Estimated incidence of disruptions to event-free survival from non-metastatic cancers in New South Wales, Australia - a population-wide epidemiological study of linked cancer registry and treatment data.

Introduction: Population cancer registries record primary cancer incidence, mortality and survival for whole populations, but not more timely outcomes such as cancer recurrence, secondary cancers or other complications that disrupt event-free survival. Nonetheless, indirect evidence may be inferred from treatment data to provide indicators of recurrence and like events, which can facilitate earlier assessment of care outcomes. The present study aims to infer such evidence by applying algorithms to linked cancer registry and treatment data obtained from hospitals and universal health insurance claims applicable to the New South Wales (NSW) population of Australia. Materials and methods: Primary invasive cancers from the NSW Cancer Registry (NSWCR), diagnosed in 2001-2018 with localized or regionalized summary stage, were linked to treatment data for five common Australian cancers: breast, colon/rectum, lung, prostate, and skin (melanomas). Clinicians specializing in each cancer type provided guidance on expected treatment pathways and departures to indicate remission and subsequent recurrence or other disruptive events. A sample survey of patients and clinicians served to test initial population-wide results. Following consequent refinement of the algorithms, estimates of recurrence and like events were generated. Their plausibility was assessed by their correspondence with expected outcomes by tumor type and summary stage at diagnosis and by their associations with cancer survival. Results: Kaplan-Meier product limit estimates indicated that 5-year cumulative probabilities of recurrence and other disruptive events were lower, and median times to these events longer, for those staged as localized rather than regionalized. For localized and regionalized cancers respectively, these were: breast - 7% (866 days) and 34% (570 days); colon/rectum - 15% (732 days) and 25% (641 days); lung - 46% (552 days) and 66% (404 days); melanoma - 11% (893 days) and 38% (611 days); and prostate - 14% (742 days) and 39% (478 days). Cases with markers for these events had poorer longer-term survival. Conclusions: These population-wide estimates of recurrence and like events are approximations only. Absent more direct measures, they nonetheless may inform service planning by indicating population or treatment sub-groups at increased risk of recurrence and like events sooner than waiting for deaths to occur.

Effects of Dietary Supplements on Iron-Loading Susceptibility Artefacts in Pelvic MRI.

We present a case of an 80-year-old male who attended an MRI scan for his prostate cancer radiotherapy planning. His safety screening did not identify any contraindications to our department's MRI safety policy; however, his MRI images displayed significant susceptibility artefacts in the sigmoid colon and rectum and were not clinically acceptable. Further history revealed he had begun regularly taking curcumin supplements at the time of his prostate cancer diagnosis. The patient was instructed to cease taking the curcumin supplements and a repeat MRI appointment was scheduled for one week later. After discontinuing curcumin, repeat imaging was artefact-free and suitable for radiotherapy planning. The chelating properties of curcumin could potentially lead to an accumulation of iron in the bowel, causing MRI susceptibility artefacts in pelvic scans and presenting a possible negative impact on the clinical utility of the images. It may be helpful to screen regular medications including health supplements with known chelation properties where MRI scan quality may be affected.

A randomised controlled trial of Standard Of Care versus RadioAblaTion in Early Stage HepatoCellular Carcinoma (SOCRATES HCC).

BACKGROUND: Therapeutic options for early-stage hepatocellular carcinoma (HCC) in individual patients can be limited by tumor and location, liver dysfunction and comorbidities. Many patients with early-stage HCC do not receive curative-intent therapies. Stereotactic ablative body radiotherapy (SABR) has emerged as an effective, non-invasive HCC treatment option, however, randomized evidence for SABR in the first line setting is lacking. METHODS: Trans-Tasman Radiation Oncology Group (TROG) 21.07 SOCRATES-HCC is a phase II, prospective, randomised trial comparing SABR to other current standard of care therapies for patients with a solitary HCC ≤ 8 cm, ineligible for surgical resection or transplantation. The study is divided into 2 cohorts. Cohort 1 will compromise 118 patients with tumors ≤ 3 cm eligible for thermal ablation randomly assigned (1:1 ratio) to thermal ablation or SABR. Cohort 2 will comprise 100 patients with tumors > 3 cm up to 8 cm in size, or tumors ≤ 3 cm ineligible for thermal ablation, randomly assigned (1:1 ratio) to SABR or best other standard of care therapy including transarterial therapies. The primary objective is to determine whether SABR results in superior freedom from local progression (FFLP) at 2 years compared to thermal ablation in cohort 1 and compared to best standard of care therapy in cohort 2. Secondary endpoints include progression free survival, overall survival, adverse events, patient reported outcomes and health economic analyses. DISCUSSION: The SOCRATES-HCC study will provide the first randomized, multicentre evaluation of the efficacy, safety and cost effectiveness of SABR versus other standard of care therapies in the first line treatment of unresectable, early-stage HCC. It is a broad, multicentre collaboration between hepatology, interventional radiology and radiation oncology groups around Australia, coordinated by TROG Cancer Research. TRIAL REGISTRATION: anzctr.org.au, ACTRN12621001444875, registered 21 October 2021.

Esophageal chemoradiotherapy with concurrent nivolumab: Pilot results in the palliative treatment of oligometastatic disease.

AIMS: Many patients diagnosed with esophageal cancer have dysphagia from their primary tumor and de novo metastatic disease. The purpose of this study was to test the safety and efficacy of nivolumab given concurrently with hypofractionated chemoradiotherapy to patients with oligometastatic and obstructing esophageal tumors. METHODS: Patients were enrolled in a planned single-arm, phase 2 clinical trial. Eligible participants had previously untreated oligometastatic (≤5 metastases on fludeoxyglucose-18 positron emission tomography scan outside the primary tumor radiotherapy field) esophageal or gastroesophageal carcinoma, dysphagia, and Eastern Cooperative Oncology Group performance status 0-1. Treatment was with 2 weeks of concurrent hypofractionated radiotherapy (30 Gy/10#) to the primary tumor, weekly carboplatin AUC2, weekly paclitaxel 50 mg/m2, and q2weekly nivolumab 240 mg, followed by nivolumab 480 mg continuing q4weekly until disease progression or 24 months total. A single metastasis was treated with stereotactic radiotherapy (SBRT) (24 Gy/3#) in week 7. RESULTS: Five patients were recruited before trial closure to new participants for logistical reasons. Existing participants continued treatment per protocol as a pilot study at one center. All five patients completed chemoradioimmunotherapy and SBRT. All patients derived an improvement in their dysphagia. Two patients completed 24 months of nivolumab without disease progression. Grade 3 adverse events (AEs) occurred in 3 patients, however, there were no grade 4 AEs, AEs due to SBRT, or AEs of special interest as defined by the protocol. CONCLUSION: Pilot results from five patients at one center found that treatment was well tolerated and effective for dysphagia relief. The efficacy of hypofractionated chemoradiotherapy with concurrent checkpoint inhibition should be tested in a multicentre study.

The impact of a regionally based translational cancer research collaborative in Australia using the FAIT methodology.

BACKGROUND: Translating research, achieving impact, and assessing impact are important aspirations for all research collaboratives but can prove challenging. The Hunter Cancer Research Alliance (HCRA) was funded from 2014 to 2021 to enhance capacity and productivity in cancer research in a regional centre in Australia. This study aimed to assess the impact and benefit of the HCRA to help inform future research investments of this type. METHOD: The Framework to Assess the Impact from Translational health research (FAIT) was selected as the preferred methodology. FAIT incorporates three validated methodologies for assessing impact: 1) Modified Payback; 2) Economic Analysis; and 3) Narrative overview and case studies. All three FAIT methods are underpinned by a Program Logic Model. Data were collected from HCRA and the University of Newcastle administrative records, directly from HCRA members, and website searches. RESULTS: In addition to advancing knowledge and providing capacity building support to members via grants, fellowships, scholarships, training, events and targeted translation support, key impacts of HCRA-member research teams included: (i) the establishment of a regional biobank that has distributed over 13,600 samples and became largely self-sustaining; (ii) conservatively leveraging $43.8 M (s.a.$20.5 M - $160.5 M) in funding and support from the initial $9.7 M investment; (iii) contributing to clinical practice guidelines and securing a patent for identification of stem cells for endometrial cell regeneration; (iv) shifting the treatment paradigm for all tumour types that rely on nerve cell innervation, (v) development and implementation of the world's first real-time patient treatment verification system (Watchdog); (vi) inventing the effective 'EAT' psychological intervention to improve nutrition and outcomes in people experiencing radiotherapy for head and neck cancer; (vi) developing effective interventions to reduce smoking rates among priority groups, currently being rolled out to disadvantaged populations in NSW; and (vii) establishing a Consumer Advisory Panel and Consumer Engagement Committee to increase consumer involvement in research. CONCLUSION: Using FAIT methodology, we have demonstrated the significant impact and downstream benefits that can be achieved by the provision of infrastructure-type funding to regional and rural research collaboratives to help address inequities in research activity and health outcomes and demonstrates a positive return on investment.

Prostate Virtual High-dose-rate Brachytherapy Boost: 5-Year Results from the PROMETHEUS Prospective Multicentre Trial.

BACKGROUND AND OBJECTIVE: Despite the high efficacy of high-dose-rate brachytherapy boost (HDRB) in the management of prostate cancer (PC), use of this approach is declining. Similar dosimetry can be achieved using stereotactic body radiotherapy or "virtual HDRB" (vHDRB). The aim of the multicentre, single-arm, phase 2 PROMETHEUS trial (ACTRN12615000223538) was to evaluate the safety and efficacy of vHDRB in patients with PC. METHODS: Patients with intermediate-risk PC or selected patients with high-risk PC were eligible for inclusion. vHDRB was given as 19-20 Gy in two fractions, delivered 1 wk apart, followed by conventionally fractionated external beam radiotherapy (EBRT) at 46 Gy in 23 fractions or 36 Gy in 12 fractions. The primary endpoint was the biochemical/clinical relapse-free rate (bcRFR). Toxicity was graded using Common Terminology Criteria for Adverse Events version 4 and quality of life (QoL) data were collected used the Expanded Prostate Cancer Index Composite-26 questionnaire. KEY FINDINGS AND LIMITATIONS: From March 2014 to December 2018, 151 patients (74% intermediate risk, 26% high risk) with a median age of 69 yr were treated across five centres. Median follow-up was 60 mo. The 5-yr bcRFR was 94.1% (95% confidence interval [CI] 90-98%) and the local control rate was 98.7%. Acute grade 2 gastrointestinal (GI) and genitourinary (GU) toxicity occurred in 6.6% and 23.2% of patients, respectively, with no acute grade 3 toxicity. At 60 mo after treatment, the prevalence of late grade ≥2 GI toxicity was 1.7% (95% CI 0.3-6.5%) and the prevalence of late grade ≥2 GU toxicity was 3.3% (95% CI 1.1-8.8%). Between baseline and 60 mo, QoL improved for urinary obstructive and hormonal domains, was stable for the bowel domain, and deteriorated slightly for the sexual and urinary incontinence domains. CONCLUSIONS: Delivery of gantry-based vHDRB followed by conventionally fractionated EBRT is feasible in a multicentre setting, with high 5-yr bcRFR and low toxicity. This approach is being compared with prostate ultrahypofractionated radiotherapy in the TROG 18.01 NINJA randomised trial (ACTRN12618001806257). PATIENT SUMMARY: The PROMETHEUS trial investigated noninvasive high-dose precision radiotherapy combined with conventional radiotherapy in patients with prostate cancer. We found that this new technique was well tolerated and resulted in better cancer control outcomes than historically reported.

Stereotactic ablative body radiotherapy for primary kidney cancer (TROG 15.03 FASTRACK II): a non-randomised phase 2 trial.

BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is a novel non-invasive alternative for patients with primary renal cell cancer who do not undergo surgical resection. The FASTRACK II clinical trial investigated the efficacy of SABR for primary renal cell cancer in a phase 2 trial. METHODS: This international, non-randomised, phase 2 study was conducted in seven centres in Australia and one centre in the Netherlands. Eligible patients aged 18 years or older had biopsy-confirmed diagnosis of primary renal cell cancer, with only a single lesion; were medically inoperable, were at high risk of complications from surgery, or declined surgery; and had an Eastern Cooperative Oncology Group performance status of 0-2. A multidisciplinary decision that active treatment was warranted was required. Key exclusion criteria were a pre-treatment estimated glomerular filtration rate of less than 30 mL/min per 1·73 m2, previous systemic therapies for renal cell cancer, previous high-dose radiotherapy to an overlapping region, tumours larger than 10 cm, and direct contact of the renal cell cancer with the bowel. Patients received either a single fraction SABR of 26 Gy for tumours 4 cm or less in maximum diameter, or 42 Gy in three fractions for tumours more than 4 cm to 10 cm in maximum diameter. The primary endpoint was local control, defined as no progression of the primary renal cell cancer, as evaluated by the investigator per Response Evaluation Criteria in Solid Tumours (version 1.1). Assuming a 1-year local control of 90%, the null hypothesis of 80% or less was considered not to be worthy of proceeding to a future randomised controlled trial. All patients who commenced trial treatment were included in the primary outcome analysis. This trial is registered with ClinicalTrials.gov, NCT02613819, and has completed accrual. FINDINGS: Between July 28, 2016, and Feb 27, 2020, 70 patients were enrolled and initiated treatment. Median age was 77 years (IQR 70-82). Before enrolment, 49 (70%) of 70 patients had documented serial growth on initial surveillance imaging. 49 (70%) of 70 patients were male and 21 (30%) were female. Median tumour size was 4·6 cm (IQR 3·7-5·5). All patients enrolled had T1-T2a and N0-N1 disease. 23 patients received single-fraction SABR of 26 Gy and 47 received 42 Gy in three fractions. Median follow-up was 43 months (IQR 38-60). Local control at 12 months from treatment commencement was 100% (p<0·0001). Seven (10%) patients had grade 3 treatment-related adverse events, with no grade 4 adverse events observed. Grade 3 treatment-related adverse events were nausea and vomiting (three [4%] patients), abdominal, flank, or tumour pain (four [6%]), colonic obstruction (two [3%]), and diarrhoea (one [1%]). No treatment-related or cancer-related deaths occurred. INTERPRETATION: To our knowledge, this is the first multicentre prospective clinical trial of non-surgical definitive therapy in patients with primary renal cell cancer. In a cohort with predominantly T1b or larger disease, SABR was an effective treatment strategy with no observed local failures or cancer-related deaths. We observed an acceptable side-effect profile and renal function after SABR. These outcomes support the design of a future randomised trial of SABR versus surgery for primary renal cell cancer. FUNDING: Cancer Australia Priority-driven Collaborative Cancer Research Scheme.

The Dedicated Imaging Post-Prostatectomy for Enhanced Radiotherapy outcomes (DIPPER) trial protocol: a multicentre, randomised trial of salvage radiotherapy versus surveillance for low-risk biochemical recurrence after radical prostatectomy.

BACKGROUND: Salvage radiation therapy (SRT) and surveillance for low-risk prostate-specific antigen (PSA) recurrence have competing risks and benefits. The efficacy of early SRT to the prostate bed with or without pelvic lymph nodes compared to surveillance in patients with PSA recurrence after radical prostatectomy and no identifiable recurrent disease evident on prostate specific membrane antigen-positron emission tomography/computer tomography (PSMA-PET/CT) is unknown. STUDY DESIGN: The Dedicated Imaging Post-Prostatectomy for Enhanced Radiotherapy outcomes (DIPPER) is an open-label, multicentre, randomised Phase II trial. ENDPOINTS: The primary endpoint is 3-year event-free survival, with events comprising one of PSA recurrence (PSA ≥0.2 ng/mL higher than baseline), radiological evidence of metastatic disease, or initiation of systemic or other salvage treatments. Secondary endpoints include patient-reported outcomes, treatment patterns, participant perceptions, and cost-effectiveness. ELIGIBILITY CRITERIA: Eligible participants have PSA recurrence of prostate cancer after radical prostatectomy, defined by serum PSA level of 0.2-0.5 ng/mL, deemed low risk according to modified European Association of Urology biochemical recurrence risk criteria (International Society for Urological Pathology Grade Group ≤2, PSA doubling time >12 months), with no definite/probable recurrent prostate cancer on PSMA-PET/CT. PATIENTS AND METHODS: A total of 100 participants will be recruited from five Australian centres and randomised 1:1 to SRT or surveillance. Participants will undergo 6-monthly clinical evaluation for up to 36 months. Androgen-deprivation therapy is not permissible. Enrolment commenced May 2023. TRIAL REGISTRATION: This trial has been registered with the Australian New Zealand Clinical Trials Registry (ACTRN: ACTRN12622001478707).

Prostate-Specific Antigen Response to Androgen Deprivation Therapy in the Neoadjuvant Setting for High-Risk Prostate Adenocarcinoma (PIRANHA): Pooled Analysis of Two Randomized Clinical Trials.

PURPOSE: A suboptimal prostate-specific antigen (PSA) response to neoadjuvant androgen deprivation therapy (ADT) among men who go on to receive definitive radiation therapy for prostate cancer might suggest the existence of castration-resistant disease or altered androgen receptor signaling. This in turn may portend worse long-term clinical outcomes, especially in men with high-risk disease. We set out to evaluate the prognostic impact of poor PSA response to neoadjuvant ADT in men with high-risk prostate cancer. METHODS AND MATERIALS: This was a post hoc analysis of the multicenter TROG 03.04 RADAR and PCS IV randomized clinical trials. Inclusion criteria for this analysis were patients with high-risk prostate cancer (defined as Gleason score ≥8, initial PSA ≥20 ng/mL, or cT3a disease or higher) who received definitive radiation therapy, at least 18 months of ADT, and had a preradiation therapy PSA level drawn after at least 3 months of neoadjuvant ADT. Poor PSA response was defined as PSA >0.5 ng/mL. Cox regression and Fine-Gray models were used to test whether poor PSA response was associated with metastasis-free survival, biochemical recurrence, prostate-cancer specific mortality, and overall survival. RESULTS: Nine hundred thirty men met inclusion criteria for this analysis. Median follow-up was 130 months (interquartile range [IQR], 89-154 months). After a median of 3 months (IQR, 3-4.2 months) of neoadjuvant ADT, the median PSA was 0.60 ng/mL (IQR, 0.29-1.59). Overall, 535 men (57%) had a PSA >0.5 ng/mL. Poor PSA response was associated with significantly worse metastasis-free survival (hazard ratio [HR], 3.93; P = .02), worse biochemical recurrence (subdistribution HR, 2.39; P = .003), worse prostate-cancer specific mortality (subdistribution HR, 1.50; P = .005), and worse overall survival (HR, 4.51; P = .05). CONCLUSIONS: Patients with PSA >0.5 mg/mL after at least 3 months of neoadjuvant ADT had worse long-term clinical outcomes and should be considered for treatment intensification.

Non-contrast based approach for liver function quantification using Bayesian-based intravoxel incoherent motion diffusion weighted imaging: A pilot study.

PURPOSE: Liver cirrhosis disrupts liver function and tissue perfusion, detectable by magnetic resonance imaging (MRI). Assessing liver function at the voxel level with 13-b value intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) could aid in radiation therapy liver-sparing treatment for patients with early impairment. This study aimed to evaluate the feasibility of IVIM-DWI for liver function assessment and correlate it with other multiparametric (mp) MRI methods at the voxel level. METHOD: This study investigates the variability of apparent diffusion coefficient (ADC) derived from 13-b value IVIM-DWI and B1-corrected dual flip angle (DFA) T1 mapping. Experiments were conducted in-vitro with QIBA and NIST phantoms and in 10 healthy volunteers for IVIM-DWI. Additionally, 12 patients underwent an mp-MRI examination. The imaging protocol included a 13-b value IVIM-DWI sequence for generating IVIM parametric maps. B1-corrected DFA T1 pulse sequence was used for generating T1 maps, and Gadoxatate low temporal resolution dynamic contrast-enhanced (LTR-DCE) MRI was used for generating the Hepatic extraction fraction (HEF) map. The Mann-Whitney U test was employed to compare IVIM-DWI parameters (Pure Diffusion, Dslow ; Pseudo diffusion, Dfast ; and Perfusion Fraction, Fp ) between the healthy volunteer and patient groups. Furthermore, in the patient group, statistical correlations were assessed at a voxel level between LTR-DCE MRI-derived HEF, T1 post-Gadoxetate administration, ΔT1%, and various IVIM parameters using Pearson correlation. RESULTS: For-vitro measurements, the maximum coefficient of variation of the ADC and T1 parameters was 12.4% and 16.1%, respectively. The results also showed that Fp and Dfast were able to distinguish between healthy liver function and mild liver function impairment at the global level, with p = 0.002 for Fp and p < 0.001 for Dfast . Within the patient group, these parameters also exhibited a moderate correlation with HEF at the voxel level. CONCLUSION: Overall, the study highlighted the potential of Dfast and Fp for detecting liver function impairment at both global and pixel levels.

Cone beam computed tomography image guidance within a magnetic resonance imaging-only planning workflow.

Background and purpose: Magnetic Resonance Imaging (MRI)-only planning workflows offer many advantages but raises challenges regarding image guidance. The study aimed to assess the viability of MRI to Cone Beam Computed Tomography (CBCT) based image guidance for MRI-only planning treatment workflows. Materials and methods: An MRI matching training package was developed. Ten radiation therapists, with a range of clinical image guidance experience and experience with MRI, completed the training package prior to matching assessment. The matching assessment was performed on four match regions: prostate gold seed, prostate soft tissue, rectum/anal canal and gynaecological. Each match region consisted of five patients, with three CBCTs per patient, resulting in fifteen CBCTs for each match region. The ten radiation therapists performed the CBCT image matching to CT and to MRI for all regions and recorded the match values. Results: The median inter-observer variation for MRI-CBCT matching and CT-CBCT matching for all regions were within 2 mm and 1 degree. There was no statistically significant association in the inter-observer variation in mean match values and radiation therapist image guidance experience levels. There was no statistically significant association in inter-observer variation in mean match values for MRI experience levels for prostate soft tissue and gynaecological match regions, while there was a statistically significant difference for prostate gold seed and rectum match regions. Conclusion: The results of this study support the concept that with focussed training, an MRI to CBCT image guidance approach can be successfully implemented in a clinical planning workflow.

Clinical target volume delineation quality assurance for MRI-guided prostate radiotherapy using deep learning with uncertainty estimation.

BACKGROUND AND PURPOSE: Previous studies on automatic delineation quality assurance (QA) have mostly focused on CT-based planning. As MRI-guided radiotherapy is increasingly utilized in prostate cancer treatment, there is a need for more research on MRI-specific automatic QA. This work proposes a clinical target volume (CTV) delineation QA framework based on deep learning (DL) for MRI-guided prostate radiotherapy. MATERIALS AND METHODS: The proposed workflow utilized a 3D dropblock ResUnet++ (DB-ResUnet++) to generate multiple segmentation predictions via Monte Carlo dropout which were used to compute an average delineation and area of uncertainty. A logistic regression (LR) classifier was employed to classify the manual delineation as pass or discrepancy based on the spatial association between the manual delineation and the network's outputs. This approach was evaluated on a multicentre MRI-only prostate radiotherapy dataset and compared with our previously published QA framework based on AN-AG Unet. RESULTS: The proposed framework achieved an area under the receiver operating curve (AUROC) of 0.92, a true positive rate (TPR) of 0.92 and a false positive rate of 0.09 with an average processing time per delineation of 1.3 min. Compared with our previous work using AN-AG Unet, this method generated fewer false positive detections at the same TPR with a much faster processing speed. CONCLUSION: To the best of our knowledge, this is the first study to propose an automatic delineation QA tool using DL with uncertainty estimation for MRI-guided prostate radiotherapy, which can potentially be used for reviewing prostate CTV delineation in multicentre clinical trials.

Multi-omic features of oesophageal adenocarcinoma in patients treated with preoperative neoadjuvant therapy.

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.

Virtual HDR Boost for Prostate Cancer: Rebooting a Classic Treatment Using Modern Tech.

Prostate cancer (PC) is the most common malignancy in men. Internal radiotherapy (brachytherapy) has been used to treat PC successfully for over a century. In particular, there is level-one evidence of the benefits of using brachytherapy to escalate the dose of radiotherapy compared with standard external beam radiotherapy approaches. However, the use of PC brachytherapy is declining, despite strong evidence for its improved cancer outcomes. A method using external beam radiotherapy known as virtual high-dose-rate brachytherapy boost (vHDRB) aims to noninvasively mimic a brachytherapy boost radiation dose plan. In this review, we consider the evidence supporting brachytherapy boosts for PC and the continuing evolution of vHDRB approaches, culminating in the current generation of clinical trials, which will help define the role of this emerging modality.

Genitourinary Quality-of-Life Comparison Between Urethral Sparing Prostate Stereotactic Body Radiation Therapy Monotherapy and Virtual High-Dose-Rate Brachytherapy Boost.

PURPOSE: Although radiation dose escalation improves prostate cancer disease control, it can cause increased toxicity. Genitourinary (GU) symptoms after prostate radiation therapy affect patient health-related quality of life (QoL). We compared patient-reported GU QoL outcomes following 2 alternative urethral sparing stereotactic body radiation therapy regimens. METHODS AND MATERIALS: Expanded Prostate Cancer Index Composite (EPIC)-26 GU scores were compared between 2 urethral sparing stereotactic body radiation therapy trials. The SPARK trial prescribed a "Monotherapy" dose of 36.25 Gy in 5 fractions to the prostate. The PROMETHEUS trial prescribed 2 phases: a 19- to 21-Gy in 2 fractions "Boost" to the prostate, followed by 46 Gy in 23 fractions or 36 Gy in 12 fractions. The biological effective dose (BED) for urethral toxicity was 123.9 Gy for Monotherapy and 155.8 to 171.2 Gy for Boost. Mixed effects logistic regression models were utilized to estimate the difference in the odds of a minimal clinically important change from baseline EPIC-26 GU score between regimens at each follow-up. RESULTS: 46 Monotherapy and 149 Boost patients completed baseline EPIC-26 scoring. Mean EPIC-26 GU scores revealed statistically superior urinary incontinence outcomes for Monotherapy at 12 months (mean difference, 6.9; 95% confidence interval [CI], 1.6-12.1; P = .01) and 36 months (mean difference, 9.6; 95% CI, 4.1-15.1; P < .01). Monotherapy also revealed superior mean urinary irritative/obstructive outcomes at 12 months (mean difference, 6.9; 95% CI, 2.0-12.9; P < .01) and 36 months (mean difference, 6.3; 95% CI, 1.9-10.8; P < .01). For both domains and at all time points, the absolute differences were <10%. There were no significant differences in the odds of reporting a minimal clinically important change between regimens at any time point. CONCLUSIONS: Even in the presence of urethral sparing, the higher BED delivered in the Boost schedule may have a small adverse effect on GU QoL compared with Monotherapy. However, this did not translate to statistically significant differences in minimal clinically important changes. Whether the higher BED of the boost arm offers an efficacy advantage is being investigated in the Trans Tasman Radiation Oncology Group 18.01 NINJA randomized trial.

Deep learning enables MV-based real-time image guided radiation therapy for prostate cancer patients.

Objective. Using MV images for real-time image guided radiation therapy (IGRT) is ideal as it does not require additional imaging equipment, adds no additional imaging dose and provides motion data in the treatment beam frame of reference. However, accurate tracking using MV images is challenging due to low contrast and modulated fields. Here, a novel real-time marker tracking system based on a convolutional neural network (CNN) classifier was developed and evaluated on retrospectively acquired patient data for MV-based IGRT for prostate cancer patients.Approach. MV images, acquired from 29 volumetric modulated arc therapy (VMAT) prostate cancer patients treated in a multi-institutional clinical trial, were used to train and evaluate a CNN-based marker tracking system. The CNN was trained using labelled MV images from 9 prostate cancer patients (35 fractions) with implanted markers. CNN performance was evaluated on an independent cohort of unseen MV images from 20 patients (78 fractions), using a Precision-Recall curve (PRC), area under the PRC plot (AUC) and sensitivity and specificity. The accuracy of the tracking system was evaluated on the same unseen dataset and quantified by calculating mean absolute (±1 SD) and [1st, 99th] percentiles of the geometric tracking error in treatment beam co-ordinates using manual identification as the ground truth.Main results. The CNN had an AUC of 0.99, sensitivity of 98.31% and specificity of 99.87%. The mean absolute geometric tracking error was 0.30 ± 0.27 and 0.35 ± 0.31 mm in the lateral and superior-inferior directions of the MV images, respectively. The [1st, 99th] percentiles of the error were [-1.03, 0.90] and [-1.12, 1.12] mm in the lateral and SI directions, respectively.Significance. The high classification performance on unseen MV images demonstrates the CNN can successfully identify implanted prostate markers. Furthermore, the sub-millimetre accuracy and precision of the marker tracking system demonstrates potential for adaptation to real-time applications.

The dosimetric error due to uncorrected tumor rotation during real-time adaptive prostate stereotactic body radiation therapy.

BACKGROUND: During prostate stereotactic body radiation therapy (SBRT), prostate tumor translational motion may deteriorate the planned dose distribution. Most of the major advances in motion management to date have focused on correcting this one aspect of the tumor motion, translation. However, large prostate rotation up to 30° has been measured. As the technological innovation evolves toward delivering increasingly precise radiotherapy, it is important to quantify the clinical benefit of translational and rotational motion correction over translational motion correction alone. PURPOSE: The purpose of this work was to quantify the dosimetric impact of intrafractional dynamic rotation of the prostate measured with a six degrees-of-freedom tumor motion monitoring technology. METHODS: The delivered dose was reconstructed including (a) translational and rotational motion and (b) only translational motion of the tumor for 32 prostate cancer patients recruited on a 5-fraction prostate SBRT clinical trial. Patients on the trial received 7.25 Gy in a treatment fraction. A 5 mm clinical target volume (CTV) to planning target volume (PTV) margin was applied in all directions except the posterior direction where a 3 mm expansion was used. Prostate intrafractional translational motion was managed using a gating strategy, and any translation above the gating threshold was corrected by applying an equivalent couch shift. The residual translational motion is denoted as T r e s $T_{res}$ . Prostate intrafractional rotational motion R u n c o r r $R_{uncorr}$ was recorded but not corrected. The dose differences from the planned dose due to T r e s $T_{res}$ + R u n c o r r $R_{uncorr}$ , ΔD( T r e s $T_{res}$ + R u n c o r r $R_{uncorr}$ ) and due to T r e s $T_{res}$ alone, ΔD( T r e s $T_{res}$ ), were then determined for CTV D98, PTV D95, bladder V6Gy, and rectum V6Gy. The residual dose error due to uncorrected rotation, R u n c o r r $R_{uncorr}$ was then quantified: Δ D R e s i d u a l $\Delta D_{Residual}$ = ΔD( T r e s $T_{res}$ + R u n c o r r $R_{uncorr}$ ) - ΔD( T res ${T}_{\textit{res}}$ ). RESULTS: Fractional data analysis shows that the dose differences from the plan (both ΔD( T r e s $T_{res}$ + R u n c o r r $R_{uncorr}$ ) and ΔD( T r e s $T_{res}$ )) for CTV D98 was less than 5% in all treatment fractions. ΔD( T r e s $T_{res}$ + R u n c o r r $R_{uncorr}$ ) was larger than 5% in one fraction for PTV D95, in one fraction for bladder V6Gy, and in five fractions for rectum V6Gy. Uncorrected rotation, R u n c o r r $R_{uncorr}$ induced residual dose error, Δ D R e s i d u a l $\Delta D_{Residual}$ , resulted in less dose to CTV and PTV in 43% and 59% treatment fractions, respectively, and more dose to bladder and rectum in 51% and 53% treatment fractions, respectively. The cumulative dose over five fractions, ∑D( T r e s $T_{res}$ + R u n c o r r $R_{uncorr}$ ) and ∑D( T r e s $T_{res}$ ), was always within 5% of the planned dose for all four structures for every patient. CONCLUSIONS: The dosimetric impact of tumor rotation on a large prostate cancer patient cohort was quantified in this study. These results suggest that the standard 3-5 mm CTV-PTV margin was sufficient to account for the intrafraction prostate rotation observed for this cohort of patients, provided an appropriate gating threshold was applied to correct for translational motion. Residual dose errors due to uncorrected prostate rotation were small in magnitude, which may be corrected using different treatment adaptation strategies to further improve the dosimetric accuracy.

Determination of hepatic extraction fraction with gadoxetate low-temporal resolution DCE-MRI-based deconvolution analysis: validation with ALBI score and Child-Pugh class.

INTRODUCTION: In this study, we aimed to investigate the feasibility of gadoxetate low-temporal resolution (LTR) DCE-MRI for voxel-based hepatic extraction fraction (HEF) quantification for liver sparing radiotherapy using a deconvolution analysis (DA) method. METHODS: The accuracy and consistency of the deconvolution implementation in estimating liver function was first assessed using simulation data. Then, the method was applied to DCE-MRI data collected retrospectively from 64 patients (25 normal liver function and 39 cirrhotic patients) to generate HEF maps. The normal liver function patient data were used to measure the variability of liver function quantification. Next, a correlation between HEF and ALBI score (a new model for assessing the severity of liver dysfunction) was assessed using Pearson's correlation. Differences in HEF between Child-Pugh score classifications were assessed for significance using the Kruskal-Wallis test for all patient groups and Mann-Whitney U-test for inter-groups. A statistical significance was considered at a P-value <0.05 in all tests. RESULTS: The results showed that the implemented method accurately reproduced simulated liver function; root-mean-square error between estimated and simulated liver response functions was 0.003, and the coefficient-of-variance of HEF was <20%. HEF correlation with ALBI score was r = -0.517, P < 0.0001, and HEF was significantly decreased in the cirrhotic patients compared to normal patients (P < 0.0001). Also, HEF in Child-Pugh B/C was significantly lower than in Child-Pugh A (P = 0.024). CONCLUSION: The study demonstrated the feasibility of gadoxetate LTR-DCE MRI for voxel-based liver function quantification using DA. HEF could distinguish between different grades of liver function impairment and could potentially be used for functional guidance in radiotherapy.