Elsevier

Lung Cancer

Volume 122, August 2018, Pages 94-99
Lung Cancer

Comparison of up-front radiotherapy and TKI with TKI alone for NSCLC with brain metastases and EGFR mutation: A meta-analysis

https://doi.org/10.1016/j.lungcan.2018.05.014Get rights and content

Highlights

  • Up-front radiotherapy and TKI showed better intracranial PFS and OS than TKI alone.

  • The published papers evaluating the role of RT had high heterogeneity.

  • Patients with less number of brain metastases benefited more from RT treatment.

Abstract

Objective

About 50–70% non-small cell lung cancer (NSCLC) patients with EGFR mutation go through brain metastases (BM). Radiotherapy is the standard treatment before the tyrosine kinase inhibitor (TKI) era. However, the TKI has more than 70% intracranial response rate. Here, we performed a meta-analysis to compare clinical outcomes of up-front radiotherapy and TKI with TKI alone for NSCLC with BM and EGFR mutations.

Methods and materials

We searched Embase, Pubmed, Web of Science, Medline, the Cochrane Library and important oncology meetings comparing the up-front radiotherapy (RT) and TKI with TKI alone in NSCLC patients with newly diagnosed BM and EGFR mutation from database inception to December 2017. We conducted meta-analyses evaluating intracranial progression-free survival (iPFS) and overall survival (OS) with hazard ratios (HR) and 95% confidence intervals (CI) based on the HR of individual study.

Results

Seven studies with 1086 patients were eligible for meta-analyses. Compared to TKI alone, up-front RT and TKI showed better iPFS (HR = 0.72, 95%CI: 0.53-0.97, p = 0.028) and OS (HR = 0.70, 95%CI 0.53–0.93, p = 0.015). Meta regression analyses and subgroup analyses demonstrated patients with limited number of brain metastases benefited more from up-front RT on OS (HR: 0.54, 95% CI: 0.41-0.72, p = 0.000).

Conclusion

Compared with TKI alone, up-front RT and TKI had a higher iPFS and OS, especially for patients with limited number of brain metastases. Larger randomized trials evaluating these two treatment arms are needed to identify optimal treatments for specific patients.

Introduction

Lung cancer is the leading cause of cancer related death worldwide [1]. The non-small cell lung cancer (NSCLC) comprised more than 80% of that and almost 50% of NSCLC are lung adenocarcinoma [2]. The finding of epidermal growth factor receptor (EGFR) mutations has leading the treatment of lung adenocarcinoma into a new era with tyrosine kinase inhibitor (TKI). Patients with EGFR-mutant have a 50–70% risk for developing brain metastasis (BM) [3]. Traditionally, up-front whole-brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS) or surgical resection is the first line treatment of BM, either alone or in combination. However, the single agent of EGFR-TKI showed much pleasing results in TKI naive patients with BM and EGFR mutation with the intracranial response rate (iRR) of 75%-88%, median intracranial progression-free survival (iPFS) is 6.6-14.5 months, and median overall survival is 15.9-21.8 months [[4], [5], [6]]. So can up-front radiotherapy (RT) be deferred or omitted due to the neurotoxicity or stick to the radiation first and mandatory?

Regrettably, no phase III clinical trial has been published to show the comparison of up-front radiotherapy and deferred RT or TKI with no RT. Soon et al. reported a systematic review and meta-analysis based on 12 non-comparative observational studies (n = 363) and reached the conclusion that up-front cranial radiotherapy resulted in improved four-month iPFS and prolonged two-year OS compared to TKI alone in 2015 [7]. Recently, some retrospective analyses have been done with difference indications however. To examine whether up-front RT prolong the iPFS and OS, we reviewed and make a meta-analysis for these retrospective trails that assessed the up-front RT in EGFR mutant BM with deferred RT or no RT.

Section snippets

Search strategy and selection criteria

We searched for published articles, abstracts and reviews comparing the up-front RT and TKI with TKI alone (or with salvage RT) in NSCLC patients with newly diagnosed brain metastasis and EGFR mutation. RT followed by TKI or started within 4 weeks after EGFR-TKI initiation were deemed as up-front RT. The salvage RT in the control group started RT after the intracranial failure from the first-line TKI treatment. The study type, prospective or retrospective, was not restricted. All types of RT,

Systematic search

Fig. 1 illustrates citation selection. Our initial search strategy yielded 545 citations after removal of duplicates. After level 1 screening of titles and abstracts, 505 citations were excluded. After level 2 screening of the remaining 40 full-text articles, 33 were excluded. Thirteen didn’t report the original data, 9 had the different comparison, 6 reported the same study, and 5 didn’t report the data needed. Ultimately, 7 articles were included [[12], [13], [14], [15], [16], [17], [18]].

Discussion

To the best of our knowledge, this is the first meta-analysis to evaluate the efficacy of radiation in the treatment of EGFR mutant patients along with TKI. Up-front radiation is associated with a statistically significant improvement in iPFS (HR: 0.72, 95% CI: 0.53–0.97, p = 0.028), as well as prolong of OS (HR 0.70, 95%CI: 0.53-0.93, p = 0.015). Among patients with NSCLC and BM, radiation is supposed to act by enhancing the blood-brain barrier permeability and radio-sensitizing effects of

Conclusion

Based on the current available evidence, patients of NSCLC with brain metastases and EGFR mutations have better OS and iPFS when they receive up-front radiotherapy and TKI than TKI alone. Furthermore, patients with limited metastases numbers benefit more from the radiation treatment. Larger randomized trials evaluating these two treatment arms are needed to identify optimal treatments for specific patients.

Conflict of interest

None declared.

Funding

This work was supported by the CAMS Initiative for Innovative Medicine (CAMS-I2M, grant number 2016-I2M-1-001).

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    These authors contributed equally to this manuscript.

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