Title Page
Patients with severe emphysema have a low risk of radiation pneumonitis
R O
O
FS
following stereotactic body radiotherapy
Moeko Ishijima MD, Hidetsugu Nakayama MD PhD, Tomohiro Itonaga MD, Yu
P
Tajima MD, Sachica Shiraishi MD, Mitsuru Okubo MD PhD, Ryuji Mikami MD
T
E
D
PhD, Koichi Tokuuye MD PhD.
E
C
Department of Radiology, Tokyo Medical University Hospital, Zip code 160-0023,
C O
R
R
6-7-1 Nishi-shinjyuku,Shinjyuku, Tokyo, Japan
Running title: Patients with severe emphysema have low risk of radiation
U
N
pneumonitis
B
JR
Corresponding author: Hidetsugu Nakayama M.D., Ph.D. Departments of Radiology, Tokyo Medical University Hospital, 6-7-1 Nishi-shinjyuku,Shinjyuku, Tokyo,
0
160-0023, Japan Tel: +81-03-3342-6111 Fax: +81-03-3348-6314
R O
O
FS
E-mail: [email protected]
Partial of this articles presented in Radiological Society of North America 2013
B
JR
U
N
C O
R
R
E
C
T
E
D
P
Annual Meeting held at Chicago.
1
Manuscript
Patients with severe emphysema have a low risk of radiation pneumonitis
B
R O
O
FS
following stereotactic body radiotherapy
Running title: Patients with severe emphysema have low risk of radiation
E
D
P
pneumonitis
T
Abstract
E
C
Objectives: To evaluate the risk of radiation pneumonitis (RP) after stereotactic
R
radiotherapy (SBRT) for patients presenting with severe pulmonary emphysema.
C O
R
Methods: This study included 40 patients with stage I non–small cell lung cancer (NSCLC) who underwent SBRT, 75 Gy given in 30 fractions, at Tokyo
U
N
Medical University between February 2010 and February 2013. The median age of patients was 79 years (range, 49-90), and the male/female ratio was
JR
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
24/16.
There were 20 T1 and 20 T2 tumors.
Seventeen patients had
emphysema, 6 had slight interstitial changes on CT images, and the remaining 17 had no underlying lung disease. The level of emphysema was classified
1
into three groups according to the modified Goddard’s criteria (severe: 3 patients, Changes in the irradiated lung following
FS
moderate: 8 patients, mild: 6 patients).
R O
O
SBRT were evaluated by CT.
Results: On CT images, RP was detected in thirty-four (85%) patients, and not Of the
P
in six (15%) patients, during a median observation period of 313 days.
Patients with severe emphysema had less risk of RP than those with
T
disease.
E
D
six patients, three had severe emphysema and three had no underlying lung
E
C
moderate emphysema (P = 0.01), mild emphysema (P = 0.04), and no
R
underlying lung disease (P = 0.01).
U
N
SBRT.
C O
R
Conclusions: Patients with severe emphysema had a low risk of RP following
Advances in knowledge: Little is known about the association between radiation
B
JR
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
pneumonitis and pulmonary emphysema. Patients with severe emphysema had less risk of radiation pneumonitis than those with no underlying lung disease. Keywords; stereotactic body radiotherapy, emphysema, adverse events
2
Introduction
FS
In addition to smoking, lung cancer has various causes, including emphysema and chronic obstructive pulmonary disease (COPD), which are
B
Stereotactic body
R O
lung diseases have a high possibility of having cancer [1].
O
common with underlying lung diseases [1, 2]. Thus, patients with underlying
P
radiotherapy (SBRT) for stage I non–small cell lung cancer (NSCLC) has an excellent overall survival rate and local control; therefore, SBRT is widely
D
considered a cure with less treatment-related toxicities [3].
Accordingly, an
T
E
increasing number of patients with co-morbidities, especially underlying lung
C
diseases, are undergoing SBRT.
E
Radiation pneumonitis (RP) is the most severe adverse event of SBRT.
R
Some potential predictors for the risk factors of RP are reported [4]; however,
R
little is known about the association between RP and underlying lung diseases,
C O
such as pulmonary emphysema. Thus, we evaluated the relation between RP
N
and pulmonary emphysema following SBRT in stage I NSCLC patients.
U
Methods Patients
JR
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
Ethical committee in this hospital approved this study. Between
February 2010 and February 2013, 40 consecutive patients with stage I NSCLC underwent SBRT, with a total dose of 75 Gy given in 30 fractions at Tokyo Medical University.
Patients’ characteristics are shown in Table 1.
The 3
median age was 79 years (range, 49-90). The male to female patient ratio was
months after surgery for the first NSCLC.
FS
24:16. Sixteen (40%) patients had metachronous NSCLC a median of 56 Twenty-six (65%) patients had a
O
history of smoking. There were 20 T1 and 20 T2 tumors. Twenty tumors were
For the
R O
located in the upper lobe, 4 in the middle lobe, and 16 in the lower lobe.
P
underlying lung diseases, 17 patients had emphysema, 6 had interstitial changes in the back side of the lung on CT, and the remaining 17 had no Interstitial changes consisted of a variety of lung
D
underlying lung disease.
E
conditions, including chronic inflammation from old tuberculosis or aspiration
C
T
pneumonia. Emphysema was assessed by the modified Goddard’s criteria [5].
E
Emphysema was classified into 5 scores according to the three slices of CT In both lungs on each
R
images taken of the apex, base, and middle of the lungs.
R
of the three slices of CT images, no underlying lung disease scored 0, up to 25%
C O
scored 1, up to 50% scored 2, up to 75% scored 3, and almost total involvement of the lung tissue scored 4 [6]. Thus, a maximum score of 24 (six times four) and
N
a minimum score of 0 (six times 0) were possible. The scores from the 17
U
patients with emphysema were classified into three groups according to severity: severe (>16, ≤24), moderate (>8, ≤16) and mild (≥0, ≤8).
There were three
B
JR
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
severe cases of emphysema, eight moderate cases, and six mild.
Radiotherapy methods An Immobilization device that compressed the abdomen to restrict the 4
respiratory movement was used. Then, the tumor respiratory motions were
FS
observed to be within the limit of 1.0 cm using an x-ray simulator for this treatment. The clinical target volume (CTV) was defined as the gross tumor
B
The planning target
R O
system (Xio ver. 4.6, Elekta AB, Stockholm, Sweden).
O
volume plus 0.7 cm in all directions on the lung image of the treatment planning
direction and 0.5 cm in all other directions.
SBRT was performed using 5 non-coplanar
E
In the three-dimensional conformal radiotherapy (3-D CRT) plan,
T
directions.
The left and right lungs were
D
delineated as organs at risk.
P
volume (PTV) was then defined as the CTV plus 1.5 cm in the cranio-caudal
In the
C
the PTV was coincident with the shape from the beam.
E
intensity-modulated radiation therapy (IMRT) plan, the intensity modulation was In the
R
generated by a compensated filter according to the IMRT planning.
R
3D-CRT plan, 100% doses were prescribed to the isocenter; while in the IMRT
C O
plan, the 95% dose line was set to cover the entire PTV. were both 75 Gy in 30 fractions.
N
Prescribed doses
Eight and 32 patients underwent radiotherapy
using 3D-CRT and IMRT, respectively.
The median V20 value was 9.1% (range,
U
0.6-16.3).
JR
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
Follow-up and statistical analysis RP after SBRT was assessed according to common terminology
criteria for adverse events (CTCAE, ver.4.0).
The diagnosis of Grade 1 RP was
made only when radiographic findings showed asymptomatic conditions not 5
interfering with activity of daily living.
Physical, laboratory, chest x-ray, and
FS
chest CT examinations were performed every three months for the first year and every six months thereafter. When the tumor recurred or RP appeared, the Factors associated
O
follow-up schedule was modified depending on the patient.
R O
with RP were evaluated with the chi-squire test and Fisher’s exact test for
A
P
categorical variables, and Wilcoxon’s rank sum test for continuous variables.
probability value (P-value) less than 0.05 was considered statistically significant.
D
The time to RP development was calculated from the beginning of SBRT.
T
E
Kaplan-Meier’s methods and log-rank tests were also used to evaluate the
E
C
incidence of RP using STATA ver.12 (Stata Co., Texas, USA).
R
Results
R
During the median observation period of 313 days, thirty-four (85%)
C O
patients experienced Grade 1 RP according to the CTCAE. from Grade 2 or more RP.
No patient suffered
The median time to RP development was 89 days.
N
Six (15%) patients did not experience RP; of these patients, three had severe
U
emphysema and three had no underlying lung disease (Fig. 1). The incidence of RP in patients with severe emphysema was statistically significantly lower
B
JR
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
compared with patients with no underlying lung disease (P = 0.008) by Fisher’s exact test. When examining the underlying lung conditions affecting RP, patients with interstitial changes suffered from RP earlier than those with no underlying 6
lung disease (P = 0.020) or emphysema (P = 0.017) (Figure 3).
B
Further
FS
analysis showed that patients with severe emphysema had less risk of RP than those with moderate (P = 0.010) and mild emphysema (P = 0.040) (Figure 4).
R O
lower or middle lobe than in the upper lobe (P = 0.041) (Figure 5).
O
In addition, RP developed earlier for patients who underwent radiotherapy in the
The patient’s smoking history (presence vs. absence, P = 0.73), (≥1000 vs.
Patients with severe emphysema have a low risk of radiation pneumonitis
R O
O
FS
following stereotactic body radiotherapy
Moeko Ishijima MD, Hidetsugu Nakayama MD PhD, Tomohiro Itonaga MD, Yu
P
Tajima MD, Sachica Shiraishi MD, Mitsuru Okubo MD PhD, Ryuji Mikami MD
T
E
D
PhD, Koichi Tokuuye MD PhD.
E
C
Department of Radiology, Tokyo Medical University Hospital, Zip code 160-0023,
C O
R
R
6-7-1 Nishi-shinjyuku,Shinjyuku, Tokyo, Japan
Running title: Patients with severe emphysema have low risk of radiation
U
N
pneumonitis
B
JR
Corresponding author: Hidetsugu Nakayama M.D., Ph.D. Departments of Radiology, Tokyo Medical University Hospital, 6-7-1 Nishi-shinjyuku,Shinjyuku, Tokyo,
0
160-0023, Japan Tel: +81-03-3342-6111 Fax: +81-03-3348-6314
R O
O
FS
E-mail: [email protected]
Partial of this articles presented in Radiological Society of North America 2013
B
JR
U
N
C O
R
R
E
C
T
E
D
P
Annual Meeting held at Chicago.
1
Manuscript
Patients with severe emphysema have a low risk of radiation pneumonitis
B
R O
O
FS
following stereotactic body radiotherapy
Running title: Patients with severe emphysema have low risk of radiation
E
D
P
pneumonitis
T
Abstract
E
C
Objectives: To evaluate the risk of radiation pneumonitis (RP) after stereotactic
R
radiotherapy (SBRT) for patients presenting with severe pulmonary emphysema.
C O
R
Methods: This study included 40 patients with stage I non–small cell lung cancer (NSCLC) who underwent SBRT, 75 Gy given in 30 fractions, at Tokyo
U
N
Medical University between February 2010 and February 2013. The median age of patients was 79 years (range, 49-90), and the male/female ratio was
JR
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
24/16.
There were 20 T1 and 20 T2 tumors.
Seventeen patients had
emphysema, 6 had slight interstitial changes on CT images, and the remaining 17 had no underlying lung disease. The level of emphysema was classified
1
into three groups according to the modified Goddard’s criteria (severe: 3 patients, Changes in the irradiated lung following
FS
moderate: 8 patients, mild: 6 patients).
R O
O
SBRT were evaluated by CT.
Results: On CT images, RP was detected in thirty-four (85%) patients, and not Of the
P
in six (15%) patients, during a median observation period of 313 days.
Patients with severe emphysema had less risk of RP than those with
T
disease.
E
D
six patients, three had severe emphysema and three had no underlying lung
E
C
moderate emphysema (P = 0.01), mild emphysema (P = 0.04), and no
R
underlying lung disease (P = 0.01).
U
N
SBRT.
C O
R
Conclusions: Patients with severe emphysema had a low risk of RP following
Advances in knowledge: Little is known about the association between radiation
B
JR
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
pneumonitis and pulmonary emphysema. Patients with severe emphysema had less risk of radiation pneumonitis than those with no underlying lung disease. Keywords; stereotactic body radiotherapy, emphysema, adverse events
2
Introduction
FS
In addition to smoking, lung cancer has various causes, including emphysema and chronic obstructive pulmonary disease (COPD), which are
B
Stereotactic body
R O
lung diseases have a high possibility of having cancer [1].
O
common with underlying lung diseases [1, 2]. Thus, patients with underlying
P
radiotherapy (SBRT) for stage I non–small cell lung cancer (NSCLC) has an excellent overall survival rate and local control; therefore, SBRT is widely
D
considered a cure with less treatment-related toxicities [3].
Accordingly, an
T
E
increasing number of patients with co-morbidities, especially underlying lung
C
diseases, are undergoing SBRT.
E
Radiation pneumonitis (RP) is the most severe adverse event of SBRT.
R
Some potential predictors for the risk factors of RP are reported [4]; however,
R
little is known about the association between RP and underlying lung diseases,
C O
such as pulmonary emphysema. Thus, we evaluated the relation between RP
N
and pulmonary emphysema following SBRT in stage I NSCLC patients.
U
Methods Patients
JR
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
Ethical committee in this hospital approved this study. Between
February 2010 and February 2013, 40 consecutive patients with stage I NSCLC underwent SBRT, with a total dose of 75 Gy given in 30 fractions at Tokyo Medical University.
Patients’ characteristics are shown in Table 1.
The 3
median age was 79 years (range, 49-90). The male to female patient ratio was
months after surgery for the first NSCLC.
FS
24:16. Sixteen (40%) patients had metachronous NSCLC a median of 56 Twenty-six (65%) patients had a
O
history of smoking. There were 20 T1 and 20 T2 tumors. Twenty tumors were
For the
R O
located in the upper lobe, 4 in the middle lobe, and 16 in the lower lobe.
P
underlying lung diseases, 17 patients had emphysema, 6 had interstitial changes in the back side of the lung on CT, and the remaining 17 had no Interstitial changes consisted of a variety of lung
D
underlying lung disease.
E
conditions, including chronic inflammation from old tuberculosis or aspiration
C
T
pneumonia. Emphysema was assessed by the modified Goddard’s criteria [5].
E
Emphysema was classified into 5 scores according to the three slices of CT In both lungs on each
R
images taken of the apex, base, and middle of the lungs.
R
of the three slices of CT images, no underlying lung disease scored 0, up to 25%
C O
scored 1, up to 50% scored 2, up to 75% scored 3, and almost total involvement of the lung tissue scored 4 [6]. Thus, a maximum score of 24 (six times four) and
N
a minimum score of 0 (six times 0) were possible. The scores from the 17
U
patients with emphysema were classified into three groups according to severity: severe (>16, ≤24), moderate (>8, ≤16) and mild (≥0, ≤8).
There were three
B
JR
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
severe cases of emphysema, eight moderate cases, and six mild.
Radiotherapy methods An Immobilization device that compressed the abdomen to restrict the 4
respiratory movement was used. Then, the tumor respiratory motions were
FS
observed to be within the limit of 1.0 cm using an x-ray simulator for this treatment. The clinical target volume (CTV) was defined as the gross tumor
B
The planning target
R O
system (Xio ver. 4.6, Elekta AB, Stockholm, Sweden).
O
volume plus 0.7 cm in all directions on the lung image of the treatment planning
direction and 0.5 cm in all other directions.
SBRT was performed using 5 non-coplanar
E
In the three-dimensional conformal radiotherapy (3-D CRT) plan,
T
directions.
The left and right lungs were
D
delineated as organs at risk.
P
volume (PTV) was then defined as the CTV plus 1.5 cm in the cranio-caudal
In the
C
the PTV was coincident with the shape from the beam.
E
intensity-modulated radiation therapy (IMRT) plan, the intensity modulation was In the
R
generated by a compensated filter according to the IMRT planning.
R
3D-CRT plan, 100% doses were prescribed to the isocenter; while in the IMRT
C O
plan, the 95% dose line was set to cover the entire PTV. were both 75 Gy in 30 fractions.
N
Prescribed doses
Eight and 32 patients underwent radiotherapy
using 3D-CRT and IMRT, respectively.
The median V20 value was 9.1% (range,
U
0.6-16.3).
JR
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
Follow-up and statistical analysis RP after SBRT was assessed according to common terminology
criteria for adverse events (CTCAE, ver.4.0).
The diagnosis of Grade 1 RP was
made only when radiographic findings showed asymptomatic conditions not 5
interfering with activity of daily living.
Physical, laboratory, chest x-ray, and
FS
chest CT examinations were performed every three months for the first year and every six months thereafter. When the tumor recurred or RP appeared, the Factors associated
O
follow-up schedule was modified depending on the patient.
R O
with RP were evaluated with the chi-squire test and Fisher’s exact test for
A
P
categorical variables, and Wilcoxon’s rank sum test for continuous variables.
probability value (P-value) less than 0.05 was considered statistically significant.
D
The time to RP development was calculated from the beginning of SBRT.
T
E
Kaplan-Meier’s methods and log-rank tests were also used to evaluate the
E
C
incidence of RP using STATA ver.12 (Stata Co., Texas, USA).
R
Results
R
During the median observation period of 313 days, thirty-four (85%)
C O
patients experienced Grade 1 RP according to the CTCAE. from Grade 2 or more RP.
No patient suffered
The median time to RP development was 89 days.
N
Six (15%) patients did not experience RP; of these patients, three had severe
U
emphysema and three had no underlying lung disease (Fig. 1). The incidence of RP in patients with severe emphysema was statistically significantly lower
B
JR
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
compared with patients with no underlying lung disease (P = 0.008) by Fisher’s exact test. When examining the underlying lung conditions affecting RP, patients with interstitial changes suffered from RP earlier than those with no underlying 6
lung disease (P = 0.020) or emphysema (P = 0.017) (Figure 3).
B
Further
FS
analysis showed that patients with severe emphysema had less risk of RP than those with moderate (P = 0.010) and mild emphysema (P = 0.040) (Figure 4).
R O
lower or middle lobe than in the upper lobe (P = 0.041) (Figure 5).
O
In addition, RP developed earlier for patients who underwent radiotherapy in the
The patient’s smoking history (presence vs. absence, P = 0.73), (≥1000 vs.
