Stereotactic radiosurgery for brain metastases

INTRODUCTION
— Brain metastases are an increasingly important cause of morbidity and mortality in cancer patients, occurring in approximately 10 to 30 percent of adults and 6 to 10 percent of children with cancer. They are the most common intracranial tumors, accounting for significantly more than one-half of brain tumors in the adult. Because of advances in the diagnosis and management of this condition, most patients receive effective palliation and the majority do not die from the metastases.

Treatment goals directly related to brain metastases are relief of neurologic symptoms and long-term tumor control. Available modalities include surgery, radiotherapy, radiosurgery, chemotherapy, and hormonal therapy. The optimal combination of therapies for the individual patient depends upon careful evaluation of numerous factors including:

  bullet The location, size and number of brain metastases (most patients have multiple lesions);
  bullet Patient age, performance status, and neurologic status;
  bullet Extent of the extracranial involvement of the cancer;
  bullet Responsiveness of the tumor to past therapy.

In general, patients with single and preferably solitary lesions are candidates for treatment. The term single brain metastasis refers to a single cerebral lesion, and no implication is made regarding the extent of extracranial disease, while the term solitary brain metastasis describes the occurrence of a single brain metastasis that is the only known site of metastatic disease. Selected patients with multiple lesions may also receive palliation.

The use of stereotactic radiosurgery and brachytherapy in the management of brain metastases will be reviewed here. Surgery and whole brain radiotherapy (WBRT) for brain metastases, as well as symptomatic management of brain metastases, are discussed separately.

STEREOTACTIC RADIOSURGERY — Stereotactic radiosurgery is a technique that utilizes multiple convergent beams to deliver a high single dose of radiation to a radiographically discrete treatment volume. Radiosurgery can be performed with high energy x-rays produced by linear accelerators, with gamma rays from the Gamma Knife, or, less frequently, with charged particles such as protons produced by cyclotrons. All of the stereotactic radiation techniques result in a rapid fall-off of dose at the edge of the target volume, resulting in a clinically insignificant radiation dose to normal nontarget tissue. Metastases are usually small (less than 3 cm), radiographically discrete, lesions that are noninvasive, making them ideal targets for radiosurgery.

Several randomized studies have shown a survival advantage for patients with a single brain metastasis who are treated with surgery and radiotherapy compared to radiotherapy alone. Many clinical investigators believe that radiosurgery can act as an alternative to surgical resection. Radiosurgery has several potential advantages over surgery.

  bullet It can be used to treat metastases in surgically inaccessible areas of the brain, such as the brainstem.
  bullet It is a noninvasive procedure that can be performed on an outpatient basis with less morbidity than surgery.
  bullet It may be more cost-effective than surgical resection. In one study, the average cost per week of survival was $310 for radiotherapy, $524 for resection plus radiation, and $270 for radiosurgery plus radiation .

Efficacy — An increasing number of uncontrolled studies suggest that the effectiveness of stereotactic radiosurgery is at least comparable to surgery in the treatment of brain metastases in selected patients. Radiosurgery produces local control rates of 73 to 94 percent and is associated with a 5 to 10 percent risk of radiation necrosis.

In the largest series to date, radiosurgery with a linear accelerator was used for the treatment of 248 patients with 421 metastatic lesions. With a median observation period of 26 months, 48 of 421 lesions (11 percent) 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 radiosurgery treatment.

The efficacy of radiosurgery is independent of the histology of the lesion, as radioresistant histologies have statistically similar control rates as other lesions. Thus, efficacy has been described with brain metastases due to renal cell carcinoma malignant melanoma, and non-small cell lung cancer.

  Craniotomy versus stereotactic radiosurgery — Ideally, a prospective randomized study comparing surgery to radiosurgery for the treatment of single brain metastases would resolve the issue of the relative efficacy of these two therapies. However, attempts at such a study have so far been unsuccessful due to poor patient accrual as a result of patient and/or physician preference for either surgery or radiosurgery.

While both surgery and stereotactic radiosurgery are believed to offer local control benefits over WBRT alone, retrospective analyses of non-randomized series have yielded conflicting data:

  bullet In one series of 97 patients with solitary brain metastases from the Mayo Clinic, all underwent cranial MRI to exclude the presence of other lesions, and were thought to be eligible for either therapy (ie, tumor <35 mm in diameter, not deep-seated or in the brainstem, no evidence for ventricular obstruction). There were 74 patients treated surgically (82 percent of whom had WBRT), and 23 who underwent stereotactic radiosurgery (96 percent receiving subsequent WBRT). With a median follow-up of 20 months, there were no significant differences in the rate of brain recurrence (30 versus 29 percent), or one year survival, but the surgically treated patients had significantly more local recurrences at the treated site (58 versus zero percent). Despite this, more stereotactically treated patients died of CNS tumor involvement than did those undergoing surgery (29 versus 11 percent).

  bullet In another study, 122 patients with a single metastasis of nonradiosensitive histology were treated with WBRT (median 37.5 Gy) followed by a radiosurgery boost (median 17 Gy). Patients were eligible for inclusion in the retrospective report if they met the eligibility requirements for a clinical trial comparing whole brain radiotherapy with or without surgery for brain metastases. The overall local control rate was 86 percent with an actuarial median survival of 56 weeks and a neurologic median survival of Karnofsky performance scale  of greater than >70 percent of 44 weeks. These results are comparable to the surgery and radiation therapy arms of two randomized trials  and better than the WBRT alone arms in these studies.

  bullet In contrast, a survival benefit for surgically treated patients was suggested in a series examining the outcomes of patients treated with stereotactic radiosurgery (n = 13) and surgery (n = 62) who were matched for their primary tumor, age, performance status, extent of systemic disease, and number of brain metastases. Both overall survival (median 16.4 versus 7.5 months) and freedom from neurologic death were significantly better in the surgically treated patients.

A randomized trial comparing both treatments is being planned by the American College of Surgeons.

In the absence of data from randomized trials, the choice of stereotactic radiosurgery over surgery in patients with solitary lesions is typically based upon the size and accessibility of the lesion, symptoms, and functional status of the patient. Because the risk of neurotoxicity and local failure increases with increasing lesion size, stereotactic radiosurgery is best reserved for lesions with a diameter of 3 cm or less. Surgery offers immediate decompression of large symptomatic lesions, while for smaller asymptomatic lesions, it is reasonable to consider either surgery or stereotactic radiosurgery.

  Multiple brain metastases — There are fewer data available on the efficacy of stereotactic radiosurgery in patients with multiple brain metastases. One study evaluated the use of gamma knife radiosurgery in the treatment of 97 patients with multiple (two to four) brain metastases. Local tumor control and neurologic improvement was achieved in 94 percent of patients. The median survival time after radiosurgery was six months overall and nine months in patients with a higher Karnofsky performance score and without extracranial manifestations; the one-year survival rate was 26 percent. The outcome appears to be worse in patients with more than two metastatic lesions

  Hypofractionated stereotactic radiotherapy — Hypofractionated stereotactic radiotherapy uses a series of treatment sessions focused on a specific target, as opposed to a single treatment course with stereotactic radiosurgery.  Two reports have suggested that this technique may give similar results to stereotactic radiosurgery, either used alone or as a boost following whole brain radiotherapy. This approach is less invasive and less expensive, and is well tolerated.

Side effects — Immediate side effects occur in less than 30 percent of patients. They are generally mild and consist of nausea, headache, and mild seizures. Delayed side effects, occurring several months after treatment, are common and result from radiation necrosis and edema. These patients present with increased seizures, headaches, or worsening neurologic deficits. These side effects can usually be treated with corticosteroids. However, 5 to 10 percent of patients develop severe symptomatic necrosis and may require surgical resection.

The symptoms of radiation necrosis may mimic those of recurrent intracranial tumor. The differentiation between these two conditions may be aided by the use of PET scanning, particularly in conjunction with cranial MRI scans.

Role of whole brain radiotherapy — The role of WBRT in patients treated with stereotactic radiosurgery is controversial, especially for those with relatively radioresistant tumors such as melanoma.

The primary goal of WBRT is to reduce the rate of in-brain failure. Such a benefit has been demonstrated in patients following surgical resection of brain metastases, although whether this impacts on long-term survival is unclear. On the other hand, the routine use of WBRT has been questioned because of the development of late treatment-related dementia, which can be debilitating in long-term survivors.

The results of adding WBRT to stereotactic radiosurgery have been conflicting in retrospective series. Two uncontrolled studies suggest that the addition of WBRT may improve local control, with a trend towards improved survival in patients without extracranial disease  or a decreased incidence of progression of brain metastases at one year. In contrast, at least one larger analysis did not demonstrate any benefit. Two small randomized studies have prospectively addressed this question:

  bullet In a trial that was stopped at interim analysis, 27 patients with two to four brain metastases (all less than or equal to25 mm in diameter) and a known primary tumor were randomized to WBRT alone or with radiosurgery. Combination therapy was associated with a much lower rate of local failure at one year (8 versus 100 percent) and a longer median time to local failure (36 versus 6 months). There was no significant improvement in median survival (11 versus 7.5 months, p = 0.22), which was related to the extent of extracranial disease.

  bullet A preliminary report of a second trial enrolled 109 patients with multiple brain metastases who were randomly assigned to receive WBRT, gamma knife radiosurgery, or both. Although there was no difference in median survival, local control for both gamma knife surgery and gamma knife surgery plus WBRT (87 and 91 percent) were improved compared to WBRT alone (62 percent). The occurrence of new brain lesions was lower in the WBRT and WBRT plus radiosurgery arms (23 and 19 percent) compared to gamma knife surgery alone (43 percent).

Despite the absence of a survival benefit, most centers performing radiosurgery for brain metastases combine this procedure with WBRT. The use of up-front radiosurgery alone is usually limited to cases in which there are no alternatives, such as prior high-dose radiation to the head and neck area or patient refusal to undergo WBRT.

Prognostic factors — Young patients with good performance status, limited extracranial disease, and one or two small lesions are particularly suited to stereotactic radiosurgery. Another positive prognostic indicator may be an interval of greater than one year from primary disease diagnosis to the development of intracranial metastasis

Poor prognostic factors are similar to those identified for surgical excision. They include poor performance status (Karnofsky performance score less than 70) , progressive systemic disease, large tumor size, infratentorial location, and multiple metastases.

Favorable prognostic factors include the absence of systemic disease, young age (less than 60 years), good performance status (Karnofsky performance status of 70 or greater), long time to development of metastasis, surgical resection, and less than three lesions.

The importance of these factors was illustrated in a multiinstitutional recursive partitioning analysis of prognostic factors in 502 patients who underwent radiosurgery and WBRT for multiple brain metastases. Three prognostic groups were identified:

  bullet Class 1 — These patients had a Karnofsky performance score 70 or higher, were less than 65 years of age with a controlled primary tumor and no extracranial metastases. The median survival was 16.1 months.
  bullet Class 3 — These patients had a Karnofsky performance score of less than 70; their median survival was 8.7 months.
  bullet Class 2 — This group included all remaining patients; they had a median survival of 10.3 months.

The median survival in all three groups was higher than in a prior RTOG recursive partitioning analysis of 1200 patients with brain metastases undergoing external beam radiation therapy with or without a radiation sensitizer. Using the same stratification factors, median survival for the radiosurgery and external beam groups were: class I, 16.1 versus 7.1 months; class II, 10.3 versus 4.2 months; class III, 8.7 versus 2.3 months. In interpreting these results, it should be kept in mind that patients who are eligible for radiosurgery may have an inherently better prognosis (ie, limited number of intracranial lesions or less systemic disease burden).

Summary — The introduction of stereotactic radiosurgery over the past decade represents one of the major advances in the treatment of brain metastases. In general, therapeutic results appear comparable to those obtained with surgical excision with significantly less morbidity. However, in the absence of randomized studies, it is difficult to recommend a new therapy in place of established treatment.

We believe that radiosurgery can probably be used as a substitute for surgery for patients with a single small asymptomatic or mildly symptomatic lesion, with comparable outcomes. In comparison, radiosurgery plays an important role in the management of patients who are not surgical candidates, who have a recurrence of brain metastasis following WBRT, and perhaps those with multiple metastases and limited systemic disease.