14-Nov APLCC: SBRT for small target, IMRT for large target in treating lung cancer

1. From SBRT (for small target)
to IMRT (for large target):
Experience @ SMC
Yong Chan Ahn, MD/PhD
Dept. of Radiation Oncology
SMC/SKKU SOM

2. Fundamental Goals of RT
•To deliver high dose to tumor
•To safely limit dose to normal tissues

3. Stereotatic Body RT (SBRT)
Stereotatic Ablative RT (SABR)

4. 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

5. 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.

6. 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

7. KOSTRO, 2008

8. Respiratory Training System
•Let patient breathe along the same respiratory signal using goggle monitor during CT simulation and each treatment sessions.

9. 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

10. Pinnacle®
Heterogeneity correction
Respiratory training for imaging & SBRT
4D CT; CTV-ITV (1.2+ cm margin around GTC-ITV)
CBCT for target localization

11. 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

12. Pre-SBRT
6 months
18 months

13. Toxicities of SBRT
•Acute:
–Fatigue, anorexia, nausea
–Pulmonary
–Skin
•Late:
–Pulmonary
–Chest wall
•Unknown:
–Heart, large vessel, etc

14. 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.

15. 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

16. 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

17. 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

18. SBRT 15 Gy*4 Fx’s Small and periph
3 Gy/Fx: Any size central Large and periph

19. 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

20. 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%

21. 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

22. 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

23. SBRT Indications at SMC
•cT1-2,N0
•Single or oligo-metastasis
•≤ 5 cm in size (preferably ≤ 3 cm)
•Location (peripheral > central, upper > lower)

25. SBRT Experience @ SMC

26. JTO, 2010

27. 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

28. 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

29. Response
# Pt (%)
CR
24 (20.2 %)
PR
74 (62.2 %)
SD
17 (14.3 %)
PD
1 ( 0.8 %)
Initial Radiologic Response
JTO, 2010

30. 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

31. Survival
Months
Probability
p = 0.036
66.4%
53.8%
JTO, 2010

32. 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

33. JTO, 2010

34. 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

35. Acta Oncologica, 2012

36. 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

37. Acta Oncologica, 2012

38. 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

39. Acta Oncologica, 2012

40. 59.7% 56.2% at 2 years at 5 years
Acta Oncologica, 2012

41. 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

42. Acta Oncologica, 2012

43. 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

44. Intensity Modulated RT (IMRT)
Comparison focused on RT techniques in CCRT for N3(+) IIIB NSCLC

45. •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

46. Example Case: Sq, cT2N3

48. •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

49. •To evaluate clinical outcomes following definitive CCRT for N3(+) NSCLC with special regard to RT techniques (IMRT vs 3D- CRT).
Purpose

50. •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

51. •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

52. •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

53. •Chemotherapy:
•Wkly docetaxel/paclitaxel + cis-/carboplatin in 67 (87.0%)
•3-weekly pemetrexed/etoposide + cisplatin in 10 (13.0%)
Treatment Detail

54. 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

55. 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
--

56. 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

57. 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)

58. Median PFS = 11.1 months

61. •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

62. •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

63. •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

64. Proton Therapy Center Samsung Medical Center

65. Example Case: Sq, cT2N3

67. Dose (Gy)
Normalized volume (%)
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

68. Normal Tissue DVH
Lowest lung dose by IMPT
Excessive cord dose by 3D-CRT

69. Normalized volume (%)
CTV DVH

70. IMPT
Tomo
IMRT
3D-CRT

71. •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

72. Different tools for same purpose!

73. Same tool for different purposes!

74. Fundamental Goals of RT
•To deliver high dose to tumor
•To safely limit dose to normal tissues

76. Lung Cancer Center @ SMC