乳腺癌辅助治疗规范的解读

乳腺癌辅助治疗规范的解读 湖北省肿瘤医院内科 于 丁 1 Treatment Guidelines are useful Guidelines provide a benchmark and integrate new findings into clinical practice They are dynamic documents, which need periodic update They are developed to reduce under-treatment, over-treatment and wrong treatment Compliance with guidelines has been shown to improve patient outcome 2 Adjuvant Therapy for Breast Cancer Treatment Guidelines 788388929598010305 8085902000 Guidelines St. Gallen NIH NCCN 96 yearly 07 如何掌握、使用？ 3 讨论内容 辅助治疗对哪些人有益？ 如何选择哪种辅助治疗方法？ 化疗方案的选择 分子靶向治疗作用 内分泌治疗方法的选择 4 Adapted from Bonadonna G. Cancer Res. 1992. All PatientsAll Patients 1 1 3 3 5 5 7 7 9 9 1111131315 years15 years LOG-RANK : P = 0.002LOG-RANK : P = 0.002 WILCOXON : P = 0.0001WILCOXON : P = 0.0001 100100 5050 0 0 % Relapse-free survival% Relapse-free survival CMFCMF SurgerySurgery 36%36% 26%26% 1 1 3 3 5 5 7 7 9 9 1111131315 years15 years LOG-RANK : P = 0.02LOG-RANK : P = 0.02 WILCOXON : P = 0.02WILCOXON : P = 0.02 100100 5050 0 0 % Overall survival% Overall survival CMFCMF SurgerySurgery 51%51% 35%35% Breast Cancer: Adjuvant CMF (12 months) or Surgery Alone PremenopausalPremenopausal 5 30 years follow up of randomised studies of adjuvant CMF in Operable breast cancer : cohort study Relapse free survival Overall survival Bonadonna BMJ 330:217, 2005 复发相对危险降低 34% HR 0.71 ( P = 0.005 ) 各种死亡降低 22% HR 0.79 ( P = 0.04 ) 6 30 years follow up of randomised studies of adjuvant CMF in Operable breast cancer : cohort study Overall survival Bonadonna BMJ 330:217, 2005 7 Comparative Efficacy of Adjuvant Comparative Efficacy of Adjuvant Chemotherapy: EBCTCG Meta-AnalysesChemotherapy: EBCTCG Meta-Analyses Therapy Reduction in Annual Odds, % RecurrenceDeath Polychemotherapy vs23.515 no chemotherapy (1995)(P 0.1 ; NS 14 1 trial with no data does not contribute to total (allocated A/E+: 211; allocated CMF: 212) * For balance, control patients in 3-way trial strata count half or twice in subtotal(s) and in final total of events/women. 1.00 (? Patients) (100 Patients) (322 Patients) (158 Patients) (2-5 cm BCIRG 006 2-5 cm 5 cm 0.00.52.51.01.52.0 0-2 cm N9831 / B-310-2 cm 5 cm ACDH10+ nodes DCarboH N- N+ N+ BCIRG 006 N- ACDH N-HERA HR Slamon et al 2006 Perez et al 2007; Smith et al 2007 40 无论年龄大小，赫赛汀均显示DFS获益 35-49 years 0.00.52.51.01.52.0 HERA 650.6 %1.3 % In both age groups about 10% of the patients had a LVEF of 50-54, about 50% of the patients had a LVEF of 55-64, and 35% had a LVEF of 65%. Average risk of early CHF for patient younger than 50 is 2 % and older than 50 is 5% This analysis from B31data alone. 43 Risk of Cardiac Events (no strong evidence of an major delayed toxicity) The only cardiac death that occurred during this study occurred in a control patient. End of Herceptin treatment period This analysis from B31 data alone. 44 Slamon et al 2006 Rastogi et al 2007 Suter et al 2007 Perez et al 2008 赫赛汀辅助治疗的心脏安全性 aData not comparable due to different assessment criteria CHF, congestive heart failure; cum, cumulative incidence LVEF, left ventricular ejection fraction; NR, not reported 3.0 NR NR 18.0 8.6 Asymptomatic LVEF decline, %a H 1 year ACPH ACPH ACDH DCarboH Arm HERA NSABP B-31 NCCTG N9831 BCIRG 006 1,678 947 570 1,068 1,056 n Severe CHF, % 0.6 3.8cum (5 yr) 3.3cum (3 yr) 1.9 0.4 Cardiac death, n 0 0 0 0 0 45 HER2状态判断 IHC免疫组化 FISH荧光原位杂交 CISH显色原位杂交 SISH银染原位杂交 46 Estimation of the epidemiological effect of trastuzumab over 20 years in five European countries ASCO 2008, abst, 6611 47 ASCO 2008, abst, 6611 Estimation of the epidemiological effect of trastuzumab over 20 years in five European countries 48 HER2阳性乳腺癌治疗原则 使早期乳腺癌患者复发风险降低36%52%,死亡风险 降低33% ACTH: ( H4 mg/kg,与首次T同时使用; 然后H 2 mg/kg维持1年。或T结束后,H6 mg/kg维持1年 ) 每3周方案, 目前推荐治疗时间为1年 在开始治疗的第3、6、9、18个月监测心脏情况 H辅助治疗的标准疗程为1年,至少应治疗6个月以保 证患者最大获益 49 St.Gallen 200350 St.Gallen 2003 51 St.Gallen 2003 52 Evolution of Adjuvant Evolution of Adjuvant Treatment of Breast CancerTreatment of Breast Cancer 19701970198019801990199020002000 非非蒽环蒽环类类 方案方案 含蒽环含蒽环类类 方案方案 含紫杉类含紫杉类 方案方案 含赫赛丁含赫赛丁 方案方案 53 54 CHEMOTHERAPY REGIMENS- ST.GALLEN 2005 IMPLICATIONS FOR PATIENT CARE AC x 4 CMF x 6 FAC, FEC x 6 CAF, CEF x 6 A (E) CMF Without Taxanes TAC AC P or D With Taxanes H 55 CHEMOTHERAPY REGIMENS- ST.GALLEN 2005 IMPLICATIONS FOR PATIENT CARE Standard Efficacy Superior Efficacy AC x 4 CMF x 6 FAC, FEC x 6 CAF, CEF x 6 A (E) CMF Without Taxanes TAC AC P or D With Taxanes Complexity Toxicity Economic cost But greater H 56 Choice of Adjuvant Regimens 57 低危患者： CMF6周期或AC、EC46周期 中危患者： FAC或FEC6周期 高危患者： ACT，FEC3T3， TAC，ATC， 密集化疗 乳腺癌按不同危险度治疗 58 Changes in chemotherapy regimens for older women with breast cancer who received adjuvant chemotherapy for stage I to III breast cancer 59 小 结 CMF有最长的远期疗效结果，至今仍用 含蒽环类化疗是目前最基础的标准方案 含紫杉类的地位已得到不断证实及巩固 (某些亚组的疗效待进一步观察) 赫赛丁可增加化疗的效果 剂量密度已开始动摇了传统的三周疗法 60 61 100个月的结果： T 21.8% A17.0% Absolute Difference: 4.8% 62 63 64 MA.17: Trial Design Primary end point: DFS Secondary end points: OS/safety/QOL *n=2575 (efficacy); 2154 (safety) in the FEMARA arm. n=2582 (efficacy); 2145 (safety) in the placebo arm. Goss et al. N Engl J Med. 2003;349:TBD. Randomization (Disease-free) Tamoxifen Placebo qd FEMARA (Letrozole) 2.5 mg qd* 5 years early adjuvant5 years extended adjuvant 65 MA.17 Results: Disease-Free Survival by Treatment Duration (contd) Goss et al. N Engl J Med. 2003;349:TBD. 87% 93% Increasing benefit in estimated DFS with treatment duration 66 67 68 69 70 71 72 73 ATAC EXEM BIG 1.98 (BIG FEMTA) TAMOXIFEN AI PLACEBO ARNO (J)MA-17 NSABP B33 EXEM 027 TEAM EXE Trial Strategies in Adjuvant Therapy: AIs 74 75 76 AI. Adjuvant Trials: DFS TAM ATACBIG 1-98 IES ABCSG /ARNO MA-17 10.820.810.60.60.5 P-values 0.01 0.003 0.00005 0.0018 0.00008 Median follow-up(m) 33 26 30.6 26 28 UPFRONT AI DELAYED AI 77 AI与TAM的随机对照临床试验 Hazard ratio Median Aromatase Disease-free Time to distant Fu(m) inhibitor survival metastases OS 初始治疗： Aromatase inhibitor vs.TAM ATAC 100 Anastrozole 0.85 0.84 0.97 BIG 1-98 51 Letozole 0.82 0.81 0.91 IES 56 Exemestane 0.76 0.83 0.85 ABCSG-8/ARNO-95 28 Anastrozole 0.60 0.54 NR ITA 64 Anastrozole 0.56 NR NR 序贯治疗： TAM 5年后Aromatase inhibitor MA.17 30 Letozole 0.58 0.60 0.82 ABCSG 6a 60 Anastrozol 0.62 0.53 0.89 NSABP B-33 30 Exemestane 0.68 0.69 1.2 78 Endocrine Treatment Strategies in Early Breast Cance