天津医科大学肿瘤医院：传统肿瘤标志物在结直肠癌中的应用现状

本文作者：段晶晶，邓婷，巴一（天津医科大学肿瘤医院　国家肿瘤临床医学研究中心　天津市肿瘤防治重点实验室　天津市恶性肿瘤临床医学研究中心，天津　300060）

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【摘要】　结直肠癌是我国常见的消化道恶性肿瘤之一，血清学肿瘤标志物以其简便、无创的特点，可辅助结直肠癌的诊断、预后判断、治疗决策制订和病情监测。随着近年来分子生物学技术的发展，涌现出众多与结直肠癌诊断和预后相关的新型标志物，如循环肿瘤DNA、循环肿瘤细胞、外泌体等，但包括癌胚抗原（carcinoembryonic antigen，CEA）和多种糖类抗原在内的传统肿瘤标志物依然在结直肠癌诊疗过程中具有不可取代的地位。本文将近年来以CEA为主的传统肿瘤标志物在结直肠癌诊疗过程中的应用进行综述。

【关键词】　结直肠癌；肿瘤标志物；癌胚抗原；糖类抗原19-9；糖类抗原125

我国结直肠癌的发病率、死亡率在全部恶性肿瘤中均位居第5位[1]，是威胁国民健康的重大公共卫生问题。肿瘤标志物作为特征性存在于肿瘤细胞或由肿瘤细胞异常产生的物质，或是宿主对肿瘤的刺激反应而产生的物质，其在肿瘤诊断和疾病复发监测中具有重要作用。随着外泌体、循环肿瘤DNA（circulating tumor DNA，ctDNA）等新型肿瘤标志物的出现，学者们也不断探索其在结直肠癌早期诊断和预后判断中的作用。但是，以癌胚抗原（carcinoembryonic antigen，CEA）为主的传统肿瘤标志物依然在常规临床诊疗工作中占据主要地位，现将近年来传统肿瘤标志物在结直肠癌中的应用综述如下。

1　癌胚抗原

CEA于1965年首次由Gold等[2]从人类结直肠癌组织中分离而来。它是一种胎儿糖蛋白，通常在出生后处于较低水平。但在肿瘤状态下，血清CEA水平会异常升高。CEA检测在结直肠癌患者预后判断和病情监测中具有重要作用，但由于其他疾病患者CEA水平也可能升高[3,4]，且许多结直肠癌患者的CEA处于正常水平，因此CEA在结直肠癌筛查和诊断中的价值尚未得到肯定。

1.1　辅助诊断　多项临床研究评估了CEA检测在结直肠癌筛查和诊断中的作用。研究显示，CEA高水平组患者结直肠癌发生率高于CEA水平正常组（4.6%∶1.3%）[5]。但CEA同时也是其他疾病的预测因子，如其他恶性肿瘤、糖尿病、慢性肺病和肝病等[6]。因此，仅利用CEA筛查结直肠癌的价值有限。研究表明，包括CEA、糖类抗原19-9（carbohydrate antigen 19-9，CA19-9）、糖类抗原125（carbohydrate antigen 125，CA125）和前列腺特异性抗原在内的生物标志物的组合，可进一步提高结直肠癌筛查的灵敏度[7,8]。最新研究发现，由血清CEA、CA19-9、角蛋白1（cytokeratin 1，CK1）和黏蛋白-1（mucin-1，MUC1）水平计算而来的结肠癌评分是一项潜在的、有价值的、无创性指标，可用于早期结肠癌的检测和筛查[9]。国内学者指出血脂水平[总胆固醇（total cholesterol，TC）、高密度脂蛋白（high density lipo-p­rotein，HDL）]联合CEA和CA19-9检测可作为辅助结肠癌诊断的有效标志物[10]，这为结肠癌的临床诊断和检测提供了新的策略。

1.2　预后判断　CEA水平与结直肠癌患者的预后相关[11]。术前CEA水平升高（＞5 ng/ml）预示着结直肠癌有较高的复发率和疾病相关死亡率[12,13]。与术前CEA水平正常的结肠癌患者相比，术前CEA水平升高患者的死亡风险增加62%，两组5年无病生存率分别为84.6%和69.8%[14]，5年总生存（overall sur­v­ival，OS）率分别为74.5%和63.4%[15]。然而，另外一项包含1990—2000年和2001—2004年两项Dukes C期结直肠癌队列的研究发现，在2001—2004年结直肠癌队列中，术前CEA水平与预后无关[16]，研究人员推测这可能与辅助化疗方案的改进相关。高危Ⅱ期肠癌患者需要接受辅助化疗预防复发，T4、低分化、淋巴结清扫数量不足等临床病理学因素可筛选出高危Ⅱ期肠癌患者，但其预测价值有限。研究发现，根据术前CEA水平和肿瘤出芽分级这两项指标可更准确地筛选出高危Ⅱ期结肠癌患者[17]。若将术前CEA水平代表的C分期添加至TNM分期中，则可以带来更准确的预后判断[18,19]。研究人员通过检测结直肠癌患者术前CEA、CA19-9、CA125和糖类抗原242（carbohydrate antigen 242，CA242）水平，发现术前肿瘤标志物水平不高的Ⅲ期结直肠癌患者的预后优于伴有3种及以上肿瘤标志物水平升高的Ⅱ期结直肠癌患者[20]，提示后者更需要辅助治疗和密集随访。此外，国内学者通过分析16 659例Ⅰ期结肠癌患者发现，伴有CEA水平升高的T1N0M0期结肠癌患者预后明显较差，此类患者术后也需要密切随访[21]。

研究人员认为利用根治性手术切断直肠癌患者CEA来源后，CEA水平会成倍下降[22]。对于CEA水平呈指数下降的结肠癌患者，其生存明显优于CEA水平保持升高的患者。故术后CEA水平下降也是一项预后指标[23]，与OS率和无病生存率的提高相关[24]。在接受R0切除的Ⅳ期结直肠癌患者中，术后CEA和CA19-9水平升高也与无病生存率降低相关[25]。同时，研究发现CEA水平与循环肿瘤细胞的存在相关[13]。若术后CEA水平未能恢复正常，常提示有残留或复发性疾病，CEA水平超过10 ng/ml则与转移性疾病密切相关。研究指出，术后CEA水平/术前CEA水平比值越低的结直肠癌患者预后越好[26]。Konishi等[27]研究发现，术前CEA水平升高，术后CEA水平恢复正常，并非预后不良的指标；但术后CEA水平升高的患者复发风险增加，特别是术后12个月内CEA水平升高的患者。

1.3　疾病复发监测　对于结直肠癌患者，CEA水平升高可能会先于临床复发出现。最近的荟萃分析显示，对接受根治术的结直肠癌患者加强监测并无生存获益[28]。有多项随机对照试验曾探索CEA水平对疾病复发的监测效果。研究显示，对于CEA水平升高的结直肠癌患者，与保守治疗相比，采用第二次剖腹手术并无生存优势，研究提前终止[29]。另有临床试验比较了结直肠癌患者接受标准随访方案和密集随访方案的生存差异[30-33]。在FACs试验中，密集CEA和CT随访提高了复发性疾病的手术切除率，但并无生存获益[33]。荷兰的CEAwatch试验探索了CEA不同的监测频率对检测疾病复发和发现可治愈复发能力的影响[31]。研究发现，与对照组（12周/次）相比，密集CEA监测（8周/次）发现可接受R0切除的复发患者更多（35%∶22%）[31]，但并未发现生存获益。

异常的CEA结果提示临床医生需对结直肠癌患者进行进一步检查，但具有临床意义的血清CEA阈值是有争议的。一项包含52项研究的荟萃分析对此进行探索，结果发现，以2.5 ng/ml作为CEA阈值时，监测疾病复发的灵敏度和特异度分别为82%和80%；以5 ng/ml作为CEA阈值时，监测疾病复发的灵敏度和特异度分别为71%和88%；以10 ng/ml作为CEA阈值时，监测疾病复发的灵敏度和特异度分别为68%和97%[34]。最终研究人员认为，应以CEA为10 ng/ml作为启动进一步检查的阈值。利用术后CEA水平诊断复发的准确性受术前CEA水平的影响。对于接受结肠癌根治术且术前CEA水平正常的患者，术后6个月检测CEA，当阈值为5 ng/ml时，诊断复发的准确率为89.1%；而对于术前CEA水平升高的患者，其诊断准确率为58.4%，而当以8 ng/ml为阈值时，诊断复发的准确率将提高至75.6%。

1.4　化疗效果预测　细胞学实验发现耐药的肠癌细胞株会高分泌CEA[35]，但治疗前CEA水平能否预测化疗或放疗反应尚未明确。研究发现，与治疗前CEA水平＜3 ng/ml的患者相比，治疗前CEA水平升高（＞9 ng/ml）的患者对放化疗的灵敏度较低[36]。但也有研究并未发现此相关性[37]。一项针对Ⅰ～Ⅲ期直肠癌患者的回顾性分析显示，CEA水平升高与新辅助治疗反应不佳相关，CEA水平不断升高的患者病理完全缓解率、肿瘤缩小率和OS率均显著降低。直肠癌患者接受新辅助放化疗后CEA水平降低具有预后价值[38]，CEA水平≤5 ng/ml与临床和病理完全缓解率增加和总体无病生存率提高相关。因此，对于治疗后CEA水平依然较高的患者可推荐密集随访监测。

Ogata等[39]认为术前CEA水平升高的Ⅱ期肠癌需要辅助化疗，但有研究发现术前CEA水平较高的ⅡA期结直肠癌患者接受辅助化疗并无生存获益，且辅助化疗期间CEA一过性升高并不影响结直肠癌患者的预后[40,41]。Huang等[42]对447例原发性肿瘤切除并接受化疗的转移性结直肠癌（metastatic colo­r­e­ctal cancer，mCRC）患者进行回顾性分析发现，6个周期化疗后CEA水平与治疗前CEA水平的比值与客观缓解率和OS率密切相关。同样地，在接受一线化疗的mCRC患者中，CEA水平变化趋势与化疗效果也密切相关[43]。这表明CEA水平及其变化在评估mCRC患者的治疗反应中具有一定作用。在FIRE-3试验中，CEA趋势可反映KRAS野生型mCRC患者对靶向治疗的反应[24]。对于CEA水平快速下降的患者，相比于接受FOLFIRI方案（伊立替康＋5-氟尿嘧啶）联合贝伐珠单抗，一线接受FOLFIRI方案联合西妥昔单抗的患者生存更好（25.0个月∶28.7个月）。在西妥昔单抗组中，与CEA无应答者相比，CEA应答者（定义为其水平至少减少75%）生存率更高。Unseld等[44]通过对48例接受瑞戈非尼治疗的mCRC患者研究发现，瑞戈非尼疗效与血清CEA、CA19-9水平无关。

此外，研究发现CEA过表达可抑制自然杀伤细胞和细胞毒性淋巴细胞的功能，从而抑制抗肿瘤免疫反应，促进肿瘤进展。而在1例非小细胞肺癌患者接受程序性死亡蛋白-1（programmed death-1，PD-1）抗体治疗过程中，也发现了CEA水平与免疫治疗效果的相关性[45]。因仅为个案报道，CEA水平与PD-1抗体疗效的相关性仍需进一步证实。

2　糖类抗原

CA19-9是胰腺癌的最佳标志物，在结直肠癌监测中也有广泛应用。但其监测结直肠癌的灵敏度低于CEA。Morita等[46]评价血清CA19-9在大肠癌患者中的作用，结果表明CA19-9水平与预后并无相关性。Papk等[47]则发现术前CA19-9水平高的患者较CA19-9水平正常的患者更易伴随淋巴浸润和神经浸润，且肿瘤更多处于晚期、更易复发。有研究通过分析367例Ⅲ期结直肠癌患者发现，术前血清CA19-9水平升高提示结直肠癌患者预后较差，推荐此类患者采用密集随访方案[48]。鉴于单一血清学指标预测预后价值不足，研究人员发现可通过术前血清CEA、CA19-9、CA242联合检测筛选出高危复发人群[49]。Hashizume等[50]对113例接受一线化疗的mCRC患者分析发现，仅治疗后血清CA19-9水平与治疗效果相关。

CA125是一种高度糖基化的黏蛋白，在80%的卵巢癌组织中观察到CA125过表达。但CA125并不具有肿瘤特异性，在乳腺癌、肺癌和结直肠癌等其他类型肿瘤中其水平也有升高。有研究通过检测80例结直肠癌患者术前肿瘤标志物水平，发现术前血清CA19-9、CEA、CA125水平与结直肠癌分期有关，这三种肿瘤标志物水平同时升高是结直肠癌患者OS的最不利预测因子，多因素分析发现术前血清CA125水平是影响结直肠癌患者OS的独立预后因素[51]。

糖类抗原724（carbohydrate antigen 724，CA724）也是一种高分子量糖类抗原，消化系统恶性肿瘤患者血清中CA724水平升高，健康人或良性肿瘤患者血清中CA724水平则较低，因此，CA724在结肠癌的辅助诊断和鉴别诊断中也具有重要价值[52]。

3　其他血液标志物

除常见的CEA和糖类抗原外，血液中的一些炎性指标也被发现与结直肠癌患者的预后相关，可作为判断预后的标志物。

术前中性粒细胞与淋巴细胞比值（neutrophil-to-lymphocyte ratio，NLR）被认为是肿瘤患者的预后因素。一项荟萃分析通过对5897例结直肠癌患者分析后发现，术前NLR可作为判断结直肠癌患者预后的有效指标，NLR的检测有助于筛选出需要其他辅助治疗的高危患者[53]。另外一项荟萃分析通过对13 719例结直肠癌患者分析后发现，术前血小板与淋巴细胞比值（platelet-lymphocyte ratio，PLR）较高的患者OS、无复发生存时间更短[54]。且有学者发现PLR高仅与左半结肠癌患者预后相关，而与右半结肠癌患者预后无关[55]。此外，国内学者利用NLR、

淋巴细胞与单核细胞比率和白蛋白/球蛋白比率构建了用于预测结直肠癌患者生存的Nomog­ram模型，该模型具有良好的预测效能[56]。但血液中炎性指标的预后价值大多基于回顾性分析得出，并无前瞻性研究结果，故其应用于临床仍需进一步证实。

4　展望

肿瘤标志物在肿瘤的诊断、预后、治疗和监测中具有重要作用。血清肿瘤标志物检测以其简便、无创等优点得到了广泛应用。近年来，随着分子生物学技术和肿瘤生物学的发展，许多与诊断、预后和患者生存有关的新型血清肿瘤标志物被发现，但这些新型标志物均暂未取代以CEA为代表的传统肿瘤标志物在结直肠癌患者诊疗过程中的地位。在未来临床工作中，多种传统肿瘤标志物的联合检测，或与新型肿瘤标志物的联合应用，将在结直肠癌患者的诊断、预后、治疗和监测中发挥更大作用。

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