Clinical features and prognostic factors of brain metastases from colorectal cancer: a single center experience

DOI: https://doi.org/10.21203/rs.3.rs-2837168/v1

Abstract

Purpose: The study aimed to investigate the clinical characteristics, prognostic factors, survival times, and therapy outcomes of brain metastases (BM) from colorectal cancer (CRC).

Methods: The clinical characteristics of 25 patients with BM from CRC were retrospectively analyzed. The time of the occurrence of BM after diagnosis of CRC was recorded. Meanwhile, the time from the occurrence of lung, bone, liver, and other extracranial metastases to the occurrence of BM was also recorded. We evaluate the time factors affecting the length of the occurrence of BM and the potential prognostic factors after BM diagnosis. The influences of patients undergoing surgery-based comprehensive treatment, radiotherapy-based comprehensive treatment, and co-medication were also assessed.

Results: In patients with BM from CRC, lung metastases (13/25) occurred at a higher frequency than liver metastases (8/25) and bone metastases (6/25). The median time to the development of BM was much shorter (3.7 vs. 25.3 months, p=0.027), with the brain being the origin site for the metastasis. The median overall survival reached 9.9 months. The interval between diagnosis of BM and bone, liver, and lung metastasis remains 3, 6.5, and 11 months, respectively. The brain lesions of patients with BM alone had higher rates in supratentorial (88.9%), while those with extracranial metastasis had a 62.5% incidence of infratentorial metastasis. The difference was statistically significant (p<0.05). The time of occurrence of BM in patients aged 67 years and younger was 16.1 and 30.1 months, respectively. The differences between them were statistically significant (p=0.043). The BM time for left- and right-sided colon cancer were 26.5 and 7.8 months, representing a statistically significant difference (p=0.015). The time to onset of BM for patients with and without the resection of primary lesions was 25.4 and 4.5 months. Statistically significant differences are shown (p=0.007). Univariate analysis demonstrated that the prognosis of patients was related to the KPS score, the number of BM, treatment methods, and the occurrence of lung metastasis (p<0.05). The multivariate analysis revealed that the treatment modality and lung metastasis were independent prognostic factors for CRC patients with BM. Right-sided CRC patients with BM have poor prognosis (8.1vs10.2months, p=0.31). Although median survival time was not significantly different between patients with and without bevacizumab combination therapy, bevacizumab therapy is associated with a better survival time (9.9 vs. 7.1 months, p = 0.27).

Conclusion: Patients with left-sided CRC, especially those with lung metastases, are prone to brain metastases, and patients with brain metastases as the first metastatic site have a higher rate of supratentorial metastases. Young patients with right hemicolon cancer, and patients who have not undergone primary lesion resection have a shorter time for the occurrence of BM. Patients with colorectal lung metastases, especially those young with right-sided CRC, require close imaging surveillance of BM. The prognosis of CRC patients with BM and lung metastases is poor, and comprehensive treatment based on surgery could significantly prolong patients' survival time.

Introduction

Colorectal cancer (CRC) is the third most common carcinoma and the second leading cause of cancer-related deaths worldwide[1, 2]. About 1.5 million people have diagnosed annually with CRC[3]. The early symptoms are not valued, and approximately 20–25% of patients with CRC present with distant metastasis at the time of diagnosis, which is the leading cause of CRC-associated mortality[1]. In general, the incidence of brain metastasis (BM) was lower to 0.6%-3.25% in CRC metastasis[4, 5]. However, the incidence of BM could reach up to 8.8% of patients present with metastatic CRC (mCRC) receiving 3rd-line therapy[6]. The distinct biological characteristics of BM exert adverse effects on therapy and the prognosis of CRC patients. Median survival is less than 7 months following metastatic spread to the brain[5, 7]. Therefore, BM developed by CRC should be given sufficient attention.

The identification of clinicopathological characteristics of BM is essential for individualized clinical decision-making and prognostic determination of patients with mCRC[8].In this study, we retrospectively reviewed the clinical characteristics of 25 CRC patients with BM and explored the interval and the factors that may affect the prognosis of BM. Meanwhile, we analyzed the influence of treatment modalities on survival outcomes, providing an essential guide for diagnosing and treating patients with BM from CRC.

Results

2.1 Clinicopathologic characteristics of CRC patients with BM

The data of 25 CRC patients (13 females, 14 males) with BM admitted to our hospital from December 2007 to December 2022 were collected. Age at diagnosis for CRC patients with BM ranged from 46 to 83, with a median of 68 years. The median age was 67 years. Among them, 18 were left colon and rectal cancer, and 7 were right colon cancer. 12 patients had a KPS score below 70. The brain is the most common metastatic site of the primary tumor located in the left hemicolon and rectum (18/25, 72%). Most patients had extracranial metastases (16/25, 64%), with the lung being the most common metastatic site (14/25). At the same time, most patients presented with a single brain metastasis, and the brain lesions were supratentorial (8/9). Almost all BM patients presented with neurologic symptoms, including headache, dizziness, nausea and vomiting, visual disturbances, consciousness, and speech-motor impairment. Of these, the most common symptom was motor impairment, followed by dizziness or headache (Table 1).

2.2 Clinicopathologic characteristics of CRC patients with BM

As shown in Table 3, patients in our group had received a single or combined treatment modality. The median survival time of patients in the monotherapy, radiotherapy, and surgery groups was 3.4, 20.1, and 29.9 months, respectively. The median survival time of the surgery group showed a significant difference compared with the monotherapy group (p < 0.05). In contrast, no significant difference was seen compared with the radiotherapy group.

The median survival time of patients receiving best supportive care (BSC), chemotherapy, and combined therapy was 1.4, 20.1, and 29.9 months, respectively. The median survival time of BSC showed a significant difference compared with the chemotherapy and combination drug chemotherapy (p < 0.05). While no significant difference was seen between chemotherapy and combination drug chemotherapy (p > 0.05). The median survival time of patients with and without bevacizumab treatment was 7.1 and 9.9 months (p = 0.23).

2.3 Time of the occurrence of BM

The time of the occurrence of BM in all the patients after CRC diagnosis is shown in Fig. 1. The time interval from the diagnosis of CRC to the development of BM was 16.3 months. The cumulative metastatic rates at 1-, 2-, and 3-years were 36% (9/25), 52% (13/25), and 84% (21/25), respectively. The time interval from extracranial metastases to the development of BM was recorded and analyzed, as shown in Table 2. The median time interval from lung metastasis, liver metastasis, and bone metastasis to the development of BM was 8.8 months (0.1–29.6 months), 10.8 months (0-68.3 months), and 3 months (0.1–27.9 months), respectively. The median time interval of patients developing brain metastases as the first site of recurrence was much shorter (3.7 versus 25.3 months, p = 0.027).

The median time for the development of BM in patients younger or older than 67 years was 16.1 months and 30.1 months, with statistically significant differences (p = 0.043). Data also shows that the median time for the occurrence of BM in patients with left- or right-sided CRC was 26.5 months and 7.8 months. Statistically, significant differences were found between the two groups (p = 0.015). Simultaneously, the median time for the occurrence of BM in CRC patients with lung metastases diagnosed at stage IV was much shorter

2.4 Univariate and multivariate analyses of survival time and outcomes in CRC patients with BM

The median follow-up time of the whole group was 49.2 months. The survival time was 0.4–79.4 months, and the median survival time was 9.9 months (Fig. 2). Our results demonstrated that the survival rates of 1, 2, and 3 years were 28%, 16%, and 12%, respectively. The potential factors that might affect survival outcomes and years in CRC patients with BM were analyzed by Log-rank analysis. On univariate analysis, age, gender, KPS score, liver metastases, lung metastases, bone metastases, and treatment were identified as candidate variables. As indicated in Table 1, the univariate analyses revealed that patients had longer survival times with the factors of KPS scores > 70, 1 metastatic lesion, a combined treatment of systemic agents and local brain therapy, and without lung metastases (p < 0.05).

In order to evaluate the potential factors on the survival rate of CRC patients with BM in multivariate analysis, Cox proportional hazards regression analysis was employed. The results revealed that the treatment mode and the occurrence of lung metastases were the independent risk factors in CRC patients with BM (p༜0.05, Table 4). Patients receiving drug treatment and local brain therapy in combination remains longer survival time than those with monotherapy. Patients with lung metastases had shorter survival times. The Kaplan–Meier curves for the lung metastasis and treatment modalities are shown in Figs. 3 and 4.

Methods

1.  Data Acquisition: A retrospective analysis of BM from CRC was performed. The data of 25 CRC patients with BM admitted to our hospital from December 2007 to December 2022 were collected. The 25 patients were diagnosed with CRC based on pathology and BM based on computed tomography or magnetic resonance imaging. Patients with BM who underwent neurosurgery also received a pathologically proven diagnosis. Depending on the actual disease situation, the patients received corresponding treatment: (1) a single treatment modality (monotherapy group): single hormone treatment, single chemotherapy, single radiotherapy, and single surgery; (2) a radiotherapy-based comprehensive treatment (radiotherapy group): whole-brain radiotherapy (WBRT) and/or stereotactic radiotherapy (SRT) and chemotherapy in combination; (3) a surgery-based comprehensive treatment (surgery group): postoperative adjuvant chemotherapy and radiotherapy, expected survival time >6 months before surgery. This study was approved by the ethics committee of Peking University First Hospital

2.  Diagnostic criteria: The diagnosis of these 25 CRC patients with BM was made by clinical histories and multimodal neuroimaging examination. Among the patients, 8 were diagnosed through neurosurgery and neuropathological examination. On computed tomography (CT), the tumors were slightly hyperdense. MRI showed hypointensity lesions in T2, and subtle enhancement was present. The central part of the lesion appeared as low signals and density. Meanwhile, perilesional edema was visible.

3.  Follow-up: Follow-up data were obtained through the following four ways: hospital record review, telephonic contact, outpatient visits, and rehospitalization, including age, gender, diagnosis date, surgical strategy, Dukes stage, postoperative chemotherapeutic regimen (targeted therapy), time of metastases site (liver, bone, and lung) and treatment, and date, site(infratentorial//supratentorial), size, number, and treatment (surgery, chemotherapy, and radiotherapy) of BM. The last follow-up date was March 2023. The survival time was defined as the date of diagnosis of BM to the date of death.

4.  Statistical analysis: Analyses were conducted in statistical software R, version 4.2.2. χ2 test was applied for enumeration data. Survival analysis was conducted by the Kaplan–Meier method and Log-rank test. Multivariate analyses were performed using multivariate Cox regression. A value of P<0.05 was considered of statistical significance.

Discussion

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.

Conclusion

In conclusion, BM from CRC has unique clinical characteristics, which provide a basis for early diagnosis. The incidence of BM from CRC is low. However, it has gradually increased, and more and more clinical cases have been reported due to the improvement of CRC treatment methods, the prolongation of patients’ survival time, and the development of the standardized diagnosis of BM. We believe that for BM from CRC, we should focus on brain imaging to monitor the presence vs. absence of BM. Also, the coordinated application of systemic treatment models may be one of the main reasons affecting the survival of patients.

Declarations

Acknowledgments 

We are grateful to the patients and their families for supporting the study.

Funding

The study was funded by National Project for Clinical Key Specialty Development. 

Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

Author contributions

The first draft of the manuscript was written by Zhao Gao and all authors commented on previous versions of the manuscript. Shikai Wu and Xuan Jin conceived of the review and edited the manuscript. Zhao Gao collected and analyzed the data. Xuan Jin analyzed the data and drafted the article. All authors read aacccnd approved the final manuscript.

Ethics approval

This study has been approved by the Ethics Committee of the Peking University First Hospital.

Availability of data and materials

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Consent to participate Not required.

Consent for publication Not required.

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Tables

Table 1   Clinical characteristics and univariate analysis of prognostic factors of CRC patients with     BM

Factors

Total

Medium OS (months)

95%Cl

P value

Gender

 

 

 

 

Male

12 (48.0%)

8.1

 

 

Female

13 (52.0%)

9.9

0.53-3.72

.494

Age

 

 

 

 

≥67

12 (48.0%)

9.9

 

 

<67

13 (52.0%)

8.1

0.74-5.01

.180

KPS

 

 

 

 

≥70

12 (48.0%)

20

 

 

<70

13 (52.0%)

3.4

1.25-9.67

.017

Side

 

 

 

 

left

18 (72.0%)

10

 

 

right

7 (28.0%)

8.1

0.58-5.58

.308

Treatment modality

 

 

 

 

Monotherapy

13 (52.0%)

3.4

 

 

Combination therapy

12 (48.0%)

20

0.11-0.77

.013

Number of BM

 

 

 

 

1

15 (60.0%)

14

 

 

≥2

10 (40.0%)

2

1.07-7.48

.036

BM alone

 

 

 

 

no

16 (64.0%)

7.1

 

 

yes

9 (36.0%)

14

0.15-1.31

.141

Size of BM (cm)

 

 

 

 

≥2

15 (60.0%)

14

 

 

<2

10 (40.0%)

5.8

0.62-4.10

.338

Site of BM

 

 

 

 

Supratentorial

12 (48.0%)

10

 

 

Combination 

2 (8.0%)

25

0.09-6.60

.821

Infratentorial 

11 (44.0%)

8.1

0.72-5.46

.188

TNM stage of the primary tumor

 

 

 

 

II-III

15 (60.0%)

9.9

 

 

IV

10 (40.0%)

8.1

0.47-3.08

.690

Liver metastases

 

 

 

 

no

17 (68.0%)

10

 

 

yes

8 (32.0%)

8.4

0.50-3.82

.525

Lung metastases

 

 

 

 

no

11 (44.0%)

30

 

 

yes

14 (56.0%)

6.9

1.03-9.54

.044

Bone metastases

 

 

 

 

no

19 (76.0%)

10

 

 

yes

6 (24.0%)

5.8

0.83-6.40

.109

Resection of the primary tumor

 

 

 

 

no

6 (24.0%)

4.8

 

 

yes

19 (76.0%)

10

0.20-1.63

.292

Bevacizumab

 

 

 

 

no

20 (80.0%)

7.1

 

 

yes

5 (20.0%)

9.9

0.10-1.92

.273

Neurological symptoms

 

 

 

 

Headache/dizziness

8

 

 

 

Nausea/vomiting

1

 

 

 

Blurred vision

2

 

 

 

Motor disturbance

9

 

 

 

Speech difficulty

4

 

 

 

Asymptomatic

7

 

 

 

Disturbance of consciousness

2

 

 

 

KPS Karnofsky performance status; BM Brain metastases; OS Overall survival.

 

Table 2   Time interval from the occurrence of extracraninal metastases to BM

Time

Patients no. (n)

Median time interval months

(range)

Time interval from the occurrence of bone metastasis to the development of BM

6

3 (0.1-27.9)

Time interval from the occurrence of liver metastasis to the development of BM

8

10.8 (0-68.3)

Time interval from the occurrence of lung metastasis to the development of BM

13

8.8 (0.1-29.6)

BM Brain metastases.

 

Table 3 Treatment modalities for brain metastasis

Treatment modality

Patients no. (n)

Unimodal treatment

 

Chemotherapy only

1

Radiotherapy only

1

 Surgery only

2

best supportive care

9

Multimodal treatment

 

Radiotherapy +Chemotherapy/ Bevacizumab/ Immunotherapy 

4

Surgery+ Radiotherapy/ Chemotherapy / Immunotherapy /Cetuximab/ Bevacizumab

8

 

Table 4 Multivariate analysis of prognostic factors in CRC patients with BM

Variables

HR

95%Cl

P value

Treatment modality

 

 

 

Unimodal treatment

 

 

 

Multimodal treatment

0.24

0.07-0.78

.018

KPS 

 

 

 

≥70

 

 

 

<70

2.19

0.56-8.51

.257

Lung metastasis

 

 

 

no

 

 

 

yes

3.88

1.06-14.20

.040

Number of BM

 

 

 

1

 

 

 

≥2

2.13

0.59-7.73

.251

KPS Karnofsky performance status; BM Brain metastases.