Michael Brada Torino 6 March 2015 Perspectives in lung cancer Stereotactic 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

staging tumour margin effect of motion Accurate target localisation define tumour extent

staging tumour margin effect 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 fields arcing 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 or Cyberknife Tomotherapy Body GK Linac Cyberknife Linac or Cyberknife Tomotherapy Body 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 datasummary 91% 88% LinacCyberkife Solda, 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 datasummary Solda, Lodge, Ashley, Whitington, Goldstraw & Brada 2013; Radiother Oncol, 109, % 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 advanced NSCLC 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) Fenwick model (solid curve) ● conventional fractionation corrected for dose fractionation/time and stage distribution Partridge, Ramos, Sardaro & Brada 2011, Radioth Oncol 99, (1) 6 -11

early stage disease Fenwick model (solid curve) localised disease locally advanced disease Dose response in non-small cell lung cancer (NSCLC) Summary of published phase I/II studies including SABR 2 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 SABR 2 year local progression free survival (corrected for stage distribution) Fenwick model (solid curve) localised disease locally advanced disease ● 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 Phase I/II dose escalation study in NSCLC 45cm 3 ≈ 4.5 cm diameter sphere time (months) % progression free survival smaller tumours ≤45cm 3 larger tumours >45cm 3

Dose response in non-small cell lung cancer (NSCLC) Summary of published phase I/II studies including SABR 2 year local progression free survival (corrected for stage distribution) Fenwick model (solid curve) localised disease locally advanced disease ● conventional fractionation ∆ hypofractionated SABR Partridge, Ramos, Sardaro & Brada 2011, Radioth Oncol 99, (1) 6 -11

Local control vs dose in SABR v an Baardwijk et al 2012 Radioth Oncol 105, 145–149 Dose comparison of SABR & accelerated RT freedom from local progression at 3 years 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 NOT stereotactic 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

Local progression free survival (%) local control survival Survival (%) 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 Amsterdam 591 patients ➞ histol. verified ➞ histol. unverified

Endpoints of efficacy of SABR in stage I NSCLC Tumour control SABR for stage I NSCLC

Endpoints of efficacy of SABR in stage I NSCLC Local progression free survival (%) Verstegen et al 2011 Radiother Oncol 101, 250–254 SABR for stage I NSCLC local control survival Survival (%) Tumour control Survival VU Amsterdam 591 patients ➞ histol. verified ➞ histol. unverified

SABR in the context of modern radiotherapy of NSCLC SABR in localised NSCLC uncertaintieswhat is it alternativesefficacy survival quality of life

SABR and quality of life (QOL) Laagerwaard et al 2012 J Thor Oncol, 7, (7); Quality of life after SABR (EORTC QLQ C30) Change in global QOL score

Management options in localised NSCLC Surgery Conventional radiotherapy SABR Radiofrequency ablation Alternatives

Management options in localised NSCLC Surgery Conventional radiotherapy SABR Radiofrequency ablation Alternatives

SABR for localised NSCLC Meta-analysis of published results January 2006 – June 2012 published SABR studies in early stage NSCLC data on 2 yr survival & local control no. studies (patients) systematic review45 (3201) Solda, Lodge, Ashley, Whitington, Goldstraw & Brada 2013 Radiother Oncol, 109, 1-7

SABR for localised NSCLC Meta-analysis of published results January 2006 – June initial search 756 duplicates removed 134 clinical studies 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 search 756 duplicates removed 134 clinical studies NSCLC analysable early stage available outcome information 2 year survival available staging available manuscript duplicates removed Meta-analysis of published results January 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 datasummary Solda, Lodge, Ashley, Whitington, Goldstraw & Brada 2013 Radiother Oncol, 109, 1-7

Meta-analysis of published results January 2006 – June 2012 SABR for localised NSCLC Comparative group IASLC cohort Groome et al 2009 Survival (%) IA IB IASLC – International Association for the Study of Lung Cancer

2 year survival Meta-analysis of SABR for stage I NSCLC individual data 3201 patients summary 70% 68% SABRsurgery Solda, Lodge, Ashley, Whitington, Goldstraw & Brada 2013 Radiother Oncol, 109, 1-7

Management options in localised NSCLC Surgery Conventional radiotherapy SABR Radiofrequency ablation Alternatives

Comparison of surgery & SABR in stage I NSCLC propensity matched – SABR vs lobectomy SEERS - Medicare 2001 – 07 10,923 patients with stage IA & IB NSCLC, aged >65 Shirvani et al 2013 Int J Radiation Oncol Biol Phys, 84, (5),

Management options in localised NSCLC Surgery Conventional radiotherapy SABR Radiofrequency ablation Alternatives

Zheng et al 2014 Int J Radiation Oncol Biol Phys; 90, (3), , Comparison of surgery & SABR in stage I NSCLC meta-analysis of published studies 40 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), , Comparison of surgery & SABR in stage I NSCLC meta-analysis of published studies 40 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), , Comparison of surgery & SABR in stage I NSCLC meta-analysis of published studies 40 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 – 07 10,923 patients with stage IA & IB NSCLC, aged >65 Shirvani et al 2013 Int J Radiation Oncol Biol Phys, 84, (5),

Comparison of surgery & SABR in stage I NSCLC propensity matched – SABR vs sublobar resection SEERS - Medicare 2001 – 07 10,923 patients with stage IA & IB NSCLC, aged >65

Management options in localised NSCLC Surgery Conventional radiotherapy SABR Radiofrequency 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) Fenwick model (solid curve) localised disease locally advanced disease ● 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 freedom from local progression at 3 years local control in stage I NSCLC

Shirvani et al 2013 Int J Radiation Oncol Biol Phys, 84, (5), Comparison of conventional RT & SABR in stage I NSCLC propensity matched – SABR vs conventional RT SEERS - Medicare 2001 – 07 10,923 patients with stage IA & IB NSCLC, aged >65

Management options in localised NSCLC Surgery Conventional radiotherapy SABR Radiofrequency ablation Alternatives

Alternatives to SABR in localised NSCLC radiofrequency ablation (RFA) Simon et al 2012 Europ J Radiol 81, 4167 survival probability 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 = 1-2 survival probability Simon et al 2012 Europ J Radiol 81, 4167

RFASABR 5 year local control58 – 68%83 – 90% 3 year survival47 – 74%38 – 85% morbidity33 – 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 ablation SABR – 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 cancer CR UK cancer statistics - England & Wales 2012

Perspectives in lung cancer Stereotactic ablative radiation therapy (SABR) in patients with inoperable NSCLC Michael Brada BSc, MB ChB, FRCP, FRCR, DSc Professor of Radiation Oncology University of Liverpool Department of Molecular and Clinical Cancer Medicine & Department of Radiation Oncology Clatterbridge Cancer Centre NHS Foundation Trust Bebington, Wirral, CH63 4JY