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Reverberi et al. Mini-invasive Surg 2020;4:43 I http://dx.doi.org/10.20517/2574-1225.2020.33 Page 5 of 10

Table 2. Central lesion
Study Fractionation Toxicity (incidence of adverse events) Survival rates
Roach et al. [20] 55 Gy/5 fr Acute Grade 3-4: 6% 2-year LC: 85%
Late Grade 3: 27% 2-year OS: 43%
Late Grade 4-5: 16%
Bezjak et al. [21] (RTOG 0813) 60 Gy/5 fr Grade ≥ 3: 7.1% 2-year LC: 87.9%
2-year OS: 72.7%
Ultra-central lesion
Tekatli et al. [22] 60 Gy/12fr Grade 3: 38% Median OS: 15.9 months
Possible treatment related death: 21% 3-year OS: 20.1%
Zhao et al. [23] 60 Gy/8 fr Grade 3: 5.1% 1 and 3-year LC: 98% & 84%
No Grade 4-5.
Fr: fraction; LC: local control; OS: overall survival

RTOG 0813 Phase II trial indicated that 12 Gy per fraction was the maximum tolerable dose for medically
inoperable patients with centrally located, early stage tumors. Outcome results were comparable with the
results of patients treated for peripheral lesions. Seventy-one patients who were not fit for surgery, mostly
elderly and with comorbidities, were recruited to receive SBRT of 60 Gy delivered in 5 fractions (12 Gy per
fraction) vs. 57.5 Gy/5 fractions (11.5 Gy per fraction), and 65% of cancers were staged as T1. The 2-year
LC rate was 87.9% in the 12 Gy per fraction cohort vs. 89.4% for the 11.5 Gy per fraction, and the 2-year
[21]
OS rate was 72.7% (12 Gy) vs. 67.9% (11 Gy) [Table 2].
Ultra-central lesions
“Ultra-central” lesions are defined as tumors with planning target volume (PTV) that mostly overlaps the
mediastinal space. A retrospective study evaluated if ultra-central lesions were at higher risk for developing
toxicity. Forty-seven ultra-central lesions were treated with 60 Gy/12 fractions (5 Gy each fraction) of SBRT
3
with a median total PTV of 104.5 cm (range 17.7-508.5), and the tumor diameter exceeded 5 cm in 60% of
patients. They reported a 38% rate of Grade 3 toxicity and a 21% rate of “possible” and “likely” treatment-
[22]
related death, including 15% of fatal pulmonary hemorrhage .

In clinical practice, mediastinal organs at risk have resulted in compromising PTV coverage in SBRT
treatment of ultra-central lesions. A retrospective study reviewed 98 patients with central and ultra-
central lesions treated with 60 Gy/8 fractions (7.5 Gy per fraction) of SBRT. Outcomes for the subgroup of
patients with ultra-central lesions were compared to the group of patients with central lesions whose PTV
did not cover mediastinal structures: no difference in beneficial outcomes as well as adverse events were
registered. The median PTV volume was 25.7 cc (range 5.1-134.5 cc) for central lesions and 42.1 cc (range
6.6-184.8 cc) for ultra-central. After a median follow-up of 22.9 months, LC rates at 1- and 2-years were
97.8 and 93.7%. On multi-variate analysis, the internal target volume (ITV) was a prognostic factor for local
control (P = 0.001). Generally, the cumulative incidence of Grade 3 toxicity was low (5.1%) and no severe
[23]
esophageal or cardiac toxicity was registered [Table 2].
Due to the very high toxicity rates reported, we do not recommend SBRT as an option in patients affected
by early-stage NSCLC when the target volume overlaps mediastinal structures.

Elderly population
Elderly patients, defined as 75 years old or older, are a subgroup of patients who may benefit from SBRT
due to higher morbidity and mortality risks related to surgery because of comorbidities and decreased
lung function. 62,213 early stage NSCLC patients older than 60 were reviewed using the Surveillance,
Epidemiology and End Results database. Data suggested that surgery declined sharply from being the
treatment of choice in 81% of patients in the 60-64 years old group to only 21% of patients older than
[24]
90 years . Compared to historical outcomes for surgery in the elderly, SBRT is considered to show similar