approaching early-stage disease: strategizing various therapeutic options (surgery vs. sbrt vs. rfa)...

Approaching Early-Stage Disease: Strategizing Various Therapeutic

Options (Surgery vs. SBRT vs. RFA)

Jeffrey D. Bradley, M.D.S. Lee Kling Professor of Radiation Oncology

Alvin J Siteman Cancer Center

Department of Radiation Oncology

Disclosures

• No financial relationships to disclose

• Chair of NRG Oncology Lung Cancer Committee (modest stipend)


Case 1: LB

• Referred by cardiologist to Dr. Meyers for evaluation of a LUL lung nodule

• Recent drug-eluting stent placed in coronary artery. On clopidrogel

• FDG-PET showed moderately increased FDG uptake with max SUV of 2.5. No other findings

• PFTs showed FEV1 of 2.64 (83%) and FEV1/FVC of 74.7 (100%)

• CT-guided needle Bx: NSCLC favor SCCA


LB SABR Images


LB: 5 Year Follow-up Images


Stage I NSCLC - Options

• Surgery• Lobectomy/ pneumonectomy• Sublobar resection

(segmentectomy, wedge)

• Radiation• SBRT• EBRT

• Observation

Medically operable

Medically inoperable

Borderline medically operable

Wouldn’t touch with a 10-foot pole

???

??

?


Results of Surgery

• IASLC project – AJCC 7th addition• 100,869 patients from 46 sources from

19 countries• 67,725 NSCLC treated between 1990-

2000

• American College of Surgeons Z4032• Randomized Phase III study of sublobar

resection +/- brachytherapy in high-risk patients with NSCLC, 3 cm or smaller (ongoing)


Stage I NSCLC - OptionsStage I NSCLC - Options• Surgery

5y LR(LCSG 1995)

6%

18%


ACOSCOG Z0432ACOSCOG Z0432


Stereotactic Body Radiation Stereotactic Body Radiation TherapyTherapy

• Not a machine, but a type of radiation delivery.

• Stereotactic = precise positioning of the target volume in 3 dimensions.

• Has become synonymous with high dose per fraction.

• Different delivery techniques (arcs, static fields, protons)


Loca

l Con

trol (

%)

0

25

50

75

100

Months after Start of SBRT0 6 12 18 24 30 36

0

25

50

75

100

0 6 12 18 24 30 36

Patientsat Risk 55 54 47 46 39 34 23

Fail: 1Total: 55

/ / / / / /// / / // / // / / / / / // / // // // //

Challenges?......What Challenges?RTOG 0236

• 1 failure within PTV, 0 within 1 cm of PTV

36 month

Primary tumor control = 98% (CI: 84-100%)

Lobar tumor control = 94%

Timmerman et al. JAMA 2010


Thermal Ablation for lung cancersThermal Ablation for lung cancers


Radiofrequency Ablation – Schneider et al. 2013Radiofrequency Ablation – Schneider et al. 2013


Radiofrequency AblationRadiofrequency Ablation

• Follow up data are now projecting 5-year results for percutaneous thermal ablation

• Pneumothorax and chest drain rates are very high

• Local recurrence rates are poor (11-57%)• Industry and investigators are evaluating

bronchoscopic ablation techniques• Consider for SBRT failures?• First-line RFA cannot be recommended


Randomized Trials comparing surgery to SBRT

• Lobectomy• Netherlands ROSEL Trial – closed due to lack of accrual• Accuray Cyberknife – closed due to lack of accrual

• High Risk• ACOSOG Z4099/RTOG 1021 – closed due to lack of

accrual• TMSC rejected amendment for cluster randomization

(5/9/13)

• One last hope?VA Medical System – VALOR TrialLobectomy vs SBRTDrew Moghanaki - PI


Histological confirmation NSCLC

and confirmatio

n N2/N3 negative lymph nodes

Registration and

Randomization

ARM 1:Sublobar

Resection ± Brachythera

py (SR)

ARM 2:Stereotactic

Body Radiation Therapy

(SBRT) 18 Gy X 3 = 54

Gy

FOLLOW

UP

ACOSOG Z4099/RTOG 1021 ACOSOG Z4099/RTOG 1021 Phase III Trial for High-risk patientsPhase III Trial for High-risk patientsOpened June 2011Opened June 2011

Endpoint: 3 year OS

Accrual = 420 patients


Histological confirmation NSCLC

and confirmatio

n N2/N3 negative lymph nodes

Registration and

Randomization

ARM 1:Sublobar

Resection ± Brachythera

py (SR)

ARM 2:Stereotactic

Body Radiation Therapy

(SBRT) 18 Gy X 3 = 54

Gy

FOLLOW

UP

ACOSOG Z4099/RTOG 1021 ACOSOG Z4099/RTOG 1021 Phase III Trial for High-risk patientsPhase III Trial for High-risk patientsOpened June 2011Opened June 2011

Endpoint: 3 year OS

Accrual = 420 patients

Closed


SBRT vs. surgery for SBRT vs. surgery for clinical stage I NSCLCclinical stage I NSCLC

• Rough comparison of OS

cT1N0 cT2N0

3y OS 5y OS 3y OS 5y OS

Surgery AJCC 6th ed 71% 61% 46% 38%

AJCC 7th ed ~68% (1a)

~58% (1b)

53% (1a)

47% (1b)

~50% (2a)

~45% (2b)

~30% (3; ≥ 7 cm)

43% (2a)

36% (2b)

26% (3; ≥ 7 cm)

SBRT RTOG 0236 (60Gy/3)

(55.8%; T1/T2)

? (55.8%; T1/T2)

?

U. Indiana (60-66Gy/3)

~50% ~20% ~35% ?


SBRT vs. surgery for SBRT vs. surgery for clinical stage I NSCLCclinical stage I NSCLC• Problem #1. . .

• Treatment groups are inherently different!

Vs.


SBRT vs. surgery for SBRT vs. surgery for clinical stage I NSCLCclinical stage I NSCLC• Problem #2. . .

• Definition of “medically operable”?

???FEV1

Diabetes

Cardiac Co-morbidity

DLCOPerformance Status

Predicted Postoperative Pulmonary Reserve

SmokingFVC


SBRT vs. surgery for SBRT vs. surgery for clinical stage I NSCLCclinical stage I NSCLC

• Medically operable• Uematsu, IJROBP 2001• Onishi, J Thorac Oncol 2007 / IJROBP 2010

• Medically inoperable / High risk operable• William Beaumont

• Grills, JCO 2010 - Wedge vs. SBRT• Cornell

• Parashar, Cancer 2010 – Wedge+Brachy vs. SBRT• Wash U

• Crabtree, J Thorac Cardiovasc Surg 2010 - Any surgery vs. SBRT

• Robinson, JTO 2012– Lobectomy/Pneumonectomy vs. SBRT


SBRT vs. surgery for SBRT vs. surgery for clinical stage I NSCLCclinical stage I NSCLCMedically operable - Onishi, J Thorac Oncol 2007

• Median F/U 38 mo (2-128 mo)

OS by medical operability

3y ~40%, 5y 35%

3y ~70%, 5y 64.8%

All 257 pts

3y 5y

OS 56.8% 47.2%

CSS 76.9% 73.2%


SBRT vs. surgery for SBRT vs. surgery for clinical stage I NSCLCclinical stage I NSCLCMedically operable - Onishi, J Thorac Oncol 2007

≥ 100Gy = 64.8%

5y overall survival 19.7% 53.9% sig

Control rates by BED10 for all pts


What dose for peripheral lung cancers?

Medically operable - Onishi, J Thorac Oncol 2007

5y OS by BED10 in medically operable

<100Gy3y ~65%, 5y ~50%

≥100 Gy3y 80.4%, 5y 70.8%

BED = nd(1+d//)Schemes >100 Gy:16 Gy x 312 Gy x 410 Gy x 5


SBRT vs. surgery for SBRT vs. surgery for clinical stage I NSCLCclinical stage I NSCLCMedically operable - Onishi, IJROBP 2010

• 87 pts w/medically operable, path proven T1 (n=65) or T2 (n=22) N0 NSCLC tx’d w/SBRT to BED > 100Gy from 1995-2004 at 14 Japanese institutions.• Subset from original 2007 study with longer follow-

up.• SBRT was 42-72.5 Gy / 3-10 fx via a variety of

stereotactic techniques.• No chemo


SBRT vs. surgery for SBRT vs. surgery for clinical stage I NSCLCclinical stage I NSCLCMedically operable - Onishi, IJROBP 2010

• Median F/U 55 mo

Local control Overall survival

5y LC 86.7% (All) 5y OS 69.5% (All) CSS 76.l%


Local Recurrence by Prescription Dose

• 2-year LR of 15% for low dose vs 4% for high dose• Grills IS et al. JTO 2012;7(9):1382-93• Elekta Consortium

1.0

0.8

0.2

0.4

0.6

0

0 4 6 82Time (Years)

Local

Recu

rren

ce

Rx BED10 ≥ 105 Gy

Rx BED10 < 105 Gy

p<0.001


SBRT vs. surgery for clinical stage I NSCLCMedically operable - Onishi, IJROBP 2010

• Median F/U 55 mo

Local control Overall survival

5y LC 86.7% (All) 5y OS 69.5% (All) CSS 76.l%


SBRT vs. surgery for SBRT vs. surgery for clinical stage I NSCLCclinical stage I NSCLCMedically inoperable / High risk operable - Grills, JCO

2010 • Median potential F/U 30 mo


J Thorac Oncol 2013; 8:192-201


RTOG 0915 Overall Survival

Videtic et al. ASTRO and IASLC 2013


Centrally-located lung cancersCentrally-located lung cancers


Reported Toxicity for Central Lung Reported Toxicity for Central Lung CancersCancers

Timmerman R. et al JCO 2006

Timmerman et al. JCO 2006


RTOG 0813 - SBRT Dose LevelsRTOG 0813 - SBRT Dose LevelsTrial completed, await f/uTrial completed, await f/u

Level 1 10 Gy x 5 50 GyLevel 2 10.5 Gy x 5 52.5 GyLevel 3 11 Gy x 5 55 GyLevel 4 11.5 Gy x 5 57.5 GyLevel 5 12 Gy x 5 60 GyDesign: Continual Reassessment Monitoring (CRM)Endpoints:

Phase I – Any Tx-related Grade 3 or greater toxicity

Phase II – 2-year primary tumor control rate

Phase I/II Dose Escalation study (N=94)


WU Data on Local ControlWU Data on Local Control

Olsen, Robinson, Bradley et al. IJROBP 2011


Conclusions: Surgery versus SBRTConclusions: Surgery versus SBRT

• Surgery is the gold standard for operable patients

• For inoperable or marginally operable patients with Stage I lung cancer, SBRT offers excellent local control and similar survival to surgical approaches

• SBRT results will be similar, regardless of delivery device. Differences are method of imaging, +/- fiducials, treatment time, etc.

• Randomized trials have failed to accrue for various reasons; patients and surgeons

approaching early-stage disease: strategizing various therapeutic options (surgery vs. sbrt vs. rfa)...

Documents

type of radiation delivery

sabr images slide

smaller ongoing slide

nsclc favor scca slide

year followup images

sbrt failures

lack of accrual tmsc

lung cancers