非小细胞肺癌的综合治疗NCCN指南2017第2版

Discussion 讨论

Treatment Approaches 治疗手段山东省肿瘤医院呼吸肿瘤内科张品良

Combined Modality Therapy
联合模式治疗

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 Non-Small Cell Lung Cancer). In patients with completely resected NSCLC, adjuvant chemotherapy has been shown to improve survival in patients with early-stage disease. Some studies suggested 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 recent 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 therapy for patients with unresectable stage III disease.
如前所述，对于无禁忌症并且能耐受手术的Ⅰ或Ⅱ期疾病患者手术是治愈的最佳机会。然而，对于不能切除的I或II期疾病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）（见本讨论及非小细胞肺癌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疾病患者的生存。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）。最近一项随机试验发现，术前与术后化疗生存无差异。NCCN指南指出，II或IIIA期（T3、N1）疾病患者如果其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期疾病患者同步放化疗优于序贯治疗。

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 improves 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 recent 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 a solitary brain metastasis may improve survival in selected patients with stage IV disease and is recommended in the NCCN Guidelines (see the NCCN Guidelines for Non-Small Cell Lung Cancer and for Central Nervous System Cancers, available at NCCN.org). Local therapy of a solitary metastasis located in sites other than the brain remains controversial and thus is a category 2B recommendation; however, SRS or SABR may be useful in these settings (see Stage IV, M1b: Solitary Site/Initial Treatment in the NCCN Guidelines for Non-Small Cell Lung Cancer). 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的患者相比，早期姑息治疗与标准治疗相结合，改善患者的生活质量、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。最近的一项研究也认为，社会支持，如结婚，与化疗一样有效。对于Ⅳ期疾病患者很少推荐手术。然而，在选择性IV期疾病患者中，单发脑转移手术切除可改善生存，因此NCCN指南推荐（见非小细胞肺癌和中枢神经系统肿瘤NCCN指南，可在NCCN.org获得）。脑外孤立转移的局部治疗仍然存在争议，因此是一个2B类推荐；然而，在这些情况下SRS（立体定向放射外科）或SABR（立体定向消融放疗）可能是有用的（见IV期、M1b：非小细胞肺癌NCCN指南单一部位/初始治疗）。推荐综合治疗的支持试验在下面的章节中讨论。

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 Non-Small Cell Lung Cancer). Recommended chemotherapy regimens for neoadjuvant and adjuvant therapy are provided in the NCCN Guidelines.
在NSCLC IA期的工作步骤中，基于下面段落中描述的试验，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（见非小细胞肺癌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 significantly 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 observed 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，分配至化疗的患者观察到显著较高的生存率（5年时45%对40%；死亡HR，0.86；95%CI，0.76 - 0.98；P < .03）和无病生存率（5年时39%对34%；HR 0.83；95%CI，0.74-0.94；P<.003）。ialt数据表明以顺铂为基础的辅助化疗提高完全切除治疗后非小细胞肺癌患者的5年生存率。然而，在7.5年的随访后，在化疗组有更多的死亡因而化疗的获益随着时间的推移降低。数据显示，辅助化疗可预防复发。< span="">化疗提高完全切除治疗后非小细胞肺癌患者的5年生存率。然而，在7.5年的随访后，在化疗组有更多的死亡因而化疗的获益随着时间的推移降低。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试验比较了辅助长春瑞滨/顺铂与观察在早期非小细胞肺癌的疗效。在JBR.10试验中，482例完全切除的IB期（T2N0）或II期（T1N1或T2N1）非小细胞肺癌患者（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个月对73个月，死亡HR，0.69，P = 0.04）和无复发生存期（未达到对47个月，复发HR，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期疾病患者辅助化疗获益，但IB期患者无益。在接受辅助化疗的II期疾病患者中，中位生存期为6.8年而那些单纯观察者为3.6年。值得注意的是，接受化疗的患者的死亡率没有增加。

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期非小细胞肺癌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；然而，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，尽管在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非小细胞肺癌的首选方案；然而，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。术后辅助化疗受益的老年患者高达80岁。

The CALGB 9633 trial assessed paclitaxel/carboplatin in patients with T2, N0, M0, stage IB lung cancer; updated results have been reported. 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 3-year survival was significant (80% vs. 73%, P = .02).
CALGB 9633试验评估了紫杉醇/卡铂治疗T2N0M0、IB期肺癌患者；已报道更新的结果。在这项试验中，344例患者随机分为紫杉醇/卡铂或观察（在切除的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，尽管3年生存率是显著的（80%对73%，P =0.02）。

The original results from CALBG suggested that the paclitaxel/carboplatin regimen improved survival in patients with stage I disease; however, the updated results did not show improved survival (although a subset analysis showed a benefit for tumors 4 cm or more). 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 Non-Small Cell Lung Cancer). However, it is important to note that the CALGB trial was underpowered for patients with stage 1B disease.
CALBG的初步结果表明，紫杉醇/卡铂方案改善I期患者的生存；然而，更新的结果并未显示改善生存（虽然一个亚组分析显示，对于肿瘤≥4cm者获益）。因此，卡铂/紫杉醇方案仅建议用于患者不能耐受顺铂的早期疾病（见非小细胞肺癌NCCN指南中新辅助和辅助治疗的化疗方案）。然而，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 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 is considered the standard of care for early-stage disease.
在手术切除的非小细胞肺癌患者中的辅助临床试验数据显示化疗的给予是一个重要的问题。在术后情况下，重要的并存疾病和术后未完全恢复往往使患者难以耐受治疗。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，但术后组只有61%完成了化疗；然而，在所有3组当中生存相当。最近一项随机试验发现，早期非小细胞肺癌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。认为对早期疾病术后化疗是标准治疗。

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疾病患者中，新辅助治疗是有益的。其他试验表明，在较早期疾病患者中新辅助治疗是有益的。一项序贯、随机组间试验（SWOG 9900）在354例IB-IIIA（非N2）期疾病患者中评价了紫杉醇/卡铂新辅助治疗与单纯手术。由于实践的改变导致该试验提前结束，因此没有适当的把握度。然而，这项SWOG试验仍显示新辅助化疗有改善PFS（33对20个月）和总生存期（62对41个月）的趋势，而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 and found improvement in overall survival in the neoadjuvant chemotherapy arm when compared with the surgery alone arm (HR, 0.84; 95% CI, 0.77–0.92; P = .0001). These results are similar to those recently 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期疾病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期疾病患者中见到显著的生存受益（HR，0.63）。Song等发表了对所有可获得的评估可切除非小细胞肺癌术前化疗随机临床试验的一项meta分析。该meta分析评估了13项随机试验，发现与单纯手术组相比，新辅助化疗组的总生存改善（HR，0.84；95% CI，0.77–0.92；P = 0.0001）。这些结果与最近另一项meta分析报道的相似（HR，0.89；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 Non-Small Cell Lung Cancer]). All 3 treatment modalities—surgical resection, chemotherapy, and radiation—may be used in 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 response to therapy but also on how well the patient tolerates therapy. Frail patients may not be able to tolerate concurrent chemoradiation.
在非小细胞肺癌中的主要争议是IIIA期疾病患者的处理（见IIIA (N2)期非小细胞肺癌患者中手术的地位[非小细胞肺癌NCCN指南中的外科治疗原则]）。手术切除、化疗和放疗这3种治疗模式均可用于治疗Ⅲ期疾病。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期疾病患者，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。病人的选择不仅要根据对治疗的应答也应根据患者对治疗的耐受性如何。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 Non-Small Cell Lung Cancer). For non-squamous NSCLC, additional concurrent chemoradiation regimens may be used including carboplatin/pemetrexed and cisplatin/pemetrexed. For the 2016 update (Version 1), a weekly paclitaxel/carboplatin regimen was added as another chemoradiation option. In addition, the different options for neoadjuvant/preoperative/induction, definitive, and adjuvant chemotherapy/RT were clarified. The NCCN Panel removed the preferred designation for the cisplatin/etoposide and cisplatin/vinblastine regimens based on preliminary data from a phase 3 randomized trial and a recent retrospective assessment of the Veterans Administration data for the 2016 update (Version 1).
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（见非小细胞肺癌NCCN指南中的放射治疗联合使用的化疗方案）。对于非鳞非小细胞肺癌，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。2016第1版更新，增加了紫杉醇/卡铂周疗方案作为另外一个化放疗选择。此外， 最后阐明了用于新辅助/术前/诱导及辅助化疗/RT的不同方案。根据一项3期随机试验的初步数据和退伍军人管理局2016更新（第1版）的一项最新回顾性评估数据，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。