extensive stage small cell lung cancer: what is the role of “consolidative” rt?
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Extensive Stage Small Cell Lung Cancer: What is the Role of “Consolidative” RT?. Walter J Curran, Jr, MD Executive Director Winship Cancer Institute of Emory University Atlanta, Georgia Group Chairman NRG Oncology. Topics for Discussion “Consolidative” RT for E-SCLC. - PowerPoint PPT PresentationTRANSCRIPT
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