Primary tumor resection provides survival benefits for the patients with brain metastases from colorectal cancer

Abstract

Background: Brain metastases (BMs), particularly synchronous brain metastases, in colorectal cancer (CRC) patients are uncommon. The survival benefit of primary tumor resection (PTR) in patients with metastatic colorectal cancer is controversial. Whether PTR can bring survival benefit to patients with BMs of CRC has not been reported.  

Methods: From 2010 to 2016, 581 CRC patients with BMs from the Surveillance, Epidemiology, and End Results (SEER) database were randomly divided into PTR and non-PTR group. The log-rank test was used to compare the survival distributions. The Kaplan-Meier method was used to estimate survival. By controlling additional prognostic factors, a Cox proportional multivariate regression analysis was used to estimate the survival benefit of PTR.

Results:  The median overall survival for CRC patients with synchronous BMs was 3 months, with a 1-year survival rate of 27.2% and a 2-year survival rate of 12.8%. The PTR group contained 171 patients (29.4%), whereas the non-PTR group had 410 patients (70.6%). Patients who underwent PTR had a 1-year survival rate of 40.2% compared to 21.7% in those who did not (p < 0.0001). Cox proportional analysis showed that patients ≥60 years (hazard ratio [HR] 1.718, 95% confidence interval [CI] 1.423-2.075, p< 0.0001) had a shorter OS than patients < 60 years of age. OS was better in CEA-negative than in CEA-positive patients (HR 0.652, 95% CI 0.472-0.899, p=0.009). Patients in whom the primary tumor was removed had a considerably improved prognosis (HR 0.654, 95% CI 0.531–0.805, p < 0.0001). Subgroup analysis revealed that the PTR group achieved a survival advantage except for patients with CEA negative.

Conclusions: Patients with BMs from CRC may benefit from primary tumor resection (PTR).

Independent prognostic risk factors for CRC patients with synchronous BMs were age, CEA level, and PTR.

Introduction

Colorectal cancer (CRC) is a main cause of cancer-related death globally, with mortality rates of 45%, 35%, and 47.8% in Europe, the United States, and worldwide, respectively [1]. The main cause of disease progression and death for CRC patients is metastasis, which is present in ~ 25% of patients at the time of diagnosis and develop in another 25% later in life [2]. The most frequent sites of metastasis in CRC are the liver and lungs. Brain metastases (BMs) are rare, with an incidence of only 0.3–9% [3], but the prognosis of these patients is very poor, as the median survival is only 2–9.6 months [4–6]. Headaches, nausea, and hemiparesis are common symptoms of BMs and they contribute to a poor quality of life.

In the NCCN and ESMO guidelines, the standardized therapeutic pathways for hepatic and pulmonary metastases depend on their resectability. If total excision is not a treatment option, preoperative chemotherapy is advised, with a subsequent re-evaluation for surgery [7]. Due to the rarity of BMs, both data on their management and therapeutic guidelines are lacking. Experimental data about these patients are scarce, and published results are inconsistent or conflicting[3, 8, 9]. Primary tumor resection (PTR) is controversial in CRC patients with unresectable metastases[10]. PTR enhances quality of life and minimizes the negative effects of systemic chemotherapy, as well as the risk of complications from the initial tumor, including as bleeding, blockage, and perforation[11]. On the other hand, PTR delays the beginning of systemic chemotherapy, with additional delays if complications emerge[12]. Many physicians choose younger and healthier patients for surgical resection of primary tumor based on their clinical experience. Given the low incidence of BMs from CRC, there are no relevant reports suggesting whether these patients can benefit from PTR.

The goal of this study was to evaluate the survival of individuals with CRC BMs who had their primary tumor surgically removed with that of patients who did not undergo surgery. To the best our knowledge, this was the first time to study the effect of PTR on their survival from CRC BMs.

Material And Methods

Results

Patient characteristics

Between 2010 and 2016, among 262,286 patients diagnosed with CRC, synchronous BMs were detected in 678, corresponding to an incidence of 0.26%. After rigorous screening, 581 CRC patients with BMs were included (Figure 1). The PTR group contained 171 patients (29.4%), whereas the non-PTR group had 410 patients (70.6%). In terms of primary tumor location, tumor grade, extrahepatic disease, T-stage, N-stage, and CEA, there was a substantial difference between the two groups. Some patients in the non-PTR group had uncertain T-stage, N-stage, or tumor differentiation, which accounted for a significant fraction of the total. Meanwhile, we discovered that the PTR group had a higher proportion of patients with RCC, M1a, and CEA negative. Of 581 patients, 206 (35.5%) had RCC, 115 (19.8%) had LCC, 170 (29.3%) had RC, and in 90 (15.5%) the CRC type was unknown. Among the total cohort of 581 patients with synchronous BMs, 410 (70.6%) had extracranial metastasis. The patient characteristics are presented in detail in Table 1.

Survival and prognostic factors

Patients with CRC and synchronous BMs had a median OS of 3 months, with a 1-year survival rate of 27.2% and a 2-year survival rate of 12.8%. Patients who underwent primary tumor resection had a 1-year survival rate of 40.2% compared to 21.7% in those who did not (p < 0.0001; Fig. 2A). Median survival was 9 months in the PTR group, compared with 4 months in the non-PTR group. A comparison of OS by age (<60 and ≥60 years) showed that median survival times were 9 months and 3 months, respectively. The difference in OS between the two groups was statistically significant (p < 0.0001; Fig. 2B). The 1-year survival rate in the CEA-positive group was 26.7%, much lower than that of the CEA-negative group’s (42%); the difference was statistically significant (p = 0.0003; Fig. 2C). Patients without extracranial metastasis also had better outcomes than those with extracranial metastasis (p = 0.001; Fig. 2D)

In univariate analysis, age, CEA level, surgical primary site, and extracranial metastasis impacted OS in CRC patients with synchronous BMs (Table 2). However, race, sex, primary tumor location, tumor grade, histological types, T stage and N stage were not significant.

A multivariate analysis that incorporated the significant variables showed that age, CEA level, and PTR were independent prognostic factors (Table 3). Patients ≥60 years (hazard ratio [HR] 1.718, 95% confidence interval [CI] 1.423-2.075, p< 0.0001) had a shorter OS than patients < 60 years of age. OS was better in CEA-negative than in CEA-positive patients (HR 0.652, 95% CI 0.472-0.899, p = 0.009). Similarly, patients in whom the primary tumor was removed had a considerably improved prognosis (HR 0.654, 95% CI 0.531–0.805, p < 0.0001). 

In order to balance the selection bias between the PTR and non-PTR groups, we further analyzed the corresponding subgroups. Figure 3 shows the adjusted HRs for OS based on the location of the primary tumor, extracranial metastases, and serum CEA level from the subgroup analysis. With the exception of CEA negative patients, other subgroups of patients with primary tumor resection achieved a survival advantage. 

Discussion

Brain metastases (BMs) in CRC are uncommon, with an incidence of only 0.3–9%[3, 6, 13]. The somewhat lower incidence in our cohort (0.26%) can be explained by the fact that our study was limited to synchronous brain metastases, which account for 3.4–43% of brain metastases in CRC [4, 13]. The prognosis of CRC patients with brain metastases is very poor, as the median survival is only 3 months (range: 2–9.6 months) [3, 6, 14–19]. BMs have a significant impact on the quality of life of CRC patients once related symptoms appear [3]. Understanding the prognostic variables for BMs is critical for determining survival and treatment options. However, there have been very few studies and a consensus on treatment for BMs in CRC is lacking. From 2010 to 2016, the SEER database included 678 CRC patients with synchronous BMs. According to multivariate Cox regression analysis performed in this study, age, CEA level, and Primary tumor resection were independent risk factors for synchronous BMs in CRC.

A growing amount of research suggests that patients who have their primary tumor removed have a better chance of surviving. In epithelial ovarian and renal cancers, improved survival results linked with surgical debulking have a well­established data foundation[20, 21]. However, in advanced CRC, the survival benefit of the PTR is debatable, and current NCCN guidelines support PTR only when symptoms are present[22]. According to some clinicians, the improvement in OS is unclear, such that the morbidity and mortality resulting from tumor resection should be avoided as it will delay the start of chemotherapy, which may in turn reduce survival [12, 23]. However, some studies have shown that primary tumor resection considerably improves OS [24, 25], as also demonstrated in our cohort of CRC patients with synchronous brain metastases. In the primary tumor resection group of this study, the 1-year survival rate was 38.8% compared to 20.9% in patients with unresected primary tumors (p < 0.0001). In order to balance the selection bias between the PTR and non-PTR groups, we further analyzed the corresponding subgroups. Our results showed that PTR had a survival benefit regardless of the site of the primary tumor and with or without extracranial metastases. The higher survival rate following PTR can be related to the decrease of cancer stem cells that are resistant to chemotherapy as well as the reduction of primary tumor load[26]. PTR significantly lowered the risk of CRC-related complications such acute bleeding, perforation, and obstruction, which might result in increased surgical mortality and morbidity[27]. Our forest plot of subgroup analysis revealed that PTR improved survival in CEA-positive CRC BMs patients, but it had no effect on CEA-negative patients. This suggests that we should be more cautious about whether to perform surgery for the primary tumor in patients with CRC BMs complicated with CEA negative.

Our results also identified age as a significant prognostic factor for brain metastases in CRC. Patients in our study were divided into two age groups: <60 and ≥ 60 years. Patients < 60 years of age had better prognosis. Yang et al. [28] found a considerably poorer prognosis in patients > 70 years than in those 40 years of age. Quan et al. [15] also defined three age groups among CRC patients: <60, 60–74, and ≥ 75 years. Similar to our findings, patients ≥ 75 years of age had the poorest prognosis, and those < 60 years had the best prognosis. In another study, older age was also identified as an unfavorable prognostic factor for BMs in CRC [8]. Because the prognosis of patients with CRC and synchronous BMs worsens with age, younger individuals should be treated more aggressively than older patients.

The tumor marker CEA is frequently used to monitor CRC patients during treatment. Among patients with metastatic disease, CEA levels are increased (> 5 ng/mL) in ~ 70% [29, 30]. Several studies have reported higher CEA levels at the time of brain metastasis diagnosis in CRC patients [31–34], but only three reported a putative predictive effect [4, 15, 35]. Consistent with those reports, our study identified CEA as an independent prognostic predictor, with a 1-year survival rate of 26.8% for CEA-positive patients and 40.3% for CEA-negative patients. Thus, CEA positivity is a poor prognostic indicator in CRC patients with brain metastases.

According to our findings, the location of the primary tumor had no prognostic impact in CRC patients with brain metastases. In a univariate analysis, Huerta et al. [36] found that patients with RCC had a poorer survival rate than those with LCC (4.6 vs. 10.7 months; HR 3.5, p = 0.025), but in a multivariate Cox regression analysis the difference was not significant. Another study found that patients with a left-sided primary tumor had a 1.5-fold better prognosis than those with a right-sided primary [37]. This may reflect differences in the division of the left and right colon. In the univariate Cox regression performed in our study, extracranial metastases were significantly related to a poor prognosis but this result was not confirmed in the multivariate Cox regression.

Our study had several limitations. First, only patients with BMs at first presentation with CRC were included, because the SEER database only records the status of BMs at the time of initial diagnosis. Second, the SEER database does not contain information on Karnofsky performance status, the number of BMs, comprehensive treatment of BMs, or molecular markers; hence, these parameters were not included in our analysis.

In conclusion, primary tumor resection (PTR) offers survival benefits to patients with BMs from CRC. Age, CEA level, and PTR were identified as independent risk factors affecting the survival of CRC patients with synchronous BMs.

Abbreviations

CRC: colorectal cancer

BMs: brain metastases

SEER: Surveillance, Epidemiology, and End Results

CEA: carcinoembryonic antigen 

RCC: right colon cancer 

LCC: left colon cancer

RC: rectal cancer 

CI: confidence interval

Declarations

The English in this document has been checked by at least two professional editors, both native speakers of English. For a certificate, please see:

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Competing Interests:

The authors declare that they have no competing interests, and all authors confirm its accuracy.

Consent for publication

Not applicable.

Ethics approval and consent to participate

The study was based on a secondary analysis of the previously collected, publicly available, and de-identified data. The SEER database holds no identifying patient information, all data are anonymous, therefore, the written informed consent is no need for this study. This investigation was conducted in accordance with the ethical standards, according to the Declaration of Helsinki, and according to national and international guidelines, and the institutional review board of our hospital approved this study.

Acknowledgments

Not applicable

Funding declaration

This study was supported by the Zhejiang Province Natural Science Foundation of China (LY19H160040).

Author contribution

Xiaofei Cheng and Yanqing Li were responsible for study conception, design of the study, data acquisition, and analysis and interpretation of results. Yanqing Li and Dong Chen were responsible for data acquisition. Feng Zhao and Xiangming Xu took part in the discussion of the paper. Xiaofei Cheng wrote the manuscript that was reviewed and revised by Fanlong Liu. All authors have read and approved the manuscript.

Data availability

The data that support the findings of this study are openly available in Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute at https://seer.cancer.gov/

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Tables

Table 1. Baseline Characteristics of Patients Between the PTR group and non-PTR group.

Abbreviations: PTR primary tumor resection, RCC right colon cancer, LCC left colon cancer, RC rectal cancer.

Table 2. Univariate Cox regression for overall survival among patients with brain metastases

Abbreviations: PTR primary tumor resection, RCC right colon cancer, LCC left colon cancer, RC rectal cancer, CI confidence interval, HR hazard ratio.

Table 3   Multivariable Cox regression for overall survival among patients with brain metastases

Abbreviations: PTR primary tumor resection, CI confidence interval, HR hazard ratio.