Walter J Curran, Jr, MDExecutive DirectorWinship Cancer Institute of Emory UniversityAtlanta, Georgia

Group ChairmanNRG Oncology

Extensive Stage Small Cell Lung Cancer:What is the Role of “Consolidative” RT?

Topics for Discussion“Consolidative” RT for E-SCLC

• Thoracic RT following any “Response” to Chemotherapy• Slotman, et al (Abstract 7502)

• PCI following Response to Chemo• Seto et al (Abstract 7503)• Slotman et al (NEJM 2007)

ES-SCLC, WHO 0-24-6 platinum-based

chemotherapy

CREST Trial Design

Any response

TRT (10 x 3Gy)

RANDOMIZE

PCIPCI PCIPCI

Stratification: •Institute•Presence of intrathoracic disease

Patient Characteristics (Slotman)TRT

(n=247)Control (n=248)

ResponseComplete response 12 ( 4.9) 13 ( 5.2)

Partial response 180 (72.8) 170 (68.6)

“Good” response 55 (22.3) 65 (26.2)

Persistent intrathor. diseaseYes 215 (87.0) 219 (88.3)

No 32 (13.0) 29 (11.7)

Overall survival

Time (mths)

OS

Pro

ba

bili

ty

0 6 12 18 24

0.0

0.2

0.4

0.6

0.8

1.0

247 147 67 26 14 Thoracic RT

248 160 61 17 5 No Thoracic RT

Thoracic RT

No Thoracic RT

12 mos OS - Thoracic RT : 32.7 ( 95% CI: 27.2 - 39.3 )

12 mos OS - No Thoracic RT : 27.6 ( 95% CI: 22.5 - 33.9 )

ITT, events/n ( 224 / 248 - 201 / 247 )

HR= 0.84 ( 95% CI: 0.69 - 1.01 )

stratified log-rank p-value 0.066

HR = 0.84 (95%CI 0.69-1.01)p=0.066

Overall survival

Time (mths)

OS

Pro

ba

bili

ty

0 6 12 18 24

0.0

0.2

0.4

0.6

0.8

1.0

247 147 67 26 14 Thoracic RT

248 160 61 17 5 No Thoracic RT

Thoracic RT

No Thoracic RT

12 mos OS - Thoracic RT : 32.7 ( 95% CI: 27.2 - 39.3 )

12 mos OS - No Thoracic RT : 27.6 ( 95% CI: 22.5 - 33.9 )

ITT, events/n ( 224 / 248 - 201 / 247 )

HR= 0.84 ( 95% CI: 0.69 - 1.01 )

stratified log-rank p-value 0.066

Survival difference @18 Months: p=0.0324 Months: p=0.004

24 months (95% CI)Thoracic RT : 13 ( 8.8 − 18.7 )No Thoracic RT : 3 ( 1.5 − 7.6 )

Thoracic RT for E-SCLC: Caveats

• Well-Executed, Adequately Powered Trial• Isolates an Important Issue for SCLC• “Good” Response: Between PR and NR?

– 24% of Those Enrolled– Was There Greater or Lesser Benefit than for True

Responders?• Is There Data Regarding Symptoms or QOL?• Rad Onc QA Issues?• Toxicity Issues?

Thoracic RT for E-SCLC: Timing

• Every Limited Disease Small Cell Trial Has Shown:– Benefit to Concurrent vs Sequential Chemo-RT– Benefit to Early vs Delayed Concurrent Chemo-RT– Little to No Benefit of Sequential Chemo-RT vs Chemo

• Why would Sequential Chemo-RT Work for E-SCLC?– Non-Curative Setting– “Debulking” Chemo-Resistant Disease

Thoracic RT for E-SCLC: Does It Work?

• Hazard Ratio Goal: 0.76• Hazard Ratio Reached: 0.84 (p =0.066)

• Time Point Comparison at 2 Years not Primary Trial Endpoint

• “Thoracic RT Improves Overall Survival” Conclusion not supported by presented data.

PCI for SCLC: Current Role

• Well Established Role in LD-SCLC Pts with Response

• EORTC Trial (NEJM 2007) Established PCI as Alternative for ED-SCLC Patients: Survival Benefit!

• New Toxicity-Mitigating Approaches Under Study

• How do these two trials compare?

Seto et al: Phase III PCI Trial

StratificationStratification byby Age (70≦ / <70), PS (0-1 / 2), Response (CR / PR+MR), InstitutionsAge (70≦ / <70), PS (0-1 / 2), Response (CR / PR+MR), Institutions

Follow-up by MR Follow-up by MR imagingimaging

Primary endpoint: Overall Survival

Secondary endpoints: Time to BM (evaluated every 3 months)

Progression-Free Survival (PFS) SafetyMini Mental State Examination (MMSE)

11stst line line chemochemo

Platinum-Platinum-based based

doubletdoublet

RR

PCI: PCI: 25 Gy25 Gy10 10

fractionsfractions

no PCIno PCI

• Any response• No BM by

MRI

assessmenassessmentt

No No responseresponse

< 6 weeks< 6 weeks

3-8 weeks3-8 weeks

Phase III PCI Study Flow (Seto et al)224 out of planed 330 pts

randomizedMarch 2009 – July 2013

1st interim analysis for 165 pts

Arm A: PCI84 pts for Efficacy

Arm B: no PCI79 pts for Efficacy

3 not received PCI

2 excluded due toincomplete data

81 pts for Safety 79 pts for Safety

Time to Brain Metastasis (Seto)

Arm A: PCIn=84

Arm B: no PCIn=79

BM at 12 months 32.4% 58.0%

Gray’s test: P < 0.001 (2-sided)

Arm B: No PCIArm A: PCI

Progression-Free Survival (Seto)Arm A: PCI

n=84Arm B: no PCI

n=79

No. of PFS Events 82 76

Hazard ratio (95%CI) 1.12 (0.82-1.54)

Median PFS (95%CI), mo

2.2 (2.0-2.6) 2.4 (2.1-2.9)

Arm B: No PCIArm A: PCI

Overall Survival (Seto)

Stratified log-rank test: P=0.091 (2-sided)

Arm B: No PCIArm A: PCI

Arm A: PCIn=84

Arm B: no PCIn=79

No. of OS Events 61 50

Hazard ratio (95%CI) 1.38 (0.95-2.02)

Median OS (95%CI), mo

10.1 (8.5-13.2) 15.1 (10.2-18.7)

Symptomatic Brain Metastases (EORTC 2007)

(months)(months)

00 44 88 1212 1616 2020 2424 2828 3232 3636

00

1010

2020

3030

4040

5050

6060

7070

8080

9090

100100

PCIPCI

ControlControl

1 year: 14.6% vs. 40.4%1 year: 14.6% vs. 40.4%

HR: 0.27 (0.16-0.44) p<0.001 HR: 0.27 (0.16-0.44) p<0.001

Months from randomizationMonths from randomizationSlotman et al., NEJM 2007Slotman et al., NEJM 2007

Failure-free survival (EORTC 2007)

(months)(months)

00 33 66 99 1212 1515 1818 2121 2424 2727

00

1010

2020

3030

4040

5050

6060

7070

8080

9090

100100

PCIPCI

ControlControl

6 months: 23.4% vs. 15.5%6 months: 23.4% vs. 15.5%

HR: 0.76 (0.59-0.96) p=0.02HR: 0.76 (0.59-0.96) p=0.02

Months from randomizationMonths from randomizationSlotmanSlotman et al., NEJM 2007 et al., NEJM 2007

Overall Survival (EORTC 2007)

(months)(months)

00 44 88 1212 1616 2020 2424 2828 3232 3636

00

1010

2020

3030

4040

5050

6060

7070

8080

9090

100100

PCIPCIControlControl

1 year: 27.1% vs. 13.3%1 year: 27.1% vs. 13.3%

HR: 0.68 (0.52-0.88) p=0.003HR: 0.68 (0.52-0.88) p=0.003

Months from randomizationSlotman et al., NEJM 2007

EORTC vs Japanese PCI Trials

EORTC (Slotman

• 286 Enrolled Pts• PCI Dose: Variable• Pre-Enro

Japan (Seto)EORTC (Slotman) Japan (Seto)

# Patients 286 Enrolled 224 of 330 Enrolled

PCI Dose/Fx Variable 25 Gy/10 Fractions

Pre-Enrollment Neuro-Imaging

Not Required MR Brain Required

Follow-up Imaging

Not Required MR Brain Required

Neuro Function Data

Limited Limited

PCI for E-SCLC: Caveats

• Japanese Trial Follows Standards of US Care in Terms of Neuro-Imaging and PCI Dose

• No Information on Neuro-Toxicity but Data on this Regimen is Well Established (RTOG 0214)

• Emphasis should be on the Lack of Effect on Survival: Which is a Perfectly Plausible Result!

• How can PCI be Delivered with Better Risk/Benefit Ratio?

Hippocampus Delineation by Software

Hippocampus Avoidance with IMRT

30 Gy30 Gy

6 Gy6 Gy

3 GY3 GY

Avoidance RegionAvoidance Region

IMRT can achieve IMRT can achieve significant RT dosesignificant RT dosereduction reduction (hippocampus), (hippocampus), while delivering 30 while delivering 30 Gy to Gy to the rest of the brainthe rest of the brain

RTOG 0933: ASTRO 2013 Plenary

• Gondi, et al• 113 Brain Met Pts Enrolled in Phase II Conformal

Avoidance of Hippocampus During WBRT• HVLT Score at 4 and 6 Months: No Change• Historic Control with WBRT: 15% Decline

• This will now be tested in NRG Oncology with NCORP support in the PCI setting for Limited Stage SCLC Pts.

Consolidative RT for E-SCLC?

• Thoracic RT Consolidation for E-SCLC (Slotman et al)– Intriguing Trial!– Did not Meet Primary Endpoint– Was the Optimal Cohort Enrolled?

• PCI for E-SCLC (Seto et al)–Reduction in Brain Mets & No Survival Effect–Very Biologic Plausible Result