Whether epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) combined with chemotherapy can delay the occurrence of brain metastasis (BM) is unclear.
Objective
This retrospective study aimed to evaluate whether EGFR–TKIs combined with chemotherapy can delay BM and decrease the incidence of BM as initial progression.
Patients and Methods
The data of 100 patients with EGFR-mutant advanced lung adenocarcinoma were retrospectively reviewed. The patients had no BM at initial diagnosis, and BM occurred during the treatment. Patients received EGFR–TKI only or EGFR–TKI combined with chemotherapy. Intracranial progression-free survival (iPFS), systemic progression-free survival (PFS), and overall survival (OS) were evaluated.
Results
The overall median OS was 39 months (95% confidence interval (CI), 35.6–42.4 months). The median OS of EGFR–TKI combined with chemotherapy and EGFR–TKI only are 41 months (95% CI 35.5–46.5 months) and 39 months (95% CI 36.8–41.2 months), respectively. Patients in the combination treatment group had longer PFS (16 vs. 10 months; P = 0.030) and iPFS (21 vs. 14 months; P = 0.026). Further, as initial progression, fewer patients developed BM in the combined treatment group compared with the EGFR–TKI-only group (30.6% vs. 52.9%, P = 0.002) with a hazard ratio of 0.64 (95% CI 0.43–0.96). After controlling for significant covariables in a multivariable model, the different treatment strategies were independently associated with improved iPFS.
Conclusions
In this retrospective analysis, EGFR–TKIs combined with chemotherapy could improve PFS. Further, the combined treatment could delay BM occurrence and decrease the incidence of BM as initial progression.
Hinweise
Changhui Li and Bo Zhang contributed equally to this work.
Epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitors (TKIs) combined with chemotherapy could delay the occurrence of brain metastasis (BM).
The combination treatment decreased the incidence of BM as initial progression.
Patients treated with EGFR–TKIs combined with chemotherapy showed superior intracranial and systemic PFS.
1 Introduction
Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide, and the brain is a common metastatic sites in NSCLC [1]. Patients with epidermal growth factor receptor (EGFR) mutations are more susceptible to develop brain metastasis (BM) compared with those with wild type EGFR, especially during the course of the disease [2]. Up to 40% of patients with advanced EGFR-driven NSCLC develop BM, which is a significant cause of morbidity and mortality [3‐6].
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Patients with NSCLC harboring sensitive EGFR mutations exhibit a favorable response to tyrosine kinase inhibitors (TKIs). EGFR–TKIs were demonstrated to provide clinical benefit over platinum-based chemotherapy and are recommended as the standard first-line therapy for NSCLC patients with EGFR-sensitive mutation [7‐10]. However, almost all patients eventually develop secondary resistance after the initial response. In addition, BM is a common complication of NSCLC. Therefore, it is necessary to delay and control BM in this disease.
Some prospective trials confirmed that the combination of first-generation EGFR–TKIs with chemotherapy in patients with advanced NSCLC provided more favorable clinical outcomes compared with EGFR–TKI alone [11‐15]. However, whether the addition of chemotherapy to EGFR–TKIs could delay the occurrence of BM is unclear. Therefore, this analysis was conducted to investigate whether EGFR–TKIs combined with chemotherapy could delay the occurrence of BM and decrease the incidence of BM as initial progression.
2 Materials and Methods
2.1 Patient Selection
This study was approved by the ethics committee and institutional review board of the Shanghai Chest Hospital (No. KS1721) and carried out in accordance with the declaration of Helsinki. Written informed consent to use patient data were obtained from all patients before any treatment.
The hospital records of 2915 patients who were treated at the Shanghai Chest Hospital between 1 June 2010 and 31 December 2016 were screened. One hundred patients met the following eligibility criteria: (1) stage IV NSCLC; (2) histologically or cytologically proven adenocarcinoma with sensitizing EGFR mutations (exon 19 deletion or exon 21 L858R mutation); (3) first-generation EGFR–TKI alone or combined with chemotherapy as first-line treatment (chemotherapy agents were mainly pemetrexed, gemcitabine, vinorelbine, or paclitaxel in combination with platinum, and administered until the occurrence of further disease progression or unacceptable toxicity; the average interval between chemotherapy was 4 weeks); and (4) without baseline BM, and with BM as a result of disease progression.
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All patients received a systemic examination as clinical baseline evaluation (including chest computed tomography (CT), magnetic resonance imaging (MRI) of the brain, bone scanning, and abdominal ultrasound examination). Responses were evaluated by chest CT and abdominal ultrasound examination after 4 weeks of first chemotherapy and then every 3–4 months until progression. Bone scanning was checked every 4–6 months. Brain MRI was repeated every 3 months. If the patients developed brain symptoms during the treatment, MRI of the brain was performed immediately. Moreover, MRI was checked every 2–3 months after the diagnosis of BM.
Patients were excluded if they had resistance mutations or EGFR mutation status was unavailable, if they were diagnosed with baseline BM or no BM occurred during the whole treatment process. Patients who did not receive first-line EGFR–TKI or did not complete at least four cycles of chemotherapy were also excluded.
2.2 Study Design
Medical records and follow-up data were collected for analysis. The detailed data were: age, sex, smoking history, EGFR mutation status, Eastern Cooperative Oncology Group (ECOG) performance status (PS), presence or absence of BM at initial diagnosis, symptoms of BM, size of the largest BM, number of BM, whether the patients underwent any surgery, whether the patients underwent any radiotherapy, and the type of radiotherapy. Patients were categorized by age (< 60 or ≥ 60 years), sex (male or female), ECOG–PS (0–1 or 2–3), smoking history (yes or no), EGFR mutation (exon 19 or exon 21), extracranial metastases at the time of BM (yes or no), symptoms of BM (yes or no), size of the largest BM (< 1 or ≥ 1 cm), number of BM (≤ 3 or > 3), surgery (yes or no), radiotherapy (yes or no) and radiotherapy type (no, whole brain radiation therapy (WBRT), or stereotactic radiosurgery (SRS)). Patients received the following treatments: EGFR–TKI alone (n = 51) or EGFR–TKI combined with chemotherapy (n = 49). The treatment responses were assessed during the therapy.
2.3 Treatments and Evaluation Criteria
For extracranial lesions, all patients were evaluated by chest CT, bone scanning, and abdominal ultrasound examination. Brain imaging evaluation was checked by brain MRI. If the patient had symptoms during the treatment, the corresponding examination and evaluation were performed immediately. The tumor response to the treatments was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines and Response Assessment in Neuro-Oncology Brain Metastases (RANO–BM) criteria, and classified into complete response (CR), partial response (PR), stable disease (SD), and progression of disease (PD).
The EGFR Mutation Detection Kit (Amoy Diagnostics, Xiamen, China), which is based on the amplification mutation refractory system technology, was used to detect the 29 most common types of EGFR mutations. All experiments were performed following the manufacturer’s instructions: 4.7 μl of DNA was added to 35.3 μl of polymerase chain reaction (PCR) master mix, containing PCR primers, fluorescent probes, PCR buffer, and Taq DNA polymerase. PCR thermal cycling was set as following: 95 °C for 5 min, followed by 15 cycles of 95 °C for 25 s, 64 °C for 20 s, 72 °C for 20 s, and then 31 cycles of 93 °C for 25 s, 60 °C for 35 s, and 72 °C for 20 s. Fluorescent signals were collected from the FAM and HEX channels.
First-generation EGFR–TKIs were given orally at a dose of 150 mg (erlotinib) daily, 250 mg (gefitinib) daily, or 125 mg (icotinib) three times daily.
Intracranial progression-free survival (iPFS) was defined as the period from the initial administration of systemic therapy to BM. Systemic progression-free survival (PFS) was defined as the period from the initial administration to tumor progression. In addition, overall survival (OS) was defined as the timeline from the initiation of therapy to death or the end of follow-up (1 May 2019).
2.4 Statistical Analysis
The characteristics of patients were compared using the χ2 test for categorical variables. iPFS, PFS, and OS were analyzed using the Kaplan–Meier method and further compared using the log-rank test. Finally, the Cox proportional hazard regression model was used for multivariate analysis to determine independent prognostic factors for iPFS and OS. A P value of less than 0.05 was considered statistically significant. All statistical analyses were carried out using SPSS software, version 23.0 (IBM Corporation, NY, USA).
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3 Results
3.1 Characteristics of Patients
A total of 2915 patients with stage IV lung adenocarcinoma were initially screened. Among them, 2815 patients were excluded because they did not meet any of the inclusion criteria. The flow chart of patient selection is shown in Fig. 1. One hundred patients were included in the final analysis.
Fig. 1
Patient selection flow-chart
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Among the 100 patients, 49 (49%) received EGFR–TKIs combined with chemotherapy and 51 (51%) received EGFR–TKIs alone. In the combined treatment group, three patients were treated with paclitaxel combined with platinum as first-line chemotherapy, 26 with pemetrexed combined with platinum, 15 with gemcitabine combined with platinum, and five with vinorelbine combined with platinum. The median follow-up time was 39 months (95% CI 35.6–42.4). The median age was 60 years (range 38–81 years) and 59 years (range 31–77 years) in the EGFR–TKI-alone and combined treatment groups, respectively. The baseline patient characteristics are given in Table 1. No difference was found between the two groups with respect to age, sex, ECOG-PS, smoking history, and EGFR mutation status.
3.2 Analysis of Intracranial Progression-Free Survival (iPFS)
Patients receiving combined treatment had a significantly longer iPFS compared to those receiving EGFR–TKIs alone [21 months (95% CI 17.08–24.91 months) versus 14 months (95% CI 11.70–16.29 months), P = 0.026] (Fig. 2a). At initial progression, the hazard ratio (HR) of BM for the combined treatment group compared with the EGFR–TKI-alone group was 0.64 (95% CI 0.43–0.96), suggesting a risk reduction of 36%. The cumulative incidence curves of BM for each group are shown in Fig. 2b. The patients in the combined treatment group had lower cumulative risks of BM at 6 months (4% vs. 18%, P < 0.0001), 12 months (14% vs. 41% P < 0.0001), and 24 months (57% vs. 78%, P < 0.0001). Further, 15 patients (30.6%) developed BM as initial progression in the combined treatment group, whereas 27 patients(52.9%)with BM as initial progression were observed in the EGFR–TKI alone group (P = 0.002) (Fig. 2c).
Fig. 2
a Intracranial progression-free survival (iPFS) is significantly improved in patients receiving Epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitors (TKIs) combined with chemotherapy versus EGFR–TKI only. b Cumulative incidence curves of brain metastasis (BM) progression for the combination and EGFR–TKI-alone groups. c Characteristics of initial progression. d Patients had a significantly longer progression-free survival (PFS) with combination therapy compared to EGFR–TKI alone. e No difference in overall survival (OS) was found between the two groups
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When BM occurred, symptoms of BM, size of the largest BM, and number of BMs were comparable in the two groups. Moreover, no difference was observed between the two groups in terms of subsequent radiotherapy, radiotherapy type, and surgery after BM. Characteristics of BM are given in Table 2.
After controlling for significant covariables of iPFS, such as age, sex, smoking history, ECOG-PS, and mutation type, in a multivariable model, the prognosis independently correlated with therapy strategy between the two groups (EGFR–TKI vs. EGFR–TKI combined with chemotherapy, adjusted HR 0.624; 95% CI 0.416–0.938, P = 0.023) (Table 3).
Table 3
Univariate and multivariable analyses for covariables associated with intracranial progression-free survival
3.3 Analysis of Progression-Free Survival (PFS) and Overall Survival (OS)
Notably, the combined treatment group showed a significantly longer PFS [16 months (95% CI 14.04–17.96) versus 10 months (95% CI 6.89–13.11); P = 0.030] compared to the EGFR–TKI-only group (Fig. 2d).
At the follow-up cut-off date of 1 May 2019, 20% (n = 20) of patients were still alive (nine receiving EGFR–TKI combined with chemotherapy; 11 receiving EGFR–TKI only). Patients treated with EGFR–TKI combined with chemotherapy failed to show superior OS [41 months (95% CI 35.5–46.5 months) vs. 39 months (95% CI 36.8–41.2 months), P = 0.397] (Fig. 2e).
After controlling for significant covariables in a multivariable model, no factor was independently associated with improved OS (Table 4).
Table 4
Univariate and multivariable analyses for covariables associated with overall survival
This study investigated the efficacy of first-generation EGFR–TKIs combined with chemotherapy as the first-line treatment for patients with lung adenocarcinoma with sensitizing EGFR mutations. A total of 100 eligible patients were analyzed. The results showed that EGFR–TKIs combined with chemotherapy could delay the occurrence of BM in patients with EGFR-mutant lung adenocarcinoma. The incidence and risk of BM as initial progression was reduced by 36% in the combined treatment group. Patients treated with EGFR–TKIs combined with chemotherapy showed superior PFS but failed to show an OS benefit.
Patients with EGFR mutations have a higher likelihood of being diagnosed with BM and the median OS for patients with BM ranges from 3 to 15 months [16, 17]. BM severely impacts patients’ quality of life (physical, cognitive, and functional impairments) [18, 19], and patients with even a single BM experience reported a decline in quality of life [20]. In addition, patients treated with EGFR–TKIs show more symptoms of BM, synchronous metastases, an increase in healthcare resource utilization, and substantial clinical, economic, and caregiver burden [21]. Therefore, continuous improvement in possible therapeutic strategies for preventing and controlling BM to improve overall disease control and quality of life becomes critical.
Several studies have explored the treatment of EGFR-sensitive mutations in patients with BM [22‐24]. However, how to delay the occurrence of BM is not clear. Osimertinib was approved in the USA as an option for the front-line treatment of EGFR-mutated NSCLC based on the phase III FLAURA trial [25]. However, according to the World Health Organization cost-effectiveness threshold criteria, osimertinib is not cost-effective for the first-line therapy of EGFR-mutated NSCLC at current costs, and hence is much less commonly used as first-line treatment in China [26, 27]. Therefore, EGFR–TKI combination with chemotherapy has been suggested as a promising method to overcome resistance, and enhance the anti-cancer effect of the individual strategies [28]. Many studies showed that this first-line combination therapy could provide a significantly longer PFS compared with EGFR–TKI alone [11‐15]. However, the efficacy of the combination of EGFR–TKI and chemotherapy for iPFS is unclear. The present study demonstrated that EGFR–TKIs combined with chemotherapy prolonged systemic PFS, and, more importantly, reduced the risk of BM.
Despite an effect on PFS, no OS benefit was found in the combination treatment group. It can be speculated that the difference in treatment options (different chemotherapy regimens, osimertinib, radiotherapy, and so on), treatment time, and treatment sequence after progression might affect OS.
The present study demonstrated that the combined therapy delayed the occurrence and reduced the risk of BM. However, the underlying mechanism remains uncertain. Preclinical results demonstrated that the combination of chemotherapy and EGFR–TKIs might have a synergistic effect on NSCLC cell growth in vitro. Some reports showed that EGFR–TKI had an important function as an ATP-binding cassette transporter inhibitor [29]. EGFR–TKIs can inhibit the multidrug resistance (MDR)-dependent efflux of several chemotherapeutic agents [30‐33]. Also, epithelial-to-mesenchymal transition (EMT) is implicated in the processes of cancer progression and metastasis [34], and experimental data imply that simultaneous treatment with EGFR–TKIs and chemotherapy enhanced cell growth inhibition and cell death, and prevented the appearance of EMT in PC9 and HCC827 cells [35]. In addition, baseline metabolic tumor burden at the level of whole-body tumor, primary tumor, nodal metastasis, and distant metastasis are independent prognostic measures [36]. Low tumor burden improves prognosis. Further, the rapid progression of the primary tumor during the development of PD was associated with inferior survival [37]. In our analysis, the combination treatment reduced tumor burden and significantly improved PFS and iPFS.
However, this study had several limitations. First, this was a retrospective, single-institution, non-randomized study. The patients received different chemotherapeutic regimens as well as different EGFR TKIs. Finally, adverse events and their impact on the patients’ quality of life were not assessed.
5 Conclusions
Patients treated with EGFR–TKIs combined with chemotherapy showed superior PFS. EGFR–TKIs combined with chemotherapy could delay BM occurrence and decrease the incidence of BM as initial progression. Therefore, EGFR–TKI combined with chemotherapy could be an option for patients with lung adenocarcinoma with EGFR mutations.
Acknowledgements
The authors greatly appreciate all patients who contributed to this study.
Compliance with Ethical Standards
Funding
This study was funded by the Science and Technology Commission of Shanghai Municipality, China (No.18441904700), and the nurture projects for basic research of Shanghai Chest Hospital (No. 2018YNJCM05).
Conflict of interest
Changhui Li, Bo Zhang, Jindong Guo, Fang Hu, Wei Nie, Xiaoxuan Zheng, Lixin Wang, Yuqing Lou, Yinchen Shen, Baohui Han, and Xueyan Zhang declare that they have no conflicts of interest that might be relevant to the content of this article.
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