【评论】奥沙利铂联合氟尿嘧啶新辅助化疗对比直接手术治疗局部进展期结肠癌的随机Ⅲ期临床研究(OPTICAL研究)

[Comment]Neoadjuvant chemotherapy with oxaliplatin and fluoropyrimidine versus upfront surgery for locally advanced colon cancer:the randomized,phaseⅢOPTICAL trial

目的新辅助化疗对结肠癌的治疗作用尚不明确。本研究探讨接受为期3个月的新辅助化疗【改良氟尿嘧啶、亚叶酸钙联合奥沙利铂方案(mFOLFOX6)或卡培他滨联合奥沙利铂方案(CAPOX)】的局部晚期结肠癌患者的预后是否相比直接手术患者的预后更好。患者与方法OPTICAL研究是一项针对临床分期为局部晚期的结肠癌患者(T3期且壁外侵犯至结肠系膜脂肪的深度≥5 mm,或T4期)的随机Ⅲ期研究,按照1∶1的比例将患者随机分配至新辅助化疗组(术前进行6个周期mFOLFOX6或4个周期CAPOX,再进行手术和辅助化疗)或直接手术组(立即手术并在术后接受由医师选择的辅助化疗)。主要研究终点是改良意向治疗人群的3年无病生存率。结果研究入组了2016年1月至2021年4月收治的752例患者,其中744例患者被纳入改良意向治疗分析(新辅助化疗组371例、直接手术组373例)。中位随访时间为48.0个月(IQR为46.0~50.1),新辅助化疗组3年无病生存率为82.1%,直接手术组相应为77.5%(分层风险比为0.74,95%CI为0.54~1.03)。在两组接受手术的患者中,R0切除率均为98%;新辅助化疗组获得7%的病理完全缓解率;与直接手术组相比,新辅助化疗组进展期肿瘤患者比例(pT3~4期,77%vs.94%)和淋巴结转移患者比例(pN1~2期,31%vs.46%)更低,而且新辅助化疗具有提高总生存率的潜在作用(分层风险比为0.44,95%CI为0.25~0.77)。结论应用mFOLFOX6或CAPOX作为新辅助化疗方案未能体现关于无病生存的明显益处。但是,这种新辅助治疗方法是安全的,可以达成明显的病理降期,对局部进展期结肠癌患者而言是可行的治疗选择。

Purpose The role of neoadjuvant chemotherapy(NAC)in colon cancer remains unclear.This trial investigated whether 3 months of modified infusional fluorouracil,leucovorin,and oxaliplatin(mFOLFOX6)or capecitabine and oxaliplatin(CAPOX)as NAC could improve outcomes in patients with locally advanced colon cancer versus upfront surgery.Patients and methods OPTICAL was a randomized,phaseⅢtrial in patients with clinically staged locally advanced colon cancer(T3 with extramural spread into the mesocolic fat≥5 mm or T4).Patients were randomly assigned 1:1 to receive six preoperative cycles of mFOLFOX6 or four cycles of CAPOX,followed by surgery and adjuvant chemotherapy(NAC group),or immediate surgery and the physician's choice of adjuvant chemotherapy(upfront surgery group).The primary end point was 3-year disease-free survival(DFS)assessed in the modified intention-to-treat(mITT)population.Results Between January 2016 and April 2021,of the 752 patients enrolled,744 patients were included in the mITT analysis(371 in the NAC group;373 in the upfront surgery group).At a median follow-up of 48.0 months(IQR,46.0-50.1),3-year DFS rates were 82.1%in the NAC group and 77.5%in the upfront surgery group(stratified hazard ratio[HR],0.74[95%CI,0.54 to 1.03]).The R0 resection was achieved in 98%of patients who underwent surgery in both groups.Compared with upfront surgery,NAC resulted in a 7%pathologic complete response rate(pCR),significantly lower rates of advanced tumor staging(pT3-4:77%v 94%),lymph node metastasis(pN1-2:31%v 46%),and potentially improved overall survival(stratified HR,0.44[95%CI,0.25 to 0.77]).Conclusion NAC with mFOLFOX6 or CAPOX did not show a significant DFS benefit.However,this neoadjuvant approach was safe,resulted in substantial pathologic downstaging,and appears to be a viable therapeutic option for locally advanced colon cancer.