,乳腺癌化疗新进展 徐兵河 中国医学科学院肿瘤医院内科,Worldwide Top 5 cancer incidence in 2000,Top 5 cancer incidence: Lung cancer: 1,239,000 Breast cancer: 1,053,000 Colorectal cancer: 944,000 Gastric cancer: 876,000 Liver cancer: 564,000,Parkin DM et al, Estimating the world cancer burden: Globocan 2000: int. J. Cancer:94,153-156(2001),In Thousands,No. of new cancer cases in Asia in 1990,Parkin DM etal, Estimating of the worldwide incidence of 25 major cancers in 1990: int. J. Cancer:80,827-841(1999),China has the largest cancer patients Gastric Cancer: 300,000 Liver cancer: 236,000 Lung Cancer: 229,000 CRC: 116,000 Breast Cancer: 61,000,In Thousands,乳腺癌患者死亡率降低原因,早诊早治 乳腺癌综合治疗的进步，包括辅助化疗的进步,1970s,1980s,1990s,2000s,乳腺癌辅助化疗的进展,非蒽环类的联合化疗 CMF, CMFVP 蒽环类联合化疗 联合方案: AC, FAC, AVCMF, FEC, CEF 序贯和替代 (Milan A & B) 剂量强度,剂量密度, HDCT 紫杉类 (Paclitaxel/Docetaxel) 序贯: A T C or AC T 联合: TA, TAC 生物反应调节剂 与化疗结合,哪些病人需要行术后辅助化疗？,不同年龄乳腺癌患者的化疗疗效,年减少率 年龄（岁） 复发（） 死亡（） 40 377 278 40-49 345 275 50-59 224 144 60-69 184 84 70 资料不足 资料不足 P值 .00003 .00007,激素受体状况与辅助化疗疗效 (EBCTCG. Lancet,1998, 351:1451-1467),年减少率 ER ER不明 ER (%) (%) (%) 年龄50 复发 407 306 338 死亡 359 236 2010 年龄50 复发 305 184 184 死亡 176 115 95,淋巴结状态与辅助治疗(NSABP B16),NSABP16（1296例）：比较腋淋巴结，ER患者术后单用TAM与TAM化疗的疗效 1、随机分组：单用TAM；AC TAM； PAFTAM 2、结果：化疗TAM组患者DFS 显著高于单用TAM组,淋巴结状态与辅助治疗(NSABP-20),NSABP20：比较ER（）、腋淋巴结（）患者术后单用TAM和TAM化疗的疗效（2363例） 1、随机分组：单用TAM；MF TAM；CMFTAM 2、结果：MFT和CMFT的疗效（OS 与DFS）优于TAM，其中在49岁 以下的患者中疗效最为显著,腋窝淋巴结阴性患者 术后辅助化疗指征,乳腺肿块直径大于1.0cm ER阴性 组织学分级为级 Her2neu阳性 脉管瘤栓,哪些患者需要术后辅助治疗？,对淋巴结阳性及具有高危复发转移因素的淋巴结阴性患者应给与辅助治疗 对受体阳性的患者应给与TAM治疗,最佳治疗方案是什么？,确定是否选择含蒽环类药方案的临床试验,研究 方案 结果 NSABP 15-B CMF6, CA4 CA=CMF NCI of Canada CEF6, CMF6 CEF优于CMF SWOG CAF 6, CMF6 CAF优于CMF,含紫杉类药方案是否优于 非紫杉类药方案？,CALGB 9344 辅助治疗研究 Update 11/00 Henderson et al,P175/3h x 4,None,N=3170 淋巴结+ 绝经前或绝经后 ER+ or PR+,随 机 化,A = Doxorubicin C = Cylophosphamide P = Paclitaxel,A60C x 4,A75C x 4,A90+G-CSFC x 4,ER+ or PR+ 患者接受Tamoxifen 治疗 5年,CALGB 9344 Update, ASCO sNDA NIH CDC 5/98 4/99 11/00 中位随访 (月) 21 30 52 事件数 复发 453 624 901 死亡 200 342 589 危险性降低 复发危险性 22%* 22%* 13%* 死亡危险性 26%* 26%* 14% *p0.05,CALGB 9344 无病生存 - 所有患者,CALGB 9344 根据受体状态分层的无病生存,受体阳性,受体阴性 /未知,CALGB 9344 总生存 - 所有患者,CALGB 9344 / Intergroup 0148,n = 3121,A: 60 = 75 = 90 mg/m2,P 175 mg/m2 (3 h),RR: Recur: 17%,RR: Death 18%,Henderson et al. JCO 2003,Recommended Tam if ER (+) After chemoRx,C: 600 mg/m2,NSABP B-28 研究设计,N=3060 淋巴结+ 绝经前或绝经后 ER+ or PR+,A = Doxorubicin C = Cylophosphamide P = Paclitaxel,P225/3h x 4,随 机 化,AC x 4,AC x 4,所有年龄 50 岁的患者或年龄 50岁但 ER+ 或 PR+ 的患者接受Tamoxifen治疗 5年,NSABP B-28: ASCO 2003 w/ med. f/u 64 Months,Rx Events RR,+P 400 0.83 - P 461 (.73-.95) p=0.008,+P 243 0.94 P 255 (.78-1.12) p=0.46,Rx Deaths RR,Adjuvant Sequential Taxanes: Summary,NSABP B-28 and CALGB 9344 support the use of paclitaxel after AC x 4 for node-positive breast cancer regardless of ER/PR status, tamoxifen, age, node #, etc. Unplanned subset analyses can yield conflicting results and should always be viewed with extreme caution.,剂量密度化疗,C 9741-CALGB 9741 A Randomized Trial of Dose Dense vs. Conventionally Scheduled and Sequential vs. Concurrent Combination Chemotherapy as Post-Operative Adjuvant Treatment of Node-Positive Primary Breast Cancer,C 9741: Trial Design,(I) Sequential: A q 3 wk T q 3 wk C q 3 wk (II) Sequential: +filgrastim A q 2 wk T q 2 wk C q 2 wk (III) Concurrent: AC q 3 wk T q 3 wk (IV) Concurrent:+ filgrastim AC q 2 wk T q 2 wk,q 2 wk (w/G-CSF),q 3 wk,22 weeks,14 weeks,21 weeks,33 weeks,Radiation therapy and tamoxifen after as appropriate Accrued 9/97-3/99 with n=1973/2005,doxorubicin 60 mg/m2,cyclophosphamide 600 mg/m2,paclitaxel 175 mg/m2 over 3 hours,CALGB 9741/Intergroup 2 x 2 Factorial Design,Improved DFS (RR= .74) & OS (RR= .69) With Dose-Dense Rx,M. Citron, et al. JCO 2003,C 9741: Eligibility Criteria,Stage: T0-3, N1-2, M0 Primary Surgery: Lumpectomy + axillary dissection or MRM with clear margins Labs: ANC 1000/l platelets 100,000/l bilirubin = normal Other: Normal CXR & EKG,C 9741: Endpoints,Primary: Disease-free survival (DFS) Defined as date of study to Local or distant recurrence Or death without relapse Secondary: Overall survival (OS) Toxicity,C 9741: Results,2005 pts accrued 9/97 & 3/99 Increased number to compensate for faster than expected accrual 32 pts did not receive therapy 1973 pts evaluable & analyzed,Multivariate Cox Proportional Hazards Model: DFS (N=1973),Disease-Free Survival by Density,p=0.0072,Citron et al, JCO 2003,Multivariate Cox Proportional Hazards Model: OS (N=1973),Overall Survival by Density,p=0.