Abstract
Objectives
Patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) are at a heightened risk of developing brain metastases (BM). EGFR-tyrosine kinase inhibitors (TKI) are standard treatment for EGFR-mutated NSCLC. However, the necessity and optimal approach of brain radiotherapy for NSCLC patients with EGFR mutation remain inconclusive. We aimed to answer these questions by retrospectively analyzing the efficacy of radiotherapy in patients with BM from NSCLC with EGFR mutations.
Methods
Patients with EGFR- mutant NSCLC and BMs who were diagnosed between January 1, 2018 and December 31, 2022 were included. According to treatment methods those patients were divided into whole brain radiotherapy (WBRT) plus EGFR-TKI (WBRT group), stereotactic radiotherapy (SRT) plus EGFR-TKI (SRT group) and EGFR-TKI alone (TKI-only group). Propensity-score-matching (PSM) was performed to minimize the effect of possible confounding factors and to balance treatment groups.
Results
A total of 142 patients were included in this study. The median follow-up time was 22 months (range, 3.0–43.0 months). In the PSM cohort, the median intracranial progression free survival (iPFS) was 14, 30, 12 months and the median overall survival (OS) was 27 months, not reach and 33 months in WBRT group, SRT group and TKI-only group, respectively. Compared with the other two groups, SRT group significantly improved iPFS and OS (p < 0.05). And the local progression rate of intracranial lesions in SRT group was significantly reduced (p < 0.05).
Conclusion
This study showed that SRT combined with TKI may improve iPFS and prolong survival in patients with EGFR mutations in BMs from NSCLC.
Keywords: Non-small cell lung cancer, EGFR, Brain metastases, Radiotherapy
Introduction
Brain metastases (BM) are the most common metastatic sites of non-small cell lung cancer (NSCLC) [1]. With the more effective systemic therapies, the survival of NSCLC patients has been prolonged, and the probability of BMs in the course of NSCLC patients has gradually increased [2]. Approximately 30% to 40% of patients with NSCLC will develop BMs during the course of the disease [3]. Patients with BMs usually have a poor prognosis and require urgent treatment [4]. Radiotherapy, including whole brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS), are still important options in the treatment of lung cancer with BMs [5].
The subgroup of NSCLC patients is those with epidermal growth factor receptor (EGFR) kinase domain activation mutations, accounting for approximately 50% of NSCLC patients in Asian [6]. Patients with EGFR mutant NSCLC have a higher likelihood of brain metastases [7]. Due to the detection of EGFR-mutant we have entered a new era of personalized therapy in the treatment of lung cancer patients driven by genotyping. Tyrosine kinase inhibitors (TKIs), especially the third-generation TKIs, targeting these mutations constitute the treatment of NSCLC patients with EGFR mutation, and significantly improve the progression-free survival (PFS) and overall survival (OS) [8, 9]. Preclinical evidence indicates that third-generation EGFR-TKI are highly distributed in the brains of mice and nonhuman primates, supporting third-generation EGFR-TKI for central nervous system penetration [10].
Considering the effective effect of EGFR-TKI on the central nervous system and the early cognitive decline caused by cranial RT, the clinical application of RT in patients with EGFR mutation and brain metastasis has been controversial, especially whether to retain RT until the disease progresses to EGFR-TKI [11, 12]. Some studies show that the efficacy of EGFR-TKI alone in the treatment of brain metastasis is not inferior to that of RT combined with EGFR-TKI [13, 14]. However, some studies have investigated the efficacy of RT combined with EGFR-TKI versus EGFR-TKI alone in the treatment of brain metastases [15, 16], and the results are inconsistent.
Currently, there is no conclusive evidence on whether or how brain radiotherapy is needed for NSCLC patients with EGFR mutation and brain metastases. Our study aims to answer these questions by retrospectively analyzing the patterns of progression after different treatment modalities in patients with brain metastases from NSCLC with EGFR mutations.
Materials and methods
Patients
We retrospectively reviewed the medical records of patients with brain metastases from NSCLC between January 1, 2018 and December 31, 2022, at Hangzhou Cancer Hospital. The inclusion criteria were as follows: (1) histologically or cytologically confirmed lung adenocarcinoma; (2) patients harboring EGFR mutation confirmed by genetic testing; (3) BMs were confirmed with enhanced magnetic resonance imaging; (4) patients were treated with EGFR-TKI after brain metastasis was diagnosed. The following baseline clinical characteristics were retrieved from the electronic medical records: age, sex, previous treatment regimens, number of BMs, extracranial metastases, and mode of brain radiotherapy.
Treatment
According to whether the patients received brain radiotherapy after brain metastasis, the patients were divided into whole brain radiotherapy (WBRT) plus TKI group (WBRT group), stereotactic radiotherapy (SRT) plus TKI group (SRT group) and TKI alone group (TKI-only group). Only patients who were treated with WBRT/SRS immediately after detection of brain metastases were classified as in the WBRT/SRS plus TKI group. Treatment with either TKI alone or TKI plus radiotherapy was decided by the clinician taking into account the patient characteristics. EGFR-TKI includes all TKIs from the first to third generations. All TKIs were administered orally at the usual dose. Radiotherapy in the WBRT/SRS plus TKI group included WBRT (30 Gy in 10 fractions and 3 Gy per fraction), and SRS (30–40 Gy in 5–8 fractions). The brain radiotherapy was decided by the radiologist under their clinical experience.
Follow-up
Intracranial lesions were followed up mainly by Gadolinium contrast-enhanced MRI, Systemic tumor reactions were mainly evaluated by enhanced computed tomography (CT). Tumor response is routinely assessed every 2–3 months from the beginning of brain metastasis treatment. Tumor response of BM and primary lesions was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, including complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD). The primary endpoint was intracranial progression free survival (iPFS). Intracranial PFS referred was defined as time from the treatment initiation to progression of disease or death owing to any cause. No intracranial progression was regarded as censored data at the last follow-up. The secondary endpoints included OS. OS is defined as the time interval between the first brain metastasis treatment and death from any cause or the last known follow-up.
Statistical analysis
Propensity-score-matching (PSM) was performed to minimize the effect of possible confounding factors and to balance treatment groups. For each subject, a propensity score was estimated using a logistic regression model based on the following baseline variables: “sex,” “age,” “performance status,” “smoking status,” “number of BM,” “size of the largest BM,” “extracranial metastasis,” and “liver metastasis.”
Intracranial DCR, and OS were estimated from the end of radiotherapy using the Kaplan–Meier calculation method. Subgroups were compared by use of the generalized Wilcoxon test for univariate analysis and the Cox proportional hazard model for multivariate analysis. All statistical analyses were performed by using GraphPad Prism software version 8.0 (GraphPad Software, Inc., USA) and SPSS statistical software version 20.0 (IBM Corp., USA). All P values were 2-sided, with P < 0.05 considered to indicate a statistically significant result.
Results
Patient characteristics
Between January 1, 2018 and December 31, 2022, we found 142 NSCLC patients with BM and EGFR mutations received EGFR-TKI in our cancer center. The baseline characteristics of patients in were shown in Table 1. Before PSM, there were 57 patients in WBRT group, 46 patients in SRT group and 39 in TKI-only group. After PSM, there were 50 patients in WBRT group, 40 patients in SRT group and 30 in TKI-only group. The last follow-up date was December 31, 2023. 78 patients were still alive, and 64 patients had died. The median follow-up time was 22 months (range, 3.0–43.0 months) for all patients.
Table 1.
Patient characteristics
| Characteristics | Before PSM | After PSM | ||||
|---|---|---|---|---|---|---|
| No./median(range) | No./median(range) | |||||
| WBRT group | SRT group | TKI-only group | WBRT group | SRT group | TKI-only group | |
| Patients | 57 | 46 | 39 | 50 | 40 | 30 |
| Sex | ||||||
| Male | 22 | 18 | 16 | 21 | 17 | 14 |
| Female | 35 | 28 | 23 | 29 | 23 | 16 |
| Age | 61 (38–76) | 65 (41–85) | 65 (56–85) | 62 (44–76) | 66 (44–85) | 65 (54–86) |
| Performance status | ||||||
| 0 | 13 | 12 | 11 | 11 | 11 | 7 |
| 1 | 37 | 31 | 25 | 34 | 26 | 21 |
| 2 | 7 | 3 | 3 | 5 | 3 | 2 |
| Smoking status | ||||||
| Current or former | 27 | 21 | 19 | 25 | 20 | 14 |
| Never | 30 | 25 | 20 | 25 | 20 | 16 |
| Number of BM | ||||||
| ≤ 3 | 27 | 36 | 18 | 24 | 30 | 14 |
| ≥ 4 | 30 | 10 | 21 | 26 | 10 | 16 |
| Size of the largest BM | ||||||
| ≥ 1 cm | 20 | 21 | 13 | 19 | 19 | 10 |
| < 1 cm | 37 | 25 | 26 | 31 | 21 | 20 |
| Extracranial metastasis | ||||||
| Yes | 37 | 28 | 29 | 33 | 25 | 22 |
| No | 20 | 18 | 10 | 17 | 15 | 8 |
| Hepatic metastases | ||||||
| Yes | 3 | 2 | 5 | 2 | 2 | 3 |
| No | 54 | 44 | 34 | 48 | 38 | 27 |
| EGFR-TKI | ||||||
| First or second generation | 30 | 18 | 15 | 27 | 16 | 14 |
| Third generation | 27 | 28 | 24 | 23 | 24 | 16 |
| EGFR mutation | ||||||
| 19del | 16 | 19 | 16 | 15 | 14 | 12 |
| L858R | 21 | 15 | 11 | 18 | 14 | 10 |
| Uncommon mutations | 5 | 3 | 4 | 5 | 3 | 1 |
| Unknown | 15 | 9 | 8 | 12 | 9 | 7 |
| Following treatment | ||||||
| Unchanged | 19 | 24 | 15 | 15 | 20 | 8 |
| Another TKI | 30 | 15 | 17 | 27 | 14 | 15 |
| Chemotherapy or immunotherapy | 8 | 7 | 7 | 8 | 6 | 7 |
Outcomes
In the PSM cohort, the iPFS of the three groups were shown in Fig. 1a. The median iPFS was 14, 30, 12 months in the WBRT group, SRT group and TKI-only group, respectively. The 1-year iPFS rate was 59.1%, 74.8% and 45.6% months in the WBRT group, SRT group and TKI-only group. Themedian iPFS and 1-year iPFS rate of the SRT group was higher than that of the other two groups (p < 0.05). There was no significant difference between WBRT group and TKI-only group (p > 0.05).
Fig. 1.
a iPFS of the three groups in the PSM cohort. b iPFS of the three groups among patients receiving TKI as first-line therapy in the PSM cohort. c iPFS of the three groups among patients receiving third-generation TKIs in the PSM cohort. d iPFS of the three groups among patients receiving first or second-generation TKIs in the PSM cohort
Figure 2a shows the OS of the three groups. In the PSM cohort, the median OS in WBRT group, SRT group and TKI-only group was 27 months, not reach and 33 months, respectively. The OS in SRT group was significantly longer than WBRT group and TKI-only group (p < 0.05). There was no significant difference between WBRT group and TKI-only group (p > 0.05).
Fig. 2.
a OS of the three groups in the PSM cohort. b OS of the three groups among patients receiving TKI as first-line therapy in the PSM cohort. c OS of the three groups among patients receiving third-generation TKIs in the PSM cohort. d OS of the three groups among patients receiving first or second-generation TKIs in the PSM cohort
A subset analysis was conducted among patients receiving TKI as first-line therapy and patients receiving first, second or third-generation TKIs.
In the PSM cohort, there were 30, 22 and 22 patients in WBRT group, SRT group and TKI-only group who had received TKI as first-line therapy. The median iPFS was 17, 30, 12 months in the WBRT group, SRT group and TKI-only group, respectively. The 1-year iPFS rate was 60.0%, 75.0% and 49.2% months in the WBRT group, SRT group and TKI-only group (Fig. 1b). The median OS in WBRT group, SRT group and TKI-only group were 30 months, not reach and 29 months, respectively (Fig. 2b). The iPFS and OS in SRT group was significantly longer than WBRT group and TKI-only group (p < 0.05). There was no significant difference between WBRT group and TKI-only group (p > 0.05).
In the PSM cohort, there were 23, 24 and 16 patients in WBRT group, SRT group and TKI-only group who had received third-generation TKIs. The median iPFS was 14, not reach, 12 months in the WBRT group, SRT group and TKI-only group, respectively. The 1-year iPFS rate was 66.9%, 77.9% and 50.0% months in the WBRT group, SRT group and TKI-only group (Fig. 1c). The median OS in WBRT group, SRT group and TKI-only group were 21 months, 38 and 36 months, respectively (Fig. 2c). The iPFS in SRT group was significant longer than WBRT group and TKI-only group (p < 0.05). The OS in SRT group was longer than WBRT group and TKI-only group, however, the difference between the three groups was not statistically significant (p > 0.05).
In the PSM cohort, there were 27, 16 and 14 patients in WBRT group, SRT group and TKI-only group who had received first or second-generation TKIs. The median iPFS was 17, 28, 12 months in the WBRT group, SRT group and TKI-only group, respectively. The 1-year iPFS rate was 61.4%, 73.3% and 42.9% months in the WBRT group, SRT group and TKI-only group (Fig. 1d). The median OS in WBRT group, SRT group and TKI-only group were 30 months, not reach and 29 months, respectively (Fig. 2d). The iPFS and OS in SRT group was significantly longer than WBRT group and TKI-only group (p < 0.05). There was no significant difference between WBRT group and TKI-only group (p > 0.05).
Figure 3 shows the progression patterns of WBRT group, SRT group and TKI-only group. The incidence of local progression, new lesions or both were 22.8%, 14.0% and 10.5% in WBRT group, 4.3%, 23.9% and 2.2% in SRT group, 23.1%, 15.4% and 17.9% in TKI-only group, respectively. Compared with the other two groups, the local progression rate of intracranial lesions in SRT group was significantly reduced (p < 0.05).
Fig. 3.
Progression patterns of the three groups
Figure 4 shows the comparison of intracranial progression time and extracranial progression time among patients in WBRT group, SRT group and TKI-only group. The results indicate that the proportions of patients experiencing intracranial progression first in WBRT group, SRT group and TKI-only group were 28.1%, 13.0%, 41.0%, respectively. The proportion of intracranial progression first in SRT group is significantly fewer than in WBRT group and TKI-only group (p < 0.05).
Fig. 4.
Time to progression of intracranial and extracranial progression
Table 2 shows the multivariate analysis for iPFS and OS in the PSM cohort, these characteristics including gender, age, performance status, smoking status, number of BMs, maximum dimension of largest BM, hepatic metastases, following treatment were not significant (p > 0.05).
Table 2.
Multivariate analysis for iPFS and OS in the PSM cohort
| Variables | Multivariate analysis for iPFS | Multivariate analysis for OS | ||
|---|---|---|---|---|
| HR (95% CI) | P value | HR (95% CI) | P value | |
| Age | 1.00 (0.97–1.03) | 0.935 | 1.02 (0.99–1.06) | 0.199 |
| Gender | 1.10 (0.66–1.83) | 0.721 | 2.88 (0.77–10.76) | 0.155 |
| Male | ||||
| Female | ||||
| Performance status | 1.39 (0.58–1.90) | 0.524 | 1.1 (0.55–2.18) | 0.795 |
| 0 | ||||
| ≥ 1 | ||||
| Smoking status | 0.95 (0.57–1.57) | 0.832 | 0.38 (0.1–1.45) | 0.155 |
| Current or former | ||||
| Never | ||||
| Maximum dimension | 1.17 (0.70–1.96) | 0.545 | 1.05 (0.6–1.84) | 0.862 |
| ≥ 1 cm | ||||
| < 1 cm | ||||
| Number of BMs | 1.88 (0.90–3.45) | 0.062 | 1.66 (0.9–3.08) | 0.105 |
| ≥ 4 | ||||
| ≤ 3 | ||||
| Brain radiotherapy | 0.51 (0.29–0.92) | 0.026 | 0.36 (0.18–0.75) | 0.006 |
| SRT | ||||
| WBRT or TKI alone | ||||
| Hepatic metastases | 0.36 (0.08–1.57) | 0.175 | 1.46 (0.52–4.1) | 0.476 |
| Yes | ||||
| No | ||||
| Following treatment | – | – | 0.89 (0.38–2.08) | 0.79 |
| TKI | ||||
| Chemotherapy or immunotherapy | ||||
Discussion
Brain metastasis often occurs in lung cancer, especially in patients with driver-positive NSCLC. TKIs and brain radiotherapy are both commonly used to treat brain metastases in driver-positive NSCLC. Nevertheless, the combination of RT and TKI for BMs is still controversial. Multiple published research reports have demonstrated that brain RT combined with EGFR-TKI prolong OS and increases the rate of BM remission [17–19]. On the other hand, several studies have shown that brain radiotherapy combined with TKI therapy does not benefit compared to TKI therapy alone [20]. Our article retrospectively analyzed the prognosis of EGFR-positive NSCLC patients with brain metastases after different treatments, providing reference for the treatment strategy selection for such patients. Based on our small-scale retrospective study, we found that the SRT in combination with EGFR-TKI was associated with longer OS and higher iPFS in patients with EGFR- mutated NSCLC with BM compared with EGFR-TKI alone. However, WBRT combined with TKI showed no significant difference compared to TKI alone in both iPFS and OS.
The presence of the blood–brain barrier (BBB) impedes the penetration of systemic therapeutic drugs into the brain, consequently leading to suboptimal control of brain metastases through systemic therapy [21]. Previous studies have indicated that brain radiotherapy can disrupt the BBB, leading to increased intracranial drug concentrations, thereby enhancing the efficacy of systemic therapy in controlling intracranial lesions [22]. However, our research findings indicate that the combination of WBRT and EGFR-TKI did not significantly improve iPFS or OS compared to TKI alone. Moreover, the progression patterns in both groups were quite similar. Therefore, it can be observed that the combination of WBRT and TKI does not confer significant benefits compared to TKI alone. This result is also similar to the findings of many previous studies [20].
Traditionally, WBRT has been the primary local treatment approach for brain metastases. When comparing SRT combined with TKI and WBRT combined with TKI, we found that both iPFS and OS were improved in the SRT combined with TKI group. Compared with WBRT, SRT can achieve higher biological equivalent dose to achieve the effect of tumor eradication, and the SRT have less effect on the neurocognitive functions [23]. Although patients with brain metastases may have microscopic metastases that are invisible, WBRT is considered to effectively control these microscopic metastases [24]. However, from the pattern of progression, the combination of WBRT and TKI does not significantly reduce the probability of new lesions appearing. In addition to its neurotoxicity and lack of impact on the survival of NSCLC patients with brain metastases, the gradual reduction of WBRT tends to favor minimally invasive strategies SRT.
For EGFR-mutated NSCLC patients, third-generation TKIs are considered to be more effective in improving PFS and OS than first generation TKIs equivalent. Preclinical models and clinical studies have shown that third-generation EGFR TKIs have better blood–brain barrier crossing ability compared to the first-generation EGFR TKIs, enabling better control of brain metastases [10]. The OCEAN study showed that osimertinib for T790M NSCLC with BM without brain radiotherapy the median brain metastasis-related PFS, median OS and overall response rate were 25.2 months, 19.8 months and 40.5%, respectively [25]. Although third-generation EGFR-TKIs have a stronger ability to penetrate the BBB compared to first- and second-generation EGFR-TKIs, resulting in better control of brain metastases, our research results show that the combination of third-generation EGFR-TKIs with SRT can still significantly improve iPFS (Fig. 1c). Since some patients developed brain metastases after progressing on first- or second-generation EGFR-TKI therapy and switched to third-generation EGFR-TKI, the OS of patients treated with TKI combined with SRT showed improvement compared to those treated with TKI combined with WBRT or TKI alone. However, the difference was not statistically significant. (Fig. 2c).
Currently, accumulating studies have confirmed that NSCLC brain metastases with EGFR mutations can benefit from early brain radiation therapy, even if third-generation EGFR-TKIs are chosen for systemic treatment [26]. Although third-generation TKIs have potent efficacy penetrating the BBB, and have a certain control effect on intracranial lesions, intracranial progression is still the most common site of treatment failure. As shown in the Fig. 4, compared to the combination of SRT with TKIs, the proportion of patients with intracranial progression occurring earlier than extracranial or both in the TKIs alone group is significantly higher. We speculate the reason for this phenomenon may be that for existing brain metastases, TKIs have limited control ability, but they have a certain ability to inhibit the emergence of new lesions. In the TKI combined SRT group, the intracranial progression time for most patients usually does not precede extracranial progression, which may occur due to TKI resistance. Conversely, in the TKI combined WBRT or TKI alone group, limited control over existing brain metastases typically leads to earlier intracranial progression.
Nevertheless, our study had some limitations. First, the conclusions drawn are constrained due to the small size of our cohort, the retrospective nature of the study conducted within a single institution, and the potential impact of treatment selection bias on the observed efficacies. Second, since it was a retrospective study, professional assessment of cognitive function was not conducted at the time, leading to missing records of complications and adverse events. Lastly, patients receiving WBRT had a relatively higher proportion of multiple brain metastases compared to those receiving SRT, which may have influenced the results. However, subsequent studies have also shown that SRT remains efficacy in treating multiple brain metastases [27].
Conclusion
We retrospectively analyzed NSCLC patients with EGFR mutations and brain metastases. The results showed that regardless of whether patients received third-generation EGFR-TKI, combined with SRT for brain metastases significantly improved iPFS and also prolonged OS. However, the improvement in prognosis with WBRT was relatively limited.
Abbreviations
- EGFR
Epidermal growth factor receptor
- BM
Brain metastases
- NSCLC
Non-small cell lung cancer
- TKI
Tyrosine kinase inhibitors
- WBRT
Whole-brain radiotherapy
- SRT
Stereotactic radiotherapy
- iPFS
Intracranial progression free survival
- OS
Overall survival
- MRI
Magnetic resonance imaging
- CT
Computed tomography
- RECIST
Response evaluation criteria in solid tumors
- CR
Complete response
- PR
Partial response
- SD
Stable disease
- PD
Progressive disease
- DCR
Disease control rate
- BBB
Blood–brain barrier
Author contributions
BX, LCZ, SLM designed the study. KCP, BW analyzed the data and wrote the manuscript, XX, JFL, YT collected the data. All authors involved in the article and approved the final manuscript. All authors reviewed the manuscript.
Funding
The study is supported by Hangzhou Municipal Health Commission (NO.20220919Y050), Hangzhou Science and Technology Development Plan Project (NO.202004A19) and Medical and Health Technology Plan of Zhejiang Province (2022KY978).
Data availability
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
This study had been approved by the Institutional Ethics Review Board of the Hangzhou Cancer Hospital (#73/HZCH-2022), and written informed consent was waived because all the data was anonymized during data processing and presentation. Consent waiver was approved by Institutional Ethics Review Board of the Hangzhou Cancer Hospital. All methods were carried out in accordance with relevant guidelines and regulations.
Consent for publication
All the authors have read and agree to the content of the paper.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Contributor Information
Bing Xia, Email: bingxia_hzch@163.com.
Lucheng Zhu, Email: zhulucheng1@outlook.com.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.