IV期NSCLC化疗基础知识

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本帖最后由 costa_na 于 2013-12-5 23:18 编辑

http://www.cancer.gov/cancertopi ... professional/page11

美国国立癌症研究所PDQ信息汇总

1.1. 综述

1.2. 联合化疗方案

1.3. 影响治疗的因子

1.4. 化疗联合贝伐单抗或西妥昔单抗

1.5. 一线化疗后的维持治疗

costa_na · 发表于 2013-12-5 15:11:05

本帖最后由 costa_na 于 2013-12-6 00:15 编辑

1.1. 综述

Cytotoxic combination chemotherapy (first line)
细胞毒性药物联合化疗（一线）

The type and number of chemotherapy drugs to be used for the treatment of patients with advanced NSCLC has been extensively evaluated in randomized controlled trials and meta-analyses.
用于治疗患有晚期NSCLC患者的化疗药物的种类和数量在数个随机控制的临床试验和荟萃分析中已经得到了广泛的评估。

Several randomized trials have evaluated various drugs combined with either cisplatin or carboplatinum in previously untreated patients with advanced NSCLC. Based on meta-analyses of the trials, the following conclusions can be drawn:
少数随机临床研究评估了在未接受治疗的晚期NSCLC患者中应用顺铂或者卡铂的药物组合方案。基于临床的荟萃分析结果，产生了以下结论：
• Certain three-drug combinations that add so-called targeted agents may result in superior survival.
添加了所谓的靶向药物的特定三药联合方案可能会有较好的生存。*

• EGFR inhibitors may benefit selected patients with EGFR mutations.
带有EGFR突变的患者可能会从EGFR抑制剂中受益。

• Maintenance chemotherapy following four cycles of platinum combination chemotherapy may improve progression-free survival (PFS).
在接受了四个联合铂类的化疗疗程之后，应用化疗作维持治疗可能延长无进展时间（PFS）。

• Platinum combinations with vinorelbine, paclitaxel, docetaxel, gemcitabine, irinotecan, and pemetrexed yield similar improvements in survival. Types and frequencies of toxic effects differ, and these may determine the preferred regimen for an individual patient. Patients with adenocarcinoma may benefit from pemetrexed.
铂类联合长春瑞滨、紫杉醇、多西他赛、吉西他滨、伊立替康和培美曲塞的方案能产生类似的生存期的提高。基于药物毒性副作用的类型和发生率的差异，可以为单个患者确定更适合的治疗方案。特别的是，肺腺癌患者更可能从培美曲赛中受益。

• Cisplatin and carboplatinum yield similar improvements in outcome with different toxic effects. Some, but not all, trials and meta-analyses of trials suggest that outcomes with cisplatin may be superior, although with a higher risk of certain toxicities such as nausea and vomiting.
顺铂和卡铂对生存期有类似的提高但具有不同的毒副作用。一些临床和基于临床的荟萃分析提出顺铂可能会有雨卡铂，虽然伴随着更高风险的特定毒性作用例如恶心和呕吐。

• Nonplatinum combinations offer no advantage to platinum-based chemotherapy, and some studies demonstrate inferiority.
相对于铂类联合，非铂类联合方案不具有优势，部分研究甚至得到了负面的结果。

• Three-drug combinations of the commonly used chemotherapy drugs do not result in superior survival and are more toxic than two-drug combinations.
相比双药联合方案来说，使用常用化疗药物的三药联合方案没有得到更佳的生存期，反而拥有更大的毒性。

*：翻译可能存在问题

costa_na · 发表于 2013-12-5 15:11:30

本帖最后由 costa_na 于 2013-12-5 15:57 编辑

1.2.联合化疗方案

1.2.1.双药联合

1. The Cochrane Collaboration group reviewed data from all randomized controlled trials published between January 1980 and June 2006, comparing a doublet regimen with a single-agent regimen or comparing a triplet regimen with a doublet regimen in patients with advanced NSCLC.[6] Sixty-five trials (13,601 patients) were identified.
科克伦协作组(Cochrane Collaboration group)回顾了从1980年1月到2006年6月间公布的所有的对比研究双药联合方案和单药方案或者三药联合方案和双药联合方案的在晚期NSCLC患者中展开的随机控制临床试验。一共有65个临床被确定。

a. In the trials comparing a doublet regimen with a single-agent regimen, a significant increase was observed in tumor response (odds ratio [OR], 0.42; 95% confidence interval [CI], 0.37– 0.47; P < .001) and 1-year survival (OR, 0.80; 95% CI, 0.70–0.91; P < .001) in favor of the doublet regimen. The absolute benefit in 1-year survival was 5%, which corresponds to an increase in 1-year survival from 30% with a single-agent regimen to 35% with a doublet regimen. The rates of grades 3 and 4 toxic effects caused by doublet regimens were statistically increased compared with rates following single-agent therapy, with ORs ranging from 1.2 to 6.2. There was no increase in infection rates in doublet regimens.
在对比双药联合方案和单药方案的临床中，在双药方案中观察到了肿瘤响应（优势比[OR], 0.42; 95%置信区间[CI], 0.37–0.47; P < .001）和1年生存率的显著提高。绝对的1年生存率获益是5%，将单药方案的1年生存率从30%提高到了35%。相比单药方案，由双药方案引起的3-4级毒副作用有统计学上的增加(OR, 1.2-6.2)。双药联合没有增加感染率。

b. There was no increase in 1-year survival (OR, 1.01; 95% CI, 0.85–1.21; P = .88) for triplet regimens versus doublet regimens. The median survival ratio was 1.00 (95% CI, 0.94–1.06; P = .97).
在三药方案和双药方案的比较中，1年生存率没有得到提高(OR, 1.01; 95% CI, 0.85–1.21; P = .88)，中位生存率为1.00(95% CI, 0.94–1.06; P = .97)。

1.2.2. 顺铂对比卡铂

2. Several meta-analyses have evaluated whether cisplatin or carboplatin regimens are superior with variable results.[7,8,9] One meta-analysis reported individual patient data for 2,968 patients entered in nine randomized trials.[7]
少数荟萃分析评估了是否顺铂相比卡铂更优。一个荟萃分析报告了入组9个随机临床的2968名患者的单独的个体数据：

a. The objective response rate was higher for patients treated with cisplatin than for patients treated with carboplatin (30% vs. 24%, respectively; OR, 1.37; 95% CI, 1.16–1.61; P < .001).
使用顺铂治疗的患者中，其客观响应率高于接受卡铂的患者(30% vs. 24%, respectively; OR, 1.37; 95% CI, 1.16–1.61; P < .001)。

b. Carboplatin treatment was associated with a non–statistically significant increase in the hazard of mortality relative to treatment with cisplatin (hazard ratio [HR], 1.07; 95% CI, 0.99–1.15; P = .100).
相对于顺铂，卡铂治疗方案与非统计学增加的死亡风险相关（风险比 [HR], 1.07; 95% CI, 0.99–1.15; P = .100）。

c. In patients with nonsquamous tumors and those treated with third-generation chemotherapy, carboplatin-based chemotherapy was associated with a statistically significant increase in mortality (HR, 1.12; 95% CI, 1.01–1.23 and HR, 1.11; 95% CI, 1.01–1.21, respectively).
在非鳞癌并且接受第三代化疗药物治疗的患者中，基于卡铂的化疗与统计学意义上显著增加的死亡率相关（HR, 1.12; 95% CI, 1.01–1.23 and HR, 1.11; 95% CI, 1.01–1.21, respectively）。

d. Treatment-related toxic effects were also assessed in the meta-analysis. More thrombocytopenia was seen with carboplatin than with cisplatin (12% vs. 6%; OR, 2.27; 95% CI, 1.71–3.01; P < .001), while cisplatin caused more nausea and vomiting (8% vs. 18%; OR, 0.42; 95% CI, 0.33–0.53; P < .001) and renal toxic effects (0.5% vs. 1.5%; OR, 0.37; 95% CI, 0.15–0.88; P = .018).
治疗相关毒性同样在荟萃分析中得到评估。相比顺铂，卡铂更多的出现血小板减少（12% vs. 6%; OR, 2.27; 95% CI, 1.71–3.01; P < .001），但顺铂导致更多的恶心和呕吐（8% vs. 18%; OR, 0.42; 95% CI, 0.33–0.53; P < .00），以及肾脏毒性（0.5% vs. 1.5%; OR, 0.37; 95% CI, 0.15–0.88; P = .018）。

e. The authors concluded that treatment with cisplatin was not associated with a substantial increase in the overall risk of severe toxic effects. This comprehensive individual-patient meta-analysis is consistent with the conclusions of other meta-analyses, which were based on essentially the same clinical trials but which used only published data.
作者总结到采用顺铂的联合治疗并未有严重毒副作用的显著增加。这个广泛的单个患者的荟萃分析与其他基于同样的临床但只采纳公布的数据的荟萃分析结论一致。

1.2.3. 铂类对比非铂类

3. Three literature-based meta-analyses have trials comparing platinum with nonplatinum combinations.[10,11,12]
三个基于文献的荟萃分析对比了铂类和非铂类的联合方案：

a. The first meta-analysis identified 37 assessable trials that included 7,633 patients.[10]
第一个荟萃分析研究了37个包含7633位患者的可评估临床
• A 62% increase in the OR for response was attributable to platinum-based therapy (OR, 1.62; 95% CI, 1.46–1.8; P < .001). The 1-year survival rate was increased by 5% with platinum-based regimens (34% vs. 29%; OR, 1.21; 95% CI, 1.09–1.35; P = .003).
在铂类联合治疗中，疾病响应率的优势比有62%的提高（OR, 1.62; 95% CI, 1.46–1.8; P < .001），1年生存率有5%的增加（34% vs. 29%; OR, 1.21; 95% CI, 1.09–1.35; P = .003）。

• No statistically significant increase in 1-year survival was found when platinum therapies were compared with third-generation-based combination regimens (OR, 1.11; 95% CI, 0.96–1.28; P = .17).
对比铂类和第三代联合用药方案，1年生存率没有统计学意义上的显著增加（OR, 1.11; 95% CI, 0.96–1.28; P = .17）。

• The toxic effects of platinum-based regimens was significantly higher for hematologic toxic effects, nephrotoxic effects, and nausea and vomiting but not for neurologic toxic effects, febrile neutropenia rate, or toxic death rate. These results are consistent with the second literature-based meta-analysis.
基于铂类的联合方案，在血液学毒性、肾毒性和恶心呕吐等副作用方面都有显著的增加，但神经毒性、发热性中性粒细胞减少和毒性相关死亡率方面没有增加。这些结果与第二个基于文献的荟萃分析一致。

b. The second meta-analysis identified 17 trials that included 4,920 patients.[11]
第二个荟萃分析研究了17个包含4920位患者的临床
• The use of platinum-based doublet regimens was associated with a slightly higher survival at 1 year (relative risk [RR], 1.08; 95% CI, 1.01%–1.16%; P = .03) and a better partial response (RR, 1.11; 95% CI, 1.02–1.21; P = .02), with a higher risk of anemia, nausea, and neurologic toxic effects
使用铂类的双药方案，1年生存率具有轻微的提高（相对风险[RR], 1.08; 95% CI, 1.01%–1.16%; P = .03），且具有更佳的部分缓解率（RR, 1.11; 95% CI, 1.02–1.21; P = .02），但同时伴随更高风险的贫血、呕吐和神经学毒性。

• In subanalyses, cisplatin-based doublet regimens improved survival at 1 year (RR, 1.16%; 95% CI, 1.06–1.27; P = .001), complete response (RR, 2.29; 95% CI, 1.08–4.88; P = .03), and partial response (RR, 1.19; 95% CI, 1.07–1.32; P = .002), with an increased risk of anemia, neutropenia, neurologic toxic effects, and nausea
在亚组分析中，基于顺铂的双药联合方案提高了1年生存率（RR, 1.16%; 95% CI, 1.06–1.27; P = .001）、完全缓解率（RR, 2.29; 95% CI, 1.08–4.88; P = .03）、以及部分缓解率（RR, 1.19; 95% CI, 1.07–1.32; P = .002），但增加了贫血、中性粒细胞减少、神经性毒性和呕吐的风险。

• Conversely, carboplatin-based doublet regimens did not increase survival at 1 year (RR, 0.95; 95% CI, 0.85–1.07; P = .43)
相反的是，联合卡铂的双药方案并未增加1年生存率（RR, 0.95; 95% CI, 0.85–1.07; P = .43）。

c. The third meta-analysis of phase III trials randomizing platinum-based versus nonplatinum combinations as first-line chemotherapy identified 14 trials.[12] Experimental arms were gemcitabine and vinorelbine (n = 4), gemcitabine and taxane (n = 7), gemcitabine and epirubicin (n = 1), paclitaxel and vinorelbine (n = 1), and gemcitabine and ifosfamide (n = 1). This meta-analysis was limited to the set of 11 phase III studies that used a platinum-based doublet (2,298 and 2,304 patients in platinum-based and nonplatinum arms, respectively).
第三个荟萃分析基于14个III期的随机对比铂类和非铂类一线治疗的临床。试验组包括吉西他滨和长春瑞滨（n=4），吉西他滨和紫杉烷（n=7），吉西他滨和表柔比星（n=1），紫杉醇和长春瑞滨（n=1）以及吉西他滨和异环磷酰胺（n=1）。该荟萃分析被限制于11个使用铂类的III期研究（2298位患者使用铂类治疗，2304位患者使用非铂类治疗）。
• Patients treated with a platinum-based regimen benefited from a statistically significant reduction in the risk of death at 1 year (OR, 0.88; 95% CI, 0.78–0.99; P = .044) and a lower risk of being refractory to chemotherapy (OR, 0.87; CI, 0.73–0.99; P = .049).
基于铂类治疗的患者受益于统计学意义上显著降低的1年死亡风险（OR, 0.88; 95% CI, 0.78–0.99; P = .044），以及具有更低的对化疗复发的风险（OR, 0.87; CI, 0.73–0.99; P = .049）。

• •Forty-four (1.9%) and 29 (1.3%) toxic-related deaths were reported for platinum-based and nonplatinum regimens, respectively (OR, 1.53; CI, 0.96–2.49; P = 0.08). An increased risk of grade 3-4 gastrointestinal and hematologic toxic effects for patients treated with platinum-based chemotherapy was statistically demonstrated. There was no statistically significant increase in risk of febrile neutropenia (OR, 1.23; CI, 0.94–1.60; P = .063)
41位（11.9%）和29位（1.3）分别接受铂类和非铂类治疗的患者死于毒性相关的死亡事件（OR, 1.53; CI, 0.96–2.49; P = 0.08）。基于铂类的治疗表现出对于患者的3-4级胃肠道毒性和血液学毒性增加的风险。但未显著增加发热性中性粒细胞减少的风险（OR, 1.23; CI, 0.94–1.60; P = .063）。

1.2.4. 剂量和给药方案

Among the active combinations, definitive recommendations regarding drug dose and schedule cannot be made, with the exception of pemetrexed for patients with adenocarcinoma.
在有效的联合方案中，药物剂量和给药方案没有最终的推荐意见，其中一个例外是建议将培美曲赛应用于肺腺癌患者中。

Evidence (drug and dose schedule):
证据（剂量和给药方案）：
1. There has been one meta-analysis of seven trials that included 2,867 patients to assess the benefit of docetaxel versus vinorelbine.[13] Docetaxel was administered with a platinum agent in three trials, with gemcitabine in two trials, or as monotherapy in two trials. Vinca alkaloid (vinorelbine in six trials and vindesine in one trial) was administered with cisplatin in six trials or alone in one trial.
对7个包括2867名患者的临床的荟萃分析评估了多西他赛对比长春瑞滨的收益。多西他赛在三个临床中联合铂类，在两个临床中联合吉西他滨，在另两个临床中作单药应用。长春花碱在六个临床中联合顺铂，在一个临床中作单药应用。
• The pooled estimate for overall survival (OS) showed an 11% improvement in favor of docetaxel (HR, 0.89; 95% CI, 0.82–0.96; P = .004). Sensitivity analyses that considered only vinorelbine as a comparator or only the doublet regimens showed similar improvements.
多西他赛表现出了对合并估算的总生存期有11%的提高（HR, 0.89; 95% CI, 0.82–0.96; P = .004）。敏感性分析显示长春瑞滨作联合用药和单药具有相似的生存期改善。

• Grade 3 to 4 neutropenia and grade 3 to 4 serious adverse events were less frequent with docetaxel-based regimens versus vinca alkaloid-based regimens (OR, 0.59; 95% CI, 0.38–0.89; P = .013 and OR, 0.68; 95% CI, 0.55–0.84; P < .001, respectively).
对比长春花碱联合方案，多西他赛联合方案具有较低频率的3-4级中性粒细胞减少和3-4级的严重副作用事件发生率（OR, 0.59; 95% CI, 0.38–0.89; P = .013 and OR, 0.68; 95% CI, 0.55–0.84; P < .001, respectivel）。

2. There have been two randomized trials comparing weekly versus every 3 weeks' dosing of paclitaxel and carboplatin, which reported no significant difference in efficacy and better tolerability for weekly administration.[14,15] Although meta-analyses of randomized controlled trials suggest that cisplatin combinations may be superior to carboplatin or nonplatinum combinations, the clinical relevance of the differences in efficacy must be balanced against the anticipated tolerability, logistics of administration, and familiarity of the medical staff for treatment decisions for individual patients.
已经有两个对比紫杉醇联合卡铂每周给药和每三周给药的随机临床试验，报告显示相对通常的每三周给药方案，每周给药在有效性和更好的耐受性方面没有显著的差别。虽然对于随机控制临床的荟萃分析建议顺铂优于卡铂或非铂类的联合，但有效性差异的临床相关性必须调整期望的耐受性、物流管理、在选择患者时对医护人员的熟悉程度等属性。

3. A large, noninferiority, phase III randomized study compared the OS in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and a PS of 0 to 1.[16] Patients received cisplatin 75 mg/m2 on day 1 and gemcitabine 1,250 mg/m2 on days 1 and 8 (n = 863) or cisplatin 75 mg/m2and pemetrexed 500 mg/m2 on day 1 (n = 862) every 3 weeks for up to six cycles.
一个大型的非劣效性phase III的随机研究比较了在IIIb期或者IV期未经过化疗且体能评分为0-1分的NSCLC患者中的总生存时间。患者接受在每3周为一个疗程的周期内，在第1天接受顺铂75mg/㎡联合第1天和第8天接受吉西他滨1250mg/㎡（n = 863）或者是在第1天接受顺铂75mg/㎡联合培美曲塞500mg/㎡（n = 862），持续治疗6个疗程。
• OS for cisplatin and pemetrexed was noninferior to cisplatin and gemcitabine (median survival, 10.3 mo vs. 10.3 mo, respectively; HR, 0.94; 95% CI, 0.84%–1.05%).
接受顺铂联合培美的患者，其OS不劣于接受顺铂联合吉西他滨的患者（中位生存期，10.3个月 vs. 10.3个月；HR, 0.94; 95% CI, 0.84%–1.05%）

• OS was statistically superior for cisplatin and pemetrexed versus cisplatin and gemcitabine in patients with adenocarcinoma (n = 847; 12.6 mo vs. 10.9 mo, respectively) and large cell carcinoma histology (n = 153; 10.4 mo vs. 6.7 mo, respectively).
在肺腺癌（n = 847; 12.6个月 vs. 10.9个月, respectively）和大细胞癌患者（n = 153; 10.4个月vs. 6.7个月）中，顺铂联合培美曲塞总是优于顺铂联合吉西他滨。

• In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin and gemcitabine versus cisplatin and pemetrexed (n = 473; 10.8 mo vs. 9.4 mo, respectively). For cisplatin and pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P ≤ .001); febrile neutropenia (P = .002); and alopecia (P < .001) were significantly lower, whereas grade 3 or 4 nausea (P = .004) was more common.
相对的，在肺鳞癌患者中，顺铂联合吉西他滨对比顺铂联合培美曲塞，总生存期有显著的提高（n = 473; 10.8个月 vs. 9.个月）。对于顺铂联合培美曲塞方案来说，3-4级的中性粒细胞减少、贫血、血小板减少，以及发热性中性粒细胞减少和脱发都有显著的降低，最常见的副作用为3-4级的呕吐。

• This study suggests that cisplatin and pemetrexed are another alternative doublet for first-line chemotherapy for advanced NSCLC and also suggests that there may be differences in outcome depending on histology.
该研究建议对于晚期NSCLC患者来说，顺铂联合培美曲塞是可选的一线化疗联合方案，但根据组织学差异可能有不同的收益。

*: 翻译可能有误

costa_na · 发表于 2013-12-5 15:14:21

本帖最后由 costa_na 于 2013-12-6 00:42 编辑

Factors influencing treatment
1.3. 影响治疗的因子

Histology
1.3.1. 组织学差异

Patients with adenocarcinoma may benefit from pemetrexed,[16] EGFR inhibitors, and bevacizumab.
肺腺癌患者更能从培美曲塞、EGFR抑制剂和贝伐单抗治疗中受益。

Age versus comorbidity
1.3.2. 年龄和合并症

Evidence supports that elderly patients with good PS and limited comorbidity may benefit from combination chemotherapy. Age alone should not dictate treatment-related decisions in patients with advanced NSCLC. Elderly patients with a good PS enjoy longer survival and a better quality of life when treated with chemotherapy compared with supportive care alone. Caution should be exercised when extrapolating data for elderly patients (aged 70–79 years) to patients aged 80 years or older because only a very small number of patients aged 80 years or older have been enrolled on clinical trials, and the benefit in this group is uncertain.[17,18]
对于老年患者来说，证据支持具有较好的体能状态和可控的合并症的患者更能从联合化疗中受益。在晚期NSCLC患者中，不应该单独使用年龄来确定治疗相关的选择。相比只接受最佳支持治疗，那些接受化疗的具有较好体能状态的老年患者拥有更长的生存时间和生活质量。当将老年患者（70-79岁）的数据推算至年龄大于等于80岁的患者的时候要特别的谨慎，因为临床很少入组年龄大于等于80岁的患者，并且这个群体从化疗中的收益也是不确定的。

Evidence (age vs. comorbidity):
证据（年龄 vs. 合并症）：

1. Platinum-containing combination chemotherapy regimens provide clinical benefit when compared with supportive care or single-agent therapy; however, such treatment may be contraindicated in some older patients because of the age-related reduction in the functional reserve of many organs and/or comorbid conditions. Approximately two-thirds of patients with NSCLC are aged 65 years or older and approximately 40% are aged 70 years or older.[19] Surveillance, Epidemiology, and End Results (SEER) data suggest that the percentage of patients aged older than 70 years is closer to 50%.
相比支持治疗或单药治疗，含有铂类的联合化疗方案提供更多的临床受益。但是因为年龄相关的许多器官的机能下降和/或共生疾病的情况，含有铂类的方案可能会在部分老年患者中禁用。接近三分之二的NSCLC患者年龄大于65岁，近40%的患者年龄大于70岁。流行病学调查及最终结果(surveillance epidemiology and end results, SEER)数据显示，（美国）肺癌的中位发病年龄已达到70岁以上。

2. A review of the SEER Medicare data from 1994 to 1999 found a much lower rate of chemotherapy use than expected for the overall population.[20] It also suggested that elderly patients may have more comorbidities or a higher rate of functional compromise that would make study participation difficult, if not contraindicated, and lack of clinical trial data may influence decisions to treat individual patients with standard chemotherapy.
一份对于从1994年到1999年SEER医疗数据的回顾发现，在全部患者群体中，化疗的应用率极大地低于预期。回顾同时表示老年患者具有更多的合并症或者更高风险的机能下降，即使没有禁止，也会造成参与临床研究的困难，并且缺乏在采用标准化疗治疗单个患者中影响选择的临床数据。

3.Single-agent chemotherapy and combination chemotherapy clearly benefit at least some elderly patients. In the Elderly Lung Cancer Vinorelbine Italian Study, 154 patients who were older than 70 years were randomly assigned to vinorelbine or supportive care.[21]
显然的，单药化疗和联合化疗至少能使一部分老年患者受益。在老年肺癌患者接受长春瑞滨的意大利研究中，154名年龄在70岁以上的患者被随机分配接受长春瑞滨或者支持治疗。

• Patients who were treated with vinorelbine had a 1-year survival rate of 32%, compared with 14% for those who were treated with supportive care alone. Quality-of-life parameters were also significantly improved in the chemotherapy arm, and toxic effects were acceptable.
接受长春瑞滨的患者1年生存率为32%，对比只接受支持治疗的患者只有14%。化疗组的生活质量有显著的改善，其毒副作用也是可以接受的。

4. A more recent trial from Japan compared single-agent docetaxel with vinorelbine in 180 elderly patients with good PS.[22]
更进一步的来自于日本的临床对比了单药多西他赛和长春瑞滨在180名拥有良好体能状态的老年患者中的情况。

• Response rates and PFS were significantly better with docetaxel (22% vs. 10%; 5.4 mo vs. 3.1 mo, respectively), whereas median and 1-year survival rates did not reach statistical significance (14.3 mo vs. 9.9 mo; 59% vs. 37%, respectively).
多西他赛组具有明显的较佳的响应率和PFS（22% vs. 10%; 5.4月 vs. 3.1月），但中位生存期和1年生存率并未达到统计学意义上的提高（14.3月 vs. 9.9月; 59% vs. 37%）。

5. Retrospective data analyzing and comparing younger (age <70 years) patients with older (age ≥70 years) patients who participated in large, randomized trials of doublet combinations have also shown that elderly patients may derive the same survival benefit, although with a higher risk of toxic effects in the bone marrow.[17,18,23-26]
回顾性数据分析对比了在一项大型随机双药联合临床中的较年轻的患者（小于70岁）和较老年的患者（大于等于70岁）之间的情况，同样表明老年患者能够获得相同的生存收益，虽然具有较高风险的骨髓抑制毒性。

Performance status (PS) PS is among the most important prognostic factors for survival of patients with NSCLC.[27] The benefit of therapy for this group of patients has been evaluated through retrospective analyses as well as through prospective clinical trials.
对于NSCLC患者来说，体能状态是最重要生存预后因子之一。这部分患者从治疗中获得的收益通过回顾性分析以及前瞻性临床试验来进行评估。

The results support further evaluation of chemotherapeutic approaches for both metastatic and locally advanced NSCLC; however, the efficacy of current platinum-based chemotherapy combinations is such that no specific regimen can be regarded as standard therapy. Outside of a clinical trial setting, chemotherapy should be given only to patients with good PS and evaluable tumor lesions, who desire such treatment after being fully informed of its anticipated risks and limited benefits.
结果支持在转移和局部晚期的NSCLC患者中进一步评估化疗的作用。但是，基于当前联合铂类的化疗的有效性已经能够将其作为标准治疗方案。除了临床试验情况外，化疗应当只被应用于具有良好的体能状态且拥有可测量病灶的患者中，并且在这部分患者在被完整告知化疗可能预期的风险和优先的受益之后，也同意进行治疗。

Evidence (performance status):
证据（体能状态）：

1. The Cancer and Leukemia Group B trial (CLB-9730), which compared carboplatin and paclitaxel with single-agent paclitaxel, enrolled 99 patients with a PS of 2 (18% of the study's population).[25]
• When compared with patients with a PS of 0 to 1, who had a median survival of 8.8 months and a 1-year survival of 38%, the corresponding figures for patients with a performance status of 2 were 3.0 months and 14%, respectively; this demonstrates the poor prognosis conferred by a lower PS. These differences were statistically significant.

• When patients with a PS of 2 were analyzed by treatment arm, those who received combination chemotherapy had a significantly higher response rate (24% vs. 10%), longer median survival (4.7 mo vs. 2.4 mo), and superior 1-year survival (18% vs. 10%), compared with those who were treated with single-agent paclitaxel.[25]

2. A subset analysis of 68 patients with a PS of 2 from a trial that randomly assigned more than 1,200 patients to four platinum-based regimens has been published.
• Despite a high incidence of adverse events, including five deaths, the final analysis showed that the overall toxic effects experienced by patients with a PS of 2 was not significantly different from that experienced by patients with a PS of 0 to 1.

• An efficacy analysis demonstrated an overall response rate of 14%, median survival time of 4.1 months, and a 1-year survival rate of 19%; all were substantially inferior to the patients with PS of 0 to 1.

3. A phase II randomized trial (E-1599) of attenuated dosages of cisplatin plus gemcitabine and carboplatin plus paclitaxel included 102 patients with a PS of 2.[28]
• Response rates were 25% and 16%, median survival times were 6.8 months and 6.1 months, and 1-year survival rates were 25% and 19%, respectively. None of these differences was statistically significant, but the survival figures were longer than expected on the basis of historical controls.

4. Results from two trials suggest that patients with a PS of 2 may experience symptom improvement.[29,30]

wyhong · 发表于 2013-12-5 21:29:21

谢谢版主，我的理解：
1，相比双药联合方案来说，使用常用化疗药物的三药联合方案没有得到更佳的生存期，反而拥有更大的毒性。，是说使用铂类+培美或者铂类+阿瓦，生存期大于铂+培+阿瓦，副作用更少
2，使用铂类的双药方案，1年生存率具有轻微的提高，和在亚组分析中，基于顺铂的双药联合方案提高了1年生存率，这个看不懂，到底是提高呢还是只有轻微提高
3，对比铂类和第三代联合用药方案，1年生存率没有统计学意义上的显著增加，什么是第三代联合用药，什么方案一年生存期没有提高？
那位老师解答一下，谢谢

costa_na · 发表于 2013-12-5 23:14:44

本帖最后由 costa_na 于 2013-12-5 23:22 编辑

Combination chemotherapy with bevacizumab or cetuximab Evidence (combination chemotherapy with bevacizumab or cetuximab):

1. Two randomized trials have evaluated the addition of bevacizumab, an antibody targeting vascular endothelial growth factor, to standard first-line combination chemotherapy. a.In a randomized study of 878 patients with recurrent or advanced stage IIIB or stage IV NSCLC, 444 patients received paclitaxel and carboplatin alone, and 434 patients received paclitaxel and carboplatin plus bevacizumab.[31] Chemotherapy was administered every 3 weeks for six cycles, and bevacizumab was administered every 3 weeks until disease progression was evident or toxic effects were intolerable. Patients with squamous cell tumors, brain metastases, clinically significant hemoptysis, or inadequate organ function or PS (ECOG PS >1) were excluded.
• The median survival was 12.3 months in the group assigned to chemotherapy plus bevacizumab, as compared with 10.3 months in the chemotherapy-alone group (HR for death, 0.79; P = .003).

• The median PFS in the two groups was 6.2 months and 4.5 months, respectively (HR for disease progression, 0.66; P < .001), with corresponding response rates of 35% and 15%, respectively (P < .001).

• Rates of clinically significant bleeding were 4.4% and 0.7%, respectively (P < .001). There were 15 treatment-related deaths in the chemotherapy-plus-bevacizumab group, including five from pulmonary hemorrhage.

• For this subgroup of patients with NSCLC, the addition of bevacizumab to paclitaxel and carboplatin may provide survival benefit.[31][Level of evidence: 1iiA]

b. Another randomized phase III trial investigated the efficacy and safety of cisplatin/gemcitabine plus bevacizumab.[32] Patients were randomly assigned to receive cisplatin (80 mg/m2) and gemcitabine (1,250 mg/m2) for up to six cycles, plus low-dose bevacizumab (7.5 mg/kg), high-dose bevacizumab (15 mg/kg), or placebo every 3 weeks until disease progression. The primary endpoint was amended from OS to PFS during the course of the study. A total of 1,043 patients were accrued (placebo group, n = 347; low-dose group, n = 345; high-dose group, n = 351).
• PFS was significantly prolonged; the HRs for PFS were 0.75 (median PFS, 6.7 mo vs. 6.1 mo for placebo group; P = .03) in the low-dose group and 0.82 (median PFS, 6.5 mo vs. 6.1 mo for placebo group; P = .03) in the high-dose group compared with the placebo group.[32][Level of evidence: 1iiB]

• Objective response rates were also improved with the addition of bevacizumab, and they were 20.1%, 34.1%, and 30.4% for placebo, low-dose bevacizumab, and high-dose bevacizumab plus cisplatin/gemcitabine, respectively.

• Incidence of grade 3 or greater adverse events was similar across arms.

• Grade 3 or greater pulmonary hemorrhage rates were 1.5% or less for all arms, despite 9% of patients receiving therapeutic anticoagulation.

• These results support the addition of bevacizumab to platinum-containing chemotherapy, but the results are far less impressive than when the carboplatin-paclitaxel combination was used.

• Furthermore, no significant difference in survival was shown in this study, as reported in abstract form.

• Altogether, these findings may suggest that the backbone of chemotherapy may be important when bevacizumab is added.

2. Two trials have evaluated the addition of cetuximab to first-line combination chemotherapy.[33,34]a.In the first trial, 676 chemotherapy-naïve patients with stage IIIB (pleural effusion) or stage IV NSCLC, without restrictions by histology or EGFR expression, received cetuximab with taxane (paclitaxel or docetaxel with carboplatin) or combination chemotherapy.[33]
• The addition of cetuximab did not result in a statistically significant improvement in PFS, the primary study endpoint, or OS.

• Median PFS was 4.40 months with cetuximab/chemotherapy versus 4.24 months with taxane/carboplatin (HR, 0.902; 95% CI, 0.761–1.069; P = .236).

• Median OS was 9.69 months with cetuximab/chemotherapy versus 8.38 months with chemotherapy (HR, 0.890; 95% CI, 0.754–1.051; P = .169).

• No significant associations were found between EGFR expression, EGFR mutation, EGFR copy number, or KRAS mutations and PFS, OS, and response in the treatment-specific analyses.[35]

b. The second trial was composed of 1,125 chemotherapy-naïve patients with advanced EGFR-expressing stage IIIB or stage IV NSCLC treated with cisplatin/vinorelbine chemotherapy plus cetuximab or chemotherapy alone.[34]
• The primary study endpoint, OS, was longer for patients treated with cetuximab and chemotherapy (median 11.3 months vs. 10.1 months; HR for death, 0.871; 95% CI, 0.762–0.996; P = .044).

• A survival benefit was seen in all histological subgroups; however, survival benefit was not seen in non-white or Asian patients. Only the interaction between the treatment and the ethnic origin was significant (P = .011).

• The main cetuximab-related adverse event was acne-like rash (10%, grade 3).

c. It is not clear whether the differences in outcome in these two studies are the result of differences in the study populations, tumor characterization for EGFR expression, or chemotherapy regimens.

costa_na · 发表于 2013-12-5 23:15:57

本帖最后由 costa_na 于 2013-12-5 23:23 编辑

Maintenance therapy following first-line chemotherapy One treatment strategy that has been investigated extensively in NSCLC is maintenance therapy following initial response to chemotherapy. Options for maintenance therapy that have been investigated include the following:

• Continuing the initial combination chemotherapy regimen.
• Continuing only single-agent chemotherapy.
• Introducing a new agent as "maintenance."
Multiple randomized trials have evaluated the efficacy of continuing first-line combination cytotoxic chemotherapy beyond three to four cycles.

Evidence (maintenance therapy following first-line chemotherapy):

1. None of the trials of continued cytotoxic combinations showed a significant OS advantage with additional or longer durations beyond four cycles.

2. Three trials found statistically significantly improved PFS or time to progression with additional chemotherapy.[42-44]

3. No consistent improvement in quality of life was reported.[43,45,46]

4. Chemotherapy-related toxicities were greater with prolonged chemotherapy.[45,46]

These data suggest that PFS, but not OS, may be improved either by continuing an effective chemotherapy beyond four cycles or by immediate initiation of alternative chemotherapy. The improvement in PFS, however, is tempered by an increase in adverse events from additional cytotoxic chemotherapy and no consistent improvement in quality of life. For patients who have stable disease or who respond to first-line therapy, evidence does not support the continuation of cytotoxic chemotherapy until disease progression or the initiation of a different chemotherapy prior to disease progression. Collectively, these trials suggest that first-line cytotoxic combination chemotherapy should be stopped at disease progression or after four cycles in patients whose disease is not responding to treatment; it can be administered for no more than six cycles.[42,43,45,46]

Evidence (first-line platinum-based combination chemotherapy followed by pemetrexed):

1. The findings of two randomized trials (NCT00102804 and NCT00789373) have shown outcomes with the addition of pemetrexed following standard first-line platinum-based combination chemotherapy.[44,47]a.In the first trial, 663 patients with stage IIIB or stage IV disease who had not progressed on four cycles of nonpemetrexed platinum-based chemotherapy were randomly assigned (2:1 ratio) to receive pemetrexed or placebo until disease progression.[47]
• Both the primary endpoint of PFS and the secondary endpoint of OS were statistically significantly prolonged with the addition of maintenance pemetrexed (median PFS, 4.3 months vs. 2.6 months; HR, 0.50; 95% CI, 0.42–0.61; P < .0001; median OS, 13.4 months vs. 10.6 months; HR, 0.79; 95% CI, 0.65–0.95; P = .012).

• Benefit was not seen in patients with squamous histology.

• Higher than grade 3 toxicity and treatment discontinuations resulting from drug-related toxic effects were higher in the pemetrexed group than in the placebo group.

• No pemetrexed-related deaths occurred.

• Relatively fewer patients in the pemetrexed group than in the placebo group received systemic post-discontinuation therapy (227 [51%] vs. 149 [67%]; P = .0001).

• Quality of life during maintenance therapy with pemetrexed was similar to placebo, except for a small increase in loss of appetite and significantly delayed worsening of pain and hemoptysis as assessed using the Lung Cancer Symptom Scale.[48] The quality-of-life results should be evaluated with caution as there was a high degree of censoring (> 50%) for the primary quality-of-life endpoint of time to worsening of symptoms.

• Trials have not evaluated maintenance pemetrexed versus pemetrexed at progression.

b. In the second trial, 539 patients with NSCLC with nonprogression following treatment with pemetrexed and cisplatin were randomly assigned to continued pemetrexed or placebo.[44] •There was a statistically significant improvement in the primary endpoint of PFS (4.1 months vs. 2.8 months (HR, 0.62; 95% CI, 0.49–0.79) but no improvement in OS.[44][Level of evidence: 1iDiii]

Evidence (maintenance erlotinib following platinum-based doublet chemotherapy):

1. One trial (NCT00556712) reported favorable outcomes with maintenance erlotinib after four cycles of platinum-based doublet chemotherapy in patients with stable disease.[49] a.In this trial, 889 patients with NSCLC but without progressive disease were randomly assigned to receive erlotinib (150 mg/day) or placebo until they experienced progressive disease or unacceptable toxicity.[49]•Median PFS was significantly longer with erlotinib than with placebo: 12.3 weeks for patients in the erlotinib group versus 11.1 weeks for those in the placebo group (HR, 0.71; 95% CI, 0.62–0.82; P < .0001).

• In the overall population, patients whose tumors had activating EGFR mutations derived the greatest PFS benefit from maintenance erlotinib treatment (n = 49; HR, 0.10; P < .0001).

• Patients whose tumors with wild-type EGFR also obtained significant PFS and OS improvements (HR, 0.78 and 0.77, respectively).

• In the subgroup of patients with stable disease whose tumors did not have activating EGFR mutations (n = 217), both PFS and OS were significantly prolonged with erlotinib (HR, 0.72; 95% CI, 0.54–0.96; P = .0231 and HR, 0.65; 95% CI, 0.48–0.87; P = .0041, respectively).

• In patients whose tumors had activating EGFR mutations (n = 30), OS was also improved with erlotinib (HR, 0.48; 95% CI, 0.14–1.62) but was not statistically significant in this analysis.[50]

• EGFR IHC [immunohistochemistry], EGFR FISH [fluorescence in situ hybridization], KRAS mutation, and EGFR CA-SSR1 [simple sequence repeat 1] repeat length status were not predictive for erlotinib efficacy.[51] KRAS mutation status was a significant, negative prognostic factor for PFS.[51][Level of evidence: 1iDiii]