International Journal of
Radiation Oncology
biology
physics
www.redjournal.org
Clinical Investigation: Thoracic Cancer
Stereotactic Ablative Radiation Therapy for Centrally
Located Early Stage or Isolated Parenchymal Recurrences
of Non-Small Cell Lung Cancer: How to Fly in a “No Fly Zone”
Joe Y. Chang, MD, PhD,* Qiao-Qiao Li, MD,* Qing-Yong Xu, MD,*
Pamela K. Allen, PhD,* Neal Rebueno, CMS,* Daniel R. Gomez, MD,*
Peter Balter, PhD,y Ritsuko Komaki, MD,* Reza Mehran, MD,z
Stephen G. Swisher, MD,z and Jack A. Roth, MDz
Departments of *Radiation Oncology, yRadiation Physics, and zThoracic and Cardiovascular Surgery, The University of
Texas MD Anderson Cancer Center, Houston, Texas
Received Dec 10, 2013, and in revised form Jan 7, 2014. Accepted for publication Jan 16, 2014.
Summary
We report the use of stereotactic ablative radiation
therapy (SABR) for 100
patients with centrally
located early stage or recurrent non-small cell lung
cancer and show tumor
control and toxicity to be
similar to those for patients
with peripheral lesions when
normal tissue constraints are
respected. We propose
modifications of normal
tissue constraints suitable for
use with SABR, with the
caveat that careful patient
selection and
Purpose: We extended our previous experience with stereotactic ablative radiation
therapy (SABR; 50 Gy in 4 fractions) for centrally located non-small cell lung cancer
(NSCLC); explored the use of 70 Gy in 10 fractions for cases in which dose-volume
constraints could not be met with the previous regimen; and suggested modified dosevolume constraints.
Methods and Materials: Four-dimensional computed tomography (4DCT)-based
volumetric image-guided SABR was used for 100 patients with biopsy-proven, central
T1-T2N0M0 (nZ81) or isolated parenchymal recurrence of NSCLC (nZ19). All
disease was staged with positron emission tomography/CT; all tumors were within
2 cm of the bronchial tree, trachea, major vessels, esophagus, heart, pericardium,
brachial plexus, or vertebral body. Endpoints were toxicity, overall survival (OS), local
and regional control, and distant metastasis.
Results: At a median follow-up time of 30.6 months, median OS time was 55.6 months,
and the 3-year OS rate was 70.5%. Three-year cumulative actuarial local, regional, and
distant control rates were 96.5%, 87.9%, and 77.2%, respectively. The most common toxicities were chest-wall pain (18% grade 1, 13% grade 2) and radiation pneumonitis (11%
grade 2 and 1% grade 3). No patient experienced grade 4 or 5 toxicity. Among the 82 patients receiving 50 Gy in 4 fractions, multivariate analyses showed mean total lung dose
>6 Gy, V20 >12%, or ipsilateral lung V30 >15% to independently predict radiation
Reprint requests to: Joe Y. Chang, MD, PhD, Department of Radiation
Oncology, Unit 97, The University of Texas MD Anderson Cancer Center,
1515 Holcombe Blvd, Houston, TX 77030. Tel: (713) 563-2337; E-mail:
jychang@mdanderson.org
Dr Xu’s current address is Department of Radiation Oncology, Harbin
Medical University Cancer Hospital, Harbin 150086, PR China.
Drs Li and Xu contributed equally to this manuscript.
This research was supported in part by National Cancer Institute (NCI)
Int J Radiation Oncol Biol Phys, Vol. 88, No. 5, pp. 1120e1128, 2014
0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ijrobp.2014.01.022
Cancer Center Support (core) grant CA016672 and NCI Clinical and
Translational Science Award UL1 RR024148 to MD Anderson Cancer
Center.
Conflict of interest: none.
AcknowledgmentsdWe thank the staff of the Thoracic Radiation
Oncology section, Division of Radiation Oncology, for their help and
Christine Wogan for editorial assistance.
Volume 88 Number 5 2014
SABR for centrally located NSCLC 1121
individualization of treatment are crucial to avoid
overdosing critical
structures.
pneumonitis; and 3 of 9 patients with brachial plexus Dmax >35 Gy experienced brachial
neuropathy versus none of 73 patients with brachial Dmax <35 Gy (PZ.001). Other toxicities were analyzed and new dose-volume constraints are proposed.
Conclusions: SABR for centrally located lesions produces clinical outcomes similar to
those for peripheral lesions when normal tissue constraints are respected.
Ó 2014 Elsevier Inc.
Introduction
Image-guided stereotactic ablative radiation therapy (SABR;
also called stereotactic body radiation therapy [SBRT]) is
replacing conventional radiation therapy for the treatment of
patients with medically inoperable, peripherally located
stage I lung cancer (1-4). A population-based study showed
that SABR produced overall survival (OS) and diseasespecific survival rates similar to those after lobectomy and
better OS than conventional radiation (5). However, for lesions that are centrally located and thus close to critical
structures, the use of SABR has been controversial (6-13).
The tumor within a 2-cm radius of the trachea and bronchial
tree has been considered a “no fly zone” for high-dose radiation and was excluded from Radiation Therapy Oncology
Group (RTOG) protocol 0236 (2) since early results of a
phase 2 trial showed a low rate of freedom from grade 3 to 5
toxicity (54% at 2 years after treatment with 60-66 Gy in 3
fractions) (6). Severe bronchial stenosis, hemoptysis, or fistula after SABR for central tumors have been reported (6, 7,
9, 13). However, other hypofractionated regimens have been
shown to be safe and well tolerated (8,10-12).
We previously reported our preliminary result and proposed dose-volume constraints that used 50 Gy in 4 fractions
to treat central lesions (8). We have continued to use SABR
for centrally located lesions, and we report here updated
information, with long-term follow-up, for 100 patients. We
further sought to analyze our dose-volume constraints and
modify them if necessary and to explore a new regimen of
70 Gy in 10 fractions for cases in which dose-volume
constraints could not be met with the previous regimen.
Methods and Materials
Patients
From February 2005 to May 2011, 100 patients with centrally
located primary stage I or isolated recurrent (T <6 cm, N0,
M0), biopsy-confirmed non-small cell lung cancer (NSCLC)
that had not been treated with thoracic radiation therapy were
prospectively registered in our image-guided SABR program.
The retrospective review reported here was approved by the
appropriate institutional review board, and all patients provided written informed consent to participate. All tumors were
within 2 cm of the bronchial tree (ending at the beginning of the
tertiary bronchus), major vessels (aorta, upper mediastinal
vessels, and pulmonary artery extending to the tertiary
bronchus), esophagus, heart, trachea, pericardium, brachial
plexus, or vertebral body; at least 1 cm from the spinal canal;
and without direct involvement of the bronchial tree or
mediastinal structures and not associated with atelectasis (8).
All patients were either unable (owing to other medical conditions) or unwilling to undergo surgery. Disease in all patients
was staged with chest computed tomography (CT), brain
magnetic resonance imaging, and positron emission tomography (PET)/CT; suspected mediastinal disease was staged
with endobronchial ultrasonographic biopsy within 3 months
before SABR.
Treatment
Techniques for patient immobilization and simulation are
described elsewhere (3, 8, 14). In brief, 4-dimensional (4D)
CT images were obtained, and internal gross tumor volumes
(iGTV) were delineated on maximum intensity projections,
and then we modified these contours by visually verifying
the coverage in each phase of the 4D-CT dataset. Breath
hold or respiration-gated treatment was used for selected
patients with tumor motion >1 cm. Three-dimensional
conformal or intensity modulated radiation therapy SABR
plans were optimized by using 6 to 12 coplanar or noncoplanar 6-MV photon beams. SABR was prescribed to a dose
of 50 Gy to the planning tumor volume (PTV) between the
85% and 95% isodose lines, created via Pinnacle calculation
algorithms (Philips HealthCare, Anover, MA) with heterogeneity correction and was delivered in 4 fractions over 4
consecutive days. Compromises to clinical tumor volume
(CTV/PTV) coverage were considered acceptable to maintain the normal structure constraints. However, in addition to
the iGTV plus a margin of 5 mm (PiGTV) to receive at least
95% of the prescribed dose, at least 95% of the PiGTV must
have been covered by at least the prescribed dose, and 100%
of the iGTV must have been covered by at least the prescribed dose. If these requirements could not be met, a
regimen consisting of 70 Gy given in 10 fractions was
considered. Daily CT-on-rail or a cone beam CT scans were
obtained during each radiation therapy fraction and used to
verify and adjust coverage of the target volume and to spare
critical structures as needed.
Follow-up evaluations
Follow-up visits included chest CT scans every 3 months for
the first 2 years, every 6 months for the next 3 years, and
annually thereafter. PET/CT was recommended at 3 to
1122 Chang et al.
12 months after SABR. Local recurrence was defined as CT
evidence of progressive soft tissue abnormalities in the same
lobe over time that corresponded to avid (maximum standardized uptake value [SUVmax] >5) areas on PET/CT images
>6 months after SABR (15). Biopsy was strongly recommended to confirm suspected recurrence. The time of recurrence was the time at which the first PET/CT image showed
abnormalities. Recurrence appearing in different lobes was
scored as distant metastasis. Regional failure was defined as
any intrathoracic lymph node relapse outside the PTV.
Toxicity was scored according to National Cancer Institute
Common Terminology Criteria for Adverse Events, version 3.
Statistical analysis
The Kaplan-Meier method was used to estimate survival
curves, with log-rank tests used to compare curves among
groups. Survival time was calculated from the beginning date of
SABR to the first occurrence of the considered event. OS was
defined as the time between the beginning date of SABR and
death from any cause. Progression-free survival (PFS) was
defined as the time between the beginning date of SABR date
and the first recurrence of disease (local-regional or distant).
Factors found to be associated with OS, PFS or toxicity in
univariate analyses were then entered into multivariate Cox
proportional hazards regression analysis. Continuous variables
and dosimetric data were divided at cut points identified as most
significant by receiver operating characteristic curves into 2
subgroups and then analyzed. Measures of association in frequency tables were analyzed with 2-sided Fisher exact tests.
Variables were entered into the Cox proportional hazards model
to provide estimates of hazard ratios (HR) and their 95% confidence intervals (CIs) for toxicity; factors with P values <.15
were included in the model. Subgroup analyses of other
continuous variables such as the dose to the bronchial tree,
major vessel, esophagus, brachial plexus, and heart were done
by using the most significant or clinically useful cut-off values.
P values of <.05 were considered statistically significance.
Results
Patient characteristics, survival, and patterns of
failure
From Feb 8, 2005, through May 9, 2011, 100 patients with
centrally located tumors were treated with SABR; 82 patients (63 patients with primary stage I and 19 patients with
isolated recurrent NSCLC after surgical resection) received
50 Gy in 4 fractions, and 18 patients received 70 Gy in 10
fractions (all with primary stage I disease). Patient characteristics are shown in Table 1. Treatment details and the
distance between tumors and critical structures are listed in
Table 2. At a median follow-up time of 30.6 months (range,
9.4-92.6 months) for all patients (40.5 months [range, 11.492.6 months] for patients alive at the time of this analysis),
the median OS time was 55.6 months and OS rates were
International Journal of Radiation Oncology Biology Physics
Table 1
Patient characteristics
Characteristic (%)
Sex
Male
Female
Age, median, y (range)
Past or current smoker
COPD
Yes
No
COPD GOLD classification*
1
2
3
4
FEV1, % predicted median (range)
DLCO, % predicted median (range)
ECOG performance status
0-1
2-3
Indication for SABR
Pulmonary insufficiency
Cardiac insufficiency
Previous surgery
Other comorbidity
Potentially operable
History of other cancer
Yes
No
Tumor type
Primary
Isolated recurrence of NSCLC of patients (%)
TNM status (nZ81)y
T1N0M0
T2N0M0
Tumor diameter, median cm (range)
Tumor histology
Adenocarcinoma
Squamous cell carcinoma
NSCLC not specified
18
[ F]FDG-PET staging
Yes
No
Planning target volume, median cm3 (range)
Radiation dose and no. of fractions
50 Gy in 4 fractions
70 Gy in 10 fractions
Radiation plan design
3D CRT
IMRT
Treatment plan
Noncoplanar
Coplanar
Value or number (%)
50
50
73
93
(50)
(50)
(50-93)
(93)
51 (51)
49 (49)
3
7
35
6
62
60
(3.0)
(7.0)
(35)
(6)
(19-122)
(20-135)
75 (75)
25 (25)
35
7
17
16
25
(35)
(7)
(17)
(16)
(25)
59 (59)
41 (41)
81 (81)
19 (19)
65 (80.2)
16 (19.8)
2.0 (0.7-5.5)
55 (55)
34 (34)
11 (11)
97 (97.0)
3 (3.0)
59.4 (4.4-280.7)
82 (82)
18 (18)
88 (88)
12 (12)
41 (41)
59 (59)
Abbreviations: 3DCRT Z 3-dimensional conformal radiation therapy; COPD Z chronic obstructive pulmonary disease;
DLCO Z diffusion capacity of the lung for carbon monoxide;
ECOG Z Eastern Cooperative Oncology Group; [18F]
FDG Z fluorine-18-labeled fluorodeoxyglucose; FEV1 Z forced
expiratory volume in 1 second; IMRT Z intensity modulated radiation
therapy; NSCLC Z non-small cell lung cancer; PET Z positron
emission tomography; SABR Z stereotactic ablative radiation therapy.
* Defined by the Global Initiative for Chronic Obstructive
Lung Disease (http://www.goldcopd.org/guidelines-copd-diagnosisand-management.html).
y
For 82 patients with primary lesions, classified according to the
seventh edition (2010) of the American Joint Committee on Cancer
Staging Manual.
70.5% at 3 years and 49.5% at 5 years (Fig. 1A). By the
date of last follow-up, 3 patients had local recurrence (2
after receiving 50 Gy in 4 fractions and 1 after receiving
70 Gy in 10 fractions), 12 had regional recurrence (9 after
Volume 88 Number 5 2014
SABR for centrally located NSCLC 1123
Table 2 SABR regimens, distance between tumor and nearby critical structures, and toxicities after stereotactic ablative radiation
therapy in 101 patients
Critical structure
near tumor
Bronchial tree
Hila major vessels
Aorta or upper mediastinal
major vessels
Vertebral body
Pericardium/heart
Brachial plexus
Trachea
Esophagus
Total
Radiation dose
and no. of
fractions
50
70
50
70
50
70
50
70
50
70
50
70
50
50
Gy
Gy
Gy
Gy
Gy
Gy
Gy
Gy
Gy
Gy
Gy
Gy
Gy
Gy
in
in
in
in
in
in
in
in
in
in
in
in
in
in
4 fx
10 fx
4 fx
10 fx
4 fx
10 fx
4 fx
10 fx
4 fx
10 fx
4 fx
10 fx
4 fx
4 fx
70 Gy in 10 fx
50 Gy in 4 fx
70 Gy in 10 fx
No. of
patients
Median distance
between tumor
and critical
structure,
mm (range)
21
2
17
7
9
4
26
7
12
5
10
3
4
3
14.0
1.1
14.5
1.8
11.0
1.1
13.8
12.3
17.4
1.0
13.4
1.5
14.9
14.0
1
100*
1.9
NA
(2.0-20.0)
(1.1)
(1.0-20.0)
(0.0-13.3)
(2.0-19.8)
(0.0-16.3)
(2.0-20.0)
(0.0-19.5)
(11.8-19.8)
(0-20.0)
(6.0-19.5)
(1.2-11.8)
(14.0-16.6)
(6.5-18.8)
No. of RP
grade 2 (%)
No. with
chest-wall
pain grade
1 no. (%)
2 (9.5)
0
1 (5.9)
1 (14.3)
1 (11.1)
0
3 (11.5)
1 (14.3)
3 (25.0)
0
1 (10.0)
0
1 (25.0)
1 (33.3)
4 (19.0)
0
1 (5.9)
0
2 (22.2)
1 (25.0)
13 (50.0)
2 (28.5)
3 (25.0)
1 (20.0)
4 (40.0)
2 (66.7)
1 (25.0)
2 (66.7)
0
11 (13.4)
1 (5.5)
0
26 (31.7)
5 (27.8)
No. of other
toxicities (%)
Grade 2
esophagitis
Grade 1-2
arrhythmia
Grade 2-3
RIBP
3 (11.5)
2 (28.5)
3 (25.0)
0
3 (30)
0
Grade 2
esophagitis
3 (100)
0
Abbreviations: fx Z fraction; RIBP Z radiation-induced brachial plexopathy; RP Z radiation pneumonitis.
* Tumors in 29 patients were near more than 1 critical structure.
50 Gy and 3 after 70 Gy), and 23 had distant metastasis (19
after 50 Gy and 4 after 70 Gy). The median PFS time was
42.5 months, and PFS rates were 68.6% at 3 years and
63.6% at 5 years (Fig. 1A). The cumulative actuarial rates
of local control, regional control, and distant control at
3 years were 96.5%, 87.9%, and 77.2%, respectively
(Fig. 1B).
Factors investigated for potential association with OS
and PFS included age, sex, performance status, type of
tumor (primary or isolated recurrence), presence of chronic
obstructive pulmonary disease (COPD), tumor operability,
T status, size, and radiation dose. Age and tumor diameter
of >2.0 cm were related to OS in both univariate and
multivariate analyses. Sex, performance status, and type of
tumor (primary or isolated recurrence) were related to PFS
in multivariate analysis. No significant differences were
found among OS, PFS, local recurrence, regional recurrence, or distant metastasis between patients treated with
50 Gy in 4 fractions and those treated with 70 Gy in 10
fractions, even though patients treated with 70 Gy tended to
have tumors that were larger or closer to one or more
critical structures.
Toxicity
Treatment-related toxicity is shown in Table 2. In the entire
group of 100 patients, the most common toxic effects were
radiation pneumonitis (RP; 11 grade 2, 1 grade 3) and
chest-wall pain (18 grade 1, 13 grade 2) (Table 2). No
narrowing or stenosis of any airway or vessel was found.
No patients developed rib fracture. Three of 10 patients
with tumor close to the brachial plexus treated with 50 Gy
in 4 fractions developed grade 2 to 3 radiation-induced
brachial plexopathy (RIBP). None of the patients with
brachial plexus Dmax 35 Gy or V30 0.2 cm3 had RIBP
after SABR to 50 Gy. None of the 3 patients with lesions
close to the brachial plexus treated with 70 Gy in 10
fractions developed RIBP. No patient experienced cardiac
toxicity (arrhythmias) or esophagitis that exceeded grade 2.
Examples of beam angle (weighting) plans optimized to
spare critical structures (esophagus, heart, aorta, and spinal
cord) using 50 Gy in 4 fractions and clinical outcome are
shown in Figure 2.
For the 82 patients treated with 50 Gy in 4 fractions,
having a mean bilateral lung dose (MLD) of >6 Gy, a lung
V5 of >30%, a V20 of >12%, an ipsilateral lung mean lung
dose (iMLD) of >10 Gy, an ipsilateral lung volume the
received 10 Gy and greater (iV10) of >35%, and an iV20 of
>25% were all predictors of RP grade 2 to 3 by univariate
analysis. In multivariate analysis, predictors of RP grade 2
to 3 were having an MLD of >6 Gy (HR, 5.88; 95% CI,
1.28-26.95; PZ.022), a V20 of >12% (HR, 4.91; 95% CI,
1.19-20.17; PZ.027), and iV30 of >15% (odds ratio [OR],
5.28; 95% CI, 1.66-16.83; PZ.005), being female (OR,
2.85; 95% CI, 1.46-5.54; PZ.002), and not having COPD
(HR, 0.48; 95% CI 0.26-0.90; PZ.021). The incidence of
RP grade 2 to 3 was almost twice as high among patients
with bronchial tree maximum dose (Dmax) of >38 Gy and
1124 Chang et al.
International Journal of Radiation Oncology Biology Physics
(PZ.002) and being 70 years old (PZ.003) were factors
associated with chest-wall pain by univariate analyses.
Discussion
Fig. 1. Kaplan-Meier curves illustrating (A) overall survival (OS) and progression-free survival (PFS) and (B)
actuarial local control (LC), regional control (RC), and
distant control (DC) over time.
V35 > 1 cm3 and 3 as high among patients with hilar
major vessel Dmax of >56 Gy or V40 > 1 cm3 as those with
values less than those cut-offs. None of the 5 patients with
lesions within 5 to 10 mm of the bronchial tree treated with
50 Gy in 4 fractions experienced hemoptysis. Having a
minimum distance of >10 mm from tumor and chest wall
In the current study, we found that the use of SABR for 100
patients with tumors near the bronchial tree or other critical
structures produced OS and local control rates comparable
to those for peripheral lesions treated by us with SABR to
50 Gy in 4 fractions (3). Comparison of our result with
those of published studies is listed in Table 3 (6-12). Hence,
we propose a reconsideration of the use of SABR for
treating centrally located tumors with the use of appropriate
dose-volume constraints for normal tissues.
Local control of lung tumors seems to require a biologically effective dose (BED) of no less than 100 Gy
(calculated with the linear-quadratic model) (4, 16). Indeed,
BEDs of <100 Gy have been shown in several studies to be
inferior for controlling centrally located lesions (Table 3)
(8, 11, 12). However, doses with a BED exceeding 100 Gy
represent a “double-edged sword” in terms of balancing
tumor control with normal tissue damage. Therefore, it is
crucial to balance coverage of the gross tumor to a BED
>100 Gy with dose constraints to avoid damage to nearby
critical structures. Use of SABR beam angle/weighting
optimization with tight aperture margins is crucial to create
a sharp dose gradient that provides adequate target
coverage while avoiding overdosing critical structures
(Fig. 2).
On the basis of our experience and our findings in this
analysis, we propose modifications of our previous normal
tissue dose-volume constraints (8) as shown in Table 4. The
new constraints for lung in particular are based on statistical analysis of our current findings, as we now have a
sufficient number of cases to assess lung toxicity. The dosevolume constraints for other organs are based on our BED
Fig. 2. Representative case is shown for SABR (50 Gy in 4 fractions) beam angle (weighting) designed to spare esophagus,
heart, aorta, and spine. A Z aorta; E Z esophagus; H Z heart; SABR Z stereotactic ablative radiation therapy.
Volume 88 Number 5 2014
Table 3
SABR for centrally located NSCLC 1125
Published reports of the use of stereotactic ablative radiation therapy for centrally located lung tumors
Study, y
(ref)
No. of
patients
Timmerman
et al, 2006
(6)
70
As in RTOG 0236
7 cm
60 Gy in 3 fx
66 Gy in 3 fx
Chang et al,
2008 (8)
27
As in current study
<4 cm
40 Gy in 4 fx
80 Gy
(nZ7)
50 Gy in 4 fx
112.5 Gy
(nZ20)
30-63 Gy in 2.5- 39-82.5 Gy
to 5-Gy fx
Tumor location
Tumor size
Total dose and
no. of fx
Milano et al,
2009 (7)
53
Mediastinum, hilum,
or same as in
RTOG 0236
Song et al,
2009 (9)
32
As in RTOG 0236
Haasbeek
et al, 2011
(10)
37
1.5-7.4 cm
As in RTOG 0236 or
1 cm from the
heart or mediastinum
60 Gy in 8 fx
Rowe et al,
2012 (11)
47
As in RTOG 0236 or
current study
1.1-5.7 cm
50 Gy in 4 fx
(57% of
patients)
Nuyttens
et al, 2012
(12)
56
<2 cm from trachea
mainstem bronchi,
main bronchi,
esophagus, heart
or mediastinum
1.2-10.5 cm 48 Gy in 6 fx
Current study
100
See text
0.7-5.5 cm
<5 cm
40 Gy in 4 fx
(nZ12)
48 Gy in 4 fx
(nZ16)
60 Gy in 3 fx
(nZ4)
45 Gy in 5 fx
50 Gy in 5 fx
60 Gy in 5 fx
50 Gy in 4 fx
(82 patients)
70 Gy in 10 fx
(18 patients)
BED
(a/b Z 10)
180 Gy
211.2 Gy
LCR
95% at 2 y for all
patients
57%
100%
Grade 3-5
radiation-related
toxicity
6 patients had grade 5
toxicity; tumor
location (hilar/
pericentral vs
peripheral) strongly
predicted toxicity.
1 patient developed
brachial plexus
neuropathy.
73% at 2 y
4 patients had grade 5
pulmonary toxicity;
tumors in 3 of those
patients abutted the
bronchus, and the
fourth was 0.5 cm
from the bronchus.
80 Gy
85.3% at 2 y
8 of 9 patients with
tumors abutting
105.6 Gy
the bronchus had
bronchial strictures; 1
180 Gy
died and 2 had grade
3-4 pulmonary
toxicity.
105 Gy
92.6% at 2 and
One patient had
5y
bronchial stenosis; 2
had grade 3 dyspnea;
1 had rib fracture.
100 Gy
94% at 2 y
4 patients had grade
(38 tumors)
3 dyspnea, 1 with
(all patients),
80-99 Gy
tumor abutting the
100% (BED (10 tumors)
bronchus died from
100 Gy) vs 80%
60-79 Gy
hemoptysis
(BED <100 Gy)
(3 tumors)
(PZ.02)
86.4-132 Gy 76% at 2 y (all
4 patients had grade
patients)
3 acute pneumonitis
85% (BED >100
and 6 had grade 3
Gy) vs. 60%
late pneumonitis. 2
(BED 100 Gy)
patients had rib
(PZ.10)
fractures.
2 patients had grade 3
112.5 Gy
3-y cumulative
pneumonitis.
actuarial
119 Gy
LCR 96.5%
Abbreviations: BED Z biologically effective dose; fx Z fraction; LCR Z local control rate; RTOG Z Radiation Therapy Oncology Group.
calculations, our previous publications, and limited findings
from case reports of toxicity of the current report. This
study provided clinical evidence-based dose-volume constraints for SABR using 50 Gy in 4 fractions that was not
listed in the American Association of Physicists in Medicine TG 101 report (17). We recommend that these new
constraints be followed until additional findings become
available, such as those from the ongoing RTOG trial 0813,
a phase 1 dose escalation study for SABR in central lesions.
For those constraints marked “preferred” on Table 4, doses
beyond these levels are allowed but not preferred. For more
challenging cases where these dose-volume constraints
cannot be met despite compromises to the CTV/PTV
coverage, as described in Methods and Materials, 70 Gy in
10 fractions (BED Z 119 Gy) is another effective regimen
that can be considered (18).
In our study, RP and chest-wall pain remained the most
common side effects in patients with central lesions, as is
true for patients with peripheral lesions (2, 3, 19). In the
current study, we found that MLD >6 Gy, V20 > 12%, and
iV30 > 15% independently predicted RP grade 2 to 3 for
patients treated with 50 Gy in 4 fractions. These cut-off
International Journal of Radiation Oncology Biology Physics
1126 Chang et al.
Table 4 Previous dose-volume constraints, dosimetric factors associated with radiation toxicity, and recommendations for new dosevolume constraints for patients undergoing stereotactic ablative radiation therapy to 50 Gy in 4 fractions
Dose-volume constraint
Toxicity and related
organs
Radiation pneumonitis
(grade 2)
Lung
Univariate analysis in current study
Previous constraintsy
V5 <40%
V10 <30%
V20 <20%
Bronchial tree
V40 1 cm3
V35 10 cm
3
Hilar major vessels
Trachea
Esophagitis (grade 2)
Esophagus
V40 1 cm3
V35 10 cm3
V35 1 cm3
V30 10 cm3
V35 1 cm3
V30 10 cm3
Brachial plexopathy
(grade 2)
Brachial plexus
Dmax <40 Gy
V35 1 cm
V30 10 cm3
3
Arrhythmia (grade 1)
Heart
Spinal cord
Spinal cord
V40 1 cm3
V35 10 cm3
No patient experienced
spinal cord toxicity
in current study
V20 1 cm3
V15 10 cm3
Skin toxicity
(grade 1 or 2)
Skin
Chest wall pain
V40 1 cm3 (within
5 mm from skin)
V35 10 cm3 (within
5 mm from skin)
NA
Dosimetric
cut-points in
current study
No. of patients with
specified toxicity (%)
P
New recommended dose-volume
constraints (ref.)
MLD 6 Gy
MLD >6 Gy
V5 30%
V5 >30%
V10 17%
V10 >17%
V20 12%
V20 >12%
V30 7%
V30 >7%
iMLD 10 Gy
iMLD >10 Gy
iV10 35%
iV10 >35%
iV20 25%
iV20 >25%
iV30 15%
iV30 >15%
Dmax 38 Gy
Dmax >38 Gy
V35 1 cm3
V35 >1 cm3
Dmax 56 Gy
Dmax >56 Gy
V40 1 cm3
V40 >1 cm3
5 of 63 (8)
6 of 19 (32)
6 of 73 (8)
5 of 9 (56)
5 of 58 (9)
6 of 24 (25)
6 of 67 (9)
5 of 15 (33)
7 of 70 (10)
4 of 12 (33)
4 of 55 (7)
7 of 27 (26)
4 of 61 (7)
7 of 21 (33)
7 of 69 (10)
4 of 13 (31)
8 of 73 (11)
3 of 9 (33)
8 of 68 (12)
3 of 14 (21)
10 of 78 (13)
1 of 4 (25)
8 of 72 (11)
3 of 10 (30)
7 of 68 (10)
4 of 14 (29)
1 tracheal V35 >1 cm3
(no related toxicity)
Dmax 35 Gy
Dmax >35 Gy
V30 1 cm3
V30 >1 cm3
1
2
1
2
of
of
of
of
78 (1)
4 (50)
78 (1)
4 (50)
.005
Dmax 35 Gy
.005
V30 1 cm3
Dmax 35 Gy
Dmax >35 Gy
V30 0.2 cm3
V30 >0.2 cm3
0
3
0
3
of
of
of
of
73
9 (33)
75
7 (43)
.001
Dmax 35 Gy
.000
V30 0.2 cm3
Dmax 45 Gy
Dmax <45 Gy
V40 1 cm3
V40 >1 cm3
1
2
1
2
of
of
of
of
75 (1)
7 (29)
77 (1)
5 (40)
.018
Dmax 45 Gy (preferred)
.009
V40 1 cm3
V20 5 cm3 (24)
11 Dmax >20 Gy
2 Dmax >25 Gy
3 V20 >1 cm3
.016*
MLD 6 Gy (preferred)
.002
V5 30% (preferred)
.056
V10 17% (preferred)
.025*
V20 12% (preferred)
.051
V30 7% (preferred)
.026
iMLD 10 Gy (preferred)
.005
iV10 35% (preferred)
.068
iV20 25% (preferred)
.097*
iV30 15% (preferred)
.389
Dmax 38 Gy (preferred)
.444
V35 1 cm3
.128
Dmax 56 Gy
.087
V40 1 cm3
V35 1 cm3
Dmax <25 Gy
V20 1 cm3
4 grade 2 skin
V30 <50 cm3 for skin toxicity
(preferred) (21)
18 grade 1 chest-wall pain
V30 <30 cm3 for chest-wall pain
(preferred) (21)
13 grade 2 chest-wall pain
Abbreviations: Dmax Z maximum dose; iV20 Z ipsilateral volume exposed to 20 Gy or more; MLD Z mean lung dose; NA Z not apply;
V5 Z volume exposed to 5 Gy or more.
* Also significant in multivariate analyses.
y
See ref. (8).
Volume 88 Number 5 2014
values are similar to those reported for patients with peripheral lesions; Barriger et al (20) reported 4.3% RP grade
2 to 4 for patients with MLD 4 Gy versus 17.6% for
patients with MLD >4 Gy (PZ.02), and others (3) have
reported that iMLD >9.1 Gy, MLD >5 Gy, V20 > 9%, and
iV30 > 10% were associated with RP grade 2 to 3 for
patients with peripheral lesions treated with 50 Gy in 4
fractions. For the chest wall pain, chest-wall V30 also
predicted chest-wall pain in our previous study, as was the
case in other studies in which V30 > 30 cm3 was associated with chest-wall pain of any grade (21-23). This
recommendation is more practical and useful because some
tumor within 10 mm of chest wall still needs to be treated
with SABR.
Reports of bronchial or tracheal toxicity related to
SABR include bronchial stenosis, hemoptysis, and bronchitis resulting in death or severe pneumonia (6, 7, 9, 13).
In our study, among patients given 50 Gy in 4 fractions, the
dose to the bronchial tree (Dmax >38 Gy, V35 > 1 cm3) or
major bronchial vessels (Dmax >56 Gy, V40 > 1 cm3)
seemed to be associated with RP grade 2 to 3, but no other
airway toxicity was found. Song et al (9) reported that none
of the patients with lesions within the “no fly zone” without
direct invasion of the bronchial tree experienced partial or
complete bronchial strictures compared with the 8 of 9
patients with tumor located bronchus who did. We do not
recommend SABR for lesions that directly invade or
physically abut the bronchial tree or other critical mediastinal structures. Keeping a 5- to 10-mm margin between
gross tumor and critical structures may be considered, using
current photon-based SABR planning techniques and image
guidance.
Other reported toxicities associated with SABR for lung
tumors include esophagitis, cardiac damage, and RIBP.
Esophagitis is a risk when central lesions are treated
without regard for esophageal dose-volume constraints (7,
12). In our study, only 3 patients experienced grade 2
esophagitis. Our proposed limit for esophageal V30
(1 cm3) for patients to be treated with 50 Gy in 4 fractions
seems to be safe and appears to limit the incidence and
severity of radiation-induced esophagitis. SABR has also
been linked with increased cardiac SUVmax when 50 Gy in
4 fractions was given and the cardiac V20 exceeded 5 cm3
(24). Our proposed constraints, to keep the cardiac Dmax
<45 Gy, V40 at 1 cm3, and V20 at <5 cm3, seem to be safe
and keep the treatment tolerable. As for RIBP, Forquer et al
(25), reporting a series of 39 patients, found an RIBP rate of
18.9% among all patients and 32% for the 19 patients with
a brachial-plexus Dmax >26 Gy after various SABR
regimens.
In the current study, no patient experienced RIBP when
the brachial plexus Dmax was kept at 35 Gy and the V30 at
<0.2 cm3 after 50 Gy in 4 fractions. Similarly, none of the
3 patients with lesions near the brachial plexus treated to
70 Gy in 10 fractions developed RIBP. The brachial plexus
may be better able to tolerate treatment given in smaller,
more numerous fractions, but the number of cases in this
SABR for centrally located NSCLC 1127
study was too small to reach firm conclusions and thus
additional study is needed.
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