1. 非小细胞肺癌的化疗评价 湖南省肿瘤医院 汪安兰

2. 1. 概 述

3. T1 T2 T3 T4 N0 N1 N2 N3 M1 Lung (Non-Small Cell Carcinomas IV IV IV IV IIIB IIIB IIIB IIIB IIIB IIIA IIIA IIIA IIIB IIIA IIA IIA IIIB IIB IB * IA

4. Relative survival rates for patients with NSCLC diagnosed in the United States in 1992 and 1993.Data from the National Cancer Data Base (commission on Cancer of the American College of Surgeons and the American Cancer Society) Lung (Non-Small Cell Carcinomas

5. 2. 早期 NSCLC 辅助治疗的新进展

21. 总体生存 观察组 化疗组 年 Jan. NEJM 2004 164 286 432 602 774 935 181 308 450 624 775 932 At risk

28. CALGB 9633 总生存曲线 生存时间 ( 月 ) 生存比例

29. CALGB 9633 无病生存曲线 Chemotherapy Observation P=0.035 无病生存率 无病生存时间 ( 月 )

30. CALGB 9633 其他原因累积死亡率 累积死亡率 时间 ( 月 ) P=0.88 Observation Chemotherapy

31. CALGB 9633 累积肺癌死亡率 P=0.018 Observation Chemotherapy 累积肺癌死亡率 时间 ( 月 )

32. COX 比例风险分析 肺癌死亡率的 多变量 预测因素 0.81 [0.52-1.26] 0.35 肿瘤分化 0.92 [0.59-1.44] 0.72 鳞癌 0.82 [0.50-1.35] 0.44 存在症状 1.07 [0.96-1.18] 0.22 肿瘤大小 0.73 [0.46-1.18] 0.20 性别 0.98 [0.96-1.003] 0.094 年龄 0.62 [0.40-0.97] 0.034 辅助化疗 危险系数 [95% 可信限 ] P- 值 预测因素

33. CALGB 9633: IB 期 NSCLC 患者辅助化疗的随机临床试验 意向治疗分析 0.95 [0.49 – 1.83] 0.88 18 (10.5%) 17 (9.8%) 其他原因死亡率 0.62 [0.41 – 0.95] 0.028 52 (30.4%) 36 (20.8%) 所有原因死亡率 0.51 [0.29 – 0.89] 0.018 34 (19.9%) 19 (11.0%) 肺癌死亡率 171 173 人数 危险系数 [95% 可信限 ] P 值 对照组 辅助化疗组

37. 肺癌辅助化疗试验 - ASCO 2004 CALGB NCI-C 9633 JBR.10 患者人数 344 482 IB 期 (%) 100 45 II 期 (%) - 53 生存率 - 中位风险系数 - 0.61 (0.0004) - 无病生存风险系数 0.69 (0.035) 0.7 (0.012) -4-5 年总生存 (%) 71 vs 59 69 vs 54 - 肺癌死亡风险系数 0.51 (0.018) -

39. 3. 晚期 NSCLC 化疗的新进展

41. 四组化疗方案对晚期初治 NSCLC 患者效果的比较 Kubota, Karmanos CRC(Abstract7106,2000.10-2002.6) 60 14.8 MO 4.0 mo 30.1 Gemcitabine 1g/m2 ,d1,8 DDP 80 mg/m2 ,d1 Repeat every 21 days GP(146n) 48 11.4 4.1 33.1 Vinorelbine 25mg/m2 ,d1,8 DDP 80 mg/m2 ,d1 Repeat every 21 days NP(145n) 59 14.2 4.7 31.0 Irinotecan 60mg/m2 ,d1,8,15 DDP 80 mg/m2 ,d1 Repeat every 28 days IP(145n) 51 12.3 MO 4.5 mo 32.4 Paclitaxel 200mg/m2 Carboplatin AUC 6 Repeat every 21 days TC(145n) One Year OS(%) Median OS Median TTP RR (%) Drug doses and schedules Regimen

42. 43 39.5 1 年 0S （ % ） 44.5(P=0.338) 38.7 中位生存期（月） 17.6 16.4 TTP( 周 ) 18.2% 20.3% 总缓解率 6.1%(P=0.017) 1.4% 关节痛 24.3(P=0.0471) 16.6% 2/3 度神经病变 3.3% 0.9% 中性粒细胞胞减少性发热 17% 17% ¢ B 期 65% 60% 男性 65 65 中位年龄 221 223 病例数 紫杉醇三周方案 紫杉醇每周方案 晚期初治 NSCLC 中卡铂 + 紫杉醇每周或三周方案比较

43. Non-Small-Cell Lung Cancer—Frontline Therapy Myelosuppression, Thtombocytopenia, Anemia,Nausea or vomiting, Neurotoxicity, Nephrotoxicity ,Constipation, or diarrhea, Dyspnea,Asthenia,Rash,Cardiotoxicity N Engl J Med 346:92,2002 J Clin Oncol 18:122,2002 J Clin Oncol 21:3025,2003 8—9.5mo 4.2—5.7mo 22—30% Cisplatin 60---100 mg/m2 IV over 2 hours day 1 Gemcitabine 1,000 mg/m2 IV over 30 minutes days 1and 8 Repeat every 21 days for 6 cycles. Cisplatin + Gemcitabine Myelosuppression ,Anemia,Thrombocytopenia, infection ,Nausea or vomiting,Neurotoxicity , Nephrotoxicity,Asthenia,Hypersensitivity, Cardiotoxicity ,Diarrhea,Anorexia J Clin Oncol 21:3016,2003 N Engl J Med 346:92,2002 7.4—11.3 mo 3.7—5.5 mo 17-31% Docetaxel 75 mg/m2 IV over 1 hour Followed by Cisplatin 75 mg/m2 IV over 2 hours Repeat every 21 days for 6 cycles. Docetaxel + Cisplatin Grade 3 and 4 Side Effects; Reference(s) Median OS Median TTP RR Drug Doses and Schedules Regimen

44. Non-Small-Cell Lung Cancer—Frontline Therapy Neutropenia,Anemia,Thrombocytopenia,Nausea,or vomiting, Diarrhea,Hypomagnesemia,Melosuppression,Cardiotoxicity,Pulmonary, Constipation,Fatigue J Clin Oncol 21:3025,2003 J Natl Cancer Inst 95:362,2003 7.5—8 mo 4.25—4.75 mo 21—25% Gemcitabine 800-1200mg/m2 IV over 30 minutes days 1 and 8 Vinorelbine 25-30 mg/m2 IV over 10 minutes days 1 and 8 Repeat every 21 days Gemcitabine + Vinorelbine Myelosuppression,Thrombocytopenia,Anemia, Nausea or vomiting ,Alopecia, Bleeding , Liver function, test elevation, Neurotoxicity , infection Lung Cancer 41:321,2003 8 mo 4.75 mo 29.2% Carboplatin AUC 6 IV over 30—60minutes day 1 Gemcitabine 1,000-1,200mg/m2 IV over 30 minutes days 1 and 8 Repeat every 21days for 6cycles Carboplatin + Gemcitabine Grade 3 and 4 Side Effects; Reference(s) Median OS Median TTP RR Drug Doses and Schedules Regimen

45. Non-Small-Cell Lung Cancer—Frontline Therapy Key point : The carboplatin dose is determined on the basis of the Calvert formula: (glomerylar filtration rate + 25) *AUC. Myelosuppression, Anemia, Thrombocytopnia Infection ,Nausea or vomiting Asthenia ,Pulmonary ,pain , Diarrhea,Anorexia J Clin Oncol 21:3016,2003 9.4 MO 5 mo 24% Docetaxel 75 mg/m2 IV over 1 hour Followed by Carboplatin AUC 6 IV over 30—60 minutes Repeat every 21 days for 6 cycles Docetaxel + Carboplatin Neutropnia , Thrombocytopenia, Anemia,Nausea or Vomiting, Neurotoxicity (sensory and motor), Fatigue ,Alopecia, ,Dehydration,Diarrhea,Myalgia or arthralgia J Clin oncol 19:3210,2001 Ann Oncol 11:799,2000 8.6-11.4 MO 4-6.5 mo 25—32% Paclitaxel 175-225 mg/m2 IV over 3 hours Followed by Carboplatin AUC 6 IV over 30—60 minutes Repeat every 21 days for 6 cycles. Paclitaxel + Carboplatin Grade 3 and 4 Side Effects ; Reference(s) Median OS Median TTP RR Drug doses and schedules Regimen

46. Small-Cell Lung Cancer—Frontline Therapy Neutropenia,Thrombocytopenia,Anemia,Leukopenia,Nausea or vomiting , Astheniam, Fever , AST or ALT elevation ,infection N Engl J Med 340:265,1999 J Clin Oncol 10:282,1992 J Natl Cancer Inst 83:855,1991 8.6-9.9 mo 4.3 mo 61-78% Cisplatin 60-100 mg/m2 IV over 2 hours day 1 Etoposide 80 -120 mg/m2 IV over 4 hours days 1-3 Repeat every 21 days. Cisplatin + Etoposide Neutropenia,Leukopenia,Anemia,Thrombocytopenia,Liver function test elevations(1-2%),Hyponatremia,infection,Arterial oxygen pressure J Clin Oncol 17:3540,1999 8.6-10.8mo 4.3-6.4 mo 61-75% Carboplatin AUC 6 IV over 30-60minutes day 1 Etoposide 100mg/m2 IV over 4hours days1-3 Repeat every 21 days Date from phase 11 trial . Carboplatin + Etoposide Grade 3 and 4 Side Effects; Reference(s) Median OS Median TTP RR Drug Doses and Schedules Regimen

47. Small-Cell Lung Cancer—Frontline Therapy Neutropenia,Leukopenia,Anemia, Throbocytopenia,Diarrhea,Nausea or vomiting ,infection ,ALT elevation ,Fever ,Arterial oxygen pressure N Engl j Med 346:85,2002 12.8 mo 6.9 mo 84.4% Cisplatin 60 mg/m2 IV over 2 hours day 1 Irinotecan 60 mg/m2 IV over 90 minutes days 1 and 8 Repeat every 21 days Cisplatin + Irinotecan Grade 3 and 4 Side Effects; Reference(s) Median OS Median TTP RR Drug Doses and Schedules Regimen

48. Non-Small-Cell Lung Cancer—Frontline Therapy Neutropenia,Anemia,Thrombocytopenia,Nausea,or vomiting, Diarrhea,Hypomagnesemia,Melosuppression,Cardiotoxicity,Pulmonary, Constipation,Fatigue J Clin Oncol 21:3025,2003 J Natl Cancer Inst 95:362,2003 7.5—8 mo 4.25—4.75 mo 21—25% Gemcitabine 800-1200mg/m2 IV over 30 minutes days 1 and 8 Vinorelbine 25-30 mg/m2 IV over 10 minutes days 1 and 8 Repeat every 21 days Gemcitabine + Vinorelbine Myelosuppression,Thrombocytopenia,Anemia, Nausea or vomiting ,Alopecia, Bleeding , Liver function, test elevation, Neurotoxicity , infection Lung Cancer 41:321,2003 8 mo 4.75 mo 29.2% Carboplatin AUC 6 IV over 30—60minutes day 1 Gemcitabine 1,000-1,200mg/m2 IV over 30 minutes days 1 and 8 Repeat every 21days for 6cycles Carboplatin + Gemcitabine Grade 3 and 4 Side Effects; Reference(s) Median OS Median TTP RR Drug Doses and Schedules Regimen

51. 晚期 NSCLC 中化疗 ± 靶向药物的临床试验 埃罗替尼组 安慰剂组 TRIBUTE 试验 （ TC ± OSI-774) 1059 例 总缓解率（ % ） 21.5 19.3 TTP （月） 5.1 4.9 中位生存期（月） 10.8 22 （ * 不吸烟者） 10.6 11 （ 不吸烟者） TALENT 试验 (GP ± OSI-774) 1172 例 TTP （月） 5.6 6.0 OS （月） 9.9 10.1 1 年 OS （ % ） 41 42

56. 22% 31% 1 年生存率 4.7 （ P=0.001 ） 6.7 中位生存期（月） 1.8 （ P=0.001 ） 2.2 至疾病进展时间（月） <1% 8.9% 总缓解率 最佳支持治疗 埃罗替尼 NSCLC 补救治疗中埃罗替尼与最佳支持治疗的比较

62. Non-Small-Cell Lung Cancer—Salvage Therapy Leukopenia,Throbocytopenia,Fatigue,Nausea or vomiting ,Pulmonary,infection , Alopcia,Cutaneous Lung Cancer 29:67,2000 J Clin Oncol 17:2081,1999 4 mo Not available 6-19% Gemcitabine 1,000 mg/m2 IV over 30 minutes days 1 ,8,and15 Repeat every 28 days . Date from phase 11 trial. Gemcitabine* Neutropenia, Anemia , Nausea or vomiting, Asthenia, Diarrhea,Cardiotoxicity,Fluid retention, Neurotoxicity,(sensory and motor), Pulmonary,Stomatitis,infection J Clin Oncol 18:2059,2000 J Clin Oncol 18:2354,2000 5.7-7 mo 2.1-2.6 mo 6.7-7.1% Docetaxel 75 mg/m2 IV over 1 hour Repeat every 21 days Docetaxel Grade 3 and 4 Side Effects; Reference(s) Median OS Median TTP RR Doses and Schedules Drug

63. Non-Small-Cell Lung Cancer—Salvage Therapy Leukopenia,Anemia,Thrombocytopenia, Neutropenia,Fever , Fatigue , Septic death Lung Cancer 29:91,2000 3.2 mo Not available 0—20% Vinorelbine 25-30mg/m2 IV over 10 minutes days 1,8,and 15 Repeat every 21-18 days Date from phase 11 trial Vinorelbine Leukopenia,Anemia,Myelosuppression , Diarrhdea, Nausea or vomiting ,Pulmonary toxicity J Clin Oncol 10:12,1992 10.5 mo 3.75 mo 31% Irinotecan 80-100 mg/m2 IV over 90 minutes days 1,8,and 15 Repeat every 21-18 days *Date from phase 11 trial in chemonaive patients Irinotecan Diarrhea,1% Rash,1% ALT elevation, 1% J clin Oncol 21:136,2003 JAMA 290:2149,2003 7-7.6 mo 2.7-7 mo 12-18.4% Gefitinib 250 mg PO daily continuously *Date from phase 11 trial Gefitinib Grade 3 and 4 Side Effects; Reference(s) Median OS Median TTP RR Drug Doses and Schedules Regimen

64. 3.3.4 PS 评分较差或老年患者 仍然能够耐受全身化疗，并从中获益

65. ECOG1599:Pacli/Cb vs GEM/DDP (PS=2) 随机Ⅱ 期临床研究 患 者 情况 N=103 PS=2 随机分组 健择 1g/m2,d1,8 顺铂 60mg/m2,d1 Q3wks 紫杉醇 200mg/m2,d1 卡铂 AUC=6 Q3wks

71. Thank you