对于早期乳腺癌术后患者，辅助化疗可显著减少复发和死亡风险，从而显著改善长期生存，其获益大小取决于化疗方案和剂量强度，紫杉类→环磷酰胺＋蒽环类＋氟尿嘧啶是早期乳腺癌术后辅助化疗获益最大的方案之一。卡培他滨（希罗达）是氟尿嘧啶的可口服前体药，已被批准用于治疗晚期乳腺癌，但是尚未被批准用于早期乳腺癌。临床前研究发现，紫杉类（多西他赛、紫杉醇）和环磷酰胺可显著提高胸苷磷酸化酶水平，该酶是卡培他滨在肿瘤内被转化为氟尿嘧啶的关键酶。那么，卡培他滨取代氟尿嘧啶能否改善早期乳腺癌术后患者的长期生存？
2022年1月12日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表芬兰赫尔辛基大学医院、坦佩雷大学医院、图尔库大学医院、奥卢大学医院、库奥皮奥大学医院、派耶特海梅中心医院、芬兰中部中心医院、瑞典耶夫勒医院、瑞典中部地区癌症中心、维斯比医院、乌普萨拉大学医院、厄勒布鲁大学医院的FinXX研究长期随访报告，对T-CEF方案（多西他赛→环磷酰胺＋表柔比星＋氟尿嘧啶）与TX-CEX方案（多西他赛＋卡培他滨→环磷酰胺＋表柔比星＋卡培他滨）辅助治疗早期乳腺癌术后患者的15年总生存进行了比较。
FinXX (NCT00114816): A Randomized Phase III Study Comparing Docetaxel Followed by Cyclophosphamide, Epirubicin and 5-FU to Docetaxel With Capecitabine Followed by Cyclophosphamide, Epirubicin and Capecitabine as Adjuvant Treatment for Early Breast Cancer
该多中心非盲随机对照三期临床研究于2004年1月27日～2007年5月29日从芬兰和瑞典20家医院入组腋窝淋巴结阳性或高风险淋巴结阴性早期乳腺癌术后患者1495例，按1∶1的比例随机分为两组进行辅助化疗：
TX-CEX组751例：多西他赛＋卡培他滨3个周期→环磷酰胺＋表柔比星＋卡培他滨3个周期
T-CEF组744例：多西他赛3个周期→环磷酰胺＋表柔比星＋氟尿嘧啶3个周期
结果，截至2020年12月31日，TX-CEX组与T-CEF组相比：
中位随访时间相似：15.3年比15.4年（四分位：14.5～16.1、14.8～16.0）
5年总生存率相似：92.7%比90.2%（风险比：0.73，95%置信区间：0.52～1.04，P=0.080）
10年总生存率相似：84.3%比82.3%（风险比：0.84，95%置信区间：0.66～1.07，P=0.15）
15年总生存率提高：77.6%比73.3%（风险比：0.81，95%置信区间：0.66～0.99，P=0.037）
根据探索性亚组分析，雌激素受体阴性、三阴性乳腺癌亚组患者接受TX-CEX治疗与接受T-CEF治疗相比，总生存显著较长。
因此，该研究随访结果表明，对于高风险早期乳腺癌术后患者，TX-CEX方案与T-CEF方案相比，15年总生存率显著提高，尤其对于雌激素受体阴性、三阴性乳腺癌患者。
相关链接
J Clin Oncol. 2022 Jan 12. Online ahead of print.
Adjuvant Capecitabine for Early Breast Cancer: 15-Year Overall Survival Results From a Randomized Trial.
Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, Jukkola A, Tanner M, Ahlgren J, Auvinen P, Lahdenpera O, Villman K, Nyandoto P, Nilsson G, Poikonen-Saksela P, Kataja V, Bono P, Junnila J, Lindman H.
Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Tampere University Hospital and Tampere University, Tampere, Finland; Turku University Hospital, Turku, Finland; EstiMates, Turku, Finland; Oulu University Hospital, Oulu, Finland; Kuopio University Hospital, Kuopio, Finland; Paijat-Hame Central Hospital, Lahti, Finland; Central Finland Central Hospital, Jyvaskyla, Finland; Gavle Hospital, Gavle, Sweden; Regional Cancer Centre of Mid-Sweden, Academic Hospital, Uppsala, Sweden; Gavle Hospital and Visby Hospital, and Uppsala University, Uppsala, Sweden; Uppsala University Hospital, Uppsala, Sweden; Orebro University Hospital, Orebro, Sweden.
PURPOSE: Few data are available regarding the influence of adjuvant capecitabine on long-term survival of patients with early breast cancer.
METHODS: The Finland Capecitabine Trial (FinXX) is a randomized, open-label, multicenter trial that evaluates integration of capecitabine to an adjuvant chemotherapy regimen containing a taxane and an anthracycline for the treatment of early breast cancer. Between January 27, 2004, and May 29, 2007, 1,500 patients with axillary node-positive or high-risk node-negative early breast cancer were accrued. The patients were randomly allocated to either TX-CEX, consisting of three cycles of docetaxel (T) plus capecitabine (X) followed by three cycles of cyclophosphamide, epirubicin, and capecitabine (CEX, 753 patients), or to T-CEF, consisting of three cycles of docetaxel followed by three cycles of cyclophosphamide, epirubicin, and fluorouracil (CEF, 747 patients). We performed a protocol-scheduled analysis of overall survival on the basis of approximately 15-year follow-up of the patients.
RESULTS: The data collection was locked on December 31, 2020. By this date, the median follow-up time of the patients alive was 15.3 years (interquartile range, 14.5-16.1 years) in the TX-CEX group and 15.4 years (interquartile range, 14.8-16.0 years) in the T-CEF group. Patients assigned to TX-CEX survived longer than those assigned to T-CEF (hazard ratio 0.81; 95% CI, 0.66 to 0.99; P = .037). The 15-year survival rate was 77.6% in the TX-CEX group and 73.3% in the T-CEF group. In exploratory subgroup analyses, patients with estrogen receptor-negative cancer and those with triple-negative cancer treated with TX-CEX tended to live longer than those treated with T-CEF.
CONCLUSION: Addition of capecitabine to a chemotherapy regimen that contained docetaxel, epirubicin, and cyclophosphamide prolonged the survival of patients with early breast cancer.
KEY OBJECTIVE: Adjuvant chemotherapy improves the survival of patients with early breast cancer. Capecitabine, an oral prodrug of fluorouracil, is approved for the treatment of advanced breast cancer, but not for adjuvant treatment. In some experimental models, docetaxel, paclitaxel, and cyclophosphamide upregulate thymidine phosphorylase, the key enzyme that converts capecitabine to fluorouracil within tumors. The randomized FinXX trial evaluated addition of capecitabine (X) to an adjuvant chemotherapy regimen consisting of docetaxel (T), followed by cyclophosphamide (C), epirubicin (E), and fluorouracil (F).
KNOWLEDGE GENERATED: The capecitabine-containing regimen (docetaxel plus capecitabine-cyclophosphamide and epirubicin plus capecitabine) improved significantly overall survival compared with docetaxel-cyclophosphamide and epirubicin plus fluorouracil during a median patient follow-up time of approximately 15 years. The 15-year survival rate was 77.6% in the capecitabine group and 73.3% in the control group.
RELEVANCE: Patients with early breast cancer lived longer when adjuvant capecitabine was administered concomitantly with chemotherapy that included docetaxel and cyclophosphamide.
PMID: 35020465
DOI: 10.1200/JCO.21.02054
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