非小细胞肺癌的治疗：综合治疗（NCCN指南2017V7）

【非小细胞肺癌NCCN指南2017第7版】

Discussion 讨论

Treatment Approaches 治疗手段

Combined Modality Therapy 综合治疗

As previously mentioned, surgery provides the best chance for cure for patients with stage I or II disease who are medically fit and can tolerate surgery. However, SABR can be considered for patients with unresectable stage I or II disease or those who refuse surgery if their disease is node negative (see Stereotactic Ablative Radiotherapy in this Discussion and see the NCCN Guidelines for NSCLC). In patients with completely resected NSCLC, adjuvant chemotherapy has been shown to improve survival in patients with early-stage disease. Some studies suggest that neoadjuvant chemotherapy (also referred to as preoperative chemotherapy or induction chemotherapy) is as effective as and better tolerated than adjuvant chemotherapy (see Neoadjuvant Chemotherapy Followed by Surgery: Trial Data in this Discussion). A randomized trial found no difference in survival with preoperative versus postoperative chemotherapy. The NCCN Guidelines state that patients with stage II or IIIA (T3, N1) disease may be treated with induction chemotherapy before surgery if they are candidates for adjuvant therapy after surgery. Concurrent chemoradiation is superior to sequential chemoradiation for patients with unresectable stage III disease. 山东省肿瘤医院呼吸肿瘤内科张品良

如前所述，对于无禁忌症且能耐受手术的Ⅰ/Ⅱ期患者手术是治愈的最佳机会。然而，对于不能切除的I/Ⅱ期或那些拒绝手术的患者如果其淋巴结阴性可以考虑SABR（立体定向消融放疗）（见本讨论及NSCLC NCCN指南中的立体定向消融放疗）。在完全切除的NSCLC患者中，已证明辅助化疗能改善早期患者的生存。某些研究表明，新辅助化疗（也称为术前化疗或诱导化疗）与辅助化疗一样有效且耐受性更好（见本讨论中的新辅助化疗然后手术：试验数据）。一项随机试验发现，术前与术后化疗生存无差异。NCCN指南指出，Ⅱ或ⅢA期（T3N1）患者如果适于术后辅助治疗可采用术前诱导化疗。对于不能切除的Ⅲ期患者同步放化疗优于序贯放化疗。

For patients with stage IV disease who have a good PS, platinum-based chemotherapy is beneficial. Data show that early palliative care combined with standard care improved quality of life, mood, and survival in patients with metastatic NSCLC, even though these patients had less aggressive therapy when compared with those receiving standard care alone. Patients should receive treatment for debilitating symptoms. A study also suggests that social support, such as being married, is as effective as chemotherapy. Surgery is rarely recommended for patients with stage IV disease. However, surgical resection of limited brain metastases may improve survival in selected patients with stage IV disease and is recommended for select patients in the NCCN Guidelines (see the NCCN Guidelines for NSCLC, available at NCCN.org). Definitive local therapy with surgical resection or RT is recommended for limited metastases located in sites other than the brain if definitive thoracic therapy is feasible (see Stage IV, M1b: Limited Sites in the NCCN Guidelines for NSCLC). The trials supporting the recommendations for combined modality therapy are discussed in the following sections. 

对于PS良好的Ⅳ期患者，以铂类为基础的化疗是有益的。数据显示，在转移性NSCLC患者中，与单纯接受标准治疗者相比，早期姑息治疗与标准治疗相结合，改善了患者的生活质量、情绪和生存，即使这些患者接受较不积极的治疗。应该处理患者的虚弱症状。一项研究也认为，社会支持，如结婚，与化疗一样有效。对于Ⅳ期患者很少推荐手术。不过，在选择性Ⅳ期患者中，手术切除局限的脑转移灶可能会改善生存，因此NCCN指南推荐用于选择性患者（见NSCLC NCCN指南，可在NCCN.org获得）。对于除了脑部以外的部位局限的转移，如果可以进行根治性胸部治疗，推荐使用手术切除或放疗的根治性局部治疗（见NSCLC NCCN指南中的IV期，M1b：部位局限）。在下面的章节中讨论推荐综合治疗的支持试验。

Surgery Followed by Chemotherapy: Trial Data 术后化疗：试验数据

In the NSCLC algorithm for stage IA disease, adjuvant chemotherapy is not recommended based on the trials described in the following paragraphs. Adjuvant chemotherapy may be considered for high-risk, margin-negative, stage IB disease (see the NCCN Guidelines for NSCLC). Recommended chemotherapy regimens for neoadjuvant and adjuvant therapy are provided in the NCCN Guidelines. 

在NSCLC IA期的工作步骤中，基于下段描述的试验，不推荐辅助化疗。对于高危、切缘阴性的IB期疾病，可考虑辅助化疗（见NSCLC NCCN指南）。NCCN指南提供了用于新辅助和辅助治疗推荐的化疗方案。

The International Adjuvant Lung Cancer Trial (IALT) reported a statistically significant survival benefit with cisplatin-based adjuvant therapy in patients with completely resected stage I, II, or III NSCLC. The study included 1867 patients with surgically resected lung cancer who were randomly assigned either to cisplatin-based adjuvant chemotherapy or to observation, with a median follow-up duration of 56 months. A higher survival rate (45% vs. 40% at 5 years; HR for death, 0.86; 95% CI, 0.76–0.98; P < .03) and disease-free survival rate (39% vs. 34% at 5 years; HR, 0.83; 95% CI, 0.74–0.94; P < .003) were reported for patients assigned to chemotherapy when compared with observation. IALT data suggest that cisplatin-based adjuvant chemotherapy improves survival 5 years after treatment in patients with completely resected NSCLC. However, after 7.5 years of follow-up, there were more deaths in the chemotherapy group and the benefit of chemotherapy decreased over time. Data show that adjuvant chemotherapy prevents recurrences. 

国际辅助肺癌试验（IALT）报道，在完全切除的I、Ⅱ或Ⅲ期NSCLC患者中，用顺铂为基础的辅助治疗，统计上有显著意义的生存获益。这项研究包括1867例手术切除的肺癌患者，他们被随机分配到以顺铂为基础的辅助化疗或观察，中位随访时间为56个月。与观察组相比，分配至化疗的患者有较高的生存率（5年时45%对40%；死亡风险比，0.86；95%CI，0.76-0.98；P<0.03）和无病生存率（5年时39%对34%；风险比0.83；95%CI，0.74-0.94；P<0.003）。IALT数据表明完全切除后NSCLC患者以顺铂为基础的辅助化疗提高5年生存率。然而，在随访7.5年后，化疗组有更多的死亡，因而化疗的获益随着时间的推移而减少。数据显示，辅助化疗可预防复发。

The NCIC CTG JBR.10 trial and the ANITA trial compared the effectiveness of adjuvant vinorelbine/cisplatin versus observation in early-stage NSCLC. In the JBR.10 trial, 482 patients (ECOG PS of 0–1) with completely resected stage IB (T2, N0) or stage II (T1, N1, or T2, N1) NSCLC were randomly assigned either to vinorelbine/cisplatin or to observation. Adjuvant chemotherapy significantly prolonged overall survival (94 vs. 73 months; HR for death, 0.69; P = .04) and relapse-free survival (not reached vs. 47 months, HR for recurrence, 0.60; P < .001) when compared with observation alone. The 5-year survival rates were 69% and 54%, respectively (P = .03). When compared with observation alone, adjuvant chemotherapy is beneficial for patients with stage II disease but not for stage IB disease as shown by updated data from JBR.10 after 9 years of follow-up. In patients with stage II disease receiving adjuvant chemotherapy, median survival is 6.8 versus 3.6 years in those who were only observed. Of note, patients receiving chemotherapy did not have an increased death rate. 

NCIC CTG JBR.10试验和ANITA试验比较了长春瑞滨/顺铂辅助治疗与观察在早期NSCLC的疗效。在JBR.10试验中，482例完全切除的IB期（T2N0）或Ⅱ期（T1N1或T2N1）NSCLC患者（ECOG PS 0–1）随机分配到长春瑞滨/顺铂或观察。与单纯观察相比，辅助化疗显著延长总生存期（94对73个月；死亡风险比，0.69；P=0.04）和无复发生存期（未达到对47个月，复发风险比，0.60；P< 0.001）。5年生存率分别为69%和54%（P=0.03）。随访9年后JBR.10更新的数据显示，与单纯观察组相比，Ⅱ期患者辅助化疗获益，但IB期患者无益。在接受辅助化疗的Ⅱ期患者中，中位生存期为6.8年，而单纯观察者为3.6年。值得注意的是，接受化疗的患者死亡率没有增加。

In the ANITA trial, 840 patients with stage IB (T2, N0), II, or IIIA NSCLC were randomly assigned either to adjuvant vinorelbine/cisplatin or to observation. Grade 3/4 toxicities were manageable in the chemotherapy group; however, 7 toxic deaths were reported. After a median follow-up of 76 months, median survival was 66 months in the chemotherapy group and 44 months in the observation group. Adjuvant chemotherapy significantly improved (8.6%) the 5-year overall survival in patients with completely resected stage II and IIIA disease, although no benefit was observed in stage I. Some clinicians consider vinorelbine/cisplatin to be the preferred regimen for completely resected early-stage NSCLC based on the number of trials and the amount of use; however, most clinicians in the United States prefer to use regimens with less toxicity. 

在ANITA试验中，840例IB（T2N0）、Ⅱ或ⅢA期NSCLC患者随机分配到辅助长春瑞滨/顺铂或观察。化疗组3/4级毒性容易管理；不过，报告了7例毒性死亡。中位随访76个月后，化疗组中位生存期为66个月，观察组为44个月。辅助化疗可显著改善（8.6%）完全切除的Ⅱ期和ⅢA期患者的5年总生存率，但是在I期患者中未观察到获益。基于许多试验和大量应用，一些临床医生认为长春瑞滨/顺铂是完全切除的早期NSCLC的首选方案；不过，美国大多数临床医生更喜欢使用毒性较低的方案。

A meta-analysis of 4,584 patients (LACE) found that postoperative cisplatin-based chemotherapy increased survival over 5 years (absolute benefit of 5.4%); there was no difference among the chemotherapy regimens (vinorelbine, etoposide, and others). A subgroup analysis found that cisplatin/vinorelbine also increased survival. The benefit was greater in patients with stage II and III disease and with good PS. Postoperative adjuvant chemotherapy benefited elderly patients up to 80 years of age. 

一项4584例患者的meta分析（LACE）发现，术后顺铂为基础的化疗增加5年生存率（绝对获益为5.4%）；化疗方案之间没有差异（长春瑞滨、依托泊苷及其他）。亚组分析发现，顺铂/长春瑞滨还延长生存。Ⅱ期和Ⅲ疾病、PS良好的患者获益更大。高达80岁的老年患者术后辅助化疗受益。

The CALGB 9633 trial assessed paclitaxel/carboplatin in patients with T2, N0, M0, stage IB lung cancer. In this trial, 344 patients were randomly assigned either to paclitaxel/carboplatin or to observation (within 4–8 weeks of resection) with a median follow-up duration of 74 months. Adjuvant chemotherapy was well tolerated with no chemotherapy-related toxic deaths. Overall survival at 6 years was not significantly different (although a subset analysis showed a benefit for tumors 4 cm or more), although 3-year survival was significant (80% vs. 73%, P = .02). Thus, the carboplatin/paclitaxel regimen is only recommended for early-stage disease if patients cannot tolerate cisplatin (see Chemotherapy Regimens for Neoadjuvant and Adjuvant Therapy in the NCCN Guidelines for NSCLC). However, it is important to note that the CALGB trial was underpowered for patients with stage 1B disease. 

CALGB 9633试验评估了紫杉醇/卡铂治疗T2N0M0、IB期肺癌患者。在这项试验中，344例患者随机分为紫杉醇/卡铂或观察（手术切除的4–8周内），中位随访时间74个月。辅助化疗耐受性良好，无化疗相关的毒性死亡。6年时的总生存率无显著差异（虽然一个亚组分析显示，肿瘤≥4cm获益），但是3年生存率差异显著（80%对73%，P =0.02）。因此，卡铂/紫杉醇方案仅建议用于不能耐受顺铂的早期患者（见NSCLC NCCN指南中新辅助和辅助治疗的化疗方案）。不过，需要注意的是，对于IB疾病患者CALGB试验效力不足。

Neoadjuvant Chemotherapy Followed by Surgery: Trial Data 新辅助化疗然后手术：试验数据

Data from adjuvant clinical trials in patients with resected NSCLCs indicate that delivery of chemotherapy is an important problem. In the postoperative setting, significant comorbidities and incomplete recovery after surgery often make it difficult for patients to tolerate systemic therapy. This problem was demonstrated in the NATCH phase 3 trial (which compared surgery alone to preoperative or postoperative chemotherapy with paclitaxel/carboplatin), because 90% of the preoperative cohort completed 3 cycles of chemotherapy but only 61% of the postoperative cohort completed chemotherapy; however, survival was equivalent among all 3 arms. A recent randomized trial found no difference in 3-year overall survival (67.4% vs. 67.7%) with preoperative versus postoperative chemotherapy in patients with early-stage NSCLC; response rate and quality of life were similar in both arms. Postoperative chemotherapy (with or without RT or reresection) is recommended and typically used for early-stage disease in the NCCN Guidelines. 

在手术切除的NSCLC患者中的辅助临床试验数据显示化疗的实施是一个重要问题。术后重要的并存疾病和术后未完全恢复往往使患者难以耐受全身治疗。在NATCH3期试验（比较单纯手术、术前或术后紫杉醇/卡铂化疗）中证实了这一问题，因为术前组90%完成了3个周期的化疗，而术后组只有61%完成了化疗；然而，3组生存相当。最近一项随机试验发现，早期NSCLC患者术前与术后化疗的3年总生存率（67.4%对67.7%）无差异；两组有效率和生活质量相似。NCCN指南推荐术后化疗（±放疗或再切除）并且通常用于早期疾病。

Several trials suggest that neoadjuvant therapy is beneficial in patients with N2 disease. Other trials suggest that neoadjuvant therapy is beneficial in patients with earlier stage disease. A follow-up, randomized intergroup trial (SWOG 9900) evaluated neoadjuvant paclitaxel/carboplatin in 354 patients with stage IB to IIIA (but not N2) disease versus surgery alone. The trial closed prematurely because of practice changes and was therefore not appropriately powered. However, this SWOG trial did show a trend toward improved PFS (33 vs. 20 months) and overall survival (62 vs. 41 months) with neoadjuvant chemotherapy, and no difference in resection rates between the 2 arms. 

若干临床试验表明，在N2患者中，新辅助治疗是有益的。其他试验表明，在较早期患者中新辅助治疗是有益的。一项序贯、随机组间试验（SWOG 9900）评价了紫杉醇/卡铂新辅助治疗与单纯手术治疗354例IB-ⅢA（非N2）期患者。由于实践的改变导致该试验提前结束，因此没有合适的把握度。不过，这项SWOG试验仍显示新辅助化疗有改善PFS（33个月对20个月）和总生存期（62个月对41个月）的趋势，且两组间切除率无差异。

Scagliotti et al published a phase 3 trial of preoperative cisplatin/gemcitabine versus surgery alone in 270 patients with stage IB to IIIA disease. Although the trial closed early, a significant survival benefit was seen in patients with stages IIB and IIIA disease who received chemotherapy (HR, 0.63). Song et al published a meta-analysis of all available randomized clinical trials evaluating preoperative chemotherapy in resectable NSCLCs. This meta-analysis evaluated 13 randomized trials; the HR suggests that overall survival in the neoadjuvant chemotherapy arm is similar to the surgery alone arm (HR, 0.84; 95% CI, 0.77–0.92; P = .0001). These results are similar to those reported in another meta-analysis (HR, 0.89; 95% CI, 0.81–0.98; P = .02). The benefit from neoadjuvant chemotherapy is similar to that attained with postoperative chemotherapy. 

Scagliotti等公布了一项3期试验，在270例IB-ⅢA期患者中对比术前顺铂/吉西他滨与单纯手术。尽管试验提前结束，但是，在接受化疗的ⅡB和ⅢA期患者中见到显著的生存受益（HR，0.63）。Song等对所有可获得的旨在评估可切除NSCLC术前化疗的随机临床试验进行了meta分析。该meta分析评估了13个随机试验；风险比提示，新辅助化疗组的总生存期与单纯手术组类似（风险比，0.84；95%CI，0.77-0.92；P=0.0001）。95% CI，0.77–0.92；P = .0001）。这些结果类似于另一项meta分析（风险比，0.89；95%CI，0.81-0.98；P=0.02）。95% CI，0.81–0.98；P = 0.02）。新辅助化疗与术后化疗的获益相似。

Chemoradiation: Trial Data 放化疗：试验数据

The major controversies in NSCLC relate to the management of patients with stage IIIA disease (see the Role of Surgery in Patients with Stage IIIA (N2) NSCLC [in Principles of Surgical Therapy in the NCCN Guidelines for NSCLC]). All 3 treatment modalities—surgical resection, chemotherapy, and radiation—may be used when treating stage III disease. The ongoing debate centers on which modalities to use and in what sequence. For patients with unresectable stage IIIA or stage IIIB disease, combined modality therapy (chemoradiation) is superior to radiation alone. Concurrent chemoradiation is superior to sequential chemoradiation. However, concurrent chemoradiation has a higher rate of grade 3 or 4 esophagitis than sequential chemoradiation. Selection of patients should be based not only on the anticipated response to therapy but also on how well the patient is anticipated to tolerate therapy. Frail patients may not be able to tolerate concurrent chemoradiation. 

NSCLC的主要争议是ⅢA期患者的处理（见ⅢA （N2）期NSCLC患者中手术的地位[NSCLC NCCN指南中的外科治疗原则]）。当治疗Ⅲ期疾病时，手术切除、化疗和放疗这3种治疗模式均可使用。正在争论的中心是用何种手段与何种顺序。对于不可切除的ⅢA或ⅢB期患者，综合模式治疗（化放疗）优于单纯放疗。同步化放疗优于序贯化放疗。然而，同步化放疗比序贯放化疗有更高的3或4度食管炎发生率。患者的选择不仅要根据治疗的预期疗效还应根据患者对治疗的预期耐受性如何。虚弱患者也许不能耐受同步放化疗。

Concurrent chemoradiation regimens that may be used for all histologies for initial treatment include cisplatin/etoposide, cisplatin/vinblastine, and carboplatin/paclitaxel (see Chemotherapy Regimens Used with Radiation Therapy in the NCCN Guidelines for NSCLC). For non-squamous NSCLC, additional concurrent chemoradiation regimens may be used including carboplatin/pemetrexed and cisplatin/pemetrexed. A weekly paclitaxel/carboplatin regimen is another chemoradiation option. The different options for neoadjuvant/preoperative/induction, definitive, and adjuvant chemotherapy/RT are described in detail in the algorithm. Recently, the NCCN Panel removed the preferred designation for the cisplatin/etoposide and cisplatin/vinblastine regimens based on data from a phase 3 randomized trial and a recent retrospective assessment of the Veterans Administration data. 

可用于所有组织学初始治疗的同步放化疗方案包括顺铂/依托泊苷、顺铂/长春花碱和卡铂/紫杉醇（见NSCLC NCCN指南中的放射治疗联合使用的化疗方案）。400,524,526,557-561 对于非鳞NSCLC，其他可以使用的同步放化疗方案包括卡铂/培美曲塞和顺铂/培美曲塞。562-564 每周1次紫杉醇/卡铂方案是另一个放化疗选择。400 在工作步骤中详述了新辅助/术前/诱导、根治以及辅助化疗/放疗的不同方案。根据一项3期随机试验的数据和退伍军人管理局的一项最新回顾性评估数据，最近，NCCN小组删除了顺铂/依托泊苷和顺铂/长春花碱方案的首选标识。