Adjuvant Treatment 辅助治疗

Chemotherapy or Chemoradiation 化疗或放化疗

Post-surgical treatment options for patients with stage IA tumors (T1ab, N0) and with positive surgical margins (R1, R2) include re-resection (preferred) or RT (category 2B). Observation is recommended for patients with T1ab-T2ab, N0 tumors and with negative surgical margins (R0). Adjuvant chemotherapy is a category 2A recommendation for patients with T2ab, N0 tumors and negative surgical margins who have high-risk features (including poorly differentiated tumors, vascular invasion, wedge resection, tumors >4 cm, visceral pleural involvement, and unknown lymph node sampling [Nx]) (see Adjuvant Treatment in the NCCN Guidelines for NSCLC). If the surgical margins are positive in patients with T2ab, N0 tumors, options include: 1) re-resection (preferred) with (or without) chemotherapy; or 2) RT with (or without) chemotherapy (chemotherapy is recommended for stage IIA). 手术切缘阳性（R1、R2）的IA期肿瘤（T1abN0）患者的术后治疗选择包括再切除术（首选）或放疗（2B类）。对于手术切缘阴性（R0）的T1ab-T2abN0肿瘤患者推荐观察。对于T2abN0、切缘阴性、具有高危特征（包括低分化的肿瘤、脉管侵犯、楔形切除术、肿瘤>4cm、脏层胸膜受累以及淋巴结取样未知[Nx]）的患者，辅助化疗是2A类推荐（见NSCLC NCCN指南中的辅助治疗）。T2abN0肿瘤患者如果手术切缘阳性，选择包括：1）再切除（首选）±化疗；或2）放疗±化疗（对于ⅡA期推荐化疗）。山东省肿瘤医院呼吸肿瘤内科张品良

The NCCN Panel recommends chemotherapy (category 1) for patients with negative surgical margins and stage II disease, including 1) T1ab–T2a, N1; 2) T2b, N1; or 3) T3, N0 disease. If surgical margins are positive in these patients, options after an R1 resection include: 1) re-resection and chemotherapy; or 2) chemoradiation (either sequential or concurrent). Options after an R2 resection include: 1) re-resection and chemotherapy; or 2) concurrent chemoradiation. Most NCCN Member Institutions favor concurrent chemoradiation for positive margins, but sequential is reasonable in frailer patients. 对于1) T1ab–T2aN1、2) T2bN1或3) T3N0的Ⅱ期、手术切缘阴性患者，NCCN小组推荐化疗（1类）。如果这些患者手术切缘阳性，R1切除后的选择包括：1）再切除加化疗；或2）放化疗（序贯或同时）。R2切除后的选择包括：1）再切除加化疗；或2）同步放化疗。对于阳性切缘，大多数NCCN成员机构支持同步放化疗，但在较虚弱患者中序贯是合理的。

Adjuvant chemotherapy can also be used in patients with stage III NSCLC who have had surgery (see the NCCN Guidelines for NSCLC). Patients with T1-3, N2 or T3, N1 disease (discovered only at surgical exploration and mediastinal lymph node dissection) and positive margins may be treated with chemoradiation; either sequential or concurrent chemoradiation is recommended for an R1 resection, whereas concurrent chemoradiation is recommended for an R2 resection (see Adjuvant Treatment in the NCCN Guidelines for NSCLC). Patients with negative margins may be treated with either 1) chemotherapy (category 1); or 2) sequential chemotherapy plus RT (for N2 only). 辅助化疗还可用于已手术的Ⅲ期NSCLC患者（见NSCLC NCCN指南）。T1-3N2或T3N1（仅在手术探查和纵隔淋巴结清扫时发现）及切缘阳性患者可以用放化疗治疗；对于R1切除者推荐序贯或同步放化疗，而对于R2切除者推荐同步放化疗（见NSCLC NCCN指南中的辅助治疗）。切缘阴性者可以接受1）化疗（1类）；或2）序贯化疗加放疗（仅针对N2）。

For stage IIIA superior sulcus tumors (T4 extension, N0–1) that become resectable after preoperative concurrent chemoradiation, resection followed by chemotherapy is recommended (see the NCCN Guidelines for NSCLC). Surgical reevaluation (including imaging) is done to determine whether the tumor is resectable after treatment. If the lesion remains unresectable after preoperative concurrent chemoradiation, the full course of definitive chemo/RT should be completed; an additional 2 cycles of chemotherapy as an adjuvant treatment can be given if full doses were not given with concurrent therapy. Among patients with chest wall lesions with T3 invasion–T4 extension, N0–1 disease, those who are initially treated with surgery (preferred) may receive chemotherapy alone if the surgical margins are negative. When surgical margins are positive, they may receive either 1) sequential or concurrent chemoradiation; or 2) re-resection with chemotherapy. As previously mentioned, most NCCN Member Institutions favor concurrent chemoradiation for positive margins, but sequential is reasonable in frailer patients. A similar treatment plan is recommended for resectable tumors of the proximal airway or mediastinum (T3–4, N0–1). 对于在术前同步放化疗后变为可切除的ⅢA期上沟瘤（T4N0-1），推荐切除后化疗（见NSCLC NCCN指南）。进行手术再评价（包括影像学）以确定在治疗后肿瘤是否可切除。如果术前同步放化疗后病变仍不可切除，应完成全部的根治性化/放疗疗程；如果同步治疗时未给予足量化疗，则追加两周期的化疗作为辅助治疗。在胸壁病变T3侵犯-T4扩散、N0–1患者中，那些初始治疗手术（首选）者如果手术切缘阴性可接受单纯化疗。当手术切缘阳性时，他们可以接受1）序贯或同步放化疗；或2）再切除加化疗。如前所述，对于阳性切缘，大多数NCCN成员机构支持同步放化疗，但在较虚弱患者中序贯是合理的。对于可切除的近端气道或纵隔肿瘤（T3-4N0-1）推荐类似的治疗方案。

For patients with stage IIIA disease and positive mediastinal nodes (T1–3, N2) with no apparent disease progression after initial treatment, recommended treatment includes surgery with (or without) RT (if not given preoperatively) and/or with (or without) chemotherapy (category 2B for chemotherapy) (see the NCCN Guidelines for NSCLC). 对于在初始治疗后疾病无明显进展的ⅢA期和纵隔淋巴结阳性（T1–3N2）的患者，推荐的治疗包括手术±放疗（如果术前未给予）和/或±化疗（对于化疗是2B类）（见NSCLC NCCN指南）。

Alternatively, if the disease progresses, patients may be treated with either 1) local therapy using RT (if not given previously) with (or without) chemotherapy; or 2) systemic therapy. In patients with separate pulmonary nodules in the same lobe (T3, N0-1) or ipsilateral non-primary lobe (T4, N0-1), surgery is recommended. In patients with N2 disease, if the margins are negative, sequential chemotherapy (category 1) with radiation is recommended. If the resection margins are positive in patients with N2 disease, concurrent chemoradiation is recommended for an R2 resection, whereas either concurrent or sequential chemoradiation is recommended for an R1 resection. Concurrent chemoradiation is often used for positive margins, but sequential is reasonable in frailer patients. 如果疾病进展，可供患者选择的治疗，1）局部放疗（如果既往未给予）±化疗；或2）全身治疗。独立肺结节在同一叶（T3N0-1）或同侧非原发叶（T4N0-1）的患者推荐手术。在N2患者中，如果切缘阴性，推荐序贯化疗加放疗（1类）。N2患者如果切缘阳性，R2切除者推荐同步放化疗，而R1切除者推荐同时或序贯放化疗。对于阳性切缘经常使用同步放化疗，但是在较虚弱患者中序贯是合理的。

Because patients with stage III disease have both local and distant failures, theoretically, the use of chemotherapy may eradicate micrometastatic disease obviously present but undetectable at diagnosis. The timing of this chemotherapy varies (see the NCCN Guidelines for NSCLC). Such chemotherapy may be given alone, sequentially, or concurrently with RT. In addition, chemotherapy could be given preoperatively or postoperatively in appropriate patients. 因为Ⅲ期患者有局部和远处两种失败，所以，从理论上讲，化疗的使用可以根除显然存在但诊断时发现不了的微转移病变。化疗时机多样（见NSCLC NCCN指南）。上述化疗可以单独、序贯或同时联合放疗给予。此外，对于合适的患者化疗可术前或术后给予。

On the basis of clinical studies on neoadjuvant and adjuvant chemotherapy for NSCLC, the NCCN Panel recommends cisplatin combined with docetaxel, etoposide, gemcitabine, or vinorelbine for adjuvant chemotherapy for all histologies in the NCCN Guidelines; other options include cisplatin combined with pemetrexed for non-squamous NSCLC (see Chemotherapy Regimens for Neoadjuvant and Adjuvant Therapy in the NCCN Guidelines for NSCLC). For patients with comorbidities or those who cannot tolerate cisplatin, carboplatin combined with paclitaxel is an option. A number of phase 2 studies have evaluated neoadjuvant chemotherapy for stage III NSCLC, with (or without) RT, followed by surgery. 基于NSCLC新辅助化疗和辅助化疗的临床研究，NCCN指南对所有组织类型的辅助化疗NCCN小组推荐顺铂联合多西他赛、依托泊苷、吉西他滨或长春瑞滨；对于非鳞NSCLC其他选择包括顺铂联合培美曲塞（见NSCLC NCCN指南中的新辅助和辅助治疗化疗方案）。对有合并症或不能耐受顺铂的患者，卡铂联合紫杉醇是一种选择。若干2期研究评估了Ⅲ期NSCLC新辅助化疗±放疗，然后手术。

Three phase 3 trials have assessed neoadjuvant chemotherapy followed by surgery compared with surgery alone in the treatment of stage III NSCLC. The S9900 trial (a SWOG study)—one of the largest randomized trials examining preoperative chemotherapy in early-stage NSCLC—assessed surgery alone compared with surgery plus preoperative paclitaxel/carboplatin in patients with stage IB/IIA and stage IIB/IIIA NSCLC (excluding superior sulcus tumors). PFS and overall survival were improved with preoperative chemotherapy. All 3 studies showed a survival advantage for patients who received neoadjuvant chemotherapy. The 2 earlier phase 3 studies had a small number of patients, while the SWOG study was stopped early because of the positive results of the IALT study. However, the induction chemotherapy-surgery approach needs to be compared with induction chemotherapy-RT in large, randomized clinical trials. 3项3期试验评估了新辅助化疗然后手术对比单纯手术治疗Ⅲ期NSCLC。S9900试验（SWOG的一项研究）——早期NSCLC术前化疗最大的随机试验之一——评估单纯手术与手术加术前紫杉醇/卡铂治疗IB/ⅡA期和ⅡB/ⅢA期NSCLC（不包括上沟瘤）。术前化疗改善PFS和总生存。所有3项研究均显示，接受新辅助化疗的患者有生存优势。两项更早的3期研究患者数量很少，而SWOG研究因为IALT研究的阳性结果而提前终止。但是，诱导化疗-手术需要在大型随机临床试验中与诱导化疗-放疗进行比较。

Radiation Therapy 放疗

After complete resection of clinical early-stage NSCLC, postoperative RT has been found to be detrimental for pathological N0 or N1 stage disease in a meta-analysis of small randomized trials using older techniques and dosing regimens and a population-based analysis of data from SEER. However, there was an apparent survival benefit of postoperative RT in patients with N2 nodal stage diagnosed surgically. The analysis of the ANITA trial also found that postoperative RT increased survival in patients with N2 disease who received adjuvant chemotherapy. A recent review of the National Cancer Data Base concluded that postoperative RT and chemotherapy provided a survival advantage for patients with completely resected N2 disease when compared with chemotherapy alone. A recent meta-analysis also concluded that postoperative RT improves survival for patients with N2 disease. Postoperative adjuvant sequential chemotherapy with RT is recommended for patients with T1–3, N2 disease and negative margins (see Adjuvant Treatment in the NCCN Guidelines for NSCLC). A meta-analysis assessed postoperative chemotherapy with (or without) postoperative RT in patients mainly with stage III disease. In this meta-analysis, 70% of the eligible trials used adjuvant chemotherapy before RT; 30% used concurrent chemo/RT. Regimens included cisplatin/vinorelbine followed by RT or concurrent cisplatin/etoposide. 一项使用更老的技术和给药方案的小型随机试验的meta分析和SEER大样本数据分析发现，在临床早期NSCLC完全切除术后，病理N0、N1期术后放疗有害。然而，在手术分期N2的患者中，术后放疗有明显的生存获益。对ANITA试验的分析也发现，在接受辅助化疗的N2患者中，术后放疗改善生存。最近一项国立癌症数据库的回顾得出的结论是，对于完全切除的N2患者，与单纯化疗相比，术后放疗和化疗具有生存优势。最近一项meta分析也得出结论，对于N2患者，术后放疗可改善生存。对于T1–3、N2且切缘阴性的患者，推荐术后辅助序贯化放疗（见NSCLC NCCN指南中的辅助治疗）。一项meta分析评估了主要是Ⅲ期患者术后化疗±术后放疗。在这项meta分析中，70%的符合试验条件者在放疗前使用了辅助化疗；30%使用同步化/放疗。方案包括顺铂/长春瑞滨序贯放疗或同步顺铂/依托泊苷。

The ACR Appropriateness Criteria(R) provide specific recommendations for postoperative adjuvant therapy. Either concurrent or sequential chemoradiation may be used for postoperative adjuvant therapy, depending on the type of resection and the setting (eg, N2 disease) (see Adjuvant Treatment in the NCCN Guidelines for NSCLC). Concurrent chemo/RT is recommended for R2 resections, whereas either sequential or concurrent chemo/RT is recommended for R1 resections. Concurrent chemoradiation is often used for positive margins, but sequential is reasonable in frailer patients. Cisplatin/etoposide, cisplatin/vinblastine, and carboplatin/paclitaxel are chemoradiation regimens recommended by the NCCN Panel for all histologies (see Chemotherapy Regimens Used with Radiation Therapy in the NCCN Guidelines for NSCLC). Pemetrexed with either cisplatin or carboplatin may be used for concurrent chemoradiation in patients with non-squamous NSCLC. When chemoradiation is recommended in the NCCN Guidelines, these regimens may be used for stage II to III disease. A recent phase 3 trial (PROCLAIM) assessed concurrent thoracic RT with cisplatin/pemetrexed versus cisplatin/etoposide followed by consolidation chemotherapy in patients with unresectable stage III non-squamous NSCLC. Both regimens were equivalent in terms of survival, but the cisplatin/pemetrexed regimen was associated with less neutropenia (24.4% vs. 44.5%; P < .001) and fewer grade 3 to 4 adverse events (64.0% vs. 76.8%; P = .001). For the 2017 update (Version 1), the NCCN Panel deleted the cisplatin/etoposide consolidation regimen based on the PROCLAIM trial. In addition, the NCCN Panel clarified that the cisplatin/pemetrexed and carboplatin/paclitaxel regimens may be followed by consolidation chemotherapy alone. ACR（美国放射学会）适宜性标准®为术后辅助治疗提供具体建议。对于术后辅助治疗，同步或序贯放化疗都可以使用，取决于切除类型与情况（如N2）（见NSCLC NCCN指南中的辅助治疗）。对于R2切除者推荐同步化/放疗，而对于R1切除者推荐序贯或同步化/放疗。对于阳性切缘经常使用同步放化疗，但是在较虚弱患者中序贯是合理的。对于所有的组织学类型，顺铂/依托泊苷、顺铂/长春花碱和卡铂/紫杉醇是NCCN小组推荐的放化疗方案（见NSCLC NCCN指南中的联合放疗使用的化疗方案）。非鳞NSCLC患者同步化放疗可使用培美曲塞联合顺铂或卡铂。当推荐放化疗时，NCCN指南中的这些方案也可用于Ⅱ-Ⅲ期疾病。最近一项3期试验（PROCLAIM）评估了胸部放疗同步顺铂/培美曲塞与顺铂/依托泊苷然后巩固化疗治疗不能切除的Ⅲ期非鳞NSCLC患者。在生存方面两种方案相当，但顺铂/培美曲塞方案中性粒细胞减少症较少（24.4%对44.5%；P<0.001）且3-4级不良事件较少（64%对76.8%；P=0.001）。基于PROCLAIM试验，2017第1版更新，NCCN小组删除了顺铂/依托泊苷巩固方案。此外，NCCN小组明确了顺铂/培美曲塞和卡铂/紫杉醇方案可以序贯单纯巩固化疗。