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