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Walter J Curran, Jr, MDExecutive DirectorWinship Cancer Institute of Emory UniversityGeorgia Cancer Coalition Distinguished ScholarRTOG Group Chair

Multi-Modality Management of Stage III NSCLC Use of PET Imaging

Good PS Stage III NSCLC: Where is There No Randomized Data?

• Use of Any Advanced Technology RT Tools?• Selection of Best Chemo to Give Concurrently with RT• Use of Functional Imaging in RT Planning/Assessment• Higher RT Dose with a Standardized Chemo Regimen• Use of “Targeted Agent” Concurrent with Chemo-RT

State III NSCLCSurvival by Local Tumor Control Status

Median Survival

• Pts with Local Control (n=674)

• 18.6 mo

• 24%

• Pts without Local Control (n=761)

• 15.5 mo

• 6%

p < 0.0001

Median Survival

• Pts with Local Control (n=674)

• 18.6 mo

• 24%

• Pts without Local Control (n=761)

• 15.5 mo

• 6%

p < 0.0001

RTOG 0617 (CALGB 30609, NCCTG N0628)Randomized Phase III Trial of Standard-Dose (60 Gy) Versus

High-Dose (74 Gy) Conformal RT w Concurrent and Consolidation Cb/P in Stage IIIA/B NSCLC

Primary Endpoint – Survival (n=512) (2 X 2 design evaluating dose and cetuximab independently)

Stratified by stage (A vs B), type of RT (3-D vs IMRT) and PS (0 vs 1)

Stage IIIA/B Stage IIIA/B

PS 0-1 PS 0-1

FEVFEV11 ≥1.5L; V ≥1.5L; V2020 <37% <37%

No Supraclav LNs No Supraclav LNs

PET recommendedPET recommended

RRAANNDDOOMM

I I ZZEE

Concurrent ChemoRT Paclitaxel 45 mg/m2 Carboplatin AUC 2 Weekly x7

RT 60 Gy (2 Gy/d)

+ Cetuximab

Concurrent ChemoRT Paclitaxel 45 mg/m2 Carboplatin AUC 2 Weekly x7

RT 74 Gy (2 Gy/d)

+ Cetuximab

Consolidation Paclitaxel 200mg/m2 Carboplatin AUC 6 q3wks x2 cycles

RTOG 0617 DMC Meeting June 2011

• DMC Meeting in early June 2011• High Dose RT Arm (74 Gy) Crossed Futility Boundary• Both 74 Gy Arms Closed to Further Accrual• Cetuximab Question at 60 Gy to be Completed• Accrual will Finish in Late 2011/Early 2012

RTOG 0617: Standard vs High RT Dose Question

• 423 Patients Evaluated in June 2011 DMC Analysis• Median Follow-up is 9 months• After 90 Deaths, High RT Dose Arm Crossed Futility

Boundary• 10 Treatment-Related Deaths:

– 3 in Standard Dose Arm– 7 in High Dose Arm

• Most other Deaths Attributed to Disease Progression

RTOG 0617 Overall Survival

• 60 Gy, 58 deaths/213

• 74 Gy, 70 deaths/204

– HR=1.45 (1.02, 2.05)

– p=0.02*

*One-sided p-value, left tail

• 60 Gy, 58 deaths/213

• 74 Gy, 70 deaths/204

– HR=1.45 (1.02, 2.05)

– p=0.02*

*One-sided p-value, left tail

Can PET/CT Assess RT or ChemoRT Efficacy Earlier?

This may be the Most Personalized Care for Stage III Patients!

FDG-PET-based Response as an Early Marker of Survival

Study N Stage PET response Criteria pMacManus 2003 73 I-III CR qualitative 0.0004

Weber 2003 57 IIIB/IV 20% SUV decrease 0.005

Hellwig 2004 47 IIB/III SUV < 4 0.001

Hoekstra 2005 47 IIIA MRglu < 0.13 0.0003

Eschmen 2007 70 III 80% SUV decrease 0.005

deGeus-Oei 2007 51 IB-IV 35% SUV decrease 0.018

Dooms 2008 30 IIIA 60% SUV decrease 0.002

Decoster 2008 31 III CR qualitative 0.004

Tanvetyanon 2008 89 IB-IIIB PR qualitative NS

(Hicks J Nuc. Med 2009)(Hicks J Nuc. Med 2009)(Hicks J Nuc. Med 2009)(Hicks J Nuc. Med 2009)

REGISTER

FDG -PET - SUV

Concurrent chemo-XRT (+/- adjuvant chemo as per M.D.)

FDG -PET – SUV to be done 12 to 16 weeks following XRT and several wks after adjuvant chemo (if given).

Sample size = 250 pts.Completed Accrual 5/14/09

P.I.: MachtayP.I.: MachtayP.I.: MachtayP.I.: Machtay

ACRIN 6668/RTOG 0235Use of PET in Response Assessment

SUVpeak (c.f. SUVmax)

SUVpeak: Circular 1 cm ROI centered around SUVmax. Then, the software is queried to determine the mean SUV within that precisely defined ROI.

ACRIN 6668/RTOG 0235Preliminary Results

AssessmentMean SUVpeak

Pearson Correlation

Local Review

Central Review

Pre-treatment GTV 9.4 9.4 0.73

Post-treatment GTV 2.5 1.8 0.86

RTOG 0235/ACRIN 6668Pre and Post- Chemo-RT SUV

Median SUV= 9.4Median SUV= 9.4 Median SUV= 2.5Median SUV= 2.5

Major Limitation . . .

12-16 week waiting period following RT before assessing response/efficacy/prognosis/prediction can seem like an eternity!

12-16 week waiting period following RT before assessing response/efficacy/prognosis/prediction can seem like an eternity!

PET during Weeks 1&2 of RT

Aerts HJWL, IJROBP 2008Aerts HJWL, IJROBP 2008

"The location of the low and high FDG uptake areas within the tumor remained stable during RT. This knowledge may enable selective boosting of high FDG uptake areas within the tumor."

"The location of the low and high FDG uptake areas within the tumor remained stable during RT. This knowledge may enable selective boosting of high FDG uptake areas within the tumor."

Mid-course FDG-PET & Outcome

Kong, JCO 2007

"Although there were not enough patients to perform survival analyses in this study, a significant association of metabolic response and peak FDG activity between during-RT and post-RT scans suggests a potential of using the during-RT PET response (at approximately 45 Gy) to predict long-term survival in lung cancer."

"Although there were not enough patients to perform survival analyses in this study, a significant association of metabolic response and peak FDG activity between during-RT and post-RT scans suggests a potential of using the during-RT PET response (at approximately 45 Gy) to predict long-term survival in lung cancer."

PET-based Adaptive Radiotherapyfor Stage III NSCLC – RTOG 1106

REGISTER

FDG-PET

Off Study – D/C RT

RT to 64 Gy.

RANDOMIZE

RT to 64 Gy + 10+ Gy boost based on FDG-PET

FDG-PETChemoRT44 Gy

SD/Response

PDPD

FDG-PET based Adaptive RT

Feng, IJROBP 2009Feng, IJROBP 2009

"Tumor metabolic activity and volume can change significantly after 40-50 Gy of RT. Using mid-RT PET volumes, tumor dose can be significantly escalated or normal tissue complication probability reduced."

"Tumor metabolic activity and volume can change significantly after 40-50 Gy of RT. Using mid-RT PET volumes, tumor dose can be significantly escalated or normal tissue complication probability reduced."

Lung Functional Region ClassificationCT and Ventilation-SPECTCT and Ventilation-SPECT

• Lung quality and ventilation-SPECT is variable between lungs

• Radiation planning identifying partially functioning, dysfunctional and functional lung can assist in individualizing therapy

• Lung quality and ventilation-SPECT is variable between lungs

• Radiation planning identifying partially functioning, dysfunctional and functional lung can assist in individualizing therapy

V/Q SPECT to Individualize Adaptive RT

The dose of a functioning lung region decreases from 30-50% to 15-30% after re-optimization.

Summary: Stage III NSCLC Chemo-RT

No Fully Personalized Therapy Thoracic RT is Becoming Anatomy and Response

Dependent RT Optimization of Interest Despite RTOG 0617 Changes in Details of Care not All Subject to

Clinical Trials

Sunday, February 12, 2012Hollywood, Florida

Co-ChairsRogerio C Lilenbaum, MDMark A Socinski, MD

Co-Chair and ModeratorNeil Love, MD

Faculty

Walter J Curran Jr, MDDavid Jablons, MDMark G Kris, MD

Suresh Ramalingam, MDAlan B Sandler, MD