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（一）指诊：
指诊可触到突出、质硬、表面凸凹不平的肿块，早期肿块可移动，浸透肠壁者则固定不移，有时可触到边缘外翻的溃疡，指套上有血迹。晚期可摸到狭窄环，手指不能伸入。一般成人食指长度为7～7.5cm，若向内加压伸入，有效长度可增加到9～10cm，蹲位增加腹压后可增加到11～12cm。
（二）直肠镜或乙状结肠镜检查：
乙状结肠镜一般可检查至距肛缘25cm处。直肠下段肿瘤，可在直肠镜中见到，高位者应做乙状结肠镜检查，但直肠下段后壁肿瘤，直肠镜比乙状结肠镜更方便。所有指诊怀疑或已诊断为直肠癌者均应行内镜检查，取活组织送病理检查以明确诊断。活组织检查必须在溃疡边缘取2～3小块组织，有时须反复检查，才能确定诊断。一次阴性决不能轻易排外肿瘤。
（三）CT、MRI、腔内B超：
主要用于了解直肠癌的浸润状况。CT对局部浸润广泛的直肠癌及直肠癌术后盆腔复发的诊断有所帮助，可以直接观察是否肿瘤侵犯盆腔肌肉、膀胱、前列腺、盆骨。MRI在了解直肠癌浸润范围及盆腔内复发上意义与CT相仿。直肠腔内B超可较细致的显示直肠癌肠壁内、外的浸润深度，对临床研究是否需要作术前放疗等方面提供参考意见。近年来螺旋CT利用三维成像原理可对空腔脏器进行检查，有望成为直肠癌检查的一种新方法。
（一）腹会阴联合切除术（APR）：
柱状经腹会阴切除术，主要是对T3、T4期低位直肠癌，病人取俯卧位，游离上端直肠系膜后中低位的直肠系膜切除通过会阴部进行。目的是通过会阴部扩大切除，使标本成为无狭窄腰部的圆柱状，增加远端直肠癌周组织的切除量，降低CRM阳性率和术中肠穿孔率，从而降低肿瘤局部复发率。
关于术前放化疗在中低位直肠癌治疗中选择的理念和策略,中日韩三个国家的医生有些不同。中国的指南接近于美国国立综合癌症网络(National Comprehensive Cancer Network,NCCN)指南,建议对于T3和(或)N+以上的可切除直肠癌患者,推荐术前放化疗;日本大多数医生对可切除的中低位直肠癌并不积极推荐术前放化疗,根据日本指南推荐,对于腹膜返折下局部进展期直肠癌的标准治疗方式为全直肠系膜切除术+侧方淋巴结清扫术;韩国的结直肠癌临床实践指南对术前放化疗的推荐与中国和美国指南类似,与中国不同的是,源于韩国政府的法定政策,韩国医生针对直肠癌患者术前放化疗开展的更为积极。
低位直肠癌新辅助治疗模式的循证医学依据已在Ⅲ期随机临床研究中得到证实。在新辅助放疗模式日趋成熟应用的同时，对于现有治疗模式的局限性和治疗的毒性需要更多的优化，如新辅助治疗合适人群的选择；如何提高肿瘤的完全消退率，以提供实施“等待观察”的非手术治疗策略的机会，也对直肠癌新辅助放化疗的疗效评价提出了新的要求。
作者单位：复旦大学附属肿瘤医院放疗中心 复旦大学上海医学院肿瘤学系
直肠癌是消化系统最常见的恶性肿瘤之一，其发病率呈逐年递增的趋势。有资料显示我国以中低位直肠癌最多见，占全部直肠癌的80%以上［1］。既往Ⅱ、Ⅲ期中低位直肠癌的治疗首选外科手术，但是单纯外科手术治疗效果不佳，根治性切除率低，术后局部复发率高，部分病人不能保肛而行造口术，使病人生活质量大为下降。2004年CAO/ARO/AIO-94研究奠定了新辅助放化疗在局部进展期直肠癌治疗中的重要地位［2］。美国国家综合癌症网络（NCCN）指南针对新辅助治疗阶段给出了３种治疗选择，包括同步放化疗、短程放疗以及新辅助化疗后同步放化疗。
临床研究的文献报道显示，直肠癌治疗中肿瘤距肛门距离是影响治疗结果的重要因素。在远端直肠由于盆腔的上宽下窄锥形骨性结构，直肠系膜在此变薄及其近端的周围器官限制，直肠系膜切除不彻底的可能性较 高位直肠大，文献［3］报道的中低位直肠癌环周切缘（CRM）阳性率也高。Brodsky等［4］报道，中低位的直肠癌淋巴结转移发生率较高，也影响其预后。在NCCN治疗指南中，直肠癌的定义为距肛缘12 cm以下，在此距离以上生物学行为更接近于结肠癌，且鉴于此距离上下癌肿的术后复发率明显不同，中低位直肠癌更须加强局部治疗为主的综合治疗。
荷兰学者报道的随机临床Ⅲ期全直肠系膜切除（TME）±术前放疗的研究中，比较了术前放疗与单纯手术的疗效，分层分析发现，低位（距肛缘≤5.0 cm）和中位直肠癌（距肛缘＞5.0~10.0 cm）病灶，新辅助放疗＋手术与单纯手术相比，局部复发率明显降低，而高位直肠癌，两种方法的局部复发率相似，可见，高位直肠癌接受新辅助放疗与单纯手术相比，局部复发率相似。而中低位直肠癌可在新辅助治疗中有更多的治疗获益。
1
低位直肠癌术前放化疗
随着精准医学及个体化治疗策略的深入开展，笔者注意到不论是确立直肠癌新辅助放化疗地位的AIO-94研究［2］，还是美国的 NCCN指南，“局部进展期直肠癌”的定义均比较模糊，凡是T3以上或淋巴结阳性都被归为“局部进展”并接受新辅助放疗。对于T4期的病人，术前新辅助放化疗对提高R0切除率疗效确切，但T3期直肠癌是一组异质性较大的肿瘤，尤其是T3N0的病人，是否都需要进行新辅助放化疗目前尚有争议。随着盆腔磁共振 （特别是高分辨率磁共振）应用于直肠癌新辅助治疗分期，除了常规的T和N分期之外，磁共振在T3的亚分期、CRM受累情况、腔外脉管侵犯（EMVI）以及盆腔淋巴结转移具有非常明显的优势，为进一步局部进展期直肠癌风险分层提供了影像学支持。欧洲肿瘤内科学会（ESMO）直肠癌新辅助治疗模式是直肠癌分层治疗策略的典范［5］。该策略以临床参数（治疗位置）和高分辨率磁共振参数［T分期、N分期、CRM或磁共振指纹识别（MRF)、EMVI和侧方淋巴结］作为风险分层指标，将直肠癌分为低危、中危和高危3组。低危病人推荐直接接受手术，手术后根据病理是否存在不良预后因素（如CRM阳性，N2）决定是否给予放化疗；中危病人推荐给予短程放疗；高危病人则推荐长程放化疗；对年老或身体状态无法耐受长程同期放化疗者亦可采用短程放疗并延长等待手术时间的策略。
Merkel等［6］的研究表明，不论淋巴结的转移情况如何，肿瘤浸润深度＜5 mm的T3a期病人5年肿瘤相关存活率为85％，显著高于浸润深度≥5 mm病人的54％（P＜0.01）。Shin等分析的291例T3期直肠癌病人中，5年无病存活率（DFS）在T3a（肿瘤浸润深度＜1 mm）、T3b（肿瘤浸润深度l～5 mm）、T3c（肿瘤浸润深度>5～15 mm）和T3 d（肿瘤浸润深度＞15 mm）4组中分别为86.5％、74.2％、58.3％和29.0％（P＜0.01）。Taylor等［7］研究发现，Ｔ3a期直肠癌病人无论是单纯手术还是接受术前放化疗，其5年长期生存差异无统计学意义，说明Ｔ3a 期病人未能从直肠癌术前放化疗中获益。笔者医院利用MRI对T3期病人再分期，发现T3a期直肠癌病人经过新辅助放化疗后，较T3b和T3c期病人更易获得病理学完全缓解（pathological complete response，pCR），约为42.9%。表明T3期直肠癌病人肿瘤浸润深度同时影响新辅助放化疗疗效。对于T3a期病人，无论是接受单纯手术还是术前放化疗都可取得较好结局。因此，对于低位直肠癌T3aN0的病人，可考虑开展降低治疗强度的策略研究，避免新辅助放化疗直接手术，或放化疗后“等待观察”（wait and see）的非手术治疗策略。
2
新辅助放疗模式基础上的综合治疗
近年来，由于放疗新技术及与化疗的联合优化，由传统的三维适形放疗到容积调强放疗，新辅助治疗疗效得以提升，除了提高低位直肠癌病人的保肛率、降低局部复发率，对于临床完全缓解（cCR）的病人又提出了新的治疗策略“等待观察”，使低位直肠癌病人可能得以保留器官及功能。这对新辅助放化疗的疗效提出了更高的要求，如何提高新辅助放化疗病人的肿瘤消退率，为此，国内外的学者也开展了多项研究，包括同期化疗药物的选择，续贯化疗的选择以及延长间隔期。
2.1 同期化疗 在氟尿嘧啶基础上联合化疗，每周联合奥沙利铂在多个临床研究中未显示治疗获益。但在德国的研究中，采用每2周间歇1周的用法，显示联合组有DFS的获益，3年DFS差异有统计学意义（72% vs.76%，P=0.03）；中山大学附属第六医院团队的FOWARC研究，同期放疗采用mFLOFOX6的方案，在放化疗组显示了比单药组和化疗组更高的pCR率，为28%，单药和化疗组分别为14.3%和6.1%（P=0.001）［8］。提示在联合方案中，改变奥沙利铂的应用方法可能有获益。2016年ASCO报道的NSABP C-07研究，在肠癌分子分型中，干细胞样型应用奥沙利铂的疗效差，提示后续研究可考虑结合分子分型，寻找获益人群。
2.2 续贯化疗 在放疗前或放疗后应用2~6程化疗，在多个Ⅱ期的研究中进行了探索。西班牙GCR-3临床Ⅱ期随机研究，108例随机分组，比较常规放化疗后辅助化疗组（A组：放化疗-手术-化疗）和新辅助化疗联合放化疗组（B组：化疗-放化疗-手术）［9］。A组与B组的5年DFS和总存活率（OS）、局部复发率和远处转移发生率差异均无统计学意义，但新辅助续贯化疗组的治疗完成率高提示新辅助治疗中续贯化疗毒性较低、完成率更好。MSKCC报道的Ⅱ期非随机研究中，比较了不同疗程数续贯化疗对pCR率的提高影响。放化疗结束后，接收的续贯化疗mFOLFOX6疗程数分别为0、2、4、6。4组的pCR率分别为18%、25%、30%和38%（P=0.0036）。各组出现的3~4级毒性反应和手术相关并发症均在可接受范围。但如何合理优化，仍值得研究，是否需要将化疗疗程全部应用在新辅助治疗中，也就是称之为“全新辅助治疗（total neoadjuvnat therapy，TNT）”，这种应用是否存在过度治疗，值得探索。欧洲在结直肠癌辅助化疗中进行的对比3个月与6个月辅助化疗的IDEA研究结果可能对此有所启示。
2.3 延长间隔期 新辅助放疗后至手术的间隔期间，肿瘤仍有退缩，基础研究提示，肿瘤在放疗开始后逐步退缩，通常在15~17周退缩程度可达到最大。经典短程放疗，手术在放疗结束后1周内，因此，其相比长程放化疗，存在肿瘤降期率低的局限，可能是由于间隔期短，肿瘤退缩时间不够。是否可通过延长放疗至手术的间隔时间，从而增加肿瘤的退缩，提高pCR率有待进一步研究。延长间隔期，可采用单纯等待，间隔期化疗（如上述的续贯化疗）方案。
3
低位直肠癌新辅助放化疗疗效评价
新辅助治疗后肿瘤的不同退缩反应可用于指导后续治疗策略的调整，提示新辅助治疗疗效评价的重要性。目前的评价方式包括肛门指诊、影像学及肠镜检查等。传统的影像学检查如内镜超声、CT或常规MRI等仅能从形态学评估疗效，预测的准确率在30％～60％。手术后病理学检查结果仍是目前诊断的金标准。随着“等待观察”（watch and wait）等治疗策略在临床的开展，如何提高临床对于cCR的诊断水平，探寻新的成像技术或检测方法对于直肠癌新辅助放化疗的疗效评价尤为重要。
3.1 MRI疗效评价 MRI可精确地预测肿瘤原发灶及转移灶，准确显示直肠系膜结构（包括直肠系膜和筋膜），目前已普遍将其应用于直肠癌新辅助放化疗的疗效评价，并且越来越多的研究采用MRI相关参数来预测放化疗疗效。目前常用的MRI指标主要包括ADC值、T2和肿瘤体积，Kim等［10］研究发现，与常规MRI检查比较，DWI对pCR的诊断效能明显提高，将DWI联合常规MRI有助于提高不同评估者对pCR诊断的准确性和一致性。
高分辨成像序列的T2WI可清楚显示直肠壁的各层结构，准确判断肿瘤的浸润深度、淋巴结转移数目、直肠系膜筋膜甚至脉管侵犯情况。从MERCURY研究经验来看，放化疗后在高分辨成像序列进行MRI的肿瘤退缩分级（mrTRG）及CRM的判断，可对病人的远期生存做出预测，且与病理TRG的符合率较高。Shihab等的研究表明，好的mrTRG评分往往与更低的局部复发率相关。Lambregts等［11］大规模多中心研究中，３名医师采用T2W序列行MRI扫描，联合DWI诊断pCR的AUC明显增加。Wu等［12］发现，DWI联合T2WI诊断pCR的敏感度（92%）高于单一采用T2WI（64%）。因此，在放化疗后应用高分辨MRI结合磁共振参数对肿瘤再次进行T、N降期的评估和TRG评分，对于疗效评估及预后预测具有重要意义。
探索更多的功能影像，如容积转运常数（Ktrans）、扩散峰度成像（DKI）以及影像组学在疗效评估中的作用。
3.2 正电子发射计算机断层（PET）-CT疗效评价 尽管MRI在评价肿瘤放化疗疗效方面有其独特的优势，但目前并不能有效区别pCR及显微镜下微病灶残留，还需要结合其他检测方法共同评估。而18F-FDG PET-CT在预测pCR方面具有较好的敏感性。新辅助放化疗后，18F-FDG PET/CT检测为阴性的病人5年总存活率和无瘤存活率分别为91％和81％［13］，与临床报道pCR病人的存活率分别为83％和73％接近。这表明SUV最大值的大小及变化不仅可以作为放化疗反应的预测因子，也能对预后做出较好的判断。van Stiphout等［14］用肿瘤长度、放化疗前后肿瘤细胞对18F-FDG最大摄取值及其变化几项指标建立了一个预测局部进展期直肠癌放化疗后pCR的模型。取得了较好的准确度（AUC=0.86）。笔者医院的研究显示，在新辅助放化疗反应较好的一组病例中，18F-FDG PET/CT测量的肿瘤代谢体积（MV）及总病变糖酵解（TLG）在放化疗前后有更为显著的差别［15］，提示这些参数也可能作为疗效预测指标。
然而，对于放化疗后复查18F-FDG PET/CT的最佳时间点尚有待进一步研究。但总体而言，SUV最大值随着放化疗结束至手术间隔时间的增加而逐渐减小。此外，也需要注意肠道炎性改变对葡萄糖摄取的影响。包括放疗诱导的炎性反应和炎性肠病及偶然的肠道穿孔等。MRI与PET-CT两者结合将会对评价直肠癌放化疗后的疗效更有帮助，也是指导下一步治疗策略的关键所在。
3.3 病理学疗效评价 目前，新辅助放化疗后病人的病理学评价仍基于TNM分期。但第7版美国癌症联合委员会（AJCC）肿瘤分期系统和美国病理学家协会（CAP）［16］及NCCN指南同时也要求，病理学检查报告应该包括对新辅助治疗疗效进行评估的内容并对治疗反应进行分级计分，即TRG评分，分别为0分（完全反应，即未发现活的肿瘤细胞）、1分（中度反应，即单个或小簇癌细胞残留）、2分（轻度反应，即残留癌灶，间质纤维化）和3分（反应不良，即少数或无肿瘤细胞消退，大量癌残留）。既往采用的TRG评分标准包括Mandard标准［17］和Dworak标准［18］等均为5个等级，但新的简化标准与之相比，对病人的预后价值相似。并在不同病理医师间有更好的可重复性［19］。
3.4 相关生物学指标 包括传统的癌胚抗原（CEA）等肿瘤指标以及近来研究增多的液态活检、CTC、循环肿瘤DNA等。其中报道较多的为循环肿瘤DNA。ctDNA与肿瘤负荷的相关［20］，根据实体瘤的疗效评价标准（RECIST标准），肿瘤越大，ctDNA越高，但CEA在这一点上的相关性比较差。2014年文献［21］报道206例Ⅳ期结直肠癌中，ctDNA越高，生存预后越差。2016年ESMO会议中一项报道，根据ctDNA浓度分组（＜0.1μg/L， 0.1~10 μg/L和＞10 μg/L），结果表明，ctDNA浓度化疗后下降至0.1 μg/L以下的病人在PFS及OS上均预后最佳，而ctDNA浓度上升的一组病人预后最差。根据化疗前后ctDNA下降的程度（差值）进行分组，结果发现，ctDNA下降比例大的病人在PFS和OS上均明显优于ctDNA下降不明显的病人。因此，ctDNA的变化可作为化疗疗效的预测指标ctDNA浓度越高，预后越差。来自澳大利亚的一项研究表明，对于Ⅱ期结肠癌，作为辅助化疗的指征，ctDNA或许比临床高危因素更有意义［22］。探索较多，但目前尚未有可达共识的指标。
综上所述，直肠癌新辅助放化疗虽然建立了其规范模式，但病例选择仍有待进一步细分，尤其对于T3期的病人。影像学和病理学是评估新辅助放化疗后近期疗效的主要手段，在目前精准医学的背景下，如何将分子分型与治疗相结合，功能影像，分子标记物等信息应用到指导评价治疗模式优化中也越来越受到关注。对于新辅助放化疗后真正获得完全缓解的病人，其下一步治疗值得更多研究进行关注。
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