本帖最后由 costa_na 于 2013-12-5 15:57 编辑
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% U; N) V" v) ?3 j; q3 i, h) @1.2.联合化疗方案
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1.2.1.双药联合4 H' Y- r4 e% X
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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.; I( k0 x# |0 W3 H, y5 u
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。
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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.
* P2 C- t# z$ P( d. K4 b" Z0 L; M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。+ x* r% K" z2 ?1 ~
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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).2 N5 S' J( ]& A8 Y; d2 q& c( D3 E
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)。
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1.2.2. 顺铂对比卡铂' s, Q/ e/ X# i3 J( B
% C) @% T* h4 s! a. `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]
) @6 s, ^! \4 e+ |8 P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:
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% k* A4 x9 _2 ka. 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).- G. g/ ^0 [" A3 }' J$ L
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)。" p$ o% x& Q6 B. n' l
; q) P' q' ]7 _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).+ Z- Z/ k8 P" Y9 v& W) K# c+ H
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)。. k2 H' d! S! U6 l/ ~% ^
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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).( |! c- g. w- T% Z Y
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)。
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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)." ^4 v5 _% s$ N, [: S- b; @
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)。
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, X1 ?5 V6 D+ K$ L& V1 ie. 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.# v0 a1 k( k N$ O
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。
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; ~8 j" A" b9 m$ u2 u1.2.3. 铂类对比非铂类! g/ p; l3 R6 v; ^; `( ~) b
- a2 S+ i5 N; u5 K8 f( x3. Three literature-based meta-analyses have trials comparing platinum with nonplatinum combinations.[10,11,12]) r }! E; s0 G5 E& @) s3 [. Q
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:
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; ]0 q" I( N Z- Ua. The first meta-analysis identified 37 assessable trials that included 7,633 patients.[10]9 K+ S: z4 j! i3 {% ?& F9 S
第一个荟萃分析研究了37个包含7633位患者的可评估临床
$ d0 T2 @9 J2 m. G• 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).
+ N5 a& e3 P* X3 a. z6 y9 q: R3 X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)。
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• 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).
1 N9 V$ R( p; t# {& N4 t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)。
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3 Y" T: i( N3 s# X5 _• 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.
5 I( o' \8 K. z H) C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。
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0 S* U" G. ?; t7 K& L7 B- z/ e; hb. The second meta-analysis identified 17 trials that included 4,920 patients.[11]
) @$ y0 o( L X- e7 N% x2 U第二个荟萃分析研究了17个包含4920位患者的临床8 ~0 U, F2 l3 ], z A
• 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
! o! H$ T& p8 v$ _4 b7 E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。5 u' {+ h e$ C+ L2 `' ]9 Y
2 o& d/ [: f* S0 N2 _0 T2 F• 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 nausea1 |* c: D3 ~! S6 u4 E( e! q7 e
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。
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• Conversely, carboplatin-based doublet regimens did not increase survival at 1 year (RR, 0.95; 95% CI, 0.85–1.07; P = .43)
4 G9 U. n. l1 H1 Z) E) q3 S+ b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)。
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" w( J% ? R* s1 kc. 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).
8 ^) Q2 O( u' M0 Y# E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)。
$ r+ ]8 d6 o' J& @0 f8 K• 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).% q6 ]0 G% P# J' x
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)。
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• •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)
# c$ C, H; `1 c$ W( A1 ]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)。* |0 z6 M& W; \' ]& m, B
- F# y( c! X5 Q9 N4 r! G0 P% G1.2.4. 剂量和给药方案
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Among the active combinations, definitive recommendations regarding drug dose and schedule cannot be made, with the exception of pemetrexed for patients with adenocarcinoma.) ~: ?% U- r$ m0 l- n" N
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。
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$ f# y1 n J7 d( xEvidence (drug and dose schedule):" h- @( B9 ?8 I' T1 X' h5 {; E
证据(剂量和给药方案):+ W; d( s% O: o
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.- C# P* O9 ^1 ?# x" E
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。+ y( @9 D+ y6 }9 W
• 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.2 ?- Z9 e5 ]* k* J
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。) m, i& {6 m5 H$ u7 h( p4 s
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• 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).
# P) d' d' s4 A/ H5 H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)。; [5 h2 \7 Z# |5 k p) f/ [: r- i- }
0 m' \9 {. e o$ g/ d1 C+ j2. 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.
& c% m+ {. Z& }+ N3 d( N4 O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。
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, n9 d5 ~0 p, s. p! {/ x3. 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.; B# A5 s" W5 b$ w+ [3 a" i( ]+ {
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。+ g5 [- H3 K# X
• 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%).
4 W& J" c$ X1 i$ i0 t+ k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%)
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• 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).! f, V' b) X- \, ?1 d8 J
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。
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• 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.
) U8 ?, H& v& ]- ]- ?- L4 H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。
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• 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.; G" X7 Q3 x# [' v
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。
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*: 翻译可能有误 |