[18]F-fluoroethyl-l-tyrosine positron emission tomography for radiotherapy target delineation: Results from a Radiation Oncology credentialing program.

Background and purpose: The [18]F-fluoroethyl-l-tyrosine (FET) PET in Glioblastoma (FIG) study is an Australian prospective, multi-centre trial evaluating FET PET for newly diagnosed glioblastoma management. The Radiation Oncology credentialing program aimed to assess the feasibility in Radiation Oncologist (RO) derivation of standard-of-care target volumes (TVMR) and hybrid target volumes (TVMR+FET) incorporating pre-defined FET PET biological tumour volumes (BTVs). Materials and methods: Central review and analysis of TVMR and TVMR+FET was undertaken across three benchmarking cases. BTVs were pre-defined by a sole nuclear medicine expert. Intraclass correlation coefficient (ICC) confidence intervals (CIs) evaluated volume agreement. RO contour spatial and boundary agreement were evaluated (Dice similarity coefficient [DSC], Jaccard index [JAC], overlap volume [OV], Hausdorff distance [HD] and mean absolute surface distance [MASD]). Dose plan generation (one case per site) was assessed. Results: Data from 19 ROs across 10 trial sites (54 initial submissions, 8 resubmissions requested, 4 conditional passes) was assessed with an initial pass rate of 77.8 %; all resubmissions passed. TVMR+FET were significantly larger than TVMR (p < 0.001) for all cases. RO gross tumour volume (GTV) agreement was moderate-to-excellent for GTVMR (ICC = 0.910; 95 % CI, 0.708-0.997) and good-to-excellent for GTVMR+FET (ICC = 0.965; 95 % CI, 0.871-0.999). GTVMR+FET showed greater spatial overlap and boundary agreement compared to GTVMR. For the clinical target volume (CTV), CTVMR+FET showed lower average boundary agreement versus CTVMR (MASD: 1.73 mm vs. 1.61 mm, p = 0.042). All sites passed the planning exercise. Conclusions: The credentialing program demonstrated feasibility in successful credentialing of 19 ROs across 10 sites, increasing national expertise in TVMR+FET delineation.

Dose-effect Relationship of Kidney Function After Stereotactic Ablative Body Radiotherapy for Primary Renal Cell Carcinoma: Trog 15.03 Fastrack Ii.

BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is a novel option to treat primary renal cell carcinoma (RCC). However, a high radiation dose may be received by the treated kidney, which may affect its function post-treatment. This study investigates the dose-effect relationship of kidney SABR with posttreatment renal function. METHODS: This was a prespecified secondary endpoint of the multicenter FASTRACK II clinical trial (NCT02613819). Patients received either 26 Gy in a single fraction (SF) for tumors with a maximal diameter of 4 cm or less, or 42 Gy in three fractions (multi-fraction (MF)) for larger tumors. To determine renal function change, 99mTc-DMSA SPECT/CT scans were acquired, and the glomerular filtration rate (GFR) was estimated at baseline, 12-, and 24-months post-treatment. Imaging datasets were rigidly registered to the planning CT where kidneys were segmented to calculate dose-response curves. RESULTS: From 71 enrolled patients, data from 36 (51%) and 26 (37%) patients were included in this study based on availability of post-treatment data at 12- and 24-months, respectively. The ipsilateral kidney GFR decreased from baseline by 42% and 39% in the SF cohort, and by 45% and 62% in the MF cohort, at 12- and 24-months respectively (p-values < 0.03). The loss in renal function was 3.6±0.8% and 4.5±1.0% in the SF cohort, and 1.7±0.1% and 1.7±0.2% in the MF cohort, at 12- and 24-months respectively. The major loss in renal function occurred in high-dose regions, where dose-response curves converged to a plateau. CONCLUSIONS: For the first time in a multicenter study, the dose-effect relationship at 12- and 24-months post-SABR treatment for primary RCC was quantified. Kidney function reduces linearly with dose up to 100 Gy BED3.

Local hero: A phase II study of local therapy only (stereotactic radiosurgery and / or surgery) for treatment of up to five brain metastases from HER2+ breast cancer. (TROG study 16.02).

Introduction, A decade ago, stereotactic radiosurgery (SRS) without whole brain radiotherapy (WBRT) was emerging as preferred treatment for oligometastatic brain metastases. Studies of cavity SRS after neurosurgery were underway. Data specific to metastatic HER2 breast cancer (MHBC), describing intracranial, systemic and survival outcomes without WBRT, were lacking. A Phase II study was designed to address this gap. Method, Adults with MHBC, performance status 0-2, ≤ five BrM, receiving/planned to receive HER2-targeted therapy were eligible. Exclusions included leptomeningeal disease and prior WBRT. Neurosurgery allowed ≤6 weeks before registration and required for BrM >4 cm. Primary endpoint was 12-month requirement for WBRT. Secondary endpoints; freedom from (FF-) local failure (LF), distant brain failure (DBF), extracranial disease failure (ECDF), overall survival (OS), cause of death, mini-mental state examination (MMSE), adverse events (AE). Results, Twenty-five patients accrued Decembers 2016-2020. The study closed early after slow accrual. Thirty-seven BrM and four cavities received SRS. Four cavities and five BrM were observed. At 12 months: one patient required WBRT (FF-WBRT 95 %, 95 % CI 72-99), FFLF 91 % (95 % CI 69-98), FFDBF 57 % (95 % CI 34-74), FFECDF 64 % (95 % CI 45-84), OS 96 % (95 % CI 74-99). Two grade 3 AE occurred. MMSE was abnormal for 3/24 patients at baseline and 1/17 at 12 months. Conclusion, At 12 months, SRS and/or neurosurgery provided good control with low toxicity. WBRT was not required in 95 % of cases. This small study supports the practice change from WBRT to local therapies for MHBC BrM.

Impact on Pulmonary Function in a Randomized Trial of Single-Fraction and Multifraction Stereotactic Body Radiation Therapy for Pulmonary Oligometastatic Disease: An Analysis of TROG 13.01 (SAFRON II).

PURPOSE: The TROG 13.01 (SAFRON II) trial was a phase 2 multicenter trial comparing single-fraction (SF) and multifraction (MF) stereotactic body radiation therapy. Patients with 1 to 3 peripheral pulmonary oligometastases were randomized 1:1 between 28 Gy in 1 fraction and 48 Gy in 4 fractions. There were no differences between arms in efficacy or toxicity. We performed an analysis to assess changes in pulmonary function tests (PFTs) between arms over time and assessed the effect of the number and total volume of targets on PFT change over time. METHODS AND MATERIALS: A linear mixed model was used to describe the PFTs by treatment arm over time. The effect of number and volume of targets on PFTs at 6 and 12 months was assessed by a simple linear model. RESULTS: Ninety patients were randomized; 87 were treated for 133 pulmonary oligometastases. Forty-four were randomized to the SF arm and 43 to the MF arm. There were no differences in absolute or relative PFT measures of forced expiratory volume in 1 second (FEV1), diffusing capacity of the lungs for carbon monoxide (DLCO), or forced vital capacity (FVC) between the 2 arms. At 12 months, there was a reduction in absolute DLCO from baseline (-1.7 mL/min/mm Hg [95% CI, -2.5 to -1.0]), relative DLCO (-5.5% [95% CI, -8.4% to -2.6%]), absolute FEV1 (-0.17 L [95% CI, -0.23 to -0.11]), and absolute FVC (-0.20 L [95% CI, -0.27 to -0.13]). In patients with multiple pulmonary targets, increase in target number (per lesion) was associated with a reduction in the absolute FEV1 at 6 months of -0.10 L (95% CI, -0.18 to -0.03; P = .007), FEV1 at 12 months of -0.10 L (95% CI, -0.20 to -0.01; P = .04), FVC at 6 months of -0.11 L (95% CI, -0.20 to -0.03; P = .014), and FVC at 24 months of -0.13 L (95% CI, -0.25 to -0.01; P = .036). Reduction in FEV1 was also seen per 10-mL increase in PTV at 12 months (-0.03 L [95% CI, -0.06 to -0.00], P = .036). The number of targets and PTV were not associated with DLCO. CONCLUSIONS: Treating multiple targets resulted in increased loss of FEV1 and FVC but not DLCO. There were no significant differences in PFT decline between SF and MF stereotactic body radiation therapy.

Delineation and agreement of FET PET biological volumes in glioblastoma: results of the nuclear medicine credentialing program from the prospective, multi-centre trial evaluating FET PET In Glioblastoma (FIG) study-TROG 18.06.

PURPOSE: The O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) PET in Glioblastoma (FIG) trial is an Australian prospective, multi-centre study evaluating FET PET for glioblastoma patient management. FET PET imaging timepoints are pre-chemoradiotherapy (FET1), 1-month post-chemoradiotherapy (FET2), and at suspected progression (FET3). Before participant recruitment, site nuclear medicine physicians (NMPs) underwent credentialing of FET PET delineation and image interpretation. METHODS: Sites were required to complete contouring and dynamic analysis by ≥ 2 NMPs on benchmarking cases (n = 6) assessing biological tumour volume (BTV) delineation (3 × FET1) and image interpretation (3 × FET3). Data was reviewed by experts and violations noted. BTV definition includes tumour-to-background ratio (TBR) threshold of 1.6 with crescent-shaped background contour in the contralateral normal brain. Recurrence/pseudoprogression interpretation (FET3) required assessment of maximum TBR (TBRmax), dynamic analysis (time activity curve [TAC] type, time to peak), and qualitative assessment. Intraclass correlation coefficient (ICC) assessed volume agreement, coefficient of variation (CoV) compared maximum/mean TBR (TBRmax/TBRmean) across cases, and pairwise analysis assessed spatial (Dice similarity coefficient [DSC]) and boundary agreement (Hausdorff distance [HD], mean absolute surface distance [MASD]). RESULTS: Data was accrued from 21 NMPs (10 centres, n ≥ 2 each) and 20 underwent review. The initial pass rate was 93/119 (78.2%) and 27/30 requested resubmissions were completed. Violations were found in 25/72 (34.7%; 13/12 minor/major) of FET1 and 22/74 (29.7%; 14/8 minor/major) of FET3 reports. The primary reasons for resubmission were as follows: BTV over-contour (15/30, 50.0%), background placement (8/30, 26.7%), TAC classification (9/30, 30.0%), and image interpretation (7/30, 23.3%). CoV median and range for BTV, TBRmax, and TBRmean were 21.53% (12.00-30.10%), 5.89% (5.01-6.68%), and 5.01% (3.37-6.34%), respectively. BTV agreement was moderate to excellent (ICC = 0.82; 95% CI, 0.63-0.97) with good spatial (DSC = 0.84 ± 0.09) and boundary (HD = 15.78 ± 8.30 mm; MASD = 1.47 ± 1.36 mm) agreement. CONCLUSION: The FIG study credentialing program has increased expertise across study sites. TBRmax and TBRmean were robust, with considerable variability in BTV delineation and image interpretation observed.

[18F]-fluoroethyl-L-tyrosine (FET) in glioblastoma (FIG) TROG 18.06 study: protocol for a prospective, multicentre PET/CT trial.

INTRODUCTION: Glioblastoma is the most common aggressive primary central nervous system cancer in adults characterised by uniformly poor survival. Despite maximal safe resection and postoperative radiotherapy with concurrent and adjuvant temozolomide-based chemotherapy, tumours inevitably recur. Imaging with O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) has the potential to impact adjuvant radiotherapy (RT) planning, distinguish between treatment-induced pseudoprogression versus tumour progression as well as prognostication. METHODS AND ANALYSIS: The FET-PET in Glioblastoma (FIG) study is a prospective, multicentre, non-randomised, phase II study across 10 Australian sites and will enrol up to 210 adults aged ≥18 years with newly diagnosed glioblastoma. FET-PET will be performed at up to three time points: (1) following initial surgery and prior to commencement of chemoradiation (FET-PET1); (2) 4 weeks following concurrent chemoradiation (FET-PET2); and (3) within 14 days of suspected clinical and/or radiological progression on MRI (performed at the time of clinical suspicion of tumour recurrence) (FET-PET3). The co-primary outcomes are: (1) to investigate how FET-PET versus standard MRI impacts RT volume delineation and (2) to determine the accuracy and management impact of FET-PET in distinguishing pseudoprogression from true tumour progression. The secondary outcomes are: (1) to investigate the relationships between FET-PET parameters (including dynamic uptake, tumour to background ratio, metabolic tumour volume) and progression-free survival and overall survival; (2) to assess the change in blood and tissue biomarkers determined by serum assay when comparing FET-PET data acquired prior to chemoradiation with other prognostic markers, looking at the relationships of FET-PET versus MRI-determined site/s of progressive disease post chemotherapy treatment with MRI and FET-PET imaging; and (3) to estimate the health economic impact of incorporating FET-PET into glioblastoma management and in the assessment of post-treatment pseudoprogression or recurrence/true progression. Exploratory outcomes include the correlation of multimodal imaging, blood and tumour biomarker analyses with patterns of failure and survival. ETHICS AND DISSEMINATION: The study protocol V.2.0 dated 20 November 2020 has been approved by a lead Human Research Ethics Committee (Austin Health, Victoria). Other clinical sites will provide oversight through local governance processes, including obtaining informed consent from suitable participants. The study will be conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Results of the FIG study (TROG 18.06) will be disseminated via relevant scientific and consumer forums and peer-reviewed publications. TRIAL REGISTRATION NUMBER: ANZCTR ACTRN12619001735145.

The Feasibility of Quality Assurance in the TOPGEAR International Phase 3 Clinical Trial of Neoadjuvant Chemoradiation Therapy for Gastric Cancer (an Intergroup Trial of the AGITG/TROG/NHMRC CTC/EORTC/CCTG).

PURPOSE: The TOPGEAR phase 3 trial hypothesized that adding preoperative chemoradiation therapy (CRT) to perioperative chemotherapy will improve survival in patients with gastric cancer. Owing to the complexity of gastric irradiation, a comprehensive radiation therapy quality assurance (RTQA) program was implemented. Our objective is to describe the RTQA methods and outcomes. METHODS AND MATERIALS: RTQA was undertaken in real time before treatment for the first 5 patients randomized to CRT from each center. Once acceptable quality was achieved, RTQA was completed for one-third of subsequent cases. RTQA consisted of evaluating (1) clinical target volume and organ-at-risk contouring and (2) radiation therapy planning parameters. Protocol violations between high- (20+ patients enrolled) and low-volume centers were compared using the Fisher exact test. RESULTS: TOPGEAR enrolled 574 patients, of whom 286 were randomized to receive preoperative CRT and 203 (71%) were included for RTQA. Of these, 67 (33%) and 136 (67%) patients were from high- and low-volume centers, respectively. The initial RTQA pass rate was 72%. In total, 28% of cases required resubmission. In total, 200 of 203 cases (99%) passed RTQA before treatment. Cases from low-volume centers required resubmission more often (44/136 [33%] vs 13/67 [18%]; P = .078). There was no change in the proportion of cases requiring resubmission over time. Most cases requiring resubmission had multiple protocol violations. At least 1 aspect of the clinical target volume had to be adjusted in all cases. Inadequate coverage of the duodenum was most common (53% major violation, 25% minor violation). For the remaining cases, the resubmission process was triggered secondary to poor contour/plan quality. CONCLUSIONS: In a large multicenter trial, RTQA is feasible and effective in achieving high-quality treatment plans. Ongoing education should be performed to ensure consistent quality during the entire study period.

Comparison of Changes in Pulmonary Function After Stereotactic Body Radiation Therapy Versus Conventional 3-Dimensional Conformal Radiation Therapy for Stage I and IIA Non-Small Cell Lung Cancer: An Analysis of the TROG 09.02 (CHISEL) Phase 3 Trial.

PURPOSE: The TROG 09.02 CHISEL trial compared conventional radiation therapy (CRT) with stereotactic body radiation therapy (SBRT) in patients with inoperable early-stage non-small cell lung cancer. Patients randomized to SBRT had less local failure and improved overall survival. This analysis reports differences in pulmonary function tests (PFTs) and the 6-minute walk test (SMWT) between patients who received SBRT and those who received CRT. METHODS AND MATERIALS: We analyzed the PFTs and SMWTs of all patients recruited to the CHISEL [trial. During this trial, patients underwent serial PFTs. Linear regression models were used to compare parameters between SBRT and CRT at 3 and 12 months after treatment. RESULTS: One hundred and one patients were enrolled; 33 patients were treated with CRT, 61 were treated with SBRT, and 7 did not receive treatment. Primary tumor size was similar between arms: SBRT 25 mm (standard deviation [SD], 9) and CRT 28 mm (SD, 9). On regression analysis, at 3 and 12 months, there was no evidence of a difference between arms in PFT decline or distance walked in the SMWT. Planning target volume size was significantly larger in the CRT arm, 142.79 cc (SD, 61.14), compared with the SBRT group, 46.15 cc (SD, 23.39). The mean biologically effective dose received by the target was significantly larger in the SBRT group, 125.92 Gy (SD, 21.58), compared with CRT, 65.49 Gy (SD, 6.32). Mean dose to the lungs minus the gross target volume incorporating motion was 8.9 Gy (SD, 2.34) in the CRT group and 4.37 Gy (SD, 1.42) in the SBRT group. CONCLUSIONS: Despite the considerably higher biologically effective doses delivered to the tumor in SBRT, there was no difference in decline in respiratory function observed between the 2 groups.

Prioritizing clinical trial quality assurance for photons and protons: A failure modes and effects analysis (FMEA) comparison.

BACKGROUND AND PURPOSE: The Global Clinical Trials RTQA Harmonization Group (GHG) set out to evaluate and prioritize clinical trial quality assurance. METHODS: The GHG compiled a list of radiotherapy quality assurance (QA) tests performed for proton and photon therapy clinical trials. These tests were compared between modalities to assess whether there was a need for different types of assessments per modality. A failure modes and effects analysis (FMEA) was performed to assess the risk of each QA failure. RESULTS: The risk analysis showed that proton and photon therapy shared four out of five of their highest-risk failures (end-to-end anthropomorphic phantom test, phantom tests using respiratory motion, pre-treatment patient plan review of contouring/outlining, and on-treatment/post-treatment patient plan review of dosimetric coverage). While similar trends were observed, proton therapy had higher risk failures, driven by higher severity scores. A sub-analysis of occurrence × severity scores identified high-risk scores to prioritize for improvements in RTQA detectability. A novel severity scaler was introduced to account for the number of patients affected by each failure. This scaler did not substantially alter the ranking of tests, but it elevated the QA program evaluation to the top 20th percentile. This is the first FMEA performed for clinical trial quality assurance. CONCLUSION: The identification of high-risk errors associated with clinical trials is valuable to prioritize and reduce errors in radiotherapy and improve the quality of trial data and outcomes, and can be applied to optimize clinical radiotherapy QA.

Radiotherapy quality assurance in the TROG 12.01 randomised trial and its impact on loco-regional failure.

Introduction: There is no consensus as to what specifically constitutes head and neck cancer radiotherapy quality assurance (HNC RT QA). The aims of this study are to (1) describe the RT QA processes used in the TROG 12.01 study, (2) review the RT QA processes undertaken for all patients with loco-regional failure (LRF), and (3) provide prospective data to propose a consensus statement regarding the minimal components and optimal timing of HNC RT QA. Materials and methods: All patients undergoing RT QA in the original TROG 12.01 study were included in this substudy. All participating sites completed IMRT credentialling and a clinical benchmark case. Real-time (pre-treatment) RT QA was performed for the first patient of each treating radiation oncologist, and for one in five of subsequent patients. Protocol violations were deemed major if they related to contour and/or dose of gross tumour volume (GTV), high dose planning target volume (PTVhd), or critical organs of risk (spinal cord, mandible, and brachial plexus). Results: Thirty HNROs from 15 institutions accrued 182 patients. There were 28 clinical benchmark cases, 27 pre-treatment RT QA cases, and 38 post-treatment cases. Comprehensive RT QA was performed in 65/182 (36%) treated patients. Major protocol violations were found in 5/28 benchmark cases, 5/27 pre-treatment cases, and 6/38 post-treatment cases. An independent review of all nine LRF cases showed major protocol violations in four of nine cases. Conclusion: Only pre-treatment RT QA can improve patient outcomes. The minimal components of RT QA in HNC are GTVs, PTVhd, and critical organs at risk. What constitutes major dosimetric violations needs to be harmonised.

SEAFARER - A new concept for validating radiotherapy patient specific QA for clinical trials and clinical practice.

BACKGROUND: The quality of radiotherapy delivery has been shown to significantly impact clinical outcomes including patient survival. To identify errors, institutions perform Patient Specific Quality Assurance (PSQA) assessing each individual radiotherapy plan prior to starting patient treatments. Externally administered Dosimetry Audits have found problems despite institutions passing their own PSQA. Hence a new audit concept which assesses the institution's ability to detect errors with their routine PSQA is needed. METHODS: Purposefully introduced edits which simulated treatment delivery errors were embedded into radiation treatment plans of participating institutions. These were designed to produce clinically significant changes yet were mostly within treatment delivery specifications. Actual impact was centrally assessed for each plan. Institutions performed PSQA on each plan, without knowing which contained errors. RESULTS: Seventeen institutions using six radiation treatment planning systems and two delivery systems performed PSQA on twelve plans each. Seventeen erroneous plans (across seven institutions) passed PSQA despite causing >5% increase in spinal cord dose relative to the original plans. Six plans (from four institutions) passed despite a >10% increase. CONCLUSIONS: This novel audit concept evolves beyond testing an institution's ability to deliver a single test case, to increasing the number of errors caught by institutions themselves, thus increasing quality of radiation therapy and impacting every patient treated. Administered remotely this audit also provides advantages in cost, environmental impact, and logistics.

Why quality assurance is necessary in gynecologic radiation oncology.

Quality assurance (QA) in radiation oncology involves all checks and processes that ensure that radiotherapy is delivered in an optimal and intended manner. QA is essential for the accurate delivery of brachytherapy and external beam radiotherapy in patients diagnosed with gynecologic malignancies. Inadequate QA can adversely impact clinical outcomes and reduce the reliability of clinical trials. This review highlights the importance of QA in gynecologic radiation oncology and explores the pertinent issues related to its implementation.

Using Ecological Momentary Assessments to Understand Black Youths' Experiences of Racism, Stress, and Safety.

Anti-Black racism, both interpersonal and systemic, is pervasive. Individual- and neighborhood-level expressions of anti-Black racism have been explored in many studies; however, Black youths' experiences of racism across routine activity locations have not been examined as extensively. To address this gap, a Youth Research Advisory Board (YRAB) recruited 75 Black youths (M (SD) = 15.53 (1.77)), living in a segregated neighborhood (93% African American) with 42% of residents living below the poverty line, to participate in research on this topic. Participants in the study completed surveys three times a day for a month (ecological momentary assessment) about their positive and negative emotions and perceptions of racism and social support in routine activity locations (n = 2041). Youths reported more racism when attending school and walking on the street. A relationship between perceptions of racism and social support in routine activity locations and positive and negative momentary emotions was found. This paper will present implications for supporting adolescent development and interrupting anti-Black racism at the level of routine activity locations, along with opportunities for engaging youth-led community-based solutions.

Personalising treatment plan quality review with knowledge-based planning in the TROG 15.03 trial for stereotactic ablative body radiotherapy in primary kidney cancer.

INTRODUCTION: Quality assurance (QA) of treatment plans in clinical trials improves protocol compliance and patient outcomes. Retrospective use of knowledge-based-planning (KBP) in clinical trials has demonstrated improved treatment plan quality and consistency. We report the results of prospective use of KBP for real-time QA of treatment plan quality in the TROG 15.03 FASTRACK II trial, which evaluates efficacy of stereotactic ablative body radiotherapy (SABR) for kidney cancer. METHODS: A KBP model was generated based on single institution data. For each patient in the KBP phase (open to the last 31 patients in the trial), the treating centre submitted treatment plans 7 days prior to treatment. A treatment plan was created by using the KBP model, which was compared with the submitted plan for each organ-at-risk (OAR) dose constraint. A report comparing each plan for each OAR constraint was provided to the submitting centre within 24 h of receiving the plan. The centre could then modify the plan based on the KBP report, or continue with the existing plan. RESULTS: Real-time feedback using KBP was provided in 24/31 cases. Consistent plan quality was in general achieved between KBP and the submitted plan. KBP review resulted in replan and improvement of OAR dosimetry in two patients. All centres indicated that the feedback was a useful QA check of their treatment plan. CONCLUSION: KBP for real-time treatment plan review was feasible for 24/31 cases, and demonstrated ability to improve treatment plan quality in two cases. Challenges include integration of KBP feedback into clinical timelines, interpretation of KBP results with respect to clinical trade-offs, and determination of appropriate plan quality improvement criteria.

Can Radiation Therapy Quality Assurance Improve Nasopharyngeal Cancer Outcomes in Low- and Middle-Income Countries: Reporting the First Phase of a Prospective International Atomic Energy Agency Study.

PURPOSE: Most new nasopharyngeal cancer cases occur in low-income and middle-income countries, and these patients experience poorer overall survival than that of new nasopharyngeal cancer cases in high-income countries. The goal of this research project is to determine whether the introduction of a radiation therapy quality assurance program can ultimately improve outcomes for nasopharyngeal cancer patients in lower-income and middle-income countries. This study reports the results of the first phase of the International Atomic Energy Agency Coordinated Research Project (325-E3-TM-47712). METHODS AND MATERIALS: This prospective study has 2 phases. Phase 1 is a survey of radiation therapy resources, patient characteristics and treatment, and results of radiation therapy quality assurance performed by the expert panel. An educational workshop reviewing phase 1 results for each center was completed before accrual of patients for phase 2. The ultimate aim of the study is to compare the first and second cohort of patients to see if quality assurance can result in fewer major protocol deviations and a 15% improvement in patients' 3-year progression-free survival. RESULTS: Of 14 participating centers, 13 (93%) had computed tomography simulators and linear accelerators (LINAC) with intensity modulated radiation therapy (IMRT) capacity, median 3 LINAC (range, 1-13), and median 10 radiation oncologists (range, 5-51). The annual number of nasopharyngeal cancer cases irradiated was median 54 (range, 10-627). Five of 14 centers (36%) had no local radiation therapy quality assurance. For the current phase 1 study, 134 patients were evaluated, 82.1% had MRI staging, 99.3% had metastatic workup, 65.6% undifferentiated histology, 51% stage 3 and 49% stage 4. Radiation therapy quality assurance revealed 81 (60.4%) of 134 patients had major protocol violations in gross tumor volume and high dose planning target volume contours and/or dosimetry, 28.4% patients had borderline plans, 15 (11.2%) acceptable, and only 6 (4.2%) had inevitable compromise due to tumor extent. CONCLUSIONS: This is the first International Atomic Energy Agency study to address the fundamental issue of treatment quality rather than altered treatment regimens. The high rate of unacceptable radiation therapy plans is a major concern, and we hope phase 2 will show a significant reduction and improved patient outcomes.

AGITG MASTERPLAN: a randomised phase II study of modified FOLFIRINOX alone or in combination with stereotactic body radiotherapy for patients with high-risk and locally advanced pancreatic cancer.

BACKGROUND: Among patients with non-metastatic pancreatic cancer, 80% have high-risk, borderline resectable or locally advanced cancer, with a 5-year overall survival of 12%. MASTERPLAN evaluates the safety and activity of stereotactic body radiotherapy (SBRT) in addition to chemotherapy in these patients. METHODS AND DESIGN: MASTERPLAN is a multi-centre randomised phase II trial of 120 patients with histologically confirmed potentially operable pancreatic cancer (POPC) or inoperable pancreatic cancer (IPC). POPC includes patients with borderline resectable or high-risk tumours; IPC is defined as locally advanced or medically inoperable pancreatic cancer. Randomisation is 2:1 to chemotherapy + SBRT (investigational arm) or chemotherapy alone (control arm) by minimisation and stratified by patient cohort (POPC v IPC), planned induction chemotherapy and institution. Chemotherapy can have been commenced ≤28 days prior to randomisation. Both arms receive 6 × 2 weekly cycles of modified FOLFIRINOX (oxaliplatin (85 mg/m2 IV), irinotecan (150 mg/m2), 5-fluorouracil (2400 mg/m2 CIV), leucovorin (50 mg IV bolus)) plus SBRT in the investigational arm. Gemcitabine+nab-paclitaxel is permitted for patients unsuitable for mFOLFIRINOX. SBRT is 40Gy in five fractions with planning quality assurance to occur in real time. Following initial chemotherapy ± SBRT, resectability will be evaluated. For resected patients, adjuvant chemotherapy is six cycles of mFOLFIRINOX. Where gemcitabine+nab-paclitaxel was used initially, the adjuvant treatment is 12 weeks of gemcitabine and capecitabine or mFOLFIRINOX. Unresectable or medically inoperable patients with stable/responding disease will continue with a further six cycles of mFOLFIRINOX or three cycles of gemcitabine+nab-paclitaxel, whatever was used initially. The primary endpoint is 12-month locoregional control. Secondary endpoints are safety, surgical morbidity and mortality, radiological response rates, progression-free survival, pathological response rates, surgical resection rates, R0 resection rate, quality of life, deterioration-free survival and overall survival. Tertiary/correlative objectives are radiological measures of nutrition and sarcopenia, and serial tissue, blood and microbiome samples to be assessed for associations between clinical endpoints and potential predictive/prognostic biomarkers. Interim analysis will review rates of locoregional recurrence, distant failure and death after 40 patients complete 12 months follow-up. Fifteen Australian and New Zealand sites will recruit over a 4-year period, with minimum follow-up period of 12 months. DISCUSSION: MASTERPLAN evaluates SBRT in both resectable and unresectable patients with pancreatic ductal adenocarcinoma. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry ACTRN12619000409178 , 13/03/2019. Protocol version: 2.0, 19 May 2019.

Organ at risk delineation for radiation therapy clinical trials: Global Harmonization Group consensus guidelines.

BACKGROUND AND PURPOSE: The Global Quality Assurance of Radiation Therapy Clinical Trials Harmonization Group (GHG) is a collaborative group of Radiation Therapy Quality Assurance (RTQA) Groups harmonizing and improving RTQA for multi-institutional clinical trials. The objective of the GHG OAR Working Group was to unify OAR contouring guidance across RTQA groups by compiling a single reference list of OARs in line with AAPM TG 263 and ASTRO, together with peer-reviewed, anatomically defined contouring guidance for integration into clinical trial protocols independent of the radiation therapy delivery technique. MATERIALS AND METHODS: The GHG OAR Working Group comprised of 22 multi-professional members from 6 international RTQA Groups and affiliated organizations conducted the work in 3 stages: (1) Clinical trial documentation review and identification of structures of interest (2) Review of existing contouring guidance and survey of proposed OAR contouring guidance (3) Review of survey feedback with recommendations for contouring guidance with standardized OAR nomenclature. RESULTS: 157 clinical trials were examined; 222 OAR structures were identified. Duplicates, non-anatomical, non-specific, structures with more specific alternative nomenclature, and structures identified by one RTQA group were excluded leaving 58 structures of interest. 6 OAR descriptions were accepted with no amendments, 41 required minor amendments, 6 major amendments, 20 developed as a result of feedback, and 5 structures excluded in response to feedback. The final GHG consensus guidance includes 73 OARs with peer-reviewed descriptions (Appendix A). CONCLUSION: We provide OAR descriptions with standardized nomenclature for use in clinical trials. A more uniform dataset supports the delivery of clinically relevant and valid conclusions from clinical trials.

Head and Neck Cancer International Group (HNCIG) Consensus Guidelines for the Delivery of Postoperative Radiation Therapy in Complex Cutaneous Squamous Cell Carcinoma of the Head and Neck (cSCCHN).

Radiation therapy (RT) consensus contouring guidelines in the postoperative setting for complex cutaneous squamous cell carcinoma of the head and neck have been developed by expert clinicians in the field of head and neck and dermato-oncology and members of the Head and Neck Cancer International Group to assist radiation oncologists involved in the management of this disease. These guidelines present a set of principles used to define postoperative RT volumes and corresponding minimum doses after resection of all macroscopic tumor with or without microscopic residual disease. It is anticipated they will promote the harmonization of postoperative RT globally and contribute to a reduction in treatment variation among clinicians, allowing for RT quality and outcomes assessment across institutions.

A remote EPID-based dosimetric TPS-planned audit of centers for clinical trials: outcomes and analysis of contributing factors.

BACKGROUND: A novel remote method for external dosimetric TPS-planned auditing of intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) for clinical trials using electronic portal imaging device (EPID) has been developed. The audit has been applied to multiple centers across Australia and New Zealand. This work aims to assess the audit outcomes and explores the variables that contributed to the audit results. METHODS: Thirty audits were performed of 21 radiotherapy facilities, 17 facilities underwent IMRT audits and 13 underwent VMAT audits. The assessment was based on comparisons between the delivered doses derived from images acquired with EPIDs and planned doses from the local treatment planning systems (TPS). Gamma pass-rate (GPR) and gamma mean value (GMV) were calculated for each IMRT field and VMAT arc (total 268 comparisons). A multiple variable linear model was applied to the GMV results (3%/3 mm criteria) to assess the influence and significance of explanatory variables. The explanatory variables were Linac-TPS combination, TPS grid resolution, IMRT/VMAT delivery, age of EPID, treatment site, record and verification system (R&V) type and dose-rate. Finally, the audit results were compared with other recent audits by calculating the incidence ratio (IR) as a ratio of the observed mean/median GPRs for the remote audit to the other audits. RESULTS: The average (± 1 SD) of the centers' GPRs were: 99.3 ± 1.9%, 98.6 ± 2.7% & 96.2 ± 5.5% at 3%, 3 mm, 3%, 2 mm and 2%, 2 mm criteria respectively. The most determinative variables on the GMVs were Linac-TPS combination, TPS grid resolution and IMRT/VMAT delivery type. The IR values were 1 for seven comparisons, indicating similar GPRs of the remote audit with the reference audits and > 1 for four comparisons, indicating higher GPRs of the remote audit than the reference audits. CONCLUSION: The remote dosimetry audit method for clinical trials demonstrated high GPRs and provided results comparable to established more resource-intensive audit methods. Several factors were found to influence the results including some effect of Linac-TPS combination.

Observer variation in the delineation of organs at risk for head and neck radiation therapy treatment planning: a systematic review protocol.

REVIEW QUESTION: The objective of this review is to examine inter- and intra-observer agreement and reliability in the delineation of head and neck organs at risk (OAR) as part of the radiation therapy treatment planning process.More specifically, the objectives are to identify.