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Introduction: Stereotactic body radiotherapy(SBRT) for early lung cancer results in excellent local control and potentially improved survival, but demands high levels of dose conformality. To achieve this with 3D-conformal radiotherapy(3D-CRT) and intensity modulated radiotherapy (IMRT) large numbers of beams, and non-coplanar techniques are often required. Hence treatment times are long, increasing the risk of patient motion. Volumetric arc therapy(VMAT) may result in improved dosimetric outcomes, and reduce treatment time. We report on a planning study comparing VMAT to coplanar (CP) and non-coplanar (NCP) 3D-CRT and IMRT, and our initial clinical results. Methods: Pinnacle VMAT, and CP and NCP 3D-CRT and IMRT plans for delivery on Elekta Linacs of 5 patients were compared. All plans were single arc, with 4 degree spacing and 1 cm MLC. The following dosimetric characteristics were assessed: target coverage (coverage with the prescribed dose), dose conformality (100% conformity indices, D2cm and volume of tissue outside PTV receiving high dose, defined as >105% of prescription dose) and V20 (volume of lung receiving 20 Gy). Results: Dosimetric Outcomes VMAT achieved equivalent radiotherapy target coverage to 3D-CRT and IMRT (>98.2%). However, 3D-CRT plans had a large volume of surrounding normal tissue receiving a high dose (24.0% and 21.3% of the PTV volume for CP and NCP respectively) when compared to VMAT and IMRT plans (3.9% and 4-5% respectively). 100% conformity indices were lowest for VMAT and NCP IMRT (1.1 for both) and highest for 3D-CRT (1.5 and 1.4 for CP and NCP respectively). D2cm was also lowest for VMAT and NCP IMRT (26.1 Gyand 25.3 Gy) and highestfor3D-CRT plans (29.4 Gy and 28.7 Gy for CP and NCP respectively). V20 was between 4.4 and 6.1% for all plans. Clinical outcomes VMAT treatment time takes 35 minutes, and beam-on time is 8 minutes. With short follow-up (range 4 weeks to 6 months), 1 patient has developed worsening dyspnoea and grade 3 pneumonitis. No other Grade 2 or greater toxicity was seen in the other 4 patients. Conclusions: Clinical implementation of VMAT was successfully demonstrated, and has resulted in fast treatment times for our SBRT lung patients. VMAT plans are similar in quality to NCP IMRT, but are much faster to deliver due to reduced gantry and couch movements. 3D-CRT plans were unable to deliver equivalent dose conformality, and a much larger region of normal tissue was exposed to a high dose when equivalent PTV coverage was achieved. Disclosure: No significant relationships. [ABSTRACT FROM AUTHOR]

Purpose: Stereotactic body radiotherapy (SBRT) has been demonstrated to provide durable local control, and palliation in patients with vertebral metastases1. SBRT spine requires highly conformal dose distributions and the complexity of plans may lead to long treatment times. Prior to the implementation of SBRT spine we assessed whether volumetric modulated arc therapy (VMAT) could deliver satisfactory dosimetric outcomes, as it may potentially result in shorter treatment times. Methods: Pinnacle VMAT plans were generated on a volume created on the imaging dataset of a patient previously treated for vertebral metastatic disease. All plans were dosed to deliver 24 Gy in 3 fractions to the planning target volume (PTV), with the dose to the thecal sac to receive 17.5 Gy point maximum dose. PTV coverage was such that at least 90% of the PTV received 90% of the prescribed dose (21.6 Gy).Constraints for other organs at risk (OAR) were as for RTOG 0618.5mm MLC leaves with a minimum gap of 3mm were used. Negative margins, double arcs and 2 degree gantry spacing were implemented in a stepwise manner. Plans were assessed for PTV coverage, dose to the thecal sac, and other OAR. Results: The technical characteristics and dosimetric outcomes of each planning trial are listed below. For each plan new technical approaches were trial led to improve dosimetry. Technical Characteristics Plan 1: Single arc plan with 4 degree spacing. Plan 2: PTV adjusted with negative margin around thecal sac, double arc plan with 4 degree spacing. Plan 3: PTV adjusted with negative margin around thecal sac. Double arc plan with 2 degree spacing. Plan 4: PTV adjusted with negative margin around thecal sac and superior and inferior edges. Double arc plan with2 degree spacing. Dosimetric outcomes: Coverage of the PTV by the 90% isodose was 98%, 92.2%, 90.7% and 90.4% for plans 1, 2,3 and 4 respectively. Point maximum dose to the thecal sac was 23.4 Gy for plan 1, which exceeded our planning requirements. Point maximum dose for plans 2, 3 and 4 were 16.9,16.1 and 15.0 Gy. Conclusion VMAT planning for spine SBRT patients is feasible. Double arc rather than single arc planning, reducing gantry spacing to 2 degrees, and the use of negative margins appears to successfully reduce dose to the thecal sac, and permit adequate coverage. 1.Gerszten, P. C. et al. Spine 32, 193-9(2007). Disclosure: No significant relationships. [ABSTRACT FROM AUTHOR]

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.)

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.)

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.)