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原创 非小细胞肺癌的辅助放化疗NCCN指南2017第2版

张品良 副主任医师 山东省肿瘤医院 呼吸肿瘤内科
2016-11-10 345人已读
张品良 副主任医师
山东省肿瘤医院

NCCN Guidelines Version 2.2017 NCCN指南2017第2版

Non-Small Cell Lung Cancer
非小细胞肺癌

Adjuvant Treatment
辅助治疗

Chemotherapy or Chemoradiation 山东省肿瘤医院呼吸肿瘤内科张品良
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, N0 tumors and with negative surgical margins (R0). Patients with T2ab, N0 tumors with negative surgical margins are usually observed. Adjuvant chemotherapy is a category 2A recommendation for patients with high-risk features (including poorly differentiated tumors, vascular invasion, wedge resection, tumors >4 cm, visceral pleural involvement, and incomplete lymph node sampling [Nx]) (see Adjuvant Treatment in the NCCN Guidelines for Non-Small Cell Lung Cancer). 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T1abN0肿瘤患者建议观察。通常观察到手术切缘阴性的T2abN0肿瘤患者。辅助化疗对具有高危特征(包括低分化肿瘤、脉管侵犯、楔形切除术、肿瘤大于4cm、脏层胸膜受累和淋巴结采样不完全[Nx])的患者是2A类推荐(见非小细胞肺癌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)。

The NCCN Panel recommends chemotherapy (category 1) for patients with negative surgical margins and stage II disease, including 1) T1ab–2a, 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–2aN1、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)。2)T2bN1;或3)T3N0。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(或序贯或同时)。R2切除后的选择包括:1)再切除加化疗;或2)同步化放疗。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 Non-Small Cell Lung Cancer). 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 Non-Small Cell Lung Cancer). Patients with negative margins may be treated with either 1) chemotherapy (category 1); or 2) sequential chemotherapy plus RT (for N2 only).
辅助化疗也可用于已经手术的III期非小细胞肺癌患者(见非小细胞肺癌NCCN指南)。T1-3N2或T3N1疾病(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切除推荐序贯或同步化放疗,而对于R2切除建议同步化放疗(见非小细胞肺癌NCCN指南中的辅助治疗)。切缘阴性患者可以接受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 convert to a resectable status (ie, become resectable) after preoperative concurrent chemoradiation, resection followed by chemotherapy is recommended (see the NCCN Guidelines for Non-Small Cell Lung Cancer). If the lesion remains unresectable after preoperative concurrent chemoradiation, the full course of definitive chemo/RT should be completed, followed by chemotherapy as an adjuvant treatment 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).
对于在术前化放疗后转换为可切除(即变为可切除)的IIIA期(T4N0–1)上沟瘤,推荐术后化疗(见非小细胞肺癌NCCN指南)。如果术前同步化放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序贯化疗作为辅助治疗。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 Non-Small Cell Lung Cancer). 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 treatment. 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.
对于在初始治疗后没有明显疾病进展的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)(见非小细胞肺癌NCCN指南)。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,对于R2切除推荐同步放化疗,而对于R1切除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 Non-Small Cell Lung Cancer). 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(见非小细胞肺癌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 has included 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 Non-Small Cell Lung Cancer). For the 2016 update (Version 1), the NCCN Panel deleted vinblastine since this agent is rarely used. For patients with comorbidities or those who cannot tolerate cisplatin, carboplatin combined with paclitaxel is an option. A phase 3 randomized trial in elderly patients (70–89 years) with advanced NSCLC reported that combined therapy with weekly paclitaxel and monthly carboplatin improved survival when compared with single-agent therapy using either gemcitabine or vinorelbine (10.3 vs. 6.2 months). A number of phase 2 studies have evaluated neoadjuvant chemotherapy for stage III NSCLC, with (or without) RT, followed by surgery.
基于非小细胞肺癌新辅助化疗和辅助化疗的临床研究,在NCCN指南中对所有组织类型的辅助化疗NCCN小组收录了顺铂联合多西他赛、依托泊苷、吉西他滨或长春瑞滨;对于非鳞非小细胞肺癌其他选择包括顺铂联合培美曲塞(见非小细胞肺癌NCCN指南中的新辅助和辅助治疗化疗方案)。2016第1版更新,NCCN小组删除了长春花碱,因为该药很少使用。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。在老年晚期非小细胞肺癌患者(70–89岁)中的一项3期随机试验报道,与吉西他滨或长春瑞滨单药治疗相比,每周一次紫杉醇和每月一次卡铂联合治疗改善生存(6.2对10.3个月)。若干2期研究评估了III期非小细胞肺癌新辅助化疗±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期非小细胞肺癌。S9900试验(SWOG的一项研究)——早期非小细胞肺癌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期非小细胞肺癌(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 in the context of 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 Non-Small Cell Lung Cancer). 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荟萃分析和SEER大样本数据分析发现,在临床早期非小细胞肺癌完全切除术后,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疾病患者中,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疾病患者,与单纯化疗相比,术后放疗和化疗具有生存优势。最近一项荟萃分析也得出结论,对于N2疾病患者,术后放疗可改善生存。对于T1–3、N2期疾病且切缘阴性的患者,推荐术后辅助序贯化放疗(见非小细胞肺癌NCCN指南中的辅助治疗)。一项荟萃分析评估了主要是Ⅲ期疾病患者术后化疗±术后放疗。在这项荟萃分析中,符合试验条件的70%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 ® 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 Non-Small Cell Lung Cancer). 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 Non-Small Cell Lung Cancer). Pemetrexed with either cisplatin or carboplatin may be used for concurrent chemoradiation in patients with non-squamous NSCLC. Chemoradiation regimens cited in the NCCN Guidelines may also be used for stage II to III disease.
对于术后辅助治疗,同步或序贯化放疗都可以使用,取决于切除类型与情况(如N2)(见非小细胞肺癌NCCN指南中的辅助治疗)。对于R2切除建议同步化/放疗,而对于R1切除建议序贯或同步化/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小组推荐的化放疗方案(见非小细胞肺癌NCCN指南中的联合放疗使用的化疗方案)。非鳞非小细胞肺癌患者同步化放疗可使用培美曲塞联合顺铂或卡铂。NCCN指南列举的化放疗方案也可用于II-III期疾病。

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张品良 副主任医师

山东省肿瘤医院 呼吸肿瘤内科

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