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. 2023 Sep 8;102(36):e34572. doi: 10.1097/MD.0000000000034572

A meta-analysis for the efficacy and safety of icotinib combined with radiotherapy in treating brain metastases of non-small cell lung cancer

Bo Zhang a,*
PMCID: PMC10489315  PMID: 37682155

Abstract

Background:

Currently, the therapies for brain metastases of non-small cell lung cancer (NSCLC) mainly include whole brain radiotherapy and icotinib. For exploring the efficacy and safety of radiotherapy and icotinib, a meta-analysis was performed based on a series of data.

Method:

A systematic search was performed on PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure and Wanfang Database. The search time was set from the database establishment to December, 2022. All randomized controlled trials evaluating the efficacy and safety of whole brain radiotherapy alone or in combination with icotinib for whole brain metastases of NSCLC were included in our meta-analysis. Clinical outcomes and adverse reactions were analyzed using Stata17.0 software.

Results:

Finally, 10 clinical studies were enrolled in this meta-analysis, including 717 patients. Briefly, compared with radiotherapy alone, icotinib combined with radiotherapy increased response rate [relative ratio (RR) = 1.240; 95% confidence interval (CI) (1.141, 1.348); P < .001] and disease control rate (RR = 1.240, 95% CI [1.141,1.348], P < .001). Besides, according to the outcomes of adverse reaction assessment exhibited, there were no significant differences between the 2 group patients in the incidence of rash (RR = 1.536, 95% CI [0.694, 3.402], P = .290), adverse reaction in gastrointestinal tract (RR = 1.060, 95% CI [0.792, 1.419], P = 1.419), hepatic injury (RR = 1.541, 95% CI [0.798,2.975], P = .198) and leukopenia (RR = 1.182, 95% CI [0.787, 1.777], P = .421). However, the patients receiving combination treatment showed much longer progression free survival than those receiving radiotherapy alone (standardized mean difference = 1.559; 95% CI [0.699, 2.419]; P < .001).

Conclusion:

Icotinib combined with radiotherapy can significantly short-term and long-term efficacy of NSCLC patients with brain metastases but not increase adverse reactions.

Keywords: brain metastases, icotinib, meta-analysis, non-small cell lung cancer (NSCLC), whole brain radiotherapy (WBRT)

1. Introduction

As one of common malignant tumors, primary lung cancer ranks the second in terms of morbidity and mortality worldwide.[1] In China, there were about 787,000 new cases of lung cancer and about 631,000 deaths in 2015.[2] Non-small cell lung cancer (NSCLC) accounts for 87% of cases of primary lung cancer.[3] The median 5-year survival rate for patients with brain metastases was < 5%.[4] Terribly, due to the high invasion of NSCLC and the lack of effective early screening, about 10% of patients have already developed brain metastases before they are diagnosed.[5] Therefore, how to improve the prognosis of NSCLC patients with brain metastases has been a hot research topic in recent years.

Chemotherapy is a routine therapy for advanced lung cancer, which can be divided into whole brain radiotherapy (WBRT) and stereotactic radiotherapy according to the range of radiotherapy. Nevertheless, the survival rate and local control rate of chemotherapy are not ideal.[6] Luckily, icotinib, as a novel anticancer agent, brings a new hope to NSCLC patients with brain metastases. More specifically, icotinib belongs to oral selective epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), which has been approved to be applied in advanced NSCLC treatment by United States Food and Drug Administration in June, 2011.[7] Also, icotinib has been approved to treat advanced NSCLC or NSCLC complicated with metastatic EGFR mutations in China in 2017.[8] Moreover, icotinib has same efficacy as gefitinib in second-line therapy for advanced NSCLC but produces lower drug-related toxicities.[9] As for that in first-line treatment, the effectiveness and safety of icotinib combined with WBRT for NSCLC have not been fully elucidated. Therefore, a systematical evaluation was performed on the efficacy and safety of icotinib combined with WBRT in the treatment of NSCLC patients with brain metastases in this study. Based on a series of data analysis, this study provided a reference for the selection of treatment strategies for NSCLC patients with brain metastases.

2. Materials and methods

2.1. Literature search

The meta-analysis was carried out through Preferred Reporting Items for Systematic Review and Meta-Analyses.[10] Specifically, the key terms were set as “icotinib,” “whole brain radiotherapy” or “WBRT,” “non-small cell lung cancer” or “NSCLC” and “brain metastases”, and the related data was searched from PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure and Wanfang Database. The search time was from the database establishment to December, 2022. Additionally, for obtaining additional potential articles, reference lists of all included relevant publications were acquired by hand searching.

2.2. Screening criterion

The inclusion criteria were shown as follows: Research subjects: patients were pathologically diagnosed as advanced NSCLC (stage IIIB/IV); Intervention measures: according to different treatment methods, the patients were divided into the control group and the observation group. The control group patients were treated with WBRT, while the observation group patients were given icotinib combined with WBRT; Outcome measures: Response rate; Disease control rate (DCR); Rash; Adverse reaction in gastrointestinal tract; Hepatic injury; Leukopenia; Progression free survival (PFS); at least one of the above outcome measures needed to be included; Research types: all included researches belonged to controlled clinical studies.

The exclusion criteria were presented as follows: Patients received antitumor treatment or suffered other cancers; The comparison of clinical outcomes between WBRT alone and icotinib combined with WBRT was not acquired; Non randomized controlled trials, case control, cohort study, literature review, meta-analysis, experimental protocol, etc.; The data failed to be extracted form studies, or the reports were duplicate.

2.3. Data extraction

Data were extracted from included articles by 2 authors. The extracted data consisted of characteristics of the included trials, author’s name, year of publication, sample size of each study group and outcome measures. The dispute would be resolved through discussion or consulting a third evaluator, and if necessary, the authors were contacted to consult data indicators not mentioned in the literature.

2.4. Statistical analysis

All statistical analyses were performed using Stata17.0 software. The heterogeneity of all studies was determined using Q test and I2 statistical methods. If there was significant heterogeneity (P < .05 and I2 > 50%), the random-effects model was used for meta-analysis; otherwise, the fixed-effect model was adopted for analysis. The relative ratio (RR) and 95% confidence interval (CI) were used for the summary statistics of binomial data. Measurement data were expressed with standardized mean difference (SMD) and 95% CI. The Begg funnel plot and the Egger test were employed for evaluation of publication bias, and the sensitivity analysis for determining the stability of the overall effect. P < .05 was considered statistically significant.

3. Results

3.1. Literature search outcomes

Flow chart of literature screening was displayed in Figure 1. Specifically, a total of 887 articles were obtained with help of preliminary search strategies, and after elimination of repetitions and irrelevant topics, 19 articles were determined and retained. Then, through full-text reading, articles without results and study types that failed to meet the requirements were excluded, and finally, 10 articles were included.[11–19] There were 717 patients enrolled in these 10 studies, including 366 in the observation group and 351 in the control group. In addition, the year of publication ranged from 2015 to 2021, and the trial time from 12 months to 48 months. All studies belonged to randomized controlled trials; age and gender were balanced and comparable between the 2 groups; and the characteristics of each study were presented in Table 1.

Figure 1.

Figure 1.

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Flow chart of literature screening.

Table 1.

Characteristics of the included studies.

NO. Author Year Duration of experiment Count Count (F/M) Intervention Age Outcomes
Observation Control Observation Control Observation Control Observation Control
1 Wu YL 2014 2011.10–2013.10 32 30 18/14 17/13 Icotinib + WBRT WBRT 60–86 61–87 ①②③④⑤⑥
2 Zheng Xiao-Ke 2016 2011.11–2013.11 38 38 20/18 21/17 Icotinib + WBRT WBRT 55–85 56–87 ①②③④⑥
3 XIA Yun 2017 2014.3–2016.3 20 20 7/13 6/14 Icotinib + WBRT WBRT 35–76 34–75 ①②③④⑤
4 JI Rong 2019 2013.6–2017.6 23 21 13/10 12/9 Icotinib + WBRT WBRT 49–70 49–74 ①②③④⑤⑥⑦
5 Ge T 2020 2018.6–2019.9 48 48 22/26 24/24 Icotinib + WBRT WBRT 52.9 ± 7.1 52.7 ± 6.9 ①②③④⑤⑥⑦
6 Wang C 2020 2016.6–2019.6 50 50 22/28 21/29 Icotinib + WBRT WBRT 64.62 ± 3.44 64.59 ± 3.41 ①②④⑥
7 LI Wenge 2020 2013.2–2016.2 51 40 25/26 22/18 Icotinib + WBRT WBRT / / ①②③④⑤⑦
8 Liu B 2021 2019.4–2020.4 35 35 15/20 14/21 Icotinib + WBRT WBRT 67.89 ± 5.68 65.71 ± 5.51 ①②④⑤⑥
9 Lu XY 2021 2016.1–2017.12 30 30 11/19 12/18 Icotinib + WBRT WBRT 59.3 ± 2.2 59.2 ± 2.1 ①②④⑥⑦
10 Huang WB 2021 2018.1–2020.1 39 39 18/21 16/23 Icotinib + WBRT WBRT 62.4 ± 2.3 62.8 ± 2.5 ③④
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① Response rate; ② Disease control rate; ③ Rash; ④ Adverse reaction in gastrointestinal tract; ⑤ Hepatic injury; ⑥ Leukopenia; ⑦ PFS, progression free survival; WBRT, whole brain radiotherapy.

F = female, M = male.

3.2. Short-term efficacy and outcome analysis of icotinib combined with whole brain radiotherapy in treating NSCLC patients with brain metastasis

A total of 9 literature reported response rate and DCR. This literature did not display obvious heterogeneity (Response rate: I2 = 0.0%, P = .604; DCR: I2 = 33.6%, P = .149), so the effect size were combined using a fixed-effect model. The results of the meta-analysis demonstrated that, compared with WBRT alone, the combination of icotinib + WBRT could effectively improve the response rate (RR = 1.550, 95 % CI [1.326,1.812], P < .001) and DCR (RR = 1.240, 95% CI [1.141,1.348], P < .001) of patients (Fig. 2A and B).

Figure 2.

Figure 2.

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A meta analysis of the short-term efficacy and outcomes. (A) Forest plot of the response rate, (B) forest plot of the disease control rate.

Next, the sensitivity analysis was preformed further on each study (Fig. 3A and B). After sequentially eliminating individual studies 1 by 1, no study was observed to significant affect the overall effect. Therefore, the results of this study were relatively stable and reliable.

Figure 3.

Figure 3.

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Sensitivity and publication bias analyses of short-term efficacy and outcomes. (A–B) Sensitivity analysis of the response rate and disease control rate, (C–D) funnel plot of the response rate and disease control rate.

In addition, the funnel plots of response rate and DCR were basically symmetrical (Fig. 3C and D). Both Begg Test and Egger test indicated no publication bias in response rate (Begg Test: Pr>|z|=0.076; Egger test: P>|t|=0.028) and DCR (Begg Test: Pr>|z|=0.175; Egger test: P>|t|=0.020).

3.3. Long-term efficacy and outcome analysis of icotinib + whole brain radiotherapy in treating NSCLC patients with brain metastasis

A total of 4 literature reported PFS, with obvious heterogeneity (I2 = 92.1%; P = .000). The analysis of random-effects model (Fig. 4A and B) revealed that the combination of icotinib and radiotherapy significantly prolonged PFS compared with the control group (SMD = 1.559, 95% CI [0.699, 2.419], P < .001). According to further sensitivity analysis results, after eliminating individual studies 1 by 1, there was no significant difference between the meta-analysis results and the original results, indicating that the results were robust and reliable.

Figure 4.

Figure 4.

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Meta-analysis for long-term efficacy and outcomes. (A) Forest plot of progression free survival, (B) sensitivity analysis of progression free survival.

3.4. Comparison of the incidence of adverse reactions

The most frequently reported adverse events included rash, adverse reaction in gastrointestinal tract, hepatic injury, and leukopenia. Rash was reported in 7 studies (Fig. 5A) with significant heterogeneity among studies (I2 = 70.1%; P = .003), so a random-effects model was employed for analysis (I2 = 70.1%; P = .003). There was no significant difference between the observation group and the control group in the incidence of rash (RR = 1.536, 95% CI [0.694,3.402], P = .290).

Figure 5.

Figure 5.

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Meta-analysis of the incidence of adverse reactions. (A–D) Forest plots of rash, adverse reaction in gastrointestinal tract, hepatic injury, and leukopenia.

Comparisons of adverse reaction in gastrointestinal tract were mentioned in 10 literature (Fig. 5B). These articles did not exhibit obvious heterogeneity (I2 = 0.0%; P = .770), and the incidence of adverse reaction in gastrointestinal tract was not significantly different between the 2 groups (RR = 1.060, 95% CI [0.792,1.419], P = 1.419).

Hepatic injury was proposed in 6 researches (Fig. 5C). Results of the fixed-effect model analysis (I2 = 0.0 %; P = .950) indicated no significant differences between the 2 group patients in the incidence of hepatic injury after treatment (RR = 1.536, 95% CI [0.694,3.402], P = .290).

There were 7 studies reporting leukopenia (Fig. 5D), without obvious heterogeneity (I2 = 0.0 %; P = .987). There was no statistical difference in the incidence of leukopenia after treatment between the 2 groups (SMD = 1.559, 95% CI [0.699,2.419], P = .000).

The sensitivity analysis (Fig. 6A–D) showed that, even the overall effect was analyzed after elimination of each study 1 by 1, the results did not change significantly but fluctuated around the estimates, indicating that the results were highly stable. In the funnel plot, except for the asymmetrical rash results, the graphics of the other 3 results were generally symmetrical (Fig. 7A–D). Moreover, the outcomes of Begg Test and Egger test exhibited that there was no publication bias for all results (adverse reaction in gastrointestinal tract: Begg Test: Pr>|z|=0.858; Egger test: P>|t|=0.610, leukopenia: Begg Test: Pr>|z|=0.548; Egger test: P>|t|=0.173) except for hepatic injury (Begg Test: Pr>|z|=0.060; Egger test: P>|t|=0.009). In other word, there may be publication bias in the results of rash and hepatic injury.

Figure 6.

Figure 6.

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Sensitivity analysis of the incidence of adverse reactions. (A–D) Sensitivity analyses for rash, adverse reaction in gastrointestinal tract, hepatic injury, and leukopenia.

Figure 7.

Figure 7.

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Publication bias analysis of the incidence of adverse reactions. (A–D) Funnel plots of rash, adverse reaction in gastrointestinal tract, hepatic injury, and leukopenia.

4. Discussion

Most of NSCLC patients develop into the advanced stage at the time of diagnosis, accompanied by poor clinical efficacy and prognosis. The available treatment options for NSCLC patients with brain metastasis include surgery, radiotherapy, chemotherapy, immunotherapy and targeted therapy.[20] Modern approaches to cancer treatment focus on the targeted and radiation related combined therapies. For example, advances in the development of molecular targeted agents, such as EGFR-TKIs and immune checkpoint inhibitors, have greatly improved clinical outcomes of NSCLC patients with brain metastases.[21] Therefore, it is necessary to retrospectively analyze the clinical effects of WBRT combined with icotinib in the treatment of whole brain metastasis of NSCLC.

After a comprehensive literature search and evaluation, a total of 10 articles were included in this study for meta-analysis. Specifically, icotinib + WBRT significantly increased the response rate and disease control rate and, on average, prolonged PFS, in the treatment of brain metastasis of NSCLC. The combination treatment was associated with the prolongation of short-term and long-term efficacy in NSCLC patients with brain metastasis. The overexpression of EGFR in tumor cells has been reported to be related to the radiation resistance. EGFR inhibitors can reduce the radiation resistance of EGFR mutant tumor cells by reducing DNA repair, proliferation and anti-apoptosis, thereby promoting the curative effect of chemotherapy.[22] As the first EGFR-TKI in China, icotinib shows good anticancer activity in vitro and in vivo.[23] Shortly speaking, icotinib can bind to adenosine triphosphate binding site of EGFR, inhibit EGFR activation, block downstream signal transmission, and then inhibit tumor proliferation and migration, and induce tumor apoptosis and other biological effects.[24] Owing to higher cost-effectiveness and better health benefits, icotinib outperforms pemetrexed, gefitinib and other EGFR-TKI.[25] Pemetrexed + radiotherapy exist hematologic toxicity risk of decreased grade 3 or 4 leukopenia and neutropenia.[26] Gefitinib, despite extending the overall survival, doubles the severity of clinically relevant toxicity, including bone marrow suppression and renal toxicity.[27] In addition, radiotherapy is an important treatment strategy for patients with NSCLC. Particularly, the implementation and introduction of image-guided radiotherapy have significantly improved the accuracy and tolerability of radiotherapy. The efficacy of most of potential brain tumor drugs is usually limited by the blood-brain barrier. Radiotherapy at a dose of 20 to 30 Gy may increase the permeability of the blood-brain barrier.[28] In locally advanced NSCLC that cannot be treated surgically, radiotherapy at above dose increases the overall survival of the patients.[29] Overall, icotinib combined with radiotherapy has the potential of synergistic effects, and can effectively treat NSCLC patients with brain metastasis.

After analysis of common adverse reactions, we found that the incidence of rash, adverse reaction in gastrointestinal tract, hepatic injury, and leukopenia was slightly increased, while the difference was not significant. All in all, icotinib + radiotherapy has a certain safety, better meets the treatment needs of patients, presents better efficacy, and has clinical application value, in the treatment of NSCLC patients with brain metastasis.

5. Limitations

There are some limitations in this study. Firstly, the dose and treatment frequency of icotinib and radiotherapy were not uniformly quantified in detail in the included studies. Secondly, the publication language was Chinese and the study site was China, so this paper can only be used to evaluate the treatment effect of patients with NSCLC in China. As for other regions, more clinical trials are still required. Last but not the least, due to the limitation of the page, this study focused on short-term and long-term clinical efficacy indicators of patients but not evaluate secondary clinical efficacy indicators (such as vascular endothelial growth factor, matrix metalloproteinase-9, and carcinoembryonic antigen levels).

6. Conclusion

To sum up, icotinib combined with radiotherapy significantly improves patients response rate and disease control rate, prolongs PFS, promotes short-term and long-term efficacy, but not increases adverse events.

Author contributions

Conceptualization: Bo Zhang.

Data curation: Bo Zhang.

Formal analysis: Bo Zhang.

Investigation: Bo Zhang.

Methodology: Bo Zhang.

Writing – original draft: Bo Zhang.

Writing – review & editing: Bo Zhang.

Abbreviations:

CI
confidence interval
DCR
disease control rate
EGFR-TKIs
epidermal growth factor receptor tyrosine kinase inhibitors
NSCLC
non-small cell lung cancer
PFS
progression free survival
RR
relative ratio
SMD
standardized mean difference
WBRT
whole brain radiotherapy

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

The authors have no funding and conflicts of interest to disclose.

How to cite this article: Zhang B. A meta-analysis for the efficacy and safety of icotinib combined with radiotherapy in treating brain metastases of non-small cell lung cancer. Medicine 2023;102:36(e34572).

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