Risk factors of brain metastasis of lung squamous cell carcinoma: a retrospective analysis of 188 patients from single center

The brain is one of the most common distant metastasis sites in non-small cell lung cancer (NSCLC). Up to 40% of NSCLC patients develop brain metastasis (BM) during the course of disease [1–4]. BM is associated with a poor quality of life (QOL) and a dismal prognosis; without treatment, the median overall survival (OS) for BM patients is only 4–7 weeks [5–7]. In patients with small cell lung cancer (SCLC), prophylactic cranial irradiation (PCI) is effective in decreasing the incidence of BM and improving OS [8, 9]. PCI has therefore been studied in NSCLC populations. While it decreases the incidence of BM, it does not affect OS [1, 2]. One likely explanation is the heterogeneous risk of BM across pathological subtypes. Most studies of BM in NSCLC suggest that SCC is associated with a lower incidence of BM than adenocarcinoma [10–13]. However, the analysis of BM in SCC is compromised by the inclusion of different histological subtypes in these studies. Furthermore, characteristics other than the incidence of BM in SCC were not examined. There is therefore a need for comprehensive studies specifically addressing the clinical features of BM in SCC.

Local therapies such as whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), and surgical resection are the standard of care for patients with BM. However, most patients die from systemic disease rather than intracranial failure. Systemic treatment with novel agents, such as tyrosine kinase inhibitors (TKIs) and pemetrexed, has been shown to be beneficial in patients with BM [14–18]. They could not only shrink the intracranial lesions, but also prolong the survival. But the efficacy was usually seen in patients with non-SCC histology. By far, none agent has previously been studied in SCC with BM. To better characterize the clinical features of BM in SCC and to investigate effective treatment strategy, we conducted a retrospective study that included 188 patients.

Patients with SCC have lower incidence of BM. Some studies reported that, the incidence of BM in patients with SCC ranged from 8% to 28%, which was lower than other histological subtypes such as adenocarcinoma, ranging from 20% to 45% [3, 4, 10, 11]. Additionally, previous studies concerning BM in NSCLC included different histological subtypes. As a result, the characteristics of BM in SCC patients have not been fully profiled. Similar to the reports of other studies, only 19.1% of patients in our study had documented BM over a decade. Therefore, it was a great challenge in releasing some convincing results with such relatively smaller samples. However, after careful analysis, there emerged some information which we believed to be worth noticing.

We found that females, those with advanced disease, with adenosquamous histology and elevated serum level of CEA at diagnosis had a significantly higher incidence of BM. Besides, female and abnormal level of CEA were independent factors which indicated higher risk of BM. We are aware of two previous studies investigating the correlation between gender and BM [19, 20]. One showed no such correlation, but the other was in agreement with our findings. The underlying biology of these correlations is unknown. In our study, bivariate analysis found that female gender had a positive correlation with EGFR mutation (p = 0.024). In NSCLC, EGFR mutation is associated with constitutive activation of a downstream signaling pathway implicated in tumor cell growth, local invasion, angiogenesis and metastasis [21–23]. Some researchers have found that, a higher incidence of BM was seen in NSCLC patients with EGFR mutations than those with wild-type EGFR [16, 24, 25]. However, the evidence is stronger for adenocarcinoma than for SCC. In our study, among 33 patients with known EGFR status, only 5 SCC patients were shown to harbor EGFR mutations and none of them developed BM. So it is impossible to draw any conclusions as to whether EGFR mutation contributes to BM in SCC patients. Larger studies are needed to examine the role of EGFR mutation in BM. In addition, the role of other signal transduction pathways should be investigated.

CEA is the most commonly used biomarker for the screening of various malignancies including lung cancer. As it was shown in our study, patients with abnormal serum levels of CEA had not only higher incidence of BM, but also higher risk of BM. In a perspective study enrolling 293 patients with staged IIIB-IV NSCLC also found, CEA ≥ 40 ng/ml was an independent risk factor of BM [26]. In another prospective study conduced by Lee et al., the association of tumor markers including CEA, Cyfra21-1, CA125, CA199 and SCC and BM were studied in 227 patients with advanced NSCLC [27]. As a result, CEA level was the only tumor marker that was found to be significantly different between patients with BM and without BM. Although some studies indicated that the prognostic value of CEA was more specific in adenocarcinoma patients than in SCC patients, it should be noticed that less than one third of patients enrolled in these studies had SCC histology [26, 28]. Since our findings were concluded in SCC patients, we believed that, at least in patients with SCC, those with abnormal serum levels of CEA at diagnosis should be considered as at risk population of BM. More concerns of BM should be paid to these patients during follow-up.

Some studies have suggested that NSCLC patients with local advanced disease have an increased risk of BM. This is confirmed in the current study, in which a higher stage at diagnosis is associated with a higher incidence of BM. Several clinical trials have therefore been carried out to explore the efficacy of PCI in patients with stage III disease [1, 2]. However, while PCI decreased the incidence of BM, no survival advantage was shown. Data from our study showed that, the incidence of BM in patients with SCC and stage III disease was only 12.5%. Even in studies of NSCLC which included patients with varying histological subtypes, the incidence of BM in stage III disease was not much higher, at 13–28% [3, 4, 11, 20]. Hence, stage was not qualified enough to define patients with higher risk of BM, especially when used as single parameter. In addition to incidence, the interval from diagnosis to BM is another factor that should be considered. For NSCLC patients with local advanced disease, the median interval from diagnosis to BM ranges from 5.7 to 12 months [4, 19, 20, 29, 30]. Although some studies have shown that patients with squamous histology have longer intervals of BM [31], our study showed that the median time to BM for SCC patients with metachronous BM was only 7 months (range 5–8 months). This was much shorter than we expected. Furthermore, females and patients with elevated serum levels of CEA at diagnosis had a significantly shorter median BMFS than their counterparts. Thus, although patients with SCC have a lower incidence of BM, those with a higher risk of BM are likely to experience BM early in the course of their disease. Based on all these findings, it is reasonable that patients with higher risk of BM, such as female and patients with abnormal CEA at diagnosis indicated in our study should be the candidates of future studies concerning BM prevention. Furthermore, comprehensive studies are needed to further valid our findings. If possible, exploring risk factors other than clinical ones is also warranted.

RPA and GPA are prognostic systems for BM which includes many clinical factors such as age, Karnofsky performance status (KPS), number of BM and status of extracranial disease at the time of BM. In our study, RPA was found to be an independent prognostic factor for BM patients in multivariate analysis. More importantly, systemic therapy in addition to local therapy was also proved to be an independent prognostic factor which indicated better post-BM survival. Combined with the fact that BM was a kind of hematogeneous metastasis, it is warranted that systemic therapy should be considered after the occurrence of BM, especially for those accompanying extracranial metastasis. A standard systemic treatment regimen has not been established for SCC patients with BM. As a result of the JMDB study, in which subgroup analysis demonstrated superior efficacy of gemcitabine in patients with squamous histology, gemcitabine has become the optimal regimen for treating SCC patients [32]. Many studies have investigated the efficacy of platin-doublets involving a third generation cytotoxic drug as the first-line regimen for advanced NSCLC [33–35]. These trials have shown no survival benefit for any of these regimens, even when analyzed by histological subtype. In the current study, no significant survival difference was seen between those treated with GP and those treated with TP (p = 0.097), either. But we attribute the negative result more to smaller samples. Furthermore, we also compared median BMFS between different chemotherapy regimens to explore their ability to prevent BM. As a result, patients who received both GP and TP before BM had the longest median BMFS (p = 0.013). However, the difference between GP group and TP group was comparable (p = 0.10). This result suggests that BMFS may not agent-dependent. It may indicate that receiving both GP and TP prolongs BMFS or it may be that those who had a longer BMFS had the opportunity to receive both regimens. In terms of TKIs, since most patients in our study had unknown EGFR status, it is insufficient to evaluate their roles in the current setting. Thus, to date, the most effective agent for BM prevention or treatment in SCC patients remains uncertain.

To our knowledge, this is the first study to explore the risk factors for BM in SCC patients. It is true that our study was limited by retrospective study design and smaller samples of documented BM. But the factors we identified will be useful for the design of future studies to investigate preventative measures, such as PCI. Furthermore, we have shown that the addition of systemic therapy could significantly improve prognosis compared with local therapy alone. However, no agent was clearly superior for BM prevention or treatment in SCC patients.