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The Chinese Guidelines for the Diagnosis and Treatment of Pancreatic Neuroendocrine Neoplasms (2020)
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摘要: 胰腺神经内分泌肿瘤具有高度异质性，患者的临床管理存在一定难度。为了应对这一挑战，中华医学会外科学分会胰腺外科学组牵头成立了由肿瘤外科、消化内科、肿瘤内科、内分泌科、影像科、病理科、核医学科等多领域学者组成的专家委员会。该委员会回顾了与胰腺神经内分泌肿瘤诊断和治疗相关的重要问题，并基于循证医学证据提出了相应的诊疗建议，以期进一步改进中国胰腺神经内分泌肿瘤患者的诊疗流程。Abstract: Pancreatic neuroendocrine neoplasms (pNENs) are highly heterogeneous, and the management of pNENs patients can be intractable. To address this challenge, an expert committee was established on behalf of the Chinese Pancreatic Surgery Association, Chinese Society of Surgery, Chinese Medical Association, which consisted of surgical oncologists, gastroenterologists, medical oncologists, endocrinologists, radiologists, pathologists, and nuclear medicine specialists. By reviewing the important issues regarding the diagnosis and treatment of pNENs, the committee concluded evidence-based statements and recommendations in this article, in order to further improve the management of pNENs patients in China.
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Keywords:
- pancreatic neoplasms /
- guidelines /
- diagnosis /
- therapy
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肺癌的发病率和死亡率居恶性肿瘤首位，由于早期无明显症状，多数患者确诊时已处于中晚期，失去了最佳治疗时机，5年总生存率仅为19.7%[1]。近年来，随着手术方式的改进，术后放化疗、靶向治疗、免疫治疗[2]等快速发展，肺癌患者的生存期及生活质量有望得到进一步改善。但放化疗在杀灭肿瘤细胞的同时，对机体正常组织也会造成损伤，如化疗药物导致的药物性肺损伤(drug induced lung injury, DILI)[3]及放疗导致的放射性肺损伤(radiation induced lung injury, RILI)[4]是肺癌患者术后辅助治疗的常见并发症，如不及时诊断与治疗，可发展为肺间质纤维化，严重者可因呼吸衰竭而死亡。
涎液化糖链抗原-6(kreb von den lungen-6, KL-6)是分子量约为200 kD的大分子量黏液糖蛋白，生理状态下主要表达于Ⅱ型肺泡上皮细胞、细支气管上皮细胞，具有促进肺纤维细胞存活、迁移和增殖的作用，有望成为特发性肺纤维化(idiopathic pulmonary fibrosis, IPF)的药物治疗靶点[5-6]。与目前应用的肺损伤诊断、病情监测工具如高分辨率计算机断层扫描(high resolution computed tomography, HRCT)、支气管镜检查、肺活检、连续肺功能测试等相比，血清KL-6检测具有创伤小、费用低、结果准确、可重复检测等优点。目前血清KL-6在肺癌辅助治疗性肺损伤中的研究主要集中于日本人群，已有文献报道血清KL-6的表达存在种族差异[7]。本研究以206例原发性非小细胞肺癌(non-small cell lung cancer, NSCLC)患者为研究对象，旨在探讨血清KL-6在中国人群NSCLC患者术后辅助治疗性肺损伤中的诊断价值。
1. 资料与方法
1.1 研究对象与分组
1.1.1 研究对象
本研究为回顾性分析，以NSCLC患者(包括术后采用辅助治疗者和仅手术者)及健康成人为研究对象。NSCLC术后辅助治疗、NSCLC手术患者分别来自2017年11月—2020年7月中国医科大学附属盛京医院肿瘤科和胸外科，健康成人来自同期中国医科大学附属盛京医院体检中心(健康对照组)。
辅助治疗性肺损伤诊断标准如下。DILI诊断标准[8]：(1)有致肺损伤药物摄入史；(2)有药物致肺损伤的临床表现，且可排除其他原因；(3)影像学证实肺部有间质性肺损伤改变；(4)停止化疗后患者临床表现得到改善。RILI诊断标准[4]：(1)有肺部放疗史；(2)肺部有相应的影像学改变，其中1级RILI仅有影像学改变，≥2级伴有咳嗽、气短、发热等临床症状；(3)排除其他原因导致的肺损伤。遵循上述诊断标准，由两名肺部肿瘤高年资医生、一名呼吸放射高年资医生共同完成DILI、RILI的诊断。
NSCLC患者纳入标准：(1)NSCLC的诊断标准符合《中国临床肿瘤学会(CSCO)原发性肺癌诊疗指南2019》[9]，且经术后组织病理活检证实；(2) TNM分期为Ⅱ~Ⅲ期；(3)术后辅助治疗患者耐受性较好，可接受化疗、放疗，具体治疗方法符合指南规定[9]；(4)行肺癌切除术患者手术方式包括胸腔镜解剖性肺切除联合肺门纵隔淋巴结清扫术、机器人辅助解剖性肺切除联合肺门纵隔淋巴结清扫术。排除标准：(1)合并精神疾病或认知功能低下，无法配合治疗者；(2)除NSCLC外，合并其他恶性肿瘤、重要器官功能障碍、全身感染患者。
健康对照组纳入标准：(1)表观正常，自觉无身体不适；(2)年龄、性别与NSCLC术后辅助治疗患者匹配；(3)肺部HRCT结果正常，无呼吸系统疾病。排除标准：存在精神疾病、认知功能障碍、结缔组织病、恶性肿瘤及各系统重大疾病者。
1.1.2 肺癌患者筛选流程
NSCLC术后辅助治疗组患者血清标本来自检验科与肿瘤科共同建立的肺癌术后辅助治疗患者血清标本库；首先从该库中筛选肺损伤患者(肺损伤组)，随机选取与肺损伤组患者性别、肺癌分型、TNM分期及术后辅助治疗方式无统计学差异，且年龄相近的无肺损伤患者为无肺损伤组。然后随机选取性别、肺癌分型、TNM分期与肺损伤组、无肺损伤组患者无统计学差异，且均在术前、术后7~10 d采集静脉血的仅手术患者为NSCLC手术组。
本研究已通过中国医科大学附属盛京医院伦理审查委员会审批(审批号：2018PS018J)。
1.2 研究方法
1.2.1 标本采集时间及血清KL-6检测
肺损伤组于肺损伤确诊当日，无肺损伤组于辅助治疗第3~4个月，NSCLC手术组于术前与术后7~10 d，健康对照组于体检当日，采集空腹静脉血3.0 mL，3500 g离心10 min，分离血清于-70 ℃冷冻保存。采用贝克曼库尔特AU5800全自动生化分析仪集中进行血清KL-6检测。试剂盒由日本积水医疗株式会社生产，购于积水医疗科技(中国)有限公司。检测方法为胶乳凝集法。根据试剂盒说明书，正常健康成人血清KL-6的参考区间为105.3~401.2 kU/L。
1.2.2 样本量估算及偏倚控制
本研究根据两独立样本均值比较的样本量计算公式：n1=n2=2[(uα+uβ)/(δ/σ)]2+1/4uα2，其中δ为两总体KL-6均数的差值；σ为总体标准差，双侧检验，检验水准α=0.05，β=0.10，uα=1.96，uβ=1.28。肺损伤组、无肺损伤组总体KL-6均值分别约为628.02、171.62 kU/L，δ=456.40，σ=362.87，δ/σ=1.3，经计算肺损伤组和无肺损伤组所需样本量均约为14例。NSCLC手术组、健康对照组总体KL-6均值分别约为249.69、189.79 kU/L，δ=59.90，σ=102.25，δ/σ=0.6，经计算NSCLC手术组和健康对照组所需样本量均约为60例。
偏倚控制：(1)血清KL-6检测试剂盒均购自同一公司，使用固定的仪器按照标准操作流程进行检测；(2)血清KL-6检测人员均经统一培训。
1.3 统计学处理
采用SPSS 26.0软件进行统计分析。采用Kolmogorov-Smirnov检验及Q-Q图对计量资料进行正态性检验。符合正态分布的计量资料(年龄)以均数±标准差表示，组间比较采用单因素方差分析；不服从正态分布的计量资料(血清KL-6)以中位数(四分位数)表示，组间比较采用Kruskal-Wallis检验或Mann-Whitney U检验。计数资料以频数(百分数)表示，组间比较采用χ2检验。采用受试者工作特征(receiver operating characteristic，ROC)曲线评估血清KL-6诊断NSCLC术后辅助治疗性肺损伤的效能。以P＜0.05为差异具有统计学意义。
2. 结果
2.1 一般临床资料
共206例NSCLC患者及103例健康对照者纳入本研究。其中肺损伤组51例、无肺损伤组52例(图 1)，NSCLC手术组103例。肺损伤组临床表现为咳嗽23例(45.10%)、呼吸困难21例(41.18%)、发热11例(21.57%)、无症状3例(5.88%)。无肺损伤组无症状51例(98.08%)，呼吸困难1例(1.92%)。4组性别(P=0.926)、合并结缔组织病(P=0.166)无统计学差异，年龄(P＜0.001)、合并慢性阻塞性肺疾病(P=0.037)存在统计学差异；肺损伤组、无肺损伤组、NSCLC手术组病理类型(P=0.634)、TNM分期(P=0.756)无统计学差异；肺损伤组、无肺损伤组辅助治疗方式(P=0.780)无统计学差异，见表 1。
表 1 患者一般资料比较指标 肺损伤组(n=51) 无肺损伤组(n=52) NSCLC手术组(n=103) 健康对照组(n=103) P值 年龄(x±s, 岁) 58.51±7.14 53.06±8.70 59.26±7.08 54.61±8.90 ＜0.001 性别(男/女，n) 33/18 32/20 66/37 62/41 0.926 病理类型(腺癌/鳞癌，n) 43/8 40/12 82/21 - 0.634 TNM分期(Ⅱ/Ⅲ期，n) 23/28 27/25 48/55 - 0.756 术后辅助治疗方式(单纯放疗/同步放化疗，n) 18/33 17/35 - - 0.780 合并慢性阻塞性肺疾病[n(%)] 4(7.84) 1(1.92) 3(2.91) 0(0) 0.037 合并结缔组织病[n(%)] 1(1.96) 0(0) 0(0) 0(0) 0.166 NSCLC：同图 1；-：不适用 2.2 血清KL-6比较
单因素方差分析显示，血清KL-6在各组间差异有统计学意义(P＜0.001)。进一步组间比较显示，血清KL-6由高至低依次为肺损伤组[512.40(322.30，819.20)kU/L]、NSCLC手术组(术前)[204.40(162.70，283.20)kU/L]、健康对照组[177.70(154.20，206.40)kU/L]、无肺损伤组[147.80(114.25，229.80)kU/L]和NSCLC手术组(术后)[143.80(111.90，247.80)kU/L]。除无肺损伤组与NSCLC手术组(术后)血清KL-6无统计学差异(P=0.879)外，其余两两比较差异均有统计学意义(P均＜0.05)，见图 2。
2.3 NSCLC术后辅助治疗性肺损伤诊断界值的初步建立
ROC曲线分析显示，以无肺损伤组患者为对照，血清KL-6诊断NSCLC术后辅助治疗性肺损伤的曲线下面积(area under the curve，AUC)为0.972(95% CI：0.948~0.997)，灵敏度、特异度、阳性似然比、阴性似然比分别为86.3%(95% CI：73.0%~94.1%)、96.2%(95% CI：86.2%~98.7%)、22.43(95% CI：5.74~87.69)、0.14(95% CI：0.07~0.28)，最佳诊断临界值为310.15 kU/L(图 3)。
3. 讨论
本研究对NSCLC手术患者、NSCLC术后辅助治疗患者及健康成人的血清KL-6进行了比较，发现NSCLC术后辅助治疗性肺损伤患者的血清KL-6显著高于辅助治疗后无肺损伤的患者、NSCLC手术患者及健康对照人群。ROC曲线分析显示，血清KL-6诊断NSCLC术后辅助治疗性肺损伤的AUC为0.972(95% CI：0.948~0.997)，灵敏度、特异度、阳性似然比、阴性似然比分别为86.3%(95% CI：73.0%~94.1%)、96.2%(95% CI：86.2%~98.7%)、22.43(95% CI：5.74~87.69)、0.14(95% CI：0.07~0.28)，最佳诊断临界值为310.15 kU/L。
肺癌患者术后辅助治疗性肺损伤包括由化疗引起的DILI及由放疗导致的RILI，均属于间质性肺疾病(interstitial lung disease, ILD)，主要累及肺泡壁，表现为Ⅰ型肺泡上皮细胞受损脱落，Ⅱ型肺泡上皮细胞异常增生。影像学检查可见弥漫性浸润阴影，肺活检病理示弥漫性肺实质、肺泡炎症和间质纤维化[10]。肺损伤患者的肺功能进行性降低，不仅严重影响生活质量，且患者可因呼吸衰竭而死亡，极大程度缩短了生存期。因此，早期发现并及时治疗对提高患者的生活质量、延长生存时间至关重要。目前，临床尚缺乏间质性肺损伤诊断的血清学标志物，HRCT是DILI、RILI诊断及病情监测的常用手段，但部分疾病如结核分枝杆菌感染、肺癌等，肺部HRCT表现与DILI、RILI影像学改变类似，单纯依据HRCT易误诊；另一方面，HRCT具有辐射性，不适于NSCLC患者短期内病情的连续监测。因此，探究来源于Ⅱ型肺泡上皮细胞的血清生物标志物在NSCLC患者术后辅助治疗性肺损伤诊断中的应用价值具有重要作用。KL-6是一种主要在Ⅱ型肺泡上皮细胞和细支气管上皮细胞中表达的高分子量黏液糖蛋白，DILI、RILI时肺泡基底膜受损，Ⅱ型肺泡上皮细胞为修复损伤而增生，导致KL-6生成增多并通过受损的基底膜进入血液。因此，血清KL-6作为间质性肺损伤的特异性标志物，在各种以Ⅱ型肺泡上皮细胞增生为特征的ILD如IPF、胶原血管病相关间质性肺炎、超敏性肺炎、急性呼吸窘迫综合征、肺结节[7]及严重急性呼吸综合征所致肺损伤[11-13]的诊断、病情严重程度评估及治疗效果监测中具有重要价值。另有研究报道，血清KL-6是预测依维莫司致肺损伤的生物标志物[3]，亦可准确预测放射性肺炎的发生及评估治疗疗效[14-15]。对于RILI、DILI，既往研究认为血清KL-6是可靠的血清生物标志物之一，但其研究对象主要为日本人群[7]，目前缺乏KL-6在中国人群NSCLC术后辅助治疗性肺损伤诊断价值的相关研究。
本研究结果显示，肺损伤组血清KL-6升高最为显著，且与其他组比较均有统计学差异，提示血清KL-6在NSCLC术后辅助治疗性肺损伤中具有诊断价值；进一步以无肺损伤组为疾病对照组，通过ROC曲线评估其诊断辅助治疗性肺损伤的临床价值，结果显示血清KL-6诊断NSCLC术后辅助治疗性肺损伤的AUC达0.972，且灵敏度和特异度均较高，提示其具有较高的诊断效能，与既往报道的血清KL-6诊断ILD的灵敏度约为70%~100%相符[7]。
本研究ROC曲线分析显示，血清KL-6诊断NSCLC术后辅助治疗性肺损伤的最佳诊断临界值为310.15 kU/L，该诊断临界值在本研究所使用试剂盒说明书提供的正常参考区间范围内。既往文献报道，血清KL-6表达水平存在种族差异[7]。本研究所使用的血清KL-6检测试剂盒说明书提供的参考区间来源于日本人群，是否适用于中国人群尚未可知。为减少偏倚、使结果更客观，本研究团队基于纳入的健康对照人群数据，初步建立中国东北地区50岁以上健康成人的血清KL-6参考区间为112.90 ~311.52 kU/L，其上限值显著低于试剂盒说明书提供的参考区间上限值，且与本研究确定的最佳诊断临界值310.15 kU/L基本一致。
有文献报道，KL-6在肺癌细胞中高度表达，其在肺癌患者中的阳性率约为30%~70%[5, 16-19]。本研究NSCLC手术组(术前)血清KL-6水平高于健康对照组，与KL-6在肺癌中的高表达有关；生理情况下，Ⅱ型肺泡上皮细胞、细支气管上皮细胞是KL-6的主要产生部位，NSCLC手术组(术后)与NSCLC术后辅助治疗无肺损伤组患者的血清KL-6水平显著低于健康对照组，可能与其肺叶切除有关。
研究的局限性：(1)本研究为单中心、单因素回顾性研究，入选病例均为TNM分期Ⅱ~Ⅲ期的NSCLC患者，需扩大肺癌人群进一步探讨。(2)肺损伤患者的HRCT表现较一致，严重肺纤维化的患者较少，无法探究血清KL-6与肺损伤严重程度的关系。(3)文献报道显示，ILD发病后患者血清KL-6水平与基线(治疗开始)的比值可预测表皮生长因子受体酪氨酸激酶抑制剂治疗的晚期NSCLC患者预后[20]。本研究未对患者进行动态监测，无法判断血清KL-6在NSCLC术后辅助治疗性肺损伤患者预后预测中的作用。
综上，NSCLC术后辅助治疗性肺损伤患者血清KL-6显著升高，其在NSCLC术后辅助治疗性肺损伤诊断中具有较高的应用价值，但仍需大样本前瞻性研究进一步验证。
志谢: “中国医学科学院医学与健康科技创新工程(2017-I2M-1-001)”对会议提供支持；北京协和医院基本外科王先泽医师对指南中参考文献的收集、更新、整理和整合工作，以及对指南历次共识会议的组织协调工作。作者贡献：赵玉沛院士领导了指南更新项目、组织了指南编辑委员会(编委会)并任命吴文铭教授和陈洁教授全权负责编委会对指南的撰写工作。吴文铭教授和陈洁教授共同起草了指南初稿，并组织编委会其他成员依照指南编写流程对指南初稿进行审校；在吴文铭教授和陈洁教授的主持和参与下，白春梅教授、依荷芭丽·迟教授、杜奕奇教授、冯仕庭教授、霍力教授、姜玉新教授、李景南教授、楼文晖教授、罗杰教授、邵成浩教授、沈琳教授、王峰教授、王理伟教授、王鸥教授、王于教授、吴焕文教授、邢小平教授、徐建明教授、薛华丹教授、薛玲教授、杨扬教授、虞先濬教授、原春辉教授、赵宏教授、朱雄增教授共同参加了三轮指南修订会议，并根据各自专业对指南的相应章节进行了修订；吴文铭教授、陈洁教授、白春梅教授、霍力教授、姜玉新教授、邢小平教授、薛华丹教授、薛玲教授作为各自章节的负责人，参加或委派代表参加了指南定稿会并对指南终稿内容进行确认；吴文铭教授和陈洁教授对指南终稿全文进行了最终审校后，所有作者均通过了指南终稿并形成指南定稿，同时签署了作者贡献声明及版权转让协议。利益冲突：无吴文铭、陈洁对本文同等贡献 -
表 1 2019年世界卫生组织第5版胃肠胰神经内分泌肿瘤病理学分类和分级标准
命名 分化程度 分级 核分裂象数a(/2 mm2) Ki-67指数(%)a 神经内分泌瘤，G1级 高分化 低 ＜2 ＜3 神经内分泌瘤，G2级 高分化 中 2~20 3~20 神经内分泌瘤，G3级b 高分化 高 ＞20 ＞20 神经内分泌癌，小细胞型 低分化c 高c ＞20 ＞20 神经内分泌癌，大细胞型 低分化c 高c ＞20 ＞20 混合性神经内分泌-非神经内分泌肿瘤 高或低分化 多样的d 多样的d 多样的d a核分裂象数表示为核分裂象计数/2 mm2(该面积等于40倍放大倍数及每个视野最大径0.5 mm情况下的10个高倍镜视野)，计数50个0.2 mm2的视野；Ki-67增殖指数通过计数高染色区域(即热点区)至少500个细胞获得；最终分级采用两种增殖指数所对应分级中的较高者；bG3级神经内分泌瘤的核分裂数和Ki-67指数未设上限，其理由是G3级神经内分泌瘤(尤其G3级胰腺神经内分泌瘤)的Ki-67指数偶可高达70%~80%，故不能仅根据Ki-67指数的高低进行分级，还需结合其形态学分化良好的特点；对难以区分的G3级神经内分泌瘤和神经内分泌癌，需进行TP53、RB1、ATRX和DAXX染色协助鉴别诊断；c神经内分泌癌根据定义为高级别，无需再分级；d在大部分混合性神经内分泌-非神经内分泌肿瘤中，神经内分泌肿瘤和非神经内分泌肿瘤成分均为低分化，且神经内分泌肿瘤成分的增殖指数与其他神经内分泌癌一致，但该类型肿瘤亦允许这两种成分均为高分化，这种情况下，应分别对两种成分进行分级；胰腺的混合性神经内分泌-非神经内分泌肿瘤包括4个亚型：混合性导管癌-神经内分泌癌(小细胞或大细胞)、混合性导管癌-神经内分泌瘤、混合性腺泡细胞癌-神经内分泌癌和混合性腺泡细胞癌-导管癌-神经内分泌癌 
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表 2 2017年AJCC第8版胰腺神经内分泌肿瘤的TNM分期标准
分期 特征 分期 特征 T分期 原发肿瘤a M分期 远处转移 TX 原发肿瘤无法评价 M0 无远处转移 T1 局限于胰腺内b，且最大径＜2 cm M1 有远处转移 T2 局限于胰腺内b，且最大径2~4 cm M1a 仅存在肝脏转移 T3 局限于胰腺内b，且最大径＞4 cm；或侵犯十二指肠或胆管 M1b 仅存在至少一个肝脏外器官转移(如肺、卵巢、非区域淋巴结、腹膜、骨) T4 侵犯邻近器官(如胃、脾、结肠、肾上腺)或大血管壁(腹腔干或肠系膜上动脉) M1c 同时存在肝脏和肝脏外器官转移 N分期 区域淋巴结 NX 区域淋巴结无法评价 N0 无区域淋巴结转移 N1 有区域淋巴结转移 AJCC：美国癌症联合委员会；a若原发肿瘤为多发，则以最大的肿瘤进行T分期；若多发肿瘤数量已知，则记为T(#)，如pT3(4)N0M0；若多发肿瘤数量未知或难以计数，则记为T(m)，如pT3(m) N0 M0；b“局限于胰腺内”定义为无邻近器官(如胃、脾、结肠、肾上腺)或大血管壁(如腹腔干或肠系膜上动脉)侵犯，肿瘤对胰周脂肪的侵犯不作为分期依据
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表 3 2017年AJCC第8版综合分期标准
分期 T分期 N分期 M分期 Ⅰ期 T1 N0 M0 Ⅱ期 T2 N0 M0 T3 N0 M0 Ⅲ期 T4 N0 M0 任何T N1 M0 Ⅳ期 任何T 任何N M1 AJCC：同表 2
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类型 年发病率(/106) 分泌激素 常见部位 恶性比率(%) 主要症状 功能性pNEN 胰岛素瘤 1~32 胰岛素 胰腺 5~10 低血糖 胃泌素瘤 0.5~21.5 胃泌素 十二指肠、胰腺 50~60 腹泻、腹痛、反酸 胰高血糖素瘤 0.01~0.1 胰高血糖素 胰腺 50~80 坏死游走性红斑、贫血、葡萄糖不耐受、体质量下降 生长抑素瘤 少见 生长抑素 胰腺、十二指肠、空肠 50~60 糖尿病、胆石症、腹泻 产生ACTH的神经内分泌瘤 少见 ACTH 胰腺 ＞90 库欣综合征 血管活性肠肽瘤 0.05~0.2 血管活性肠肽 胰腺 40~80 水样泻、低钾血症 无功能性pNEN 可能有激素水平的升高但未引起相关临床症状 胰腺 60~90 无特异性症状，常为肿瘤压迫、侵袭、转移引起的相关症状，如消化道梗阻、出血、腹痛、黄疸等 pNEN：胰腺神经内分泌肿瘤；ACTH：促肾上腺皮质激素
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附表 1 本指南使用的指南证据特征分类
类别 水平 来源 专家共识度 1A 高 严谨的Meta分析、大型随机对照临床研究 一致共识 1B 高 严谨的Meta分析、大型随机对照临床研究 基本一致共识，但争议小 2A 稍低 一般质量的Meta分析、小型随机对照研究、设计良好的大型回顾性研究、病例对照研究 一致共识 2B 稍低 一般质量的Meta分析、小型随机对照研究、设计良好的大型回顾性研究、病例对照研究 基本一致共识，但争议小 3 低 非对照的单臂临床研究、病例报告、专家观点 无共识，且争议大
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附表 2 本指南使用的指南证据等级分类
推荐等级 标准 Ⅰ级推荐 一般情况下，将1A类证据和部分专家共识度高且在中国可及性好的2A类证据作为Ⅰ级推荐。具体来说，Ⅰ级推荐具有如下特征：可及性好的普适性诊治措施(包括适应证明确)，肿瘤治疗价值相对稳定，基本为国家医保所收录；Ⅰ级推荐的确定，不因商业医疗保险而改变，主要考虑的因素是患者的明确获益性 Ⅱ级推荐 一般情况下，将1B类证据和部分专家共识度稍低或在中国可及性不太好的2A类证据作为Ⅱ级推荐。具体来说，Ⅱ级推荐具有如下特征：在国际或国内已有随机对照的多中心研究提供的高级别证据，但是可及性差或者效价比低，已超出平民经济承受能力的药物或治疗措施；对于获益明显但价格昂贵的措施，以肿瘤治疗价值为主要考虑因素，也可以作为Ⅱ级推荐 Ⅲ级推荐 对于正在探索的诊治手段，虽然缺乏强有力的循证医学证据，但是专家组具有一致共识的，可以作为Ⅲ级推荐供医疗人员参考 不推荐或反对 对于已有充分证据证明不能使患者获益的，甚至导致患者伤害的药物或者医疗技术，专家组具有一致共识的，应写明“专家不推荐”或者必要时“反对”。可以是任何类别等级的证据
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