มะเร็งปอด ประชุมองค์กรแพทย์ 2003 ppt

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มะเร็งปอด ประชุมองค์กรแพทย์ 2003 ppt

  1. 1. Therapeutic Options for First Line Advanced Non Small Cell Lung Cancer นพ.จิรเจษฎ์ สุขสุเพิ่ม อายุรแพทย์โรคมะเร็ง ศูนย์มะเร็ง รพ.จุฬารัตน์ 9
  2. 2. นพ.จิรเจษฎ์ สุขสุเพิ่ม อายุรแพทย์โรคมะเร็ง ศูนย์มะเร็ง รพ.จุฬารัตน์ 9 ศูนย์มะเร็ง รักษามะเร็งปอด และ ให ้คาแนะนาเกี่ยวกับ - Medical Pleurodesis for malignant Pleural effusion - Conventional Intraveneous Chemotherapy ทุกชนิด : Carbo/Gemcitabine - Choice of Oral chemo : Navelbine , Etoposide - Intraveneous Anti Vascular Growth Factor (Avastin) - Oral targeted TKIs : Gefitinib , Erlotinib - Oral targeted Anti-ALK : Crizotinib •
  3. 3. นพ.จิรเจษฎ์ สุขสุเพิ่ม อายุรแพทย์โรคมะเร็ง ศูนย์มะเร็ง รพ.จุฬารัตน์ 9 ศูนย์มะเร็ง รักษามะเร็งปอด และ ให ้คาแนะนาเกี่ยวกับ Growth factors support : - Filgastrim for Neutropenia (มี PEG filgastrim form ฉีดเข็มเดียว=แบบ ODx5) - Oral Eltrombopax for Thrombocytopenia (Platelet drop from chemo) - PAIN control Solution Non Opioid to all Opioid (MO syrup is in process) - Zoledronic acid (Zometa/Local brand) for releive Bone PAIN - RadioTherapy : Convention, IMRT 3มิติ (ศูนย์มะเร็งกรุงเทพ ซ.อารีย์) - ให ้คาแนะนา BrachyTherapy (ฝังแร่) และ ประสานส่งตัว - Contact of Bone scan (อุรุพงษ์) PET Scan (ศูนย์จุฬาภรณ์) - Genetic test : EGFR mutation, ALK rearrange (N-health)
  4. 4. Lung Cancer: A Leading Cause of Cancer-Related Deaths  221,130 new cases of lung cancer  156,940 deaths due to lung cancer Men Lung and bronchus 28% Prostate 11% Colon and rectum 8% Pancreas 6% Leukemia 4% Women Lung and bronchus 26% Breast 15% Colon and rectum 9% Pancreas 7% Ovary 6% Leading Sites* by Sex, United States, 2010 Estimates *Excludes basal and squamous cell skin cancer, and in situ carcinomas except urinary bladder. American Cancer Society. Cancer Facts & Figures 2011.
  5. 5. Risk Factors for Lung Cancer  Smoking  Lung cancer deaths due to smoking  ~ 91% males and 80% females[1]  Environmental factors[2]  Second-hand smoke 3% to 5%  Radon 3% to 5%  Industrial pollution 0% to 5%  Radiation exposureRare  Asbestos, radon, radiation, silicosis, and berylliosis  Arsenic exposure, talc, obesity, genetic factors 1. CDC. Lung Cancer. 2011. 2. American Cancer Society. Lung Cancer. 2011.
  6. 6. Lung Cancer Subtypes  The WHO classification for primary lung cancer recognizes 4 major histology types[1] Small-cell carcinoma 13.0% Large-cell carcinoma 5.0% Adenocarcinoma 38.3% 19.7% Squamous cell carcinoma Other* 24.0% Percent distribution by histology among histologically confirmed lung cancer cases, 2001-2004[2] 1. Brambilla E, et al. Eur Respir J. 2001;18:1059-1068.2. SEER Database. Lung and Bronchus Cancer (Invasive), 1975-2004. *Including adenosquamous carcinoma; carcinomas with pleomorphic, sarcomatoid or sarcomatous elements; carcinoid tumor; carcinomas of salivary gland type; and unclassified carcinoma
  7. 7. 6th Edition Descriptor 7th Edition N0 N1 N2 N3 T1 (≤ 2 cm) T1a IA IIA IIIA IIIB T1 (> 2-3 cm) T1b IA IIA IIIA IIIB T2 (> 3 to ≤ 5 cm) T2a IB IIA IIIA IIIB T2 (> 5-7) T2b IIA IIB IIIA IIIB T2 (> 7 cm) T3 IIB IIIA IIIA IIIB T3 invasion IIB IIIA IIIA IIIB T4 (same lobe nodules) IIB IIIA IIIA IIIB T4 (extension) T4 IIIA IIIA IIIB IIIB M1 (ipsilateral lung) IIIA IIIA IIIB IIIB T4 (pleural effusion) M1a IV IV IV IV M1 (contralateral lung) IV IV IV IV M1 (distant) M1b IV IV IV IV 7th Edition of TNM Staging Goldstraw P, et al. J Thorac Oncol. 2007;2:706-714.
  8. 8. Chemotherapy vs Best Supportive Care in Advanced NSCLC: Meta- Analysis  Meta-analysis of 8 trials (778 patients) using cisplatin-based chemotherapy[1]  Absolute improvement in survival of 10% at 1 yr[1]  Median survival, BSC vs chemo: 4 vs 8+ mos, respectively  Median survival now 12+ mos in more recent trials  VEGF-targeted therapy plus platinum doublet[2]  Quality-of-life benefit from chemotherapy[3] 1. NSCLC Collaborative Group, et al. BMJ. 1995;311:899-909. 2. Herbst R, et al. Clin Lung Cancer. 2009;10:20-27 3. Klastersky J, et al. Lung Cancer. 2001;34(suppl 4):S95-S101.
  9. 9. First-line Treatment: 2 Agents Are More Effective Than 1  Meta-analysis: 65 trials (N = 13,601) between 1980-2001  Compared efficacy of  Doublet vs single-agent regimens  Triplet vs doublet regimens Delbaldo C, et al. JAMA. 2004;292:470-484. Survival Outcome Doublet vs Single-Agent Regimens Triplet vs Doublet Regimens 1-yr OS Doublet > single-agent  OR: 0.80; 95% CI: 0.70-0.91; P < .001  5% absolute benefit Triplet = doublet  OR: 1.01; 95% CI: 0.85-1.21; P = .88 Median OS Doublet > single-agent  MR: 0.83; 95% CI: 0.79-0.89; P < .001 Triplet = doublet  MR: 1.00; 95% CI: 0.94-1.06; P = .97
  10. 10. Agents With Activity in Advanced NSCLC *Not all drugs listed have FDA approval. Older Agents* Newer Agents*  Carboplatin  Cisplatin  Etoposide  Ifosfamide  Mitomycin C  Vinblastine  Vindesine  Docetaxel  Gemcitabine  Irinotecan  Paclitaxel  Topotecan  Vinorelbine  Pemetrexed  Gefitinib  Erlotinib  Bevacizumab  Cetuximab  Crizotinib
  11. 11. History of Therapy in Advanced NSCLC: FDA Approval Dates First line Second line Third line Maintenance Not approved 1970 1980 1990 2000 Median OS (mos) 12+ ~ 6 ~ 2-4 BSC Single-agent platinum Doublets Bevacizumab + PC Carboplatin* 1989 Erlotinib Pemetrexed 2004 Docetaxel 1999 Paclitaxel Gemcitabine 1998 Vinorelbine 1994 Docetaxel 2002 Bevacizumab 2006 Gefitinib 2003 Standard therapies *Label does not include NSCLC-specific indication Pemetrexed 2008/2009 Histology-directed therapy ~ 8-10 Cisplatin* 1978 1. FDA Web site. 2. NCCN. Clinical practice guidelines in oncology. v.3.2011. 3. Schrump, et al. Non-small cell lung cancer. In: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.
  12. 12. Paclitaxel 225 mg/m2 over 3 hrs on Day 1 Carboplatin AUC 6.0 mg/mL/min on Day 1 3-wk cycle Docetaxel 75 mg/m2 on Day 1 Cisplatin 75 mg/m2 on Day 1 3-wk cycle Gemcitabine 1000 mg/m2 on Days 1, 8, 15 Cisplatin 100 mg/m2 on Day 1 4-wk cycle Reference Arm Paclitaxel 135 mg/m2 over 24 hrs on Day 1 Cisplatin 75 mg/m2 on Day 2 3-wk cycle ECOG 1594: Comparison of 4 First-line Doublet Regimens in Advanced NSCLC Stratified by:  ECOG PS (0/1 vs 2)  Weight loss in previous 6 mos (< 5% vs ≥ 5%)  Disease stage (IIIB vs IV or recurrent)  Brain metastases (yes vs no) Advanced-stage, previously untreated NSCLC patients (N = 1207) Schiller JH, et al. N Engl J Med. 2002;346:92-98.
  13. 13. ECOG 1594: OS Schiller JH, et al. N Engl J Med. 2002;346:92-98. 1.0 0.8 0.6 0.4 0.2 0 Proportionofpatients Mos 0 5 10 15 20 25 30 Survival by Treatment Group All Randomized Cases Cisplatin/paclitaxel Cisplatin/gemcitabine Cisplatin/docetaxel Carboplatin/paclitaxel
  14. 14. Advanced-stage, previously untreated NSCLC patients (N = 1725) Cisplatin 75 mg/m2 on Day 1 Gemcitabine 1250 mg/m2 on Days 1 and 8 Six 3-wk cycles Cisplatin 75 mg/m2 on Day 1 Pemetrexed 500 mg/m2 on Day 1 Six 3-wk cycles Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551. CONSORT: Phase III Gemcitabine or Pemetrexed + Cisplatin as First-line Therapy Stratified by:  ECOG PS (0 vs 1)  Disease stage (IIIB vs IV)  Brain metastases (yes vs no)  Sex (male vs female)  Pathologic diagnosis (histologic vs cytologic)  Treatment center
  15. 15. Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551. Survival Pemetrexed + Cisplatin (n = 862) Gemcitabine + Cisplatin (n = 863) HR (95% CI) P Value Median OS, mos 10.3 10.3 0.94 (0.84-1.05) Noninferior Adenocarcinoma (N = 847) 12.6 10.9 0.84 (0.71-0.99) .03 Large-cell carcinoma (N = 153) 10.4 6.7 0.67 (0.48-0.96) .03 Squamous cell carcinoma (N = 473) 9.4 10.8 1.23 (1.00-1.51) .05 CONSORT: Efficacy
  16. 16. Chemotherapy Today and the Need for Targeted Therapies  Doublet chemotherapy for 4-6 cycles is standard  Can now select chemotherapy based on histology  Future selection by other markers (ie, ERCC1)  There is a need for “targeted” chemotherapy and other agents  Antiangiogenesis: VEGF targeted (bevacizumab, etc)  EGFR-targeted antibody (cetuximab), TKI (erlotinib, etc)  Newer targets (ALK and others)  Recent identification of “driver mutations” in 50% of NSCLC adenocarcinomas
  17. 17. The Angiogenic Switch Small tumor  Nonvascular  “Dormant” Larger tumor  Vascular  Metastatic potential 1-2 mm Angiogenic Switch VEGF
  18. 18. Bevacizumab
  19. 19. E4599: Efficacy RR: 15% for Paclitaxel/Carboplatin vs 35% for Paclitaxel/Carboplatin + Bevacizumab PFS(%) 0 20 40 60 80 100 OS(%) 0 6 12 18 24 30 42 Mos PCB group (305 events in 417 patients) PC group (344 events in 433 patients) .Sandler A, et al. N Engl J Med. 2006;355:2542-2550. 0 20 40 60 80 100 0 6 12 18 24 30 Mos 36 HR: 0.79 (P = .003) HR: 0.66 (P < .001) PCB group (374 events in 417 patients) PC group (405 events in 433 patients)
  20. 20. Bevacizumab in Special Populations: Summary  Caution with elderly patients; ongoing trials  Hemoptysis remains an issue, but anticoagulation can be considered cautiously  Safe in patients with treated brain metastases  Squamous histology still a major bleeding risk
  21. 21. EGFR and NSCLC  EGF binds to the EGFR to regulate cell growth, proliferation, and differentiation  Erlotinib and gefitinib are inhibitors of the TK enzyme in the EGFR  Cetuximab is a monoclonal human-murine chimeric antibody against EGFR with some NSCLC activity Baselga J. Oncologist. 2002;7(suppl 4):2-8. Lynch TJ, et al. N Engl J Med. 2004;350:2129-2139. Shepherd FA, et al. N Engl J Med. 2005;353:123-132. Rosell R, et al. N Engl J Med. 2009;361:958-967.
  22. 22. Gefitinib,Erlotinib,Afatinib Crizotinib
  23. 23. Previously untreated patients with stage IIIB/IV NSCLC; never or light ex-smokers; PS 0-2 (N = 1217) Up to six 3-wk cycles Gefitinib 250 mg/day PO (n = 609) Paclitaxel 200 mg/m2 IV on Day 1 + Carboplatin AUC 5-6 mg/mL/min IV on Day 1 (n = 608) Mok TS, et al. N Engl J Med. 2009;361:247-257. IPASS: Gefitinib vs Carboplatin/Paclitaxel in Select Patients With Advanced NSCLC  Primary endpoint: PFS (noninferiority)  Secondary endpoints: ORR, OS, QoL, safety, disease-related symptoms  Exploratory endpoints: EGFR mutation, EGFR gene copy number, EGFR protein expression Randomized from March 2006 to October 2007
  24. 24. IPASS: PFS in EGFR Mutation– Positive vs –Negative Patients EGFR Mutation Positive EGFR Mutation Negative Treatment by subgroup interaction test, P < .001 HR: 0.48 (95% CI: 0.36-0.64) P < .001 No. events gefitinib,: 97 (73.5%) No. events C/P,: 111 (86.0%) Gefitinib (n = 132) Carboplatin/paclitaxel (n = 129) HR: 2.85 (95% CI: 2.05-3.98) P < .001 No. events gefitinib: 88 (96.7%) No. events C/P: 70 (82.4%) 132 71 31 11 3 0 129 37 7 2 1 0 108 103 0 4 8 12 16 20 24 Gefitinib C/P 0 0.2 0.4 0.6 0.8 1.0 ProbabilityofPFS At risk: 91 4 2 1 0 0 85 14 1 0 0 0 21 58 Gefitinib (n = 91) Carboplatin/paclitaxel (n = 85) Mos Incidence of EGFR mutation on IPASS participants: 261/437 (59.7%) Mok TS, et al. N Engl J Med. 2009;361:947-957. 0 4 8 12 16 20 24 0 0.2 0.4 0.6 0.8 1.0 ProbabilityofPFS Mos
  25. 25. EURTAC: First-line Erlotinib vs Chemo in European Patients With EGFR Mutations  174 patients  Trial run in Europe (lead by Spanish group) Outcome CT Erlotinib HR P Value Response rate, % 15 58 - NR Median PFS, mos 5.2 9.7 0.37 < .0001 Median OS, mos NR NR 0.80 .42 Most common toxicities, % ALT elevation: 72 Anemia: 46 Neutropenia: 36 ALT elevation: 80 Rash: 80 Diarrhea: 57 Rosell R, et al. ASCO 2011. Abstract 7503.
  26. 26. EURTAC: PFS in ITT Population Erlotinib (n = 86) Chemotherapy (n = 87) HR: 0.37 (95% CI: 0.25- 0.54; log-rank P < .0001) PFSProbability 1.0 0.8 0.6 0.4 0.2 0 0 3 6 9 12 15 18 21 24 27 30 33 Mos 5.2 9.7 Patients at Risk, n Erlotinib Chemo 86 87 63 49 54 20 32 8 21 5 17 4 9 3 7 1 4 0 2 0 2 0 0 0 Rosell R, et al. ASCO 2011. Abstract 7503.
  27. 27. EURTAC vs Asian Trials in EGFR Mutated NSCLC: RR and PFS  None of the EGFR-TKI vs chemo as first-line therapy trials in EGFR mut NSCLC have shown a significant OS benefit Study Response Rate, % PFS, Mos (HR) EURTAC 58.0 vs 14.9 9.7 vs 5.2 (0.37) OPTIMAL 83 vs 36 13.1 vs 4.6 (0.16) NEJ 002 74 vs 31 10.8 vs 5.4 (0.30) WJTOG 3405 62 vs 31 9.2 vs 6.3 (0.49) Rosell R, et al. J Clin Oncol. 2011;29(suppl). Abstract 7503.
  28. 28. Summary: First-line NSCLC Therapy  Doublet chemotherapy still standard backbone regimen  Some selection possible; histology  Targeted drugs can add to doublet chemotherapy  Bevacizumab and cetuximab with survival benefit  MANY with NO benefit in unselected patients in this setting  EGFR-TKIs, VEGFR-TKIs, MMPs, immunomodulators  Targeted agents where target is known can replace first-line chemotherapy (EGFR-TKI in EGFR mutants)  Better biomarkers will lead to better targeting

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