Paclitaxel in the Management of Breast Cancer

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1 現代醫學控制癌症的方法 Surgery Remove known tumor masses Radiation Chemotherapy Hormonal therapy 分子標靶治療 Kill rapidly dividing tumor cells, including tumor cells in adjacent tissues Kill rapidly dividing tumor cells Inhibit the growth and survival of hormone-dependent tumor cells 特異性地抑制腫瘤細胞生長所必需的分子路徑

2 化學治療 Chemotherapy 全身性的治療相對藥物作用特異性不高可使用劑量被可能毒性反應限制療效也為潛在的或後天得來的抗藥性所限

3 化學治療可以 Primary chemotherapy Palliative chemotherapy Neoadjuvant & Concommitent radiosensitizer 改善臨床的治療方式

4 多變相的乳癌 ER/PR Status Menopausal Status Her2/neu Status Axillary Node Status Other Prognostic Factors Histological Feature Mastectomy /Lumpectomy +/-Axillary Dissection Radiation Therapy Adjuvant Therapy Chemotherapy regimen? Hormonal therapy Tamoxifen? AI? Neoadjuvant Therapy Sentinal Node Biopsy Biological Therapy HER2 IHC -FISH Herceptin Single/Chemo Combination Hormonal Therapy Palliative Therapy Chemotherapy regimen? Hormonal therapy? Chemotherapy regimen? Combo/sequence? Hormonal therapy Tamoxifen? AI? Sequence?

5 晚期乳癌化學治療的演進 Vinorelbine Jones 1995 Mitomycin C/ vinblastine Nabholtz 1999 Taxotere Nabholtz 1999 Melphalan Jones 1995 平均存活 (months)

6 E1193: Combination therapy more effective than sequential therapy? R A N D O M I Z A T I O N First-line Doxorubicin 60mg/m 2 Paclitaxel 175mg/m 2 Doxorubicin 50mg/m 2 + paclitaxel 150mg/m 2 + G-CSF Second-line Paclitaxel 175mg/m 2 Doxorubicin 60mg/m 2 Sledge G et al. J Clin Oncol 2003;21:588 92

7 晚期乳癌的化學治療 E1193 RR% CR% TTF(mo.) 存活期 (mo.) A T AT P= A T A T 0.057

8 Intergroup/ECOG 1193 Delay of disease progression but no impact on survival A Taxol TTF 6.0? Survival 19.1 R Taxol A TTF 6.3? Survival 22.5 ATaxol TTF 8.6 Survival 22.4 Median Months

9 Combinations... For Whom? Younger Patients? Visceral Dominant Disease? Aggressive Molecular Phenotype? Tempo of Disease Progression? Short relapse-free interval after adjuvant therapy? Lack of durable (or any) response to prior mono-chemotherapy for MBC? Rapid Volumetric tempo of progression?

10 Combination Chemotherapy Chemo-naïve: Anthracyclines containing regimens FAC, FEC Cardiac risk CMF Prior anthracyclines(s/p Adjuvant) XT (capecitabine/doxetaxel) GT (gemcitabine/paclitaxel)

11 >>2nd line Chemotherapy Prior anthracyclines(2 nd line) XT GT After Anthracyclines/taxanes Single agent preferred Capecitabine Navelbine

12 Chemotherapy for MBC Fragile patient, poor performance Usually single agent Consider liver and renal function Closed monitoring May worth trying due to good chance of response

13 Her-2(+) MBC Taxol (weekly) +/- Carboplatin Taxotere Navelbine In combination with Herceptin

14 乳癌輔助性化學治療可以減少術後復發增加治癒的機會

16 5-Year Survival 乳癌 : 五年存活期相對於陽性淋巴結的數目 80% 60% 40% 20% 0% >20 Number of Positive Nodes Harris J, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;

17 10 年無病存活比率與淋巴結的數目 4 MDACC FAC Studies (N=982) Groups 第二期 % 73% 86% 65% % 49% 56% 51% % 28% 22% 36% 第三期 32% 31% 37% 41% Buzdar A, et al, Adjuvant Therapy of Cancer VIII, 1997

18 Breast Cancer: Adjuvant CMF (12 months) or Surgery Alone All Patients Premenopausal % Relapse-free survival 100 CMF Surgery 100 % Overall survival CMF Surgery % 36% 35% LOG-RANK : P = WILCOXON : P = % LOG-RANK : P = 0.02 WILCOXON : P = years years Adapted from Bonadonna G. Cancer Res BCIRG JUNE 23, 2002

19 BREAST CANCER Commonly assessed prognostic factors Number of positive axillary nodes Nuclear grade Tumor size Lymphatic and vascular invasion Histologic tumor type Estrogen/progesterone receptors HER2/neu overexpression Histologic grade Slamon DJ. Chemotherapy Foundation. 1999;46. Harris J, et al. Cancer: Principles & Practice of Oncology. 1997;

20 Disease-Free Survival: 1998 EBCTCG Meta-Analysis of Doxorubicin Polychemotherapy vs CMF Study Therapy N Better than CMF Worse than CMF NASBP B-15 4AC 3CMF vs 6CMF (+R) 1552/1562 SECSG2 6FAC vs 6CMF 260/268 ONCOFRANCE 12FACV vs 12CMF 138/113 Austrian BCSG 3 6CMFVA vs 6CMF 121/124 NSABC Israel 2CMF+4AVbCMF vs 6CMF 55/50 SE Swedenl 8AC vs 7CMF (+R) 21/22 Meta Analysis (6 studies) 2157/ P = Analysis derived from EBCTCG Lancet. 1998; Data on file, Pharmacia Hazard Ratio (Compared to CMF)

21 Disease-Free Survival: 1998 EBCTCG Meta-Analysis of Epirubicin Polychemotherapy vs CMF Study Therapy Better than CMF N Worse than CMF NCI-C MA-5 6CEF vs 6CMF 356/360 Brussels, Belgium 8EC vs 6CMF 462/464 ICCG CharingCross 8/6FEC vs 6CMF 256/259 GABG Germany 6FEC vs 6CMF ( Tam) 142/146 GUN-3 Naples, Italy) 6CMFEV vs 6CMF 105/115 Meta Analysis (5 studies) 1321/ P = Analysis derived from EBCTCG Lancet. 1998; Data on file, Pharmacia Hazard Ratio (Compared to CMF)

22 NCIC CTG MA.5 Trial: CEF-120 vs CMF in Node-Positive Breast Cancer N = 710 Patient Population Pre- or perimenopausal Node-positive Stratification Total vs partial mastectomy HR status No. + nodes R A N D O M I Z A T I O N * No prophylactic G-CSF administered. Levine et al. J Clin Oncol. 1998;16: C 75 mg/m 2 po q d days 1 14 E 60 mg/m 2 IV days 1 and 8 q 4 wk x 6 F 500 mg/m 2 IV days 1 and 8 + Prophylactic antibiotics* C 100 mg/m 2 po q d days 1 14 M 40 mg/m 2 IV days 1 and 8 q 4 wk x 6 F 600 mg/m 2 IV days 1 and 8 = Cyclophosphamide = Epirubicin = Fluorouracil = Methotrexate

24 Design F A C 5-FU 500 mg/m 2 Doxorubicin 50 mg/m 2 Cyclophosphamide 500 mg/m 2 R Every 3 weeks x 6 cycles Stratification: Nodes: Center T A C Docetaxel 75 mg/m 2 Doxorubicin 50 mg/m 2 Cyclophosphamide 500 mg/m 2 Dexamethasone premedication, 8 mg bid, 3 days Prophylactic ciprofloxacin 500 mg bid, day 5-14

26 NSABP B-31 Control: AC T Arm 1 Arm 2 NCCTG N9831 Arm A Arm B Investigational: AC T+H Arm C = doxorubicin/cyclophosphamide (AC) 60/600 mg/m2 q 3 wk x 4 = paclitaxel (T) 175 mg/m2 q 3 wk x 4 = paclitaxel (T) 80 mg/m2/wk x 12 = trastuzumab (H) 4mg/kg LD + 2 mg/kg/wk x 51

27 Can Doxorubicin Be Eliminated? BCIRG 006 AC T 4 x AC 4 x Docetaxel 60/600 mg/m mg/m 2 HER2 + FISH N=3150 AC TH TCH 1 Year Trastuzumab 6 x Docetaxel and Platinum salts 75 mg/m 2 75 mg/m 2 or AUC 6 1 Year Trastuzumab

28 傳統化學治療藥物非特異性及細胞毒殺對正常組織也有作用療效與腫瘤特性有關腫瘤縮小視為療效有療效不見得存活上有助益

29 標靶治療選擇性的同時也是 Cytostatic 毒性低有標靶才有活性療效不一定須見到腫瘤縮小

30 化學治療的演進目前在使用的藥物 Biosynthetic Enzymes DNA Topoisomerase Tubulin Hormonal Manipulation 發展中的藥物 Signal Transduction (Her2, EGFR) Angiogenesis (MMPI S, VEGF) Cell Cycle (cdk s) Apoptosis (bcl2) Immunotherapy /Vaccines Gene Therapy/Antisense Monoclonal Antibodies

31 癌細胞相關重要分子路徑 Aberant signal transduction Growth factor and receptor deregulation Autocrine growth factor secretion Angiogenic factors secretion Matrix Metaloproteinase secretion Oncogene expression Loss of tumor supressor genes

32 理想的標靶藥物大部分有該癌症的患者均有存在標靶與腫瘤發生或形成相關對腫瘤細胞而言是必須的正常細胞不須此標靶相關的功能

33 表皮生長因子藉接受器將訊號傳入細胞而引起反應細胞膜 B1 B1 抗凋亡 Anti-Apoptosis 細胞核細胞分裂組織侵犯分泌生長因子轉移

34 乳癌的 Her-2 表現增加會引起 HER2 overexpression is the result of HER2 gene amplification 3 1. Gene amplification increased gene copies 2. 增加 mrna transcription 3. 增加 HER2 受體的數目 protein overexpression 4. Released extracellular domain (ECD, sher2) 1 2 4

35 Effect of HER2 amplification on human breast cancer cells Human breast cancer cells DNA synthesis 50 75% Cell growth rate 30 50% MCF-7 HER2 ve Transfect with HER2 gene MCF-7 HER2 +ve Growth in soft agar 225% Tumourigenicity in nude mice Metastatic potential 220% in nude mice Transformed phenotype

36 Cumulative probability 1.00 Her-2 表現程度與早期乳癌手術後的預後有關 Not amplified Amplified Amplified: >10 copies/nucleus Not amplified: <3 copies/nucleus Borderline: excluded Log rank p< Time to death (months) Ross JS, Fletcher JA. Stem Cells 1998; 16:

Trastuzumab: Humanized Anti-HER2 Antibody HER2 epitopes recognized by hypervariable murine antibody fragment Human IgG-1 Targets HER2 protein High

37 Trastuzumab: Humanized Anti-HER2 Antibody HER2 epitopes recognized by hypervariable murine antibody fragment Human IgG-1 Targets HER2 protein High affinity (K d = 0.1 nm) and specificity 95% human, 5% murine Decreases potential for immunogenicity Increases potential for recruiting immune effector mechanisms

Probability of survival Herceptin 在晚期乳癌合併使用化學治療的療效 FISH+ FISH 1.0 Trast. + CT (n = 176) CT (n = 169) 1.0 Trast. + CT (n = 50) CT (n = 56) 0.8 RR = 0.71 p = 0.007 0.8 RR = 1.

38 Probability of survival Herceptin 在晚期乳癌合併使用化學治療的療效 FISH+ FISH 1.0 Trast. + CT (n = 176) CT (n = 169) 1.0 Trast. + CT (n = 50) CT (n = 56) 0.8 RR = 0.71 p = RR = 1.11 p = NS mo 26.2 mo mo 24.0 mo Months Months Update of Mass. Proc Am Soc Clin Oncol. 2001;20:22a. Abstract 85.

39 晚期乳癌的化學治療 M77001 HER2-positive MBC (IHC 3+ and/or FISH+) n=188 n=94 Two patients did not receive study medication n=92 Docetaxel* 100mg/m 2 q3w x 6 *Patients progressing on docetaxel alone could crossover to receive Herceptin Docetaxel 100mg/m 2 q3w x 6 + Herceptin 4mg/kg loading, 2mg/kg weekly until PD

Estimated probability M77001: 疾病平均惡化期 1.0 0.8 Herceptin + docetaxel Docetaxel alone 0.6 0.4 0.

40 Estimated probability M77001: 疾病平均惡化期 Herceptin + docetaxel Docetaxel alone p= Months Intent-to-treat population, 12-month cut-off

Estimated probability M77001: 存活期比較 1.0 0.8 Herceptin + docetaxel Docetaxel alone 0.6 0.4 0.2 p=0.

41 Estimated probability M77001: 存活期比較 Herceptin + docetaxel Docetaxel alone p= Months 8.4 months Intent-to-treat population, 12-month cut-off Documented crossover = 48%

42 M77001: 治療效果總結 Outcome Herceptin + docetaxel (n=92) Docetaxel alone (n=94) p-value 緩解比率 DR (median, months) TTP (median, months) 平均存活期 *Kaplan-Meier estimate Intent-to-treat population, 12-month cut-off

43 NSABP B-31 Control: AC T Arm 1 Arm 2 NCCTG N9831 Arm A Arm B Arm C Investigational: AC T+H = doxorubicin/cyclophosphamide (AC) 60/600 mg/m2 q 3 wk x 4 = paclitaxel (T) 175 mg/m2 q 3 wk x 4 = paclitaxel (T) 80 mg/m2/wk x 12 = trastuzumab (H) 4mg/kg LD + 2 mg/kg/wk x 51

44 THE HERA TRIAL Women with HER2 POSITIVE invasive breast cancer IHC3+ or FISH+ centrally confirmed Surgery + (neo)adjuvant chemotherapy (CT) radiotherapy Stratification Nodal status, adjuvant CT regimen, hormone receptor status and endocrine therapy, age, region Randomization Trastuzumab 8 mg/kg 6 mg/kg 3 weekly x 2 years Trastuzumab 8 mg/kg 6 mg/kg 3 weekly x 1 year Observation

45 Does adjuvant trastuzumab improve disease-free survival? 輔助性的治療可否延長無病存活期? 使用 Herceptin 可否減少復發甚至避免復發?

46 Disease-Free Survival AC TH % AC T 87% 75% 85% 67% N Events AC T AC TH HR=0.48, 2P=3x10-12 Years From Randomization B31/N9831

47 % alive and disease free 乳癌的術後輔助化學治療無病存活期

Ethnic Difference Japanese Study 1 Carolina Breast Cancer Study 2 Japanese Non-AA AA No. of Pts. 793 300 196 Luminal A 63.3% 54.0% 47.

48 Ethnic Difference Japanese Study 1 Carolina Breast Cancer Study 2 Japanese Non-AA AA No. of Pts Luminal A 63.3% 54.0% 47.4% Luminal B 19.5% 17.3% 12.8% HER2+/ER- 6.9% 5.7% 8.2% Basal-like 8.4% 16.0% 26.5% Unclassified 1.8% 7.0% 5.1% Prognosis Good Poor 49

一、口朊給藥護理技術操作標準

一、口朊給藥護理技術操作標準乳癌壹疾病導因一定義乳癌是由於乳管細胞或乳小葉細胞變性或異常增生而形成發生的位置最常見於乳房外上方, 但乳頭或其他部分亦可能發生乳癌除了侵犯乳房外, 更可能轉移到遠處器官如骨骼肺肝腻等在台灣, 乳癌好發年齡在 45-55