emerging role of SBRT in lung cancer and challenges it poses to surgery

1. Stereotactic Body Radiation Vs Surgery Therapy
for Early stage NSCLC
DR RUCHIR BHANDARI
Dept of Radiation Oncology
B.R.A.I.R.C.H, AIIMS
MODERATOR
Dr KP Haresh

2. SBRT definition
Stereotactic body radiation therapy (SBRT) is a novel
treatment modality in radiation oncology that delivers a very
high dose of radiation to the tumor target with high
precision using single or a small number of fractions
(typically 5 or less)
Critical Reviews in Oncology/ Hematology (2012)
Regardless of the treatment delivery unit used, one feature
in common is the image-guided therapy capability that
enables verification of the location of the tumor or
target volume before treatment delivery

3. Stereotactic Body Radiotherapy
• High ablative dose
– SRS= single Fx SBRT= 2-5 Fx
– BED important? (>100)
• Short time (1-5 treatments)
• Tight targets and rapid dose fall-off
– Damages everything in high dose area
– Overwhelms repair/repopulation mechanisms
– It is Critical to limit toxicity
– Need target tracking or gating system
20Gy x 3 = 180Gy
12Gy x 5 = 132Gy
12Gy x 4 = 106Gy
16Gy x 3 = 125Gy
18Gy x 3 = 151Gy
XRT BED
60 Gy/30 fr = 72 Gy
70 Gy/35 fr = 84 Gy

4. The Radiobiology of SBRT
The 4 R’s of Radiobiology do not apply to SRS & SBRT.
 Interphase death , caused by vascular damage,
 Negligible repopulation
 tumours with low a/b  greatest benefit
 SBRT could be eliminating stem cells (in the perivascular
niche)  Superior local control

5. Several recent studies have
demonstrated comparable recurrence
and survival rates for lobectomy and
sublobar resection, even in good-risk
patients with stage I lung cancer
1. Christopher Cao et al.Meta-analysis of intentional sublobar resections
versus lobectomy for early stage non-small cell lung cancer : CORE group
STUDY, Ann cardiothoracic surgery, 2014
2. Amgad El-Sherif,Outcomes of Sublobar Resection Versus Lobectomy
for Stage I Non–Small Cell Lung Cancer: A 13-Year
Analysis, Ann Thorac Surg 2006; 82:408 –16
3.Okada M et al. Radical sublobar resection for small-sized NSCLC: a
multicenter study. J Thorac Cardiovasc Surg 2006;132:769-75
4. Watanabe A et al. Feasibility of VATS segmentectomy for selected
peripheral lung carcinomas. Eur J Cardiothorac Surg 2009;35:775-80

6. SBRT can accomplish more than conventional
XRT…
Historical control
 SBRT 54 Gy in 3 #, 98% (local), (RTOG 0236)
 EBRT 60-66 Gy / 30-33 #, ~50% (Qiao, Lung Cancer 2003)
Beaumont experience (Lanni, Am J Clin Oncol 2011)
 3y LC, 88% vs. 66% (p=0.10) in favor of SBRT
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)
The poor outcome achievable with Conventional Radiotherapy is
reflected in the SEER study, showing a poor global CSS @ 5-yr --> 15%.

7. Conventional Radiation vs. SBRT
Conventional Radiotherapy SBRT
Entire course of Rx in 1-2 wks; 20-60 min/treatment, 1-5 Rxs; no sedation
or anesthesia, outpatient Rx; immediate return to activities

8. Radiation therapy - ARSENAL

9.  Medically inoperable – PFT ( FEV1 or DLCO < 40%),
DM/CAD, cerebral disease, Pul. HTN
 Patient choice to avoid surgery
 PS 0-2
 Stage T1-2, N0 following PET-CT
 Max tumour size < 5cm
 Not adjacent to major vessels, heart, esophagus etc
 Able to lie flat for at least one hour
Patient selection criteria for SBRT in early stage
NSCLC

10. The work flow
 SBRT selected as a preferred treatment by a
multidisciplinary team
Lung SBRT protocol at PMH, JTO, 2008
Pre-SBRT work up
Simulation (+/- 4DCT )
Tumor & OAR contouring
Plan analysis & acceptance
Trial setup & off line CBCT
Treatment delivery & review
Follow up & data collection

11. Challenge #1: Target Definition
Treatment Planning PET-CT scansPET/CT fusion

12. Immobilization
WITH BLUEBAG BODYFIX

13. Challenge #2: Target Motion
Solution: Respiratory Gating
- 4DCT ; MIP
- Multislice CT & dynamic scans
- Abdominal compression
- evaluation of the target
position during maximum
inspiration and expiration.
4DCT with
bellows

14. OR ROUTINE CT WITH
ACTIVE BREATHING CONTROL (ABC)
• Temporarily immobilizes patient’s breathing
• The inspiration and expiration paths of airflow are closed at a
predetermined flow direction

15. • MIP images for Target
volume contouring
• GTV= CTV=ITV (MIP)
• Contouring on lung
windows
• Image fusion to
confidently identify
target margin
• PTV= ITV+ 3-5 mm
• GTV= Gross tumor volume, CTV= Clinical
target volume, PTV= planning target
volume
Contouring

16. Stephans et al. l SBRT for Central Lung Tumors l 10/4/11 l 16
Beam placements

17. Compact intermediate dose
This accounts for toxicity.
All of this dose is in normal tissues
Very large low dose volume
A little dose to a lot of normal tissue is
better than a lot of dose to a little normal
tissue

18. Stereotactic Radiation for Stage I NSCLC
• Lung SBRT is gaining a track record of efficacy, now
reaching the intermediate term, in more robust
patients.
– Long term Japanese, IU and VUmc data
– Multi-institutional RTOG 0236 , JCOG 0406
– Many single institutional series
– Japanese, VUmc data for operable patients
– Need larger, cooperative databases
- started at the Swedish Karolinska University hospital in 1991 with tumors in the liver
and lungs . Simultaneously in Japan and clinically introduced in 1994 for lung tumors.
- During the last 5 years of the 1990s, SBRT started in Europe and the US

19. 14 Institutions ; Japan , 1993 - 2003
3yr OS 69% when BED > 100 Gy
3yr OS 81% when BED > 100 Gy ( for
operable pts.)

20. Vrije university, Amsterdam
676 Patients, (stage 1 & 2 ) single
institution , all pet staged
• DOSE= 60GY/ 3 – 8 # ( risk adapted )
• Median f/u = 33 months
• 124 ( 18% ) RECURRENCES
82 (66%) -distant
42(34%) – locoregional
• LR( 10%), LRR( 12.7%) DR (20%)
• Median survival: 41 months
5 year CSS > 60%
5yrs LC – 90%

21. Multicenter Phase II Trials Medically Inoperable
• Dutch Investigators
- 206 patients with Stage I
- Risk adapted approach well tolerated
- Primary tumor recurrence 3%, regional failure 9%, 2 year OS 64%
• JCOG 0403
- Peripheral T1a, N0, M0, inoperable
- 100 patients ,15 centres
- 3yr OS (60%), 3yr LRFS(53%)
- S/E = Gr4(1%), Gr3 (9% Dyspnoea)
• Nordic Study Group
- peripheral T1-T2, N0, M0
- completed accrual of 57 patients in 2005
- Primary tumor recurrence 7%, 2 year OS 65%

22. The evidence for SBRT: Lung
cancer

24.  55 evaluable patients, 34 month median follow-up.
 Only 1 local failure (3-year LC 98%)
 3 same-lobe failures (3-year lobar control 90 %)
 2 nodal failures (3-year loco-regional control 87 %)
 11 distant failures (3-year distant failure rate 22 %)
Timmerman R, et al. JAMA 303:1070-1076, 2010
DFS @ 3yr – 48 %
OS @ 3yr – 56 %

26. 2nd edition, Michael W. Mulholland and Gerard M. Dohert

27. • SBRT has become a standard of care for medically inoperable
patients
 No randomized trial deemed necessary
 Up to 10,000 patients treated per year in US
• Successful clinical model using hypofractionated radiotherapy:
 Rigorously conducted, highly scrutinized
 Multicenter QA
 Rapid and widespread acceptance
A recent survey in the USA reported that 64% of RO are currently practicing
SBRT  lung (89.3%), liver (54.5%) ,spine (67.5%).
Pan H, Simpson DR et al. A survey of stereotactic body radiotherapy use in the United States. Cancer 2011;117(19):4566e4572.

28. CAUTION
• 6 possibly treatment related deaths
- 4 bacterial pneumonia
- 1 pericardial effusion
- 1 hemoptysis*
(ascribed to carinal recurrence)
Using risk-adapted treatment schedules
(60 Gy / 7.5 Gy #), excellent control rates also
in central tumours with comparable toxicity
profiles. *
* Haasbeek CJ et al J Thorac Oncol 2011;6:2036–43.21.
* Milano MT et al Radiother Oncol 2009;91:301–6.

29. 1. GTV < 13 cc
2. Stage 1A
* Radiation pneumonitis-
1. total lung V5 of >37% and c/L lung V5 > 26%
2. higher V40 -- > faster RP
3. MLD
** Chest wall toxicity-
1. Chest wall dosimetry : V30 < 30 mm3
V60 < 3 mm3
2. Tumors > 1 - 2 cm from the chest wall
and 5 cm from the posterior skin -- > low risk
PREDICTORS FOR TOXICITY
GOOD PROGNOSTIC FACTORS
- Umberto Ricardi et al , LUNG CANCER 2014
*Dutch study
*Michael strauder, Green journal 2012
** Kevin I Stephans, Red Journal 2012

30. Cancer, 2010
Median age = 79 years
80% medically inoperable, and 20% refused surgery.
Severe COPD in 25% of patients.
Risk-adapted SRT schemes were used.
The actuarial LC @ 3 years  89%.
Acute toxicity was uncommon, and late Gr 3 toxicity seen in <10% of
patients.
20 Gy x 3 # ( T1 tumors )
12 Gy x 5 # ( T1 tumors with broad
contact with chest wall ; T2 tumors)
7.5 Gy x 8 # ( tumors adjacent to heart,
large vessels, hilus, brachial plx,
mediastinum).

31. 16 % absolute increased use of SABR in aged >75years from 26% (1999–
2001) to 42% (2005–2007) resulting in significant increase in OS rate ( 16
m 21 m )

32. Sashendra Senthi , Suresh Senan
2014

33. 2009
LC (5 yrs)  92% ( IA) 73% ( IB)
Pulmonary complications > Gr 2 seen in 1 patient (1.1%)

34. Retrospective data: SBRT for Operable pts?
* Onishi, Int J Radiat Oncol Biol Phys 2011; 81: 1352-58; ** Lagerwaard, Int J Radiat Oncol Biol Phys 2012; 83: 348-353;
Study *Japan data (87 pts) **Netherlands (177 pts)
Age 74 yrs 76 yrs
T1, T2 65, 22 pts (2.5 cm) 106, 71 pts (2.6 cm)
RT dose 42-72.5 Gy in 3-10 # 60 Gy in 3-8 #
Median FU 55 months 31.5 mo
5 yr OS 69.5% 51.3% (median: 61.5 mo)
5 yr LC (T1, T2) 92%, 73% 93% @ 3 yrs
Grade 3 RP 1.1% 2%
30 day mortality 0% 0%
PET scan for staging, LN staging limited, Biopsy done in only 33%, Prognostic factors:
female

35. Prospective studies: SBRT for Operable pts
*Nagata, ASTRO 2012, **Timmerman, ASCO 2013

36. 2013
45 reports ( 2006 - 2012) containing 3771 patients, stage 1 NSCLC
SABR  2yr LC 91% , OS 70% ( 95% CI : 67-72)
Surgery  68% (95% CI: 66–70)
No survival or local PFS difference with different radiotherapy technologies used for
SABR.
 patients with early stage NSCLC treated with SBRT had similar DFS, CSS, LC and
DC as patients treated with surgery but worse 3-year OS ( ?? Better patient profile)
 Phase 3 randomised direct comparison  highly recommended

37. Frank J. Lagerwaard, Neil K. Aaronson, Chad M. Gundy, Cornelis J.A. Haasbeek, Ben J. Slotman and Suresh
Senan
 SABR is a highly effective treatment for stage I NSCLC, with limited toxicity.
 In contrast to surgery, SABR does not lead to significant worsening of QOL in the
first year after treatment
2012
 Quality of life was maintained, and emotional functioning improved significantly
after SBRT for stage I NSCLC, while
 survival was acceptable, local tumor control was high, and toxicity was low.
2010Noelle C Van der Voort et al.

38. 2014
“ In conclusion, probably surgery has a potential rival in early
stage NSCLC, and in the future SABR might be more usedin one
patients’ subgroup “
At the same time, quality assurance procedures and
standardisation of stereotactic treatments ( dose prescription,
delivery techniques ) are warranted.

39. Cost-Effectiveness of SBRT vs. Surgery
Mean cost (USA) Mean cost (INDIA)
SBRT (MO) $42,094 2 – 2.5 lacs
SBRT (CO) $40,107 2 – 2.5 lacs
Wedge resection $51,487 3 – 3.5 Lacs
Lobectomy $49,093 3 – 3.5 Lacs
Shah, Cancer 2013: 119: 3123-32
 Clearly operable SBRT is most effective
 Lobectomy is more cost effective than wedge resection

40. Future Directions
 Randomized comparison of Surgery vs SABR for
operable patients ( stage 1)
ROSEL STUDY (Vumc & Dutch study group)
- lobectomy Vs SBRT
ACOSOG Z4099/RTOG 1021
- Wedge vs SABR
*STARS Trial  Lobectomy vs SABR
*MAYO Trial  sublobar Sx Vs SABR
*ACCURAY Trial

41. Relapse Patterns from all RT series
Study Local Nodal Distant
CALGB 39904 8% 5% 18% (T2: 30%)
Grills 8% -- 26%
VU 4% 9% 23% @ 2 yrs
Japan 3% 8% 20%
RTOG 0236 3% 5% 22% @ 3 yrs (T2: 47%)
 Can adjuvant systemic therapy improve outcomes for
early stage inoperable patients?
CALGB/RTOG – SABR +/- chemo for 2-5cm T1 tumors

42. Senan C et al. Lancet Oncol 2013; 14: e270–74

43. - Palma; JCO November 2010
Time Trend Analysis: Use of SBRT vs. Observation
vs. Surgery
• 875 pts , Stage I NSCLC: SBRT introduction was associated with 16% increase
in the use of RT and increase in OS (16 Vs 21 mo, HR= 0.70 ).

44. Conclusions
• Multidisciplinary management the Gold-standard Rx approach
• Stage I: Extent of surgery and surgical expertise matters
– Good pulmonary function: Lobectomy is standard of care
• SBRT is a competitive and less morbid option than limited resection for an
Elderly, Borderline operable who can only tolerate limited lung resection
(particularly wedge) or in medically inoperable cases
• At present SBRT not a rival to Surgery….it gives chance of cure for more
localized lung cancers who were otherwise ignored
• But BEWARE about FUTURE…
• SBRT going to be a challenge to Surgery in fit operable patients
• Randomized trails are needed…But will the Surgeons allow us to do
this????

45. Thank you
The world is moving ahead BUT are we ready ???

46. Recurrence Patterns After SBRT
Senthi S et al. Lancet Oncol 2012; 13: 802–09

47. A Matched Pair Analysis of Stage I Non-Small Cell Lung Cancer
Treated With Lobectomy, Stereotactic Radiation Therapy
(SBRT), or Wedge Resection
• 286 pts: L (89), W (69), or SBRT (128): 39 pts in each of 3 well-matched groups. 90
day mortality “0” in all groups
ASTRO 2013, Int J of Rad Onc Bio Phy Vol. 87 (2), S10