张品良

吉非替尼加白介素2治疗既往化疗过的晚期非小细胞肺癌患者。已有研究证明通过吉非替尼治疗可活化淋巴细胞。在这个Ⅱ期预试验中，作者探索IL-2和吉非替尼在非小细胞肺癌(NSCLC)治疗时潜在的协同作用。从2003年9月到2006年11月，70连续收治的既往化疗过的晚期、渐进性NSCLC患者，接受了吉非替尼口服250mg qd。山东省肿瘤医院呼吸肿瘤内科张品良最初39例患者仅仅接受吉非替尼(G组)。另外31例还接受了皮下注射IL-2(GIL-2组)：1MIU/㎡(百万国际单位/㎡)第1、2天每天两次、每周第3、4、5天每天一次连续用4周休息4周。中位随访时间25.2个月。吉非替尼的Ⅲ-Ⅳ度毒性表现为皮疹(7%)、乏力/厌食(6%)和腹泻(7%)；接受IL-2治疗的患者2-3度发热(46%)、疲乏(21%)和关节痛(13%)。在GIL-2组和G-组中，我们分别观察到：总有效率16.1%(6.4%完全缓解)和5.1%(只有部分缓解)；疾病控制率41.9%和41%；中位至进展时间3.5(CI 95%=3.2-3.8)和4.1(CI 95%=2.6-5.7)个月；中位总生存期20.1(CI 95%=5.1-35.1)和6.9(CI 95%=4.9-8.9)个月(p =0.002)；1年精算生存率54%和30%。皮肤毒性(p<0.001；HR =0.29；CI 95%=0.16-0.54)和应用IL-2(p<0.001；HR =0.33；CI 95%=0.18-0.60)与生存改善独立相关。在这个序贯、非随机化晚期非小细胞肺癌患者群中，应用IL-2增强了吉非替尼的疗效。Bersanelli M, Buti S, Camisa R, et al. Gefitinib plus interleukin-2 in advanced non-small cell lung cancer patients previously treated with chemotherapy. Cancers (Basel). 2014. 6(4): 2035-48.

Discussion讨论Treatment Approaches治疗手段Targeted Therapies 靶向治疗Ceritinib 色瑞替尼Ceritinib is approved by the FDA for patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib. The approval is based on an expanded phase 1 study (ASCEND-1) showing overall response rates of 56% to ceritinib in patients (92/163) who had previously received crizotinib; the median duration of response was 8.3 months (6.8-9.7). Common grade 3 to 4 adverse events included increased alanine aminotransferase (73 [30%] patients) and increased aspartate aminotransferase (25 [10%]). Some patients with CNS lesions responded to ceritinib. Based on the study and the FDA approval, the NCCN Panel recommends ceritinib as subsequent therapy for patients with ALK-positive NSCLC who have progressed after crizotinib; patients who do not tolerant crizotinib may be switched to ceritinib or alectinib. A recent phase 2 trial (ASCEND-2) assessed ceritinib in patients who had previously received at least 2 or more treatments, had progressed on crizotinib, and had brain metastases. The overall response rate was 38%; the duration of response was 9.7 months (95% CI, 7.1–11.1 months). The intracranial overall response rate was 45.0% (95% CI, 23.1%–68.5%). FDA批准了色瑞替尼用于克唑替尼进展或不能耐受、ALK阳性的转移性NSCLC患者。批准是根据一项扩展的1期研究（ASCEND-1）显示，在既往已接受克唑替尼治疗的患者中，色瑞替尼治疗的总有效率为56%（92/163）；中位疗效持续时间是8.3个月（6.8-9.7）。常见的3-4级不良事件包括丙氨酸氨基转移酶升高（73例[30%]）及天冬氨酸转氨酶升高（25例[10%]）。某些具有CNS病变的患者对色瑞替尼应答。基于该研究和FDA的批准，研究小组建议色瑞替尼作为ALK阳性的NSCLC患者在克唑替尼进展后的后续治疗；不耐受克唑替尼的患者可以转换至色瑞替尼或阿雷替尼。最近一项2期试验（ASCEND-2）评估了色瑞替尼治疗既往曾接受过至少2个或以上治疗、克唑替尼进展并有脑转移的患者。总有效率是38%；疗效持续时间是9.7个月（95%CI，7.1-11.1个月）。颅内病变总有效率为45.0%（95%CI，23.1%-68.5%）。山东省肿瘤医院呼吸肿瘤内科张品良A recent phase 3 trial assessed ceritinib versus platinum-based chemotherapy as first-line therapy for patients with ALK-positive metastatic NSCLC. The data show that PFS was improved when using ceritinib when compared with platinum-based chemotherapy; the median PFS was 16.6 months (95% CI, 12.6–27.2) for ceritinib and 8.1 months (CI, 5.8–11.1) for chemotherapy (hazard ratio 0.55 [95% CI, 0.42–0.73]; P<.00001). For ceritinib, common adverse events included diarrhea (85% [160/189] of patients), nausea (69% [130/189]), vomiting (66% [125/189), and an increase in alanine aminotransferase (60% [114/189]). For chemotherapy, common adverse events included nausea (55% [97/175 patients], vomiting (36% [63/175]), and anemia (35% [62/175]). For the 2017 update (Version 5), the NCCN Panel now recommends (category 1) ceritinib as first-line therapy for patients with ALK-positive metastatic NSCLC based on this phase 3 trial. 最近一项3期试验评估了色瑞替尼与以铂为基础的化疗作为ALK-阳性转移性非小细胞肺癌患者的一线治疗。数据显示，与以铂为基础的化疗相比，使用色瑞替尼延长无进展生存期；中位无进展生存期色瑞替尼是16.6个月（95%CI，12.6-27.2），化疗是8.1个月（CI，5.8-11.1）（风险比为0.55[95% CI，0.42-0.73]；P<0.00001）。色瑞替尼常见的不良反应包括腹泻（85% [160/189]）、恶心（69%[130/189]）、呕吐（66%[125/189）和丙氨酸氨基转移酶升高（60%[114/189]）。化疗常见的不良反应包括恶心（55%[97/175]）、呕吐（36%[63/175]）和贫血（35%[62/175]）。根据该3期试验，2017第5版更新，NCCN小组目前推荐（1类）色瑞替尼作为ALK阳性转移性非小细胞肺癌患者的一线治疗。

EMERGING TARGETED AGENTS FOR PATIENTS WITH GENETIC ALTERATIONS具有遗传学改变患者的新兴靶向药物山东省肿瘤医院呼吸肿瘤内科张品良

OverviewThe American Cancer Society estimates that 234,190 Americans will be diagnosed with invasive breast cancer and 40,730 will die of the disease in the United States in 2015. Breast cancer is the most frequently diagnosed cancer globally and is the leading cause of cancer-related death in women.山东省肿瘤医院呼吸肿瘤内科张品良The lifetime risk for breast cancer for women in the United States has increased from 1 in 11 in the 1970s to 1 in 8 today, a change related to shifting breast cancer risk factor demographics and the increased use of screening mammography.Breast cancer incidence peaked around 2000 then decreased to current rates with some variation among racial and socioeconomic groups.Between 2006 and 2010, breast cancer incidence increased slightly among African American women, decreased among Hispanic women, and was stable among whites, Asian Americans/Pacific Islanders, and American Indians/Alaska Natives.Historically, white women have had the highest breast cancer incidence rates among women aged 40 years and older; however, incidence rates are converging among white and African American women, particularly among women aged 50 years to 59 years.Since 1991, breast cancer mortality has been declining suggesting a benefit from the combination of early detection and more effective treatment.The etiology of the vast majority of breast cancer cases is unknown.However, numerous risk factors for the disease have been established.These risk factors include: female gender; increasing patient age; family history of breast cancer at a young age; early menarche; late menopause; older age at first live childbirth; prolonged hormone replacement therapy; previous exposure to therapeutic chest wall irradiation; benign proliferative breast disease; increased mammographic breast density; and genetic mutations such as of the BRCA1/2 genes.However, except for female gender and increasing patient age, these risk factors are associated with only a minority of breast cancers.Women with a strong family history of breast cancer should be evaluated according to the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian.Women at increased risk for breast cancer (generally those with ≥1.7% 5-year risk for breast cancer using the Gail model of risk assessment) may consider risk reduction strategies (see NCCN Guidelines for Breast Cancer Risk Reduction).Proliferative abnormalities of the breast are limited to the lobular and ductal epithelium.In both the lobular and ductal epithelium, a spectrum of proliferative abnormalities may be seen, including hyperplasia, atypical hyperplasia, in situ carcinoma, and invasive carcinoma.Approximately 85% to 90% of invasive carcinomas are ductal in origin.The invasive ductal carcinomas include unusual variants of breast cancer, such as mucinous, adenoid cystic, and tubular carcinomas, which have especially favorable natural histories.讨论概述美国癌症协会估计在2015年美国将有234190例美国人被诊断为侵袭性乳腺癌且40730例将死于该疾病。乳腺癌是全球最常见的癌症并且是女性肿瘤相关死亡的主要原因。美国女性一生中患乳腺癌的风险从上个世纪七十年代的1/11升高至现在的1/8，这一变化与乳腺癌危险因素人口资料改变和筛查乳腺摄影的应用增加有关。乳腺癌发病率大约在2000年达到高峰然后降低至当前的发病率，在不同种族与社会经济群体当中具有一些差异。在2006年与2010年间，乳腺癌发病率在非洲裔美国女性当中略有升高，在西班牙女性当中降低，而在白种人、亚裔美国人/太平洋岛民以及美国印地安人/阿拉斯加当地人当中稳定。历史上，在40岁及以上女性当中白人女性乳腺癌发病率最高；但是，在白种人与非洲裔美国女性特别是年龄50至59岁女性当中发病率逐渐一致。自1991年以来，乳腺癌死亡率已经下滑提示从早期发现与更有效的治疗中受益。绝大多数乳腺癌病例的病因不明。但是，该疾病很多的危险因素已公认。这些危险因素包括：女性性别；患者年龄增加；在年轻时乳腺癌家族史；月经初潮早；绝经晚；初次分娩时年龄较大；长期的激素替代治疗；既往治疗性胸壁照射；乳腺良性增生性疾病；乳房摄影乳腺密度增加；以及诸如BRCA1/2基因遗传突变。但是，除了女性性别和患者年龄增加之外，这些危险因素只与少数乳腺癌有关。有明显乳腺癌家族史的女性应该按照遗传性/家族性高危性评估：乳腺与卵巢NCCN指南进行评估。在女性乳腺癌风险增加时(通常是那些利用Gail风险评估模型乳腺癌5年风险≥1.7%者)可以考虑降低风险的策略(见NCCN降低乳腺癌风险指南)。乳腺异常增生仅限于小叶和导管上皮。在小叶和导管上皮中都可能见到各种各样的增殖异常，包括增生、非典型增生、原位癌以及侵袭癌。大约85%至90%的浸润性癌是导管来源。浸润性导管癌包括罕见的乳腺癌变种，如粘液性癌、腺样囊性癌和管状癌，其具有特别有利的自然发展过程。

机械装置——癌症相关的静脉血栓栓塞症（NCCN 2014V2）间歇充气压力泵(IPC)IPC装置的主要优势之一是没有相关的出血风险。但是，缺点包括可能妨害走动并且需要保持该装置在适当位置差不多持续到患者完全不卧床为止。分级加压弹力袜(GCS)作为一个物理预防手段可联合使用IPC装置。山东省肿瘤医院呼吸肿瘤内科张品良腔静脉滤器腔静脉滤器适用于由于对治疗性抗凝绝对禁忌或抗凝并发症不能抗凝患者肺栓塞的预防。但是，下腔静脉滤器的放置不能预防深静脉血栓并且复发性深静脉血栓风险增加。一项随机对照试验评价了下腔静脉滤器联合抗凝比较单纯抗凝治疗在治疗急性静脉血栓栓塞中的疗效和安全性。但是，该关键性试验没有检验临床常见情况下、没有同期使用抗凝患者中应用下腔静脉滤器的疗效。还不清楚在没有骼-腘下肢下腔静脉或骨盆深静脉血栓的情况下放置下腔静脉滤器是否是有益的。下腔静脉滤器可用可回收的(“不是必需的”)或永久性滤器；然而，可回收滤器的回收时限是有限的。来自对702例放置下腔静脉滤器患者的一项回顾群组调查研究结果显示接受可回收滤器的患者只有15.5%试图取回滤过器，而且只有70%的尝试成功。在两种过滤方式之间没有观察到肺栓塞预防或发症发生率方面的显著差异，虽然平均随访时间只有有限的11.5个月。最近一项对接受Bard G2或回收型滤过器的病例系列研究指出在分别平均随访24和50个月后高达25%的受者滤过器撑杆断裂。仍不清楚是否该并发症的发生是装置特有的还是所有滤过器的一个特征。直到可获得更多的资料为止，该经验强调只有在收益超过风险的患者中放置滤过器的重要性，而且只要有可能挽救滤过器。

CHEMOTHERAPY REGIMENS FOR RECURRENT OR METASTATIC BREAST CANCERPreferred single agents:Anthracyclines●Doxorubicin●Pegylated liposomal doxorubicinTaxanes●Paclitaxel Anti-metabolites●Capecitabine●GemcitabineOther microtubule inhibitors山东省肿瘤医院呼吸肿瘤内科张品良●Vinorelbine●EribulinOther single agents:●Cyclophosphamide●Carboplatin●Docetaxel●Albumin-bound paclitaxel●Cisplatin●Epirubicin●IxabepiloneThere is no compelling evidence that combination regimens are superior to sequential single agents.Randomized clinical trials in metastatic breast cancer document that the addition of bevacizumab to some first- or second-line chemotherapy agents modestly improves time to progression and response rates but does not improve overall survival. The time-to- progression impact may vary among cytotoxic agents and appears greatest with bevacizumab in combination with weekly paclitaxel.复发或转移性乳腺癌化疗方案首选的单药：蒽环类抗生素●阿霉素●聚乙二醇脂质体阿霉素紫杉烷类●紫杉醇抗代谢药●卡培他滨●吉西他滨其它微管抑制剂●长春瑞滨●艾日布林其它的单药：●环磷酰胺●卡铂●多西他赛●白蛋白结合型紫杉醇●顺铂●表柔比星●伊沙匹隆联合方案优于单药序贯没有令人信服的证据。转移性乳腺癌随机临床试验证明贝伐单抗加入到某些一线或二线化疗药物适度改善至进展时间和有效率但没有改善总生存。在细胞毒药物之间至进展时间影响可能不同，贝伐单抗联合每周1次紫杉醇影响似乎最大。

NSCLC NCCN2016V4 PRINCIPLES OF DIAGNOSTIC EVALUATION 诊断评估原则* Patients with a strong clinical suspicion of stage I or II lung cancer (based on risk factors and radiologic appearance) do not require a biopsy before surgery.山东省肿瘤医院呼吸肿瘤内科张品良 *临床高度怀疑I或II期肺癌的患者（基于危险因素和影像学表现）不需要术前活检。△A biopsy adds time, costs, and procedural risk and may not be needed for treatment decisions. △活检增加时间、成本和诉讼风险，治疗决策可能不需要。△A preoperative biopsy may be appropriate if a non-lung cancer diagnosis is strongly suspected that can be diagnosed by core biopsy or fine-needle aspiration (FNA). △如果强烈怀疑非肺癌诊断，术前活检可能是恰当的，可经空芯针活检或细针穿刺（FNA）确诊。△A preoperative biopsy may be appropriate if an intraoperative diagnosis appears difficult or very risky. △如果术中诊断看上去好像困难或非常危险，术前活检可能是合理的。△If a preoperative tissue diagnosis has not been obtained, then an intraoperative diagnosis (ie, wedge resection, needle biopsy) is necessary before lobectomy, bilobectomy, or pneumonectomy. △如果尚未获得术前诊断，则在双肺叶或全肺切除术之前必须术中诊断（即楔形切除、针吸活检）。* Bronchoscopy should preferably be performed during the planned surgical resection, rather than as a separate procedure. *支气管镜检查最好是在计划的手术切除期间，而不是作为一个单独的措施。△Bronchoscopy is required before surgical resection (see NSCL-2). △术前要求支气管镜检查（见NSCL-2）。△A separate bronchoscopy may not be needed for treatment decisions before the time of surgery and adds time, costs, and procedural risk. △在手术过程之前可能不需要单独的支气管镜检查来确定治疗决策，因增加时间、费用和诉讼风险。△A preoperative bronchoscopy may be appropriate if a central tumor requires pre-resection evaluation for biopsy, surgical planning (eg, potential sleeve resection), or preoperative airway preparation (eg, coring out an obstructive lesion). △中心性肿瘤如果需要切除前评估，术前支气管镜对于活检、手术计划（如，袖状切除的可能性）或术前气道准备（如，阻塞性病变钻心复张）可能是合适的。* Invasive mediastinal staging is recommended before surgical resection for most patients with clinical stage I or II lung cancer (see NSCL-2). *对于大多数临床I或II期肺癌患者在手术切除前建议纵隔分期（见NSCL-2）。△Patients should preferably undergo invasive mediastinal staging as the initial step before the planned resection (during the same anesthetic procedure), rather than as a separate procedure. △在计划的切除术前患者最好接受侵袭性纵隔分期作为最初的步骤（在同一的麻醉过程中），而不是作为一个单独的措施。△A separate staging procedure adds time, costs, coordination of care, inconvenience, and an additional anesthetic risk. △单独的分期程序增加了时间、成本、护理协调、不便和额外的麻醉风险。△Preoperative invasive mediastinal staging may be appropriate for a strong clinical suspicion of N2 or N3 nodal disease or when intraoperative cytology or frozen section analysis is not available. △对于临床高度怀疑N2或N3淋巴结病变或无法获得术中细胞学或冰冻切片分析时，术前侵袭性纵隔分期可能是合理的。* In patients with suspected non-small cell lung cancer (NSCLC), many techniques are available for tissue diagnosis. *在可疑非小细胞肺癌（NSCLC）患者中，许多技术可用于组织学诊断。△Diagnostic tools that should be routinely available include: △可以获得的常规诊断工具应包括：→ Sputum cytology → 痰细胞学检查→ Bronchoscopy with biopsy and transbronchial needle aspiration (TBNA) → 支气管镜活检和经支气管针吸活检（TBNA）→ Image-guided transthoracic needle core biopsy (preferred) or FNA → 影像引导下经皮肺穿刺活检（首选）或细针穿刺活检→ Thoracentesis → 胸腔穿刺术→ Mediastinoscopy → 纵隔镜检查→ Video-assisted thoracic surgery (VATS) and open surgical biopsy → 电视胸腔镜手术（VATS）和开放手术活检△Diagnostic tools that provide important additional strategies for biopsy include: △可提供其他重要策略的活检诊断工具包括：→ Endobronchial ultrasound (EBUS)–guided biopsy → 支气管内超声（EBUS）引导下活检→ Endoscopic ultrasound (EUS)–guided biopsy → 内镜超声（EUS）引导下活检→ Navigational bronchoscopy → 导航支气管镜* The preferred diagnostic strategy for an individual patient depends on the size and location of the tumor, the presence of mediastinal or distant disease, patient characteristics (such as pulmonary pathology and/or other significant comorbidities), and local experience and expertise. *个体患者首选的诊断策略取决于肿瘤的大小和位置、存在纵隔或远隔病变、患者特征（如肺病理学和/或其他重要的合并症）以及本地医生的经验和专业知识。△Factors to be considered in choosing the optimal diagnostic step include: △选择最佳诊断步骤应考虑的因素包括：→ Anticipated diagnostic yield (sensitivity) → 预期的诊断阳性率（敏感性）→ Diagnostic accuracy including specificity and particularly the reliability of a negative diagnostic study (ie, true negative) → 诊断准确性包括特异性，特别是阴性诊断的可靠性（即，真阴性）→ Adequate volume of tissue specimen for diagnosis and molecular testing → 用于诊断和分子检测的组织标本足够大→ Invasiveness and risk of procedure → 操作的侵袭性与风险→ Efficiency of evaluation → 评估的效能– Access and timeliness of procedure – 操作的获取和时效性– Concomitant staging is beneficial, because it avoids additional biopsies or procedures. – 同时分期是有益的，因为这避免了额外的活检或步骤。It is preferable to biopsy the pathology that would confer the highest stage (ie, to biopsy a suspected metastasis or mediastinal lymph node rather than the pulmonary lesion). 最高级别的活检病理更好（即，对可疑转移灶或纵隔淋巴结而非肺部病变进行活检）。Therefore, PET imaging is frequently best performed before a diagnostic biopsy site is chosen in cases of high clinical suspicion for aggressive, advanced-stage tumors. 因此，在临床高度怀疑侵袭性、晚期肿瘤的情况下，在选择诊断活检部位之前，进行PET成像常常是最佳的。→ Technologies and expertise available → 现有的技术和专业知识→ Tumor viability at proposed biopsy site from PET imaging. → PET成像提议的活检部位的肿瘤活性。△Decisions about the optimal diagnostic steps for suspected stage I to III lung cancer should be made by thoracic radiologists, interventional radiologists, and board-certified thoracic surgeons who devote a significant portion of their practice to thoracic oncology. △疑似I-III期肺癌诊断的最佳步骤应该由胸部放射科医师、介入放射科医师以及将胸部肿瘤作为其实践的重要部分、通过职业认证的胸外科医生决定。Multidisciplinary evaluation should also include a pulmonologist or thoracic surgeon with expertise in advanced bronchoscopic techniques for diagnosis. 多学科评估还应包括具有先进支气管镜诊断专业技巧的肺脏专家或胸外科医生。△The least invasive biopsy with the highest yield is preferred as the first diagnostic study. △首次诊断检查首选收益最高、侵袭性最小的活检。→ Patients with central masses and suspected endobronchial involvement should undergo bronchoscopy. → 中心性肿块以及怀疑支气管受累的患者应行支气管镜检查。→ Patients with peripheral (outer one-third) nodules may benefit from navigational bronchoscopy, radial EBUS, or TTNA. → 周围性（外1/3）结节患者可能受益于导航支气管镜、径向支气管内超声（EBUS）或经胸腔针吸活检（TTNA）。→ Patients with suspected nodal disease should be biopsied by EBUS, EUS, navigational bronchoscopy, or mediastinoscopy. → 具有可疑淋巴结病变的患者应通过支气管内超声（EBUS）、超声内镜（EUS）、导航支气管镜或纵隔镜活检。– EBUS provides access to nodal stations 2R/2L, 4R/4L, 7, 10R/10L, and other hilar nodal stations if necessary. – 如有必要，支气管内超声（EBUS）可进入2R/2L、4R/4L、7、10R/10L和肺门淋巴结区。– EUS–guided biopsy provides additional access to stations 5, 7, 8, and 9 lymph nodes if these are clinically suspicious. – 超声内镜（EUS）引导的穿刺活检可进一步进入5、7、8和9淋巴结区，如果这些区域临床可疑。– TTNA and anterior mediastinotomy (ie, Chamberlain procedure) provide additional access to anterior mediastinal (station 5 and 6) lymph nodes if these are clinically suspicious. – 经胸腔针吸活检（TTNA）和前纵隔切开术（即Chamberlain手术）可进一步进入前纵隔（5和6区）淋巴结，如果这些临床可疑。→ EUS also provides reliable access to the left adrenal gland. → 超声内镜（EUS）同样可以可靠地进入左侧肾上腺。→ Lung cancer patients with an associated pleural effusion should undergo thoracentesis and cytology. → 合并胸腔积液的肺癌患者应进行胸腔穿刺细胞学检查。A negative cytology result on initial thoracentesis does not exclude pleural involvement. 初始穿刺细胞学阴性并不能排除胸膜受累。An additional thoracentesis and/or thoracoscopic evaluation of the pleura should be considered before starting curative intent therapy. 在开始根治性治疗前，应该考虑追加胸腔穿刺和/或胸腔镜胸膜评估。→ Patients suspected of having a solitary site of metastatic disease should have tissue confirmation of that site if feasible. → 怀疑有孤立性转移灶的患者，如果可行的话，该病灶应该有组织学证实。→ Patients suspected of having metastatic disease should have confirmation from one of the metastatic sites if feasible. → 怀疑有转移性疾病的患者，如果可行的话，应该确认其中的一个转移灶。→ Patients who may have multiple sites of metastatic disease-based on a strong clinical suspicion—should have biopsy of the primary lung lesion or mediastinal lymph nodes if it is technically difficult or very risky to biopsy a metastatic site. → 可能有多部位转移性疾病的患者——根据临床强烈怀疑——如果技术上困难或转移部位活检非常危险，应该活检肺原发灶或纵隔淋巴结。

Adjuvant Treatment 辅助治疗Chemotherapy or Chemoradiation 化疗或放化疗Post-surgical treatment options for patients with stage IA tumors (T1ab, N0) and with positive surgical margins (R1, R2) include re-resection (preferred) or RT (category 2B). Observation is recommended for patients with T1ab-T2ab, N0 tumors and with negative surgical margins (R0). Adjuvant chemotherapy is a category 2A recommendation for patients with T2ab, N0 tumors and negative surgical margins who have high-risk features (including poorly differentiated tumors, vascular invasion, wedge resection, tumors >4 cm, visceral pleural involvement, and unknown lymph node sampling [Nx]) (see Adjuvant Treatment in the NCCN Guidelines for NSCLC). If the surgical margins are positive in patients with T2ab, N0 tumors, options include: 1) re-resection (preferred) with (or without) chemotherapy; or 2) RT with (or without) chemotherapy (chemotherapy is recommended for stage IIA). 手术切缘阳性（R1、R2）的IA期肿瘤（T1abN0）患者的术后治疗选择包括再切除术（首选）或放疗（2B类）。对于手术切缘阴性（R0）的T1ab-T2abN0肿瘤患者推荐观察。对于T2abN0、切缘阴性、具有高危特征（包括低分化的肿瘤、脉管侵犯、楔形切除术、肿瘤>4cm、脏层胸膜受累以及淋巴结取样未知[Nx]）的患者，辅助化疗是2A类推荐（见NSCLC NCCN指南中的辅助治疗）。T2abN0肿瘤患者如果手术切缘阳性，选择包括：1）再切除（首选）±化疗；或2）放疗±化疗（对于ⅡA期推荐化疗）。山东省肿瘤医院呼吸肿瘤内科张品良The NCCN Panel recommends chemotherapy (category 1) for patients with negative surgical margins and stage II disease, including 1) T1ab–T2a, N1; 2) T2b, N1; or 3) T3, N0 disease. If surgical margins are positive in these patients, options after an R1 resection include: 1) re-resection and chemotherapy; or 2) chemoradiation (either sequential or concurrent). Options after an R2 resection include: 1) re-resection and chemotherapy; or 2) concurrent chemoradiation. Most NCCN Member Institutions favor concurrent chemoradiation for positive margins, but sequential is reasonable in frailer patients. 对于1) T1ab–T2aN1、2) T2bN1或3) T3N0的Ⅱ期、手术切缘阴性患者，NCCN小组推荐化疗（1类）。如果这些患者手术切缘阳性，R1切除后的选择包括：1）再切除加化疗；或2）放化疗（序贯或同时）。R2切除后的选择包括：1）再切除加化疗；或2）同步放化疗。对于阳性切缘，大多数NCCN成员机构支持同步放化疗，但在较虚弱患者中序贯是合理的。Adjuvant chemotherapy can also be used in patients with stage III NSCLC who have had surgery (see the NCCN Guidelines for NSCLC). Patients with T1-3, N2 or T3, N1 disease (discovered only at surgical exploration and mediastinal lymph node dissection) and positive margins may be treated with chemoradiation; either sequential or concurrent chemoradiation is recommended for an R1 resection, whereas concurrent chemoradiation is recommended for an R2 resection (see Adjuvant Treatment in the NCCN Guidelines for NSCLC). Patients with negative margins may be treated with either 1) chemotherapy (category 1); or 2) sequential chemotherapy plus RT (for N2 only). 辅助化疗还可用于已手术的Ⅲ期NSCLC患者（见NSCLC NCCN指南）。T1-3N2或T3N1（仅在手术探查和纵隔淋巴结清扫时发现）及切缘阳性患者可以用放化疗治疗；对于R1切除者推荐序贯或同步放化疗，而对于R2切除者推荐同步放化疗（见NSCLC NCCN指南中的辅助治疗）。切缘阴性者可以接受1）化疗（1类）；或2）序贯化疗加放疗（仅针对N2）。For stage IIIA superior sulcus tumors (T4 extension, N0–1) that become resectable after preoperative concurrent chemoradiation, resection followed by chemotherapy is recommended (see the NCCN Guidelines for NSCLC). Surgical reevaluation (including imaging) is done to determine whether the tumor is resectable after treatment. If the lesion remains unresectable after preoperative concurrent chemoradiation, the full course of definitive chemo/RT should be completed; an additional 2 cycles of chemotherapy as an adjuvant treatment can be given if full doses were not given with concurrent therapy. Among patients with chest wall lesions with T3 invasion–T4 extension, N0–1 disease, those who are initially treated with surgery (preferred) may receive chemotherapy alone if the surgical margins are negative. When surgical margins are positive, they may receive either 1) sequential or concurrent chemoradiation; or 2) re-resection with chemotherapy. As previously mentioned, most NCCN Member Institutions favor concurrent chemoradiation for positive margins, but sequential is reasonable in frailer patients. A similar treatment plan is recommended for resectable tumors of the proximal airway or mediastinum (T3–4, N0–1). 对于在术前同步放化疗后变为可切除的ⅢA期上沟瘤（T4N0-1），推荐切除后化疗（见NSCLC NCCN指南）。进行手术再评价（包括影像学）以确定在治疗后肿瘤是否可切除。如果术前同步放化疗后病变仍不可切除，应完成全部的根治性化/放疗疗程；如果同步治疗时未给予足量化疗，则追加两周期的化疗作为辅助治疗。在胸壁病变T3侵犯-T4扩散、N0–1患者中，那些初始治疗手术（首选）者如果手术切缘阴性可接受单纯化疗。当手术切缘阳性时，他们可以接受1）序贯或同步放化疗；或2）再切除加化疗。如前所述，对于阳性切缘，大多数NCCN成员机构支持同步放化疗，但在较虚弱患者中序贯是合理的。对于可切除的近端气道或纵隔肿瘤（T3-4N0-1）推荐类似的治疗方案。For patients with stage IIIA disease and positive mediastinal nodes (T1–3, N2) with no apparent disease progression after initial treatment, recommended treatment includes surgery with (or without) RT (if not given preoperatively) and/or with (or without) chemotherapy (category 2B for chemotherapy) (see the NCCN Guidelines for NSCLC). 对于在初始治疗后疾病无明显进展的ⅢA期和纵隔淋巴结阳性（T1–3N2）的患者，推荐的治疗包括手术±放疗（如果术前未给予）和/或±化疗（对于化疗是2B类）（见NSCLC NCCN指南）。Alternatively, if the disease progresses, patients may be treated with either 1) local therapy using RT (if not given previously) with (or without) chemotherapy; or 2) systemic therapy. In patients with separate pulmonary nodules in the same lobe (T3, N0-1) or ipsilateral non-primary lobe (T4, N0-1), surgery is recommended. In patients with N2 disease, if the margins are negative, sequential chemotherapy (category 1) with radiation is recommended. If the resection margins are positive in patients with N2 disease, concurrent chemoradiation is recommended for an R2 resection, whereas either concurrent or sequential chemoradiation is recommended for an R1 resection. Concurrent chemoradiation is often used for positive margins, but sequential is reasonable in frailer patients. 如果疾病进展，可供患者选择的治疗，1）局部放疗（如果既往未给予）±化疗；或2）全身治疗。独立肺结节在同一叶（T3N0-1）或同侧非原发叶（T4N0-1）的患者推荐手术。在N2患者中，如果切缘阴性，推荐序贯化疗加放疗（1类）。N2患者如果切缘阳性，R2切除者推荐同步放化疗，而R1切除者推荐同时或序贯放化疗。对于阳性切缘经常使用同步放化疗，但是在较虚弱患者中序贯是合理的。Because patients with stage III disease have both local and distant failures, theoretically, the use of chemotherapy may eradicate micrometastatic disease obviously present but undetectable at diagnosis. The timing of this chemotherapy varies (see the NCCN Guidelines for NSCLC). Such chemotherapy may be given alone, sequentially, or concurrently with RT. In addition, chemotherapy could be given preoperatively or postoperatively in appropriate patients. 因为Ⅲ期患者有局部和远处两种失败，所以，从理论上讲，化疗的使用可以根除显然存在但诊断时发现不了的微转移病变。化疗时机多样（见NSCLC NCCN指南）。上述化疗可以单独、序贯或同时联合放疗给予。此外，对于合适的患者化疗可术前或术后给予。On the basis of clinical studies on neoadjuvant and adjuvant chemotherapy for NSCLC, the NCCN Panel recommends cisplatin combined with docetaxel, etoposide, gemcitabine, or vinorelbine for adjuvant chemotherapy for all histologies in the NCCN Guidelines; other options include cisplatin combined with pemetrexed for non-squamous NSCLC (see Chemotherapy Regimens for Neoadjuvant and Adjuvant Therapy in the NCCN Guidelines for NSCLC). For patients with comorbidities or those who cannot tolerate cisplatin, carboplatin combined with paclitaxel is an option. A number of phase 2 studies have evaluated neoadjuvant chemotherapy for stage III NSCLC, with (or without) RT, followed by surgery. 基于NSCLC新辅助化疗和辅助化疗的临床研究，NCCN指南对所有组织类型的辅助化疗NCCN小组推荐顺铂联合多西他赛、依托泊苷、吉西他滨或长春瑞滨；对于非鳞NSCLC其他选择包括顺铂联合培美曲塞（见NSCLC NCCN指南中的新辅助和辅助治疗化疗方案）。对有合并症或不能耐受顺铂的患者，卡铂联合紫杉醇是一种选择。若干2期研究评估了Ⅲ期NSCLC新辅助化疗±放疗，然后手术。Three phase 3 trials have assessed neoadjuvant chemotherapy followed by surgery compared with surgery alone in the treatment of stage III NSCLC. The S9900 trial (a SWOG study)—one of the largest randomized trials examining preoperative chemotherapy in early-stage NSCLC—assessed surgery alone compared with surgery plus preoperative paclitaxel/carboplatin in patients with stage IB/IIA and stage IIB/IIIA NSCLC (excluding superior sulcus tumors). PFS and overall survival were improved with preoperative chemotherapy. All 3 studies showed a survival advantage for patients who received neoadjuvant chemotherapy. The 2 earlier phase 3 studies had a small number of patients, while the SWOG study was stopped early because of the positive results of the IALT study. However, the induction chemotherapy-surgery approach needs to be compared with induction chemotherapy-RT in large, randomized clinical trials. 3项3期试验评估了新辅助化疗然后手术对比单纯手术治疗Ⅲ期NSCLC。S9900试验（SWOG的一项研究）——早期NSCLC术前化疗最大的随机试验之一——评估单纯手术与手术加术前紫杉醇/卡铂治疗IB/ⅡA期和ⅡB/ⅢA期NSCLC（不包括上沟瘤）。术前化疗改善PFS和总生存。所有3项研究均显示，接受新辅助化疗的患者有生存优势。两项更早的3期研究患者数量很少，而SWOG研究因为IALT研究的阳性结果而提前终止。但是，诱导化疗-手术需要在大型随机临床试验中与诱导化疗-放疗进行比较。Radiation Therapy 放疗After complete resection of clinical early-stage NSCLC, postoperative RT has been found to be detrimental for pathological N0 or N1 stage disease in a meta-analysis of small randomized trials using older techniques and dosing regimens and a population-based analysis of data from SEER. However, there was an apparent survival benefit of postoperative RT in patients with N2 nodal stage diagnosed surgically. The analysis of the ANITA trial also found that postoperative RT increased survival in patients with N2 disease who received adjuvant chemotherapy. A recent review of the National Cancer Data Base concluded that postoperative RT and chemotherapy provided a survival advantage for patients with completely resected N2 disease when compared with chemotherapy alone. A recent meta-analysis also concluded that postoperative RT improves survival for patients with N2 disease. Postoperative adjuvant sequential chemotherapy with RT is recommended for patients with T1–3, N2 disease and negative margins (see Adjuvant Treatment in the NCCN Guidelines for NSCLC). A meta-analysis assessed postoperative chemotherapy with (or without) postoperative RT in patients mainly with stage III disease. In this meta-analysis, 70% of the eligible trials used adjuvant chemotherapy before RT; 30% used concurrent chemo/RT. Regimens included cisplatin/vinorelbine followed by RT or concurrent cisplatin/etoposide. 一项使用更老的技术和给药方案的小型随机试验的meta分析和SEER大样本数据分析发现，在临床早期NSCLC完全切除术后，病理N0、N1期术后放疗有害。然而，在手术分期N2的患者中，术后放疗有明显的生存获益。对ANITA试验的分析也发现，在接受辅助化疗的N2患者中，术后放疗改善生存。最近一项国立癌症数据库的回顾得出的结论是，对于完全切除的N2患者，与单纯化疗相比，术后放疗和化疗具有生存优势。最近一项meta分析也得出结论，对于N2患者，术后放疗可改善生存。对于T1–3、N2且切缘阴性的患者，推荐术后辅助序贯化放疗（见NSCLC NCCN指南中的辅助治疗）。一项meta分析评估了主要是Ⅲ期患者术后化疗±术后放疗。在这项meta分析中，70%的符合试验条件者在放疗前使用了辅助化疗；30%使用同步化/放疗。方案包括顺铂/长春瑞滨序贯放疗或同步顺铂/依托泊苷。The ACR Appropriateness Criteria(R) provide specific recommendations for postoperative adjuvant therapy. Either concurrent or sequential chemoradiation may be used for postoperative adjuvant therapy, depending on the type of resection and the setting (eg, N2 disease) (see Adjuvant Treatment in the NCCN Guidelines for NSCLC). Concurrent chemo/RT is recommended for R2 resections, whereas either sequential or concurrent chemo/RT is recommended for R1 resections. Concurrent chemoradiation is often used for positive margins, but sequential is reasonable in frailer patients. Cisplatin/etoposide, cisplatin/vinblastine, and carboplatin/paclitaxel are chemoradiation regimens recommended by the NCCN Panel for all histologies (see Chemotherapy Regimens Used with Radiation Therapy in the NCCN Guidelines for NSCLC). Pemetrexed with either cisplatin or carboplatin may be used for concurrent chemoradiation in patients with non-squamous NSCLC. When chemoradiation is recommended in the NCCN Guidelines, these regimens may be used for stage II to III disease. A recent phase 3 trial (PROCLAIM) assessed concurrent thoracic RT with cisplatin/pemetrexed versus cisplatin/etoposide followed by consolidation chemotherapy in patients with unresectable stage III non-squamous NSCLC. Both regimens were equivalent in terms of survival, but the cisplatin/pemetrexed regimen was associated with less neutropenia (24.4% vs. 44.5%; P < .001) and fewer grade 3 to 4 adverse events (64.0% vs. 76.8%; P = .001). For the 2017 update (Version 1), the NCCN Panel deleted the cisplatin/etoposide consolidation regimen based on the PROCLAIM trial. In addition, the NCCN Panel clarified that the cisplatin/pemetrexed and carboplatin/paclitaxel regimens may be followed by consolidation chemotherapy alone. ACR（美国放射学会）适宜性标准®为术后辅助治疗提供具体建议。对于术后辅助治疗，同步或序贯放化疗都可以使用，取决于切除类型与情况（如N2）（见NSCLC NCCN指南中的辅助治疗）。对于R2切除者推荐同步化/放疗，而对于R1切除者推荐序贯或同步化/放疗。对于阳性切缘经常使用同步放化疗，但是在较虚弱患者中序贯是合理的。对于所有的组织学类型，顺铂/依托泊苷、顺铂/长春花碱和卡铂/紫杉醇是NCCN小组推荐的放化疗方案（见NSCLC NCCN指南中的联合放疗使用的化疗方案）。非鳞NSCLC患者同步化放疗可使用培美曲塞联合顺铂或卡铂。当推荐放化疗时，NCCN指南中的这些方案也可用于Ⅱ-Ⅲ期疾病。最近一项3期试验（PROCLAIM）评估了胸部放疗同步顺铂/培美曲塞与顺铂/依托泊苷然后巩固化疗治疗不能切除的Ⅲ期非鳞NSCLC患者。在生存方面两种方案相当，但顺铂/培美曲塞方案中性粒细胞减少症较少（24.4%对44.5%；P<0.001）且3-4级不良事件较少（64%对76.8%；P=0.001）。基于PROCLAIM试验，2017第1版更新，NCCN小组删除了顺铂/依托泊苷巩固方案。此外，NCCN小组明确了顺铂/培美曲塞和卡铂/紫杉醇方案可以序贯单纯巩固化疗。

NCCN Guidelines Version 3.2017 NCCN指南2017第3版Non-Small Cell Lung Cancer 非小细胞肺癌山东省肿瘤医院呼吸肿瘤内科张品良Discussion 讨论Staging 分期A new edition of the AJCC Cancer Staging Manual (8th edition) was published in late 2016 and will be effective for all cancer cases recorded on or after January 1, 2018. The NCCN Guidelines will use the AJCC (7th edition) staging system for lung cancer until January 1, 2018. The definitions for TNM and the stage grouping are summarized in Tables 1 and 2 of the staging tables (see Definitions for T,N,M and Staging in the NCCN Guidelines for NSCLC). The descriptors of the TNM classification scheme are summarized in Table 3 of the staging tables (see Staging). The lung cancer staging system was revised by the International Association for the Study of Lung Cancer (IASLC). And was adopted by the AJCC. With the AJCC staging, locally advanced disease is stage III; advanced disease is stage IV. Pathologic staging uses both clinical staging information (which is noninvasive and includes medical history, physical examination, and imaging) and other invasive staging procedures (eg, thoracotomy, examination of lymph nodes using mediastinoscopy). 新版AJCC癌症分期手册（第8版）已在2016年底出版，将在2018年1月1日或以后的所有癌症病例记录中实施。NCCN指南使用的AJCC （第7版） 肺癌分期系统将在2018年1月1日终止。TNM定义、分期组合总结在分期表1和2（见非小细胞肺癌NCCN指南中的T、N、M及分期定义）。TNM分期组合描述总结在分期表中的表3（见分期）。肺癌分期系统由国际肺癌研究协会（IASLC）修订。并被AJCC采用。对于AJCC分期，局部晚期疾病是III期；晚期疾病是IV期。病理分期使用临床分期信息（为无创性，包括病史、体格检查与影像学）和其他侵袭性分期措施（如开胸术、纵隔镜淋巴结检查）两者的信息。From 2006 to 2012, the overall 5-year relative survival rate for lung cancer was 17.7% in the United States. Of lung and bronchial cancer cases, 16% were diagnosed while the cancer was still confined to the primary site; 22% were diagnosed after the cancer had spread to regional lymph nodes or directly beyond the primary site; 57% were diagnosed after the cancer had already metastasized; and for the remaining 5% the staging information was unknown. The corresponding 5-year relative survival rates were 55% for localized, 28% for regional, 4.3% for distant, and 7.4% for unstaged. However, these data include SCLC, which has a poorer prognosis. 从2006年到2012年，美国肺癌的5年总生存率为17.7%。在肺和支气管癌的病例中，有16%在癌症仍局限于原发部位时被确诊；22%是在癌症已经扩散到区域淋巴结或直接超出了原发部位后确诊；57%是在癌症已经转移后确诊；其余的5%分期信息不明。相应的5年相对生存率是局部55%、区域28%、远处4.3%、未分期7.4%。然而，这些数据包括预后较差的小细胞肺癌。Five-year survival after lobectomy for pathologic stage I NSCLC ranges from 45% to 65%, depending on whether the patient has stage 1A or 1B disease and on the location of the tumor. Another study in patients with stage I disease (n = 19,702) found that 82% had surgical resection and their 5-year overall survival was 54%; however, for untreated stage I NSCLC, 5-year overall survival was only 6%. Of patients with stage I disease who refused surgery (although it was recommended), 78% died of lung cancer within 5 years. 病理I期非小细胞肺癌在叶切除术后的5年生存率为45%到65%，取决于患者是IA还是IB期疾病以及肿瘤的位置。另一项I期疾病患者（n = 19702）的研究发现，82%的手术切除，其5年总生存率为54%；然而，对于未治疗的Ⅰ期非小细胞肺癌，5年总生存率仅为6%。在拒绝手术（尽管建议）的I期患者中，78%在5年内死于肺癌。

Cancer-Associated Venous Thromboembolic Disease Version 1.2016癌症相关静脉血栓栓塞症2016年第1版山东省肿瘤医院呼吸肿瘤内科张品良Updates in Version 1.2016 of the NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease from Version 1.2015 include: 2016年第1版的NCCN癌症相关静脉血栓栓塞症指南自2015年第1版的更新包括：General 总体* “pomalidomide” was added to “thalidomide/lenalidomide” as appropriate throughout the guidelines. *将“泊马度胺”添加到“沙利度胺/来那度胺”贯穿整个指南是合适的。Venous Thromboembolism 静脉血栓栓塞VTE-1 * At-Risk Population *高危人群▶ 3rd bullet: Revised “Providers are encouraged to discuss VTE risk factors, risks and benefits of VTE prevention, and the importance of patient adherence to care programs.” (Also for VTE-2) ▶第3项核心：修改为“鼓励医生探讨静脉血栓栓塞危险因素、风险和VTE预防的收益以及患者遵守医疗计划的重要性。”(同样适用于VTE-2)* Footnote “c” was revised: “Discuss prevention and risks/benefits of VTE prophylactic anticoagulation by pharmacologic intervention. Discuss VTE prevention and the risks/benefits of pharmacologic and mechanical VTE prophylaxis. A systematic approach to patient risk assessment is recommended. Institutions are strongly encouraged to implement best practice programs to monitor provider and patient adherence to VTE prophylaxis.” *修订了脚注“c”：“探讨通过药物干预静脉血栓栓塞预防性抗凝治疗的预防与风险/收益。探讨VTE预防以及药物和机械预防VTE的风险/效益。建议的一个系统评估患者风险的方法。学会强烈鼓励实施最佳实践方案来监控医生和病人对VTE预防的依从性。”VTE-2 * At-Risk Population *高危人群▶ Recommendations for “Surgical oncology patient” were revised to: “Out-of-hospital primary VTE prophylaxis is recommended for up to four weeks post-operation (particularly for high-risk abdominal or pelvic cancer surgery patients.)” ▶对“肿瘤外科患者”的建议修订为：“院外初级VTE预防推荐手术后最多4周(特别是对于高危腹或盆腔癌症手术患者)”▶ For “Medical oncology patient” treated in “Other outpatient settings”, footnote was removed: “Consider patient conversation about risks and benefits of VTE prophylaxis in patients with a Khorana score ≥3. (See Khorana Predictive Model [VTE-A 3 of 3]).” ▶对于“其他情况的门诊患者”中的“内科肿瘤患者”，删除了脚注：“在Khorana评分≥3的患者中考虑与患者交谈有关静脉血栓栓塞预防的风险与收益。（见Khorana预测模型VTE-A 3/3）。”Acute Deep Vein Thrombosis (DVT) and Acute Superficial Vein Thrombosis (SVT) 急性深静脉血栓形成（DVT）与急性浅静脉血栓形成（SVT）* Deep or Superficial Vein Thrombosis (DVT/SVT) was divided into two new pages. *深或浅静脉血栓形成（DVT/SVT）分到两个新页。SVT-1 * “Acute Superficial Vein Thrombosis (SVT)” was extensively revised. *广泛修订了“急性浅静脉血栓形成（SVT）”。DVT-1 * “Acute Deep Vein Thrombosis (DVT)” was extensively revised. *广泛修订了“急性深静脉血栓形成（DVT）”。DVT-3 * Treatment *治疗▶ DTV, no contraindication, 1st bullet was revised: “Anticoagulation for at least 3 months or as long as catheter CVAD is in place if catheter removed, total duration of therapy is at least 3 months” ▶DTV，无禁忌症，第一项核心修订：“抗凝至少3个月或只要导管CVAD存在就要抗凝；如果导管拔除，总的治疗持续时间是至少3个月”▶ No DVT, bullet was revised from “Consider further imaging/testing with another modality if clinical suspicion is high and initial imaging failed to show” to “Consider further diagnostic imaging/testing if initial testing is unrevealing and clinical suspicion remains high” ▶无DVT，“如果临床高度怀疑而初步的影像未显示，则考虑用另外的方式进一步影像/检测”核心修订为“如果初步检测未发现而临床仍高度怀疑，则考虑进一步影像/检测”▶ Footnote “k” is new: “Consider longer duration anticoagulation in patients with poor flow, persistent symptoms, or unresolved thrombus.” ▶脚注“K”是新的：“在血流不畅、症状持续或血栓未解决的患者中，考虑更长时间的抗凝治疗。”Acute Pulmonary Embolism (PE) 急性肺栓塞（PE）PE-1 * Diagnosis and Evaluation ＊诊断与评估▶ Under “Diagnosis”, a bullet was removed: “Incidental PE” ▶在“诊断”下面，删除了：“偶发性PE”▶ “Unsuspected PE” pathway is new, with the evaluation: “If not already performed: Comprehensive medical history, and physical examination; CBC with platelet count; PT, aPTT; Liver and kidney function tests; EKG,” then referred to: “See PE Treatment (PE-2)” ▶“不受怀疑的PE”路径是新的，增加了评价：“如果尚未完成：全面的病史和体格检查；CBC加血小板计数；PT，aPTT；肝肾功能检测；EKG，”则参考：“见PE治疗（PE-2）”▶ Clinical suspicion of PE, Imaging, 3rd bullet was revised: “... (if patient has renal insufficiency or uncorrectable allergy to contrast allergy refractory to anaphylaxis prophylaxis)” ▶临床、影像学怀疑PE，修订了第三项核心：“... （如果病人有肾功能不全或对造影剂过敏无法纠正过敏预防措施抵抗）”▶ Footnote “c” was revised: “Repeat imaging and diagnostic studies are is not routinely needed in patients with incidental PE. Consider outpatient management for these patients.” *修订了脚注“c”：“在偶发PE患者中不常规要求重复影像和诊断性研究。对于这些患者考虑门诊管理。"PE-2 * Treatment *治疗▶ Footnote was removed from risk stratification procedures: “The Pulmonary Embolism Severity Index (PESI) clinical prediction rule can also be considered, but should not be substituted for the risk stratification procedures indicated above. (Donze J, Le Gal G, Fine MJ, et al. Prospective validation of the Pulmonary Embolism Severity Scale. Throm Haemost 2008;100:943-948). Consideration can also be given to the RIETE Cancer Score (den Exter P, Gómez V, Jiménez D, et al. A clinical prognostic model for the identification of low-risk patients with acute symptomatic pulmonary embolism and active cancer. Chest 2013;143:138-145.)” ▶从危险分层方法中删除了脚注：“也可以考虑肺栓塞严重指数(PESI)临床预测规则，但是不应该取代上面所述的危险分层方法。（Donze J, Le Gal G, Fine MJ,等。肺栓塞严重程度量表的前瞻性证实。Throm Haemost 2008;100:943-948）。也可考虑给予RIETE癌症评分（den Exter P, Gómez V, Jiménez D, 等。用于识别低危急性症状性肺栓塞与癌症活跃患者的一个临床预后模型。Chest 2013;143:138-145。）”Heparin-Induced Thrombocytopenia (HIT) 肝素诱导的血小板减少症(HIT)HIT-1 * Diagnosis and Treatment of HIT ＊HIT的诊断与治疗▶ “Low” pathway: Fourth bullet removed: “Consider HIT antibody test (enzyme-linked immunosorbent assay [ELISA]) for select patients (See HIT antibody test results HIT-2)” ▶“低”路径：删除了第4项核心：“对于选择性的患者考虑HIT抗体检测(酶联免疫吸附测定[ELISA])(见HIT抗体检测结果HIT-2)”▶ “Moderate/High” pathway: ▶“中/高”路径♢ 1st bullet was revised from “Eliminate unfractionated and LMWH exposure from all sources, including treatment, prophylaxis, flush doses, and coated catheters” to “Eliminate UFH/LMWH exposure from all sources (treatment, prophylaxis, line flushes, coated catheters)” 第1项核心“消除来自所有来源的普通与低分子肝素暴露，包括治疗、预防、冲管用药以及涂层导管”修订为“消除暴露于UFH/LMWH的各种来源（治疗、预防、冲管、涂层导管）”♢ 2nd bullet was revised from “For patients receiving warfarin, discontinue it and reverse with vitamin K” to “Discontinue and reverse warfarin (and other vitamin K antagonists) with vitamin K” ♢第2项核心“对于正在接受华法林的患者，停止华法林并用维生素K对抗”修订为“停止并用维生素K对抗华法林（以及其他维生素K拮抗剂）”▶ Footnote “c” was revised: “A “low” pre-test probability score combined with a negative antibody test is useful in ruling out a diagnosis of HIT; a positive test increases the suspicion for HIT. Sending for the HIT antibody test should be individualized and based on clinical judgment. Patients with 4T scores<4 are very unlikely to have HIT, so routine HIT antibody testing in these patients is probably not advisable. In non-cancer patients with 4T scores of 1–3, the risk of HIT is small but not zero, but this has not been validated in cancer patients. Based on clinical judgment HIT antibody testing may be warranted in select patients of concern.” *修订了脚注“c”：修订为：“验前概率评分“低”结合抗体检测阴性在排除HIT诊断方面是有用的；测试阳性增加了对HIT的怀疑。应该个体化送肝素诱导的血小板减少症抗体检测并以临床判断为基础。4T评分<4的患者不太可能是HIT，因此在这些患者中常规HIT抗体检测可能是不明智的。在4T评分1–3的非癌症患者 中，HIT风险很小但并不是没有，不过这未在癌症患者中验证。根据临床判断，在选择性的担心的患者中，HIT抗体检测可能是必要的。”▶ Footnote “e” is new: “Data supporting use of fondaparinux is limited; however, among experienced clinicians it is commonly used for outpatient management in low-risk patients.” ▶脚注“e”是新的：“支持使用磺达肝素的数据是有限的；不过，在有经验的临床医生中，它通常用于低危患者的门诊管理。”Therapeutic Options for HIT HIT的治疗方案HIT-B 1 of 2 * Direct Thrombin Inhibitors (Preferred); Argatroban: *直接凝血酶抑制剂（首选）；阿加曲班：▶ 1st sub-bullet was revised: “Normal liver function, non-ICU patient: 1 2 mcg/kg/min adjusted to aPTT ratio (first check in 4 hours)” ▶修订了第1项次核心：“肝功能正常，非ICU患者：1 2μg/kg/min根据aPTT比调整（首次复查在4小时内）”▶ 2nd sub-bullet was revised: “Abnormal liver function (total bilirubin 1.8–3.6 mg/dL; aspartate transaminase/alanine transaminase [AST/ALT] 150–600 IU/L) or ICU, heart, or multi-organ failure patient: 0.25 0.5 mcg/kg/min” ▶修订了第2项次核心：“肝功能异常（总胆红素1.8 - 3.6mg/dL；天冬氨酸转氨酶/丙氨酸转氨酶[AST/ALT]150-600IU/L)或ICU、心脏或多器官衰竭患者：0.25 0.5μg/kg/min”* Footnote “3” is new: “Prescribing information: Argatroban injection, for intravenous infusion only. 2016.” *脚注“3”是新的：“处方信息：阿加曲班注射液，只能用于静脉输液。2016.” HIT-B 2 of 2 * Indirect Factor Xa Inhibitor, fondaparinux, 1st sub-bullet was revised: “For patients with CCr 30–50 mL/min (clearance reduced by ≥40%): Use caution Consider using a DTI” *Ⅹa因子间接抑制剂，磺达肝癸，修订了第1项次核心：“对于Ccr 30–50ml/min（清除率降低≥40%）的患者：慎重使用考虑使用DTI”* Footnote “6” was added: “Prescribing information: Fondaparinux sodium, solution for subcutaneous injection. 2009” *添加了脚注“6”：“处方信息：磺达肝素钠，溶液用于皮下注射。2009”Splanchnic Vein Thrombosis (SPVT) 内脏静脉血栓(SPVT)SPVT-1 * Footnote “a”, Risk factors relevant to cancer population for SPVT; 8th sub-bullet was revised: “Myeloproliferative disorder (polycythemia vera, essential thrombocythemia) neoplasms associated with the JAK2 V617F mutation (most common) or CALR mutation (rare)” *脚注“a”，与癌症人群SPVT有关的危险因素；修订了第8项核心：“骨髓增殖异常（真性红细胞增多症、原发性血小板增多症）肿瘤与JAK2 V617F突变（最常见）或CALR突变（罕见）相关”SPVT-2 * Footnote “d” was revised: “Duration of anticoagulation should be at least 6 months for triggered events (eg, postsurgical) and indefinite if active cancer, thrombophilic state, or idiopathic thrombosis persistent thrombophilic state or unprovoked thrombotic event.” *修订了脚注“d”：“对于触发事件（如术后）且不确定是否癌症活跃、易栓状态或特发性血栓持续易栓状态或无缘无故的血栓事件，抗凝持续时间应该至少6个月。”VTE Risk Factors In Cancer Patients 癌症患者VTE危险因素VTE-A 1 of 3 * High-risk outpatients on chemotherapy, based on combinations of the following risk factors; 5th bullet was revised: “Use of erythropoietic erythropoiesis-stimulating agents” *高危门诊化疗患者，具有下列危险因素；修订了第5项核心：“红细胞生成的红细胞生成刺激药物的使用”VTE-A 2 of 3 * Risk Factors, Myeloma Therapy: *危险因素，骨髓瘤治疗：▶ 1st bullet was revised: “Thalidomide or lenalidomide IMiD in combination with:” ▶修订了第1项核心：“沙利度胺或来那度胺IMiD联合：”▶ Footnote “2” is new: “Immunomodulator drugs (IMiDs), including thalidomide, lenalidomide, and pomalidomide.” ▶脚注“2”是新的：“免疫调节药物（IMiDs），包括沙利度胺、来那度胺和 泊马度胺。”* Footnote “1” was revised: “Reproduced Adapted with permission from Nature Publishing Group. Palumbo A, Rajkumar SV, Dimopolous MA et al, Prevention of thalidomide-and lenalidomide-associated thrombosis in myeloma. Leukemia 2008;22:414-423. Copyright 2008. http://www.nature.com/leu/journal/v22/n2/full/2405062a.htm” *修订了脚注“1”：“自然出版集团允许转载改编。Palumbo A, Rajkumar SV, Dimopolous MA等，多发性骨髓瘤中沙利度胺和来那度胺相关的血栓形成的预防。Leukemia 2008;22:414-423.版权所有2008。 http://www.nature.com/leu/journal/v22/n2/full/2405062a.htm ”VTE-A 3 of 3 * Title was revised: “VTE Risk Factors in Cancer Outpatients.” *修订了标题：“门诊癌症患者VTE的危险因素。”VTE-B * Contraindications To Prophylactic or Therapeutic Anticoagulation Treatment *预防性或治疗性抗凝治疗禁忌症。▶ 8th bullet under “Relative” was added: “Interventional spine and pain procedures” ▶在“相对”下面增加了第8项核心：“脊柱介入和痛苦的操作”▶ Footnote “1” was revised: “Refer to institutional-specific anesthesia practice guidelines, if available. Twice daily prophylactic dose UFH (5000 units every 12 hours) and once daily LMWH (eg, enoxaparin 40 mg once daily) may be used with neuraxial anesthesia. Twice daily prophylactic dose LMWH (eg, enoxaparin 30 mg every 12 h), prophylactic dose fondaparinux (2.5 mg daily), and therapeutic dose anticoagulation should be used with extreme caution with neuraxial anesthesia. The safety of thrice daily prophylactic dose UFH in conjunction with neuraxial anesthesia has not been established. (Horlocker TT, Wedel DJ, Rowlingson JC, et al. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines (Third Edition). Reg Anesth Pain Med 2010;35:64-101.) *修订了脚注“1”：“如果可得到的话，参考学会具体的麻醉实践指南。预防剂量的UFH bid（5000u q12h）和LMWH qd（如依诺肝素40mg qd）可以与硬膜外麻醉一起使用。预防剂量的LMWH bid（如依诺肝素30mg q12h）、预防剂量的磺达肝素（2.5mg qd）以及治疗剂量的抗凝与硬膜外麻醉一起使用应该格外谨慎。预防剂量的UFH每日3次与硬膜外麻醉一起使用的安全性尚未确定。（Horlocker TT, Wedel DJ, Rowlingson JC, et al.正在接受抗凝或溶栓治疗患者的局部麻醉：美国局部麻醉与疼痛医学协会循证指南（第三版）。Reg Anesth Pain Med 2010;35:64-101.)Therapeutic Anticoagulation for Venous Thromboembolism 静脉血栓栓塞症的治疗性抗凝VTE-D 1 of 2 * Footnote “2” was revised: “Follow institutional standard operating procedures (SOPs) for dosing schedules. If no SOPs then use the American College of Chest Physicians (ACCP) recommendations. (Kearon C, Kahn SR, Agnelli G, Goldhaber S, et al. Antithrombotic therapy for venous thromboembolic disease: American College of Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008;133[suppl]:454S-545S. [www.chestjournal.org]) Garcia DA , Baglin TP, Weitz JI, Samama MM. Parenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e24S-43S.” *修订了脚注“2”：“关于给药计划遵循学会的标准操作规程（SOPs）。如果没有标准操作规程则使用美国胸内科医师学会（ACCP）的推荐。(Kearon C, Kahn SR, Agnelli G, Goldhaber S, et al.静脉血栓栓塞性疾病的抗血栓治疗：美国医师学会循证临床指南(第8版)。Chest 2008;133[suppl]:454S-545S.[www.chestjournal.org]) Garcia DA , Baglin TP, Weitz JI, Samama MM.肠道外抗凝剂：抗栓治疗和血栓形成预防，第九版：美国胸内科医师协会循证临床指南。Chest 2012;141:e24S-43S.”Reversal of Anticoagulation in the Event of Life-Threatening Bleeding or Emergent Surgery 如果发生致命性出血或紧急手术抗凝逆转VTE-E 1 of 9 * Statement was revised: “In the event of bleeding or the need for urgent/emergent invasive procedures, anticoagulant effect must be reversed promptly. It is incumbent on the provider to keep in stock the recommended reversal agents for all anticoagulants included in this table. This includes: protamine; vitamin K oral (phytonadione), and IV solution; fresh frozen plasma (FFP); 4-factor prothrombin complex concentrate (4-factor PCC), 3-factor PCC, rhFVIIa, activated prothrombin complex concentrates (aPCC) (anti-inhibitor coagulant complex, vapor heated), desmopressin (DDAVP), idarucizumab, and oral charcoal.” *修订了声明：“如果出血或需要紧急/突发的侵袭性操作，抗凝剂作用必须被及时逆转。本表中推荐的所有逆转抗凝剂保持库存是医生义不容辞的。这包括：鱼精蛋白；口服的维生素K（植物甲萘醌）和静脉注射液；新鲜冰冻血浆（FFP）；4-因子凝血酶原复合浓缩物（4-因子PCC）、3-因子PCC、rhFVIIa、活化凝血酶原浓缩物（aPCC）（蒸汽加热的抗-凝血复合物抑制剂）、去氨加压素（DDAVP）、 idarucizumab（达比加群酯的特异性拮抗剂）以及口服木炭。”* Low-molecular-weight heparin (LMWH) (Half-life 3–7 hours); 4th bullet was revised: “Administer protamine by slow IV infusion (≤ 5 mg/min) (no faster than 5 mg per min)” *低分子肝素（LMWH）（半衰期3–7小时）；修订了第4项核心：“鱼精蛋白缓慢静脉滴注（≤5mg/min）（不超过5mg/min）VTE-E 6 of 9 * Reversal of Anticoagulation for “Dabigatran” *“达比加群”的抗凝逆转▶ 2nd bullet is new: “Administer idarucizumab, 5 g IV” ▶第2项核心是新的：“给予idarucizumab，5g IV”▶ 3rd bullet was revised: “No specific antidote exists, but beneficial effects have been ascribed to the following For special situations with slow or incomplete clearance (eg, renal dysfunction or failure), consider adding to idarucizumab:” ▶修订了第3项核心：“目前没有特异性解毒药，但下列是有益的作用对于清除缓慢或不完全（如肾功能异常或衰竭）的特殊情况，考虑加idarucizumab：”▶ Statement was removed: “May be helpful based on in vitro or animal models aPCC (anti-inhibitor coagulant complex, vapor heated 25–50 units/kg IV) rhFVIIa 90 mcg/kg IV” ▶删除了声明：“基于体外或动物模型，aPCC（蒸汽加热的抗-凝血复合物抑制剂，25–50u/kg IV）rhFVIIa 90μg/kg IV也许会有帮助”* Precautions/Additional Considerations for “Dabigatran” *“达比加群”的注意事项/其他需要考虑的事项▶ 3rd bullet revised: “In patients with renal failure/severe renal insufficiency, dialysis may be the most helpful in addition to idarucizumab.” ▶第3项核心修订：”在肾衰竭/严重肾功能不全患者中，除了idarucizumab之外，透析可能是最有用的。VTE-E 8 of 9 * This is a new page with recommendations for reversal of edoxaban anticoagulation in the event of life-threatening bleeding or emergent surgery. *万一发生致命性出血或紧急手术，对于依度沙班抗凝逆转的建议这是新的一页。VTE-J * A new box was added listing indications for thrombolysis: *新包装增加了溶栓适应症列表：▶ “Limb-threatening/life-threatening acute proximal DVT ▶“威胁肢体/危及生命的急性近端DVT▶ Symptomatic ileal femoral thrombosis ▶有症状的回肠股动脉血栓▶ Massive/life-threatening PE ▶巨大/致命性PE▶ Intestinal SPVT with high risk of ischemia” ▶肠SPVT与高危缺血”Perioperative Management of Anticoagulation and Antithrombotic Therapy 围手术期抗凝的管理与抗血栓形成治疗PMA-A 1 of 2 * Types of Surgery or Procedures＊手术或措施的类型▶ 8th bullet for high bleeding risk was added: “Head and neck surgery” ▶对于出血高危增加了第8项核心：“头颈外科”

CHEMOTHERAPY REGIMENS USED WITH RADIATION THERAPY 用于放射治疗的化疗方案山东省肿瘤医院呼吸肿瘤内科张品良Concurrent Chemotherapy/RT Regimens 同期化疗/放疗方案* Cisplatin 50 mg/m2 on days 1, 8, 29, and 36; etoposide 50 mg/m2 days 1–5, 29–33; concurrent thoracic RT △▲ *顺铂50mg/㎡ d1、8、29、36；依托泊苷50mg/㎡ d1–5、29–33；同期胸部放疗△▲* Cisplatin 100 mg/m2 days 1 and 29; vinblastine 5 mg/m2 /weekly x 5; concurrent thoracic RT △▲ *顺铂100mg/㎡ d1、29；长春花碱5mg/㎡ /周×5；同期胸部放疗△▲* Carboplatin AUC 5 on day 1, pemetrexed 500 mg/m2 on day 1 every 21 days for 4 cycles; concurrent thoracic RT (nonsquamous) △▲ *卡铂AUC 5 d1，培美曲塞500mg/㎡ d1，每21天为1周期，共4周期；同期胸部放疗（非鳞癌）△▲* Cisplatin 75 mg/m2 on day 1, pemetrexed 500 mg/m2 on day 1 every 21 days for 3 cycles; concurrent thoracic RT (nonsquamous) △▲± additional 4 cycles of pemetrexed 500 mg/m2 ▲ *顺铂75mg/㎡ d1，培美曲塞500mg/㎡ d1，每21天重复共3周期；同期胸部放疗（非鳞癌）△▲±追加4周期的培美曲塞500mg/㎡▲* Paclitaxel 45–50 mg/m2 weekly; carboplatin AUC 2, concurrent thoracic RT △▲ ± additional 2 cycles of paclitaxel 200 mg/m2 and carboplatin AUC 6 ▲ *紫杉醇45-50mg/㎡每周1次；卡铂AUC 2，同期胸部放疗△▲±追加2周期紫杉醇200mg/㎡加卡铂AUC 6▲Sequential Chemotherapy/RT Regimens (Adjuvant) 序贯化疗/放疗方案（辅助）* Cisplatin 100 mg/m2 on days 1 and 29; vinblastine 5 mg/m2 /weekly on days 1, 8, 15, 22, and 29; followed by RT *顺铂100mg/㎡，d1、29；长春花碱5mg/㎡/周，d1、8、15、22、29；序贯放疗* Paclitaxel 200 mg/m2 over 3 hours on day 1; carboplatin AUC 6 over 60 minutes on day 1 every 3 weeks for 2 cycles followed by thoracic RT *紫杉醇200mg/㎡，3小时以上，d1；卡铂AUC 6，60分钟以上，d1，每3周为1周期共2周期，然后胸部放疗△Regimens can be used as neoadjuvant/preoperative/induction chemoradiotherapy. △方案可作为新辅助/术前/诱导化放疗使用。▲Regimens can be used as adjuvant or definitive concurrent chemotherapy/RT. ▲方案可作为辅助或根治性同步化/放疗使用。

CHEMOTHERAPY REGIMENS FOR NEOADJUVANT AND ADJUVANT THERAPY新辅助与辅助治疗化疗方案* Cisplatin 50 mg/m2 days 1 and 8; vinorelbine 25 mg/m2 days 1, 8, 15, 22, every 28 days for 4 cycles顺铂50mg/㎡ d1、8；长春瑞滨25mg/㎡ d1、8、15、22，每28天为1周期，共4周期山东省肿瘤医院呼吸肿瘤内科张品良* Cisplatin 100 mg/m2 day 1; vinorelbine 30 mg/m2 days 1, 8, 15, 22, every 28 days for 4 cycles顺铂100mg/㎡ d1；长春瑞滨30mg/㎡ d1、8、15、22，每28天为1周期，共4周期* Cisplatin 75–80 mg/m2 day 1; vinorelbine 25–30 mg/m2 days 1 + 8, every 21 days for 4 cycles顺铂75-80mg/㎡ d1；长春瑞滨25–30mg/㎡ d1、8，每21天为1周期，共4周期* Cisplatin 100 mg/m2 day 1; etoposide 100 mg/m2 days 1–3, every 28 days for 4 cycles 顺铂100mg/㎡ d1；依托泊苷100mg/㎡ d1–3，每28天为1周期，共4周期* Cisplatin 75 mg/m2 day 1; gemcitabine 1250 mg/m2 days 1, 8, every 21 days for 4 cycles顺铂75mg/㎡ d1；吉西他滨1250mg/㎡ d1、8，每21天为1周期，共4周期* Cisplatin 75 mg/m2 day 1; docetaxel 75 mg/m2 day 1 every 21 days for 4 cycles 顺铂75mg/㎡ d1；多西他赛75mg/㎡ d1，每21天为1周期，共4周期* Cisplatin 75 mg/m2 day 1, pemetrexed 500 mg/m2 day 1 for nonsquamous every 21 days for 4 cycles对于非鳞癌：顺铂75mg/㎡ d1，培美曲塞500mg/㎡ d1，每21天为1周期，共4周期Chemotherapy Regimens for Patients with Comorbidities or Patients Not Able to Tolerate Cisplatin有合并症或不能耐受顺铂患者的化疗方案Paclitaxel 200 mg/m2 day 1, carboplatin AUC 6 day 1, every 21 days紫杉醇200mg/㎡ d1，卡铂AUC 6 d1，每21天为1周期CHEMOTHERAPY REGIMENS USED WITH RADIATION THERAPY联合放疗的化疗方案Concurrent Chemotherapy/RT Regimens同步化/放疗方案* Cisplatin 50 mg/m2 on days 1, 8, 29, and 36; etoposide 50 mg/m2 days 1–5, 29–33; concurrent thoracic RT *,**顺铂50mg/㎡ d1、8、29、36；依托泊苷50mg/㎡ d1–5、29–33；同期胸部放疗*,*** Cisplatin 100 mg/m2 days 1 and 29; vinblastine 5 mg/m2 /weekly x 5; concurrent thoracic RT *,**顺铂100mg/㎡ d1、29；长春花碱5mg/㎡ /周×5；同期胸部放疗*,*** Carboplatin AUC 5 on day 1, pemetrexed 500 mg/m2 on day 1 every 21 days for 4 cycles; concurrent thoracic RT (nonsquamous)*,** 卡铂AUC 5 d1，培美曲塞500mg/㎡ d1，每21天为1周期，共4周期；同期胸部放疗（非鳞癌）*,*** Cisplatin 75 mg/m2 on day 1, pemetrexed 500 mg/m2 on day 1 every 21 days for 3 cycles; concurrent thoracic RT (nonsquamous)*,** ± additional 4 cycles of pemetrexed 500 mg/m2 ** 顺铂75mg/㎡ d1，培美曲塞500mg/㎡ d1，每21天重复共3周期；同期胸部放疗（非鳞）*,**±追加4周期的培美曲塞500 mg/㎡ d2 *** Paclitaxel 45–50 mg/m2 weekly; carboplatin AUC 2, concurrent thoracic RT *,** ± additional 2 cycles of paclitaxel 200 mg/m2 and carboplatin AUC 6** 紫杉醇45-50mg/㎡每周1次；卡铂AUC 2，同期胸部放疗*,**±追加2周期紫杉醇200mg/㎡加卡铂AUC 6 **Sequential Chemotherapy/RT Regimens (Adjuvant)序贯化/放疗方案（辅助）* Cisplatin 100 mg/m2 on days 1 and 29; vinblastine 5 mg/m2 /weekly on days 1, 8, 15, 22, and 29; followed by RT顺铂100mg/㎡，d1、29；长春花碱5mg/㎡/周，d1、8、15、22、29；序贯放疗* Paclitaxel 200 mg/m2 over 3 hours on day 1; carboplatin AUC 6 over 60 minutes on day 1 every 3 weeks for 2 cycles followed by thoracic RT 紫杉醇200mg/㎡，3小时以上，d1；卡铂AUC 6，60分钟以上，d1，每3周为1周期共2周期，然后胸部放疗*Regimens can be used as neoadjuvant/preoperative/induction chemoradiotherapy. 方案可作为新辅助/术前/诱导化放疗使用。**Regimens can be used as adjuvant or definitive concurrent chemotherapy/RT.方案可作为辅助或根治性同步化/放疗使用。SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC DISEASE 晚期或转移性疾病的全身治疗ADVANCED DISEASE:晚期疾病：* The drug regimen with the highest likelihood of benefit with toxicity deemed acceptable to both the physician and the patient should be given as initial therapy for advanced lung cancer.应该给予最可能受益的、毒性对医患双方都可接受的药物方案作为晚期肺癌的初始治疗。* Stage, weight loss, performance status, and gender predict survival.分期、体重减轻、一般情况以及性别预测生存。* Platinum-based chemotherapy prolongs survival, improves symptom control, and yields superior quality of life compared to best supportive care.与最佳支持治疗相比，以铂类为基础的化疗延长生存期、提高症状控制率并可获得更好的生活质量。* Histology of NSCLC is important in the selection of systemic therapy.在全身治疗的选择方面非小细胞肺癌的组织学是重要的。* New agent/platinum combinations have generated a plateau in overall response rate (≈ 25%–35%), time to progression (4–6 mo), median survival (8–10 mo), 1-year survival rate (30%–40%), and 2-year survival rate (10%–15%) in it patients.患者接受新药/铂二联的疗效有个平台：总有效率（≈25%–35%）、至进展时间（4–6个月）、中位生存期（8–10个月）、1年生存率（30%–40%）、2年生存率（10%–15%）。* Unit patients of any age (performance status 3–4) do not benefit from cytotoxic treatment, except erlotinib, afatinib, or gefitinib for EGFR mutation-positive and crizotinib for ALK-positive tumors of nonsquamous NSCLC or NSCLC NOS. PS 3–4、任何年龄段的患者均不能从细胞毒性治疗中获益，除了厄洛替尼、阿法替尼或吉非替尼用于治疗EGFR突变阳性和克唑替尼用于治疗ALK阳性的非鳞非小细胞肺癌或非小细胞肺癌非特指患者。First-line Therapy一线治疗* There is superior efficacy and reduced toxicity for cisplatin/pemetrexed in patients with nonsquamous histology, in comparison to cisplatin/gemcitabine. 在组织学非鳞癌患者中，与顺铂/吉西他滨相比，顺铂/培美曲塞有优越的疗效和较低的毒性。* There is superior efficacy for cisplatin/gemcitabine in patients with squamous histology, in comparison to cisplatin/pemetrexed.在组织学鳞癌患者中，与顺铂/培美曲塞相比，顺铂/吉西他滨有优越的疗效。* Two drug regimens are preferred; a third cytotoxic drug increases response rate but not survival. Single-agent therapy may be appropriate in select patients. 首选两药方案；第3个细胞毒药物增加有效率，但不改善生存。在选择性的患者中单药治疗可能是合理的。* Response assessment after 2 cycles, then every 2–4 cycles with CT of known sites of disease with or without contrast or when clinically indicated. 两周期后评估疗效，然后每2-4周期或有临床指征时对已知部位强化或平扫CT检查。Maintenance Therapy维持治疗* Continuation maintenance refers to the use of at least one of the agents given in first line, beyond 4–6 cycles, in the absence of disease progression. Switch maintenance refers to the initiation of a different agent, not included as part of the first-line regimen, in the absence of disease progression, after 4–6 cycles of initial therapy. 继续维持治疗是指在4至6周期后疾病无进展者，使用至少一种一线给予的药物。转换维持治疗是指在4-6周期初始治疗后疾病无进展者，启动一线方案中不包含的另一个不同的药物。Subsequent Therapy后续治疗* Response assessment with CT of known sites of disease with or without contrast every 6–12 weeks.每6-12周对已知病变部位强化或平扫CT检查评估疗效。First-line Systemic Therapy Options一线全身治疗方案Adenocarcinoma, Large Cell, NSCLC NOS (PS 0-1)腺癌、大细胞肺癌、非小细胞肺癌非特指（PS 0-1）* Bevacizumab/carboplatin/paclitaxel (category 1) 贝伐单抗/卡铂/紫杉醇（1类） *,**,**** Bevacizumab/carboplatin/pemetrexed贝伐单抗/卡铂/培美曲塞*,**,**** Bevacizumab/cisplatin/pemetrexed贝伐单抗/顺铂/培美曲塞*,**,**** Carboplatin/albumin-bound paclitaxel (category 1)卡铂/白蛋白结合型紫杉醇（1类）* Carboplatin/docetaxel (category 1)卡铂/多西他赛（1类）* Carboplatin/etoposide (category 1)卡铂/依托泊苷（1类）* Carboplatin/gemcitabine (category 1)卡铂/吉西他滨（1类）* Carboplatin/paclitaxel (category 1)卡铂/紫杉醇（1类）* Carboplatin/pemetrexed (category 1)卡铂/培美曲塞（1类）* Cisplatin/docetaxel (category 1)顺铂/多西他赛（1类）* Cisplatin/etoposide (category 1)顺铂/依托泊苷（1类）* Cisplatin/gemcitabine (category 1)顺铂/吉西他滨（1类）* Cisplatin/paclitaxel (category 1)顺铂/紫杉醇（1类）* Cisplatin/pemetrexed (category 1)顺铂/培美曲塞（1类）* Gemcitabine/docetaxel (category 1)吉西他滨/多西他赛（1类）* Gemcitabine/vinorelbine (category 1)吉西他滨/长春瑞滨（1类）Adenocarcinoma, Large Cell, NSCLC NOS (PS 2)腺癌，大细胞肺癌，非小细胞肺癌非特指（PS 2）* Albumin-bound paclitaxel白蛋白结合型紫杉醇* Carboplatin/albumin-bound paclitaxel卡铂/白蛋白结合型紫杉醇* Carboplatin/docetaxel卡铂/多西他赛* Carboplatin/etoposide卡铂/依托泊苷* Carboplatin/gemcitabine卡铂/吉西他滨* Carboplatin/paclitaxel卡铂/紫杉醇* Carboplatin/pemetrexed卡铂/培美曲塞* Docetaxel多西他赛* Gemcitabine吉西他滨* Gemcitabine/docetaxel吉西他滨/多西他赛* Gemcitabine/vinorelbine吉西他滨/长春瑞滨* Paclitaxel紫杉醇* Pemetrexed培美曲塞+ Albumin-bound paclitaxel may be substituted for either paclitaxel or docetaxel in patients who have experienced hypersensitivity reactions after receiving paclitaxel or docetaxel despite premedication, or for patients where the standard premedications (ie, dexamethasone, H2 blockers, H1 blockers) are contraindicated. 在接受紫杉醇或多西他赛的患者中，尽管预处理用药仍有过敏反应者，或标准预处理用药（即地塞米松、H2受体阻滞剂、H1受体阻滞剂）禁忌者，白蛋白结合型紫杉醇可以取代紫杉醇或多西他赛。*Bevacizumab should be given until progression. 应该给予贝伐单抗直至疾病进展。**Any regimen with a high risk of thrombocytopenia and the potential risk of bleeding should be used with caution in combination with bevacizumab.任何具有血小板减少高危和潜在出血风险的方案，联合贝伐单抗时均应谨慎。***Criteria for treatment with bevacizumab: non-squamous NSCLC, and no recent history of hemoptysis. Bevacizumab should not be given as a single agent, unless as maintenance if initially used with chemotherapy.联合贝伐单抗是标准治疗：非鳞非小细胞肺癌并且近期无咯血史。贝伐单抗不应单药给予，除非最初联合化疗使用然后作为维持。First-line Systemic Therapy Options一线全身治疗方案Squamous Cell Carcinoma (PS 0-1)鳞状细胞癌（PS 0-1）* Carboplatin/albumin-bound paclitaxel (category 1)卡铂/白蛋白结合型紫杉醇（1类）* Carboplatin/docetaxel (category 1)卡铂/多西他赛（1类）* Carboplatin/gemcitabine (category 1)卡铂/吉西他滨（1类）* Carboplatin/paclitaxel (category 1)卡铂/紫杉醇（1类）* Cisplatin/docetaxel (category 1)顺铂/多西他赛（1类）* Cisplatin/etoposide (category 1)顺铂/依托泊苷（1类）* Cisplatin/gemcitabine (category 1)顺铂/吉西他滨（1类）* Cisplatin/paclitaxel (category 1)顺铂/紫杉醇（1类）* Gemcitabine/docetaxel (category 1)吉西他滨/多西他赛（1类）* Gemcitabine/vinorelbine (category 1)吉西他滨/长春瑞滨（1类）Squamous Cell Carcinoma (PS 2)鳞状细胞癌（PS 2）* Albumin-bound paclitaxel白蛋白结合型紫杉醇* Carboplatin/albumin-bound paclitaxel卡铂/白蛋白结合型紫杉醇* Carboplatin/docetaxel卡铂/多西他赛* Carboplatin/etoposide卡铂/依托泊苷* Carboplatin/gemcitabine卡铂/吉西他滨* Carboplatin/paclitaxel卡铂/紫杉醇* Docetaxel多西他赛* Gemcitabine吉西他滨* Gemcitabine/docetaxel吉西他滨/多西他赛* Gemcitabine/vinorelbine吉西他滨/长春瑞滨* Paclitaxel紫杉醇+ Albumin-bound paclitaxel may be substituted for either paclitaxel or docetaxel in patients who have experienced hypersensitivity reactions after receiving paclitaxel or docetaxel despite premedication, or for patients where the standard premedications (ie, dexamethasone, H2 blockers, H1 blockers) are contraindicated. 在接受紫杉醇或多西他赛的患者中，尽管预处理用药仍有过敏反应者，或标准预处理用药（即地塞米松、H2受体阻滞剂、H1受体阻滞剂）禁忌者，白蛋白结合型紫杉醇可以取代紫杉醇或多西他赛。++ Cisplatin/gemcitabine/necitumumab in the first-line setting and erlotinib or afatinib in the second-line setting are not used at NCCN institutions for these indications related to the efficacy and safety of these agents compared to the efficacy and safety of other available agents.在NCCN机构中对于这些适应症，基于这些药物的疗效与安全性和其他可用药物的疗效与安全性相比较，顺铂/吉西他滨/奈昔妥珠单抗不用于一线、厄洛替尼或阿法替尼不用于二线。

NSCLC NCCN2016V4 Discussion 讨论Pathologic Evaluation of Lung Cancer 肺癌的病理学检查山东省肿瘤医院呼吸肿瘤内科张品良Pathologic evaluation is performed to classify the histologic type of the lung cancer, determine the extent of invasion, determine whether it is primary lung cancer or metastatic cancer, establish the cancer involvement status of the surgical margins (ie, positive or negative margins), and do molecular diagnostic studies to determine whether certain gene alterations are present (eg, epidermal growth factor receptor [EGFR] mutations) (see Principles of Pathologic Review in the NCCN Guidelines for Non-Small Cell Lung Cancer). 进行病理学检查是为了对肺癌进行组织学分型、确定浸润范围、判断是原发性肺癌还是转移癌、确定手术切缘的癌症累及情况（即阳性或阴性切缘），并进行分子诊断研究以确定是否存在某些基因改变（如，表皮生长因子受体[EGFR]突变（见非小细胞肺癌NCCN指南中的病理学检查原则）。Data show that targeted therapy is potentially very effective in patients with specific gene mutations or rearrangements (see EGFR Mutations and ALK Gene Rearrangements in this Discussion). 数据显示，在特定基因突变或重排的患者中靶向治疗有可能非常有效（见本讨论中的EGFR突变和ALK基因重排）。Preoperative evaluations include examination of the following: bronchial brushings, bronchial washings, sputum, FNA biopsy, core needle biopsy, endobronchial biopsy, and transbronchial biopsy. 术前评估包括下列检查：支气管刷检、支气管灌洗、痰液、FNA活检、空心针穿刺活检、支气管内活检和经支气管肺活检。Minimally invasive techniques can be used to obtain specimens in patients with advanced unresectable NSCLC; however, diagnosis may be more difficult when using small biopsies and cytology. 在晚期不可切除的NSCLC患者中，可以用微创技术来获取标本；然而，当使用小活检和细胞学时，诊断可能会更困难。The mediastinal lymph nodes are systematically sampled to determine the staging and therapeutic options. 对纵隔淋巴结进行系统采样，以确定分期和治疗方案。Other lung diseases also need to be ruled out (eg, tuberculosis, sarcoidosis). 还需要排除其他肺部疾病（如结核病、结节病）。Lobectomy or pneumonectomy specimens are evaluated intraoperatively to determine the surgical resection margin status, diagnose incidental nodules discovered at the time of surgery, or evaluate the regional lymph nodes. 术中评估肺叶或全肺切除标本以确定手术切缘情况、确诊手术时偶然发现的结节或评估区域淋巴结。Postoperative evaluation provides the pathology characteristics necessary for the classification of tumor type, staging, and prognostic factors. 术后评估为肿瘤分型、分期和预后因素提供必要的病理特征。The surgical pathology report should include the WHO histologic classification for carcinomas of the lung. 手术病理报告应包括WHO肺癌组织学分类。In 2011, the classification for lung adenocarcinoma was revised by an international panel (see Adenocarcinoma in this Discussion). 在2011年，国际专家组修订了肺腺癌分类（见此讨论中的腺癌）。The revised classification requires immunohistochemical, histochemical, and molecular studies (see Principles of Pathologic Review in the NCCN Guidelines for Non-Small Cell Lung Cancer). 修订后的分类需要免疫组织化学、组织化学和分子研究（见非小细胞肺癌NCCN指南中的病理学检查原则）。In addition, the revised classification recommends that use of general categories (eg, NSCLC) should be minimized, because more effective treatment can be selected when the histology is known. 此外，修订的分类法建议，应尽量减少使用总分类（如，NSCLC），因为当组织学已知时，可以选择更有效的治疗。Adenocarcinoma 腺癌In the revised classification for adenocarcinoma, the categories of BAC or mixed subtype adenocarcinoma are no longer used. 在修订的腺癌分类法中，不再使用BAC或混合腺癌亚型分类。If necessary, former BAC can be used. 如果有必要，可以使用以前的BAC。The categories for adenocarcinoma include: 1) AIS (formerly BAC), which is a preinvasive lesion; 2) MIA; 3) invasive adenocarcinoma (includes formerly nonmucinous BAC); and 4) variants of invasive adenocarcinoma (includes formerly mucinous BAC). 腺癌的类型包括：1）AIS（原位腺癌，原来的BAC），这是一种癌前病变；2）MIA（微浸润腺癌）；3）浸润腺癌（包括以前的非黏液性BAC）；和4）浸润腺癌的变异型（包括以前的黏液性BAC）。Both AIS and MIA are associated with excellent survival if they are resected. AIS（原位腺癌）和MIA（微小浸润性腺癌）如果切除两者均具有极好的生存。The international panel and NCCN recommend that all patients with adenocarcinoma be tested for EGFR mutations; the NCCN Panel also recommends that these patients be tested for anaplastic lymphoma kinase (ALK) gene rearrangements and other genetic alterations. 国际性组织和NCCN推荐对所有腺癌患者进行EGFR突变检测；NCCN小组还建议对这些患者进行间变性淋巴瘤激酶（ALK）基因重排以及其他基因改变检测。The terms--AIS, MIA, and large cell carcinoma---should not be used for small samples because of challenges with cytology specimens. 对于小样本，由于面临细胞学标本的挑战，不应使用AIS（原位腺癌）、MIA（微浸润腺癌）和大细胞癌术语。Immunohistochemical Staining 免疫组化染色Immunostains are used to differentiate primary pulmonary adenocarcinoma from metastatic adenocarcinoma to the lung (eg, breast, prostate, colorectal), to distinguish adenocarcinoma from malignant mesothelioma, and to determine the neuroendocrine status of tumors. 免疫标记用于鉴别原发性肺腺癌和肺转移性腺癌（如乳腺、前列腺、结肠）、鉴别恶性间皮瘤的腺癌并确定肿瘤的神经内分泌状态。Immunohistochemical staining is described in the NSCLC algorithm (see Principles of Pathologic Review in the NCCN Guidelines for Non-Small Cell Lung Cancer). 免疫组化染色在NSCLC工作步骤中描述（见非小细胞肺癌NCCN指南中的病理学检查原则）。However, limited use of IHC in small tissue samples is recommended to conserve tumor tissue for molecular studies, especially in patients with advanced disease. 然而，在小的组织标本中IHC应用受限，建议保存肿瘤组织进行分子研究，尤其是在晚期患者中。For the 2016 update (Version 1), the NCCN Panel added a recommendation that IHC should be judiciously used to preserve tissue for molecular testing. 2016年第1版更新，NCCN小组增加了一个对于保存用于分子检测的组织应审慎使用IHC。Before using IHC, all findings should be assessed including routine H&E histology, clinical findings, imaging studies, and the patient’s history. 在使用IHC之前，应评估所有的检查结果包括常规H&E组织学、临床表现、影像学检查及患者的病史。Although cytology can be used to distinguish adenocarcinomas from squamous cell carcinomas, IHC is also useful for poorly differentiated NSCLC in small biopsy and/or cytology specimens. 虽然细胞学可以用来区分腺癌与鳞状细胞癌，但是对于小活检的低分化NSCLC和/或细胞学标本IHC也是有用的。Squamous cell carcinomas are often TTF-1 negative and p63 positive, whereas adenocarcinomas are usually TTF-1 positive. 鳞状细胞癌通常是TTF-1阴性和p63阳性，而腺癌通常是TTF-1阳性。These 2 markers may be sufficient to distinguish adenocarcinomas from squamous cell carcinomas. 这两个标记可能足以区分腺癌与鳞状细胞癌。Other markers (eg, p40, Napsin A) may also be useful in distinguishing adenocarcinoma from squamous cell carcinoma. 其他标记（如p40、Napsin A）在区分腺癌与鳞状细胞癌方面可能也是有用的。Immunohistochemistry (IHC) is valuable for distinguishing between malignant mesothelioma and lung adenocarcinoma. 对于区分恶性间皮瘤和肺腺癌，免疫组织化学（IHC）是有价值的。However, the NCCN Panel feels that malignant mesothelioma and lung adenocarcinoma can be distinguished using clinical impression, imaging, and a limited panel of immunomarkers (if needed) to preserve tissue for molecular testing. 然而，NCCN小组认为恶性间皮瘤和肺腺癌可以使用临床印象、影像以及对保存的用于分子检测的组织用一组限定的免疫标记（如果需要）来区分。The stains that are positive for adenocarcinoma include carcinoembryonic antigen (CEA), B72.3, Ber-EP4, MOC-31, CD15, claudin-4, and TTF-1; these stains are negative for mesothelioma. 对于腺癌，阳性染色包括癌胚抗原（CEA）、CA724（B72.3）、Ep-CAM（上皮特异性抗原，Ber-EP4)、MOC-31、CD15、紧密连接蛋白-4和甲状腺转录因子-1（TTF-1）；对于间皮瘤，这些染色是阴性的。Stains that are sensitive and specific for mesothelioma include WT-1, calretinin, D2-40 (podoplanin antibody), HMBW-1, and cytokeratin 5/6. 对于间皮瘤，敏感且特异的染色包括WT-1、钙结合蛋白、D2-40（平足蛋白抗体）、HMBW-1和细胞角蛋白5/6。If needed, a panel of 4 markers can be used to distinguish mesothelioma from adenocarcinoma-2 are positive in mesothelioma and 2 are positive in adenocarcinoma but negative in mesothelioma-including calretinin, cytokeratin 5/6 (or WT-1), CEA, and MOC-31 (or B72.3, Ber-EP4, or BG-8). 如果需要，一组4个标记可以用来区分间皮瘤与腺癌--两个在间皮瘤中阳性、两个在腺癌中阳性但在间皮瘤中阴性--包括钙结合蛋白、细胞角蛋白5/6（或WT-1）、CEA和MOC-31（或B72.3、Ber-EP4或BG-8）。An appropriate panel of immunohistochemical stains is recommended to rule out metastatic carcinoma to the lung if the primary origin of the carcinoma is uncertain. 如果癌的原发灶不确定，建议用一组合理的免疫组化染色以排除肺转移性癌。TTF-1 is very important for distinguishing primary lung adenocarcinoma from metastatic adenocarcinoma, because most primary adenocarcinomas are TTF-1 positive. 对于识别原发肺腺癌与转移性腺癌TTF-1是非常重要的，因为大多数原发性腺癌是TTF-1阳性的。TTF-1 is typically negative for squamous cell carcinoma. 鳞状细胞癌TTF-1通常是阴性的。However, TTF-1 is positive in tumors from patients with thyroid cancer. 然而，甲状腺癌患者的肿瘤TTF-1是阳性的。In addition, thyroglobulin is present in tumors from patients with thyroid cancer, while it is negative in lung cancer tumors. 此外，甲状腺球蛋白存在于甲状腺癌患者的肿瘤中，而在肺癌肿瘤中是阴性的。Pulmonary adenocarcinoma of the lung is usually CK7+ and CK20-, whereas metastatic adenocarcinoma of the colorectum is usually CK7- and CK20+. 肺的肺腺癌通常是CK7+和CK20-，而结直肠的转移性腺癌通常是CK7-和CK20+。CDX2 is a marker for metastatic gastrointestinal malignancies that can be used to differentiate them from primary lung tumors. CDX2（肠道特异性转录因子2）是转移性胃肠道恶性肿瘤的一个标记物，可用于与原发性肺肿瘤的区分。All typical and atypical carcinoid tumors are positive for chromogranin and synaptophysin, whereas SCLC is negative in 25% of cases. 所有典型与不典型类癌嗜铬粒蛋白和突触素均是阳性的，而25%的SCLC病例是阴性的。Although the cytologic diagnosis of NSCLC is generally reliable, it is more difficult to diagnose SCLC. 虽然NSCLC的细胞学诊断通常是可靠的，但是诊断SCLC更困难。However, many patients with SCLC have characteristic CT and clinical findings (eg, massive lymphadenopathy, mediastinal invasion). 然而，许多SCLC患者具有特征性的CT和临床表现（如淋巴结肿大、纵隔侵犯）。Most SCLCs are immunoreactive for TTF-1; they are typically negative for CK34βE12 and p63. 对于TTF-1大多数SCLCs是阳性的；对于CK34βE12和p63他们通常是阴性的。Many SCLCs also stain positively for markers of neuroendocrine differentiation, including chromogranin A, neuron-specific enolase, neural cell adhesion molecule, and synaptophysin. 对于神经内分泌分化的标记，包括嗜铬粒蛋白A、神经元特异性烯醇化酶、神经细胞黏附分子和突触素，许多SCLCs染色也是阳性的。However, these markers alone cannot be used to distinguish SCLC from NSCLC, because approximately 10% of NSCLCs are immunoreactive for at least one of these neuroendocrine markers. 然而，这些标记不能用来区分SCLC和NSCLC，因为大约10%的NSCLCs这些神经内分泌标记中至少一个是阳性的。Data suggest that microRNA expression can be used to distinguish SCLC from NSCLC. 数据表明，microRNA表达可以用来区分SCLC和NSCLC。Staging 分期The NCCN Guidelines use the AJCC (7th edition) staging system for lung cancer. NCCN指南使用AJCC （第7版） 肺癌分期系统。The definitions for TNM and the stage grouping are summarized in Tables 1 and 2 of the staging tables (see Definitions for T,N,M and Staging in the NCCN Guidelines for Non-Small Cell Lung Cancer). TNM定义、分期组合总结在分期表1和2（见非小细胞肺癌NCCN指南中的T、N、M分期定义）。The descriptors of the TNM classification scheme are summarized in Table 3 of the staging tables (see Staging). TNM分期方案的描述总结在分期表中的表3（见分期）。The lung cancer staging system was revised by the International Association for the Study of Lung Cancer (IASLC) and was adopted by the AJCC. 肺癌分期系统由国际肺癌研究协会（IASLC）修订并被AJCC采用。With the AJCC staging, locally advanced disease is stage III; advanced disease is stage IV. 对于AJCC分期，局部晚期疾病是III期；晚期疾病是IV期。Pathologic staging uses both clinical staging information (which is noninvasive and includes medical history, physical examination, and imaging) and other invasive staging procedures (eg, thoracotomy, examination of lymph nodes using mediastinoscopy). 病理分期使用临床分期信息（无创性，包括病史、体格检查和影像）和其他侵袭性分期措施（如开胸手术、纵隔镜淋巴结检查）两者的信息。From 2005 to 2011, the overall 5-year relative survival rate for lung cancer was 17.4% in the United States. 从2005年到2011年，在美国，肺癌的5年总生存率为17.4%。Of lung and bronchial cancer cases, 16% were diagnosed while the cancer was still confined to the primary site; 22% were diagnosed after the cancer had spread to regional lymph nodes or directly beyond the primary site; 57% were diagnosed after the cancer had already metastasized; and for the remaining 5% the staging information was unknown. 在肺和支气管癌的病例中，有16%被诊断为癌症，而癌症仍局限于原发部位；22%是在癌症已经扩散到区域淋巴结或直接超出了原发部位后确诊；57%是在癌症已经转移后确诊；而其余的5%分期信息不明。The corresponding 5-year relative survival rates were 54.8% for localized, 27.4% for regional, 4.2% for distant, and 7.5% for unstaged. 相应的5年相对生存率是局部54.8%、区域27.4%、远处4.2%、未分期7.5%。However, these data include SCLC, which has a poorer prognosis. 然而，这些数据包括预后较差的SCLC。Five-year survival after lobectomy for pathologic stage I NSCLC ranges from 45% to 65%, depending on whether the patient has stage 1A or 1B disease and on the location of the tumor. 病理I期NSCLC在叶切除术后的5年生存率为45%到65%，取决于患者是IA还是IB期疾病以及肿瘤的位置。Another study in patients with stage I disease (n = 19,702) found that 82% had surgical resection and their 5-year overall survival was 54%; however, for untreated stage I NSCLC, 5-year overall survival was only 6%. 另外一项Ⅰ期疾病患者（n=19702）的研究发现，手术切除的82%中，其5年总生存率是54%；然而，对于未治疗的Ⅰ期NSCLC，5年总生存率仅为6%。Of patients with stage I disease who refused surgery (although it was recommended), 78% died of lung cancer within 5 years. 在拒绝手术（虽然建议）的I期患者中，78%在5年内死于肺癌。

讨论部分的中文翻译。

SYSTEMIC THERAPY FOR METASTATIC OR LOCALLY ADVANCED CANCER (WHERE LOCAL THERAPY IS NOT INDICATED) 转移性或局部晚期恶性肿瘤（无局部治疗指征）的系统治疗FIRST-LINE THERAPY 一线治疗山东省肿瘤医院呼吸肿瘤内科张品良Trastuzumab (with chemotherapy) 曲妥珠单抗(联合化疗)Trastuzumab 8 mg/kg IV loading dose on Day 1 of cycle 1, then 第1周期的第1天曲妥珠单抗负荷量8mg/kg IV，然后Trastuzumab 6 mg/kg IV every 21 days 每14天6mg/kg IVor 或Trastuzumab 6 mg/kg IV loading dose on Day 1 of cycle 1, then 4 mg/kg IV every 14 days 曲妥珠单抗6mg/kg静脉注射负荷剂量第1周期的第1天，然后4mg/kg静脉注射每14天重复PREFERRED REGIMENS 首选方案Fluoropyrimidine and cisplatin 氟嘧啶和顺铂Cisplatin 75–100 mg/m2 IV on Day 1 顺铂75-100mg/㎡ IV d1Fluorouracil 750–1000 mg/m2 IV continuous infusion over 24 hours daily on Days 1–4 氟尿嘧啶750-1000mg/㎡持续静脉输注24小时以上每天1次 d1-4Cycled every 28 days 每28天为1周期Cisplatin 50 mg/m2 IV daily on Day 1 顺铂50mg/㎡ IV每天1次 d1Leucovorin 200 mg/m2 IV on Day 1 亚叶酸钙200mg/㎡ IV d1Fluorouracil 2000 mg/m2 IV continuous infusion over 24 hours daily on Day 1 氟尿嘧啶2000mg/㎡持续静脉输注24小时以上每天1次 d1Cycled every 14 days 每14天为1周期Cisplatin 80 mg/m2 IV daily on Day 1 顺铂每天80mg/㎡ IV d1Capecitabine 1000 mg/m2 PO BID on Days 1–14 卡培他滨1000mg/㎡口服每日两次 d1-14Cycled every 21 days 每21天重复Fluoropyrimidine and oxaliplatin 氟嘧啶和奥沙利铂Oxaliplatin 85 mg/m2 IV on Day 1 奥沙利铂85mg/㎡ IV d1Leucovorin 400 mg/m2 IV on Day 1 亚叶酸钙400mg/㎡ IV d1Fluorouracil 400 mg/m2 IV Push on Day 1 氟尿嘧啶400mg/㎡ IV d1Fluorouracil 1200 mg/m2 IV continuous infusion over 24 hours daily on Days 1 and 2 氟尿嘧啶1200mg/㎡持续静脉输注24小时以上每天1次 d1、2Cycled every 14 days 每14天为1周期Oxaliplatin 85 mg/m2 IV on Day 1 奥沙利铂85mg/㎡ IV d1Leucovorin 200 mg/m2 IV on Day 1 亚叶酸钙200mg/㎡ IV d1Fluorouracil 2600 mg/m2 IV continuous infusion over 24 hours on Day 1 氟尿嘧啶2600mg/㎡持续静脉输注24小时以上 d1Cycled every 14 days 每14天为1周期Capecitabine 1000 mg/m2 PO BID on Days 1–14 卡培他滨1000mg/㎡口服每日两次 d1-14Oxaliplatin 130 mg/m2 IV on Day 1 奥沙利铂130mg/㎡ IV d1Cycled every 21 days 每21天重复DCF modifications 改良的DCFDocetaxel 40 mg/m2 IV on Day 1 多西他赛40mg/㎡ IV d1Leucovorin 400 mg/m2 IV on Day 1 亚叶酸钙400mg/㎡ IV d1Fluorouracil 400 mg/m2 IV on Day 1 氟尿嘧啶400mg/㎡ IV d1Fluorouracil 1000 mg/m2 IV continuous infusion over 24 hours daily on Days 1 and 2 氟尿嘧啶1000mg/㎡持续静脉输注24小时以上每天1次 d1、2Cisplatin 40 mg/m2 IV on Day 3 顺铂40mg/㎡ IV d3Cycled every 14 days 每14天为1周期Docetaxel 50 mg/m2 IV on Day 1 多西他赛50mg/㎡ IV d1Oxaliplatin 85 mg/m2 IV on Day 1 奥沙利铂85mg/㎡ IV d1Fluorouracil 1200 mg/m2 IV continuous infusion over 24 hours daily on Days 1 and 2 氟尿嘧啶1200mg/㎡持续静脉输注24小时以上每天1次 d1、2Cycled every 14 days 每14天为1周期Docetaxel 75 mg/m2 IV on Day 1 多西他赛75mg/㎡ IV d1Carboplatin AUC 6 IV on Day 2 卡铂AUC6 IV d2Fluorouracil 1200 mg/m2 IV continuous infusion over 24 hours daily on Days 1–3 氟尿嘧啶1200mg/㎡持续静脉输注24小时以上每天1次 d1-3Cycled every 21 days 每21天重复OTHER REGIMENS 其他方案Paclitaxel with cisplatin or carboplatin 紫杉醇联合顺铂或卡铂Paclitaxel 135–200 mg/m2 IV on Day 1 紫杉醇135-200mg/㎡ IV d1Cisplatin 75 mg/m2 IV on Day 2 顺铂75mg/㎡ IV d2Cycled every 21 days 每21天重复Paclitaxel 90 mg/m2 IV on Day 1 紫杉醇90mg/㎡ IV d1Cisplatin 50 mg/m2 IV on Day 1 顺铂50mg/㎡ IV d1Cycled every 14 days 每14天为1周期Paclitaxel 200 mg/m2 IV on Day 1 紫杉醇200mg/㎡ IV d1Carboplatin AUC 5 IV on Day 1 卡铂AUC5 IV d1Cycled every 21 days 每21天重复Docetaxel and cisplatin 多西他赛和顺铂Docetaxel 70–85 mg/m2 IV on Day 1 多西他赛70-85mg/㎡ IV d1Cisplatin 70–75 mg/m2 IV on Day 1 顺铂70-75mg/㎡ IV d1Cycled every 21 days 每21天重复Fluoropyrimidine 氟嘧啶Leucovorin 400 mg/m2 IV on Day 1 亚叶酸钙400mg/㎡ IV d1Fluorouracil 400 mg/m2 IV Push on Day 1 氟尿嘧啶400mg/㎡ IV d1Fluorouracil 1200 mg/m2 IV continuous infusion over 24 hours daily on Days 1 and 2 氟尿嘧啶1200mg/㎡持续静脉输注24小时以上每天1次 d1、2Cycled every 14 days 每14天为1周期Fluorouracil 800 mg/m2 IV continuous infusion over 24 hours daily on Days 1–5 氟尿嘧啶800mg/㎡持续静脉输注24小时以上每天1次 d1-5Cycled every 28 days 每28天为1周期Capecitabine 1000–1250 mg/m2 PO BID on Days 1–14 卡培他滨1000-1250mg/㎡口服每日两次 d1-14Cycled every 21 days 每21天重复Taxane 紫杉烷Docetaxel 75–100 mg/m2 IV on Day 1 多西他赛75-100mg/㎡ IV d1Cycled every 21 days 每21天重复Paclitaxel 135–250 mg/m2 IV on Day 1 紫杉醇135-250mg/㎡ IV d1Cycled every 21 days 每21天重复Paclitaxel 80 mg/m2 IV on Day 1 weekly 紫杉醇80mg/㎡ IV d1每周1次Cycled every 28 days 每28天为1周期Fluorouracil and irinotecan 氟尿嘧啶和伊立替康Irinotecan 180 mg/m2 IV on Day 1 伊立替康180mg/㎡ IV d1Leucovorin 400 mg/m2 IV on Day 1 亚叶酸钙400mg/㎡ IV d1Fluorouracil 400 mg/m2 IV Push on Day 1 氟尿嘧啶400mg/㎡ IV d1Fluorouracil 1200 mg/m2 IV continuous infusion over 24 hours daily on Days 1 and 2 氟尿嘧啶1200mg/㎡持续静脉输注24小时以上每天1次 d1、2Cycled every 14 days (only for adenocarcinoma) 每14天为1周期(只适用于腺癌)Irinotecan 80 mg/m2 IV on Day 1 伊立替康80mg/㎡ IV d1Leucovorin 500 mg/m2 IV on Day 1 亚叶酸钙500mg/㎡ IV d1Fluorouracil 2000 mg/m2 IV continuous infusion over 24 hours on Day 1 氟尿嘧啶2000mg/㎡持续静脉输注24小时以上 d1Weekly for 6 weeks followed by 2 weeks off treatment 每周1次连续6周然后休息2周ECF Epirubicin 50 mg/m2 IV on Day 1 表柔比星50mg/㎡ IV d1Cisplatin 60 mg/m2 IV on Day 1 顺铂60mg/㎡ IV d1Fluorouracil 200 mg/m2 IV continuous infusion over 24 hours daily on Days 1–21 氟尿嘧啶200mg/㎡持续静脉输注24小时以上每天1次 d1-21Cycled every 21 days 每21天重复ECF modifications 改良的ECFEpirubicin 50 mg/m2 IV on Day 1 表柔比星50mg/㎡ IV d1Oxaliplatin 130 mg/m2 IV on Day 1 奥沙利铂130mg/㎡ IV d1Fluorouracil 200 mg/m2 IV continuous infusion over 24 hours daily on Days 1–21 氟尿嘧啶200mg/㎡持续静脉输注24小时以上每天1次 d1-21Cycled every 21 days 每21天重复Epirubicin 50 mg/m2 IV on Day 1 表柔比星50mg/㎡ IV d1Cisplatin 60 mg/m2 IV on Day 1 顺铂60mg/㎡ IV d1Capecitabine 625 mg/m2 PO BID on Days 1–21 卡培他滨625mg/㎡口服每日两次 d1-21Cycled every 21 days 每21天重复Epirubicin 50 mg/m2 IV on Day 1 表柔比星50mg/㎡ IV d1Oxaliplatin 130 mg/m2 IV on Day 1 奥沙利铂130mg/㎡ IV d1Capecitabine 625 mg/m2 PO BID on Days 1–21 卡培他滨625mg/㎡口服每日两次 d1-21Cycled every 21 days 每21天重复SECOND-LINE THERAPY二线治疗PREFERRED REGIMENS 首选方案Ramucirumab and paclitaxel (for adenocarcinoma only) 雷莫芦单抗和紫杉醇（只适用于腺癌）Ramucirumab 8 mg/kg IV on Days 1 and 15 雷莫芦单抗8mg/kg IV d1、15Paclitaxel 80 mg/m2 on Days 1, 8, and 15 紫杉醇80mg/㎡ IV d1、15Cycled every 28 days 每28天为1周期Taxane 紫杉烷Docetaxel 75–100 mg/m2 IV on Day 1 多西他赛75-100mg/㎡ IV d1Cycled every 21 days 每21天重复Paclitaxel 135–250 mg/m2 IV on Day 1 紫杉醇135-250mg/㎡ IV d1Cycled every 21 days 每21天重复Paclitaxel 80 mg/m2 IV on Day 1 weekly 紫杉醇80mg/㎡ IV d1每周1次Cycled every 28 days 每28天为1周期Paclitaxel 80 mg/m2 IV on Days 1, 8, 15 紫杉醇80mg/㎡ IV d1、8、15Cycled every 28 days 每28天为1周期Irinotecan 伊立替康Irinotecan 250–350 mg/m2 IV on Day 1 伊立替康250-350mg/㎡ IV d1Cycled every 21 days 每21天重复Irinotecan 150–180 mg/m2 IV on Day 1 伊立替康150-180mg/㎡ IV d1Cycled every 14 days 每14天为1周期Irinotecan 125 mg/m2 IV on Days 1 and 8 伊立替康125mg/㎡ IV d1、8Cycled every 21 days 每21天重复Ramucirumab (for adenocarcinoma only) 雷莫芦单抗（只适用于腺癌）Ramucirumab 8 mg/kg IV on Day 1 雷莫芦单抗8mg/kg IV d1Cycled every 14 days 每14天为1周期OTHER REGIMENS 其他方案Irinotecan and cisplatin 伊立替康和顺铂Irinotecan 65 mg/m2 IV on Days 1 and 8 伊立替康65mg/㎡ IV d1、8Cisplatin 25–30 mg/m2 IV on Days 1 and 8 顺铂25-30mg/㎡ IV d1、8Cycled every 21 days 每21天重复Irinotecan and fluoropyrimidine 伊立替康加氟嘧啶Irinotecan 250 mg/m2 IV on Day 1 伊立替康250mg/㎡ IV d1Capecitabine 1000 mg/m2 PO BID on Days 1–14 卡培他滨1000mg/㎡口服每日两次 d1-14Cycled every 21 days 每21天重复Irinotecan 180 mg/m2 IV on Day 1 伊立替康180mg/㎡ IV d1Leucovorin 400 mg/m2 IV on Day 1 亚叶酸钙400mg/㎡ IV d1Fluorouracil 400 mg/m2 IV Push on Day 1 氟尿嘧啶400mg/㎡ IV d1Fluorouracil 1200 mg/m2 IV continuous infusion over 24 hours daily on Days 1 and 2 氟尿嘧啶1200mg/㎡持续静脉输注24小时以上每天1次 d1、2Cycled every 14 days (only for adenocarcinoma) 每14天为1周期(只适用于腺癌)Docetaxel and irinotecan 多西他赛和伊立替康Docetaxel 35 mg/m2 IV on Days 1 and 8 多西他赛35mg/㎡ IV d1、8Irinotecan 50 mg/m2 IV on Days 1 and 8 伊立替康50mg/㎡ IV d1、8Cycled every 21 days 每21天重复The selection, dosing, and administration of anticancer agents and the management of associated toxicities are complex. Modifications of drug dose and schedule and initiation of supportive care interventions are often necessary because of expected toxicities and because of individual patient variability, prior treatment, nutritional status, and comorbidity. The optimal delivery of anticancer agents therefore requires a health care delivery team experienced in the use of anticancer agents and the management of associated toxicities in patients with cancer. 抗癌药物的选择、剂量和给药以及相关毒性的处理是复杂的。因为预期的毒性以及个体患者的差异、既往治疗、营养状况及并存疾病，常常有必要调整药物剂量与给药计划并启动支持治疗干预。因此最理想的抗癌药物实施需要有在癌症患者中抗癌药物使用与相关毒性处理经验的保健医疗团队。食管/食管胃结合处癌 NCCN指南2016v1

二甲双胍与索拉非尼对甲状腺未分化癌细胞及其干细胞生长的协同抗增殖作用。索拉非尼，一个多激酶抑制剂，最近已被批准用于放射性碘难治的甲状腺癌的治疗。然而，毒副作用可能导致减量。在目前的研究中，我们分析联合二甲双胍治疗是否可能允许索拉非尼减量的同时效果毫无损失。 在HTh74甲状腺未分化癌(ATC)细胞及其源自对阿霉素耐药的HTh74Rdox细胞系中，研究索拉非尼加或不加二甲双胍的生长抑制作用。此外，分析对索拉非尼应答的细胞周期阻滞以及综合疗法诱导凋亡的能力。另外，评价对干细胞球的克隆生长及形成的影响。山东省肿瘤医院呼吸肿瘤内科张品良 通过分析胞外信号调节激酶(ERK)磷酸化研究索拉非尼与二甲双胍对丝裂原激活的蛋白(MAP)激酶路径的影响。索拉非尼与二甲双胍协同抑制这两个甲状腺癌细胞系的生长，对阿霉素耐药的HTh74Rdox细胞系作用更显著。这两个药物也协同减小球体形成，提示对甲状腺癌干细胞具有特殊作用。 二甲双胍的加入能够降低25%的索拉非尼用量而其生长抑制效果毫无损失。索拉非尼与二甲双胍协同降低甲状腺未分化癌细胞系以及源自癌症干细胞生长物的增殖。联合处理能够显著降低索拉非尼的剂量。Synergistic anti-proliferative effect of metformin and sorafenib on growth of anaplastic thyroid cancer cells and their stem cells. Oncol Rep. 2015 .

——癌症相关的静脉血栓栓塞症（NCCN 2014V2）静脉血栓栓塞预防物理预防间歇充气压力泵(IPC)装置与分级加压弹力袜(GCS)是主要用于有药理学预防禁忌症患者或在很高危静脉血栓栓塞患者中与药理学药物同时使用的物理预防选择。山东省肿瘤医院呼吸肿瘤内科张品良物理预防不应用于具有急性深静脉血栓或严重的房性功能不全的患者(后者适于分级加压弹力袜)。另外，在存在下列情况下应该权衡考虑风险与收益：巨大血肿、血小板减少症(血小板计数＜20000/mcL )、皮肤溃疡或伤口(其可能更担心GCS)、轻度动脉功能不全(其只适于GCS)或外周神经病(其只适于GCS；见关于物理预防禁忌症指南部分，VTE-B)。无论何时使用物理预防，应采取措施以确保其正确使用并持续应用。在静脉血栓栓塞预防方面间歇充气压力泵装置研究不及抗凝治疗的使用充分。物理预防疗效方面的数据大部分来自外科人群。例如，在一项比较妇科肿瘤手术患者接受低剂量肝素每天3次(手术前一天开始并持续至术后7天或更长时间)或腓部间歇充气压力泵静脉血栓栓塞发生率的研究中，在这两种手段之间没有见到差异。一项高危结直肠手术患者接受物理预防没有抗凝治疗的回顾性评价显示间歇充气压力泵装置在预防术后静脉血栓栓塞方面是有效的。然而，来自一项839例妇科恶性肿瘤接受腹部手术并接受气体压缩与早日下床活动预防静脉血栓栓塞的患者超过2年时间回顾性研究的结果发现在癌症患者中肺栓塞的发生率(4.1%)超过良性疾病患者肺栓塞发生率的14倍(0.3%)。因此，间歇充气压力泵装置只应仅仅应用于抗凝剂预防禁忌的患者静脉血栓栓塞预防。已证明与非预防相比分级加压弹力袜显著降低静脉血栓栓塞而且当与其它预防疗法联合使用时提供十分显著的防护。然而，这些研究的多数是十多年前进行的并且使用纤维蛋白原摄取扫描作为主要结果估量——一种目前过时的诊断方法。另外，这些患者几乎没有被记录有恶性肿瘤。此外，在接受髋部手术的患者中一项随机对照试验发现在接受磺达肝素2.5mg/d 第5-9天的患者中分级加压弹力袜在防止静脉血栓栓塞方面没有提供显著的额外帮助，提示在能够接受更强形式的静脉血栓栓塞预防患者中分级加压弹力袜可能没有显著的临床获益。同样，来自CLOTS1试验的最新结果，卒中1周内的患者随机分配至常规照顾±分级加压弹力袜，发现在这些患者中分级加压弹力袜没有降低深静脉血栓的发生率并且与皮肤溃疡和坏死发生率增加4倍有关。然而，在CLOTS1试验中研究的患者群与这些指南中描述的患者群相当不一致。此外，在机构中长时间延迟预防以及长期持续使用分级加压弹力袜(超过70%达到30天)造成分级加压弹力袜的安全性和有效性在不同人群、各种情况下的研究中可能各异。因此，已经批准进一步研究。在获得数据前，在癌症患者中分级加压弹力袜不应被依赖作为静脉血栓栓塞预防的唯一方法。此外，嘱咐癌症患者分级加压弹力袜用于静脉血栓栓塞预防应该仔细监视皮肤并发症。

Discussion讨论Treatment Approaches治疗手段Targeted Therapies 靶向治疗Afatinib 阿法替尼A randomized phase 3 trial reported that first-line therapy with afatinib improved PFS when compared with cisplatin/pemetrexed in patients with metastatic adenocarcinoma who have sensitizing EGFR mutations (11.1 vs. 6.9 months, P = .001). The FDA has approved afatinib for first-line treatment of patients with metastatic NSCLC who have sensitizing EGFR mutations. Based on this phase 3 randomized trial and the FDA approval, the NCCN Panel recommends afatinib for first-line therapy (category 1) in patients with metastatic non-squamous NSCLC who have sensitizing EGFR mutations (see the NCCN Guidelines for NSCLC). Afatinib may also be continued in patients who have progressed if patients do not have multiple systemic symptomatic lesions (see Continuation of Erlotinib, Gefitinib, or Afatinib After Progression in this Discussion). However, afatinib is not recommended as subsequent therapy based on a recent phase 3 randomized trial (see Second-Line and Beyond (Subsequent) Systemic Therapy in this Discussion). 一项3期随机试验报告，在敏感EGFR突变的转移性腺癌患者中，与顺铂/培美曲塞相比，一线治疗用阿法替尼改善PFS（11.1个月对6.9个月，P=0.001）。FDA已批准阿法替尼用于具有敏感EGFR突变的转移性NSCLC患者的一线治疗。基于这项3期随机试验和FDA的批准，NCCN专家组推荐阿法替尼用于有敏感EGFR突变的转移性非鳞NSCLC患者的一线治疗（1类）（见NSCLC NCCN指南）。在已经进展的患者中，如果病人没有全身多发有症状的病变，也可以继续给予阿法替尼（见本讨论中的在厄洛替尼、吉非替尼或阿法替尼进展后的延续）。然而，根据最近一项3期随机试验，不推荐阿法替尼作为后续治疗（见本讨论中的二线和更多线[后续]全身治疗）。山东省肿瘤医院呼吸肿瘤内科张品良A recent phase 2B trial assessed afatinib compared with gefitinib for first-line therapy in patients with metastatic adenocarcinoma and sensitizing EGFR mutations. The PFS was essentially the same in patients receiving afatinib when compared with those receiving gefitinib (median PFS, 11.0 months [95% CI, 10.6–12.9] with afatinib vs. 10.9 months [9.1–11.5] with gefitinib; HR, 0.73 [95% CI, 0.57–0.95]; P=.017). These slight PFS differences are not clinically relevant and the NCCN Guidelines do not state that one EGFR TKI is more efficacious than another (see the NCCN Evidence Blocks for NSCLC, available at NCCN.org). Overall survival data are not yet available. Patients receiving afatinib had more serious treatment-related side effects when compared with those receiving gefitinib (11% [17/160] for afatinib vs.4% [7/159] for gefitinib). One patient receiving gefitinib died from treatment-related hepatic and renal failure; other deaths were not considered to be related to treatment (9% vs. 6% [15/160 vs. 10/159]). More patients receiving afatinib had diarrhea (13% vs. 1%), whereas more patients receiving gefitinib had elevations in liver enzyme levels (0% vs. 9%). For the 2017 update (Version 1), the NCCN Panel revised the afatinib evidence block for efficacy to highly effective (ie, the highest rating of 5), so the value is now the same as that for erlotinib and gefitinib (see the NCCN Evidence Blocks for NSCLC, available at NCCN.org). However, afatinib is rated as slightly less safe than erlotinib or gefitinib (ie, a rating of 3 for afatinib versus 4 for erlotinib and gefitinib). 最近一项2B期试验评估了阿法替尼对比吉非替尼一线治疗EGFR敏感突变的转移性腺癌患者。与接受吉非替尼者相比，接受阿法替尼的患者PFS基本上是相同的（中位PFS，阿法替尼11个月[95% CI，10.6–12.9]对吉非替尼10.9个月[9.1–11.5]；风险比，0.73 [95%CI，0.57-0.95]；P=0.017）。这些轻微的PFS差异没有临床相关性，因此NCCN指南没有说明一个EGFR TKI比另一个更有效（见NSCLC的NCCN证据组成，可在NCCN.org获得）。总生存数据尚未公布。与接受吉非替尼者相比，接受阿法替尼的患者有更严重的治疗相关副作用（阿法替尼11%[17/160]对吉非替尼4%[7/159]）。一例接受吉非替尼的患者死于治疗相关的肝肾功能衰竭；并不认为其他死亡与治疗相关（9%[15/160]对6%[10/159]）。接受阿法替尼的患者腹泻更多（13%对1%），而接受吉非替尼的患者肝酶水平升高更多（0%对9%）。2017第1版更新，NCCN小组修改阿法替尼疗效非常有效的证据组成（即最高等级5），所以现在与厄洛替尼和吉非替尼的价值相同（见NSCLC的NCCN证据组成，可在NCCN.org获得）。然而，阿法替尼等级安全性比厄洛替尼或吉非替尼略差（即阿法替尼等级3对厄洛替尼和吉非替尼等级4）。

非小细胞肺癌NCCN指南2017第4版讨论:靶向治疗山东省肿瘤医院呼吸肿瘤内科张品良Pembrolizumab 派姆单抗For the 2017 updates (Versions 1 and 2), the NCCN Panel now recommends pembrolizumab (category 1) as first-line therapy for patients with PD-L1 expression levels of 50% or more and with negative or unknown tests results for EGFR mutations, ALK rearrangements, and ROS1 rearrangements based on a recent phase 3 randomized trial (Keynote-024) comparing pembrolizumab versus platinum-based chemotherapy; the FDA recently approved pembrolizumab for first-line therapy based on this trial. At 6 months, the rate of overall survival was 80.2% in the pembrolizumab group versus 72.4% in the chemotherapy group (HR for death, 0.60; 95% CI, 0.41–0.89; P=.005). Reponses were higher in the pembrolizumab group than in the chemotherapy group (44.8% vs. 27.8%). There were fewer severe treatment-related adverse events (grades 3-5) in patients receiving pembrolizumab compared with those receiving chemotherapy (26.6% vs. 53.3%). 2017第1版和第2版更新，根据最近一项比较派姆单抗与铂类为基础的化疗的3期随机试验（Keynote-024），NCCN小组目前推荐派姆单抗（1类）作为PD-L1表达水平≥50%或EGFR突变、ALK重排以及ROS1重排检测结果阴性或未知患者的一线治疗；基于该试验FDA最近批准了派姆单抗用于一线治疗。在6个月时，总生存率派姆单抗组为80.2%，化疗组为72.4%（死亡风险比，0.60；95%CI，0.41–0.89；P=0.005)。派姆单抗组疗效明显高于化疗组（44.8%对27.8%）。与接受化疗的患者相比，接受派姆单抗的患者严重的治疗相关的不良事件（3-5级）较少（26.6%对53.3%）。For the 2017 update (Version 1), the NCCN Panel now recommends (category 2A) IHC testing for PD-L1 expression before first-line treatment in patients with metastatic NSCLC with negative or unknown tests results for EGFR mutations, ALK rearrangements, and ROS1 rearrangements. Although it is not an optimal biomarker, PD-L1 expression is currently the best available biomarker to assess whether patients are candidates for pembrolizumab. PD-L1 expression is continuously variable and dynamic; thus, a cutoff value for a positive result is artificial. Patients with PD-L1 expression levels just below and just above 50% will probably have similar responses. Unique anti-PD-L1 IHC assays are being developed for each one of the different immune checkpoint inhibitors currently in clinical trials. The definition of a positive PD-L1 test result varies depending on which biomarker assay is used. 2017第1版更新，在EGFR突变、ALK重排和ROS1重排检测结果阴性或未知的转移性NSCLC患者中，NCCN小组目前推荐（2A类）在一线治疗前免疫组化检测PD-L1的表达。尽管它不是一个最佳的生物标志物，但是目前评估患者是否适合派姆单抗，PD-L1的表达是最好的生物标志物。PD-L1的表达是持续动态变化的；因此，阳性截断值是人为的。PD-L1表达水平略低于和略高于50%的患者有可能具有相似的疗效。正在开发针对每个不同免疫检查点抑制剂的特异性抗PD-L1免疫组化检测，目前在临床试验中。PD-L1检测结果阳性的定义取决于使用的生物标记法。Ideally, PD-L1 expression levels are assessed in patients with negative or unknown test results for EGFR mutations, ALK rearrangements, or ROS1 rearrangements. Every effort needs to be made to establish the genetic alteration status. However, if the risk of biopsy is high and genetic alteration testing is not feasible and therefore technically unknown, then it is appropriate to test for PD-L1 expression levels. Of note, there are blood assays to evaluate for EGFR mutations and ALK rearrangements although they are less sensitive than tissue assays. 理想情况下，在EGFR突变、ALK重排或ROS1重排检测结果阴性或未知的患者中评估PD-L1表达水平。需要尽力确定遗传改变情况。不过，如果活检的风险很高、遗传学改变检测不可行、在技术上来说未知，那么检测PD-L1表达水平是合适的。值得注意的是，有EGFR突变和ALK重排的血液检测评估，尽管比组织检测敏感性差。The NCCN Panel also recommends pembrolizumab (category 1) as subsequent therapy for patients with metastatic non-squamous or squamous NSCLC and PD-L1 expression based on the randomized phase 2/3 trial (KEYNOTE-010), the phase 1 KEYNOTE-001 trial, and FDA approval. In addition, the NCCN Panel recommends immune checkpoint inhibitors as preferred agents for subsequent therapy. As previously mentioned, human immune-checkpoint–inhibitor antibodies inhibit the PD-1 receptor or PD-L1, which improves antitumor immunity; PD-1 receptors are expressed on activated cytotoxic T-cells. Pembrolizumab inhibits the PD-1 receptor. 基于2/3期随机试验（KEYNOTE-010）、1期KEYNOTE-001试验和FDA的批准，NCCN小组也推荐派姆单抗作为PD-L1表达的转移性非鳞或鳞型NSCLC患者的后续治疗（1类）。此外，NCCN小组推荐免疫检查点抑制剂作为后续治疗的首选药物。如前所述，人免疫检查点抑制剂抗体抑制PD-1或PD-L1，提高抗肿瘤免疫；在活化的细胞毒性T细胞上表达PD-1受体。派姆单抗抑制PD-1受体。A randomized phase 2/3 trial (KEYNOTE-010) assessed pembrolizumab in patients with previously treated advanced non-squamous and squamous NSCLC who were PD-L1 positive (≥ 1%); most patients were current or former smokers. There were 3 arms in this trial: pembrolizumab at 2 mg/kg, pembrolizumab at 10 mg/kg, and docetaxel at 75 mg/m2 every 3 weeks. The median overall survival was 10.4 months for the lower dose of pembrolizumab, 12.7 months for the higher dose, and 8.5 months for docetaxel. Overall survival was significantly longer for both doses of pembrolizumab when compared with docetaxel (pembrolizumab 2 mg/kg: HR, 0.71; 95% CI, 0.58–0.88; P=.0008) (pembrolizumab 10 mg/kg: HR, 0.61; CI, 0.49–0.75; P<.0001). For those patients with at least 50% PD-L1 expression in tumor cells, overall survival was also significantly longer at either dose of pembrolizumab when compared with docetaxel (pembrolizumab 2 mg/kg: 14.9 vs. 8.2 months; HR, 0.54; 95% CI, 0.38–0.77; P=.0002) (pembrolizumab 10 mg/kg: 17.3 vs. 8.2 months; HR, 0.50; CI, 0.36–0.70; P<.0001). When compared with docetaxel, there were fewer grade 3 to 5 treatment-related adverse events at either dose of pembrolizumab (pembrolizumab 2 mg/kg: 13% [43/339] of patients, pembrolizumab 10 mg/kg: 16% [55/343], and docetaxel: 35% [109/309]). A total of 6 treatment-related deaths occurred in patients receiving pembrolizumab (3 at each dose) and 5 treatment-related deaths occurred in the docetaxel arm. 一项随机2/3试验（KEYNOTE-010）评估了派姆单抗治疗既往治疗过的、PD-L1阳性（≥1%）的晚期非鳞和鳞型NSCLC患者；大部分都是当前或既往吸烟者。在这项试验中有3组：派姆单抗2mg/kg、派姆单抗10mg/kg、多西他赛75mg/㎡每3周1次。中位总生存期：派姆单抗较低剂量组为10.4个月、高剂量组为12.7 个月，而多西他赛组为8.5个月。与多西他赛相比，两个剂量的派姆单抗组总生存期显著更长（派姆单抗2mg/kg：HR 0.71；95%CI，0.58–0.88；P =0.0008）（派姆单抗10mg/kg：HR 0.61；CI，0.49–0.75；P<0.0001)。对于那些至少50%的肿瘤细胞表达PD-L1的患者，与多西他赛相比，派姆单抗两个剂量中的任一剂量总生存期也显著更长（派姆单抗2mg/kg：14.9对8.2个月；HR 0.54；95%CI，0.38-0.77；P =0.0002) (派姆单抗10mg/kg：17.3对8.2个月；HR 0.50；CI，0.36-0.70；P <0.0001)。与多西他赛相比，任一剂量的派姆单抗3-5度治疗相关不良事件较少（派姆单抗2mg/kg：13% [43/339]、派姆单抗10mg/kg：16% [55/343]，而多西他赛：35% [109/309]）。在接受派姆单抗的患者中共有6例治疗相关死亡（每个剂量各3例），而在多西他赛组中发生5例治疗相关死亡。A phase I trial (KEYNOTE-001) assessed the safety and efficacy of pembrolizumab for patients with metastatic NSCLC. Among all patients, the response rate was 19%, the median duration of response was 12.5 months, PFS was 3.7 months, and median overall survival was 12.0 months. Patients with a PD-L1 expression score of at least 50% had a response rate of 45%, PFS of 6.3 months, and overall survival was not reached. Current or former smoking status also correlated with the response rate. Less than 10% of patients had serious grade 3 or more toxicity. 一项I期试验（KEYNOTE-001）评估了派姆单抗治疗转移性NSCLC患者的安全性和有效性。在所有患者中，有效率是19%，中位疗效持续时间是12.5个月，PFS是3.7个月，中位总生存期是12.0个月。PD-L1表达评分至少50%的患者有效率为45%，PFS为6.3个月，总生存期是尚未达到。目前或以前的吸烟情况也与有效率有关。有严重的3级或以上毒性的患者不到10%。Similar to nivolumab, immune-mediated adverse events may also occur with pembrolizumab. For patients with immune-mediated adverse events, intravenous high-dose corticosteroids should be administered based on the severity of the reaction. Pembrolizumab should also be discontinued for patients with severe or life-threatening pneumonitis and should be withheld or discontinued for other severe or life-threatening immune-mediated adverse events when indicated (see prescribing information). The FDA has approved pembrolizumab as subsequent therapy for patients with metastatic NSCLC whose disease has progressed after platinum-based chemotherapy if their tumors express PD-L1. The FDA has approved a companion diagnostic biomarker test for assessing PD-L1 expression and determining which patients are eligible for pembrolizumab therapy. Other immunotherapeutic agents are being investigated. 与尼鲁单抗相似，派姆单抗也可能发生免疫介导的不良事件。对于有免疫介导的不良事件患者，应该根据反应的严重程度给予静脉大剂量糖皮质激素。对于重度或危及生命的肺炎患者也应该停止派姆单抗，并且对于其他严重或危及生命的免疫介导不良事件当有指征时（见处方信息）应该拒绝或中止给药 。FDA已经批准派姆单抗作为转移性NSCLC患者在铂基化疗后疾病进展者的后续治疗，如果其肿瘤表达PD-L1。FDA已经批准了一种评估PD-L1表达的辅助诊断性生物标志物检测，以确定哪些患者适于派姆单抗治疗。其他免疫治疗药物正在研究中。