Sublobar Wedge Resection or Stereotactic Radiotherapy Treatment of High-risk Patients With Early-stage Lung Cancer

Overview

In low-risk patients with stage I non-small cell lung cancer (NSCLC) surgical treatment with an anatomical resection is currently the standard of care. For medically inoperable patients with stage I NSCLC, radiation therapy is currently the standard treatment. The latest generation of radiation therapy modalities is Stereotactic Body Radiation Therapy (SBRT). In high-risk patients, minimal invasive surgery in terms of sublobar resection (wedge resection) with lymph node sampling is currently the recommended treatment approach for these patients, even though the evidence is limited. Additionally, SBRT is an alternative treatment option but the use in these patients is also based on weak evidence. So, it is highly warranted to compare these two treatment options in this group of patients in a randomized, controlled trial where selection bias can be eliminated. It is the specific aim of this study to provide such a trial allowing an evidence-based approach when deciding between surgery and SBRT as treatment for NSCLC in high-risk patients. The STRADOS study (STereotactic RADiotherapy Or Surgery) is an open randomized, controlled national multicenter study in which high-risk patients with stage I non-small-cell lung cancer (NSCLC) are randomized to receive either surgical treatment with minimal invasive wedge resection with lymph node sampling, or SBRT. The overall purpose of the study is to investigate the disease-free survival (DFS) after surgical treatment when compared to SBRT. The primary endpoint is DFS after 3 years. Secondary endpoint is quality of life after 1, 3, 6, 12 and 36 months. Tertiary endpoints are overall survival (OS) after 3 and 5 years; DFS after 5 years; re-admission adverse events and complications after 1, 3, 6, 12 and 36 months; health-care related costs within 12 and 36 months; PRO data - other than quality of life (QoL) (health condition, symptoms and functional level) after 1, 3, 6, 12 and 36 months and lung function test after 12 month.

BACKGROUND: Lung cancer is the most frequently diagnosed cancer type worldwide with approximately 2.5 million new cases and 1.8 million deaths annually, making it a leading cause of cancer-related mortality. The incidence of early-stage lung cancer is increasing likely due factors such as incidental findings, screening, increased awareness and the introduction of cancer packages. In low-risk patients with stage I non-small cell lung cancer (NSCLC) surgical treatment with an anatomical resection is currently the standard of care. For medically inoperable patients with stage I NSCLC, radiation therapy is currently the standard treatment. The latest generation of radiation therapy modalities is Stereotactic Body Radiation Therapy (SBRT). In high-risk patients' minimal invasive surgery with sublobar resection known as surgical wedge resection (SWR) with lymph node sampling is currently the recommended treatment approach for these patients but based on weak evidence. EXISTING KNOWLEDGE: SBRT has been reported to achieve 3-year overall survival (OS) rates ranging from 35 % - 65 %. There are several different possible reasons for the variability in outcome is multifactorial e.g., inclusion criteria's, co-morbidity and risk factors of patients. Existing non-randomized trials comparing SBRT to SWR indicate that SWR may confer a survival advantage in terms of higher OS and DFS. SWR has a lower risk of local recurrence, locoregional recurrence and regional recurrence and no lymph staging is performed in SBRT. The latter may lead to potential understaging and hence impact the indication for adjuvant therapy. However, it is extremely difficult to draw any firm conclusions due to selections bias of the conducted trials. In most studies SBRT patients have more risk factors than SWR patients, and selection bias is evident despite using advanced statistical method in terms of e.g. propensity matching. The published systematic reviews and meta-analysis concluded that based on the non-randomized studies the outcome after SWR is probably better than after SBRT, but they all called for randomized, controlled trials. Two randomized, controlled trials have been initiated but both terminated before inclusion of the number of planned patients were reached due to slow recruiting. In the two trials, merely 58 patients were included, and analysis indicated better outcome in the SBRT group. In terms of quality of life, Wisnivesky et al found in a non-randomized study from 2024 that SBRT provided a better quality of life immediately after treatment compared with SWR. However, both treatment groups reported similar quality of life at later time points, with a return to baseline quality of life suggesting that SWR and SBRT have a similar impact on the quality of life. This has been confirmed by others, but never tested in a randomized setting, which is necessary in order to draw any firm conclusions. ONGOING TRIALS: In Clinicaltrials.gov three studies of interest are registered. In the POSTILV study (NCT01753414) (https://clinicaltrials.gov/study/NCT01753414?term=NCT01753414\&rank=1) it is planned to investigate anatomical resections (segmentectomy and lobectomy) with SBRT in low-risk patients. This is also the case in the VALOR study (NCT02984761) (https://clinicaltrials.gov/study/NCT02984761?term=NCT02984761\&rank=1) Accordingly, these two studies differ significantly from ours as these studies include low risk patients. The STABLE-MATE study (NCT02468024) (https://clinicaltrials.gov/expert-search?term=NCT02468024) is actively recruiting. The study compares SWR to SBRT in high-risk patients with 3-year OS as primary outcome. The study is a multi-center study (48 sites) initiated in USA and predominantly recruiting patients from USA sites. Informed consent in the STABLE-MATE study will be obtained after patients are made aware of the randomized assignment, which entails attrition bias, i.e. patients may prefer SBRT and will refuse participation when randomized to surgery. In addition, secondary endpoints are merely progression free survival and radiation toxicity. The STRADOS trial will include e.g. quality of life and health care cost, and it is a national trial including all relevant sites in Denmark. Despite the differences in the STABLE-MATE study and our study, the results are very likely to complement each other. NOVELTY: This project will address a critical gap in the treatment of lung cancer of how to best to treat this relatively large group of high-risk patients with lung cancer. It will have both national and international impact, especially because of the randomized design and being a national study including all relevant departments and hence including all applicable patients in Denmark PURPOSE: The overall purpose of this randomized, controlled trial is to investigate the 3-year DFS among high-risk patients with stage I NSCLC comparing SWR including lymph node sampling with SBRT (intervention). ACRONYM: STRADOS: STereotactic RADiotherapy Or Surgery METHODS: In the context of this study, a high-risk patient is defined as a patient that fulfills at minimum one of the main-risk criteria and/or two of the secondary criteria: Main criteria: * FEV-1 ≤ 50% and/or * DLCO ≤ 50% Secondary criteria: * Age ≥ 80 * FEV-1 = 51-60% and/or DLCO = 51-60% * Known pulmonary hypertension with PAP ≥40 mm Hg diagnosed \< 6 months before inclusion * Known LVEF ≤ 40% diagnosed \< 6 months before inclusion Patients: Inclusion criteria: * Patient fulfills the "high-risk patient" criteria outlined above * Age ≥ 18 years * Biopsy-proven NSCLC * Diagnostic codes: DC34, DC 34.1, DC 34.2, DC 34.3 or DC 34.9 * Clinical stage I NSCLC according to the 9th edition of TNM (24) (cT1aN0M0, cT1b-cN0M0, cT1cN0M0 and cT2aN0M0) * Performed diagnostic PET-CT and supplementary invasive procedures for staging purposes in accordance with the Danish national reference program for the staging and treatment of lung cancer * Tumor is localized in the outer third of the lung and considered technically resectable by SWR, as well as treatable with peripheral SBRT when assessed during MDT conference * Eastern Cooperative Oncology Group (ECOG) performance status (PS) = 0-2. * Preoperative pulmonary function test according to national guidelines performed within 6 weeks before the MDT conference Exclusion criteria: * Declared terminally ill or life expectancy shorter than one year. * Multifocal disease * PS ≥ 3 * Centrally located tumors not eligible to SBRT * Previous ipsilateral lung surgery * Pregnancy or breastfeeding. * Inability to understand oral and written informed consent * Intravenous substance abuse or severe alcohol abuse (\> 25 units per week) * Not amendable for surgery in general anesthetic * Previous radiotherapy to the thorax, which may limit the feasibility or increase the risk of stereotactic reirradiation due to cumulative dose constraints and potential toxicity * Diagnosed with Interstitial lung disease (ILD) Design: * Randomized, controlled study * Not blinded (open label) * National multicenter study including all thoracic surgical departments and relevant departments of oncology and pulmonology in Denmark * Endpoint are measured with the date of randomization as index Pre-randomization investigations: Standard assessment according to the Danish national reference program for the assessment and treatment of lung cancer. Sample size and power calculation: The sample size calculation is based on the primary endpoint: 3-year DFS. The standard/control treatment is SWR, and the comparator/intervention is SBRT, and it set to be 70% and 50%, respectively. The sample size is calculated with the 2-sided significance level of 0.05 and 80% statistical power, and hence 182 patients' needs to be included (91 patients in each of the two groups), and with an expected dropout of approximately 10%, a total of 200 patients will be included. Data analyses: Data extraction is done from RedCap database. Before data analysis a statistical analysis plan will be presented. Data analysis is performed using STATA 18 (StataCorp LLC, Texas, USA). Endpoints for the individual group will be described with median and percentile, as we assume that data are not normally distributed. We will use the ANOVA test to analyze repeated measurements (e.g. PROs) with treatment and time as systematic effects and patient as a random effect. The Χ2 test will be used when comparing the two treatments. All data are analyzed according to the intention to treat (ITT) principle, but a per protocol analysis will also be performed. Data management: All data are entered in a Case Report Form in RedCap (Research Electronic Data Capture - REDCap Consortium, Vanderbilt University Medical Center, Tennessee, USA). The Danish Data Inspectorate's guidelines are followed when handling, processing, and archiving collected data. All personally identifiable data are deleted at the end of the study. All collected data are stored at the at Aarhus University. Data collection media are REDCap and electronic patient records. Ethical considerations and inclusion of patients: There is currently no evidence nor evidence-based consensus on which of the treatments investigated in this study is best (minimal invasive SWR or SBRT). The individual patient will not benefit immediately from participating in this study, and the results of the study will only benefit future patients. The procedure inclusion of patients and obtaining informed consent above ensures that the individual patient has the possibility to use or abstain from the usual 24 hours to consider study participation. From an ethical perspective the latter is important since some patients will wish to prioritize both study participation and at the same time not want a delay in time for referral though this is typically 24 hours. In the study population, a 24-hour delay in referral for definite treatment will not influence the outcome of the treatment or at a long term for the patient (e.g., mortality, and morbidity). 1. Whether the patient meets the inclusion criteria and should be offered participation is decided and recorded at the MDT conference. 2. Eligible patients possibly interested in study participation will receive both written and oral information about the study. When the pulmonologist informs the patient about the MDT results, the STRADOS project and possibility of participation in the study is presented. In current clinical practice, the result of the MDT is given to the patient in an outpatient clinic setting, using video consultation, or telephone. If the patient does not wish to participate, he/she will be referred to surgery as this is currently considered standard of practice. If the patient does not want operation, further referral will depend on patient preferences and current clinical practice guidelines for alternative treatment options incl. SBRT 3. The patient is allowed 24 hours to consider whether they want to participate in the study. Risk: The risks of surgical resection are predominantly bleeding, conversion to open surgery (thoracotomy), cardiac arrhythmias, postoperative air leakage from the lung, dyspnea, pain (both acute and chronic), and redo-surgery. The risks of SBRT are mainly pain, rash, rib fracture and radiation-induced pneumonitis. Overall, we believe that the knowledge gained from this study outweighs the disadvantages that patients might experience by participating. Study approvals and registration: The project is carried out in accordance with the Helsinki II Declaration and European regulations. The Scientific Ethics Committees for Denmark, the Data Protection Agency, is applied for permission to complete the program. Information concerning the patients is protected under the Personal Data Processing Act and the Health Act. The trial is registered at www.clinicaltrials.gov. ORGANISATION: A steering committee is responsible for the design, conduct, analysis and reporting the results of the trial. The multidisciplinary steering committee includes Thomas Decker Christensen MD, PhD (thoracic surgery) (PI), Christian B. Laursen, MD, PhD (respiratory medicine) (Co-PI), Peter Licht MD, PhD (thoracic surgery), Rene Horsleben Petersen MD, PhD (thoracic surgery), Tine Schytte MD, PhD (oncology) Weronika Maria Szejniuk MD, PhD (oncology) and Asger Roer Pedersen MSc, PhD (statistical supervisor). A total of approximately 33 Danish and international health care professionals with a multi-disciplinary background (e.g., oncologist, thoracic surgeons, respiratory physicians and radio physics) has read, commented and accepted the protocol and the initiation of the study. International project collaborators and advisors: Thoracic Surgery: * Professor Hiran C. Fernando. Inova Fairfax Hospital, Falls Church, Virginia, USA. * Professor Yaron Shargall, Chair at Division of Thoracic Surgery, McMaster University, Canada * Professor Babu Naidu. Department of Thoracic Surgery, Queen Elisabeth Hospital, Birmingham, UK. Oncology: * Professor Robert Timmerman. Harold C. Simmons Comprehensive Cancer Center, Dallas, Texas, USA * Professor Matthias Guckenberger. Department of Radiation Oncology, University Hospital Zurich and University of Zurich. Respiratory Medicine: • Professor Najib N. Rahman. Nuffield Department of Medicine, Clinical Director, Oxford Respiratory Trials Unit, University of Oxford, UK Implementation: This is a pragmatic, national, multicenter study conducted within a well-established national reference program for lung cancer diagnosis and treatment. Regardless of whether the results are positive or negative, they can be rapidly integrated into the national reference program, minimizing the time from clinical research to clinical implementation. At the end of the study a one-day seminary dedicated to ensuring an implementation strategy of study results into the national reference program is planned. Clinical and national and international perspective: This project will address a critical gap in the treatment of lung cancer of how to best to treat this relatively large group of patients with lung cancer. The results of the trial will impact evidence-based treatment both nationally and internationally. Ultimately, the project aims to improve morbidity and reduce morbidity and improve quality of life.