Owing to advancements in therapeutic approaches, the overall survival (OS) rates of patients diagnosed with colorectal cancer (CRC) have increased (1). However, as survival rates have improved, a corresponding increase in the incidence of brain metastasis (BM) has been observed in patients with CRC (2,3), with the reported occurrence of BM arising from CRC ranging from 0.1–11% (2). Regarding the timing of BM development, synchronous BM indicates that metastasis occurs around the same time or shortly after a primary cancer. By contrast, metachronous BM refers to cases where a significant interval exists between the diagnosis of a primary tumor and the development of BM (4). The exact time interval for defining synchronous or metachronous BM remains inconclusive in the literature.

The impact of the timing of BM development has been discussed in several studies; however, most of these studies have primarily focused on patients with BM originating from lung cancer or renal cell carcinoma (4–6). Despite the emergence of studies focusing on treatment strategies and prognostic factors for survival outcomes in patients with BM from CRC, uncertainties remain regarding treatment strategies and prognostic factors (7–9), and studies on the impact of synchronous BM and metachronous BM specifically in patients with CRC are limited.

According to the literature, synchronous BM is more likely to be associated with poorly differentiated histology, right-sided CRC and aggressive histopathological features, including higher tumor and lymph node stages (10). Distinguishing between synchronous and metachronous BM may impact the choice of therapeutic interventions, such as considering more aggressive approaches for synchronous BM or prioritizing systemic therapy for metachronous cases (6). Moreover, understanding the timing of BM can facilitate discussions with patients regarding their prognosis, enabling clinicians to tailor communication and support strategies based on the expected disease course. Therefore, the aim of the present study was to assess whether the timing of BM development affects the survival outcomes of patients with BM from CRC by performing a comprehensive review of the published literature and a meta-analysis to quantitatively assess this clinical question.

The present study performed a comprehensive review of the existing literature and a meta-analysis to assess the relationship between BM timing and survival outcomes in patients with CRC. The results demonstrated no significant difference in OS between patients with synchronous or metachronous BM. This finding suggests that the timing of BM diagnosis may not be a substantial factor in OS outcome for patients with CRC, highlighting the importance of individualized treatment strategies that consider other patient-specific factors.

Previous studies evaluating this relationship in different cancer types yielded mixed results. Flannery et al (24) reported that patients with non-small-cell lung cancer and solitary metachronous BM had greater rates of survival compared with those with synchronous BM. Similarly, Ruste et al (4) reported lower survival rates in patients with clear cell renal cell carcinoma with synchronous BM compared with those with metachronous BM. However, a more recent study by Potthoff et al (5), reported no significant impact of BM timing on survival in a broader patient population with BM from several primary cancers. Notably, the inclusion of different primary cancer types in their study led to substantial variations in the characteristics of the included patients. The present study focused on BM from CRC, and the results demonstrated that the synchronous or metachronous nature of BM did not significantly affect the survival outcome.

Currently, the primary local treatment options for BM from CRC consist of surgical resection, radiotherapy or a combination of both (8). Surgical resection is considered feasible and appropriate for specific cases of BM from CRC. This approach is often employed for solitary or limited BMs and can help in reducing tumor burden and alleviating symptoms (25). Radiosurgical modalities, such as Gamma Knife or CyberKnife, are specialized techniques that deliver highly focused radiation to the BM while minimizing the impact on surrounding healthy tissues. These modalities are commonly used for small and well-defined metastatic lesions that may not be amenable to surgical resection (26). Whole brain radiotherapy is employed when multiple metastases are present throughout the brain, and can be used as adjuvant therapy following surgical resection to target remaining or potential microscopic metastases (27). We hypothesize that the status of BM as synchronous or metachronous can potentially impact subsequent treatment approaches, which in turn may affect OS. Thus, the need for further research in this area is crucial.

Although the results of the present study demonstrated that the synchronous or metachronous nature of BM did not significantly impact the survival outcome, these findings should be interpreted with caution. Despite no significant statistical heterogeneity demonstrated in the meta-analysis results, differences were observed among the included studies. For instance, in the study by Mege et al (19), the mean OS after BM was 12 months, which is similar to that reported in the study by Potthoff et al (5), which was not included in this research as it included several types of BM rather than just BM from CRC. In the study by Potthoff et al, the mean survival was also around 12–13 months. However, Roussile et al (20), reported a worse survival rate, with the OS for the synchronous and metachronous groups demonstrated to be 9.7 and 4.8 months, respectively. These differences may be attributed to the complex nature of the patients with cancer themselves and variations in treatment modalities and patient selection. Furthermore, the present study was unable to ascertain whether the treatments received by the synchronous and metachronous groups differed within each study.

The present meta-analysis has several limitations that should be acknowledged. Firstly, all the studies included in the analysis were retrospective in nature. As patients with cancer belong to a complex population, multiple potential factors can introduce bias and limitations in data collection, which may have impacted the accuracy and reliability of the findings. For example, our previous study (8) reported that surgery for CRC BM had improved survival outcomes compared with radiotherapy. However, the analysis in the present study focused on BM timing. The lack of detailed treatment information in the present analysis may impact the accuracy of the results. Secondly, despite the fact that a comprehensive search was performed, the number of studies that ultimately met the inclusion criteria and reported synchronous and metachronous BM was relatively small. Furthermore, certain studies included in the analysis did not provide comparative results between the two groups, but rather reported noncomparative measures, such as median survival times. Therefore, direct comparative data for the analysis were limited. Thirdly, owing to insufficient information in the included studies, the present study was unable to determine whether the distributions of treatments differed between the synchronous and metachronous BM groups within each study. Fourthly, the definition of synchronous and metachronous BM varied across the included studies and certain studies did not explicitly define or specify the timing criteria for synchronous BM. Lastly, the impact of primary tumor location on outcomes is also worth exploring, such as comparisons between the rectum and colon or between the right-sided and left-sided colon. However, the studies included in the present analysis did not assess both the timing of BM and the primary tumor location simultaneously. Therefore, a subgroup analysis based on the included studies could not be performed and is an aspect that requires further research in the future. Nevertheless, despite these limitations, the present study is the first meta-analysis to assess this clinical question that comprises large patient samples from multicenter data with low heterogeneity, to our best knowledge. Further research, including large, randomized prospective cohort studies with standardized definitions of synchronous BM and treatment protocols, is warranted.

In conclusion, the findings of the present meta-analysis indicate that there is no difference in OS between patients with synchronous and metachronous BM arising from CRC. Given the limitations of the present study, further research with prospective designs and larger sample sizes is needed to obtain more robust and conclusive evidence.