BACKGROUND AND OBJECTIVE:Prostate-specific membrane-antigen positron emission tomography (PSMA-PET) has transformed management of prostate cancer biochemical recurrence (BCR) with higher diagnostic accuracy than previous imaging modalities. 64Cu-SAR-bisPSMA PET/computed tomography (CT) (64Cu-bisPSMA) is a bivalent-PSMA-peptide with 12.7-hr half-life. The study objective was detection rate (per-patient) comparison between 64Cu-bisPSMA and 68GaPSMA-11 PET/CT (68Ga-PSMA) in BCR post radical prostatectomy (RP) (NCT06907641). METHODS:This prospective imaging trial enrolled 50 participants with BCR (PSA 0.2-0.75 ng/ml). 64Cu-bisPSMA (1 and 24 hr) and 68Ga-PSMA were acquired within 3-wk. Images were prospectively reported, and triple read for concordance. Management impact was evaluated after 68Ga-PSMA and 64Cu-bisPSMA. A reference standard (RS) for accuracy included biopsy, targeted treatment response (no androgen deprivation therapy), PSA increase/decrease on observation or repeat imaging (64Cu-bisPSMA). The primary endpoint was mean per-participant lesional difference. Paired t tests and mixed-effects Poisson regression assessed lesion number differences between scans. KEY FINDINGS AND LIMITATIONS:Median prostate specific antigen (PSA) was 0.43 (interquartile range: 0.31-0.63). Mean per-participant lesions were higher in 64Cu-bisPSMA (1.26) versus 68GaPSMA (0.48), difference 0.78 (95% CI: 0.52-1.04), ratio 2.63 (95% CI: 1.64-4.20) (p < 0.0001). At a per-participant level 78% (39/50) were positive on 24-hr 64Cu-bisPSMA compared to 36% (18/50) on 68GaPSMA. Management changed between scans in 22/50 (44%). 64Cu-bisPSMA were triple concordant in 84% (42/50) and 68Ga-PSMA reads in 80% (40/50). RS-true positive was 71% (24/34) versus 29% (10/34) and RS-false negative rate was 21% (7/34) versus 65% (22/34) for 64Cu-bisPSMA versus 68Ga-PSMA, respectively. CONCLUSION AND CLINICAL IMPLICATIONS:64Cu-bisPSMA-PET/CT identifies a higher number of disease recurrences than 68Ga PSMA-PET/CT with substantial management impact and a high RS true positive rate in men with BCR post RP.

PURPOSE:Stereotactic Body Radiation Therapy (SBRT) schedules for prostate cancer are emerging as a standard treatment approach. However, although high efficacy is achieved in clinical trials, additional efforts at accurate treatment delivery are necessary to maximize the therapeutic ratio in the community setting. Kilovoltage Intrafraction Monitoring (KIM) is a technology developed to address the unmet clinical need of accurate intrafraction motion management without a requirement for additional hardware on standard linear accelerators. This paper describes the journey from bench to bedside of KIM. METHODS AND MATERIALS:The concept of KIM emerged in 2008 in a series of simulations, progressing to phantom experiments commencing in 2010, culminating in the first clinical trial starting in 2014. A series of technical innovations integrating rotational prostate movements, quality assurance, and dynamic multileaf collimator tracking were included within the multi-institutional Trans-Tasman Radiation Oncology Group 15.01 Stereotactic Prostate Adaptive Radiation therapy using KIM clinical trial for prostate SBRT. RESULTS:Submillimeter accuracy of KIM was observed in simulations, phantom experiments, and clinical trials. The Stereotactic Prostate Adaptive Radiation therapy using KIM trial demonstrated multicenter feasibility of use, a high rate of intrafraction motion triggering a gating event, and a significant dosimetric impact of KIM deployment for target volume coverage. KIM is being made available through commercialization with an industry partner, and through a 300-patient, 10-center clinical trial. CONCLUSIONS:The collaboration between researchers, clinicians, and industry has led to KIM being developed from a concept to clinical trials, enabling the safe delivery of prostate cancer SBRT in the presence of intrafraction motion. This journey provides a template for similar bench-to-bedside translational research.

Purpose Intrafraction monitoring of prostate position during stereotactic body radiotherapy (SBRT) can correct stochastic displacement but often relies on fiducial markers. This retrospective study employed prostate monitoring data to determine time-based probability of prostate displacement, which was used to recommend an optimised mid-treatment imaging interval for prostate SBRT in patients without fiducials, where the probability of displacement greater than tolerance is less than 5%. Methods and materials Retrospective monitoring data from 70 patients treated with kilovoltage intrafraction monitoring (KIM) software was used to determine when the probability of displacement exceeding 3 mm first reached 5%, representing the recommended mid-treatment imaging interval, and repeated for displacement magnitudes of 1 and 2 mm. Monitoring data from an additional 10 patients treated with KIM software was analysed to evaluate the imaging intervals determined. Results Within the 70 patient cohort (1998 fractions), 5% probability of 3 mm of displacement first occurred at 190 s, while the 5% probability of 1 and 2 mm of displacements occurred at 40 and 95 s, respectively. When correcting the prostate position every 190 s, the likelihood of >3 mm displacement in the 10 patient cohort (50 fractions) remained below 5% for most time points. Conclusion This study recommended and validated a prostate SBRT mid-treatment imaging interval of 190 s, derived from time-based probability analysis of large cohort intrafraction prostate displacement data. It is compatible with 3D imaging included on standard teletherapy equipment without requiring fiducials. The generated probability distributions may inform imaging intervals tailored for specific clinical workflows or patient populations.

BACKGROUND:Salivary gland malignancy (SGM) is a rare and heterogeneous head and neck neoplasm. Curative treatment often mandates upfront surgery. Patients with high-risk features receive adjuvant radiotherapy. This study aims to investigate the clinicopathological characteristics, survival outcomes and prognostic factors for primary SGM in an Australian population. METHODS:A retrospective cohort study of adult patients with primary SGM diagnosed between January 2001 and December 2024 at our institution was conducted. Clinicopathological and treatment characteristics were collected. Overall survival (OS), recurrence-free survival (RFS) and disease-free survival (DFS) were calculated. Log-rank univariate analysis and multivariate Cox regression analysis were conducted to determine prognostic factors for OS and DFS. RESULTS:A total of 149 patients were included. The median follow-up time was 59 months (IQR 22.75-96 months). Patients were mostly male (57.7%) with a median age of 59 years (IQR 48-71 years). Tumours were most commonly located in the parotid gland (81.2%). The most common histological subtype was mucoepidermoid carcinoma (26.2%). The 5- and 10-year OS, RFS and DFS were 81.9% and 77.9%, 78.5% and 71.8% and 84.6% and 82.6%, respectively. Independent prognostic factors for OS were ECOG 2/3 (HR 19.059, 95% CI [3.061-118.664]), T3/4 (HR 6.925 [2.871-16.703]) and intermediate/high grade (HR 3.310 [1.122-9.761]). Independent prognostic factors for DFS were ECOG 2/3 (HR 64.267 [7.758-532.400]), T3/4 (HR 8.085 [3.008-21.729]) and intermediate/high grade (HR 8.065 [1.774-36.660]). CONCLUSIONS:Survival outcomes for primary SGM significantly differ between subtypes. Independent prognostic factors for OS and DFS are ECOG 2/3, T3/4 and intermediate/high grade.

Background Prostate-specific membrane antigen (PSMA) PET/CT provides sensitive whole-body assessment in prostate cancer, yet the prognostic role of total tumour volume (TTV) is not fully defined in metastatic hormone-sensitive disease and needs further exploration. Methods We retrospectively reviewed patients with de novo metastatic prostate cancer undergoing baseline PSMA PET/CT at Royal North Shore Hospital between 2014-2019. TTV was quantified using a standardized Standard Uptake Value (SUV) threshold, and patients were stratified by median TTV. Associations between TTV, progression-free survival (PFS), and overall survival (OS) were assessed using Kaplan–Meier and Cox regression analyses. Results Fifty-nine patients were included in the study. Patients in the high-TTV group demonstrated reduced OS but no significant difference in PFS. Higher PSMA-derived TTV correlated with increased prostate-specific antigen (PSA) at diagnosis and higher rates of skeletal related events. Higher SUVmax was not associated with longer PFS or OS, nor was it associated with increased skeletal related events. Conclusion Baseline PSMA PET/CT-derived tumour volume is an independent prognostic biomarker in metastatic hormone-sensitive prostate cancer, associated with inferior overall survival. Incorporating TTV into existing risk models may refine patient selection for treatment intensification.

Background: Surgical resection is the mainstay of curative treatment for localised salivary gland malignancies of the head and neck, with adjuvant radiation therapy (RT) indicated in the presence of high-risk features to reduce the risk of recurrence. Most patients survive for many decades after locoregional treatment and thus understanding the impact of treatment(s), particularly RT, on long term quality of life (QOL) is critical. This study aimed to investigate the long-term QOL of patients treated with surgery and adjuvant RT for primary salivary gland malignancies of the head and neck, and to assess for potential predictors of QOL which might guide refinement of current treatments and improve survivorship care. Methods: This retrospective cohort study included patients who underwent surgery and post-operative RT for primary malignant salivary gland tumours of the head and neck at a single tertiary cancer centre between 2006 and 2022. Patient, tumour and treatment information was extracted from a prospectively maintained database. Patients who were still alive were contacted to complete a QOL survey. Kaplan-Meier survival analysis was used to summarise overall survival (OS) and disease-free survival (DFS), with log-rank test used to assess prognostic factors. Univariate binary logistic regression model was used to identify factors associated with worse QOL. Results: Sixty-seven patients underwent surgery and RT during the study period. Median follow up was 4.4 years [interquartile range (IQR), 2.4-7.4 years] for all patients and 5.2 years (IQR, 3.9-9.2 years) for patients who completed the QOL survey 5-year OS and DFS and local failure rates were 79%, 79% and 3% respectively (all patients). Twenty-nine patients completed the QOL survey, of which 93% were in remission. Most patients (79%) reported their health as the same or better than before RT. Almost all patients (90%) had no treatment regret regarding receipt of adjuvant RT. Conclusions: Surgery and adjuvant RT achieves durable local control, excellent patient reported QOL and low levels of treatment regret in patients with high-risk primary salivary gland malignancies. However, survivorship care remains a key issue in patents with potentially lengthy survival. Future prospective studies may identify novel biomarkers to further refine patient selection for adjuvant RT, while longitudinal QOL assessment will assist in further refining survivorship protocols.

Androgen deprivation therapy (ADT) for prostate cancer adversely affects quality of life. Whilst exercise is effective for ameliorating many side effects, most people are inactive, with lack of motivation a key barrier. Self-determination theory (SDT) specifies the quality, rather than quantity, of motivation as essential for optimal engagement. We aimed to explore exercise motivation in men on ADT through the theoretical lens of SDT. As part of a mixed-method longitudinal study, semi-structured interviews exploring exercise behaviour and perceptions, were conducted with people receiving ADT for prostate cancer. Thematic analysis identified motivation themes aligned with SDT concepts. Twenty-four men participated (median age 74 years; ECOG 0: 92

Introduction: Long term survival for adenoid cystic carcinoma (ACC) arising from the head and neck declines for many decades after initial treatment due to late disease relapse. Follow up and surveillance imaging practices vary due to limited evidence as well as a lack of international guidelines (until 2021). Methods: A retrospective cohort study was conducted for patients treated curatively for ACC between 2007 and 2024 at a single institution. Clinicopathologic information, treatment details, patterns of follow-up (including radiologic investigations) and oncological outcomes are reported. Results: 51 patients comprised the study cohort. Median age was 50 years; 96% of patients underwent surgery and adjuvant radiation therapy. Median follow-up was 7.65 years. 5-year overall survival (OS) and disease-free survival (DFS) were 88% and 73% respectively. 18% and 61% of patients underwent surveillance imaging within 3- and 12-months of treatment completion respectively. 80% of first recurrences were detected on surveillance imaging. Half the episodes of first disease recurrence occurred within 5 years of initial treatment, a further 25% within 10 years and the remaining 25% occurred > 10 years post treatment. Conclusion: This cohort of patients curatively treated for ACC at a single institution highlights the propensity for late distant relapse as well as heterogeneity of surveillance imaging. A local institutional protocol is proposed based upon the 2021 ASCO guidelines to standardise clinical and radiologic follow-up for this group.

BACKGROUND:During radiation therapy, the natural movement of organs can lead to underdosing the cancer and overdosing the healthy tissue, compromising treatment efficacy. Real-time image-guided adaptive radiation therapy can track the tumour and account for the motion. Typically, fiducial markers are implanted as a surrogate for the tumour position due to the low radiographic contrast of soft tissues in kilovoltage (kV) images. A segmentation approach that does not require markers would eliminate the costs, delays, and risks associated with marker implantation. METHODS:We trained patient-specific conditional Generative Adversarial Networks for prostate segmentation in kV images. The networks were trained using synthetic kV images generated from each patient's own imaging and planning data, which are available prior to the commencement of treatment. We validated the networks on two treatment fractions from 30 patients using multi-centre data from two clinical trials. RESULTS:Here, we present a large-scale proof-of-principle study of x-ray-based markerless prostate segmentation for globally available cancer therapy systems. Our results demonstrate the feasibility of a deep learning approach using kV images to track prostate motion across the entire treatment arc for 30 patients with prostate cancer. The mean absolute deviation is 1.4 and 1.6 mm in the anterior-posterior/lateral and superior-inferior directions, respectively. CONCLUSIONS:Markerless segmentation via deep learning may enable real-time image guidance on conventional cancer therapy systems without requiring implanted markers or additional hardware, thereby expanding access to real-time adaptive radiation therapy.

Simulation-free radiation therapy (SFRT) is an emerging patient-centered paradigm for palliative radiation therapy. Feasibility and clinical benefits have been demonstrated by several groups; however, guidance to overcome technical barriers to adoption is limited. This report describes practical recommendations for offline preliminary studies, patient selection, image selection and formatting, planning and treatment considerations, and quality control. These suggestions aim to enable safe, scalable, and effective clinical implementation of SFRT.

Background:A significant minority of patients in high income countries with symptomatic mucosal head and neck squamous cell carcinomas (HNSCC) warrant treatment of their locoregional disease but are not suitable for standard high dose radiation therapy (RT) with or without concurrent chemotherapy. This study aimed to determine the factors associated with locoregional control (LRC) and survival for patients undergoing high dose palliative-intent RT, to help improve patient selection for this treatment approach. Materials and methods:This retrospective cohort study included all patients with HNSCC who received high dose RT (50-55 Gy in 20 fractions over 4 weeks) with palliative-intent from 2007-2024 at an academic Australian cancer centre. Results:53 patients comprised the study cohort, of which 92% completed the prescribed RT in full. Median overall survival was 21.6 months and in-field LRC at 12-months was 80%. Acute toxicities were low [Common Terminology Criteria for Adverse Events (CTCAE) grade 3 mucositis 17%, local pain 6.5%, and dysphagia 4.4%, with no grade 4-5 toxicities], with resolution of majority by six months post RT (7% grade 2, no grade 3 or higher toxicities). Larger primary tumours (T3 or T4) and more advanced stage disease [American Joint Committee on Cancer (AJCC) stage III-IV, 8th edition] were associated with worse in-field LRC. Conclusions:High dose palliative-RT in patients with mucosal HNSCC not suitable for definitive chemoradiotherapy provided durable local control with low toxicities after 12 months. In-field locoregional failures were more likely for more advanced disease.

BACKGROUND:Poorly differentiated thyroid carcinoma (PDTC) accounts for 5% of all thyroid cancers and is responsible for a large proportion of thyroid cancer-related deaths. The optimal treatment approach is not clear. This study aimed to evaluate the effect of postoperative intensity-modulated radiotherapy (IMRT) on the treatment of resectable PDTC. Additionally, treatment-related morbidity, characteristics of 131I-refractory disease, and factors affecting survival were assessed. METHODS:The study included consecutive PDTC cases from 1997 to 2018, defined according to Turin criteria and treated in two tertiary referral centers. Surgery, IMRT, 131I, and systemic therapies were administered based on multidisciplinary team recommendations. The primary study outcome was 5-year local control after IMRT in cases with positive resection margins (micro- and macroscopic). The secondary outcomes were treatment-related morbidity within 30-days after completion of treatment (Clavien-Dindo and Common Terminology Criteria for Adverse Events [CTC-AE] 5.0), 131I-refractory disease characteristics using standardized definitions, and factors influencing survival. RESULTS:Among 51 PDTC cases, 53% presented with metastatic disease. Adjuvant IMRT improved 5-year local control (100% vs. 17.5%; p = 0.02), with a higher number of grades 1 to 3 complications (p = 0.005) versus cases without IMRT. Within 13 months, 131I-refractory disease occurred in 62.7% of the patients and was more common in non-survivors (86.6% vs. 52.8%; p = 0.01). Positive resection margins and extrathyroidal extension were associated with poor survival in the univariate analysis, but were not significant in the multiple regression analysis. CONCLUSION:Adjuvant IMRT may reduce thyroid bed recurrence in resectable PDTC with positive resection margins, but is associated with increased treatment-related complications. 131I-refractory disease occurs frequently, with non-survivors progressing earlier to 131I resistance.

Gliomas are the most common primary brain malignancy in adults, with treatment advances limited by challenges like the blood-brain barrier, tumour heterogeneity, and an immunosuppressive microenvironment. Tumour vaccines, such as adenoviral vector and mRNA-based vaccines, may overcome these barriers, but the ability of glioma patients to mount an immune response to these therapies remains unclear. This study assesses immune responses to adenoviral DNA and mRNA-based COVID-19 vaccinations in a glioma-enriched population as a model for glioma-based vaccine therapies. COVID-19 naïve glioma and non-glioma solid tumour patients, along with healthy volunteers, were recruited between May 2021 and December 2022. Blood samples were collected at various time points: pre-vaccination, between the first and second doses, and at 1-, 3-, and 4-6-months post 2nd vaccination, including after a third booster dose. SARS-CoV-2 specific immune responses were evaluated using ELISA and ELISPOT assays. A total of 91 participants were analysed. At 1-month post 2nd vaccination, no significant differences in seroconversion rates were observed. By 3 months, glioma and non-glioma patients had significantly lower rates compared to healthy volunteers. Memory B and T cell responses were similar between glioma patients and healthy volunteers, but non-glioma patients showed decreased responses. Vaccine efficacy was comparable across all cohorts. This study demonstrates that glioma patients can mount meaningful immune responses to DNA and mRNA vaccines, suggesting that glioma-based vaccine therapies are feasible and warrant further exploration.

Poorly differentiated thyroid carcinoma (PDTC) accounts for 5

Background Gliomas are the most common primary brain malignancy in adults, with treatment advances limited by challenges like the blood-brain barrier, tumour heterogeneity, and an immunosuppressive microenvironment. Tumour vaccines, such as adenoviral vector and mRNA-based vaccines, may overcome these barriers, but the ability of glioma patients to mount an immune response to these therapies remains unclear. This study assesses immune responses to adenoviral DNA and mRNA-based COVID-19 vaccinations in a glioma-enriched population as a model for glioma-based vaccine therapies. Methods COVID-19 naïve glioma and non-glioma solid tumour patients, along with healthy volunteers, were recruited between May 2021 and December 2022. Blood samples were collected at various time points: pre-vaccination, between the first and second doses, and at 1-, 3-, and 4-6-months post 2nd vaccination, including after a third booster dose. SARS-CoV-2 specific immune responses were evaluated using ELISA and ELISPOT assays. Results A total of 91 participants were analysed. At 1-month post 2nd vaccination, no significant differences in seroconversion rates were observed. By 3 months, glioma and non-glioma patients had significantly lower rates compared to healthy volunteers. Memory B and T cell responses were similar between glioma patients and healthy volunteers, but non-glioma patients showed decreased responses. Vaccine efficacy was comparable across all cohorts. Conclusion This study demonstrates that glioma patients can mount meaningful immune responses to DNA and mRNA vaccines, suggesting that glioma-based vaccine therapies are feasible and warrant further exploration.

Anaplastic thyroid cancer (ATC), a rare and highly aggressive malignancy, is characterized by an exceptionally poor prognosis, where the majority of patients present with extensive local invasion and/or distant metastases. 20-30% of ATCs harbor the BRAF-V600E mutation. Neoadjuvant BRAF-targeted therapy may have the potential to downstage and facilitate surgical resection for patients with locally advanced and unresectable primary tumors with BRAF mutation and may convey a survival advantage in those with metastatic disease. There is emerging evidence to support the use of other targeted agents, including multikinase inhibitors, as well as the incorporation of immunotherapy into the treatment regimen. Rapid molecular and pathological diagnosis and expert multidisciplinary discussion at specialized treatment centers are critical to expedite investigations and initiate treatment for this complex and rapidly progressive disease.

Background:Nodal only recurrence post radical prostatectomy (RP) is increasingly recognised in the PSMA scan era. Management is controversial with a curative approach usually incorporating prostate bed and nodal irradiation (PB + NRT) in combination with long-term hormonal therapy. It is unknown whether omitting prostate-bed irradiation (PBRT) is safe in a subgroup of these patients. Purpose:To document the outcomes for pelvic nodal only salvage radiation therapy (NRT) plus concurrent androgen deprivation therapy (ADT) for patients with PSMA PET documented nodal relapses. Methods and materials:Eligible patients included PSMA PET documented nodal only relapses post RP who received NRT with or without PBRT at Royal North Shore Hospital (NSCC), Gosford Hospital (CCCC) or Genesis Care (GC) between January 2015 and December 2021. Baseline demographics, surgical pathology, radiation details, ADT use and outcomes were documented. Results:Forty-six patients were identified, 22 in the PB + NRT cohort and 24 in the NRT cohort. Compared to the PBRT + NRT group, the NRT cohort had lower stage disease (pT2 = 7 (29 %), pT3a = 15 (63 %), pT3b = 1 (4 %) vs pT2 = 0, pT3a = 10 (45 %), pT3b = 12 (55 %)) (p=<0.001) and lower rates of R1 resection (0 % vs 63.6 % (n = 14)) (p < 0.001) respectively. The median follow-up from radiotherapy was 3.9 years.Four-year biochemical failure- free survival (BFFS) was 64 % in the NRT group vs 67 % in the PB + NRT group. Of the ten (41.6 %) failures in the NRT group, 1 (4 %) was a biochemical failure only, 2 (8 %) recurred in the PB and received further salvage treatment, 4 (17 %) had nodal failure outside the pelvis and 3 (13 %) had distant metastases.One patient (4 %) in the NRT group recorded late grade ≥2 GU toxicity compared with 7 (32 %) in the PB + NRT. No patients in the NRT group recorded late grade ≥2 GI toxicity compared with 2 (9 %) in the PB + NRT cohort. Conclusion:This study provides early evidence for the feasibility of PBRT sparing to avoid local toxicity. Most patients in this cohort failed distantly. This data suggests that for selected men PB-avoidance may be considered given informed consent.

Purpose/Objective(s) The feasibility of simulation-free radiotherapy (SFRT) has been demonstrated but information regarding its impact on routine care is lacking. The hypothesis was that SFRT is scaleable and beneficial in routine care. Key endpoints of this single institution study were SFRT utilization, impact on consultation-to-RT time and on-couch treatment duration. Materials/Methods All patients receiving palliative RT in the study period were eligible for consideration of SFRT unless mask immobilization, a stereotactic technique, or a definitive dose was required. Timing metrics were compared to a contemporary local cohort that received simulation-based palliative RT using unadjusted medians (Wilcoxon rank-sum test) and a propensity score-weighted regression. Electronic patient-reported outcomes (ePROs) captured 2-week toxicity and pain response. Results Between April 2018 and February 2024, there were 2845 palliative radiation courses were delivered, of which 1904 were eligible for this study. One thousand of the 1904 courses (52.5% SFRT utilization) were treated using the SFRT protocol, including 668 with IMRT/VMAT. Median patient age was 71 years with 60% being male and 32% being ECOG 2-4. SFRT reduced median consultation-to-RT time from 7.0 to 5.1 days (P < 0.0001) corresponding to an adjusted average treatment effect (aATE) of -2.3 days (95% CI = -2.9 to -1.7). SFRT increased median on-couch treatment duration from 16 min to 18 min (P < 0.0001; aATE 2.0 min, 95% CI = 0.2 to 3.9). SFRT utilization in eligible courses increased from 41% to 54% between the years 2018 and 2019 and 2022 and 2024. PRO-CTCAE grade 3 acute toxicity was 9% and at 4 weeks post RT patients with moderate/severe pain at baseline (≥ 5/10) had had a mean pain reduction of 3.5 points (7.1 to 3.6). Conclusion Using widely available technologies the SFRT-1000 cohort demonstrates routine care scalability with patient-centered and workflow benefits. SFRT is an attractive new palliative RT paradigm implementable in most settings.