Systematic review: brain metastases from colorectal cancer—Incidence and patient characteristics

Worldwide, colorectal cancer (CRC) is the third most common cancer in men and second in women. CRC is the fourth most common reason for cancer-related death, and it is responsible for an estimated 8 % of deaths resulting from cancer [1].

Brain metastases (BM) are a common complication of lung cancer (40–50 % of cases), breast cancer (5–15 %), testicular cancer (10–15 %), and melanoma (10 %). BM from CRC are, however, relatively rare. BM are reported to develop late in the disease, and the patients normally have metastases to other organs before BM are diagnosed [2, 3]. The reported incidence of BM from CRC may be increasing because of improved diagnostics and increased survival of patients, but this is not well documented [2].

A diagnosis of BM is associated with increased morbidity and mortality. The reported median survival after a diagnosis of BM is 2.6 to 7.4 months, and only very few patients survive more than 1 year [4‐6]. Intensified surveillance of patients at risk of BM development could potentially lead to earlier detection, hereby increasing the number of treatment options available and improving prognosis [4]. To identify patients at risk of developing BM, knowledge about patient characteristics associated with BM is important.

We conducted a systematic review of the current literature, following PRISMA guidelines [5], to describe the incidence of BM from CRC, and to identify characteristics associated with increased risk of BM.

The complete search strategy in PubMed was ((brain AND (metastases OR metastasis)) OR (brain neoplasms AND (metastases OR metastasis)) OR cerebral metastasis OR cerebral metastases OR cerebellar metastasis OR cerebellar metastases OR CNS metastasis OR CNS metastases) AND (colorectal cancer OR colorectal neoplasms OR cancer of the colon OR cancer of the rectum OR adenocarcinoma colon OR adenocarcinoma rectum OR adenocarcinoma colorectal OR colonic carcinoma OR rectal carcinoma OR colonic neoplasm OR rectal neoplasm). In EMBASE, the search was conducted by combining subject headings brain metastases/with colorectal adenoma/or colorectal cancer/or colorectal carcinoma/or colorectal disease/or colorectal surgery/or colorectal tumor/or metastatic colorectal cancer.

No automatic filters were applied to the searches. We included pre-reviewed, human studies in English in patients with CRC in which the incidence of BM or characteristics of patients developing BM were reported. We excluded reviews, studies older than 1980, and studies comprising less than 25 patients with CRC. We also excluded studies with a mixed tumor population in which data from CRC patients were not presented separately. If two studies described the same cohort of patients, only the newest was included.

Full articles were obtained and analyzed when appropriate. Reference lists of retrieved relevant articles were screened for additional material. Two authors (TDC and DN) independently surveyed the literature. In case of ambiguity or disagreement, a verdict was reached by consensus.

In order to analyze incidence and patient characteristics, eligible studies were selected for pooling of data and calculation of weighted means. Studies were deemed eligible if they included all patients diagnosed with CRC and identified BM patients from this cohort. Studies were only eligible if a diagnosis of BM was made while the patients were alive. Studies were ineligible for pooling of data if they identified their BM patients from various populations consisting of selected patients with CRC, e.g. patients with metastatic CRC (mCRC), or if it was not clearly stated from what population patients with BM were identified. Weighted mean of incidence was calculated by dividing the sum of BM patients in relevant studies with the sum of CRC patients in the same studies. Weighted means of characteristics were calculated as the sum of BM patients with the specific characteristic in relevant studies divided by the sum of BM patients in those studies.

To compare stage of disease at primary diagnosis, Dukes and Astler-Coller classifications were translated to the TNM staging system (stage A = stage 1, stage B = stage 2, stage C = 3, and stage D = stage 4). If not stated in the studies, 95 % confidence intervals (95 % CI) were calculated for the incidence of BM, using the Clopper-Pearson method for binomial data. A 95 % CI was not possible to calculate for data with continuous outcome because most studies did not report the sampling variability.

The searches were conducted on April 15, 2015 (Fig. 1, consort diagram), and revealed 908 articles from PubMed and 505 from EMBASE. Totally, 93 studies were found eligible. Thirty-six were duplicates. Two studies described the same cohort of patients, and the oldest were excluded [6]. A further three relevant studies were identified from reference lists and included, increasing the total number to 59 studies (Table 1). All studies were retrospective. Thirty-one studies had consecutively included patients. The rest either did not include consecutively or did not clearly state how patients were included [4, 7‐64].

Forty-one studies either identified BM patients from patient populations that did not include all patients diagnosed with CRC, or did not report from what population patients with BM were identified, and were not eligible for pooling of data. Eighteen studies identified patients with BM from populations including all patients diagnosed with CRC (Table 1). Two of the 18 studies were autopsy studies and were therefore excluded from further analysis, giving a total of 16 studies eligible for data pooling [7, 8, 10‐16, 18‐24]. In all 16 studies, follow-up on CRC patients continued until death or end of study period, and none performed routine follow-up screening for BM.

In this study we reviewed the current literature to describe the incidence of BM from CRC, and to identify possible characteristics associated with BM development. Table 3 summarizes our findings.

BM are a quite rare event in CRC patients. The incidence of BM in CRC patients was reported to be anything from 0.6 to 3.2 % in the studies included in this review, and the weighted mean was 1.55 % (95 % CI 1.48–1.63 %). The difference reflects the small sample sizes and statistical variation as well as regional differences, with Asian studies generally reporting a lower incidence than studies from Europe and North America. The true incidence of BM might be higher than what has been reported in clinical studies because some patients had no symptoms, others did not receive brain scans because of short life expectancy, and still others were alive after the end of the study period. Autopsy studies, however, report an incidence of 0.9 and 2.7 %, which is comparable to what is found in clinical studies [9, 17]. It has been suggested that the incidence of BM from CRC is increasing due to better diagnostic options and CRC patients living longer, but so far this has remained speculative [2]. Smedby et al. showed that the incidence of BM from all cancer types increased from 1987 to 2006 from 7/100,000 to 14/100,000 [46]. A study by Schouten et al. did not, however, find any increase in the incidence of BM [22]. In this review, we did not see an association between years of data collection and incidence of BM from CRC.

BM are a late stage phenomenon in CRC, and naturally more common in patients who already have metastatic disease, with an incidence ranging from 2.5to 23 % [9, 12, 23, 26‐29]. In the studies included in this review, BMFI was between 20 and 40 months, and was shorter in patients with stage 4 disease compared to stages 1–3 [19, 43, 48], and higher in patients receiving more therapy between primary diagnosis and BM than in those receiving less [19]. This was also consistent with the observation that the BMFI increased from the 1980s to the 2000s, probably resulting from better treatment and earlier diagnosis of primary disease [52]. The shorter BMFI observed in patients receiving less therapy could be a result of a selection of patients who develop BM shortly after primary diagnosis.

Only a few studies have reported patient age at primary CRC diagnosis; nevertheless, it is possible to conclude that patients with BM are usually younger than the average patient with CRC. In the studies included in our review, the median age at BM diagnosis was 62 years or less in half of the studies, and only a few studies reported it to be higher than 65 years. This can be compared with the median age at primary diagnosis in CRC patients being 67 years for men and 71 years for women according to the US SEER register, and a similar result was found by Hugen et al. in a European population [9, 65]. The young age could be a consequence of the long BMFI, which makes it more likely for a young and healthy individual to develop BM than an older patient with several comorbidities, or it might reflect a more aggressive disease in younger patients.

One observation drawn from this review is that more men than women develop BM, but this difference has not been investigated very thoroughly. The explanation for this observation is likely that more male than female patients develop CRC. Around 55 % of CRC patients are male according to the GLOBOCAN 2012 [1]. This small difference could possibly be the result of statistical variation, but it cannot be ruled out that being male increases the risk of BM, and new studies need to investigate this.

In the studies included in this review, more than half of the studies reported that 48 % or more of patients had rectal primaries, and in studies eligible for data pooling, the weighted mean was 48.5 %. This was a much higher number than what should be expected, since the incidence of colon cancer was normally reported to be three times higher than the incidence of rectal cancer [9, 65], and therefore rectal cancer seems to be associated with an increased risk of BM. However, this was only investigated in a few studies and data were conflicting [9, 25, 27, 36]. Opposing this theory are two studies that looked at patients with colon cancer only and found an incidence of 2.5–4 %, which was higher than the incidence found in CRC patients in general [39, 40].

Lung metastases have often been hypothesized to increase the risk of BM development, and CRC patients with lung metastases have an incidence of BM between 6.2 and 22.6 %, which is considerably higher than the average incidence of BM even in mCRC patients [25, 37, 38]. A few authors also showed that patients with lung metastases had a statistically significant increased risk of BM [25, 26]. However, liver metastases did not seem to increase the risk of BM, and the incidence after liver metastases was reported to be 1.3–5 % [25, 33‐36, 38]. Patients with liver metastases might even have a decreased risk of BM compared to patients with lung metastases [25, 38]. In our review, we found that about 70 % of BM patients had lung metastases at diagnosis and about 40 % had liver metastases. This deviated from the normal pattern of metastases from CRC. In mCRC, liver metastases are found in 70 % and pulmonary metastases only in 30 % [9]. This suggests that there is a relationship between lung metastases and BM, whereas it looks like there may be a reverse relationship between BM and liver metastases.

Several authors have presented theories to explain the different metastatic patterns in patients with BM. The most common hypothesis is that the pattern reflects the vascular anatomy; the cancer can spread to the brain through three principle routes: 1. through the portal vein to the liver, and from there to the lung and thereafter brain. 2. through the cava vein directly to the lung and thereafter the brain. 3. through the vertebral plexus directly to the brain [40, 48, 53]. The hypothesis explains why fewer patients with liver than lung metastases develop BM as well as the shorter BMFI after lung metastases compared to liver metastases. It also explains why rectal primaries increase the risk of BM, since the rectum drains more often through the cava vein than the colon.

A different hypothesis is that different molecular patterns of the cancer explain the pattern of metastases [11]. RAS mutations are the most thoroughly investigated, and RAS mutations have been associated with both increased incidence of BM and lung metastases [16, 26, 31, 33, 48]. However, this does not seem to explain why more BM patients have rectal primaries than average CRC patients, since RAS mutations are more often found in right-sided colon tumors than in rectal tumors [26, 33]. The association between BM and mutation in PIK3CA and BRAF, expression of NCAM, EGFR, and CXCR4, MGMT methylation and increase in the tumor marker CA19.9 have also been investigated, but only in one or two studies each and on small samples, so the possible predictive potential is hard to determine [11, 16, 26, 29, 31, 44, 59, 64]. The tumor marker CEA has been found elevated at BM diagnosis in several studies [7, 16, 18, 40, 41, 50], but only one study showed a possible predictive role of CEA, while one did not [36, 37]. CEA is usually used to monitor patients with CRC during therapy [66], and CEA is elevated (above 5 ng/ml) in approximately 70 % of patients with metastatic disease [67]. None of the studies have shown that an increase in CEA observed in patients with BM differs from that seen in patients with extracranial progression. Therefore CEA should not be considered as a specific marker of BM development, but as a general marker of tumor activity. However, one could argue that in the absence of visible extracranial tumor progression and increased CEA, brain involvement should be suspected. Besides these biomarkers investigated in clinical studies and presented here, several potential biomarkers have been found in animal and in vitro models elsewhere [68].

Increased awareness of specific characteristics can potentially increase the chance of early diagnosis of BM, which may lead to lower total number of BM and better performance status, ultimately increasing the potential number of treatment options [4]. From our review, it is clear that BM from CRC is a rare event, and it is not necessary to screen all patients. However, in patients with rectal primary, lung metastases, and/or KRAS mutation, increased awareness of BM is advisable.

This study had some limitations. First, we only had access to published material from the included studies. Second, in many of the included studies it was not possible to determine whether patients were consecutively included or not. This, in combination with all studies being retrospective, leads to a risk of publication bias. Many of the papers presented incidence from a population spanning long periods of time, limiting the conclusion on temporal variations. Most of the present studies contained few BM patients, and did not have sufficient strength or the right study design to clarify which factors increase the risk of BM. We recommend that physicians enter new large scale prospective clinical studies, preferably as international collaborations, to determine risk factors for brain involvement.