晚期非小细胞肺癌的维持治疗 NCCN指南2016V4

NSCLC NCCN2016V4 Discussion
讨论

Maintenance Therapy
维持治疗山东省肿瘤医院呼吸肿瘤内科张品良

Maintenance therapy refers to systemic therapy that may be given for patients with advanced NSCLC after 4 to 6 cycles of first-line chemotherapy.
维持治疗是指对于晚期NSCLC患者在4至6个周期的一线化疗后，可给予的全身治疗。

However, patients are only candidates for maintenance therapy if they have responded to their previous treatment (ie, tumor response) or have stable disease and their tumors have not progressed.
然而，只有对其既往治疗有应答（即肿瘤缓解）或疾病稳定且肿瘤无进展的患者才适于维持治疗。

Continuation maintenance therapy refers to the use of at least one of the agents that was given in the first-line regimen.
继续维持治疗是指使用在一线方案中给予的至少一种药物。

Switch maintenance (category 2B) therapy refers to the initiation of a different agent that was not included as part of the first-line regimen.
转换维持（2B类）治疗是指启用一种一线方案中没有的不同药物。

Selection of appropriate maintenance therapy depends on several factors (eg, histologic type, presence of mutations or gene rearrangements, PS).
恰当维持治疗的选择取决于几个因素（如，组织学类型，存在突变或基因重排、PS）。

Maintenance therapy is an option in the NCCN Guidelines for select patients with tumor response or stable disease and is not considered the standard of care for all patients (eg, not recommended for PS 3-4, those with progression); close observation (category 2A) is also a valid treatment option (see the NCCN Guidelines for Non-Small Cell Lung Cancer).
在NCCN指南中，对于所有选择的肿瘤有效或病情稳定、且不考虑标准护理的患者（如，对于PS 3-4、进展者不推荐），维持治疗是一种选择；密切观察（2A类）也是一种有效的处理选择（见非小细胞肺癌NCCN指南）。

Continuation Maintenance Therapy
继续维持治疗

For continuation maintenance therapy, select agents (which were initially given in combination with conventional chemotherapy) may be continued until evidence of disease progression or unacceptable toxicity, as per the design of the clinical trials that led to their approval.
对于继续维持治疗，根据批准的临床试验设计，选择的（在最初传统化疗联合中给予的）药物可以持续直至出现疾病进展的证据或无法接受的毒性。

Single-agent bevacizumab (category 1) may be continued beyond 4 to 6 cycles of initial therapy (ie, platinum-doublet chemotherapy given with bevacizumab) in patients with non-squamous NSCLC who are negative for ALK rearrangements or sensitizing EGFR mutations.
在ALK重排或敏感EGFR突变阴性的非鳞NSCLC患者中，在4至6周期初始治疗（即铂二联化疗联合贝伐单抗）之外可以继续给予单药贝伐单抗（1类）。

Single-agent pemetrexed (category 1) may also be given as continuation maintenance therapy in patients with non-squamous NSCLC (who are negative for ALK rearrangements or sensitizing EGFR mutations).
在非鳞NSCLC患者（ALK重排或敏感EGFR突变阴性者）中，也可以给予单药培美曲塞（1级）作为继续维持治疗。

A recent phase 3 randomized trial (PARAMOUNT) found that continuation maintenance therapy with pemetrexed slightly increased PFS when compared with placebo (4.1 vs. 2.8 months).
最近一项3期随机试验（PARAMOUNT）发现，与安慰剂相比，培美曲塞继续维持治疗略微改善PFS（4.1对2.8个月）。

Results show that continuation maintenance therapy with pemetrexed also improves overall survival (13.9 vs. 11.0 months).

结果表明，培美曲塞继续维持治疗也改善总生存（13.9对11个月）。

Based on the recent trial and the FDA approval, the NCCN Panel recommends single-agent pemetrexed as continuation maintenance therapy (category 1) in patients with non-squamous NSCLC but without ALK rearrangements or sensitizing EGFR mutations.
基于最近的试验和FDA的批准，NCCN小组推荐单药培美曲塞作为非鳞NSCLC但是无ALK重排或敏感EGFR突变患者的继续维持治疗（1类）。

Continuation maintenance therapy with cetuximab was recently removed from the NCCN Guidelines, because the first-line regimen of cetuximab/cisplatin/vinorelbine was removed (see Cetuximab in this Discussion).
西妥昔单抗继续维持治疗最近从NCCN指南删除，因为西妥昔单抗/顺铂/长春瑞滨的一线方案被删除（见本讨论中的西妥昔单抗）。

Continuation maintenance therapy using bevacizumab/pemetrexed is also an option in patients with non-squamous NSCLC but without ALK rearrangements or sensitizing EGFR mutations; this is a category 2A recommendation.
使用贝伐单抗/培美曲塞继续维持治疗也是非鳞NSCLC但是无ALK重排或敏感EGFR突变患者的一个选择；这是一个2A类推荐。

Data from the recent POINTBREAK study showed a very slight improvement in PFS (6 vs. 5.6 months) when comparing bevacizumab/pemetrexed versus bevacizumab alone as maintenance therapy; the initial regimens were either bevacizumab/carboplatin/pemetrexed or bevacizumab/carboplatin/paclitaxel.
POINTBREAK最新研究数据表明，与单独贝伐单抗维持治疗相比，贝伐单抗/培美曲塞非常轻微的改善PFS（6对5.6个月）；初始方案是贝伐单抗/卡铂/培美曲塞或贝伐单抗/卡铂/紫杉醇。

It is important to note that the pemetrexed-based arm was associated with less toxicity (eg, less neurotoxicity, less neutropenia, less hair loss) than the paclitaxel-based arm.
需要注意的是，培美曲塞联合组比紫杉醇联合组具有更少的毒性（如，更少的神经毒性、更少的中性粒细胞减少症、更少的脱发）。

When using bevacizumab/pemetrexed versus bevacizumab alone as maintenance therapy, data from the recent AVAPERL study showed a 3.7-month increase in PFS (7.4 vs. 3.7 months); the initial regimen was bevacizumab/cisplatin/pemetrexed.
AVAPERL研究的最新数据显示，与单独贝伐单抗相比，使用贝伐单抗/培美曲塞维持治疗，PFS延长了3.7个月（7.4对3.7个月）；初始方案是贝伐单抗/顺铂/培美曲塞。

A phase 3 randomized trial compared using maintenance therapy with either gemcitabine or erlotinib after first-line therapy with cisplatin-gemcitabine.
一项3期随机试验比较了在顺铂-吉西他滨一线治疗后使用吉西他滨或厄洛替尼维持治疗。

Data show that continuation maintenance therapy with single-agent gemcitabine increased PFS to a greater extent (3.8 months) than switch maintenance therapy with erlotinib (2.9 months) when compared with observation (1.9 months).
数据显示，PFS与观察相比（1.9个月），单药吉西他滨继续维持治疗（3.8个月）比用厄洛替尼转换维持治疗（2.9个月）改善程度更大。

Another phase 3 randomized trial assessed continuation maintenance therapy with gemcitabine versus best supportive care after an initial regimen of cisplatin/gemcitabine.
另外一项3期随机试验评估了在初始顺铂/吉西他滨方案后吉西他滨继续维持治疗对比最佳支持治疗。

The data showed a slight difference in PFS but no difference in overall survival.
数据显示，PFS略有差异，但总生存无差异。

The NCCN Guidelines recommend using gemcitabine (category 2B) as continuation maintenance therapy regardless of histology in patients without ALK rearrangements or sensitizing EGFR mutations.
NCCN指南推荐使用吉西他滨（2B类）作为无ALK重排或敏感EGFR突变患者的继续维持治疗，不管组织学如何。

Use of continuation maintenance therapy depends on several factors such as whether the patient had minimal toxicity during treatment.
继续维持治疗的使用取决于几个因素，如患者在治疗过程中是否有最小限度的毒性。

A drug vacation may be more appropriate for some patients.
暂停药物治疗可能更适于某些患者。

Some clinicians feel that continuation maintenance therapy is only appropriate for select patients, because it has not been shown to improve overall survival or quality of life, although it has been shown to improve PFS.
一些临床医生认为，继续维持治疗只适于选择的患者，因为尚未证明改善总生存或生活质量，尽管已证明可以改善PFS。

In addition, maintenance therapy has not been shown to be superior to subsequent therapy, which is initiated at disease progression.
此外，尚未证明维持治疗优于在疾病进展时开始后续治疗。

Data from a phase 3 randomized trial suggest that conventional cytotoxic agents should not be continued beyond 4 to 6 cycles of therapy; however, many patients assigned to a longer duration of therapy did not receive the planned number of cycles (see Maintenance Therapy in this Discussion).
一项3期随机试验数据提示，传统细胞毒药物不应持续治疗超过4至6周期；然而，许多患者被分配到一个持续时间更长的治疗但没有接受计划的周期数（见本讨论中的维持治疗）。

Switch Maintenance Therapy
转换维持治疗

Issues have been raised about switch maintenance therapy, including the design of the trials, modest survival benefits, quality of life, and toxicity.

关于转换维持治疗的争议增加，包括试验设计、适度的生存获益、生活质量和毒性。

Therefore, switch maintenance therapy is a category 2B recommendation in the NCCN Guidelines.
因此，转换维持治疗在NCCN指南中是2B类推荐。

Two phase 3 randomized trials have shown a benefit in PFS and overall survival with the initiation of pemetrexed or erlotinib after first-line chemotherapy (4-6 cycles) in patients with no apparent disease progression.
两项3期随机试验已经证明，在一线化疗（4-6周期）后疾病无明显进展的患者开始培美曲塞或厄洛替尼在PFS和总生存方面均获益。

Switch maintenance therapy with pemetrexed is recommended (category 2B) in patients with non-squamous cell carcinoma who are negative for ALK rearrangements or sensitizing EGFR mutations.
在ALK重排或敏感EGFR突变阴性的非鳞状细胞癌患者中，推荐用培美曲塞转换维持治疗（2B类）。

The FDA has approved maintenance therapy with pemetrexed.
FDA已经批准了培美曲塞维持治疗。

Likewise, switch maintenance therapy with erlotinib is recommended (category 2B) in patients with non-squamous NSCLC but without ALK rearrangements or sensitizing EGFR mutations.
同样，在非鳞NSCLC但是无ALK重排或敏感EGFR突变的患者中推荐用厄洛替尼转换维持治疗（2B类）。

For the 2016 update (Version 1), the NCCN Panel deleted the recommendation for switch maintenance therapy with erlotinib in patients with squamous cell NSCLC, because overall survival and quality of life were not improved.
因为总生存和生活质量未改善，2016年第1版更新，NCCN小组删除了在鳞状细胞NSCLC患者中用厄洛替尼转换维持治疗的推荐。

Both erlotinib and pemetrexed have a category 2B recommendation for switch maintenance therapy in patients with non-squamous NSCLC.
在非鳞NSCLC患者中厄洛替尼和培美曲塞两者都是转换维持治疗的2B类推荐。

The FDA has approved maintenance therapy with erlotinib.
FDA已经批准了厄洛替尼维持治疗。

A phase 3 trial assessed switch maintenance therapy with docetaxel given either immediately after chemotherapy or delayed until progression.
一项3期试验评估了在化疗后立即或延迟至进展给予多西他赛转换维持治疗。

Switch maintenance therapy with docetaxel is a category 2B recommendation in the NCCN Guidelines for patients with squamous cell carcinoma, because many patients in the delayed chemotherapy arm did not receive docetaxel.
在NCCN指南中多西他赛转换维持治疗对于鳞状细胞癌患者是2B类推荐，因为在延迟化疗组中很多患者未接受多西他赛。