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ORIGINAL ARTICLE
Year : 2017  |  Volume : 54  |  Issue : 1  |  Page : 104-114
 

A meta-analysis: Evaluation of safety and efficacy of the epidermal growth factor receptor-tyrosine kinase inhibitor monotherapy versus platinum-based doublets chemotherapy in East Asia


Department of Thoracic Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, China

Date of Web Publication1-Dec-2017

Correspondence Address:
Dr. C H Liu
Department of Thoracic Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.219586

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 » Abstract 

OBJECTIVE: Several clinical trials have shown that advanced nonsmall cell lung cancer (NSCLC) patients can benefit from treatment with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) monotherapy than receiving platinum-based doublets chemotherapy in the first-line treatment of advanced NSCLC; the objective of this study was to evaluate whether patients could be treated with EGFR-TKI for advanced NSCLC in the first-line setting. PATIENTS AND METHODS: A literature search was conducted on the Cochrane Controlled Trials Register Databases, MEDLINE, EMBASE, Web of Science databases, and Chinese Biomedical Literature Database without exclusion of material published in any language. We performed a meta-analysis of five randomized studies that compared EGFR-TKI with platinum-based doublets chemotherapy for the patients of advanced NSCLC in the first-line setting. The primary end-point was the progression-free survival (PFS) of each treatment arm. The secondary end-points were overall survival (OS), objective response rate (ORR), adverse effects, and quality of life (qol). RESULTS: Five randomized controlled trials totaling 2080 patients were included in the review. Meta-analysis results are as follows: There were statistically significant differences in overall PFS (hazard ratio [HR] =0.47; 95% confidence interval [CI]: [0.27, 0.83], P = 0.009) and the PFS of the EGFR-M + subgroup (HR = 0.29; 95% CI: [0.17–0.51], P < 0.0001). Compared with patients receiving the platinum-based doublets chemotherapy group, there were no statistically significant differences between the two groups with regard to overall OS (HR = 0.92; 95% CI: [0.80–1.06], P = 0.25). CONCLUSION: Compared with the platinum-based doublets chemotherapy, EGFR-TKI significantly prolonged PFS, increased ORR, improved qol, not significantly increased the nonhematologic toxicity and at the same time decreased the nonhematologic toxicity but not significantly increased the transaminase toxicity for advanced NSCLC patients in East Asia. Although there is convincing evidence to confirm the results mentioned herein, they still need to be confirmed by large-sample trials.


Keywords: Advanced nonsmall cell lung cancer, epidermal growth factor receptor-tyrosine kinase inhibitor, first-line treatment, meta-analysis, platinum-based doublets chemotherapy


How to cite this article:
Zhang X F, De-Sheng L V, Li M, Sun G E, Liu C H. A meta-analysis: Evaluation of safety and efficacy of the epidermal growth factor receptor-tyrosine kinase inhibitor monotherapy versus platinum-based doublets chemotherapy in East Asia. Indian J Cancer 2017;54:104-14

How to cite this URL:
Zhang X F, De-Sheng L V, Li M, Sun G E, Liu C H. A meta-analysis: Evaluation of safety and efficacy of the epidermal growth factor receptor-tyrosine kinase inhibitor monotherapy versus platinum-based doublets chemotherapy in East Asia. Indian J Cancer [serial online] 2017 [cited 2020 Apr 6];54:104-14. Available from: http://www.indianjcancer.com/text.asp?2017/54/1/104/219586



 » Introduction Top


Lung cancer is the leading cause of cancer-related mortality worldwide, with nearly 1.4 million deaths each year. Of the 1.6 million new cases of lung cancer diagnosed each year, approximately 222,520 individuals (116,750 men and 105,770 women) will be diagnosed with lung cancer and 157,300 individuals (86,220 men and 71,080 women) will die from lung cancer in the USA by the end of 2010.[1] Lung cancer is diagnosed at an advanced stage in a majority of patients, which is the primary reason behind the high mortality rate associated with this disease. Early detection continues to be an elusive goal, and substantial numbers of patients diagnosed as localized disease are often unsuitable for curative resection procedures due to concomitant medical illness.[2] Nonsmall cell lung cancer (NSCLC) comprises approximately 80% of all lung cancers [3] and presents an increasing clinical challenge particularly as 50%–60% of newly diagnosed patients have locally advanced or metastatic disease.[4] The current first-line chemotherapy options for patients with advanced NSCLC, such as platinum-based combination chemotherapy, seem to have reached a plateau in terms of efficacy.[5] The poor outlook even for patients with advanced NSCLC who receive such chemotherapy has prompted a search for new therapeutic approaches.

Epidermal growth factor receptor (EGFR)-dependent pathway plays an important role in the development and progression of human epithelial cancers, including NSCLC. Activation of EGFR pathway could promote tumor growth and progression, stimulate cancer cell proliferation, invasion, and metastasis, and inhibit apoptosis.[6] EGFR mutation has been confirmed as predictors of efficacy for EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Gefitinib and erlotinib are two similarly small, orally active, selective, and reversible EGFR-TKIs molecules, which have been extensively used in NSCLC. Treatment with EGFR-TKIs is more effective in female, never smoker, Asian, and patients with pulmonary adenocarcinomas. In these subpopulations, EGFR-TKIs are associated with favorable objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).[7],[8],[9],[10]

Several randomized trials have been conducted with the aim of comparing the EGFR-TKI (gefitinib or erlotinib) with the standard doublet chemotherapy (platinum plus third-generation new agents) as the first-line treatment in advanced NSCLC patients.[11],[12],[13],[14],[15],[16],[17] However, the small sample size of each single trial might not have sufficient power to detect potentially relevant differences in efficacy of the different arms. Therefore, we undertook this meta-analysis to compare the EGFR-TKI monotherapy with the platinum-based doublet chemotherapy as the first-line treatment for the patients in advanced NSCLC from East Asia. The main objective of this meta-analysis, based on individual patient data, is to compare efficacy and safety of EGFR-TKI and platinum-based doublet chemotherapy, with a statistical power much higher than each trial. Data regarding the EGFR-TKI and platinum-based doublet chemotherapy were collected and analyzed.


 » Patients and Methods Top


Inclusion and exclusion criteria

Inclusion criteria

  • All included trials must be randomized controlled clinical trials (irrespective of language or publication status); multiple reports of a single study were considered as one publication, and only the most recent article was examined; abstracts or unpublished data were included only if sufficient information on interventions and outcomes was available and if the final results were confirmed by contact with the first author
  • Patients were eligible for inclusion if they were 18 years of age or older, had histologically or cytologically confirmed advanced or recurrent stage IIIB or IV NSCLC, had an Eastern Cooperative Oncology Group performance status of 0–2, and not previously being treated by chemotherapy
  • Trials of comparing EGFR-TKI monotherapy with platinum-based doublets chemotherapy for the patients of advanced NSCLC in the first-line treatment
  • Trials in which the primary outcome was PFS of each treatment arm and the secondary end-points were OS, ORR, toxic effects, and quality of life (qol). The PFS was defined as the time from random assignment until the 1st day of progression or until death in the absence of progression. The OS was calculated as the time from random assignment until the date of death resulting from any cause. The ORR (proportion of intention-to-treat population with complete and partial response) was based on the Response Evaluation Criteria in Solid Tumors. Toxic effects were assessed according to the National Cancer Institute Common Terminology Criteria version 3.0.


Exclusion criteria

  • Patients were excluded from the study if they had uncontrolled brain metastases or had received previous systemic anticancer therapy for advanced disease (adjuvant or neoadjuvant therapy was allowed for nonmetastatic disease, in which relapse had occurred ≥6 months after final treatment)
  • Patients were not eligible if they had a history of interstitial lung disease, severe drug allergy, active infection or other serious disease condition, poorly controlled pleural effusion, pericardial effusion or ascites necessitating drainage, active double cancer. Patients in pregnancy or lactation or whose participation in the trial was judged to be inappropriate by the attending doctor were not eligible.


Literature search

The Cochrane Central Register of Controlled Trials in The Cochrane Library, PubMed, EMBASE, Web of Science databases, and Chinese Biomedical Literature Database were searched for randomized controlled trials (RCTs) comparing EGFR-TKI monotherapy with platinum-based doublets chemotherapy for the patients of the advanced NSCLC in the first-line treatment without language restriction. Moreover, Google Scholar and reference lists of all the included studies were searched for additional reports. Contact with the authors was initiated by E-mail or telephone if any information was not available. The search strategies used the following major terms: “gefitinib or iressa or erlotinib or tarceva or EGFR-TKI or epidermal growth factor receptor-tyrosine kinase inhibitor or icotinib,” “nonsmall cell lung carcinoma or NSCLC or nonsmall cell lung cancer,” “ first-line treatment.”

Data extraction and quality assessment

The search strategy described was used to obtain titles and abstracts of RCTs that were relevant to this review. Two reviewers independently assessed the titles and abstracts of all identified trials to confirm fulfillment of inclusion criteria; data abstraction was performed independently by two reviewers. Any difference of opinion or disagreement that arose in the course of search, data abstraction, quality assessment, or other related work between the two investigators was resolved by mutual discussions.

The risk of bias of the included RCTs was assessed according to the Cochrane Handbook 5.0.2 by two reviewers independently [18] and was judged using the following criteria: Adequate sequence generation; allocation sequence concealment; blinding of participants, incomplete outcome data; free of selective reporting; and free of other bias.[19] Each entry was definitively judged by an answer (yes/no/unclear): “yes” indicates low risk of bias, “no” indicates high risk of bias, and “unclear” indicates unclear or unknown risk of bias.[18] Disagreements were resolved by referring to a third reviewer until consensus was reached. If any information was unavailable, contact with the authors was initiated through E-mail or telephone.

Statistical analysis

Treatment arms with both EGFR-TKI monotherapy and platinum-based doublets chemotherapy were combined regardless of dosage, regimen, or previous treatment. Patients obtaining complete response or partial response were considered as ORR. ORR data estimates of the treatment effects were obtained from the number of events reported in each arm of the trials. Hazard ratios (HRs) with 95% confidence intervals (CIs) were extracted from papers and/or presentations for PFS and OS.[20],[21],[22] The statistical analysis was conducted using the Cochrane software RevMan 5.1(Cochrane Collaboration, London).[18] The log HR (ln[HR]) and its standard error (SE) were used as the outcome measure for data combination.[21],[22] The SE was obtained as ln (upper 95% CI) − ln(lower 95% CI)/3.92.

The ln(HR) and its SE were calculated from the reported data directly by HR and its 95% CI. The risk ratio with 95% CI for dichotomous variables and standardized mean difference with 95% CI for continuous variables were calculated using the fixed-effect model or random-effect model.[23] Heterogeneity between studies was assessed by the χ2 test, with P < 0.10 being used to indicate statistical significance. I2 was calculated to measure the quantity of heterogeneity, with I2>>50% indicating significant heterogeneity.[24] The meta-analysis was conducted using the fixed-effect model if there was no statistically significant heterogeneity (P ≥ 0.10, I2< 50%); otherwise, the possible reasons were explored or the random-effect model was used for the significant heterogeneity (P< 0.10, I2 > 50%). Sensitivity analysis was carried out by omitting poor-quality studies that have a high risk of bias. Intention-to-treat analysis was not performed because of insufficient information about loss to follow-up in treatment and control groups. The qol was assessed with descriptive analysis. The publication bias was analyzed using the funnel plot.[25]


 » Results Top


Description of studies

The flowchart of literature screening is presented in [Figure 1]. According to the established search strategy used, a total of 1841 potentially relevant literature items were identified in the databases. After screening the titles and abstracts of the studies, 1810 irrelevant studies were excluded, leaving 31 studies for further assessment. After the full-text review of the 31 studies, we excluded 26 of them. Therefore, five trials [13],[14],[15],[16],[17] that fulfilled the inclusion criteria were included.
Figure 1: The flowchart of literature screening

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Characteristics of included studies

The characteristics of included studies are shown in [Table 1]. Two trials [14],[15] were performed in Japan, and other trails [13],[16],[17] were performed in Korea, China, and East Asia. Both groups were well matched at baseline from the information in all of the trials.
Table 1: The characteristics of included studies

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Risk of bias in included studies

The risk of bias in the included trials is summarized in [Table 2]. All trials were randomized, one [15] of which was randomized by computer-generated numbers, one [16] of which was randomized by mini randomization software, and one [17] of which was randomized by hospital order, and allocation concealment was reported in two trials.[15],[16] Moreover, the allocation concealment was used by fax and E-mail/telephone; blinding was not reported in any trial.
Table 2: Risk of bias in included studies

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 » Meta-Analysis Results Top


The progression-free survival

The PFS was reported in five trials.[13],[14],[15],[16],[17] The random-effect model was used to perform meta-analysis because there was significant heterogeneity between trials (I2 = 95%, P < 0.1). The meta-analysis result of overall PFS showed that there was significantly different between the two groups (HR = 0.47; 95% CI: [0.27–0.83], P = 0.009) [Figure 2]. In the subgroup analysis, the EGFR-TKI significantly prolonged PFS over platinum-based doublets front-line chemotherapy in EGFR-M + NSCLC patients (HR = 0.29; 95% CI: [0.17–0.51], P < 0.0001) with significant heterogeneity (I2 = 85%, P < 0.1). In the subgroup of lung adenocarcinoma, because there was significant heterogeneity between trials (I2 = 92%, P < 0.1), the PFS was assessed with descriptive analysis. First-SIGNAL [13] reported that the median PFS was 5.8 months (95% CI: 4.1–6.5 months) in the gefitinib arm and 6.4 months (95% CI: 5.8–7.0 months) in the gemcitabine and cisplatin (GP) arm (HR = 1.198; 95% CI: [0.944–1.520], P = 0.138). The PFS curves crossed at 7 months, favoring GP during the first 7 months and gefitinib thereafter. IPASS [17] reported that the median PFS was 5.7 months in the gefitinib group and 5.8 months in the carboplatin-paclitaxel group. The study met its primary objective of demonstrating noninferiority and showed the superiority of gefitinib as compared with carboplatin-paclitaxel for PFS (HR = 0.74; 95% CI: [0.65–0.85], P < 0.001).
Figure 2: The meta-analysis of progression-free survival progression-free survival

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The overall survival

The OS was reported in four trials.[13],[14],[15],[17] The fixed-effect model was used to perform meta-analysis because there was no significant heterogeneity between trials (I2 = 0%, P > 0.1). The meta-analysis result of the overall OS showed that there was no significantly different between the two groups (HR = 0.92; 95% CI: [0.80–1.06], P = 0.25) [Figure 3]. In the subgroup analysis, the fixed-effect model was used to perform meta-analysis in lung adenocarcinoma group because there was no significant heterogeneity between trials (I2 = 0%, P > 0.1). The meta-analysis result of the OS showed that there was no significantly different between the two groups in lung adenocarcinoma group (HR = 0.92; 95% CI: [0.79–1.07], P = 0.26) and the EGFR mutation-positive group (HR = 0.94; 95% CI: [0.65–1.38], P = 0.77).
Figure 3: The meta-analysis of overall survival

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The objective response rate

The ORR was reported in five trials.[13],[14],[15],[16],[17] The random-effect model was used to perform meta-analysis because there was significant heterogeneity between trials (I2 = 89%, P < 0.1). The meta-analysis result of the ORR showed that there was significantly different between the two groups (OR = 3.21; 95% CI: [1.64–6.28], P = 0.0007) [Figure 4]. In the subgroup analysis, the meta-analysis result of the ORR showed that there was significantly different between the two groups in lung adenocarcinoma group (OR = 1.56; 95% CI: [1.27–1.92], P < 0.0001). The EGFR-TKI significantly increased the ORR over platinum-based doublets front-line chemotherapy in EGFR-M + NSCLC patients (OR = 5.81; 95% CI: [3.59–9.40], P < 0.00001).
Figure 4: The meta-analysis of objective response rate

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The toxic effects

The toxic effects were assessed according to the National Cancer Institute Common Terminology Criteria version 3.0; the toxic effects were reported in five trials,[13],[14],[15],[16],[17] which included hematologic toxicity and nonhematologic toxicity. The toxicity in the included trials is summarized in [Table 3]. With the nonhematologic toxicity, the meta-analysis result showed that EGFR-TKI can increase the rash rate, dry skin rate, diarrhea rate, paronychia rate, and stomatitis rate and at the same time decrease fatigue rate, nausea rate, constipation rate, and alopecia rate in all grade toxic effects. With the hematologic toxicity, the meta-analysis result showed that EGFR-TKI can increase alanine transaminase (ALT) rate and at the same time decrease leukocytopenia rate, thrombocytopenia rate, neutropenia rate, and anemia rate in all grade toxic effects; in the grade ≥ 3 toxic effect, the result was the same as all grades toxic effect, except for fatigue rate, paronychia rate, and stomatitis rate. They had the same toxic effects.
Table 3: The meta-analysis result of the toxic effects in included studies

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The quality of life

Four trails [13],[16],[17],[26] investigated the qol. First-SIGNAL [13] reported that qol was measured by the patient-completed European Organisation for Research and Treatment of Cancer qol Questionnaire C30 and the lung cancer-specific module LC13.[27] Compliance up to week 21 was excellent; 60% of patients in the gefitinib arm and 50% of patients in the GP arm were available for qol evaluation.

Seventy-two patients (46%) in the gefitinib arm and 22 patients (15%) in the GP arm completed qol questionnaires at week 30. Analysis of the functional scales of the C30 questionnaire showed that significant differences in the evolution of physical (P< 0.001), role (P< 0.001), and social (P = 0.013) functions were reported in favor of gefitinib. There was no significant difference between emotional and cognitive functions. Analysis of the symptom scales of the C30 questionnaire showed that nausea/vomiting was more severe in the GP arm (P = 0.003) and diarrhea was more severe in the gefitinib arm (P = 0.015). In analysis of symptoms from the LC13 questionnaire, hemoptysis (P = 0.014), sore mouth (P = 0.001), and dysphagia (P = 0.010) were reported more frequently in the gefitinib arm, but alopecia was more frequent in the GP arm (P< 0.001). OPTIMAL [16] reported that the qol and lung cancer symptoms were assessed every 6 weeks with the functional assessment of cancer therapy-lung (FACT-L) questionnaire and the lung cancer subscale (LCS). Logistic regression analysis with performance status, smoking history, and sex as covariates or mutation type, smoking history, and histological type as covariates showed that patients who received erlotinib had a significant improvement in their total FACT-L (P< 0.0001 for both covariate analyses) and LCS scores (P< 0.0001 for both covariate analyses) compared with those who received chemotherapy. IPASS [17] reported that qol was assessed with the use of the FACT-L questionnaire (in which scores range from 0 to 136, with higher scores indicating better qol) and the trial outcome index (TOI, which is the sum of the physical well-being, functional well-being, and LCS scores of FACT-L; scores range from 0 to 84, with higher scores indicating better qol), and symptoms were assessed with the use of the LCS score (scores range from 0 to 28, with higher scores indicating fewer symptoms). Significantly, more patients in the gefitinib group than in the carboplatin-paclitaxel group had a clinically relevant improvement in qol as assessed by scores on the FACT-L questionnaire (odds ratio [OR] = 1.34; 95% CI: 1.06–1.69; P = 0.01) and by scores on the TOI (OR = 1.78; 95% CI: 1.40–2.26; P < 0.001). Rates of reduction in symptoms, as assessed on the basis of the LCS scores, were similar between patients who received gefitinib and those who received carboplatin-paclitaxel (OR with gefitinib, 1.13; 95% CI: 0.90–1.42; P = 0.30). NEJ002[26] reported that The Care Notebook,[28] which has been previously validated and reported,[29],[30] was used to assess qol. The Care Notebook is a self-administered, cancer-specific questionnaire that asks about cancer patients' conditions during 1 week regarding 24 items that are structured in multidimensional scales. The questionnaire consists of three major scales: Physical well-being, mental well-being, and life well-being. This qol analysis clearly demonstrated superior qol in NSCLC patients with mutated EGFR receiving gefitinib compared with patients receiving chemotherapy. The qol analysis of the NEJ 002 study clearly demonstrated that gefitinib maintained patient qol longer than carboplatin plus paclitaxel during the first-line treatment. A longer PFS interval with a better qol during the first-line treatment is valuable for advanced NSCLC patients with limited survival times.


 » Discussion Top


Lung cancer is a major cause of cancer-related mortality worldwide. Platinum doublet chemotherapy consisting of a platinum agent plus a third-generation cytotoxic agent such as gemcitabine, paclitaxel, or docetaxel is the standard first-line treatment for advanced NSCLC. However, current standard platinum doublet therapy seems to have reached a therapeutic plateau although it has recently been shown that patients with nonsquamous histology who are treated with pemetrexed disodium have better survival than if they are treated with older drugs.

EGFR-TKIs are the most promising development in the treatment of advanced NSCLC. Inhibitors of the EGFR tyrosine kinase have clinical efficacy, as compared with the best supportive care or standard chemotherapy,[10] when given as the second-line or third-line therapy for advanced NSCLC. Targeted therapies are actively being developed to improve efficacy in selected patient populations. Small-molecule TKIs that target the EGFRs, such as gefitinib and erlotinib, are the first targeted drugs to enter clinical use for the treatment of lung cancer. Subgroups of patients of East Asian origin, female sex, adenocarcinoma, and no history of smoking have been shown to be significantly associated with a favorable response to EGFR-TKIs.[31],[32]

This meta-analysis was based on five RCTs that included 2080 patients. All patients in both groups were reported to be well-matched for age, sex, and type of tumor.

Randomization was performed in all trials. However, of the five included studies, only three trials [15],[16],[17] mention the adequate sequence generation; it can produce selective bias. Allocation concealment was reported in two trials [15],[16] which might lead to unclear risk of selection bias because it was possible for those responsible for recruiting the participants to alter their assignment if allocation was concealed. Blinding was not reported in any trial [13],[14],[15],[16],[17] which might cause a high risk of performance bias or detection bias. Future research should clearly spell out how to implement blinding. Although a comprehensive literature search was conducted, some published and unpublished trials might have been missed, which would lead to nonpublication bias. Publication bias might exist. No trials were multicenter; pharmacogenomic difference could exist among different countries. Future study should pay attention to the impact of geographic differences. We still need more high-quality, multicenter, randomized controlled trials from other countries and regions.

The meta-analysis results are as follows: In the overall PFS, the meta-analysis result showed that there was significantly different between the two groups (HR = 0.47; 95% CI: [0.27–0.83], P = 0.009). In the subgroup analysis, the EGFR-TKI significantly prolonged PFS over platinum-based doublets front-line chemotherapy in EGFR-M + NSCLC patients (HR = 0.29; 95% CI: [0.17–0.51], P < 0.0001). In the subgroup of lung adenocarcinoma, the PFS was assessed with descriptive analysis. First-SIGNAL [13] reported that the median PFS was 5.8 months (95% CI: 4.1–6.5 months) in the gefitinib arm and 6.4 months (95% CI: 5.8–7.0 months) in the GP arm (HR = 1.198; 95% CI: [0.944–1.520], P = 0.138). The PFS curves crossed at 7 months, favoring GP during the first 7 months and gefitinib thereafter. IPASS [17] reported that the median PFS was 5.7 months in the gefitinib group and 5.8 months in the carboplatin-paclitaxel group. The study met its primary objective of demonstrating noninferiority and showed the superiority of gefitinib as compared with carboplatin-paclitaxel for PFS (HR = 0.74; 95% CI: [0.65–0.85], P < 0.001). The meta-analysis result showed that there was no significantly different between the two groups (HR = 0.92; 95% CI: [0.80–1.06], P = 0.25) in the overall OS, lung adenocarcinoma subgroup (HR = 0.92; 95% CI: [0.79–1.07], P = 0.26), and EGFR mutation-positive subgroup (HR = 0.94; 95% CI: [0.65–1.38], P = 0.77). In the ORR, the meta-analysis result of the overall ORR showed that there was significantly different between the two groups (OR = 3.21; 95% CI: [1.64–6.28], P = 0.0007). In the subgroup analysis, the meta-analysis result of the ORR showed that there was significantly different between the two groups in the lung adenocarcinoma subgroup (OR = 1.56; 95% CI: [1.27–1.92], P < 0.0001), and the EGFR-TKI significantly increased the ORR over platinum-based doublets front-line chemotherapy in EGFR-M + NSCLC patients subgroup (OR = 5.81; 95% CI: [3.59–9.40], P < 0.00001).

The meta-analysis results of the toxic effects are as follows: With the nonhematologic toxicity, the meta-analysis result showed that EGFR-TKI can increase rash rate (OR = 8.63; 95% CI: [6.96–10.71], P < 0.00001), dry skin rate (OR = 16.48; 95% CI: [5.70–47.7], P < 0.00001), diarrhea rate (OR = 3.61; 95% CI: [2.07–6.30], P < 0.00001), paronychia rate (OR = 70.07; 95% CI: [16.91–290.40], P < 0.00001), and stomatitis rate (OR = 2.26; 95% CI: [1.64–3.10], P < 0.00001) and at the same time decrease fatigue rate (OR = 0.19; 95% CI: [0.12–0.30], P < 0.00001), nausea rate (OR = 0.18; 95% CI: [0.14–0.23], P < 0.00001), constipation rate (OR = 0.31; 95% CI: [0.23–0.40], P < 0.00001), and alopecia rate (OR = 0.06; 95% CI: [0.02–0.18], P < 0.00001) in the all grade toxic effect. With the hematologic toxicity, the meta-analysis result showed that EGFR-TKI can increase ALT increased rate (OR = 2.13; 95% CI: [1.36–3.34], P = 0.001) and at the same time decrease thrombocytopenia rate (OR = 0.12; 95% CI: [0.03–0.48], P = 0.003), neutropenia rate (OR = 0.02; 95% CI: [0.01–0.04], P < 0.00001), and anemia rate (OR = 0.09; 95% CI: [0.03–0.33], P = 0.0002) in the all grade toxic effect; in the grade ≥ 3 toxic effect, with the nonhematologic toxicity, the meta-analysis result showed that EGFR-TKI can increase rash rate (OR = 3.28; 95% CI: [1.54–6.98], P = 0.002), and diarrhea rate (OR = 2.94; 95% CI: [1.40–6.18], P = 0.005) and at the same time decrease fatigue rate (OR = 1.19; 95% CI: [0.34–4.17], P = 0.78) and nausea rate (OR = 0.25; 95% CI: [0.08–0.82], P = 0.002). There was no significantly different in the paronychia rate (OR = 4.03; 95% CI: [0.45–36.24], P = 0.21) and stomatitis rate (OR = 1.57; 95% CI: [0.20–12.06], P = 0.66). With the hematologic toxicity, the meta-analysis result showed that EGFR-TKI can increase the ALT increased rate (OR = 10.62; 95% CI: [3.18–35.42], P = 0.0001) and at the same time decrease the leukocytopenia rate (OR = 0.03; 95% CI: [0.01–0.05], P < 0.00001), thrombocytopenia rate (OR = 0.02; 95% CI: [0.00–0.15], P < 0.0001), neutropenia rate (OR = 0.01; 95% CI: [0.00–0.03], P < 0.00001), and anemia rate (OR = 0.11; 95% CI: [0.02–0.76], P = 0.03).

The meta-analysis results of the qol are as follows:First-SIGNAL [13] reported that analysis of the functional scales of the C30 questionnaire showed that significant differences in the evolution of physical (P< 0.001), role (P< 0.001), and social (P = 0.013) functions were reported in favor of gefitinib. There was no significant difference between emotional and cognitive functions. Analysis of the symptom scales of the C30 questionnaire showed that nausea/vomiting was more severe in the GP arm (P = 0.003) and diarrhea was more severe in the gefitinib arm (P = 0.015). In analysis of symptoms from the LC13 questionnaire, hemoptysis (P = 0.014), sore mouth (P = 0.001), and dysphagia (P = 0.010) were reported more frequently in the gefitinib arm, but alopecia was more frequent in the GP arm (P< 0.001). OPTIMAL [16] reported that the patients who received erlotinib had a significant improvement in their total FACT-L (P< 0.0001 for both covariate analyses) and LCS scores (P< 0.0001 for both covariate analyses) compared with those who received chemotherapy. IPASS [17] reported that significantly, more patients in the gefitinib group than in the carboplatin-paclitaxel group had a clinically relevant improvement in qol as assessed by scores on the FACT-L questionnaire (OR = 1.34; 95% CI: 1.06–1.69; P = 0.01) and by scores on the TOI (OR = 1.78; 95% CI: 1.40–2.26; P < 0.001). Rates of reduction in symptoms were similar between patients who received gefitinib and those who received carboplatin-paclitaxel (OR with gefitinib, 1.13; 95% CI: [0.90–1.42]; P = 0.30). NEJ002[26] reported that this qol analysis clearly demonstrated superior qol in NSCLC patients with mutated EGFR receiving gefitinib, compared with patients receiving chemotherapy. The qol analysis of the NEJ 002 study clearly demonstrated that gefitinib maintained patient qol longer than carboplatin plus paclitaxel during the first-line treatment. A longer PFS interval with a better qol during the first-line treatment is valuable for advanced NSCLC patients with limited survival times.

Clinical trials comparing TKIs and placebos have produced controversial results. It seems that not all NSCLC patients benefit from these drugs. Different selection criteria for patients will produce different results. Five trials reported the results of EGFR-TKI treatment versus chemotherapy in patients with an EGFR mutation, showing that these patients benefitted more from EGFR-TKI treatment. Based on both the response and PFS, the results of these five trials confirm the superiority of EGFR-TKIs compared with chemotherapy for patients with an EGFR mutation. The OS for patients with an EGFR mutation was similar to chemotherapy, but there are too many factors that will interfere the survival. The interference of the survival not only on the patients received TKIs on the second line but also on the different chemotherapy regimen or some patients without second-line therapy. The results of the meta-analysis confirmed the survival of the TKIs is similar with the chemotherapy in patients with advanced NSCLC, especially with EGFR mutations while the ORR and PFS of TKIs were dramatically superior. Moreover, the qol of the advanced NSCLC patients receiving EGFR-TKI was better. Patients should receive TKI treatment when their EGFR mutation status is confirmed. When all NSCLC patients with poor performance status or who were unfit for chemotherapy were given EGFR-TKI or placebo in the first-line setting, in some special situations involving patients with unknown EGFR status or who are not fit for chemotherapy, a trial of EGFR-TKI may be reasonable according to clinical criteria, provided that the patient and family members have been informed of the possible worsening of symptoms and disease.

We performed this meta-analysis to better quantify the benefits and toxicities of EGFR-TKI as compared to chemotherapy in patients of advanced NSCLC. The results of our meta-analysis confirm the results of the individual trials: Initial EGFR-TKI is associated with a higher ORR and PFS as well as superior toxicity and qol profiles as compared to chemotherapy. These benefits are seen in Asian patients who are selected by clinicopathological characteristics associated with the presence of an EGFR mutation but are even more pronounced in patients with known EGFR mutations. Our pooled data showed EGFR-TKI as the first-line treatment conferred substantial clinical benefit in terms of PFS in patients of advanced NSCLC, especially with EGFR mutations. The superiority of EGFR-TKI as compared with chemotherapy suggested that EGFR-TKI can be the standard of care in a first-line setting in histologically or molecularly defined populations. Furthermore, EGFR-TKI monotherapy seemed to be an effective strategy for patients with the EGFR mutant. Similarly, an advantage is achieved in terms of ORR taking into consideration that patients often derive a clinically significant symptomatic benefit from tumor shrinkage. These data constitute a historical landmark in NSCLC, in which treatment advances have been modest and incremental at best for at least two reasons. First, the degree of benefit achieved with EGFR-TKI over classical cytotoxic chemotherapy is striking if compared with the benefit of chemotherapy versus best supportive care in the same setting. Second, such impressive benefit could be achieved only as a consequence of an intensive translational effort that has clearly identified sensitizing EGFR mutations as the preferential molecular target of EGFR-TKI. Importantly, this benefit was not gained at the expense of an increased toxicity rate; hematological toxic effects were significantly decreased in patients receiving EGFR-TKI, thus further increasing the therapeutic index of such a targeted approach.

However, we did not find any survival advantage in the group of patients with the advanced NSCLC, especially with EGFR mutation treated with EGFR-TKI monotherapy. There might be several possible explanations: Only five randomized controlled studies reported the OS. The nonsufficient data about OS and the relatively shorter time of follow-up might influence statistical result. More importantly, differences in OS are potentially affected by the subsequent drugs cross-over, and a relevant number of patients assigned to chemotherapy arm finally received EGFR-TKIs (gefitinib or erlotinib) as second- or third-line treatment after disease progression. The high proportion of cross-over may decrease the benefit associated with the administration of gefitinib. A substantial number of patients treated with systemic chemotherapy as the first-line treatment received EGFR-TKI as a subsequent treatment. Most progression treatments may have diluted the survival effect and make improvement of the OS end-point a difficult outcome to obtain. The substantial minimal burden of toxicity of EGFR-TKIs should especially lead to a preference for these agents in patients with poor performance status or contraindications for chemotherapy or in elderly patients who are unable to tolerate platinum agents. At the same time, a gross tumor burden should also be a criterion of choice for EGFR-TKIs. Hence, PFS but not OS will be more properly to be a primary end-point in NSCLC. Although the survival data are not statistically significant difference between the two arms, there is a trend that these patients with EGFR-TKI had a numerically longer OS time. Patients with advanced NSCLC treated with chemotherapy had a median OS of around 8–10 months. Now, patients with EGFR mutations treated with gefitinib or erlotinib have a median OS of around 18–30 months. Furthermore, two phase III trials had confirmed the predictive value of EGFR mutations for the responsiveness of advanced NSCLC to EGFR-TKI as compared with chemotherapy.[14],[15] In the five trials, the magnitude of the survival benefit in patients with lung adenocarcinoma was somewhat smaller than that in patients with EGFR mutations. In the IPASS study for patients with lung adenocarcinoma with no or former light smoking history, the curves of PFS crossed at about the time that chemotherapy stopped and gefitinib continued (initially, chemotherapy was better, whereas gefitinib was better later).

However, these analyses should be interpreted with caution as there are a number of caveats to this meta-analysis. The first problem is that our analysis showed some heterogeneity within the study results, and the current best evidence is limited by variations in study methodologies, patient ethnicity, and test interpretation criteria. Second, the sample size of included trials for analysis was too small for a funnel plot to detect the publication bias. Third, relatively little information on the methods and analyses of this published trial made detailed quality assessments challenging. Lacking “head-to-head” RCT comparing gefitinib to erlotinib, now, it is hard for us to select gefitinib or erlotinib for patients with advanced NSCLC. However, some retrospective study had found that there was no significant difference between gefitinib and erlotinib. Despite these limitations, these data contribute to a better understanding of the optimal use of gefitinib as the first-line treatment for previously untreated patients with NSCLC. Before our meta-analysis, no system review and meta-analysis had reported the difference between the two arms in East Asia patients. We found that first-line treatment with gefitinib (gefitinib monotherapy or sequential gefitinib therapy after chemotherapy) conferred prolonged PFS and ORR than treatment with systemic chemotherapy in a molecularly or histologically defined (i.e., EGFR mutant, adenocarcinoma) population of patients with NSCLC and improved survival in the subgroup of patients with lung adenocarcinoma.

The findings of this meta-analysis will benefit a substantial part of NSCLC patients, especially the Chinese NSCLC patients. As we know, the morbidity and mortality of NSCLC is quite high in China, together with the huge national population, which make China the biggest NSCLC patients' population country in the world. The frequency of EGFR mutations in Chinese NSCLC patients is also significantly higher than that in Caucasian. As a result, these results will in turn help clinicians to choose a proper drug for NSCLC patients with activated EGFR mutation. In conclusion, the EGFR-TKI regimen significantly prolonged PFS and increased ORR when compared with platinum-based doublet chemotherapy in the previously untreated advanced NSCLC patients, especially the EGFR mutation positive patient. As EGFR mutations are predictor of benefit from TKIs, prospective EGFR mutation should be routinely tested before the initiation of treatment in advanced NSCLC patients.

Limitations and implications for RCTs and meta-analysis in review; some limitations should be considered and some improvements should be made for further studies. (1) In five trials, the type of EGFR-TKI and platinum-based doublets chemotherapy are different; the meta-analysis result may be influenced. (2) This review is limited by the methodological quality of the included RCTs. Some information is insufficient to permit defined judgment. Although every attempt was made to contact the authors of the included trials through E-mail or telephone, it is also recommended that additional RCTs be performed and reported according to the CONSORT Statement which offers a standard way to improve the quality of research. (3) Currently, there are few data to compare EGFR-TKI versus platinum-based doublets chemotherapy as the first-line treatment for advanced NSCLC patients in East Asia. Therefore, additional RCTs should be conducted in these specific subgroups. (4) Rigorous test design should be conducted before test to reduce bias.


 » Conclusion Top


The meta-analysis result showed that using EGFR-TKI as the first-line chemotherapy for advanced NSCLC patient from East Asia can offer the same clinically meaningful in the OS, grade ≥3 paronychia rate, and grade ≥3 stomatitis, and significantly improve the PFS, ORR, and qol, the nonhematologic toxicity (the fatigue rate, nausea rate, constipation rate, and alopecia rate) and hematologic toxicity (the leukocytopenia rate, thrombocytopenia rate, neutropenia rate, and anaemia rate), but not significantly increase the nonhematologic toxicity (the rash rate, the dry skin rate, diarrhea rate, all grade paronychia rate, and all grade stomatitis rate) and transaminase toxicity. Hence, EGFR-TKI treatment is justified for patients with unknown EGFR status, those who cannot tolerate chemotherapy owing to advanced age or who have poor performance status and those with other medical conditions, when selected according to clinical factors. Especially the patients of the NSCLC with EGFR mutation–positive in fact should be offered the opportunity to be treated with an EGFR-TKI in the first-line treatment. Although there is convincing evidence to confirm the results mentioned herein, they still need to be confirmed by large-sample, multicenter, randomized controlled trials.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]

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