Developments of stereotactic body radiotherapy in the metastatic setting and for central lung tumors

Stereotactic body radiotherapy (SBRT) is a cornerstone of modern radiotherapy. As a non- invasive, high-dose radiotherapy treatment that provides high local tumor control and mild side effects, SBRT is a successfully used antitumoral local treatment with increasing application in primary and metastatic cancer.

With the rapid development of SBRT, the treatment of central lung tumors has shown to be an area of its limitation, where lack of knowledge about dose tolerance to central organs at risk (OARs) when using high-dose radiotherapy has resulted in fatal toxic events. How to integrate SBRT as local treatment alone and in combination with systemic therapy in metastatic disease needs to be better characterized to deliver a personalized and beneficial antitumoral treatment.

Project I is a retrospective pooled multicentre analysis of patients from the Nordic countries, including patients treated in the prospective phase II HILUS trial (1) and in a retrospective expansion cohort. In total, 230 patients were treated with SBRT in 8 fractions (56 Gy) for a lung tumor (primary lung cancer or metastasis) located within 2 cm from the tracheobronchial tree (i.e the trachea, the mainstem bronchi, the intermediate bronchus and the lobar bronchi). Fatal toxicity developed in 30 patients, of which 20 events presented as bronchopulmonary bleedings after a median time of 15 (11-22) months after SBRT. We identified tumor compression of the tracheobronchial tree and maximum dose to the mainstem and the intermediate bronchus as significant risk factors for fatal toxicity and bronchopulmonary bleedings.

Project II is a retrospective subanalysis of project I, evaluating the clinical benefit of curative SBRT for 72 patients with inoperable central early-stage non-small cell lung cancer (ES NSCLC), T1-T3N0M0. Relapse was seen in 17 patients and distant recurrence was the most common form of relapse. We observed limited progression-free survival (31% at 3-year) and short survival (38% at 3 years), largely explained by comorbidities and a high incidence of fatal toxicity (17%). Despite excellent local tumor control (97% at 3- year) and favorable lung cancer-specific survival (76% at 3-year), the toxic profile of SBRT in the investigated approach outweighed the clinical benefit for the patients.

Project III is a retrospective study of 70 patients treated with 1st line tyrosine kinase inhibitors (TKIs) (1st-2nd generation) for a metastatic EGFR-mutated NSCLC at Karolinska University Hospital between 2010-2017. The project was done in collaboration between the radiology and radiotherapy departments. By analyzing the radiological tumor response to TKIs, we could identify 25 patients with oligometastatic disease (OMD), defined as maximum 5 metastases +/- primary tumor, after a median of 4 (1-10) months with TKIs. Patients with primary disseminated metastatic disease who develop OMD in response to TKIs (induced persistent OMD (pOMD)) had the greatest benefits in terms of progression-free survival (median 16 months) and overall survival (median 30 months). Retrospectively, 90% of the patients with induced pOMD were considered eligible for consolidation radiotherapy. We found the "oligometastatic window" for induced pOMD limited to less than 1 year, which provide guidance on the optimal timing for consolidation SBRT in prospective studies.

Project IV is a retrospective analysis including 85 patients treated with SBRT for a colorectal cancer metastasis at Karolinska University Hospital between 2008-2016. The benefit, time-to-relapse (TTR), after SBRT was identified by applying clinical variables prior SBRT significant for TTR (age, performance status, number of colorectal primaries, carcinoembryonic antigen (CEA) value, number of active metastases in the body prior SBRT) in the CLInical Categorical Algorithm (CLICALº). CLICALO categorized 4 subgroups (signature I-IV) of patients with different benefits (TTR) after SBRT. The greatest benefit of SBRT was seen for patients in signature III-IV who received high-dose SBRT to all metastases (curative intent) or to lung metastases only. Patients in signature I-II had a short TTR, why SBRT for these patients was judged non-beneficial. The study results are valuable for decision-making about who should be treated with SBRT for metastases from colorectal cancer.

List of scientific papers

I. Lindberg S et al. Expanded HILUS Trial: A Pooled Analysis of Risk Factors for Toxicity from Stereotactic Body Radiation Therapy of Central and Ultra central Lung Tumors. International Journal of Radiation Oncology Biology Physics. July 2023. https://doi.org/10.1016/j.ijrobp.2023.06.246

II. Lindberg S et al. Stereotactic body radiation therapy (SBRT) of centrally located medically inoperable early-stage non-small cell lung cancer (T1- T3N0M0), - A subgroup analysis of the expanded HILUS study. Lung cancer. March 2025. https://doi.org/10.1016/j.lungcan.2025.108527

III. Lindberg S et al. Analysis of tumor response to Tyrosine Kinase Inhibitors (TKIs) in advanced stage non-small cell lung cancer (NSCLC) with mutation in epidermal growth factor receptor (EGFR) - identifying candidates for consolidation with stereotactic body radiotherapy (SBRT). [Manuscript]

IV. Lindberg S et al. Predicting the benefit of stereotactic body radiotherapy of colorectal metastases. Clinical Translational Radiation Oncology. Sep 2022. https://doi.org/10.1016/j.ctro.2022.07.006