Seminar at Samsung Changwaon Hospital to celebrate opening of Radiation Oncology Department.

1. 폐암의 방사선치료
RT for NSCLC
Yong Chan Ahn, MD, PhD
Dept. of Radiation Oncology
Samsung Medical Center
Sungkyunkwan University School of Medicine

2. 21,577 Consultations (1994~2006)
Hepatobi l i ary
5.9%
Lymphoma &
Leuk emi a
6.8%
H&N
11.4%
Esophagus
1.8%
Stomach
4.5%
Lung
18.2%
Breast
13.6%
Cervi x &
uterus
8.2%
Col orectal
13.6%
Others
9.1%
Prostate
1.4%
Brai n
5.5%

3. Staging System
• AJCC 7th edition since January 2010
• Anatomical extent of disease is expressed by
TNM classification:
– Prediction of prognosis
– Therapeutic decision
• 1/6 patients will be classified in to a different
stage category

4. Primary Tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ
T1
T1a
T1b
Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of
invasion more proximal than the lobar bronchus (i.e., not in the main bronchus)*
Tumor ≤2 cm in greatest dimension
Tumor >2 cm but ≤3 cm in greatest dimension
T2
T2a
T2b
Tumor >3 cm but ≤7 cm or tumor with any of the following features (T2 tumors with these features are
classified T2a if ≤5 cm)
Involves main bronchus, ≥2 cm distal to the carina
Invades visceral pleura (PL1 or PL2)
Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve
the entire lung
Tumor >3 cm but ≤5 cm in greatest dimension
Tumor >5 cm but ≤7 cm in greatest dimension
T3 Tumor >7 cm or one that directly invades any of the following: parietal pleural (PL3) chest wall (including
superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium; or tumor in the
main bronchus (<2 cm distal to the carina* but without involvement of the carina; or associated atelectasis or
obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe
T4 Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent
laryngeal nerve, esophagus, vertebral body, carina, separate tumor nodule(s) in a different ipsilateral lobe
* The uncommon superficial spreading tumor of any size with its invasive component limited to the bronchial
wall, which may extend proximally to the main bronchus, is also classified as T1a.

7. Regional Lymph Nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar
lymph nodes and intrapulmonary nodes, including involvement
by direct extension
N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph
node(s)
N3 Metastasis in contralateral mediastinal, contralateral hilar,
ipsilateral or contralateral scalene, or supraclavicular lymph
node(s)

9. Distant Metastasis (M)
M0 No distant metastasis (no pathologic M0; use clinical M to
complete stage group)
M1
M1a
M1b
Distant metastasis
Separate tumor nodule(s) in a contralateral lobe; tumor with
pleural nodules or malignant pleural (or pericardial) effusion*
Distant metastasis
* Most pleural (and pericardial) effusions with lung cancer are
due to tumor. In a few patients, however, multiple
cytopathologic examinations of pleural (pericardial) fluid are
negative for tumor, and the fluid is non-bloody and is not an
exudate. Where these elements and clinical judgment dictate
that the effusion is not related to the tumor, the effusion should
be excluded as a staging element and the patient should be
classified as M0.

11. AJCC Stage Group (7th edition)
T1a/b T2a T2b T3 T4
N0 IA IB IIA IIB IIIA
N1 IIA IIA IIB IIIA IIIA
N2 IIIA IIIA IIIA IIIB
N3 IIIB IIIB IIIB IIIB

12. Multi-modality Tx

13. Treatment Modalities for Cancer
• Loco-regional:
– Surgery
– Radiation therapy
• Systemic:
– Chemotherapy
– Immunotherapy

14. Radiation and Surgery
Rationale
Radiation usually fails in tumor center, and
rarely doses at periphery
Surgery usually fails at periphery because of
microscopic tumor cells left behind
Sequence of radiation and surgery
Preoperative radiation
Postoperative radiation
Intraoperative radiation

15. Limited Surgery and Radiation
Using surgery as boost technique
Full courses of radiation combined with
tumorectomy
Surgery can be done before or after the
irradiation
Examples
Breast – lumpectomy + definitive radiation
H/N cancer – definitive radiochemotherapy +
adjuvant neck dissection

16. Radiation and Chemotherapy
Purpose is not to decrease radiation dose
to gain the same effect, but rather to
increase therapeutic index
3 strategies:
Drugs directly modifying radiation survival
curve (synergy, sensitizer, potentiator)
Drugs specifically affecting tumor response
to radiation (hypoxic sensitizers)
Drugs with independent action or additivity

17. Theoretic Rationales of CMT
 Spatial cooperation
 Toxicity independence
 Reduction of toxicity
 Enhanced tumor response
 Prevention of emergence of resistant clones

18. Treatment Selection Factors
 Treatment-related factors
 Tumor-related factors
 Patient-related factors
 Physician-related factors
지피지기 (知彼知己)
백전백승 (百戰百勝)
Knowing oneself and one's opponent,
invincibility!

19. Tx Principle

20. 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

21. 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

22. Stage I/II
• Whenever possible, surgery is recommended
first.
• After surgery, CTx and/or RT may be
recommended to decrease recurrence risk.
• RT alone is recommended if surgery is not
feasible due to severe lung disease or other
underlying medical problems.
• A few individualized RT techniques and dose
schedules are used.

23. Stage III
• There is no one “best” treatment for stage III
NSCLC.
– Choice of Tx modality depends upon several factors
including size and location of tumor, N stage, and
physiologic status of patient.
• Whenever possible, combination of RT and CTx
(CCRT) is recommended first.
• Either RT or CTx alone is considered if
aggressive CCRT is not feasible.

24. Radiation Therapy:
From Basic to Up-to-date

26. How radiation kills cancer?
 Ionization --> Damage to DNA or membrane
--> Mutation, Cell death
 metabolically active for the time-being
 die out at time of cell division due to aberrant
reproduction
 takes time before cancer cells disappear

27. DNA Damage & Chromosome Aberration

28. DNA Damage & Chromosome Aberration

29. Direct vs Indirect Actions
Incident X-ray
(photon)
Fast electron (e-)
(10-15 sec)
Ion radical
(10-10 sec)
Free radical
(10-5 sec)
Chemical changes
(hours~years)
Biological effects

30. Discrepancy in Clinical and
Pathologic Responses

32. Patient-specific Radiation Therapy
• Individualized
• Customized
• Adaptive

33. Preparation for Radiation Therapy
• Acquisition of CT (MR, PET-CT)
• Contouring:
– Targets (GTV, CTV, ITV)
– Organs at risk
• Determination of beam arrangement, intensity
to achieve the most optimal plan among rival
plans
• Quality assurance

34. Image Guided RT
• RT procedure using image guidance at various
stages of its process (patient data acquisition,
treatment planning, treatment simulation,
patient setup, and target localization before
and during treatment)

35. To identify and correct problems
arising from inter- and intra-
fractional variations in patient setup
and anatomy

36. Image Guidance Technology
• Portal & radiographic imager (EPID)
• In-Room CT
• KV cone-beam CT
• MV cone-beam CT (Tomotherapy)

38. Stereotactic Body RT
• High ablative dose
• To small tumor (usually <3~4 cm)
• Within a few fractions
• Using multiple non-coplanar beams
• With adequate immobilization and motion
control

39. SBRT
• One of the state-of-the-art RT techniques
– 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

40. 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
Moderate High
Radiobiology
Moderately well
understood
Still poorly understood
Interaction with
systemic therapy
Currently active Will become active

41. Toxicities of SBRT
• Acute:
– Fatigue, anorexia, nausea
– Pulmonary
– Skin
• Late:
– Pulmonary
– Chest wall
• Unknown:
– Heart
– Large vessel
– Etc

44. SBRT Experience at SMC

45. 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.

46. Importance of tumor size Importance of RT duration

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

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

49. Respiratory Training
(Respiratory Signal Analysis Program)

50. Pre-SBRT
6 months
18 months

51. JTO, 2010

52. 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

53. 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

54. 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%
1.0Adenoca (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%
0.01960 Gy/5 Fx’s (72) 88.9%
60 Gy/4 Fx’s (36) 100%JTO, 2010

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

56. 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

57. 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

58. Acta Oncologica, 2012

59. 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

60. Acta Oncologica, 2012

61. 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

62. Acta Oncologica, 2012

63. 59.7% 56.2%
at 2 years at 5 years
Acta Oncologica, 2012

64. 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

65. Acta Oncologica, 2012

66. Conclusion
• SBRT for single or oligo-metastasis seems
quite effective and safe.
• Tumor size, disease-free interval, and presence
of extrathoracic disease are prognosticators for
survival.
Acta Oncologica, 2012

68. Management of N2 Disease

69. Introduction
• Remarkable improvements in diagnosis of N2
disease -- CT, FDG PET-CT, mediastinoscopy,
VATS, and EBUS
• A few different ways of classifying N2 disease --
clinical vs surgical, minimal vs bulky etc…
• N2 disease is a very important prognostic
factor in NSCLC.
• There is no single answer that defines the best
treatment option for N2(+) NSCLC.

70. Trimodality for N2 Disease @ SMC
• TRT
– 45 Gy/25 Fx’s (’97~Sep ’09)
– 44 Gy/22 Fx’s (Oct ’09~)
• CTx
– EP #2 q 4 weeks (’97~Apr ’01)
– Weekly DP #5 (Mar ’01~)
• Surgery in 3-4 weeks
• Optional postop TRT (18~20 Gy/2 weeks)
• Optional CTx (usually sequential)

72. Acta Oncol, 2001

73. Acta Oncol, 2001
43.2%
51.8%
25.6%
37.2%
49.1%
35.5%

74. Summary (Acta Oncol, 2001)
• Preoperative CCRT resulted in fair pathologic
response, down-staging (68.2%), less radical
surgery, and 2-year OS with tolerable
morbidity.
• Surgery added to CCRT did not affect OS, but
altered failure pattern only.
Acta Oncol, 2001

78. Preop CCRT
(N=410)
Patients (June ’97~Aug ’11)
Surgical resection
(N=396)
Postop TRT (+)
(N=228)
Postop TRT (-)
(N=144)
Incomplete Tx,
progression, refusal (14)
Periop deaths (19)
Systemic progression (5)
Presented at ACOS, KOSRO, ASTRO meetings in 2012

79. Patients’ Characteristics (N=396)
Age Median 59 (18-76) years
Gender Male
Female
310 (78.3%)
86 (21.7%)
Histology Adenoca
Squamous cell ca
Large cell ca
Non-small cell ca, NOS
213 (53.8%)
157 (39.6%)
11 (2.8%)
15 (3.8%)
cT stage cT1
cT2
cT3
99 (25.0%)
239 (60.4%)
62 (15.6%)
Tumor size Mean 33 (9-128) mm
cN2 status (CT and/or PET-CT) Bulky
Minimal
276 (69.7%)
120 (30.3%)
Pathologic confirmation of N2 No
Yes
41 (10.4%)
355 (89.6%)
Number of (+) nodal station Single
Multiple
250 (63.1%)
146 (36.9%)

80. Preop Tx
TRT 45 Gy in 25 Fx’s (1997’ ~ Oct 2009’)
44 Gy in 22 Fx’s (Sep 2009’ ~ )
293 (74.0%)
103 (26.0%)
CTx EP q 3 weeks (1997’ ~ Jul 2001’)
Weekly DP (Jul 2001’ ~ )
48 (12.1%)
348 (87.9%)
Surgery
Sublobar resection
(Bi-)Lobectomy
Pneumonectomy
2 ( 0.5%)
335 (84.6%)
59 (14.9%)
Postop Tx
TRT No or incomplete
Yes (18-20 Gy in 10 Fx’s)
177 (44.7%)
219 (55.3%)
CTx No
Yes
301 (76.0%)
95 (24.0%)
Treatment Characteristics (N=396)

81. Factors No. of Pts
ypT stage* 0
1
2
3
4
65 (16.4%)
161 (40.7%)
126 (31.8%)
38 ( 9.6%)
6 ( 1.5%)
ypN stage* 0
1
2
3
164 (41.4%)
53 (13.4%)
177 (44.7%)
2 ( 0.5%)
ypM stage* 0
1a
394 (99.5%)
2 ( 0.5%)
TNM stage* 0
I
II
III
IV
55 (13.9%)
97 (24.5%)
57 (14.4%)
185 (46.7%)
2 ( 0.5%)
Factors No. of Pts
Tumor size Mean 24 (0-110) mm
Pleural
invasion
PL0
PL1
PL2
PL3
319 (80.6%)
10 ( 2.5%)
44 (11.1%)
23 ( 5.8%)
Resection
margin
Positive
Close (1-5 mm)
Negative
20 ( 5.1%)
24 ( 6.1%)
352 (88.8%)
No. of positive
N2 station
None
Single
Multiple
217 (54.8%)
102 (25.8%)
77 (19.4%)
N0. (+) LN Mean 2.4 (0-26)
Downstaging Yes
No
211 (53.3%)
185 (46.7%)
Pathologic Findings (N=396)
* AJCC 7Th ed.

82. Median 3-year 5-year
OS 46 (35-58) mo 56.9% 44.2%
PFS 21 (16-26) mo 37.5% 33.3%
LRC Not reached 76.2% 71.6%
DMFS 28 (21-34) mo 42.1% 37.7%
Survival Outcomes (N=396)
 Median F/U = 33 (4-156) months

83. Prognostic Factors – Multivariate analysis
P value
Factors LRC PFS OS
Age < 60 vs. ≥ 60 years 0.174 0.389 0.002
Gender Female vs. Male 1.000 0.578 0.291
Histology Adenoca vs. non-Adenoca 0.629 0.009 0.662
cT stage cT1-2 vs. cT3 0.847 0.847 0.481
Chemo regimen EP q 3 weeks vs. weekly DP 0.243 0.092 0.009
Op. type Lobectomy vs. Pneumonectomy 0.070 0.001 0.004
ypT stage ypT0-2 vs. ypT3-4 0.284 0.182 0.064
ypN stage ypN0 vs. ypN1-3 0.001 <0.001 <0.001
Resection margin Negative vs. Close/positive 0.294 0.380 0.811
Postop TRT No/incomplete vs. Yes 0.163 0.198 0.003
Postop chemo No vs. Yes 0.291 0.600 0.050

84. Summary
Excellent clinical outcomes (Median survival =
46 months; 5-year OS = 44.2%) with trimodality
therapy.
Pathologic nodal down-staging was the most
important prognostic factor.
SWOG 8805 RTOG 0229 INT 0139 SMC
Median 13 months 26.6 months 23.6 months 46 months
OS 27% (3-Yr) 54% (2-Yr) 27% (5-Yr) 44.2% (5-Yr)

85. Conclusions
• There definitely is positive role of surgical resection
following preoperative CCRT in cN2 disease.
• Benefit of surgery is summarized as improved loco-
regional control at no excess morbidity.
• Without loco-regional control,
real cure cannot be expected,
and surgery remains essential
under multi-disciplinary spirit.

86. Team Approach!

87. Multidisciplinary
approach

88. Multidisciplinary
approach

90. 2007 헬스조선
2008 중앙일보