Conjoint Professor Jarad Martin

Oesophageal adenocarcinoma is a poor prognosis cancer and the molecular features underpinning response to treatment remain unclear. We investigate whole genome, transcriptomic and methylation data from 115 oesophageal adenocarcinoma patients mostly from the DOCTOR phase II clinical trial (Australian New Zealand Clinical Trials Registry-ACTRN12609000665235), with exploratory analysis pre-specified in the study protocol of the trial. We report genomic features associated with poorer overall survival, such as the APOBEC mutational and RS3-like rearrangement signatures. We also show that positron emission tomography non-responders have more sub-clonal genomic copy number alterations. Transcriptomic analysis categorises patients into four immune clusters correlated with survival. The immune suppressed cluster is associated with worse survival, enriched with myeloid-derived cells, and an epithelial-mesenchymal transition signature. The immune hot cluster is associated with better survival, enriched with lymphocytes, myeloid-derived cells, and an immune signature including CCL5, CD8A, and NKG7. The immune clusters highlight patients who may respond to immunotherapy and thus may guide future clinical trials.

Objective: This study assesses whether fusion or cognitive magnetic resonance imaging (MRI)-guided prostate targeted and systematic transperineal biopsies (TPB) increase detection of clinically significant prostate cancer (csPCa). Materials and Methods: A retrospective analysis was completed of patients (2018¿2020) undergoing 3-Tesla multiparametric prostate MRI informing targeted (either cognitive or MIM software fusion approach) and systematic TPB. ISUP (International Society of Urological Pathology) grade group ¿ 2 was considered csPCa. Results: A total of 355 cases from 4 urologists were included; 131 were fusion and 224 were cognitive MRI-guided biopsies. Of all csPCa found, 86.8% (n = 171) of cases were confirmed to be at the MRI-indicated location and 11.6% were found as part of active surveillance. In all, 45.0% of the fusion group were found to have csPCa, compared to 62.05% (n = 139) in the cognitive group (p = 0.002). csPCa detection rates varied between urologists (41% to 78%, p < 0.001), so a subgroup analysis was performed on Urologist A; 45.0% of fusion and 41.3% of cognitive biopsies had csPCa (p = 0.644). Multinomial logistic regression analysis showed that biopsy type, being on active surveillance, number of biopsy cores, iPSA (initial Prostate Specific Antigen) value or PIRADS (Prostate Imaging-Reporting and Data System) score made no significant difference in whether csPCa was found. Conclusion: Cognitive and fusion targeting had similar csPCa detection rates. Further prospective studies would be beneficial to validate these findings. Level of evidence: 2b (according to Oxford Centre for Evidence-Based Medicine)

Urinary toxicity is common following pelvic radiotherapy and can have a substantial negative effect on survivorship. Due to its prevalence and the increasing number of related clinical trials, localised prostate cancer radiotherapy is a useful illustrative tool to explore urinary toxicity. A good understanding of the interplay between anatomy, radiation-sensitive cell populations, and treatment sequencing is necessary for optimal outcomes. Emerging evidence suggests that the prostatic urethra is a radiation-sensitive structure, not only for stricture development, but also chronic irritative symptoms. Tools now exist not only to identify the urethra, but also to direct radiation dose away from the urethra, with early data suggesting that this reduces moderate-to-severe late urinary toxicity. Coupled with new evidence supporting dominant nodule microboosting and ultrahypofractionation as emerging standards of care, urethral sparing radiotherapy is a powerful tool against radiation induced urinary toxicity while also maximising disease control.

Volume delineation quality assurance (QA) is particularly important in clinical trial settings where consistent protocol implementation is required, as outcomes will affect future as well current patients. Currently, where feasible, this is conducted manually, which is time consuming and resource intensive. Although previous studies mostly focused on automating delineation QA on CT, magnetic resonance imaging (MRI) is being increasingly used in radiotherapy treatment. In this work, we propose to perform automatic delineation QA on prostate MRI for both the clinical target volume (CTV) and organs-at-risk (OARs) by using delineations generated by 3D Unet variants as benchmarks for QA. These networks were trained on a small gold standard atlas set and applied on a multicentre radiotherapy clinical trial dataset to generate benchmark delineations. Then, a QA stage was designed to recommend 'pass', 'minor correction' and 'major correction' for each manual delineation in the trial set by thresholding its Dice similarity coefficient to the network generated delineation. Among all 3D Unet variants explored, the Unet with anatomical gates in an AtlasNet architecture performed the best in delineation QA, achieving an area under the receiver operating characteristics curve of 0.97, 0.92, 0.89 and 0.97 for identifying unacceptable (major correction) delineations with a sensitivity of 0.93, 0.73, 0.74 and 0.90 at a specificity of 0.93, 0.86, 0.86 and 0.95 for bladder, prostate CTV, rectum and gel spacer respectively. To the best of our knowledge, this is the first study to propose automated delineation QA for a multicentre radiotherapy clinical trial with treatment planning MRI. The methods proposed in this work can potentially improve the accuracy and consistency of CTV and OAR delineation in radiotherapy treatment planning.

Purpose: Recent evidence shows the noninferiority of hypofractionated radiation therapy regimens compared with conventional regimens in the treatment of prostate cancer (PCa). Hypofractionation has benefits for both the patient and health care system, because of the shorter treatment duration. Despite this advantage, the uptake of hypofractionation can be slow. Here we investigate the factors influencing the changing use of moderate hypofractionation (HypoRT) for the treatment of PCa. Methods and Materials: We conducted a population-based, retrospective, consecutive cohort study using the 2014 to 2018 Outpatient Radiation Oncology Data from public and private treatment facilities in New South Wales, Australia. Included participants had a PCa diagnosis of any risk, and they completed curative-intent external beam radiation therapy without treatment to lymph nodes. Factors potentially affecting use of HypoRT were examined using a 3-level hierarchical logistic regression model. The effects were reported using adjusted, median, or interval odds ratios. Results: The study included 4915 patients. Of these, 4053 patients (82.5%) received conventional fractionation, and 862 patients (17.5%) received HypoRT. HypoRT utilization increased from 5.2% in 2014 to 40.3% in 2018. The treating radiation oncologist, treatment facility, and increasing distance to treatment centers had the greatest influence on HypoRT uptake. The main limitation was the lack of stratification by PCa risk categorization. Conclusions: Although HypoRT uptake has considerably increased between 2014 and 2018, it remains variable among facilities and treating radiation oncologists. Strategies are being explored to reduce inter-clinician variability.

Radiation therapy is a key component of modern-day cancer therapy and can reduce the rates of recurrence and death from cancer. However, it can increase risk of cardiovascular (CV) events, and our understanding of the timeline associated with that risk is shorter than previously thought. Risk mitigation strategies, such as different positioning techniques, and breath hold acquisitions as well as baseline cardiovascular risk stratification that can be undertaken at the time of radiotherapy planning should be implemented, particularly for patients receiving chest radiation therapy. Primary and secondary prevention of cardiovascular disease (CVD), as appropriate, should be used before, during, and after radiation treatment in order to minimize the risks. Opportunistic screening for subclinical coronary disease provides an attractive possibility for primary/secondary CVD prevention and thus mitigation of long-term CV risk. More data on long-term clinical usefulness of this strategy and development of appropriate management pathways would further strengthen the evidence for the implementation of such screening. Clear guidelines in initial cardiovascular screening and cardiac aftercare following radiotherapy need to be formulated in order to integrate these measures into everyday clinical practice and policy and subsequently improve post-treatment morbidity and mortality for these patients.

IMPORTANCE Randomized clinical trials in prostate cancer have reported noninferior outcomes for hypofractionated radiation therapy (HRT) compared with conventional RT (CRT); however, uptake of HRT across jurisdictions is variable. OBJECTIVE To evaluate the use of HRT vs CRT in men with nonmetastatic prostate cancer and compare patient-reported outcomes (PROs) at a population level. DESIGN, SETTING, AND PARTICIPANTS Registry-based cohort study from the Australian and New Zealand Prostate Cancer Outcomes Registry (PCOR-ANZ). Participantswere men with nonmetastatic prostate cancer treated with primary RT (excluding brachytherapy) from January 2016 to December 2019. Data were analyzed in March 2021. EXPOSURES HRT defined as 2.5 to 3.3 Gy and CRT defined as 1.7 to 2.3 Gy per fraction. MAIN OUTCOMES AND MEASURES Temporal trends and institutional, clinicopathological, and sociodemographic factors associated with use of HRT were analyzed. PROs were assessed 12 months following RT using the Expanded Prostate Cancer Index Composite (EPIC)-26 Short Form questionnaire. Differences in PROs were analyzed by adjusting for age and National Comprehensive Cancer Network risk category. RESULTS Of 8305 men identified as receiving primary RT, 6368 met the inclusion criteria for CRT (n = 4482) and HRT (n = 1886). The median agewas 73.1 years (IQR, 68.2-77.3 years), 2.6%(168) had low risk, 45.7%(2911) had intermediate risk, 44.5%(2836) had high-/very high-risk, and 7.1% (453) had regional nodal disease. Use of HRT increased from 2.1% (9 of 435) in the first half of 2016 to 52.7%(539 of 1023) in the second half of 2019, with lower uptake in the high-/very high-risk (1.9% [4 of 215] to 42.4%[181 of 427]) compared with the intermediate-risk group (2.2%[4 of 185] to 67.6%[325 of 481]) (odds ratio, 0.26; 95%CI, 0.15-0.45). Substantial variability in the use of HRT for intermediate-risk disease remained at the institutional level (median 53.3%; range, 0%-100%) and clinician level (median 57.9%; range, 0%-100%) in the last 2 years of the study period. There were no clinically significant differences across EPIC-26 urinary and bowel functional domains or bother scores. CONCLUSIONS AND RELEVANCE In this cohort study, use of HRT for prostate cancer increased substantially from 2016. This population-level data demonstrated clinically equivalent PROs and supports the continued implementation of HRT into routine practice. The wide variation in practice observed at the jurisdictional, institutional, and clinician level provides stakeholders with information that may be useful in targeting implementation strategies and benchmarking services.

Background and purpose: Magnetic resonance imaging (MRI)-only treatment planning is gaining in popularity in radiation oncology, with various methods available to generate a synthetic computed tomography (sCT) for this purpose. The aim of this study was to validate a sCT generation software for MRI-only radiotherapy planning of male and female pelvic cancers. The secondary aim of this study was to improve dose agreement by applying a derived relative electron and mass density (RED) curve to the sCT. Method and materials: Computed tomography (CT) and MRI scans of forty patients with pelvic neoplasms were used in the study. Treatment plans were copied from the CT scan to the sCT scan for dose comparison. Dose difference at reference point, 3D gamma comparison and dose volume histogram analysis was used to validate the dose impact of the sCT. The RED values were optimised to improve dose agreement by using a linear plot. Results: The average percentage dose difference at isocentre was 1.2% and the mean 3D gamma comparison with a criteria of 1%/1 mm was 84.0% ± 9.7%. The results indicate an inherent systematic difference in the dosimetry of the sCT plans, deriving from the tissue densities. With the adapted REDmod table, the average percentage dose difference was reduced to -0.1% and the mean 3D gamma analysis improved to 92.9% ± 5.7% at 1%/1 mm. Conclusions: CT generation software is a viable solution for MRI-only radiotherapy planning. The option makes it relatively easy for departments to implement a MRI-only planning workflow for cancers of male and female pelvic anatomy.

Introduction: The prostatic urethra is an organ at risk for prostate radiotherapy with genitourinary toxicities a common side effect. Many external beam radiation therapy protocols call for urethral sparing, and with modulated radiotherapy techniques, the radiation dose distribution can be controlled so that maximum doses do not fall within the prostatic urethral volume. Whilst traditional diagnostic MRI sequences provide excellent delineation of the prostate, uncertainty often remains as to the true path of the urethra within the gland. This study aims to assess if a high-resolution isotropic 3D T2 MRI series can reduce inter-observer variability in urethral delineation for radiotherapy planning. Methods: Five independent observers contoured the prostatic urethra for ten patients on three data sets; a 2¿mm axial CT, a diagnostic 3¿mm axial T2 TSE MRI and a 0.9¿mm isotropic 3D T2 SPACE MRI. The observers were blinded from each other¿s contours. A Dice Similarity Coefficient (DSC) score was calculated using the intersection and union of the five observer contours vs an expert reference contour for each data set. Results: The mean DSC of the observer vs reference contours was 0.47 for CT, 0.62 for T2 TSE and 0.78 for T2 SPACE (P¿<¿0.001). Conclusions: The introduction of a 0.9¿mm isotropic 3D T2 SPACE MRI for treatment planning provides improved urethral visualisation and can lead to a significant reduction in inter-observer variation in prostatic urethral contouring.

Background: Patients with oesophageal/gastro-oesophageal junction adenocarcinoma (EAC) not showing early metabolic response (EMR) to chemotherapy have poorer survival and histological response rates <5%. We investigated whether tailoring neoadjuvant therapy can improve outcomes in these patients. Patients and methods: Patients with resectable EAC were enrolled and randomised into two single-arm, multicentre phase II trials. After induction cisplatin and 5-fluorouracil (CF), all were assessed by day 15 positron emission tomography (PET). Patients with an EMR [maximum standardised uptake values (SUVmax) =35% reduction from baseline to day 15 PET] received a second CF cycle then oesophagectomy. Non-responders were randomised 1: 1 to two cycles of CF and docetaxel (DCF, n = 31) or DCF + 45 Gy radiotherapy (DCFRT, n = 35) then oesophagectomy. The primary end point was major histological response (<10% residual tumour) in the oesophagectomy specimen; secondary end points were overall survival (OS), progression-free survival (PFS), and locoregional recurrence (LR). Results: Of 124 patients recruited, major histological response was achieved in 3/45 (7%) with EMR, 6/30 (20%) DCF, and 22/35 (63%) DCFRT patients. Grade 3/4 toxicities occurred in 12/45 (27%) EMR (CF), 13/31 (42%) DCF, and 25/35 (71%) DCFRT patients. No treatment-related deaths occurred. LR by 3 years was seen in 5/45 (11%) EMR, 10/31 (32%) DCF, and 4/35 (11%) DCFRT patients. PFS [95% confidence interval (CI)] at 36 months was 47% (31% to 61%) for EMR, 29% (15% to 45%) for DCF, and 46% (29% to 61%) for DCFRT patients. OS (95% CI) at 60 months was 53% (37% to 67%) for EMR, 31% (16% to 48%) for DCF, and 46% (29% to 61%) for DCFRT patients. Conclusions: EMR is associated with favourable OS, PFS, and low LR. For non-responders, the addition of docetaxel augmented histological response rates, but OS, PFS, and LR remained inferior compared with responders. DCFRT improved histological response and PFS/LR outcomes, matching the EMR group. Early PET/CT has the potential to tailor therapy for patients not showing an early response to chemotherapy. Trial registration: ACTRN12609000665235.

Purpose: Kilovoltage intrafraction monitoring (KIM) is a novel software platform implemented on standard radiation therapy systems and enabling real-time image guided radiation therapy (IGRT). In a multi-institutional prospective trial, we investigated whether real-time IGRT improved the accuracy of the dose patients with prostate cancer received during radiation therapy. Methods and Materials: Forty-eight patients with prostate cancer were treated with KIM-guided SABR with 36.25 Gy in 5 fractions. During KIM-guided treatment, the prostate motion was corrected for by either beam gating with couch shifts or multileaf collimator tracking. A dose reconstruction method was used to evaluate the dose delivered to the target and organs at risk with and without real-time IGRT. Primary outcome was the effect of real-time IGRT on dose distributions. Secondary outcomes included patient-reported outcomes and toxicity. Results: Motion correction occurred in =1 treatment for 88% of patients (42 of 48) and 51% of treatments (121 of 235). With real-time IGRT, no treatments had prostate clinical target volume (CTV) D98% dose 5% less than planned. Without real-time IGRT, 13 treatments (5.5%) had prostate CTV D98% doses 5% less than planned. The prostate CTV D98% dose with real-time IGRT was closer to the plan by an average of 1.0% (range, ¿2.8% to 20.3%). Patient outcomes showed no change in the 12-month patient-reported outcomes compared with baseline and no grade =3 genitourinary or gastrointestinal toxicities. Conclusions: Real-time IGRT is clinically effective for prostate cancer SABR.

Purpose: Kilovoltage intrafraction monitoring (KIM) allows for real-time image guidance for tracking tumor motion in six-degrees-of-freedom (6DoF) on a standard linear accelerator. This study assessed the geometric accuracy and precision of KIM used to guide patient treatments in the TROG 15.01 multi-institutional Stereotactic Prostate Ablative Radiotherapy¿with KIM trial and investigated factors affecting accuracy and precision. Methods: Fractions from 44 patients with prostate cancer treated using KIM-guided SBRT were analyzed across four institutions, on two different linear accelerator models and two different beam models (6 MV¿and 10¿MV FFF). The geometric accuracy and precision of KIM was assessed from over 33¿000¿images (translation) and over 9000 images (rotation) by comparing the real-time measured motion to retrospective kV/MV triangulation. Factors potentially affecting accuracy, including contrast-to-noise ratio (CNR) of kV images and incorrect marker segmentation, were also investigated. Results: The geometric accuracy and precision did not depend on treatment institution, beam model or motion magnitude, but was correlated with gantry angle. The centroid geometric accuracy and precision of the KIM system for SABR prostate treatments was 0.0¿±¿0.5, 0.0¿±¿0.4 and 0.1¿±¿0.3¿mm for translation, and¿-0.1¿±¿0.6°, -0.1¿±¿1.4° and¿-0.1¿±¿1.0° for rotation in the AP, LR and SI directions respectively. Centroid geometric error exceeded 2¿mm for 0.05% of this dataset. No significant relationship was found between large geometric error and CNR or marker segmentation correlation. Conclusions: This study demonstrated the ability of KIM to locate the prostate with accuracy below other uncertainties in radiotherapy treatments, and the feasibility for KIM to be implemented across multiple institutions.

Introduction: Support and investment in increasing a research-active culture in clinical practice needs to be translated at the department and hospital levels as well as regional, state and national levels. We aimed to improve the research culture of our department, to enable more clinical staff to become more research competent and research active. Methods: We describe and discuss the appointment of a Director of Research and a Research Coordinator into our already-research-active department and the interactions at the research¿clinical interface. By identifying barriers and instituting enablers which ameliorate their effect, we explore how a clinical department can utilize the resources already available with the goal of developing a more confident and competent clinician-researcher culture as measured by a range of research metrics. Results: We observed an improved research culture within our department. Our department's improved research culture was reflected by increased numbers of peer-reviewed publications (of 30%), research students/supervisions (of 60%) and engagement of external speakers. We also observed double the number of first-authored peer-reviewed articles and a growth in conference presentations, posters and speaker invitations/awards. In the majority of the research performance metrics tracked, there was a steady improvement noted over the four years monitored. Conclusions: By responding to the barriers of staff (such as time, expertise and ideas) with structural and personal enablers, as well as funded resources, it is possible to develop research capacity and confidence in a clinical setting.

Three large randomised controlled trials have been published in the last year demonstrating the non-inferiority of moderate hypofractionation compared to conventional fractionation for localised prostate cancer with respect to both disease control and late toxicity at 5¿years. Furthermore, no clinically significant differences in patient-reported outcomes have emerged. More mature follow-up data are now also available from phase 2 studies confirming that moderate hypofractionation is associated with low rates of significant toxicity at 10¿years. Moving forward it is likely that appropriate patient selection, integration of androgen deprivation and attention to optimising technique will play a more important role than modest differences in dose-fractionation schedules. Here we briefly review the evidence, discuss issues of patient selection and provide an approach to implementing moderately hypofractionated radiation therapy for prostate cancer in clinical practice.

A urologist referred a 69-year-old man for a radiotherapy opinion regarding a recently diagnosed adenocarcinoma of the prostate. Annual serum prostate-specific antigen (PSA) testing over 7 years demonstrated a rise in PSA from 1.36 ng/mL to 5.8 ng/mL, prompting a transrectal ultrasound that revealed a heterogeneous 37-mL gland containing no visualized hypoechoic nodules. Biopsy disclosed a Gleason score 314 (grade group 2) adenocarcinoma of the prostate. The synoptic report stated that six of 14 cores and 17% of the tissue were involved, with the greatest core involvement being 80% at the right apex. Perineural invasion was present without lymphovascular invasion. Disease was present bilaterally at the base, midgland, and apex.His medical history was significant only for treated peptic ulcer disease and he was taking no medication. His International Prostate Symptom Score was six of 35, and he reported being sexually active with good erectile function. There was no family history of prostate cancer. He is retired. Digital rectal examination revealed moderate benign prostatic hypertrophy with no suspicious nodules. A staging computerized tomography (CT) scan of the abdomen and pelvis and a whole-body bone scan ordered by his referring urologist reported no evidence of metastatic disease. The patient had discussed surgical options with his urologist and now wished to consider radiotherapy approaches.

Objectives: To improve imaging utilisation and reduce the widespread overuse of staging investigations, in the form of computed tomography (CT) and whole-body bone scans for men with newly diagnosed prostate cancer in the Hunter region of NSW, Australia, by implementation of a multifaceted clinician-centred behaviour change programme. Patients and Methods: Records of all patients with a new diagnosis of prostate cancer were reviewed prior to the intervention (July 2014 to July 2015), and the results of this audit were presented to participating urologists by a clinical champion. Urologists then underwent focused education based on current guidelines. Patterns of imaging use for staging were then re-evaluated (November 2015 to July 2016). Patients were stratified into low-, intermediate- and high-risk groups as described by the D'Amico classification system. Results: A total of 144 patients were retrospectively enrolled into the study cohort. The use of diagnostic imaging for staging purposes significantly decreased in men with low- and intermediate-risk disease post intervention. In low-risk patients, the use of CT decreased from 43% to 0% (P = 0.01). A total of 21% of patients underwent bone scans in the pre-intervention group compared with18% in the post-intervention group (P = 0.84). In intermediate-risk patients, the use of CT decreased from 89% to 34% (P < 0.001), whilst the use of bone scan decreased from 63% to 37% (P = 0.02). In high-risk patients, the appropriate use of imaging was maintained, with CT performed in 87% compared with 85% and bone scan in 87% compared with 65% (P = 0.07). Conclusion: Our results show that a focused, clinician-centred education programme can lead to improved guideline adherence at a regional level. The assessment of trends and application of such a programme at a state-based or national level could be further assessed in the future with the help of registry data. This will be particularly important in future with the advent of advanced imaging, such as prostate-specific membrane antigen positron-emission tomography.

Aim: Continued smoking in patients diagnosed with cancer affects treatment outcomes and overall survival. With national surveys of Australian medical oncologists (MO) and radiation oncologists (RO) we sought to determine current clinical practices, preferences and barriers in providing patient smoking cessation support. Methods: Oncologist members of the Medical Oncology Group of Australia (n¿=¿452) and Trans-Tasman Radiation Oncology Group (n¿=¿230) were invited to participate in a multiple choice survey exploring smoking cessation practices and beliefs. Results: The survey response rate was 43%. At first consultations more than 90% of MO and RO regularly asked patients if they smoke or use tobacco products, closely followed by documentation of duration of smoking history and current level of consumption. Less common was asking the patient if they intended to quit (MO 63%, RO 53%) and advising cessation (MO 70%, RO 72%). Less than 50% of oncologists regularly asked about current smoking in follow-up consultations. Although a range of referral options for smoking cessation care were used by oncologists, only 2% of MO and 3% of RO actively managed the patients¿ smoking cessation themselves and this was the least preferred option. The majority believed they require more training in cessation interventions (67% MO, 57% RO) and cited multiple additional barriers to providing cessation care. Conclusions: Oncologists strongly prefer smoking cessation interventions to be managed by other health workers. A collaborative approach with other health professionals is needed to aid the provision of comprehensive smoking cessation care tailored to patients with cancer.

Purpose To explore the prostate-specific membrane antigen (PSMA)¿avid distribution of prostate cancer (PC) on positron emission tomography (PET), both at the time of initial diagnosis and at the time of relapse after definitive local treatment. Methods and Materials A total of 179 PSMA PET scans in patients with nil or =3 lesions on conventional imaging were retrospectively categorized into 3 subgroups: group A, high-risk PC with no prior definitive therapy (n=34); group B, prior prostatectomy (n=75); and group C, prior radiation therapy (n=70). The numbers and locations of the PSMA-avid lesions were mapped. The PSMA-positive lesions were identified subjectively by a nuclear medicine physician on the basis of clinical experience and taking into account the recent literature and artefacts. Results A total of 893 PSMA-avid lesions were identified; at least 1 lesion was detected in 80% of all scans. A high detection rate was present even at very low serum PSA levels (eg, at PSA =0.20 ng/mL in group B, the detection rate was 46%). Thirty-eight percent of studies revealed extrapelvic disease (41%, 31%, and 46% in groups A, B, and C, respectively). Almost one-third of all studies showed only oligometastases (24%, 36%, and 31% in groups A, B, and C, respectively). A large proportion of these (40%) were a solitary lesion. Conclusions Prostate-specific membrane antigen PET demonstrated a large number of otherwise unknown metastatic lesions. Therefore we recommend PSMA PET for more accurate assessment of disease burden in initial staging of high-risk PC, as well as for restaging in patients with prostate-specific antigen relapse after primary therapies. Furthermore, a high proportion of oligometastases on PSMA PET provides a prime opportunity to investigate the role of targeted local therapies for oligometastatic PCs.

Introduction: High rectal doses are associated with increased toxicity. A rectal displacement device (RDD) reduces rectal dose in prostate stereotactic body radiation therapy (SBRT). This study investigates any dosimetric difference between two methods of rectal displacement (Rectafix and SpaceOAR) for prostate SBRT. Methods: Rectal dosimetry of 45 men who received SBRT within the PROMETHEUS trial was retrospectively examined, across two radiation therapy centres using the two RDD's. Men received a total dose (TD) of 19 or 20 Gy in two fractions followed by 46 Gy in 23 fractions. Centre 1 contributed 16 Rectafix and 10 SpaceOAR patients. Centre 2 contributed 19 Rectafix patients. Rectal dose volume histogram (DVH) data were recorded as a TD percentage at the following volume intervals; V1%, V2%, V5%, V10% and then 10% increments to V80%. As only one centre employed both RDD's, three sequential rectal dosimetry comparisons were performed; (1) centre 1 Rectafix versus centre 1 SpaceOAR; (2) centre 1 Rectafix versus centre 2 Rectafix and (3) centre 1+ centre 2 Rectafix versus centre 1 SpaceOAR. Results: In comparison (1) Rectafix demonstrated lower mean doses at 9 out of 11 measured intervals (P = 0.0012). Comparison (2) demonstrated a moderate difference with centre 2 plans producing slightly lower rectal doses (P = 0.013). Comparison (3) further demonstrated that Rectafix returned lower mean doses than SpaceOAR (P < 0.001). Although all dose levels were in favour of Rectafix, in absolute terms differences were small (2.6¿9.0%). Conclusions: In well-selected prostate SBRT patients, Rectafix and SpaceOAR RDD's provide approximately equivalent rectal sparing.

Purpose: Men with localized prostate cancer often are treated with external radiotherapy (RT) over 8 to 9 weeks. Hypofractionated RT is given over a shorter time with larger doses per treatment than standard RT. We hypothesized that hypofractionation versus conventional fractionation is similar in efficacy without increased toxicity. Patients and Methods: We conducted a multicenter randomized noninferiority trial in intermediate-risk prostate cancer (T1 to 2a, Gleason score # 6, and prostate-specific antigen [PSA] 10.1 to 20 ng/mL; T2b to 2c, Gleason # 6, and PSA # 20 ng/mL; or T1 to 2, Gleason = 7, and PSA # 20 ng/mL). Patients were allocated to conventional RT of 78 Gy in 39 fractions over 8 weeks or to hypofractionated RT of 60 Gy in 20 fractions over 4 weeks. Androgen deprivation was not permitted with therapy. The primary outcome was biochemical-clinical failure (BCF) defined by any of the following: PSA failure (nadir + 2), hormonal intervention, clinical local or distant failure, or death as a result of prostate cancer. The noninferiority margin was 7.5% (hazard ratio,, 1.32). Results: Median follow-up was 6.0 years. One hundred nine of 608 patients in the hypofractionated arm versus 117 of 598 in the standard arm experienced BCF. Most of the events were PSA failures. The 5-year BCF disease-free survival was 85% in both arms (hazard ratio [short v standard], 0.96; 90% CI, 0.77 to 1.2). Ten deaths as a result of prostate cancer occurred in the short arm and 12 in the standard arm. No significant differences were detected between arms for grade = 3 late genitourinary and GI toxicity. Conclusion: The hypofractionated RT regimen used in this trial was not inferior to conventional RT and was not associated with increased late toxicity. Hypofractionated RT is more convenient for patients and should be considered for intermediate-risk prostate cancer.

Objectives: To explore changes in bone mineral density (BMD) measured by DEXA and MRS fat fraction (FF), Dixon FF, and ADC in lower spinal vertebral bodies in men with prostate cancer treated with androgen deprivation therapy (ADT). Methods: Twenty-eight men were enrolled onto a clinical trial. All received ADT. DEXA imaging was performed at baseline and 12¿months. L-spine MRI was done at baseline and 6¿months. Results: The number of patients who underwent DEXA, Dixon, ADC, and MRS at baseline/follow-up were 28/27, 28/26, 28/26, and 22/20. An increase in FF was observed from T11 to S2 (average 1¿%/vertebra). There was a positive correlation between baseline MRS FF and Dixon FF (r = 0.85, p < 0.0001) and a negative correlation between MRS FF and ADC (r = -0.56, p = 0.036). Over 6¿months, MRS FF increased by a median of 25¿% in relative values (p = 0.0003), Dixon FF increased (p < 0.0001) and ADC values decreased (p = 0.0014). Men with >5¿% BMD loss after 1¿year had triple the percentage increase in MRS FF at 6¿months (61.1¿% vs. 20.9¿%, p = 0.19). Conclusions: Changes are observed on L-spine MRI after 6¿months of ADT. Further investigation is warranted of MRS change as a potential predictive biomarker for later BMD loss. Key Points: ¿ Spinal marrow fat fraction increases after 6¿months of androgen deprivation therapy. ¿ More inferior vertebral bodies tend to have higher fat fractions. ¿ MRS fat fraction changes were associated with later changes in DEXA BMD.

Purpose: The optimal management of early squamous cell carcinoma of the anal canal (AC) is yet to be determined. This study investigated current practice in the management of early AC. Methods: A patterns of care survey was completed by Australian surgeons and radiation oncologists. Specific topics addressed were as follows: geographical location of practice, staging of disease, treatment approaches to T1N0 tumours and grade 3 anal intra-epithelial neoplasia (AIN3) lesions, radiotherapy planning, toxicities, follow-up and clinical trial involvement. Results: Sixty-four responses were obtained. For the management of T1N0 disease, half the respondents recommended standard dose chemo-radiotherapy (CRT) and one third recommended wide local excision (WLE). For the management of AIN3, half recommended WLE while a quarter advocated observation. Conclusions: This study reveals a significant variation in the management of early AC. The development of guidelines specific to the treatment of early AC could standardise treatment while further research is required to define the optimal management of T1N0 AC and AIN.

Purpose/Objectives: To explore patients' experiences of and preferences for preparation for radiation therapy. Research Approach: Qualitative study. Participants: 26 individuals who recently received radiation therapy for cancer. Setting: One Australian radiation oncology clinic located within a tertiary referral hospital in New South Wales. Methodologic Approach: Semistructured interviews were conducted and analyzed based on a qualitative descriptive approach and content analysis of the transcribed interviews. Findings: Four main themes related to preparation techniques were identified: (a) psychological preparation (frame of mind, downward comparison, coping mechanisms, and reassurance); (b) information preparation (format, content, and knowledge from patients' own or others' experiences); (c) quality of health care; and (d) social support. Two themes related to outcomes of preparation were identified: feeling psychologically prepared and knowing what to expect. Overall, participants' accounts of preparation for radiation therapy revealed that provision of information was satisfactory. Some participants would have liked more information and support primarily in relation to side effects and the practicalities of what would happen during treatment. Conclusions: The information gained in this study indicates what strategies may best prepare patients for radiation therapy. Interpretation: Providing patients with information that creates a realistic expectation of what radiation therapy involves both before and after treatment seems particularly important in helping them feel prepared.

Active shape models (ASMs) have proved successful in automatic segmentation by using shape and appearance priors in a number of areas such as prostate segmentation, where accurate contouring is important in treatment planning for prostate cancer. The ASM approach however, is heavily reliant on a good initialisation for achieving high segmentation quality. This initialisation often requires algorithms with high computational complexity, such as three dimensional (3D) image registration. In this work, we present a fast, self-initialised ASM approach that simultaneously fits multiple objects hierarchically controlled by spatially weighted shape learning. Prominent objects are targeted initially and spatial weights are progressively adjusted so that the next (more difficult, less visible) object is simultaneously initialised using a series of weighted shape models. The scheme was validated and compared to a multi-atlas approach on 3D magnetic resonance (MR) images of 38 cancer patients and had the same (mean, median, inter-rater) Dice's similarity coefficients of (0.79, 0.81, 0.85), while having no registration error and a computational time of 12-15 min, nearly an order of magnitude faster than the multi-atlas approach.

Purpose To validate automatic substitute computed tomography CT (sCT) scans generated from standard T2-weighted (T2w) magnetic resonance (MR) pelvic scans for MR-Sim prostate treatment planning. Patients and Methods A Siemens Skyra 3T MR imaging (MRI) scanner with laser bridge, flat couch, and pelvic coil mounts was used to scan 39 patients scheduled for external beam radiation therapy for localized prostate cancer. For sCT generation a whole-pelvis MRI scan (1.6 mm 3-dimensional isotropic T2w SPACE [Sampling Perfection with Application optimized Contrasts using different flip angle Evolution] sequence) was acquired. Three additional small field of view scans were acquired: T2w, T2*w, and T1w flip angle 80° for gold fiducials. Patients received a routine planning CT scan. Manual contouring of the prostate, rectum, bladder, and bones was performed independently on the CT and MR scans. Three experienced observers contoured each organ on MRI, allowing interobserver quantification. To generate a training database, each patient CT scan was coregistered to their whole-pelvis T2w using symmetric rigid registration and structure-guided deformable registration. A new multi-atlas local weighted voting method was used to generate automatic contours and sCT results. Results The mean error in Hounsfield units between the sCT and corresponding patient CT (within the body contour) was 0.6 ± 14.7 (mean ± 1 SD), with a mean absolute error of 40.5 ± 8.2 Hounsfield units. Automatic contouring results were very close to the expert interobserver level (Dice similarity coefficient): prostate 0.80 ± 0.08, bladder 0.86 ± 0.12, rectum 0.84 ± 0.06, bones 0.91 ± 0.03, and body 1.00 ± 0.003. The change in monitor units between the sCT-based plans relative to the gold standard CT plan for the same dose prescription was found to be 0.3% ± 0.8%. The 3-dimensional ¿ pass rate was 1.00 ± 0.00 (2 mm/2%). Conclusions The MR-Sim setup and automatic sCT generation methods using standard MR sequences generates realistic contours and electron densities for prostate cancer radiation therapy dose planning and digitally reconstructed radiograph generation.

Purpose To explore site- and clinician-level factors associated with protocol violations requiring real-time-review (RTR) resubmission in a multicenter clinical trial to help tailor future quality assurance (QA) protocols. Methods and Materials RAVES (Radiation Therapy-Adjuvant vs Early Salvage) (Trans-Tasman Radiation Oncology Group 08.03) is a randomized trial comparing adjuvant with early salvage radiation therapy in men with positive surgical margins or pT3 disease after prostatectomy. Quality assurance in RAVES required each clinician and site to submit a credentialing dummy run (DR) and for each patient's radiation therapy plan to undergo external RTR before treatment. Prospectively defined major violations from trial protocol required remedy and resubmission. Site and clinician factors associated with RTR resubmission were examined using hierarchical modeling. Results Data were collected from 171 consecutive patients, treated by 46 clinicians at 32 hospitals. There were 47 RTR resubmissions (27%) due to 65 major violations. The relative rate of resubmission decreased by 29% per year as the study progressed (odds ratio OR. 0.71, P=.02). The majority of resubmissions were due to contouring violations (39 of 65) and dosimetric violations (22 of 65). For each additional patient accrued, significant decreases in RTR resubmission were seen at both clinician level (OR 0.75, P=.02) and site level (OR 0.72, P=.01). The rate of resubmission due to dosimetric violations was only 1.6% after the first 5 patients. Use of IMRT was associated with lower rates of resubmission compared with 3-dimensional conformal radiation therapy (OR 0.38, P=.05). Conclusion Several low- and high-risk factors that may assist with tailoring future clinical trial QA were identified. Because the real-time resubmission rate was largely independent of the credentialing exercise, some form of RTR QA is recommended. The greatest benefit from QA was derived early in trial activation and clinician experience.

The purpose of this study was to investigate performance of the couch and coil mounts designed for MR-simulation prostate scanning using data from ten volunteers. Volunteers were scanned using the standard MR scanning protocol with the MR coil directly strapped on the external body and the volunteer lying on the original scanner table. They also were scanned using a MR-simulation table top and pelvic coil mounts. MR images from both setups were compared in terms of body contour variation and image quality effects within particular organs of interest. Six-field conformal plans were generated on the two images with assigned bulk density for dose calculation. With the MR-simulation devices, the anterior skin deformation was reduced by up to 1.7 cm. The hard tabletop minimizes the posterior body deformation which can be up to 2.3 cm on the standard table, depending on the weight of volunteer. The image signal-to-noise ratio reduced by 14% and 25% on large field of view (FOV) and small FOV images, respectively, after using the coil mount; the prostate volume contoured on two images showed difference of 1.05 ± 0.66 cm³. The external body deformation caused a mean dose reduction of 0.6 ± 0.3 Gy, while the coverage reduced by 22% ± 13% and 27% ± 6% in V98 and V100, respectively. A dedicated MR simulation setup for prostate radiotherapy is essential to ensure the agreement between planning anatomy and treatment anatomy. The image signal was reduced after applying the coil mount, but no significant effect was found on prostate contouring.

To clinically implement MRI simulation or MRI-alone treatment planning requires comprehensive end-to-end testing to ensure an accurate process. The purpose of this study was to design and build a geometric phantom simulating a human male pelvis that is suitable for both CT and MRI scanning and use it to test geometric and dosimetric aspects of MRI simulation including treatment planning and digitally reconstructed radiograph (DRR) generation. A liquid filled pelvic shaped phantom with simulated pelvic organs was scanned in a 3T MRI simulator with dedicated radiotherapy couch-top, laser bridge and pelvic coil mounts. A second phantom with the same external shape but with an internal distortion grid was used to quantify the distortion of the MR image. Both phantoms were also CT scanned as the gold-standard for both geometry and dosimetry. Deformable image registration was used to quantify the MR distortion. Dose comparison was made using a seven-field IMRT plan developed on the CT scan with the fluences copied to the MR image and recalculated using bulk electron densities. Without correction the maximum distortion of the MR compared with the CT scan was 7.5 mm across the pelvis, while this was reduced to 2.6 and 1.7 mm by the vendor's 2D and 3D correction algorithms, respectively. Within the locations of the internal organs of interest, the distortion was <1.5 and <1 mm with 2D and 3D correction algorithms, respectively. The dose at the prostate isocentre calculated on CT and MRI images differed by 0.01% (1.1 cGy). Positioning shifts were within 1 mm when setup was performed using MRI generated DRRs compared to setup using CT DRRs. The MRI pelvic phantom allows end-to-end testing of the MRI simulation workflow with comparison to the gold-standard CT based process. MRI simulation was found to be geometrically accurate with organ dimensions, dose distributions and DRR based setup within acceptable limits compared to CT.

Background: A prospective clinical trial was conducted to evaluate the feasibility of a novel approach to the treatment of patients with high risk prostate cancer (HRPC) through the use of a nomogram to tailor radiotherapy target volumes. Methods: Twenty seven subjects with HRPC were treated with a mildly hypofractionated radiotherapy regimen using image-guided IMRT technique between Jun/2013-Jan/2015. A set of validated prognostic factors were inputted into the Memorial-Sloan-Kettering Cancer Center (MSKCC) prostate cancer nomogram to estimate risk of loco-regional spread (LRS). The nomogram risk estimates for extra-capsular extension (ECE), seminal vesicles involvement (SVI), and pelvic lymph nodes involvement (LNI) were used to adapt radiotherapy treatment volumes based on a risk threshold of =15% in all cases. A planning guide was used to delineate target volumes and organs at risk (OAR). Up to three dose levels were administered over 28 fractions; 70Gy for gross disease in the prostate +/- seminal vesicles (2.5Gy/fraction), 61.6Gy for subclinical peri-prostatic disease (2.2Gy/fraction) and 50.4Gy to pelvic nodes (1.8Gy/fraction). Data regarding protocol adherence, nomogram use, radiotherapy dose distribution, and acute toxicity were collected. Results: Nomogram use 100% of patients were treated for ECE, 88.9% for SVI, and 70.4% for LNI. The three areas at risk of LRS were appropriately treated according to the study protocol in 98.8% cases. The MSKCC nomogram estimates for LRS differed significantly between the time of recruitment and analysis. Contouring protocol compliance Compliance with the trial contouring protocol for up to seven target volumes was 93.0% (159/171). Compliance with protocol for small bowel contouring was poor (59.3%). Dose constraints compliance Compliance with dose constraints for target volumes was 97.4% (191/196). Compliance with dose constraints for OAR was 88.2% (285/323). Acute toxicity There were no grade 3 acute toxicities observed. 20/27 (74.1%) and 6/27 (22.2%) patients experienced a grade 2 genitourinary and gastrointestinal toxicity respectively. Conclusions: We have demonstrated the feasibility of this novel risk-adapted radiation treatment protocol for HRPC. This study has identified key learning points regarding this approach, including the importance of standardization and updating of risk quantification tools, and the utility of an observer to verify their correct use. Trial registration: ClincialTrials.gov identifier NCT01418040. Hunter New England Human Research Ethics Committee (HNEHREC) reference number 12/08/15/4.02

Results: The median age was 70¿years, median PSA was 14.1, and the median Gleason score was 9. The median 5-year risk of progression of disease using a validated nomogram was 39¿%. Five out of 36 patients (14¿%, 95¿% CI 5¿30¿%) had CTCs detected in their circulation. Four patients had only 1 CTC per 7.5¿mL of blood detected. One patient had 3 CTCs per 7.5¿mL of blood detected, which included a circulating tumor microemboli. Both on univariate analysis and multivariate analysis, there were no correlations found between CTC positivity and the classic prognostic factors including PSA, Gleason score, T-stage and age.

Australian and New Zealand radiation oncologists with an interest in uro-oncology were invited to undertake a pattern of practice survey dealing with issues encountered in the management of high-risk prostate cancer in the post-prostatectomy setting. Responses from practitioners revealed a lack of consensus regarding the optimal timing of radiation therapy the use of whole pelvic radiation therapy and the use of androgen deprivation therapy. A review of the literature outlining the current body of knowledge and the clinical studies that will inform future practice is presented. © 2013 The Royal Australian and New Zealand College of Radiologists.

Australian and New Zealand radiation oncologists with an interest in uro-oncology were invited to participate in a pattern-of-practice survey dealing with the management of intact high-risk prostate cancer. Responses from 46 practitioners (representing 73% of all potential respondents) revealed that high-dose radiation therapy is the standard of care. However, there is variability in practice with regard to the methods used to achieve dose escalation, the use of whole-pelvic radiation therapy and the optimal duration of androgen deprivation therapy employed. A review of the literature outlining the current body of knowledge and the planned and ongoing studies in intact high-risk prostate cancer is presented. © 2013 The Authors. Journal of Medical Imaging and Radiation Oncology published by Wiley Publishing Asia Pty Ltd on behalf of Royal Australian and New Zealand College of Radiologists.