小细胞肺癌NCCN指南2017第二版讨论（第一部分）

Small Cell Lung Cancer 小细胞肺癌

NCCN Guidelines Version 2.2017 NCCN指南2017第2版山东省肿瘤医院呼吸肿瘤内科张品良

Discussion
讨论

Overview
概述

Neuroendocrine tumors account for approximately 20% of lung cancers; most (approximately 14%) are small cell lung cancer (SCLC). In 2016, an estimated 31,000 new cases of SCLC will occur in the United States. Nearly all cases of SCLC are attributable to cigarette smoking. Although the incidence of SCLC has been decreasing, the incidence in women is increasing and the male-to-female incidence ratio is now 1:1. Management of SCLC and other lung neuroendocrine tumors (LNTs) is described in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines(R)) for SCLC and for LNTs, which include the algorithms and this supporting Discussion text (see also Lung Neuroendocrine Tumors in this Discussion). The Summary of the Guidelines Updates section in the algorithm describes the most recent revisions, which have been incorporated into this revised Discussion (see the NCCN Guidelines(R) for SCLC). For the 2017 update for SCLC, nivolumab and nivolumab with ipilimumab were added as new options for second-line and beyond (ie, subsequent) systemic therapy; new imaging guidelines for response assessment after systemic therapy were also added in addition to other changes as outlined in the summary updates. The NCCN Guidelines for SCLC were originally published 20 years ago and have been subsequently updated at least once every year (see NCCN.org).
神经内分泌肿瘤约占肺癌的20%；大多数（约14%）是小细胞肺癌（SCLC）。估计2016年美国将有31000例新发小细胞肺癌病例。几乎所有的小细胞肺癌病例都是由吸烟引起的。虽然小细胞肺癌的发病率一直呈下降趋势，但是在女性中的发病率升高，男女发病率之比现在是1:1。小细胞肺癌与其他肺神经内分泌肿瘤（LNTs）的管理在NCCN肿瘤学临床实践指南（NCCN指南®）中的小细胞肺癌和LNTs描述，包括工作步骤和此支持讨论（此外见本讨论中的肺神经内分泌肿瘤）。在工作步骤中总结的指南更新部分介绍了最近的修订，已纳入到本修订的讨论中（见小细胞肺癌NCCN指南®）。小细胞肺癌2017版更新，增加了尼鲁单抗和尼鲁单抗联合伊匹单抗作为一个新的二线及二线以上（即后续）全身治疗选择；除了在扼要更新概述的其他变化外，还增加了全身治疗后疗效评估新的影像指南。小细胞肺癌的NCCN指南最初发表于20年前，随后至少每年更新一次（见NCCN.org）。

SCLC is characterized by a rapid doubling time, high growth fraction, and early development of widespread metastases. Most patients with SCLC present with hematogenous metastases; approximately one third present with limited disease confined to the chest. SCLC is highly sensitive to initial chemotherapy and radiotherapy; however, most patients eventually die of recurrent disease. In patients with limited-stage SCLC, the goal of treatment is cure using chemotherapy plus thoracic radiotherapy. In patients with extensive-stage disease, chemotherapy alone can palliate symptoms and prolong survival in most patients; however, long-term survival is rare. Note that the definitions for limited-stage and extensive-stage SCLC incorporate TNM staging (see the NCCN Guidelines for SCLC and Staging in this Discussion). Surgery is only appropriate for a few patients (2%–5%) with surgically resectable stage I SCLC. Clinical trials generally represent state-of-the-art treatment for patients with SCLC. Despite recent advances, the standard therapy for SCLC as outlined by these NCCN Guidelines still needs to be improved. Thus, participation in clinical trials should be strongly encouraged.
小细胞肺癌的特点是倍增时间短、增殖比率高以及广泛转移发生早。大多数小细胞肺癌患者有血行转移；约三分之一的局限期疾病局限于胸部。小细胞肺癌对初始化疗和放疗高度敏感；然而，大多数患者最终死于复发性疾病。局限期小细胞肺癌患者，治疗的目标是采用化疗加胸部放疗治愈。广泛期疾病患者，单纯化疗可减轻大多数患者的症状、延长生存；然而，长期生存罕见。要注意的是，局限期和广泛期小细胞肺癌的定义结合TNM分期（见本讨论中的小细胞肺癌NCCN指南与分期）。手术只适合少数手术可切除的I期小细胞肺癌患者（2%–5%）。临床试验通常为小细胞肺癌患者提供最先进的治疗。虽然最近有进步，但是这些NCCN指南所概括的小细胞肺癌的标准治疗仍有待改进。因此，应强烈鼓励参与临床试验。

Smoking cessation should be strongly promoted in patients with SCLC and other high-grade neuroendocrine carcinomas (see the NCCN Guidelines for Smoking Cessation, available at NCCN.org). Former smokers should be strongly encouraged to remain abstinent. Patients with SCLC who continue to smoke have increased toxicity during treatment and shorter survival. Programs using behavioral counseling combined with FDA–approved medications that promote smoking cessation can be very useful.
应强烈提倡小细胞肺癌和其他高级别神经内分泌癌患者戒烟（见戒烟NCCN指南，可在NCCN.org获得）。应该强烈鼓励既往吸烟者保持戒烟。在治疗期间继续吸烟的小细胞肺癌患者毒性增加且生存期更短。使用行为咨询计划并结合FDA批准的促进戒烟的药物可能是非常有用的。

Literature Search Criteria and Guidelines Update
文献检索标准与指南更新

Methodology
方法学

Before the update of this version of the NCCN Guidelines for SCLC, an electronic search of the PubMed database was performed to obtain key literature in SCLC—published between April 1, 2015 and May 1, 2016— using the following search term: small cell lung cancer. The PubMed database was chosen, because it is the most widely used resource for medical literature and indexes only peer-reviewed biomedical literature. The search results were narrowed by selecting studies in humans published in English. Results were confined to the following article types: Clinical Trial, Phase 1; Clinical Trial, Phase 2; Clinical Trial, Phase 3; Clinical Trial, Phase 4; Guideline; Randomized Controlled Trial; Meta-Analysis; Systematic Reviews; and Validation Studies.
在更新本版本的小细胞肺癌NCCN指南之前，使用small cell lung cancer搜索词电子搜索PubMed数据库中在2015年4月1日与2016年5月1日之间发表的文献以获取小细胞肺癌的关键文献。选择PubMed数据库是因为它是使用最广泛的医学文献资源并且只有同行评议过的生物医学文献。挑选的用英语发表的研究搜索结果是有限的。结果限于以下文章类型：1期临床试验；2期临床试验；3期临床试验；4期临床试验；指南；随机对照试验；Meta分析；系统综述；和验证研究。

The PubMed search resulted in 253 citations and their potential relevance was examined. The data from key PubMed articles as well as articles from additional sources deemed as relevant to these NCCN Guidelines and discussed by the panel have been included in this version of the Discussion section (eg, e-publications ahead of print, meeting abstracts). Recommendations for which high-level evidence is lacking are based on the panel’s review of lower-level evidence and expert opinion. The complete details of the development and update of the NCCN Guidelines are available on the NCCN webpage.
PubMed检索共检出253篇参考文献及其关联文献。PubMed关键文献以及其他来源的、认为与这些NCCN指南相关的文献（如印刷前的电子出版物、会议摘要）数据由小组进行讨论，并收录到本版的讨论部分。根据小组对较低水平证据的评审与专家意见，缺乏用于推荐的高级别证据。NCCN指南发展与更新的全部细节可在NCCN网页上获得。

Small Cell Lung Cancer
小细胞肺癌

Diagnosis
诊断

Screening
筛检

Ideally, a screening test should detect disease at an early stage when it is still curable. Currently, no effective screening test is available to detect early-stage SCLC; the disease is typically diagnosed when patients present with symptoms indicative of advanced-stage disease. The National Lung Screening Trial (NLST) reported that screening with annual, low-dose, spiral CT scans decreased lung cancer–specific mortality in asymptomatic high-risk individuals (see the NCCN Guidelines for Lung Cancer Screening, available at NCCN.org).
理想情况下，筛查应检出早期仍可治愈的疾病。目前，没有有效的筛选检查可以检出早期小细胞肺癌；通常是当患者出现晚期疾病症状时才确诊。国家肺癌筛查试验（NLST）报道，每年1次低剂量螺旋CT扫描筛查，在无症状高危个体中肺癌特异性死亡率下降（见NCCN肺癌筛查指南，可在NCCN.org获得）。

Although low-dose CT screening can detect early-stage non-small cell lung cancer (NSCLC), it does not seem to be useful for detecting early-stage SCLC. Low-dose CT screening is probably not useful because of the aggressiveness of SCLC, which results in the development of symptomatic disease between annual scans, thereby limiting the potential effect on mortality.
虽然低剂量CT筛检可以发现早期非小细胞肺癌（NSCLC），但似乎对检出早期小细胞肺癌没有用。低剂量CT筛检可能没有用是因为小细胞肺癌的侵袭性，导致在每年1次的检查之间发展为有症状的疾病，因此限制了对死亡率的潜在影响。

Manifestations
表现

SCLC typically presents as a large hilar mass and bulky mediastinal lymphadenopathy that cause cough and dyspnea. Frequently, patients present with symptoms of widespread metastatic disease, such as weight loss, debility, bone pain, and neurologic compromise. It is uncommon for patients to present with a solitary peripheral nodule without central adenopathy. In this situation, fine-needle aspiration (FNA) may not adequately differentiate small cell carcinoma (which is a high-grade neuroendocrine carcinoma) from low-grade (typical carcinoid), intermediate-grade (atypical carcinoid), or large-cell neuroendocrine carcinoma (LCNEC) (which is also a high-grade neuroendocrine carcinoma) (see the NCCN Guidelines for Lung Neuroendocrine Tumors and Lung Neuroendocrine Tumors in this Discussion).
小细胞肺癌的典型表现为肺门大肿块和纵隔巨大淋巴结，引起咳嗽和呼吸困难。患者常常出现广泛的转移性疾病症状，如体重减轻、乏力、骨痛和神经损害。无中央淋巴结的孤立性周围型结节患者罕见。在这种情况下，细针穿刺抽吸（FNA）或许不能充分地区分小细胞癌（这是一种高级别的神经内分泌癌）、低级别（典型类癌）、中等级别（不典型类癌）或大细胞神经内分泌癌（LCNEC）（这也是一种高级别神经内分泌癌）（见NCCN肺神经内分泌肿瘤指南和本讨论中的肺神经内分泌肿瘤）。

Many neurologic and endocrine paraneoplastic syndromes are associated with SCLC. Neurologic syndromes include Lambert-Eaton myasthenic syndrome, encephalomyelitis, and sensory neuropathy. Patients with the Lambert-Eaton syndrome present with proximal leg weakness that is caused by antibodies directed against the voltage-gated calcium channels. Paraneoplastic encephalomyelitis and sensory neuropathy are caused by the production of an antibody (anti-Hu) that cross-reacts with both small cell carcinoma antigens and human neuronal RNA-binding proteins resulting in multiple neurologic deficits.
许多神经系统和内分泌副肿瘤综合征与小细胞肺癌有关。神经系统症状包括兰伯特-伊顿肌无力综合征、脑脊髓炎以及感觉神经病变。有兰伯特-伊顿综合征（类重症肌无力综合征）的患者表现为近端下肢无力，是由抗电压门控钙通道抗体引起的。副肿瘤性脑脊髓炎和感觉神经病变是由一种抗体（抗-Hu）引起的，该抗体既能与小细胞癌抗原结合，又能与人神经元RNA结合蛋白相互作用导致多神经损伤。

SCLC cells sometimes produce polypeptide hormones, including vasopressin (antidiuretic hormone [ADH]) and adrenocorticotropic hormone (ACTH), which cause hyponatremia of malignancy (ie, syndrome of inappropriate ADH secretion [SIADH]) and Cushing syndrome, respectively. In patients with SCLC, SIADH occurs more frequently than Cushing syndrome. Cancer treatment and/or supportive care may also cause hyponatremia (eg, cisplatin, opiates). Treatment for SIADH includes fluid restriction (which is difficult for patients because of increased thirst), demeclocycline, or vasopressin receptor inhibitors (ie, conivaptan, tolvaptan) (see Principles of Supportive Care in the NCCN Guidelines for SCLC). ADH levels and hyponatremia usually improve after successful treatment for SCLC.
小细胞肺癌细胞有时会产生多肽激素，包括加压素（抗利尿激素[ ADH ]）和促肾上腺皮质激素（ACTH），分别引起恶性低钠血症（即抗利尿激素分泌异常综合征[SIADH ]）和库欣综合征。在小细胞肺癌患者中，抗利尿激素分泌异常综合征（SIADH）比库欣综合征更常见。癌症治疗和/或支持治疗也可能导致低钠血症（如顺铂、阿片类）。抗利尿激素分泌异常综合征（SIADH）的治疗包括限制液体（因为口渴，这对患者是困难的）、地美环素或加压素受体抑制剂（即考尼伐坦、托伐普坦）（见小细胞肺癌NCCN指南中支持治疗的原则）。在小细胞肺癌治疗成功后，ADH（抗利尿激素）水平与低钠血症通常改善。

Pathology
病理学

SCLC is a malignant epithelial tumor consisting of small cells with scant cytoplasm, ill-defined cell border:1px solid #000;"EN-US">
小细胞肺癌是一种恶性上皮性肿瘤，由缺乏细胞质的小细胞组成，细胞边界不清、核染色质细颗粒状、核仁缺乏或不明显。细胞圆形、椭圆形或梭形；核型显著。有丝分裂计数高。典型且独特的苏木精和伊红（H&E）组织学能够足以识别小细胞肺癌；它是一种低分化肿瘤，归类为一种高级别的神经内分泌癌。小细胞肺癌患者中尸检高达30%显示非小细胞肺癌分化区域；在既往治疗过的患者标本中更常检出这一发现，因此认为，肺癌发生在一个能沿不同途径分化的多能干细胞。

Although 95% of small cell carcinomas originate in the lung, they can also arise from extrapulmonary sites, including the nasopharynx, gastrointestinal tract, and genitourinary tract. Both pulmonary and extrapulmonary small cell carcinomas have a similar clinical and biologic behavior, leading to a high potential for widespread metastases.
虽然95%的小细胞癌起源于肺，但也可以起源于肺外部位，包括鼻咽、胃肠道和泌尿生殖道。肺和肺外小细胞癌两者均有相似的临床和生物学行为，广泛转移的潜能高。

Nearly all SCLCs are immunoreactive for keratin, epithelial membrane antigen, and thyroid transcription factor–1 (TTF-1). Most SCLCs also stain positively for markers of neuroendocrine differentiation, including chromogranin A, neuron-specific enolase, neural cell adhesion molecule (NCAM; CD56), and synaptophysin. However, these markers alone cannot be used to distinguish SCLC from NSCLC, because approximately 10% of NSCLCs will be immunoreactive for at least one of these neuroendocrine markers.
几乎所有的小细胞肺癌对角蛋白、上皮膜抗原和甲状腺转录因子-1（TTF-1）免疫反应阳性。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（NCAM；CD56）和突触素，大部分小细胞肺癌染色也是阳性的。然而，这些标记不能用来区分小细胞肺癌和非小细胞肺癌，因为大约10%的非小细胞肺癌这些神经内分泌标记至少有一个阳性。

Staging
分期

The NCCN Panel adopted a combined approach for staging SCLC using both the AJCC TNM staging system and the older Veterans Administration (VA) scheme for SCLC (see the following 2 paragraphs). Historically, contralateral mediastinal and ipsilateral supraclavicular lymphadenopathy were generally classified as limited-stage disease, whereas the classification of contralateral hilar and supraclavicular lymphadenopathy is more controversial and treatment is individualized for the patients. Approximately 66% of patients present with overt hematogenous metastases, which commonly involve the contralateral lung, liver, adrenal glands, brain, bones, and/or bone marrow. The AJCC is currently revising the TNM staging system for SCLC; new staging guidelines will be published in late 2016. The SCLC panel will continue to use the combined VA/TNM system for staging SCLC after publication of the 8th edition of the AJCC Cancer Staging Manual.
对于小细胞肺癌分期，NCCN小组采用AJCC TNM分期系统和退伍军人管理局（VA）小细胞肺癌方案两者相结合的方法（见下列两段）。过去，对侧纵隔和同侧锁骨上淋巴结肿大一般分为局限期，而对侧肺门和锁骨上淋巴结肿大的分类更具争议，应个体化治疗。约66%的患者有明显的血行转移，通常累及对侧肺、肝、肾上腺、脑、骨和/或骨髓。目前AJCC正在修订小细胞肺癌的TNM分期系统；新的分期指南将于2016年底公布。在AJCC癌症分期手册第8版出版后，小细胞肺癌小组将继续联合使用VA/AJCC系统分期小细胞肺癌。

In 2010, the lung cancer TNM staging system was revised by the International Association for the Study of Lung Cancer (IASLC) and adopted by the AJCC (7th edition, 2010) (see Tables 2 and 3 in the NCCN Guidelines for SCLC). This TNM staging system is applicable to both NSCLC and SCLC based on studies that showed the prognostic significance of the various stage designations in both diseases. In the combined approach for staging SCLC, limited-stage SCLC is defined as stage I to III (T any, N any, M0) that can be safely treated with definitive radiation therapy, excluding T3–4 due to multiple lung nodules that are too extensive or have tumor/nodal volume that is too large to be encompassed in a tolerable radiation plan (see Table 1 in the NCCN Guidelines for SCLC). Extensive-stage SCLC is defined as stage IV (T any, N any, M1a/b) or T3–4 due to multiple lung nodules that are too extensive or have tumor/nodal volume that is too large to be encompassed in a tolerable radiation plan.
在2010年，肺癌TNM分期系统由国际肺癌研究协会（IASLC）修订并被AJCC采用（第七版，2010年）（见小细胞肺癌NCCN指南中的表2和表3）。研究表明，该TNM分期系统既适用于非小细胞肺癌又适用于小细胞肺癌，两个疾病的不同分期均显示预后意义。在小细胞肺癌的联合分期中，局限期小细胞肺癌定义为I-III期（任何T，任何N，M0），排除多个肺结节、太广泛的T3–4或肿瘤/淋巴结体积太大无法在一个可以耐受的放疗计划中完成，可以安全地给予根治性放疗（见小细胞肺癌NCCN指南中的表1）。广泛期小细胞肺癌定义为IV期（任何T，任何N，M1a/b）或由于多个肺结节、太广泛的T3–4或肿瘤/淋巴结体积太大无法在一个可以耐受的放疗计划中完成。

The VA Lung Study Group’s 2-stage classification scheme is also used to define the extent of disease in patients with SCLC: 1) limited-stage disease is disease confined to the ipsilateral hemithorax, which can be safely encompassed within a radiation field; and 2) extensive-stage disease is disease beyond the ipsilateral hemithorax, including malignant pleural or pericardial effusion or hematogenous metastases.
退伍军人肺研究组的两期分类方案也用于确定小细胞肺癌患者的病变范围：1）局限期疾病是病变局限于同侧半胸，可安全地包含在一个放射野内；和2）广泛期疾病是病变超出同侧半胸以外，包括恶性胸腔或心包积液或血行转移。

Because most of the literature on SCLC classifies patients based on the VA’s definitions of limited-stage or extensive-stage disease, these definitions are often used for clinical decision making. However, the TNM system is useful for selecting patients with T1-2, N0 disease who are eligible for surgery and for radiation treatment planning. Clinical research studies should begin to use the TNM system, because it will allow for more precise assessments of prognosis and specific therapy in the future.
因为大多数小细胞肺癌的文献是基于退伍军人管理局定义的局限期或广泛期将患者分类，这些定义常用于临床决策。无论如何，TNM系统对选择适合手术和放射治疗计划的T1-2、N0患者是有用的。临床科研合作研究应该开始使用TNM系统，因为这将允许更准确地评估预后和将来的特殊治疗。

All patients with SCLC, even those with radiographically limited-stage disease (per the VA’s definition), require systemic therapy either as primary or adjuvant therapy. Therefore, staging provides a therapeutic guideline for thoracic radiotherapy, which is indicated primarily for patients with limited-stage disease. Full staging includes a history and physical examination; CT scan (with intravenous contrast) of the chest, liver, and adrenal glands; and brain imaging using MRI (preferred) or CT scan (with intravenous contrast). However, once a patient has been found to have extensive-stage disease, further staging is optional, except for brain imaging. Unilateral bone marrow aspirates and biopsies may be indicated in select patients with nucleated red blood cells on peripheral blood smear, neutropenia, or thrombocytopenia suggestive of bone marrow infiltration and with no other evidence of metastatic disease. Bone marrow involvement as the only site of extensive-stage disease occurs in fewer than 5% of patients. If limited-stage disease is suspected, a PET/CT scan can be performed to assess for distant metastases. A bone scan can be performed if PET/CT is equivocal or not available.
所有的小细胞肺癌患者，即使是那些放射影像局限期患者（退伍军人管理局的定义），均需要全身治疗作为初始或辅助治疗。因此，分期为胸部放疗提供了治疗指南，主要适用于限期疾病的患者。充分的分期包括病史和体格检查;胸部、肝脏和肾上腺CT扫描（静脉造影）；以及脑MRI（首选）或CT扫描（静脉造影）。然而，一旦发现患者有广泛期病变，则除脑显像外，还可选择进一步分期。在外周血涂片中发现有核红细胞、中性粒细胞减少或血小板减少提示骨髓浸润而没有其他转移性疾病证据的选择性患者中，可能需要单侧骨髓抽吸和活检。骨髓受累为唯一部位的广泛期疾病的发生率不到患者的5%。如果怀疑是局限期疾病，可以用PET/CT扫描评估远处转移。如果PET/CT可疑或不可用，可进行骨扫描。

PET scans can increase staging accuracy in patients with SCLC, because SCLC is a highly metabolic disease. PET/CT is superior to PET alone. Approximately 19% of patients who undergo PET are upstaged from limited- to extensive-stage disease, whereas only 8% are downstaged from extensive- to limited-stage disease. For most metastatic sites, PET/CT is superior to standard imaging; however, PET/CT is inferior to MRI or CT for the detection of brain metastases (see the NCCN Guidelines for Central Nervous System Cancers, available at NCCN.org). Changes in management based on PET staging were reported in approximately 27% of patients, mainly because of alterations in the planned radiation field as a result of improved detection of intrathoracic sites of disease. Although PET/CT seems to improve staging accuracy in SCLC, pathologic confirmation is still required for PET/CT–detected lesions that result in upstaging.
PET扫描可以提高小细胞肺癌患者分期的准确性，因为小细胞肺癌是一种高代谢疾病。PET/CT优于单纯的PET。接受PET的患者中大约19%从局限期升级到广泛期，而只有8%从广泛期降期到局限期。对于大多数的转移部位，PET/CT优于标准影像；但是，对脑转移瘤的检测PET/CT不如CT或MRI（见NCCN中枢神经系统肿瘤指南，可在NCCN.org获得）。基于PET分期，大约27%的患者管理发生改变，主要因为增加了疾病胸内部位的检出，结果导致计划的放射野改变。虽然PET/CT似乎提高小细胞肺癌分期的准确性，但是PET/CT检出的导致升期的病变仍然要求病理确认。

Before surgical resection, pathologic mediastinal staging is required to confirm PET/CT scan results in patients who seem to have clinical stage T1–2, N0 disease. However, mediastinal staging is not required if the patient is not a candidate for surgical resection or if non-surgical treatment is planned. Invasive mediastinal staging can be performed either by conventional mediastinoscopy or by minimally invasive techniques such as transesophageal endoscopic ultrasound–guided FNA (EUS-FNA), endobronchial ultrasound–guided transbronchial needle aspiration (EBUS-TBNA), or video-assisted thoracoscopy (VATS).
在临床分期似乎是T1–2N0的患者中，在手术切除、病理纵隔分期前需确认PET/CT扫描结果。但是，如果不是手术切除候选者或如果是计划非手术治疗的患者，纵隔分期不是必需的。侵袭性纵隔分期可以通过常规的手术也可以通过微创技术，如经食管超声内镜引导下细针穿刺活检（EUS-FNA）、经支气管超声引导针吸活检（EBUS-TBNA）或电视辅助胸腔镜（VATS）。

Thoracentesis with cytologic analysis is recommended if a pleural effusion is large enough to be safely accessed via ultrasound guidance. If thoracentesis does not show malignant cells, then thoracoscopy can be considered to document pleural involvement, which would indicate extensive-stage disease. The effusion should be excluded as a staging element if: 1) multiple cytopathologic examinations of the pleural fluid are negative for cancer; 2) the fluid is not bloody and not an exudate; and 3) clinical judgment suggests that the effusion is not directly related to the cancer. Pericardial effusions are classified using the same criteria.
如果胸腔积液量足够大，可安全地通过超声引导到达，推荐胸腔穿刺细胞学检查。如果胸腔穿刺未发现恶性细胞，则可以考虑胸腔镜检查以证明胸膜受累，这将预示广泛期疾病。作为一个分期要素，积液应该被排除，如果：1）多次胸膜液细胞病理学检查癌症均为阴性；2）液体是非血性、非渗出液；以及3）临床判断认为，积液与癌症并不直接相关。心包积液使用同样的标准分类。

Staging should not focus only on sites of symptomatic disease or on sites suggested by laboratory tests. Bone scans are positive in up to 30% of patients without bone pain or an abnormal alkaline phosphatase level. Bone imaging with radiographs or MRI may be appropriate if PET/CT is equivocal. Brain imaging (MRI preferred or CT scan) can identify central nervous system (CNS) metastases in 10% to 15% of patients at diagnosis, of which approximately 30% are asymptomatic. Early treatment of brain metastases results in less chronic neurologic morbidity, arguing for the usefulness of early diagnosis in asymptomatic patients. Because of the aggressive nature of SCLC, staging should not delay the onset of treatment for more than 1 week; otherwise, many patients may become more seriously ill in the interval, with a significant decline in their performance status (PS).
分期不应只关注疾病症状的部位或实验室检查提示的部位。在无骨痛或碱性磷酸酶水平异常的患者中高达30%骨扫描阳性。如果PET/CT意义不明确，X线片或MRI骨显像可能是合理的。10%-15%的患者在确诊时脑成像（首选磁共振或CT扫描）可以发现中枢神经系统（CNS）转移，其中约30%是无症状的。脑转移早期治疗带来的是慢性神经病发病率较低，支持对无症状患者的早期诊断是有用的。由于小细胞肺癌的侵袭性，分期不应延迟启动治疗超过1周；否则，在这期间，许多患者的疾病可能会变得更严重，其功能状态（PS）显著下降。

Prognostic Factors
预后因素

Poor PS (3–4), extensive-stage disease, weight loss, and markers associated with excessive bulk of disease (such as lactate dehydrogenase [LDH]) are the most important adverse prognostic factors. Female gender, age younger than 70 years, normal LDH, and stage I disease are associated with a more favorable prognosis in patients with limited-stage disease. Younger age, good PS, normal creatinine level, normal LDH, and a single metastatic site are favorable prognostic factors in patients with extensive-stage disease.
PS差（3–4）、广泛期疾病、体重减轻以及与病变过大相关的标志物（如乳酸脱氢酶[LDH]）是最重要的不良预后因素。在局限期患者中，女性、年龄小于70岁、LDH正常、I期疾病与预后更好有关。较年轻、PS良好、肌酐水平正常、LDH正常以及单一转移部位是广泛期疾病患者良好的预后因素。