1. Stereotactic Body Radiation Therapy
for Non-small Cell Lung Cancer
John H. Suh
Professor and Chairman, Dept. of Radiation Oncology
Taussig Cancer Institute
Rose Ella Burkhardt Brain Tumor and Neuro-oncology Center

2. Conflicts of interest
• Abbott Oncology Consultant
• Varian Travel stipend

3. Outline
• Define lung stereotactic body radiation therapy
• Review the historic outcomes with radiation therapy for
early stage lung cancer
• Discuss the advantages of lung SBRT compared to
surgery
• Highlight ongoing and completed prospective studies
• Review the toxicities associated with lung SBRT

4. Sample case of lung SBRT
• 77 year old female with left
upper lobe lung
adenocarcinoma, T1aN0M0,
stage IA; medically inoperable
due to impaired PFTs
• Representative axial CT
image at simulation
• Representative axial CT
image one year post SRS

5. What is lung SBRT?
• Form of high precision radiotherapy delivery (1-8 fx)
– Needs to account for tumor motion
– Needs to be accurate
– Needs to have reproducible setup prior to treatment
– Has good patient compliance
– Has good resource utilization
• Represents one of the significant advances in the
curative therapy of lung cancer
• Also known as SABR (stereotactic ablative body
radiotherapy)

6. Stereotactic Ablative Radiotherapy
for Lung Cancer
Treatment Planning Treatment Delivery
Assessment of tumor motion Large doses per fraction
Complex beam arrangement Monitoring of breathing
Advanced planning
Image-guided targeting
algorithms
Senan et al. 2012

7. SBRT can accomplish more than conventional XRT
• Local Control
Historic comparisons
– SBRT 54 Gy in 3 fx, 98% (local), 91% (lobe) (RTOG 0236)
– EBRT 60-66 Gy / 30-33 fx, ~50% (Qiao, Lung Cancer
2003)
Beaumont experience (Lanni, Am J Clin Oncol 2011)
– SBRT (48-60 Gy in 4-5 fx, n=45) vs. EBRT (70 Gy/ 35 fx,
n=41)
– 3y LC, 88% vs. 66% (p=0.10)
• Meta-analysis (Grutters, Radiother Oncol 2010)
SBRT (n=895) vs. EBRT (n=1326)
– 2-year OS, 70% vs. 53% (p=<0.001)
– 2-year DFS, 83.4% vs. 67.4% (p=0.006)

8. Stephans et al. l SBRT for Central Lung Tumors l 10/4/11 l 9

9. Stereotactic Radiation for Stage I NSCLC
• Lung SBRT is gaining a track record of efficacy,
now reaching the intermediate term, in more
robust patients.
– Japanese data with 10 year survivors
– Long term IU and VUmc data
– Multi-institutional RTOG 0236 data
– Many single institutional series
– Japanese, VUmc data for operable patients
– Need larger, cooperative databases
–Intermodality data, better matching

10. Peripheral Tumors
Peripheral Tumors
• Dealing primarily with “parallel” tissues, therefore there may be no
point dose limit (if really only parallel).
• Where does the dose-response curve plateau?
Wulf et al., Radiother Oncol. 2005

11. Medically Inoperable: Peripheral Tumors

12. • 55 evaluable patients, 34 month med follow-up.
• Only 1 local failure (3-year LC 97.6%)
• 3 same-lobe failures (3-year lobar control 90.6%)
• 2 nodal failures (3-year loco-regional control 87.2%)
• 11 distant failures (3-year distant failure rate 22.1%)
Timmerman R, et al. JAMA 303:1070-1076, 2010

13. Peripheral Tumors: The “Right” Dose
Wulf et al., Radiother Oncol. 2005
Wash U, Olsen et al.,
IJROBP 2011 CCF early retrospective data
(Stephans et al., JTO 2009)

14. Randomized Phase II Study Comparing Two SBRT Schedules
for Medically Inoperable Patients with Stage I Peripheral NSCLC
RTOG 0915
T1, T2 (< 5 cm) R
R 34 Gy/1 fraction
Clinically node A
A
negative by PET N
Stratify N
Peripherally D
located T stage D 48 Gy/ 4 fractions
Zubrod
Primary endpoint: rate of 1-year grade 3 or higher AE
Secondary endpoint: 1-year tumor control
1-year OS and DFS
PET SUV changes
PFT test

15. Central Tumors
3 year local control 92%
JTO, Dec 2011

16. Central Tumors
Central Tumors both parallel (target, normal lung), and
• Now dealing with
some serial tissue (trachea, bronchial tree, esophagus),
as well as imperfectly categorized heart/great vessels.
• Can we reach plateau without concerns of unreasonable
normal tissue toxicity? (yes)
Wulf et al., Radiother Oncol. 2005

17. Notes of Caution (Central Tumors)
• 6 possibly treatment related deaths
- 4 bacterial pneumonia
- 1 pericardial effusion
- 1 hemoptysis*
(ascribed to carinal recurrence)

18. Central Tumors – Treated Safely with SBRT
• Early Japanese data didn’t report significant toxicity.
– Used smaller fraction sizes (typically 10-12 Gy/fx)
– (Onishi et al., Onimaru et al, Uematsu et al., and Nagata et al).
– These studies did not use any particular avoidance criteria for
organs at risk.
• VUmc experience in 63 patients (37 central, 26
“cardiac”) also demonstrates excellent safety
profile.
– 60 Gy in 8 fractions
– Haasbeek et al. JTO 2011

21. Stage I NSCLC:
Spectrum of Health
Medically “High risk” Medically
Operable Operable Inoperable
Lobectomy SBRT

22. Potential Advantages of Surgical Resection
• Confirmation of cancer diagnosis
• Pathological staging
• Nodal dissection
• Information for adjuvant therapy
• Clear measures of outcome to allow salvage

23. Pathological Staging and Node Dissection
• ACOSOG study demonstrates no difference in OS
between nodal sampling and dissection for early stage
NSCLC (Darling et al. JTCVS)
– This is different than no sampling, but improved radiographic
staging and EBUS while not the same as surgical sampling
allow improved non-invasive sampling
(Okada 2005, Miller 2002, Meyers 2006, Crabtree 2010)
• Even if nodal upstaging is 10% with dissection (2-17%),
benefit of adjuvant chemo (provided the patient can
tolerate) is only 5%.
– ie. 10% * 5% = potential 0.5% OS benefit for population
discovering occult node + disease.

24. Lack of biopsy in some SBRT series
• Wash U data also suggests no
difference by radiographic v
pathological diagnosis
– Robinson, IJROBP 2012
• Two separate Netherlands
reports suggest same
(Laagerward et al, ASTRO
2011), and worse (Palma JCO
2010) outcome in non-biopsied
patients.
Stephans, CCF, JTO 2010

25. Caveats for comparisons of SBRT and Surgery
• Overall
– What medical “risk” patient population?
– Tumor stage / size?
– Type of staging?
• Surgery
– Lobar? Sublobar? Both?
– Open vs. VATS?
– Skill set of surgeon/institution?
• SBRT . . .rapidly learning. . .heterogeneity of data. . .
– Dose / fractionation?
– BED = Biologically Effective Dose
– < 100 Gy10 results in worse LC and OS!
– Dose / location relative to organs at risk?
– Central tumors, Chest wall, Lung

26. Comparisons of SBRT and Surgery
• Lowest level evidence
– Raw comparisons of surgery and SBRT (i.e., my
paper vs. your paper)
– Easily confounded by imbalances in patient, tumor,
and treatment factors.
– As it turns out, also confounded by practices for
coding failures.
– The individual data itself is great, but
comparisons are for now, nearly worthless, (it’s
a start).

27. Comparisons of SBRT and Surgery
• Reports of SBRT for “medically operable” pts?
– Retrospective
– Uematsu, et al (IJROBP 2001)
– Onishi, et al (JTO 2007; IJROBP 2010)
– Amsterdam (Senan et al, ASCO 2011)
– Prospective (final results pending)
– JCOG 0403
– Stage IA NSCLC. Phase II (n=65), 48 Gy /4 fx.
– RTOG 0618
– Stage I/II NSCLC. Phase II (n=33), 60 Gy/ 3 fx.

28. Comparisons of SBRT and Surgery
Uematsu, IJROBP 2001
– 50 pts w/T1 (n=24) or T2 (n=26) N0 NSCLC tx’d w/SBRT (10/94-06/99)
– 29 pts were medically operable but refused surgery
– Mix of SBRT doses, prior radiation, etc.
All 50 29 medically operable
3y LC 94%
CSS 88%
OS 66% 3y OS 86%

30. Comparisons of SBRT and Surgery
• Lagerwaard, IJROBP in-press
– 177 pts w/medically operable, T1 (n=60%) or T2 (n=40%) N0 NSCLC tx’d w/SBRT
from 2003-2010 in the Netherlands.
– SBRT delivered using “risk adapted” scheme (60 Gy in 3, 5, or 8 fractions)
– Median age 76
– Median F/U 32 mo
– 3-year LC 93%
– 3-year OS 84.7%, median OS 61.5 mo

31. Comparisons of SBRT and Surgery (source bias)
Study Clinical Stage/Group OS
Sugi (World J Surg 2000) IA; 52 open, 48 VATS 5y 85%/90%
LCSG (Ginsberg, Ann Thorac IA; 122 wedge, 125 lobe 5y ~60%/~70%
Surg 1995)
AJCC 6th IA/IB 5y 61% (T1), 38% (T2)
AJCC 7th IA/IB 5y 47-52% (T1), 36-43%
(T2)
Uematsu IA/IB (3y) 86%
Onishi IA/IB 5y 76 (T1)%, 64% (T2)
Amsterdam IA/IB (3y) 85%

32. Comparisons of SBRT and Surgery
Crabtree, JTCVS 2010

33. Crabtree et al., Wash Univ, JTCVS 2010

34. Crabtree et al., Wash Univ, JTCVS 2010
All were not significant

35. • Analysis of patients with Gold’s III/IV COPD, or predicted post-op FEV1 <40%
• 176 VUmc SBRT patients
• Meta-analysis identified 75 additional SBRT patients, and 121 surgical
patients from 4 studies meeting search and review criteria
Palma IJROBP, March 2012

36. Palma et al., VUmc, IJROBP 2012

37. Markov Modeling Comparisons
(Puri et al., JTCVS 2011, and Louie et al., IJROBP 2010)
• Attempt to model a comparison of SBRT and surgery
using available data
– Demonstrate Surgery to be cost effective…
– … However, outcome highly sensitive to surgical mortality rate
• When surgical mortality exceeds 4% model favors SBRT (Louie)
Low risk High risk (n=57)
Operative 2.7% 7%
Mortality
Any 38% 43.8%
complications
Arrhythmia 22.7% 21%
Respiratory 19.9% 27%
Crabtree et al, Wash Univ data

38. PET scan after lung SBRT
Henderson et al., IJROBP 2010 Mar 1;76(3)

39. RTOG 0618: Phase II trial of SBRT for patients with
operable Stage I/II NSCLC

40. Quality of Life Comparisons:
SBRT
Videtic et al., CCF Data van der Voort van Zyp, IJROBP 2010 (Netherlands)

41. Comparisons of SBRT and Surgery
• Highest level evidence
– Randomized trials
– None completed
– Two trials of SBRT vs. lobectomy for medically operable pts
– ROSEL
– Terminated early
– STARS
– Struggling
– Question asked too early. . .???
– One trial SBRT vs. sublobar resection for “high risk” operable pts
–ACOSOG Z4099/RTOG 1021

42. Comparisons of SBRT and Surgery – Toxicity?
SBRT Surgery
• Skin toxicity? • Death?
• Fatigue? • Post-op pain?
• Chest wall toxicity? • Infection?
• Pneumonitis? • Atrial fibrillation?
• Brachial plexopathy? • Extended hospital stay?
• Bleeding? • Decreased pulmonary
• Fistula or stenosis? function?
• Esophageal toxicity? • Post-thoracotomy pain?

43. Pulmonary Function
• Studies have been mixed on PFT changes
• IU Phase I protocol described transient decline followed by
return to baseline
- Timmerman et al., Chest 2003;124(5)
• IU Phase II protocol showed no change in FEV1 but DLCO ↓
1.11 mg/min/mm Hg/y
- Henderson et al., IJROBP 2008 Oct 1;72(2)
• RTOG 0236 showed 1 grade 4 (2%) and 8 grade 3 (15%)
pulmonary/upper respiratory events (included PFT
changes).
- Timmerman et al., JAMA 2010 March 17;303(11)

44. Toxicity - Pneumonitis
• Most studies report pneumonitis as 0-5%:
• 25 patients treated at U. Tokyo to 48 Gy in 4
fractions prescribed to isocenter.
- Grade 2-5 RP 29%, including 3 pt’s w grade 5
- RP correlated with high conformality index
- In general had high conformality, 7 pts > 2.00
Yamashita et al., Rad Oncol 2007;2:21

46. IJROBP 2012 82:2

47. TE CT CHANGES (≤ 6 months) LATE CT CHANCES (> 6 months)
Description Description
Consolidation > 5 cm in largest Consolidation, loss of volume,
Modified
Diffuse dimension. The involved region bronchiectasis similar to conventional
conventional
consolidation contains more consolidation than radiation fibrosis, but usually less
pattern
aerated lung. extensive. May be associated with GGO.
Well-circumscribed focal consolidation
Consolidation ≤ 5 cm in largest dimension
Patchy limited to area surrounding the tumor.
and/or the involved region contains more Mass-like
consolidation The abnormality must be larger than the
consolidation than aerated lung.
orginal tumor size
> 5 cm of GGO, (without consolidation). Linear opacity in the region of the
Diffuse GGO The involved region contains more Scar-like
tumor, associated with loss of volume
GGO than normal lung
No new abnormalities. Includes patients
≤ cm of GGO, (without consolidation), No evidence of with tumors that are stable, regressing or
Patchy GGO and/or the involved region contains increased resolved, or fibrosis in the position of the
less GGO than normal lung density original tumor that is not larger than the
original tumor
Senan et al. 2012

48. Importance of the multi-disciplinary team
• Radiation oncologist
• Radiologists
• Nuclear medicine physicians
• Pulmonologists
• Pathologists

49. Conclusions
• Lung SBRT is an effective, efficient, and
safe radiation technique for patients with
early stage NSCLC
• Peripheral lesions may be treated more
aggressively compared to centrally located
lesions
• Clinical trials are underway to better
understand the role of lung SBRT

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