Initial Therapy 初始治疗
As previously mentioned, accurate pathologic assessment and staging are essential before treatment for NSCLC, because management varies depending on the stage, histology, presence of genetic alterations, and PS. 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 NSCLC).Principles of Radiation Therapy recommends doses for RT (see the NCCN Guidelines for NSCLC). 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 NSCLC). Targeted therapy is recommended for patients with metastatic NSCLC and positive test results for ALK or ROS1 rearrangements, or sensitizing EGFR mutations.
如前所述，在NSCLC治疗前必须进行准确的病理评估和分期，因为管理取决于分期、组织学、基因改变的存在和一般情况。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NSCLC 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NSCLC NCCN指南）。此外，NCCN指南也推荐了化疗和放化疗方案（见NSCLC 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）。对于ALK或ROS1重排或敏感EGFR突变检测结果阳性的转移性NSCLC患者推荐靶向治疗。
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; RT 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 NSCLC). 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）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NSCLC患者，推荐根治性放疗，尤其是立体定向消融放疗。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和NSCLC NCCN指南中Ⅰ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，并且治疗（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。
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 NSCLC).
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 NSCLC). 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 (including CT ± PET/CT). For patients with unresectable tumors (T4 extension, N0–1) in the superior sulcus, definitive concurrent chemoradiation is recommended. Two additional cycles of full-dose chemotherapy can be given if full-dose chemotherapy was not given concurrently with RT.
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 as concurrent treatment, then an additional 2 cycles of full-dose chemotherapy can be administered (see Adjuvant Treatment in the NCCN Guidelines for NSCLC).
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 NSCLC). 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 NSCLC). For patients with (T1–3) 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 NSCLC). Recommended therapy for metastatic disease depends on whether disease is in a solitary site or is widespread (see the NCCN Guidelines for NSCLC).
对于大多数Ⅲ期NSCLC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NSCLC 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NSCLC NCCN指南）。对于（T1–3）N2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放化疗（见NSCLC 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NSCLC 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%. 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 NSCLC). 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 NSCLC).
肺转移通常存在于全身其他部位发生转移的患者中；预后差。因此，许多这些患者都不适于手术；不过，推荐全身治疗。虽然少见，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%。对于术后N2的患者，切缘阳性和R2切除者推荐给予同步化放疗；R1切除后推荐序贯或同步放化疗。对于阳性切缘，大多数NCCN成员机构支持同步放化疗，但在较虚弱的患者中序贯放化疗是合理的。对于N2和切缘阴性者，建议序贯化、放疗（1类）。对于N0-1者推荐单纯化疗（见NSCLC 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小组推荐将其当作两个原发性肺肿瘤治疗（见NSCLC 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 NSCLC). 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 NSCLC). 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; or 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NSCLC 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NSCLC 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，但是治疗前未建立明确的方法。常用于诊断多发性肺癌的Martini-Melamed标准如下：1）组织学不同；或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 or low risk of becoming symptomatic (see Initial Treatment in the NCCN Guidelines for NSCLC). Patients should be evaluated in a multidisciplinary setting (eg, surgeons, radiation oncologists, medical oncologists). In patients eligible for definitive local therapy, parenchymal-sparing resection is preferred (see the Principles of Surgical Therapy in the NCCN Guidelines for NSCLC). 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 CT scans; some of these nodules can be followed with imaging, whereas others need to be biopsied or excised (see the Diagnostic Evaluation of Incidental Lung Nodules in this Discussion and 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）以及肺癌有无症状，或出现症状的风险高或低（见NSCLC NCCN指南中的初始治疗）。应该对患者进行多学科（即外科医生、放射肿瘤学家、内科肿瘤学家）评估。在适合根治性局部治疗的患者中，首选保留肺组织的切除术（见NSCLC 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。CT扫描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（见本讨论中偶发肺结节的诊断评估和肺癌筛查NCCN指南，可在NCCN.org获得）。
Stage IIIB Disease ⅢB期疾病
Stage IIIB tumors comprise 2 unresectable groups, including: 1) T1–3, N3 tumors; and 2) T4, N2–3 tumors, which 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 NSCLC). 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 imaging tests are negative, then treatment options for the appropriate nodal status should be followed (see the NCCN Guidelines for NSCLC). If N3 disease is confirmed, definitive concurrent chemoradiation (category 1) is recommended; 2 additional cycles of full-dose chemotherapy can be given if full-dose chemotherapy was not 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 for limited or metastatic disease.
ⅢB肿瘤包括两个不能切除的组，包括：1）T1–3N3；和2）T4N2–3，包括对侧纵隔淋巴结（T4N3）。T1–3N3患者不建议手术切除。不过，疑似N3的患者，NCCN指南推荐病理证实淋巴结情况（见NSCLC NCCN指南中的治疗前评估）。此外，治疗前评估还应包括FDG PET/CT扫描（如果以前没有做过）和脑MRI（强化）。如果这些影像学检查均阴性，则应遵循相应淋巴结状态的治疗方案（见NSCLC NCCN指南）。如果证实为N3，推荐根治性同步放化疗（1类）；如果同步放疗时未给予足量化疗，可追加两周期的足量化疗。对于经FDG PET/CT扫描和MRI（强化）证实的转移性疾病，其治疗在局限或转移性疾病NCCN指南中描述。
For patients with T4, N2–3 disease (stage IIIB), surgical resection is not 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 NSCLC). 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 NSCLC).
对于T4N2–3（ⅢB期）患者，不推荐手术切除。初始检查包括N3和N2淋巴结活检。如果活检阴性，治疗方案与ⅢA期（T4N0–1）所使用的相同（见NSCLC 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足量化疗，则推荐根治性同步放化疗序贯两周期足量化疗（1类）（见NSCLC 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 NSCLC). In addition, palliative treatment, including RT, may be needed during the disease course to treat localized symptoms, diffuse brain metastases, or bone metastases (see Therapy for Recurrence and Metastases in the NCCN Guidelines for NSCLC). 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 NSCLC). 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 NSCLC). 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 for malignancy (M0), recommended treatment is based on the confirmed T and N stage (see the NCCN Guidelines for NSCLC). 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 NSCLC).
通常情况下，对于转移性患者推荐全身治疗（见NSCLC NCCN指南中晚期或转移性疾病的全身治疗）。此外，在病程期间，为了处理局部症状、弥漫性脑转移或骨转移可能需要姑息治疗，包括放疗（见NSCLC NCCN指南中的复发和转移的治疗）。本节着重于局限性转移患者；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NSCLC 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。有胸腔积液的T4分类为Ⅳ期、M1a（见NSCLC NCCN指南中分期表3）。尽管90%-95%的患者胸腔积液是恶性的，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，推荐采用胸腔或心包穿刺病理证实恶性积液。在某些情况下，胸腔穿刺不能确定，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。如果认为胸腔积液不是恶性的（M0），推荐的治疗是基于确认的T和N分期（见NSCLC NCCN指南）。不过，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、胸膜固定术和心包开窗术）（见NSCLC NCCN指南）。
Management of patients with distant metastasis in limited sites (ie, stage IV, M1b) and good PS depends on the location and number of the metastases; the diagnosis 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 futile 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, brain metastases) and otherwise limited disease in the chest may benefit from aggressive local therapy to both the primary chest and metastatic sites. For the 2017 update (Version 1), the NCCN Panel revised the recommendations for treatment of limited brain metastases by decreasing recommendations for whole brain RT (see Whole Brain RT and Stereotactic Radiosurgery in this Discussion text). Clinicians are not using whole brain RT as often in patients with limited brain metastases because of concerns about neurocognitive problems. Aggressive local therapy may comprise surgery and/or definitive RT including SRS and SABR, and may be preceded or followed by chemotherapy. After progression on TKIs, patients with EGFR mutations may be able to continue with their current TKIs; local therapy can be considered to treat their limited metastases (eg, SRS to brain metastases or other sites, SABR for thoracic disease).
一般情况好、部位局限的远处转移（即Ⅳ期M1b）患者的管理，取决于转移的部位和数量；通过纵隔镜、支气管镜、FDG PET/CT扫描和脑MRI（强化）辅助诊断。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，从而使某些患者避免不必要的无用的手术。不过，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。局限寡转移病变（如脑或肾上腺转移）患者及其他胸部局限性病变可能获益于对原发胸部和转移部位积极的局部治疗。2017第1版更新，NCCN小组修订了局限性脑转移瘤的治疗推荐，减少了全脑放疗的推荐（见本讨论中的全脑放疗和立体定向放射治疗）。在局限性脑转移患者中，临床医生往往不使用用全脑放疗，因为担心神经认知问题。积极的局部治疗可包括手术和/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。在TKIs进展后，EGFR突变的患者可以继续使用其当前的TKIs；可以考虑局部治疗来处理其局限的转移灶（如对于脑或其他部位的转移灶使用立体定向放疗，对胸腔病变使用立体定向消融放疗）。
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 NSCLC). 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.