2011年_St_Gallen早期乳腺癌初_省略__与中国抗癌协会乳腺癌专业委员
ASCO2020丨昨天、今天、明天——徐兵河教授谈新型ADC药物带来的新希望
ASCO2020⼁昨天、今天、明天——徐兵河教授谈新型ADC药物带来的新希望编者按HER2阳性晚期乳腺癌在⼀线双靶抗HER2治疗、⼆线T-DM1治疗耐药后，没有标准⽅案可供选择。
DS-8201的出现，使晚期HER2阳性乳腺癌的后线治疗柳暗花明，作为新型的ADC药物，其以独特的偶联化疗药物、超⾼的药物抗体⽐和旁观者效应发挥了极好的疗效。
在Destiny-Breast 01研究中，ORR可达60.9%，PFS达16.4个⽉，2020ASCO年会对其不同亚组的疗效进⼀步分析，给患者带来更坚实的信念和希望。
同时，后续⼀系列的Destiny-Breast 02、03、04研究将进⼀步验证其疗效，给患者更多治疗选择。
《肿瘤瞭望》特邀中国医学科学院肿瘤医院的徐兵河教授为您带来新型ADC药物的昨天、今天和明天。
回望昨天，HER2阳性乳腺癌后线治疗的柳暗花明ASCO 2020HER2阳性乳腺癌患者约占乳腺癌总体⼈群的15-20%，曾经⼀度以难治著称。
抗HER2靶向药物的问世，极⼤地改善了患者的预后。
对于晚期HER2阳性乳腺癌患者，曲妥珠单抗帕妥珠单抗双靶联合化疗为标准的⼀线治疗⽅案，⼆线可选药物⼗分有限，EMILIA研究显⽰ADC药物T-DM1 在⼆线治疗患者中位PFS9.6个⽉，ORR仅43.6%，成为主要选择，然⽽若再度耐药则患者⼏乎⽆药可⽤。
⼭重⽔复疑⽆路的时候，新型ADC药物DS-8201横空出世，Destiny-Breast 01更是证实对于平均治疗6线的HER2阳性晚期乳腺癌的ORR可达60.9%，PFS达16.4个⽉，即使是T-DM1经治的患者，ORR也达64.5%。
因此DS-8201迅速获得FDA批准，并被NCCN指南推荐⽤于既往HER2靶向治疗⼆线失败之后的乳腺癌转移患者。
DS-8201a⾼效的作⽤源⾃于其独特的药理机制，其偶联的化疗药物为既往很少⽤于乳腺癌患者的拓扑异构酶抑制剂Dxd，⽽第⼀代ADC药物偶联的抗微管类药物（如紫杉类）则已⼴泛地⽤于乳腺癌的化疗中，因此，相较于第⼀代ADC，DS-8201a具有独特的治疗优势；其次，DS-8201a中药物抗体⽐为8:1，远⾼于第⼀代ADC药物，即单个单抗所偶联的化疗药物更多，抗肿瘤作⽤更强；第三，DS-8201a偶联的化疗药物在精准杀灭HER-2⾼表达肿瘤细胞后，可以通过有效的跨膜作⽤，发挥旁观者效应，对周边HER-2低表达或不表达肿瘤细胞产⽣杀伤作⽤，因此，对于HER-2低表达的乳腺癌DS-8201a同样具有治疗的潜⼒。
乳腺癌术前空芯针穿刺活检与手术标本检测Ki-67表达的差异及影响因素
乳腺癌术前空芯针穿刺活检与手术标本检测Ki-67表达的差异及影响因素张春; 徐硕; 解云涛; 禹雪; 张永辉; 付芬芬; 张冬洁; 谢凌铎; 褚福涛; 栗辰; 王芹芹【期刊名称】《《中国微创外科杂志》》【年(卷),期】2019(019)011【总页数】5页(P977-980,992)【关键词】空芯针穿刺活检; 乳腺癌; Ki-67表达指数【作者】张春; 徐硕; 解云涛; 禹雪; 张永辉; 付芬芬; 张冬洁; 谢凌铎; 褚福涛; 栗辰; 王芹芹【作者单位】北京大学国际医院乳腺外科北京 102206【正文语种】中文超声引导空芯针穿刺活检(core needle biopsy，CNB)是乳腺癌新辅助治疗前获取乳腺癌病灶雌激素受体(estrogen receptor，ER)、孕激素受体(progesterone receptor，PR)、人表皮生长因子受体2(human epidermal growth factor receptor 2，HER2)、增殖细胞相关的核抗原Ki-67表达情况的主要方法[1]，根据分子标记物的表达确定乳腺癌分子分型，从而选择进一步的系统治疗方案。
乳腺癌Ki-67表达指数反映肿瘤细胞增殖活性，治疗前Ki-67表达水平可预测病灶对新辅助内分泌治疗及新辅助化疗的敏感性，治疗后水平降低者可获得更好的预后[2～4]。
因此，CNB检测Ki-67表达的准确性至关重要。
以往对CNB检测Ki-67表达准确性的研究结果存在较大差异。
本研究选取我科2016年9月～2018年12月CNB病理为浸润性乳腺癌99例103个病灶，与手术切除的病理结果进行对比，分析CNB在检测乳腺癌Ki-67中的准确性。
1 临床资料与方法1.1 一般资料本组99例，均为女性，平均年龄54岁(25～88岁)。
共103个病灶(1例为同侧3个病灶，2例为同侧2个病灶)，乳腺超声提示病灶最大径中位数1.7 cm(0.6～6.3 cm)，其中0.6～0.9 cm 10个，1.0～1.9 cm 50个，2.0～2.9 cm 26个，3.0～3.9 cm 11个，4.0～4.9 cm 2个，≥5 cm 4个。
乳腺癌内分泌治疗
[14] ATAC. Lancet 2010. [15] BIG 1-98. N Engl J Med 2005;353:2747-57. [16] MA.17R. N Engl J Med 2016.
5.3 绝经前晚期乳腺癌内分泌治疗
20世纪80年代开始GnRHa在绝经前晚期乳腺癌的探索：最早在 1982年Klijin [17]报道了布舍瑞林用于绝经前晚期乳腺癌。Tylor 等[18]于1998年在《临床肿瘤学杂志》报道了一项随机对照Ⅲ期 研究，证实了戈舍瑞林与手术去势（即双侧卵巢切除术）疗效 相似；该研究奠定了药物去势在绝经前晚期乳腺癌的治疗地位。 NCCN 2016第2版推荐对于绝经前晚期乳腺癌，应先给予卵巢去 势治疗达到“人工绝经”状态，再按照绝经后晚期乳腺癌进行 处理。 TAM在绝经前晚期乳腺癌内分泌治疗：1986年报道了TAM对比 卵巢切除术用于绝经前晚期乳腺癌的两个研究，均发表于《临 床肿瘤学杂志》 [19, 20]；证实了TAM与卵巢切除术疗效相似。
aaa623
Primary extramedullary plasmacytoma: similarities with and differences from multiple myeloma revealed by interphase cytogeneticsKarin Bink,1Eugenia Haralambieva,2Marcus Kremer,3German Ott,4Christine Beham-Schmid,5 Laurence de Leval,6Suat Cheng Peh,7Hubert R. Laeng,8Uta Jütting,9Peter Hutzler,1Leticia Quintanilla-Martinez,1and Falko Fend31Institutes of Pathology,Helmholtz Center Munich,German Research Center for Environmental Health,Neuherberg, Oberschleissheim; 2University of Würzburg;3Technical University of Munich; 4Robert Bosch Hospital,Stuttgart, Germany; 5University of Graz,Austria;6University of Liège,Belgium;7University of Malaya,Malaysia;8Kantonsspital Aarau,Switzerland; 9Institute of Biomathematics and Biometry,Helmholtz Center Munich,German Research Center for Environmental Health,Neuherberg,Oberschleissheim,GermanyBrief ReportABSTRACTPrimary extramedullary plasmacytoma is an indolent neoplasm that infrequently converts to multiple myeloma.Since cytogenetic data on extramedullary plasmacytoma are lacking,we studied 38 cases of this type of neoplasm by fluorescence in situ hybridization.Fourteen cases (37%) contained IGH breaks,including six with a t(4;14) translocation.No translocations t(11;14),t(14;16),t(8;14),nor breaks involving MALT1,BCL6or FOXP1were found.Loss of 13q (40%),as well as chromosomal gains (82%) were common.There was no cor-relation between chromosomal alterations and clinical features or local relapse.Cytogenetically,extramedullary plasmacytoma and multi-ple mueloma are closely related.However,the distribution of IGH translocation partners,with the notable absence of t(11;14),is different. Key words: extramedullary plasmacytoma,multiple myeloma,cytogenetics,IGH translocation,fluorescence in situ hybridization.Citation:Bink K,Haralambieva E,Kremer M,Ott G,Beham-Schmid C,de Leval L,Peh SC,Laeng HR,Jütting U,Hutzler P,Quintanilla-Martinez L,and Fend F.Primary extramedullary plasmacytoma: similarities with and differences from multiple myeloma revealed by interphase cytogenetics.Haematologica 2008 Apr; 93(4):623-626.doi: 10.3324/haematol.12005©2008 Ferrata Storti Foundation.This is an open-access paper.IntroductionPrimary extramedullary plasmacytoma (EMP) is defined as an extraosseous proliferation of neoplastic plasma cells without evidence of bone or bone marrow involvement as evidenced by morphological bone marrow examination and radiographic studies.1EMP accounts for about 4% of plasma cell tumors, and more than 80% occur in the upper aerodigestive tract. EMP usually shows an indolent clinical course with good response to local radiotherapy, a tendency to local relapse and infrequent conversion to multiple myeloma (MM).2-4Despite these marked differences in clinical presentation and prognosis, infiltrates of EMP are morphologically indistinguishable from MM spreading to extramedullary locations,5and there are no well defined parameters predicting which patients with EMP are at risk of developing MM. On the other hand, some authors have specu-lated that EMP may represent a form of extranodal marginal zone B-cell lymphoma (MALT-type lymphoma) with extreme plasmacytic differentiation.6In recent years, the introduction of interphase fluorescence in situ hybridization (FISH)has enabled identification of clinically and prognostically relevant MM subgroups defined by recurrent chromosomal aberrations.7,8Fifty to 70% of cases of MM have translocations involving the immunoglobulin heavy chain (IGH) gene locus at 14q32. In contrast to most translocations in non-Hodgkin’s lymphoma, a large number of different chromosomal partners of 14q32 have been identified in MM, including the t(11;14)(q13;q32) involving the CCND1(cyclin D1) locus in 15-25% of patients, and the t(4;14)(p16;q32) involving the fibroblast growth factor receptor 3 (FGFR3) locus in 10-15% of cases.8,9A frequent numerical aberration is loss of chromosome 13 or parts of its long arm, which occurs in about half of MM patients.8 Furthermore, about half of MM patients exhibit hyperdiploidy, characterized by non-random chromosomal gains. Based on these data, two main types of MM of prognostic relevance have been defined, namely hyperdiploid cases with lower frequencies of recurrent 14q32 translocations or chromosome 13 abnormal-ities, and pseudo- or hypodiploid cases with a high incidence ofAcknowledgments: we would like to thank all the clinicians who contributed clinical data.The skilful technical assistance of Ulrike Buchholz is gratefully acknowledged.We thank Dr.Mark Raffeld for providing the KMS11,KMS12,KMS18 and OPM-2 cell lines.Funding:this study was supported in part by grant FE 597-1/1-2 from the Deutsche Forschungsgemeinschaft (DFG) to FF,LQ-M and MK.Manuscript received July 18,2007.Revised version arrived on September 28,2007.Accepted October 29,2007.Correspondence:Falko Fend,M.D.,Institute of Pathology,University Hospital Tuebingen,Eberhard-Karls-University,Liebermeisterstrasse 8,72076 Tuebingen,Germany.E-mail: falko.fend@med.uni-tuebingen.deThe online version of this article contains a supplemental appendix.haematologica | 2008; 93(4) | 623|K. Bink et al.| 624| haematologica | 2008; 93(4)FISH in extramedullary plasmacytomahaematologica | 2008; 93(4) | 625|K. Bink et al.| 626| haematologica | 2008; 93(4)References1.Kyle RA. Criteria for the classification of monoclonal gammopathies, multi-ple myeloma and related disorders: a report of the international myeloma working group. Br J Haematol 2003;121:749-57.2.Galieni P , Cavo M, Pulsoni A, Avvisati G, Bigazzi C, Neri S, et al. Clinical out-come of extramedullary plasmacy-toma. Haematologica 2000;8547-51.3.Batsakis JG , Medeiros JL, Luna MA,El-Naggar AK. Plasma cell dyscrasias and the head and neck. Ann Diagn Pathol 2002;6:129-40.4.Alexiou C, Kau RJ, Dietzfelbinger H,Kremer M, Spiess JC, Schratzenstaller B, et al. Extramedullary plasmacy-toma: tumor occurrence and thera-peutic concepts. Cancer 1999; 85:2305-14.5.Kremer M, Ott G, Nathrath M, Specht K, Stecker K, Alexiou C, et al. Primary extramedullary plasmacytoma and multiple myeloma: phenotypic differ-ences revealed by immunohisto-chemical analysis. J Pathol 2005;205:92-101.6.Hussong JW, Perkins SL, Schnitzer B,Hargreaves H, Frizzera G . Extra-medullary plasmacytoma. A form of marginal zone cell lymphoma? Am J Clin Pathol 1999; 111:111-6.7.Avet-Loiseau H, Facon T, Grosbois B,Magrangeas F , Rapp MJ, Harousseau JL, et al. Oncogenesis of multiple myeloma: 14q32 and 13q chromoso-mal abnormalities are not randomly distributed, but correlate with natural history, immunological features, and clinical presentation. Blood 2002;99:2185-91.8.Fonseca R, Barlogie B, Bataille R,Bastard C, Bergsagel PL, Chesi M, et al. Genetics and cytogenetics of mul-tiple myeloma: a workshop report.Cancer Res 2004;64:1546-58.9.Chesi M, Nardini E, Brents LA,Schrock E, Ried T, Kuehl WM, et al.Frequent translocation t(4;14) (p16.3;q32.3) in multiple myeloma is associ-ated with increased expression and activating mutations of fibroblast growth factor receptor 3. Nat G enet 1997;16:260-4.10.Chng WJ, Santana-Davila R, Van Wier SA, Ahmann G J, Jalal SM, Bergsagel PL, et al. Prognostic factors for hyper-diploid-myeloma: effects of chromo-some 13 deletions and IgH transloca-tions. Leukemia 2006; 20:807-13.11.Fonseca R, Blood E, Rue M,Harrington D, Oken MM, Kyle RA, et al. Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood 2003; 101:4569-75.12.Avet-Loiseau H, Facon T, Daviet A,Godon C, Rapp MJ, Harousseau JL, et al. 14q32 translocations and mono-somy 13 observed in monoclonal gammopathy of undetermined signif-icance delineate a multistep process for the oncogenesis of multiple myeloma. Intergroupe Francophone du Myelome. Cancer Res 1999;59:4546-50.13.Bartl R, Frisch B, Fateh-Moghadam A,Kettner G , Jaeger K, Sommerfeld W.Histologic classification and staging of multiple myeloma: a retrospective and prospective study of 674 cases.Am J Clin Pathol 1987; 87:342-55.14.Haralambieva E, Adam P , Ventura R,Katzenberger T, Kalla J, Höller S, et al.Genetic rearrangement of FOXP1 is predominantly detected in a subset of diffuse large B-cell lymphomas with extranodal presentation.Leukemia 2006;20:1300-3.15.Specht K, Haralambieva E, Bink K,Kremer M, Mandl-Weber S, Koch I, et al. Different mechanisms of cyclin D1overexpression in multiple myeloma revealed by fluorescence in situ hybridization and quantitative analy-sis of mRNA levels. Blood 2004;104:1120-6.16.Perfetti V, Coluccia AM, Intini D,Malgeri U, Vignarelli MC, Casarini S,et al. Translocation t(4;14) (p16.3;q32)is a recurrent genetic lesion in primary amyloidosis. Am J Pathol 2001;158:1599-603.17.Shaughnessy J Jr., G abrea A, Qi Y,Brents L, Zhan F , Tian E, et al. Cyclin D3 at 6p21 is dysregulated by recur-rent chromosomal translocations to immunoglobulin loci in multiple myeloma. Blood 2001;98:217-23.18.Avet-Loiseau H, G erson F , Magran-geas F , Minvielle S, Harousseau JL,Bataille R. Rearrangements of the c-myc oncogene are present in 15% of primary human multiple myeloma tumors. Blood 2001;98:3082-6.19.Konigsberg R, Ackermann J,Kaufmann H, Zojer N, Urbauer E,Kromer E, et al. Deletions of chromo-some 13q in monoclonal gammopa-thy of undetermined significance.Leukemia 2000;14:1975-9.20.Chng WJ, Van Wier SA, Ahmann GJ,Winkler JM, Jalal SM, Bergsagel PL, et al. A validated FISH trisomy index demonstrates the hyperdiploid and nonhyperdiploid dichotomy in MGUS. Blood 2005;106:2156-61.21.Ott G , Katzenberger T, G reiner A,Kalla J, Rosenwald A, Heinrich U, et al. The t(11;18)(q21;q21) chromo-some translocation is a frequent and specific aberration in low-grade but not high-grade malignant non-Hodgkin's lymphomas of the mucosa-associated lymphoid tissue (MALT-) type. Cancer Res 1997; 57:3944-8.22.Streubel B, Lamprecht A, Dierlamm J,Cerroni L, Stolte M, Ott G , et al.T(14;18)(q32;q21) involving IG H and MALT1 is a frequent chromosomal aberration in MALT lymphoma.Blood 2003;101:2335-9.23.Streubel B, Vinatzer U, Lamprecht A,Raderer M, Chott A. t(3;14)(p14.1;q32) involving IGH and FOXP1is a novel recurrent chromosomal aberration in MALT lymphoma.Leukemia 2005;19:652-8.。
三阳性乳腺癌271例临床病理特征与生存分析
三阳性乳腺癌271例临床病理特征与生存分析管小青;郑向欣;顾书成;吴骥;江小玲;侍孝红;袁牧;陆柏林;邱兴;袁振【摘要】目的探讨三阳性乳腺癌(TPBC)的临床病理特征和生存情况.方法收集271例TPBC患者,并与随机抽取的283例HER-2阴性的Luminal B Ⅰ型患者进行对比,对其临床病理特征和生存情况进行分析.结果本组271例TPBC患者2a内远处转移89例(32.84％),而随机选取的Luminal B Ⅰ型患者283例2a内远处转移有32例(11.31％),比较差异有统计学意义(P ＜0.05);TPBC患者5 a内远处转移137例(50.55％),而Luminal B Ⅰ型患者为52例(18.37％),比较差异有统计学意义(P＜0.05).无病生存率和总生存率方面的比较:TPBC患者和Luminal B Ⅰ型患者的1 a无病生存率和总生存率均为100.00％,2a无病生存率分别为64.94％(176/271)、86.22％(244/283),2 a总生存率分别为85.24％(231/271)、95.76％(271/283),3 a无病生存率分别为54.98％(149/271)、81.98％ (232/283),3 a总生存率分别为69.74％(189/271)、80.92％(229/283),5 a无病生存率分别为43.54％(118/271)、76.33％(216/283),5 a总生存率分别为47.23％(128/271)、67.49％ (191/283),比较差异均有统计学意义(P均＜0.05).结论 TPBC具有生物学行为差、肿块较大、病理分级多为Ⅲ级、常有脉管或神经浸润、腋窝淋巴结转移、高增殖指数和高肿瘤负荷等病理特征;TPBC远处复发早,无病生存率和总生存率较低;根据患者的激素受体和Ki-67表达情况选择个体化、有针对性治疗方案可使此类患者获益.【期刊名称】《肿瘤基础与临床》【年(卷),期】2017(030)006【总页数】5页(P507-511)【关键词】三阳性乳腺癌;临床病理学特征;无病生存率;总生存率【作者】管小青;郑向欣;顾书成;吴骥;江小玲;侍孝红;袁牧;陆柏林;邱兴;袁振【作者单位】徐州医科大学附属宿迁医院甲乳外科,江苏宿迁223800;徐州医科大学附属宿迁医院甲乳外科,江苏宿迁223800;徐州医科大学附属宿迁医院甲乳外科,江苏宿迁223800;徐州医科大学附属宿迁医院甲乳外科,江苏宿迁223800;徐州医科大学附属宿迁医院病理科,江苏宿迁223800;徐州医科大学附属宿迁医院病理科,江苏宿迁223800;徐州医科大学附属宿迁医院甲乳外科,江苏宿迁223800;徐州医科大学附属宿迁医院甲乳外科,江苏宿迁223800;徐州医科大学附属宿迁医院甲乳外科,江苏宿迁223800;宿迁市人事和劳动保障局医疗保险处,江苏宿迁223800【正文语种】中文【中图分类】R737.9我国女性乳腺癌的发病率现在已经上升为女性恶性肿瘤的第1位，其死亡率也迅速上升[1-2]。
TAX327
The new england journal of medicinen engl j med 351;15october 7, 20041502 Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate CancerIan F. Tannock, M.D., Ph.D., Ronald de Wit, M.D., William R. Berry, M.D.,Jozsef Horti, M.D., Anna Pluzanska, M.D., Kim N. Chi, M.D.,Stephane Oudard, M.D., Christine Théodore, M.D.,Nicholas D. James, M.D., Ph.D., Ingela Turesson, M.D., Ph.D., Mark A. Rosenthal, M.D., Ph.D., and Mario A. Eisenberger, M.D.,for the TAX 327 InvestigatorsFrom the Department of Medical Oncology and Hematology, Princess Margaret Hos-pital and University of Toronto, Toronto (I.F.T.); the Department of Medical Oncol-ogy, Erasmus University Medical Centre,Rotterdam, the Netherlands (R.W .); Raleigh H ematology Oncology Associates, Cary,N.C. (W .R.B.); the Department of Chemo-therapy and Clinical Pharmacology, Nation-al Institute of Oncology, Budapest, Hunga-ry (J.H.); the Department of Chemotherapy,Medical University, Lodz, Poland (A.P.);BC Cancer Agency, Vancouver, B.C., Cana-da (K.N.C.); H ôpital Européen Georges Pompidou, Paris (S.O.); Institut Gustav Roussy, Villejuif, France (C.T.); Cancer Re-search UK Institute for Cancer Studies, Bir-mingham, United Kingdom (N.D.J.); the Section of Oncology, Uppsala University Hospital, Uppsala, Sweden (I.T.); Cancer Trials Australia, Victoria, Australia (M.A.R.);and the Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins University,Baltimore (M.A.E.). Address reprint re-quests to Dr. Tannock at the Department of Medical Oncology and Hematology,Princess Margaret Hospital, 610 Universi-ty Ave., Toronto, ON M5G 2M9, Canada,or at ian.tannock@uhn.on.ca.N Engl J Med 2004;351:1502-12.Copyright © 2004 Massachusetts Medical Society.backgroundMitoxantrone plus prednisone reduces pain and improves the quality of life in men with advanced, hormone-refractory prostate cancer, but it does not improve survival.We compared such treatment with docetaxel plus prednisone in men with this disease.methodsFrom March 2000 through June 2002, 1006 men with metastatic hormone-refractory prostate cancer received 5 mg of prednisone twice daily and were randomly assigned to receive 12 mg of mitoxantrone per square meter of body-surface area every three weeks,75 mg of docetaxel per square meter every three weeks, or 30 mg of docetaxel per square meter weekly for five of every six weeks. The primary end point was overall survival.Secondary end points were pain, prostate-specific antigen (PSA) levels, and the quality of life. All statistical comparisons were against mitoxantrone.resultsAs compared with the men in the mitoxantrone group, men in the group given doce-taxel every three weeks had a hazard ratio for death of 0.76 (95 percent confidence in-terval, 0.62 to 0.94; P=0.009 by the stratified log-rank test) and those given weekly docetaxel had a hazard ratio for death of 0.91 (95 percent confidence interval, 0.75 to 1.11; P=0.36). The median survival was 16.5 months in the mitoxantrone group, 18.9months in the group given docetaxel every 3 weeks, and 17.4 months in the group giv-en weekly docetaxel. Among these three groups, 32 percent, 45 percent, and 48 percent of men, respectively, had at least a 50 percent decrease in the serum PSA level (P<0.001for both comparisons with mitoxantrone); 22 percent, 35 percent (P=0.01), and 31percent (P=0.08) had predefined reductions in pain; and 13 percent, 22 percent (P=0.009), and 23 percent (P=0.005) had improvements in the quality of life. Adverse events were also more common in the groups that received docetaxel.conclusionsWhen given with prednisone, treatment with docetaxel every three weeks led to superi-or survival and improved rates of response in terms of pain, serum PSA level, and qual-ity of life, as compared with mitoxantrone plus prednisone.n engl j med 351;15october 7, 2004docetaxel versus mitoxantrone for prostate cancer1503rostate cancer is the most com -mon cancer among men, with approximate-ly 220,000 cases and 29,000 deaths annu-ally in the United States. 1 About 10 to 20 percent of men with prostate cancer present with metastatic disease, and in many others, metastases develop despite treatment with surgery or radiotherapy.Treatment of metastatic prostate cancer is pal-liative. In about 80 percent of men, primary andro-gen ablation leads to symptomatic improvement and a reduction in serum levels of prostate-specific antigen (PSA), but in all patients the disease even-tually becomes refractory to hormone treatment.The options then include symptomatic care with narcotic analgesics, radiotherapy to dominant sites of bone pain, treatment with bone-seeking isotopes such as strontium-89, and cytotoxic chemothera-py. Bisphosphonates may reduce skeletal compli-cations, 2-4 and low-dose prednisone or hydrocor-tisone may be palliative in some patients. 5,6Chemotherapy can reduce serum PSA levels in patients with hormone-refractory prostate cancer and relieves pain in some patients, but tolerability is of concern, particularly since most patients are elderly and many have other medical problems. 7 A randomized trial showed that mitoxantrone plus low-dose prednisone relieved pain and improved the quality of life more frequently than did pred-nisone alone. 8,9 Consistent benefits of mitoxantro-ne plus a corticosteroid were observed in other ran-domized trials, but none found that this approach improved survival. 10-12 These trials established mi-toxantrone plus a corticosteroid as the treatment of reference for hormone-refractory prostate cancer.Phase 2 studies of the taxane docetaxel have re-ported PSA responses (defined as a reduction in serum PSA levels of at least 50 percent) in up to 50percent of patients. 13-16 Studies of docetaxel plus either estramustine or calcitriol have shown PSA responses in up to 80 percent of patients. 17-19 How-ever, outcomes of single-group studies are subject to bias. 20We conducted a phase 3 study, the TAX 327Study, comparing docetaxel (given either every three weeks or weekly) plus daily prednisone with mito-xantrone plus prednisone. The docetaxel regimens were selected on the basis of their dose equivalence (a dose intensity of 25 mg per square meter of body-surface area per week and a maximal cumulative dose of 750 mg per square meter) and their activi-ty and tolerability in phase 2 studies. The primary hypothesis was that treatment with docetaxel plusprednisone would improve overall survival as com-This randomized, nonblinded, phase 3 study in-volved centers in 24 countries. Eligible patients had histologically or cytologically confirmed adeno-carcinoma of the prostate with clinical or radiolog-ic evidence of metastatic disease, had had disease progression during hormonal therapy, and were re-ceiving primary androgen-ablation therapy as main-tenance therapy. At least four weeks had to have elapsed between the withdrawal of antiandrogens (six weeks in the case of bicalutamide) and enroll-ment, so as to avoid the possibility of confounding as a result of the response to antiandrogen with-drawal. 21,22Another requirement was disease pro-gression, as indicated by increasing serum levels of PSA on three consecutive measurements obtained at least one week apart or findings on physical ex-amination or imaging studies.Eligible patients had a Karnofsky performance-status score of at least 60 percent, no prior treat-ment with cytotoxic agents (except estramustine)or radioisotopes, no history of another cancer with-in the preceding five years (except basal or squa-mous-cell skin cancer), no brain or leptomeningeal metastases, no symptomatic peripheral neurop-athy of grade 2 or higher, and no other serious medical condition. At least four weeks had to have elapsed between prior surgery or radiotherapy (lim-ited to no more than 25 percent of the bone mar-row) and enrollment. Prior treatment with cortico-steroids was allowed. Normal cardiac function was required. Laboratory criteria for eligibility included a neutrophil count of at least 1500 per cubic milli-meter, a hemoglobin level of at least 10.0 g per deci-liter, a platelet count of at least 100,000 per cubic millimeter, a total bilirubin level below the upper limit of the normal range for each institution, and serum alanine aminotransferase, aspartate amino-transferase, and creatinine levels that were no more than 1.5 times the upper limit of the normal range.A clinical history was obtained, and a physical examination, with radiographic imaging, comput-ed tomography, and bone scanning, was performed within 14 days before randomization. Blood tests including measurement of serum PSA, electrocar-diography, and an evaluation of the left ventricu-lar ejection fraction by means of a multiple gatedpThe new england journal of medicine1504acquisition scan or echocardiography were per-formed. Pain, analgesic intake, and the quality oflife were assessed at baseline. Pain was assessed bymeans of the Present Pain Intensity (PPI) scale fromthe McGill–Melzack questionnaire, which uses ver-bal descriptors; scores can range from 0 to 5, withhigher scores indicating greater pain.23 Patientsrecorded their daily PPI score and analgesic use ina diary. A daily analgesic score was calculated byassigning a score of 4 for a standard dose of a nar-cotic analgesic (e.g., 10 mg of morphine) and a scoreof 1 for a standard dose of a nonnarcotic analgesic.Patients were required to have stable levels of painfor at least seven days before randomization, de-fined by a daily variation of no more than 1 in thePPI score or of no more than 25 percent in the anal-gesic score. The quality of life was assessed withthe Functional Assessment of Cancer Therapy–Pros-tate (FACT-P) questionnaire; scores on this self-administered questionnaire can range from 0 to156, with higher scores indicating a better qualityof life.24,25All patients provided written informed consent,and the study was approved by all institutional re-view boards in accordance with the internationalstandards of good clinical practice. An independentdata and safety monitoring committee was estab-lished.randomization and treatmentRandomization was centralized with the use of astratified, permuted-block allocation scheme ac-cording to the baseline pain level (pain was classi-fied as present, as defined by a median PPI score ofat least 2 or a mean analgesic score of at least 10,or as absent, as defined by a median PPI score ofless than 2 and a mean analgesic score of less than10) and the baseline Karnofsky performance-statusscore (70 percent or less vs. 80 percent or more).Patients who were randomly assigned to the doc-etaxel groups received either 75 mg of docetaxel(Taxotere, Aventis) per square meter as a 1-hour in-travenous infusion on day 1 every 21 days or 30 mgof docetaxel per square meter as a 30-minute in-travenous infusion on days 1, 8, 15, 22, and 29 of a6-week cycle. Patients who were randomly assignedto the standard-therapy group received 12 mg ofmitoxantrone (Novantrone, Immunex and Wyeth–Ayerst) per square meter as a 30-minute infusionon day 1 every 21 days. All patients received 5 mgof prednisone (or prednisolone, if prednisone wasnot available) orally twice daily starting on day 1. Pre-medication with dexamethasone was required inthe docetaxel groups (8 mg given 12 hours, 3 hours,and 1 hour before the docetaxel infusion in thegroup treated every three weeks and 8 mg given1 hour before docetaxel in the group treated week-ly). Antiemetic medication was prescribed accord-ing to local practice.Up to 10 cycles of treatment were planned forthe group given docetaxel every three weeks andthe mitoxantrone group and up to 5 cycles (of sixweeks each) in the weekly-docetaxel group. Treat-ment delays of up to two weeks and up to two dosereductions were allowed. Dose reductions werespecified for patients who had had grade 4 neutro-penia for at least seven days, an infection, or grade3 or4 neutropenia with an oral temperature of atleast 38.5°C. A dose reduction or treatment delaywas also stipulated for patients who had an abso-lute neutrophil count of less than 1500 per cubicmillimeter (for those on three-week schedules) orless than 1000 per cubic millimeter (for those re-ceiving weekly docetaxel) on a treatment day andfor those with grade 3 or 4 thrombocytopenia. Treat-ment with granulocyte colony-stimulating factorwas allowed for patients with febrile neutropenia.Systemic corticosteroids (other than dexametha-sone and prednisone) and bisphosphonates werenot permitted.follow-up and outcomesPhysical examinations and baseline blood testswere repeated at three-week intervals. I magingstudies to determine the extent of disease were per-formed at intervals of six to nine weeks and repeat-ed after four weeks to identify those with a response.The primary end point was overall survival. Sec-ondary end points were predefined reductions inpain, an improvement in the quality of life, a reduc-tion in serum PSA levels of at least 50 percent, andobjective tumor responses.Patients with a PPI score of at least 2, an analgesicscore of at least 10, or both (averaged over the pre-vious week) at baseline were assessed for the painresponse at three-week intervals. A pain responsewas defined as a two-point reduction in the PPIscore from baseline without an increase in the an-algesic score or as a reduction of at least 50 percentin the analgesic score without an increase in thePPI score, either of which was maintained for atleast three weeks. Pain progression was defined asan increase in the PPI score of at least one pointfrom the nadir, an increase from baseline of at leastn engl j med 351; october 7, 2004n engl j med 351;15october 7, 2004docetaxel versus mitoxantrone for prostate cancer150525 percent in the analgesic score, or a requirement for palliative radiotherapy.Serum PSA was measured every three weeks,and a response (for patients with a baseline PSA level of at least 20 ng per milliliter) was defined as a reduction from baseline of at least 50 percent that was maintained for at least three weeks, whereas PSA progression was defined as an increase from the nadir of either at least 25 percent for men with no PSA response or at least 50 percent for all oth-ers. The duration of the PSA response and the pain response was defined as the time between the first and last evaluations at which the response criteria were met. For patients with at least one bidimen-sionally measurable lesion, tumor response was evaluated with the use of World Health Organiza-tion criteria. 26The quality of life was assessed with the FACT-P questionnaire at baseline, every three weeks dur-ing therapy, and every month after the completion of therapy. All patients who answered the question-naire at baseline were included in the evaluation,and the FACT-P score was compared with the base-line value for each of these patients. Patients were defined as having a quality-of-life response if they had a 16-point improvement in their FACT-P score,as compared with baseline, on two measurements obtained at least three weeks apart.Adverse events were classified according to the Common Toxicity Criteria of the National Cancer Institute (version 2). Serious adverse events were fatal or life-threatening, required or prolonged hos-pitalization, resulted in persistent or substantial disability or incapacity, or were considered im-portant medical events. Treatment was stopped for any of the following reasons: completion of planned treatment, progression of disease, severe adverse events, or withdrawal of consent.statistical analysisThere were three comparisons of interest between the docetaxel and mitoxantrone groups: docetaxel given every three weeks was compared with mito-xantrone, weekly docetaxel was compared with mi-toxantrone, and the combined docetaxel groups were compared with mitoxantrone. The study was designed to detect with 90 percent power a hazard ratio of 0.75 for death in the docetaxel groups as compared with the mitoxantrone group, with a two-sided type I error of 0.05 and with the data analyzed according to the intention to treat. The sample size was established as 1002 patients, andanalysis was planned after 535 deaths had occurred.To allow for multiple comparisons, a P value of 0.04 was considered to indicate statistical signif-icance for the comparison of the combined doce-taxel groups with the mitoxantrone group, and a P value of 0.0175 was considered to indicate sta-tistical significance for the comparison of each docetaxel group with the mitoxantrone group (all P values were two-sided), thus ensuring an overall significance level of 0.05.In the primary analysis, overall survival was an-alyzed by means of the Kaplan–Meier method,with log-rank comparisons stratified according to the level of pain and the Karnofsky performance-status score. Pain, PSA, tumor, and quality-of-life responses were compared by means of the Coch-ran–Mantel–Haenszel test. All randomized patients were included in the analysis of survival, and all treated patients were included in the evaluation of adverse effects.Hazard ratios for death were calculated after adjustment for any chance imbalance in potential prognostic factors between the groups. The follow-ing factors were entered into a full stratified Cox proportional-hazards model and a backward selec-tion model in which nonsignificant factors were eliminated sequentially at a P level of 0.10: age (less than 65 years vs. 65 years or older); visceral involve-ment (yes vs. no); liver involvement (yes vs. no);number of prior hormonal therapies (two or fewer vs. more than two); prior estramustine (yes vs. no);presence of rising serum PSA levels alone, as com-pared with the presence of other indications of pro-gression; baseline hemoglobin level; and baseline serum level of alkaline phosphatase. One planned interim analysis of safety was conducted after the recruitment of 120 patients. No interim analysis for efficacy was performed.The study was designed by Dr. Tannock in col-laboration with Aventis personnel, and the proto-col was finalized after being reviewed by the other study cochairs, Drs. de Wit and Eisenberger. The data were collected and maintained by Aventis, but the cochairs handled all questions regarding the management of the study. Only the data and safety monitoring committee saw the results of the inter-im safety analysis; no analysis was undertaken nor were the results seen by Aventis, the study cochairs,or any other investigator until the predefined num-ber of events had occurred. The protocol contained a plan for analysis and publication at that time. All data were provided to the cochairs at the comple-The new england journal of medicine1506tion of the study. Aventis personnel undertook thestatistical analysis. The article was drafted by Dr.Tannock and modified after being reviewed by thecochairs and other coauthors. Aventis reviewed themanuscript, but its final content was entirely deter-mined by the investigators.and treatmentA total of 1006 patients underwent randomiza-tion from March 2000 through June 2002. The da-*All patients were included in the intention-to-treat analysis. Because of rounding, not all percentages total 100.†Hormonal manipulation was defined as bilateral orchiectomy or hormone therapy.‡Pain was defined by a score of 2 or more on the Present Pain Intensity scale or an analgesic score of at least 10.§Patients may have more than one indication for progression of disease.n engl j med 351; october 7, 2004n engl j med 351;15october 7, 2004 docetaxel versus mitoxantrone for prostate cancer1507tabase was locked on August 6, 2003, after the req-uisite number of deaths, specified in the statistical plan, had occurred.The baseline characteristics of the patients were well balanced among the three treatment groups (Table 1). The median age was 68 years; about 20percent of the patients were at least 75 years old.About 45 percent had pain, and about 40 percent had measurable soft-tissue lesions. The most com-mon indicators of disease progression before study entry were an increasing serum PSA level and evi-dence of an increase in bone metastases on bone scanning.Only nine patients (1 percent) did not receive chemotherapy and prednisone (Table 2). Patients tended to receive more cycles of the regimen in which docetaxel was given every three weeks than of the regimen in which mitoxantrone was given every three weeks. Most patients received the pre-scribed doses on schedule, with 8 to 12 percent requiring a dose reduction and 21 to 34 percent requiring at least one chemotherapy infusion to be delayed. Twenty percent of the patients who were randomly assigned to receive mitoxantrone sub-sequently received docetaxel, and 27 percent of those in the group given docetaxel every three weeks received subsequent mitoxantrone, as did 24 percent of those in the weekly-docetaxel group.efficacyThe median duration of follow-up was similar among the three groups: 20.8 months in the group given docetaxel every 3 weeks and 20.7 months in the other two groups. There were 166 deaths (50percent; hazard ratio for death, 0.76; 95 percent confidence interval, 0.62 to 0.94) in the group giv-en docetaxel every three weeks and 190 deaths (57percent; hazard ratio, 0.91; 95 percent confidence interval, 0.75 to 1.11) in the group given weekly docetaxel, as compared with 201 deaths (60 per-cent) in the mitoxantrone group. When the two docetaxel groups were combined and compared with the mitoxantrone group, the hazard ratio for death was 0.83 (95 percent confidence interval, 0.70to 0.99; P=0.04). As compared with the survival rate in the mitoxantrone group, the survival rate was significantly higher (P=0.009) in the group given docetaxel every three weeks but not in the group given weekly docetaxel (P=0.36). The medi-an duration of survival was 18.9 months (95 per-cent confidence interval, 17.0 to 21.2) in the group given docetaxel every 3 weeks, 17.4 months (95 per-* Percentages relate to the number of patients treated in each group. Because ofrounding, not all percentages total 100.The new england journal of medicine1508cent confidence interval, 15.7 to 19.0) in the group given weekly docetaxel, and 16.5 months (95 per-cent confidence interval, 14.4 to 18.6) in the mito-xantrone group. Kaplan–Meier survival curves for the three groups are shown in Figure 1.The result of the sensitivity analysis, in which survival was adjusted for possible imbalances in potential prognostic factors, was consistent with the primary result. The hazard ratio for death in the group given docetaxel every three weeks, as com-pared with the mitoxantrone group, was 0.76 with-out adjustment and 0.74 and 0.75 after adjustment in the full stratified and backward Cox propor-tional-hazards models, respectively. As expected, visceral involvement, a high baseline alkaline phos-phatase level, and a low hemoglobin level were negative prognostic factors in the multivariate mod-els, whereas a rising serum PSA as the sole indica-tor of progression was a favorable factor. Post hoc analysis indicated that a high Gleason score (8, 9, or 10) was an adverse prognostic factor for survival. The survival benefit of docetaxel given every three weeks was consistent across subgroups defined ac-cording to the presence or absence of pain at base-line, the Karnofsky performance-status score (70 percent or less vs. 80 percent or more), and age (younger than 65 years vs. 65 years or older) (data not shown).A reduction in pain was more frequent among patients receiving docetaxel every three weeks than among those treated with mitoxantrone (35 per-cent vs. 22 percent, P=0.01) (Table 3), but the per-centage of patients with reduced pain in the weekly docetaxel group (31 percent) did not differ signifi-cantly from that of the mitoxantrone group. The median duration of reduced pain was 3.5 to 5.6 months and did not differ significantly among the groups.Rates of PSA response were significantly higher in the docetaxel groups (45 percent in the group given docetaxel every three weeks and 48 percent in the group given weekly docetaxel, P<0.001 for both comparisons) than in the mitoxantrone group (32 percent) (Table 3). The median duration of the PSA response ranged from 7.7 to 8.2 months and did not differ significantly among the three groups.Although patients with measurable soft-tissue lesions who received docetaxel every three weeks had a somewhat higher rate of tumor response than such patients who received mitoxantrone every three weeks (12 percent vs. 7 percent, P=0.11), this difference was not significant (Table 3).*P values are for comparisons with the mitoxantrone group. CI denotes confi-dence interval.†A pain response was defined as a two-point reduction in the Present Pain In-tensity (PPI) score without an increase in the analgesic score or a reduction ofat least 50 percent in the analgesic score without an increase in the PPI score,which was maintained for at least three weeks.‡Data on 54 percent and 63 percent of patients were censored in the Kaplan–Meier analysis of the median duration of pain and PSA response, respectively.The chief reason for data censoring was further antitumor therapy after pro-gression of disease as defined by other criteria.§A response was defined by a 16-point improvement from baseline in the Func-tional Assessment of Cancer Therapy–Prostate (FACT-P) score on two mea-surements obtained at least three weeks apart.n engl j med 351; october 7, 2004n engl j med 351;15october 7, 2004docetaxel versus mitoxantrone for prostate cancer1509adverse eventsThe incidence of grade 3 and 4 neutropenia was relatively low, and febrile neutropenia was rare (Ta-ble 4). Two patients died from sepsis during treat-ment, one in the docetaxel group and one in the mitoxantrone group. There was a higher incidence of cardiac events among patients who received mi-toxantrone (Table 4). Most other types of adverse events were more frequent among patients receiv-ing docetaxel, and there was no trend toward a low-er frequency with weekly docetaxel than with doce-taxel given every three weeks. Low-grade adverse events that occurred in at least 15 percent of pa-tients in one of the groups included fatigue, nausea or vomiting or both, alopecia, diarrhea, nail chang-es, sensory neuropathy, anorexia, changes in taste,stomatitis, dyspnea, tearing, peripheral edema, and epistaxis (Table 4). More patients in the docetaxel groups than in the mitoxantrone group had at least one serious adverse event, with rates of 26 percent among those in the group given docetaxel every three weeks, 29 percent among those given weekly docetaxel, and 20 percent among those given mito-xantrone. Five deaths were probably related to treat-ment, three of them in the mitoxantrone group.More patients in the mitoxantrone group stopped treatment because of disease progression than was the case in the docetaxel groups, and more stopped treatment because of completion of treatment or adverse events in the docetaxel groups (Table 2).Adverse events that led to the discontinuation of treatment included fatigue, musculoskeletal or nail changes, sensory neuropathy, and infection in the docetaxel groups and cardiac dysfunction in the mitoxantrone group.quality of lifeThe quality of life was evaluated in 815 patients,a group that made up the intention-to-treat popu-lation from countries in which a local translation of the FACT-P was available (Table 3). The percentage of patients who had an improvement in the quali-ty of life was similar in the two docetaxel groups (22 percent in the group given docetaxel every three weeks and 23 percent in the group given weekly docetaxel) and significantly higher than that in the mitoxantrone group (13 percent; P=0.009 and P=0.005, respectively). Figure 2 shows the greatest changes in the scores and the median changes in the scores for individual domains of the FACT-P during treatment. The greatest benefit in the doc-etaxel groups was in the subscale representingprostate-specific concerns (including weight loss,appetite, pain, physical comfort, and bowel andadministered with prednisone were compared with mitoxantrone plus prednisone, the standard che-motherapy for hormone-refractory prostate can-cer. The median overall survival was higher for the group that received docetaxel every three weeks*P≤0.05 by Fisher’s exact test for the comparison with the mitoxantrone group.†P≤0.0015 by Fisher’s exact test for the comparison with the mitoxantrone group. A Bonferroni adjustment for multiplicity was used to obtain the nomi-nal significance level of 0.0015 (approximately 0.05÷34), on the basis of two tests being carried out on the 17 adverse events, with at least 20 events in at least one of the three treatment groups.‡A major decrease in the left ventricular ejection fraction (LVEF) was defined as a decrease of at least 10 percent in the absolute value to below the lower limit of the normal range.。
乳腺癌前哨淋巴结
a: 乳腺淋巴系统的解剖学研究和多中心临床研究结果支 持多中心乳腺癌患者接受SLNB； b: 高危患者在行预防性乳腺切除时，可以考虑接受SLNB； c: 部分研究在先前进行过保乳和腋窝手术后同侧乳房复 发的患者中进行SLNB取得了成功，但在其作为常规应用 前还需要更多循证医学证据的支持；
d: 导管内癌患者接受乳房切除术或保乳手术范围可能影 响到随后的SLNB时推荐进行SLNB； e: 临床查体和影像学检查可疑的腋窝淋巴结可以通过超
进入的第一个蓝染淋巴结，仔细检出所有蓝染的 淋巴管是避免遗漏SLN、降低假阴性率的关键。 核素法SLN的阈值是超过淋巴结最高计数10%以 上的所有淋巴结，术中γ探测仪探头要缓慢移动， 有序检测，贴近计数。应用染料法和(或)核素法 检出SLN后应对腋窝区进行触诊，触诊发现的肿 大质硬淋巴结也应作为SLN单独送检。
6 SLNB替代ALND患者的随访
❖ 除常规复查项目外，常规行 双侧腋窝、锁骨区超声检查，有 条件的可考虑MRI检查。临床或 超声检查异常腋窝淋巴结应在超 声引导下行细针穿刺或空芯针活 检，必要时行切开活检手术。
1开展SLNB的必要条件
❖ 1.2 学习曲线
❖ 完整的学习曲线对于提高SLNB成功率、降 低SLNB假阴性率非常重要，开展SLNB替代 ALND的医疗单位必须通过资料收集和结果分析 以确保整个团队熟练掌握SLNB技术。中国医生 乳腺癌SLNB学习曲线的研究正在进行中 (CBCSG001b)，目前，建议在采用SLNB替代 ALND前，应完成一定数量(如40例)以上SLNB 后直接行ALND，使SLNB的成功率达到90%， 假阴性率低于10%。
4 S L N 的病理组织学、细胞学和分
❖ 4 .1 SLN的术中子诊生断物学诊断
乳腺癌GnRH-a使用常见的临床问题
19
200
28
177
HR
8年DFS
差异
E+OFS
T+OFS
88.1%
82.7%
+5.4%
76.92% 82.7% 88.6% 91.9% 92.6%
68.7% 75.6% 83.8% 87.4% 86.2%
+8.2% +7.1% +4.8% +4.5% +8.4%
DRFI
所有患者 随机时的年龄 <35岁 35-39岁 40-44岁 45-49岁 50+
Francis PA,et al. N Engl J Med. 2015 Jan 29;372(5):436-46（Supplementary Appendix）
SOFT 5年 化疗亚组 BCFI&DFS
• 5年BCFI绝对获益：4.5%(T+OFS vs T)
• 5年DFS
Francis PA, et al. N Engl J Med. 2015 Jan 29;372(5):436-46(SupplementaryAppendix).
中危a
高危b
OFS+AI/他莫西芬
徐兵河, 等. 中国癌症杂志. 2016;26(8):712-720.
乳腺癌风险类别
自2005 St Gallen 共识定义后至今原则上保持未变
抗癌协会 2017
OFS+AI/TAM是 高危 或 接受辅助化疗的中危 患 者的标准治疗方案
OFS获益人群： 高风险患者 接受辅助化疗的中
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不同年龄亚组的治疗疗效(HER2-阴性)
常见肿瘤靶区勾画之欧阳与创编
作者：中国医学科学院肿瘤医院放疗科刘跃平李晔雄王维虎房辉来源：中国医学论坛报日期：2012-03-30随着人均寿命的延长，我国老年人口的不断增加，前列腺癌的发病率逐年上升。
放疗是前列腺癌根治性治疗手段之一，从局限低、中、高危前列腺癌到盆腔淋巴结转移，甚至远处转移前列腺癌，放疗均有广泛的应用。
对于局限期前列腺癌，放疗可取得与手术相当的疗效且并发症的发生较少。
近年来，随着各种放疗新技术的出现和发展，前列腺癌的放疗越来越准确，正常组织的保护则更可靠，因此，接受放疗的患者越来越多。
我们参照美国放疗肿瘤学研究组（RTOG）关于前列腺癌的放疗靶区勾画建议、美国国立综合癌症网络（NCCN）和欧洲泌尿协会制定的前列腺癌诊治指南，并结合我们的临床实践，对局限期前列腺癌根治性放疗的靶区勾画提出参考性建议，旨在使前列腺癌放疗靶区定义规范化和合理化。
从表1得知，前列腺癌靶区勾画主要包括前列腺、精囊腺及盆腔淋巴引流区，对局限期前列腺癌根治性放疗的靶区确定，我们提出如下建议。
1CT定位及放疗·定位前时排空膀胱和直肠，口服1000 ml稀释的肠道对比剂，然后憋尿充盈膀胱。
CT定位采取仰卧位，体模固定，层厚3 mm扫描，扫描范围从腰4椎体下缘至坐骨结节下3 cm。
·建议采用3D-CRT或IMRT，若放疗剂量≥78 Gy，建议使用图像引导放疗（IGRT）。
2前列腺及精囊腺靶区勾画·局限低危前列腺癌放疗靶区只包括前列腺；局限中危前列腺癌或盆腔淋巴结转移几率≤15%的局限高危前列腺癌放疗靶区包括前列腺和精囊腺。
·前列腺癌往往为多发灶，且CT和磁共振成像（MRI）无法检测出前列腺内的全部病灶，因此，前列腺癌难以勾画大体靶区（GTV，转移淋巴结除外），我们只勾画临床靶区（CTV）（图1）。
·前列腺靶区勾画自前列腺底至前列腺尖的全部前列腺组织（图1），若前列腺存在钙化，须包全全部钙化区域。
中国抗癌协会乳腺癌诊治指南与规范_2015版_
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·专家论坛·2011年《St．Gallen早期乳腺癌初始治疗国际专家共识》与中国抗癌协会乳腺癌专业委员会指南之比较胡夕春王碧芸邵志敏2011年6月《Annals of Oncology》杂志公布了最新版《St．Gallen早期乳腺癌初始治疗国际专家共识》（以下简称《St．Gallen共识》）。
与此同时，中国抗癌协会乳腺癌专业委员会（CBCS）也更新了《乳腺癌诊治指南与规范》（以下简称《CBCS指南》）。
现将两部指南的主要更新点作一介绍。
1共同点1．1乳腺癌分子亚型乳腺癌不再是一个单一疾病，按照固有的基因类型，主要是基因芯片的结果至少可以分为4个亚型，腔上皮（Luminal）A型、Luminal B型、人表皮生长因子受体（HER-2）阳性和基底样乳腺癌［1-3］。
Luminal型表达大量的Luminal角蛋白和正常乳腺组织腔上皮的遗传性标志物。
HER-2阳性乳腺癌显示ERBB2基因和ERBB2扩增子的扩增和过度表达。
基底样乳腺癌不表达雌激素受体（ER）、孕激素受体（PR）和ER相关基因，正常乳腺组织肌上皮细胞特异性标志物，如Luminal角蛋白、平滑肌特异性标志物和某些整合素表达水平也不高［1］。
乳腺癌的分子分型与乳腺癌的临床病理特征、疾病的转归、预后及治疗反应密切相关。
但是，在实际的临床工作中，多数专家认为可根据免疫组化检测的ER、PR、HER-2和Ki67结果，将乳腺癌划分为4个类型，以作为近似替代。
这4种类型是Luminal A型、Luminal B型、HER-2阳性和三阴性乳腺癌［4］。
Luminal A型Ki67和HER-2均为低表达；Luminal B型又分为2种，一种是Ki67为任何水平但HER-2阳性，另外一种是Ki67指数增高亚型。
ER、PR和HER-2的检测均有相应的指南或规定以及需要注意的事项［5-7］。
有关Ki67的检测还存在很多问题，相关检测指南正在制定之中［8］。
在目前情况下，如果无可靠的Ki67标记指数检测方法，可以用组织学分级来替代。
《CBCS指南》同样推荐所有医院除检测ER、PR和HER-2外，也应把Ki67的作者单位：200032上海，复旦大学附属肿瘤医院乳腺癌研究所检测列为常规检测项目。
1．2曲妥珠单克隆抗体辅助治疗对于肿瘤直径＞0．5cm的HER-2阳性早期乳腺癌患者，两部指南均推荐1年的辅助曲妥珠单克隆抗体治疗。
短于1年使用曲妥珠单克隆抗体并不是最佳方案，但是用比不用者疗效好［8］。
2011年St．Gallen会议上，在100多个需要表决的问题中，“对于HER-2阳性早期乳腺癌，1年的辅助曲妥珠单克隆抗体治疗是否是一个治疗标准”是唯一的100%专家投赞成票的问题。
对于肿块最大直径为0．5 1cm的乳腺癌，也有78.7%的专家投了赞成票。
在低收入国家中，可否使用短于1年的曲妥珠单克隆抗体治疗？也有71%的专家投了赞成票。
《CBCS指南》同样强调了这个理念。
2不同点2．1腋窝淋巴结切除对于哪些患者可以免除腋窝淋巴结切除术（ALND），《St．Gallen共识》指出不需要做ALND的一种情况是前哨淋巴结阴性，另外一种是临床腋窝淋巴结阴性、病理检查有1 2枚前哨淋巴结宏转移、行保乳治疗和切线野放射治疗的病例。
该共识的更新主要是依据Giuliano等［9］的ACOSOG试验结果。
该试验入组的是临床腋窝淋巴结阴性、行保乳治疗和切线野放射治疗、病理检查有1 2枚前哨淋巴结宏转移的病例，中位随访6．3年后，发现这部分患者完全可以避免腋窝淋巴结切除手术。
但是，以下几种情况仍旧需要ALND，包括行乳房切除术、不行全乳切线野放射治疗、前哨淋巴结转移数目超过2枚和接受过新辅助化疗的病例。
《CBCS指南》对此未作更新。
2．2辅助化疗适应证对于乳腺癌辅助化疗的适应证，2011版的《CBCS指南》包括以下几个条件：肿瘤直径＞2cm，淋巴结阳性，激素受体阴性，HER-2阳性，组织学分级为3级。
而2011年《St．Gallen共识》包括以下几个条件：高Ki67指数，三阴性乳腺癌、激素受体阴性，HER-2阳性，组织学分级为3级［8］。
适应证的差异主要源于中国的实际情况：肿瘤大小和淋巴结状态的判定比较客观，容易发现复发风险高的患者，而高Ki67指数和三阴性乳腺癌的诊断标准尚未统一，临床工作中执行起来容易发生偏差。
在《St．Gallen共识》中，分子分型对化疗的主要影响是Luminal A型患者不宜积极化疗。
对三阴性乳腺癌患者考虑剂量密集性化疗，目前证据不支持推荐使用铂类药物和抗血管生成药物［8］。
《CBCS指南》没有推荐具体的不同分子分型乳腺癌的辅助化疗方案，因为以往的临床试验均不是依据分子分型来设计研究的。
2．3辅助内分泌治疗《St．Gallen共识》强调，并非所有绝经后激素受体阳性乳腺癌患者均需要芳香化酶抑制剂（AI）治疗，但是淋巴结阳性患者最好选择AI治疗［8］。
《CBCS指南》根据中国大多数乳腺癌发生于绝经前女性的特点，特别细化了这部分诊断是绝经前而在辅助治疗过程中变为绝经后的患者内分泌药物的使用［10］。
判定是否绝经必须考虑患者年龄、停经时间及血液中雌激素、卵泡刺激素和黄体生成素水平等，只有综合判定患者为绝经后才可使用芳香化酶抑制剂治疗。
在服药期间，一旦出现可能是月经原因造成的出血，应立即停药，同时进行激素水平检测和相关妇科检查。
如果临床诊断为月经恢复，应中止治疗，后续用药可以采用雌激素受体调变剂加或不加去势。
《CBCS指南》特别指出，所有这些患者在服用芳香化酶抑制剂期间均应采取除激素类避孕药之外的有效避孕措施。
2．4曲妥珠单克隆抗体和化疗用药顺序关于曲妥珠单克隆抗体和化疗用药顺序问题，首推曲妥珠单克隆抗体和化疗联合使用，但是也可以在所有辅助化疗结束后再使用曲妥珠单克隆抗体。
因为Perez等［11］在2009年St．Antonio会议上报道了NCCTG N9831临床试验的最新结果，提示联合使用化疗和曲妥珠单克隆抗体相对于序贯使用，能提高无瘤生存率。
《CBCS指南》对此未作更新。
2011年版CBCS指南的指导思想与2011年《St．Gallen共识》基本一致，均强调了分子分型在治疗抉择中的主导地位。
同时，它是根据中国患者的特征和国内实际临床工作特点制定的指南，因而与《St．Gallen共识》又有所不同。
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