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A meta-analysis of paclitaxel-based chemotherapies administered once every week compared with once every 3 weeks first-line treatment of advanced non-small-cell lung cancer
Lung Cancer 76 (2012) 380–386
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A meta-analysis of paclitaxel-based chemotherapies administered once every week compared with once every 3 weeks first-line treatment of advanced non-small-cell lung cancer Guanghui Gao a , Haiqing Chu a,∗ , Lan Zhao a , Tao Gui a , Qinghua Xu a , Jianping Shi b a b
Department of Respiratory Diseases, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China Department of Respiratory Diseases, Wuxi No. 3 People’s Hospital, Jiangsu Province 214041, China
a r t i c l e
i n f o
Article history: Received 20 August 2011 Received in revised form 1 December 2011 Accepted 3 December 2011 Keywords: Carcinoma Non-small-cell lung Paclitaxel Weekly schedule Meta-analysis
a b s t r a c t Objective: The published data on the curative effects of comparing the once weekly paclitaxel-based chemotherapies (W-paclitaxel) with the standard every 3 weeks paclitaxel-based chemotherapies (S-paclitaxel) in the first-line treatment of advanced non-small-cell lung cancer (NSCLC) were still controversial. To derive a more precise estimation of the two regimens, a meta-analysis was performed. Methods: Medical databases and conference proceedings were searched for randomized controlled trials which compared W-paclitaxel with S-paclitaxel in patients with first-line treatment of advanced NSCLC. The following keywords were used: “paclitaxel”, “weekly schedule” and “non-small cell lung cancer”. Reference lists of original articles and review articles were also examined. The published languages and years were not limited. Endpoints were overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and adverse events. Statistical tests for heterogeneity were one-sided; statistical tests for effect estimates were two-sided. Results: Five eligible trials involved 940 patients were identified. They were all published as full-text articles. The intention to treatment (ITT) analysis demonstrated that the ORR of W-paclitaxel regimens patients was 30.89% (143/463), whereas the ORR of S-paclitaxel regimens patients was 27.09% (123/454). The overall pooled relative ratio (RR) for ORR was 1.24 (95% confidence intervals (CI) = 0.93–1.66; P = 0.14) when W-paclitaxel regimens patients were compared with S-paclitaxel regimens patients. Although the patients with W-paclitaxel regimens had an similar OS and PFS in comparison with S-paclitaxel regimens (median OS was 9.8 versus 10.7 months; hazard ratio (HR) = 1.00; 95%CI = 0.86–1.17; P = 0.99; median PFS was 5.2 versus 4.7 months; HR = 0.90; 95%CI = 0.79–1.03; P = 0.13, respectively), the W-paclitaxel regimens led to significantly less frequent adverse events of hematological toxicities and nonhematological toxicities. Conclusion: These results suggest that the W-paclitaxel is not superior than S-paclitaxel regimens. The paclitaxel-based chemotherapies given by every 3 weeks are still standard regimens. For patients, especially for the elder or the people with poor conditions who cannot tolerate the standard regimen, the weekly schedule can be considered. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Lung cancer is one the most common forms of cancer in the world, in terms of incidence and mortality. It is projected that 221,130 individuals (115,060 men and 106,070 women) will be diagnosed with lung cancer, and that 156,940 individuals (85,600
∗ Corresponding author at: Department of Respiratory Diseases, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Zhengmin Road No. 507, Shanghai, China. Tel.: +86 21 65115006x2123; fax: +86 21 65111298. E-mail addresses: [email protected] (G. Gao), [email protected] (H. Chu). 0169-5002/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2011.12.001
men and 71,340 women) will die from lung cancer in the USA by the end of 2011 [1], and the annual number of new cases is expected to exceed 338,000 by 2030 [2]. Non-small-cell lung cancer (NSCLC) accounts for at least 80% of all lung cancer cases, presenting as local advanced disease in approximately 25–30% of cases and as metastatic disease in approximately 40–50% of cases [3]. The prognosis of the patients with NSCLC remains poor, approximately 80% of patients die within one year of diagnosis, and the 5-year survival rate is estimated of 15% in the USA and 10% in Europe [4]. For these patients with local advanced or metastatic disease, the main treatment is limited in supportive care and chemotherapy, and the operation is inapplicable (except for a very limited number of patients, who suffer from stage IV NSCLC with solitary metastasis
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should be considered for surgery). Doublet chemotherapies consisting of the platinums plus third-generation new agent (taxane, gemcitabine, vinorelbine) for patients with advanced non-smallcell lung cancer (NSCLC) have become the most common approach worldwide, based on the evidence of a small survival advantage compared with supportive care in a meta-analysis [5]. Another meta-analysis showed that an increase for response and 1-year survival rate was attributable to platinum-based therapy comparing to non-platinum-based therapy [6]. The overall response rate and 1-year survival rate of cisplatin-based and carboplatin-based regimens were also similar [7]. A lot of randomized trials and metaanalysis performed during recent years have unequivocally shown that there are no substantial differences in the efficacy among several combinations containing cisplatin or carboplatin and one of these new drugs [8–11]. Paclitaxel, particularly the combination of carboplatin and paclitaxel is commonly used regimen as first-line treatment of advanced NSCLC in many countries. Its efficacy has been established and has been selected as the reference arm in several phase III trials [12,13]. Although a meta-analysis [11] showed the risk for immediate progression is significantly higher when paclitaxel-containing regimens are used (patients receiving paclitaxel showed a 22% higher risk for having progression disease as the best response), the meta-analysis was based only on response and not survival data. Standard administration of carboplatin/paclitaxel is based on an every 3-week schedule. However, myelosuppression and peripheral neuropathy with this paclitaxel schedule is extremely frequent and severe, especially for grade 3–4 neutropenia and febrile neutropenia. Weekly scheduling of paclitaxel may improve the toxicity profile of the drug in NSCLC patients without decreasing antitumor activity. Particularly, a marked reduction in the occurrence of severe and febrile neutropenia is reported when paclitaxel is administered in a weekly schedule, compared with the classic administration schedule of 3 weeks [14,17]. On the basis of this evidence, several randomized trials have been conducted, with the aim of comparing the once weekly paclitaxel-based chemotherapies schedule (W-paclitaxel) with the standard every 3 weeks paclitaxel-based chemotherapies schedule (S-paclitaxel) in the first-line treatment of advanced NSCLC [15–19]. However, sample size of each single trial had insufficient power to detect potentially relevant differences in efficacy. We performed this meta-analysis, including five randomized trials, to compare the efficacy and adverse events of the two different schedules of paclitaxel in the first-line treatment of advanced NSCLC and try to confirm whether the once weekly paclitaxel-based chemotherapies schedule (W-paclitaxel) has increased efficacy and meanwhile decreased toxicity.
2. Materials and methods 2.1. Literature search To ensure retrieval of all relevant trials, we used a broad search strategy in which key words and text words related to lung cancer and paclitaxel were combined with a validated methodological filter, as described by Dickersin et al. [20]. The following keywords were used: “paclitaxel”, “weekly schedule” and “non-small cell lung cancer”. We used this strategy to search a variety of electronic databases, including the PubMed database (1966–July 2010), the Cochrane Controlled Trials Register (issue 3, 2010), EMBASE (1974–July 2010) and Chinese Biomedical database (1978–July 2010). We also manually searched the conference proceedings of the American Society of Clinical Oncology (ASCO) and the European Society of Medical Oncology (ESMO) from the year of 1995–2010 for relevant clinical trials. Reference lists from studies selected for this
381
review, and from other published systematic reviews and practice guidelines were also hand-searched. 2.2. Inclusion criteria We included in this analysis only randomized controlled trials that enrolled patients who were older than 18 years and who had pathologically proven NSCLC and in clinical III–IV stage, untreated and that compared the once weekly paclitaxel-based chemotherapies schedule (W-paclitaxel) with the standard every 3 weeks paclitaxel-based chemotherapies schedule (S-paclitaxel). Trials were included regardless of publication status, date of publication, and language. We excluded ongoing studies, interim analyses, nonrandomized studies, and studies with 10 or fewer patients per study arm. 2.3. Study selection, quality assessment, and data extraction Two reviewers (Guanghui Gao and Lan Zhao) independently screened the titles and abstracts of all studies identified in the literature search to verify compliance with the inclusion. When this information was unsatisfactory, full-text was retrieved and inclusion criteria were applied. Disagreements between the two reviewers were resolved by consensus involving a third reviewer (Haiqing Chu). The same reviewers who screened the studies independently performed data extraction and quality assessment of all included articles. The methodological quality of the studies included in the meta-analysis was scored using the Jadad composite scale. This is a five-point scale, and one point was given when one quality criterion was met [21]. All included studies, regardless of whether they were published or not, were assessed for internal validity parameters, with particular emphasis on randomization, masking of patients and clinicians, concealment of allocation, documentation of dropouts and withdrawals, and intent-to-treat analysis. Follow-up was arbitrarily defined as complete if trial enrollment was closed, all patients were accounted, and less than 10% were lost in follow-up. 2.4. Outcome measures The primary outcome was overall survival (as defined by Therasse et al. [22]). Secondary outcomes included progressionfree survival, overall response rate and adverse events. 2.5. Data analysis and statistical methods A random-effect model was assumed in all meta-analysis. The hazard ratio (HR) was used for overall survival and progression-free survival. For binary data, the relative risks (RR) were used for overall response rate; the odds ratio (OR) was used for treatment toxicity. A statistical test with a P-value less than 0.05 was considered significant. An HR > 1 reflects more deaths or progression in the once weekly paclitaxel-based chemotherapies (W-paclitaxel) schedule. An RR > 1 reflects a favorable outcome in the W-paclitaxel arm for response, and an OR > 1 indicates more toxicity in the W-paclitaxel arm. A funnel plot was generated or a linear regression test [23] was performed to examine whether there was publication bias. In our paper, publication bias was not found according to funnel plot, Begg’s test (P = 0.806), and Egger’s test (P = 0.307). Potential causes of heterogeneity were explored by performing sensitivity analyses to evaluate effects of stage, study duration, study quality, the source of the data of the W-paclitaxel treatment. Particular emphasis was placed on the evaluation of additional side effects of W-paclitaxel in comparison to S-paclitaxel. Side effects were defined as any adverse event occurring during treatment, including death (according to National Cancer Institute Common Toxicity Criteria).
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All Articles (n=1858)
Potential Appropriate Articles (n=12)
Excluded: 1. Review Article(n=812) 2. Phase I/II Studies(n=317) 3. Cohort Studies(n=199) 4. Others (inappropriate abstracts, comments, ongoing studies, interim analyses, ect)(n=518)
Excluded: 1.Non-randomized Treatment Comparison (n=4) 2. sub-group analysis of one RCT (n=1) 3. RCT, But Nonidentical Treatment Regimens between two group (n=2)
Fully Articles (n=5) Fig. 1. Flow chart showing the progress of trials through the review (RCT, randomized controlled trial).
Analyses were performed using the STATA SE 11.0 package (StataCorp., College Station, TX). Statistical tests for heterogeneity were one-sided; statistical tests for effect estimates and publication bias were two-sided. 3. Results 3.1. Identification of studies The flow chart of our study is shown in Fig. 1. The literature search identified 1858 trials, of which 12 were considered potentially relevant. The remaining 12 articles were selected for analysis and were evaluated in more detail. Of these, 7 were excluded for the following reasons: one trial [26] was sub-group analysis of one RCT cited in our paper [17]; two trials did not use identical chemotherapy in the control arm; four trials were not randomized. The remaining five randomized controlled trials (Table 1), which involved 940 adult patients, met all the inclusion and exclusion criteria and were included in the meta-analysis. Among which, one trial was phase III RCT [17], the others were phase II RCTs. There was no placebo-controlled double-blinded trial. The chemotherapy regimens used included: paclitaxel and carboplatin [15,17,19]; paclitaxel and gemcitabine [16]; paclitaxel, carboplatin and cetuximab [18]. All trials compared the once weekly paclitaxel-based chemotherapies schedule (W-paclitaxel) with the standard every 3 weeks paclitaxel-based chemotherapies schedule (S-paclitaxel). Median age of enrolled patients was above 60 in all trials, and in one trial [19], the median age of patients was older than 70 years (Table 1).
3.3. Overall survival (5 trials, 940 patients) The median OS was 9.8 months versus 10.7 months when W-paclitaxel regimens patients were compared with S-paclitaxel regimens patients. The pooled HR for OS showed that there was no significant difference in the two groups (HR = 1.00; 95%CI = 0.86–1.17; P = 0.99; Fig. 2). Subgroup analysis of carboplatin/paclitaxel based regimens also revealed that there was no significant difference in the two groups (HR = 0.99; 95%CI = 0.78–1.25; P = 0.91; Fig. 2). 3.4. Progression-free survival (4 trials, 781 patients) The median PFS was 5.2 months versus 4.7 months in the two groups. The pooled HR for PFS showed that there was no significant difference when W-paclitaxel regimens patients were compared with S-paclitaxel regimens patients (HR = 0.90; 95%CI = 0.79–1.03; P = 0.13; Fig. 3). Subgroup analysis of carboplatin/paclitaxel based regimens also revealed that there was no significant difference in the two groups (HR = 0.94; 95%CI = 0.80–1.11; P = 0.44; Fig. 3). 3.5. Overall response rate (5 trials, 917 patients) The ITT analysis demonstrated that the overall response rate of the W-paclitaxel group was 30.89% and S-paclitaxel regimen group was 27.09%. There was no significant difference in the two groups (RR = 1.24; 95%CI = 0.93–1.66; P = 0.14; Fig. 4). Furthermore, Subgroup analysis of carboplatin/paclitaxel based regimens also revealed that there was no significant difference in the two groups (RR = 1.38; 95%CI = 0.98–1.95; P = 0.06; Fig. 4).
3.2. Study quality 3.6. Adverse events Quality assessment of the included trials is shown in Table 1. All studies were reported in full text and described by the authors as randomized. All trials reported the allocation concealment, withdrawals and drop-outs.
Adverse events were not uniformly described. The most often reported grades 3 and 4 adverse events were hematologic toxicity (i.e., anemia, leukocytopenia, thrombocytopenia, or
G. Gao et al. / Lung Cancer 76 (2012) 380–386
383
Study
%
ID
HR (95% CI)
Weight
Socinski/2006
0.76 (0.53, 1.11)
16.67
Belani/2008
1.09 (0.88, 1.36)
46.46
Sakakibara/2010
1.13 (0.66, 1.93)
7.99
Subtotal (I-squared = 31.3%, p = 0.233)
0.99 (0.78, 1.25)
71.12
Belani/2007
0.79 (0.48, 1.30)
9.25
Socinski/2009
1.10 (0.78, 1.54)
19.62
Subtotal (I-squared = 13.6%, p = 0.282)
0.98 (0.72, 1.34)
28.88
1.00 (0.86, 1.17)
100.00
PC
.
Non-PC
.
Overall (I-squared = 2.0%, p = 0.395)
NOTE: Weights are from random effects analysis .5
1
Favours W-paclitaxel
1.5
Favours S-paclitaxel
Fig. 2. Meta-analysis of overall survival among patients receiving weekly paclitaxel (W-paclitaxel) or standard paclitaxel (S-paclitaxel). The pooled HR for OS showed that there was no significant difference in the two groups (P = 0.99). Subgroup-analysis of carboplatin/paclitaxel based regimens also revealed the same conclusion (P = 0.91). PC: carboplatin/paclitaxel regimens. Non-PC: non-carboplatin/paclitaxel based regimens.
Table 1 Baseline characteristics of the 5 trials comparing weekly paclitaxel (W-paclitaxel) with standard paclitaxel (S-paclitaxel) for advanced NSCLC. First author
Quality scores
Group
n
Eligible for evaluation
PS 0–1 (%)
Stage IV (%)
Mean age
Male (%)
CR + PR
PFS OS 1-y OS Months Months (%)
Socinski [15]
3
PTX 75 mg/m2 d1,qw + CBP(AUC = 6) d1,q3w PTX 225 mg/m2 ,d1,q3w; CBP(AUC = 6) d1,q3w PTX 100 mg/m2 ,d1,8,q3w; GEM 1000 mg/m2 d1,8,q3w PTX 200 mg/m2 ,d1,q3w; GEM 1000 mg/m2 d1,8,q3w PTX 100 mg/m2 ,d1,8,15,q4w; CBP(AUC = 6) d1,q3w PTX 225 mg/m2 ,d1,q3w; CBP(AUC = 6) d1,q3w PTX 100 mg/m2 ,d1,8,15,q4w CBP(AUC = 6) d1,q3w;Cetuximabb PTX 225 mg/m2 ,d1,q3w CBP(AUC = 6) d1,q4w;Cetuximabb PTX 70 mg/m2 d1,qw CBP(AUC = 6) d1,q3w PTX 200 mg/m2 d1,q3w; CBP(AUC = 6) d1,q3w
80
80
100c
88
60
62
28
–
8.7
27
81
81
100c
88
61
67
26
–
6.6
16
51
50
88
82
62
52
11
5.8
10.3
42
52
50
86
78
66
56
11
4.7
7.9
34
223
217
84
82
65
65
60
4.8
9.7
37.8
221
214
88
83
65
60
41
4.2
10.7
41.3
84
84
96.4
83.3
62.1
52.4
21
4.3
9.8
39.3
84
84
97.6
89.3
61.2
53.6
24
4.7
11.4
47.7
42
42
100c
60
74
90
23
6.0
14.7
60
40
c
55
75
78
21
5.6
15.5
67
Belani [16]
Belani [17]
Socinski [18]
Sakakibara [19]
3
3
3
3
40
100
a Quality scores of Jadad scores; PTX, Paclitaxel; CBP, Carboplatin; GEM, Gemcitabine. PS: Zubrod-ECOG-WHO; CR: Complete Response; PR: Partial Response; PFS: progressionfree survival; OS: overall survival; 1-y OS: 1-year overall survival rate. b Cetuximab:400 mg/m2 day 1 followed by weekly 250 mg/m2 . c Karnofsky ≥ 70.
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Study
%
ID
HR (95% CI)
Weight
Belani/2007
0.71 (0.47, 1.06)
10.78
Socinski/2009
0.90 (0.68, 1.18)
23.48
Subtotal (I-squared = 0.0%, p = 0.344)
0.84 (0.66, 1.05)
34.27
Belani/2008
0.96 (0.80, 1.15)
54.17
Sakakibara/2010
0.84 (0.57, 1.25)
11.57
Subtotal (I-squared = 0.0%, p = 0.545)
0.94 (0.80, 1.11)
65.73
0.90 (0.79, 1.03)
100.00
Non-PC
.
PC
.
Overall (I-squared = 0.0%, p = 0.591)
NOTE: Weights are from random effects analysis .5
1
Favours W-paclitaxel
1.5
Favours S-paclitaxel
Fig. 3. Meta-analysis of progression-free survival for patients receiving weekly paclitaxel (W-paclitaxel) or standard paclitaxel (S-paclitaxel). The pooled HR for PFS showed that there was no significant difference in the two groups (P = 0.13). Subgroup-analysis of carboplatin/paclitaxel based regimens also revealed the same conclusion (P = 0.44). PC: carboplatin/paclitaxel regimens. Non-PC: non-carboplatin/paclitaxel based regimens.
granulocytopenia), fever, and peripheral neuropathy. The pooled odds ratio (OR) for developing neutropenia, febrile neutropenia and grade 2 or 4 of peripheral neuropathy was statistically significantly less in patients treated with W-paclitaxel than in patients treated with S-paclitaxel (OR = 0.47; 95%CI = 0.27–0.83; P = 0.009; OR = 0.46; 95%CI = 0.21–0.98; P = 0.04 and OR = 0.50; 95%CI = 0.33–0.76; P = 0.001, respectively). The pooled OR for developing anemia was statistically significantly higher in patients treated with W-paclitaxel than in patients treated with S-paclitaxel (OR = 2.08; 95%CI = 1.20–3.58; P = 0.009) (Table 2). There was no difference between two groups with respect to the risk of treat-related deaths. 4. Discussion The carboplatin/paclitaxel based on an every 3-week schedule is the current standard chemotherapy in the first-line treatment of advanced NSCLC. The regimen provides response rates of 20–40%, with median survival time of 8–10 months. However, the hematological toxicities and nonhematological toxicities (such as myelosuppression, peripheral neuropathy and so on) with this paclitaxel schedule is extremely frequent and severe. Many patients, especially for the elder or the people with poor conditions, cannot tolerate the toxicities and obtain the benefit from chemotherapy. The Weekly scheduling of paclitaxel may improve the toxicity profile of the drug in NSCLC patients without decreasing antitumor activity. The studies were relatively heterogeneous with respect to patient population with different treatment regimen and treatment duration. Given this clinical heterogeneity our
decision to meta-analyze for overall response rate, progressionfree survival, overall survival, and key adverse event rates could be questioned. We believe that the meta-analysis was appropriate and helpful in this case. Our results showed that there were no significant differences between W-paclitaxel schedule or S-paclitaxel schedule in OS, PFS and ORR. And the similar results were found in sub-analysis. But the W-paclitaxel regimens led to significantly less hematological toxicities and nonhematological toxicities. Considering there was no statistical significance in survival and treatment response between W-paclitaxel and S-paclitaxel regimens, the efficacy may not be the only factor which might affect physician’s decision when choosing W-paclitaxel or S-paclitaxel regimens for patients with advanced NSCLC and acceptable toxicity profile of the two regimens should also be considered for the patients with advanced NSCLC. More than 50% of cases of advanced NSCLC are diagnosed in patients over the age of 65 years [24]. Treatment of the elderly patient population is influenced by the presence of comorbid illness, concomitant use of medications, functional status, and vital organ functions (hepatic, renal, and bone marrow) [25]. Traditional combination regimens were associated with more toxic events. Elderly patients are often treated with suboptimal regimens because of misconceptions among oncologists and patients of the risk-benefit ratio of chemotherapy. Therefore, alternative schedules of combination regimens with the potential for less toxicity may be a more appealing therapeutic option for elderly patients. Ramalingam et al. [26] reported a study of comparing weekly schedule (paclitaxel, 100 mg/m2 weekly for 3 of 4 weeks; carboplatin, AUC = 6 on Day 1 every 4 weeks) with the standard schedule
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Table 2 Summary of toxicity meta-analyses of for patients receiving weekly paclitaxel (W-paclitaxel) or standard paclitaxel (S-paclitaxel) for advanced NSCLC. Analyses
Incidence rate
3/4 Grade anemia 3/4 Grade neutropenia 3/4 Grade febrile neutropenia 3/4 Grade thrombocytopenia 3/4 Grade nausea and vomiting 2/4 Grade peripheral neuropathy 3/4 Grade fatigue
W-paclitaxel group (%)
S-paclitaxel group (%)
9.15 21.7 2.13 6.44 4.40 10.00 7.41
4.75 32.61 4.54 4.97 5.24 17.92 8.12
P-value for homogeneity
OR
95%CI
P-value
0.57 0.02 0.55 0.10 0.13 0.26 0.97
2.08 0.47 0.46 1.31 0.84 0.50 0.91
1.20–3.58F 0.27–0.83R 0.21–0.98F 0.75–2.27F 0.44–1.62F 0.33–0.76F 0.52–1.58F
0.009 0.009 0.04 0.34 0.60 0.001 0.73
OR, odds ratio; CI, confidence interval; R, random effect model; F, fixed effect model.
%
Study RR (95% CI)
Weight
Socinski/2006
1.14 (0.59, 2.20)
19.75
Belani/2008
1.61 (1.03, 2.53)
41.68
Sakakibara/2010
1.10 (0.46, 2.61)
11.29
Subtotal (I-squared = 0.0%, p = 0.591)
1.38 (0.98, 1.95)
72.72
Belani/2007
1.30 (0.50, 3.40)
9.21
Socinski/2009
0.79 (0.40, 1.57)
18.07
Subtotal (I-squared = 0.0%, p = 0.411)
0.94 (0.54, 1.64)
27.28
1.24 (0.93, 1.66)
100.00
ID
PC
.
Non-PC
.
Overall (I-squared = 0.0%, p = 0.543)
NOTE: Weights are from random effects analysis .5
Favours S-paclitaxel
1
5
Favours W-paclitaxel
Fig. 4. Meta-analysis of overall response rate for patients receiving weekly paclitaxel (W-paclitaxel) or standard paclitaxel (S-paclitaxel). The pooled RR for ORR showed that there was no significant difference in the two groups (P = 0.14). Subgroup-analysis of carboplatin/paclitaxel based regimens also revealed the same conclusion (P = 0.06). PC: carboplatin/paclitaxel regimens. Non-PC: non-carboplatin/paclitaxel based regimens.
(paclitaxel, 225 mg/m2 ; carboplatin, AUC = 6 on Day 1 every 21 days) in 136 elderly patients (over the age of 70 years). They found that the overall response rate (26% versus 19%), median survival (37 weeks versus 31 weeks) and 1-year survival rates (31% versus 33%) were similar in the two groups, but the hematological toxicities and nonhematological toxicities (neuropathy, Nausea and emesis) were less frequent on the weekly schedule. This result coincides with our results. So the W-paclitaxel may be a better choice for the elder or the people with poor conditions. Although publication bias was not found according to funnel plot, Begg’s test, and Egger’s test, these results need to be interpreted very cautiously because there were only five RCTs. Our analysis were limited to the data presented by authors of the source studies. In some cases we had incomplete information. Our metaanalysis was based on aggregate study and substudy data, not on
individual patient data. Despite the limitations of our study, we believe that it makes an important contribution to the NSCLC field. Prior to our meta-analysis, no systemreview and meta-analysis had reported the difference between the two arms, our analysis confirms that the W-paclitaxel schedule was not inferior than the S-paclitaxel chemotherapies schedule. The paclitaxel-based chemotherapies given by every 3 weeks are still standard regimens.
5. Conclusion No significant difference was demonstrated between weekly and 3-weekly schedules. The W-paclitaxel may be a better choice for some patients, who cannot tolerate the standard regimen, especially for the elder or the people with poor conditions.
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[12] Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxelcarboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542–50. [13] Kubota K, Kawahara M, Ogawara M, Nishiwaki Y, Komuta K, Minato K, et al. Vinorelbine plus gemcitabine followed by docetaxel versus carboplatin plus paclitaxel in patients with advanced non-small-cell lung cancer: a randomised, open-label, phase III study. Lancet Oncol 2008;9:1135–42. [14] Inoue A, Usui K, Ishimoto O, Matsubara N, Tanaka M, Kanbe M, et al. A phase II study of weekly paclitaxel combined with carboplatin for elderly patients with advanced non-small cell lung cancer. Lung Cancer 2006;52:83–7. [15] Socinski MA, Ivanova A, Bakri K, Wall J, Baggstrom MQ, Hensing TA, et al. A randomized phase II trial comparing every 3-weeks carboplatin/paclitaxel with every 3-weeks carboplatin and weekly paclitaxel in advanced non-small cell lung cancer. Ann Oncol 2006;17:104–9. [16] Belani CP, Dakhil S, Waterhouse DM, Desch CE, Rooney DK, Clark RH, et al. Randomized phase II trial of gemcitabine plus weekly versus three-weekly paclitaxel in previously untreated advanced non-small-cell lung cancer. Ann Oncol 2007;18:110–5. [17] Belani CP, Ramalingam S, Perry MC, LaRocca RV, Rinaldi D, Gable PS, et al. Randomized, phase III study of weekly paclitaxel in combination with carboplatin versus standard every-3-weeks administration of carboplatin and paclitaxel for patients with previously untreated advanced non-small-cell lung cancer. J Clin Oncol 2008;26:468–73. [18] Socinski MA, Saleh MN, Trent DF, Dobbs TW, Zehngebot LM, Levine MA, et al. A randomized, phase II trial of two dose schedules of carboplatin/paclitaxel/cetuximab in stage IIIB/IV non-small-cell lung cancer (NSCLC). Ann Oncol 2009;20:1068–73. [19] Sakakibara T, Inoue A, Sugawara S, Maemondo M, Ishida T, Usui K, et al. Randomized phase II trial of weekly paclitaxel combined with carboplatin versus standard paclitaxel combined with carboplatin for elderly patients with advanced non-small-cell lung cancer. Ann Oncol 2010;21:795–9. [20] Dickersin K, Scherer R, Lefebvre C. Identifying relevant studies for systematic reviews. BMJ 1994;309:1286–91. [21] Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary. Control Clin Trials 1996;17:1–12. [22] Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000;92:205–16. [23] Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629–34. [24] Owonikoko TK, Ragin CC, Belani CP, Oton AB, Gooding WE, Taioli E, et al. Lung cancer in elderly patients: an analysis of the surveillance, epidemiology, and end results database. J Clin Oncol 2007;25:5570–7. [25] McLean AJ, Le Couteur DG. Aging biology and geriatric clinical pharmacology. Pharmacol Rev 2004;56:163–84. [26] Ramalingam S, Perry MC, La Rocca RV, Rinaldi D, Gable PS, Tester WJ, et al. Comparison of outcomes for elderly patients treated with weekly paclitaxel in combination with carboplatin versus the standard 3-weekly paclitaxel and carboplatin for advanced nonsmall cell lung cancer. Cancer 2008;113: 542–6.
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A meta-analysis of paclitaxel-based chemotherapies administered once every week compared with once every 3 weeks first-line treatment of advanced non-small-cell lung cancer Guanghui Gao a , Haiqing Chu a,∗ , Lan Zhao a , Tao Gui a , Qinghua Xu a , Jianping Shi b a b
Department of Respiratory Diseases, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China Department of Respiratory Diseases, Wuxi No. 3 People’s Hospital, Jiangsu Province 214041, China
a r t i c l e
i n f o
Article history: Received 20 August 2011 Received in revised form 1 December 2011 Accepted 3 December 2011 Keywords: Carcinoma Non-small-cell lung Paclitaxel Weekly schedule Meta-analysis
a b s t r a c t Objective: The published data on the curative effects of comparing the once weekly paclitaxel-based chemotherapies (W-paclitaxel) with the standard every 3 weeks paclitaxel-based chemotherapies (S-paclitaxel) in the first-line treatment of advanced non-small-cell lung cancer (NSCLC) were still controversial. To derive a more precise estimation of the two regimens, a meta-analysis was performed. Methods: Medical databases and conference proceedings were searched for randomized controlled trials which compared W-paclitaxel with S-paclitaxel in patients with first-line treatment of advanced NSCLC. The following keywords were used: “paclitaxel”, “weekly schedule” and “non-small cell lung cancer”. Reference lists of original articles and review articles were also examined. The published languages and years were not limited. Endpoints were overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and adverse events. Statistical tests for heterogeneity were one-sided; statistical tests for effect estimates were two-sided. Results: Five eligible trials involved 940 patients were identified. They were all published as full-text articles. The intention to treatment (ITT) analysis demonstrated that the ORR of W-paclitaxel regimens patients was 30.89% (143/463), whereas the ORR of S-paclitaxel regimens patients was 27.09% (123/454). The overall pooled relative ratio (RR) for ORR was 1.24 (95% confidence intervals (CI) = 0.93–1.66; P = 0.14) when W-paclitaxel regimens patients were compared with S-paclitaxel regimens patients. Although the patients with W-paclitaxel regimens had an similar OS and PFS in comparison with S-paclitaxel regimens (median OS was 9.8 versus 10.7 months; hazard ratio (HR) = 1.00; 95%CI = 0.86–1.17; P = 0.99; median PFS was 5.2 versus 4.7 months; HR = 0.90; 95%CI = 0.79–1.03; P = 0.13, respectively), the W-paclitaxel regimens led to significantly less frequent adverse events of hematological toxicities and nonhematological toxicities. Conclusion: These results suggest that the W-paclitaxel is not superior than S-paclitaxel regimens. The paclitaxel-based chemotherapies given by every 3 weeks are still standard regimens. For patients, especially for the elder or the people with poor conditions who cannot tolerate the standard regimen, the weekly schedule can be considered. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Lung cancer is one the most common forms of cancer in the world, in terms of incidence and mortality. It is projected that 221,130 individuals (115,060 men and 106,070 women) will be diagnosed with lung cancer, and that 156,940 individuals (85,600
∗ Corresponding author at: Department of Respiratory Diseases, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Zhengmin Road No. 507, Shanghai, China. Tel.: +86 21 65115006x2123; fax: +86 21 65111298. E-mail addresses: [email protected] (G. Gao), [email protected] (H. Chu). 0169-5002/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2011.12.001
men and 71,340 women) will die from lung cancer in the USA by the end of 2011 [1], and the annual number of new cases is expected to exceed 338,000 by 2030 [2]. Non-small-cell lung cancer (NSCLC) accounts for at least 80% of all lung cancer cases, presenting as local advanced disease in approximately 25–30% of cases and as metastatic disease in approximately 40–50% of cases [3]. The prognosis of the patients with NSCLC remains poor, approximately 80% of patients die within one year of diagnosis, and the 5-year survival rate is estimated of 15% in the USA and 10% in Europe [4]. For these patients with local advanced or metastatic disease, the main treatment is limited in supportive care and chemotherapy, and the operation is inapplicable (except for a very limited number of patients, who suffer from stage IV NSCLC with solitary metastasis
G. Gao et al. / Lung Cancer 76 (2012) 380–386
should be considered for surgery). Doublet chemotherapies consisting of the platinums plus third-generation new agent (taxane, gemcitabine, vinorelbine) for patients with advanced non-smallcell lung cancer (NSCLC) have become the most common approach worldwide, based on the evidence of a small survival advantage compared with supportive care in a meta-analysis [5]. Another meta-analysis showed that an increase for response and 1-year survival rate was attributable to platinum-based therapy comparing to non-platinum-based therapy [6]. The overall response rate and 1-year survival rate of cisplatin-based and carboplatin-based regimens were also similar [7]. A lot of randomized trials and metaanalysis performed during recent years have unequivocally shown that there are no substantial differences in the efficacy among several combinations containing cisplatin or carboplatin and one of these new drugs [8–11]. Paclitaxel, particularly the combination of carboplatin and paclitaxel is commonly used regimen as first-line treatment of advanced NSCLC in many countries. Its efficacy has been established and has been selected as the reference arm in several phase III trials [12,13]. Although a meta-analysis [11] showed the risk for immediate progression is significantly higher when paclitaxel-containing regimens are used (patients receiving paclitaxel showed a 22% higher risk for having progression disease as the best response), the meta-analysis was based only on response and not survival data. Standard administration of carboplatin/paclitaxel is based on an every 3-week schedule. However, myelosuppression and peripheral neuropathy with this paclitaxel schedule is extremely frequent and severe, especially for grade 3–4 neutropenia and febrile neutropenia. Weekly scheduling of paclitaxel may improve the toxicity profile of the drug in NSCLC patients without decreasing antitumor activity. Particularly, a marked reduction in the occurrence of severe and febrile neutropenia is reported when paclitaxel is administered in a weekly schedule, compared with the classic administration schedule of 3 weeks [14,17]. On the basis of this evidence, several randomized trials have been conducted, with the aim of comparing the once weekly paclitaxel-based chemotherapies schedule (W-paclitaxel) with the standard every 3 weeks paclitaxel-based chemotherapies schedule (S-paclitaxel) in the first-line treatment of advanced NSCLC [15–19]. However, sample size of each single trial had insufficient power to detect potentially relevant differences in efficacy. We performed this meta-analysis, including five randomized trials, to compare the efficacy and adverse events of the two different schedules of paclitaxel in the first-line treatment of advanced NSCLC and try to confirm whether the once weekly paclitaxel-based chemotherapies schedule (W-paclitaxel) has increased efficacy and meanwhile decreased toxicity.
2. Materials and methods 2.1. Literature search To ensure retrieval of all relevant trials, we used a broad search strategy in which key words and text words related to lung cancer and paclitaxel were combined with a validated methodological filter, as described by Dickersin et al. [20]. The following keywords were used: “paclitaxel”, “weekly schedule” and “non-small cell lung cancer”. We used this strategy to search a variety of electronic databases, including the PubMed database (1966–July 2010), the Cochrane Controlled Trials Register (issue 3, 2010), EMBASE (1974–July 2010) and Chinese Biomedical database (1978–July 2010). We also manually searched the conference proceedings of the American Society of Clinical Oncology (ASCO) and the European Society of Medical Oncology (ESMO) from the year of 1995–2010 for relevant clinical trials. Reference lists from studies selected for this
381
review, and from other published systematic reviews and practice guidelines were also hand-searched. 2.2. Inclusion criteria We included in this analysis only randomized controlled trials that enrolled patients who were older than 18 years and who had pathologically proven NSCLC and in clinical III–IV stage, untreated and that compared the once weekly paclitaxel-based chemotherapies schedule (W-paclitaxel) with the standard every 3 weeks paclitaxel-based chemotherapies schedule (S-paclitaxel). Trials were included regardless of publication status, date of publication, and language. We excluded ongoing studies, interim analyses, nonrandomized studies, and studies with 10 or fewer patients per study arm. 2.3. Study selection, quality assessment, and data extraction Two reviewers (Guanghui Gao and Lan Zhao) independently screened the titles and abstracts of all studies identified in the literature search to verify compliance with the inclusion. When this information was unsatisfactory, full-text was retrieved and inclusion criteria were applied. Disagreements between the two reviewers were resolved by consensus involving a third reviewer (Haiqing Chu). The same reviewers who screened the studies independently performed data extraction and quality assessment of all included articles. The methodological quality of the studies included in the meta-analysis was scored using the Jadad composite scale. This is a five-point scale, and one point was given when one quality criterion was met [21]. All included studies, regardless of whether they were published or not, were assessed for internal validity parameters, with particular emphasis on randomization, masking of patients and clinicians, concealment of allocation, documentation of dropouts and withdrawals, and intent-to-treat analysis. Follow-up was arbitrarily defined as complete if trial enrollment was closed, all patients were accounted, and less than 10% were lost in follow-up. 2.4. Outcome measures The primary outcome was overall survival (as defined by Therasse et al. [22]). Secondary outcomes included progressionfree survival, overall response rate and adverse events. 2.5. Data analysis and statistical methods A random-effect model was assumed in all meta-analysis. The hazard ratio (HR) was used for overall survival and progression-free survival. For binary data, the relative risks (RR) were used for overall response rate; the odds ratio (OR) was used for treatment toxicity. A statistical test with a P-value less than 0.05 was considered significant. An HR > 1 reflects more deaths or progression in the once weekly paclitaxel-based chemotherapies (W-paclitaxel) schedule. An RR > 1 reflects a favorable outcome in the W-paclitaxel arm for response, and an OR > 1 indicates more toxicity in the W-paclitaxel arm. A funnel plot was generated or a linear regression test [23] was performed to examine whether there was publication bias. In our paper, publication bias was not found according to funnel plot, Begg’s test (P = 0.806), and Egger’s test (P = 0.307). Potential causes of heterogeneity were explored by performing sensitivity analyses to evaluate effects of stage, study duration, study quality, the source of the data of the W-paclitaxel treatment. Particular emphasis was placed on the evaluation of additional side effects of W-paclitaxel in comparison to S-paclitaxel. Side effects were defined as any adverse event occurring during treatment, including death (according to National Cancer Institute Common Toxicity Criteria).
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All Articles (n=1858)
Potential Appropriate Articles (n=12)
Excluded: 1. Review Article(n=812) 2. Phase I/II Studies(n=317) 3. Cohort Studies(n=199) 4. Others (inappropriate abstracts, comments, ongoing studies, interim analyses, ect)(n=518)
Excluded: 1.Non-randomized Treatment Comparison (n=4) 2. sub-group analysis of one RCT (n=1) 3. RCT, But Nonidentical Treatment Regimens between two group (n=2)
Fully Articles (n=5) Fig. 1. Flow chart showing the progress of trials through the review (RCT, randomized controlled trial).
Analyses were performed using the STATA SE 11.0 package (StataCorp., College Station, TX). Statistical tests for heterogeneity were one-sided; statistical tests for effect estimates and publication bias were two-sided. 3. Results 3.1. Identification of studies The flow chart of our study is shown in Fig. 1. The literature search identified 1858 trials, of which 12 were considered potentially relevant. The remaining 12 articles were selected for analysis and were evaluated in more detail. Of these, 7 were excluded for the following reasons: one trial [26] was sub-group analysis of one RCT cited in our paper [17]; two trials did not use identical chemotherapy in the control arm; four trials were not randomized. The remaining five randomized controlled trials (Table 1), which involved 940 adult patients, met all the inclusion and exclusion criteria and were included in the meta-analysis. Among which, one trial was phase III RCT [17], the others were phase II RCTs. There was no placebo-controlled double-blinded trial. The chemotherapy regimens used included: paclitaxel and carboplatin [15,17,19]; paclitaxel and gemcitabine [16]; paclitaxel, carboplatin and cetuximab [18]. All trials compared the once weekly paclitaxel-based chemotherapies schedule (W-paclitaxel) with the standard every 3 weeks paclitaxel-based chemotherapies schedule (S-paclitaxel). Median age of enrolled patients was above 60 in all trials, and in one trial [19], the median age of patients was older than 70 years (Table 1).
3.3. Overall survival (5 trials, 940 patients) The median OS was 9.8 months versus 10.7 months when W-paclitaxel regimens patients were compared with S-paclitaxel regimens patients. The pooled HR for OS showed that there was no significant difference in the two groups (HR = 1.00; 95%CI = 0.86–1.17; P = 0.99; Fig. 2). Subgroup analysis of carboplatin/paclitaxel based regimens also revealed that there was no significant difference in the two groups (HR = 0.99; 95%CI = 0.78–1.25; P = 0.91; Fig. 2). 3.4. Progression-free survival (4 trials, 781 patients) The median PFS was 5.2 months versus 4.7 months in the two groups. The pooled HR for PFS showed that there was no significant difference when W-paclitaxel regimens patients were compared with S-paclitaxel regimens patients (HR = 0.90; 95%CI = 0.79–1.03; P = 0.13; Fig. 3). Subgroup analysis of carboplatin/paclitaxel based regimens also revealed that there was no significant difference in the two groups (HR = 0.94; 95%CI = 0.80–1.11; P = 0.44; Fig. 3). 3.5. Overall response rate (5 trials, 917 patients) The ITT analysis demonstrated that the overall response rate of the W-paclitaxel group was 30.89% and S-paclitaxel regimen group was 27.09%. There was no significant difference in the two groups (RR = 1.24; 95%CI = 0.93–1.66; P = 0.14; Fig. 4). Furthermore, Subgroup analysis of carboplatin/paclitaxel based regimens also revealed that there was no significant difference in the two groups (RR = 1.38; 95%CI = 0.98–1.95; P = 0.06; Fig. 4).
3.2. Study quality 3.6. Adverse events Quality assessment of the included trials is shown in Table 1. All studies were reported in full text and described by the authors as randomized. All trials reported the allocation concealment, withdrawals and drop-outs.
Adverse events were not uniformly described. The most often reported grades 3 and 4 adverse events were hematologic toxicity (i.e., anemia, leukocytopenia, thrombocytopenia, or
G. Gao et al. / Lung Cancer 76 (2012) 380–386
383
Study
%
ID
HR (95% CI)
Weight
Socinski/2006
0.76 (0.53, 1.11)
16.67
Belani/2008
1.09 (0.88, 1.36)
46.46
Sakakibara/2010
1.13 (0.66, 1.93)
7.99
Subtotal (I-squared = 31.3%, p = 0.233)
0.99 (0.78, 1.25)
71.12
Belani/2007
0.79 (0.48, 1.30)
9.25
Socinski/2009
1.10 (0.78, 1.54)
19.62
Subtotal (I-squared = 13.6%, p = 0.282)
0.98 (0.72, 1.34)
28.88
1.00 (0.86, 1.17)
100.00
PC
.
Non-PC
.
Overall (I-squared = 2.0%, p = 0.395)
NOTE: Weights are from random effects analysis .5
1
Favours W-paclitaxel
1.5
Favours S-paclitaxel
Fig. 2. Meta-analysis of overall survival among patients receiving weekly paclitaxel (W-paclitaxel) or standard paclitaxel (S-paclitaxel). The pooled HR for OS showed that there was no significant difference in the two groups (P = 0.99). Subgroup-analysis of carboplatin/paclitaxel based regimens also revealed the same conclusion (P = 0.91). PC: carboplatin/paclitaxel regimens. Non-PC: non-carboplatin/paclitaxel based regimens.
Table 1 Baseline characteristics of the 5 trials comparing weekly paclitaxel (W-paclitaxel) with standard paclitaxel (S-paclitaxel) for advanced NSCLC. First author
Quality scores
Group
n
Eligible for evaluation
PS 0–1 (%)
Stage IV (%)
Mean age
Male (%)
CR + PR
PFS OS 1-y OS Months Months (%)
Socinski [15]
3
PTX 75 mg/m2 d1,qw + CBP(AUC = 6) d1,q3w PTX 225 mg/m2 ,d1,q3w; CBP(AUC = 6) d1,q3w PTX 100 mg/m2 ,d1,8,q3w; GEM 1000 mg/m2 d1,8,q3w PTX 200 mg/m2 ,d1,q3w; GEM 1000 mg/m2 d1,8,q3w PTX 100 mg/m2 ,d1,8,15,q4w; CBP(AUC = 6) d1,q3w PTX 225 mg/m2 ,d1,q3w; CBP(AUC = 6) d1,q3w PTX 100 mg/m2 ,d1,8,15,q4w CBP(AUC = 6) d1,q3w;Cetuximabb PTX 225 mg/m2 ,d1,q3w CBP(AUC = 6) d1,q4w;Cetuximabb PTX 70 mg/m2 d1,qw CBP(AUC = 6) d1,q3w PTX 200 mg/m2 d1,q3w; CBP(AUC = 6) d1,q3w
80
80
100c
88
60
62
28
–
8.7
27
81
81
100c
88
61
67
26
–
6.6
16
51
50
88
82
62
52
11
5.8
10.3
42
52
50
86
78
66
56
11
4.7
7.9
34
223
217
84
82
65
65
60
4.8
9.7
37.8
221
214
88
83
65
60
41
4.2
10.7
41.3
84
84
96.4
83.3
62.1
52.4
21
4.3
9.8
39.3
84
84
97.6
89.3
61.2
53.6
24
4.7
11.4
47.7
42
42
100c
60
74
90
23
6.0
14.7
60
40
c
55
75
78
21
5.6
15.5
67
Belani [16]
Belani [17]
Socinski [18]
Sakakibara [19]
3
3
3
3
40
100
a Quality scores of Jadad scores; PTX, Paclitaxel; CBP, Carboplatin; GEM, Gemcitabine. PS: Zubrod-ECOG-WHO; CR: Complete Response; PR: Partial Response; PFS: progressionfree survival; OS: overall survival; 1-y OS: 1-year overall survival rate. b Cetuximab:400 mg/m2 day 1 followed by weekly 250 mg/m2 . c Karnofsky ≥ 70.
384
G. Gao et al. / Lung Cancer 76 (2012) 380–386
Study
%
ID
HR (95% CI)
Weight
Belani/2007
0.71 (0.47, 1.06)
10.78
Socinski/2009
0.90 (0.68, 1.18)
23.48
Subtotal (I-squared = 0.0%, p = 0.344)
0.84 (0.66, 1.05)
34.27
Belani/2008
0.96 (0.80, 1.15)
54.17
Sakakibara/2010
0.84 (0.57, 1.25)
11.57
Subtotal (I-squared = 0.0%, p = 0.545)
0.94 (0.80, 1.11)
65.73
0.90 (0.79, 1.03)
100.00
Non-PC
.
PC
.
Overall (I-squared = 0.0%, p = 0.591)
NOTE: Weights are from random effects analysis .5
1
Favours W-paclitaxel
1.5
Favours S-paclitaxel
Fig. 3. Meta-analysis of progression-free survival for patients receiving weekly paclitaxel (W-paclitaxel) or standard paclitaxel (S-paclitaxel). The pooled HR for PFS showed that there was no significant difference in the two groups (P = 0.13). Subgroup-analysis of carboplatin/paclitaxel based regimens also revealed the same conclusion (P = 0.44). PC: carboplatin/paclitaxel regimens. Non-PC: non-carboplatin/paclitaxel based regimens.
granulocytopenia), fever, and peripheral neuropathy. The pooled odds ratio (OR) for developing neutropenia, febrile neutropenia and grade 2 or 4 of peripheral neuropathy was statistically significantly less in patients treated with W-paclitaxel than in patients treated with S-paclitaxel (OR = 0.47; 95%CI = 0.27–0.83; P = 0.009; OR = 0.46; 95%CI = 0.21–0.98; P = 0.04 and OR = 0.50; 95%CI = 0.33–0.76; P = 0.001, respectively). The pooled OR for developing anemia was statistically significantly higher in patients treated with W-paclitaxel than in patients treated with S-paclitaxel (OR = 2.08; 95%CI = 1.20–3.58; P = 0.009) (Table 2). There was no difference between two groups with respect to the risk of treat-related deaths. 4. Discussion The carboplatin/paclitaxel based on an every 3-week schedule is the current standard chemotherapy in the first-line treatment of advanced NSCLC. The regimen provides response rates of 20–40%, with median survival time of 8–10 months. However, the hematological toxicities and nonhematological toxicities (such as myelosuppression, peripheral neuropathy and so on) with this paclitaxel schedule is extremely frequent and severe. Many patients, especially for the elder or the people with poor conditions, cannot tolerate the toxicities and obtain the benefit from chemotherapy. The Weekly scheduling of paclitaxel may improve the toxicity profile of the drug in NSCLC patients without decreasing antitumor activity. The studies were relatively heterogeneous with respect to patient population with different treatment regimen and treatment duration. Given this clinical heterogeneity our
decision to meta-analyze for overall response rate, progressionfree survival, overall survival, and key adverse event rates could be questioned. We believe that the meta-analysis was appropriate and helpful in this case. Our results showed that there were no significant differences between W-paclitaxel schedule or S-paclitaxel schedule in OS, PFS and ORR. And the similar results were found in sub-analysis. But the W-paclitaxel regimens led to significantly less hematological toxicities and nonhematological toxicities. Considering there was no statistical significance in survival and treatment response between W-paclitaxel and S-paclitaxel regimens, the efficacy may not be the only factor which might affect physician’s decision when choosing W-paclitaxel or S-paclitaxel regimens for patients with advanced NSCLC and acceptable toxicity profile of the two regimens should also be considered for the patients with advanced NSCLC. More than 50% of cases of advanced NSCLC are diagnosed in patients over the age of 65 years [24]. Treatment of the elderly patient population is influenced by the presence of comorbid illness, concomitant use of medications, functional status, and vital organ functions (hepatic, renal, and bone marrow) [25]. Traditional combination regimens were associated with more toxic events. Elderly patients are often treated with suboptimal regimens because of misconceptions among oncologists and patients of the risk-benefit ratio of chemotherapy. Therefore, alternative schedules of combination regimens with the potential for less toxicity may be a more appealing therapeutic option for elderly patients. Ramalingam et al. [26] reported a study of comparing weekly schedule (paclitaxel, 100 mg/m2 weekly for 3 of 4 weeks; carboplatin, AUC = 6 on Day 1 every 4 weeks) with the standard schedule
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385
Table 2 Summary of toxicity meta-analyses of for patients receiving weekly paclitaxel (W-paclitaxel) or standard paclitaxel (S-paclitaxel) for advanced NSCLC. Analyses
Incidence rate
3/4 Grade anemia 3/4 Grade neutropenia 3/4 Grade febrile neutropenia 3/4 Grade thrombocytopenia 3/4 Grade nausea and vomiting 2/4 Grade peripheral neuropathy 3/4 Grade fatigue
W-paclitaxel group (%)
S-paclitaxel group (%)
9.15 21.7 2.13 6.44 4.40 10.00 7.41
4.75 32.61 4.54 4.97 5.24 17.92 8.12
P-value for homogeneity
OR
95%CI
P-value
0.57 0.02 0.55 0.10 0.13 0.26 0.97
2.08 0.47 0.46 1.31 0.84 0.50 0.91
1.20–3.58F 0.27–0.83R 0.21–0.98F 0.75–2.27F 0.44–1.62F 0.33–0.76F 0.52–1.58F
0.009 0.009 0.04 0.34 0.60 0.001 0.73
OR, odds ratio; CI, confidence interval; R, random effect model; F, fixed effect model.
%
Study RR (95% CI)
Weight
Socinski/2006
1.14 (0.59, 2.20)
19.75
Belani/2008
1.61 (1.03, 2.53)
41.68
Sakakibara/2010
1.10 (0.46, 2.61)
11.29
Subtotal (I-squared = 0.0%, p = 0.591)
1.38 (0.98, 1.95)
72.72
Belani/2007
1.30 (0.50, 3.40)
9.21
Socinski/2009
0.79 (0.40, 1.57)
18.07
Subtotal (I-squared = 0.0%, p = 0.411)
0.94 (0.54, 1.64)
27.28
1.24 (0.93, 1.66)
100.00
ID
PC
.
Non-PC
.
Overall (I-squared = 0.0%, p = 0.543)
NOTE: Weights are from random effects analysis .5
Favours S-paclitaxel
1
5
Favours W-paclitaxel
Fig. 4. Meta-analysis of overall response rate for patients receiving weekly paclitaxel (W-paclitaxel) or standard paclitaxel (S-paclitaxel). The pooled RR for ORR showed that there was no significant difference in the two groups (P = 0.14). Subgroup-analysis of carboplatin/paclitaxel based regimens also revealed the same conclusion (P = 0.06). PC: carboplatin/paclitaxel regimens. Non-PC: non-carboplatin/paclitaxel based regimens.
(paclitaxel, 225 mg/m2 ; carboplatin, AUC = 6 on Day 1 every 21 days) in 136 elderly patients (over the age of 70 years). They found that the overall response rate (26% versus 19%), median survival (37 weeks versus 31 weeks) and 1-year survival rates (31% versus 33%) were similar in the two groups, but the hematological toxicities and nonhematological toxicities (neuropathy, Nausea and emesis) were less frequent on the weekly schedule. This result coincides with our results. So the W-paclitaxel may be a better choice for the elder or the people with poor conditions. Although publication bias was not found according to funnel plot, Begg’s test, and Egger’s test, these results need to be interpreted very cautiously because there were only five RCTs. Our analysis were limited to the data presented by authors of the source studies. In some cases we had incomplete information. Our metaanalysis was based on aggregate study and substudy data, not on
individual patient data. Despite the limitations of our study, we believe that it makes an important contribution to the NSCLC field. Prior to our meta-analysis, no systemreview and meta-analysis had reported the difference between the two arms, our analysis confirms that the W-paclitaxel schedule was not inferior than the S-paclitaxel chemotherapies schedule. The paclitaxel-based chemotherapies given by every 3 weeks are still standard regimens.
5. Conclusion No significant difference was demonstrated between weekly and 3-weekly schedules. The W-paclitaxel may be a better choice for some patients, who cannot tolerate the standard regimen, especially for the elder or the people with poor conditions.
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