Colorectal cancer metastasis to the brain: A scoping review of incidence, treatment, and outcomes

Abstract

BACKGROUND

Over 150000 new diagnoses of colorectal cancer (CRC) are diagnosed yearly, and 1 in 5 patients have distant metastases on diagnosis. Previous estimates approximate that brain metastases (BM) occur in 0.6% to 3.2% of patients with CRC.

AIM

To describe the updated literature about the incidence and risk factors of BM in CRC as well as their treatment with surgery, chemotherapy, and radiation.

METHODS

We systematically searched the literature published between January 1, 2010 and April 1, 2025 in PubMed, Cochrane, Scopus, and EMBASE. All studies about BM from CRC were included. Studies only containing information about the treatment of primary CRC or primary brain tumors were not included. Articles were categorized and described as incidence, surgery, chemotherapy, or radiation to provide an overview of the state of research on BM from CRC.

RESULTS

Our primary search resulted in 1648 articles that were eventually screened to 147. These articles were analyzed to provide the state of current literature on incidence and risk factors of BM from CRC as well as how these metastases are treated with chemotherapy, radiation, and surgery.

CONCLUSION

Prognosis is influenced by tumor burden, performance status, and emerging molecular markers. Stereotactic radiotherapy and surgical resection provide favorable outcomes for select patients, whereas chemotherapy and immunotherapy remain areas of limited evidence. Continued research is needed to identify high-risk patients and optimize multidisciplinary treatment approaches.

Key Words: Colorectal cancer; Brain tumor; Metastasis; Carcinoembryonic antigen; Kirsten rat sarcoma viral oncogene homolog; Human epidermal growth factor receptor 2; Whole-brain radiotherapy; Stereotactic ablative radiotherapy; Neurosurgery

Core Tip: Brain metastases (BM) from colorectal cancer are becoming more common as overall survival increases. Socioeconomic factors are associated with worse prognosis in colorectal cancer BM but not an increased incidence. Primary colorectal tumor characteristics that increase the incidence of brain metastasis and have a worse prognosis are right-sidedness, rectal origin, adenocarcinoma histology, and high carcinoembryonic antigen. Kirsten rat sarcoma viral oncogene homolog and human epidermal growth factor 2-mutated colorectal tumors have a higher incidence of BM but inconclusive prognostic value. Patients with smaller, less numerous BM can be treated with stereotactic ablative radiotherapy while patients with larger, more numerous tumors should receive whole-brain radiotherapy and surgical resection.

INTRODUCTION

The increased survival of patients with colorectal cancer (CRC) has increased the likelihood of late complications, including the occurrence of brain metastases (BM)[1]. BM represent the least common metastatic site for CRC[2], with incidence ranging from 0.1% to 3%[3-5]. Despite its uncommon presentation in CRC, BM continue to be researched due to its high mortality rates and clinical significance as a terminal-stage cancer[6,7]. The role of radiation therapy in the local treatment of BM to CRC is becoming well established[8-12]. Surgical resection is often employed for larger tumors and in conjunction with radiotherapy and chemotherapy[13]. Targeted chemotherapy for BM of CRC is difficult because of the blood-brain barrier[14].

This scoping review provides information describing the updated literature on the incidence and risk factors of BM in CRC as well as their treatment with surgery, chemotherapy, and radiation.

MATERIALS AND METHODS

We systematically searched the literature on the incidence and risk factors of BM in CRC, as well as their treatment with surgery, chemotherapy, and radiation published between January 1, 2010 and April 1, 2025 in PubMed, Cochrane, Scopus, and EMBASE databases. Our PubMed search strategy included search query ("Colorectal Neoplasms"[Mesh] OR "Colorectal Cancer" OR "Colorectal Tumors" OR "Colorectal Carcinoma") AND ("Neoplasm Metastasis"[Medical Subject Headings (Mesh)] OR "Metastases" OR "Metastatic" OR "Secondary") AND ("Central Nervous System"[Mesh] OR "CNS" OR "Brain"). Our Cochrane search strategy included the search query (MeSH descriptor: [Colorectal Neoplasms] OR "Colorectal Cancer" OR "Colorectal Tumors" OR "Colorectal Carcinoma") AND (MeSH descriptor: [Neoplasm Metastasis] OR "Metastases" OR "Metastatic" OR "Secondary") AND (MeSH descriptor: [Central Nervous System] OR "CNS" OR "Brain"). Our Scopus search strategy included the search query (TITLE-ABS("Colorectal Neoplasms" OR "Colorectal Cancer" OR "Colorectal Tumors" OR "Colorectal Carcinoma")) AND (TITLE-ABS("Neoplasm Metastasis" OR "Metastases" OR "Metastatic" OR "Secondary")) AND (TITLE-ABS("Central Nervous System" OR "CNS" OR "Brain")). Our EMBASE search strategy included the search terms ('colorectal neoplasm'/exp OR 'colorectal cancer': Ti,ab OR 'colorectal tumors': Ti,ab OR 'colorectal carcinoma': Ti,ab) AND ('neoplasm metastasis'/exp OR metastases: Ti,ab OR metastatic: Ti,ab OR secondary: Ti,ab) AND ('central nervous system'/exp OR cns: Ti,ab OR brain: Ti,ab). In EMBASE, articles were filtered to only include articles of type “Medicine”. All clinical trials, clinical studies, meta-analyses, and systematic reviews about BM from CRC written in English were included. Two authors (Hutchinson HJ and Gonzalez M) screened all articles to determine which ones were relevant to the review. Studies only containing information about the treatment of primary CRC or primary brain tumors were not included. Articles were categorized and described as incidence, surgery, chemotherapy, or radiation to provide an overview of the state of research on BM from CRC. Each category was assigned to an author for appraisal of the current literature, risk of bias, and gaps in need of future research.

RESULTS

Our primary search resulted in 1648 articles that were eventually screened to 147. These articles were analyzed to provide the state of the current literature on incidence and risk factors of BM from CRC as well as how these metastases are treated with chemotherapy, radiation, and surgery. Figure 1 diagrams the results of the search process. Figure 2 displays the proportion of screened articles in each category. Of the studies included in the review, 99 (67.3%) were related to incidence and risk factors, 20 (13.6%) were related to radiotherapy, 18 were related to surgery (12.2%), and 10 (6.6%) were related to chemotherapy.

Figure 1 Diagram of the literature search process. NA: Not available.

Figure 2  Topic distribution of the included articles.

Incidence and risk factors

De novo metastasis to the brain is correlated with a 10-fold increased risk of mortality[15]. BM from CRC portend a poor prognosis with an estimated survival of less than 1 year[3,6,16]. The initial diagnosis of BM is often delayed due to the disease’s asymptomatic presentation[16], although it may infrequently present with neurological symptoms such as ataxia, dizziness, or headache[17,18]. Studies suggest that improvements in the identification and evaluation of prognostic factors could facilitate an earlier BM diagnosis and guide physician decision-making regarding treatment plans[18,19]. Further research may seek to implement similar prognostic scores for screening patients at high risk of developing CRC BM. Table 1 summarizes the literature on prognostic factors in CRC BM.

Table 1 Summary of literature on factors influencing incidence and prognosis of colorectal cancer brain metastases.

Factor	Incidence	Prognosis	Ref.
Advanced age	Inconclusive	Inconclusive	[3,20-30]
Sex	Inconclusive	Inconclusive	[13,22,24,28,30-33]
African American race	Inconclusive	Worse	[15,25]
Poor access to health insurance	Inconclusive	Worse	[33]
Residence in urban areas	Inconclusive	Worse	[35]
Synchronicity with primary tumor	Lower	Inconclusive	[39-41]
Rectal primary tumor	Higher	Worse	[4,17,20,25,26,27,33,39,43]
Right-sided primary tumor	Higher	Worse	[4,17,25,33,43]
Tumor stage	Inconclusive	Worse	[5,25,35,44,45]
Adenocarcinoma histology	Higher	Worse	[20,22,24,25,26,46-49]
CEA levels	Higher	Inconclusive	[26,46,50]
HCMV infection	Inconclusive	Worse	[2,34,51]
Size of primary tumor	Higher	Inconclusive	[2]
Size of BM	-	Worse	[3,28,47,52,54]
Number of BMs	-	Inconclusive	[16,23,41,54]
Location of BM	-	Inconclusive	[25,30,34,56-59]
Multiple extracranial metastatic lesions	-	Worse	[60]
Concomitant lung metastasis	Higher	Worse	[18,24,22,38,44,52]
Concomitant liver metastasis	Higher	Inconclusive	[3,18,23,24,30,38,41,62,63]
Concomitant bone metastasis	Higher	Inconclusive	[5]
KPS > 70	-	Worse	[41,42,51,52,65,66,68,69]
Higher RPA score	-	Worse	[42,64]

BM: Brain metastases; CEA: Carcinoembryonic antigen; HCMV: High-grade human cytomegalovirus; KPS: Karnofsky performance status; RPA: Recursive partitioning analysis.

Sociological factors

The influence of demographic and socioeconomic factors on the prognosis of CRC BM remains controversial. Advanced age is associated with BM and may serve as an indicator of overall survival[3,20]. However, the definition of advanced age in the setting of CRC BM is not well established and has led to inconclusive findings. Most studies report prolonged survival and favorable prognosis in patients with CRC BM under the age of 65[21-24], whereas older age groups experience worse survival outcomes[24,25]. Conversely, few studies have found young age to be associated with an increased risk of developing BM[26,27]. Due to limitations in cohort sample size, there are limited findings that indicate there is no significant survival difference between age groups[28-30]. Moreover, several studies have suggested that there is no statistically significant difference in prognosis of BM and survival between men and women[22,24,28,30-32]. Some articles mentioned that women displayed a more favorable prognostic factors compared to men[13,33]. Race has also been significantly associated with early death from CRC BM[34], with African Americans experiencing disproportionally worse outcomes compared to Caucasians and Hispanics[15,25]. Additional socioeconomic factors such as accessible healthcare, health insurance[33], and residence in urban areas tend to portend better outcomes[35]. While the prognostic value of these sociological factors is variable, future research should address these gaps by investigating how sex and racial differences may impact clinical presentation, time to BM diagnosis, treatment, and overall survival[36].

Primary tumor characteristics

CRC is a heterogeneous disease characterized by individual differences in primary tumor location, metastatic preference, histological, and molecular features, which complicates standardization of prognostic scoring[33]. CRC metastatic patterns to the brain can be further classified as metachronous or synchronous. Metachronous is the development of BM months after the primary CRC, whereas synchronous is the simultaneous development of CRC and BM in the patient at the time of diagnosis[37]. Although metachronous metastatic disease is more closely associated with rectal primaries[38] and an increased risk of developing BM[39]. Meta-analyses have revealed no significant difference in survival outcomes between synchronous and metachronous BM[40,41]. The location of the primary tumor plays a significant role in the tumor’s metastatic pattern due to innate differences in the vascular anatomy between the proximal and distal segments of the colon[28]. The most common primary tumor site for CRC with subsequent BM was the distal colon, which is composed of the sigmoid and rectum[17,28,42]. Specifically, rectal cancer was invariably associated with an increased risk of developing BM[20,26,27,39] and worse survival outcomes compared to primary colonic cancers[20,29]. Right-sided CRC consistently displayed a higher incidence rate for BM and significantly shorter survival compared to left-sided CRC[4,17,25,33,43]. These results support the inclusion of CRC location and sidedness as a valuable prognostic variable in BM risk assessments.

An array of CRC histological findings have also been linked to the development and prognosis of BM. Higher grade tumors with advanced T and N staging were predictors of BM development[5,25,44], with N staging having the highest correlation to increased mortality[35,45]. Of note, research indicates that differences in cellular differentiation (i.e. undifferentiated, moderately, poorly) were independently associated with BM progression but hold limited prognostic value[26,46]. Interestingly, the distinction between mucinous and adenocarcinoma is a more reliable prognostic factor for evaluating CRC BM. Mucinous cancer was associated with significantly lower odds of presenting with synchronous BM[26] and reduced risk of developing metachronous BM[20]. Adenocarcinoma portends a worse prognosis due to its more extensive metastatic pattern, including a higher propensity for BM[20,26]. Molecular findings, primarily carcinoembryonic antigen (CEA) levels, serve as a cancer tumor marker and are commonly used in CRC surveillance as a serum marker for recurrence[22]. In the setting of CRC BM, elevated CEA levels may represent a negative prognostic factor[25,47] and is associated with shorter survival time compared to patients with CEA-negative tumors[24,48]. Positive CEA levels also significantly increased the odds of developing BM at the time of initial diagnosis[26,46]. These elevated CEA levels indicate patients with CRC with BM have disproportionately higher tumor deposits[49] and overall tumor burdens[46]. By contrast, other studies have revealed that CEA levels have limited survival predictive value[22], and negligible differences were found among histological types, tumor staging, and grading subgroups[22,24]. The literature contains conflicted findings regarding the prognostic significance of CEA. A novel research study recently discovered that BM with high-grade human cytomegalovirus (HCMV) infection and increased levels of HCMV-IE protein had shorter overall survival and rapid tumor progression[50].

Clinical BM prognosis

The evolution and prognosis of BM in the clinical setting relies on tumor size, number of BM, and lesion location. Tumor size is considered a risk factor for early death and poorer prognosis amongst CRC BM subgroups[2,34,51]. CRC BM are more likely to occur in patients with larger primary tumor size[2], frequently ranging from 4 cm to 7 cm[2]. The number of BM lesions has been linked to cancer survival[41,48], with longer survival times observed in patients with single BM[21-23,52,53]. The presence of multiple BM is a poor prognostic factor indicative of advanced CRC requiring aggressive treatment[3,47,52]. Few studies dispute this stance due to findings of minimal survival differences between solitary and multiple BM lesions[28,54]. Although the cerebellum was the most frequently involved site for BM[55], cerebral BM lesions convey favorable prognosis with prolonged overall survival[16]. There remains controversy in the prognostic validity of supratentorial and infratentorial sites of BM, with limited data suggesting that supratentorial BM are favorable[23], whereas others describe no survival differences based solely on brain lesion sites[41,54].

Extracranial metastases

The isolated incidence of solitary BM is relatively rare in CRC[5] and more commonly presents with extracranial metastases to the lung[17], liver[35], and bone[5,42]. Inversely, having three or more sites of metastasis significantly increases the odds of developing BM[20,26]. Multiple extracranial metastatic lesions have been consistently linked with a worse prognosis[25,30,56] and shorter survival[34,57-59], especially concomitant metastasis to the lung and liver[18,24,38]. The presence of lung metastasis in CRC is an independent risk factor for developing BM[3,5,20,39] and negatively impacts overall survival[60]. Large liver metastases and bone metastases are underrepresented in the CRC BM literature and provide inconsistent data on prognostic value[22,44,52].

Prognostic assessments

In addition to the prognostic variables, performance status assessments continue to be the most validated prognostic tool for BM[41,61]. The Karnofsky performance status (KPS) is the most frequently implemented tool[41] because of its accurate evaluation of a patient’s functional status[41]. Multiple studies suggest a KPS score ≥ 70 is a favorable prognostic factor that is significantly associated with prolonged survival in patients with CRC with BM[23,30,41,62,63]. Individuals with low KPS scores (< 70) have dismal outcomes with no long-term survival[3,62]. Postoperative neurological performance scores are a reliable parameter that can further complement the KPS prognosis[58]. Studies have shown that recursive partitioning analysis (RPA) is helpful in distinguishing prognostic classifications of patients with CRC BM[42,64]. RPA consists of the following: Class I includes patients under 65 years old with KPS > 70, controlled primary disease, and no extracranial metastases; Class III includes patients with KPS < 70; and Class II encompasses all remaining patients[41,65,66]. Median survival after BM diagnosis is significantly different across the three RPA classes[42] with the longest survival observed in RPA Class I[52,65]. Lastly, an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-1 represents better overall survival[21,67], whereas scores of 3-4 are negative prognostic factors[13]. Current and future research is focused on the development and calibration of nomogram prediction models. However, these new scoring systems[51,68,69] continue to rely on pre-existing performance scores such as the KPS, RPA, and ECOG, and have yet to perform better than standard of care prognostic protocols.

Molecular characteristics

Many genetic mutations are implicated in CRC BM. The molecular profile of CRC BM is distinct from other BM such as those from lung and breast cancers[70,71]. The molecular profile of CRC BM is also different from other CRC metastases[72]. Infratentorial CRC BM are most common with no predilection for vascular distribution[73]. Recent efforts have shifted towards categorizing and phenotyping clusters of co-occurring mutations in CRC into consensus molecular subtypes (CMS) instead of individual mutations[74]. This effort was fruitful in CRC BM. In a molecular transcriptomic screen of 61 CRC metastases, CMS3 was identified significantly more often in the 23 CRC BMs compared to other BMs[75]. The CMS3 subtype is categorized as “metabolic” and is enriched in genes such as phosphoinositide-3-kinase regulatory subunit gamma, RET, carbonic anhydrase-related protein, and UDP glycosyltransferase 8, all of which are involved in the oxidative phosphorylation pathway[75]. Future studies of CMS clustering in larger groups of CRC BM tumors could provide additional information about CRC BM-specific drug targets and serve as the basis for a screening tool of which patients with CRC should receive closer monitoring for BM.

The rat sarcoma (RAS) protooncogene is mutated in approximately 50% of CRC tumors and until recently was considered an undruggable target[76]. However, new evidence has shown the Kirsten rat sarcoma viral oncogene homolog (KRAS) inhibitor adagrasib combined with cetuximab improves survival vs cetuximab alone in heavily pretreated patients with CRC with mutated KRAS G12C tumors[77]. In light of this evidence, adagrasib in combination with cetuximab recently gained accelerated United States Food and Drug Administration approval for KRAS G12C-mutated CRC[78]. This is especially good news for CRC BM because RAS mutations have been correlated with BM of CRC in several molecular studies, often at a higher rate than in primary CRC or other metastases[62,79-90]. One of these studies specifically found that KRAS mutations were a specific predictor of metachronous BM[79]. However, the literature on overall prognosis for patients with CRC BM with vs without RAS mutations is heterogenous[75,80-90]. A retrospective study of 23 CRC BM found in our search showed a lower overall survival and cause-specific survival in patients with wild-type RAS[75]. On the other hand, the retrospective HEROES study of 22 CRC BM found longer progression-free survival in patients with KRAS-mutated tumors[91]. Yet another molecular study found a higher risk of BM recurrence with KRAS mutations[89]. All of these studies are retrospective in nature and have a small sample size, so it is impossible to make a definitive conclusion about the prognosis of RAS-mutated CRC BM; however, RAS mutations are a risk factor for the development of CRC BM[75,80-90].

Human epidermal growth factor 2 (HER2) mutations are another area of exploration in CRC BM, initiated because of the analogous evidence that HER2 mutations increase the risk of BM from breast cancer. Current evidence supports a similar relationship in CRC. The HEROES study found HER2+ CRC BMs in 4 of 22 resected tumors, and 3 of these 4 had HER2+ primary CRC tumors using next-generation sequencing[91]. The connection of HER2 to CRC BM is exciting because of the potential therapeutics already available for other HER2+ solid tumors[92]. Trastuzumab, a monoclonal antibody targeting HER2/neu, provided an 11% absolute risk reduction of death at 1 year in patients with BM from breast cancer when used in conjunction with chemotherapy vs chemotherapy alone[93,94]. Other genetic analyses of patients with CRC BM with immunohistochemistry and molecular methods have also found HER2+ CRC BM[95-97]. Prognosis in patients with HER2+ CRC BM is also uncertain. Some research has shown shorter progression-free survival in patients with HER2+ CRC BM. Other studies have shown longer progression-free survival in patients with HER2-amplified CRC BM[91,96,98] and HER2+ immunohistochemical tissue sections[97]. This discrepancy may be because of an interaction of autocrine signaling of neurotrophin-3 from primary CRC tumors, as one study found a poorer prognosis in CRC BM to be linked to patients with HER2+ and neurotrophin 3-positive primary CRC[98]. Unfortunately, intravenous trastuzumab infusions are unlikely to work at the BM itself because they do not cross the blood-brain barrier[99]. However, HER2+ could serve as a biomarker in CRC for tumors with a high risk of BM that could be alleviated with trastuzumab or another HER2/neu inhibitor.

Other molecular markers have less evidence supporting their link to CRC BM. A single nucleotide polymorphism array of patient primary CRC tumors and their metastases found matching 20q11.1 gains in all 4 patient tumors with BM[100]. This mutation is found on 20% of human pluripotent stem cells and is amplified in 20% of human cancers[101]. O6-methylguanine-DNA methyltransferase methylation is also found in more than half of primary CRC tumors and CRC BM[102]. Two studies found an association between V600E B-rapidly accelerated fibrosarcoma (BRAF) gene mutations and incidence of CRC BM[103,104], which is promising because immunotherapies targeting V600E BRAF are already being explored in treating metastatic CRC; however, more randomized controlled trials are needed to prove its efficacy[105]. Integrin inhibitors are an emerging therapeutic modality for treating metastatic cancer[106]. Mutations in αvβ5 integrins, which allow for the extravasation of primary CRC to extravasate and metastasize, are also being studied[107]. Table 2 summarizes the current literature on genetic mutations implicated in CRC BM.

Table 2 Summary of the literature on molecular mutations influencing incidence and prognosis of colorectal cancer brain metastases.

Mutation	Incidence	Prognosis	Ref.
CMS3	Higher	Inconclusive	[75]
KRAS	Higher	Inconclusive	[75,80-91]
HER2	Higher	Inconclusive	[91-94,96,98]
HER2 & NT-3	Inconclusive	Worse	[98]
20q11.1 gain	Higher	Inconclusive	[100]
MGMT methylation	Higher	Inconclusive	[102]
V600E BRAF	Higher	Inconclusive	[103,104]

BRAF: B-rapidly accelerated fibrosarcoma; HER2: Human epidermal growth factor 2; KRAS: Kirsten rat sarcoma viral oncogene homolog; MGMT: O6-methylguanine-DNA methyltransferase; NT-3: Neurotrophin-3.

Radiotherapy

Primary colorectal tumors have a low radiosensitivity[8-11]. The primary treatment modality of BM and CRC BM is external beam radiation therapy, including whole-brain radiotherapy (WBRT) and stereotactic ablative radiotherapy (SABR)[12]. There has been little research into radiopharmaceutical therapy for treating BM, but a Phase I trial demonstrated improved imaging potential when combining radiolabeled M5A with a positron emission tomography emitting radionuclide, which detected two unknown BM in their study population[108].

WBRT

WBRT is the former mainstay of treating CRC BM and the preferred current treatment of large BM (maximum diameter of ≥ 2-4 cm or a volume of ≥ 4-15 cm³) or multiple metastases, and involves fractionated radiation therapy, with the standard dose of 3 Gray (Gy) in 10 fractions (10 × 3 Gy) or 2 Gy in 4 or 5 fractions (4 or 5 × 2 Gy)[8,9,12,109-112]. When considering WBRT, it is imperative to determine the survival prognosis of the patient to properly tailor the treatment[8,9,111]. Thus, several prognostic factors and scores have been identified and developed[8,9,111].

A study by Meyners et al[8], which identified prognostic factors in those who received only WBRT for BM from radioresistant tumors, concluded that patients whose WBRT schedule had doses higher than 30 Gy total, higher KPS, fewer BM, lacking extracerebral metastases, and lower RPA class were associated with improved survival and that higher KPS, fewer brain BM, and lower RPA class were associated with better local control. Dziggel et al[9] produced a score specifically designed to estimate the survival of patients with BM from radioresistant primary tumors when only treated with WBRT. For those who scored a poor survival prognosis, patients may likely benefit from a short course of WBRT such as 4 Gy in 5 fractions. Furthermore, those who scored a favorable survival prognosis could be considered for longer WBRT schedules such as 2 Gy in 20 fractions. Those with an intermediate survival prognosis may likely benefit from the standard WBRT of 10 × 3 Gy. Meyners et al[8] and Dziggel et al[9] concluded that those with favorable prognosis may benefit from undergoing more aggressive treatments such as neurosurgery or SABR[8,9].

Rades et al[111] developed a score explicitly based on CRC BM and patients who were only treated with 10 × 3 Gy WBRT (WBRT-30-CRC), which appeared precise in identifying patients with CRC BM who will die within and survive past 6 months following WBRT. Tsao et al[109] examined 54 published trials with a total of 11898 participants, not limited to radioresistant BM, on augmenting WBRT used in treatment of newly diagnosed multiple BM with lower and higher doses, radiosensitizers, and WBRT in addition to SABR. Overall, there were no improvements to outcomes with any augmenting factors besides improved local and distant brain control in WBRT added to SABR[109].

SABR

SABR is recommended and preferred in those whose prognosis is greater than 3 months and have either a single brain metastasis larger than 3 cm to 4 cm if surgically removed, a single metastasis smaller than 3 cm to 4 cm, or 2 cm to 3 metastasis if all are smaller than 3 cm to 4 cm[11,12,112-117]. SABR is a high Gy dose, which is dependent on each clinical scenario, over a single or few fractions[10-12,115,116,118-120]. Specifically for CRC BM, SABR has a proven effectiveness with reported excellent overall survival, with some studies reporting higher Gy doses required in CRC BM[10-12,115,116,118-121].

Akin to WBRT, prognostic factors are critical in selecting SABR treatment, with Paix et al[117], Matsunaga et al[10], and Taori et al[121] outlining the following for patients with CRC BM: KPS; number of BM; surgical resection of BM; and the control of extracranial disease, and age. Improved OS was associated with KPS > 70 or > 80 KPS, less than five BM, no extracranial metastases, and if possible, a surgical resection[10,117,121,122]. For local tumor control (LTC), there has been variability between studies; however, in patients with CRC, the tumor volume and margin dose have been significantly associated with LTC, and Taori et al[121] found that those with ≥ 3 BM was significantly correlated with the risk of developing additional BM after initial SABR[121]. However, prognostic factors such as previous WBRT status, number of BM, margin dose, and active systemic disease had no effect on overall survival or LTC[121]. Similar to WBRT, several scores can be employed in the usage of SABR: RPA, RPA, II, Graded Prognostic Assessment (GPA), disease-specific GPA, and basic score for BM[115].

For augmenting SABR, a study by Li et al[120] focusing exclusively on CRC BM found that simultaneous bevacizumab had significant improvements in quality of life and OS along with improved symptoms of radiation-induced brain necrosis[120]. Rades et al[112] developed a scoring tool to predict which patients with SABR may benefit from supplemental WBRT, with those with a score of 2 benefiting from additional WBRT, a score of 3 requiring individual treat decisions, and a score of 4 not benefiting from additional WBRT[112]. Gorovets et al[123] developed a nomogram to select which patients may benefit from upfront SABR alone vs WBRT in addition to SABR, which could prevent erroneous neurocognitive toxicities of WBRT[123]. Mondaca et al[122], a retrospective analysis of 1154 patients, found that treatment of CRC BM with surgery, when possible, followed by SABR, can provide longer survival times[122].

The selection of WBRT or SABR is highly dependent on the clinical scenario, with those having fewer and smaller CRC BM likely benefiting from SABR while those with larger and more numerous BM likely benefiting from WBRT. Some studies have shown that higher doses of WBRT may have better outcomes in CRC BM. Figure 3 diagrams the process for determining which radiotherapy modality to use for CRC BM.

Figure 3  Flow diagram for determining radiotherapy modality for colorectal cancer brain metastasis.

Surgery

Surgical resection remains one of the core treatment modalities for metastasis to the brain. Multiple studies support its efficacy in treatment, often in combination with radiotherapy. Resection of tumors can help provide relief of symptoms caused by increased intracranial pressure and mass effect including headache, dizziness, change in mental status, and aphasia[124]. In fact, Kim et al[125] found surgery to provide a greater rate of symptom relief at 6 months, compared with gamma-knife radiosurgery (72.7% vs 18.5%; P = 0.005)[125]. Brain resection also includes the opportunity to conduct molecular testing on the tumor[124]. In today's age of increasingly individualized care, molecular markers can guide treatment plans.

Indications

Multiple factors may be considered when determining if a patient is a candidate for surgery including tumor size, location, number of BM, and performance status. Studies have found that patients with improved performance scores experience greater benefit from surgical resection; performance scores include RPA, KPS, ECOG status, and Katz score[126,127]. However, performance status may also be a limitation in assessing the effectiveness of surgical interventions, since it is used as an exclusion criterion in studies[126-128]. For instance, one retrospective study noted that only 1.6% of the patients who received surgery were in RPA class 3[129]. Therefore, any retrospective studies that assess surgical treatment must take this factor into account.

Extracranial metastases are associated with worse outcomes and survival in patients with BM[13,126,130-134]. Gui et al[130] found that those who underwent surgery were likely to have fewer extracranial metastases (P = 0.048)[130]. This may be connected to performance scores in that extensive metastases impact patients’ activities and need for assistance.

For tumors > 3 cm in diameter, surgical resection remains the most common treatment[136]. Gui et al[130] found that patients with BM from CRC who underwent surgery had larger lesions than those who received stereotactic radiosurgery (SRS) alone (diameter of 3.1 cm and 0.8 cm, respectively; P < 0.001)[130]. Similar results were found by Kim et al[125], where those who underwent surgery were more likely to have lesions > 3 cm, compared with those who had gamma-knife radiosurgery[125]. Interestingly, the morphology of the brain lesion can also impact prognosis. Although rarer, Zancana et al[129] found that cystic lesion morphology was associated with a worse overall survival compared to solid morphology (6.66 months vs 22.4 months; P = 0.001)[127].

Integration in multimodal therapy

Although sometimes used alone, surgery is frequently employed with adjuvant radiotherapy as treatment for BM. Radiotherapy is conventionally used postoperatively to treat the resection site for microscopic tumor remnants and prevent future recurrence. However, there has been interest in assessing the use of preoperative SRS, as there has been evidence of reduced adverse radiation effect and meningeal disease[135]. In a study that compared preoperative and postoperative dosimetry plans of patients, Cheok et al[136] found the preoperative plans to be more conformal to the lesion (P < 0.001), along with having a sharper dose drop-off (P = 0.0018)[136]. There are clinical trials in process to assess the timing for SRS pre-operatively and post-operatively (NCT05438212, NCT04474925, NCT05124236).

Patients with BM often receive systemic therapy to treat primary CRC disease. In a meta-analysis, it was reported that patients who received chemotherapy before BM ranged from 45% to 82%, whereas those who received chemotherapy after BM diagnosis ranged from 24% to 75%[126]. Biological therapy is also increasing in use; Mondaca et al[122] reported that 50% of patients had received biological therapeutics prior to BM diagnosis[122].

Outcomes

Multiple studies have demonstrated that patients with BM secondary to CRC who undergo surgical resection have better survival outcomes compared with those who do not[13,122,126,130-132,137-139]. Results from regression analyses of factors associated with overall survival are described in Table 3. Chang et al[126] and Wong et al[137] offered valuable insights, as surgery was compared with radiotherapy, as opposed to other retrospective studies that compared surgical intervention with no local therapy[13,130-132]. Furthermore, although not assessed by regression analysis, Kim et al[138], also found that patients treated with surgery and SRS had a longer median survival than those treated with SRS alone and WBRT alone (P = 0.016). A multicenter metastatic colorectal registry was used by Rico et al[139], where it was found that patients who underwent craniotomy and radiotherapy had a longer survival of 8.5 months compared with patients who only received WBRT (2.2 months). However, this study was limited in that other patient characteristics, including performance status and disease extent, could not be reported due to the nature of the registry[139]. Similar results were described by Mondaca et al[139], where patients who received WBRT had shorter overall survival of 2.4 months compared with those who received surgery and WBRT, with overall survival of 16.2 months (P = 0.003)[122]. In a systematic review of 23 articles, Silva et al[140] report a median survival time of 10.3 months following surgical intervention. Overall, multiple studies focusing on patients with BM from CRC have supported the use of surgical resection for treatment.

Table 3 Analysis of surgical resection compared with other treatment modalities in patients with brain metastases from colorectal carcinoma.

Ref.	Group 1	Group 2	Outcome	HR/OR	95%CI	Statistical significance	Analysis method
Chang et al[126], 2022	Surgery	Radiotherapy	Survival outcomes	HR = 0.53	0.47-0.6	I2 = 0%	Univariate analysis
Gui et al[130], 2025	Surgical resection	No resection	Overall survival	HR = 0.58	0.39-0.86	P = 0.006	Univariate analysis
Gui et al[130], 2025	Surgical resection	No resection	Overall survival	HR = 0.81	0.52-1.25	P = 0.3	Multivariate analysis
Suzuki et al[131], 2014	Surgical resection	No resection	Overall survival	HR = 0.26	0.17-0.41	P < 0.0001	Multivariate analysis
Kye et al[132], 2012	Conservative management	Treatment modality	Overall survival	HR = 7.973	1.487-42.761	P = 0.015	Multivariate analysis
Bonadio et al[13], 2021	Surgery alone	No local therapy	Overall survival	HR = 0.56	0.34-0.90	P = 0.018	Multivariate analysis
Bonadio et al[13], 2021	Surgery + radiotherapy	No local therapy		HR = 0.27	0.16-0.43	P < 0.001	Multivariate analysis
Wong et al[137], 2024	Surgery	WBRT	Overall survival	OR = 0.540	0.233-1.250	P = 0.150	Multivariate analysis
Wong et al[137], 2024	Surgery + WBRT	WBRT		OR = 0.232	0.107-0.504	P < 0.001	Multivariate analysis

CI: Confidence interval; HR: Hazard ratio; OR: Odds ratio; WBRT: Whole-brain radiotherapy.

However, this finding was not always consistent. The significant survival benefit associated with surgical resection by Gui et al[130] was lost upon multivariate analysis, where P = 0.3 (Table 3)[132]. Furthermore, while Suzuki et al[131] reported improved overall survival for patients who received neurosurgical intervention compared with those who did not (Table 3), there was no significant difference in prognosis between patients who received SRS vs those who had curative neurosurgical resection (P = 0.13)[132].

It is important to note that most of these cited studies are retrospective; the indications for surgery discussed above may influence the studies’ results, since surgery is more frequently performed on patients with better performance scores and fewer extracranial metastases. Furthermore, one retrospective study reported that those who underwent surgical resection were younger than those who received gamma-knife radiosurgery (56 years vs 66 years; P = 0.014)[126]. Therefore, differences in patient population may play a role in the improved outcomes from surgical resections when compared to other treatment modalities.

In a Cochrane systematic review comparing surgery with SRS for patients with single or solitary BM, only two randomized controlled trials, with 85 total participants, met the inclusion criteria[128]. No difference was found in overall survival, progression-free survival, or adverse events between the treatment modalities[128]. However, Fuentes et al[128] rated the certainty of the evidence to be very low or low due to risk of bias and imprecision of the data. This lack of strong evidence supports the need for improved randomized controlled trials, especially in the setting of BM from CRC, since these patients have a worse prognosis than patients with BM from other primary tumors[133]. Nonetheless, while stronger studies are required, surgery still plays a crucial role in treatment for BM.

Chemotherapy

The current literature specific to chemotherapy options for CRC BM is limited. Adjuvant chemotherapy treatment regimens in metastatic CRC often consists of a cytotoxic chemotherapy regimen of 5-fluorouracil, leucovorin, and capecitabine with either oxaliplatin or camptothecin[141]. Immunotherapy is also being investigated in CRC BM[142]. Although regorafenib, a multi-kinase inhibitor, has shown efficacy as a late-line agent in metastatic CRC, it has shown reduced efficacy and contraindications in patients with BM or liver metastases[143]. Clinical trials have also found dabrafenib, a BRAF kinase inhibitor, to be an efficacious immunotherapy in the setting of melanoma brain metastasis; future studies may show generalizability to other cancers with BM[144]. Although trastuzumab and lapatinib are advanced-line immunotherapies targeting HER2-positive mCRC, their molecular properties inhibit the drug’s permeability across the blood-brain barrier and limit their utility in the treatment of BM[14]. Retrospective studies have also found that palliative anti-angiogenic immunotherapy, such as bevacizumab, increases overall survival, intracranial progression-free survival, and neurogenic event-free survival[145-148]. However, a higher level of evidence is needed to make conclusions about the effectiveness of specific therapies in CRC BM.

Data regarding novel chemotherapies for CRC BM were not found in our search of the current literature, despite a recent renaissance in immunotherapies such as immune checkpoint inhibitors, chimeric antigen receptor T-cell (CAR-T) therapy, and technologies to cross the blood-brain barrier[149]. The KEYNOTE-177 trial provided evidence that the programmed death ligand 1-binding monoclonal antibody, pembrolizumab, improves progression-free survival in metastatic microsatellite instability or mismatch repair-deficient CRC tumors in comparison to cytotoxic chemotherapy[150]. However, the study did not specifically report data on checkpoint inhibitors for CRC BM[150]. CAR-T therapy has also been shown to be safe in metastatic BM; however, trials of its efficacy in any CRC metastasis have yet to proceed[151]. The delivery of specific or non-specific drugs to BM to disrupt the tumor microenvironment are still in development and have not been tested in CRC BM[152-154].

DISCUSSION

Overall, conclusive data regarding prognosis and factors predisposing patients to CRC BM are scarce. Distal primary CRC tumors tend to develop more BM and are more likely to be metachronous. Outcomes in metachronous vs synchronous CRC BM are similar, which provides evidence that initial scanning for BM after CRC diagnosis may be unnecessary. Solitary CRC BM is rare, meaning that the detection of another CRC metastasis should prompt imaging to search for CRC. Patients of higher socioeconomic status who develop CRC BM generally fare better. Based on current evidence that time of BM detection does not affect prognosis, these disparities seem to reflect unequal access to treatment, not screening. Molecular markers in primary CRC tumors such as KRAS and HER2 mutations are also associated with CRC BM, which may be another indication to image for BM when found in a primary CRC tumor. Future technologies such as cell-free tumor DNA may provide less invasive methods to monitor for CRC BM. Because the current data are largely retrospective with a small sample size, it is difficult to decide the appropriate course of action when a patient is diagnosed with CRC BM. Most of the current literature on CRC BM in our screening was biased by sample size, selection bias, and confounding. Prospective studies using cell-free tumor DNA or the presence of CRC BM molecular markers as tools to prompt further screening, such as increased frequency of head imaging, could provide evidence-based tools for earlier recognition of CRC BM.

Treatment of CRC BM is multi-faceted, with tumors less than 3 cm to 4 cm currently being treated with SABR. Larger tumors are surgically resected and treated with WBRT, which can also be used palliatively. The optimal combination and indications for radiotherapy and surgery are yet to be discovered, as high-quality randomized controlled trials addressing this question are rare. Performance scores can be used to predict prognosis and guide plans for treatment. Chemotherapy for CRC BM is often targeted at the primary tumor, as many chemotherapies cannot cross the blood-brain barrier. However, future advances in technologies such as nanoparticles for chemotherapeutic delivery could allow targeted treatment of tumors with known target mutations with therapeutic options such as KRAS and HER2[152]. Because of the rarity of CRC BM, the majority of articles found in our search were retrospective and based on a small number of patients, which makes it difficult to make conclusions on the optimal treatment of CRC BM. Discrepancies in reported prognoses for certain genetic factors, such as KRAS mutations, are likely due to methodological limitations, including biased sample selection and inadequate study size. The retrospective nature of this evidence also means that conclusions of causality are impossible to make. More prospective studies following the development of BM after CRC diagnosis stratified by tumor mutations would provide better evidence on whether these mutations affect patient outcomes. More basic science research is needed to explore why BM from CRC are less likely than tumors of other organs such as the breast and lung[155], and how CRC BM are mediated by the gut-brain axis[156]. Other directions of future research to improve outcomes in CRC BM include prospective studies on specific mutations found in CRC BM to better individualize prognosis and trials of immunotherapies targeting KRAS and HER2 to determine if they decrease the incidence of CRC BM.

CONCLUSION

BM from CRC remain rare but increasingly recognized due to improved overall survival from primary disease. Prognosis is influenced by socioeconomoic status tumor burden, performance status, and emerging molecular markers. Stereotactic radiotherapy and surgical resection provide favorable outcomes for select patients, whereas chemotherapy and immunotherapy remain areas of limited evidence. Additional prospective studies are needed to develop better tools to predict the incidence and prognosis of CRC BM and targeted chemotherapies. Better treatments for CRC BM require new chemotherapy drugs that can effectively penetrate the blood-brain barrier. Continued research is also needed to identify high-risk patients and optimize multidisciplinary treatment approaches.