Clinical outcomes of stage I and IIA non-small cell lung cancer patients treated with stereotactic body radiotherapy using a real-time tumor-tracking radiotherapy system
Katoh et al. Radiation Oncology
Clinical outcomes of stage I and IIA non- small cell lung cancer patients treated with stereotactic body radiotherapy using a real- time tumor-tracking radiotherapy system
Norio Katoh 0 1
Itaru Soda 2
Hiroyasu Tamamura 5
Shotaro Takahashi 4
Yusuke Uchinami 3
Hiromichi Ishiyama 2
Kiyotaka Ota 5
Tetsuya Inoue 1
Rikiya Onimaru 3
Keiko Shibuya 4
Kazushige Hayakawa 2
Hiroki Shirato 0 3
0 Global Station for Quantum Medical Science and Engineering, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University , Sapporo , Japan
1 Department of Radiation Oncology, Hokkaido University Hospital , North-14 West-5, Kita-ku, Sapporo , Japan
2 Department of Radiology and Radiation Oncology, Kitasato University School of Medicine , Sagamihara
3 Department of Radiation Medicine, Hokkaido University Graduate School of Medicine , Sapporo , Japan
4 Department of Therapeutic Radiology, Yamaguchi University Graduate School of Medicine , Ube , Japan
5 Department of Nuclear Medicine, Fukui Prefectural Hospital , Fukui , Japan
Purpose: To investigate the clinical outcomes of stage I and IIA non-small cell lung cancer (NSCLC) patients treated with stereotactic body radiotherapy (SBRT) using a real-time tumor-tracking radiotherapy (RTRT) system. Materials and methods: Patterns-of-care in SBRT using RTRT for histologically proven, peripherally located, stage I and IIA NSCLC was retrospectively investigated in four institutions by an identical clinical report format. Patterns-ofoutcomes was also investigated in the same manner. Results: From September 2000 to April 2012, 283 patients with 286 tumors were identified. The median age was 78 years (52-90) and the maximum tumor diameters were 9 to 65 mm with a median of 24 mm. The calculated biologically effective dose (10) at the isocenter using the linear-quadratic model was from 66 Gy to 126 Gy with a median of 106 Gy. With a median follow-up period of 28 months (range 0-127), the overall survival rate for the entire group, for stage IA, and for stage IB + IIA was 75%, 79%, and 65% at 2 years, and 64%, 70%, and 50% at 3 years, respectively. In the multivariate analysis, the favorable predictive factor was female for overall survival. There were no differences between the clinical outcomes at the four institutions. Grade 2, 3, 4, and 5 radiation pneumonitis was experienced by 29 (10.2%), 9 (3.2%), 0, and 0 patients. The subgroup analyses revealed that compared to margins from gross tumor volume (GTV) to planning target volume (PTV) ≥ 10 mm, margins < 10 mm did not worsen the overall survival and local control rates, while reducing the risk of radiation pneumonitis. Conclusions: This multi-institutional retrospective study showed that the results were consistent with the recent patterns-of-care and patterns-of-outcome analysis of SBRT. A prospective study will be required to evaluate SBRT using a RTRT system with margins from GTV to PTV < 10mm.
Stereotactic body radiotherapy; Non-small cell lung cancer; Real-time tumor-tracking radiotherapy; Gated radiotherapy; Image-guided radiotherapy
Surgical resection is the standard of care for patients
with early stage non-small cell lung cancers (NSCLC).
However, patients with early stage NSCLC often cannot
tolerate surgical resection because of age and/or
comorbidities such as chronic obstructive pulmonary and
cardiac diseases. With the advent of stereotactic body
radiation therapy (SBRT) and appropriate image-guidance
in the radiotherapy, it is now possible to administer very
high radiation doses to peripheral early stage NSCLC
over a short treatment time period without high risks of
complications [1–5]. Recent multivariable analysis has
shown improved overall survival with SBRT compared
with patients who received no treatment (hazard ratio,
0.64; p < .001) . The SBRT is now recommended for
patients with early stage NSCLC who are medically
inoperable or refuse surgery . Whether SBRT should be
the first choice of treatment for high risk patients rather
than surgical resection is still to be determined in a
prospective randomized trial [8–10].
Since inoperable early stage NSCLC patients often
suffer from poor respiratory functions, it is critically
important to reduce the irradiated volume to normal lung
tissue in the treatment of lung tumors with SBRT, and
there have been many investigations to reduce the
uncertainty of tumor location due to respiration [11–14].
Inadequate respiratory motion management in SBRT has
been one of the causes of local recurrences . Motion
management is essential in SBRT of lung tumors to be
able to deliver the treatment dose accurately.
Fourdimensional treatment planning, gating with a linear
accelerator, and real-time tracking of the internal tumor
motion have been shown to reduce the uncertainties due
to respiratory motion [16–18]. In 1999, a real-time
tumor-tracking radiotherapy (RTRT) system was
developed and put into use for SBRT. This RTRT system uses
two sets of fluoroscopes in the treatment room for the
real-time tracking of the internal fiducial markers
implanted in or near the lung tumor, tracking at 30 times a
second . In the system, the linear accelerator is gated
to irradiate the tumor only when the implanted fiducial
marker is within 2 mm of the planned position which
has been determined in 4days treatment planning .
Although the RTRT system was introduced in several
institutions in Japan and has been used for the SBRT of
early stage NSCLC for a decade, clinical results were
reported from only one institution [20–22] and no
multi-institutional clinical results of SBRT using the
RTRT system have been published.
The purpose of the present study is to evaluate clinical
results of SBRT for stage I and IIA NSCLC used with
this RTRT system in four institutions in Japan over the
last twelve years by patterns-of-care and
We obtained written informed consent to administer
SBRT using the RTRT system from all patients and
approval from the institutional review boards of all four
institutions for this retrospective study. We reviewed
patients treated with SBRT using the RTRT system from
September 2000 to April 2012, diagnosed with
histologically proven NSCLC and peripherally located clinical
stage I and IIA as determined by the seventh edition of
the Union for International Cancer Control staging
criteria. A peripherally located tumor was defined as a
tumor located outside a volume 2 cm in all directions
around the proximal bronchial tree. In principle, all the
patients with histologically proven, peripherally located,
stage I and IIA NSCLC were treated by SBRT using
RTRT in the four institutions during this period.
Patients were excluded from the study if they had received
thoracic radiation therapy for simultaneous malignant
tumors within three months before or after the start
dates of the SBRT.
A total of 283 patients with 286 tumors were
identified. The median age was 78 years (52–90). Among the
286 tumors, 155, 67, 41, and 23 tumors were treated in
the four institutions. The maximum tumor diameters
were from 9 to 65 mm with a median of 24 mm. Patient
characteristics are detailed in Table 1.
SBRT using an RTRT system
The RTRT system has been described in detail elsewhere
[19, 23]. In brief, the process for synchronizing the
tracking of a marker with the irradiation was as follows.
Before treatment, 1.5-mm or 2-mm gold markers were
implanted near the tumor by bronchoscopy, principally
within 5 cm of the center of the gross tumor volume
(GTV). After the insertion of the fiducial markers,
computed tomography was performed, usually while the
patient held the breath at the end of expiration. The
fluoroscopic RTRT system consists of four sets of
diagnostic fluoroscopic, image-processor units, a
triggercontrol unit, an image-display unit, and a conventional
linear accelerator with multileaf collimators. The linear
accelerator is gated to irradiate the tumor only when the
gold marker is within 2.0 mm of the planned coordinates
relative to the isocenter in the lateral, craniocaudal, and
Patterns-of-care in SBRT using RTRT was
retrospectively investigated in the four institutions. To evaluate
the radiation dose, the biologically effective dose (BED)
was calculated using the linear-quadratic model,
defined as nd*(1 + d/(α/β)), where n is the number of
fractions and d is the dose per fraction, assuming an
α/β of 10 for tumors.
Table 1 Patient characteristics and treatments
78 (range 52–90) 79 (52–89)
28 (range 0–127) 30 (0–127)
Observation period (months)
Maximum tumor diameter (mm)
Number of tumors
Right Upper Lobe 74
Right Middle Lobe 18
Right Lower Lobe 69
Left Upper Lobe
Left Lower Lobe
SCC squamous cell carcinoma
24 (range 9–65) 23 (9–65)
Follow-up examinations and computed tomography (CT)
scans were commonly performed every 3 to 6 months
after the SBRT. The definition of local failure was as
follows: sequential enlarging opacity for more than 6 months
on CT images, enlarging opacity corresponding to
FDGPET abnormalities and/or histologic confirmation.
Absence of local disease recurrence was defined as a
locally controlled disease. Toxicities were assessed with
Common Terminology Criteria for Adverse Events v3.0.
The follow-up duration was calculated from the start
date of the SBRT. The Kaplan-Meier method was used
for calculating overall survival (OS) and local control
(LC) rates. The log-rank test was used to compare
subgroups. Multivariate analysis was performed using a Cox
proportional hazards regression model. The hazard ratio
(HR), 95% confidence interval (95%CI), and p value were
calculated. The rates for Grade 2 or higher radiation
pneumonitis were compared in subgroups using the
univariate and multivariate logistic regression analyses
where the odds ratio (OR) and 95%CI were estimated. A
p value of < 0.05 was considered statistically significant.
The JMP version 12 (SAS, Cary, NC) was used for the
Patterns-of-care in SBRT
Patterns-of-care in SBRT using RTRT are shown in
Table 2. For the clinical target volume (CTV) margins, a
margin of 0 mm was most frequently used. One
institution usually adopted a CTV margin of 6 to 8 mm added
to the GTV uniformly to include the microscopic tumor
spread based on Giraud et al.’s report . In another
institution, a part of the GTV was expanded manually to
ensure that the CTV included the tumor spiculations,
which were not visualized on the planning CT images,
but appeared on the diagnostic high-resolution CT
images. Thus, all of 9 mm or wider CTV margins were
delineated non-uniformly and adopted only in this
institution, and were the maximum distance between
the GTV and CTV contours. For the planning target
volume (PTV) margin, which is comprised of the internal
and the set-up margins, a margin of 5 mm was most
frequently used. It varied from 3 to 12 mm depending on
patient condition, the visibility of fiducial markers, and
other factors. All SBRT plans were generated using
three-dimensional conformal treatment planning
techniques with a median of 6 static ports (range, 4–9).
Thirty-nine treatment plans were calculated using the
Clarkson method and 247 treatment plans used the
Superposition method. A total dose of 35–60 Gy was
administered in 4–9 fractions. The dose was prescribed at
the isocenter in 189 treatment plans and the most
frequent schedule was 48 Gy in 4 fractions in 149
treatment plans. The dose was prescribed for the 95%
volume of the PTV (PTVD95) in 97 treatment plans and
the most frequent schedule was 40 Gy in 4 fractions in
94 treatment plans. Among 286 treatment plans, a total
of 234 treatment plans (137 prescribed at the isocenter
Table 2 Patterns-of-care in SBRT using RTRT
Table 2 Patterns-of-care in SBRT using RTRT (Continued)
Number of ports
X-ray energy (MV)
CTV margin (mm)
PTV margin (mm)
Margin from GTV to PTV (mm)
BED (10) at the Isocenter (Gy)
BED (10) at the Isocenter (Gy)
BED biologically effective dose, CTV clinical target volume, Fr fractions, GTV
gross tumor volume, Gy gray, MV megavoltage, PTV planning target
volume, RTRT real-time tumor-tracking radiotherpay, SBRT stereotactic
and 97 prescribed to the PTV D95) were available for
analysis of the dose to the PTVD95. The calculated BED (10)
at the isocenter using the linear-quadratic model was from
66 Gy to 126 Gy with a median of 106 Gy in 286
treatment plans. The BED (10) to the PTVD95 was from 44 Gy
to 106 Gy with a median of 80 Gy in 234 treatment plans.
Overall survival and Local control
The median follow-up period was 28 months (range, 0–
127). In the 283 patients, the OS rates for all patients,
stage IA, and stage IB + IIA were 75%, 79%, and 65% at
2 years, and 64%, 70%, and 50% at 3 years, respectively
(Fig. 1). There was no significant difference in OS rates
among institutions. The results of the univariate analysis
of OS rates are shown in Table 3. There was a
statistically significant difference in the OS rates between the
subgroups with females and males (3-year: 83% and 58%,
respectively; p = 0.0016).
In the 286 tumors, the LC rates for all tumors, T1a +
T1b, and T2a + T2b tumors were 81%, 84%, and 74% at 2
years, and 75%, 79%, and 64% at 3 years (Fig. 2). There
were no significant differences in the LC rates among
institutions. The results of the univariate analysis of LC rates
are shown in Table 4. There was a statistically significant
difference in the LC rates between the subgroups with
BED (10) at the isocenter ≥ 90Gy and BED (10) < 90 Gy
(3-year: 78% and 42%, respectively; p = 0.0001), but no
significant difference between BED (10) ≥ 100 Gy at the
isocenter and BED (10) < 100 Gy (3-year: 74% and 76%,
respectively; p = 0.8987, not listed in Table 4). There were
no significant differences in the LC rates between BED
(10) ≥ 80 Gy to the PTVD95 and BED (10) < 80 Gy (3-year:
81% and 72%, respectively; p = 0.1963, not listed in
Table 4). Adenocarcinomas also showed more favorable
LC rates than squamous cell carcinomas (SCC) (3-year:
80% and 62%, respectively; p = 0.0002). There were no
Fig. 1 Overall survival rates in all patients (a), patients with stage IA and with stage IB + IIA (b), respectively
significant differences in the OS and LC rates between
margins from GTV to PTV ≥ 10 mm and margin < 10
mm, and also no significant differences in the OS and LC
rates among the upper/middle and the lower lobes.
In the multivariate analysis, all clinical factors showed
similar trends to those in the univariate analysis. In the
OS rate, gender was a significant predictive factor (HR
2.393, 95%CI [1.380–4.418], p = 0.0015, Table 3). In the
LC rate, significant factors were histology (HR 2.366,
95%CI [1.311–4.301], p = 0.0044) and BED (10) of 90 Gy
at the isocenter (HR 3.465, 95%CI [1.656–6.706], p =
0.0017), respectively (Table 4).
Fiducial marker insertion
Among the 286 procedures of the fiducial marker
insertions, data were available for 280 procedures. The
number of fiducial markers implanted in each patient was
from 1 to 7 (median: 4). The number of fiducial markers
at the start date of the SBRT was from 1 to 6 (median:
4). At the start date of the SBRT there were 918 fiducial
markers out of a total of 1100 inserted. During the
treatment, replanning was required in 3 patients due to
inter-fractional migration of fiducial markers.
Pneumothorax related to the insertion of the fiducial markers
was observed in 3 patients (Grade 1: one patient, Grade
2: two patients). One patient showed Grade 2
tachycardia. No patients experienced Grade 3 or higher
The median of the PTV was 52.4 cc (5.7–313 cc) in
the 252 plans which were available for analysis. Lung
volume was defined as the bilateral lung volume
minus the PTV volume. The median of the lung
volumes was 3093 cc (1325–6886 cc) in the 257 plans.
The median of the mean lung dose (MLD) was 355
Table 3 Univariate and multivariate analysis results of overall survival rates
Upper and Middle
BED (10) IC (Gy)
Margins from GTV to PTV (mm)
BED biologically effective dose, CI confidence interval, GTV gross tumor volume, HR hazard ratio, IC isocenter, OS overall survival, PTV planning target volume, SCC
squamous cell carcinoma
Fig. 2 Local control rates of all tumors (a), T1a + T1b tumors and T2a + T2b tumors (b), respectively
cGy (101–996 cGy) in 239 plans. The median of the
percentage of lung volume receiving a dose of 5 Gy
or more (V5) and a dose of 20 Gy or more (V20)
were 19.7% (6.2–45.4%) in 228 plans and 5.0% (1.0–
16.0%) in 246 plans, respectively.
Radiation related pneumonitis with the SBRT could be
assessed for 275 treatments. Nine patients had Grade 3
radiation pneumonitis. Grade 2 or higher radiation
pneumonitis were observed in 38 patients (Grade 2: 29,
Grade 3: 9). No patients experienced Grade 4 or 5
radiation pneumonitis. One of nine patients with Grade 3
radiation pneumonitis developed Grade 5 infectious
pneumonia. This male patient received 40 Gy to the
PTVD95 in 4 fractions for a 2.5 cm diameter tumor at
the left upper lobe. Here MLD, V5 and V20 were 494
cGy, 23.7% and 10.1%, respectively. This patient
experienced Grade 3 radiation pneumonitis 2 months after the
SBRT. Although the radiation pneumonitis was
improved by steroid therapy, the patient subsequently
developed cytomegalovirus pneumonia 4 months after
the SBRT and passed away, likely due to
immunosuppression caused by the steroids.
The results of the univariate and multivariate analyses
of the rates of radiation pneumonitis are shown in
Table 5. Among the 271 treatments in which it was
possible to evaluate both radiation pneumonitis and
margins from GTV to PTV, Grade 2 or higher radiation
pneumonitis was observed in 32 (21.2%) of 151
treatments with margins from GTV to PTV ≥ 10 mm, and
there were 5 (4.2%) of 120 treatments with margins < 10
mm. In the univariate analysis, a statistically significant
difference was observed in the rates of Grade 2 or higher
radiation pneumonitis between these two subgroups.
There was also a statistically significant difference
observed between the subgroups with BED (10) at the
isocenter ≥ 90 Gy and BED (10) < 90 Gy (14.8% vs. 0.0%,
Table 4 Univariate and multivariate analysis results of local control rates
Upper and Middle
BED (10) IC (Gy)
Margins from GTV to PTV (mm)
BED biologically effective dose, CI confidence interval, GTV gross tumor volume, HR hazard ratio, IC isocenter, LC local control, PTV planning target volume, SCC
squamous cell carcinoma
Table 5 Univariate and multivariate analysis results of Grade 2 or higher radiation pneumonitis rate
Grade 2 ≥ Radiation Pneumonitis Univariate Analysis
n Rates (%) OR (95%CI)
189 13.2 Reference
Upper and Middle 160
1.168 (0.552–2.377) 0.6760
1.381 (0.590–3.121) 0.4485
1.553 (0.698–3.817) 0.2902
1.492 (0.608–3.963) 0.3896
1.257 (0.567–2.632) 0.5600
1.298 (0.525–3.099) 0.5643
1.661 (0.834–3.329) 0.1481
2.281 (1.042–5.063) 0.0392
BED (10) IC (Gy)
Margins from GTV to PTV (mm) ≥10
6.185 (2.530–18.579) <0.0001 6.479 (2.558–19.988) <0.0001
BED biologically effective dose, CI confidence interval, GTV gross tumor volume, HR hazard ratio, IC isocenter, NE not estimable, PTV planning target volume,
SCC squamous cell carcinoma
p = 0.0154), but no significant difference between BED
(10) ≥ 100 Gy at the isocenter and BED (10) < 100 Gy
(14.7% vs. 11.5%, p = 0.4839, not listed in Table 5). In the
multivariate analysis, significant risk factors for Grade 2
or higher radiation pneumonitis were GTV to PTV
margin ≥ 10 mm (OR 6.479, 95% CI [2.558–19.988], p <
0.0001), BED (10) at the isocenter ≥ 90 Gy (OR not
estimable (NE), 95%CI [1.803–NE], p = 0.0118) and
lower lobe tumors (OR 2.281, 95%CI [1.042–5.063], p =
0.0392), respectively (Table 5).
Other treatment related toxicities
One patient experienced Grade 3 dermatitis, and 10
patients reported Grade 2 thoracic wall pain. No other
toxicities were recorded.
Guckenberger et al. have pointed out that
imageguidance, gating, and real-time tracking can improve
accuracy in pulmonary stereotactic body radiotherapy .
They investigated the required safety margins in SBRT
by pre- and post-treatment cone-beam CT imaging in
43 patients, and found that stereotactic patient
positioning and image-guidance based on the bony anatomy
required safety margins of 12 mm and 9 mm, respectively.
Four-dimensional image-guidance targeting of the tumor
itself and intra-fractional tumor tracking made it possible
to reduce margins to < 5 mm and < 3 mm, respectively.
That study suggested that additional safety margins are
required to compensate for breathing motion. Shimizu et al.
and others have shown that the RTRT system can reduce
the additional PTV margins for interfractional as well as
intrafractional target motion taking account of baseline
shift/drift and fluctuations in the amplitude during the
treatment [12, 13, 26].
Inoue et al. have reported the experience with RTRT
in a single institution where the 5-year LC rate was 78%
and the 5-year OS rate was 64% for 109 patients (79
T1N0M0 and 30 T2N0M0) with a median follow-up
period of 25 months (range, 4 to 72 months) . In the
present multi-institutional retrospective study, the OS
rates for Stage I and IIA NSCLC were 75% and 64% at 2
and 3 years respectively. This is consistent with the 70%
(95% CI: 67–72%) OS rates at 2 years for 3201 patients
in a systematic review  and a 47% 3-years OS of 582
patients in the recent patterns-of-care and
patterns-ofoutcome analysis of SBRT for Stage I NSCLC .
A recent review article summarized the LC rates of
SBRT for Stage I NSCLC and showed that the 3-year local
control rates were widely distributed, from 40% to 92%, in
studies which had a longer than 2-year follow-up .
The wide variation in LC rates may be ascribed to the
difficulty of ensuring a uniform definition of LC because of
the radiological changes after SBRT for periods of years
. The LC rates for Stage I and IIA NSCLC was 75% at
3 years in this series. This is consistent with the recent
patterns-of-care and patterns-of-outcome analysis which
showed 3-years of freedom from local progression of
79.6% . A significant difference in the LC rate was
found at a BED (10) of 90 Gy at the isocenter but not at
100 Gy or higher. The threshold for a high LC in the
previous studies of SBRT for stage I NSCLC has been reported
to be 100 Gy or higher in BED (10) at the isocenter .
A recently published report, in which local tumor
control probability (TCP) in SBRT was evaluated, showed
that a strong dose–response relationship was observed
in the primary NSCLC and the dose to achieve 90% TCP
was BED (10) at the isocenter > 176 Gy . According
to the dose response curve demonstrated in that report,
BED (10) of 90 Gy at the isocenter would result in a
local control of about 75%, matching the results of this
study. As both BED (10) of 90 Gy and 100 Gy were in
the steep part of the dose response curve, the difference
between the threshold for LC BED (10) of 90 Gy in this
study and 100 Gy in Onishi et al.’s report  could arise
from differences in heterogeneity (tumor, patients,
treatment and other factors) between these studies.
In our multivariate analysis, female was a significant
predictive factor for OS and adenocarcinoma was
significant for the LC rate. It is still not commonly agreed
whether tumor histology is related to clinical outcomes
in NSCLC treated with SBRT. Some studies have
reported an absence of statistically significant differences
in the survival or recurrence rates of adenocarcinomas
and SCC [32, 33]. Matsuo et al. analyzed 101 patients
with histologically confirmed stage I NSCLC who
underwent SBRT , and reported that females had a
significantly better prognosis than males and that histology
was less significant. They suggested that this result may
be caused by the proportion of lung adenocarcinomas in
females being higher than in males. In our study, the
situation was similar, with female patients having a
significantly higher proportion of adenocarcinomas
(Additional file 1) and a higher OS rate than males. In
the LC rate, gender differences were not statistically
significantly different but adenocarcinoma was a
statistically significant predictive factor. One possible
explanation for this is that gender differences in tumor
histology may result in higher survival rates in females
and higher LC rates in adenocarcinomas. Future study
will be needed to further investigate the relationships
between gender and tumor histology.
The potential benefit of the RTRT system strongly
depends on the reproducibility of the position of the
marker and the target volume. The relationship between
the marker and the tumor position has been investigated
in detail. As there is a learning curve for the insertion of
fiducial markers through bronchial fiberscopy [14, 35] a
strictly observed verification routine before treatment is
mandatory , clinical training of the pulmonologists
and radiation oncologists must be conducted in all
institutions which install the RTRT system. The present
study showed that there were no differences in the OS
and LC rates among the different institutions. This
absence of differences does not preclude a dependence of
the clinical outcome on the insertion techniques but is
encouraging and implies that any effect of a learning
curve is minimal provided that proper training of the
staff is available.
The distance between the fiducial marker and the
target volume may change more in the lower lobe than in
the middle or upper lobes during irradiation .
However, we did not see any difference in the OS and LC
rates among the upper, middle, and lower lobes. Again
here, any similarity in the OS and LC rates does not
preclude a dependence of the clinical outcome to arise from
differences in the location of the tumor but the effect as
determined in this study is suggested to be minimal.
It is well known that the risk of radiation pneumonitis
is correlated to the mean lung dose or other parameters
which are related to dose volume statistics [38–43]. The
RTRT is expected to reduce the volume of normal lung
tissue which receives radiation doses that could give rise
to the development of radiation pneumonitis. In the
present study, Grade 2, 3, 4, and 5 radiation pneumonitis
was experienced by 29 (10.2%), 9 (3.2%), 0, and 0
patients, respectively among 283 patients. Inoue et al. have
reported the RTRT experience in a single institution and
found that Grade 2, 3, 4, and 5 radiation pneumonitis
was experienced by 15 (13.8%), 3 (2.8%), 0, and 0
patients, respectively in 109 patients . In a Japanese
multi-institutional prospective trial of SBRT 48 Gy was
prescribed at the isocenter in 4 fractions for T1N0M0
NSCLC , the Grade 3, 4, and 5 radiation pneumonitis
incidence was as follows: 9 (5.9%), 1 (0.6%), and 0
patients, respectively in 169 patients (Grade 2 incidence
was data not shown). Although attention must be paid
to compare the results from a retrospective study with
those from a prospective study, the low complication
rate in this study is consistent with other SBRT studies.
We have however seen one (0.3%) Grade 5 adverse
event, which is consistent with the Nagata et al. report
in which there were 14 (0.6%) Grade 5 complications
among 1111 patients who were treated with lung SBRT
. Since the complication rate has been reported to be
very low in other SBRT studies, it is not certain whether
RTRT was effective to reduce the complication rate
below that of other SBRT technologies. Subgroup
analyses demonstrated that there were no significant
differences in the OS and the LC rates between margins from
GTV to PTV ≥ 10 mm and margins < 10 mm, whereas
the subgroup with margins ≥ 10 mm showed higher rate
of Grade 2 or higher radiation pneumonitis. A
prospective study will be required to determine whether RTRT
with margins from GTV to PTV < 10mm would allow
increasing the dose to the tumor and reduce the risk of
This multi-institutional retrospective study of SBRT
using a RTRT system for stage I and IIA NSCLC showed
that the OS and LC rates were consistent with the recent
patterns-of-care and patterns-of-outcome analysis of
SBRT. The subgroup analyses revealed that smaller
margins from GTV to PTV did not worsen the OS and the
LC rates, while reducing the risk of radiation
pneumonitis. A prospective study will be required to evaluate
SBRT using an RTRT system with margins from GTV to
PTV < 10mm.
Additional file 1: Table S1. Number of tumors by histology in male
and female. (DOCX 32 kb)
BED: Biologically effective dose; CI: Confidence interval; CTV: Clinical target
volume; Fr: Fractions; GTV: Gross tumor volume; Gy: Gray; HR: Hazard ratio;
LC: Local control; MLD: Mean lung dose; MV: Megavoltage; NE: Not
estimable; NSCLC: Non-small cell lung cancer; OR: Odds ratio; OS: Overall
survival; PTV: Planning target volume; RTRT: Real-time tumor-tracking radiotherapy;
SBRT: Stereotactic body radiotherapy; SCC: Squamous cell carcinoma
A preliminary version of this study was presented at the 55th Annual
Meeting of the American Society for Radiation Oncology, September 22–25,
2013, Atlanta, GA.
We wish to thank Yoichi M. Ito (Department of Biostatistics, Hokkaido
University Graduate School of Medicine) for valuable advice about the
This work was supported by JSPS KAKENHI Grant Number JP15H04768 and
the Global Institution for Collaborative Research and Education (GI-CoRE),
Hokkaido University, founded by the Ministry of Education, Culture, Sports,
Science and Technology MEXT, Japan.
Availability of data and material
NK and HS contributed in the study design, analysis of data and drafting of
the manuscript. NK and HS provided the conception of this study. NK, IS, HT,
ST, HI, KO, TI, RO, KS, and KH collected patient clinical data. YU analyzed the
clinical data and drafted the manuscript. YU, TI, and RO provided the
administrative support. HT, KS, and KH provided significant intellectual
contributions. HS supervised the project and provided the final approval of
the version to be published. And all authors read and approved the final
R.O. has received personal fees from Shimadzu Corporation, outside the
submitted work. H.S. has received grants from the Government, during the
conduct of the study; grants from Hitachi, Ltd., grants and personal fees from
Mitsubishi Heavy Industries, Ltd., grants and personal fees from Shimadzu
Corporation, grants and personal fees from Varian Medical Systems, Inc., and
personal fees from Olympus Corporation, outside the submitted work. In
addition, H.S. holds a patent, US 6,307,914, with royalties paid.
Consent for publication
Ethics approval and consent to participate
We obtained written informed consent to administer SBRT using the RTRT
system from all patients and approval from the institutional review boards of
all four institutions for this retrospective study.
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