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Up to 40% of patients with non-small cell lung cancer (NSCLC) develop central nervous system (CNS) metastases. Current treatments for this subgroup of patients with advanced NSCLC include local therapies (surgery, stereotactic radiosurgery, and, less frequently, whole-brain radiotherapy), targeted therapies for oncogene-addicted NSCLC (small molecules, such as tyrosine kinase inhibitors, and antibody-drug conjugates), and immune checkpoint inhibitors (as monotherapy or combination therapy), with multiple new drugs in development. However, confirming the intracranial activity of these treatments has proven to be challenging, given that most lung cancer clinical trials exclude patients with untreated and/or progressing CNS metastases, or do not include prespecified CNS-related endpoints. Here we review progress in the treatment of patients with CNS metastases originating from NSCLC, examining local treatment options, systemic therapies, and multimodal therapeutic strategies. We also consider challenges regarding assessment of treatment response and provide thoughts around future directions for managing CNS disease in patients with advanced NSCLC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: 18 F-fluorothymidine (FLT) positron emission tomography (PET) enables sensitive imaging of bone marrow (BM) proliferation. Sequential FLT-PET/computed tomography scans before and during chemoradiation therapy (CRT) for non-small cell lung cancer were repurposed to investigate the dose-response effects of radiation on BM proliferation., Methods and Materials: Twenty-six non-small cell lung cancer patients underwent platinum-based CRT to 60 Gy in 30 fractions with FLT-PET/computed tomography scans at baseline, week 2 (20 Gy), and week 4 (40 Gy). FLT uptake in BM was isolated using Medical Image Merge software. Weeks 2 and 4 FLT-PET BM scans were fused with contemporaneous radiation isodose distributions. Relationships between radiation dose and FLT BM uptake (highest standardized uptake values within the volume and visual parameters) were analyzed using generalized linear and restricted cubic spline models. Percentage volumes of total BM without appreciable FLT uptake ("ablated") on weeks 2 and 4 FLT-PET scans were calculated by comparisons with baseline scans., Results: Thoracic FLT uptake was ablated in BM regions exposed to cumulative radiation doses ≥3 Gy by week 2. In all cases, BM FLT's highest standardized uptake values within the volume declined rapidly as the radiation dose increased. BM proliferation significantly decreased by >95% after ≥3 to 4 Gy at 2 weeks and ≥4 to 5 Gy at 4 weeks. The ablated BM volume increased from week 2 to week 4 as BM in the penumbra accumulated radiation dose. The median percentage of total BM ablated was 13.1% (range, 5.6%-20.3%) at 2 weeks and 15.7% (range, 9.2%-24.1%) at 4 weeks. Mean lymphocyte counts fell from a baseline of 2.01 × 10 9 /L to 0.77 at week 2 and 0.60 at week 4. Lymphocyte decline strongly correlated with the percentage of total BM ablated by week 4 (y = -46 to 1.64x; R 2 adj = 0.34; P = .001)., Conclusions: BM ablation associated with low-dose radiation exposure during CRT correlated significantly with lower week 4 lymphocyte counts. BM is a potential organ at risk, and reducing the BM volume exposed to ≥3 Gy may help preserve lymphocytes, which is essential for effective adjuvant immunotherapy., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Patients with advanced non-small-cell lung cancer (NSCLC) with activating mutations in the epidermal growth factor receptor ( EGFR ) gene are a heterogeneous population who often develop brain metastases (BM). The optimal management of patients with asymptomatic brain metastases is unclear given the activity of newer-generation targeted therapies in the central nervous system. We present a protocol for an individual patient data (IPD) prospective meta-analysis to evaluate whether the addition of stereotactic radiosurgery (SRS) before osimertinib treatment will lead to better control of intracranial metastatic disease. This is a clinically relevant question that will inform practice., Methods: Randomised controlled trials will be eligible if they include participants with BM arising from EGFR- mutant NSCLC and suitable to receive osimertinib both in the first-line and second-line settings (P); comparisons of SRS followed by osimertinib versus osimertinib alone (I, C) and intracranial disease control included as an endpoint (O). Systematic searches of Medline (Ovid), Embase (Ovid), Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL (EBSCO), PsychInfo, ClinicalTrials.gov and the WHO's International Clinical Trials Registry Platform's Search Portal will be undertaken. An IPD meta-analysis will be performed using methodologies recommended by the Cochrane Collaboration. The primary outcome is intracranial progression-free survival, as determined by response assessment in neuro-oncology-BM criteria. Secondary outcomes include overall survival, time to whole brain radiotherapy, quality of life, and adverse events of special interest. Effect differences will be explored among prespecified subgroups., Ethics and Dissemination: Approved by each trial's ethics committee. Results will be relevant to clinicians, researchers, policymakers and patients, and will be disseminated via publications, presentations and media releases., Prospero Registration: CRD42022330532., Competing Interests: Competing interests: SL: research funding and honoraria from AstraZeneca. YYS: honoraria from AstraZeneca and Janssen. AGS: research grants (institution) from Elekta AB, Varian, Seagen and BrainLAB; consulting fees from Varian, Elekta (Gamma Knife Icon), BrainLAB, Merck, Abbvie and Roche; honoraria from AstraZeneca, Elekta AB, Varian, BrainLAB, Accuray and Seagen. MBP: speaker fees from AZ, BMS, MSD and Roche. AN: research grants from Varian Medical Systems. RAS: advisory board with Amgen, Astra-Zeneca, Bayer, BMS, Boehringer Ingelheim, Janssen, Lily, Merck, Merck Serono, Novartis, Pfizer, Puma Biotechnology, Roche, Taiho, Takeda, Thermo Fisher and Yuhan Corporation; research grant from Astra-Zeneca and Boehringer Ingelheim. FHJ: clinical trial funding, received honoraria and participated in advisory boards for Astra Zeneca; received payments and honoraria from BeiGene and MSD for lectures and presentations; supported by the Peter Mac Foundation and the Victorian Cancer Agency. BJS: advisory board/honoraria from AstraZeneca, Pfizer, Novartis, Roche, Takeda, Merck, Bristol Mysers Squibb, Janssen, Amgen and Eli Lilly. IWKT: honorarium from Elekta and MSD. CH: advisory boards with Abbvie, Amgen, AstraZeneca, Bayer, BMS, Eisai, EMD Serono, Janssen, Jazz, Merck, Novartis, Pfizer, Roche, Sanofi and Takeda; research grants from AstraZeneca, EMD Serono and Roche. CKL: advisory board with Amgen, Astra Zeneca, GSK, Merck KGA, Norvatis, Pfizer, Roche, Takeda, Boehringer-Ingelheim and Yuhan; research funding (institution) from Astra Zeneca, Roche, Merck KGA and Amgen. KPR, AP, MD, DBS, AGS, JT, CNL, WYK, YH, YLEA, JL, CY, MCL and APT have no competing interests. CH, SL, FHJ, CKL, YYS, RAS and IWKT are study chairs on the included trials., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: During a phase 0 clinical trial of an investigational programmed cell death ligand-1 (PD-L1) PET tracer in patients with non-small cell lung cancer (NSCLC), three patients received booster doses of COVID-19 vaccines before PD-L1 imaging., Methods: Five patients underwent whole-body PET/CT imaging with a novel PD-L1 tracer, constructed by attaching 89 Zr to the anti PD-L1 antibody durvalumab. Intramuscular (deltoid) booster doses of mRNA BNT162b2 COVID-19 mRNA vaccine were coincidentally given to three patients in the month before PD-L1 tracer injection., Results: Two recently-vaccinated patients, in remission of NSCLC and receiving non-immunosuppressive cancer therapies (immunotherapy and tyrosine kinase inhibitor respectively), showed increasing PD-L1 tracer uptake in ipsilateral axillary lymph nodes. No asymmetric nodal uptake was seen in a third recently-vaccinated patient who was receiving immunosuppressive chemotherapy, or in two patients not recently-vaccinated., Conclusion: Immune response to mRNA BNT162b2 vaccination may involve regulation by PD-L1 positive immune cells in local draining lymph nodes in immunocompetent patients., Trial Registration: This trial was registered with the Australian New Zealand Clinical Trials Registry. Registration number ACTRN12621000171819. Date of Trial Registration 8/2/2021. Date of enrolment of 1st patient 11/4/2021. URL of trial registry record: https://www.australianclinicaltrials.gov.au/anzctr/trial/ACTRN12621000171819 ., (© 2024. The Author(s).)

Background: Exercise rehabilitation is a promising strategy for reducing cardiovascular disease risk among patients with breast cancer. However, the evidence is primarily derived from programs based at exercise centers with in-person supervised delivery. Conversely, most patients report a preference for home-based rehabilitation. As such, there is a clear need to explore strategies that can provide real-time supervision and coaching while addressing consumer preferences. Evidence from cardiac rehabilitation has demonstrated the noninferiority of a smartphone-based telerehabilitation approach (REMOTE-CR) to improve cardiorespiratory fitness in people with cardiovascular disease compared to a center-based program., Objective: This study aims to assess the feasibility, safety, and preliminary efficacy of the REMOTE-CR program adapted for patients with breast cancer at risk of cardiotoxicity (REMOTE-COR-B). We will also assess the satisfaction and usability of REMOTE-COR-B., Methods: We will conduct a single-arm feasibility study of the REMOTE-COR-B program among patients with stage I-III breast cancer who are at risk of cardiotoxicity (taking treatment type and dose, as well as other common cardiovascular disease risk factors into account) and who are within 24 months of completing primary definitive treatment. Participants (target sample size of 40) will receive an 8-week smartphone-based telerehabilitation exercise program involving remotely delivered real-time supervision and behavior change support. The platform comprises a smartphone and wearable heart rate monitor, as well as a custom-built smartphone app and web application. Participants will be able to attend remotely monitored exercise sessions during set operating hours each week, scheduled in both the morning and evening. Adherence is the primary outcome of the trial, assessed through the number of remotely monitored exercise sessions attended compared to the trial target (ie, 3 sessions per week). Secondary outcomes include additional trial feasibility indicators (eg, recruitment and retention), safety, satisfaction, and usability, and objective and patient-reported efficacy outcomes (cardiovascular fitness, quality of life, fatigue, self-reported exercise, self-efficacy, habit strength, and motivation). Adherence, feasibility, and safety outcomes will be assessed during the intervention period; intervention satisfaction and usability will be assessed post intervention; and objective and patient-reported efficacy outcomes will be assessed at baseline, post intervention (2-month postbaseline assessment), and at follow-up (5-month postbaseline assessment)., Results: Recruitment for this trial commenced in March 2023, and 7 participants had been recruited as of the submission of the manuscript. The estimated completion date for the project is October 2024, with results expected to be published in mid-2025., Conclusions: The REMOTE-COR-B intervention is a novel and promising approach to providing exercise therapy to patients with breast cancer at risk of cardiotoxicity who have unique needs and heightened safety risks. This project will provide important information on the extent to which this approach is satisfactory to patients with breast cancer, safe, and potentially effective, which is necessary before larger-scale research or clinical projects., Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12621001557820; www.anzctr.org.au/ACTRN12621001557820.aspx., International Registered Report Identifier (irrid): DERR1-10.2196/53301., (©Camille E Short, Jonathan C Rawstorn, Tamara L Jones, Lara Edbrooke, Sandra C Hayes, Ralph Maddison, Sophie Nightingale, Hilmy Ismail, Richard De Boer, Fiona Hegi-Johnson, Aaron L Sverdlov, Robyn Bell, Irene Halligan, Linda Denehy. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 05.04.2024.)

Introduction: Smoking is a risk factor for the development of lung cancer and reduces life expectancy within the general population. Retrospective studies suggest that non-smokers have better outcomes after treatment for lung cancer. We used a prospective database to investigate relationships between pre-treatment smoking status and survival for a cohort of patients with stage III non-small-cell lung cancer (NSCLC) treated with curative-intent concurrent chemoradiotherapy (CRT)., Methods: All patients treated with CRT for stage III NSCLC at a major metropolitan cancer centre were prospectively registered to a database. A detailed smoking history was routinely obtained at baseline. Kaplan-Meier statistics were used to assess overall survival and progression-free survival in never versus former versus current smokers., Results: Median overall survival for 265 eligible patients was 2.21 years (95 % Confidence Interval 1.78, 2.84). It was 5.5 years (95 % CI 2.1, not reached) for 25 never-smokers versus 1.9 years (95 % CI 1.5, 2.7) for 182 former smokers and 2.2 years (95 % CI 1.3, 2.7) for 58 current smokers. Hazard ratio for death was 2.43 (95 % CI 1.32-4.50) for former smokers and 2.75 (95 % CI 1.40, 5.40) for current smokers, p = 0.006. Actionable tumour mutations (EGFR, ALK, ROS1) were present in more never smokers (14/25) than former (9/182) or current (3/58) smokers. TKI use was also higher in never smokers but this was not significantly associated with superior survival (Hazard ratio 0.71, 95 % CI 0.41, 1.26)., Conclusions: Never smokers have substantially better overall survival than former or current smokers after undergoing CRT for NSCLC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Epidermal growth factor receptor (EGFR) mutations are detected in up to one third of patients with unresectable stage III non-small cell lung cancer (NSCLC). The current standard of care for unresectable stage III NSCLC is consolidation durvalumab for patients who have not progressed following concurrent chemoradiotherapy (the 'PACIFIC regimen'). However, the benefit of immunotherapy, specifically in patients with EGFR mutation-positive (EGFRm) tumors, is not well characterized, and this treatment approach is not recommended in these patients, based on a recent ESMO consensus statement. EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated significant improvements in patient outcomes in EGFRm metastatic NSCLC. The benefits of these agents have also translated to patients with EGFRm early-stage resectable disease as adjuvant therapy. The role of EGFR-TKIs has yet to be prospectively characterized in the unresectable setting. Preliminary efficacy signals for EGFR-TKIs in unresectable EGFRm stage III NSCLC have been reported from a limited number of subgroup and retrospective studies. Several clinical trials are ongoing assessing the safety and efficacy of EGFR-TKIs in this patient population. Here, we review the current management of unresectable EGFRm stage III NSCLC. We outline the rationale for investigating EGFR-TKI strategies in this setting and discuss ongoing studies. Finally, we discuss the evidence gaps and future challenges for treating patients with unresectable EGFRm stage III NSCLC., Competing Interests: Declaration of competing interest Terufumi Kato reports consulting/advisory roles: AstraZeneca, BeiGene, Daiichi-Sankyo, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer; honoraria: Amgen Inc., AstraZeneca, BeiGene, Boehringer Ingelheim, Chugai Pharmaceuticals Co., Ltd., Daiichi-Sankyo, Eli Lilly and Company, GlaxoSmithKline, Janssen, Merck KGaA, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical Co., Ltd., Pfizer, Taiho Pharmaceutical, Takeda; employment (spouse): Eli Lilly and company; research support (to institution): AbbVie Inc., Amgen Inc., AstraZeneca, BeiGene, Blueprint Medicines, Chugai Pharmaceutical Co., Ltd., Daiichi-Sankyo, Eli Lilly and Company, HaiHe Biopharma, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron Pharmaceuticals Inc., Takeda, Turning Point Therapeutics Inc. Ignacio Casarini reports local principal investigator role: AstraZeneca, Bristol-Myers Squibb, Exelixis, Lilly, Merck Sharp & Dohme, Novartis, Roche (non-financial and for institution); principal investigator role for multiple clinical studies: AstraZeneca, Bristol-Myers Squibb, Exelixis, Lilly, Merck Sharp & Dohme, Novartis; principal investigator role for one clinical study: Roche. Corinne Faivre-Finn reports research funding: AstraZeneca, and Elekta; travel expenses: AstraZeneca, Elekta, Peter MacCallum Cancer Centre, and CF-F’s institution; and uncompensated relationships: AstraZeneca, Elekta, and Merck Sharpe & Dohme. CF-F is supported by a grant from the National Institute for Health Research (NIHR) Manchester Biomedical Research Centre. Fiona Hegi-Johnson reports research funding: AstraZeneca; honoraria: AstraZeneca; payment or honoraria for lectures and presentations: BeiGene, Merck Sharpe & Dohme. Participation on an advisory board: AstraZeneca. FH-J is supported by the Victorian Cancer Agency. Shun Lu reports consulting/advisory roles: AstraZeneca, Boehringer Ingelheim, GenomiCare Biotechnology, Hutchison MediPharma Ltd., Pfizer, prIME Oncology, Roche, Simcere Pharmaceutical Group, Yuhan, Zai Lab; speaker’s bureau: AstraZeneca, Hansoh Pharmaceutical Group Co. Ltd., Hengrui Pharmaceuticals Company Ltd., Roche; research funding (to institution): AstraZeneca, BeiGene, Bristol-Myers Squibb, Hansoh Pharmaceutical Group Co. Ltd., Hengrui Pharmaceuticals Company Ltd., Hutchison MediPharma Ltd., Lilly Suzhou Pharmaceutical Co. Ltd., Roche. Mustafa Özgüroğlu reports consulting/advisory roles: Astellas (to self and institution), Janssen, Sanofi; honoraria: Astellas (to self and institution), Janssen, Novartis, Roche, Sanofi. Suresh S. Ramalingam reports consulting/advisory roles: Amgen Inc., AstraZeneca, Bristol-Myers Squibb, Genentech, Merck & Co. Inc., Takeda Inc., Tesaro; research funding: Amgen Inc., Advaxis Inc., AstraZeneca, Bristol-Myers Squibb, Genmab, Merck & Co. Inc., Takeda, Tesaro Inc. Manuel Cobo declares no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: The aim of this study was to report pulmonary function tests (PFTs) and clinician-reported and patient-reported quality-of-life (QoL) outcomes on a cohort of patients with non-small cell lung cancer (NSCLC) treated with SABR., Methods and Materials: A total of 119 patients with NSCLC were treated with SABR in the prospective cohort SSBROC study of patients with T1-T2N0M0 NSCLC. PFTs and QoL measures were obtained at baseline pretreatment and at 6-month intervals. Here we report on the 6- to 18-month time points. Analysis of covariance (ANCOVA) methods adjusting for baseline analyzed potential predictors on outcomes of PFTs and patient-reported dyspnea at 18 months., Results: The only statistically significant decline in PFTs was seen in forced expiratory volume in 1 second (FEV 1 ) at 18 months post-SABR, with a decline of -0.11 L (P = .0087; 95% CI, -0.18 to -0.02). Of potential predictors of decline, only a 1-unit increase in smoking pack-years resulted in a -0.12 change in diffusing capacity for carbon monoxide (P = .026; 95% CI, -0.02 to -0.23) and a 0.003 decrease in FEV 1 (P = .026; 95% CI, -0.006 to -0.0004). For patient-reported outcomes, statistically significant worsening in both the European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire (QLQ-C30 Version 3) and the lung module (QLQ-LC13) dyspnea scores occurred at the 18-month time point, but not earlier. No potential predictors of worsening dyspnea were statistically significant. There was no statistically significant decline in clinician-reported outcomes or global QoL scores., Conclusions: We found a statistically significant decline in FEV 1 at 18 months posttreatment. Smoking pack-years was a predictor for decline in diffusing capacity for carbon monoxide and FEV 1 at 18 months. Worsening of patient-reported dyspnea scores was observed, consistent with the expected progression of lung comorbid disease., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Objectives: 89 Zr-labelled proteins are gaining importance in clinical research in a variety of diseases. To date, no clinical study has been reported that utilizes an automated approach for radiosynthesis of 89 Zr-labelled radiopharmaceuticals. We aim to develop an automated method for the clinical production of 89 Zr-labelled proteins and apply this method to Durvalumab, a monoclonal antibody targeting PD-L1 immune-checkpoint protein. PD-L1 expression is poorly understood and can be up-regulated over the course of chemo- and radiotherapy treatment. The ImmunoPET multicentre study aims to examine the dynamics of PD-L1 expression via 89 Zr-Durvalumab PET imaging before, during, and after chemoradiotherapy. The developed automated technique will enable reproducible clinical production of [ 89 Zr]Zr-DFOSq-Durvalumab for this study at three different sites., Methods: Conjugation of Durvalumab to H 3 DFOSqOEt was optimized for optimal chelator-to-antibody ratio. Automated radiolabelling of H 3 DFOSq-Durvalumab with zirconium-89 was optimized on the disposable cassette based iPHASE technologies MultiSyn radiosynthesizer using a modified cassette. Activity losses were tracked using a dose calibrator and minimized by optimizing fluid transfers, reaction buffer, antibody formulation additives and pH. The biological profile of the radiolabelled antibody was confirmed in vivo in PD-L1+ (HCC827) and PD-L1- (A549) murine xenografts. Clinical process validation and quality control were performed at three separate study sites to satisfy clinical release criteria., Results: H 3 DFOSq-Durvalumab with an average CAR of 3.02 was obtained. Radiolabelling kinetics in succinate (20 mM, pH 6) were significantly faster when compared to HEPES (0.5 M, pH 7.2) with >90 % conversion observed after 15 min. Residual radioactivity in the 89 Zr isotope vial was reduced from 24 % to 0.44 % ± 0.18 % (n = 7) and losses in the reactor vial were reduced from 36 % ± 6 % (n = 4) to 0.82 % ± 0.75 % (n = 4) by including a surfactant in the reaction and formulation buffers. Overall process yield was 75 % ± 6 % (n = 5) and process time was 40 min. Typically, 165 MBq of [ 89 Zr]Zr-DFOSq-Durvalumab with an apparent specific activity of 315 MBq/mg ± 34 MBq/mg (EOS) was obtained in a volume of 3.0 mL. At end-of-synthesis (EOS), radiochemical purity and protein integrity were always >99 % and >96 %, respectively, and dropped to 98 % and 65 % after incubation in human serum for 7 days at 37 °C. Immunoreactive fraction in HEK293/PD-L1 cells was 83.3 ± 9.0 (EOS). Preclinical in vivo data at 144 h p.i. showed excellent SUV max in PD-L1+ tumour (8.32 ± 0.59) with a tumour-background ratio of 17.17 ± 3.96. [ 89 Zr]Zr-DFOSq-Durvalumab passed all clinical release criteria at each study site and was deemed suitable for administration in a multicentre imaging trial., Conclusion: Fully automated production of [ 89 Zr]Zr-DFOSq-Durvalumab for clinical use was achieved with minimal exposure to the operator. The cassette-based approach allows for consecutive productions on the same day and offers an alternative to currently used manual protocols. The method should be broadly applicable to other proteins and has the potential for clinical impact considering the growing number of clinical trials investigating 89 Zr-labelled antibodies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SP is the director of iPHASE technologies Pty Ltd. (Melbourne, Australia). AN receives institutional funding from AstraZeneca Pty Ltd. (Cambridge, UK) for clinical trials and translational science unrelated to this work. PSD and SER are listed as inventors on intellectual property relating to the use of DFOSq that has been licensed from the University of Melbourne to Telix Pharmaceuticals. This work was supported by AstraZeneca Pty Ltd. (Cambridge, UK) and Telix Pharmaceuticals Limited (Melbourne, Australia)., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: ImmunoPET is a multicentre, single arm, phase 0-1 study that aims to establish if 89 Zr-durvalumab PET/CT can be used to interrogate the expression of PD-L1 in larger, multicentre clinical trials., Methods: The phase 0 study recruited 5 PD-L1+ patients with metastatic non-small cell lung cancer (NSCLC). Patients received 60MBq/70 kg 89 Zr-durva up to a maximum of 74 MBq, with scan acquisition at days 0, 1, 3 or 5±1 day. Data on (1) Percentage of injected 89 Zr-durva dose found in organs of interest (2) Absorbed organ doses (µSv/MBq of administered 89 Zr-durva) and (3) whole-body dose expressed as mSv/100MBq of administered dose was collected to characterise biodistribution.The phase 1 study will recruit 20 patients undergoing concurrent chemoradiotherapy for stage III NSCLC. Patients will have 89 Zr-durva and FDG-PET/CT before, during and after chemoradiation. In order to establish the feasibility of 89 Zr-durva PET/CT for larger multicentre trials, we will collect both imaging and toxicity data. Feasibility will be deemed to have been met if more than 80% of patients are able complete all trial requirements with no significant toxicity., Ethics and Dissemination: This phase 0 study has ethics approval (HREC/65450/PMCC 20/100) and is registered on the Australian Clinical Trials Network (ACTRN12621000171819). The protocol, technical and clinical data will be disseminated by conference presentations and publications. Any modifications to the protocol will be formally documented by administrative letters and must be submitted to the approving HREC for review and approval., Trial Registration Number: Australian Clinical Trials Network ACTRN12621000171819., Competing Interests: Competing interests: FH-J has clinical trial funding, has received honoraria and participated in advisory boards for Astra Zeneca. She has received payments and honoria from BeiGene and MSD for lectures and presentations. Her work is supported by the Peter Mac Foundation and the Victorian Cancer Agency. SER and PSD are inventors on intellectual property relating to the use of DFOSq that have been licensed from the University of Melbourne to Telix Pharmaceuticals. TJ has received payments and honoraria from BMS and Astra Zeneca for lectures and presentations, and sits on Data Safety and Monitoring Boards or Advisory boards for Roche, BMS, Astra Zeneca, Novartis, Amgen, Puma, MSD and Merck. SF has received payments and honoraria from Astra Zeneca, Roche, Amgen, Novartis, Bayer, GSK, BMS, MSD and Janssen for lectures and presentations. KB has received payments and honoraria from Bayer and Abbvie for lectures and presentations and participates on Data Safety and Monitoring boards for Novartis., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Immune checkpoint inhibitors and related molecules can achieve tumour regression, and even prolonged survival, for a subset of cancer patients with an otherwise dire prognosis. However, it remains unclear why some patients respond to immunotherapy and others do not. PET imaging has the potential to characterise the spatial and temporal heterogeneity of both immunotherapy target molecules and the tumor immune microenvironment, suggesting a tantalising vision of personally-adapted immunomodulatory treatment regimens. Personalised combinations of immunotherapy with local therapies and other systemic therapies, would be informed by immune imaging and subsequently modified in accordance with therapeutically induced immune environmental changes. An ideal PET imaging biomarker would facilitate the choice of initial therapy and would permit sequential imaging in time-frames that could provide actionable information to guide subsequent therapy. Such imaging should provide either prognostic or predictive measures of responsiveness relevant to key immunotherapy types but, most importantly, guide key decisions on initiation, continuation, change or cessation of treatment to reduce the cost and morbidity of treatment while enhancing survival outcomes. We survey the current literature, focusing on clinically relevant immune checkpoint immunotherapies, for which novel PET tracers are being developed, and discuss what steps are needed to make this vision a reality., (© 2022. The Author(s).)

Delivering radiotherapy to patients in an upright position can allow for increased patient comfort, reduction in normal tissue irradiation, or reduction of machine size and complexity. This paper gives an overview of the requirements for the delivery of contemporary arc and modulated radiation therapy to upright patients. We explore i) patient positioning and immobilization, ii) simulation imaging, iii) treatment planning and iv) online setup and image guidance. Treatment chairs have been designed to reproducibly position seated patients for treatment and can be augmented by several existing immobilisation systems or promising emerging technologies such as soft robotics. There are few solutions for acquiring CT images for upright patients, however, cone beam computed tomography (CBCT) scans of upright patients can be produced using the imaging capabilities of standard Linacs combined with an additional patient rotation device. While these images will require corrections to make them appropriate for treatment planning, several methods indicate the viability of this approach. Treatment planning is largely unchanged apart from translating gantry rotation to patient rotation, allowing for a fixed beam with a patient rotating relative to it. Rotation can be provided by a turntable during treatment delivery. Imaging the patient with the same machinery as used in treatment could be advantageous for online plan adaption. While the current focus is using clinical linacs in existing facilities, developments in this area could also extend to lower-cost and mobile linacs and heavy ion therapy., Competing Interests: NH and TK receive collaborative research funding from Varian Medical Systems and Reflexion Medical for unrelated projects. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hegarty, Hardcastle, Korte, Kron, Everitt, Rahim, Hegi-Johnson and Franich.)

Competing Interests: FH-J has received clinical trial funding from AstraZeneca. MM declares no competing interests.

Introduction: Stereotactic ablative radiotherapy (SABR) for lung cancer is a modality of treatment that has improved outcomes for lung cancer patients. However, radiotherapy for lung cancer is underutilized and fewer than half of elderly patients with non-small cell lung cancer (NSCLC) receive active treatment. The purpose of this study is to report on a collaboration in implementing an NSCLC SABR (stereotactic ablative body radiation) program safely, efficiently, and uniformly across several centers, including regional sites. The first aim of this paper is to detail the collaboration and implementation that started in 2013 and is ongoing. The second aim of this paper is to document early toxicities and quality of life outcomes., Method: A tripartite approach was used to develop the protocol and networks required for the implementation of SABR across multiple sites in NSW. Departments starting the programmes were supported and physics credentialing with central site submission was required before commencing the treatment. Additional ongoing support was available via an email discussion group involving all members of the collaboration., Results: Between July 22, 2013 and February 22, 2016, 41 patients were enrolled with 34 patients in active follow up. The toxicity profile so far is similar to those of published studies with no appreciable effect on quality of life outcomes., Conclusion: The collaboration formed an effective framework in facilitating the implementation of SABR across several sites in NSW and could be used as a model for the safe and uniform implementation of new technologies in Australia., (© 2019 John Wiley & Sons Australia, Ltd.)

Computed Tomography Ventilation Imaging (CTVI) is an experimental imaging modality that derives regional lung function information from non-contrast respiratory-correlated CT datasets. Despite CTVI being extensively studied in cross-modality imaging comparisons, there is a lack of consensus on the state of its clinical validation in humans. This systematic review evaluates the CTVI clinical validation studies to date, highlights their common strengths and weaknesses and makes recommendations. We performed a PUBMED and EMBASE search of all English language papers on CTVI between 2000 and 2018. The results of these searches were filtered in accordance to a set of eligibility criteria and analysed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines. One hundred and forty-four records were identified, and 66 full text records were reviewed. After detailed assessment, twenty-three full text papers met the selection criteria and were included in the final review. This included thirteen prospective studies, with 579 human subjects. Studies used diverse methodologies, with a large amount of heterogeneity between different studies in terms of the reference ventilation imaging modality (e.g. nuclear medicine, hyperpolarised gas MRI), imaging parameters, DIR algorithm(s) used, and ventilation metric(s) applied. The most common ventilation metrics used deformable image registration to evaluate the exhale-to-inhale motion field Jacobian determinant (DIR-Jac) or changes in air volume content based on Hounsfield Units (DIR-HU). The strength of correlation between CTVI and the reference ventilation imaging modalities was moderate to strong when evaluated at the lobar or global level, with the average ± S.D. (number of studies) linear regression correlation coefficients were 0.73 ± 0.25 (n = 6) and 0.86 ± 0.11 (n = 12) for DIR-Jac and DIR-HU respectively, and the SPC were 0.45 ± 0.31 (n = 6) and 0.41 ± 0.11 (n = 5) for DIR-Jac and DIR-HU respectively. We concluded that it is difficult to make a broad statement about the validity of CTVI due to the diverse methods used in the validation literature. Typically, CTVI appears to show reasonable cross-modality correlations at the lobar/whole lung level but poor correlations at the voxel level. Since CTVI is seeing new implementations in prospective trials, it is clear that refinement and standardization of the clinical validation methodologies are required. CTVI appears to be of relevance in radiotherapy planning, particularly in patients whose main pulmonary impairment is not a gas exchange problem but alternative imaging approaches may need to be considered in patients with other pulmonary diseases (i.e. restrictive or gas exchange problems)., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Stage III non-small cell lung cancer (NSCLC) makes up a third of all NSCLC cases and is potentially curable. Despite this 5-year survival rates remain between 15% and 20% with chemoradiation treatment alone given with curative intent. With the recent exciting breakthroughs in immunotherapy use (durvalumab) for stage III NSCLC, further improvements in patient survival can be expected. Most patients with stage III NSCLC present initially to their general practitioner (GP). The recommended time from GP referral to first specialist appointment is less than 14 days with treatment initiated within 42 days. Our review found that there is a shortfall in meeting these recommendations, however a number of initiatives have been established in Australia to improve timely and accurate diagnosis and treatment patterns. The lung cancer multidisciplinary team (MDT) is critical to consistency of evidence-based diagnosis and treatment and can improve patient survival. We aimed to review current patterns of care and clinical practice recommendations for stage III NSCLC across Australia and identify opportunities to improve practice in referral, diagnosis and treatment pathways., (© 2019 John Wiley & Sons Australia, Ltd.)

Purpose: CT ventilation imaging (CTVI) is being used to achieve functional avoidance lung cancer radiation therapy in three clinical trials (NCT02528942, NCT02308709, NCT02843568). To address the need for common CTVI validation tools, we have built the Ventilation And Medical Pulmonary Image Registration Evaluation (VAMPIRE) Dataset, and present the results of the first VAMPIRE Challenge to compare relative ventilation distributions between different CTVI algorithms and other established ventilation imaging modalities., Methods: The VAMPIRE Dataset includes 50 pairs of 4DCT scans and corresponding clinical or experimental ventilation scans, referred to as reference ventilation images (RefVIs). The dataset includes 25 humans imaged with Galligas 4DPET/CT, 21 humans imaged with DTPA-SPECT, and 4 sheep imaged with Xenon-CT. For the VAMPIRE Challenge, 16 subjects were allocated to a training group (with RefVI provided) and 34 subjects were allocated to a validation group (with RefVI blinded). Seven research groups downloaded the Challenge dataset and uploaded CTVIs based on deformable image registration (DIR) between the 4DCT inhale/exhale phases. Participants used DIR methods broadly classified into B-splines, Free-form, Diffeomorphisms, or Biomechanical modeling, with CT ventilation metrics based on the DIR evaluation of volume change, Hounsfield Unit change, or various hybrid approaches. All CTVIs were evaluated against the corresponding RefVI using the voxel-wise Spearman coefficient r S , and Dice similarity coefficients evaluated for low function lung ( DSC low ) and high function lung ( DSC high )., Results: A total of 37 unique combinations of DIR method and CT ventilation metric were either submitted by participants directly or derived from participant-submitted DIR motion fields using the in-house software, VESPIR. The r S and DSC results reveal a high degree of inter-algorithm and intersubject variability among the validation subjects, with algorithm rankings changing by up to ten positions depending on the choice of evaluation metric. The algorithm with the highest overall cross-modality correlations used a biomechanical model-based DIR with a hybrid ventilation metric, achieving a median (range) of 0.49 (0.27-0.73) for r S , 0.52 (0.36-0.67) for DSC low , and 0.45 (0.28-0.62) for DSC high . All other algorithms exhibited at least one negative r S value, and/or one DSC value less than 0.5., Conclusions: The VAMPIRE Challenge results demonstrate that the cross-modality correlation between CTVIs and the RefVIs varies not only with the choice of CTVI algorithm but also with the choice of RefVI modality, imaging subject, and the evaluation metric used to compare relative ventilation distributions. This variability may arise from the fact that each of the different CTVI algorithms and RefVI modalities provides a distinct physiologic measurement. Ultimately this variability, coupled with the lack of a "gold standard," highlights the ongoing importance of further validation studies before CTVI can be widely translated from academic centers to the clinic. It is hoped that the information gleaned from the VAMPIRE Challenge can help inform future validation efforts., (© 2018 American Association of Physicists in Medicine.)

Radiotherapy is used in >50% of patients with cancer, both for curative and palliative purposes. Radiotherapy uses ionizing radiation to target and kill tumour tissue, but normal tissue can also be damaged, leading to toxicity. Modern and precise radiotherapy techniques, such as intensity-modulated radiotherapy, may prevent toxicity, but some patients still experience adverse effects. The physiopathology of toxicity is dependent on many parameters, such as the location of irradiation or the functional status of organs at risk. Knowledge of the mechanisms leads to a more rational approach for controlling radiotherapy toxicity, which may result in improved symptom control and quality of life for patients. This improved quality of life is particularly important in paediatric patients, who may live for many years with the long-term effects of radiotherapy. Notably, signs and symptoms occurring after radiotherapy may not be due to the treatment but to an exacerbation of existing conditions or to the development of new diseases. Although differential diagnosis may be difficult, it has important consequences for patients.

Purpose: Computed tomography ventilation imaging (CTVI) is a highly accessible functional lung imaging modality that can unlock the potential for functional avoidance in lung cancer radiation therapy. Previous attempts to validate CTVI against clinical ventilation single-photon emission computed tomography (V-SPECT) have been hindered by radioaerosol clumping artifacts. This work builds on those studies by performing the first comparison of CTVI with 99m Tc-carbon ('Technegas'), a clinical V-SPECT modality featuring smaller radioaerosol particles with less clumping., Methods: Eleven lung cancer radiotherapy patients with early stage (T1/T2N0) disease received treatment planning four-dimensional CT (4DCT) scans paired with Technegas V/Q-SPECT/CT. For each patient, we applied three different CTVI methods. Two of these used deformable image registration (DIR) to quantify breathing-induced lung density changes (CTVI DIR-HU ), or breathing-induced lung volume changes (CTVI DIR-Jac ) between the 4DCT exhale/inhale phases. A third method calculated the regional product of air-tissue densities (CTVI HU ) and did not involve DIR. Corresponding CTVI and V-SPECT scans were compared using the Dice similarity coefficient (DSC) for functional defect and nondefect regions, as well as the Spearman's correlation r computed over the whole lung. The DIR target registration error (TRE) was quantified using both manual and computer-selected anatomic landmarks., Results: Interestingly, the overall best performing method (CTVI HU ) did not involve DIR. For nondefect regions, the CTVI HU , CTVI DIR-HU , and CTVI DIR-Jac methods achieved mean DSC values of 0.69, 0.68, and 0.54, respectively. For defect regions, the respective DSC values were moderate: 0.39, 0.33, and 0.44. The Spearman r-values were generally weak: 0.26 for CTVI HU , 0.18 for CTVI DIR-HU , and -0.02 for CTVI DIR-Jac . The spatial accuracy of CTVI was not significantly correlated with TRE, however the DIR accuracy itself was poor with TRE > 3.6 mm on average, potentially indicative of poor quality 4DCT. Q-SPECT scans achieved good correlations with V-SPECT (mean r > 0.6), suggesting that the image quality of Technegas V-SPECT was not a limiting factor in this study., Conclusions: We performed a validation of CTVI using clinically available 4DCT and Technegas V/Q-SPECT for 11 lung cancer patients. The results reinforce earlier findings that the spatial accuracy of CTVI exhibits significant interpatient and intermethod variability. We propose that the most likely factor affecting CTVI accuracy was poor image quality of clinical 4DCT., (© 2017 American Association of Physicists in Medicine.)

Purpose: Computed tomography ventilation imaging derived from four-dimensional cone beam CT (CTVI 4DCBCT ) can complement existing 4DCT-based methods (CTVI 4 DCT ) to track lung function changes over a course of lung cancer radiation therapy. However, the accuracy of CTVI 4 DCBCT needs to be assessed since anatomic 4DCBCT has demonstrably poor image quality and small field of view (FOV) compared to treatment planning 4DCT. We perform a direct comparison between short interval CTVI 4 DCBCT and CTVI 4 DCT pairs to understand the patient specific image quality factors affecting the intermodality CTVI reproducibility in the clinic., Methods and Materials: We analysed 51 pairs of 4DCBCT and 4DCT scans acquired within 1 day of each other for nine lung cancer patients. To assess the impact of image quality, CTVIs were derived from 4DCBCT scans reconstructed using both standard Feldkamp-Davis-Kress backprojection (CTVIFDK4DCBCT) and an iterative McKinnon-Bates Simultaneous Algebraic Reconstruction Technique (CTVIMKBSART4DCBCT). Also, the influence of FOV was assessed by deriving CTVIs from 4DCT scans that were cropped to a similar FOV as the 4DCBCT scans (CTVIcrop4DCT), or uncropped (CTVIuncrop4DCT). All CTVIs were derived by performing deformable image registration (DIR) between the exhale and inhale phases and evaluating the Jacobian determinant of deformation. Reproducibility between corresponding CTVI 4 DCBCT and CTVI 4 DCT pairs was quantified using the voxel-wise Spearman rank correlation and the Dice similarity coefficient (DSC) for ventilation defect regions (identified as the lower quartile of ventilation values). Mann-Whitney U-tests were applied to determine statistical significance of each reconstruction and cropping condition., Results: The (mean ± SD) Spearman correlation between CTVIFDK4DCBCT and CTVIuncrop4DCT was 0.60 ± 0.23 (range -0.03-0.88) and the DSC was 0.64 ± 0.12 (0.34-0.83). By comparison, correlations between CTVIMKBSART4DCBCT and CTVIuncrop4DCT showed a small but statistically significant improvement with = 0.64 ± 0.20 (range 0.06-0.90, P = 0.03) and DSC = 0.66 ± 0.13 (0.31-0.87, P = 0.02). Intermodal correlations were noted to decrease with an increasing fraction of lung truncation in 4DCBCT relative to 4DCT, albeit not significantly (Pearson correlation R = 0.58, P = 0.002)., Conclusions: This study demonstrates that DIR based CTVIs derived from 4DCBCT can exhibit reasonable to good voxel-level agreement with CTVIs derived from 4DCT. These correlations outperform previous cross-modality comparisons between 4DCT-based ventilation and nuclear medicine. The use of 4DCBCT scans with iterative reconstruction and minimal lung truncation is recommended to ensure better reproducibility between 4DCBCT- and 4DCT-based CTVIs., (© 2017 American Association of Physicists in Medicine.)

The uptake of stereotactic ablative body radiation therapy (SABR)/stereotactic body radiation therapy (SBRT) worldwide has been rapid. The Australian and New Zealand Faculty of Radiation Oncology (FRO) assembled an expert panel of radiation oncologists, radiation oncology medical physicists and radiation therapists to establish guidelines for safe practice of SABR. Draft guidelines were reviewed by a number of international experts in the field and then distributed through the membership of the FRO. Members of the Australian Institute of Radiography and the Australasian College of Physical Scientists and Engineers in Medicine were also asked to comment on the draft. Evidence-based recommendations (where applicable) address aspects of departmental staffing, procedures and equipment, quality assurance measures, as well as organisational considerations for delivery of SABR treatments. Central to the guidelines is a set of key recommendations for departments undertaking SABR. These guidelines were developed collaboratively to provide an educational guide and reference for radiation therapy service providers to ensure appropriate care of patients receiving SABR., (© 2015 The Royal Australian and New Zealand College of Radiologists.)

Background: There is a clear link between irregular breathing and errors in medical imaging and radiation treatment. The audiovisual biofeedback system is an advanced form of respiratory guidance that has previously demonstrated to facilitate regular patient breathing. The clinical benefits of audiovisual biofeedback will be investigated in an upcoming multi-institutional, randomised, and stratified clinical trial recruiting a total of 75 lung cancer patients undergoing radiation therapy., Methods/design: To comprehensively perform a clinical evaluation of the audiovisual biofeedback system, a multi-institutional study will be performed. Our methodological framework will be based on the widely used Technology Acceptance Model, which gives qualitative scales for two specific variables, perceived usefulness and perceived ease of use, which are fundamental determinants for user acceptance. A total of 75 lung cancer patients will be recruited across seven radiation oncology departments across Australia. Patients will be randomised in a 2:1 ratio, with 2/3 of the patients being recruited into the intervention arm and 1/3 in the control arm. 2:1 randomisation is appropriate as within the interventional arm there is a screening procedure where only patients whose breathing is more regular with audiovisual biofeedback will continue to use this system for their imaging and treatment procedures. Patients within the intervention arm whose free breathing is more regular than audiovisual biofeedback in the screen procedure will remain in the intervention arm of the study but their imaging and treatment procedures will be performed without audiovisual biofeedback. Patients will also be stratified by treating institution and for treatment intent (palliative vs. radical) to ensure similar balance in the arms across the sites. Patients and hospital staff operating the audiovisual biofeedback system will complete questionnaires to assess their experience with audiovisual biofeedback. The objectives of this clinical trial is to assess the impact of audiovisual biofeedback on breathing motion, the patient experience and clinical confidence in the system, clinical workflow, treatment margins, and toxicity outcomes., Discussion: This clinical trial marks an important milestone in breathing guidance studies as it will be the first randomised, controlled trial providing the most comprehensive evaluation of the clinical impact of breathing guidance on cancer radiation therapy to date. This study is powered to determine the impact of AV biofeedback on breathing regularity and medical image quality. Objectives such as determining the indications and contra-indications for the use of AV biofeedback, evaluation of patient experience, radiation toxicity occurrence and severity, and clinician confidence will shed light on the design of future phase III clinical trials., Trial Registration: This trial has been registered with the Australian New Zealand Clinical Trials Registry (ANZCTR), its trial ID is ACTRN12613001177741 .