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Hak Choy, MD UT Southwestern Medical Center

Emerging Novel Combined Modality Treatment Approaches to Improve Outcomes for Locally Advanced NSCLC Combined Modality Therapy of Stage III NSCLC State of the Art. Hak Choy, MD UT Southwestern Medical Center. Case Presentation Stage IIIB NSCLC. A 59 year old man presents with persistent cough

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Hak Choy, MD UT Southwestern Medical Center

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  1. Emerging Novel Combined Modality Treatment Approaches to Improve Outcomes for Locally Advanced NSCLCCombined Modality Therapy of Stage III NSCLCState of the Art Hak Choy, MD UT Southwestern Medical Center

  2. Case PresentationStage IIIB NSCLC • A 59 year old man presents with persistent cough • Smoking history: 20 pack-year • Chest X-ray reveals a left upper lobe mass • CT confirms a LUL mass with multiple mediastinal lymph nodes 2L Nodes LUL Mass Precarinal Nodes

  3. LUL Mass 2L Lymphadenopathy Precarinal Lymph Nodes Case PresentationStage IIIB NSCLC

  4. Case PresentationStage IIIB NSCLC Initial Staging PET Scan • Left suprahilar mSUV 13.9 • Precarinal LN mSUV 5.0 • 2R LN mSUV 4.7 • 2L LN mSUV 8.7 • LN anterior to aortic arch mSUV 3.3

  5. Case PresentationStage IIIB NSCLC • Which treatment option would you recommend? • Radiotherapy alone • Chemotherapy alone • Sequential chemoradiotherapy • Concurrent chemoradiotherapy • Other

  6. Emerging Novel Combined Modality Treatment Approaches to Improve Outcomes for Locally Advanced NSCLCCombined Modality Therapy of Stage III NSCLCState of the Art Hak Choy, MD UT Southwestern Medical Center

  7. Background: Stage III NSCLC • Traditionally considered surgically unresectable & incurable • Stage III NSCLC is heterogeneous (many distinct subsets) • Radiotherapy (RT) alone remained standard of care for unresectable stage III NSCLC until early 1990s • Traditional RT dose and technique yielded poor survival rates: • 2-year: 15% • 5-year: 5% • Combined modality therapy (chemotherapy + radiotherapy and/or surgery) has now emerged as the standard of care

  8. Sequential Chemoradiation Therapy Improves Survival Compared to Radiation Alone Locally Advanced NSCLC – 1980’s • 2-year Overall Survival • Trial Pts. RT CT RT • Finnish 238 17% 19% • NCCTG 107 16% 21% • CALGB 155 13% 26% • IGR-French 331 14% 21%

  9. Locally Advanced NSCLC – 1990’s • What is the optimal sequence of chemoradiation and radiation fractionation?

  10. West Japan LC Group Sequential: MVP x 2  Stn RT Day 50 Concurrent: MVP x 2/Stn RT Day 1 RTOG 9410 Sequential: Vinb/CisP x 2 Stn RT Day 50 Conc D: Vinb/CisP x 2/Stn RT Day 1 Conc BID: CisP/Eto x 2/BID RT Day 1 French Trial Sequential: CisP/NavStn RT Day 50 Concurrent : CisP/Etop x2/RT CisP/Etop Czech Trial Sequential: Cisp/Nav X4 RT Concurrent: Cisp/Nav/RTCisp/Nav LAMP Sequential: Paclitaxel/Carbo  RT Induction  Conc: Paclitaxel/Carbo  p/c/RT Conc Consolidation:p/c/RT Paclitaxel/Carbo BROCAT Sequential: Paclitaxel/Carbo x 2 RT alone Concurrent: Paclitaxel/Carbo x 2 Wkly Paclitaxel/RT Optimal Sequence of Chemoradiation

  11. 17 (n=709) 14 (n=716) Survival Comparison Between Sequential and Concurrent Chemoradiation Therapy P < 0.05 (Kruskal-Wallis Test)

  12. RTOG 9410 WJLCG 21% 19% % 4 yr OS % 5 yr OS 12% 9% Is Concurrent Chemoradiation now Standard of Care? Yes: for good performance status & pulmonary function; low comorbidities Long Term Survival Comparison Between Sequential and Concurrent Chemoradiation Therapy

  13. 9.8 13.8 17.7 Survival Improvement with Chemoradiotherapy in Stage III NSCLC since 1980’s

  14. Clinical Research Issues in Chemoradiotherapy of Stage III NSCLC • Optimizing radiotherapy • Total dose: are higher doses better? • Target volume • Fractionation: daily vs twice daily? • Sterotactic body radiotherapy (SBRT) • Optimizing chemotherapy • New drugs: are they better? • Dose Schedule: full dose vs low dose? • Induction or consolidation? • Prevention of brain metastases • Integration of molecular targeted therapies • Improved staging techniques (functional imaging)

  15. Issues: 1. STDF: Can not deliver High Dose RT Increased Pneumonitis, Esophagitis 2. IF: Need reliably defined target ( T1/2, T3/4 ?) Immobilization Risk of not treating LN may be too high ! 3. We need a prospective trial comparing STDF vs. IF STDF IF Tumor = Tumor 50 Gy 50 Gy 63 Gy 63 +Gy Optimizing Radiotherapy Involved Volume Approaches

  16. Stage III NSCLC: ChemoChemo/RT (200 patients randomized) 2 yr LF 1yr OS 2 yr OS 3 yr OS ENI 49 59.7 25.6 19.2 IFRT 41 67.2 38.7 27.3 P = 0.048 Tumor Tumor 50Gy 50Gy 60-64Gy 68-74Gy Optimizing Radiotherapy Involved Volume Approaches STDF IF Yuan , ASCO 2006, Abstract # 7044

  17. GroupRT DoseMedian Sv RTOG 9410 63 Gy 17.1 mos RTOG 0117* 74 Gy 21.6 mos NCCTG N0028* 74 Gy 37 mos CALGB 30105* 74 Gy 24.6 mos North Carolina* 74 Gy 24 mos Optimizing Radiotherapy High Dose Approaches * Low dose weekly chemo/RT

  18. STD Dose High Dose Tumor Tumor 64 cGy 74 cGy Optimizing Radiotherapy High Dose Approaches VS

  19. A Randomized Phase III Comparison of Standard Dose (63 Gy) vs High-Dose Conformal Radiotherapy (74 Gy) with Concurrent Consolidation Carboplatin/Paclitaxel in Patients with Stage IIIA/B NSCLC • Participating Groups • RTOG 0617 • NCCTG • CALGB • ECOG?

  20. Accrual target is 512 patients Target accrual of 9 pts/month = 56 mos Estimated MS for control arm = 17.1 mos vs 24 mos for experimental arm STD Dose High Dose Tumor Tumor 64 cGy 74 cGy Optimizing Radiotherapy High Dose Approaches VS

  21. Chemotherapeutic Agents for Concurrent Chemoradiation Therapy: 1990’s–2000’s • Paclitaxel • Irinotecan • Docetaxel • Vinorelbine • Gemcitabine • Pemetrexed

  22. Stage III NSCLC Treatment Outcome Based on Agent Study-RT (Gy) Chemo MS (mos) 1 yr (%) 2 yr (%) Paclitaxel/RT 20.0 66 36 P/C/RT 20.5 54 46 P/C/HFX RT 14.3 18.1 61 61 35 41 P/C/3-D RT 26 70 51 P/C/RT(CALGB) 14 56 43 P(tw)/C/RT 17 - 40 Docetaxel/RT 12 48 - Docetaxel/RT 13.6 59 Doc/CisP/RT 23 18.2 74 63 41 44 Doc/CisP/RT 15 55 43 PE/RT-Doc 27 78 54 CPT-11/RT - 61 38 CPT-11/Carbo/RT - 55 62 51 45 CPT-11/CisP/RT - 72 Gem/RT(CALGB) 18 65 40 Nav/RT (CALGB) 17 68 38

  23. 100% 80% N Events Median Survival 83 62 26 mos 60% 40% 20% 0% 0 24 48 72 96 Months After Registration Optimizing ChemotherapyPhase II Trial of Cisplatin/Etoposide + RT → Consolidation Docetaxel (SWOG 9504) Requires Confirmation 3 year survival 37% 4 year survival 29% 5 year survival 29% Gandara: ASCO 05

  24. ChemoRT InductionCisplatin 50 mg/m2 d 1,8,29,36Etoposide 50 mg/m2 IV d 1-5 & 29-33Concurrent RT 59.4 Gy (1.8 Gy/fr) Optimizing ChemotherapyConfirmation Study for Consolidation Hoosier Oncology Group (LUN 01-24) CR, PR, or SD;ECOG PS 0-2 Randomize Taxotere 75 mg/m2 q 3 wk  3 Observation

  25. Molecular-Targeted Combined-Modality Therapy • Novel strategy resulting from increased understanding of underlying pathways and key molecules involved in tumor growth and progression • Specificity of molecular-targeted therapy should improve therapeutic window by affecting tumor cells and sparing normal cells

  26. IMC-C225 Loading Dose IMC-C225 Maintenance Doses Week 1 2 3 4 5 6 7 8 RTX (qd or bid) Registration, Stratify: 1, T1-3 vs. T4 2, N0 vs. N1 3. Fractionation 4. KPS (60 - 80% vs. 90-100%) RTX Alone (qd or bid) Head and NeckPhase III Randomized Trial of Cetuximab Bonner JA, et al. NEJM 2006

  27. Phase III Randomized Trial of Cetuximab Locoregional Control P = 0.02 Probability Months Bonner JA, et al. NEJM 2006

  28. 1.0 0.8 P = 0.02 0.6 Probability 0.4 0.2 0.0 0 6 12 18 24 30 36 42 48 54 60 Months Phase III Randomized Trial of Cetuximab Overall Survival Bonner JA, et al. NEJM 2006

  29. Phase III Randomized Trial of Cetuximab Most Common Adverse Events *P < 0.05 ** Grade 4 in ( ) *** Listed for its relationship to Erbitux Bonner JA, et al. NEJM 2006

  30. ZD1839 250 SWOG 0023: A Phase III Trial in Unresectable Stage III NSCLC Definitive TXConsolidationMaintenance RANDOMIZE CDDP/VP-16 XRT Docetaxel Placebo CDDP/VP-16 XRT Docetaxel

  31. ZD1839 250 SWOG 0023: A Phase III Trial in Unresectable Stage III NSCLC Definitive TXConsolidationMaintenance RANDOMIZE CDDP/VP-16 XRT Docetaxel Placebo CLOSED – Gefitinib Not Better CDDP/VP-16 XRT Docetaxel

  32. Preliminary Results of SWOG 0023 Causes of Deaths by Treatment Arm

  33. Day 8: C225: 250 mg/m² wkly/7 Taxol/Carbo RT: 63Gy Day 1: C225 400 mg/m2 IV loading dose Taxol/Carbo C225: 250mg/m² weekly x 6 RTOG 0234: A Phase II Study of Cetuximab in Combination with Chemoradiation in Subjects with Stage IIIA/B NSCLC Closed in 5/05 - 93 patients

  34. Carboplatin AUC 6 q3 week x 4 cycles Pemetrexed 500 mg/m² q3 week x 8 cycles XRT - 6600 cGy over 7 weeks R A N D O M I Z E Arm A Carboplatin AUC 6 q3 week x 4 cycles Pemetrexed 500 mg/m² q3 week x 8 cycles XRT - 6600 cGy over 7 weeks + Cetuximab 400 mg/m² loading and 250 mg/m² weekly Arm B CALGB Concurrent Carboplatin, Pemetrexed, and Radiation Therapy followed by Carboplatin, Pemetrexed with or without Cetuximab for Patients with Unresectable Stage III NSCLC A Randomized Phase II Trial

  35. Cohort 1(A introduced after Chemoradiotherapy) Concurrent Chemoradiotherapy  Consolidation Chemotherapy Concurrent Chemotherapy X X X X RT Consolidation Chemotherapy DA DA DA Cohort 2(A introduced on day 8 during Chemoradiotherapy) Concurrent Chemoradiotherapy  Consolidation Chemotherapy Concurrent Chemotherapy X XA XAX RT Consolidation Chemotherapy DA DA DA Cohort 3(A introduced on day 1 of Chemoradiotherapy) Concurrent Chemoradiotherapy  Consolidation Chemotherapy Concurrent Chemotherapy XA X XA X RT Consolidation Chemotherapy DA DA DA XX: Cisplatin/Etoposide; D: Docetaxel; A: Bevacizumab S0533: Integration of Bevacizumab into Chemoradiation

  36. Lun 56 Lun 63 SWOG9504 Sites #of Pts. #of Pts. #of Pts. Brain Only 5 5 8 Brain & Other 2 4 15 Other Sites 3 4 3 TOTAL 10 13 29 Brain mets 7/10 9/13 23/29 Pattern of Metastatic Disease CNS Relapse 70% 69% 79% Rate

  37. Observation Stage III NSCLC Patients Evaluate Neurotoxicity N = 1058 PCI: 30 Gy/15 fx A Phase III Comparison of Prophylactic Cranial Irradiation vs Observation in Patients with Locally Advanced Non-small Cell Lung Cancer (RTOG 0214) *Patients with partial response to locoregional therapy and Zubrod Performance Score 0 or 1 (KPS 70-100) or have complete response to therapy and Zubrod Performance Score 0-2 (KPS 50-100).

  38. Survival Improvement with Chemoradiotherapy in Stage III NSCLC Since 1980–2010 ? +PCI

  39. Case PresentationStage IIIB NSCLC • A 59 year old man presents with persistent cough. • Smoking history: 20 pack-year • Chest X-ray reveals a left upper lobe mass • CT confirms a LUL mass with multiple mediastinal lymph nodes 2L Nodes LUL Mass Precarinal Nodes

  40. Case PresentationStage IIIB NSCLC • Which treatment option would you recommend? • Radiotherapy alone • Chemotherapy alone • Sequential chemoradiotherapy • Concurrent chemoradiotherapy • Other

  41. Resolution of 2L Lymphadenopathy Resolution of LUL Mass and Precarinal Lymph Nodes Following Completion of Concurrent Cisplatin/Etoposide + Radiation  Consolidation Docetaxel

  42. Case PresentationStage IIIB NSCLC Follow up PET Scan Shows Complete Remission

  43. Locally Advanced NSCLCConclusions • Combined modality therapy has improved the survival of stage III NSCLC, providing long term survival in a subset of patients • Current research efforts are attempting to optimize chemotherapy and radiotherapy • Studies integrating new molecular targeted therapies are ongoing

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