JAMA Oncology
编者按：每周四是一个神奇的日子，从英国的柳叶刀、英国医学杂志、自然，到美国的新英格兰医学杂志、美国医学会杂志、科学、细胞，都会不约而同发表一些重要的研究报告。由于时差关系，中国读者要等到周五才能看到。因此，每到周五，总能在朋友圈看到的TGIF，莫非就是这个意思？
Thank God It's Friday!
2017年3月2日（周四）《美国医学会杂志肿瘤学分册》在线发表芬兰（赫尔辛基大学、坦佩雷大学、图尔库大学、奥卢大学、坎塔海梅中心医院、库奥皮奥大学、科特卡中心医院、拉赫蒂派亚特海梅中心医院、瓦萨中心医院、4Pharma CRO）、瑞典（耶夫勒医院、厄勒布鲁大学、乌普萨拉大学）的随机临床研究（FinXX）探索性亚组分析报告，比较了两种早期乳腺癌联合辅助化疗方案的十年生存率。
方案一：T→CEF（多西他赛→环磷酰胺＋表柔比星＋氟尿嘧啶）
方案二：TX→CEX（多西他赛＋卡培他滨→环磷酰胺＋表柔比星＋卡培他滨）
FinXX：Docetaxel Followed by CEF (Cyclophosphamide, Epirubicin and 5-Fluorouracil) Compared to Docetaxel and Capecitabine Followed by CEX (Cyclophosphamide, Epirubicin and Capecitabine) as Adjuvant Treatment for Breast Cancer
虽然卡培他滨不被认为是早期乳腺癌辅助治疗的标准药物，但是卡培他滨加入紫杉类和蒽环类化疗方案，能否提高早期乳腺癌辅助治疗的生存率？FinXX研究结果表明，卡培他滨加入多西他赛＋表柔比星＋环磷酰胺辅助化疗方案仅可改善早期三阴性乳腺癌患者的生存结局。在FinXX研究中位随访10.3年期间，被随机分配接受有卡培他滨方案的患者与无卡培他滨治疗患者相比，生存未见延长。有卡培他滨方案仅在治疗三阴性乳腺癌（TNBC）患者亚组时，生存时间较长。因此，卡培他滨加入辅助化疗不延长生存，但是三阴性乳腺癌患者可能从卡培他滨获益。
该探索性亚组分析探讨了卡培他滨对早期乳腺癌患者长期生存结局的影响，尤其对于按照乳腺癌雌激素受体（ER）、孕激素受体（PR）、人表皮生长因子受体2（HER2）水平进行分类的亚组患者。
该多中心随机临床研究（FinXX）于2004年1月27日～2007年5月29日在芬兰和瑞典入组1500例早期乳腺癌女性进行随机分组，747例接受3个周期多西他赛→3个周期环磷酰胺＋表柔比星＋氟尿嘧啶（T→CEF），753例接受3个周期多西他赛＋卡培他滨→3个周期环磷酰胺＋表柔比星＋卡培他滨（TX→CEX）。2004年1月27日～2015年12月31日进行数据分析，主要结局衡量指标为无复发生存。
最后从意向治疗人群剔除5例不符合研究方案的患者（3例在随机时有明显远处转移，2例撤回知情同意书），其余1495例在研究入组时中位年龄为53岁、157例（11%）腋窝淋巴结阴性、1142例（76%）ER阳性、282例（19%）HER2阳性。随机分配后的中位随访时间为10.3年。
结果发现，卡培他滨组的无复发生存、总生存、乳腺癌相关生存虽然略胜一筹，但是差异均无统计学意义（风险比分别为：0.88、0.84、0.79，95%置信区间分别为：0.71～1.08、0.66～1.07、0.60～1.04，P值分别为：0.23、0.15、0.10）。
所有患者的无复发生存曲线
—卡培他滨组—非卡培他滨组
所有患者的总生存曲线
—卡培他滨组—非卡培他滨组
不过，当根据激素受体状态（ER或PR有阳性，ER和PR均阴性）和HER2状态（阳性，阴性）进行亚组比较时，卡培他滨组三阴性乳腺癌患者亚组的无复发生存、总生存有显著改善（风险比分别为：0.53、0.55，95%置信区间分别为：0.31～0.92、0.31～0.96，P值分别为：0.02、0.03）。
三阴性乳腺癌患者亚组的无复发生存曲线
—卡培他滨组—非卡培他滨组
三阴性乳腺癌患者亚组的总生存曲线
—卡培他滨组—非卡培他滨组
总之，卡培他滨＋多西他赛＋表柔比星＋环磷酰胺与标准药物方案相比，并不延长所有乳腺癌患者的无复发生存或总生存。在探索性亚组分析中，当卡培他滨方案治疗三阴性乳腺癌患者时，获得有利的生存结局。
当然，亚组分析虽然有时能够带来意外惊喜，但是也存在样本量减少的问题，例如在该研究1495例患者中，三阴性乳腺癌仅202例，其中卡培他滨组仅93例，故该研究结果还有待于在更大样本三阴性乳腺癌人群中进行验证。这也再次告诉我们，药物本身并无好坏之分，也不可能适用于所有患者，还是要靠医生精准地用于合适的患者才可能有效。
此外，该研究在方案一使用了氟尿嘧啶，而且仅在用完多西他赛后使用，方案二却同时、序贯都用卡培他滨，这多多少少有些奇怪。
JAMA Oncol. 2017 Mar 2, 2017. [Epub ahead of print]
Adjuvant Capecitabine in Combination With Docetaxel, Epirubicin, and Cyclophosphamide for Early Breast Cancer: The Randomized Clinical FinXX Trial.
Heikki Joensuu; Pirkko-Liisa Kellokumpu-Lehtinen; Riikka Huovinen; Arja Jukkola-Vuorinen; Minna Tanner; Riitta Kokko; Johan Ahlgren; Paivi Auvinen; Outi Lahdenpera; Sanna Kosonen; Kenneth Villman; Paul Nyandoto; Greger Nilsson; Paula Poikonen-Saksela; Vesa Kataja; Jouni Junnila; Petri Bono; Henrik Lindman.
Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Tampere University Hospital and University of Tampere, Tampere, Finland; Turku University Central Hospital, Turku, Finland; Oulu University Hospital, Oulu, Finland; Kanta-Hame Central Hospital, Hameenlinna, Finland; Gavle Hospital, Gavle, Sweden; Kuopio University Hospital, Kuopio, Finland; Kotka Central Hospital, Kotka, Finland; Orebro University Hospital, Orebro, Sweden; Paijat-Hame Central Hospital, Lahti, Finland; Uppsala University Hospital, Uppsala, Sweden; Vaasa Central Hospital, Vaasa, Finland; 4Pharma, Turku, Finland.
This randomized clinical trial compares 10-year survival rates for 2 adjuvant combination therapies for early breast cancer: docetaxel followed by cyclophosphamide, epirubicin, and fluorouracil vs docetaxel plus capecitabine followed cyclophosphamide, epirubicin, and capecitabine.
KEY POINTS
QUESTION: Does integration of capecitabine into a taxane- and anthracycline-containing chemotherapy regimen improve survival as adjuvant treatment of early breast cancer?
FINDINGS: In the FinXX trial, patients randomly allocated to receive a capecitabine-containing regimen did not survive longer than patients treated without capecitabine during a median follow-up of 10.3 years. The subset of patients with triple-negative breast cancer (TNBC) survived longer when treated with the capecitabine-containing regimen.
MEANING: Integration of capecitabine into adjuvant chemotherapy did not prolong survival, but patients with TNBC may benefit from capecitabine.
ABSTRACT
IMPORTANCE: Capecitabine is not considered a standard agent in the adjuvant treatment of early breast cancer. The results of this study suggest that addition of adjuvant capecitabine to a regimen that contains docetaxel, epirubicin, and cyclophosphamide improves survival outcomes of patients with triple-negative breast cancer (TNBC).
OBJECTIVE: To investigate the effect of capecitabine on long-term survival outcomes of patients with early breast cancer, particularly in subgroups defined by cancer estrogen receptor (ER) and progesterone receptor (PR) content, and HER2 content (human epidermal growth factor receptor 2).
DESIGN, SETTING, AND PARTICIPANTS: This is an exploratory analysis of the multicenter FinXX randomized clinical trial that accrued 1500 women in Finland and Sweden between January 27, 2004, and May 29, 2007. About half received 3 cycles of docetaxel followed by 3 cycles of cyclophosphamide, epirubicin, and fluorouracil (T+CEF), while the other half received 3 cycles of docetaxel plus capecitabine followed by 3 cycles of cyclophosphamide, epirubicin, and capecitabine (TX+CEX). Data analysis took place between January 27, 2004, and December 31, 2015.
MAIN OUTCOMES AND MEASURES: Recurrence-free survival (RFS).
RESULTS: Following random allocation, 747 women received T+CEF, and 753 women received TX+CEX. Five patients were excluded from the intention-to-treat population (3 had overt distant metastases at the time of randomization; 2 withdrew consent). The median age of the remaining 1495 patients was 53 years at the time of study entry; 157 (11%) had axillary node-negative disease; 1142 (76%) had ER-positive cancer; and 282 (19%) had HER2-positive cancer. The median follow-up time after random allocation was 10.3 years. There was no significant difference in RFS or overall survival between the groups (hazard ratio [HR], 0.88; 95% CI, 0.71-1.08; P=.23; and HR, 0.84, 95% CI, 0.66-1.07; P=.15; respectively). Breast cancer-specific survival tended to favor the capecitabine group (HR, 0.79; 95% CI, 0.60-1.04; P=.10). When RFS and survival of the patients were compared within the subgroups defined by cancer steroid hormone receptor status (ER and/or PR positive vs ER and PR negative) and HER2 status (positive vs negative), TX+CEX was more effective than T+CEF in the subset of patients with TNBC (HR, 0.53; 95% CI, 0.31-0.92; P=.02; and HR, 0.55, 95% CI, 0.31-0.96; P=.03; respectively).
CONCLUSIONS AND RELEVANCE: Capecitabine administration with docetaxel, epirubicin, and cyclophosphamide did not prolong RFS or survival compared with a regimen that contained only standard agents. Patients with TNBC had favorable survival outcomes when treated with the capecitabine-containing regimen in an exploratory subgroup analysis.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00114816
DOI: 10.1001/jamaoncol.2016.6120
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