A 45 year old pre-menopausal woman is diagnosed with breast cancer.
一位45岁的绝经前妇女被诊断为乳腺癌。
Tumor characteristics at the time of primary diagnosis（初诊时的肿瘤特征）：
· Size（大小）:
· Pathology（病理）:
· ER:
· PR:
· S-Phase（S-期）:
· HER-2
· Axillary nodes（腋窝淋巴结） 3 cm
poorly differentiated （分化差）
Negative （阴性）
Negative（阴性）
10%
Negative by FISH
3/16 are positive （3/16 阳性）
Treatment （治疗）:
Lumpectomy followed by 6 courses of CMF (cyclophosphamide, methotrexate, fluorouracil).
手术后行6个疗程CMF （环磷酰胺，甲氨喋呤，氟尿嘧啶）的辅助化疗。
Clinical course（临床病程）:
Five months after completing CMF treatment she complains of poor appetite and a metallic taste in her mouth. She has lost 3 kilograms. She has fatigue and has difficulty completing her housework. Physical examination reveals hepatomegaly with the liver edge being tender and palpable 4cm below the right costal margin. The remaining physical examination shows no recurrence of her cancer. Hematocrit 31%, WBC 5800, platelet count 500,000. Biochemical profile reveals normal bilirubin. 20% elevation of alkaline phosphatase, SGOT, SGPT, and LDH. Chest X-ray is normal. CT scan of the abdomen reveals 5 filling defects in the liver, the largest measures 2.1 cm. She has no ascites. FNA of the liver reveals metastatic carcinoma consistent with the previous breast cancer.
CMF治疗完成后5个月，此患者诉食欲差，口中有金属味觉，体重减轻3公斤，感觉疲劳，做家务有困难。体检发现肝大，右肋缘下4cm可触，肝缘软。其它检查表明原发灶无复发。红细胞压积31%，WBC 5800, 血小板500,000。生化检测显示胆红素正常，碱性磷酸酶、SGOT、SGPT和LDH 升高20％。胸透正常。腹部CT发现肝脏有5处充盈缺损，最大的为2.1 cm。患者无腹水。肝脏穿刺显示为与乳腺癌原发灶一致的转移癌。 徐兵河教授
医科院肿瘤医院内科副主任，博士生导师
中国抗癌协会临床肿瘤学协作中心执委会委员
本病例具有以下病理和临床特征：
1、 肿块不大（3cm），但已经有腋窝淋巴结转移（3/16），提示肿瘤恶性程度较高。
2、 ER和PR均阴性，HER-2阴性。
3、 无病生存期短，化疗后5个月出现远处转移。
4、 转移部位为内脏转移（肝脏）且有症状。
晚期转移性乳腺癌的治疗非常困难，治疗的主要目的是改善患者的生活质量，延长生存期。虽然有各种各样的治疗方法，但主要方法是内分泌治疗和化疗。
正确选择治疗方法，特别是一线治疗方法对延长患者生存期，改善患者生活质量至关重要。对本患者，首选化疗抑或内分泌治疗要根据患者肿瘤的病理和临床特征来决定。由于本患者肿瘤HER2阴性，因此不考虑用生物治疗（Herceptin）。
一般认为，对术后无病生存期较长（通常2年以上），受体阳性，骨和软组织转移或无症状的内脏转移的患者，可首选内分泌治疗。而对无病生存期较短（通常小于2年），ER和PR阴性，有症状的内脏转移的患者，可考虑首选化疗。内分泌治疗对发展较慢的肿瘤效果较好，显效较慢，一般需3～4周起效；而化疗适合于病变发展较快的乳腺癌，起效较快，一般1～2周显效。
本例肿瘤分化差，恶性程度较高，术后1年内出现复发转移，ER和PR均阴性，肝脏转移且有明显症状，说明肿瘤发展快，需要采用能迅速控制症状和肿瘤发展的治疗手段。故对本患者，应考虑首选化疗而不是内分泌治疗。
对晚期乳腺癌有效的药物较多，单药治疗有效率＞40％的药物有阿霉素、表阿霉素、泰索帝和紫杉醇。一线联合方案往往以上述药物为基础。
临床上采用的主要给药方法有单药序贯、联合、大剂量化疗联合干细胞或骨髓移植等。由于许多临床研究发现大剂量化疗并不能提高晚期患者的生存率,赫赛汀，故后者已基本不用。
单药序贯治疗是目前国外一些医师较推崇的方法，这种方法副作用较小，而疗效较好，因此较适合晚期乳腺癌的治疗。联合化疗有效率较高，但副作用可能较大，适用于病变发展迅速，需要较快控制病情的晚期乳腺癌患者。本病例在较短时间内出现肝脏多发转移，由于肝脏转移导致肝功能的异常，伴有明显的自觉症状，但肝酶升高没有超过正常值的2.5倍，基于以上陈述，对本病例，我个人的意见应以联合化疗为佳。
在国外，泰索帝＋希罗达的联合方案主要批准用于蒽环类耐药性晚期乳腺癌的解救治疗。对以前辅助治疗中没有用过蒽环类药物者，一般认为在复发转移后，应首先考虑选用含蒽环类药物的联合方案。
紫杉类与蒽环类的联合方案是目前临床上证实对乳腺癌最有效的联合方案，这种联合广泛应用于晚期乳腺癌治疗、新辅助治疗以及术后辅助治疗中，这种联合优于经典的AC方案。对本例患者，紫杉醇或泰索帝联合蒽环类药可能都是比较合理的选择。
然而，从循证医学的角度，我们就会发现：(1)在有效率和TTP方面，泰索帝与阿霉素的随机分组试验结果显示，两者有效率分别为48％于33％（p<0.05；TAX 303 group， JCO1999），而泰索帝和阿霉素分别为25％与41％（p<0.05；EORTC. JCO,2000）以及34％与36%（Intergroup. ASCO，1997）；上述三组试验的TTP分保为6.1与4.9个月、3.9与7.5个月(P<0.05)和5.9与6.2个月。说明泰索帝的疗效优于阿霉素，而泰素比阿霉素的疗效低或相似。（2）泰索帝与阿霉素联合方案优于阿霉素与环磷酰胺方案。（3）一些研究显示泰索帝对乳腺癌肝转移有较高的缓解率。因此，我个人的看法是，以上7种选择方案中，以选择泰索帝联合蒽环类药方案（第4种）更为合理。我很高兴，我和多数医生的选择答案是一致的。
Dr. Martine Piccart, MD, PhD
Professor of Internal Medicine Oncology
Jules Bordet Institute
Brussels, Belgium
This unfortunate young patient presents with "high-risk" metastatic breast cancer based on the following parameters:
1. A short disease-free interval (DFI) (< 1 year)
2. Involvement of a vital organ (the liver)
3. The presence of symptoms and a reduced performance status
4. A primary tumor negative for hormone-receptors1
基于以下参数，此不幸的年轻病人具有“高危”转移性乳腺癌的特征：
1. 无病间期短（< 1年）
2. 生命器官（肝脏）受累
3. 有症状，体能状况变差
4. 原发灶激素受体阴性1
Chemotherapy is clearly the only available systemic therapy for her. Hormone therapy is ineffective given the negative hormone receptors, and the primary tumor was HER-2 negative by FISH, so there is no role for Herceptin chemotherapy. There is a high degree of concordance of HER-2 expression_r between a primary breast tumor and metastases2 thus we can be confident that the HER-2 status of her metastatic disease is also negative.
While many oncologists nowadays have a preference for using single active agents at their maximum tolerated dose rather than combination chemotherapy3 there remain clinical situations where most of us would favour combinations. This patient, in my view, is in such a situation. She has a low probability of responding to any type of chemotherapy by virtue of the short disease free interval since adjuvant chemotherapy. In addition, a rapid response is clearly needed given that her disease has resulted in impaired liver function tests and a reduced performance status.
Options #4 and #5 both combine Taxane and Anthracycline. Such a combination is most attractive in this clinical setting, given
1. The short interval since adjuvant CMF chemotherapy (which implies relative "resistance" of this tumor to these 3 agents)
2. Anthracyclines and taxanes are currently our most active drugs against breast cancer and are non-cross resistant
3. The study by G. Sledge, which showed clear superiority for Adriamycin + Taxol in terms of response rate and progression-free survival over either agent used alone in a randomized phase III comparison.4
对此患者而言，化疗显然是唯一可行的全身治疗方案。考虑到激素受体阴性，所以激素治疗无效。原发灶经FISH检查HER-2阴性，因此也无法用赫赛汀治疗。乳腺癌原发灶与转移灶的HER-2表达一致性很高2，因此我们可以确信她的转移灶也是HER-2阴性。
虽然现在很多肿瘤医生倾向于用单药以最大耐受剂量治疗而不是联合化疗3，但在某些临床实践中我们很多人还是喜欢用联合用药。以我的观点，这个患者就是处于这种情况。鉴于她辅助化疗后无病间期很短，所以她可能对许多化疗方案的反应不佳。另外，考虑到她的肝功能受损、体能状况变差，该患者需要能产生快速缓解的治疗方案。症状选项#4和#5为紫杉类与蒽环类联合。考虑到以下原因，在这样的临床情况下此种联合用药是最常选择的。
1. CMF辅助化疗后无病间期短（这提示肿瘤对此3种药物相对“抗拒”）
2. 蒽环类和紫杉类药物是目前治疗乳腺癌最有活性的药物，且无交叉耐药
3. G. Sledge的随机III期临床研究表明，阿霉素＋泰素不论在有效率和无病生存上均优于任何一个单药4
Unfortunately, a study of a similar design has not been performed with Taxotere. This agent, on the other hand, has shown:
1. A higher response rate (47%) compared to single agent Adriamycin (33%) in patients who had received previous alkylating agent-containing chemotherapy, including the subgroup with liver involvement and a relapse within 12 months of completing adjuvant chemotherapy.5
2. A superior response rate when combined with Adriamycin (60%) over the "classic" Adriamycin-cyclophosphamide combination (47%)6. Here again, superiority was observed for the entire study population and in the poorest prognosis groups, including liver and other visceral involvement, and prior adjuvant chemotherapy.
很可惜，泰索帝未做类似设计的临床研究。但另一方面，泰索帝显示：
1. 在曾接受含烷化剂化疗（CMF）的患者中，泰索帝有效率比阿霉素单药更高（47％对33％），其中包括肝脏受累和辅助化疗后12个月内复发的亚组5。
2. 泰索帝与阿霉素联合比“经典”AC方案有效率更高（60％对47％）6。再一次地，这种优势体现在整个研究人群和预后最差的亚组，包括肝脏和其它内脏受累及曾接受辅助化疗的患者。
No direct comparison exists between Adriamycin (A) + Taxol, A + Taxotere, Epiadriamycin (E) + Taxol, and E + Taxotere. The Phase III data on Adriamycin + taxane combinations are more mature than those exploring the value of Epiadriamycin. On this basis, my preference in clinical practice is the former combination. Between the two taxanes, both Taxol and Taxotere are reasonable options to combine with Adriamycin for our patient. The latter, however, would be my first choice, based on the highly consistent results Taxotere has demonstrated in clinical trials of metastatic breast cancer, including in women with liver metastases.
目前没有直接比较阿霉素＋泰素，阿霉素＋泰索帝，表阿霉素＋泰素，表阿霉素＋泰索帝的资料。对阿霉素＋紫杉类的III期临床数据要比研究表阿霉素联合化疗更加成熟。基于此，我在临床实践中更倾向用含阿霉素的联合方案。在2个紫杉类药物中，泰素和泰索帝与阿霉素联合均为合理的选择。但是基于泰索帝在转移性乳腺癌临床试验中表现出的很一致的疗效结果（包括肝转移的患者），我的首选是泰索帝联合蒽环类。
One important feature of anthracycline + taxane combinations is the higher risk of febrile neutropenia than is seen with single-agent therapy and with Adriamycin + Cytoxan. This patient should be duly informed about this risk, and should be instructed as to the circumstances that should lead her to seek medical assistance. In contrast, the risk of congestive heart failure is not increased.
蒽环类与紫杉类联合的一个重要特点是与单药治疗和阿霉素＋环磷酰胺相比，发生发热性中性粒细胞减少的危险增高。应适时地通知患者此风险，并指导她何时需向医生寻求支持。相比而言，充血性心衰的危险并未增加。
Option #6, Taxotere + Xeloda was compared to Taxotere monotherapy in a randomized trial of first line chemotherapy for metastatic breast cancer. Preliminary results report increased survival for the combination.7 Full publication of this trial is awaited to determine whether this benefit was seen in patients with "high risk" metastatic disease. In the absence of this information, and given that Xeloda is a fluoropyrimidine, with which this patient has already been treated in the adjuvant setting, I would not favour this combination over Taxotere + Adriamycin in this patient.
选项＃6，泰索帝＋希罗达曾在转移性乳腺癌的一线化疗中与泰索帝单药做过随机对照研究。初步结果显示联合用药改善了生存。在“高危”转移性乳腺癌患者中是否有同样的益处尚待此研究全部完成后的报告。在缺少此信息的情况下，考虑到希罗达为氟尿嘧啶类药物，而此患者已在辅助治疗中用过此类药物，因而对此患者我倾向用泰索帝＋阿霉素而不是泰索帝＋希罗达。
In summary, a combination chemotherapy regimen is desirable in this patient due to her symptomatic disease, reduced performance status, and perturbation of liver function tests. These factors also mitigate the higher toxicity profile associated with combination chemotherapy. Given the high likelihood of drug resistance implicit in the patient's short disease free interval from adjuvant therapy, the use of the most active drugs in breast cancer, and drugs that her tumor has not already been exposed to, is the strategy with the highest probability of producing a response and meaningful palliation. Finally, robust evidence supports high activity of Taxotere both alone and with anthracyclines, making this my preferred taxane to combine with Adriamycin, the anthracycline with the most mature data in anthracycline-taxane combinations.In conclusion I agree with those who choose Option #4, Taxotere and Anthracycline.
简而言之，由于此患者的症状表现、体能状况下降和肝功能的异常，她更适合用联合化疗。这些因素减轻了联合化疗毒性反应高的顾虑。考虑到辅助化疗后很短的无病间期，提示患者具有较高的耐药可能性，因此最有可能产生疗效和缓解病情的治疗策略为:采用治疗乳腺癌最有效的及未使用过的药物。最后，很多证据表明泰索帝单药和与蒽环类联合均有很高疗效，因此在紫杉类中我首选泰索帝与阿霉素联合（阿霉素是与紫杉类联合资料最成熟的蒽环类药物）。总之，我与选择第4项（泰索帝＋蒽环类）的同道意见一致。
Dr. George Sledge, MD
Professor of Oncology
Indiana University of Medicine
Indianapolis, Indiana, USA
The treatment of metastatic breast cancer requires the mind of a biologist and the heart of a caring physician. Because metastatic breast cancer is, with very rare exceptions, an incurable disease, the art of medicine is to provide the patient with the care most likely to prolong life while simultaneously maintaining quality of life.
转移性乳腺癌的治疗需要我们具有生物学家的头脑和医生的人道主义精神。因为转移性乳腺癌是不可治愈的疾病（除极少数病例外），药物治疗的目的在于延长患者的生命同时维持其生活质量。
In the current case, we are dealing with a patient who has suffered a rapid (and symptomatic) relapse of her breast cancer following adjuvant chemotherapy. Because her initial tumor was steroid receptor negative, she is highly unlikely to benefit from a hormonal approach. Similarly, because her tumor is HER-2 negative, she is unlikely to benefit from administration of trastuzumab. Chemotherapy therefore represents the appropriate treatment option for this patient.
就此病例而言，我们碰到了一个在辅助化疗后很快复发而且有症状的患者。由于她的原发肿瘤激素受体阴性，她基本不可能从激素治疗中获益。类似地，因为她的HER-2受体阴性，她不大可能从曲妥珠单抗治疗中获益。因此化疗是此患者的合适治疗选择。
All of the options offered here are reasonable ones; therefore, no one could be faulted for picking one over the other. Anthracyclines, taxanes, and (more recently) capecitabine have all been shown to prolong survival in patients with metastatic breast cancer and, therefore, should all be considered at some time during the course of the disease.
此次病例讨论中的所有选择项均为合理的选择，因此选哪一个都没有错。蒽环类、紫杉类及卡培他滨均显示可延长转移性乳腺癌患者的生存期，因此在病程中的某些时间均值得考虑。
The first decision one needs to make in this setting is the role of combination as opposed to single-agent sequential chemotherapy for recurrent disease. Whereas the standard dogma of a decade ago would have been to routinely offer a combination regimen, several recent studies have suggested that sequential agent chemotherapy can result in similar long-term survival rates with somewhat lower levels of toxicity. Overall quality of life appears similar for sequential as opposed to combination chemotherapy. While there is nothing whatsoever wrong with combination chemotherapy, my bias in recent years has been to offer patients sequential single-agent therapy.
对复发的乳腺癌患者，第一个需要做的决定是选择单药序贯化疗还是联合化疗。十年前的标准方案为常规给予联合化疗，而最近的几个研究显示序贯化疗能产生相似的长期生存率且具有更低的毒性水平。从总体生活质量来看，序贯化疗与联合化疗类似。虽然联合化疗谈不上有什么不对，但本人近年来还是倾向于给患者采用序贯化疗。
Which therapy should be first? Again, there is little to chose here. Option #2, Docetaxel has been reported by Chan and colleagues to result in a higher response rate as front-line therapy for liver metastases, though with no evidence for an improvement in overall survival or quality of life. We have no head-to-head front-line data comparing capecitabine with any of the other agents (as single-agent therapy). My bias would be to treat this patient initially with a taxane (probably single-agent docetaxel), with subsequent therapy at time of progression to a single-agent anthracycline or capecitabine.
先选哪一个药物进行治疗？此处几乎没有选择。选项＃2，Chan及同事曾报道多西紫杉醇（泰索帝）可在乳腺癌肝转移一线治疗中产生较阿霉素更高的缓解率，但总生存和生活质量与阿霉素组相近。我们没有卡培他滨与任何其它药物（单药治疗）在一线直接对照的数据。本人倾向于先用紫杉类（可能为多西紫杉醇－泰索帝单药），进展后再用蒽环类单药或卡培他滨单药序贯治疗。
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