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

In particular, the authors found no difference in chest wall severe adverse events. Compared to RTOG 0236,
the rate of toxicity was lower and outcome results were comparable as the 2-year OS rate was 61.3% in 34
[15]
Gy/1 fraction schedule and 77.7% in fractionated SBRT, respectively . No significant difference in LC, OS,
adverse events and lung function in patients treated with 30 Gy in a single fraction vs. 60 Gy/3 fractions
(20 Gy per fraction) was reported. Toxicity rate was 16% in the single fraction arm vs. 12% in the multi-
[16]
fractions regimen . Retrospective propensity-matched comparison between the 3 fractions regimen (total
dose 60 Gy, 20 Gy per fraction) and the 5 fractions schedule (total dose 50 Gy, 10 Gy per fraction), showed
[17]
no significant differences in OS, PFS, local failure and distant relapse at 2 years . No significant conclusions
about optimal dose fractionation in peripheral lesions can be derived so far. Both single and multi-fraction
SBRT produce comparable outcomes and limited adverse events. The 1- and 2-year LC rate ranged between
93%-95% and 88%-90% in patients treated with single fraction SBRT (30 Gy/1 fraction) over a fractionated
regimen (50 Gy/5 fractions: 10 Gy per fraction). OS was significantly longer in patients treated with
fractionated SBRT (1- and 2-year OS rates were 84% and 61% with one fraction group vs. 85% and 70% in
the fractionated schedule, P = 0.01), unless the baseline tumor size was imbalanced across groups and the
[18]
fractionated schedule cohort presented a larger treatment volume . Results of a large single institution
series suggested that 54 Gy/3 fractions (18 Gy per fraction) of SBRT led to improved LC compared to
30-34 Gy/single fraction and 48-50 Gy/4-5 fractions (10-12 Gy per fraction). The lung toxicity rate (any
Grade) was slightly higher with the 3 fractions schedule at 5.1% vs. 3.2% and 3.8% in the single and 4-5
fractions schedule, respectively. Moreover, chest wall toxicity was more common in the 3 fractions (23.7%)
[19]
compared to 8.6% and 7.7% in the single and 4-5 fractions schedule, respectively .

Central and ultra-central lesions
Central lesions
Currently, lung tumors located around the proximal bronchial tree are defined as “Central”. This refers to
the zone 2 cm distal to the trachea, carina, and major lobar bronchi up to their first bifurcation. Patients
treated for central lesions were more likely to experience treatment related side effects, as demonstrated
by a phase II trial, which enrolled NSCLC patients who were clinically staged as T1-3 (< 7 cm), not
candidates for surgery, and received 60-66 Gy/3 fractions (20-22 Gy each fraction) of SBRT. The authors
reported that the peri-hilar/peri-central tumor location was a stronger predictor of toxicity in both uni-
[10]
and multi-variate analyses (P = 0.004) . Medically inoperable patients with central lesions were recruited
in a prospective phase I/II trial to investigate the toxicity and efficacy of four dose levels (from 9 to 12 Gy
per fraction), measured as an objective 2-year LC rate > 80%. They defined all lesions located within 2 cm
around the proximal bronchial tree, or 5 mm by the mediastinal pleura or parietal pericardium as central.
The reported acute Grade 3-4 toxicity rate was 6%, while 27% developed late Grade 3 toxicity and 16% had
[20]
grade 4-5 late adverse events . Thereafter, a phase I-II dose-escalation study (RTOG 0813) was designed
to determine the maximum tolerable dose for central tumors. Patients were assigned to receive SBRT in a 5
fractions schedule, with each dose per fraction ranging from 10-12 Gy; dose limiting toxicity was defined
as any Grade ≥ 3 adverse event that occurred in the first year after treatment. The maximum tolerable dose
[21]
was 12 Gy per fraction (total dose 60 Gy) which reported 7.2% Grade ≥ 3 toxicity .
Several studies have investigated the optimal dose of treatment for centrally located lesions by balancing
survival outcomes and toxicity. SBRT for patients with central tumors achieved markedly better local
control compared to conventional radiotherapy. A prospective, phase II trial investigated an alternative
treatment schedule to the 60 Gy/3 fractions scheme, which is not recommended in central lesions due
to its high toxicity rate. Patients who were medically inoperable were treated with 55 Gy/5fractions
(11 Gy per fraction) of SBRT achieved an estimated 2-year LC and OS of 85% and 43%, respectively. With
a 2-year local control rate > 80%, the phase II trial achieved its primary end point after a median follow
up of 17 months. Most of the tumors were located centrally (84%), within 2 cm of the proximal bronchial
[20]
tree; 16% were located within 5 mm of the mediastinal or pericardial pleura (ultra-central lesions) . The