compared with radiotherapy alone in the 20-fraction cohort [54/111 (49%) versus 7/49 (14%), P < 0.001] but not in the 32-fraction cohort (P = 0.355). Grade 2+ gastrointestinal toxicity was highest for gemcitabine, with evidence of significant differences across therapies in the 32-fraction cohort (P = 0.006), with a similar pattern but no significant differences in the 20-fraction cohort (P = 0.099). There was no evidence of differences in grade 2+ genitourinary toxicity between concomitant therapies in either the 20- or 32-fraction cohorts.ConclusionGrade 2+ acute adverse events are common. The toxicity profile varied by type of concomitant therapy; the gastrointestinal toxicity rate seemed to be higher in patients receiving gemcitabine.

446 Background: The bladder is a mobile, deformable structure which makes radiotherapy (RT) delivery challenging. Plan of the day (POD) adaptive image guided RT and tumour boost dose escalation can optimise treatment. We aimed to define a feasible, safe schedule for muscle invasive bladder cancer (BC) using these techniques. Methods: RAIDER (ISRCTN 26779187) is a 3-arm, international phase II trial. Participants (pts) had unifocal T2-T4a urothelial BC and were randomized (1:1:2) to: standard whole bladder RT (WBRT), standard dose adaptive tumour focused RT (SART) or dose escalated adaptive tumour boost RT (DART). Two fractionation (f) schedules recruited independently. WBRT and SART dose was 64Gy/32f or 55Gy/20f and DART was 70Gy/32f or 60Gy/20f. For SART and DART, POD (small, medium, large) was chosen daily. Neoadjuvant chemotherapy (NAC) and concomitant radiosensitising therapy (CTh) were permitted. Primary endpoint is proportion of pts with RT related CTCAE grade≥3 (G≥3) toxicity 6-18 months (m) after RT. A non-comparative design to rule out >20% G≥3 toxicity in DART pts required 57 evaluable DART pts in each fractionation cohort (90% power, 5% 1-sided alpha). Adverse events (AE) are treatment emergent with RT relatedness assessed blind to treatment allocation. In each fractionation cohort, toxicity analysis is by treatment received in the evaluable population (pts with at ≥1 toxicity assessment between 6-18m). 3m local control was assessed by cystoscopic biopsy. Cancer outcomes are analysed by intention-to-treat with fractionation cohorts combined. Results: 345 pts were randomised (Oct 2015 - Apr 2020): 46/41 WBRT, 46/41 SART and 90/81 DART pts in 32f/20f cohorts respectively. Baseline characteristics for 32f/20f were median age 73 years (IQR 67, 79)/ 72 (67, 79); 83%/ 78% T2; 46%/ 52% had NAC and 71%/ 70% CTh. Median follow-up was 32f: 38.2m (IQR 26.2, 50.2), 20f: 42.1m (35.6, 50.1). 3588/6222 (58%) fractions delivered to SART and DART pts used small or large POD. Late toxicity outcomes are shown in table. RT related G≥3 in 20f DART was 1/58 (90% CI 0.1, 7.9) and in 32f DART was 0/57. 3m local control was achieved in 44/51 (86%) WBRT, 45/53 (85%) SART and 82/92(89%) DART. 2 year survival was 79% (95% CI: 69, 86) WBRT, 74% (63, 82) SART and 80% (73, 85) DART. Conclusions: Late G≥3 toxicity was low in all treatment groups. 20f and 32f DART was safe and feasible to deliver with toxicity rates below predefined thresholds. Local control for image guided (chemo)RT was good. CTCAE G≥3 and G≥2 treatment emergent toxicity 6-18m after RT. Clinical trial information: 26779187 . [Table: see text]

INTRODUCTION:Around 300 children in Australia and New Zealand (ANZ) undergo a course of radiation treatment (RT) each year. A fortnightly videoconference for radiation oncologists managing children started in 2013. We conducted an audit of the videoconference to assess its influence on the care of children who receive RT in ANZ.METHODS:De-identified data from minutes (August 2013-December 2019) were analysed retrospectively using three categories: meeting participation, case presentations and management decisions.RESULTS:There were 119 meetings and 334 children discussed over the six-year audit period with regular attendance from four of 11 centres treating children in ANZ. Most cases (80%) were discussed prior to RT. A change in the overall management plan was recommended for around one in eight patients (35/334, 13%). RT plan reviews were performed in 79 cases (23%). Adjustments were made to the target volume contours or treatment plan in 8% (6/79).CONCLUSION:Increasing the frequency of the meeting to weekly and compliant with the RANZCR Peer Review Audit Tool has the capacity to review all paediatric RT patients in ANZ prior to RT and initiate changes for as many as one in eight children treated by RT each year. The meeting should be considered a core component necessary to maintain expertise in paediatric RT in all centres providing RT for children in ANZ while also acting as a proton referral panel as more children are referred abroad for proton therapy before the Australian Bragg Centre for Proton Therapy opens in Adelaide in 2024.

503 Background: Level 1 evidence exists for the use of both neoadjuvant chemotherapy (NAC) and concomitant radiosensitization (CRS) to improve outcomes in patients receiving radical radiotherapy (RT) for muscle invasive bladder cancer, but uptake has been patchy. We report here the current patterns of usage in an ongoing trial of adaptive radiotherapy. Methods: RAIDER is an international randomized phase II trial recruiting patients with unifocal T2-T4a urothelial carcinoma of the bladder suitable for RT (ISCRTN:26779187). Patients are randomized in a 1:1:2 ratio to one of 3 arms: Standard whole bladder RT (control); Standard dose adaptive tumour focused RT; Dose escalated (DE) adaptive tumour boost RT. Standard dose patients are treated to either 64Gy/32f or 55Gy/20f and DE patients to 70Gy in 32f or 60Gy in 20f. Patients are encouraged to receive NAC and CRS. The primary endpoint is the rate of late toxicity 6-18 months post treatment in arm 3, with secondary endpoints of patient reported and disease related outcomes. Results: To August 2019, 285 patients had been recruited. Median age is 72 years (IQR 67-79). Stage of disease is T2 79%, T3 19%, T4 2%; 19% have hydronephrosis. Patients receiving NAC were more likely to be PS 0 at trial entry (70% v 45%). Variation in frequency of CRS use is seen across sites, with some offering to >90% of participants and some <50%. Data on NAC and CRS use is available for 249 patients recruited to date is shown in table. Conclusions: In this ongoing clinical trial the majority of patients are receiving NAC and/or CRS. However, uptake is not universal with ~30% of patients not receiving low dose CRS, including some who have received NAC. Clinical trial information: 26779187. [Table: see text]

IntroductionThe aim of the study is to review the long-term oncological outcomes and adverse effects of post-operative radiotherapy (PORT) for Stage I/II seminoma patients in an Australian radiation treatment centre.MethodsThis is a retrospective study of 125 patients with Stage I/II seminoma treated with PORT at the Alfred Health Radiation Oncology Service between 1992 and 2013. Patients were linked to the Victorian Cancer Registry to enable confirmation of survival and diagnosis of secondary malignancies (SM). The relapse-free survival (RFS), testicular-cancer-specific survival (TCSS), overall survival (OS) and SM-free survival (SMFS) were estimated with Kaplan-Meier methods.ResultsThe median age at diagnosis was 36 (range 20-62). The median time between diagnosis and PORT was 1.6 months (range: 0.5-4.5). Fifty patients (40%) had PORT to the para-aortic (PA) target alone, while the remaining had PORT to PA and ipsilateral or bilateral iliac lymph nodes. There were no acute adverse effects requiring admission. The median follow-up after PORT was 7.8 years (range = 0.1-19.1). There were two relapses, both of which occurred within 1 year of PORT (estimated 10-year RFS = 98.4%). Five deaths were reported, none of which were testicular cancer-related death (estimated 10-year TCSS = 100%, 10-year OS = 97.3%). There were seven SM (one lower lip cancer, one upper shoulder melanoma, one mesothelioma, two prostate cancer, one acute myeloid leukaemia and one contralateral testicular seminoma) reported in six patients, with estimated 10-year SMFS of 92.9%.ConclusionOur series confirms excellent oncological outcomes among patients with Stage I/II seminoma treated with PORT, with uncommon occurrence of SM.

Collected real-life clinical target volume (CTV) displacement data show that some patients undergoing external beam radiotherapy (EBRT) demonstrate significantly more fraction-to-fraction variability in their displacement ('random error') than others. This contrasts with the common assumption made by historical recipes for margin estimation for EBRT, that the random error is constant across patients. In this work we present statistical models of CTV displacements in which random errors are characterised by an inverse gamma (IG) distribution in order to assess the impact of random error variability on CTV-to-PTV margin widths, for eight real world patient cohorts from four institutions, and for different sites of malignancy. We considered a variety of clinical treatment requirements and penumbral widths. The eight cohorts consisted of a total of 874 patients and 27 391 treatment sessions. Compared to a traditional margin recipe that assumes constant random errors across patients, for a typical 4 mm penumbral width, the IG based margin model mandates that in order to satisfy the common clinical requirement that 90% of patients receive at least 95% of prescribed RT dose to the entire CTV, margins be increased by a median of 10% (range over the eight cohorts -19% to +35%). This substantially reduces the proportion of patients for whom margins are too small to satisfy clinical requirements.

Poster: 2014 CSM / R-0195 / Demonstration of the quality assurance benefits of a new in vivo source position verification system for high dose-rate prostate brachytherapy by: J. Millar, R. Smith, B. Matheson, B. Hindson, A. Haworth, M. Taylor, L. McDermott, R. Franich; MELBOURNE/AU

Background and purpose: Erectile function (EF) is commonly affected following prostate cancer treatment. We aim to evaluate the long-term EF following seed brachytherapy (BT) treatment.Materials and methods: The study consisted of 366 patients treated with BT at our institution, who completed the IIEF-5 questionnaire and reported no or mild erectile dysfunction (ED) pre-BT. The probability of EF preservation post-BT was estimated using the Kaplan-Meier methods. The difference in EF preservation by patient-, tumour- and treatment-related factors was assessed using the log-rank test. Multivariate Cox regression was used to estimate the effect of each factor on EF preservation.Results: Of the 366 patients, 277 (76%) reported normal EF, and 89 (24%) reported mild ED. The patients were followed-up for a median of 41 months (range: 3-124), and the 5-year actuarial rate of EF preservation was 59%. Age at BT seed implant, presence of medical comorbidities, Gleason score and the biologically effective dose (BED) are associated with EF preservation (P < 0.005). The association for these four factors remains statistically significant in multivariate analysis, with Gleason score having the strongest effect (HR = 3.7; 95% Cl = 2.6-5.4).Conclusion: The 5-year actuarial rate of EF preservation post-BT in our cohort is 59%, and is influenced by multiple factors. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

We report mature disease-control outcomes for men treated at a single Australian institution with permanent implant brachytherapy to the prostate (PIBT) with 125I seeds. This was a prospective cohort study of consecutive men treated with PIBT monotherapy for prostate cancer (PCa) between December 1998 and 31 May 2009. Men were treated using a "Seattle-type" approach with TRUS volume study prior to the implant with 125I seeds, preloaded into transperineal needles; the planned prescribed dose was 145 Gy; implants were performed using TRUS and fluoroscopy guidance. Computed tomogram based post-implant dosimetry was performed a month after implant and post-implant dose metrics recorded. Patients returned for followup (FU) as clinically indicated, but generally at 6 months, and then every year. The endpoints were "biochemical failure" ("BF", Phoenix), death from any cause (overall survival, OS) and death from PCa (PCa-specific survival, PCSS). Univariate and multivariable analysis (STATA 12) was used to identify factors associated with BF-free survival (BFFS) and 2-sided significance testing with P<0.05 considered statistically significant. The median age of 582 implanted men was 62 years (yr): 86% had cT2a or less; the median PSA was 5.6 ng/mL (4% >10); 19% had Gleason score 7; and 74% had low-risk (LR), with the remainder intermediate-risk disease (IR). Cytoreductive androgen deprivation was used in 13% for a median period of 180 days. The median D90 was 148 Gy (interquartile range 131-158 Gy), and the median V100%, V150%, and V200% were 90%, 49%, and 20% respectively. There was no perioperative mortality. The mean PSA after implant showed the "bounce" peak at 2 yr; by 5 yr, 84% of all men had PSA of <0.5 ng/mL; by 8 yr this proportion was 88%. The median PSA at last FU of men without BF was 0.1 ng/mL; 81% of last PSA measurements were ≤0.40 ng/mL and 66% ≤0.2 ng/mL. The median FU was 6.0 yr. BF occurred in 36 men; 13 have commenced AD salvage. Bone metastases occurred in ten men. There were 28 deaths, five from prostate cancer; the other 23 from unrelated causes. The 5- and 8-yr OS's were 97% and 94%. The estimated PCSS's and BFFS's at the same times were 99.6% and 95%, and 99.6% and 91%, respectively. For men with LR disease, the 5- and 8-yr BFFS's were 95% and 92%. For IR men, they were 95% and 82%, respectively (P=0.2027). Biochemical control at last FU was highly associated with reaching a nadir PSA of <0.5 mg/mL. These biochemical control rates from the largest Australian series reported to date at five and eight years fall into the middle of the range of results reported by European and North American centers. The disease control rates we report support the the use of PIBT as effective treatment in men with LR and IR PCa.

Curative radiotherapy, with or without concurrent chemotherapy, is recognized as a standard treatment option for muscle-invasive bladder cancer. It is commonly used for two distinct groups of patients: either for those medically unfit for surgery, or as part of a bladder preserving management plan incorporating the possibility of salvage cystectomy. However, in both situations, the approach to radiotherapy varies widely around the world. The Australian and New Zealand Faculty of Radiation Oncology Genito-Urinary Group recognised a need to develop consistent, evidence-based guidelines for patient selection and radiotherapy technique in the delivery of curative radiotherapy. Following a workshop convened in May 2009, a working party collated opinions and conducted a wide literature appraisal linking each recommendation with the best available evidence. This process was subject to ongoing re-presentation to the Faculty of Radiation Oncology Genito-Urinary Group members prior to final endorsement. These Guidelines include patient selection, radiation target delineation, dose and fractionation schedules, normal tissue constraints and investigational techniques. Particular emphasis is given to the rationale for the target volumes described. These Guidelines provide a consensus-based framework for the delivery of curative radiotherapy for muscle-invasive bladder cancer. Widespread input from radiation oncologists treating bladder cancer ensures that these techniques are feasible in practice. We recommend these Guidelines be adopted widely in order to encourage a uniformly high standard of radiotherapy in this setting, and to allow for better comparison of outcomes.

PURPOSE:High-dose-rate brachytherapy is an established technique to deliver a conformal dose of radiation to patients with prostate cancer. The William Buckland Radiotherapy Center has been performing high-dose-rate brachytherapy with external beam radiation treatment for prostate cancer since 1998 and has an extensive prospective database on all patients treated. The purpose of this analysis was to assess the risk of stricture formation and identify the predictive or causative factors. METHODS AND MATERIALS:Three hundred fifty-four patients were treated between 1998 and 2008. Patients received one of three differing dose schedules: 20Gy in four treatments (20Gy/4), 18Gy/3, and 19Gy/2 during three sequential time periods. Nelson-Aalen cumulative hazard modeling was used to estimate risk of events over time. Potential risk factors, including dose, were identified and used in the analysis. RESULTS:There were 45 patients who developed at least one stricture, an overall risk of 8.2% at 2 years. The 2-year risk of stricture formation was 3.4%, 2.3%, and 31.6% for 18Gy/3, 20Gy/4, and 19Gy/2, respectively. Most strictures occurred in the bulbomembranous urethra (50%) or external sphincter region (33%). On multivariable analysis, the dose schedule used was the only significant predictor for increased stricture formation. CONCLUSIONS:In our patients, those who received 19Gy/2 were at a significantly higher risk of stricture formation. Most of these strictures were mild, requiring only one intervention but a 2-year stricture risk of 31.6% was striking, and we have modified our protocol.

Early approaches to characterizing errors in target displacement during a fractionated course of radiotherapy assumed that the underlying fraction-to-fraction variability in target displacement, known as the 'treatment error' or 'random error', could be regarded as constant across patients. More recent approaches have modelled target displacement allowing for differences in random error between patients. However, until recently it has not been feasible to compare the goodness of fit of alternate models of random error rigorously. This is because the large volumes of real patient data necessary to distinguish between alternative models have only very recently become available. This work uses real-world displacement data collected from 365 patients undergoing radical radiotherapy for prostate cancer to compare five candidate models for target displacement. The simplest model assumes constant random errors across patients, while other models allow for random errors that vary according to one of several candidate distributions. Bayesian statistics and Markov Chain Monte Carlo simulation of the model parameters are used to compare model goodness of fit. We conclude that modelling the random error as inverse gamma distributed provides a clearly superior fit over all alternatives considered. This finding can facilitate more accurate margin recipes and correction strategies.