Chin Med J 2013;126 (17)

3348

Meta analysis
Chemotherapy with or without gefitinib in patients with advanced
non-small-c...
Chinese Medical Journal 2013;126 (17)

searched the electronic databases Medline, EmBase, and
the Cochrane Central Registe...
Chin Med J 2013;126 (17)

3350
Table 1. Baseline characteristics for included trials
Trials
ISEL (2005)14
INVITE (2008)15
...
Chinese Medical Journal 2013;126 (17)

3351

Overall, we noted that gefitinib
therapy yielded a clinically and
statistical...
Chin Med J 2013;126 (17)

3352
Table 3. Subgroup analysis for the effect of Gefitinib therapy on OS and PFS
Variables
OS
N...
Chinese Medical Journal 2013;126 (17)

different control arms. No other significant differences
were identified between th...
Chin Med J 2013;126 (17)

3354

as an adjunctive therapy could improve PFS, ORR, and
could lessen drug-related toxicities ...
Chinese Medical Journal 2013;126 (17)

20.	

21.	

22.	

23.	
24.	

25.	

26.	

27.	

compared with placebo in chemotherap...
Upcoming SlideShare
Loading in …5
×

Chemotherapy+with+or+without+gefitinib+in+patients+with+advanced+non small-cell+lung+cancer +a+meta-analysis+of+6844+patients

202 views

Published on

Published in: Health & Medicine, Business
0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total views
202
On SlideShare
0
From Embeds
0
Number of Embeds
1
Actions
Shares
0
Downloads
3
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide

Chemotherapy+with+or+without+gefitinib+in+patients+with+advanced+non small-cell+lung+cancer +a+meta-analysis+of+6844+patients

  1. 1. Chin Med J 2013;126 (17) 3348 Meta analysis Chemotherapy with or without gefitinib in patients with advanced non-small-cell lung cancer: a meta-analysis of 6844 patients ZHOU Hang, ZENG Chao, WANG Li-yang, XIE Hua, ZHOU Jin, DIAO Peng, YAO Wen-xiu, ZHAO Xin and WEI Yang Keywords: non-small-cell-lung cancer; gefitinib; meta-analysis Background Gefitinib is widely used in patients with advanced non-small-cell lung cancer (NSCLC), in whom chemotherapy had failed. Previous trials reported inconsistent findings regarding the efficacy of gefitinib on overall survival (OS) and progression free survival (PFS). This study was to evaluate the effects of chemotherapy plus gefitinib versus chemotherapy alone on survival of patients with NSCLC. Methods We systematically searched Medline, EmBase, the Cochrane Central Register of Controlled Trials, reference lists of articles, and proceedings of major meetings for relevant literature. Randomized controlled trials (RCTs) comparing chemotherapy with and without gefitinib in the treatment of patients with advanced NSCLC were included in our analysis. The primary endpoints were OS and PFS. Results Of 182 relevant studies, 12 were included in the final analysis, which consisted of 6844 patients with NSCLC. Overall, we noted that gefitinib therapy had an 8% improvement in the OS as compared to the gefitinib-free therapy, but this difference was not statistically significant (HR, 0.92; 95% CI: 0.85–1.00; P=0.051). Furthermore, gefitinib therapy had significantly longer PFS compared to gefitinib-free therapy (HR, 0.72; 95% CI 0.60–0.87, P=0.001). Patients receiving gefitinib therapy also had a more frequent objective response rate (ORR) than the control arm (OR, 2.51; 95% CI, 1.67– 3.78, P <0.001). Rashes, diarrhea, dry skin, pruritus, paronychia, and abnormal hepatic function were more frequent in the gefitinib therapy group. Conclusions Treatment with gefitinib had a clear effect on PFS and ORR, and it might contribute considerably to the OS. Furthermore, there was some evidence of benefit for gefitinib therapy among patients with adenocarcinoma. Chin Med J 2013;126 (17): 3348-3355 N on-small-cell lung cancer (NSCLC) accounts for approximately 80%–85% of all cases of lung cancer, and is the most common cause of cancer death in industrialized countries.1,2 In patients with locally advanced and metastatic NSCLC short-lived responses to aggressive chemotherapy are observed in approximately 30% of the patients; the impact on the patients’ survival has been modest.1,3 The treatment armamentarium for advanced NSCLC has expanded to include molecular targeted therapies that act specifically against key components of cellular pathways involved in tumor growth, progression, and cell death.4,5 Gefitinib is an orally administered tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR), which has already clinically validated therapeutic targets in NSCLC. It inhibits growth and causes regressions in the human tumor xenografts with EGFR overexpression. Furthermore, unlike conventional chemotherapy, gefitinib did not cause myelosuppression, neuropathy, or significant alopecia.5-7 Despite all of these improvements, the benefits associated with gefitinib are modest and serve to stress the need for novel therapeutic approaches. In addition, several largescale randomized controlled trials investigating the use of gefitinib therapy have been performed. Some studies illustrated that gefitinib therapy had beneficial effects on the OS or PFS when compared to the traditional chemotherapy,8-13 while others showed little effect and some trials even found that gefitinib therapy could induce some harmful effects.14-19 To better understand the effect of gefitinib therapy on OS and PFS in patients with NSCLC, data from these recent trials need to be evaluated to formulate a conclusion regarding the efficacy of gefitinib therapy. We therefore undertook a meta-analysis to update the results and resolve the uncertain efficacy of gefitinib in patients with NSCLC. Furthermore, we also reported the efficacy of gefitinib treatment in some specific subgroups. METHODS Publication search For inclusion in our research, randomized controlled trials of gefitinib therapy in English literature were eligible for inclusion in our meta-analysis, regardless of the publication status (published, unpublished, in press, and in progress). Relevant trials were identified by the following procedure: (1) Electronic searches: we DOI: 10.3760/cma.j.issn.0366-6999.20122920 Department of Chemotherapy, Sichuan Cancer Hospital, Chengdu, Sichuan 610041, China (Zhou H, Wang LY, Xie H, Zhou J, Diao P, Yao WX, Zhao X and Wei Y) Department of Gastroenterology, Third People’s Hospital of Chengdu, Chengdu, Sichuan 610031, China (Zeng C) Correspondence to: Dr. YAO Wen-xiu, Department of Chemotherapy, Sichuan Cancer Hospital, Chengdu, Sichuan 610041, China (Tel & Fax: 86-28-85420847. Email: yaowenxiu_2011@126.com)
  2. 2. Chinese Medical Journal 2013;126 (17) searched the electronic databases Medline, EmBase, and the Cochrane Central Register of Controlled Trials for articles up to 20 January 2012, using “gefitinib”, “clinical trial” and “randomized controlled trial” as the search terms. All reference lists from reports on non-randomized controlled trials were searched manually for additional eligible studies; (2) Other sources: we contacted authors to obtain any possible additional published or unpublished data, and searched the proceedings of annual meetings in the Cochrane Cardiovascular Disease Group Specialized Register. The relevant reviews and meta-analyses regarding the role of gefitinib therapy for NSCLC patients were examined for potential inclusive trials. In addition, we searched for ongoing randomized controlled trials, which had been registered as completed but not yet published, in the metaRegister of Controlled Trials. Medical subject headings and methods, patient population, and intervention were used to identify the relevant trials. Inclusion criteria The literature search was undertaken independently by three authors (Zhou H, Zeng C, and Wang LY) with a standardized approach, and any disagreement between these three authors was settled by a fourth author (Yao WX) until a consensus was reached. All completed randomized controlled trials assessing the effects of gefitinib therapy compared to the effects of a non-gefitinib therapy, and reporting at least one of the primary outcomes were included as eligible trials. Data extraction and quality assessment Two investigators (Xie H and Zhou J) independently extracted and collected data using a standardized dataextraction protocol. Disagreements were adjudicated by a third reviewer (Wei Y) after referring to the original articles. The data collected included baseline patient characteristics (number of patients, age, sex, pre-existing diseases, interventions, disease status, treatment status, and duration of follow-up), publication details, and methodological components. The outcomes investigated included overall survival (OS), progression free survival (PFS), objective tumor response rate (ORR), and possible drug-correlated adverse reactions. The quantitative 5-point Jadad score20 was used to assess the quality of the inclusive trials based on randomization, concealment of treatment allocation, blinding, completeness of follow-up, and use of intentionto-treat analysis (Diao P and Zhao X). Statistical analysis The primary efficacy outcomes of our meta-analysis were OS and PFS. The log hazard ratios (HRs) and their variances were estimated using the methods proposed by Parmar21 and confidence intervals (CIs) of HRs were reported. The summary of HRs and their 95% CIs were estimated using a general variance-based method. For ORR and possible drug-correlated adverse reactions, the pooled estimation plotted as odd ratios (ORs) were obtained. The 3349 subgroup analyses were prospectively planned according to number of patients, median age, gender, control drug, treatment status, follow-up, smoker, racial, disease status, pre-existent disease, EGFR FISH, and Jadad score. Heterogeneity between trials was evaluated by the Chisquare test and I-squared statistic. These indices assess the percentage of variability across studies attributable to heterogeneity rather than chance. Statistical heterogeneity was considered significant when P <0.10.22 Although the fixed-effects model and random-effects model yielded similar conclusions, we chose to use the random-effects model, which assumed that the true underlying effect varied among included trials. Moreover, many investigators consider the random-effects model to be a more natural choice than the fixed effects model in medical decisionmaking contexts.23,24 The probability of publication bias was assessed with the funnel plots and the Egger test.25 All reported P values were two-sided and P values less than 0.05 were regarded as statistically significant. Statistical analyses were carried out using STATA 10.0 (StataCorp, USA). RESULTS Search of the published literature We identified 182 potentially relevant trials from our initial electronic search, and excluded 136 trials after a preliminary review. The remaining 46 studies were assessed in detail and 12 randomized controlled trials met the inclusion criteria (Figure 1), which included 6844 patients with NSCLC. All the included trials were published in full text. Table 1 summarized the baseline characteristics of the participants and the design of the studies included. Characteristics of the included studies The trials included in this study compared gefitinib therapy with the non-gefitinib control. The follow-up for patients ranged from 7.2 to 60.0 months, with a mean of 33 months. The population of the trials ranged from 161–1692 patients, with a mean of 570. Jadad scale was used to assess the quality of the included trials. Seven trials had a score of 4, Figure 1. Diagram of the literature search and trial selection process.
  3. 3. Chin Med J 2013;126 (17) 3350 Table 1. Baseline characteristics for included trials Trials ISEL (2005)14 INVITE (2008)15 V-15-32 (2008)16 SWOG S0023 (2008)17 INTEREST (2008)18 INSTEP (2009)19 IPASS (2009)8 Number of Median age Sex, male Stage IIIB Patients (years) (%) or IV (%) 1692 62 67 81 196 74 76 100 489 20 years or older 62 83 243 61 63 52 1466 61 65 79 201 75 61 NG 1217 57 21 100 ISTANA (2010)9 WJTOG 3405 (2010)10 161 172 57 64 61 31 100 59 North-East Japan (2010)11 230 63 36 91 WJTOG 0203 (2010)12 604 62 64 100 EORTC 08021/ILCP 01/03 (2011)13 173 62 77 100 and the remaining five trials had a score of 3. Overall survival Data for OS were available from 11 trials, which consisted of 6614 patients with NSCLC. We noted that gefitinib therapy had an 8% improvement in the OS as compared to the gefitinib-free treatment arm (HR, 0.92; 95% CI: 0.85–1.00; P=0.051; Figure 2) under a random-effect model, but was not associated with a statistically significant Second line First line First line Second line Second line Second line First line Follow-up (months) 7.2 20 36 60 7.6 24 24 OS, ORR OS, PFS, ORR OS, PFS, ORR OS, PFS OS, PFS, ORR OS, PFS, ORR OS, PFS, ORR 4 3 3 3 4 4 4 Second line Second line 15 40 OS, PFS, ORR OS, PFS, ORR 3 3 First line 42 PFS, ORR 4 First line 60 OS, PFS, ORR 4 Second line 60 OS, PFS, ORR 4 Intervention Treatment status Gefitinib; placebo Gefitinib; vinorelbine Gefitinib; docetaxel Gefitinib; placebo Gefitinib; docetaxel Gefitinib; placebo Gefitinib; carboplatin plus paclitaxel Gefitinib; docetaxel Gefitinib; cisplatin plus docetaxel Gefitinib; paclitaxel and carboplatin Gefitinib; platinumdoublet chemotherapy Gefitinib; placebo Main endpoint Jadad score improvement in the OS. In addition, heterogeneity was observed in the magnitude of the effect across the trials included. According to a sensitivity analysis, we excluded the V-15-32 study.16 This trial specifically included patients were more younger, and the proportion of IIIB or IV was less than other trials. After this, we could conclude that gefitinib therapy yielded a clinically and statistically significant 9% improvement in OS compared with gefitinibfree therapy (HR, 0.91; 95% CI: 0.84–0.98; P=0.015; Table 2. Summary of the odds ratios of all toxicities outcomes assessed Outcomes Rash Diarrhoea Nausea Anorexia Vomiting Dry skin Constipation Pruritus Pyrexia Asthenic condition Cough Dyspnea Stomatitis Hemoptysis Pneumonia Cancer pain Edema peripheral Paronychia Fatigue Anemia Hypokalemia Neutropenia Leukopenia Febrile neutropenia Upper abdominal pain Abnormal hepatic function Insomnia Alopecia Myalgia Neurotoxicity Arthralgia Dyspepsia Dizziness Sensory disturbance Thrombocytopenia Included studies 8–16,18,19 8–16,18,19 8–10,12,14–16,18,19 8,9,11,12,14–16,18,19 8,9,11,12,14–16,18,19 8,9,11,12,14–16,18,19 8–10,12,14–16,18,19 8,9,14,16,19 14–16,18 8,9,14,15,18 9,13,14,18 9,10,13–15,18,19 8–10,12,14,16,18, 9,14 11–14,18,19 9,13,14 14–16,18,19 8–10,14,16 10–13,15,16,19 10–13,15,18,19 13,15 10–13,15,16,18 10,12,15,16 8,12,15,16,18 9,15,19 13,16 9,16,19 8–10,16,18 8,9,16,18 8,9,13,16 8,9,13 9,11,13 9,13 10–12 10–13 OR and 95% CI 8.73 (6.13, 12.45) 2.63 (1.96, 3.52) 0.47 (0.28, 0.79) 0.70 (0.47, 1.06) 0.88 (0.54, 1.45) 10.37 (5.98, 18.01) 0.56 (0.40, 0.78) 3.03 (1.67, 5.49) 0.79 (0.41, 1.53) 0.45 (0.25, 0.80) 0.94 (0.76, 1.17) 0.96 (0.79, 1.17) 1.24 (0.77, 2.00) 1.34 (0.86, 2.11) 0.97 (0.70, 1.34) 0.69 (0.37, 1.28) 0.47 (0.33, 0.68) 14.00 (1.14, 171.75) 0.35 (0.19, 0.63) 0.29 (0.14, 0.61) 0.34 (0.09, 1.34) 0.05 (0.01, 0.28) 0.08 (0.01, 0.69) 0.19 (0.05, 0.70) 0.61 (0.20, 1.82) 5.76 (3.15, 10.55) 1.36 (0.60, 3.10) 0.06 (0.05, 0.09) 0.18 (0.14, 0.24) 0.19 (0.05, 0.65) 0.15 (0.04, 0.55) 0.45 (0.05, 3.89) 1.09 (0.40, 2.93) 0.13 (0.02, 0.77) 0.37 (0.20, 0.71) P values <0.001 <0.001 0.004 0.09 0.62 <0.001 <0.001 <0.001 0.48 0.006 0.59 0.68 0.38 0.20 0.85 0.24 <0.001 0.04 <0.001 0.001 0.12 <0.001 0.02 0.01 0.37 <0.001 0.46 <0.001 <0.001 0.008 0.004 0.47 0.87 0.02 0.003 Heterogeneity (%) 77 73 93 87 87 64 76 79 85 91 0 0 79 0 13 31 38 87 78 84 0 98 97 88 53 0 66 38 4 95 83 88 0 86 51 P values for heterogeneity <0.001 <0.001 <0.001 <0.001 <0.001 0.004 <0.001 <0.001 <0.001 <0.001 0.61 0.79 <0.001 0.37 0.33 0.23 0.17 <0.001 <0.001 <0.001 0.38 <0.001 <0.001 <0.001 0.12 0.68 0.05 0.17 0.37 <0.001 0.003 <0.001 0.45 <0.001 0.11
  4. 4. Chinese Medical Journal 2013;126 (17) 3351 Overall, we noted that gefitinib therapy yielded a clinically and statistically significant 28% improvement in PFS as compared to the traditional chemotherapy without gefitinib (HR, 0.72; 95% CI 0.60–0.87, P=0.001, Figure 3). Although there was some evidence of heterogeneity across the studies included, however, after sequential exclusion of each trial from all pooled analysis, the results were not affected by the exclusion of any specific trial. Overall response rate Data for ORR was available from 11 trials including 6601 patients. Overall, we noted that gefitinib therapy increased the objective response rate by 151% when compared to gefitinibfree therapy (OR, 2.51; 95% CI: 1.67‒3.78, P <0.001, Figure 4). Furthermore, there was a evidence of heterogeneity for ORR among the included trials (Figure 4). A sensitivity analysis indicated that the results were not affected by sequential exclusion of any particular trial from all pooled analysis. Toxicity Data concerning AEs were e x t r a c t e d f r o m 11 t r i a l s ; a summary of the drug-related toxicities was shown in Table 2. Overall, the pooled OR of each kind of toxicity indicated that a significant increase associated with gefitinib therapy was observed for ashes, diarrhea, dry skin, pruritus, paronychia, abnormal hepatic function compared to traditional chemotherapy. C o n v e r s e l y, w e a l s o n o t e d that gefitinib protected against nausea, constipation, asthenic condition, peripheral edema, Figure 2. Comparison of the overall survival between gefitinib therapy and gefitinib-free therapy. Figure 3. Comparison of the progression-free survival between gefitinib therapy and gefitinib-free fatigue, anemia, neutropenia, therapy. leukopenia, febrile neutropenia, Figure 4. Comparison of the objective response rate between gefitinib therapy and gefitinib-free alopecia, myalgia, neurotoxicity, therapy. arthralgia, sensory disturbance, and thrombocytopenia, when compared to gefitinib-free Figure 2). therapy. Furthermore, we noted that heterogeneity among trials was found in these analyses, possibly due to the Progression-free survival use of different agents at various dosages and the use of Eleven trials including 5152 patients provided PFS results.
  5. 5. Chin Med J 2013;126 (17) 3352 Table 3. Subgroup analysis for the effect of Gefitinib therapy on OS and PFS Variables OS Number of patients ≥1000 <1000 Median age <64 ≥64 Gender (male, %) >65% <65% Control drug Traditional chemotherapy Placebo Treatment status First line Second line Follow-up ≥36 months <36 months Smoker Never smoker Current/former smoker Racial Asian Non-Asian Disease status (IIIB or IV) ≥90% <90% Pre-existent diseases Adenocarcinoma Non-adenocarcinoma EGFR FISH Positive Negative Jadad score 4 <4 PFS Number of patients ≥1000 <1000 Mean age <64 ≥64 Gender (male, %) >65% <65% Drug Traditional chemotherapy Placebo Treatment status First line Second line Follow-up ≥36 months <36 months Smoker Never smoker Current/former smoker Racial Asian Non-Asian Disease status (IIIB or IV) ≥90% <90% Pre-existent diseases Adenocarcinoma Non-adenocarcinoma EGFR FISH Positive Negative Jadad score 4 <4 Hazard ratio (HR) P values Heterogeneity (%) P values for heterogeneity 0.95 (0.87−1.04) 0.90 (0.78−1.03) 0.266 0.110 16.1 32.2 0.304 0.171 0.92 (0.84−1.00) 0.96 (0.73−1.26) 0.061 0.761 36.1 19.5 0.141 0.289 0.95 (0.88−1.04) 0.90 (0.79−1.03) 0.282 0.126 0 39.5 0.414 0.128 0.97 (0.89−1.06) 0.85 (0.76−0.95) 0.517 0.004 7.7 0 0.369 0.397 0.94 (0.84−1.06) 0.90 (0.79−1.02) 0.319 0.085 11.9 40.0 0.333 0.125 0.90 (0.73−1.12) 0.94 (0.87−1.02) 0.345 0.124 59.6 0 0.042 0.666 0.76 (0.59−0.98) − 0.034 − 19.0 − 0.291 − 0.91 (0.78−1.06) 0.87 (0.78−0.97) 0.216 0.015 48.5 0 0.084 0.409 0.88 (0.79−0.98) 0.96 (0.81−1.13) 0.025 0.593 0 62.6 0.964 0.030 0.85 (0.76−0.95) − 0.005 − 0 − 0.599 − 1.14 (0.18−7.16) 0.89 (0.59−1.33) 0.14 0.59 87.9 0 0.004 0.539 0.93 (0.86−0.99) 0.94 (0.73−1.21) 0.031 0.646 0 55.2 0.505 0.063 0.88 (0.63−1.23) 0.68 (0.54−0.86) 0.447 0.001 92.8 83.8 <0.001 <0.001 0.70 (0.56−0.87) 0.79 (0.49−1.27) 0.002 0.329 89.4 83.6 <0.001 0.002 0.92 (0.65−1.29) 0.66 (0.54−0.81) 0.623 <0.001 82.5 82.3 0.003 <0.001 0.71 (0.56−0.91) 0.73 (0.61−0.89) 0.006 0.001 90.7 7.7 <0.001 0.339 0.70 (0.51−0.95) 0.75 (0.58−0.95) 0.024 0.017 90.9 79.6 <0.001 <0.001 0.60 (0.45−0.81) 0.88 (0.72−1.08) 0.001 0.228 86.2 78.5 <0.001 0.001 0.48 (0.33−0.70) − <0.001 − 0 − 0.832 − 0.62 (0.48−0.79) 0.83 (0.63−1.08) <0.001 0.161 86.6 64.5 <0.001 0.037 0.66 (0.50−0.86) 0.81 (0.62−1.06) 0.002 0.128 87.4 80.8 <0.001 0.001 0.63 (0.42−0.93) − 0.021 − 76 − 0.041 − 0.76 (0.22−2.65) 1.29 (0.53−3.15) 0.665 0.579 91.0 90.9 <0.001 <0.001 0.67 (0.50−0.88) 0.80 (0.62−1.03) 0.005 0.080 92.2 70.2 <0.001 0.009
  6. 6. Chinese Medical Journal 2013;126 (17) different control arms. No other significant differences were identified between the effect of gefitinib therapy and control for adverse events. Subgroup analysis Subgroup analyses were carried out for overall survival and progression free survival. Overall, we noted that gefitinib therapy was associated with an improvement of the overall survival when compared to placebo, never smoker, nonAsian, IIIB or IV ≥90%, patients with adenocarcinoma, or Jadad score more than 3. Similarly, gefitinib therapy produced a statistically significant improvement of PFS when the number of patients was <1000, mean age <64, the proportion of male <65%, compared to traditional chemotherapy/placebo, first-line, second-line, followup more than 36 months, never smoker, Asian, IIIB or IV ≥90%, patients with adenocarcinoma, or Jadad score more than 3. Publication bias We used Egger’s test25 to check for potential publication bias, which showed no evidence of publication bias for the outcomes of OS (P value for Egger’s test, 0.643) , PFS (P value for Egger’s test, 0.170), and ORR (P value for Egger’s test, 0.105). DISCUSSION The goal of the treatment of NSCLC was to prolong survival time and prevent disease recurrence after therapy.5 Current third-line chemotherapy regimens provide little benefit, and the small survival benefits obtained with these treatment regimens are commonly balanced by their substantial toxic effects. For patients who are refractory to or intolerant of the current chemotherapy regimens, currently treatment options are limited and new therapies are needed.5,26,27 Several strategies were proposed to overcome this lowvalid. The most important one was that gefitinib therapy, which was the first targeted drug to enter clinical use for the treatment of lung cancer.28,29 However, several randomized controlled trials reported an inconsistent conclusion on OS, PFS, and ORR by gefitinib therapy in patients with NSCLC as compared to the traditional chemotherapy or placebo. Therefore, the goal of our research was to perform a comprehensive, updated meta-analysis of randomized controlled trials, which included all currently available clinical trials. This large quantitative review included 6844 patients with NSCLC in 12 trials with a broad range of baseline characteristics. The main finding of our research suggested that gefitinib therapy had a clear effect on PFS and ORR; furthermore, a sensitivity analysis and subgroup analysis indicated that gefitinib therapy might contribute an important role for OS. In addition, gefitinib was associated with significantly less toxicity than traditional chemotherapy and improved quality-of-life. 3353 In contrast with previous research, 30 these findings supported that as an adjunctive therapy gefitinib does not have significant benefits or harm in OS; however, subgroup analysis demonstrated that gefitinib therapy had a clear effect in the improvement of OS when compared to placebo. The reason for these could be that although traditional chemotherapy contributed a little, which are commonly a balanced gefitinib effect on the overall survival. Similarly, we also noted that gefitinib produced an important role for OS in patients who previously never smoke. The reason could be that patients currently smoking or who were formerly smoking with impaired lung function, could contribute an important role in the lessened therapy effect by gefitinib. Furthermore, gefitinib produced a clear effect when proportion of IIIB or IV ≥90%, and patients with adenocarcinoma, the reason could be that gefitinib has emerged as a new drug commonly used for advanced NSCLC. Our research also supported that nonAsian patients gained more benefit from gefitinib in times of treatment failure. These results are also consistent with previous randomized controlled trials. The results of our research demonstrated that gefitinib yielded a statistically significant benefit in PFS as compared to gefitinib-free therapy; however, it should be noted that progression-free survival was not improved when the number of patients was more than 1000, median age was more than 64, the proportion of male was more than 65, the follow-up time was less than 36 months, non-Asian, the proportion of IIIB or IV was lesser than 90, EGFR FISH positive or negative, Jadad score less than 4. The reason could be that less trials reported progression-free survival data in some subsets, while other reasons similarly to the overall survival. In contrast with previous meta-analysis, improvement in the objective response rate also detected between gefitinib and gefitinib-free therapies. Previous research31,32 indicated that gefitinib was active in NSCLC, with confirmed objective response rates of 12%–18%. The significant improvements in time to treatment failure and objective response rate seen with gefitinib in our research are consistent with these previous studies. Some drug-related toxicity was significantly more frequent in patients who received gefitinib therapy. We noted that rashes, diarrhea, dry skin, pruritus, paronychia, and abnormal hepatic function were more frequent in the gefitinib therapy group. In addition, gefitinib also protected against nausea, constipation, asthenia condition, peripheral edema, fatigue, anemia, neutropenia, leucopenia, febrile neutropenia, alopecia, myalgia, neurotoxicity, arthralgia, sensory disturbance, and thrombocytopenia as compared to traditional chemotherapy. We easily concluded that gefitinib was a promising therapy in patients with NSCLC, which contributed to less toxicity than the traditional chemotherapy and significantly improved the quality-oflife. Although the benefit of gefitinib therapy may be lessened or balanced by some drug-related toxicity, however, gefitinib
  7. 7. Chin Med J 2013;126 (17) 3354 as an adjunctive therapy could improve PFS, ORR, and could lessen drug-related toxicities compared to traditional chemotherapy. In addition, we should considered patients’ baseline characteristics before any therapeutic decision is made to ensure the patients with the best therapy. The main purpose of our research was to present all available evidence in a systematic, quantitative, and unbiased fashion. The findings of this meta-analysis suggested that gefitinib therapy produced a significant improvement in the progression-free survival, objective response rate, and it might also play an important role in the overall survival. Compared to previous research, our research provided a more detailed conclusion on OS and drug-related toxicities information. As compared to individual trials, our research provided a conclusion for the effect of gefitinib therapy in patients with advanced NSCLC. The limitations of our research are as follows: (1) although subgroup analysis suggested that gefitinib significantly improved the OS and PFS for patients with adenocarcinoma, however, these results may be variable because of the small number of trials (only three trials) that provided such a subset of survival data; (2) data on quality of life were rarely available in these trials and no conclusions could be drawn; (3) inherent assumptions made for any meta-analysis, because the analysis used pooled data either published or provided by individual study authors, and individual patients survival data or original data were unavailable, which restricted us from doing a more detailed and relevant analysis and obtaining more comprehensive results. In conclusion, the findings of this study also supported previous findings that the gefitinib therapy had a clear effect on the PFS and ORR. A sensitivity analysis and subgroup analysis also demonstrated that gefitinib therapy might play an important role on the OS. Future focus will be on the identification of predictive markers which may enable treatments to be targeted to specific patient groups and thereby translate it into improved outcomes. Furthermore, subgroup analysis in individual trial needs a more detailed and formulated report. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. REFERENCES 1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin 2009; 59: 225-249. 2. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for nonsmall-cell lung cancer. N Engl J Med 2006; 355: 2542-2550. 3. Eton DT, Fairclough DL, Cella D, Yount SE, Bonomi P, Johnson DH, et al. Early change in patient-reported health during lung cancer chemotherapy predicts clinical out-comes beyond those predicted by baseline report: results from Eastern Cooperative Oncology Group Study 5592. J Clin Oncol 2003; 21: 1536-1543. 4. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for 16. 17. 18. 19. advanced non-small-cell lung cancer. N Engl J Med 2002; 346: 92-98. Cohen MH, Williams GA, Sridhara R, Chen G, Pazdur R. FDA drug approval summary: gefitinib (ZD1839) (Iressa) tablets. Oncologist 2003; 8: 303-306. Hirsch FR, Marileila VG, Bunn PA Jr, Franklin WA, Dziadziuszko R, Thatcher N, et al. Molecular predictors of outcome with Gefitinib in a Phase III Placebo-controlled study in advanced non-small cell lung cancer. J Clin Oncol 2006; 24: 5034-5042. Kris MG, Natale RB, Herbst RS, Lynch TJ Jr, Prager D, Belani CP, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 2003; 290: 2149-2158. The [IPASS] study. Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma. N Engl J Med 2009; 361: 947-957. The ISTANA study. Randomized phase III trial of gefitinib versus docetaxel in non-small cell lung cancer patients who have previously received platinum-based chemotherapy. Clin Cancer Res 2010; 16: 1307-1314. The WJTOG 3405 study. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 2010; 11: 121-128. The North-East Japan Study Group. Gefitinib or chemotherapy for non small cell lung cancer with mutated EGFR. N Engl J Med 2010; 362: 2380-2388. The WJTOG 0203 study. Randomized Phase III trial of platinum-doublet chemotherapy followed by Gefitinib compared with continued platinum-doublet chemotherapy in Japanese patients with advanced non-small-cell lung cancer: results of a West Japan Thoracic Oncology Group Trial (WJTOG0203). J Clin Oncol 2010; 28: 753-760. The EORTC 08021/ILCP 01/03 study. A double-blind, randomised, placebo-controlled phase III intergroup study of gefitinib in patients with advanced NSCLC, non-progressing after first line platinum-based chemotherapy (EORTC 08021/ ILCP 01/03). Eur J Cancer 2011; 47: 2331-2340. The ISEL study. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005; 366: 1527-1537. The INVITE study. Gefitinib versus Vinorelbine in chemotherapy-naive elderly patients with advanced non-smallcell lung cancer (INVITE): a randomized, phase II study. J Clin Oncol 2008; 26: 4253-4260. The V-15-32 study. Phase III Study, V-15-32, of Gefitinib versus Docetaxel in previously treated japanese patients with nonsmall-cell lung cancer. J Clin Oncol 2008; 26: 4244-4252. The SWOG S0023 study. Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J Clin Oncol 2008; 26: 2450-2456. The INTEREST study. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 2008; 372: 1809-1818. The INSTEP study. Randomized phase II study of gefitinib
  8. 8. Chinese Medical Journal 2013;126 (17) 20. 21. 22. 23. 24. 25. 26. 27. compared with placebo in chemotherapy-naive patients with advanced non-small-cell lung cancer and poor performance status. J Clin Oncol 2009; 27: 2253-2260. 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. Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 1998; 17: 2815-2834. Deeks JJ, Higgins JPT, Altman DG. Analyzing data and undertaking meta-analyses. In: Higgins J, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions 5.0.1. Oxford, UK: The Cochrane Collaboration; 2008: chapter 9: 1-2. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7: 177-188. Ades AE, Lu G, Higgins JP. The interpretation of random-effects meta-analysis in decision models. Med Decis Making 2005; 25: 646-654. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315: 629-634. Inoue A, Suzuki T, Fukuhara T, Maemondo M, Kimura Y, Morikawa N, et al. Prospective phase II study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations. J Clin Oncol 2006; 24: 3340-3346. Tamura K, Okamoto I, Kashii T, Negoro S, Hirashima T, Kudoh S, et al. Multicentre prospective phase II trial of gefitinib for 3355 28. 29. 30. 31. 32. advanced non-small-cell lung cancer with epidermal growth factor receptor mutations: results of the West Japan Thoracic Oncology Group trial (WJTOG0403). Br J Cancer 2008; 98: 907-914. Massarelli E, Andre F, Liu DD, Lee JJ, Wolf M, Fandi A, et al. A retrospective analysis of the outcome of patients who have received two prior chemotherapy regimens including platinum and docetaxel for recurrent non-small-cell lung cancer. Lung Cancer 2003; 39: 55-61. Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O’Rourke M, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000; 18: 2095-103. Ku GY, Haaland BA, de Lima Lopes, Lopes G Jr. Gefitinib vs. chemotherapy as first-line therapy in advanced non-small cell lung cancer: meta-analysis of phase III trials. Lung Cancer 2011; 74: 469-473. Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced nonsmall-cell lung cancer. J Clin Oncol 2003; 21: 2237-2246. Miller VA, Kris MG, Shah N, Patel J, Azzoli C, Gomez J, et al. Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. J Clin Oncol 2004; 22: 1103-1109. (Received October 23, 2012) Edited by CUI Yi

×