The liver, lung, and peritoneal cavity are the most common metastatic sites in patients with CRC, while BM is relatively rare[7]. The crude incidence of brain BM from CRC is 0.27%, while in metastatic colorectal cancer, it increases to 1.36%[9]. The incidence of BM from CRC has increased with the technological progress of imaging modalities and the development of multimodality therapy. However, head CT and MRI were not routine examinations in clinical[10].
BM from CRC derived from the rectum accounted for 58%-85.5%[11–13]. The present study revealed that colorectal brain metastases derived from the rectum and colon accounted for 40% and 60%, respectively. The incidence of BM in patients with colon cancer is slightly higher than in those with rectal cancer. Several studies reported that a considerable proportion of CRC patients with BM also had other extracranial metastases, around 88.3%~91.3%[11, 14]. In our study, 56.0% of CRC patients with BM combined with other extracranial metastases are lower than reported in previous literature. The possible reason is that the proportion of cancers in the colon is higher in our groups. While the rectum is richer in blood supply than colon, the tumor cells are more easily spread through the portal vein and the inferior rectal vein to brain. These complex metastatic pathways lead to a high rate of extracranial metastases before BM in rectum cancer. In the study of Bergen et al.[15], 42(14.9%, 42/281) patients with right colon cancer had metastases in the brain. Furthermore, the study revealed that the following patients might have poor outcomes. In our present group, the primary tumors were in the right-sided colon in 7 (28.0%) patients, and 18 (72.0%) were in the left-sided colon and rectum. The median survival time of patients with right-sided colon cancer was 8.1 months, which was lower than those with left-sided colon and rectum cancer (10.2 months). However, we did not find a great statistical difference between the two groups (p = 0.32).
Quan et al.[16]analyzed BM in 52 patients with CRC and concluded that the lung (59.6%) was the most common extracranial metastasis location, followed by the liver (36.5%) and bone (21.2%). The results were consistent with those in the study by Xiao-Dong Gu[17] and Christensen[6] et al. In our study, data demonstrated that out of the 25 identified CRC with BM cases, only BM was observed in 11 patients, and 16 patients had concomitant extracranial metastases, including 13 patients with lung metastases, 8 with liver metastases, and 6 with bone metastases. This result indicates that the probability of developing lung metastases (13/25) is higher than liver metastases (8/25). It is in agreement with previous reports with the results reported in previous literature. BM from CRC was tightly associated with hematogenous metastasis of CRC, which mainly counts on venous return. There are three routes for BM caused by the venous drainage of the colon and rectum: 1. via the portal vein, liver, inferior vena cava, and pulmonary circulation to other organs of the body; 2. via the inferior rectal vein, inferior vena cava, and pulmonary circulation (bypassing the portal venous system) to other organs of the body; 3. tumor cells could migrate to Batson venous plexus, and being transferred to the brain via prevertebral venous plexus. These theories explain that the most common site of metastasis was the lung. Meanwhile, the minority of patients with no other extracranial metastases would develop BM as the initial symptom. 9 patients with BM were not detected with lung and liver metastases could also be explained. CRC patients with pure BM mainly metastasize to the supratentorial, which is considered to be related to the pathway of BM from CRC. Tumor cells metastasize to the brain through the vertebral artery system, most of which occur in supratentorial locations. Following the liver, the lung is the second most common site of metastasis. The progression is characterized by slow and indolent growth and a better prognosis. Due to the longer survival time of CRC patients with CRC, monitoring the brain imaging and extracranial metastasis would be beneficial for patients. Unfortunately, there are no guidelines regarding the follow-up period.
The critical factors causing mortality of patients with CRC include cerebral hemorrhage, carcinomatous meningitis, and the progression of brain tumors. However, extracranial tumor progression would be the main reason[18]. In our study, the survival analysis indicates that the occurrence of lung metastasis before BM and the treatment mode of the brain are independent factors for survival. The 1-, 2-, and 3-year survival rates of the patients were 28%, 16%, and 12%. The median survival time was 9.9 months, similar to the outcomes reported in the literature[19]. These clinical characteristics occur may be due to the differences in venous drainage from the colorectum[20]. The shed tumor cells of patients with lung metastases are more accessible to enter the systemic circulation and develop BM. We contemplate that patients with BM through the pulmonary circulation are more likely to have large-scale metastases throughout the body, and poor prognosis.
Despite the blood-brain barrier (BBB) permeability being highly increased during BM, the majority of the clinical chemotherapy drugs are not able to get through the BBB[20, 21]. The previous treatment for BM, usually including neurosurgery, radiotherapy, and medical therapy, did not work as expected[14, 22]. Moreover, standard treatment guidelines for CRC patients with BM have not been established. Lu et al. [23] analyzed 80 BM patients from CRC. It was observed that the median OS of patients receiving monotherapy was only 4 months. Nevertheless, multimodal treatment approach, combining radiotherapy (WBRT and stereotactic radiosurgery), chemotherapy, and surgery may prolong survival time (median OS = 11 months). Dong-Yeop Kim et al.[20] reached to the similar conclusions. Li et al.[7] found that combined treatment modalities were independent prognosis factors (p = .000). Our study suggested that the median survival time of the combination therapy group was 20 months, remarkably higher than that of the monotherapy group by 3.4 months. The difference was of great significance (p = 0.012).
Surgery therapy has been constantly emphasized in managing metastatic brain tumors[24]. A previous study revealed that surgery alone could prolong the median survival time to 9.0 months of BM patients from CRC[25]. The median survival time of BM patients receiving surgery was 11.5 months, which is longer than those receiving WBRT (4.0 months) and Gamma Knife treatment (9.5 months)[5]. Most studies have proved that the combination of postoperative radiotherapy and chemotherapy could furtherly prolong the survival time[26, 27]. In our study, the median survival time for the surgery combination group (29.9 months) was significantly higher than those in other groups. Hence, surgery combined with chemotherapy or radiotherapy resulted in the longest survival time for BM patients from CRC. Chemotherapy and radiotherapy in combination could enhance the therapeutic effect of BM. This could be due to the increased permeability of the BBB caused by radiotherapy, which improves the permeability of chemotherapeutic drugs. The two effects could synergistically increase the local control rate. Meanwhile, the combination with chemotherapy could control systemic tumor progression[28]. The median survival time of patients in the radiotherapy combination group (20.1 months) was longer than those in the monotherapy group (3.4 months). However, this difference was not statistically significant, likely due to the small number of samples.
Our study demonstrated that patients receiving chemotherapy combined with immunotherapy and target therapy lead a higher survival time (29.9 months) than best supportive care (1.4 months) and chemotherapy alone (20.1 months) (p < 0.05). Given the occurrence of a cerebral hemorrhage in pharmacokinetics, previous BM patients did not receive bevacizumab[29, 30]. However, no reports showed an increased risk of developing cerebral hemorrhage while on treatment with bevacizumab in daily clinical practice. In a retrospective study with 5 patients, bevacizumab was used as a neoadjuvant therapy for CRC patients with BM. The data revealed a 14.2-month median survival time, and no evidence of intracranial hemorrhage was observed[31]. In the study of Li et al.[7], patients who received bevacizumab experienced an improved survival time (10 months) compared to those who did not receive bevacizumab (5 months). In the present study, patients who received bevacizumab showed better survival time than those who did not receive bevacizumab. While the lack of significant association could be due to the small sample size.