中国三阴性乳腺癌术后强化治疗新策略
三阴性乳腺癌与乳腺癌亚型相比，标准方案治疗后复发率较高、结局较差，故亟待减少复发风险和死亡风险的新策略。低剂量高频率化疗（又称节拍化疗）针对两种癌症转移机制（血管生成和免疫逃逸）发挥其抗癌活性，可能阻止三阴性乳腺癌转移。卡培他滨是被广泛用于治疗晚期乳腺癌的口服化疗药物，也是低剂量高频率给药以预防复发的潜在候选疗法。FinXX、NO17629、CREATE-X、CBCSG 010、GEICAM 2003-11 / CIBOMA 2004-01等临床研究将高剂量卡培他滨加入乳腺癌术后标准辅助化疗方案，研究结果不一，存在较大争议。
2020年12月10日，国际四大医学期刊之一《美国医学会杂志》正刊发表中山大学附属肿瘤医院、廉江市人民医院、哈尔滨医科大学附属肿瘤医院、广州市第一人民医院、中山大学附属第一医院、广西医科大学第一附属医院、广州医科大学附属第二医院、解放军***总医院、深圳市第二人民医院、海口市人民医院、广东省中医院、广东省妇幼保健院、佛山市第一人民医院、澳门大学、瑞典卡罗林斯卡学院的华南乳腺癌临床研究协作组（SCBCG）SYSUCC-001研究报告，探讨了低剂量高频率卡培他滨维持治疗对早期三阴性乳腺癌术后标准辅助治疗后患者的有效性和安全性。
SYSUCC-001 (NCT01112826): Phase III Study of Adjuvant Capecitabine Metronomic Chemotherapy in Triple-negative Operable Breast Cancer
该全国多中心随机对照三期临床研究于2010年4月～2016年12月从中国13家医院入组术后完成标准辅助化疗的早期三阴性乳腺癌患者443例，按1∶1的比例随机分为两组：
卡培他滨组222例：口服卡培他滨650mg/m²，每天2次，连续1年
观察对照组221例
最终随访日期为2020年4月30日。主要终点为无病生存。次要终点包括远处无病生存、总体生存、局部区域无复发生存、不良事件。
结果，其中9例退出研究，434例（98.0%）完成研究（卡培他滨组221例、观察对照组213例，平均年龄46±9.9岁，T1或T2期占93.1%，淋巴结阴性占61.8%）。
中位随访61个月（四分位44～82）期间，发生94例复发或死亡事件，卡培他滨组与观察对照组相比：
复发：37例比56例
死亡：32例比40例
5年无病生存率：82.8%比73.0%，复发或死亡减少36%（风险比：0.64，95%置信区间：0.42～0.95，P=0.03）
5年远处无病生存率：85.8%比75.8%，远处转移或死亡风险减少40%（风险比：0.60，95%置信区间：0.38～0.92，P=0.02）
5年总体生存率：85.5%比81.3%，总体死亡风险减少25%（风险比：0.75，95%置信区间：0.47～1.19，P=0.22）
5年局部区域无复发生存率：85.0%比80.8%，局部区域复发或死亡风险减少28%（风险比：0.72，95%置信区间：0.46～1.13，P=0.15）。
最常见的卡培他滨相关不良事件为手足综合征（45.2%），其中3级不良事件占7.7%。
因此，该研究结果表明，对术后完成标准辅助化疗的早期三阴性乳腺癌患者，低剂量卡培他滨维持治疗与观察相比，5年无病生存率和5年远处无病生存率显著较高，5年总体生存率和5年局部区域无复发生存率相似。
对此，美国哈佛大学医学院、达纳法伯癌症研究院、布莱根医院和波士顿妇女医院发表同期编者评论：三阴性乳腺癌术后卡培他滨辅助治疗个体化推荐意见新策略。
相关链接
JAMA. 2020 Dec 10. Online ahead of print.
Effect of Capecitabine Maintenance Therapy Using Lower Dosage and Higher Frequency vs Observation on Disease-Free Survival Among Patients With Early-Stage Triple-Negative Breast Cancer Who Had Received Standard Treatment: The SYSUCC-001 Randomized Clinical Trial.
Wang X, Wang SS, Huang H, Cai L, Zhao L, Peng RJ, Lin Y, Tang J, Zeng J, Zhang LH, Ke YL, Wang XM, Liu XM, Chen QJ, Zhang AQ, Xu F, Bi XW, Huang JJ, Li JB, Pang DM, Xue C, Shi YX, He ZY, Lin HX, An X, Xia W, Cao Y, Guo Y, Su YH, Hua X, Wang XY, Hong RX, Jiang KK, Song CG, Huang ZZ, Shi W, Zhong YY, Yuan ZY; South China Breast Cancer Group (SCBCG).
Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China; Lianjiang People's Hospital, Lianjiang, China; The Affiliated Tumour Hospital of Harbin Medical University, Harbin, Heilongjiang, China; Guangzhou First People Hospital, Guangzhou, Guangdong, China; The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China; The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China; General Hospital of PLA Guangzhou Military Area, Guangzhou, Guangdong, China; Shenzhen Second People's Hospital, Shenzhen, Guangdong, China; Haikou People's Hospital, Haikou, Hainan, China; Traditional Chinese Medicine Hospital of Guangdong Province, Guangzhou, Guangdong, China; Maternal and Child Health Care Hospital of Guangdong Province, Guangzhou, Guangdong, China; Foshan First People's Hospital, Foshan, Guangdong, China; Karolinska Institutet, Stockholm, Sweden; University of Macau, Macao, China.
This randomized trial compares the effects of low-dose high-frequency capecitabine maintenance therapy vs observation after standard adjuvant chemotherapy on 5-year disease-free survival among women with early-stage triple-negative breast cancer.
QUESTION: Does therapy with low-dose capecitabine maintenance after standard adjuvant chemotherapy reduce the risk of relapse and death in early-stage triple-negative breast cancer?
FINDINGS: In this randomized clinical trial of 434 women with early-stage triple-negative breast cancer who received standard adjuvant treatment, low-dose capecitabine maintenance therapy for 1 year, compared with observation, resulted in significantly higher 5-year disease-free survival (82.8% vs 73.0%; hazard ratio for risk of recurrence or death, 0.64).
MEANING: Among women with early-stage triple-negative breast cancer, maintenance therapy with low-dose capecitabine significantly improved disease-free survival at 5 years.
IMPORTANCE: Among all subtypes of breast cancer, triple-negative breast cancer has a relatively high relapse rate and poor outcome after standard treatment. Effective strategies to reduce the risk of relapse and death are needed.
OBJECTIVE: To evaluate the efficacy and adverse effects of low-dose capecitabine maintenance after standard adjuvant chemotherapy in early-stage triple-negative breast cancer.
DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial conducted at 13 academic centers and clinical sites in China from April 2010 to December 2016 and final date of follow-up was April 30, 2020. Patients (n = 443) had early-stage triple-negative breast cancer and had completed standard adjuvant chemotherapy.
INTERVENTIONS: Eligible patients were randomized 1:1 to receive capecitabine (n = 222) at a dose of 650 mg/m2 twice a day by mouth for 1 year without interruption or to observation (n = 221) after completion of standard adjuvant chemotherapy.
MAIN OUTCOMES AND MEASURES: The primary end point was disease-free survival. Secondary end points included distant disease-free survival, overall survival, locoregional recurrence-free survival, and adverse events.
RESULTS: Among 443 women who were randomized, 434 were included in the full analysis set (mean [SD] age, 46 [9.9] years; T1/T2 stage, 93.1%; node-negative, 61.8%) (98.0% completed the trial). After a median follow-up of 61 months (interquartile range, 44-82), 94 events were observed, including 38 events (37 recurrences and 32 deaths) in the capecitabine group and 56 events (56 recurrences and 40 deaths) in the observation group. The estimated 5-year disease-free survival was 82.8% in the capecitabine group and 73.0% in the observation group (hazard ratio [HR] for risk of recurrence or death, 0.64 [95% CI, 0.42-0.95]; P = .03). In the capecitabine group vs the observation group, the estimated 5-year distant disease-free survival was 85.8% vs 75.8% (HR for risk of distant metastasis or death, 0.60 [95% CI, 0.38-0.92]; P = .02), the estimated 5-year overall survival was 85.5% vs 81.3% (HR for risk of death, 0.75 [95% CI, 0.47-1.19]; P = .22), and the estimated 5-year locoregional recurrence-free survival was 85.0% vs 80.8% (HR for risk of locoregional recurrence or death, 0.72 [95% CI, 0.46-1.13]; P = .15). The most common capecitabine-related adverse event was hand-foot syndrome (45.2%), with 7.7% of patients experiencing a grade 3 event.
CONCLUSIONS AND RELEVANCE: Among women with early-stage triple-negative breast cancer who received standard adjuvant treatment, low-dose capecitabine maintenance therapy for 1 year, compared with observation, resulted in significantly improved 5-year disease-free survival.
TRIAL REGISTRATION: NCT01112826
PMID: 33300950
DOI: 10.1001/jama.2020.23370
JAMA. 2020 Dec 10. Online ahead of print.
Adjuvant Capecitabine in Triple-Negative Breast Cancer: New Strategies for Tailoring Treatment Recommendations.
Parsons HA, Burstein HJ.
Dana-Farber Cancer Institute, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts.
PMID: 33300953
DOI: 10.1001/jama.2020.23371