Lung cancer remains the leading cause of cancer-related deaths worldwide [
Pemetrexed is a new antifolate drug, and its combination with platinum drugs (cisplatin or carboplatin) has been widely recognized as the mainstay in first-line chemotherapy of NSCLC. Pemetrexed works by disrupting folic-acid-dependent metabolic processes that are critical to cancer cells. Gefitinib is one of the first-generation reversible EGFR-TKIs, and it is usually used in second-line or third-line treatment for advanced NSCLC [
This study comprehensively compared the efficacy and safety of gefitinib and pemetrexed in the second-line treatment of locally advanced and metastatic NSCLC with a systematic evaluation method. We hope that this study can provide more evidences for the rational choice of second-line drugs in the treatment of locally advanced and metastatic NSCLC.
Randomized controlled trials (RCTs).
Patients who were diagnosed with locally advanced and metastatic (stage III b or IV) NSCLC by pathology or cytology Patients who had undergone at least one course of platinum-based chemotherapy but failed Patients who had at least one measurable focus Patients who had an ECOG PS score of 0-2 Patients who had no obvious contraindications to chemotherapy
Gefitinib was given by oral in the test group, while pemetrexed was given for systemic chemotherapy in the control group.
Objective response rate (ORR): according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.0) [ Disease control rate (DCR): Progression-free survival (PFS): time (months) from the start of treatment to disease progression or the last follow-up visit without progression Overall survival (OS): time (months) from the start of treatment to death due to any cause Adverse events (AEs) of all grades: according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 of the National Cancer Institute [
Non-English or non-Chinese literature Repeatedly published literature Patients who had already been treated by pemetrexed or gefitinib or other micromolecular TKIs Patients who had been treated by gefitinib or pemetrexed as first-line treatment or maintenance treatment Patients who had other small cell lung cancers or other malignant tumors
Databases including PubMed, the Cochrane Library, Embase, CNKI, and Web of Science were searched to find RCTs about the use of pemetrexed and gefitinib in the second-line treatment of locally advanced and metastatic NSCLC from foundation to April 2020. The search was performed using free words and subject terms together. Retrieval keywords and related medical subject headings (MeSHs) are as follows: “gefitinib”, “pemetrexed”, and “non-small cell lung cancer”. References from the conforming articles were also searched manually to check other related articles.
Literature screening and data extraction were done by two researchers independently. The data were cross-checked, and if there was a discrepancy, they would discuss or ask for a third party. Data were extracted with a self-designed extraction form, including (1) basic information of the included literature, such as the first author and the published year; (2) baseline characteristics, such as case number, gender ratio, age, and follow-up time; and (3) outcome indexes and measurement data. The risk of bias for the included literature was evaluated by the bias risk assessment tool recommended in Cochrane 5.1.0 [
Meta-analysis was conducted using RevMan 5.3. The odds ratio (OR) was used as the effect indicator for enumeration data, and the hazard ratio (HR) was used for measurement data. The effect size was provided with a point estimate value and a 95% confidence interval (CI). The chi-square test was used to study the heterogeneity of the study results (test standard,
Totally, 522 references were initially obtained, 116 duplicates were eliminated, and 14 RCTs were eventually involved in the study after further screening by reading the title, the abstract, and the whole text [
Flow chart for literature screening.
Primary characteristics of the eligible studies in more detail.
Author | Year | Country | Treatment | No. of patients | Gender (male/female) | Median age | Median follow-up time | Outcomes |
---|---|---|---|---|---|---|---|---|
Hong J | 2010 | Korea | C: pemetrexed | 20 | 17/3 | 62 | 12.1 months | ORR, DCR, PFS, OS, AE |
T: gefitinib | 20 | 9/11 | 61 | |||||
Sun JM | 2012 | Korea | C: pemetrexed | 67 | 10/57 | 64 | 15.9 months | ORR, PFS, OS, AE |
T: gefitinib | 68 | 10/58 | 58 | |||||
Dai HY | 2013 | China | C: pemetrexed | 23 | 14/9 | 61 | NR | ORR, DCR, PFS, AE |
T: gefitinib | 23 | 15/8 | 62 | |||||
Zhou Q | 2014 | China | C: pemetrexed | 76 | 47/29 | 55.9 | 10.6 months | ORR, DCR, PFS, OS, AE |
T: gefitinib | 81 | 54/27 | 57.5 | |||||
Kim YS | 2016 | Korea | C: pemetrexed | 47 | 33/14 | 64 | 60.6 months | ORR, DCR, PFS, OS, AE |
T: gefitinib | 48 | 35/13 | 67 | |||||
Xu YH | 2015 | China | C: pemetrexed | 94 | NR | NR | NR | ORR, DCR, AE |
T: gefitinib | 94 | NR | NR | |||||
Lin L | 2016 | China | C: pemetrexed | 48 | 36/12 | 57 | 25 months | ORR, DCR, PFS, OS, AE |
T: gefitinib | 53 | 29/24 | 59 | |||||
Liu XM | 2015 | China | C: pemetrexed | 22 | 13/9 | 61.3 | NR | ORR, DCR, PFS, AE |
T: gefitinib | 20 | 13/7 | 62.3 | |||||
Song TT | 2015 | China | C: pemetrexed | 60 | 36/24 | 54.9 | NR | ORR, DCR, AE |
T: gefitinib | 60 | 38/22 | 55.7 | |||||
Wang MQ | 2012 | China | C: pemetrexed | 38 | 25/13 | 63.3 | NR | ORR, DCR, AE |
T: gefitinib | 37 | 23/14 | 64.2 | |||||
Zhang DG | 2016 | China | C: pemetrexed | 55 | 30/25 | 65 | NR | ORR, DCR, AE |
T: gefitinib | 50 | 17/33 | 67 | |||||
Zhang J | 2012 | China | C: pemetrexed | 40 | 26/14 | NR | 6 months | ORR, DCR, AE |
T: gefitinib | 40 | 19/21 | NR | |||||
Zhang YH | 2009 | China | C: pemetrexed | 32 | 13/15 | 56 | NR | ORR, DCR, AE |
T: gefitinib | 35 | 12/23 | 58 | |||||
Zhao LH | 2013 | China | C: pemetrexed | 41 | NR | NR | NR | ORR, DCR, AE |
T: gefitinib | 42 | NR | NR |
NR: no report; T: treatment group; C: control group; ORR: overall response rate; DCR: disease control rate; PFS: progression-free survival; OS: overall survival; AE: adverse event.
Cochrane’s bias risk assessment.
Overall risk of bias
Risk of bias for each RCT
Fourteen RCTs were involved. The results of meta-analysis using a random-effects model showed that the difference in ORR between the gefitinib group and the pemetrexed group was not statistically significant (
Comparison of ORR between the gefitinib group and the pemetrexed group.
Thirteen RCTs were involved. The results of the meta-analysis using a random-effects model showed that the difference in DCR between the gefitinib group and the pemetrexed group was not statistically significant (
Comparison of DCR between the gefitinib and pemetrexed groups.
Seven RCTs were involved to study patient’s PFS. The results of meta-analysis using a random-effects model showed that there was no statistically significant difference in PFS between the gefitinib group and the pemetrexed group (
Comparison of PFS between the gefitinib and pemetrexed groups.
Comparison of PFS between the gefitinib and pemetrexed groups in the treatment of NSCLC with EGFR mutations.
Comparison of PFS between the gefitinib and pemetrexed groups in the treatment of NSCLC with wild-type EGFR.
Comparison of OS between the gefitinib and pemetrexed groups.
Thirteen RCTs were involved. The results of meta-analysis on a random-effects model showed that the occurrence rate of rash in the gefitinib group was markedly higher than that in the pemetrexed group and the difference was statistically significant (
Comparison of rash occurrence rate between the gefitinib and pemetrexed groups.
Fourteen RCTs were involved. The results of meta-analysis on a random-effects model showed that the occurrence rate of diarrhea in the gefitinib group was markedly higher than that in the pemetrexed group and the difference was statistically significant (
Comparison of diarrhea occurrence rate between the gefitinib and pemetrexed groups.
Eleven RCTs were involved. The results of meta-analysis on a random-effects model showed that the occurrence rate of neutropenia in the gefitinib group was markedly lower than that in the pemetrexed group and the difference was statistically significant (
Comparison of neutropenia occurrence rate between the gefitinib and pemetrexed groups.
Ten RCTs were involved. The results of meta-analysis on a random-effects model showed that the occurrence rate of fatigue in the gefitinib group was markedly lower than that in the pemetrexed group and the difference was statistically significant (
Comparison of fatigue occurrence rate between the gefitinib and pemetrexed groups.
Visually, the funnel plots were basically symmetrical (Figure
Funnel plots.
ORR
DCR
PFS
OS
As a routine therapy for NSCLC, first-line chemotherapy can prolong a patient’s lifetime to some extent, yet its efficacy in patients with advanced NSCLC is poor and patients always have an unfavorable prognosis [
Pemetrexed is a multitargeted antimetabolite drug and a thymidylate synthase/dihydrofolate reductase inhibitor. It has a strong inhibitory effect on several folate-dependent enzymes. It can inhibit the synthesis of pyrimidine and purine by many methods, thus playing an antitumor role and reducing drug resistance [
This study has some limitations. First of all, most studies included were conducted in China, and the results may not fully reflect the treatment situation in other countries, and the sample size is small. Second, in the included studies, there are biases in the length of follow-up time, treatment strategy, and time, which may cause the heterogeneity of clinical results to a certain extent. Although we conducted a subgroup analysis regarding the wild/mutant EGFR, there was still a large heterogeneity in the results, which may be related to the small cohort for EGFR mutations. Third, different first-line treatment methods may have an impact on final clinical outcomes. For example, a review discussed the necessity of EGFR-TKIs in first-line treatment for NSCLC, so as to provide the most effective therapeutic regimen in initial treatment [
In conclusion, gefitinib and pemetrexed for the treatment of locally advanced and metastatic NSCLC patients with failed first-line chemotherapy have similar efficacy and safety. In the future, more well-designed RCTs are needed for further verification.
The data used to support the findings of this study are included within the article. The data and materials in the current study are available from the corresponding author on reasonable request.
Consent is not applicable.
The authors declare that they have no potential conflicts of interest.
All authors contributed to data analysis and drafting and revising the article, gave final approval of the version to be published, and agreed to be accountable for all aspects of the work.