非小细胞肺癌初始治疗NCCN指南2017第2版

NCCN Guidelines Version 2.2017 NCCN指南2017第2版

Non-Small Cell Lung Cancer
非小细胞肺癌

Initial Therapy
初始治疗

Before treatment, it is strongly recommended that determination of tumor resectability be made by board-certified thoracic surgeons who perform lung cancer surgery as a prominent part of their practice (see Principles of Surgical Therapy in the NCCN Guidelines for Non-Small Cell Lung Cancer). Principles of Radiation Therapy recommends doses for RT (see the NCCN Guidelines for Non-Small Cell Lung Cancer). In addition, the NCCN Guidelines also recommend regimens for chemotherapy and chemoradiation (see Chemotherapy Regimens for Neoadjuvant and Adjuvant Therapy, Chemotherapy Regimens Used with Radiation Therapy, and Systemic Therapy for Advanced or Metastatic Disease in the NCCN Guidelines for Non-Small Cell Lung Cancer). 山东省肿瘤医院呼吸肿瘤内科张品良
在治疗前，强烈建议由在实践中以肺癌手术为主、通过职业认证的胸外科医生确定肿瘤的可切除性（见非小细胞肺癌NCCN指南中的外科治疗原则）。放射治疗原则推荐的放疗剂量（见非小细胞肺癌NCCN指南）。此外，NCCN指南也推荐了化疗和放化疗方案（见非小细胞肺癌NCCN指南中的新辅助与辅助治疗化疗方案、联合放疗的化疗方案以及晚期或转移性疾病的全身治疗）。

Stage I, Stage II, and Stage IIIA Disease
I、II和IIIA期疾病

Depending on the extent and type of comorbidity present, patients with stage I or a subset of stage II (T1–2, N1) tumors are generally candidates for surgical resection and mediastinal lymph node dissection. Definitive RT, particularly SABR, is recommended for patients with early-stage NSCLC who are medically inoperable or refuse surgery, and can be considered as an alternative to surgery in patients at high risk of complications (see Stereotactic Ablative Radiotherapy in this Discussion and see Initial Treatment for Stage I and II in the NCCN Guidelines for Non-Small Cell Lung Cancer). In some instances, positive mediastinal nodes (N2) are discovered at surgery; in this setting, an additional assessment of staging and tumor resectability must be made, and the treatment (ie, inclusion of systematic mediastinal lymph node dissection) must be modified accordingly. Therefore, the NCCN Guidelines include 2 different tracks for T1–3, N2 disease (ie, stage IIIA disease): 1) T1–3, N2 disease discovered unexpectedly at surgical exploration; and 2) T1–3, N2 disease confirmed before thoracotomy. In the second case, an initial brain MRI (with contrast) and FDG PET/CT scan (if not previously done) are recommended to rule out metastatic disease.
取决于病变范围与并存疾病的类型，I期或II期亚组（T1–2N1）肿瘤患者一般适于手术切除和纵隔淋巴结清扫术。对于因内科因素不能手术或拒绝手术的早期非小细胞肺癌患者，推荐根治性放疗，特别是立体定向消融放疗，可考虑作为高危合并症患者的手术替代选择（见本讨论中的立体定向消融放疗以及见非小细胞肺癌NCCN指南中的I期和II期初始治疗）。在某些情况下，手术时发现阳性的纵隔淋巴结（N2）；在这种情况下，必须另外评估分期和肿瘤的可切除性，治疗（即，包括系统性纵隔淋巴结清扫）必须进行相应的调整。因此，对于T1–3N2期（即IIIA期）疾病NCCN指南包括两个不同的路径：1）T1–3N2期，在手术探查时意外发现；和2）T1–3N2期，在开胸手术前确诊。在第二种情况下，建议早期脑MRI（强化）和FDG PET/CT扫描（如果以前没有做过）以排除转移性疾病。

For patients with clinical stage IIB (T3, N0) and stage IIIA tumors who have different treatment options (surgery, RT, or chemotherapy), a multidisciplinary evaluation is recommended. For the subsets of stage IIB (T3, N0) and stage IIIA (T4, N0–1) tumors, treatment options are organized according to the location of the tumor such as the superior sulcus, chest wall, proximal airway, or mediastinum. For each location, a thoracic surgeon needs to determine whether the tumor is resectable (see Principles of Surgical Therapy in the NCCN Guidelines for Non-Small Cell Lung Cancer).
对于临床IIB期（T3N0）和IIIA期肿瘤患者有不同的治疗方案（手术、放疗或化疗），建议多学科评估。对于IIB期亚组（T3N0）和IIIA期（T4N0–1）肿瘤，根据肿瘤的部位如肺上沟、胸壁、近端气道或纵隔安排有序的治疗选择。对于每个部位，胸外科医生均需要确定肿瘤是否可切除（见非小细胞肺癌NCCN指南中的外科治疗原则）。

For patients with resectable tumors (T3 invasion, N0–1) in the superior sulcus, the NCCN Panel recommends preoperative concurrent chemoradiation therapy followed by surgical resection and chemotherapy (see Initial Treatment for Superior Sulcus Tumors in the NCCN Guidelines for Non-Small Cell Lung Cancer). Preoperative concurrent chemoradiation followed by surgical resection of a superior sulcus tumor has shown 2-year survival in the 50% to 70% range. The overall 5-year survival rate is approximately 40%. Patients with possibly resectable superior sulcus tumors should undergo preoperative concurrent chemoradiation before surgical re-evaluation. For patients with unresectable tumors (T4 extension, N0–1) in the superior sulcus, definitive concurrent chemoradiation is recommended followed by 2 cycles of full-dose chemotherapy if full-dose chemotherapy was not initially given concurrently with RT.
对于可切除的上沟肿瘤（T3侵犯、N0–1）患者，NCCN小组建议术前同步化放疗然后手术切除和化疗（见非小细胞肺癌NCCN指南中的上沟瘤的初始治疗）。肺上沟瘤术前同步放化疗然后手术切除两年生存率50%-70%。5年总生存率约为40%。潜在可切除的肺上沟瘤患者在外科再评估前应接受术前同步放化疗。对于不能手术切除的上沟肿瘤（T4N0–1）患者，如果最初同步放疗时未给予全量化疗，推荐根治性同步化放疗序贯两周期的全量化疗。

Surgical resection is the preferred treatment option for patients with tumors of the chest wall, proximal airway, or mediastinum (T3–4, N0–1). Other treatment options include chemotherapy or concurrent chemoradiation before surgical resection. For unresectable T4, N0–1 tumors without pleural effusion, definitive concurrent chemoradiation (category 1) is recommended. If full-dose chemotherapy was not given initially as concurrent treatment, then an additional 2 cycles of full-dose chemotherapy can be administered (see Adjuvant Treatment in the NCCN Guidelines for Non-Small Cell Lung Cancer).
对于胸壁、近端气道或纵隔肿瘤（T3–4N0–1）患者，手术切除是首选治疗。其它的治疗选择包括外科切除术前化疗或同步化放疗。对于不能切除的T4N0–1无胸腔积液肿瘤，建议根治性同步化放疗（1类）。如果最初同步治疗没有给予全量化疗，那么可给予追加两周期的全量化疗（见非小细胞肺癌NCCN指南中的辅助治疗）。

Multimodality therapy is recommended for most patients with stage III NSCLC. For patients with stage IIIA disease and positive mediastinal nodes (T1–3, N2), treatment is based on the findings of pathologic mediastinal lymph node evaluation (see Adjuvant Treatment in the NCCN Guidelines for Non-Small Cell Lung Cancer). Patients with negative mediastinal biopsy findings are candidates for surgery. For those patients with resectable lesions, mediastinal lymph node dissection or lymph node sampling should be performed during the operation. Those individuals who are medically inoperable should be treated according to the clinical stage (see the NCCN Guidelines for Non-Small Cell Lung Cancer). For patients with (T1–2 or T3) N2 node-positive disease, a brain MRI (with contrast) and FDG PET/CT scan (if not done previously) are recommended to search for distant metastases. When distant metastases are not present, the NCCN Panel recommends that the patient be treated with definitive concurrent chemoradiation therapy (see the NCCN Guidelines for Non-Small Cell Lung Cancer). Recommended therapy for metastatic disease depends on whether disease is in a solitary site or is widespread (see the NCCN Guidelines for Non-Small Cell Lung Cancer).
对于大多数III期非小细胞肺癌患者，推荐多学科治疗。对于纵隔淋巴结阳性（T1–3N2）的IIIA期患者，根据纵隔淋巴结病理评估结果进行治疗（见非小细胞肺癌NCCN指南中的辅助治疗）。纵隔活检结果阴性的患者适于手术。对于这些病灶可切除的患者，手术时应该进行纵隔淋巴结清扫术或淋巴结取样。那些因内科因素不能手术者应根据临床分期治疗（见非小细胞肺癌NCCN指南）。对于（T1–2或T3）N2淋巴结阳性患者，建议脑MRI（增强）和FDG PET/CT扫描（如果以前未做）寻找远处转移。当不存在远处转移时，NCCN专家组推荐的治疗是根治性同步化放疗（见非小细胞肺癌NCCN指南）。对于转移性疾病，推荐的治疗取决于病变是单发还是广泛播散（见非小细胞肺癌NCCN指南）。

When a lung metastasis is present, it usually occurs in patients with other systemic metastases; the prognosis is poor. Therefore, many of these patients are not candidates for surgery; however, systemic therapy is recommended. Although uncommon, patients with lung metastases but without systemic metastases have a better prognosis and are candidates for surgery (see Multiple Lung Cancers in this Discussion). Patients with separate pulmonary nodule(s) in the same lobe (T3, N0-1) or ipsilateral non-primary lobe (T4, N0-1) without other systemic metastases are potentially curable by surgery; 5-year survival rates are about 30%. Intrapulmonary metastases were downstaged in the TNM staging (ie, AJCC 7th edition). For those with N2 nodes after surgery, concurrent chemoradiation is recommended for those with positive margins and a R2 resection; either sequential or concurrent chemoradiation is recommended after an R1 resection. Most NCCN Member Institutions favor concurrent chemoradiation for positive margins, but sequential chemoradiation is reasonable in frailer patients. For those with N2 nodes and negative margins, sequential chemotherapy (category 1) with RT is recommended. Chemotherapy alone is recommended for those with N0-1 nodes (see Adjuvant Treatment in the NCCN Guidelines for Non-Small Cell Lung Cancer). In patients with synchronous solitary nodules (contralateral lung), the NCCN Panel recommends treating them as 2 primary lung tumors if both are curable, even if the histology of the 2 tumors is similar (see the NCCN Guidelines for Non-Small Cell Lung Cancer).
当存在肺转移时，通常发生在全身其他部位转移的患者中；预后差。因此，许多这些患者都不适于手术；但是，建议全身治疗。虽然少见，但是无全身转移的肺转移患者预后较好，并适于手术（见本讨论中的多发性肺癌）。独立肺结节在同一叶（T3N0-1）或同侧非原发叶（T4N0-1）无全身其他部位转移的患者有可能手术治愈；5年生存率约为30%。在TNM分期（如AJCC第7版）中肺内转移分期被降低。对于那些术后N2的患者，推荐对切缘阳性和R2切除者给予同步化放疗；R1切除后推荐序贯或同步放化疗。对于阳性切缘，大多数NCCN成员机构支持同步化放疗，但在较虚弱的患者中序贯放化疗是合理的。对于那些N2和切缘阴性者，建议序贯化、放疗（1类）。对于那些N0-1者推荐单纯化疗（见非小细胞肺癌NCCN指南中的辅助治疗）。在同时发生的孤立性结节（对侧肺）患者中，如果两者都是可以治愈的，即使两个肿瘤的组织学类似，NCCN小组建议将其当作两个原发性肺肿瘤治疗（见非小细胞肺癌NCCN指南）。

Multiple Lung Cancers
多发性肺癌

Patients with a history of lung cancer or those with biopsy-proven synchronous lesions may be suspected of having multiple lung cancers (see Clinical Presentation in the NCCN Guidelines for Non-Small Cell Lung Cancer). It is important to determine whether the multiple lung cancers are metastases or separate lung primaries (synchronous or metachronous), because most multiple lung tumors are metastases. Therefore, it is essential to determine the histology of the lung tumor (see Principles of Pathologic Review in the NCCN Guidelines for Non-Small Cell Lung Cancer). Infection and other benign diseases also need to be ruled out (eg, inflammatory granulomas). Although criteria have been established for diagnosing multiple lung cancers, no definitive method has been established before treatment. The Martini and Melamed criteria are often used to diagnose multiple lung cancers as follows: 1) the histologies are different; 2) the histologies are the same but there is no lymph node involvement and no extrathoracic metastases.
有肺癌病史或活检证实的同期病变患者可怀疑有多发性肺癌（见非小细胞肺癌NCCN指南中的临床表现）。重要的是确定多发性肺癌是转移还是独立的肺原发癌（同时或异时性），因为大部分多发性肺肿瘤是转移性的。因此，必需确定肺肿瘤的组织学（见非小细胞肺癌NCCN指南中的病理学检查原则）。还需要排除感染和其他良性疾病（如炎性肉芽肿）。尽管已经建立了诊断多发性肺癌的标准，但是治疗前公认的方法未建立。常用于诊断多发性肺癌的Martini-Melamed标准如下：1）组织学不同；2）组织学相同但无淋巴结受累且无胸外转移。

Treatment of multiple lung cancers depends on status of the lymph nodes (eg, N0–1) and on whether the lung cancers are asymptomatic, symptomatic, or at high risk of becoming symptomatic (see Initial Treatment in the NCCN Guidelines for Non-Small Cell Lung Cancer). In patients eligible for definitive local therapy, parenchymal-sparing resection is preferred (see the Principles of Surgical Therapy in the NCCN Guidelines for Non-Small Cell Lung Cancer). VATS or SABR are reasonable options depending on the number and distribution of the tumors requiring local treatment. Multiple lung nodules (eg, solid, subsolid nodules) may also be detected on low-dose CT scans; some of these nodules can be followed with imaging, whereas others need to be biopsied or excised (see the NCCN Guidelines for Lung Cancer Screening, available at NCCN.org).
多发性肺癌的治疗取决于淋巴结情况（如，N0–1）以及肺癌是无症状还是有症状，或很可能出现症状（见非小细胞肺癌NCCN指南中的初始治疗）。在适合根治性局部治疗的患者中，首选保留实质组织切除术（见非小细胞肺癌NCCN指南中的外科治疗原则）。电视胸腔镜（VATS）或立体定向消融放疗（SABR）是合理的选择，取决于需要局部治疗的肿瘤数量和分布。在低剂量CT扫描时也可能检出双肺多发结节（如实性、半实性结节）；这些结节有些可用影像学随访，而另外一些需要活检或切除（见肺癌筛查NCCN指南，可在NCCN.org获得）。

Stage IIIB Disease
IIIB期疾病

Stage IIIB tumors comprise 2 groups, including: 1) T1–3, N3 tumors; and 2) T4, N2–3 tumors, which are unresectable and include contralateral mediastinal nodes (T4, N3). Surgical resection is not recommended in patients with T1–3, N3 disease. However, in patients with suspected N3 disease, the NCCN Guidelines recommend pathologic confirmation of nodal status (see Pretreatment Evaluation in the NCCN Guidelines for Non-Small Cell Lung Cancer). In addition, FDG PET/CT scans (if not previously done) and brain MRI (with contrast) should also be included in the pretreatment evaluation. If these tests are negative, then treatment options for the appropriate nodal status should be followed (see the NCCN Guidelines for Non-Small Cell Lung Cancer). If N3 disease is confirmed, definitive concurrent chemoradiation (category 1) is recommended followed by 2 cycles of full-dose chemotherapy if full-dose chemotherapy was not initially given concurrently with RT. For metastatic disease that is confirmed by FDG PET/CT scan and brain MRI (with contrast), treatment is described in the NCCN Guidelines.
IIIB肿瘤分为两组，包括：1）T1–3N3；和2）T4N2–3，是不可切除的，包括对侧纵隔淋巴结（T4N3）。T1–3N3疾病患者不建议手术切除。然而，在疑似N3患者中，NCCN指南建议病理证实淋巴结状态（见非小细胞肺癌NCCN指南中的治疗前评估）。此外，治疗前评估也应包括FDG PET/CT扫描（如果以前没有做过）和脑MRI（对比剂）。如果这些检查阴性，则应遵循相应淋巴结状态的治疗方案（见非小细胞肺癌NCCN指南）。如果证实是N3，初始治疗未给予同步放疗联合全量化疗，则推荐根治性同步化放疗序贯两周期全量化疗（1类）。对于FDG PET/CT扫描和MRI（强化）证实的转移性疾病，其治疗在NCCN指南中描述。

For patients with T4, N2–3 disease (stage IIIB), surgical resection is not generally recommended. The initial workup includes biopsies of the N3 and N2 nodes. If these biopsies are negative, the same treatment options may be used as for stage IIIA (T4, N0–1) disease (see the NCCN Guidelines for Non-Small Cell Lung Cancer). If either the contralateral or ipsilateral mediastinal node is positive, definitive concurrent chemoradiation therapy is recommended (category 1) followed by 2 cycles of full-dose chemotherapy if full-dose chemotherapy was not given concurrently with RT as initial treatment (see the NCCN Guidelines for Non-Small Cell Lung Cancer).
对于T4N2–3（IIIB期）患者，一般不推荐手术切除。初始检查包括N3和N2淋巴结活检。如果这些活检阴性，治疗方案与IIIA期（T4N0–1）疾病所使用的相同（见非小细胞肺癌NCCN指南）。如果对侧或同侧纵隔淋巴结阳性，初始治疗未给予同步放疗联合全量化疗，则建议根治性同步化放疗治疗序贯两周期全量化疗（1类）（见非小细胞肺癌NCCN指南）。

Stage IV Disease
IV期疾病

In general, systemic therapy is recommended for patients with metastatic disease (see Systemic Therapy for Advanced or Metastatic Disease in the NCCN Guidelines for Non-Small Cell Lung Cancer). This section focuses on patients with limited metastatic disease; management of widespread distant metastases is described in another section (see Treatment of Recurrences and Distant Metastases in this Discussion and Systemic Therapy for Metastatic Disease in the NCCN Guidelines for Non-Small Cell Lung Cancer). Pleural or pericardial effusion is a criterion for stage IV, M1a disease. T4 with pleural effusion is classified as stage IV, M1a (see Table 3 in Staging in the NCCN Guidelines for Non-Small Cell Lung Cancer). Although pleural effusions are malignant in 90% to 95% of patients, they may be related to obstructive pneumonitis, atelectasis, lymphatic or venous obstruction, or a pulmonary embolus. Therefore, pathologic confirmation of a malignant effusion by using thoracentesis or pericardiocentesis is recommended. In certain cases, where thoracentesis is inconclusive, thoracoscopy may be performed. In the absence of nonmalignant causes (eg, obstructive pneumonia), an exudate or sanguinous effusion is considered malignant regardless of the results of cytologic examination. If the pleural effusion is considered negative, recommended treatment is based on the confirmed T and N stage (see the NCCN Guidelines for Non-Small Cell Lung Cancer). However, all pleural effusions, whether malignant or not, are associated with unresectable disease in 95% of cases. In patients with effusions that are positive for malignancy, the tumor is treated as M1a with local therapy (ie, ambulatory small catheter drainage, pleurodesis, and pericardial window) in addition to treatment as for stage IV disease (see the NCCN Guidelines for Non-Small Cell Lung Cancer).
通常情况下，对于转移性疾病患者推荐全身治疗（见非小细胞肺癌NCCN指南中晚期或转移性疾病的全身治疗）。本节着重于局限转移性疾病患者；广泛远处转移的处理在另外一节中描述（见本讨论中复发和远处转移的治疗以及非小细胞肺癌NCCN指南中转移性疾病的全身治疗）。胸腔或心包积液是一个IV期、M1a疾病标准。具有胸腔积液的T4分类为IV期、M1a（见非小细胞肺癌NCCN指南中分期表3）。尽管在90%-95%的患者中胸腔积液是恶性的，但是，其可能与阻塞性肺炎、肺不张、淋巴或静脉阻塞或肺栓塞有关。因此，建议采用胸腔或心包穿刺病理证实恶性积液。在某些情况下，胸腔穿刺不确定，则可以进行胸腔镜检查。在没有非恶性病因（如阻塞性肺炎）的情况下，渗出液或血性积液被认为是恶性的而不管细胞学检查结果。如果认为胸腔积液是阴性的，推荐的治疗是基于确认的T和N分期（见非小细胞肺癌NCCN指南）。然而，所有的胸腔积液，无论恶性与否，95%的病例不能手术切除。在恶性肿瘤阳性的积液患者中，肿瘤治疗除了按照IV期疾病治疗外还要按照M1a局部治疗（即不卧床细导管引流术、胸膜固定术、心包开窗术）（见非小细胞肺癌NCCN指南）。

Management of patients with distant metastasis in limited sites (ie, stage IV, M1b) depends on the location of the metastases—a few nodules in the brain or adrenal gland—the diagnosis of which is aided by mediastinoscopy, bronchoscopy, FDG PET/CT scan, and brain MRI (with contrast). The increased sensitivity of FDG PET/CT scans, compared with other imaging methods, may identify additional metastases and, thus, spare some patients from unnecessary surgery. However, positive FDG PET/CT scan findings for distant disease need pathologic or other radiologic confirmation. If the FDG PET/CT scan is positive in the mediastinum, the lymph node status needs pathologic confirmation. Patients with limited oligometastatic disease (eg, single brain or adrenal metastasis) and otherwise limited disease in the chest may benefit from aggressive local therapy to both the primary chest and metastatic sites. Aggressive local therapy may comprise surgery or definitive RT including SABR to each site, and may be preceded or followed by chemotherapy. Recent data suggest that erlotinib combined with SABR or SRS may also be useful.
远处转移部位有限（即IV期、M1b）患者的处理取决于该转移的位置——脑或肾上腺的几个结节——通过纵隔镜、支气管镜、FDG PET/CT扫描和脑MRI（强化）协助诊断。与其它影像手段相比，FDG PET/CT扫描的敏感性增加，可能发现其他的转移灶，某些患者从而避免不必要的手术。然而，对于FDG PET/CT扫描发现的阳性远隔病变需要病理或其他影像学确认。如果FDG PET/CT扫描纵隔淋巴结阳性，该淋巴结情况需要病理学证实。局限的寡转移性疾病（如脑或肾上腺转移）患者及其他胸部局限性疾病可能获益于原发胸部和转移部位积极的局部治疗。积极的局部治疗可包括对每个部位手术或根治性放疗包括立体定向消融放疗，可在化疗前或化疗后实施。最新数据表明，厄洛替尼联合立体定向消融放疗或立体定向放射手术也可能是有用的。

Metastases to the adrenal gland from lung cancer are a common occurrence, with approximately 33% of patients having such disease at autopsy. In patients with otherwise resectable primary tumors, however, many solitary adrenal masses are not malignant. Any adrenal mass found on a preoperative CT scan in a patient with lung cancer should be biopsied to rule out benign adenoma. Local therapy (category 2B) of the adrenal lesion has produced some long-term survivors when an adrenal metastasis has been found and the lung lesion has been curable (see the NCCN Guidelines for Non-Small Cell Lung Cancer). Some NCCN Panel Members feel that local therapy for adrenal metastases is only advisable if the synchronous lung disease is stage I or possibly stage II (ie, resectable). Systemic therapy is another treatment option for adrenal metastasis.
肺癌肾上腺转移是一个常见的现象，在尸检时约33%的患者存在这种情况。然而，在其他可切除的原发肿瘤患者中，许多孤立性肾上腺肿块不是恶性的。肺癌患者术前CT扫描发现的任何肾上腺肿块均应该活检以排除良性腺瘤。当发现肾上腺转移且肺部病变已治愈，肾上腺病变的局部治疗（2B类）已经有一些长期存活患者（见非小细胞肺癌NCCN指南）。一些NCCN小组成员认为如果同期肺部疾病是I期或II期（即，可切除）肾上腺转移灶局部治疗才是可取的。全身性治疗是肾上腺转移的另一种治疗选择。