Michael Brada Torino 6 March 2015 Perspectives in lung cancer Stereotactic ablative radiation...

Michael BradaTorino 6 March

2015

Perspectives in lung cancerStereotactic ablative radiation therapy (SABR)in patients with inoperable NSCLC

SABR in the context of modern radiotherapy of NSCLC

SABR in localised NSCLC

uncertaintieswhat is it

alternativesefficacy

SABR in the context of modern radiotherapy of NSCLC

SABR in localised NSCLC

uncertaintieswhat is it

alternativesefficacy

SABR in the context of modern radiotherapy of NSCLC

SABR in localised NSCLC

uncertaintieswhat is it

alternativesefficacy

SABR in the context of modern radiotherapy of NSCLC

SABR in localised NSCLC

Deconstructing SABR

High precision Conformal High dose Hypofractionated

High precision localised radiotherapy

SABR – what is it?

Deconstructing SABR

High precision Conformal High dose Hypofractionated

Technology

High precision localised radiotherapy

SABR – what is it?

Requirements of high precision

High precision localised radiotherapy for NSCLC

accurate definition of target accurate delivery

stagingtumour margineffect of motion

Accurate target localisation

define tumour extent

staging

tumour margineffect of motion

Accurate target localisation

define tumour extent

Requirements of high precision

High precision localised radiotherapy for NSCLC

accurate definition of target accurate delivery

Localised delivery of SABR

multiple non-coplanar fixed fieldsarcing IMRT (VMAT/RapidArc/Tomotherapy)robotic mounted linac (cyberknife)

High precision localised radiotherapy for NSCLC

% reported studies % patients

Meta-analysis of SABR for stage I NSCLC

Technology used for delivery of SABR

Linac

Cyberknife

Linac orCyberknife

TomotherapyBody GK

Linac

CyberknifeLinac orCyberknife

TomotherapyBody GK

76%86%

Solda, Lodge, Ashley, Whitington, Goldstraw & Brada 2013; Radiother Oncol, 109, 1-7

Linac – linear accelerator, GK – gamma knife, Cyberknife – robotic arm mounted small linac

2 year local control

Meta-analysis of SABR for stage I NSCLC – delivery technology

individual data summary

91% 88%

Lina

c

Cyb

erki

feSolda, Lodge, Ashley, Whitington, Goldstraw & Brada 2013; Radiother Oncol, 109, 1-7

Linac – linear accelerator, Cyberknife – robotic arm mounted small linac

2 year survival

Meta-analysis of SABR for stage I NSCLC – delivery technology

individual data summary

Solda, Lodge, Ashley, Whitington, Goldstraw & Brada 2013; Radiother Oncol, 109, 1-7

69%73%

Linac – linear accelerator, Cyberknife – robotic arm mounted small linac

Deconstructing SABR

High precision Conformal High dose Hypofractionated

Biology

SABR – what is it?

Phase I/II

Locally advancedNSCLC

increasing RT dose(related to normal lung DVH)

Improving lung cancer radiotherapy

Radical radiotherapy – dose escalation

Dose response in non-small cell lung cancer (NSCLC)

Summary of published phase I/II studies (1201 patients, 8 publications)

2 year local progression free survival (corrected for stage distribution)

40 60 80 100 1200

0.2

0.4

0.6

0.8

1

BED [Gy]

2 y

ea

r d

ise

ase

-fre

e s

urv

iva

lFenwick model(solid curve)

● conventional fractionation

corrected for dose fractionation/time and stage distribution

Partridge, Ramos, Sardaro & Brada 2011, Radioth Oncol 99, (1) 6-11

40 60 80 100 1200

0.2

0.4

0.6

0.8

1

BED [Gy]

2 y

ea

r d

ise

ase

-fre

e s

urv

iva

l

early stage disease

Fenwick model(solid curve)

localiseddisease

locally advanceddisease

Dose response in non-small cell lung cancer (NSCLC)

Summary of published phase I/II studies including SABR2 year local progression free survival

● conventional fractionation∆ hypofractionated SABR

Partridge, Ramos, Sardaro & Brada 2011, Radioth Oncol 99, (1) 6-11

Dose response in non-small cell lung cancer (NSCLC)

Summary of published phase I/II studies including SABR2 year local progression free survival (corrected for stage distribution)

40 60 80 100 1200

0.2

0.4

0.6

0.8

1

BED [Gy]

2 y

ea

r d

ise

ase

-fre

e s

urv

iva

lFenwick model(solid curve)

localiseddisease

locally advanceddisease

● conventional fractionation∆ hypofractionated SABR

Partridge, Ramos, Sardaro & Brada 2011, Radioth Oncol 99, (1) 6-11

Tumour size and disease control

Werner-Wasik et al 2008 Int. J. Radiation Oncology Biol Phys, 70, (2), 385–390

RTOG 93-11 Phase I/II dose escalation study in NSCLC

45cm3 ≈ 4.5 cm diameter sphere

time (months)

% p

rogr

essi

on fr

ee s

urvi

val

smaller tumours ≤45cm3

larger tumours >45cm3

Dose response in non-small cell lung cancer (NSCLC)

Summary of published phase I/II studies including SABR2 year local progression free survival (corrected for stage distribution)

40 60 80 100 1200

0.2

0.4

0.6

0.8

1

BED [Gy]

2 y

ea

r d

ise

ase

-fre

e s

urv

iva

lFenwick model(solid curve)

localiseddisease

locally advanceddisease

● conventional fractionation∆ hypofractionated SABR

Partridge, Ramos, Sardaro & Brada 2011, Radioth Oncol 99, (1) 6-11

Local control vs dose in SABR

van Baardwijk et al 2012 Radioth Oncol 105, 145–149

Dose comparison of SABR & accelerated RT

freed

om fr

om lo

cal p

rogr

essio

n at

3 y

ears

local control in stage I NSCLC

SABR in the context of modern radiotherapy of NSCLC

accurate definition of tumour extent dose fractionation

Current uncertainties

Deconstructing SABR

High precision Conformal High dose Hypofractionated

High precision localised radiotherapy

SABR – what is it?

Deconstructing SABR

High precision Conformal High dose Hypofractionated

High precision localised radiotherapy

SABR – what it is NOTstereotactic ablative

SABR in the context of modern radiotherapy of NSCLC

SABR in localised NSCLC

uncertaintieswhat is it

alternativesefficacy

SABR in the context of modern radiotherapy of NSCLC

SABR in localised NSCLC

uncertaintieswhat is it

alternativesefficacy

Loca

l pro

gres

sion

free

sur

viva

l (%

)local control

survival

Surv

ival

(%)

Endpoints of efficacy of SABR in stage I NSCLC

SABR for stage I NSCLC

Tumour control

Verstegen et al 2011 Radiother Oncol 101, 250–254

VU Amsterdam591 patients➞ histol. verified➞ histol. unverified

Endpoints of efficacy of SABR in stage I NSCLC

6.9.13 22.1.15

Tumour control

SABR for stage I NSCLC

Endpoints of efficacy of SABR in stage I NSCLC

Loca

l pro

gres

sion

free

sur

viva

l (%

)

Verstegen et al 2011 Radiother Oncol 101, 250–254

SABR for stage I NSCLC

local control

survival

Surv

ival

(%)

Tumour control

Survival

VU Amsterdam591 patients➞ histol. verified➞ histol. unverified

SABR in the context of modern radiotherapy of NSCLC

SABR in localised NSCLC

uncertaintieswhat is it

alternativesefficacy

survivalquality of life

SABR and quality of life (QOL)

Laagerwaard et al 2012 J Thor Oncol, 7, (7); 1148-1194

Quality of life after SABR (EORTC QLQ C30)

Change in global QOL score

Management options in localised NSCLC

SurgeryConventional radiotherapySABRRadiofrequency ablation

Alternatives

Management options in localised NSCLC

SurgeryConventional radiotherapySABRRadiofrequency ablation

Alternatives

SABR for localised NSCLC

Meta-analysis of published resultsJanuary 2006 – June 2012

published SABR studiesin early stage NSCLC

data on 2 yr survival & local control

no. studies (patients)

systematic review 45 (3201)

Solda, Lodge, Ashley, Whitington, Goldstraw & Brada 2013 Radiother Oncol, 109, 1-7

SABR for localised NSCLC

Meta-analysis of published resultsJanuary 2006 – June 2012

2456 • initial search756

• duplicates removed

134 • clinical studies

83 77 70

67 62 57

• NSCLC

• analysable

• early stage

• available outcome information

• 2 year survival available

• staging available

Solda, Lodge, Ashley, Whitington, Goldstraw & Brada 2013 Radiother Oncol, 109, 1-7

2456 • initial search756

• duplicates removed

134 • clinical studies

83 77 70

67 62 57

• NSCLC

• analysable

• early stage

• available outcome information

• 2 year survival available

• staging available

• manuscript57

45 • duplicates removed

Meta-analysis of published resultsJanuary 2006 – June 2012

SABR for localised NSCLC

Solda, Lodge, Ashley, Whitington, Goldstraw & Brada 2013 Radiother Oncol, 109, 1-7

Meta-analysis of SABR for stage I NSCLC

2 year local control

individual data summary

Solda, Lodge, Ashley, Whitington, Goldstraw & Brada 2013 Radiother Oncol, 109, 1-7

Meta-analysis of published resultsJanuary 2006 – June 2012

SABR for localised NSCLC

Comparative group IASLC cohort1990 - 2000

Groome et al 2009

Surv

ival

(%)

IAIB

IASLC – International Association for the Study of Lung Cancer

2 year survival

Meta-analysis of SABR for stage I NSCLC

individual data3201 patients

summary

70% 68%

SAB

R

surg

ery

Solda, Lodge, Ashley, Whitington, Goldstraw & Brada 2013 Radiother Oncol, 109, 1-7

Management options in localised NSCLC

SurgeryConventional radiotherapySABRRadiofrequency ablation

Alternatives

Comparison of surgery & SABR in stage I NSCLC

propensity matched – SABR vs lobectomy

SEERS - Medicare 2001 – 0710,923 patients with stage IA & IB NSCLC, aged >65

Shirvani et al 2013 Int J Radiation Oncol Biol Phys, 84, (5), 1060-1070

Management options in localised NSCLC

SurgeryConventional radiotherapySABRRadiofrequency ablation

Alternatives

Zheng et al 2014 Int J Radiation Oncol Biol Phys; 90, (3), 603-611,

Comparison of surgery & SABR in stage I NSCLC

meta-analysis of published studies40 SABR studies (4850 pts) and 23 surgery studies (7071 patients)

surgery IA

SABR IA

SABR IB

surgery IB

survival

Zheng et al 2014 Int J Radiation Oncol Biol Phys; 90, (3), 603-611,

Comparison of surgery & SABR in stage I NSCLC

meta-analysis of published studies40 SABR studies (4850 pts) and 23 surgery studies (7071 patients)survival and operability

(lobectomy)(limited lung resection)

Zheng et al 2014 Int J Radiation Oncol Biol Phys; 90, (3), 603-611,

Comparison of surgery & SABR in stage I NSCLC

meta-analysis of published studies40 SABR studies (4850 pts) and 23 surgery studies (7071 patients)survival and age

(lobectomy)(limited lung resection)

Comparison of surgery & SABR in stage I NSCLC

propensity matched – SABR vs lobectomy

SEERS - Medicare 2001 – 0710,923 patients with stage IA & IB NSCLC, aged >65

Shirvani et al 2013 Int J Radiation Oncol Biol Phys, 84, (5), 1060-1070

Shirvani et al 2013 Int J Radiation Oncol Biol Phys, 84, (5), 1060-1070

Comparison of surgery & SABR in stage I NSCLC

propensity matched – SABR vs sublobar resection

SEERS - Medicare 2001 – 0710,923 patients with stage IA & IB NSCLC, aged >65

Management options in localised NSCLC

SurgeryConventional radiotherapySABRRadiofrequency ablation

Alternatives

Dose response in non-small cell lung cancer (NSCLC)

Summary of published phase I/II studies including SBRT 2 year local progression free survival (corrected for stage distribution)

40 60 80 100 1200

0.2

0.4

0.6

0.8

1

BED [Gy]

2 y

ea

r d

ise

ase

-fre

e s

urv

iva

lFenwick model(solid curve)

localiseddisease

locally advanceddisease

● conventional fractionation∆ hypofractionated SBRT

Partridge, Ramos, Sardaro & Brada 2011, Radioth Oncol 99, (1) 6-11

Local control vs dose in SABR

van Baardwijk et al 2012 Radioth Oncol 105, 145–149

Dose comparison of SABR & accelerated RT

free

dom

from

loca

l pro

gres

sion

at 3

yea

rs

local control in stage I NSCLC

Shirvani et al 2013 Int J Radiation Oncol Biol Phys, 84, (5), 1060-1070

Comparison of conventional RT & SABR in stage I NSCLC

propensity matched – SABR vs conventional RT

SEERS - Medicare 2001 – 0710,923 patients with stage IA & IB NSCLC, aged >65

Management options in localised NSCLC

SurgeryConventional radiotherapySABRRadiofrequency ablation

Alternatives

Alternatives to SABR in localised NSCLC

radiofrequency ablation (RFA)

Simon et al 2012 Europ J Radiol 81, 4167

surv

ival

pro

babi

lity

2 yrs

82 patients stages I, II, III (9%) (Brown University, Providence)

62%

Alternatives to SABR in localised NSCLC

radiofrequency ablation & comorbidity

CCI – Charleson Comorbidity Index

CCI = 5+

CCI = 3-4

CCI = 1-2su

rviv

al p

roba

bilit

y

Simon et al 2012 Europ J Radiol 81, 4167

RFA SABR

5 year local control 58 – 68% 83 – 90%

3 year survival 47 – 74% 38 – 85%

morbidity 33 – 100% 3 – 38%

Renaud et al 2013 Interactive CardioVascular and Thoracic Surgery 16, 68–73

Comparison of RFA & SABR in NSCLC

review of literature

RFA – radiofrequency ablationSABR – stereotactic ablative body radiotherapy

SABR in the context of modern radiotherapy of NSCLC

SABR in localised NSCLC

uncertaintieswhat is it

alternativesefficacy

Deconstructing SABR

High precision Conformal High dose Hypofractionated

High precision localised radiotherapy

Technology

Biology

SABR – what is it?

Renaud et al 2013 Interactive CardioVascular and Thoracic Surgery 16, 68–73

Deconstructing SABR

High precision Conformal High dose Hypofractionated

High precision localised radiotherapy

Technology

Biology

SABR – future“The end of the beginning or the beginning of the end?”

Brada, Pope & Baumann 2015 Radiotherapy & Oncology (epub)

Lung cancer in England and Wales

I

II

III

IV

nk

Stage distribution of lung cancerCR UK cancer statistics - England & Wales 2012

Perspectives in lung cancerStereotactic ablative radiation therapy (SABR)in patients with inoperable NSCLC

Michael Brada BSc, MB ChB, FRCP, FRCR, DScProfessor of Radiation OncologyUniversity of Liverpool

Department of Molecular and Clinical Cancer Medicine& Department of Radiation OncologyClatterbridge Cancer Centre NHS Foundation TrustBebington, Wirral, CH63 4JY

michael.brada@liverpool.ac.uk