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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