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

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.

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

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  1. 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

  2. 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)

  3. CREST Trial Design 4-6 platinum-based chemotherapy ES-SCLC, WHO 0-2 Stratification: • Institute • Presence of intrathoracicdisease RANDOMIZE Any response TRT (10 x 3Gy) PCI PCI

  4. Patient Characteristics (Slotman)

  5. Overall survival HR = 0.84 (95%CI 0.69-1.01) p=0.066

  6. Overall survival 24 months (95% CI) Thoracic RT : 13 ( 8.8 − 18.7 ) No Thoracic RT : 3 ( 1.5 − 7.6 ) Survival difference @ 18 Months: p=0.03 24 Months: p=0.004

  7. 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?

  8. 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

  9. 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.

  10. 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?

  11. Seto et al: Phase III PCI Trial No response PCI: 25 Gy 10 fractions 1st line chemo Platinum-based doublet • Any response • No BM by MRI assessment R no PCI < 6 weeks 3-8 weeks Follow-up by MR imaging StratificationbyAge (70≦ / <70), PS (0-1 / 2), Response (CR / PR+MR), Institutions Primary endpoint: Overall Survival Secondary endpoints: Time to BM (evaluated every 3 months) Progression-Free Survival (PFS) Safety Mini Mental State Examination (MMSE)

  12. Phase III PCI Study Flow (Seto et al) 224 out of planed 330 pts randomized March 2009 – July 2013 1st interim analysis for 165 pts 2 excluded due to incomplete data Arm A: PCI 84pts for Efficacy Arm B: no PCI 79 pts for Efficacy 3 not received PCI 81 pts for Safety 79 pts for Safety

  13. Time to Brain Metastasis (Seto) Arm A: PCI Arm B: No PCI

  14. Progression-Free Survival (Seto) Arm A: PCI Arm B: No PCI

  15. Overall Survival (Seto) Arm A: PCI Arm B: No PCI Stratified log-rank test: P=0.091 (2-sided)

  16. Symptomatic Brain Metastases (EORTC 2007) 100 90 1 year: 14.6% vs. 40.4% HR: 0.27 (0.16-0.44) p<0.001 80 70 60 50 40 Control 30 20 PCI 10 0 (months) 0 4 8 12 16 20 24 28 32 36 Months from randomization Slotman et al., NEJM 2007

  17. Failure-free survival (EORTC 2007) 100 90 6 months: 23.4% vs. 15.5% HR: 0.76 (0.59-0.96) p=0.02 80 70 PCI 60 50 40 30 20 Control 10 0 (months) 0 3 6 9 12 15 18 21 24 27 Months from randomization Slotman et al., NEJM 2007

  18. Overall Survival (EORTC 2007) 100 90 1 year: 27.1% vs. 13.3% HR: 0.68 (0.52-0.88) p=0.003 80 70 60 50 40 30 PCI 20 Control 10 0 (months) 0 4 8 12 16 20 24 28 32 36 Months from randomization Slotman et al., NEJM 2007

  19. EORTC vs Japanese PCI Trials EORTC (Slotman Japan (Seto) • 286 Enrolled Pts • PCI Dose: Variable • Pre-Enro

  20. 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?

  21. Hippocampus Delineation by Software

  22. Hippocampus Avoidance with IMRT Avoidance Region 30 Gy 6 Gy 3 GY IMRT can achieve significant RT dose reduction (hippocampus), while delivering 30 Gy to the rest of the brain

  23. 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.

  24. 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

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