摘要
背景和目的 在欧美国家,贝伐珠单抗联合化疗业已成为治疗晚期转移性结直肠癌（m CRC）的标准方案。在我国,贝伐珠单抗的注册临床研究亦显示贝伐珠单抗联合化疗可以提高m CRC客观缓解率和显著改善生存预后。但是,缺乏贝伐珠单抗联合化疗治疗国人m CRC的大样本资料,特别是安全性数据。为此,我们开展了上市后临床研究——REACT研究（REal world study of Avastin in Colorec Tal cancer;注册号：NCT 01319877）,系统观察和评价真实世界（real world）中贝伐珠单抗联合氟尿嘧啶类药物为基础的化疗方案治疗国人m CRC的安全性和有效性。方法 本研究为一项前瞻性、非干预性、全国多中心的上市后临床研究。根据预设的入排标准,纳入m CRC一线或二线治疗患者,采用贝伐珠单抗联合氟尿嘧啶类药物为基础的常规化疗方案进行治疗。主要终点指标是评估治疗的安全性,次要终点指标为评估总体缓解率（ORR）、无进展生存期（PFS）、总生存期（OS）、KRAS突变状态和贝伐珠单抗用药周期（〈8或≥8周期）对疗效以及生活质量（Qo L）的影响。分别采用RECIST 1.1版和NCI-CTC AE 4.03版评价客观疗效和不良反应。结果 自2011年3月至2013年12月,24家研究中心共纳入606例m CRC,中位年龄56.6岁（22-81岁）,ECOG PS 0-1占76.7%;其中,一线患者453例,二线患者153例。贝伐珠单抗中位用药周期为5.0个（3.0-8.0个）周期。安全性方面：有102例患者（16.8%）发生≥3级不良事件（AE）;66例（10.9%）发生≥3级可能与贝伐珠单抗有关的AE。特别关注的不良事件（AESI）为高血压（1.8%）、蛋白尿（0.8%）、胃肠穿孔（0.5%）、出血（3.3%）、动脉血栓栓塞（0.3%）、静脉血栓栓塞（1.0%）、肠瘘（0.8%）以及伤口愈合并发症（0.2%）。有效性方面：ORR为18.3%（95%CI：15.3%-21.6%）,一线患者和二线患者的ORR分别为21.0%（95%CI：17.3%-25.0%）和10.5%（95%CI：6.1%-16.4%）（P=0.0035）;中位无进展生存期（m PFS）为9.1个月（95%CI：8.1-9.8个月）;中位总生存期（m OS）为21.9个月（95%CI：17.1-25.7个月）。一线患者与二线患者的m PFS和m OS差异均无统计学意义（m PFS：P=0.6530;m OS：P=0.3695）。按治疗周期划分,应用贝伐珠单抗〈8周期患者的m PFS和m OS分别为7.8个月（95%CI：6.2-8.9个月）和17.6个月（95%CI：14.9-24.8个月）;用药≥8周期患者的m PFS和m OS分别为11.6个月（95%CI：10.9-14.4个月）和30.8个月（95%CI：21.3个月-未达）。用药≥8周期患者的生存获益明显优于〈8周期患者（m PFS：P=0.0001;m OS：P=0.001）。按KRAS突变状态划分,KRAS野生型和突变型患者的m PFS分别为9.8个月（95%CI：6.7-12.3个月）和8.6个月（95%CI：6.2-9.9个月）,差异无统计学意义（P=0.2784）。KRAS野生型和突变型患者的m OS分别为25.7个月（95%CI：16.9个月-未达）和14.3个月（95%CI：10.3-21.9个月）,差异无统计学意义（P=0.1015）。结论 REACT研究结果表明,贝伐珠单抗联合氟尿嘧啶类药物为基础的化疗,用于一线或二线治疗国人m CRC患者的总体安全性良好,临床获益明显;贝伐珠单抗联合含氟尿嘧啶类药物化疗使用时间长（≥8周期）的患者比使用时间短（〈8周期）的患者,具有更佳生存获益。这与欧美国家和中国注册临床研究的情况类似,值得临床上进一步推广应用。
Background ＆ Objective Bevacizumab （BV） combined with fluorouracil drugs-based chemotherapy for meta- static colorectal cancer （mCRC） acting as a standard therapy has been recognized and practiced in European and America. Post-mar- keting surveillance of patients who received BV was required because of very limited clinical data, especially safety profile in China pts. In order to understand real world practical use of BV and guide clinical practice in China, we have studied safety and efficacy of BV combined with fluorouracil based chemotherapy （CT） in 1st- or 2nd-line treatment for pts with mCRC in REACT trial （REal world study of Avastin in ColorecTal cancer; Clinical Trail No. NCT01319877）. Methods That study was a prospective, non-interventional and post-marketing muhicenter study conducted in 24 Chinese cancer centers. Patients were treated with BV plus fluorouracil based CT for mCRC as 1st- or 2hal-line therapy. The primary endpoint was to investigate the safety profile of the treatments. The secondary end- points were overall response rate （ORR）, progression-free survival （ PFS）, overall survival （OS） and quality of life （QoL）. RECIST 1.1 and NCI CTC AE 4. 03 criteria were used to evaluate the efficiency and safety, respectively. Results The recruitment was from March 2011 to December 2013. A total of 606 patients, median age 56. 6 （range, 22-81） years and 76.7% with ECOG PS （0-1）, were enrolled and treated with BV plus fluorouracil based CT as 1st-line （n = 453） or 2nd-line （n = 153） therapy. The median cycles on BV treatment were 5.0 （3.0-8. 0） cycles. Total 102 patients（ 16. 8%） experienced grade≥3 AEs. In which grade≥3 AEs related to BV were reported in 66 patients （ 10. 9% ）. AESIs defined in this study were hypertension （ 1.8% ）, proteinuria （0. 8% ）, gastroin- testinal perforation （ 0. 5% ）, bleeding （ 3.3% ）, arterial thromboembolism （ 0. 3% ）, colon venous thromboembolism （ 1.0% ）, fistula formation （0. 8%） and wound healing complications （0. 2%）. The ORR was 15. 3% （95%CI： 15.3%-21.6%）. The ORB of lst- and 2nd-line therapy were 21.0% （95%CI： 17.3%-25.0%） and 10. 5% （95%CI： 6. 1%-16.4%）, respectively （P=0. 0035）. The me- dian PFS （mPFS） and median OS （mOS） were 9. 1 （95%CI： 8. 1-9. 8） and 21.9 months （95%CI： 17. 1-25.7）, respectively. First- line patients had similar mPFS or mOS with 2nd-line patients （P = 0. 6530 and 0. 3695, respectively）. The mPFS and mOS in the pa- tients （treatment cycles〈8） were 7.8 （95%CI： 6. 2-8. 9） and 17.6 months （95%CI： 14. 9-24. 8）, respectively. The mPFS and mOS in patients （treatment cycles≥8） were 11.6 （95%CI： 10. 9-14.4） and 30. 8 months （95%CI： 21.3-）, respectively. The mPFS and mOS in the patients （ treatment cycles ≥ 8） were longer than the patients （ treatment cycles 〈 8 ） （ P = 0. 0001 and P = 0. 001, respec- tively）. The mPFS were 9. 8 months （95%CI： 6.7-12. 3） in KRAS wild-type patients and 8.6 months （95%CI： 6.2-9. 9） in KRAS mutant patients （P = 0. 2784）, respectively. The mOS were 25.7 months （95% CI： 16. 9-） in KRAS wild-type patients and 14. 3 months （95%CI： 10. 3-21.9） in KRAS mutant patients （P=0. 1015）, respectively. Conclusion The safety profile, such as BV-re- lated AEs in REACT study seemed well tolerated in Chinese patients and compatible with those date reported from other pivotal studies in European and America as well as Chinese registration trial. BV combined with fluorouracil based CT, is effective as observed in this trial. And the patients who received longer treatment （ ≥ 8 cycles） trend to have better treatment outcomes compared with those shorter treatment duration （〈8 cycles）.Thus, BV combined fluorouracil based CT worth further wide use in Chinese clinical practice.
出处
《临床肿瘤学杂志》
CAS
2016年第10期865-873,共9页
Chinese Clinical Oncology
