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

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:

• Life quality [Срок оценки: 1, 3, 6, 12 and 36 months]
• Life quality [Срок оценки: 1, 3, 6, 12 and 36 months]
• Life quality [Срок оценки: 1, 3, 6, 12 and 36 months]