SBRT is the gold standard for medically inoperable patients with early-stage non-small cell lung cancer (NSCLC) and is increasingly applied in the treatment of oligometastatic/oligoprogredient patients with pulmonary metastases. Usually, pulmonary SBRT is well tolerated with only mild toxicity. Pulmonary SBRT is even a treatment option for patients with interstitial lung disease or severly reduced lung function. Common toxicities include pneumonitis or lung fibrosis in 9%-49% (Liu et al., Radioth Oncol 2020) as well as rib fractures in less than 10% of the cases (Dunlap et al., IJROBP 2010), however side-effects are usually mild and well treatable.
Challenges are encountered when applying higher doses for more centrally located tumors. Initial studies reported high grade toxicity in up to 20% of the patients with bronchopulmonary hemorrhage, central airways necrosis or even treatment-realted death (Timmerman et al., JCO 2006 and Corradetti, NEJM 2012). The hilar/pericentral tumor location was identified as the main factor a the highly increased toxicity rate, leading to the definition and rapid adoption of the so called “no-fly zone”: a 2 cm radius in all directions around the proximal bronchial tree.
However, when employing more moderate fractionation schemes comparable toxicity rates for both peripheral and central pulmonary SBRT have been reported (Haasbeek et al., JTO 2011, Mangona et al., IJROBP 2015). The Radiation Therapy Oncology Group (RTOG) 0813 trial, a prospective multi-institutional study of SBRT, accrued 120 patients with early-stage central NSCLCs into a dose-escalating, five-fraction SBRT schedule and reported a maximum tolerated dose (MTD) of 12 Gy per fraction. This level was associated with only 7.2% dose-limiting toxicity (DLT) and high rates of local control (Bezjak et al., JCO 2019).
More recently, a new high-risk category termed ultracentral tumors has emerged, in which the planning target volume (PTV) overlaps the proximal bronchial tree or the esophagus. Concerns over especially severe complications following SBRT of ultracentral tumors even with the above-mentioned risk-adapted fractionation schedules were raised when several reports described significantly increased grade 3 toxicity in up to 40% of the patients including fatal pulmonary hemorrhage (Tekatli et al., JTO 2016). The recently published HILUS trial which included 65 patients with ultracentral lung tumors treated with 8 x 7 Gy prescribed to the 67% isodose reported, despite promisng local control, highly increased grade 3 to 5 toxicity noted in 22 patients, including 10 cases of treatment-related death (bronchopulmonary hemorrhage, n = 8; pneumonitis, n = 1; fistula, n = 1). By contrast, others did not detect significant differences in higher grade toxicity when comparing pulmonary SBRT for ultracentral to central tumors (Chang et al., Radiother Oncol 2018). The ongoing SUNSET trial might further shed light on a safe dose-fractionation regimen for treating ultracentral tumors with SBRT (Giuliani et al., Clin Lung Cancer 108)
Nevertheless, in order to also balance toxicity in pulmonary ultracentral SBRT, either more defensive dose schedules that avoid critical overdoses in adjacent organs-at-risk (OARs), but potentially underdose the tumor might be applied or modern high-precision image-guided radiation techniques might bear the potential to enable safer dose escalation. fRecently, magnetic resonance guided radiotherapy (MRgRT) has become clinically available allowing for more individualized radiation treatments by daily on-table plan adaptation to the current patient and tumor anatomy. Hence, MRgRT might be a promising tool to offer a balance between keeping the dose to closely located radiosensitive OARs below tolerance levels, while simultaneously maintaining adequate dose coverage of the target. Few studies have already reported promising results (Henke et al., Adv Radiat Oncol 2018, Fianzzi et al., IJROBP 2020, Regnery et al., ESTRO 2023) and prospective trials are recruiting (STAR-LUNG STUDY (NCT05354596) and MAGELLAN (NCT04925583)).