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Page 2 of 10 Reverberi et al. Mini-invasive Surg 2020;4:43 I http://dx.doi.org/10.20517/2574-1225.2020.33

tumor board meeting involving the thoracic surgeon, lung specialist, clinical and radiation oncologist,
radiologist, nuclear medicine physician and pathologist. Together, they will define the operability of the
case and discuss the best treatment options. Currently, national and international guidelines purpose
definitive radiotherapy as an alternative in the event patients are not candidates for surgery or if they refuse
[3,4]
resection . Historically, studies have demonstrated that the local control (LC) rate with convectional
radiotherapy was inadequate compared to surgery. Dose escalation studies have found that LC and survival
were improved with doses ≥ 80 Gy. Thus, several accelerated radiotherapy regimens have been tested to
achieve better results in terms of outcomes and toxicity. Limiting the dose to the surrounding tissues is
an important goal, particularly because early stage NSCLC patients who are not suitable for surgery, are
usually fragile due to age or other comorbidities. The stereotactic body radiotherapy (SBRT) technique has
been developed for the treatment of localized lung lesions because it is a highly conformal and focused
ablative treatment delivered precisely to a delineated target volume over a short period. Literature data have
[6]
[5]
also demonstrated that the LC rate after SBRT ranges around 85%-100% . The SPACE trial was the first
clinical trial to compare the outcomes of SBRT vs. conventional fractionated radiotherapy: it randomized
102 patients to receive 66 Gy of SBRT over three fractions or 3D conformal radiotherapy of 70 Gy over 35
fractions. It demonstrated non-inferiority of SBRT with no difference in progression free survival (PFS)
[7]
and overall survival (OS) among groups with a comparable toxicity profile. Recently, the CHISEL trial
proved that SBRT had a favorable toxicity profile and achieved superior LC compared to conventional
radiotherapy: the 2-year LC rates were 89% vs. 65%, respectively. Thus, SBRT is considered the treatment of
choice for patients with early stage NSCLC who are not candidates for surgery and it has seen widespread
uptake in clinical practice. Despite rapid and wide adoption of SBRT, there still exists substantial variation
in patient selection, staging, radiotherapy technique (planning and delivery), the prescribed dose and dose
per fraction, duration and modality of follow-up. This paper aims to review the main questions regarding
the use of SBRT in clinical practice, by reviewing the most important data published so far. We discuss the
maximum tolerable dose of SBRT, toxicity, LC and OS outcomes for peripheral, central and ultra-central
lesions, and we investigate its effectiveness and tolerability in the elderly subpopulation. Finally, we review
the most relevant data comparing SBRT with surgery.

Peripheral lesions
A peripheral lesion is defined as a non-central lesion: it includes all tumors arising from the lung
parenchyma at least 2 cm from the principal bronchial tree. Several dose escalations studies have
demonstrated that LC is improved by delivering a higher biological effective dose (BED) to the target. The
[8]
main stone study published by Onishi et al. reported that LC highly correlates with radiation dose. The
authors documented that the 5-year LC was statistically and significantly higher (91.6% vs. 57.1%) in the
group of patients treated with a BED ≥ 100 Gy compared to those treated with less than 100 Gy (assuming
lung cancer α/β = 10). These observations were confirmed by subsequent prospective studies. In the
series published by researchers from Washington University, it was found that higher maximum doses led
to higher rates of local tumor control. Moreover, on multivariate analysis, only maximum tumor doses
[9]
correlated with tumor control .
Patients with peripheral lesions had an excellent outcome after SBRT as the 2-year LC and OS rates were
95% and 57.6%, respectively. Patients with peripheral lesions tolerate larger doses per fraction, even in
those considered unfit for surgery because of comorbidities and poor lung function [Table 1].

The rate of 2-year toxicity-free interval, after SBRT dose of 60-66 Gy/3 fractions (20-22 Gy per fraction)
given over a period of 1.5-2 weeks, was significantly higher in patients with peripheral lesions compared to
[10]
central lesions at 83% and 54%, respectively . No treatment-related deaths were observed for high dose
SBRT (BED 150 Gy) in the Radiation Therapy Oncology Group (RTOG) 0236 trial, and the Grade 3-4
toxicity rate was 27.2%. The RTOG 0236 trial involved 59 patients with peripheral T1-2 (< 5 cm) NSCLC