乳腺癌的化疗进展

乳腺癌的化疗进展 桂林医学院附属医院肿瘤一科 康马飞 乳腺癌化疗的历史回顾 l70年代： CMF l80年代： 蒽环类（anthracyclines） l90年代： 紫杉类（taxanes) l21世纪：化疗生物靶向治疗 l常规剂量密集 TX方案与AC方案比较 ldocetaxel/capecitabine (TX) lADM / CTX(AC) l目的：无蒽环类方案与含蒽环类方案比较 。 l3期单中心随机试验。 Lee KS, et al. Breast Cancer Res Treat. 2007 TX方案与AC方案比较 l209 例腋窝淋巴结阳性， II/III 期BC行4周期TX or AC . lTX与AC比, 增加了 pCR (21% / 10%, P = 0.024) ，RR (84% / 65%, P = 0.003). lTX恶心、呕吐少，但口腔炎、腹泻, 肌肉痛，皮 肤及指甲改变比AC明显。 lDFS无差别 (P = 0.932). lpCR 者复发少(P = 0.025; hazard ratio, 0.189; 95% CI, 0.044-0.815). Lee KS, et al. Breast Cancer Res Treat. 2007 Phase III trial comparing AC with TC ldoxorubicin and cyclophosphamide (AC) ldocetaxel and cyclophosphamide (TC) l1016 例 AC (n = 510) TC (n = 506), every 3 weeks. 完成化疗后给予放疗，受体阳性者给予 tamoxifen, Jones SE, et al. J Clin Oncol. 2006 ; 24(34): 5381-5387. Phase III trial comparing AC with TC l结果: TC的 5年 DFS 明显高于AC (86% v 80%, P =0 .015). ORR: TC / AC 90% / 87%, P =0 .13. 肌肉痛、关节痛、水肿、粒细胞减少在TC 组多见。 恶心、呕吐，充血性心衰在AC组多见。 Jones SE, et al. J Clin Oncol. 2006 ; 24(34): 5381-5387. A phase II trial of docetaxel as second-line chemotherapy in patients with MBC l docetaxel 100 mg/m(2) every 3 weeks lRR: 35% lMS: 12M lMTTP: 4M ldocetaxel 是治疗MBC的有效2线药物，特 别是对 anthracycline耐药的病人。 Baur M, et al. J Cancer Res Clin Oncol. 2007 lNab-paclitaxel (ABI-007, Abraxane) 是将 paclitaxel包裹在白蛋白里。 Henderson IC, et al. Expert Rev Anticancer Ther. 2007 ; 7(7):919-943. Nab-paclitaxel for breast cancer: a new formulation with an improved safety profile and greater efficacy Nab-paclitaxel for breast cancer: a new formulation with an improved safety profile and greater efficacy l随机 II 期临床试验提示 每周一次nab- paclitaxel 比每3周一次nab-paclitaxel或 docetaxel更有效、更安全。 lnab-paclitaxel 的优势在于安全性提高，可 以增加剂量，且进入肿瘤细胞内的药物比 例更高。 Henderson IC, et al. Expert Rev Anticancer Ther. 2007 ; 7(7):919-943. The trastuzumab and vinorelbine or taxane study. l此为一项前瞻性、多中心、随机对照研究。 l方法: HER2过度表达的 MBC ，未进行过化疗的 病人随机分为 trastuzumab vinorelbine 每周一次。 trastuzumab taxane 每周一次。 l结论: vinorelbine/trastuzumab 和 taxane/trastuzumab 一线治疗HER2阳性的 MBC 疗效无差异。 Burstein HJ, et al. Cancer. 2007 A phase-III trial of doxorubicin and docetaxel versus doxorubicin and paclitaxel in metastatic breast cancer: results of the ERASME 3 study. lMBC患者随机分为AD 组或AP 组，每3周 一次。 AD4- docetaxel4 AP4- paclitaxel4 Cassier PA, et al. Breast Cancer Res Treat. 2007 A phase-III trial of doxorubicin and docetaxel versus doxorubicin and paclitaxel in metastatic breast cancer: results of the ERASME 3 study. l结果: RR: 39.6% for AD and 41.8% for AP. median PFS 和 median OS： 8.7 M和 21.4 M( AD) ； 8.0M 和 27.3 M(AP) (p = 0.977 and 0.081), lAD 的血液学毒性比AP 重(p 0.0000）3-4 度疲劳AD重 (p = 0.03). l而神经病变在AP组多见 (p = 0.03)。 Cassier PA, et al. Breast Cancer Res Treat. 2007 A phase-III trial of doxorubicin and docetaxel versus doxorubicin and paclitaxel in metastatic breast cancer: results of the ERASME 3 study. l结论： AD与AP在生活质量和有效率无差别，但在 副作用方面有差别。 Cassier PA, et al. Breast Cancer Res Treat. 2007 Evidence-based use of taxanes in the adjuvant setting of breast cancer. A review of randomized phase III trials. l6个大型临床试验。验证 taxanes 在乳腺癌 辅助治疗中的作用。各种不同的以 anthracycline为主的方案作为对照组。 l有充分证据支持常规使用taxanes 治疗乳腺 癌是有益的，包括激素受体阳性和Her-2阳 性的病人。 EstvezEstvez LG LG, et al. , et al. Cancer Treat Rev.Cancer Treat Rev. 2007 2007 Combining chemotherapy and low-molecular-weight heparin for the treatment of advanced breast cancer: l凝血激活在肿瘤进展中起作用，低分子肝素可影 响肿瘤生长，显示低分子肝素可影响化疗疗效。 lEnoxaparin , 0, 5 or 1.0 mg/kg ，每天一次。 Docetaxel 35-45 mg/m(2)，每周一次。 lPR: 36%; SD:36 SeeholzerSeeholzer N N, et al. , et al. Blood Blood CoagulCoagul FibrinolysisFibrinolysis. . 2007 ;18(5):415-423. 2007 ;18(5):415-423. Vinorelbine/docetaxel combination treatment of metastatic breast cancer: a phase I study l方法: DOC: 60 or 70 mg /m2, day 1 NVB: 20 to 25 mg /m2 for i.v. on day 1, 60 mg/ m2 on day 8 or day 15 for oral, every 3 weeks. BonneterreBonneterre J J, et al. , et al. Cancer Cancer ChemotherChemother PharmacolPharmacol. . 2007 ; 60(3):365-373. 2007 ; 60(3):365-373. A phase II clinical trial of ZD1839 (Iressatrade mark) in combination with docetaxel as first-line treatment in patients with advanced breast cancer. lgefitinib 250 mg ，once daily docetaxel 75 mg/m(2) ，every 3 weeks, until tumor progression, toxicity or other reasons for discontinuation. Dennison SK, et al. Invest New Drugs. 2007Dennison SK, et al. Invest New Drugs. 2007 A phase II clinical trial of ZD1839 (Iressatrade mark) in combination with docetaxel as first-line treatment in patients with advanced breast cancer. l33例，中位治疗周期为5周期。临床受益率 为51.5%。 lCR: 1; PR: 12; SD: 4; ORR: 39.4%。 Dennison SK, et al. Invest New Drugs. 2007Dennison SK, et al. Invest New Drugs. 2007 A phase II clinical trial of ZD1839 (Iressatrade mark) in combination with docetaxel as first-line treatment in patients with advanced breast cancer. lCONCLUSION: The combination of gefitinib and docetaxel is an active regimen in patients with previously untreated MBC. Dennison SK, et al. Invest New Drugs. 2007Dennison SK, et al. Invest New Drugs. 2007 Multicenter phase II trial of neoadjuvant therapy with trastuzumab, docetaxel, and carboplatin for human epidermal growth factor receptor-2- overexpressing stage II or III breast cancer: results of the GETN(A)-1 trial. l方法: HER-2-阳性患者。 trastuzumab 4 mg/kg (day 1), followed by 2 mg/kg weekly, docetaxel 75 mg/m2， every 3 weeks, carboplatin (area under curve, 6) for six cycles CoudertCoudert BP BP, et al. , et al. J J ClinClin OncolOncol. . 2007; 25(19):2678-2684. 2007; 25(19):2678-2684. Multicenter phase II trial of neoadjuvant therapy with trastuzumab, docetaxel, and carboplatin for human epidermal growth factor receptor-2- overexpressing stage II or III breast cancer: results of the GETN(A)-1 trial. l RESULTS: Sixty-seven patients, HER-2-positive, completed six cycles of therapy. CR and PR: 95% (85% and 10%). Grade 3/4 neutropenia and febrile neutropenia were 2%. No symptomatic cardiac dysfunction occurred. CoudertCoudert BP BP, et al. , et al. J J ClinClin OncolOncol. . 2007; 25(19):2678-2684. 2007; 25(19):2678-2684. Multicenter phase II trial of neoadjuvant therapy with trastuzumab, docetaxel, and carboplatin for human epidermal growth factor receptor-2- overexpressing stage II or III breast cancer: results of the GETN(A)-1 trial. l CONCLUSION: Trastuzumab plus docetaxel and carboplatin achieved a good pCR rate and favorable tolerability in stage II or III HER- 2-positive breast cancer. CoudertCoudert BP BP, et al. , et al. J J ClinClin OncolOncol. . 2007; 25(19):2678-2684. 2007; 25(19):2678-2684. Pathologic complete response with six compared with three cycles of neoadjuvant epirubicin plus docetaxel and granulocyte colony- stimulating factor in operable breast cancer: results of ABCSG-14. lepirubicin 75 mg/m2 docetaxel 75 mg/m2 on day 1 granulocyte colony-stimulating factor on days 3 through 10 , ED+G every 21 days, three or six cycles. Steger GGSteger GG, et al. , et al. J J ClinClin OncolOncol. . 2007; 25(15):2012-2018. 2007; 25(15):2012-2018. Pathologic complete response with six compared with three cycles of neoadjuvant epirubicin plus docetaxel and granulocyte colony- stimulating factor in operable breast cancer: results of ABCSG-14. lSix cycles of ED+G, compared with three cycles, resulted in a significantly higher pCR rate (18.6% v 7.7%, P = .0045), a higher percentage of patients with negative axillary status (56.6% v 42.8%, P = .02). lRates of adverse events were similar, and no patients died on treatment. Steger GGSteger GG, et al. , et al. J J ClinClin OncolOncol. . 2007; 25(15):2012-2018. 2007; 25(15):2012-2018. Phase II study of neoadjuvant docetaxel/ vinorelbine followed by surgery and adjuvant doxorubicin/cyclophosphamide in women with stage II/III breast cancer. lbefore surgery with 6 cycles of docetaxel 60 mg/m2 and vinorelbine 45 mg/m2, repeated every 2 weeks with granulocyte colony-stimulating factor and quinolone prophylaxis. LimentaniLimentani SA, et al. SA, et al. ClinClin Breast Cancer. Breast Cancer. 2006;6(6):511-517. 2006;6(6):511-517. . . Phase II study of neoadjuvant docetaxel/ vinorelbine followed by surgery and adjuvant doxorubicin/cyclophosphamide in women with stage II/III breast cancer. lRESULTS: 59 patients, RR: 98%, CR:63%. Grade 3/4 neutropenia (95%), neutropenic fever (22%), mucositis (5%), and pulmonary toxicity (5%). LimentaniLimentani SA, et al. SA, et al. ClinClin Breast Cancer. Breast Cancer. 2006;6(6):511-517. 2006;6(6):511-517. . . Dosage of capecitabine and cyclophosphamide combination therapy in patients with metastatic breast cancer loral capecitabine 628 to 829 mg/m2 twice daily (bid) oral cyclophosphamide 33 to 50 mg/m2 bid, on days 1 to 14 a cycle every 21 days. OhnoOhno S S, et al. , et al. Anticancer Res.Anticancer Res. 2007;27(2):1009-1013. 2007;27(2):1009-1013. Dosage of capecitabine and cyclophosphamide combination therapy in patients with metastatic breast cancer lCONCLUSION: The capecitabine/cyclophosphamide combination regimen is well tolerated and active in MBC, and is being evaluated in a phase II study in anthracycline-pretreated MBC. OhnoOhno S S, et al. , et al. Anticancer Res.Anticancer Res. 2007;27(2):1009-1013. 2007;27(2):1009-1013. Phase I/II trial of adjuvant dose-dense docetaxel/epirubicin/cyclophosphamide (TEC) in stage II and III breast cancer. ldocetaxel (T) 75 mg/m(2), epirubicin (E) 75 mg/m(2) (cohort 1, n = 3) or 100 mg/m(2) (cohort 2, n = 12), cyclophosphamide (C) 500 mg/m(2) day 1, with pegfilgrastim 6 mg subcutaneously on day 2, every 2 weeks for six cycles. Burdette-Burdette-RadouxRadoux S, et al. S, et al. Breast J.Breast J. 2007;13(3):274-280. 2007;13(3):274-280. Phase I/II trial of adjuvant dose-dense docetaxel/epirubicin/cyclophosphamide (TEC) in stage II and III breast cancer. l结论: 剂量密度 TEC 化疗是可行的。与TAC等剂 量时 (docetaxel 75 mg/m(2), epirubicin 75 mg/m(2), cyclophosphamide 600 mg/m(2), 毒性反应中等。 Burdette-Burdette-RadouxRadoux S, et al. S, et al. Breast J.Breast J. 2007;13(3):274-280. 2007;13(3):274-280. Gemcitabine Plus Doxorubicin as First-Line Treatment in Advanced or Metastatic Breast Cancer (MBC), A Phase II Study. lgemcitabine 1250mg/m2 IV on days 1 , 8 doxorubicin 60mg/m2 IV on day 1 every 21 days, for 6 cycles. El El SerafiSerafi MM, et al. MM, et al. J Egypt J Egypt NatlNatl CancCanc Inst. Inst. 2006;18(3):209-215. 2006;18(3):209-215. Gemcitabine Plus Doxorubicin as First-Line Treatment in Advanced or Metastatic Breast Cancer (MBC), A Phase II Study. lRESULTS: CR:17.1% PR40% SD: 22.9% ORR: 57.1%. MTTP: 7 months The overall survival at 1 and 2 years was 74.2% and 34.2%; El El SerafiSerafi MM, et al. MM, et al. J Egypt J Egypt NatlNatl CancCanc Inst. Inst. 2006;18(3):209-215. 2006;18(3):209-215. Gemcitabine in the management of metastatic breast cancer: a systematic review. l共83个试验，包括4个III 期随机临床试验，全部III 期临床 试验均为一线用药。 l结果：其中2个III期试验证明含gemcitabine方案治疗 MBC疗效高，副作用小。而另外2个III期试验却 认为没有 临床受益，而副作用大。 l结论: Gemcitabine taxane一线或二线治疗MBC疗效 显著。 Dent S, et al. Breast Cancer Res Treat. 2007Dent S, et al. Breast Cancer Res Treat. 2007 Low dose Gemcitabine plus cisplatin in a weekly-based regimen as salvage therapy for relapsed breast cancer after taxane- anthracycline-containing regimens. lgemcitabine (G) (initial dose 750 mg/m(2), or 600 mg/m(2) if the patient had received more than two previous CT lines) plus cisplatin (P) (initial dose 30 mg/m(2), or 20 mg/m(2) in case of /=3 prior CT lines) on days 1 and 8 of a 21- day cycle. Treatment was postponed to day 15 if it could not be given on day 8, without dose reduction. If treatment could not be given on day 15, a 20% dose reduction was allowed and treatment given the next week. Snchez-EscribanoSnchez-Escribano MorcuendeMorcuende R R, et al. , et al. ClinClin TranslTransl OncolOncol. . 2007; 9(7):459-464. 2007; 9(7):459-464. Low dose Gemcitabine plus cisplatin in a weekly-based regimen as salvage therapy for relapsed breast cancer after taxane- anthracycline-containing regimens. lAll had prior anthracyclines and taxanes. Other agents used included 5- FU/eniluracil, MTX, RPR 109881A, trastuzumab, cisplatin, VP16, vinorelbine, capecitabine and irinotecan. l72.7% had received radiotherapy l 68.1% hormonal therapy. Snchez-EscribanoSnchez-Escribano MorcuendeMorcuende R R, et al. , et al. ClinClin TranslTransl OncolOncol. . 2007; 9(7):459-464. 2007; 9(7):459-464. Low dose Gemcitabine plus cisplatin in a weekly-based regimen as salvage therapy for relapsed breast cancer after taxane- anthracycline-containing regimens. lResults: PR: 9.1%, SD: 36.4%. Clinical Benefit Rate (PR+SD): 45.5% MTTP: 4 months Median survival: 8 months Toxicities grade 3 were neutropenia 35% and thrombocytopenia 15%. Snchez-EscribanoSnchez-Escribano MorcuendeMorcuende R R, et al. , et al. ClinClin TranslTransl OncolOncol. . 2007; 9(7):459-464. 2007; 9(7):459-464. Low dose Gemcitabine plus cisplatin in a weekly-based regimen as salvage therapy for relapsed breast cancer after taxane- anthracycline-containing regimens. l结论: 曾进行过多次化疗的， PS较好的 MBC. 每周一次的 cisplatin-gemcitabine 是 安全有效的挽救治疗方案。 Snchez-EscribanoSnchez-Escribano MorcuendeMorcuende R R, et al. , et al. ClinClin TranslTransl OncolOncol. . 2007; 9(7):459-464. 2007; 9(7):459-464. Dose-finding study of capecitabine in combination with weekly paclitaxel for patients with anthracycline-pretreated metastatic breast cancer. l CONCLUSION: capecitabine 1,000 mg/m(2) twice daily, days 1-14, paclitaxel 60 mg/m(2)/week. paclitaxel 剂 量大于60 mg/m(2)/week 是不合适的，因 出现严重的皮肤毒性。 SusnjarSusnjar S S, et al. , et al. J BUON.J BUON. 2007;12(2):189-196. 2007;12(2):189-196. A phase II study of trastuzumab and capecitabine for patients with HER2- overexpressing metastatic breast cancer: Japan Breast Cancer Research Network (JBCRN) 00 Trial. l59 例病人由6 个中心提供。进行 trastuzumab capecitabine治疗乳腺癌的 研究。86接受过化疗 。 CMF (7.1%), anthracyclines (28.6%), taxanes (25.0%), 或两种方案化疗(25.0%)。 Yamamoto DYamamoto D, et al. , et al. Cancer Cancer ChemotherChemother PharmacolPharmacol. . 2007 2007 . . A phase II study of trastuzumab and capecitabine for patients with HER2- overexpressing metastatic breast cancer: Japan Breast Cancer Research Network (JBCRN) 00 Trial. lRR：65.0% (trastuzumab + capecitabine 作为MBC的一线治疗 ) ，有效者62.5% 在 HER2 +3的患者中, 二线或三线治疗者也有 许多有效。 ltrastuzumab capecitabine 作为一线治疗 比作为二、三线治疗有更长的 TTP 和OS。 Yamamoto DYamamoto D, et al. , et al. Cancer Cancer ChemotherChemother PharmacolPharmacol. . 2007 2007 . . Phase II study of capecitabine plus trastuzumab in human epidermal growth factor receptor 2 overexpressing metastatic breast cancer pretreated with anthracyclines or taxanes. l27例HER-2-过度表达的MBC，曾用 anthracyclines and/or taxanes 治疗，给予口服 capecitabine 1,250 mg/m(2)， bid， 114 天。 trastuzumab 4 mg/kg ，第1天，以后每周 2 mg/kg。 lRR: 45%, CR: 15%, PR:30%. SD: 33%. MOS: 28 M. MPFS: 6.7 M. Schaller GSchaller G, et al. , et al. J J ClinClin OncolOncol. . 2007;25(22):3246-50. 2007;25(22):3246-50. Vinorelbine and cisplatin for metastatic breast cancer: a salvage regimen in patients progressing after docetaxel and anthracycline treatment. l Cisplatin : 75 mg/m2 on day 1 VNR: 25 mg/m2 on days 1 , 8 every 3 weeks. lCR: 5.6% ; PR: 41.6%; OR: 47.2% lneutropenia grade : 47%. Thrombocytopenia grade 3/4 :11%. There were no treatment-related deaths. VassilomanolakisVassilomanolakis M M, et al. , et al. Cancer Invest.Cancer Invest. 2003;21(4):497-504. 2003;21(4):497-504. Vinorelbine and cisplatin for metastatic breast cancer: a salvage regimen in patients progressing after docetaxel and anthracycline treatment. l结论: DDP / VNR 耐受好，且对anthracyclines 和docetaxel 耐药的病人有效。. VassilomanolakisVassilomanolakis M M, et al. , et al. Cancer Invest.Cancer Invest. 2003;21(4):497-504. 2003;21(4):497-504. Trastuzumab plus vinorelbine or taxane chemotherapy for HER2- overexpressing metastatic breast cancer: The trastuzumab and vinorelbine or taxane study. l trastuzumab with weekly vinorelbine therapy or weekly taxane therapy (paclitaxel or docetaxel at the investigators choice). Burstein HJ, et al. Cancer. 2007Burstein HJ, et al. Cancer. 2007 Trastuzumab plus vinorelbine or taxane chemotherapy for HER2- overexpressing metastatic breast cancer: The trastuzumab and vinorelbine or taxane study. l RESULTS.: RR: vinorelbine/trastuzumab 51% taxane/trastuzumab 40% (P = 0.37). MTTP: vinorelbine 8.5 months , taxane 6.0 months (P = 0.09) Burstein HJ, et al. Cancer. 2007Burstein HJ, et al. Cancer. 2007 Docetaxel-ifosfamide combination in patients with advanced breast cancer failing prior anthracycline-based regimens: results of a phase I-II study. l docetaxel 70-100 mg/m(2) over 1 h on day 1 lfollowed by ifosfamide 5-6 g/m(2) divided over days 1+2 (2.5-3.0 g/m(2)/day over 1 h), every 21 days. Kosmas CKosmas C, et al. , et al. J J ChemotherChemother. . 2007;19(3):322-331. 2007;19(3):322-331. Docetaxel-ifosfamide combination in patients with advanced breast cancer failing prior anthracycline-based regimens: results of a phase I-II study. lRR: 56%; lmedian TTP 6.5M lmedian OS 13 M lGrade 3/4 toxicities included: neutropenia in 72% of patients, with 60% developing grade 4 neutropenia (1y), Yap YS, et al. Breast. 2007;16(4):420-424. Yap YS, et al. Breast. 2007;16(4):420-424. Phase I/II study of capecitabine and vinorelbine in pretreated patients with metastatic breast cancer. lCapecitabine: 1000 mg/m(2) ,Bid, d1-14. 停1周，再重复，6周为一个周期。 Vinorelbine 25 mg/m(2) 或30 mg/m(2) days 1, 8, 22 , 29. lORR: 55% . Welt AWelt A, et al. , et al. Ann Ann OncolOncol. . 2005;16(1):64-69. 2005;16(1):64-69. Pilot study of primary systemic chemotherapy with docetaxel (DOC), epirubicin (EPI) and capecitabine (Xeloda) in patients with advanced breast cancer lXLD (2,400 or 3,000 mg/day) d1-14 DOC (60 or 70 mg/m2) ,d8 EPI (50 or 60 mg/m2) ,d8. every 3 weeks. lRR: 77.8%. TagayaTagaya N, N, et al. et al. GanGan To Kagaku To Kagaku RyohoRyoho. . 2006;33(1):39-42. 2006;33(1):39-42. Dose-dense adjuvant chemotherapy in node-positive breast cancer: docetaxel follow