|Year : 2014 | Volume
| Issue : 7 | Page : 86-91
The comparisons of the efficacy and toxicity between gefitinib and docetaxel for patients with advanced nonsmall-cell lung cancer: A meta-analysis from randomized controlled clinical trials
YL Zhao1, S Han2, R Pu3, LW Shi4
1 School of Pharmaceutical Science, Peking University, Beijing 100191, China
2 School of Public Health; International Research Center of Medicinal Administration, Peking University, Beijing 100191, China
3 China National Center for Biotechnology Development, Beijing 100039, China
4 School of Pharmaceutical Science; International Research Center of Medicinal Administration, Peking University, Beijing 100191, China
|Date of Web Publication||27-Mar-2015|
L W Shi
School of Pharmaceutical Science; International Research Center of Medicinal Administration, Peking University, Beijing 100191
Source of Support: None, Conflict of Interest: None
Background: The extent of the benefit of gefitinib in the treatment of advanced nonsmall-cell lung cancer (NSCLC) is till controversial, when compared with docetaxel. We performed this meta-analysis to compare the efficacy and toxicity of gefitinib with docetaxel for different patients with advanced NSCLC. Materials and Methods: We searched PubMed, Cochrane Library, and identified 5 randomized controlled clinical trials published within 2000-2013. After further full-text screening, 4 clinical trials were included in the final meta-analysis. Results: The outcomes of treatment efficacy included progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). Comparing gefitinib to docetaxel for advanced NSCLC patients, the pooled hazard ratio (HR) of PFS was 0.91, (95% confidential index [CI] = 0.83-0.99), the pooled HR of OS was 1.02, (95% CI = 0.93-1.13), the pooled risk ratio of ORR was 1.57, (95% CI = 1.01-2.47). Conclusions: Gefitinib was found to significantly improve patients' PFS and response rate compared with docetaxel. There is no difference of OS between gefitinib and docetaxel.
Keywords: Docetaxel, gefitinib, meta-analysis, NSCLC
|How to cite this article:|
Zhao Y L, Han S, Pu R, Shi L W. The comparisons of the efficacy and toxicity between gefitinib and docetaxel for patients with advanced nonsmall-cell lung cancer: A meta-analysis from randomized controlled clinical trials. Indian J Cancer 2014;51, Suppl S3:86-91
|How to cite this URL:|
Zhao Y L, Han S, Pu R, Shi L W. The comparisons of the efficacy and toxicity between gefitinib and docetaxel for patients with advanced nonsmall-cell lung cancer: A meta-analysis from randomized controlled clinical trials. Indian J Cancer [serial online] 2014 [cited 2021 May 13];51, Suppl S3:86-91. Available from: https://www.indianjcancer.com/text.asp?2014/51/7/86/154070
| » Introduction|| |
Lung cancer is a common cause of cancer-related mortality worldwide, ,, in which nonsmall-cell lung cancer (NSCLC) accounts for approximately 80-85% of all cases of lung cancer, and presents as locally advanced NSCLC in 25-30% of cases and as metastatic disease in 40-50% of cases.  Usually, surgical resection (lobectomy and pneumonectomy) is the first option for the curative intent. Even though, recurrence was still occurred to many patients with advanced NSCLC who undergo complete resection, and the 5-year survival is <25% for those treated with surgery alone.  For those that are unable to tolerate surgical operations, chemotherapy or best supportive care are the principal therapies. But the response rates are disappointing, and recurrence eventually occurred in most patients.
Cytotoxic agents, like docetaxel, and targeted treatment such as gefitinib, an epidermal growth-factor receptor (EGFR) family tyrosine kinase inhibitor, are two promising alternatives.  Two phase III trials have approved Docetaxel as the second-line treatment for advanced NSCLC, for docetaxel improved the survival and quality of life (QoL) when compared with best supportive care or vinorelbine or ifosfamide. , However, severe side-effects, such as diarrhea, neuropathy and frequent grade 3 and 4 neutropenia, were accompanied with docetaxel. 
Molecular-targeted agents, such as gefitinib and erlotinib, have been suggested as potential alternatives to increase efficacy and decrease toxic effects in patients with advanced or recurrent NSCLC.  Two randomized, phase II trials demonstrated that treatment with gefitinib (250 mg/day, orally) provided symptom relief and showed a QoL improvement as a second-line or third-line treatment. , Furthermore, gefitinib has been indicated as a first-line treatment for patients with advanced NSCLC, especially for those with activating EGFR mutations and high EGFR gene-copy number. , Interestingly, a subsequent erlotinib administration after gefitinib failure as first-line therapy represent a better therapeutic option for advanced NSCLC patients with poor performance status. 
Based on these, several clinical trials were conducted to compare the efficacy and toxicity of gefitinib with docetaxel. However, their results were inconsistent attributed to different inclusion and exclusion criteria. To this end, we performed an updated meta-analysis to systematically study the efficacy of gefitinib for advanced NSCLC patients. Our meta-analysis is different from the previous one in providing more information for future research, which will help make evidence-based clinical decisions for the treatment of advanced NSCLC.
| » Materials and Methods|| |
An electronic search on the PubMed database and the Cochrane Central Register of Controlled Trials database were performed, with the keywords ("NSCLC" OR "Neoplasm, nonsmall-cell Lung" OR "NSCLC") AND ("gefitinib" OR "Iressa"). The published language was limited to English and the years were limited from January 2000 to December 2013. Also, the reference lists of related articles and review articles were screened.
Eligible references were selected carefully based on the following criteria: (1) Randomized controlled trial (RCT); (2) patients with historically or cytologically confirmed stage IIIB, stage IV or recurrent NSCLC; (3) studies comparing the efficacy and toxicity of gefitinib with docetaxel; (4) information collected including response rate, hazard ratio (HR) for progression-free survival (PFS) and overall survival (OS), along with the 95% confidential indexes (CIs).
When included references referred to same studies, the most recently published papers were chosen.
The Jadad scale, a 5-point scale system, was used to evaluate the methodological quality of trials, which assessed randomization (0-2 points), double-blind (0-2 points), and follow-up (0-1 points).  The Jadal scale has total scores ranged from 0 to 5, and clinical trials are defined as "good" when the score is from 3 to 5.
Two reviewers independently extracted all the data with the use of standardized data-abstraction forms. Disagreements were resolved by consensus. The following information were collected from each study, although some information was not contained in some trials: Trial's name, first author, year of publication, number of patients enrolled in each trial, patient characteristics (including median age, gender, smoking history, WHO performance status, tumor histology, previous response to chemotherapy, and EGFR mutation status), type of first-line chemotherapy, number of centers, study design (blinded or not) and outcomes. Outcomes included objective response rate (ORR), median PFS and OS, HRs for PFS and OS and their 95% CIs, and side-effects (such as nausea, vomiting, diarrhea, neutropenia, fatigue and rash).
All the analysis was performed in RevMan 5.3 software (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). The pooled HRs for PFS, OS, pooled risk ratios (RRs) for ORR, FACT-L, TOI, and LCS were calculated. The statistical heterogeneity between trials was evaluated by the Chi-squared Q-test based on the fixed-effect model. When the P value of the Q-test was less than 0.1, or when I2 was greater than 50%, it represented heterogeneous between clinical trials. Then, a random effect model was used to accommodate the heterogeneity. Furthermore, we performed the leave-one-out strategy to test the influence of each trial on the heterogeneity.
| » Results|| |
After systematic database searched and manual review of reference lists in the eligible studies, a total of 164 publications were preliminarily included. Based on the selection criteria, 5 clinical trials comparing the efficacy and toxicity of gefitinib with docetaxel in advanced NSCLC were included in the present this meta-analysis. ,,,, After full-text reviewed, only one trial, named IFCT-0301, compared the efficacy of gefitinib with docetaxel as the first-line treatment for NSCLC patients with performance status of 2 and 3, in which they only provided median PFS and median survival time.  The flow of this search strategy is shown in [Figure 1].
The characteristics of all these five clinical trials, such as the basic information of the enrolled patients, their performance status, histological status, smoking history, and previous treatment regimens, were listed in [Table 1]. Briefly, all these 5 clinical trials are multicenter, randomized, and open-label studies. Two of them were phase II trials , and the other three were phase III RCT [Table 2]. The quality of these enrolled trials was scored according to Jadad's scale and listed in [Table 2]. In total, 2344 enrolled patients were randomly assigned to receive either gefitinib (250 mg/d orally, 1171 patients) or docetaxel (75 mg/m 2 intravenously every 3 weeks, 1173 patients). All patients received treatment until disease progression, intolerable toxicity, or discontinuation for another reason, except ISTANA trial, in which it limited the maximum docetaxel administration to 6 cycles.
In these four trials, the HRs for PFS were derived from the supportive adjusted model. The pooled HR for PFS showed significant difference between gefitinib and docetaxel group [HR = 0.91, 95% CI = 0.83-0.99, P = 0.04, [Figure 2]], indicating a gefitinib advantage over docetaxel for patients with advanced NSCLC.
|Figure 2: Forest plot of comparison for progression-free survival (PFS) between gefitinib and docetaxel in advanced NSCLC|
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The pooled HRs for OS displayed no significant difference between gefitinib and docetaxel groups [HR = 1.02, 95% CI = 0.93-1.13, [Figure 3]a]. Three trials reported 6-month survival rate, ,, whereas another three trials reported 1-year survival rate. ,, The pooled OR for 6-month survival rate was 1.97, [95% CI = 1.18-3.32, [Figure 3]b, and for 1-year survival rate was 1.09, [95% CI = 0.90-1.32, [Figure 3]b], indicating no significant difference between these two groups. However, a great heterogeneity was exhibited in these two subgroups (I2 = 84% and 86%, respectively), although a random-effect model was performed. By leave-one-out strategy, we found that Morere's trial was the attribution of the heterogeneity for 6-month survival rate, whereas Maruyama's trial was the one for 1-year survival rate. After excluding this trial, the I2 for 6-month and 1-year survival rate was 19% and 16%, respectively. Meanwhile, the pooled OR for 6-month survival rate was 1.97 (95% CI = 1.18-3.32) after excluding the trial, suggesting a significant difference between gefitinib and docetaxel (data not shown). However, the pooled OR for 1-year survival rate has no change when the trial was exclusion. Overall, the noninferiority of gefitinib to docetaxel was proved in terms of survival rate.
|Figure 3: (a) Forest plot of comparison for the overall survival (OS) between gefitinib and docetaxel group. (b) Forest plot of comparison for the 6-month and one-year survival rate between gefitinib and docetaxel group|
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Objective response rate
The pooled RRs for ORR were significantly different between gefitinib and docetaxel group [RR = 1.57, 95% CI = 1.01-2.47, [Figure 4], indicating gefitinib benefit in the ORR. However, there was a great heterogeneity between these two groups (I2 = 59%), although a random-effect model was performed. Then, the leave-one-out strategy was used to test the influence of each individual trial on the heterogeneity. After Lee's trial was excluded,  it showed no heterogeneity (I2 = 14%, data not shown), while the pooled RRs for ORR exhibited no significant difference (RR = 1.34, 95% CI = 0.99-1.80, data not shown).
|Figure 4: Forest plot of comparison for the objective response rate (ORR) between gefitinib and docetaxel group|
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Quality of life
All the 4 trials reported the FACT-L data, while 3 trials reported the TOI and LCS, respectively. The pooled RRs for FACT-L and TOI, were 1.54 (95% CI = 1.26-1.89) and 1.85 (1.42-2.40), respectively, indicating gefitinib treatment improved the patients life quality when compared with docetaxel [Figure 5]. The pooled RR for LCS was 1.17 (95% CI = 0.97-1.42), implying no difference between these two groups. There was no heterogeneity in each subgroup.
|Figure 5: Forest plot of comparison for the quality of life (QoL) between gefitinib and docetaxel group|
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As expectancy, docetaxel resulted in more grade 3 or 4 common toxicity criteria (CTC) than gefitinib. The pooled OR was 0.16 [95% CI = 0.13-0.20, [Figure 6]], indicating less toxicity of gefitinib compared with docetaxel. However, a great heterogeneity (I2 = 76%) was exhibited between gefitinib and docetaxel, even though a random-effect model was performed. By leave-one-out strategy, Lee's trial was the source of heterogeneity. After excluding the data of Lee's trial, I2 was 0% and OR was similar (data not shown).
|Figure 6: Forest plot of comparison for toxicity between gefitinib and docetaxel group|
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| » Discussion|| |
Previously, Jiang et al. published a similar meta-analysis using the same four RCTs. We obtained the same results as Jiang's according to OS, ORR, and QoL. We showed a different result of PFS and we provided 6-month and 1-year-survival rate, which they did not analyze. 
In this systematic review, 5 included randomized clinical trials indicated that gefitinib had noninferior efficacy to docetaxel with an improvement of QoL and tolerability profile. In this updated meta-analysis, we showed that gefitinib significantly improved ORR and QoL. Besides, gefitinib prolonged PFS significantly after using the supportive adjusted model. However, gefitinib showed equivalent OS as docetaxel group, mainly attributed to the cross-over to alternative therapy at disease progression, which made it impossible to detect an OS benefit for almost all patients received both treatments. Moreover, we found there was no significant difference of 6-month and 1-year survival rate between gefitinib and docetaxel. Same as the previous result, did gefitinib show less toxicity and more tolerable than docetaxel.
In subgroup analysis, only two trials reported the data based on EGFR mutation or EGFR gene-copy number. In the INTEREST trial, superiority of gefitinib in patients with high EGFR-gene-copy number was not proven based on the equivalent median survival time (8.4 vs. 7.5 months for gefitinib and docetaxel, respectively), and similar 1-year survival rate (32% vs. 35%).  In another trial, V-15-32, EGFR mutation-positive patients appeared to have better PFS than EGFR mutation-negative patients on both treatments (gefitinib-positive vs. gefitinib-negative: HR = 0.33, 95% CI = 0.11-0.97, n = 17; docetaxel: HR = 0.15, 95% CI = 0.04-0.57, n = 15). Besides, EGFR fluorescence in situ hybridization (FISH)-positive patients appeared to have better PFS than EGFR mutation-negative patients on both treatments (gefitinib-positive vs gefitinib-negative: HR = 0.75, 95% CI = 0.28-1.98, n = 18; docetaxel: HR = 0.45, 95% CI = 0.14-1.41, n = 16). The ORRs for EGFR FISH-positive patients in gefitinib and doxetaxel were 46% and 33%, respectively, for EGFR mutation-positive were 67% and 46%, respectively, and for EGFR expression-positive patients, the ORRs were 36% and 31%, respectively.  The conflicting results of these two trials with previous knowledge that gefitinib is potentially effective for advanced NSCLC patients with EGFR mutation and high EGFR gene-copy number may attributed to the cross-over to the alternative therapy at disease progression. Another possible explanation was that the primary objective was not met in some cases and some subgroups were small.
Clinical factors, such as never-smoker, female sex, adenocarcinoma histology and performance status, are implied as predictors of PFS in advanced NSCLC patients. , In the subgroups of clinical factors, the efficacy was compared between gefitinib and docetaxel in three trials, ,, in two of which it consistently reported that these factors had significantly longer survival than their opposite subgroups on both gefitinib and docetaxel. , The subgroups associated with a gefitinib benefit were consistent with previous knowledge while it was unexpectedly that they also did well on docetaxel, since docetaxel produced similar survival in all patients. Notably, Morère et al. performed the comparisons of gefitinib, gemcitabine, and docetaxel as a first-line treatment in selected NSCLC patients with performance status of 2 and 3.  Disappointedly, they did not show a difference in PFS, OS or response rate for patients treated with either gemcitabine or gefitinib. Although it achieved better survival and response rates in patients treated with docetaxel, the difference did not reach statistical significance, and severe adverse effects occurred. Based on this result, it is urgently needed more clinical trials to compare the efficacy and toxicity of gefitinib with docetaxel in a selected population according to both EGFR status and clinical factors. 
| » Conclusion|| |
We presented an higher efficacy and a more tolerable adverse effects of gefitinib, in terms of PFS, QoL, and grade 3 or 4 CTC, than docetaxel, although similar OS and survival rate. Therefore, gefitinib is a potential and valid treatment alternative for patients with advanced NSCLC. In the future, biomarkers prediction, such as EGFR status in this case, and clinical factors should be introduced into the analysis for more confirmative results and better-personalized medication.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2]