INTRODUCTION — Metastases are the most common intracranial tumor in adults, accounting for more than one-half of all intracranial tumors. The primary approaches to the treatment of brain metastases include whole brain radiation therapy (WBRT), surgery, and stereotactic radiosurgery (SRS). Although WBRT was the mainstay of treatment beginning in the 1970s, occasional long-term survivors were seen following surgical resection in patients without extracranial disease.

Analysis of large series of patients with brain metastases has identified those factors that predict a favorable response to treatment and improved survival. The key prognostic determinants and the management of patients with a favorable prognosis will be reviewed here.

FAVORABLE VERSUS POOR PROGNOSIS — The median survival of patients who receive supportive care and are treated only with corticosteroids is approximately one to two months. The use of WBRT in large series increased the average survival to three to six months, and larger gains were seen in carefully selected subsets

The key parameters that determine survival after the diagnosis of brain metastases are performance status, the extent of extracranial disease, and age. The importance of these factors in determining outcome was illustrated by the use of recursive partitioning analysis (RPA) to analyze prognostic factors in 1200 patients from three Radiation Therapy Oncology Group (RTOG) brain metastases trials.

Three prognostic classes were identified and the outcome correlated with median survival

• Class 1 — The best prognosis was seen in patients who had a Karnofsky performance score 70 or higher, were less than 65 years of age with a controlled primary tumor, and had no extracranial metastases. Median survival was 7.1 months. These patients are considered to have a favorable prognosis.

• Class 3 — Patients with a Karnofsky performance score less than 70 constituted the worst prognostic subset and had a median survival of 2.3 months. This group is considered to have a poor prognosis.

• Class 2 — This intermediate prognosis group included those with a Karnofsky performance score 70 or higher, but with other unfavorable characteristics. Median survival was 4.2 months.

These patients may be classified either as favorable or poor prognosis, depending largely upon the likelihood of controlling systemic disease.

These results were subsequently validated in another RTOG trial that included 445 patients with brain metastases. The median survival was 6.2 months for class 1 patients and 3.8 months for those in class 2.

In the original RTOG analysis, approximately 20, 65, and 15 percent of the patients were in classes 1, 2, and 3, respectively. Although the trials used for this analysis excluded patients with small cell lung cancer (SCLC), a subsequent analysis of 154 patients with brain metastases from SCLC has confirmed the validity of RPA in this population as well

TREATMENT OF FAVORABLE PROGNOSIS PATIENTS — On the basis of these results, patients in RPA class 1 and some of those in class 2 are considered to have a favorable prognosis. For these, aggressive treatment is indicated to eradicate a single or limited number of brain metastases.

Occasional patients will have a synchronous brain metastasis at their initial presentation, without other evidence of metastatic disease. If both the primary tumor and the brain metastasis can be successfully treated, the prognosis may be better than for other patients with disseminated disease

Advances in both neurosurgical techniques and SRS have made these approaches the preferred options:

• For patients with a single metastasis in a surgically accessible location, resection may offer the best opportunity for local control. Surgery is also used in some patients with a limited number of metastases.

• SRS is an effective alternative for local control if a metastasis is smaller than 3 cm in diameter, is in a surgically inaccessible location, or if the patient is not a candidate for surgery. SRS may be preferred over surgery in patients who have more than one small metastasis

• WBRT can be useful in conjunction with surgery or SRS to prevent local recurrence or the growth of small undetected intracranial metastases.

Some patients who present with disseminated metastatic disease may have asymptomatic, occult brain metastases detected with contemporary imaging techniques. Although initial therapy directed against the brain metastases remains the standard of care, initial systemic therapy followed by RT may be an alternative to RT followed by chemotherapy in carefully selected patients.

SURGERY — Surgery is used to provide rapid relief of symptoms resulting from the mass effect of a large tumor, to improve local control of brain metastases, and to establish a histologic diagnosis when a brain metastasis is suspected. 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

However, complications are not rare. In a series of 400 craniotomies patients with brain tumors (206 with gliomas and 194 with metastasectomy), 13 percent suffered major complications including neurologic worsening (8.5 percent) and meningitis (1 percent). In another series of 382 patients operated on for brain metastases, there was one death (respiratory, in a patient who had a previous pneumonectomy) and 27 other complications (7 percent). These included three cerebral hemorrhages and three cerebral infarcts.

The patient's performance status and the extent of extracranial disease are the most important factors in determining whether or not surgery is appropriate. Patients with extensive or uncontrolled systemic disease generally have a poor prognosis and only rarely benefit from surgery. Other factors affecting prognosis and hence the appropriateness of surgery include the number and location of brain metastases. A short interval between diagnosis of the primary tumor and the development of a brain metastasis is generally associated with a poor prognosis.

In patients treated with surgery, WBRT is often used postoperatively.

Efficacy — Initial recommendations for surgery were based upon anecdotal case reports and retrospective series with prolonged survival following resection of brain metastases, usually in patients without evidence of other intracranial or systemic disease.

The superiority of the combination of surgery plus WBRT compared to WBRT alone or surgery alone has been demonstrated in randomized trials.

Surgery plus WBRT versus WBRT alone — Three randomized clinical trials have compared surgery plus WBRT to WBRT alone. Two of these demonstrated a survival benefit and provided an indication of those patients who can benefit from this combined approach

• In the first trial, 48 patients with a single brain metastasis were treated with either surgical resection followed by WBRT or WBRT alone. Patients whose treatment included surgery had significantly fewer local recurrences (20 versus 52 percent), significantly improved survival (40 versus 15 weeks), and 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. 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 to 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 score at baseline were included and a higher proportion of cases had extracranial disease

Surgery plus WBRT versus surgery alone — The rationale of adding postoperative WBRT following surgery in patients with brain metastases is to eliminate residual cancer cells at the site of resection as well as elsewhere within the brain, thereby reducing the recurrence rate. Retrospective studies suggested that the addition of WBRT reduced the rate of recurrence and possibly prolonged survival

In a randomized multicenter trial, 95 patients who had undergone complete resection of a single brain metastasis were randomly assigned to either postoperative WBRT or observation. WBRT significantly decreased the incidence of relapse in the brain (18 versus 80 percent with observation), both at the site of original resection (10 versus 46 percent) and at remote sites (14 versus 37 percent). Patients receiving postoperative WBRT were less likely to die of neurologic causes (14 versus 44 percent), but there was no difference in overall survival or the duration of functional independence.

In some centers, surgery is followed by SRS to the tumor bed in the hope that whole brain radiation can be deferred. Local control was comparable to whole brain radiation. Such an approach might be particularly appropriate for patients with relatively radioresistant tumors.

Perioperative anticonvulsants — Patients with brain metastases who undergo a neurosurgical procedure are typically placed on anticonvulsants in the perioperative period. However, we recommend that anticonvulsants be tapered and discontinued after the first postoperative week in patients who have not had a seizure.

STEREOTACTIC RADIOSURGERY — SRS delivers a high single dose of radiation 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.

Metastases are usually small (less than 3 cm), radiographically discrete, lesions that do not infiltrate surrounding brain, making them ideal targets for SRS. Advantages of SRS compared to neurosurgical resection include the following:

• Ability to treat surgically inaccessible areas of the brain, such as the brainstem

• Noninvasiveness and suitability for outpatient treatment

• Ability to treat multiple lesions

• Cost-effectiveness compared to neurosurgical resection

Efficacy — An increasing number of uncontrolled studies suggest that SRS is at least as effective as surgery for the treatment of brain metastases in selected patients. SRS produces local control rates of 65 to 94 percent, although it is associated with a 5 to 10 percent risk of radiation necrosis

Treatment results from a series of 248 patients with 421 metastatic lesions illustrate the potential utility of SRS. With a median observation period of 26 months, 11 percent of lesions progressed within the radiosurgery volume. The actuarial one, two, and three-year local control rates were 85, 65, and 65 percent, respectively. The median survival for the whole group was 9.4 months, measured from the initial SRS treatment.

Factors that influence tumor control include both the dose of radiation and the tumor volume. 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).

In contrast to WBRT, the efficacy of SRS is independent of the primary tumor type. Relatively radioresistant histologies (eg, renal cell carcinoma and melanoma have control rates similar to radiosensitive tumor types.

The role of SRS has been compared with that of surgery through observational studies, suggesting similar levels of efficacy. Randomized trials have established the utility of this approach in conjunction with WBRT.

SRS versus surgery — Much of the comparative data supporting the use of SRS has come from reports in which SRS was used in conjunction with WBRT. No prospective randomized trials have been reported comparing SRS with or without WBRT to surgery. Only observational studies of limited value are available.

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). 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

Two other studies, with very few patients treated with SRS, compared the outcomes to those treated with surgery with conflicting results: one suggested no difference in the rate of recurrence and the other suggested better outcomes with surgery

Results from these retrospective studies may be biased by how patients were assigned to surgery or SRS. In the absence of a direct comparison, the choice of SRS over surgery in patients with brain metastases is usually based upon the size of a lesion, its surgical accessibility, symptoms, and the functional status of the patient.

For large lesions, surgery offers immediate decompression. In addition, neurotoxicity and local failure after treatment with SRS increase with increasing lesion size. Thus, consideration of SRS rather than surgery should be limited to lesions with a diameter of 3 cm or less.

SRS plus WBRT versus WBRT alone — The benefit of adding an SRS boost to WBRT has been shown in at least two randomized trials of 333 and 27 patients. In the much larger trial sponsored by the Radiation Therapy Oncology Group (RTOG), 333 patients with one to three brain metastases (maximum diameter 4 cm) were randomly assigned to WBRT with or without SRS The following findings were noted:

• Patients receiving SRS were significantly more likely to have a stable or improved performance status at six months (43 versus 27 percent).

• When the entire group was considered survival was similar with and without the SRS (6.5 and 5.7 months, respectively). However, survival was significantly longer with SRS in patients with a single brain metastasis (median survival time 6.5 versus 4.9 months) and in patients with favorable prognosis (ie, under the age of 65, Karnofsky performance score 70 or higher, a controlled primary tumor, and no extracranial metastases) (11.6 versus 9.6 months).

SRS plus WBRT versus SRS alone — The role of WBRT to prevent local recurrence and prevent the development of new metastases in patients treated with SRS has been evaluated in randomized and prospective clinical trials, and retrospective analyses of case series

In a Japanese trial, 132 patients with one to four brain metastases were randomly assigned to SRS plus WBRT or SRS alone. The patients who received the combination were significantly less likely to have a brain recurrence at 12 months (47 versus 76 percent, with SRS alone) and less likely to require retreatment (15 versus 43 percent). However, overall survival was not significantly different in the two groups (one year survival 7.5 versus 8.0 months), and death due to neurologic progression was similar in the two groups (23 versus 19 percent).

These findings were consistent with an evidence-based review by the American Society of Therapeutic Radiology and Oncology (ASTRO) that concluded that the addition of WBRT to SRS improved local tumor control but did not increase survival.

Summary — Although there is no consensus, we suggest combining SRS with WBRT for patients with a limited number of brain metastases based upon the findings in three randomized trials and the ASTRO report. While there appears to be no survival advantage from adding WBRT to SRS for patients with brain metastases, the combination clearly reduces recurrence rates within the brain and the need for further treatment.

WBRT might be withheld in carefully selected patients with a single brain metastasis, when the development of additional brain lesions is less likely. The patient can be retreated if there is a new metastasis or a recurrence. This approach may avoid the long-term toxicity of WBRT in patients with a prolonged survival.

Tumor histology — The delivery of a single large fraction of radiation with SRS circumvents the relative radioresistance seen in certain tumor types (eg, renal cell carcinoma, melanoma, sarcoma) with the fractionated schedules that are required for WBRT.

As an example, the effectiveness of SRS in patients with brain metastases from renal cell carcinoma was illustrated in an observational study of 86 patients with 376 brain metastases who were treated with SRS The local tumor control rate was 94 percent, and the median survival was 11 months after treatment, with most patients dying of progressive systemic disease.

Similar results have been reported in patients with brain metastases from radiosensitive tumors such as non-small cell lung cancer and breast cancer. As an example, in one series of 504 patients with non-small cell lung cancer, 835 metastases were treated using SRS. The one-year local control rate for the treated lesions was 94 percent, and the median survival was 15 months

Complications — 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.

RADIATION THERAPY — As discussed above, WBRT is frequently used in conjunction with surgery and with SRS to prevent local recurrence or the development of new metastases elsewhere in the brain. (

WBRT remains the preferred treatment for patients with a poor performance status and for those with extensive intracranial disease.

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.

CHEMOTHERAPY — For highly chemosensitive cancers (ie, testicular germ cell tumors, gestational trophoblastic disease, primary central nervous system lymphoma), chemotherapy has been integrated into the primary management of patients with disseminated disease, even when central nervous system (CNS) disease is present.

BRACHYTHERAPY — Brachytherapy 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. This permits the delivery of higher radiation doses than can be achieved with external beam therapy, while limiting radiation to the surrounding brain.

Brachytherapy has been used in conjunction with surgery, as the primary modality in selected patients with nonresectable metastases, and after recurrence following previous WBRT or surgery. Although brachytherapy has been largely replaced by SRS for small lesions, it may retain a role in patients with metastases that are too large for SRS

The clinical experience with brachytherapy is limited to small observational series . The outcomes with this approach were illustrated in a study of 93 patients, most of whom had solitary metastases: 38 patients received brachytherapy in conjunction with external beam radiotherapy, 34 received brachytherapy alone, and 21 received brachytherapy after failing previous radiotherapy and/or surgery. Median survival for the three groups was 17, 15, and 6 months, respectively.

Brachytherapy for brain metastases is generally well tolerated. Side effects have included bone flap infection and a cerebrospinal fluid leak Symptomatic radiation necrosis is uncommon.

A later strategy for brachytherapy involves the use of a photon radiosurgery system. This is a battery-powered miniature x-ray generator with an attached probe that can be placed stereotactically into the metastasis at the time of craniotomy to deliver a single fraction of high-dose radiation (6 to 15 Gy) over less than one hour

Another alternate form of brachytherapy uses an inflatable balloon catheter containing a liquid I-125 radioisotope (GliaSite) inserted at the time of surgical resection of a primary or metastatic brain tumor

Experience with both the photon radiosurgery system and GliaSite is limited.

RECURRENT DISEASE — Both surgery and SRS can be used to retreat patients who develop recurrent, symptomatic CNS disease and have stable extracranial disease. Careful selection of patients is critical in this setting. As with the initial evaluation, the absence of active systemic disease and a Karnofsky performance score of at least 70 are important. Factors indicating a probable poor outcome include a short time to recurrence, age less than 40 years, and breast cancer or melanoma

The potential benefits are illustrated by a series 48 patients who underwent reoperation for recurrent metastatic disease. Seventy five percent of the patients improved symptomatically with a median survival of 12 months after surgery. Similar findings were noted in another report, which reviewed the outcome of 109 patients with recurrent brain metastases from non-small cell lung cancer Thirty-two patients (30 percent) underwent reoperation and had a five month longer median survival than the remaining patients.

Resection of second recurrences may also be feasible, if systemic disease remains inactive

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 corticosteroids, the treatment of seizures, and the management of venous thromboembolic disease. These issues are discussed elsewhere.

SUMMARY AND RECOMMENDATIONS — Although brain metastases most frequently occur in the context of advanced systemic disease, brain metastases can be effectively palliated with aggressive local treatment in selected patients. Since life expectancy is usually limited by extracranial disease, aggressive therapy is generally reserved for those who are expected to survive long enough to benefit from aggressive treatment of their brain metastases.

Recursive partitioning analysis of large numbers of patients with brain metastases has found that the factors associated with prolonged survival include a Karnofsky performance status of 70 or more age less than 65 years, and with a controlled primary tumor with the brain as the sole site of metastases.

For patients with all or most of these characteristics, we recommend the following:

• Tumor specific treatment — We recommend aggressive treatment with surgical resection or SRS to eradicate brain metastases in favorable prognosis patients

    — We suggest neurosurgical resection for a single or limited number of metastases in a surgically accessible location. Stereotactic radiosurgery (SRS) is appropriate for patients with lesions in surgically inaccessible locations and those who are not surgical candidates or refuse surgery

    — We suggest WBRT following surgery or SRS to reduce the incidence of local recurrence and new brain metastases, although this is not associated with an increase in survival

• Retreatment — We recommend the use of either surgery or SRS to retreat patients who have relapsed in the brain and who continue to have a good performance status and controlled or minimal extracranial disease

• Symptom management — We recommend medical management with corticosteroids to control peritumoral edema. Treatment for other tumor-related complications (eg, seizures, venous thromboembolic disease) may also be required.

For patients with a poor performance status, a relatively short life expectancy due to extracranial disease, or extensive brain metastases, we recommend WBRT or supportive care. T