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

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

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 = 180Gy12Gy x 5 = 132Gy12Gy x 4 = 106Gy16Gy x 3 = 125Gy18Gy x 3 = 151Gy

XRT BED

60 Gy/30 fr = 72 Gy

70 Gy/35 fr = 84 Gy

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

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, 20142. Amgad El-Sherif,Outcomes of Sublobar Resection Versus Lobectomyfor Stage I Non–Small Cell Lung Cancer: A 13-YearAnalysis, Ann Thorac Surg 2006; 82:408 –163.Okada M et al. Radical sublobar resection for small-sized NSCLC: a multicenter study. J Thorac Cardiovasc Surg 2006;132:769-754. Watanabe A et al. Feasibility of VATS segmentectomy for selected peripheral lung carcinomas. Eur J Cardiothorac Surg 2009;35:775-80

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%.

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

Radiation therapy - ARSENAL

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

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

Challenge #1: Target Definition

Treatment Planning PET-CT scansPET/CT fusion

ImmobilizationWITH BLUEBAG BODYFIX

Challenge #2: Target MotionSolution: Respiratory Gating

- 4DCT ; MIP- Multislice CT & dynamic scans- Abdominal compression- evaluation of the targetposition during maximum inspiration and expiration.

4DCT with bellows

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

• 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

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

Beam placements

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

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

14 Institutions ; Japan , 1993 - 2003

3yr OS 69% when BED > 100 Gy

3yr OS 81% when BED > 100 Gy ( for operable pts.)

Vrije university, Amsterdam676 Patients, (stage 1 & 2 ) single institution , all pet staged• DOSE= 60GY/ 3 – 8 # ( risk adapted )• Median f/u = 33 months

• 124 ( 18% ) RECURRENCES82 (66%) -distant42(34%) – locoregional

• LR( 10%), LRR( 12.7%) DR (20%)• Median survival: 41 months

5 year CSS > 60%5yrs LC – 90%

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%

The evidence for SBRT: Lung cancer

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 %

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

• 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.

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.

1. GTV < 13 cc2. 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 mm32. 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

Cancer, 2010

Median age = 79 years80% 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).

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 )

Sashendra Senthi , Suresh Senan

2014

2009

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

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

Prospective studies: SBRT for Operable pts

*Nagata, ASTRO 2012, **Timmerman, ASCO 2013

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

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.

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.

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

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

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

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

- 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 ).

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????

Thank you

The world is moving ahead BUT are we ready ???

Recurrence Patterns After SBRT

Senthi S et al. Lancet Oncol 2012; 13: 802–09

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 groupsASTRO 2013, Int J of Rad Onc Bio Phy Vol. 87 (2), S10