RTOG1106: Randomized Phase IIR Trial of RTOG1106: Randomized Phase IIR Trial of Personalized Adaptive Radiotherapy Based Personalized Adaptive Radiotherapy Based

on Mid-treatment FDG-PET in Locally on Mid-treatment FDG-PET in Locally Advanced NSCLCAdvanced NSCLC

P.I.: Feng-Ming (Spring) Kong, M.D., Ph.D.

Study TeamMitchell Machtay, M.D.Jeffrey D. Bradley, M.D.

Jean Moran, Ph.D.Vera Hirsh, M.D.

Barry Siegel, M.D.

RTOG 1106/ACRINxxxxRTOG 1106/ACRINxxxx

Estimated Sample size: ~120 patients(85% power to detect 20% difference in 2-yr. local PFS)

RTOG 0617 arm:Standard dose script

Study arm:Individualadaptive RT

Treatment includingTreatment includingRadiation Therapy Radiation Therapy

post-treatmentpost-treatmentoutcomeoutcome

Weeks to monthsWeeks to months Months Months to yearsto years

The Traditional ApproachThe Traditional ApproachCTCT

PETPET1-3 months1-3 months

Background - 1Background - 1

ACRIN 6668/RTOG 0235: FDG-PET

REGISTER

FDG-PET with SUV

Chemo-RT +/- ‘adjuvant’

chemo

Eligibility

Stage III NSCLC plan for conc. chemo-RT

PS 0-1

Primary Endpoint: Survival as a function of post-RT SUV

Sample Size: 250

FDG-PET with SUV

2-3 months after XRT

ACRIN 6668/RTOG 0235 Update

Activation Date: 3/1/2005.

Closed to Accrual: 5/15/2009.

Total Accrual: 251 pts.236 verified eligible (94%).

Total # Participating Sites: 37.

Central Review in Process.Qualitative, SUVpeak, MTV

Primary Outcome Analysis in Early/mid 2011.

RTOG 0515 Results

Exploratory trial of pre-Tx FDG-PET for XRT planningN=47

Variable CT Only PET/CT Difference p

Mean GTV (cc) 98.7 86.2 -12.5% <0.0001

Mean # involved nodes

2.1 2.4 14% 0.41

Mean Lung dose (Gy)

19 Gy 17.8 Gy -6% 0.06

Mean esophageal dose (Gy)

28.7 Gy 27.1 Gy -6% 0.30

Bradley et al. ASTRO 2009

HypothesesHypotheses

Use of mid-treatment FDG-PET is as useful or more useful than pre-RT FDG-PET and/or 3-month post-RT PET.Mid treatment PET can be used to individualize (and escalate) XRT dose will result in improved outcomes (2-yr. LPFS) compared with standard XRT.

Treatment includingTreatment includingRadiation Therapy Radiation Therapy

post-treatmentpost-treatmentoutcomeoutcome

Weeks to monthsWeeks to months Months Months to yearsto years

The Traditional ApproachThe Traditional ApproachCTCT

PETPET1-3 months1-3 months

•Post-RT PET response is highly correlated with pathologic response.•Post-RT PET is predictive of long term survival and pattern of failure(Mac Manus et al, 2003)RTOG235/Acrin688 results awaited.

However, post-RT PET tumor response does not provide an opportunity to change the treatment plan.

When should PET be done?When should PET be done?

PET during RT?PET during RT?

PET scan can be performed during-RT University of Michigan study, ASTRO 2005 MAASTRO study, ASTRO 2005 Stanford study, ASTRO 2007 Princess Margaret Hospital, ASTRO 2008

UM has demonstrated that PET response at 45 Gy during-RT was highly correlated with post-RT response in a small pilot study.

The above finding has been recently validated in another 50+ patients from Michigan.

Kong et al, JCO, 2007Kong et al, JCO, 2007

Individualized RT Escalation Is Feasible

Michigan trial usees PET-MTV guided isotoxicity adaptive plan to escalate tumor dose: 30 daily treatments, 2.2-3.8 Gy per fraction, 66 Gy~85.5 Gy To NTCP of 17% (mean lung dose 20 Gy), with concurrent and

adjuvant carbo and taxol, maximum at102 Gy in 2 Gy equivalent dose for lung (=ED2) (92 Gy ED2 for tumor).

14 patients completed treatments per study, all patients treated >74 Gy ED2 (median=92 Gy for tumor), majority of them received the maximum dose.

6 patients followed up for 1.5 years, no local failure thus far, 2 brain mets, only 1 death thus far from GI bleeding (gastric and esophageal ulcers).

Tumor Response During-RTTumor Response During-RT

Pre- RTPre- RT

HeartHeart

HeartHeart

TumorTumor TumorTumor

TumorTumor TumorTumorDuring-RT at 45 GyDuring-RT at 45 Gy

Example-1

CT-lunGwindow CT-mediastinum window FDGPET

Pre-RT

During-RT

3 mo post

9 mo post

16 mo post

UM002

MTV: 353 cm3GTV: 468 cm3

GTV: 402 cm3MTV: 268 cm3

GTV: 174 cm3

MTV: 12 cm3

This 48 YO male received 85.5 Gy(120 Gy BED) had grade 0 clinical toxicity thus far.He works full time now with heavy duty.

Patient-2

FDG Activity & PET-MTV Reduction

NMTA-max Change

02468

10121416182022

Pre-RT During-RT Post-RT

NMTA

Change in PET-MTV

04080

120160200240280320360400

Pre-RT During-RT Post-RTPE

T-M

TV (c

c)

PET results during RT correlates well with post-RT results

PET-MTV Decreased More than CT-GTVPET-MTV Decreased More than CT-GTV

CTCTPETPET

Pre-RTPre-RT

During-RTDuring-RT

During-RTDuring-RT

50 pts 88 tumors50 pts 88 tumors

Mid-course FDG-PET and PFSMid-course FDG-PET and PFS1 Year Progression-Free Survival1 Year Progression-Free Survival

(Kong et al, ASTRO 2009)(Kong et al, ASTRO 2009)

Mid-course FDG-PET and SurvivalMid-course FDG-PET and Survival

NSUV During-RT < 3.0

NSUV During-RT > 3.0NSUV During-RT > 3.0

NSUV During-RT < 3.0

(Kong et al, ASTRO 2009)(Kong et al, ASTRO 2009)

Overall SurvivalOverall SurvivalLocal Progression Free SurvivalLocal Progression Free Survival

NSUV=tumor SUVmax/Aorta SUVmean.

Proposed RTOG/ACRIN Trial

Followup to ACRIN 6668/RTOG 0235.FDG-PET during RTValidate UM resultsStudy adaptive RT/dose escalationRandomization to assess the efficacy of

mid-treatment FDG-PET

Opportunity to study a novel tracer (e.g. F-Miso) in limited institution sub-study.

RTOG 1106/ACRINxxxxRTOG 1106/ACRINxxxx

Estimated Sample size: ~120 patients(85% power to detect 20% difference in 2-yr. local PFS)

RTOG 0617 arm:Standard dose script

Study arm:Individualadaptive RT

Secondary AimsSecondary Aims

To compare toxicity between such a PET image-guided adaptive dose escalation and conventional RT.

To validate recent findings from a single institution that a tumor metabolic response during-RT predicts long term local tumor control, LPFS and overall survival.

To perform a pilot study to assess whether a novel PET tracer (F-Miso) is more predictive than FDG-PET.

To obtain blood and tissue samples to explore relationships between imaging findings, biomarkers and outcomes (both anti-tumor efficacy and toxicity).

FLT versus F-Miso

FLT F-Miso

Ease of use √ √

Sensitivity relative to FDG

Specificity relative to FDG √

Relevance to Radioresistance √

Which is the ‘better’ exploratory agent?

Other Issues Still to be Resolved

ACRIN Co-PI TBA.

Radiotherapy Fractionation issues.

Randomization, stratification issues.

Sample size for FLT/FMISO sub-study.

Insurance company reimbursement for mid course PET.

Backup