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摘要:
随着对胃癌综合治疗研究的不断深入,FLOT方案开始用于胃癌患者的治疗。FLOT方案新辅助治疗可显著提高局部进展期胃癌患者R0切除率,延长总生存时间。FLOT方案联合免疫检查点抑制剂、靶向药物、腹腔热灌注化疗在胃癌新辅助治疗中具有较大潜力。笔者结合团队临床实践经验对胃癌FLOT方案新辅助治疗的发展历史及最新临床研究进展进行分析和探讨。
Abstract:With the deepening research of comprehensive treatment for gastric cancer, the FLOT regimen has begun to be used for the treatment of gastric cancer patients. FLOT neoadjuvant regimen can significantly improve the R0 resection rate and prolong the overall survival time of locally advanced gastric cancer patients. FLOT regimen combined with immune‑checkpoint inhibi-tors, targeted therapy and hyperthermic intraperitoneal chemotherapy have great potential in neo-adjuvant therapy for gastric cancer. The authors systematically analyse the development history and latest clinical research progress of FLOT neoadjuvant regimen for gastric cancer based on their clinical practice experience.
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Keywords:
- Stomach neoplasms /
- Tumor therapy /
- Neoadjuvant chemotherapy /
- Peri-operative treatment /
- FLOT
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胃癌是全世界发病率排名第5、死亡率排名第4的恶性肿瘤,在亚洲的发病率最高,我国胃癌发病率和死亡率分别占全世界的42.6%和45.0%[1‑2]。我国大部分胃癌患者在确诊时已处于中晚期,仅依靠外科手术难以实现病理学根治性切除,且术后化疗获益有限[3]。因此,新辅助治疗理念逐渐引起重视,有望进一步改善患者预后。1项针对欧洲人群的研究结果显示：由5‑氟尿嘧啶（5‑Fluorouracil,5‑FU）、亚叶酸钙、奥沙利铂及多西他赛组成的围手术期FLOT化疗方案可提高局部进展期胃癌（locally advanced gastric cancer,LAGC）患者的R0切除率至94%,5年生存率可达45%,其疗效引起全世界研究者广泛关注[4]。笔者结合团队临床实践对胃癌FLOT方案新辅助治疗的发展历程及最新临床研究进展进行深入分析和探讨。
一、FLOT方案的演变
FLOT方案由CF方案（5‑FU+顺铂）演变而来,其中5‑FU为细胞周期特异性药物,主要作用于S期；顺铂属于细胞周期非特异性药物,主要通过与DNA 形成铂‑DNA复合物实现抗肿瘤作用[5‑6]。在FLOT方案提出之前,晚期胃癌的化疗方案主要以5‑FU和顺铂2种药物为基础,但采用CF方案治疗患者的总缓解率及总生存时间（overall survival,OS）均不理想（总缓解率为25%、中位OS为8.6个月、1年生存率为32%）[7]。已有的研究结果显示：5‑FU大剂量静脉滴注是一种治疗晚期胃癌有效且可耐受的给药方式[7‑8]。Webb等[9]将CF方案联合表柔比星（ECF方案）治疗晚期胃癌,研究结果显示：该方案可改善胃癌晚期化疗总缓解率（45%）及患者生存（中位OS为8.9个月、1年生存率为36%）,其对应的WHO 3级和4级中性粒细胞及WBC 减少症的发生率分别为58%和39%[9]。多西他赛属于第二代紫杉烷类药物,主要作用于M期,通过多级纺锤体的形成提高染色体不稳定性,干扰肿瘤细胞有丝分裂[10]。V325研究联合CF方案与多西他赛（DCF方案）,可改善晚期胃癌患者的总缓解率（37%）和预后（中位OS为9.6个月、1年生存率为40%）,WHO 3级和4级血液学不良反应发生率较高（中性粒细胞和WBC减少症发生率分别为82%和65%）[7]。
为提高化疗疗效,降低毒性,FLOT1试验将CF方案中顺铂替换为奥沙利铂,提出了FLO方案（5‑FU+亚叶酸钙+奥沙利铂）[11‑12]。奥沙利铂为第三代铂类药物,疗效优于顺铂且毒性更低[13]。FLO方案：奥沙利铂85 mg/m2、亚叶酸钙500 mg/m2静脉滴注2 h后,5‑FU 2.6 g/m2持续静脉滴注24 h,与FOLFOX方案比较,FLO方案能够显著降低奥沙利铂（100 mg/m2）和5‑FU（400 mg/m2静脉推注后再给予2.4~3.0 g/m2静脉滴注48 h）的剂量[14]。FLOT1‑Ⅱ期试验结果显示：FLO方案具有较高的安全性（未发生WHO 3级和4级中性粒细胞减少症、3级和4级WBC减少症发生率为4.9%）,但该研究样本量较小（41例）[11]。FLOT1‑Ⅲ期试验进一步扩大样本量（112例）,结果显示：FLO方案在改善缓解率及生存方面（总缓解率为34.8%、中位OS为10.7个月、1年生存率为45%）与ECF方案、DCF方案及FOLFOX方案（总缓解率为45%、中位OS为8.6个月、1年生存率为53%）相当,但WHO 3级和4级血液学不良反应事件发生率（中性粒细胞和WBC减少症发生率分别为11.6%、6.3%）远低于ECF方案、DCF方案及FOLFOX方案（中性粒细胞和WBC减少症发生率分别为38%和19%）[7,9,11‑12,14]。
为进一步提高化疗疗效,Al‑Batran等[15]开展了FLOT2试验,在DCF方案的基础上将多西他赛纳入FLO方案中,最终入组德国10家医学中心的54例患者,研究结果显示：FLOT方案可改善晚期胃癌患者的总缓解率（58%）,延长生存时间（中位OS为11.1个月、1年生存率为42%）,血液学不良事件为其主要不良反应（WHO 3级和4级中性粒细胞、WBC减少发生率分别为48.1%和27.8%）,发生率远低于DCF方案。已有的研究结果证实：5‑FU或其前体药物联合奥沙利铂的胃癌术后辅助化疗方案疗效确切,ACTS⁃GC试验中S⁃1单药辅助化疗的5年生存率较单纯手术提高11%（72%比61%）,CLASSIC试验报道XELOX方案（奥沙利铂+卡培他滨）辅助化疗可提高5年生存率（78%比69%）[16‑17]。研究者开展FLOT3试验（NCT00849615）、FLOT4试验（NCT0121 6644）、FLOT5试验（NCT02578368）旨在评估术前使用FLOT方案治疗可切除或局限性转移性胃癌患者的疗效；FLOT6试验（NCT02581462）、FLOT7试验（NCT02661971）对围手术期FLOT方案联合靶向治疗的安全性及有效性进行了评估；FLOT8试验（NCT03421288）、FLOT9试验（NCT 04447352）则分别对FLOT方案与免疫治疗及腹腔热灌注化疗（hyperthermic intraperitoneal chemotherapy,HIPEC）的联合应用效果进行了探索[4,18‑23]。
二、FLOT方案与新辅助治疗
胃癌新辅助治疗作为综合治疗方法日益受到关注[24‑26]。LAGC患者未在FAMTX方案（5‑FU+多柔比星+甲氨蝶呤）新辅助治疗中获益[27]。后期ECF方案（表柔比星+顺铂+5‑FU）取代FAMTX方案。2006年的MAGIC试验结果显示：ECF新辅助治疗可显著提高LAGC患者的疾病无进展生存时间及OS（5年总生存率为36.3%）[28]。法国的FFCD9703试验也证实：围手术期采用CF方案与单纯手术比较,前者可显著改善食管胃结合部癌患者生存时间,5年生存率提高14%（38%比24%,P<0.02）[29]。MAGIC和FFCD9703试验使新辅助治疗正式成为胃癌综合治疗模式中的重要组成部分。多项研究结果显示：新辅助治疗可显著改善LAGC患者预后[4, 30‑31]。但最优新辅助治疗方案仍处于不断探索中。
胃癌新辅助治疗虽然经历了长期探索,但LAGC患者获益甚微。因此,研究者开展了一系列FLOT方案相关新辅助治疗试验,以期改善LAGC患者的生存预后[4,18‑23]。FLOT4试验对照组为术前、术后各行 3个周期ECF方案治疗,试验组为术前、术后各行4个周期FLOT方案治疗,研究结果显示：试验组手术切除率和R0切除率均高于对照组（94%比87%,P=0.001；85%比78%,P=0.0162）；试验组T1期或N0期比例明显高于对照组（25%比15%,P=0.008；49%比41%,P=0.025）；试验组中位无病生存时间（disease free survival,DFS）、中位OS、5年生存率均优于对照组（30个月比18个月,P=0.0036；50个月比35个月,P=0.012；45%比36%,P=0.012）；两组不良反应比较,差异无统计学意义[4]。因此,胃癌新辅助治疗中FLOT方案比ECF方案更具优势。亚洲对于可切除LAGC新辅助治疗的研究起步较晚,LAGC患者仍施行D2根治术序贯辅助化疗的治疗模式。笔者团队研究结果显示：胃癌患者术前行3个周期、术后行6个周期FLOT方案治疗,总有效率为44.7%；与直接手术组比较,前者可提高5年生存率（43.8%比26.8%）,且术后淋巴结转移率更低（N0期40.5%比7.7%,N1期18.9%比18.9%,N2期18.9%比30.8%,N4期21.6%比43.6%）[32]。胃癌患者行FLOT方案新辅助治疗安全、有效,除WHO 3级或4级贫血外并无严重血液学不良事件发生[33]。得益于FLOT4试验结果,FLOT方案已成为可切除LAGC新辅助治疗的新标准。
基于2017年公布的FLOT4试验中期结果,美国国立综合癌症网络（NCCN）胃癌指南2018年第2版首次将FLOT方案以Ⅰ类证据作为围手术期化疗推荐方案,将ECF围手术期化疗方案从指南中去除。中国临床肿瘤学会（CSCO）胃癌指南2018.V1版也首次提出,对于临床T3~4期、伴或不伴淋巴结转移、无远处转移胃癌患者,FLOT方案以2A类证据作为新辅助治疗推荐方案,推荐等级为Ⅱ级[34‑35]。随着2019年FLOT4试验最终结果的公布,NCCN胃癌指南2020年第4版则将FLOT方案调整为围手术期化疗首选方案；CSCO胃癌指南2020版对于非食管胃结合部癌患者,FLOT方案新辅助治疗为ⅠB类证据、Ⅱ级推荐,食管胃结合部癌患者该治疗方式为ⅠB类证据、Ⅰ级推荐[36]。《局部进展期胃癌围手术期治疗中国专家共识（2021版）》对于体能状况好的胃癌患者可优先推荐FLOT方案行新辅助治疗[37]。
三、FLOT方案新辅助治疗联合其他治疗方法
（一）与免疫检查点抑制剂联合
免疫检查点抑制剂（immune checkpoint inhibitors,ICIs）已广泛应用于胃癌治疗,包括：细胞毒性T淋巴细胞抗原‑4（cytotoxic T lymphocyte antigen‑4,CTLA‑4）单克隆抗体、PD‑1单克隆抗体、PD‑L1单克隆抗体以及淋巴细胞活化基因‑3（lymphocyte activation gene‑3,LAG‑3）单克隆抗体[38⁃40]。一项前瞻性单臂Ⅱ期临床试验（NCT04341857）结果显示：术前FLOT方案联合Sintilimab可显著提高进展期可切除胃癌或食管胃结合部腺癌患者的R0切除率（93.8%）及病理学完全缓解（pathologic complete remission,pCR）率（18.8%）,且并未发生与药物不良反应相关的手术延误或并发症[41]。英国的ICONIC试验（NCT03399071）中期分析结果显示：已入组的15例患者中,13例完成全周期FLOT方案联合Avelumab治疗,无患者因术前治疗相关并发症而延迟或未能手术,15例患者均实现R0切除[42]。由此可见,术前FLOT方案联合PD‑1抗体可显著提高进展期胃癌患者的R0切除率,但是关于术前免疫治疗的剂量及周期尚未达成共识。FLOT方案与LAG‑3单克隆抗体（NCT04062656）联用的新辅助治疗相关临床试验正在进行中。上述研究结果有望为FLOT方案联合ICIs的临床应用提供更高级别证据。
（二）与靶向药物联合
目前胃癌中常见的分子靶点主要为人表皮生长因子受体‑2（human epidermal growth factor receptor 2,HER‑2）和VEGFR。已有的研究结果显示：FLOT方案联合靶向HER‑2和VEGFR的药物可明显提高新辅助治疗疗效[20‑21,43⁃44]。HER‑FLOT试验（NCT01472029）结果显示：对于可切除LAGC和进展期食管胃结合部腺癌患者,围手术期Trastuzumab联合FLOT方案治疗后R0切除率为92.9%,12例患者（21.4%）达到pCR,中位DFS为42.5个月,3年总生存率为82.1%[43]。FLOT6试验结果显示：与围手术期单用FLOT方案比较,FLOT方案联合Trastuzumab或Pertuzumab时pCR率（35%比12%,P=0.02）与病理学淋巴结阴性率（68%比39%）显著提高,但腹泻（41%比5%）和WBC减少症（23%比13%）的发生率也随之增高[20]。HER‑FLOT试验、FLOT6试验与FLOT4试验均由同一研究机构开展,纳入标准除HER‑2状态外均相同,在3项试验中围手术期FLOT方案均采取“4+4”模式进行,HER‑FLOT试验与FLOT4试验中HER‑2单克隆抗体用药剂量及周期相似。3项研究结果均显示：围术期FLOT方案联合Trastuzumab或Pertuzumab可显著改善HER‑2阳性胃癌患者的生存预后,但腹泻发生率较高。FLOT方案联合VEGFR单克隆抗体的FLOT7试验结果显示：与单用FLOT方案比较,围手术期FLOT方案联合Ramucirumab治疗可提高LAGC和进展期食管胃结合部腺癌的R0切除率（96%比82%,P=0.0078）[21]。这与联合用药组术前疾病进展患者减少（6%比1%）,行根治性手术患者比例更高（97%比88%）有关[21]。
（三）与HIPEC联合
术中HIPEC可有效清除腹腔内残存的游离肿瘤细胞,在行R0手术切除基础上使用HIPEC可有效预防术后肿瘤腹膜复发[45]。研究结果显示：预防性HIPEC可改善进展期胃癌患者的OS和DFS,降低腹膜转移率[46]。德国FLOT9试验（NCT04447352）和波兰CHIMERA试验（NCT04597294）旨在评估围手术期FLOT方案联合术中HIPEC与单独FLOT方案,治疗可切除LAGC和进展期食管胃结合部腺癌患者中的疗效和安全性,两项研究中HIPEC使用的化疗药物分别为顺铂和伊利替康,研究正在进行中,期待结果公布[23]。
四、小结
综上,FLOT方案已成为欧洲和亚洲可切除LAGC新辅助治疗的标准治疗方案。FLOT方案联合Trastuzumab、Pertuzumab、Ramucirumab等药物用于LAGC围手术期治疗安全有效。围手术期FLOT方案与HIPEC联合治疗亦处于探索阶段,临床研究设计及临床实践仍存在以下问题：（1）FLOT方案不良反应包括WBC减少症、腹泻和恶心等[47]。因此,仍需对FLOT方案的用药剂量、剂型进一步探索。（2）FLOT方案联合免疫治疗、靶向治疗的最佳用药次序、剂量以及用药周期还需要大样本临床试验进一步确定。（3）CSCO胃癌指南2021版中对于FLOT方案新辅助治疗的证据级别及推荐级别并未提高。因此,研究者需针对我国胃癌人群开展多中心、大样本临床试验,提供更高质量证据[48]。（4）人源化肿瘤模型、影像组学、血液学指标以及其他临床预测模型等有望早期精准预测胃癌患者对FLOT方案新辅助治疗及联合治疗的反应性,早期制订针对LAGC患者的个体化治疗方案,从而进一步提高FLOT方案的疗效,改善患者预后。
所有作者均声明不存在利益冲突王涛, 王科深, 周辉年, 等. FLOT方案在胃癌新辅助治疗中的研究进展[J]. 中华消化外科杂志, 2022, 21(6): 822-826. DOI: 10.3760/cma.j.cn115610-20220422-00226.http://journal.yiigle.com/LinkIn.do?linkin_type=cma&DOI=10.3760/cma.j.cn115610-20220422-22226
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