Locally Advanced Nsclc

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  • Locally Advanced Nsclc

    1. 1. 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
    2. 2. Case Presentation Stage IIIB NSCLC <ul><li>A 59 year old man presents with persistent cough </li></ul><ul><li>Smoking history: 20 pack-year </li></ul><ul><li>Chest X-ray reveals a left upper lobe mass </li></ul><ul><li>CT confirms a LUL mass with multiple mediastinal lymph nodes </li></ul>LUL Mass 2L Nodes Precarinal Nodes
    3. 3. Case Presentation Stage IIIB NSCLC LUL Mass 2L Lymphadenopathy Precarinal Lymph Nodes
    4. 4. Case Presentation Stage IIIB NSCLC <ul><li>Left suprahilar mSUV 13.9 </li></ul><ul><li>Precarinal LN mSUV 5.0 </li></ul><ul><li>2R LN mSUV 4.7 </li></ul><ul><li>2L LN mSUV 8.7 </li></ul><ul><li>LN anterior to aortic arch mSUV 3.3 </li></ul>Initial Staging PET Scan
    5. 5. Case Presentation Stage IIIB NSCLC <ul><li>Which treatment option would you recommend? </li></ul><ul><ul><li>Radiotherapy alone </li></ul></ul><ul><ul><li>Chemotherapy alone </li></ul></ul><ul><ul><li>Sequential chemoradiotherapy </li></ul></ul><ul><ul><li>Concurrent chemoradiotherapy </li></ul></ul><ul><ul><li>Other </li></ul></ul>
    6. 6. 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
    7. 7. Background: Stage III NSCLC <ul><li>Traditionally considered surgically unresectable & incurable </li></ul><ul><li>Stage III NSCLC is heterogeneous (many distinct subsets) </li></ul><ul><li>Radiotherapy (RT) alone remained standard of care for unresectable stage III NSCLC until early 1990s </li></ul><ul><ul><li>Traditional RT dose and technique yielded poor survival rates: </li></ul></ul><ul><ul><ul><li>2-year: 15% </li></ul></ul></ul><ul><ul><ul><li>5-year: 5% </li></ul></ul></ul><ul><li>Combined modality therapy (chemotherapy + radiotherapy and/or surgery) has now emerged as the standard of care </li></ul>
    8. 8. Locally Advanced NSCLC – 1980’s <ul><li>Sequential Chemoradiation Therapy Improves Survival Compared to Radiation Alone </li></ul><ul><li> 2-year Overall Survival </li></ul><ul><ul><li>Trial Pts. RT CT RT </li></ul></ul><ul><ul><li>Finnish 238 17% 19% </li></ul></ul><ul><ul><li>NCCTG 107 16% 21% </li></ul></ul><ul><ul><li>CALGB 155 13% 26% </li></ul></ul><ul><ul><li>IGR-French 331 14% 21% </li></ul></ul>
    9. 9. Locally Advanced NSCLC – 1990’s <ul><li>What is the optimal sequence of chemoradiation and radiation fractionation? </li></ul>
    10. 10. Optimal Sequence of Chemoradiation <ul><li>West Japan LC Group </li></ul><ul><li>Sequential: MVP x 2  Stn RT Day 50 </li></ul><ul><li>Concurrent: MVP x 2/Stn RT Day 1 </li></ul><ul><li>RTOG 9410 </li></ul><ul><li>Sequential: Vinb/CisP x 2  Stn RT Day 50 </li></ul><ul><li>Conc D: Vinb/CisP x 2/Stn RT Day 1 </li></ul><ul><li>Conc BID: CisP/Eto x 2/BID RT Day 1 </li></ul><ul><li>French Trial </li></ul><ul><li>Sequential: CisP/Nav  Stn RT Day 50 </li></ul><ul><li>Concurrent : CisP/Etop x2/RT  CisP/Etop </li></ul><ul><li>Czech Trial </li></ul><ul><li>Sequential: Cisp/Nav X4  RT </li></ul><ul><li>Concurrent: Cisp/Nav/RT  Cisp/Nav </li></ul><ul><li>LAMP </li></ul><ul><li>Sequential: Paclitaxel/Carbo  RT </li></ul><ul><li> Induction  Conc: Paclitaxel/Carbo  p/c/RT </li></ul><ul><li>Conc  Consolidation:p/c/RT  Paclitaxel/Carbo </li></ul><ul><li>BROCAT </li></ul><ul><li>Sequential: Paclitaxel/Carbo x 2  RT alone </li></ul><ul><li>Concurrent: Paclitaxel/Carbo x 2  Wkly Paclitaxel/RT </li></ul>
    11. 11. Survival Comparison Between Sequential and Concurrent Chemoradiation Therapy P < 0.05 (Kruskal-Wallis Test) 14 (n=716) 17 (n=709)
    12. 12. Long Term Survival Comparison Between Sequential and Concurrent Chemoradiation Therapy WJLCG % 5 yr OS 9% 19% RTOG 9410 % 4 yr OS 12% 21% Is Concurrent Chemoradiation now Standard of Care? Yes: for good performance status & pulmonary function; low comorbidities
    13. 13. Survival Improvement with Chemoradiotherapy in Stage III NSCLC since 1980’s 9.8 13.8 17.7
    14. 14. Clinical Research Issues in Chemoradiotherapy of Stage III NSCLC <ul><li>Optimizing radiotherapy </li></ul><ul><ul><li>Total dose: are higher doses better? </li></ul></ul><ul><ul><li>Target volume </li></ul></ul><ul><ul><li>Fractionation: daily vs twice daily? </li></ul></ul><ul><ul><li>Sterotactic body radiotherapy (SBRT) </li></ul></ul><ul><li>Optimizing chemotherapy </li></ul><ul><ul><li>New drugs: are they better? </li></ul></ul><ul><ul><li>Dose Schedule: full dose vs low dose? </li></ul></ul><ul><ul><li>Induction or consolidation? </li></ul></ul><ul><li>Prevention of brain metastases </li></ul><ul><li>Integration of molecular targeted therapies </li></ul><ul><li>Improved staging techniques (functional imaging) </li></ul>
    15. 15. Optimizing Radiotherapy Involved Volume Approaches <ul><li>Issues: </li></ul><ul><li>1. STDF: Can not deliver High Dose RT </li></ul><ul><li>Increased Pneumonitis, Esophagitis </li></ul><ul><li>2. IF: Need reliably defined target ( T1/2, T3/4 ?) </li></ul><ul><li>Immobilization </li></ul><ul><li>Risk of not treating LN may be too high ! </li></ul><ul><li>3. We need a prospective trial comparing STDF vs. IF </li></ul>Tumor = 50 Gy 63 Gy STDF Tumor 50 Gy 63 +Gy IF
    16. 16. Optimizing Radiotherapy Involved Volume Approaches <ul><li>Stage III NSCLC: Chemo  Chemo/RT (200 patients randomized) </li></ul><ul><ul><ul><ul><li>2 yr LF 1yr OS 2 yr OS 3 yr OS </li></ul></ul></ul></ul><ul><li>ENI 49 59.7 25.6 19.2 </li></ul><ul><li>IFRT 41 67.2 38.7 27.3 </li></ul><ul><li>P = 0.048 </li></ul>STDF IF Yuan , ASCO 2006, Abstract # 7044 Tumor 50Gy 60-64Gy Tumor 50Gy 68-74Gy
    17. 17. Optimizing Radiotherapy High Dose Approaches <ul><li>Group RT Dose Median Sv </li></ul><ul><li>RTOG 9410 63 Gy 17.1 mos </li></ul><ul><li>RTOG 0117* 74 Gy 21.6 mos </li></ul><ul><li>NCCTG N0028* 74 Gy 37 mos </li></ul><ul><li>CALGB 30105* 74 Gy 24.6 mos </li></ul><ul><li>North Carolina* 74 Gy 24 mos </li></ul>* Low dose weekly chemo/RT
    18. 18. Optimizing Radiotherapy High Dose Approaches VS STD Dose Tumor 64 cGy High Dose Tumor 74 cGy
    19. 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 <ul><li>Participating Groups </li></ul><ul><ul><li>RTOG 0617 </li></ul></ul><ul><ul><li>NCCTG </li></ul></ul><ul><ul><li>CALGB </li></ul></ul><ul><ul><li>ECOG? </li></ul></ul>
    20. 20. Optimizing Radiotherapy High Dose Approaches <ul><li>Accrual target is 512 patients </li></ul><ul><li>Target accrual of 9 pts/month = 56 mos </li></ul><ul><li>Estimated MS for control arm = 17.1 mos vs 24 mos for experimental arm </li></ul>VS STD Dose Tumor 64 cGy High Dose Tumor 74 cGy
    21. 21. Chemotherapeutic Agents for Concurrent Chemoradiation Therapy: 1990’s–2000’s <ul><li>Paclitaxel </li></ul><ul><li>Irinotecan </li></ul><ul><li>Docetaxel </li></ul><ul><li>Vinorelbine </li></ul><ul><li>Gemcitabine </li></ul><ul><li>Pemetrexed </li></ul>
    22. 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 CPT-11/RT - 61 38 CPT-11/Carbo/RT - 55 62 51 45 CPT-11/CisP/RT - 72 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 Gem/RT(CALGB) 18 65 40 Nav/RT (CALGB) 17 68 38
    23. 23. Optimizing Chemotherapy Phase II Trial of Cisplatin/Etoposide + RT -> Consolidation Docetaxel (SWOG 9504) 3 year survival 37% 4 year survival 29% 5 year survival 29% Gandara: ASCO 05 Requires Confirmation 0% 20% 40% 60% 80% 100% 0 24 48 72 96 Months After Registration N 83 Events 62 Median Survival 26 mos
    24. 24. Optimizing Chemotherapy Confirmation Study for Consolidation Hoosier Oncology Group (LUN 01-24) <ul><li>ChemoRT Induction Cisplatin 50 mg/m 2 d 1,8,29,36 Etoposide 50 mg/m 2 IV d 1-5 & 29-33 Concurrent RT 59.4 Gy (1.8 Gy/fr) </li></ul>CR, PR, or SD; ECOG PS 0-2 Taxotere 75 mg/m 2 q 3 wk  3 Observation Randomize
    25. 25. Molecular-Targeted Combined-Modality Therapy <ul><li>Novel strategy resulting from increased understanding of underlying pathways and key molecules involved in tumor growth and progression </li></ul><ul><li>Specificity of molecular-targeted therapy should improve therapeutic window by affecting tumor cells and sparing normal cells </li></ul>
    26. 26. Head and Neck Phase III Randomized Trial of Cetuximab Bonner JA, et al. NEJM 2006 RTX Alone (qd or bid) RTX (qd or bid) Week 1 2 3 4 5 6 7 8 IMC-C225 Maintenance Doses IMC-C225 Loading Dose Registration, Stratify: 1, T1-3 vs. T4 2, N0 vs. N1 3. Fractionation 4. KPS (60 - 80% vs. 90-100%)
    27. 27. Phase III Randomized Trial of Cetuximab Locoregional Control P = 0.02 Probability Months Bonner JA, et al. NEJM 2006 36 mos 19 mos Median Survival 90 105 Events 211 213 Patients RT + E RT
    28. 28. Phase III Randomized Trial of Cetuximab Overall Survival Bonner JA, et al. NEJM 2006 54 mos 28 mos Median Survival 93 117 Events 211 213 Patients RT + E RT Probability 0.0 0.2 0.4 0.6 0.8 1.0 0 6 12 18 24 30 36 42 48 54 60 Months P = 0.02
    29. 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 3*(1) 14* – 2 Infusion reaction*** 4 (<1) 52 5 (1 ) 50 Fatigue/Malaise 4 ( –) 64 3 ( –) 70 Xerostomia 25 (<1) 64 30 (1) 63 Dysphagia 54 (6) 91 52 (4) 93 Mucositis/Stomatitis 34*(2) 97* 18 (<1) 91 Skin reaction G /4** All Gr. G /4** All Gr. % with toxicity RT+E (N=208) RT (N=212)
    30. 30. SWOG 0023: A Phase III Trial in Unresectable Stage III NSCLC CDDP/VP-16 XRT Docetaxel Placebo Definitive TX Consolidation Maintenance CDDP/VP-16 XRT RANDOMIZE Docetaxel ZD1839 250
    31. 31. SWOG 0023: A Phase III Trial in Unresectable Stage III NSCLC CDDP/VP-16 XRT Docetaxel Placebo Definitive TX Consolidation Maintenance CDDP/VP-16 XRT RANDOMIZE Docetaxel CLOSED – Gefitinib Not Better ZD1839 250
    32. 32. Preliminary Results of SWOG 0023 Causes of Deaths by Treatment Arm 32 43 Dead 6 5 Under Review 0 1 Toxicity from Chemo/RT 4 2 Other Causes 3 2 Disease + Toxicity 0 1 Toxicity 19 (59%) 32 (74%) Disease 99 81 Alive Placebo (n=146) Gefitinib (n=138) Parameter
    33. 33. 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 Day 8: C225 : 250 mg/m² wkly /7 Taxol/Carbo RT : 63Gy Day 1 : C225 400 mg/m 2 IV loading dose Taxol/Carbo C225 : 250mg/m² weekly x 6
    34. 34. 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 R A N D O M I Z E Arm A Arm B Carboplatin AUC 6 q3 week x 4 cycles Pemetrexed 500 mg/m² q3 week x 8 cycles XRT - 6600 cGy over 7 weeks 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
    35. 35. S0533: Integration of Bevacizumab into Chemoradiation Cohort 1 ( A introduced after Chemoradiotherapy) Concurrent Chemoradiotherapy  Consolidation Chemotherapy Concurrent Chemotherapy X X X X RT Consolidation Chemotherapy D A D A D A Cohort 2 ( A introduced on day 8 during Chemoradiotherapy) Concurrent Chemoradiotherapy  Consolidation Chemotherapy Concurrent Chemotherapy X X A X A X RT Consolidation Chemotherapy D A D A D A Cohort 3 ( A introduced on day 1 of Chemoradiotherapy) Concurrent Chemoradiotherapy  Consolidation Chemotherapy Concurrent Chemotherapy X A X X A X RT Consolidation Chemotherapy D A D A D A XX: Cisplatin/Etoposide; D: Docetaxel; A: Bevacizumab
    36. 36. Pattern of Metastatic Disease <ul><li>Lun 56 Lun 63 SWOG9504 </li></ul><ul><li>Sites #of Pts. #of Pts. #of Pts. </li></ul><ul><li>Brain Only 5 5 8 </li></ul><ul><li>Brain & Other 2 4 15 </li></ul><ul><li>Other Sites 3 4 3 </li></ul><ul><li>TOTAL 10 13 29 </li></ul><ul><li>Brain mets 7/10 9/13 23/29 </li></ul>CNS Relapse 70% 69% 79% Rate
    37. 37. 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). Stage III NSCLC Patients Observation PCI: 30 Gy/15 fx Evaluate Neurotoxicity N = 1058
    38. 38. Survival Improvement with Chemoradiotherapy in Stage III NSCLC Since 1980–2010 ? +PCI
    39. 39. Case Presentation Stage IIIB NSCLC <ul><li>A 59 year old man presents with persistent cough. </li></ul><ul><li>Smoking history: 20 pack-year </li></ul><ul><li>Chest X-ray reveals a left upper lobe mass </li></ul><ul><li>CT confirms a LUL mass with multiple mediastinal lymph nodes </li></ul>LUL Mass 2L Nodes Precarinal Nodes
    40. 40. Case Presentation Stage IIIB NSCLC LUL Mass 2L Lymphadenopathy Precarinal Lymph Nodes
    41. 41. Case Presentation Stage IIIB NSCLC <ul><li>Left suprahilar mSUV 13.9 </li></ul><ul><li>Precarinal LN mSUV 5.0 </li></ul><ul><li>2R LN mSUV 4.7 </li></ul><ul><li>2L LN mSUV 8.7 </li></ul><ul><li>LN anterior to aortic arch mSUV 3.3 </li></ul>Initial Staging PET Scan
    42. 42. Case Presentation Stage IIIB NSCLC <ul><li>Which treatment option would you recommend? </li></ul><ul><ul><li>Radiotherapy alone </li></ul></ul><ul><ul><li>Chemotherapy alone </li></ul></ul><ul><ul><li>Sequential chemoradiotherapy </li></ul></ul><ul><ul><li>Concurrent chemoradiotherapy </li></ul></ul><ul><ul><li>Other </li></ul></ul>
    43. 43. Following Completion of Concurrent Cisplatin/Etoposide + Radiation  Consolidation Docetaxel <ul><li>Resolution of 2L Lymphadenopathy </li></ul>Resolution of LUL Mass and Precarinal Lymph Nodes
    44. 44. Case Presentation Stage IIIB NSCLC Follow up PET Scan Shows Complete Remission
    45. 45. Locally Advanced NSCLC Conclusions <ul><li>Combined modality therapy has improved the survival of stage III NSCLC, providing long term survival in a subset of patients </li></ul><ul><li>Current research efforts are attempting to optimize chemotherapy and radiotherapy </li></ul><ul><li>Studies integrating new molecular targeted therapies are ongoing </li></ul>
    46. 46. Emerging Novel Combined Modality Treatment Approaches to Improve Outcomes for Locally Advanced NSCLC Combined Modality Therapy of Stage III NSCLC State of the Art DISCUSSION

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