Breast cancer survivors are at increased risk of cardiovascular disease due to shared risk factors and the cardiotoxic effects of some cancer treatments. Exercise rehabilitation may reduce cardiovascular risk, but most evidence comes from centre-based programs involving in-person supervision. Smartphone-based telerehabilitation may offer a scalable alternative that provides real-time supervision while improving access to home-based rehabilitation. This study aimed to evaluate the feasibility of REMOTE-COR-B, a smartphone-based telerehabilitation program for women with breast cancer at increased cardiovascular risk. Secondary aims were to assess safety, satisfaction, usability, trial feasibility, and preliminary effects on physical activity, fitness, fatigue, and quality of life. Women with stage I-III breast cancer at risk of cardiovascular disease participated in an 8-week, smartphone-based exercise program, involving remotely-delivered exercise supervision and behaviour change support. The primary feasibility outcome was adherence, defined as completion ≥70 % of monitored sessions. Secondary outcomes included recruitment, safety, satisfaction, usability, and effect outcomes. Assessments occurred at baseline, post-intervention and five-months post-baseline. Objective fitness was assessed in a subsample. Recruitment was slower than expected. Of 21 participants recruited, 20 commenced the intervention and 17 completed it. Weekly sessions were completed by 94% of participants, and 47% met the adherence target. No serious adverse events occurred. Satisfaction was high (mean Client Satisfaction Questionnaire score = 24.2, SD = 3.8), while usability was below the acceptable threshold (mean System Usability Scale score = 63.0, SD = 21.6). Post-intervention, participants reported significant improvements in physical activity (mean change = 7.5 units on the Godin-Shepard Leisure-Time Physical Activity Questionnaire, 95% CI 0.7,14.3) and clinically meaningful improvements in cardiorespiratory fitness (mean increase incremental shuttle walk test = 64 m, 95% CI 6.3 to 122.3; n = 7). Positive trends were observed for fatigue and breast cancer-specific quality of life. REMOTE-COR-B was feasible, safe, and acceptable, with promising early benefits. Recruitment protocols, session attendance expectations, and usability issues need consideration before a larger controlled trial. Australian New Zealand Clinical Trials Registry Study ID number: ACTRN12621001557820. Prospectively registered 09 August 2021. RR2-10.2196/53301

Lung cancer remains the leading cause of cancer-related mortality worldwide. Although small cell lung cancer (SCLC) accounts for a smaller percentage of lung cancer cases, it has remained a significant contributor to the overall mortality burden because of its inherently aggressive nature. Over several years, and until recently, there have been no major breakthroughs in the management of SCLC. Concurrent chemoradiation with platinum doublet chemotherapy has remained the mainstay of treatment in limited-stage disease, with chemotherapy being the main and only treatment in extensive stage. Despite having an initial good response to those treatments in most patients, progression of cancer has been nearly inevitable, with no additional effective therapeutic options, and the majority of patients with SCLC dying of their disease. Fortunately, the last decade has witnessed some major scientific advances addressing the huge unmet needs in the realm of SCLC management and ushered in renewed hope in the lung cancer community. From approval of immune checkpoint inhibitors and lurbinectedin, a newer chemotherapy agent, to novel immunotherapies such as tarlatamab, a DLL3-CD3 bispecific T-cell engager, and other upcoming promising drugs, the therapeutic armamentarium for SCLC is steadily expanding. In this study, we review the current landscape of both systemic therapy as well as radiation therapy for SCLC, with a focus on major developments over the past decade, current standards of care, and novel therapeutics that are expected to revolutionize the treatment of this aggressive malignancy.

INTRODUCTION:Clinical guidelines recommend upfront osimertinib monotherapy for asymptomatic brain metastases (BM) in EGFR-mutant NSCLC, despite a lack of randomized trial evidence. We conducted two randomized phase II trials, OUTRUN and LUOSICNS, to evaluate the efficacy and safety of upfront stereotactic radiosurgery (SRS) plus osimertinib versus osimertinib in this patient population. METHODS:Participants with up to ten BM amenable to SRS were randomized 1:1 to SRS followed by osimertinib (80 mg daily) or osimertinib monotherapy. SRS was delivered as a single or multi-fraction regimen. The primary end point was 12-month intracranial progression-free survival (ic-PFS). Key secondary end points include overall survival (OS), patterns of intracranial progression, and safety. Data from both trials were prospectively pooled for a joint analysis. RESULTS:Overall, 79 participants were randomized. At a median follow-up of 39.0 months, 12-month ic-PFS was not significantly different between SRS plus osimertinib (n = 39) than osimertinib monotherapy (n = 40) (11%, 95% CI: -10% to 32%, p = 0.31; median ic-PFS 21.9 mo versus 17.2 mo). Median OS was 46.1 versus 29.1 months. Among those with intracranial progression, 35% in the SRS plus osimertinib group and 57% in the osimertinib monotherapy group underwent SRS at progression. Grade 3/4 radionecrosis occurred in 5% of participants treated with SRS plus osimertinib. CONCLUSIONS:Adding upfront SRS to osimertinib did not significantly improve 12-month ic-PFS in EGFR-mutant NSCLC with BM. This represents the first randomized evidence supporting the use of osimertinib monotherapy as upfront therapy in minimally symptomatic patients with low-burden BM. CLINICALTRIALS: GOV IDENTIFIER:OUTRUN: NCT03497767; LUOSICNS: NCT03769103.

Background Definitive concurrent chemoradiotherapy (CRT) is the primary curative-intent treatment option for unresectable locally advanced nonsmall-cell lung cancer (NSCLC). Completion of CRT is generally required for eligibility for consolidation durvalumab, which significantly improves survival. We sought to establish CRT completion rates at a comprehensive cancer center. Patients and Methods 265 patients were treated with concurrent CRT over the decade 2012-2022, during which durvalumab became available. 63% were male, median age was 67, and 91% had performance status 0-1. All patients were recruited into the AURORA prospective cohort study which captured baseline demographics and comorbidities, and prospectively updated treatment and outcome data at subsequent hospital visits. Data were analyzed retrospectively to evaluate CRT completion rates, reasons for noncompletion, and survival outcomes. Survival was also analyzed based on durvalumab availability and administration. Results CRT was completed as planned by 246/265 (93%) patients. Reasons for noncompletion included treatment related toxicity (n = 6/19), unrelated illnesses (n = 7/19), local disease progression (n = 2/19), and distant progression (n = 4/19). Median overall survival (OS) was 2.2 years (95% CI, 1.7-2.8) for the entire cohort and 1.0 years (95% CI, 0.2-1.5) for those who ceased CRT early. No specific baseline characteristics predicted noncompletion of CRT. Consolidation durvalumab was associated with improved OS (HR 0.39; 95% CI, 0.21-0.72, P = .002). Conclusion With appropriate supportive care, most patients initially considered suitable for CRT could complete it and access consolidation durvalumab. Consolidation durvalumab was associated with improved survival in this “real-world” stage III NSCLC cohort.

e20063 Background: Neoadjuvant chemoimmunotherapy (CI) is the standard of care for locally advanced, resectable non-small cell lung cancer (NSCLC). Due to their synergistic effects, the addition of radiotherapy to neoadjuvant CI may improve therapeutic outcomes. This study aims to compare the safety and efficacy of neoadjuvant radio-chemoimmunotherapy (RCI) with neoadjuvant CI in patients with resectable NSCLC. Methods: We searched PubMed and Embase databases for prospective studies featuring 10 or more patients with resectable NSCLC. The primary outcome was the pathological major response rate (MPR), and secondary outcomes included the pathological complete response rate (pCR), overall resection rate, and rates of adverse events. Odds ratios were calculated using pooled outcome data. The review protocol was registered with PROSPERO (CRD42024537822). Results: We identified five studies that included 149 patients (74% male, median age range 62-66, 92% with stage 3 disease) treated with neoadjuvant RCI, including one randomised trial and four single-arm trials. Fifteen studies included 2010 patients (75% male, median age range 43-67, 75% with stage 3 disease) treated with neoadjuvant CI, including eight randomised trials and seven single-arm trials. The odds of achieving a MPR and pCR were significantly higher for those treated with neoadjuvant RCI (MPR: OR 2.44, 95% CI 1.73 – 3.45, p<0.001 and pCR: OR 1.89, 95% CI 1.34 – 2.66, p<0.001). There was no significant difference in resection rate between groups; 13% failed to complete resection after neoadjuvant RCI compared to 18% after neoadjuvant CI (OR 0.65, 95% CI 0.37 - 1.07, p=0.083). There was no significant difference between groups in the rate of Grade 3+ adverse events (OR 0.72, 95% CI 0.50 - 1.02, p=0.055). Conclusions: Neoadjuvant radio-chemoimmunotherapy may lead to improved major and complete pathological response rates than neoadjuvant chemoimmunotherapy, without an increase in toxicity or reduction in resection rates.

Shortening treatment time with moderately hypofractionated radiotherapy benefits patients by reducing inconvenience and costs, but its use in the definitive treatment of unresectable Stage 3 non-small cell lung cancer is controversial due to lack of level one evidence and toxicity concerns. Pivotal systemic therapy trials utilize conventionally fractionated chemoradiation at 2 Gy per fraction given over 6 weeks. In practice, 4 weeks of chemoradiation at 2.75 Gy per fraction is sometimes employed to reduce the treatment burden for selected patients, especially those who are older or have comorbidities. It is uncertain if the two fractionation regimens are similar in biological effectiveness, especially with varying systemic therapy. This systematic review aimed to collate the survival and toxicity outcomes for 4 weeks of moderately hypofractionated chemoradiation, using > 50 -60 Gy in 20 fractions. Eight studies met the eligibility criteria; seven studies were from a database search of MEDLINE, EMBASE, Cochrane Library, and Web of Science and one study was added later. Two studies were prospective randomized trials and six were retrospective cohort studies. No study included immunotherapy. The historical evidence has been limited, but emerging data is promising, especially when compared to outcomes of standard chemoradiation. Thus, further investigation of this strategy is justified.

BackgroundThe conventional lying down position for radiation therapy can be challenging for patients due to pain, swallowing or breathing issues. To provide an alternative upright treatment position for these patients, we have developed a portable rotating radiation therapy platform which integrates with conventional photon treatment machines. The device enables cone-beam computed tomography (CBCT) imaging of patients in an upright position, and the future delivery of therapeutic radiation.PurposeTo design, manufacture, and test a device for upright radiation therapy. A collaborative partnership between physicists, engineers, radiation therapists, radiation oncologists, implementation researchers and consumers was established, to create a device that meets both the clinical and technical requirements of upright radiation therapy. The device is central to a clinical trial (ACTRN12623000498695) which will evaluate upright image quality in the context of future image guided radiation therapy for patients with lung cancer or head and neck cancer.MethodsThe weight and physical constraints of the device were assessed with respect to the American civilian population. The final design was evaluated with a series of tests to characterize the angular accuracy of the platform rotation and the reproducibility of the platform setup position in a radiation treatment room. To acquire an upright CBCT, the platform movement system was synchronized to the kilo-voltage fluoroscopic imaging on an existing treatment machine. The accuracy of the synchronization was evaluated by assessing the positional reproducibility of upright CBCT imaging of a chest phantom.ResultsThe platform has a weight limit of up to 125 kg which is suitable for approximately 90% of males and 95% of females. The platform has physical constraints that accommodate approximately 95.6% of males and 99.6% of females: a maximum seated height of 97.5 cm, a maximum hip breadth of 63.0 cm, and maximum elbow to knuckle length of 46.5 cm. The angular accuracy of the motion system is within +/- 0.15 degrees over a full rotation, which is within the guidelines for machine movement accuracy in radiation therapy (1 mm/1 degrees). The platform is a portable device and can be reproducibly positioned in a radiation therapy treatment room with a translational range within +/- 0.04 mm and a rotational range within +/- 0.025 degrees. The CBCT imaging can reproducibly detect the position of a chest phantom with a translational uncertainty of +/- 0.07 mm and a rotational uncertainly of +/- 0.22 degrees, when imaging is acquired following a strict procedure.ConclusionThe upright radiation therapy platform is suitable for the evaluation of CBCT imaging in the context of image guided radiation therapy. The platform will allow the investigation of open questions in upright radiation therapy in the areas of patient experience, positional stability, anatomical changes, and treatment delivery. Improvements to the materials in the radiation beam line, synchronization with the existing treatment machine, and increasing the device weight limit are suggested prior to delivery of future upright treatments.

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

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 89Zr 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 .

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.

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.

PURPOSE:18F-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 × 109/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; R2adj = 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.

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.

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.

Despite decades of commitment to improving diversity in radiation oncology, the parameters remain stubbornly difficult to shift.

COPYRIGHT © 2023 Hegi-Johnson and Higgins. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. TYPE Editorial PUBLISHED 09 February 2023 DOI 10.3389/fonc.2023.1148340