INTRODUCTION — Metastases are the most common intracranial tumors in adults, accounting for more than one-half of all intracranial tumors. The primary approaches to the treatment of brain metastases include surgery, stereotactic radiosurgery (SRS), and whole brain radiation therapy (WBRT).
Treatment of brain metastases has become increasingly individualized as surgical and radiosurgical techniques have evolved over the past several decades, and as improved systemic therapies have begun to offer greater potential for both systemic and intracranial disease control for certain cancer types and genotypes.
While WBRT remains a primary treatment modality for many patients with a high intracranial tumor burden, the routine role of WBRT as adjunctive therapy in patients who are candidates for SRS or surgical resection has evolved as randomized trials have shown that despite improved rates of intracranial disease control, adjunctive WBRT does not improve overall survival and may decrease quality of life due to side effects and neurocognitive decline. The role of prophylactic cranial irradiation in patients with small cell lung cancer (SCLC) is reviewed separately. (See "Prophylactic cranial irradiation for patients with small cell lung cancer".)
The etiology, clinical manifestations, and diagnosis of brain metastases are discussed elsewhere. Management of brain metastases in patients with melanoma, breast cancer, and non-small cell lung cancer (NSCLC) are also reviewed separately. (See "Epidemiology, clinical manifestations, and diagnosis of brain metastases" and "Brain metastases in breast cancer" and "Management of brain metastases in melanoma" and "Brain metastases in non-small cell lung cancer".)
PROGNOSTIC ASSESSMENT — Survival of patients with brain metastases has improved since the era when whole brain radiation therapy (WBRT) was the mainstay of treatment and median overall survival was routinely less than six months [1-3]. Based on contemporary data, median survival exceeds six months for all major cancer types and ranges from approximately 8 to 16 months, depending on the primary tumor [4,5].
While performance status (table 1), extent of extracranial disease, and age remain important prognostic factors, historical models such as the recursive partitioning analysis (RPA) (table 2) [6] are no longer adequate to predict survival on an individual patient basis. Prognostic assessment is increasingly individualized by cancer type and molecular genetic diagnosis.
The diagnosis-specific graded prognostic assessment (GPA) was originally developed based upon an analysis of nearly 4000 patients with newly diagnosed brain metastases treated between 1985 and 2007 [7,8]. In 2020, it was updated based on nearly 7000 patients diagnosed between 2006 and 2017 at multiple centers [5]. For each major cancer type, components of the model were derived and validated separately, resulting in good separation among four GPA risk groups for each cancer type. Subsequent updates are incorporated into a publicly available online calculator.
Elements of the GPA score and median survival by GPA group are as follows [5]:
●Lung adenocarcinoma – Karnofsky Performance Status (KPS), age, presence of extracranial metastases (ECM), number of brain metastases, and epidermal growth factor receptor (EGFR) mutation and ALK gene fusion status; median survival 7, 13, 25, and 46 months for GPA groups 1 to 4, respectively (15 months overall). In a subsequent study, programmed cell death ligand 1 (PD-L1) positivity (in the primary lung tumor) was identified as an additional factor associated with improved survival [9]. With PD-L1 status included as a variable, median survival estimates for GPA groups 1 to 4 were 6, 15, 30, and 52 months, respectively (17 months overall).
●Lung nonadenocarcinoma – KPS, age, ECM, and number of brain metastases; median survival 5, 10, and 13 months for GPA groups 1 to 3, respectively (9 months overall). Revised estimates from a larger patient cohort stratified into four GPA groups predict median survival of 2, 5, 10, and 19 months for GPA groups 1 to 4, respectively (eight months overall) [9].
●Small cell lung cancer – KPS, age, ECM, and number of brain metastases; median survival 4, 8, 13, and 23 months for GPA groups 1 to 4, respectively (10 months overall).
●Breast cancer – KPS, age, ECM, number of brain metastases, and subtype (basal, luminal A, human epidermal growth factor receptor 2 [HER2], or luminal B) (table 3); median survival 6, 13, 24, and 36 months for GPA groups 1 to 4, respectively (16 months overall).
●Melanoma – KPS, age, ECM, number of brain metastases, and BRAF mutation status (table 4); median survival 5, 8, 16, and 34 months for GPA groups 1 to 4, respectively (10 months overall).
●Renal cell carcinoma – KPS, ECM, number of brain metastases, and hemoglobin (table 5); median survival 4, 12, 17, and 35 months for GPA groups 1 to 4, respectively (12 months overall).
●Gastrointestinal cancers – KPS, age, ECM, and number of brain metastases (table 6); median survival 3, 7, 11, and 17 months for GPA groups 1 to 4, respectively (8 months overall).
SYMPTOM MANAGEMENT — Treatment of patients with brain metastases is similar to the approach used in those with primary brain tumors. Key components include the control of peritumoral edema and increased intracranial pressure with glucocorticoids (algorithm 1), the treatment of seizures, and the management of venous thromboembolic disease. These issues are discussed elsewhere. (See "Management of vasogenic edema in patients with primary and metastatic brain tumors" and "Seizures in patients with primary and metastatic brain tumors" and "Treatment and prevention of venous thromboembolism in patients with brain tumors".)
PATIENTS WITH GOOD PERFORMANCE STATUS — The goals of therapy in patients with a good performance status are to achieve durable control of central nervous system disease, minimize early and late adverse effects of therapy, and maintain quality of life. The selection of initial local therapy depends largely on the number, location, and size of brain metastases.
The approaches outlined below are generally consistent with consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) and joint guidelines from the American Society of Clinical Oncology, the Society for Neuro-Oncology, and the American Society for Radiation Oncology [10-14].
Role of underlying histology and systemic therapy — As improved systemic therapies have begun to offer greater potential for both systemic and intracranial disease control for certain cancer types and genotypes, the management of brain metastases has become increasingly multidisciplinary and individualized [11,14]. While surgery and radiation remain the mainstays of treatment in most patients, all therapies should be considered in the context of the underlying histology, systemic disease status, and availability of systemic therapies with potential for intracranial disease control.
In particular, patients with brain metastases from melanoma, breast cancer, certain genotypes of non-small cell lung cancer (NSCLC; eg, activating mutations in the EGFR gene, translocations in the ALK gene), and renal cell carcinoma are optimally treated in a multidisciplinary fashion. Such patients may be candidates for early use of systemic therapies with central nervous system (CNS) activity as well as for clinical trials of novel or existing systemic therapies. Care of these patients is discussed in more detail in the following topics:
●Patients with melanoma (see "Management of brain metastases in melanoma")
●Patients with breast cancer (see "Brain metastases in breast cancer")
●Patients with EGFR-mutant NSCLC (see "Brain metastases in non-small cell lung cancer", section on 'Patients with oncogenic drivers')
●Patients with ALK fusion oncogene positive NSCLC (see "Brain metastases in non-small cell lung cancer", section on 'ALK translocations')
●Patients with renal cell carcinoma (see "Overview of the treatment of renal cell carcinoma", section on 'Brain metastases, treatment naïve')
Single brain metastasis — Important factors to consider in patients presenting with a single brain mass suspected to be a metastatic tumor include tumor size and location, degree of mass effect and edema, presence or absence of symptoms, functional status and extent of systemic disease, and patient preferences with regard to invasive therapy.
Confidence in the diagnosis of metastasis versus an alternative etiology, such as a malignant primary brain tumor, abscess, or subacute infarction, also influences decision making. In the randomized trial that first showed a survival advantage to surgical resection plus whole brain radiation therapy (WBRT) over biopsy plus WBRT for single brain metastases, 11 percent of screened patients had an alternative diagnosis at the time of biopsy [15].
Large tumor or diagnostic uncertainty — For patients with a single, surgically accessible metastasis that is large or associated with significant edema and mass effect, surgical resection achieves rapid symptom relief and local control. In carefully selected patients, resection has been shown to improve survival and decrease the risk of neurologic death compared with a radiation-alone approach. (See 'Efficacy of surgery' below.)
Surgery is also favored for single lesions when there is uncertainty regarding the histologic diagnosis, either based on clinical grounds (eg, cancer history is remote, primary tumor is not known to be metastatic or rarely spreads to brain) or radiographic findings (eg, prominent diffusion restriction raising suspicion for abscess or heterogenous, irregularly shaped centrally necrotic mass lesion suggestive of malignant glioma). For such lesions that are surgically inaccessible, stereotactic biopsy may be indicated to guide further therapy. (See "Epidemiology, clinical manifestations, and diagnosis of brain metastases", section on 'Diagnosis'.)
Efficacy of surgery — Advances in neuroanesthesia and neurosurgery have significantly improved the safety of surgical resection of brain metastases, making this approach applicable to a larger number of patients, including lesions in both eloquent and noneloquent regions of the brain [16,17].
Three randomized clinical trials have compared surgery plus WBRT with WBRT alone in patients with single brain metastases. Two of these demonstrated a survival benefit and provided an indication of those patients who can benefit from this combined approach [15,18,19]:
●In the first trial, 48 patients with a single brain metastasis were treated with either surgical resection followed by WBRT or WBRT alone [15]. Patients whose treatment included surgery had significantly fewer local recurrences (20 versus 52 percent), significantly improved survival (40 versus 15 weeks), and had a better quality of life. Factors that correlated significantly with increased survival in addition to surgical treatment were the absence of extracranial disease, longer time to the development of the brain metastasis, and younger age.
●In the second trial of 63 patients with a single brain metastasis, the overall survival with surgery and WBRT was significantly longer (10 versus 6 months), and patients remained functionally independent for a longer period [18,19]. The benefit from surgery was seen primarily in patients with stable extracranial disease (median survival 12 months). Patients with active extracranial disease had a median survival of only five months and did not appear to benefit from surgery. Survival was shorter in patients older than 60 years of age compared with younger patients.
Although the third trial did not show improved outcomes, a survival benefit in favorable prognosis patients may have been missed because patients with a lower Karnofsky Performance Status (KPS) at baseline (table 2) were included and a higher proportion of cases had extracranial disease [20,21].
In patients treated with surgery, postoperative radiation is generally indicated to improve local control. (See 'Postoperative radiation' below.)
Risks and complications — The major risks associated with surgical resection include postoperative neurologic worsening, infection, intracranial hemorrhage, and perioperative stroke [17,22]. Nevertheless, hospitalization time tends to be relatively short (less than five days), and one-month neurologic outcomes are either stable or improved in approximately 90 percent of patients [22]. The risk of permanent paresis with surgery is estimated to be approximately 8 to 9 percent [17,23]. Risk factors for postoperative weakness in one study included preoperative chemotherapy or radiation therapy and recursive partitioning analysis (RPA) class III [23].
Patients with brain metastases who undergo a neurosurgical procedure are often placed on a prophylactic antiseizure medication in the perioperative period. Patients who remain seizure free can then be tapered off the antiseizure medication, typically after the first postoperative week. The risk of seizures and the use of perioperative antiseizure medications is discussed elsewhere. (See "Seizures in patients with primary and metastatic brain tumors", section on 'Postoperative prophylaxis'.)
Postoperative radiation — Patients who undergo surgical resection of a single brain metastasis have a 50 to 60 percent risk of local recurrence at the surgical site within the next 6 to 12 months [24-26]. Postoperative WBRT reduces the risk of both local and distant failure at other sites in the brain by more than half but does not improve overall survival [24]; in addition, WBRT is associated with fatigue, alopecia, and an increased risk of neurocognitive impairment that may reduce quality of life. (See 'Role of adjunctive WBRT' below.)
Stereotactic radiosurgery (SRS) to the surgical cavity has become the preferred alternative to postoperative WBRT in most patients who undergo resection of a brain metastasis and have either no other lesions or a limited number, which are all amenable to SRS. This practice is supported by observational studies [27-38] as well as two randomized trials showing that postoperative SRS decreases the risk of neurocognitive decline compared with WBRT [39] and improves local control compared with observation [26].
●In a multicenter cooperative group trial, 194 patients with resected brain metastases were randomly assigned to postoperative SRS (12 to 20 Gy in a single fraction depending on cavity volume) or WBRT (30 Gy in 10 fractions or 37.5 Gy in 15 fractions) [39]. At six months, patients assigned to SRS had a lower risk of cognitive deterioration compared with those who were assigned to WBRT (52 versus 85 percent) and similar median overall survival (12.2 versus 11.6 months). Notably, SRS was associated with worse rates of surgical site control (80 versus 87 percent at 6 months and 61 versus 81 percent at 12 months) as well as overall intracranial control (55 versus 81 percent at 6 months and 41 versus 81 percent at 12 months) compared with WBRT [39,40]. One possible explanation for the relatively high rate of surgical site recurrence after SRS seen in this trial is that 40 percent of cavities were wider than 3 cm and thereby received a lower single fraction dose, which may have been insufficient to control microscopic disease [41].
●A second randomized single-center trial compared postoperative SRS (12 to 16 Gy in a single fraction) with observation in 132 patients who underwent complete resection of one to three brain metastases [26]. With a median follow-up of 11 months, local control rates were higher for SRS compared with observation (85 versus 66 percent at 6 months and 72 versus 43 percent at 12 months), and median overall survival was similar (17 versus 18 months). In patients treated with SRS, the most important risk factor for local recurrence was preoperative tumor diameter >2.5 cm.
Dose and fractionation of focal radiation is tailored based on factors such as size of the cavity, location, and underlying histology. Single fraction SRS can be used for small cavities (eg, <3 cm in diameter), whereas multiple fraction (hypofractionated) SRS may offer better local control rates for larger cavities and preoperative tumor size >2.5 cm while minimizing the risk of radiation necrosis [42-44]. Low-dose cesium-131 cavitary brachytherapy is also being explored as a potential alternative to SRS for large resected metastases [45,46]. (See 'Complications of SRS' below.)
The risk of distant recurrence in the brain (outside the postoperative SRS field) remains unaddressed by focal radiation, and brain magnetic resonance imaging (MRI) should be performed every two to three months after completion of radiation to monitor for recurrent disease. In the trials reviewed above, the rate of salvage WBRT in patients treated with SRS alone ranged from 20 to 38 percent [26,39]. The rate of salvage radiation is much higher when radiation is deferred entirely after resection (65 percent in one trial, with a median time to progression of only four months after surgery) [47]. (See 'Surveillance after initial therapy' below and 'Recurrent disease' below.)
Small or inaccessible tumor — SRS is a reasonable alternative to surgery or WBRT for small tumors that are not surgically accessible. Of note, neurotoxicity and local failure after SRS increase with increasing lesion size, and thus consideration of SRS rather than surgery should generally be limited to lesions with a diameter of 3 cm or less. (See 'Limited number of tumors, all <3 cm' below.)
For patients with single brain metastases who are equally appropriate candidates for surgery and SRS, the choice should be individualized. No adequately powered randomized trials have been completed comparing SRS alone with surgery plus postoperative radiation [48].
Much of the comparative data supporting the use of SRS for single brain metastases have come from reports in which SRS was used in conjunction with WBRT. Only observational studies, which are of limited value as they may be biased by how patients were assigned to surgery or SRS, are available. Examples include the following:
●In one report, 122 patients with a single metastasis of nonradiosensitive histology were treated with WBRT (median 37.5 Gy) followed by a SRS boost (median 17 Gy) [49]. The overall local control rate was 86 percent with an actuarial median survival of 56 weeks. These results are similar to the surgery plus WBRT arms of two randomized trials and significantly better than the WBRT alone arms in these trials [15,18,19].
●Two other studies, with very few patients treated with SRS, compared the outcomes with those treated with surgery with conflicting results: one suggested no difference in the rate of recurrence [50] and the other suggested better outcomes with surgery [51].
As in other patients with a limited number of brain metastases, we defer adjunctive WBRT in most patients who receive SRS for a single brain metastasis, with the rationale that most patients value the avoidance of early and late side effects from WBRT more highly than avoidance of recurrent brain metastases, which can often be treated effectively with repeat SRS or delayed WBRT. (See 'Role of adjunctive WBRT' below and 'Recurrent disease' below.)
Multiple brain metastases — The approach to patients with multiple brain metastases has evolved over the last decade, particularly for patients with a limited number of tumors, as SRS has become more widely available and as more effective systemic therapies have become available for certain cancer types that may improve both systemic and intracranial disease control.
Limited number of tumors, all <3 cm — Convergent data from multiple randomized trials support the use of SRS alone in the initial management of patients with a limited number of brain metastases that are appropriate targets for SRS (ie, <3 cm in diameter).
There is no consensus on what defines a limited number in this context, and expert groups vary [10,52-55]. We and others recommend SRS alone as initial therapy for up to four brain metastases, based on randomized trial data [11,25,56-60]. We also suggest SRS alone in most patients with 5 to 10 brain metastases, based on prospective, nonrandomized evidence of safety [56]. (See 'Efficacy of SRS alone' below.)
While initial trials supporting the efficacy and safety of SRS for up to four brain metastases utilized WBRT in both treatment arms [57,61], subsequent trials then studied SRS plus WBRT versus SRS alone in this patient group [25,58,60,62]. These trials found that although adjunctive WBRT reduces the relative risk of intracranial disease progression by approximately 50 percent compared with SRS alone, it does not extend overall survival and is associated with increased risk of side effects, including neurocognitive decline [59,60,62]. (See 'Role of adjunctive WBRT' below.)
Efficacy of SRS alone — SRS delivers single or very limited number of high doses to a radiographically discrete treatment volume by using multiple convergent beams. This results in a rapid fall-off of dose at the edge of the target volume and a clinically insignificant dose to adjacent normal tissue. High-energy x-rays produced by linear accelerators, gamma rays from the Gamma Knife, and less frequently, charged particles such as protons produced by cyclotrons have all been utilized. (See "Stereotactic cranial radiosurgery".)
SRS can treat deep-seated lesions or lesions near eloquent brain structures that are not amenable to surgical resection [63-65]. SRS is often given as a single high dose of radiation, but may also be given over two to five medium-dose fractions (ie, "hypofractionation") for targets that are larger-sized or near critical normal tissues such as the brainstem or the optic apparatus [66-68].
In controlled studies in patients with tumors up to 3 cm in diameter, SRS produces local control rates of approximately 70 percent at one year following treatment [25,58,62]. Although traditionally used to treat a limited number of tumors, prospective nonrandomized data in patients with newly diagnosed brain metastases suggest that up to 10 tumors with a total cumulative volume ≤15 mL may be treated in a single session with similar efficacy and no increase in toxicity [56,69].
Factors that influence tumor control include both the dose of radiation and the tumor volume [70,71]. As an example, multivariate analysis of results from the treatment of 80 patients with 126 lesions revealed that the minimum tumor dose was the only significant factor determining whether or not relapse would occur (local control rates for ≥14 Gy versus <14 Gy were 90 and <50 percent, respectively) [70]. In other large retrospective studies, lesion phenotype is an additional factor that independently influences tumor control, with cystic and necrotic tumors more likely to relapse than solid tumors [71,72].
In contrast with WBRT, the efficacy of SRS appears to be independent of the primary tumor type. Relatively radioresistant histologies (eg, renal cell carcinoma [73-75], melanoma [49,76]) have control rates similar to relatively radiosensitive tumor types such as breast cancer and NSCLC [77-81]. The radiobiology of SRS is discussed separately. (See "Stereotactic cranial radiosurgery", section on 'Radiobiology'.)
Recurrence rates after SRS alone — When patients are treated with SRS alone, new or recurrent brain metastases develop in approximately 25 to 50 percent of patients within the first 6 to 12 months [82-86]. Risk factors for early recurrence after SRS alone include the presence of progressive or widespread systemic disease, increased number of brain metastases, and certain tumor histologies and subtypes (eg, triple negative breast cancer, melanoma).
In a retrospective study of 464 patients with brain metastases treated with SRS alone as primary therapy, the median time to distant brain failure was 4.9 months; 27 percent of patients received salvage WBRT at a median of 5.6 months from initial therapy [82]. Time to salvage WBRT was longest for patients with human epidermal growth factor receptor 2 (HER2) positive breast cancer (9.5 months) and shortest for those with poorly differentiated lung cancer (3 months) and melanoma (3.3 months). A larger retrospective study used these and other pretreatment risk factors to generate a nomogram for prediction of 6- and 12-month WBRT-free survival probability after treatment with SRS alone which may prove useful in counseling patients [84,87].
Patients treated with SRS alone should therefore be followed closely with serial imaging, with the goal of detecting new disease early to allow for effective salvage therapy. (See 'Surveillance after initial therapy' below and 'Recurrent disease' below.)
Complications of SRS — Acute neurologic symptoms from SRS may be due to transient swelling that begins 12 to 48 hours after therapy. Symptoms can include mild nausea, dizziness or vertigo, seizures, or new headache. A short course of steroids around the time of radiosurgery may be useful to prevent or minimize acute SRS-related toxicity. (See "Acute complications of cranial irradiation", section on 'Stereotactic radiosurgery'.)
The most common delayed complication of SRS for treatment of brain metastases is radiation necrosis, which occurs in approximately 10 percent of treated tumors anywhere from six months to several years after treatment [25,64,88-91]. Reported rates of radiation necrosis after postoperative SRS range from 4 to 18 percent [27,29,35,37].
The two most important risk factors for radiation necrosis in patients with brain metastases are prior radiation (either SRS or WBRT) to the same lesion and lesion size (with larger tumor volumes associated with higher risk). For tumors treated with prior SRS, the risk of symptomatic adverse radiation effects may be as high as 20 percent within 12 months of retreatment [90]. Use of hypofractionated rather than single fraction SRS for tumors >2 cm may decrease the risk of radiation necrosis [67,68].
Targeted therapy and immunotherapy may also increase the risk of radiation necrosis [92-97]. Most of the evidence consists of case series and retrospective studies, and the role, if any, of sequence and timing of therapy in relation to SRS is not well understood [98]. In a retrospective study of 180 patients who underwent SRS for brain metastases over a six-year period, 22 percent developed treatment-related imaging changes or biopsy-proven necrosis at a median 9.5 months after SRS [92]. The risk was higher in patients receiving immunotherapy (38 percent) or targeted therapy (25 percent) compared with cytotoxic chemotherapy (17 percent). A larger observational study found that the risk of radiation necrosis after SRS was 2.5-fold higher in patients who had received immunotherapy, independent of underlying histology [95]. In a separate study of 137 patients with melanoma brain metastases, all of whom received immunotherapy (mostly ipilimumab), the rate of radiation necrosis was 27 percent at a median of six months after SRS [93]. (See "Management of brain metastases in melanoma".)
Patients with radiation necrosis may be asymptomatic (approximately 50 percent) or present with focal neurologic signs and symptoms related to cerebral edema. Imaging typically shows increased enhancement at the site of prior SRS accompanied by surrounding edema. Treatment is largely symptomatic with corticosteroids. Resection may be required or bevacizumab may be useful in severe cases or in those patients who have become steroid dependent. (See "Delayed complications of cranial irradiation", section on 'Brain tissue necrosis'.)
The long-term effects of SRS on neurocognition have not been well studied, but the available data are reassuring [69]. Radiographically, periventricular and subcortical white matter changes (ie, leukoencephalopathy) do accumulate in patients treated with SRS alone, although at a lower rate than is seen after WBRT. In one study that included 92 patients treated with SRS and other therapies and followed over a median of 40 months, the prevalence of leukoencephalopathy of any grade was 42, 60, 73, and 84 percent at one, two, three, and four years after SRS [99]. Although patients who received WBRT (25 percent of the cohort) were at higher risk, the changes also accrued in patients treated with SRS alone. Additional risk factors included higher number of treated tumors and higher integral SRS dose to the skull. The clinical significance of these changes is not yet known.
Role of adjunctive WBRT — The role of adjunctive WBRT in patients with a limited number of brain metastases who are eligible for treatment with SRS to all lesions has evolved over time. While it was once considered standard of care, experts have increasingly favored a more individualized approach as accumulating data from randomized trials have found that improvements in intracranial disease control are often offset by side effects, and that omission does not sacrifice overall survival [25,58-60,62,100-102].
The lack of benefit on overall survival may be due to competing risks of death from other causes and possibly the availability of more effective salvage options, including repeat SRS and in some cases, more effective systemic therapies. Examples of diseases in which systemic therapies now exist that have comparable extracranial and intracranial response rates include melanoma and certain subtypes of NSCLC (eg, those with EGFR mutations or ALK translocation). (See "Management of brain metastases in melanoma" and "Brain metastases in non-small cell lung cancer", section on 'Patients with oncogenic drivers'.)
A 2014 meta-analysis that included five randomized trials (663 patients) found that the addition of WBRT to SRS or surgery decreased the relative risk of intracranial disease progression at one year by 53 percent (risk ratio [RR] 0.47, 95% CI 0.34-0.66) but did not improve overall survival (hazard ratio [HR] 1.11, 95% CI 0.83-1.48) [59].
In the largest individual trial, 359 patients with one to three brain metastases were randomly assigned to WBRT or observation following definitive treatment of their metastases with either SRS (n = 199) or surgery (n = 160) [25]. Key results of this trial included the following:
●WBRT following definitive therapy significantly decreased the rate of relapse at two years at the initial site compared with observation (59 versus 27 percent in those initially treated with surgery, and 31 versus 19 percent in those initially managed with SRS). WBRT also decreased the rate of relapse at new sites (42 versus 23 percent following initial surgery and 48 versus 33 percent following SRS).
●Global health-related quality of life scores in the subset of patients who completed baseline and follow-up questionnaires (45 percent of participants still alive at 12 months) were better in the observation arm at nine months but similar to the WBRT arm at one year [103]. Scores in several other domains (eg, physical functioning, fatigue) were also better in the observation arm at early time points but similar at one year. Formal neurocognitive testing was not performed.
●There was no significant difference in overall survival (median 10.9 and 10.7 months with WBRT and observation, respectively).
Concerns that WBRT might impair cognitive function and quality of life were also raised by a small randomized trial that found that adding WBRT to SRS alone increased the likelihood of a decline in learning and memory function compared with treatment with SRS alone [60].
These effects were corroborated by a larger randomized trial conducted by the North Central Cancer Treatment Group (Alliance) [62]. In this trial, 213 patients with one to three brain metastases (68 percent lung primary) were randomly assigned to SRS plus WBRT or SRS alone. Cognitive deterioration, defined as a decline >1 standard deviation (SD) from baseline in any of six cognitive tests at three months, was more likely in the WBRT plus SRS group (92 versus 64 percent). Similar to other trials, the addition of WBRT improved intracranial tumor control rates compared with SRS alone (88 versus 65 percent at 6 months; 85 versus 50 percent at 12 months) but did not improve overall survival (HR 1.02, 95% CI 0.75-1.38). A subsequent trial in surgical patients also found worse cognitive outcomes with WBRT versus SRS and no difference in overall survival [39]. (See 'Postoperative radiation' above and "Delayed complications of cranial irradiation", section on 'Neurocognitive effects'.)
High tumor burden or multiple large tumors — In most patients with a very high overall tumor burden, including those with multiple, large tumors, WBRT remains the standard approach to initial treatment. Occasional patients with innumerable metastases but a single large, dominant mass may benefit from surgical resection of the dominant mass prior to radiation therapy. (See 'Large tumor or diagnostic uncertainty' above.)
Initial systemic therapy with deferred radiation and close brain surveillance is increasingly an alternative to initial radiation therapy in carefully selected patients, especially those with melanoma and NSCLC with an oncogenic driver mutation. (See "Management of brain metastases in melanoma" and "Brain metastases in non-small cell lung cancer", section on 'Patients with oncogenic drivers'.)
Efficacy of WBRT — The main goal of WBRT in patients with a good performance status who are not eligible for SRS or surgery is to improve neurologic deficits caused by the metastases and surrounding edema and to prevent any further deterioration of neurologic function. In randomized trials composed primarily of patients with NSCLC and breast cancer, the median survival in patients treated with WBRT ranges from four to six months [1-3].
The use of WBRT is associated with an overall response rate of approximately 40 to 60 percent [1,2]. Radiographic responses are more common in patients with breast cancer and small cell lung cancer (SCLC), and relatively less common in patients with histologies such as melanoma or renal cell carcinoma [104]. Small, solid tumors are more likely to respond than large, necrotic or cystic tumors.
Rates of neurologic improvement with WBRT are generally less favorable, with approximately 25 to 40 percent of patients achieving stable or improved symptoms after WBRT [2,3,57].
Hippocampal avoidance and memantine — For most patients who require WBRT, both memantine and hippocampal avoidance intensity-modulated radiation therapy (IMRT) are suggested to help prevent cognitive decline [11]. Patients with metastases within 5 mm of the hippocampi should receive conventional WBRT. We use a slow up-titration of memantine, beginning at 5 mg daily with initiation of WBRT and increasing once a week by 5 mg to reach a target dose of 10 mg twice daily. Memantine is continued for up to six months after completion of WBRT. These strategies are reviewed separately. (See "Delayed complications of cranial irradiation", section on 'Prevention'.)
Dose and fractionation — The most commonly used regimen is a total dose of 30 Gy in 10 daily fractions of 3 Gy. The decision in an individual case depends upon the severity of neurologic symptoms, the extent of systemic disease, and clinician preference.
The dose and fractionation schedule should take into account the overall clinical status of the patient to maximize symptom palliation and minimize the risk of long-term complications. For patients with a relatively poor prognosis, we use 30 Gy in 3 Gy daily fractions. By contrast, those with a more favorable prognosis may be treated with prolonged fractionation to decrease the likelihood of late CNS toxicity. In these patients, we prefer a higher total dose in smaller fractions (eg, 40 to 45 Gy in 1.8 to 2.0 Gy daily fractions).
Studies exploring the use of ultrarapid fractionation schedules [105], dose escalation in favorable prognosis subgroups [106], accelerated fractionation [107], and the use of radiosensitizers [108-110] failed to show any benefit over conventional radiation therapy [102].
Early and delayed side effects — The most common acute side effects of WBRT are fatigue and alopecia. (See "Acute complications of cranial irradiation", section on 'Standard fractionated radiation therapy'.)
Cerebral edema may be induced or worsened after the initiation of WBRT. As a result, WBRT should be preceded by corticosteroid therapy for at least 48 hours if there is evidence of significant edema and mass effect, regardless of the dose and fractionation schedule. In these patients, corticosteroids should be continued throughout the course of radiation and then the dose decreased as tolerated. Patients with small metastases and no mass effect may not need corticosteroids. The recommended steroid regimen is presented separately. (See "Management of vasogenic edema in patients with primary and metastatic brain tumors", section on 'Dexamethasone dose and schedule'.)
Concurrent administration of targeted therapies such as EGFR inhibitors, trastuzumab-emtansine, and BRAF inhibitors during WBRT should generally be avoided based on their potential to increase toxicities, including cutaneous reactions [98,111,112]. (See "Management of brain metastases in melanoma", section on 'Radiation sensitization with BRAF inhibitors' and "Brain metastases in non-small cell lung cancer", section on 'Sequencing of TKI with local therapies' and "Brain metastases in breast cancer", section on 'Choosing between options'.)
Although most patients treated with WBRT for brain metastases have a limited survival, patients with longer survival may have debilitating late complications. These include the following:
●Leukoencephalopathy and brain atrophy, leading to neurocognitive deterioration and dementia
●Radiation necrosis, with symptoms related to the site of necrosis
●Normal pressure hydrocephalus, causing cognitive, gait and bladder dysfunction
●Neuroendocrine dysfunction, most commonly hypothyroidism
●Cerebrovascular disease
The risk for late complications is related to the total radiation dose, fraction size, patient age, extent of disease, and neurologic impairment at presentation. Delayed complications of WBRT are discussed in more detail elsewhere. (See "Delayed complications of cranial irradiation".)
PATIENTS WITH POOR PERFORMANCE STATUS — Aggressive treatment for brain metastases in patients with a poor prognosis and/or poor performance status generally is not warranted. For most of these patients, overall survival is more likely to be determined by the activity and extent of extracranial disease than by the success of treatment in controlling brain metastases. The decision to proceed with whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), or supportive care alone should be individualized based on symptoms, patient preferences, intracranial disease burden, and availability of additional systemic therapies.
WBRT has traditionally been the preferred approach if active treatment is indicated, but experience with SRS in this setting is growing. At least one study has suggested that aggressive treatment with SRS may be associated with improved survival when brain metastases are responsible for the poor performance status and are not accompanied by uncontrolled systemic disease [113].
In addition, there is a growing trend to use SRS instead of WBRT in poor prognosis patients with a limited number of lesions, since this can be accomplished in a one-day outpatient procedure instead of the multiple visits required for fractionated WBRT [114]. (See 'Limited number of tumors, all <3 cm' above.)
Although WBRT is generally thought to improve survival by several months compared with use of corticosteroids based on observational studies [108,115-117], there is a paucity of randomized trials that directly compared WBRT with supportive care alone in patients with a poor prognosis.
The only prospective data compiled to date are from the Medical Research Council trial comparing WBRT (20 Gy in 5 daily fractions) with best supportive care in patients with brain metastases from non-small cell lung cancer (NSCLC) not amenable to surgical resection or SRS [118]. The trial was designed to randomize over 1000 patients but had slower than expected accrual and ultimately enrolled 538 patients over a period of seven years. Overall survival was similar among patients assigned to WBRT versus optimal supportive care (9.2 versus 8.5 weeks). The primary outcome measure of mean quality-adjusted life-years was also similar (46 versus 42 days). It is not clear whether these results are generalizable to patients with histologies other than NSCLC; in addition, the short median overall survival in both treatment groups (approximately two months) compared with the WBRT control arm of other contemporary trials [1,2,57] suggests an enrollment bias towards patients with a poor perceived prognosis (40 percent of patients in the trial had a Karnofsky Performance Status [KPS] less than 70).
SURVEILLANCE AFTER INITIAL THERAPY — Brain metastases should be followed with brain magnetic resonance imaging (MRI) (or contrast-enhanced computed tomography [CT] if MRI is not possible) to detect early evidence of recurrence or new lesions, particularly when adjunctive whole brain radiation therapy (WBRT) has been omitted.
We typically reimage at one month after initial therapy and then repeat imaging every two to three months thereafter. The timing of ongoing central nervous system surveillance in patients who survive more than a year can be individualized based on clinical symptoms, status of systemic and intracranial disease control, and systemic therapies.
RECURRENT DISEASE — Up to 50 percent of surviving patients with brain metastases will develop new lesions or progression of previously treated lesions within six months to one year of initial therapy. Recurrent disease may be amenable to treatment with salvage stereotactic radiosurgery (SRS), surgery, or whole brain radiation therapy (WBRT), depending on the overall condition of the patient and the extent and location of the disease.
Lesions previously treated with SRS — In lesions previously treated with SRS, care must be taken to distinguish early recurrence from treatment effects, sometimes referred to as pseudoprogression. The spectrum of treatment effects ranges from an asymptomatic small increase in the amount of enhancement and edema surrounding a lesion that later regresses to biopsy-proven radiation necrosis. (See "Delayed complications of cranial irradiation", section on 'Brain tissue necrosis'.)
When in doubt, particularly for minimally symptomatic lesions, it is often best to follow radiographic changes conservatively with serial imaging at short intervals before committing a patient to further tumor-directed therapy. Biopsy is occasionally required to distinguish treatment effects from progressive tumor and guide further therapy. (See "Delayed complications of cranial irradiation", section on 'Diagnosis'.)
Additional radiation — SRS is increasingly used to treat new or recurrent tumors that arise after initial therapy in patients with a good performance status and stable extracranial disease [119-122]. Local control rates for previously untreated tumors are expected to be similar to those achieved with initial therapy. Risk factors for local failure include melanoma histology and increasing tumor size [120,123]. (See 'Efficacy of SRS alone' above.)
The dose and fractionation of SRS should be tailored to lesion size and prior therapies. The risk of radiation necrosis is higher in patients who have previously received WBRT or SRS to the target lesion. (See 'Complications of SRS' above.)
Retreatment with WBRT or partial brain reirradiation may provide some benefit for carefully selected patients who are not candidates for surgery or SRS [124]. There is no consensus on dose fractionation; dosing in small studies has ranged from 8 Gy in two weeks to 30.6 Gy in three weeks with a median of approximately 20 Gy in two weeks [124-127].
It is not known how early after the initial course of radiation therapy reirradiation can be administered. We suggest an interval of at least four to six months. Reirradiation is likely to exceed the brain's tolerance and may result in delayed toxicity if the patient survives long enough. However, the risk of symptomatic late radiation-induced neurotoxicity must be weighed against short-term symptom palliation in patients with a limited life expectancy.
Surgery — Surgical reresection is occasionally indicated for a dominant brain metastasis that recurs or progresses despite radiation therapy. This is typically only done when patients are symptomatic from the recurrent mass, have failed other therapies, and have systemic disease that is otherwise well controlled or absent.
Brachytherapy, which involves the local use of radiation in or near a tumor, through the implantation of radioactive sources directly into an intracerebral mass or surgical cavity, is occasionally used in conjunction with surgery for previously treated lesions [128-132]. Brachytherapy permits the delivery of higher radiation doses than can be achieved with external beam therapy, while limiting radiation to the surrounding brain.
Other local techniques, such as laser interstitial thermal therapy, are also under investigation for recurrent brain metastases as well as radiation necrosis [133,134].
Systemic therapy — The role of systemic therapy in the control of intracranial metastatic disease is evolving, as immunotherapy and targeted therapies have begun to offer greater potential for both systemic and intracranial disease control for certain cancer types.
Advances have been most apparent in melanoma and certain subtypes of non-small cell lung cancer (NSCLC; eg, those with EGFR mutations or ALK translocation). (See "Management of brain metastases in melanoma" and "Brain metastases in non-small cell lung cancer".)
In other patients, traditional cytotoxic agents occasionally result in meaningful, if temporary, responses in patients with recurrent or progressive brain metastases. (See "Brain metastases in breast cancer".)
DRIVING — The appropriate recommendations regarding driving or operating hazardous equipment in individuals with brain metastases who have not experienced a seizure is unclear.
In patients whose cognitive functions and detailed neurologic examination are essentially normal, there is no medical contraindication to driving. However, for patients with any neurologic deficit, reflexes may be slower and judgment may not be entirely normal. A formal driving evaluation may be useful if there is any question of slow reflexes or impaired judgment.
Driving by patients who have experienced a seizure is discussed separately. (See "Driving restrictions for patients with seizures and epilepsy".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Brain metastases (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Multidisciplinary care – Management of brain metastases has become increasingly individualized and multidisciplinary. While surgery and radiation remain the mainstays of treatment in most patients, all treatment decisions should be considered in the context of the patient's tumor type, systemic disease status, and availability of systemic therapies with potential for intracranial disease control. (See 'Role of underlying histology and systemic therapy' above.)
●Prognostic assessment – Performance status, age, extracranial disease burden, and underlying cancer histology and genotype are the most important prognostic factors in patients with brain metastases. Disease-specific prognostic tools are available online. (See 'Prognostic assessment' above.)
●Symptom management – Glucocorticoids are used to control symptomatic or extensive edema. Treatment for other tumor-related complications (eg, seizures, venous thromboembolic disease) may also be required. (See "Management of vasogenic edema in patients with primary and metastatic brain tumors" and "Seizures in patients with primary and metastatic brain tumors" and "Treatment and prevention of venous thromboembolism in patients with brain tumors".)
●Local therapy – In patients with a relatively favorable prognosis based on good performance status and limited burden of systemic disease, selection of local therapy is based on the number, size, and location of brain metastases, as well as consideration of the underlying cancer histology and available systemic therapies. In the absence of an effective systemic therapy option, our approach is as follows:
•Single brain metastasis – In patients with a single brain metastasis, we recommend surgical resection or stereotactic radiosurgery (SRS) rather than whole brain radiation therapy (WBRT) alone (Grade 1B). (See 'Single brain metastasis' above.)
Surgical resection is typically indicated for large, symptomatic tumors; tumors with extensive edema; and when there is diagnostic uncertainty. SRS is a reasonable alternative to surgery for small or inaccessible single tumors. (See 'Large tumor or diagnostic uncertainty' above and 'Small or inaccessible tumor' above.)
In most patients who undergo surgical resection, we suggest focal radiation to the surgical cavity (single or multiple fraction SRS) rather than adjunctive WBRT or observation (Grade 2B). (See 'Postoperative radiation' above.)
•Two to 10 brain metastases – In patients with two to four small brain metastases (<3 cm), we recommend SRS alone rather than SRS plus adjunctive WBRT or WBRT alone (Grade 1B). We also suggest SRS alone in most patients with 5 to 10 small brain metastases (Grade 2C). While WBRT improves intracranial disease control, it does not improve overall survival in this patient population and may decrease quality of life due to side effects and neurocognitive decline. (See 'Limited number of tumors, all <3 cm' above and 'Role of adjunctive WBRT' above.)
•Greater than 10 brain metastases – WBRT remains the mainstay of treatment for many good performance status patients who are not eligible for SRS or surgery due to a high a number of tumors or multiple bulky tumors and who do not have good systemic therapy options.
When patients are selected for WBRT, in order to decrease the risk of neurotoxicity, we recommend use of hippocampal avoidance intensity-modulated radiation therapy (IMRT) (Grade 1B); we also suggest use of memantine (Grade 2C). Patients with metastases within 5 mm of the hippocampi should receive conventional WBRT. Supporting evidence and administration are reviewed separately. (See "Delayed complications of cranial irradiation", section on 'Prevention'.)
●Patients with poor prognosis – In patients with a poor performance status or a relatively short life expectancy due to extracranial disease, the decision to proceed with WBRT, SRS, or supportive care alone should be individualized based on symptoms, patient preferences, intracranial disease burden, and availability of additional systemic therapies. (See 'Patients with poor performance status' above.)
