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14-Nov APLCC: SBRT for small target, IMRT for large target in treating lung cancer
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From SBRT (for small target)
to IMRT (for large target):
Experience @ SMC
Yong Chan Ahn, MD/PhD Dept. of Radiation Oncology
SMC/SKKU SOM
Fundamental Goals of RT
• To deliver high dose to tumor
• To safely limit dose to normal tissues
Stereotatic Body RT (SBRT)
Stereotatic Ablative RT (SABR)
SBRT
• Highly conformal and accurate radiation delivery
– Conformal high dose
– Compact intermediate dose
– Very large low dose volume
– High fractional dose (10~20 Gy * ≤4 fractions)
– Within short period of time (within 1 week)
– Patient-specific Tx planning
Rationale of SBRT in Stage I NSCLC
• RT is better than doing nothing.
• (+) dose-response relationship has been
confirmed with respect to local control.
• The smaller the tumor, the higher the local
control and survival by RT.
• Incidence of lymphatic metastasis is known to be
very low.
• Shorter RT duration is better than protracted RT
schedule in survival.
Conventional RT SBRT
Dose/fraction 1.8~3.0 Gy 10~20 Gy
Fraction number 10~30 fractions 1~5 fractions
Target delineation GTV, CTV, (ITV),
PTV
GTV, CTV, ITV, PTV
(GTV CTV)
Margins cm range mm range
Need for mechanical
accuracy Low to medium Very high
Need for respiratory
motion control Low to medium High
Radiobiology Moderately well
understood
Still poorly
understood
Interaction with
systemic therapy Currently active Will become active
KOSTRO, 2008
Respiratory Training System
• Let patient breathe along the same respiratory
signal using goggle monitor during CT
simulation and each treatment sessions.
Respiratory Pattern Analysis
• Guided-breathing was
more stable and regular
than free breathing.
• Respiratory training
system was effective in
improving temporal
regularity and
maintaining a more even
tidal volume.
Good candidate
Poor candidate
Pinnacle®
Heterogeneity correction
Respiratory training for imaging & SBRT
4D CT; CTV-ITV (1.2+ cm margin around GTC-ITV)
CBCT for target localization
1. Simulation CT as reference 2. Cone-beam CT taken before each SBRT
3. Fusion of reference CT & CBCT 4. Matching of reference CT & CBCT
Pre-SBRT 6 months
18 months
Toxicities of SBRT
• Acute:
– Fatigue, anorexia, nausea
– Pulmonary
– Skin
• Late:
– Pulmonary
– Chest wall
• Unknown:
– Heart, large vessel, etc
SBRT
• SBRT can lead to very high local tumor
control and ablative damage of surrounding
normal structures “Stereotactic Ablative
Radiation Therapy (SABR)”
• SBRT should be wisely and reasonably limited
only to patients with relatively small, discrete,
and isolated tumor.
SBRT
• High local control rate (> 85-97%)
• SBRT is mainly for small peripheral tumors!
J Clin Oncol 24:4833-4839
83% vs 54% at 2 years
Staging W/U for NSCLC at SMC
• Standard: Chest CT, PFT, Broncho, PET-CT
• Optional: Brain MR (if AD)
Medically operable vs Medically inoperable
Early, vs Advanced –M1 or wet T4
Locally advanced
Resectable
Potentially resectable
Unresectable
Mediastinoscopy &/or EBUS
for all potentially resectable
candidate
Tx Guideline for NSCLC at SMC
T
T1 T2 T3 T4
N
N0 IA-IIB
Op ± RT/CTx/CRT
Definitive RT alone
IIIB
(except wet T4)
Definitive
CCRT or RT
alone
N1 IIIA (T3N1)
N2
IIIA
Preop. CCRT + Op + RT
Definitive CCRT or RT alone
N3
SBRT 15 Gy*4 Fx’s
Small and periph
3 Gy/Fx: Any size central
Large and periph
SBRT 15 Gy*4 Fx’s
Small and periph
3 Gy*20 Fx’s Any size
Close to Eso
4 Gy*15 Fx’s Large and periph Any size, central Remote from Eso
Medically Inoperable cT1-3N0 OS Local control
Untreated Median 9 Mos --
Conv Fx RT:
- 60~66 Gy by 2 Gy/Fx
Av med ~18 Mos
Av: 30~45%
Medically Inoperable cT1-3N0 OS Local control
Untreated Median 9 Mos --
Conv Fx RT:
- 60~66 Gy by 2 Gy/Fx
Av med ~18 Mos
Av: 30~45%
PMH (’11, IJROBP):
- 48~60 Gy by 4 Gy/Fx
51.0% @ 2-Yrs
76.2% @ 2-Yrs
Medically Inoperable cT1-3N0 OS Local control
Untreated Median 9 Mos --
Conv Fx RT:
- 60~66 Gy by 2 Gy/Fx
Av med ~18 Mos
Av: 30~45%
PMH (’11, IJROBP):
- 48~60 Gy by 4 Gy/Fx
51.0% @ 2-Yrs
76.2% @ 2-Yrs
SMC (’13, JTO):
- 54~60 Gy by 3 Gy/Fx
59.6% @ 2-Yrs
57.9% @ 2-Yrs
SMC (’14, APLCC):
- 60 Gy by 3 Gy/Fx
- 60 Gy by 4 Gy/Fx
56.4% @ 2-Yrs
89.2% @ 2-Yrs
59.9% @ 2-Yrs
67.7% @ 2-Yrs
SBRT Indications at SMC
• cT1-2,N0
• Single or oligo-metastasis
• ≤ 5 cm in size (preferably ≤ 3 cm)
• Location (peripheral > central, upper > lower)
SBRT Experience @ SMC
JTO, 2010
Characteristics # Pt (%)
Age Median 69 (39~88) years
Sex Male 98 (84.5%)
Female 18 (15.5%)
Tumor nature Primary 38 (32.8%)
Metastatic 78 (67.2%)
Lung 32 (41.0 %)
GI Track 24 (30.8 %)
Head & Neck 9 (11.5 %)
Others 13 (16.7 %)
Patients’ Characteristics I (116 Patients: ’01/Feb~’10/Nov)
JTO, 2010
Characteristics # Pt (%)
Tumor size ≤ 2.0 cm 58 (50.0%)
> 2.0 cm 58 (50.0%)
RT dose 50 Gy/5 Fx’s (’01/Jun~’02/May) 8 ( 6.9%)
60 Gy/5 Fx’s (’02/June~’09/Dec) 72 (62.1%)
60 Gy/4 Fx’s (’10/Jan~’10/Dec) 36 (31.0%)
Patients’ Characteristics II (116 Patients: ’01/Feb~’10/Nov)
JTO, 2010
Response # Pt (%)
CR 24 (20.2 %)
PR 74 (62.2 %)
SD 17 (14.3 %)
PD 1 ( 0.8 %)
Initial Radiologic Response
JTO, 2010
Prognosticators on Local Control Characteristics Crude LC p
Tumor nature Primary (38) 92.1%
1.0 Metastatic (78) 91.0%
Pathology
Squamous (41) 90.2%
1.0 Adenoca (34) 91.2%
Others (41) 92.7%
Tumor size ≤ 2.0 cm (58) 100%
0.001 > 2.0 cm (58) 82.8%
RT dose
50 Gy/5 Fx’s (8) 75.0%
0.019 60 Gy/5 Fx’s (72) 88.9%
60 Gy/4 Fx’s (36) 100% JTO, 2010
Survival
Months
Pro
bab
ilit
y
p = 0.036
66.4%
53.8%
JTO, 2010
Grade # Pt (%)
Grade 0 80 (69.0 %)
Grade 1 30 (25.9 %)
Grade 2 4 ( 3.4 %)
Grade 3 2 ( 1.7 %)
Symptomatic Radiation Pneumonitis
JTO, 2010
JTO, 2010
Summary
• SBRT to lung cancer at SMC:
– High local control (90%)
– Favorable 5 year survival (primary/metastatic –
66.4%/53.8%)
– Very low risk of complication (Grade 2/3 –
3.4%/1.7%)
– Highly effective and curative modality to patients
who are unfit for surgery.
JTO, 2010
Acta Oncologica, 2012
SBRT for Lung Metastasis
• SBRT to 57 patients, 67 metastatic lesions
• Sep. 2001~Nov. 2010
• Lung toxicity:
– Grade 2 in 4 patients (6.0%)
– Grade 5 in 1
Acta Oncologica, 2012
Acta Oncologica, 2012
Response at 1 month:
- CR in 17 (25%)
- PR in 40 (60%)
- SD in 10 (15%)
Local progression in 3 (5%)
94.5% at 3 years
Acta Oncologica, 2012
Follow-up by ct and PET-CT alternatingly
Acta Oncologica, 2012
59.7% 56.2%
at 2 years at 5 years
Acta Oncologica, 2012
Presence of extrathoracic disease was
the only significant factor (p=0.049)
on multivariate analysis.
64.0% vs 38.9%
at 3 years
66.1% vs 0%
at 3 years 71.1% vs 51.1%
at 3 years
Acta Oncologica, 2012
Acta Oncologica, 2012
Conclusion
• Tumor size, disease-free interval, and presence
of extrathoracic disease are prognosticators for
survival.
• SBRT for single or oligo-metastasis seems
quite effective and safe.
Acta Oncologica, 2012
Intensity Modulated RT (IMRT)
Comparison focused on RT techniques in
CCRT for N3(+) IIIB NSCLC
• Definitive CCRT is the standard.
• Delivery of high radiation dose is often limited by
lung toxicity risk.
• Heterogeneous extent of primary tumor and
regional LN involvement.
• Difficult to safely cover the whole disease extent
using 3D-CRT technique.
N3(+) Stage IIIB NSCLC
Example Case: Sq, cT2N3
• IMRT can Improve target coverage, while
sparing normal tissues within safe levels.
• IMRT in treating NSCLC patients is still
uncovered by Korean National Health
Insurance plan.
• IMRT has to be recommended for those who
were at excessive toxicity risk if treated by 3D-
CRT, based on disease extent.
IMRT
• To evaluate clinical outcomes following
definitive CCRT for N3(+) NSCLC with
special regard to RT techniques (IMRT vs 3D-
CRT).
Purpose
• 81 N3(+) NSCLC patients received definitive
CCRT (2010.5 - 2012.11)
– Two underwent surgery following CCRT
– Two received combined 3D-CRT and IMRT
– 77 patients were retrospectively reviewed
Patients
• RT technique selection was individualized based
on disease extent and estimated toxicity risks.
• IMRT was primarily offered if DVH parameters
were unfavorable (if treated by 3D-CRT) :
– V20>40%
– MLD>25 Gy
– Spinal cord Dmax>50 Gy
Selection of RT Technique
• RT:
• Median 66 Gy in 33 fractions
• 3D-CRT in 48 (62.3%): 3-4 portal, 4-10 MV
• IMRT in 29 (37.7%): median 6 portals, 6 MV
• Normal tissue constraints:
• Spinal cord: DMax<46 Gy
• Lung: V20<35%, V5<65%, Mean<20 Gy
Treatment Detail
• Chemotherapy:
• Wkly docetaxel/paclitaxel + cis-/carboplatin
in 67 (87.0%)
• 3-weekly pemetrexed/etoposide + cisplatin in
10 (13.0%)
Treatment Detail
Characteristics 3D-CRT (48) IMRT (29) p
Median age 62 (44-72) years 59 (40-80) years 0.7441
Gender Male
Female
35 (72.9%)
13 (27.1%)
18 (62.1%)
11 (37.9%) 0.3904
Smoking Yes
No
34 (70.8%)
14 (29.2%)
17 (58.6%)
12 (41.4%) 0.2722
ECOG PS 0
1
10 (20.8%)
38 (79.2%)
6 (20.7%)
23 (79.3%) 0.9880
Median FEV1 2.49 (1.17-3.90) L 2.50 (1.46-3.71) L 0.7909
Histology
Adeno
Sq cell ca
Others
31 (64.6%)
15 (31.2%)
2 (4.2%)
22 (75.9%)
3 (10.3%)
4 (13.8%)
0.0533
Characteristics 3D-CRT (48) IMRT (29) p
Median tumor size 3.8 (1.3-12.2) cm 3.7 (1.0-9.2) cm 0.7852
cT-stage cT1-2
cT3-4
34 (70.8%)
14 (29.2%)
23 (79.3%)
6 (20.7%) 0.4111
Primary Upper/Middle
Lower lobe
39 (81.3%)
9 (18.7%)
13 (44.8%)
16 (55.2%) 0.0009
N3
Contralat
SCN
Both
29 (60.4%)
26 (54.2%)
7 (14.6%)
7 (24.1%)
24 (82.8%)
2 (6.9%)
0.0020
0.0108
--
Variables 3D-CRT (48) IMRT (29) p
CTV:
Median (cm3)
<300 cm3
≥300 cm3
279.3 (89.4-1543.3)
28 (59.3%)
20 (41.7%)
357.5 (89.3-762.7)
10 (34.5%)
19 (65.5%)
0.7064
0.0425
Lung:
Mean dose (Gy)
V5 (%)
V10 (%)
V15 (%)
V20 (%)
18.4 (9.3-28.0)
57.2 (29.8-72.9)
48.6 (24.5-63.5)
40.6 (18.1-54.5)
32.8 (14.3-50.0)
19.6 (14.6-25.2)
65.1 (48.4-90.0)
51.8 (41.8-62.9)
42.3 (34.7-53.6)
35.6 (28.2-45.9)
0.0306
0.0002
0.1072
0.0519
0.0612
Esophagus:
Max dose (Gy)
Mean dose (Gy)
V30 (%)
V45 (%)
67.1 (55.3-74.7)
33.2 (12.5-55.8)
52.1 (15.2-87.7)
44.2 (3.7-74.9)
68.4 (60.0-77.3)
35.1 (16.1-52.0)
55.9 (15.8-79.6)
48.8 (1.2-76.5)
0.0071
0.1114
0.5196
0.5255
Heart Dmean (Gy) 8.6 (0.5-42.4) 16.4 (1.5-35.0) 0.0013
Spinal cord Dmax (Gy) 43.9 (10.5-57.4) 43.1 (32.3-48.4) 0.7075
3D-CRT (48) IMRT (29) Total (77) p
Esophagitis
Grade ≤2
Grade 3
41 (85.4%)
7 (14.6%)
21 (72.4%)
8 (27.6%)
62 (80.5%)
15 (19.5%)
0.1627
Pneumonitis
Grade 1
Grade ≥2
32 (66.7%)
16 (33.3%)
22 (75.9%)
7 (24.1%)
54 (70.1%)
23 (29.9%)
0.3930
Disease progression 24 (50.0%) 21 (72.4%) 45 (58.4%) 0.0531
Time to progression
Median (months)
Range
9.1
(3.9-35.0)
6.0
(2.5-15.9)
8.2
(2.5-35.0)
-
Patterns of failure
Locoregional
Distant
Both
4 (8.3%)
17 (35.4%)
3 (6.3%)
2 (6.9%)
15 (51.7%)
4 (13.8%)
6 (7.8%)
32 (41.6%)
7 (9.1%)
-
• Median F/U: 21.7 months (2.3 – 43.1 months)
Median PFS = 11.1 months
• IMRT technique has enabled to encompass larger
disease extent at high and homogenous radiation dose
volume, which could not have been achieved by 3D-
CRT technique.
• Toxicity profiles (esophagitis, pneumonitis) were not
increased even though with IMRT group had more
unfavorable DVH parameters than 3D-CRT group.
Summary
• Early appearance of distant metastases was most
important factor in PFS, which could be explained by
high proportion of adenocarcinoma histology and
corresponding large disease extent in current study.
• OS might have been improved probably by effective
systemic treatment following progression (including
targeting agents).
Summary
• Frequent and early appearance of distant
metastasis, associated with adenocarcinoma
histology, would require modification of systemic Tx
in concurrent &/or salvage phases.
• Development for RT technique selection guideline
would be required considering expensiveness of
IMRT under Korean NHI setting.
Future Directions
Proton Therapy Center
Samsung Medical Center
Example Case: Sq, cT2N3
Dose (Gy)
No
rmal
ized
vo
lum
e (%
)
Dose-volume Histogram (DVH)
0
10
20
30
40
50
60
70
80
90
100
0 10 20 30 40 50 60 70 80
Proton PTV
Proton Spinal Cord
Proton Both Lungs
IMRT PTV
IMRT Spinal Cord
IMRT Both Lungs
3DCRT PTV
3DCRT Spinal Cord
3DCRT Both Lungs
Tomo PTV
Tomo Spinal Cord
Tomo Both Lungs
Normal Tissue DVH
Lowest lung dose by IMPT
Excessive cord dose by 3D-CRT
No
rmal
ized
vo
lum
e (%
)
CTV DVH
IMPT
Tomo IMRT
3D-CRT
• Dosimetric study clearly showed that more focal dose
distribution at lower toxicity risk could be achieved
by IMPT than IMRT and 3D-CRT.
• Again, development for RT technique selection
guideline would be required considering cost-
effectiveness.
Future Directions
Different tools for same purpose!
Same tool for different purposes!
Fundamental Goals of RT
• To deliver high dose to tumor
• To safely limit dose to normal tissues
Lung Cancer Center @ SMC