乳腺癌术前化疗失败后的卡培他滨辅助疗法安全有效
HER2阴性乳腺癌患者术前接受新辅助化疗后，如果未达病理学完全缓解、仍有浸润癌残留，提示预后不佳。术后辅助化疗对于这些患者的获益尚不明确。
2017年6月1日，美国麻省（马萨诸塞州）医学会官方期刊《新英格兰医学杂志》正式发表日本和韩国的JBCRG04（CREATE-X）研究报告，发现乳腺癌术前化疗失败后的卡培他滨辅助疗法安全有效。
该研究于2007年2月～2012年7月入组I～IIIB期、年龄20～74岁、ECOG体力状态评分0或1、HER2阴性浸润性乳腺癌新辅助化疗（蒽环类、紫杉类或两者）后未达病理学完全缓解患者910例（日本62个机构606例，韩国22个机构304例）按1∶1随机分配接受标准术后治疗±卡培他滨。主要终点为无病生存（定义：5年无死亡、复发或第二癌症），次要终点包括总生存（定义：5年无死亡）。该研究的日本大学医学信息网络（UMIN）临床研究注册登记编号：UMIN000000843。
由于预设中期分析结果达到主要终点，故本研究提前终止。
最终分析显示，卡培他滨组（443例）与对照组（444例）相比：
无病生存率较高（74.1%比67.6%），死亡、复发或第二癌症风险降低30%（风险比：0.70，95%置信区间：0.53～0.92，P=0.01）
总生存率较高（89.2%比83.6%），死亡风险降低41%（风险比：0.59，95%置信区间：0.39～0.90，P=0.01）
三阴性乳腺癌亚组分析显示，卡培他滨组（139例）与对照组（147例）相比：
无病生存率较高（69.8%比56.1%），死亡、复发或第二癌症风险降低42%（风险比：0.58，95%置信区间：0.39～0.87）
总生存率较高（78.8%比70.3%），死亡风险降低48%（风险比：0.52，95%置信区间：0.30～0.90）
卡培他滨组最常见的不良反应为手足综合征，发生率为73.4%。
因此，对于蒽环类、紫杉类或两者的标准新辅助化疗后，病理学检查仍有浸润性病变残留的HER2阴性乳腺癌患者，加入卡培他滨辅助疗法，可以安全有效地延长无病生存和总生存。
该研究得到日本先端医疗研究支援机构（ACRO）、日本乳腺癌研究组织（JBCRG）资助，并分别于2013年第36届、2015年第38届美国圣安东尼奥乳腺癌研讨会（SABCS）公布安全性、有效性的首次中期分析摘要和口头报告，此次全文正式发表。
N Engl J Med. 2017 Jun 1;376(22):2147-2159.
Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy.
Norikazu Masuda, Soo-Jung Lee, Shoichiro Ohtani, Young-Hyuck Im, Eun-Sook Lee, Isao Yokota, Katsumasa Kuroi, Seock-Ah Im, Byeong-Woo Park, Sung-Bae Kim, Yasuhiro Yanagita, Shinji Ohno, Shintaro Takao, Kenjiro Aogi, Hiroji Iwata, Joon Jeong, Aeree Kim, Kyong-Hwa Park, Hironobu Sasano, Yasuo Ohashi, Masakazu Toi.
National Hospital Organization Osaka National Hospital, Osaka; Hiroshima City Hiroshima Citizens Hospital, Hiroshima; Kyoto Prefectural University of Medicine; Graduate School of Medicine, Kyoto University, Kyoto; Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Chuo University, Tokyo; Gunma Prefectural Cancer Center, Ota; National Hospital Organization Kyushu Cancer Center, Fukuoka; Hyogo Cancer Center, Akashi; National Hospital Organization Shikoku Cancer Center, Matsuyama; Aichi Cancer Center Hospital, Nagoya; Tohoku University, Sendai, Japan; Yeungnam University Hospital, Daegu, Samsung Medical Center, Sungkyunkwan University School of Medicine, Cancer Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Severance Hospital, Gangnam Severance Hospital, Yonsei University College of Medicine, Asan Medical Center, University of Ulsan College of Medicine, Korea University Guro Hospital, Korea University Anam Hospital, Seoul; National Cancer Center, Goyang-si, South Korea.
BACKGROUND: Patients who have residual invasive carcinoma after the receipt of neoadjuvant chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative breast cancer have poor prognoses. The benefit of adjuvant chemotherapy in these patients remains unclear.
METHODS: We randomly assigned 910 patients with HER2-negative residual invasive breast cancer after neoadjuvant chemotherapy (containing anthracycline, taxane, or both) to receive standard postsurgical treatment either with capecitabine or without (control). The primary end point was disease-free survival. Secondary end points included overall survival.
RESULTS: The result of the prespecified interim analysis met the primary end point, so this trial was terminated early. The final analysis showed that disease-free survival was longer in the capecitabine group than in the control group (74.1% vs. 67.6% of the patients were alive and free from recurrence or second cancer at 5 years; hazard ratio for recurrence, second cancer, or death, 0.70; 95% confidence interval [CI], 0.53 to 0.92; P=0.01). Overall survival was longer in the capecitabine group than in the control group (89.2% vs. 83.6% of the patients were alive at 5 years; hazard ratio for death, 0.59; 95% CI, 0.39 to 0.90; P=0.01). Among patients with triple-negative disease, the rate of disease-free survival was 69.8% in the capecitabine group versus 56.1% in the control group (hazard ratio for recurrence, second cancer, or death, 0.58; 95% CI, 0.39 to 0.87), and the overall survival rate was 78.8% versus 70.3% (hazard ratio for death, 0.52; 95% CI, 0.30 to 0.90). The hand-foot syndrome, the most common adverse reaction to capecitabine, occurred in 73.4% of the patients in the capecitabine group.
CONCLUSIONS: After standard neoadjuvant chemotherapy containing anthracycline, taxane, or both, the addition of adjuvant capecitabine therapy was safe and effective in prolonging disease-free survival and overall survival among patients with HER2-negative breast cancer who had residual invasive disease on pathological testing.
Funded by the Advanced Clinical Research Organization and the Japan Breast Cancer Research Group; CREATE-X UMIN Clinical Trials Registry number, UMIN000000843.
Presented in part at the Annual Meetings of the San Antonio Breast Cancer Symposium (SABCS), San Antonio, TX. The first interim analysis for safety was presented at the 36th Annual Meeting of the SABCS, December 10-14, 2013, and the first efficacy analysis at the 38th Annual Meeting of the SABCS, December 8-12, 2015.
DOI: 10.1056/NEJMoa1612645