小细胞肺癌NCCN指南2017第1版（讨论2）

Treatment治疗

Chemotherapy化疗

For all patients with SCLC, chemotherapy is an essential component of appropriate treatment. Adjuvant chemotherapy is recommended for those who have undergone surgical resection. For patients with limited-stage SCLC and good PS (0–2), recommended treatment consists of chemotherapy with concurrent thoracic radiotherapy (category 1). For patients with extensive-stage disease, chemotherapy alone is the recommended treatment, although radiotherapy may be used in select patients for palliation of symptoms (see Initial Treatment and Principles of Chemotherapy in the NCCN Guidelines for Small Cell Lung Cancer). In patients with extensive disease and brain metastases, chemotherapy can be given either before or after whole-brain radiotherapy depending on whether the patient has neurologic symptoms (see Initial Treatment in the NCCN Guidelines for Small Cell Lung Cancer).对于所有SCLC患者，化疗是合理治疗的重要组成部分。对那些已接受手术切除者建议进行辅助化疗。对于PS良好（0–2）的局限期SCLC患者，推荐的治疗包括化疗同时胸部放疗（1类）。对于广泛期疾病患者，推荐的治疗是单纯化疗，虽然放疗可用于选择性患者缓解症状（见NCCN小细胞肺癌指南中的初始治疗与化疗原则）。在广泛期疾病以及脑转移患者中，化疗可以在全脑放疗前、后给予，这取决于患者是否有神经系统症状（见NCCN小细胞肺癌指南中的初始治疗）。

Single-agent and combination chemotherapy regimens have been shown to be active in SCLC. Etoposide and cisplatin (EP) is the most commonly used initial combination chemotherapy regimen (see Principles of Chemotherapy in the NCCN Guidelines for Small Cell Lung Cancer). This combination replaced alkylator/anthracycline-based regimens based on its superiority in both efficacy and toxicity in the limited-stage setting. EP plus concurrent thoracic radiotherapy is the recommended therapy for patients with limited-stage disease (category 1).已证明单药和联合化疗方案治疗SCLC是有效的。依托泊苷和顺铂（EP）是最常用的初始联合化疗方案（见NCCN小细胞肺癌指南中的化疗原则）。基于疗效和毒性两方面均具有优势，在局限期情况下该联合取代了烷化剂/蒽环类药物为基础的方案。对于局限期疾病患者，EP加同步放化疗是推荐的治疗方法（1类）。

In combination with thoracic radiotherapy, EP causes an increased risk of esophagitis, pulmonary toxicity, and hematologic toxicity. The use of myeloid growth factors is not recommended (category 1) in patients undergoing concurrent chemoradiation. In clinical practice, carboplatin is frequently substituted for cisplatin to reduce the risk of emesis, neuropathy, and nephropathy. However, the use of carboplatin carries a greater risk of myelosuppression. Small randomized trials have suggested similar efficacy of cisplatin and carboplatin in patients with SCLC. A meta-analysis of 4 randomized studies compared cisplatin-based versus carboplatin-based regimens in patients with SCLC. Of 663 patients included in this meta-analysis, 32% had limited-stage disease and 68% had extensive-stage disease. No significant difference was observed in response rate (67% vs. 66%), progression-free survival (5.5 vs. 5.3 months), or overall survival (9.6 vs. 9.4 months) in patients receiving cisplatin- versus carboplatin-containing regimens, suggesting equivalent efficacy in patients with SCLC.与胸部放疗联合，EP引起食管炎、肺毒性和血液学毒性的风险增加。正在进行同步放化疗的患者不推荐使用骨髓生长因子（1类）。在临床实践中，经常用卡铂代替顺铂以减少呕吐、神经病变和肾病风险。然而，卡铂的使用带来的骨髓抑制风险更大。小型随机试验提示在SCLC患者中顺铂和卡铂的疗效相似。4项随机研究的一项meta分析比较了以顺铂与卡铂为基础的联合化疗方案治疗SCLC患者。在这项meta分析的663例患者中，32%为局限期疾病，68%为广泛期疾病。在接受含顺铂与含卡铂方案的患者中，有效率（67%对66%）、无进展生存期（5.5对5.3个月）或总生存期（9.6对9.4个月）均未观察到显著差异，提示在SCLC患者中疗效相当。

Many other combinations have been evaluated in patients with extensive-stage disease, with little consistent evidence of benefit when compared with EP. The combination of irinotecan and a platinum agent has provided the greatest challenge to EP. Initially, a small phase III trial performed in Japan reported that patients with extensive-stage SCLC who were treated with irinotecan plus cisplatin experienced a median survival of 12.8 months compared with 9.4 months for patients treated with EP (P = .002). In addition, the 2-year survival was 19.5% in the irinotecan plus cisplatin group versus 5.2% in the EP group. However, 2 subsequent large phase III trials performed in the United States comparing irinotecan plus cisplatin with EP failed to show a significant difference in response rate or overall survival between the regimens.已经在广泛期疾病患者中评估了许多其他联合，与EP相比，几乎没有一致的获益证据。伊立替康和一种铂类药物联合是EP的最大挑战。最初，日本开展的一项小型III期试验报道，伊立替康加顺铂治疗的广泛期SCLC患者中位生存期12.8个月，而EP治疗的患者为9.4个月（P = .002）。此外，2年生存率伊立替康加顺铂组为19.5%而EP组为5.2%。然而，随后在美国进行的两项大型III期试验比较了伊立替康加顺铂与EP方案，方案之间的有效率或总生存期未能显示显著差异。

A phase III randomized trial (n = 220) found that median overall survival was slightly improved with irinotecan and carboplatin compared with carboplatin and oral etoposide (8.5 vs. 7.1 months, P = .04). Based on these findings, the carboplatin and irinotecan regimen has been added to the NCCN Guidelines as an option for patients with extensive-stage disease. A meta-analysis suggests an improvement in PFS and overall survival with irinotecan plus platinum regimens compared with etoposide plus platinum regimens. However, this meta-analysis was not performed using data from individual patients. In addition, the relatively small absolute survival benefit needs to be balanced against the toxicity profile of irinotecan-based regimens. Therefore, the NCCN Panel continues to consider etoposide plus platinum as the standard regimen for patients with either limited-stage or extensive-stage SCLC.一项III期随机试验（n = 220）发现，与卡铂和依托泊苷相比，伊立替康加卡铂中位总生存期略有改善（8.5对7.1个月，P =.04）。基于这些发现，卡铂联合伊立替康方案已经加入到NCCN指南中作为广泛期疾病治疗的一个选择。一项meta分析表明，与依托泊苷加铂类方案相比，伊立替康加铂类方案改善PFS和总生存期。然而，这项meta分析的完成没有使用来自具体患者的数据。此外，绝对生存获益相对小，需要平衡对抗伊立替康为基础的方案的毒性。因此，NCCN小组仍旧认为依托泊苷加铂类为局限期或广泛期SCLC患者的标准治疗方案。

In patients with limited-stage disease, response rates of 70% to 90% are expected after treatment with EP plus thoracic radiotherapy, whereas in extensive-stage disease, response rates of 60% to 70% can be achieved with combination chemotherapy alone. Unfortunately, median survival rates are only 14 to 20 months and 9 to 11 months for patients with limited- and extensive-stage disease, respectively. After appropriate treatment, the 2-year survival rate is approximately 40% in patients with limited-stage disease, but less than 5% in those with extensive-stage disease. Thoracic radiotherapy improves local control rates by 25% in patients with limited-stage disease and is associated with improved survival. Data suggest that chemoradiotherapy may be indicated for patients with limited-stage disease who have cytologically negative or indeterminate pleural effusions, but not for those with pericardial effusions.在局限期疾病患者中，EP加胸部放疗后预计有效率70%至90%，而在广泛期疾病患者中，单纯联合化疗可获得60%至70%的有效率。令人遗憾的是，局限期和广泛期疾病患者的中位生存期分别只有14-20个月和9-11个月。经过适当的治疗后，局限期疾病患者的两年生存率约为40%，但在广泛期疾病患者中，不到5%。在局限期疾病患者中，胸部放疗提高25%的局部控制率，并改善生存。数据表明，放化疗可能适用于胸腔积液细胞学阴性或不确定的局限期患者，但不适于那些有心包积液的患者。

Many strategies have been evaluated in an effort to improve on the standard treatment for extensive-stage SCLC, including the addition of a third agent to standard 2-drug regimens. In 2 trials, the addition of ifosfamide (or cyclophosphamide plus an anthracycline) to EP showed a modest survival advantage for patients with extensive disease. However, these findings have not been uniformly observed, and the addition of an alkylating agent, with or without an anthracycline, significantly increases hematologic toxicity when compared to EP alone. Similarly, the addition of paclitaxel to either cisplatin or carboplatin plus etoposide yielded promising results in phase II trials but did not improve survival, and was associated with unacceptable toxicity in a subsequent phase III study. The use of maintenance or consolidation chemotherapy beyond 4 to 6 cycles of standard treatment produces a minor prolongation of duration of response without improving survival and carries a greater risk of cumulative toxicity. A recent meta-analysis reported that maintenance chemotherapy did not prolong overall survival.已经评估了许多策略以期改善广泛期SCLC标准治疗，包括增加第3个药物到标准的两药方案中。在两项试验中，增加异环磷酰胺（或环磷酰胺加一个蒽环类）至EP方案治疗广泛期疾病患者显示适度的生存优势。然而，这些研究观察均不一致，而且，与单纯EP相比，添加烷化剂联合或不联合蒽环类，显著增加血液学毒性。同样，在一项II期试验中，增加紫杉醇至顺铂或卡铂加依托泊苷取得了可喜的成果，但并未改善生存，并且与随后的III期研究中不可接受的毒性相关。在4至6个周期的标准治疗之外应用维持或巩固化疗，轻微延长疗效持续时间，而未改善生存，并且带来更大的累积毒性风险。最近一项meta分析报道，维持化疗未延长总生存期。

The inability to destroy residual cells, despite the initial chemosensitivity of SCLC, suggests the existence of cancer stem cells that are relatively resistant to cytotoxic therapy. To overcome drug resistance, alternating or sequential combination therapies have been designed to expose the tumor to as many active cytotoxic agents as possible during initial treatment. However, randomized trials have failed to show improved PFS or overall survival with this approach.尽管SCLC最初对化疗敏感，但是无法消灭残余细胞，提示存在相对耐细胞毒药物治疗的癌症干细胞。为了克服耐药性，在初始治疗期间，已设计交替或序贯联合治疗以使肿瘤暴露于尽可能多的有效的细胞毒药物。然而，随机试验未能显示这种方法改善PFS和总生存。

Multidrug cyclic weekly therapy was designed to increase dose intensity. Early phase II results of this approach were promising, although favorable patient selection was of some concern. Nevertheless, no survival benefits were documented in randomized trials, and excessive treatment-related mortality was noted with multidrug cyclic weekly regimens. The role of higher-dose therapy for patients with SCLC remains controversial. Higher complete and partial response rates, and modestly longer median survival times, have been observed in patients receiving high doses when compared with those given conventional doses of the same agents. In general, however, randomized trials comparing conventional doses to an incrementally increased dose intensity up to 2 times the conventional dose have not consistently shown an increase in response rate or survival. In addition, a meta-analysis of trials that compared standard versus dose-intense variations of the cyclophosphamide, doxorubicin, and vincristine (CAV) and EP regimens found that increased relative dose intensity resulted in only a small, clinically insignificant enhancement of median survival in patients with extensive-stage disease.设计多药循环每周疗法以增加剂量强度。早期II期结果显示这种方法是有前途的，虽然让人有些担忧患者的选择是良好的。然而，随机试验证明没有生存获益，多药循环每周方案观察到过度治疗相关的死亡。对于SCLC患者，更高剂量治疗的地位仍有争议。与那些给予相同方案常规剂量的患者相比，在接受高剂量的患者中，观察到完全和部分缓解率更高，且中位生存期适度更长。然而，总的来说，随机试验中，与常规剂量相比，剂量递增方案增加的剂量强度高达常规剂量的两倍，但并未一致证明改善有效率或生存。此外，一项试验的meta分析比较了标准与各种剂量强度的环磷酰胺、阿霉素和长春新碱（CAV）和EP方案发现，在广泛期疾病患者中，相对剂量强度的增加仅带来少许、临床上微不足道的中位生存期改善。

Currently available cytokines (eg, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor) can ameliorate chemotherapy-induced myelosuppression and reduce the incidence of febrile neutropenia, but cumulative thrombocytopenia remains dose limiting. Although trials involving patients with SCLC were instrumental in obtaining FDA approval for the clinical use of cytokines, maintenance of dose intensity with growth factors does not prolong disease-free or overall survival. Thus, the routine use of growth factors at the initiation of chemotherapy is not recommended.目前可用的细胞因子（如粒细胞-巨噬细胞集落刺激因子、粒细胞集落刺激因子）可以改善化疗引起的骨髓抑制并降低发热性中性粒细胞减少的发生率，但累积性血小板减少仍是剂量限制性的。尽管包括SCLC患者的试验临床使用的细胞因子获得了FDA批准，但是用生长因子维持的剂量强度并不能延长无病或总生存期。因此，不推荐在化疗开始时常规使用生长因子。

The benefits of antiangiogenic therapy are being evaluated in SCLC. In patients with limited-stage SCLC, a phase II study of irinotecan, carboplatin, and bevacizumab with concurrent radiotherapy followed by maintenance bevacizumab was terminated early because of an unacceptable incidence of tracheoesophageal fistulae. In extensive-stage SCLC, phase II trials of platinum-based chemotherapy plus bevacizumab have yielded promising response and survival data. However, at least one randomized trial has demonstrated no survival benefit for the addition of bevacizumab to standard chemotherapy. Other randomized phase III trials are ongoing in patients with extensive-stage SCLC. Currently, the NCCN Panel does not recommend use of bevacizumab in patients with SCLC.正在评估抗血管生成治疗在SCLC中的收益。在局限期SCLC患者中，伊立替康、卡铂与贝伐单抗联合同步放疗序贯贝伐单抗维持的一项II期研究被提前终止，因为气管食管瘘的发生率不可接受。在广泛期SCLC中，以铂类为基础的化疗加贝伐单抗的铂II期临床试验均取得了可喜的疗效及生存数据。然而，至少一项随机试验已证明贝伐单抗加入到标准化疗中无生存获益。广泛期SCLC患者的其他随机III期试验正在进行中。目前，NCCN小组不推荐在SCLC患者中使用贝伐单抗。

Overall, attempts to improve long-term survival rates in patients with SCLC through the addition of more agents or the use of dose-intense chemotherapy regimens, maintenance therapy, or alternating non–cross-resistant chemotherapy regimens have failed to yield significant advantages when compared to standard approaches.总的来说，与标准方法相比，通过增加更多的药物或使用剂量密集化疗方案、维持治疗或交替使用非交叉耐药的化疗以试图改善SCLC患者的长期生存率均未产生显著的优势。

Elderly Patients老年患者

The incidence of lung cancer increases with age. Although the median age at diagnosis is 70 years, elderly patients are under-represented in clinical trials. Although advanced chronologic age adversely affects tolerance to treatment, the functional status of an individual patient is much more useful than age in guiding clinical decision making (see the NCCN Guidelines for Senior Adult Oncology). Older patients who are functional in terms of the ability to perform activities of daily living should be treated with standard combination chemotherapy (and radiotherapy, if indicated). However, myelosuppression, fatigue, and lower organ reserves are encountered more frequently in elderly patients; therefore, they must be watched carefully during treatment to avoid excessive risk.肺癌的发病率随着年龄的增长而升高。虽然在诊断时平均年龄为70岁，但是，在临床试验中并未充分代表老年患者。虽然年老的生理年龄对治疗的耐受性产生不利影响，但是在指导临床决策方面个体患者的功能状态远比年龄更有用（见老年肿瘤NCCN指南）。日常生活活动功能正常的老年患者应采用标准的联合化疗（如果有指征，联合放疗）治疗。然而，骨髓抑制、疲劳和较低的器官储备在老年患者中更常遇到；因此，在治疗过程中必须仔细观察，以避免过度的风险。

Greater attention to the needs and support systems of elderly patients is recommended to provide optimal care. Overall, elderly patients have a similar prognosis as stage-matched younger patients. Randomized trials have indicated that less-intensive treatment (eg, single-agent etoposide) is inferior to combination chemotherapy (eg, platinum plus etoposide) in elderly patients with good PS (0–2). Several other strategies have been evaluated in elderly patients with SCLC. The use of 4 cycles of carboplatin plus etoposide seems to yield favorable results, because the area-under-the-curve (AUC) dosing of carboplatin takes into account the declining renal function of the aging patient. However, targeting carboplatin to an AUC of 5, rather than 6, may be more reasonable in this population. The usefulness of short-course, full-intensity chemotherapy has also been explored in elderly or infirm patients, and the results with only 2 cycles of chemotherapy seem to be acceptable, although this approach has not been directly compared with standard therapy.建议更多关注老年患者的需求和支持系统，以提供最佳的护理。总体而言，老年患者具有与分期匹配的年轻患者相似的预后。随机试验表明，在PS良好（0–2）的老年患者中，较不强烈的治疗（如单药依托泊苷）不如联合化疗（如铂加依托泊苷）。其他一些策略已在老年SCLC患者中进行了评估。使用4周期的卡铂加依托泊苷似乎得到良好的效果，因为卡铂曲线下面积（AUC）剂量需要考虑老年患者肾功能下降。然而，卡铂目标AUC为5而不是6，在该人群中可能更合理。也已在年老体弱患者中探索了短程、足量化疗的有效性，仅用两周期化疗的结果似乎是可以接受的，尽管这种方法未直接与标准治疗对比。

Second-Line and Third-Line (Subsequent) Therapy二线和三线（后续）治疗

Although SCLC is very responsive to initial treatment, most patients relapse with relatively resistant disease. These patients have a median survival of only 4 to 5 months when treated with further chemotherapy. Second-line and third-line (ie, subsequent) chemotherapy provides significant palliation in many patients, although the likelihood of response is highly dependent on the time from initial therapy to relapse. If this interval is less than 3 months (refractory or resistant disease), response to most agents or regimens is poor (≤10%). If more than 3 months have elapsed (sensitive disease), expected response rates are approximately 25%. If patients relapse more than 6 months after first-line treatment, then treatment with their original regimen is recommended.虽然SCLC对初始治疗是非常敏感的，但是大多数患者复发时相对抵抗。当接受进一步的化疗时，这些患者的中位生存期只有4至5个月。在许多患者中二线和三线（即后续）化疗明显缓解，虽然应答可能高度依赖于初始治疗至复发的时间。如果该时间间隔少于3个月（抵抗或难治性疾病），对大部分药物或方案的应答差（≤10%）。如果时间超过3个月（敏感性疾病），预期有效率约为25%。如果患者在一线治疗后超过6个月复发，则建议采用原方案治疗。

Subsequent chemotherapy generally involves single-agent therapy. Based on phase II trials, active subsequent agents include paclitaxel, docetaxel, topotecan, irinotecan, vinorelbine, gemcitabine, ifosfamide, temozolomide, and oral etoposide (see Principles of Chemotherapy in the NCCN Guidelines for Small Cell Lung Cancer). Preliminary data suggest that temozolomide may be useful for patients with SCLC, especially those with brain metastases and methylated O6-methylguanine-DNA methyltransferase (MGMT). Alisertib, an oral selective inhibitor of aurora kinase A, yielded a partial response rate of 21% (10/48) in patients with high aurora kinase A levels who had previously received treatment for SCLC. A phase 2 randomized trial is currently ongoing comparing alisertib/weekly paclitaxel versus weekly paclitaxel alone. Immune checkpoint inhibitors (eg, ipilimumab, nivolumab) are also being investigated for patients with SCLC.随后的化疗一般包括单药治疗。基于II期试验，有效的后续药物包括紫杉醇、多西他赛、拓扑替康、伊立替康、长春瑞滨、吉西他滨、异环磷酰胺、替莫唑胺以及口服依托泊苷（见NCCN小细胞肺癌指南中的化疗原则）。初步数据表明，替莫唑胺对于SCLC患者是有用的，尤其是那些脑转移瘤以及O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）甲基化的患者。Alisertib（MLN8237），一种口服的选择性极光激酶A抑制剂，在既往治疗过的、极光激酶A高水平的SCLC患者中部分缓解率为21%（10／48）。目前正在进行的一项2期随机试验比较Alisertib/每周紫杉醇与单药紫杉醇。也正在研究免疫检查点抑制剂（如伊匹单抗、纳武单抗）用于SCLC患者。

A randomized phase III trial compared single-agent intravenous topotecan with the combination regimen CAV. Both arms had similar response rates and survival, but intravenous topotecan caused less toxicity. In another phase III trial, oral topotecan improved overall survival when compared with best supportive care (26 vs. 14 weeks). Single-agent topotecan is approved by the FDA as subsequent therapy for patients with SCLC who experience initial response to chemotherapy but then experience progression after 2 to 3 months. In the algorithm, topotecan is recommended as a subsequent agent for patients with relapsed SCLC (category 1 for relapse >2–3 months for up to 6 months; category 2A for relapse<2–3 months). Either oral or intravenous topotecan may be used, because efficacy and toxicity seem to be similar with either route.一项随机III期试验比较单药静脉注射盐酸拓扑替康与CAV联合方案。两组有效率和生存均相似，但静脉拓扑替康引起的毒性较小。在另外一项III期试验中，与最佳支持治疗相比，口服拓扑替康改善总生存期（26对14周）。单药拓扑替康被FDA批准作为最初对化疗有应答但随后2到3个月进展的SCLC患者的后续治疗。在工作步骤中，建议拓扑替康作为一个后续药物用于复发性SCLC患者（复发>2–3个月至6个月1类；复发<2–3个月2a类）。可以使用口服或静脉注射拓扑替康，因为两者之中任一途径的疗效和毒性似乎均类似。< span="">

Many practicing oncologists have noted excessive toxicity with the standard regimen of 1.5 mg/m2 of intravenous topotecan for 5 days, and studies suggest that an attenuated dose may be equally efficacious with lower toxicity. Published studies have yielded conflicting data regarding the usefulness of weekly topotecan in patients with relapsed SCLC, and this approach remains under investigation. Amrubicin is an active drug in patients with relapsed or refractory SCLC. However, grade 3–4 toxicity, primarily neutropenia, is common. A recent phase III trial reported that amrubicin did not improve overall survival as second-line treatment for SCLC when compared to topotecan, except in a subset of patients with refractory disease.许多临床肿瘤学家已经注意到静脉拓扑替康1.5mg/㎡连续5天的标准方案毒性严重，研究表明，减毒剂量可能同样有效具有较低的毒性。已发表的有关每周托泊替康治疗复发性SCLC患者有用性的研究数据相互矛盾，因此这种方法仍在调查研究。在难治性或复发性SCLC患者中，氨柔比星是一种有效的药物。然而，3-4级毒性，主要是中性粒细胞减少症常见。最近一项III期试验报道，作为SCLC的二线治疗，与拓扑替康相比，氨柔比星并不能提高总生存期，除了在难治性疾病患者亚组。

The optimal duration of subsequent chemotherapy has not been fully explored, although its duration is usually short and the cumulative toxicity is frequently limiting even in patients who experience response. For these reasons, subsequent chemotherapy should be continued until 2 cycles beyond best response, progression of disease, or development of unacceptable toxicity. Additional subsequent chemotherapy (eg, third-line chemotherapy) can be considered if patients are still PS 0-2.后续化疗的最佳持续时间尚未充分研究，虽然其持续时间通常短，蓄积毒性是常见的限制性毒性，即使是应答的患者。对于这些原因，后续化疗应持续到两周期，直至接近最佳应答、疾病进展或发生无法接受的毒性。如果患者PS仍然是0-2，可以考虑追加后续化疗（如三线化疗）。

Radiotherapy放射治疗

The Principles of Radiation Therapy in the algorithm describe the radiation doses, target volumes, and normal tissue dose volume constraints for mainly limited-stage SCLC, and include references to support the recommendations; prophylactic cranial irradiation (PCI) and treatment of brain metastases are also discussed (see the NCCN Guidelines for Small Cell Lung Cancer). The American College of Radiology (ACR) Appropriateness Criteria are a useful resource. The Principles of Radiation Therapy for NSCLC in the algorithm may also be useful (eg, general principles of radiotherapy, palliative radiotherapy) (see the NCCN Guidelines for Non-Small Cell Lung Cancer). This section describes the studies supporting the NCCN recommendations.在工作步骤中放疗原则描述了放射剂量、靶区以及正常组织剂量体积限制，主要针对局限期SCLC患者，包括支持建议的参考；预防性脑照射（PCI）和脑转移瘤的治疗也进行了讨论（见小细胞肺癌NCCN指南）。美国放射学会（ACR）适宜性标准是一个有用的资源。NSCLC工作步骤中的放射治疗原则也可能是有用的（如，放射治疗的一般原则、姑息性放射治疗）（见非小细胞肺癌NCCN指南）。本节描述了支持NCCN建议的研究。

Thoracic Radiotherapy胸部放疗

Trial Data试验数据

The addition of thoracic radiotherapy has improved survival for patients with limited-stage disease. Meta-analyses that included more than 2000 patients show that thoracic radiation for limited-stage disease yields a 25% to 30% reduction in local failure, and a corresponding 5% to 7% improvement in 2-year survival when compared with chemotherapy alone. However, achieving long-term local control using conventional chemoradiotherapy for patients with limited-stage SCLC remains a challenge.对于局限期疾病患者增加胸部放疗改善生存。包括2000多例患者的meta分析显示，与单纯化疗相比，局限期疾病的胸部放射局部失败率降低25%至30%，相应改善2年生存率5%至7%。然而，对于局限期SCLC患者，使用常规放化疗实现长期局部控制仍是一个挑战。

The administration of thoracic radiotherapy requires the assessment of several factors, including the timing of chemotherapy and radiotherapy (concurrent vs. sequential), timing of radiotherapy (early vs. late), volume of the radiation port (original tumor volume vs. shrinking field as the tumor responds), dose of radiation, and fractionation of radiotherapy. Early concurrent chemoradiotherapy is recommended for patients with limited-stage SCLC based on randomized trials. A randomized phase III trial by the Japanese Cooperative Oncology Group assessed sequential versus concurrent thoracic radiotherapy combined with EP for patients with limited-stage disease. They reported that patients treated with concurrent radiotherapy lived longer than those treated with sequential radiotherapy. Another randomized phase III trial (by the National Cancer Institute of Canada)—comparing radiotherapy beginning with either cycle 2 or cycle 6 of chemotherapy—showed that early radiotherapy was associated with improved local and systemic control and with longer survival. A systematic review on the timing of thoracic radiotherapy in limited-stage SCLC determined that early concurrent radiotherapy results in a small, but significant improvement in overall survival when compared with late concurrent or sequential radiotherapy. Another meta-analysis also found that early concurrent thoracic radiation with platinum-based chemotherapy increases 2- and 5-year overall survival in patients with limited-stage SCLC.胸部放疗的管理需要评估一些因素，包括化疗与放疗的时机（同步与序贯）、放射治疗的时机（早与晚）、放射入口体积（原始肿瘤体积与因肿瘤应答缩野）、放射剂量以及放疗分割。根据随机试验，对于局限期SCLC患者，推荐早期同步放化疗。日本肿瘤学协作组的一项随机III期试验评估序贯与同步胸部放疗联合EP治疗局限期疾病患者。他们报道，接受同步放疗的患者比序贯放疗的患者寿命更长。另一项随机III期试验（加拿大国家癌症研究所）比较在化疗的第2周期或第6周期开始放疗，结果显示，早期放疗改善局部和全身性控制并且生存期更长。一项局限期SCLC胸部放疗时机的系统回顾发现，与晚期同步或序贯放疗相比，早期同步放疗带来少许、却显著改善总生存。另一项meta分析也发现，早期同步胸部放疗联合铂类为基础的化疗增加局限期SCLC患者的2年和5年总生存率。

The ECOG/Radiation Therapy Oncology Group compared once-daily to twice-daily radiotherapy with EP. In this trial, 412 patients with limited-stage SCLC were treated with concurrent chemoradiotherapy using a total dose of 45 Gy delivered either twice a day over 3 weeks or once a day over 5 weeks. The twice-daily schedule produced a survival advantage, but a higher incidence of grade 3–4 esophagitis was seen when compared with the once-daily regimen. Median survivals were 23 versus 19 months (P = .04), and 5-year survival rates were 26% versus 16% in the twice-daily and once-daily radiotherapy arms, respectively. A significant criticism of this trial is that the doses of radiation in the 2 arms were not biologically equivalent. In light of this, ongoing trials are evaluating biologically equivalent doses of 45 Gy delivered twice daily versus 60 to 70 Gy delivered once daily. Another concern regarding hyperfractionation is that twice-daily thoracic radiation is technically challenging for patients with bilateral mediastinal adenopathy.ECOG/肿瘤放射治疗协作组比较了每日一次与每日两次放疗联合EP。在这项试验中，412例局限期SCLC患者DT45Gy bid 3周以上或qd 5周以上同步放化疗。每天两次方案获得了生存优势，但与每天一次方案相比，3-4级食管炎的发病率较高。在每日两次次和每日1次放疗组中，中位生存时间分别为23个月和19个月（P = .04），5年生存率分别为26%和16%。该试验一个值得注意的诟病是，两组中的放射剂量不是生物等效剂量。鉴于此，正在进行的试验评估45Gy的生物等效剂量每天两次对60-70Gy每天一次。关于超分割的另一个担心是，对于双侧纵隔淋巴结肿大的患者，每日两次胸部放疗是技术上的挑战。

Another randomized phase III trial showed no survival difference between once-daily thoracic radiotherapy to 50.4 Gy with concurrent EP and a split-course of twice-daily thoracic radiotherapy to 48 Gy with concurrent EP. However, split-course radiotherapy may be less efficacious because of interval tumor regrowth between courses. Overall, patients selected for combined modality treatment that incorporates twice-daily radiotherapy must have an excellent PS and good baseline pulmonary function.另一项随机III期试验表明，每天一次胸部放疗至50.4Gy联合EP与每天两次分割胸部放疗至48Gy联合EP相比，无生存差异。然而，超分割放射治疗可能不太有效，因为在放射之间的间隔之间肿瘤再生长。总之，患者选择综合方式治疗，采用每天两次放疗的患者必须具有很好的PS和良好的基线肺功能。

NCCN GuidelinesNCCN指南

For limited-stage disease, the NCCN Guidelines recommend that radiotherapy should be used concurrently with chemotherapy and that radiotherapy should start with the first or second cycle (category 1). The optimal dose and schedule of radiotherapy have not been established. However, 45 Gy in 3 weeks (twice-daily regimen) is superior to 45 Gy once daily in 5 weeks. For twice-daily radiotherapy, the recommended schedule is 1.5 Gy twice daily to a total dose of 45 Gy in 3 weeks (category 1). For once-daily radiotherapy, the recommended schedule is 2.0 Gy once daily to a total dose of 60 to 70 Gy (see Principles of Radiation Therapy in the NCCN Guidelines for Small Cell Lung Cancer). Concurrent chemoradiotherapy (category 1) is preferable to sequential therapy in patients with limited-stage disease and good PS (0–2) when chemoradiation is recommended.对于局限期患者，NCCN指南推荐放疗应该同步化疗，并且放疗应该在第一或第二周期开始（1类）。放疗的最佳剂量和方案尚未确定。然而，45Gy/3周（每日两次方案）优于45Gy/5周每天一次。对于每日两次放疗，推荐的计划是1.5Gy，每日两次，至总剂量45Gy/3周（1类）。对于每日一次放射治疗，推荐的计划是2.0Gy每日一次，总剂量为60-70Gy（见小细胞肺癌NCCN指南中的放射治疗原则）。在局限期疾病且PS良好（0–2）的患者中，当建议放化疗时，同步放化疗（1类）优于序贯治疗。

The minimum standard for thoracic irradiation is CT-planned 3-D conformal radiotherapy. More advanced technologies may also be used when needed (eg, 4DCT) (see Principles of Radiation Therapy in the NCCN Guidelines for Small Cell Lung Cancer). The radiation target volumes can be defined on the PET-CT scan obtained at the time of radiotherapy planning using definitions in reports 50 and 62 from the International Commission on Radiation Units & Measurement (ICRU). However, the prechemotherapy PET-CT scan should be reviewed to include the originally involved lymph node regions in the treatment fields.胸部照射的最低标准是CT计划的三维适形放疗。当需要时也可以使用更先进的技术（如4DCT）（见小细胞肺癌NCCN指南中的放射治疗原则）。在PET-CT扫描时获得的图像可以确定放射治疗计划时国际辐射单位与测量委员会（ICRU）在50和62报告中定义的放射靶区。然而，为了将最初累及的淋巴结区包括在治疗野内，应复阅化疗前PET-CT扫描。

The normal tissue constraints used for NSCLC are appropriate for SCLC when using similar radiotherapy doses (see the NCCN Guidelines for Non-Small Cell Lung Cancer). When using accelerated schedules (eg, 3–5 weeks), the spinal cord constraints from the CALCB 30610/RTOG 0538 protocol can be used as a guide (see Principles of Radiation Therapy in the NCCN Guidelines for Small Cell Lung Cancer). Intensity-modulated radiation therapy (IMRT) may be considered in select patients (see Principles of Radiation Therapy in the NCCN Guidelines for Small Cell Lung Cancer and the NCCN Guidelines for Non-Small Cell Lung Cancer).当使用相似的放疗剂量时，用于NSCLC的正常组织限制对于SCLC是适合的（见非小细胞肺癌NCCN指南）。当使用加速计划时（如3–5周），CALCB 30610/RTOG 0538协议的脊髓限制可以作为指导（见小细胞肺癌NCCN指南中的放射治疗原则）。在选择性的病人中可以考虑调强放疗（IMRT）（见小细胞肺癌NCCN指南和非小细胞肺癌NCCN指南中的放射治疗原则）。

Based on the results of a randomized trial by Jeremic et al, the addition of sequential thoracic radiotherapy may be considered in select patients with low-bulk metastatic disease who have a complete or near complete response after initial chemotherapy. In this trial, patients experiencing a complete response at distant metastatic sites after 3 cycles of EP were randomized to receive either 1) further EP; or 2) accelerated hyperfractionated radiotherapy (ie, 54 Gy in 36 fractions over 18 treatment days) in combination with carboplatin plus etoposide. The investigators found that the addition of radiotherapy resulted in improved median overall survival (17 vs. 11 months). In patients with extensive-stage SCLC who responded to chemotherapy, a recent phase III trial by Slotman et al (Dutch Crest trial) reported that the addition of sequential thoracic radiotherapy did not improve the primary endpoint of 1-year overall survival (33% vs. 28%, P = .066), but a secondary analysis did find improvement in 2-year overall survival (13% vs. 3%, P = .004) when compared with patients who did not receive sequential thoracic radiotherapy.基于Jeremic等人的一项随机试验结果，在选择性的小肿块转移性疾病、在初始化疗后已完全或接近完全缓解的患者中可以考虑加入序贯胸部放疗。在这项试验中，在3周期的EP后远处转移灶完全缓解的患者随机接受1）进一步EP；或2）加速超分割放疗（即54Gy/36f治疗18天以上）联合卡铂加依托泊苷。研究者发现，加入放疗延长了中位总生存期（17对11个月）。在化疗有效的广泛期SCLC患者中，Slotman等人的最近一项III期试验（荷兰CREST研究）报道，与未接受序贯胸部放疗的患者相比，序贯胸部放疗的加入并不能改善1年总生存率的主要终点（33%对28%，P = .066），但二次分析发现改善2年总生存率（13%对3%，P = .004）。

Prophylactic Cranial Irradiation预防性脑照射

Intracranial metastases occur in more than 50% of patients with SCLC. Randomized studies have shown that PCI is effective in decreasing the incidence of cerebral metastases, but most individual studies did not have sufficient power to show a meaningful survival advantage. A meta-analysis of all randomized PCI trials (using data from individual patients) reported a 25% decrease in the 3-year incidence of brain metastases, from 58.6% in the control group to 33.3% in the PCI-treated group. Thus, PCI seems to prevent (and not simply delay) the emergence of brain metastases. This meta-analysis also reported a 5.4% increase in 3-year survival in patients treated with PCI, from 15.3% in the control group to 20.7% in the PCI group. Although the number of patients with extensive-stage disease was small in this meta-analysis, the observed benefit was similar in patients with both limited- and extensive-stage disease. A retrospective study of patients with limited-stage disease also found that PCI increased survival at 2, 5, and 10 years compared with those who did not receive PCI. A randomized trial from the EORTC assessed PCI versus no PCI in 286 patients with extensive-stage SCLC whose disease had responded to initial chemotherapy. PCI decreased symptomatic brain metastases (14.6% vs. 40.4%) and increased the 1-year survival rate (27.1% vs. 13.3%) compared with controls. Preliminary data from a recent Japanese phase III trial suggest that PCI did not improve survival in patients with extensive-stage disease.超过50%的SCLC患者发生颅内转移。随机研究表明，预防性脑照射（PCI）在降低脑转移瘤的发病率方面是有效的，但大多数独立的研究并没有足够的能力显示有意义的生存优势。所有随机PCI试验（使用具体患者的数据）的一项meta分析报告3年脑转移发病率从对照组的58.6%到PCI治疗组的33.3%，下降了25%。因此，PCI似乎预防（而不是仅仅延迟）脑转移的出现。该meta分析还报告PCI治疗的患者3年生存率从对照组的15.3%到PCI组的20.7%，增加了5.4%。虽然在这项meta分析中广泛期疾病患者的数量少，但是在局限期和广泛期疾病患者中观察到的获益均是相似的。局限期疾病患者的一项回顾性研究也发现，与那些未接受PCI的患者相比，PCI增加2、5和10年生存率。EORTC的一项随机试验评估了286例对初次化疗应答的广泛期SCLC患者PCI与没有PCI。与对照组相比，PCI减少了症状性脑转移（14.6%对40.4%），并增加了1年生存率（27.1%对13.3%）。最近一项日本III期试验的初步数据表明，在广泛期疾病患者中，PCI并未改善生存。

Late neurologic sequelae have been attributed to PCI, particularly in studies using fractions greater than 3 Gy and/or administering PCI concurrently with chemotherapy. Thus, PCI is not recommended for patients with poor PS (3–4) or impaired neurocognitive function. Older age (>60 years) has also been associated with chronic neurotoxicity. When given after the completion of chemotherapy and at a low dose per fraction, PCI may cause less neurologic toxicity. Symptomatic brain metastases result in major morbidity, which frequently does not completely resolve with therapeutic cranial irradiation.迟发性神经系统后遗症被认为是PCI造成的，特别是在使用分割大于3Gy和/或PCI与化疗同时使用的研究中。因此，对于PS差（3–4）或神经认知功能受损的患者不建议PCI。老年（>60岁）也与慢性神经毒性相关。当化疗结束后且每次分割低剂量时，PCI可能会导致较少的神经毒性。症状性脑转移是严重的并发症，治疗性颅脑放疗往往不能彻底解决。

Before the decision is made to administer PCI, a balanced discussion between the patient and physician is necessary. PCI is recommended (category 1) for patients with either limited- or extensive-stage disease who attain a complete or partial response. PCI is also recommended for all patients who have had a complete resection (see Principles of Surgical Resection in the NCCN Guidelines for Small Cell Lung Cancer) . The recommended regimens for PCI include: 25 Gy in 10 daily fractions (2.5 Gy/fraction), 30 Gy in 10 to 15 daily fractions, or 24 Gy in 8 daily fractions (see Principles of Radiation Therapy in the NCCN Guidelines for Small Cell Lung Cancer). For the 2015 update, the NCCN Panel felt that a shorter course of PCI may be appropriate (eg, 20 Gy in 5 fractions) for selected patients with extensive-stage disease. Higher doses (eg, 36 Gy) increased mortality and toxicity when compared with standard doses (25 Gy). PCI should not be given concurrently with systemic chemotherapy, and high total radiotherapy dose (>30 Gy) should be avoided because of the increased risk of neurotoxicity. Fatigue, headache, and nausea/vomiting are the most common acute toxic effects after PCI. After the acute toxicities of initial therapy have resolved, PCI can be administered.在决定实施PCI之前，病人和医生之间的权衡讨论是必要的。对于达到完全或部分缓解的局限期或广泛期疾病患者推荐PCI（1类）。PCI也建议所有的患者完全切除（见小细胞肺癌NCCN指南手术切除原则）。推荐的PCI方案包括：25Gy/10f qd（2.5 Gy/f），30Gy/10-15f qd，或24 Gy/8f qd（见小细胞肺癌NCCN指南中的放射治疗原则）。对于2015年更新，NCCN专家小组认为，对于选择性的广泛期疾病患者，短程PCI可能是适当的（如20Gy/5f）。与标准剂量（25Gy）相比，更高剂量（如36Gy）增加死亡率和毒性。PCI不应与全身化疗同时给予，并且应避免放疗总量高（>30 Gy），因为增加神经毒性风险。PCI后，疲劳、头痛和恶心/呕吐是最常见的急性毒性作用。在初始治疗的急性毒性解决后，可以给予PCI。

Palliative Radiotherapy姑息性放疗

For patients with localized symptomatic sites of disease (ie, painful bony lesions, spinal cord compression, obstructive atelectasis) or with brain metastases, radiotherapy can provide excellent palliation (see Initial Treatment in the NCCN Guidelines for Small Cell Lung Cancer and the NCCN Guidelines for Non-Small Cell Lung Cancer). Orthopedic stabilization may be useful in patients at high risk for fracture because of osseous structural impairment. Because patients with SCLC often have a short life span, surgery is not usually recommended for spinal cord compression. Whole-brain radiotherapy is recommended for brain metastases in patients with SCLC due to the frequent occurrence of multiple metastases (see Principles of Radiation Therapy in the NCCN Guidelines for Small Cell Lung Cancer and the NCCN Guidelines for Central Nervous System Cancers). Although late complications may occur with whole-brain radiotherapy (eg, neurocognitive impairment), this is less of an issue in patients with SCLC because long-term survival is rare. The recommended dose for whole-brain radiotherapy is 30 Gy in 10 daily fractions. In patients who develop brain metastases after PCI, stereotactic radiosurgery may be considered.对于有症状的病变局部（即痛性骨损害、脊髓压迫、阻塞性肺不张）或脑转移患者，放疗可以极好的缓解（见小细胞肺癌NCCN指南和非小细胞肺癌NCCN指南中的初始治疗）。在因为骨结构损害的骨折高危患者中，矫形稳定可能是有用的。因为SCLC患者往往寿命很短，通常不推荐手术治疗脊髓压迫。对于SCLC患者脑转移，由于常常出现多发转移，因此推荐全脑放疗（见小细胞肺癌NCCN指南和中枢神经系统肿瘤NCCN指南中的放射治疗原则）。虽然全脑放疗可能发生晚期并发症（如，神经认知障碍），但是在SCLC患者中这不是个大问题，因为长期生存罕见。推荐的全脑放疗剂量为30Gy/10f，每日1次。在PCI后出现脑转移的患者中，可以考虑立体定向放射外科。

Surgical Resection of Stage I SCLC

I期SCLC的手术切除

The Principles of Surgical Resection for SCLC are described in the NCCN algorithm; studies supporting these recommendations are described in this section. Briefly, the NCCN Guidelines state that surgery should only be considered for patients with stage I (T1–2, N0) SCLC in whom mediastinal staging has confirmed that mediastinal lymph nodes are not involved. Data show that patients with clinically staged disease in excess of T1–2,N0 do not benefit from surgery. Note that only 5% of patients with SCLC have true stage I SCLC. SCLC手术切除的原则在NCCN工作步骤中描述；在这一章节中描述了支持这些建议的研究。简而言之，NCCN指南指出，手术应该仅仅考虑用于纵隔分期证实的纵隔淋巴结未累及的I期（T1–2N0）SCLC患者。数据显示，疾病临床分期超过T1–2N0的患者，手术不能获益。值得注意的是，只有5%的SCLC患者为真正的I期SCLC。

Trial Data试验数据

The Lung Cancer Study Group conducted the only prospective randomized trial evaluating the role of surgery in SCLC. Patients with limited-stage disease, excluding those with solitary peripheral nodules, received 5 cycles of chemotherapy with CAV; those showing a response to chemotherapy were randomly assigned to undergo resection plus thoracic radiotherapy or thoracic radiotherapy alone. The overall survival rates of patients on the 2 arms were equivalent, suggesting no benefit to surgery in this setting. However, only 19% of enrolled patients had clinical stage I (T1–2, N0, M0) disease.肺癌研究小组实施了唯一一项前瞻性随机试验评估手术在SCLC中地位。排除孤立性周围性肺结节的局限期患者，接受了5周期的CAV化疗；那些化疗有效的患者被随机分配至接受切除术加胸部放疗或单纯胸部放疗。两组患者的总生存率相同，这表明在这种情况下手术没有受益。然而，只有19%的入组患者为临床I期（T1–2N0M0）。

Most data regarding the benefit of surgery are from retrospective reviews. These studies report favorable 5-year survival rates of 40% to 60% in patients with stage I disease. In most series, survival rates decline significantly in patients with more advanced disease, leading to the general recommendation that surgery should only be considered in those with stage I disease. Interpretation of these results is limited by the selection bias inherent in retrospective reviews and by the variable use of chemotherapy and radiotherapy in these studies.几乎所有的有关手术获益的数据均来自回顾分析。这些研究报告在I期患者中良好的5年生存率为40%-60%。在大多数群组中，更晚期疾病患者的生存率下降显著，因此一般建议，只有在I期情况下才考虑手术。这些结果的解释是在回顾性研究中固有的选择偏差是有限的，而这些研究中化疗和放疗的使用是多变的。

Analyses of the SEER database also suggest that surgery may be appropriate for some patients with localized disease. However, these studies are limited by the lack of information on chemotherapy use in the database. In addition, comparison of the survival of surgical patients to all those who did not undergo surgery is inherently flawed by selection bias. Ultimately, the role of surgery in SCLC will not be fully defined until results are available of trials comparing surgery plus adjuvant chemotherapy to concurrent chemoradiotherapy in patients who are rigorously staged. SEER数据库的分析也表明，对于某些局限期患者手术可能是恰当的。然而，数据库中的这些研究受限于缺乏化疗使用的信息。此外，比较手术患者与所有未接受手术患者的生存，固有的缺陷是选择偏倚。最终，手术在SCLC中的地位不能充分明确，除非是在严格分期的患者中可得到比较手术加辅助化疗与同步放化疗试验的结果。

NCCN Guidelines NCCN指南

In all patients with clinical stage I (T1–2, N0) SCLC who are being considered for surgical resection, occult nodal disease should be ruled out through mediastinal staging before resection. If resection is performed, the NCCN Panel favors lobectomy and does not feel that segmental or wedge resections are appropriate for patients with SCLC. After complete resection, adjuvant chemotherapy or chemoradiation is recommended. Adjuvant chemotherapy alone is recommended for patients without nodal metastases, whereas concurrent chemotherapy and postoperative mediastinal radiotherapy are recommended for patients with nodal metastases (see Adjuvant Treatment in the NCCN Guidelines for Small Cell Lung Cancer). Although panel members agree that postoperative mediastinal radiotherapy is recommended in this setting, it should be based on the extent of nodal sampling/dissection and extent of nodal positivity; however, there are no data to support this recommendation. PCI should be considered after adjuvant therapy in select patients, because it can improve survival (see Prophylactic Cranial Irradiation in this Discussion and Adjuvant Treatment in the NCCN Guidelines for Small Cell Lung Cancer).考虑手术切除的所有临床Ⅰ期（T1–2N0）SCLC患者，均应在切除前通过纵隔分期排除隐匿性淋巴结病变。对于SCLC患者，如果进行切除，NCCN小组支持叶切除术而非段或楔形切除。建议在完全切除术后辅助化疗或放化疗。对于无淋巴结转移的患者，建议单纯辅助化疗，而对于淋巴结转移的患者建议同步化疗加术后纵隔放疗（见小细胞肺癌NCCN指南中的辅助治疗）。虽然小组成员同意在这种情况下建议术后纵隔放疗，但是应该基于广泛的淋巴结采样/解剖和广泛的淋巴结阳性；然而，没有数据支持该建议。在选择性患者中辅助治疗后应考虑PCI，因为可改善生存（见本讨论中的预防性脑照射和小细胞肺癌NCCN指南中的辅助治疗）。

Surveillance监测

The schedule for follow-up examinations is shown in the algorithm (see Surveillance in the NCCN Guidelines for Small Cell Lung Cancer); the frequency of surveillance decreases during subsequent years because of the declining risk of recurrence. PET-CT or brain MRI (or CT) is not recommended for routine follow-up. If a new pulmonary nodule develops, it should prompt evaluation for a new primary lung cancer, because second primary tumors are a frequent occurrence in patients who are cured of SCLC. Smoking cessation should be encouraged for all patients with SCLC, because second primary tumors occur less commonly in patients who quit smoking (see the NCCN Guidelines for Smoking Cessation). Former smokers should be encouraged to remain abstinent.随访方案显示在工作步骤中（见小细胞肺癌NCCN指南中的监测）；在随后的几年中，降低监测频率，因为复发风险下降。不推荐PET-CT或脑MRI（或CT）用于常规随访。如果发生一个新的肺结节，应作为一个新的原发性肺癌及时评估，因为在治愈的SCLC患者中经常发生第二原发肿瘤。应鼓励所有SCLC患者戒烟，因为第二原发肿瘤在戒烟的患者中较少见（见NCCN戒烟指南）。应该鼓励既往吸烟者保持戒烟。

Lung Neuroendocrine Tumors肺神经内分泌肿瘤

LNTs encompass a wide spectrum of disease. Using the 2004 WHO criteria, LNTs are characterized as: 1) high-grade neuroendocrine carcinomas (SCLC and LCNEC); 2) intermediate-grade neuroendocrine carcinomas (atypical carcinoids); or 3) low-grade neuroendocrine carcinomas (typical carcinoids). SCLC and LCNEC are poorly differentiated tumors that often have a poor prognosis, whereas typical carcinoid is a well-differentiated neuroendocrine tumor that usually has a good prognosis. Atypical carcinoid is a moderately differentiated neuroendocrine cancer and, as such, carries an intermediate prognosis. Although many carcinoids occur in the GI tract (68%), they also occur in the bronchopulmonary system (25%). Carcinoids are rare tumors, but a SEER analysis suggests that their incidence is increasing.肺神经内分泌肿瘤（LNTs）包括多种疾病。使用2004年WHO标准，LNTs的特征为：1）高分级神经内分泌癌（SCLC和LCNEC）；2）中分级神经内分泌癌（不典型类癌）；3）低分级神经内分泌癌（典型类癌）。SCLC和大细胞神经内分泌癌（LCNEC）是低分化肿瘤，通常预后很差，而典型类癌是一种分化良好的神经内分泌肿瘤，通常具有良好的预后。非典型类癌是一种中度分化的神经内分泌癌，因此，预后中等。虽然许多类癌发生在胃肠道（68%），但是也可出现在支气管肺系统（25%）。类癌是罕见肿瘤，但SEER分析表明，其发病率正在上升。

Diagnosis and Staging诊断和分期

Most LNTs are SCLCs, which are managed using the NCCN Guidelines for Small Cell Lung Cancer. LCNEC is associated with smoking and is managed using the NCCN Guidelines for Non-Small Cell Lung Cancer, because the conceptual algorithm used to manage these patients is the same as that for patients with NSCLC. However, data suggest that chemotherapy regimens used for SCLC may be a better option for LCNEC if systemic therapy is indicated. Low-grade and intermediate-grade lung neuroendocrine carcinomas (typical and atypical carcinoids) account for 1% to 2% of lung cancers and are managed using the NCCN Guidelines for Lung Neuroendocrine Tumors. Both histologic and cytologic features can be useful for distinguishing LNTs from SCLC and LCNEC, although diagnosis can be difficult (see the NCCN Guidelines for Neuroendocrine Tumors and the NCCN Guidelines for Non-Small Cell Lung Cancer). CD56, chromogranin, and synaptophysin are useful immunohistochemical markers for identifying neuroendocrine tumors. The proliferative marker Ki-67 may also be useful. Larger surgical specimens are often needed to diagnose atypical carcinoids or LCNEC, which may be difficult to diagnose using small biopsies or cytology.大多数肺神经内分泌肿瘤（LNTs）是SCLCs，其使用小细胞肺癌NCCN指南管理。大细胞神经内分泌癌（LCNEC）与吸烟有关，使用非小细胞肺癌NCCN指南管理，因为概念上用于管理这些患者的工作步骤与NSCLC患者相同。然而，数据表明，对于LCNEC，如果有全身治疗的适应症，用于SCLC的化疗方案可能是一个更好的选择。分化良好与分化中等的肺神经内分泌癌（典型和非典型类癌）占肺癌的1%-2%，使用肺神经内分泌肿瘤的NCCN指南管理。组织学和细胞学特征二者均可有助于从SCLC和LCNEC中鉴别LNTs，尽管诊断是困难的（见神经内分泌肿瘤NCCN指南和非小细胞肺癌NCCN指南）。CD56、嗜铬素和突触素是识别神经内分泌肿瘤有用的免疫组化标记。增殖标志物Ki-67可能也是有用的。诊断非典型类癌或LCNEC通常需要更大的手术标本，使用小活检或细胞学检查可能难以诊断。

LNTs are staged using the 7th edition of the AJCC staging system for lung tumors (see Tables 2 and 3 in the NCCN Guidelines for Small Cell Lung Cancer). Both low-grade and intermediate-grade LNTs are usually stage I at diagnosis, although lymph node metastases (stages II–III) are more commonly seen in intermediate-grade tumors. Compared with other lung carcinomas, the prognosis is excellent for many patients with low-grade and intermediate-grade LNTs. LNTs使用第7版AJCC肺肿瘤分期系统进行分期（见小细胞肺癌NCCN指南中的表2和表3）。分化良好与分化中等的LNTs在诊断时两者通常均是I期，虽然淋巴结转移（II–III期）在分化中等的肿瘤中更常见。与其他肺癌相比，许多分化良好与分化中等的LNTs患者的预后极好。

Treatment治疗

Surgery is recommended for patients with stage I, II, or IIIA low-grade or intermediate-grade LNTs (ie, typical or atypical carcinoids) (see Primary Treatment in the NCCN Guidelines for Small Cell Lung Cancer). After surgical resection, 5- and 10-year survival rates are more than 90% for patients with typical carcinoids, whereas 5- and 10-year survival rates are 70% and 50% to 60% for patients with atypical carcinoids. Lymph node involvement decreases long-term survival in both typical and atypical carcinoid. For the 2015 update, the NCCN Panel slightly revised the primary treatment guidelines for patients with stage IIIA LNTs. If surgery is not feasible, external-beam radiotherapy is recommended for stage IIIA typical carcinoids, and cisplatin/etoposide plus radiotherapy is recommended for stage IIIA atypical carcinoids. Cisplatin/etoposide with or without RT is recommended for stage IIIB LNTs except for T4 due to multiple lung nodules. Systemic therapy (eg, cisplatin/etoposide, temozolomide ± capecitabine, sunitinib, everolimus) is recommended for patients with unresectable or advanced disease, although response rates are modest and there is no evidence for a preferred regimen. Octreotide (including long-acting release [LAR]) may be considered for select patients with positive octreotide scans or symptoms of carcinoid syndrome.对于I、II或IIIA期分化良好或分化中等的LNTs（即典型或非典型类癌）患者，推荐手术（见小细胞肺癌NCCN指南中的初始治疗）。手术切除后，5、10年生存率典型类癌患者超过90%，而不典型类癌患者分别为70%和50%-60%。在典型和不典型类癌患者中淋巴结受累均降低二者的长期生存。对于2015年的更新，NCCN小组稍微修改了IIIA期LNTs患者的初始治疗指南。对于IIIA期典型类癌，如果手术不可行，则推荐外照射放疗，而对于IIIA期非典型类癌推荐顺铂/依托泊苷加放疗。对于除了多发肺结节T4的IIIB期LNTs，推荐顺铂/依托泊苷加或不加RT。对于不能手术切除的或晚期患者，推荐全身治疗（如顺铂/依托泊苷、替莫唑胺±卡培他滨、舒尼替尼、依维莫司），尽管有效率适中，却没有证据推荐首选方案。卡培他滨，舒尼替尼，依维莫司）推荐用于不能手术切除的晚期病患者，虽然响应率是温和的，没有任何证据的优选方案。对于奥曲肽扫描阳性或有类癌综合征症状的选择性患者，可考虑奥曲肽（包括长效释放[LAR]）。